1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899
NEUROLOGY AND CLINICAL NEUROSCIENCE
ISBN-13: 978-0-323-03354-1 ISBN-10: 0-323-03354-7
Copyright © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail:
[email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions.”
Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher
Library of Congress Cataloging-in-Publication Data Neurology and clinical neuroscience / editor, Anthony H.V. Schapira; associate editors, Edward Byrne . . . [et al.]. p. ; cm. ISBN 0-323-03354-7 1. Neurology—Textbooks. 2. Neurosciences—Textbooks. 3. Nervous system—Diseases—Textbooks. I. Schapira, Anthony H. V. (Anthony Henry Vernon). II. Byrne, Edward, M.D. [DNLM: 1. Nervous System Diseases. 2. Neurology. WL 140 N49269 2007] RC346.N4514 2007 616.8—dc22 2006046665
Acquisitions Editor: Susan Pioli Developmental Editor: Heather Krehling Publishing Services Manager: Frank Polizzano Senior Project Manager: Peter Faber Design Direction: Steven Stave
Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org
Printed in China Last digit is the print number:
9
8
7
6
5
4
3
2
1
To my wife, Laura, and my daughter, Sarah
CONTRIBUTORS
Rasheed A. Afinowi, MBBS, MSc
Clinical Research Fellow, Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom Intracranial Hemorrhage: Aneurysmal, Idiopathic, and Hypertensive
Rexford S. Ahima, MD, PhD
Doris-Eva Bamiou, MD, MSc, MPhil
Honorary Senior Lecturer, Institute of Child Health, University College London; Consultant in Audiological Medicine, National Hospital for Neurology and Neurosurgery, London, United Kingdom Vestibular System Disorders
Associate Professor of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine; Endocrinologist, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Neurology of Endocrinology
Christopher Bass, MA, MD, FRCPsych
Marta Altieri MD, PhD
Michel Baulac, MD
Department of Neurological Sciences, 1st Faculty of Medicine and Surgery, University of Roma La Sapienza, Rome, Italy Cerebral Venous Thrombosis
Hortensia Alvarez, MD
Neuroradiologist, Diagnostic and Therapeutic Vascular, Neuroradiology, Bicetre Hospital, Kremlin Bicetre, France Arteriovenous Malformations of the Brain and Spinal Cord
Shalini A. Amukotuwa, MBBS(Hons), BMedSci
Departmental Research Fellow, Department of Neurosciences, St. Vincent’s Hospital, Melbourne, Victoria, Australia Spinal Disease: Neoplastic, Degenerative, and Infective Spinal Cord Diseases and Spinal Cord Compression
Yaacov Anziska, MD
Associate in Neurology, Columbia University College of Physicians and Surgeons; Resident in Clinical Neurophysiology, NewYork–Presbyterian Hospital, New York, New York Metabolic, Immune-Mediated, and Toxic Neuropathies
Honarary Senior Clinical Lecturer in Psychiatry, University Department of Psychiatry, Warneford Hospital; Consultant in Liaison Psychiatry, John Radcliffe Hospital, Oxford, United Kingdom Conversion and Dissociation Syndromes Professor of Neurology and Head, Epileptology Unit, Clinique Paul Castaigne, Hôpital de la Pitié-Salpêtrière, Paris, France Clinical Spectrum [Epilepsy]
Antonio Belli, MD, FRCS(SN)
Neurologist, Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom Intracranial Hemorrhage: Aneurysmal, Idiopathic, and Hypertensive
Paul Bentley, MA, MRCP
Specialist Registrar–Neurology, St. Mary’s Hospital, London, United Kingdom Prothrombotic States and Related Conditions
Italo Biaggioni, MD
Professor of Medicine and Pharmacology, Vanderbilt School of Medicine, Nashville, Tennessee Orthostatic Hypotension
Marcelo E. Bigal, MD, PhD
Gregory J. Artz, MD
Fellow, Department of Neurotology, Michigan Ear Institute, Farmington Hills, Michigan Auditory System Disorders
Assistant Professor of Neurology, Albert Einstein College of Medicine of Yeshiva University; Director of Research, Montefiore Headache Center, Bronx, New York; Director of Research, The New England Center for Headache, Stamford, Connecticut Chronic Daily Headache
Messoud Ashina, MD, PhD, DMedSci
Rolfe Birch, MChir, FRCS, FRCS(Eng)
Associated Professor of Neurology, University of Copenhagen School of Medicine; Staff Neurologist, Danish Headache Center—University of Copenhagen, Copenhagen, Denmark Tension-Type Headache
Professor in Neurological Orthopaedic Surgery, University College London, London; Head, Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, United Kingdom Tumors of the Peripheral Nerve
vii
viii
Contributors
Bastiaan R. Bloem, MD, PhD
Neurologist, University Medical Center, Nijmegen, The Netherlands Gait Disturbances and Falls
Georgina Burke, BSc, MBBS, MRCP
Specialist Registrar–Neurology, Wessex Neurological Centre, Southampton General Hospital, Southampton, United Kingdom Neuromuscular Junction Disorders
Bradley F. Boeve, MD
Associate Professor of Neurology, Mayo Clinic College of Medicine; Consultant, Divisions of Behavioral Neurology and Movement Disorders and Mayo Sleep Disorders Center, Mayo Clinic, Rochester, Minnesota Dementia with Lewy Bodies
Jean Lud Cadet, MD
Lysa Boissé, MD, MSc
John N. Caviness, MD
Resident in Neurology, Queen’s University/Kingston General Hospital, Kingston, Ontario, Canada Neurological Disorders Associated with Human Immunodeficiency Virus Infection
Karen I. Bolla, PhD
Chief, Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland Environmental Toxins Professor of Neurology, Mayo Clinic College of Medicine; Consultant, Division of Movement Disorders, Mayo Clinic Scottsdale, Scottsdale, Arizona Huntington Disease
Associate Professor of Neurology, Psychiatry and Behavior Sciences, and Environmental Health Sciences, Neurology, Johns Hopkins School of Public Health; Director of Neuropsychology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Environmental Toxins
Stephen D. Cederbaum, MD
John G. F. Boughey, MBChB, MRCP
Professor of Physiology, Faculty of Medicine, Université Aix-Marseille; Head, Department of Clinical Neurophysiology, Hôpital de la Timone; Director, U751 Epilepsy and Cognition, INSERM, Marseille, France Developmental Defects and Pathophysiology [Epilepsy]
Behavioral Neurology Fellow, Department of Neurology, Mayo Clinic, Jacksonville, Florida Alzheimer’s Disease
Professor of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California Urea Cycle Disorders
Patrick Chauvel, MD
Kevin B. Boylan, MD
Assistant Professor, Department of Neurology, Mayo Medical School; Mayo Clinic, Jacksonville, Florida Amyotrophic Lateral Sclerosis
Robert Brenner, MD, FRCP
Consultant Neurologist, Department of Academic Neuroscience, Royal Free Hospital, London, United Kingdom Investigations in Multiple Sclerosis
Edward B. Bromfield, MD, MEd
Associate Professor of Neurology, Harvard Medical School; Chief, Division of Epilepsy and Sleep, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Drug Treatment [Epilepsy]
Patrick F. Chinnery, MBBS(Hons), PhD, MRCPath, FRCP
Professor of Neurogenetics, The University of Newcastle upon Tyne; Honorary Consultant Neurologist, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom Metabolic Myopathies (Including Mitochondrial Disorders)
Soke Miang Chng, MD
Neuroradiologist, Diagnostic and Therapeutic Vascular Neuroradiology, Bicetre Hospital, Kremlin Bicetre, France Arterionenous Malformations of the Brain and Spinal Cord
Mark J. Cook, MD
Professor of Clinical Neurology, Columbia University College of Physicians and Surgeons; Director, Department of Neurology, Harlem Hospital Center, New York, New York Neurology of Drug and Alcohol Addictions
Professor of Neurology, University of Melbourne School of Medicine, Parkville; Director, Department of Neurology, St. Vincent’s Hospital, Melbourne, Victoria, Australia Disorders of Taste and Smell; Spine and Spinal Cord: Developmental Disorders; Spinal Disease: Neoplastic, Degenerative, and Infective Spinal Cord Diseases and Spinal Cord Compression
Camilla Buckley, BM, BCh, MRCP, DPhil
John R. Crawford, PhD
John C. M. Brust, MD
Lecturer in Clinical Neurology, Department of Clinical Neurology, University of Oxford; Honorary Specialist Registrar, Neurosciences Group, Radcliffe Infirmary, Oxford, United Kingdom Neuromuscular Junction Disorders
Professor, School of Psychology, University of Aberdeen, Aberdeen, UK; Consultant Clinical Neuropsychologist, Grampian University Hospitals NHS Trust, Aberdeen, United Kingdom Executive Function and Its Assessment
contributors
Eric A. Crombez, MD
Assistant Professor, Department of Pediatrics, Division of Medical Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California Urea Cycle Disorders
Jeffrey L. Cummings, MD
The Augustus S. Rose Professor of Neurology, David Geffen School of Medicine at UCLA; Director, UCLA Alzheimer’s Disease Center; Director, Deane F. Johnson Center for Neurotherapeutics, UCLA Medical Center, Los Angeles, California Affective Disorders
Marinos C. Dalakas, MD
Chief, Neuromuscular Diseases Section, National Institutes of Health, Bethesda, Maryland; Professor of Neurology, University of Athens Medical School; Chief, Section of Neuroimmunology and Neuromuscular Diseases, Department of Pathophysiology, University Hospital, Athens, Greece Inflammatory Myopathies
Josep Dalmau, MD, PhD
Associate Professor of Neurology, University of Pennsylvania School of Medicine; Neurologist, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Paraneoplastic Disorders of the Nervous System
Pe¯teris Da¯ rzin¸sˇ , BMBS, PhD, FRACP, FRCPC
Associate Professor in Geriatric Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University; Consultant Physician, Rehabilitation and Aged Services Program, Southern Health; Monash Ageing Research Centre, Kingston Centre—Monash University, Melbourne, Victoria, Australia Delirium
Bruce Day, MBBS, FRACP
Honorary Lecturer, Department of Medicine, Monash University; Director of Neurophysiology, Alfred Hospital, Melbourne, Victoria, Australia The Persistent Vegetative State (Prolonged Postcoma Unresponsiveness) and Posthypoxic Brain Injury
H. Gordon Deen, MD
Associate Professor of Neurosurgery, Mayo Clinic College of Medicine, Rochester, Minnesota; Consultant in Neurosurgery, Mayo Clinic Jacksonville, Jacksonville, Florida Head Trauma
Rajas Deshpande, MD, DM
Senior Consultant and Head, Neurology Department, Aditya Birla Memorial Hospital, Therzaon, India Clinical Spectrum: Definition and Natural Progression [Multiple Sclerosis and Demyelinating Disorders]
ix
Günther Deuschl, MD
Professor of Neurology, University of Kiel; Head of Department, Klinik für Neurologie, Universitats Klinikum Schleswig-Holstein, Campus Kiel, Germany Tremor
David W. Dodick, MD
Professor of Neurology, Mayo Clinic College of Medicine; Neurology Consultant, Mayo Clinic, Scottsdale, Arizona Other Secondary Headache Disorders
Erika D. Driver-Dunckley, MD
Clinical Instructor, Mayo Clinic College of Medicine, Scottsdale; Senior Associate Consultant, Mayo Clinic Hospital, Phoenix, Arizona Huntington Disease
James Evans, MD
Assistant Professor, Department of Neurosurgery, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Trigeminal Neuralgia and Other Facial Pain
Steven K. Feske, MD
Associate Professor of Neurology, Harvard Medical School; Chief, Division of Stroke and Neurovascular Diseases, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Neurology of Pregnancy and the Puerperium
John K. Fink, MD
Professor, Department of Neurology, University of Michigan Medical School; Physician-Scientist, Geriatric Research, Education, and Clinical Center, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan Hereditary Spastic Paraplegias
April L. Fitzsimmons, MD
Clinical Fellow, Department of Neurology, Harvard Medical School; Fellow in Neuro-oncology, Brigham and Women’s Hospital, Boston, Massachusetts Tumors of the Spinal Cord
Deborah I. Friedman, MD
Associate Professor of Ophthalmology and Neurology, University of Rochester School of Medicine and Dentistry; Attending Physician, Strong Memorial Hospital, Rochester, New York Idiopathic Intracranial Headache
Ilan S. Freedman, MBBS
Orthopaedic Registrar, Department of Orthopaedic Surgery, Western and Alfred Hospitals, Melbourne, Victoria, Australia Spinal Trauma
Simon C. Gandevia, MD, PhD, DSc
Professor, University of New South Wales School of Medical Sciences, Sydney; Deputy Director, Prince of Wales Medical Research Institute, Randwick, New South Wales, Australia Organization: Pyramidal and Extrapyramidal System [Motor System and Motor Diseases]
x
Contributors
Felix Geser, MD, PhD
Richard Greenwood, MB, BCh, MD, FRCP
Nir Giladi, MD
Amparo Gutierrez, MD
Visiting Scholar, Center of Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Primary Autonomic Failure
Senior Lecturer, Sackler School of Medicine, Tel Aviv University; Director, Movement Disorders Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Gait Disturbances and Falls
Recognised Teacher, Institute of Neurology, University of London; Consultant Neurologist, Acute Brain Injury Service, National Hospital for Neurology and Neurosurgery, and Regional Neurological Rehabilitation Unit, Homerton University Hospital NHS Trust, London, United Kingdom Rehabilitation of Stroke Associate Professor of Clinical Neurology, Louisiana State University Health Sciences Center School of Medicine, New Orleans, Louisiana Anatomy and Physiology of Muscle and Nerve
M. John Gill, BSc, MB, ChB, MSc
Maxime Guye, MD, PhD
Professor, Departments of Medicine, Microbiology, and Infectious Disease, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada Neurological Disorders Associated with Human Immunodeficiency Virus Infection
Neurophysiology and Neuropsychology Laboratory, Faculty of Medicine, Université de la Méditerranée; Neurologist, Clinical Neurophysiology Service, CHU la Timone, and Center for Biological and Medical Magnetic Resonance (CNRS UMR 6612), CHU la Timone, Marseille, France Developmental Defects and Pathophysiology [Epilepsy]
Peter J. Goadsby MD, PhD, DSc
Glenda M. Halliday, PhD
Professor, Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom TACs and SUNCT
Graeme M. Gonzales, MD
Department of Neurology, University of Melbourne, Parkville, Victoria, Australia Disorders of Taste and Smell
Neill R. Graff-Radford, MBBCh, FRCP(Lond)
Professor of Neurology, Mayo College of Medicine; Mayo Clinic Jacksonville, Jacksonville, Florida Alzheimer’s Disease
Elizabeth Graham, FRCP, FRCOphth
Consultant Medical Ophthalmologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Retinal Disease
Robin Grant, MBChB, MD, FRCP(Glasg), FRCP(Edin)
Honorary Senior Lecturer in Neurology, Division of Clinical Neurosciences, University of Edinburgh Faculty of Medicine; Consultant Neurologist, Western General Hospital, Edinburgh, United Kingdom Neurological Complications of Treatments
John E. Greenlee, MD
Professor and Interim Chair, Department of Neurology, University of Utah School of Medicine; Neurologist, Veterans Administration Medical Center, Salt Lake City, Utah Bacterial Meningitis (Including Lyme Disease, TB, and Syphilis)
Professor of Medicine, University of New South Wales School of Medical Sciences; National Health and Medical Research Council Principal Research Fellow, Prince of Wales Medical Research Institute, Sydney, New South Wales, Australia Organization: Pyramidal and Extrapyramidal System
Cynthia L. Harden, MD
Associate Professor of Neurology, Weill Medical College of Cornell University, New York, New York Management of Status Epilepticus
Jeffrey M. Hausdorff, BSE, MSME, PhD
Senior Lecturer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Lecturer in Medicine, Harvard Medical School, Boston, Massachusetts; Director, Laboratory of Gait and Neurodynamics, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Gait Disturbances and Falls
Robert C. Hermann, Jr., MD
Clinical Professor of Medicine and Neurology and Director, Neurology EMG Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas Peripheral Nerve Injury
Rhonda O. Holmes, BSpPathol
Senior Clinician, Neurosciences, and Speech Pathologist, Austin Health, Heidelberg, Victoria, Australia Motor Speech and Swallowing Disorders
Alan C. Jackson, MD, FRCPC
Professor of Medicine (Neurology) and Microbiology and Immunology, Queen’s University Faculty of Medicine; Attending Staff, Department of Medicine (Neurology), Kingston General Hospital, Kingston, Ontario, Canada Viral Meningitis and Encephalitis
contributors
Malaka B. Jackson, MD
John B. Kerrison, MD
Kim Jeffs, MBBS, FRACP
Joshua C. Kershen, MD
Endocrinology Fellow, Division of Pediatric Endocrinology, University of Pennsylvania/Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Neurology of Endocrinology
Honorary Fellow, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne; Consultant Geriatrician, The Northern Hospital, Epping; Research Fellow, Northern Clinical Research Centre, The Northern Hospital, Melbourne, Victoria, Australia Delirium
Richard T. Johnson, MD, FRCP
Distinguished Service Professor of Neurology, Microbiology, and Neuroscience, Johns Hopkins University School of Medicine and Bloomberg School of Public Health; Neurologist, Johns Hopkins Hospital, Baltimore, Maryland Acute Disseminated Encephalomyelitis and Progressive Multifocal Leukoencephalopathy
Heinz Jungbluth, MD, PhD
Clinical Research Fellow, Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital; Consultant Paediatric Neurologist, Evelina Children’s Hospital, St. Thomas’ Hospital, London, United Kingdom Congenital Myopathies
Padmaja Kandula, MD
Assistant Attending Neurologist, Weill Medical College of Cornell University, New York, New York Management of Status Epilepticus
Raju Kapoor, DM, FRCP
Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Pathophysiology of Multiple Sclerosis: Demyelination and Axonal Injury
Horacio Kaufmann, MD
The Alex and Shirley Aidekman Professor of Neurology, Mount Sinai School of Medicine; Director, Autonomic Disorders Research and Treatment Program, Mount Sinai Medical Center, New York, New York Orthostatic Hypotension
Andrew H. Kaye, MBBS, MD, FRACS
Professor and Head, Department of Surgery, University of Melbourne, Parkville; Director of Neurosurgery, Royal Melbourne Hospital, Parkville, Victoria, Australia Hydrocephalus Including Normal-Pressure Hydrocephalus
Noojan J. Kazemi, MBBS
Research Fellow, University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria, Australia Hydrocephalus Including Normal-Pressure Hydrocephalus
xi
Charleston Neuroscience Institute; St. Francis Hospital and Trident Hospital; Retina Consultants of Charleston, Charleston, South Carolina Genetic Causes of Blindness
Assistant Professor, Department of Neurology, Tufts University School of Medicine; Neurologist, Tufts-New England Medical Center, Boston, Massachusetts Infective Neuropathies
Desmond Kidd, MD, FRCP
Honorary Senior Lecture, Royal Free and University College School of Medicine; Consultant Neurologist, Royal Free Hospital, London, United Kingdom Examination of the Visual System
Glynda Kinsella, DiplPhysiol, MSc, PhD
Associate Professor of Psychological Science, La Trobe University; Clinical Neuropsychologist, Caulfield General Medical Centre, Melbourne, Victoria, Australia Principles of Neuropsychometric Assessment; Executive Function and Its Assessment
Laurence J. Kinsella, MD, FAAN
Professor of Neurology, Saint Louis University School of Medicine; Chief, Neurology and Neurophysiology, Forest Park Hospital, St. Louis, Missouri Vitamin Deficiencies
Neil Kitchen, MD, FRCS(SN)
Consultant Neurosurgeon and Associate Clinical Director, National Hospital for Neurology and Neurosurgery, London, United Kingdom Intracranial Hemorrhage: Aneurysmal, Idiopathic, and Hypertensive
Autumn M. Klein, MD, PhD
Instructor in Neurology, Harvard Medical School; Fellow in Clinical Neurophysiology, Division of Epilepsy and Sleep, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Neurology of Pregnancy and the Puerperium
Andrew J. Kornberg, MD
Professor of Paediatrics, Faculty of Medicine, Dentistry and Health Science, University of Melbourne; Director, Department of Neurology, Royal Children’s Hospital; Attending, St. Vincent’s Hospital, Parkville, Victoria, Australia Spine and Spinal Cord: Developmental Disorders
Thomas Kossmann, MD, FRACS
Professor and Director, Department of Trauma Surgery, and Director, National Trauma Research Institute, The Alfred Hospital/Monash University, Melbourne, Victoria, Australia Spinal Trauma
xii
Contributors
John W. Krakauer, MD
Assistant Professor of Neurology, Columbia University College of Physicians and Surgeons; Assistant Attending Neurologist, NewYork–Presbyterian Hospital, New York, New York Ischemic Stroke: Mechanisms, Evaluation, and Treatment
Richard B. Lipton, MD
Professor of Neurology, and Epidemiology and Population Health and Vice-Chair, Department of Neurology, Albert Einstein College of Medicine of Yeshiva University; Director, Montefiore Headache Center, Bronx, New York Chronic Daily Headache
Marcelo Kremenchutzky, MD
Assistant Professor, Department of Clinical Neurological Sciences, University of Western Ontario; Neurologist, London Health Sciences Centre, London, Ontario, Canada Clinical Spectrum: Definition and Natural Progression [Multiple Sclerosis and Demyelinating Disorders]
Jan D. Lünemann, MD
Brian C. Kung, MD
Hanns Lochmüller, MD
Resident, Otolaryngology—Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Examination of Hearing and Balance
University of Munich Hospital, Neurology Clinic and Outpatient Service, Friedrich-Baur Institute, Munich, Germany Muscular Dystrophies
Richard P. Lango, MD
James R. Lupski, MD, PhD
Instructor in Neurology, Department of Neurology/Neuroimmunology, University of Rochester School of Medicine and Dentistry; Fellow in Neurology, Strong Memorial Hospital, Rochester, New York Treatment of Multiple Sclerosis
The Rockfeller University Christopher H. Browne Center for Immunology and Immune Diseases, Laboratory of Viral Immunobiology, New York, New York Epidemiology and Genetics of Multiple Sclerosis
Cullen Professor of Molecular and Human Genetics and Professor of Pediatrics, Baylor College of Medicine; Attending Pediatrician and Consulting Medical Geneticist, Texas Children’s Hospital and Ben Taub General Hospital, Houston, Texas Inherited Neuropathies
Pierre Lasjaunias, MD, PhD
Neuroradiologist, Bicetre Hospital, Kremlin Bicetre, France Arteriovenous Malformations of the Brain and Spinal Cord
Ramon C. Leiguarda, MD
Professor of Neurology, University of Buenos Aires School of Medicine; Chairman, Department of Cognitive Neurology, Institute of Neurological Research–Fleni, Buenos Aires, Argentina Apraxia
Peter J. Lennarson, MD
Neurologic Surgeon, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska Coma and Brain Death
Gian-Luigi Lenzi, MD, FRCP
Professor, Department of Neurological Sciences, 1st University of Roma La Sapienza, Rome, Italy Cerebral Venous Thrombosis
Francois Lette, MD
Senior Associate Consultant, Division of Executive and International Medicine, Mayo Clinic, Jacksonville, Florida Parasitic and Fungal Infections
Bernardo Liberato, MD
Director, Neurovascular Service, Hospital Copa D’Or, Rio de Janeiro, Brazil Ischemic Stroke: Mechanisms, Evaluation, and Treatment
Linda M. Luxon, BSc, MBBS, FRCP
Professor of Audiological Medicine, University of London; UCL Institute of Child Health, Great Ormond Street Hospital for Children; Consultant Audiological Physician and Lead Clinician, Department of Neuro-Otology, National Hospital for Neurology and Neurosurgery, London, United Kingdom Vestibular System Disorders
John M. Lynch, MB, MRCPI
Clinical Research Fellow, National Hospital for Neurology and Neurosurgery, London, United Kingdom Genetics [Epilepsy]
Richard A. L. Macdonnell, MD, FRACP
Associate Professor, Faculty of Medicine, University of Melbourne, Melbourne; Deputy Director of Neurology, Austin Health, Heidelberg, Victoria, Australia Motor Speech and Swallowing Disorders
Eric T. MacKenzie, PhD
Director of Research, University of Caen; Staff, University Medical Center, Caen, France Anatomy and Physiology of Cerebral and Spinal Cord Circulation
Boby Varkey Maramattom, MD, DM
Consultant, Division of Critical Care Neurology, Department of Neurology, Lourdes Hospital, Kochi, Kerala, India Neurology of Pulmonology and Acid-Base Disturbance
contributors
Gad A. Marshall, MD
Clinical Instructor in Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California Affective Disorders
xiii
Francesco Muntoni, MD
Professor of Pediatric Neurology, Department of Pediatrics, Hammersmith Hospital Campus, Imperial College, London, United Kingdom Congenital Myopathies
Roland Martin, MD
National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Bethesda, Maryland; Universita Autonoma de Barcelona/Hospital Universitari Vall d’Hebron, Unitat de Neuroimmunologia Clínica, Barcelona, Spain Epidemiology and Genetics of Multiple Sclerosis
Kaye Murray, MBChB, BMedSci
Research Registrar, National CJD Surveillance Unit, University of Edinburgh; Specialist Registrar in Neurology, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom Prion Diseases
John H. Menkes, MD
Professor Emeritus of Neurology and Pediatrics, David Geffen School of Medicine at UCLA; Director Emeritus of Pediatric Neurology, Cedars Sinai Medical Center, Los Angeles, California Wilson Disease
Alessio Mercurio, MD
Department of Neurological Sciences, 1st University of Roma La Sapienza, Rome, Italy Cerebral Venous Thrombosis
Geoffrey Miller, MA, MB, ChB, MPhil, MD, FRCP, FRACP
Professor of Pediatrics and Neurology, Department of Pediatrics, Yale University School of Medicine; Clinical Director, Pediatric Neurology Service, Yale–New Haven Children’s Hospital, New Haven, Connecticut Neurology of Cerebral Palsy
Neil R. Miller, MD
Professor of Ophthalmology, Neurology, and Neurosurgery and Frank B. Walsh Professor of Neuro-Ophthalmology, Johns Hopkins University School of Medicine; Full-Time Faculty Member, Johns Hopkins Hospital, Baltimore, Maryland Optic Neuropathies
Bahram Mokri, MD
Professor of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota Low CSF Headache
Maria Cristina Morganti-Kossmann, PhD
Assistant Professor and Associate Director, Basic Research, National Trauma Research Institute, The Alfred Hospital/Monash University, Melbourne, Victoria, Australia Spinal Trauma
Hugo W. Moser, MD
Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Director, Neurogenetics Research Center, Kennedy Krieger Institute, Baltimore, Maryland Leukodystrophies
Sakkubai Naidu, MD
Professor of Pediatrics and Neurology, Johns Hopkins University School of Medicine; Director, Neurogenetics Unit, Kennedy Krieger Institute, Baltimore, Maryland Leukodystrophies
Peter J. Nestor, MBBS, PhD, FRACP
Senior Research Associate, University of Cambridge; Honorary Consultant Neurologist, Addenbrooke’s Hospital, Cambridge, United Kingdom Disorders of Memory
Nancy J. Newman, MD
Leo Delle Jolley Professor of Ophthalmology, Professor of Ophthalmology and Neurology, and Instructor in Neurological Surgery, Emory University School of Medicine, Atlanta; Lecturer in Ophthalmology, Harvard Medical School, Boston; Director of NeuroOphthalmology, Emory Eye Center, Atlanta, Georgia Genetic Causes of Blindness
Fiona L. M. Norwood, MD
Consultant Neurologist, King’s Neuroscience Centre, King’s College Hospital, London, United Kingdom Channelopathies of Muscle (Including Myotonic Dystrophy)
Wolfgang H. Oertel, MD
Professor of Neurology, Philipps University School of Medicine, Marburg, Germany Restless Legs Syndrome
Michael D. Osborne, MD
Assistant Professor in Physical Medicine and Rehabilitation and Assistant Professor in Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota; Consultant, Mayo Clinic, Jacksonville, Florida Neurorehabilitation
Michael L. Oshinsky, PhD
Assistant Professor of Neurology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Headache Pathogenesis
xiv
Contributors
Eoin P. O’Sullivan, MD
Consultant Ophthalmologist, Mayday University Hospital, Croydon, United Kingdom Retinal Disease
Mark A. Paine, MBBS, FRACP
Jan Raethjen, MD
Lecturer, University of Kiel; PD, Klinik für Neurologie, Universitäts Klinikum Schleswig-Holstein, Campus Kiel, Germany Tremor
Consultant Neurologist, Department of Clinical Neurosciences, St Vincent’s Hospital, and Neuroophthalmology Unit and Vestibular Investigation Unit, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia Primary Myelopathies (Degenerative, Infective, Metabolic)
Jeremy Rees, PhD, FRCP
Carlos A. Pardo-Villamizar, MD
Sylvain Rheims, MD
Assistant Professor of Neurology and Pathology, Division of Neuroimmunology and Neuroinfections Disorders, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland Neurosarcoidosis and Behçet Disease
Juan M. Pascual, MD, PhD
Associate Professor of Neurology and Physiology, University of Texas Southwestern Medical School; Attending Neurologist and Pediatrician, University of Texas Southwestern Medical Center Hospitals and Children’s Medical Center, Dallas, Texas Encephalopathies
Milena K. Pavlova, MD
Instructor in Neurology, Harvard Medical School; Medical Director, Sleep Disorders Center, Division of Epilepsy and Sleep, Brigham and Women’s Hospital/Faulkner Department of Neurology, Boston, Massachusetts Primary Disorders of Sleep
Ronald F. Pfeiffer, MD
Professor and Vice Chair, Department of Neurology, University of Tennessee School of Medicine, Memphis, Tennessee Bladder and Sexual Function and Dysfunction; Neurology of Gastroenterology and Hepatology
Werner Poewe, MD
Chairman, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria Parkinson Plus Disorders
Christopher Power, MD, FRCPC
Professor of Medicine, Microbiology, and Immunology, University of Alberta Faculty of Medicine; CINR Investigator/AllFMK Scholar, University of Alberta, Edmonton, Alberta, Canada Neurological Disorders Associated with Human Immunodeficiency Virus Infection
Gary Price, MBChB, MSc, MRCPsych
Clinical Research Fellow in Neuropsychiatry, Institute of Neurology, University College London; Honorary Specialist Registrar, National Hospital for Neurology and Neurosurgery, London, United Kingdom Schizophrenia and Schizophrenia-like Psychosis
Senior Lecturer in Medical Neuro-oncology and Honorary Consultant Neurologist, Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom Tumors of the Brain Hospices Civils de Lyon, Lyon, France Assessment and Management Principles [Epilepsy]
George P. A. Rice, MD, FRCPC
Professor, Department of Clinical Neurological Sciences, University of Western Ontario; Multiple Sclerosis Clinic Director, London Health Sciences Centre, London, Ontario, Canada Clinical Spectrum: Definition and Natural Progression [Multiple Sclerosis and Demyelinating Disorders]
Nicole J. Rinehart, MClin Psych, PhD, MAPS
Senior Lecturer, Centre for Developmental Psychiatry and Psychology, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, Victoria, Australia Autism and Attention Deficit/Hyperactivity Disorder
Thomas D. Rizzo, Jr., MD
Assistant Professor in Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota; Chair, Department of Physical Medicine and Rehabilitation, Mayo Clinic, Jacksonville, Florida Neurorehabilitation
Mary M. Robertson, MBChB, MD, DPM, MRCPCH, FRCP, FRCPsych
Emeritus Professor of Neuropsychiatry and UCL Visiting Professor, St. George’s Hospital Medical School; Honorary Consultant Neuropsychiatrist and St. George’s Hospital Senior Visiting Fellow, Institute of Neurology, London, United Kingdom; UCL Honorary Medical Advisor, Tourette Syndrome (UK) Association Tourette’s Syndrome, Tics, and Obsessive-Compulsive Disorders
Georges Rodesch, MD
Neuroradiologist, Diagnostic and Therapeutic Vascular Neuroradiology, Foch Hospital, Suresnes, France Arteriovenous Malformations of the Brain and Spinal Cord
Timothy A. Roehrs, PhD
Professor, Department, Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine; Director of Research, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan The Physiology of Sleep
contributors
Gustavo C. Roman, MD
Professor of Medicine/Neurology, University of Texas School of Medicine at San Antonio, San Antonio, Texas Vascular Dementia
xv
Thomas D. Sabin
Professor and Vice-Chair, Department of Neurology, Tufts University School of Medicine; Acting Chief of Neurology, Tufts-New England Medical Center, Boston, Massachusetts Infective Neuropathies
Maria A. Ron, PhD, FRCP, FRCPsych
Professor in Neuropsychiatry, Institute of Neurology, University College London; Consultant Psychiatrist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Schizophrenia and Schizophrenia-like Psychosis
Michael R. Rose, MD, FRCP
Mohammad Salajegheh, MD
Clinical Associate, Neuromuscular Diseases Section, National Institutes of Health, Bethesda, Maryland Inflammatory Myopathies
Michael M. Saling, PhD
Honorary Senior Lecturer, Department of Neurosciences, King’s College Medical School; Consultant Neurologist, King’s Neuroscience Centre, King’s College Hospital, London, United Kingdom Channelopathies of Muscle (Including Myotonic Dystrophy)
Associate Professor, Department of Psychology, School of Behavioral Science, University of Melbourne, Melbourne; Director of Neuropsychology, Austin and Heidelberg Repatriation Hospitals, Melbourne, Victoria, Australia Disorders of Language
Richard B. Rosenbaum, MD
Martin A. Samuels, MD, DSc(hon), FAAN, MACP
Clinical Professor of Neurology, Department of Neurology, Oregon Health Sciences University School of Medicine and The Oregon Clinic, Portland, Oregon Neurology of Rheumatology, Immunology, and Transplantation
Jeffrey V. Rosenfeld, MBBS, MD, MS, FRACS, FRCS(Edin), FACS
Professor and Head, Department of Surgery, Central and Eastern Clinical School, Monash University; Director, Department of Neurosurgery, The Alfred Hospital, Melbourne, Victoria, Australia Coma and Brain Death
Myrna R. Rosenfeld, MD, PhD
Associate Professor of Neurology, University of Pennsylvania School of Medicine; Division Chief, Neurooncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Paraneoplastic Disorders of the Nervous System
Thomas Roth, PhD
Professor, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine; Divison Head, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan The Physiology of Sleep
Devon I. Rubin, MD
Assistant Professor, Mayo Clinic College of Medicine, Rochester, Minnesota; Consultant, Department of Neurology, Mayo Clinic, Jacksonville, Florida Peripheral Nerve Injury
Philippe Ryvlin, MD, PhD
Professor of Neurology, Université Claude Bernard Lyon 1; Praticien Hospitalier, Hospices Civils de Lyon, Lyon, France Assessment and Management Principles [Epilepsy]
Professor of Neurology, Harvard Medical School; Neurologist-in-Chief and Chairman, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Neurology of Cardiology, Cardiac Surgery, and Vascular Medicine; Neurology of Hematology; The Neurology of Common Electrolyte Disorders
Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci
Chairman and Professor, Department of Clinical Neurosciences, Royal Free and University College Medical School; and Professor of Neurology, National Hospital for Neurology and Neurosurgery and Institute of Neurology, London, United Kingdom Parkinson’s Disease
Anette Schrag, MD, PhD
Senior Lecturer and Honorary Consultant Neurologist, Department of Clinical Neurosciences, Royal Free and University College Medical School, London, United Kingdom Tourette’s Syndrome, Tics, and Obsessive-Compulsive Disorders
Todd J. Schwedt, MD
Assistant Professor of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri Other Secondary Headache Disorders
Steven R. Schwid D, MD
Associate Professor of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York Treatment of Multiple Sclerosis
Neil J. Scolding, PhD, FRCP
Professor of Clinical Neurosciences, Department of Neurology, University of Bristol Institute of Clinical Neurosciences; Consultant Neurologist, Frenchay Hospital, Bristol, United Kingdom The Neurological Vasculitides
xvi
Contributors
Julian L. Seifter, MD
Associate Professor of Medicine, Harvard Medical School; Division of Nephrology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts The Neurology of Common Electrolyte Disorders
Jon Sen, BSc(Hon), MB, BS, MSc
Research fellow, Institue of Neurology, Queen Square, London, United Kingdom Intracranial Hemorrhage: Aneursymal, Idiopathic, and Hypertensive
Caroline A. Sewry, BSc, PhD, FRCPath
Professor of Muscle Pathology, Dubowitz Neuromuscular Centre, Imperial College Faculty of Medicine, Hammersmith Hospital, London; Centre for Inherited Neuromuscular Disorders, Department of Histopathology, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom Congenital Myopathies
Pankaj Sharma, MD, PhD, MRCP, DHMSA
Honorary Senior Lecturer in Neurology, Imperial College London; Consultant Neurologist, Hammersmith Hospital Acute Stroke Unit, Charing Cross Hospital, London, United Kingdom Prothrombotic States and Related Conditions
Hiroshi Shibasaki, MD, PhD
Emeritus Professor, Kyoto University Graduate School of Medicine; Consultant, Takeda General Hospital, Kyoto, Japan Myoclonus
Stephen D. Silberstein, MD, FACP
Professor of Neurology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Migraine
Karin Stiasny-Kolster, MD
Department of Neurology, Philipps University School of Medicine, Marburg, Germany Restless Legs Syndrome
Alan Stiles, DMD
Clinical Instructor, Department of Oral and Maxillofacial Surgery, Jefferson Medical College of Thomas Jefferson University; Clinical Staff, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Trigeminal Neuralgia and Other Facial Pain
Elsdon Storey, MBBS, DPhil, FRACP
Professor of Neuroscience, Monash University–Alfred Hospital Campus School of Medicine; Head, Neurology Unit, Alfred Hospital, Melbourne, Victoria, Australia Principles of Neuropsychometric Assessment; The Neglect Syndrome; Executive Function and Its Assessment; Hydrocephalus Including Normal-Pressure Hydrocephalus
Austin J. Sumner, MD
Chairman, Neurology, Louisiana State University Health Sciences Center, New Orleans, Louisiana Anatomy and Physiology of Muscle and Nerve
Kinga Szigeti, MD
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Inherited Neuropathies
Valerie S. Tay, MBBS(Hons), FRACP
Neurology Fellow, Royal Children’s Hospital and St. Vincent’s Hospital, Melbourne, Victoria, Australia Spine and Spinal Cord: Developmental Disorders
Zelalem Temesgen, MD
Assistant Professor of Medicine, Mayo Clinic College of Medicine; Consultant, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota Parasitic and Fungal Infections
Zoë Terpening, BPsych Marco Sinisi, MD
Neurosurgeon, Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, United Kingdom Tumors of the Peripheral Nerve
Intern Clinical Neuropsychologist, Department of Clinical Psychology, University of Sydney; Intern Clinical Neuropsychologist, Neuropsychology Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Higher Visuoperceptual Disorders and Disorders of Spatial Cognition (Excluding Hemi-inattention/Neglect)
Sanjay M. Sisodiya, PhD, FRCP
Pierre Thomas, MD, PhD
Reader in Neurology, Institute of Neurology, University College London; Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Genetics [Epilepsy]
Kenneth J. Smith, BSc, PhD
Professor of Neurophysiology, Department of Clinical Neurosciences, King’s College London, London, United Kingdom Pathophysiology of Multiple Sclerosis: Demyelination and Axonal Injury
Professor of Neurology, Université de Nice-Sofia-Antipolis; Praticien Hospitalier, Hôpital Pasteur, Nice, France Assessment and Management Principles [Epilepsy]
Bruce J. Tonge, MBBS, MD, DPM, MRCPsych, FRANZCP, CertChildPsych, RANZCP
Professor, Centre for Developmental Psychiatry and Psychology, School of Psychology, Psychiatry, and Psychological Medicine, Monash University, Melbourne, Victoria, Australia Autism and Attention Deficit/Hyperactivity Disorder
contributors
Omar Touzani, PhD
Lecturer, University of Caen; Staff, University Medical Center, Caen, France Anatomy and Physiology of Cerebral and Spinal Cord Circulation
Douglass M. Turnbull, MBBS, MD, PhD, FRCP
Professor of Neurology, The University of Newcastle upon Tyne; Honorary Consultant Neurologist, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom Metabolic Myopathies (Including Myochondrial Disorders)
Ryan J. Uitti, MD
Professor of Neurology, Mayo Medical School, Rochester, Minnesota; Chair, Department of Neurology, Mayo Clinic, Jacksonville, Florida Inherited Ataxias
Dennis Velakoulis, MBBS, FRANZCP
Clinical Director, Melbourne Neuropsychiatry Centre, University of Melbourne; Director, Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia Clinical Assessment of Mental Status
Angela Vincent, MBBS, MSc, FRCPathol
Professor of Neuroimmunology, University of Oxford; Honorary Consultant in Immunology, Neurosciences Group, John Radcliffe Hospital, Oxford, United Kingdom Neuromuscular Junction Disorders
Maggie C. Walter, MD
Privat-Docent, University of Munich Medical Center, Neurology Clinic and Outpatient Service, Friedrich-Baur Institute, Munich, Germany Muscular Dystrophies
Mark Walterfang, MBBS, FRANZCP
Research Fellow, Melbourne Neuropsychiatry Centre, University of Melbourne; Consultant Neuropsychiatrist, Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia Clinical Assessment of Mental Status
xvii
John D. G. Watson, DPhil, MB, BS, BSC, FRACP
Associate Professor of Medicine, University of Sydney Faculty of Medicine, Sydney; Visiting Neurologist, Sydney Adventist Hospital, Wahroonga, and Hornsby Ku-Ring-Gai Hospital, Sydney, New South Wales, Australia Higher Visuoperceptual Disorders and Disorders of Spatial Cognition (Excluding Hemi-inattention/Neglect)
Louis H. Weimer, MD
Associate Clinical Professor of Neurology, Columbia University College of Physicians and Surgeons and Neurological Institute of New York; Associate Attending, NewYork–Presbyterian Hospital, New York, New York Metabolic, Immune-Mediated, and Toxic Neuropathies
Patrick Y. Wen, MD
Associate Professor of Neurology, Harvard Medical School; Director, Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Tumors of the Spinal Cord
Gregor K. Wenning, MD, PhD
Head, Clinical Neurobiology Unit, and Head, Autonomic Function Unit; Senior Fellow, Movement Disorder Unit; Vice-Chairman, European MSA Study Group; Department of Neurology, University Hospital/Medical University, Innsbruck, Austria Primary Autonomic Failure; Parkinson Plus Disorders
Nathaniel Robb Whaley, MD
Neurology Resident, Mayo Clinic, Jacksonville, Florida Inherited Ataxias
William N. Whiteley, MD, MRCP
Clinical Research Fellow, Division of Clinical Neurosciences, University of Edinburgh; Specialist Registrar in Medical Neurology, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom Neurological Complications of Treatments
Nick S. Ward, MBBS, MD, MRCP
Lecturer, Institute of Neurology, University College London; Wellcome Advanced Fellow, Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery and Institute of Neurology, London, United Kingdom Rehabilitation of Stroke
Thomas T. Warner, MD, PhD, FRCP
Reader in Clinical Neurosciences, Royal Free and University College Medical School; Consultant Neurologist, Royal Free Hospital; Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom Dystonia
Robert G. Will, MA, MD, MBBCh, FRCP
Professor of Clinical Neurology, University of Edinburgh; Consultant Neurologist, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom Prion Diseases
Thomas O. Willcox, Jr., MD
Associate Professor, Department of Otolaryngology–Head and Neck Surgery, Jefferson Medical College of Thomas Jefferson University; Attending Surgeon, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Examination of Hearing and Balance; Auditory System Disorders
xviii
Contributors
Adrian J. Williams, MBBS, FRCP, AASM
Consultant Physician and Director, Lang Fox Respiratory Unit and Sleep Disorders Centre, Guy’s and St. Thomas’ Foundation NHS Trust, London, United Kingdom Sleep Apnea
John W. Winkelman, MD, PhD
Associate Professor in Psychiatry, Harvard Medical School; Medical Director, Sleep Health Center, Brigham and Women’s Hospital, Boston, Massachusetts Primary Disorders of Sleep
Bryan K. Woodruff, MD
Clinical Instructor, Mayo Clinic College of Medicine, Scottsdale; Senior Associate Consultant, Mayo Clinic Hospital, Phoenix, Arizona Frontotemporal Dementia
P R E FA C E
Many have regarded the practice of clinical neurology as an arcane art, and non-neurologists often are daunted by the prospect of managing neurological cases. In large part, this perception of neurology is a legacy from not so long ago, when few if any investigations were available and diagnosis rested on meticulous documentation and evaluation of clinical features. Although neurology remains quintessentially a clinical art, it has benefited greatly from advances in both the investigational and the basic neurosciences. The advent of imaging with CT, MRI, MRS, PET, SPECT, and other technologies has transformed clinical practice, improving our understanding of diseases and their diagnosis and management. Progress in the molecular sciences has had a particular impact on neurology. A substantial proportion of neurological disorders are the consequence of inheritance. The identification of the genetic basis of various neurological diseases, including neurodegenerative and neuromuscular disorders, migraine, and stroke, has provided insight into pathogenesis and has further refined diagnosis and management. These and other advances have made neurology and the neurosciences the most exciting and probably the most rapidly evolving sector of medicine today. Neurologists already are blessed with a number of outstanding textbooks in either single or multiple volumes. What then was the driver to bring this newcomer—Neurology and Clinical Neuroscience—into the field? The primary intention was to provide a comprehensive and up-to-date review of clinical neurology for both experienced practitioners and neurologists-in-training. Integral to this approach was a desire to include as much clinical neuroscience as was relevant and appropriate so that the clinician could understand the basis for the rapid progress in management of specific diseases, especially regarding application of advances in the molecular neurosciences to neurological disease. An important and novel aspect of the book is its emphasis on illustrations in full color, ensuring both clarity and readability. The organization of this book does not range far from the formula that has proved successful for neurology texts over several decades: A review of consciousness, cognition, and the special senses is an appropriate place to begin, because much of neurology rests on a sound understanding of these concepts. Sleep medicine, neuropsychiatry, neuro-ophthalmology, neurootology, and disorders of the autonomic nervous system are essential components of neurological practice. Into these sections we have introduced chapters on assessment to aid or remind neurologists of the techniques involved in clinical evaluation. Other sections that follow the main topic areas of clin-
ical neurology practice include the cerebrovascular, demyelinating, infective, inflammatory, and neurodegenerative diseases; neuromuscular disorders; headache; and epilepsy. Neuro-oncology has become an important component of neurological practice, both as a result of the direct effects of tumors of the nervous system and also because of the consequences of treatment of these and other tumors on brain, spinal cord, and peripheral nerve function. This area has therefore been covered in some detail. A substantial part of the work of a clinical neurologist is the assessment, diagnosis, and management of neurological disease in general medical practice. We have included a comprehensive section on this topic, in acknowledgment of this fundamentally important area. In the preparation of this book, it has been my privilege to work with some of the foremost leaders in the field of clinical neurology. The eminent section editors, Ed Byrne, Billi DiMauro, Richard Frackowiak, Richard Johnson, Yoshikuni Mizuno, Martin Samuels, Stephen Silberstein, Elsdon Storey, and Zbigniew Wszolek have worked tirelessly to ensure the success of this book. Their input into its composition and content has been invaluable. The contributing authors represent an outstanding collection of experts in their respective fields. It is with great gratitude that I thank them for their hard work and congratulate them on their excellent contributions. We, the editors, are greatly indebted to them and hope that they feel the final product justifies their efforts and our cajoling! Three special people deserve particular thanks and recognition for their contributions to the successful production of this book. The first is Susan Pioli, Director of Medical Publishing for Butterworth Heinemann for many years and now head of Neurology for Elsevier. Her support for this text was essential, and it is true to say that she was the midwife at its birth, ensuring its safe and successful entry into this world. Her knowledge of the field and her longstanding friendships and contacts within neurology have been invaluable. It has been a privilege, an education, and a delight to work with her. Heather Krehling has been the ringmaster, coordinating the receipt and production of manuscripts, gently cajoling and always hyper-efficient. The monumental task of assembling the materials for the numerous chapters of this book was a responsibility she discharged with brilliance, humor, and charm. It is a great credit to her. Finally, I thank Rebecca Gaertner of Elsevier for her wonderful help and support in seeing this project through to a successful conclusion. TONY SCHAPIRA
xix
1
CHAPTER
CLINICAL ASSESSMENT MENTAL STATUS ●
●
●
OF
●
Dennis Velakoulis and Mark Walterfang
Since the mid-1980s, the relationship between the clinical neurosciences of neurology, neuropsychology, and psychiatry has been the subject of several important textbooks that seek to cross these disciplinary boundaries.1-6 Lishman7 succinctly described the overlap between neurology and psychiatry as a “delicate balance . . . between our knowledge and understanding of the brain and our knowledge and understanding of people.” Neuropsychology, as a relative newcomer to this field, has added a third element to this balance, and the advent of new investigative imaging modalities and molecular biology technologies has further assisted in “closing the great divide.”8 At the heart of these converging relationships lies an increasing appreciation that a thorough assessment and formulation of individual patients is incomplete without reference to the knowledge and skills of other disciplines. The logical conclusion to this convergence is that disciplinary hybrids such as neuropsychiatry, behavioral neurology, and cognitive neuropsychology may be better replaced by the broader concept of a clinical neuroscience. Although the core expertise of each discipline may differ, the clinical assessment always includes the documentation of a detailed history and the performance of an examination that is driven by a process of hypothesis testing. The major difference in assessment between disciplines is determined by their specific expertise, whether it be the neurological examination, the psychiatric mental state examination, or a detailed neuropsychological assessment. An element common to all is the assessment of cognition, which in neurological practice has been termed the mental status examination.9 In psychiatric practice, the term mental state/status examination refers to a broader assessment of the patient’s mental state and incorporates the cognitive assessment. Because most neurologists and psychiatrists are restricted to bedside assessments of patients and have limited access to neuropsychological expertise, all possible information must be incorporated into decisions regarding the patient’s cognitive abilities. The clinical skill of cognitive assessment extends far beyond the administration of a test and the generation of a score. A common error among junior clinicians is to base diagnosis on a test score and ignore the richness of cognitive information available from the remainder of their interaction with the patient. This chapter takes a broad approach to cognitive assessment as a process that should incorporate all information available to the clinician from the moment a referral is initiated through
2
cognitive testing to the process of feedback to the patient. Neuropsychological assessment, although seen as the “gold standard” of cognitive assessment, is not always available because of limited service resources, cost, or geographical issues. Even if neuropsychological expertise is available, it may be limited by the patient’s inability or refusal to undertake formal testing. In such situations, clinical needs may still necessitate an assessment of the patient’s cognitive state, and the clinician needs to form a judgment on the basis of all available information.
NEUROCOGNITIVE HISTORY General Principles The neurocognitive history begins from the moment the patient is referred. The information provided in a referral may include the following: ■ Mode of referral: urgency, triggers for referral ■ Presenting symptoms ■ Longitudinal course: acute, subacute, gradual, fluctuating,
progressive ■ Medical or psychiatric history ■ Investigations with positive or negative findings ■ The referral question
The neurocognitive history begins with the events precipitating the referral or assessment, particularly the first symptom of change, an understanding of gross functional capacity, and a sense of the longitudinal course of symptoms. From this basic “sketch” of an individual’s function, more specific questions can be directed toward specific cognitive domains; the presence or absence of neurobehavioral symptoms or signs; an individual’s capacity to function in social, occupational, and interpersonal roles; and relevant previous and related history.
Informant History Although the key informant is usually a relative or caretaker, the clinician should seek information from as wide a range of sources as possible. Key informants may include a nursing
chapter 1 clinical assessment of mental status home worker, neighbor, friend, or primary care physician. Such information may be crucial if the validity of the patient’s history is limited by impairments in insight regarding the nature of their deficits. The patient and the informant should be interviewed separately, if possible. Informants are most likely to provide a full and frank history when interviewed alone. Caretakers may not wish to disclose the extent of their concerns with the patient present, for fear of distressing him or her. This is especially relevant if caretakers have not discussed their concerns with the patient or if the content of their concerns is experienced as a betrayal of trust, which in extreme circumstances may put the caretaker at risk.
3
of such a critical event may provide useful information about the type of disturbance and its onset but, perhaps more important, the nature guides future management through emphasis of issues such as safety, competence, and suitability of placement. A similar situation can occur when a patient’s environment is radically changed, such as a residential shift from a highly structured environment to a less structured one, or the loss of a crucial source of support, such as with the illness or death of a spouse. A gradually developing impairment may, however, manifest abruptly when it reaches a critical threshold for caretakers or relatives whose capacity to accommodate the deficits of the patient has been exhausted.
Evolution of Symptoms Patient History The content of the history provided by the patient is meaningful, because many patients are aware of their difficulties to a degree and may proffer a straightforward problem list. Equally revealing is the patient who is seemingly unaware of any difficulties and denies problems as a result of cognitive impairments or psychiatric disturbance. Most patients respond well to an open-ended question about their presentation, such as “What is your understanding of why you are seeing me today?” In some circumstances, it is also appropriate to reveal the concerns of others: for example, “I understand that you have been having difficulties with your memory recently.” The process of the provision of historical information may be equally revealing. Patients may betray language difficulties through word-finding problems, psychosis through thought disorder, depressed mood through a lengthy latency in response time, or executive impairment through an empty or concrete account of events.
Integration of Neurobehavioral and Neurocognitive History Neurobehavioral disturbances such as depression or psychosis are often the initial presenting feature in patients with neurocognitive impairment. Conversely, patients who initially present with the neurocognitive features of dementia may later exhibit psychotic symptoms; disinhibited, stereotypical, or inappropriate behavior; or mood and anxiety disturbance.10 Psychiatric disorders with associated behavioral disturbance may themselves manifest with neurocognitive impairments, such as the difficulties with sustained attention, memory, and processing speed seen in major depression11 or the working memory impairments seen in schizophrenia.12 Neurobehavioral impairment may herald future neurocognitive impairment, and vice versa. For example, frontotemporal dementias commonly manifest with neurobehavioral disturbance,13 and late-life depression may herald Alzheimer’s disease.14
Assessment Trigger Assessment may be triggered by a critical event such as a patient’s putting himself or herself at risk or endangering others or such as significant interpersonal conflict. The nature
The longitudinal course of illness is most commonly established through informants, and a complete history may need to be obtained from a number of sources. The nature of the onset of symptoms and the context in which they occur may be diagnostically discriminatory. For example, delirium usually manifests rapidly over a couple of days in the context of significant medical insult, whereas neurocognitive impairment associated with a central nervous system (CNS) neoplasm usually manifests over a few months, frequently in concert with other neurological symptoms. Many caretakers of patients with a dementing illness report subtle and insidious changes occurring for a year or more before assessment. Exceptions to this may occur, such as a subacute delirium or a rapidly progressive dementia. The longitudinal course may allow diagnostic differentiation particularly within the dementias. Alzheimer’s disease and frontotemporal dementias usually show gradual progression, whereas the time course of vascular dementia is often, but not always, stepwise. Rapid cognitive decline is suggestive of a prion dementia or a potentially reversible cause such as vasculitis or neoplasia. The sequence of symptoms can be similarly informative. Depressed mood and neurovegetative disturbance for 3 months before the onset of memory problems are likely to indicate a depressive “pseudodementia.” An initial presentation of apathy, disinhibition, or stereotypical behaviors before memory or language impairment are suggestive of a frontotemporal dementia, whereas impaired new learning as the first symptom would be more suggestive of an Alzheimer’s-type dementia. The age at symptom onset may narrow the list of differential diagnoses. Cognitive impairment in early adult life may be associated with adult-onset forms of inherited metabolic disorders, such as leukodystrophies, but are more frequently associated with potentially reversible causes of impairment, such as CNS infections, inflammatory disorders, or neoplasia. When impairment manifests in the fourth through sixth decades, early-onset dementias, such as frontotemporal dementia or familial Alzheimer’s disease, or the early manifestation of undiagnosed vascular disease should be considered. In later decades, most such illnesses are vascular or degenerative. Finally, the presence of fluctuations in the mental state and functioning may provide clues to etiology. Fluctuations in the level of arousal and orientation over days are seen in delirium. Late afternoon and early evening deteriorations may reflect the “sundowning” seen in dementias, whereas episodes of undiagnosed confusion occurring over a number of months may point to a diagnosis of Lewy body dementia.
4
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 1–1. Evaluation of Functional Impairment Personal function: eating, toileting, bathing, dressing, grooming Home function: cooking, cleaning, household maintenance Interpersonal: relationships with spouse and family, friends, colleagues Occupational: performance, punctuality, promotion/demotion, conflict Financial: management of cash and change, bill paying, financial planning Transport: driving, public transport, geographical orientation Leisure: hobbies, pastimes
Gross Functional Capacity Patients and caretakers do not always have a specific complaint of “cognitive impairment.” Functional impairment as noticed by caretakers, relatives, or colleagues is commonly a precipitant for assessment. A thorough history of the pattern and nature of functional impairment provides valuable diagnostic information and may help treatment planning (Table 1–1).
Attention and Orientation Attention is not a unitary construct. Sustained, directed attention is the ability to attend to a specific stimulus without being distracted by extraneous internal or environmental stimuli. Other aspects of attention include the ability to share attention between simultaneous tasks (divided attention), the ability to switch attention between tasks, and the ability to attend to stimuli at different spatial locations. Disturbance of sustained, directed attention is most commonly reported in delirium (see Chapter 11) but may also be present with anxiety or mood disturbance, executive dysfunction (see Chapter 7), or dementias. Orientation is a more complex function involving the capacity to attend to stimuli and to process and retain information regarding locale and point in time. The following questions are useful guides to areas for evaluation: ■ Can the patient attend to, and persevere with, most tasks, or
■
Neurocognitive Baseline An understanding of an individual’s premorbid neurocognitive function allows an estimate of the degree and rate of decline. In impaired individuals with superior premorbid intellect, cross-sectional assessment may be within accepted norms for age. Commonly used screening instruments such as the MiniMental State Examination (MMSE) have a significant ceiling effect (see Chapter 2 on neuropsychological assessment) and are likely to be insensitive to this decline.15 Conversely, individuals with long-standing premorbid intellectual impairment may be incorrectly classified as suffering a degenerative process such as dementia, when in fact their neurocognitive function is stable. Baseline function can be estimated grossly from the patient’s maximal educational and occupational attainment and from mental state features such as vocabulary and capacity for abstract thinking. A number of assessment tools for estimating premorbid intellectual function have been devised and rely on the stability of semantic language functions independent of disease or age. The most well-known and widely used is the National Adult Reading Test.16 This probes reading ability for irregular words, which has been shown to be relatively preserved in many disorders.17 Other similar tools include the Wechsler Test of Adult Reading18 and the Cambridge Contextual Reading Test.19 This issue is also addressed in Chapter 2 on neuropsychological assessment.
FUNCTION IN NEUROCOGNITIVE DOMAINS For the purposes of history taking, neurocognitive function is usefully categorized into the domains of attention, language, visuospatial function, memory, and executive function. Very few neurocognitive functions are discrete, however, and most functions are distributed across more than one domain: for example, remembering a list of three items relies on receptive and expressive speech, in addition to memory. The presence of any impairments in hearing and vision should be established as early as possible in an interview.
■ ■ ■
does the patient demonstrate difficulties completing a task or take much longer than would be expected (a measure of sustained, directed attention)? Can the patient attend to the television or to reading of a newspaper article, a magazine, or a book (sustained, directed attention)? Can the patient ignore distractions? Can the patient converse while doing something else (a measure of divided attention)? Is the patient aware of the time of day or day of the week, and does he or she act accordingly with regard to mealtimes or daily tasks?
Language Language is the basic tool of human communication and a basic component of many cognitive abilities. Language functions are commonly ascribed to the dominant hemisphere, and because cerebral dominance for language is closely allied to handedness, it is useful to be aware of the patient’s handedness before language function is assessed. Most of the conditions that produce disorders of language affect the left hemisphere and are commonly of vascular, traumatic, neoplastic, or degenerative origin. Disorders of language are separated into aphasia (partial or total inability to articulate ideas or comprehend spoken or written language), alexia (inability to read), and agraphia (inability to write). An understanding of the large group of aphasias has been complicated by various nomenclatures, although the most recognized is that originally proposed by Benson and Geschwind,20 which divides the group into Broca’s, Wernicke’s, global, conduction, anomic, and transcortical aphasias. This is discussed in more detail in Chapter 3. The following questions are useful guides to areas for evaluation: ■ Has the patient had any difficulties with speech, such as in
finding the right word or using the wrong word? ■ Can the patient pronounce words correctly, or does he or
she make errors in pronunciation? Are these errors consistent? ■ Has there been a change in the patient’s grammar or sentence construction?
chapter 1 clinical assessment of mental status ■ Has there been any reduction in the patient’s quantity or
■ ■ ■ ■
fluency of speech or in how much detail he or she provides in relating events? Has the patient had difficulties in understanding or following conversation? Does the patient miss the “gist” of the conversation? Does he or she misunderstand jokes or puns? Does the patient’s speech jump about from idea to idea or drift off the topic? Has there been a change in the amount, legibility, quality, sophistication, or size of the patient’s handwriting?
Visuospatial Functions Visuospatial functions allow persons to orient themselves in space, enable safe locomotion, facilitate interaction with other individuals and objects, and allow for the expression and understanding of visual symbols of communication. Such functions are often related to pathology affecting the parietal cortex, which also contains contralateral motor and sensory representations of the body soma. Many disorders or diseases that disturb visuospatial functions are associated with significant motor or sensory impairment. Visuospatial disturbance is common in dementias of all types, but it is most commonly seen with Alzheimer’s-type dementia. It is the presenting and dominant feature in the posterior variant, posterior cortical atrophy. Vascular or other acquired focal lesions of the parietal regions may also manifest with visuospatial difficulties. Aspects of visuoperceptual disturbance are discussed further in Chapter 5. The following questions are useful guides to areas for evaluation: ■ Is the patient able to dress himself or herself appropriately?
■
■
■ ■
■ ■
Does he or she wear items of clothing the wrong way around, inside out, or fitted incorrectly? Of importance, however, is that often a dressing apraxia may result from visuoperceptual disturbances or spatial inattention. Can the patient find his or her way around the house, to the shops, and in unfamiliar environments when directions are provided? Can the patient still use everyday objects—eating utensils, grooming items (toothbrush, comb), or tools of his or her trade—appropriately? Can the patient tell the time from an analog clock or watch? Can the patient use more complicated household items, such as an oven, washing machine, television, video recorder, or compact disc player? Disturbances of these functions may also arise from various forms of apraxia. Does the patient ever get left and right mixed up? Does the patient seem to ignore one side of his or her body when bathing, shaving, or dressing or one side of his or her environment when eating, walking/driving, or interacting socially?
Memory Anterograde episodic memory is a general term for the registration, acquisition, storage, and subsequent retrieval of new information. Anterograde episodic memory impairment is perhaps the most common manifestation of neurocognitive disturbance. Anterograde episodic memory consists of several stages, beginning with the reception and registration of the
5
information by a sensory modality, followed by the holding of the information temporarily in working memory (defined as the current content of consciousness); then storage in a more permanent form, which is enhanced by association with other already stored information and augmented by practice or rehearsal; and, finally, the process of retrieval. Each of these steps requires the integrity of the preceding steps, and any interruption in this hierarchy may disrupt anterograde episodic memory function. A detailed discussion of the various memory systems and their disorders is presented in Chapter 4. Patients with dementia, particularly Alzheimer’s disease and vascular dementias, usually present to clinicians with memory disturbance before the onset of other neurocognitive or neurobehavioral disturbances. Memory impairment occurs commonly in brain disorders acquired from such causes as traumatic injury, postinfection states, and chronic exposure to CNS toxins such as alcohol. The following questions are useful guides to areas for evaluation: ■ Can the patient recall recent conversations and accurately
relate recent family news? ■ Is the patient able to describe or relate recent world or local
events that may have been heard on the radio, seen on television, or read in the newspaper? ■ Has the patient missed birthdays, anniversaries, or other special events? ■ Does the patient tend to relate events or occasions from the more distant past when questioned about, or discussing in conversation, more recent events? ■ Has the patient had difficulties recalling the names of people, places, or things?
Executive Function Executive functions are a group of complex functions that are based on the interaction with and executive control of basic processes such as attention, memory, and language. The prefrontal lobes and connected subcortical structures are crucial to the integrity of executive function, personality, and behavior. Cognitive functions that have been attributed to these networks include adaptive behavior, abstract conceptual ability, set-shifting/mental flexibility, problem-solving, planning, initiation, sequencing of behavior, and personality factors such as drive, motivation, and inhibition. Patients with the dysexecutive syndrome fail to anticipate changes, show poor planning ability, and do not learn from their errors. They are poor at selfguided learning and goal-setting, in that they perform normally on externally driven tasks but are poor at self-motivated tasks. Such patients are sensitive to interference from irrelevant stimuli, and may display both motor and cognitive perseveration. A more detailed overview of executive function and dysfunction can be found in Chapter 7. Disorders that commonly manifest with executive dysfunction include frontotemporal dementias, traumatic brain injury, chronic alcohol abuse, and focal disease caused by vascular lesions or neoplasms. Of importance, but not as well recognized, is that patients with schizophrenia may exhibit subtle but often disabling disturbances of executive dysfunction. The following questions are useful guides to areas for evaluation:
6
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
■ Has the patient shown a “personality change”? ■ Has there been any decline in appropriate social judgment,
■ ■ ■
■
such as inappropriate familiarity with strangers or disinhibited sexual or aggressive behavior? Of note is that not all patients with executive dysfunction display these features. Has there been any change in the patient’s degree of motivation or drive? Has the patient developed a set of purposeless repetitive behaviors? Can the patient plan and organize daily activities appropriately, or has he or she begun to struggle to keep work, home, or social life running smoothly? Is the patient making sound judgments, or have there been “out of character” decisions recently?
FUNCTION IN NEUROBEHAVIORAL DOMAINS A thorough neurobehavioral assessment is essential for the neurocognitive history, because a number of disorders cause both psychological and cognitive dysfunction, and neurological diseases may manifest initially with psychological disturbance. Failing to recognize neurobehavioral disturbance can delay correct diagnosis, increase caregiver burden, and cause unnecessary, although relievable, suffering for patients and their families. The neurobehavioral assessment is largely synonymous with the psychiatric “mental state examination.” In contrast to the traditional medical view of the history as a description of symptoms and the examination as a description of signs, the mental state examination includes elements of both the history and the phenomena observed by the examiner. The mental state examination includes descriptions of the patient, his or her behavior, and a summary of his or her responses to questions regarding mental phenomena. Like the cognitive assessment, mental state assessment should not be confined to only the part of the interview in which symptoms are being elicited. The patient who denies hallucinations but frequently and suddenly looks askance while muttering or overtly vocalizing can reasonably be inferred to be responding to hallucinations.
Appearance and Behavior There is much to be gained by careful observation of the patient’s appearance, especially if the interviewer has obtained a good sense of the patient’s premorbid state. The patient’s personal grooming, dress, and general state of health provide important information about functional abilities. Even the state of the patient’s hands may reveal important information. The dry, chaffed hands of a repetitive washer, the nicotine-stained fingers of a patient with schizophrenia, and the tremor of a patient with alcohol dependence are some examples. Patients with chronic schizophrenia may be disheveled and dress unusually, with many layers of clothes or with seemingly little regard for their appearance. They may look around the room in a suspicious manner and on occasion may look for monitoring devices. Depressed patients may sit stooped, with slowing of their movements, or may be restless and agitated, rubbing and wringing their hands. Patients with a pseudodementia may find the interview too difficult and resort to frequent “I don’t know” answers. Anxious patients are visibly anxious, sweaty, and restless. Patients with a dysexecutive syndrome may make inappropriate sexual suggestions or be impul-
sive. The presence of abnormal movements or postures during the interview may be more informative than when the patient is being examined formally. The patient’s interactions with the examiner, administrative staff, or nursing staff may provide invaluable information.
Speech In addition to the language disturbances just described, the examiner should note the rate and quantity of speech. Often the reaction of the examiner to the patient’s speech provides diagnostic clues. The slowed, labored speech of the patient with depression may make the interview long and tedious, whereas the rapid, pressured speech of the manic patient may leave the examiner feeling frustrated and exhausted. The disordered speech of the patient with schizophrenia leaves an interviewer perplexed.
Mood Mood is the sustained level of emotional tone, whereas affect refers to the patient’s emotional behavior. The emotional response of the examiner to the patient provides a further indicator of the patient’s emotional state. Patients with disorders of mood such as major depressive disorder often show impairments in attention and psychomotor speed.21,22 Bipolar disorder is associated with impairments in attention, verbal memory, and executive function. High rates of comorbid mood disturbance are associated with Parkinson’s disease,23 Huntington’s disease,24 and multiple sclerosis.25 Late-onset depression is being increasingly seen as a prodrome to the dementias.14 Inquiries about a patient’s mood state may include the following: “How have you been feeling recently?” “Do you have periods of time when you are always down?” In patients with speech disorders, responding to such questioning may not be possible, and close informants can be asked directly, “Does he/she seem unhappier to you than usual?” Informants are able to comment on the reactivity of mood, inasmuch as depressed patients are often unable to “brighten up.” Patients who are depressed may describe themselves as feeling sad, unhappy, hopeless, useless, blue, or “flat.” This mood state is often accompanied by disturbances in sleep, appetite, concentration, and motivation. The depressed patient conveys sadness and misery or presents as anxious and irritable. Commonly used tools for rating the severity of depressive symptoms include the patient-rated Beck Depression Inventory26 and the clinician-rated Hamilton Depression Rating Scale.27 Patients with elevated mood states display euphoria, elation, and irritability in association with overactivity, accelerated thoughts, disinhibited behavior, reduced sleep, and grandiose ideas. Examiners who find themselves regularly suppressing a smile or giggle in interviews with patients should always ask themselves whether the patient’s mood is elevated. Reduced intensity and narrowing of affective responses is termed blunting of affect and is a key feature of schizophrenia.
Anxiety Anxiety, a normal and adaptive component of human psychological function that allows for the identification of danger or
chapter 1 clinical assessment of mental status threat, may become inappropriate and/or excessive. Anxiety disorders include panic disorder, characterized by panic attacks (discrete, relatively brief periods of intense anxiety accompanied by somatic symptoms of sympathetic drive), agoraphobia (recurrent fear of inability to escape from situations such as being in a crowd or an enclosed area), social anxiety (fear of social situations), specific phobia (of a discrete object, such as heights or water), and generalized anxiety, which leads to diffuse anxiety on most days.28 Pathological anxiety states have been associated with stroke,29 Huntington’s30 and Parkinson’s diseases,31 temporal lobe epilepsy,32 and thyrotoxicosis.33 A history of anxiety can be sought through inquiries about increasing or frequent worrying, its source, and the presence of concomitant physiological signs such as sweating, tachycardia, shortness of breath, and tremor and whether the degree of worry seems excessive to the patient or caretaker. An anxiety disorder with a strong relationship to neurological disorders is obsessive-compulsive disorder, which is associated with intrusive recurrent thoughts (obsessions) and repetitive behaviors or mental acts (compulsions such as counting, checking, or cleaning). Obsessive-compulsive disorder has been strongly associated with Gilles de la Tourette syndrome34 and with the pediatric neuropsychiatric disorder pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS).35 Symptoms of obsessive-compulsive disorder can be ascertained by questions about compulsive behaviors, such as “Do you find yourself checking/cleaning things more than once or more often than you need to?”, and obsessions, such as “Do you have recurrent, intrusive thoughts/ideas/images/impulses?” Severe anxiety states can lead to depersonalization and derealization. These conditions can be difficult for patients to describe, but descriptions can be elicited by asking the following questions: “Have you ever had the sense that the world around you is different or changed?” (derealization) “Have you ever felt detached from the world around you or as if you are an observer of yourself?” (depersonalization) Both these states may be described by patients in the prodrome of complex partial seizures, although are most commonly seen in patients with anxiety or panic disorders. Patients with panic disorder describe symptoms lasting many minutes with a buildup of anxiety symptoms such as a sense of fear, palpitations, hyperventilation, and perioral numbness. The symptoms associated with complex partial seizures are usually stereotyped and much briefer than those seen in panic disorder.
Thought Content and Form In a number of neurological disorders, patients may develop abnormalities in their beliefs about themselves or the environment around them. Thought content can be seen as a spectrum from normal, reality-based thinking to delusions, which are fixed false ideas out of keeping with the patient’s cultural background or education.28 Delusions are categorized by the nature of their content, such as persecutory, grandiose, somatic, and erotomanic delusions or delusions of jealousy or reference. Delusions are classically associated with schizophrenia but are seen in patients with Huntington’s disease, temporal lobe
7
epilepsy, leukodystrophies, systemic lupus erythematosus, and most forms of dementia.36 Persecutory delusions are commonly seen in delirium and substance intoxication. Organic delusions are particularly associated with diseases affecting the limbic system.37 In schizophrenia, delusions tend to be very well systematized (generally static and supported by an extensive belief system) and often have a bizarre nature, whereas in neurological disorders they are often poorly systematized and are predominantly persecutory.38 Informants may provide the most valid and reliable history about delusional ideas, although they may be unaware of them if the patient has not voiced his or her beliefs. It is useful to directly but gently inquire about delusional ideas, using questions such as “Sometimes people feel that they are being watched, that others are planning to hurt them, or that they have special abilities that other people don’t. Have you ever felt like that?” Mood or anxiety disorders are associated with altered thought content. Depression is associated with thoughts such as “Everything seems black,” “I will not get better,” or “Life is not worth living” or with suicidal ideas. Mania is associated with thoughts such as “I am immortal,” whereas anxious patients may express thoughts such as “Something terrible is going to happen.” Suicidal ideation or other thoughts involving harm should always be carefully asked about and documented, including ideas, plans, and intent. When patients clearly express all three, the patient can be seen to be at grave risk of acting on these ideas and usually requires hospitalization. Thought form refers to the structure of thought and is necessarily conveyed through speech. The form of thought may be fragmented and interspersed with pauses in the delirious patient. Thoughts that progressively veer away from the question (tangentiality) or that do not follow logically from each other (loosening of associations) are almost pathognomonic of schizophrenia. The manic patient with flight of ideas displays a flow of thought that is rapid and determined by factors other than the logical flow of ideas, such as the sounds of words (clanging).
Perception Perceptual experience occurs on a continuum, with “true” perception of stimuli at one end and frank hallucinations at the other.39 Hallucinations are defined as percept-like experiences in the absence of an external stimulus that are spontaneous and unwilled and cannot be readily controlled.40 Illusions, which are distortions or elaborations of a normal stimulus, also belong to this continuum. Hallucinations can be well formed and complex or poorly formed and simple,41 and they are categorized according to sensory modality. Complex and elaborate auditory hallucinations are the hallmark of schizophrenia but can occur in severe affective psychotic states. Poorly formed, fragmented auditory hallucinations may be present in organic states such as delirium. Special note should be made of complex visual hallucinations, which are often a feature of organic states. Examples include the Charles Bonnet syndrome and peduncular hallucinosis, where lesions to the visual pathways and to their terminations or ascending inhibitory afferent pathways, respectively, can result in strikingly vivid formed scenes, complex patterns, or groups of miniature figures or animals.42
8
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Olfactory, gustatory, and tactile hallucinations are not commonly experienced in psychiatric illness and should alert the clinician to the possibility of neurological conditions such as complex partial seizures or neoplasia. For patients who are reluctant or unable to discuss their experiences, questioning caretakers about behavior that might represent a reaction to perceptual disturbance, such as responding to voices or gaze movements in response to visual phenomena, may prove useful.
Vegetative Function Vegetative functions such as sleep, appetite, and sexual drive are often disturbed in patients with neurobehavioral disturbances, particularly disturbances of mood.43 Patients may complain of appetite disturbance with weight loss or gain; sleep disturbance with insomnia in initial, middle, or terminal sleep phases (the last known as early morning wakening, a characteristic of severe depression); altered libido; disturbances in energy and motivation; and impaired capacity to enjoy usual pursuits.
Insight and Judgment A patient’s lack of insight into illness may reduce the validity of a history, such as the patient’s self-report of memory complaints44 or of adherence to prescribed treatments.45 Insight has been traditionally viewed in both psychological and cognitive frames. In the psychological frame, insight relates to acceptance of illness and the need for its treatment. Insight is impeded by denial of illness, which occurs to varying degrees and reflects psychological coping mechanisms that allow the patient to deal with the fear, hopelessness, or shame associated with sickness and its treatment.46 Cognitive models focus on the neurocognitive capacity of an individual to internalize, retain, and cognitively process the awareness of symptoms, attribute these to an illness, and appreciate the likely effects of accepting or refusing treatment.47 Cognitive models of insight were devised from the strong association of disorders in which disrupted frontalexecutive function is the cognitive hallmark, such as frontotemporal dementia and schizophrenia, with poor insight.45,48 An apparent change in insight is likely to reflect an organic process, inasmuch as the psychological mechanisms that relate to insight tend to be personality based and thus relatively stable.49 The concept of insight overlaps with the neurological symptom of anosognosia, a lack of awareness of neurological deficit, first described by Babinski50 and most commonly seen in right hemisphere stroke. Although it most commonly characterizes a lack of awareness of hemiparesis, anosognosia can also occur for amnesia, apraxia, aphasia, cortical blindness, and prosopagnosia.51 The observation that most lesions associated with anosognosia involve the parietal lobes or related connections reinforces the role of the parietal lobe in awareness of illness and, in particular, the role of the right inferior parietal cortex in attention.52 A patient’s insight can be inquired about with open-ended questions such as “Why do you think you have come to see me today?” and “In what way does this problem affect you?” More direct, closed-ended questioning such as “What would happen if you stopped your tablets?” is appropriate afterward.
OTHER ABNORMAL BEHAVIORS A range of other neurobehavioral disturbances may alert the clinician to the possibility of associated cognitive or neurological impairment. Apathy, disinhibition, and stereotypies can prove diagnostically challenging because they may initially mimic other disorders. These behaviors are often seen in frontotemporal dementia, itself a mimicker of other neurobehavioral disorders, and are elements of the three behavioral subtypes of these disorders53 (see also Chapter 7). Apathy may manifest as apparent depression, disinhibition as mood elevation, and stereotypies as compulsive behaviors or dyskinesias. Utilization behavior and echo phenomena (echopraxia, echolalia) are uncommon but important neurobehavioral syndromes that may be easily missed or ignored. Finally, catatonia constitutes a medical emergency for which the underlying cause must be determined quickly to ensure appropriate treatment.
Apathy Apathy is best defined as a state of reduced or absent motivation.54 In practice, apathy manifests as a reduction in the initiation of goal-directed behavior. Apathy is most common in disorders that disrupt the frontal-subcortical circuit, considered to be the substrate for motivated behavior. This circuit includes the anterior cingulate cortex, nucleus accumbens, globus pallidus, and thalamus.55 Disruption to these circuits with consequent apathy is seen in frontal-subcortical dementias such as Parkinson’s disease, Huntington’s disease,56,57 and frontotemporal dementia; traumatic brain injury58; schizophrenia59; and vascular insult.60 Apathy in many of these syndromes may respond to stimulant medication,61 and in schizophrenia, atypical antipsychotic agents may reduce apathy through increased dopamine release in the frontal cortex.62 On history, the differentiation of apathy from depression can be difficult, although patients with pure apathy often blandly deny feeling depressed and do not transmit a depressed affect. The other cardinal features of depression, such as neurovegetative disturbance, are often absent. Family and caretakers may become angry or resentful at a patient whose worsening apathy is perceived as a voluntary withdrawal. The distinction between apathy and depression is important, so that an apathetic patient with frontotemporal dementia does not receive an incorrect diagnosis of depression, which leads to delays in appropriate management, or, conversely, so that patient with a reversible clinical depression does not remain untreated.63
Disinhibition Inhibition is the capacity to cognitively “cancel” a thought, response, or activity that is considered unintended, unwanted, or inappropriate. Social disinhibition is associated with insults to the nondominant inferior frontal cortex64 and linked subcortical structures. Lesions to these regions result in release of motor, affective, instinctive, or cognitive behaviors such as hyperactivity, elevated mood, hyperorality and hypersexuality, and accelerated or grandiose thinking.65 Disorders that produce disinhibition include focal vascular, neoplastic or traumatic lesions,66 and frontotemporal dementia.67 Cognitive disinhibition of automatic responses to stimuli is associated with lesions
chapter 1 clinical assessment of mental status of the anterior cingulate cortex and impaired performance on tasks such as the Stroop test. (See also Chapter 7.) Many patients may not be able to relate disinhibited behavior but can be questioned about behaviors that they “wouldn’t usually do,” such as excessive spending, substance use, social or sexual inappropriateness, or risk-taking behavior. Understandably, caretakers are usually able to relate a history of such behaviors, particularly if it represents a change from previous behavior.
Stereotypies Stereotypies are repetitive, rhythmical, and invariant motor behaviors, without an apparent purpose or function, that can vary from simple motor behaviors such as rocking or hand waving to extraordinarily complex acts and rituals.68 They are one of the defining features of autism and are common in patients with mental retardation.69 Stereotypies are seen in adults with lesions or disorders affecting the frontostriatal circuit running between the dorsolateral frontal cortex and the head of the caudate nucleus.70 Frontotemporal dementias commonly manifest with stereotypic behaviors resulting from degeneration of the dorsolateral prefrontal cortex.71 Stimulant medications can produce complex stereotypies through a dopaminergic effect on the basal ganglia.72 Other repetitive motor behaviors such as compulsive behaviors and tics are seen in patients with Gilles de la Tourette syndrome and obsessive-compulsive disorder, both of which are considered to be associated with basal ganglia pathology.72,73 Of importance is that stereotypies, compulsions, complex tics, mannerisms (unusual or pathological styles of performing goal-directed activities, such as a bizarre gait and unusual ways of greeting people), and habits can often be difficult to distinguish purely on the basis of subjective observation. The context and history of the motor phenomena provide important diagnostic information.
9
dromes such as latah.79 Echolalia has been described in patients with dysphasia and left hemispheric lesions.80
Catatonia Catatonia is a disorder associated with a number of behavioral, motor, and cognitive phenomena. Catatonic patients may be mute or akinetic; exhibit stereotypic and manneristic movements; adopt unusual postures; or exhibit negativism, waxy flexibility, mitmachen (automatic motion obedience), and gegenhalten (an increase in muscle tone in response to passive movement). Echopraxia, echolalia, and palilalia (perseverative repetition of a syllable or word) may also be present. Catatonia may be associated with psychotic illnesses such as schizophrenia or bipolar disorder, or it may be secondary to metabolic encephalopathies or primary neurological conditions, including post-encephalitic states, brain tumors, and seizure disorders. The distinction between primary psychiatric and secondary catatonias is one extreme example of the need to make a diagnosis regarding the cause of the patient’s mental state on the basis of the informant history, background history, and the physical examination alone.
RELEVANT HISTORY Medical History
Utilization behavior refers to the phenomenon in which patients grasp and purposively use objects within their reach, even though this action may be inappropriate or out of context.74,75 It reflects an inability to inhibit an automatic action cued by an environmental stimulus. It has been described in patients with lesions affecting the prefrontal/subcortical circuits.75,76 Examples given by Lhermitte75 included “pouring” from an empty jug into a glass, using a knife and fork on a plate without food, and lighting multiple cigarettes for the examine while the first remains unsmoked. An awareness of utilization behavior is important because it may be misinterpreted as odd, eccentric, or even antisocial behavior by the inexperienced examiner.
A history of traumatic brain injury, epilepsy, stroke, meningitis, encephalitis, or cerebral hemorrhage points toward the likelihood of neurocognitive or neurobehavioral disturbance. Systemic diseases with CNS involvement, such as autoimmune disorders, syphilis, and malignancy, may be revealed through the medical history. A history of infection with or risk factors for human immunodeficiency virus (HIV) should always be inquired about because of the wide-ranging effects of HIVrelated illness on cognition, mood, and behavior. Smoking, diabetes, hypertension, and hypercholesterolemia increase the risk of strokes and may provide clues to the presence of vascular CNS disease. The effects of therapeutic drugs on the CNS must always be considered. Dopaminergic agents used in the treatment of Parkinson’s disease may cause psychosis,81 and anticholinergic agents impair cognition.82 Treatments used for systemic disorders may produce neurobehavioral states, as is seen in the depression associated with β-interferon used for viral hepatitis83 and the mania secondary to corticosteroid use for autoimmune disorders.84 Polypharmacy, particularly in the elderly, increases the likelihood of medication neurotoxicity.85 The possibility of drug withdrawal states warrants specific inquiry about the use of benzodiazepines, sedatives, hypnotics, and alcohol.
Echolalia and Echopraxia
Psychiatric History
Echo phenomena are the unsolicited and stereotyped repetition of another person’s speech (echolalia) or actions (echopraxia). These phenomena are commonly observed in patients with schizophrenia, especially during acute illness or in catatonic states. They have been well described in patients with neurodevelopmental disorders, including Gilles de la Tourette syndrome and autism,77,78 and with various complex startle syn-
A psychiatric history allows the clinician to differentiate between a relapse of an established disorder and new-onset disease. The neurocognitive deficits of chronic schizophrenia may manifest as a dementing illness86; “hypofrontal” disinhibition and poor judgment may be the presenting symptoms of mania87; and patients with depression may present with a “pseudodementia.”88
Utilization Behavior
10
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Family History Because of the strong genetic basis for many neurobehavioral and neurocognitive disorders, a detailed family history is essential. This should include age; cause of death; history of neurological, neurobehavioral, or systemic disease; and a history of consanguinity. In some jurisdictions, cases of disorders such as Creutzfeldt-Jakob disease must be reported to the appropriate authority, such as the Centers for Disease Control and Prevention, and it may be possible to consult disease registers to confirm a family history, inasmuch as about 10% of cases of Creutzfeldt-Jakob disease are dominantly inherited.
Substance Use History A thorough longitudinal alcohol history is essential for the verification of Korsakoff’s amnesia, alcoholic dementia, delirium tremens, and alcoholic hallucinosis, A smoking history should be obtained, including total exposure and past or current related illnesses. Stimulants such as amphetamines may produce neurobehavioral symptoms such as delusions and hallucinations,89 chronic marijuana usage may lead to psychosis and cognitive impairment,90 and inhalant solvent abuse has been associated with acute and chronic cognitive impairment, depression, and psychosis.91
NEUROBEHAVIORAL RATING SCALES The use of validated scales allows a rapid snapshot of neurobehavioral disturbance and the longitudinal monitoring of illness progression and treatment response within a patient. Although most physicians are familiar with cognitive screening tools such as the MMSE, noncognitive neurobehavioral scales are not yet in widespread use. The use of validated scales such as the Neuropsychiatric Inventory (NPI) and Neurobehavioral Rating Scale (NRS) is slowly moving from research to clinical settings.
Neuropsychiatric Inventory The NPI92 is a semistructured clinician interview of caretakers in which the severity and frequency of disturbance in 12 symptom domains is rated (Table 1–2). The NPI shows good interrater and test-retest reliability.92 It has been modified and validated for use in nursing homes (NPI-NH)93 and in various non-English versions.94-97 Scoring in subscales of the NPI has been shown to correlate strongly with those in other wellvalidated symptomatic scales, such as the Behavioral Patho-
T A B L E 1–2. Symptom Domains Rated by the Neuropsychiatric Inventory Hallucinations Delusions Agitation/aggression Depression Anxiety Elation/euphoria
Apathy/indifference Disinhibition Irritability/lability Aberrant motor behavior Nighttime behavior* Appetite/eating change*
*Additional domains in the Neuropsychiatric Inventory for nursing homes.
logic Rating Scale for Alzheimer’s Disease (BEHAVE-AD) and Hamilton Rating Scale for Depression.98 The performance characteristics of the NPI have been established in a range of neurological conditions, including Alzheimer’s disease,99 Parkinson’s disease,100 frontotemporal dementia,101 progressive supranuclear palsy,102 corticobasal degeneration,103 mild cognitive impairment,104 Tourette disorder,105 subcortical vascular ischemia,106 multiple sclerosis,107 and Huntington’s disease.30 The NPI has a key role alongside cognitive scales in monitoring the noncognitive improvements with cholinesterase inhibitor treatment of various dementias, and it has been shown to reliably detect improvement in individuals treated with donepezil,108 galantamine,109 and rivastigmine.110
Neurobehavioral Rating Scale The NRS is a 27-item, multidimensional instrument designed to measure neurobehavioral disturbance after traumatic brain injury.111 Based on the Brief Psychiatric Rating Scale,112 the NRS is a brief structured patient interview that takes 15 to 20 minutes to complete. It includes ratings of neurobehavioral symptoms, basic tests of cognition, and questions about the patient’s current level of function. The NRS has demonstrable utility in assessing a number of different organic neurobehavioral states, including traumatic brain injury,113-116 dementia,117,118 Parkinson’s disease,119 HIV-related dementia,120 and the post-endarterectomy state.121 As with the NPI, translations of the NRS into other languages have been made and are of proven validity.121
NEUROCOGNITIVE EXAMINATION Many clinicians assess cognitive function by using standardized instruments such as the MMSE,122 which offer a brief, validated, and easily communicable approach. However, because most commonly used instruments have limitations, an understanding of the how to assess separate cognitive domains allows the clinician to tailor the examination to an individual presentation. The necessity of performing a formal neurocognitive examination warrants emphasis, because in the absence of a thorough and structured assessment, it is possible to miss a clear deficit. For example, patients who perform well verbally may mask significant impairments in other cognitive domains, such as memory or visuoperceptual function. Few neurologists would consider their assessment complete without a physical neurological examination of the patient or a careful history of the presenting symptoms. Although a complete neurocognitive assessment may be unnecessary for all patients, it is similarly a key component of the clinical assessment in a number of circumstances. This section describes an approach to a largely qualitative bedside cognitive assessment and serves as an introduction to the subject. More details regarding the examination of each domain and the disorders that such an examination may reveal can be found in subsequent chapters.
Principles of Cognitive Assessment When to undertake neurocognitive examination A neurocognitive examination should be undertaken whenever the reported complaint is a cognitive one, in clinical cir-
chapter 1 clinical assessment of mental status cumstances in which cognitive impairment occurs frequently (postsurgically, in cerebrovascular disease, in neoplasia, or in trauma), or when there is an unexplained history of personality, functional, or behavioral change. In many countries, standardized cognitive assessment is mandatory before the prescription of cholinesterase inhibitors for dementia.
General observation Much can be gained from general observation of both patient and informant and from the physical examination. A patient’s grooming and state of hygiene can be indicators of impoverished motivation and drive or of hemineglect. Alterations in gross motor activity, such as agitation or retardation, and the presence focal movements such as tremor, tics, or choreiform movements should be noted. The state of a patient’s sensorium can be ascertained by his or her capacity to sustain attention during the interview process and his or her capacity to filter out extraneous stimuli. Memory impairments may become obvious during clinical interview if a patient is unable to provide a history of recent events or the illness, as may a history that is poorly elaborated or impoverished. Impairments in insight into illness may be apparent at the outset if a patient denies any abnormality, if the history is discrepant with that obtained from an informant, or if a patient is unable to make the link between subjective complaints (such as impaired memory) and functional decline (such as driving difficulties or home safety concerns).
Setting The examiner should ensure that enough time is allowed for the examination; that the environment is quiet, well-lit, and nondistracting; and that the patient’s usual sensory aids such
11
as glasses or hearing aids are available. At the outset of examination, the role of the caregiver in this aspect of the assessment should be clearly defined. Many patients manage cognitive difficulties through reference to or reliance on a spouse or caretaker. It is important that this is not replicated in the assessment situation, in which a caretaker might subtly assist the patient during neurocognitive testing. When necessary, the participation of appropriately trained interpreters, who do not “help” the patient and who are skilled in the translation of linguistically difficult or culturally specific items, is invaluable. Finally, due consideration should be given to the patient’s level of fatigue and cooperation. Patients who have completed a long clinical history and physical examination may not be able to perform optimally during neurocognitive assessment, and it may be necessary to schedule a second session at which the assessment can be completed.
Quantitative versus qualitative data When quantitative screening or assessment instruments are used to gauge cognition in patients, it is important for the clinician to look beyond the quantitative result in making a diagnosis. For example, a score of 22 of 30 on the MMSE is below most accepted cutoffs for dementia, but it may not point definitively to organic cognitive impairment. Such a score may be seen, for example, in individuals of limited education, in patients sedated by medication, or in patients with psychiatric illness such as major depression or schizophrenia. The quality of a patient’s performance is as important as the numeric measure in many or most quantitative tests; examples include perseveration displayed on a serial subtraction task or in a copying or clock-drawing task (Fig. 1–1). Further details of the quantitative aspects of neuropsychological testing may be found in Chapter 2
■
Figure 1–1. Perseveration in a copying task and in a clock-drawing task.
12
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Examination of Attention and Orientation Testing of orientation to time is more sensitive to cerebral dysfunction than testing of orientation to place, and impaired orientation to person should raise the possibility of a psychogenic fugue state. Successful completion of tests of orientation requires intact memory and expressive language; that is, these are not “pure” tests of attention. When time orientation is tested, orientation to the approximate time of day (within 1 hour), should be assessed as well as that to the day of the week, month, and year, and is perhaps the most reliable and sensitive. Disorientation as to the exact date has a very high base rate in the normal population and is rarely clinically useful. Marked disorientation to time is most com-mon in patients with delirium or Korsakoff’s amnesia. Orientation is often preserved in early dementia. Attention has traditionally been tested by serial subtraction tasks and reverse spelling of words, such the serial sevens and “WORLD” backwards tasks in the MMSE. Such tasks are dependent on working memory, as well as on calculation and spelling, respectively, both of which are strongly related to educational background and both of which may be disrupted by focal lesions that do not otherwise impair attention.123 Reciting an overlearned sequence such as days of the week or months of the year in reverse order requires sustained attention and intact working memory; this test is very sensitive to disturbance of attentional processes and is generally understood across cultures and languages. Repeating a spoken sequence of digits, starting with two digits and increasing the length of the sequence with each correct attempt, is also a sensitive marker of attention, particularly when the patient needs to repeat the sequence in reverse, which is more difficult and places a greater load on working memory. Most subjects correctly complete 7 ± 2 digits forward and 5 ± 1 in reverse. Digit span testing depends on intact working memory, the frontal lobe–mediated brief store of visual or auditory information in current consciousness (e.g., remembering a telephone number before writing it down). Continuous performance tasks, which require the patient to respond when a particular stimulus is presented (e.g., the letter “A” in a list of random letters read by the examiner9) are minimally dependent on working memory but are good measures of sustained, directed attention. Finally, it is important for the clinician to be aware that attentional impairment may impair performance in other parts of the cognitive examination. If attention is markedly impaired, poor results on testing in other domains may not necessarily indicate that function in those domains is also impaired (Table 1–3).
Examination of Language As with attentional disturbance, impaired language can affect many other aspects of the neurocognitive examination and
T A B L E 1–3. Tests of Attentional Function Serial sevens/WORLD backwards Orientation to time/place Overlearned sequences (days of week, months of year) Digit span: forward and reverse Continuous performance task
hence should be tested early. A significant subjective understanding of the patient’s capacity for language can be gained during the clinical interview with regard to the degree of spontaneous speech, articulation, capacity for word-finding, and comprehension (Table 1–4). Comprehension of language is often aided by nonverbal communication, and patients with language disturbance may be able to respond appropriately to verbal communication by relying on nonverbal cues. Comprehension should be tested in a variety of tasks of different degrees of difficulty to detect subtle impairment and, ideally, should be tested in both written and verbal form. Where expressive speech is not possible, motor rather than verbal responses indicating comprehension should be sought. At its most simple, it can be tested by yes/no responses to simple/rhetorical questions (“Is today Friday?”) and also to more difficult ones (e.g., “If the lion and the tiger have a fight, and the lion is eaten by the tiger, is the tiger still alive?”) Comprehension is also frequently tested with multistage commands, such as the paper-folding item in the MMSE, but these too are dependent on working memory. Reading comprehension can be tested by asking the patient to read through a short paragraph from a newspaper or magazine article. Repetition should similarly be tested with a graded series of tasks of increasing linguistic complexity and may be impaired in isolation in the presence of intact comprehension or expression. Initially starting with monosyllabic or oligosyllabic words, the examiner should progress to simple phrases and to more complex sentences, such as the commonly used “No ifs, ands, or buts” phrase and more difficult-to-articulate phrases, such as “The orchestra played, and the audience applauded.” Naming to confrontation is commonly impaired in aphasias, and such impairment is commonly associated with wordfinding difficulties in spontaneous speech. Anomia, the inability to name objects, can be objectively tested with a confrontation naming task. When this test is conducted at the bedside, objects from various categories should be used (colors, body parts, room objects, parts of objects), and it is important to use uncommon items (“knuckle” on the hand, “winder” of a watch), as well as common items such as pens, shoes, and watches, because many aphasic patients reveal their anomia only when confronted with uncommon items. As with poor performances in other domains, naming difficulties may also arise from other causes, such as visual agnosia. Reading is the language task in which performance is most determined by educational status, and poor literacy is not uncommon in many patient populations. The capacities to read aloud and to understand written language are potentially dissociable and should be tested separately. Patients should be asked to read simple and then complex words, particularly comparing the pronunciation of orthographically regular (sounded as spelled) words such as “shed” to irregular words such as “rough,” as well as phrases such as “Close your eyes.” Writing should be tested to detect agraphia, which frequently accompanies aphasia. Agraphia is diagnosed when basic language errors, gross spelling errors, or paragraphias (word or syllable substitutions) are present. The patient should be asked to write sentences both spontaneously and in response to dictation, with the latter ideally containing a number of orthographically irregular words and/or homonyms (“The boy’s aunt made a large pie out of steak and dough”). Further details of language assessment can be found in Chapter 3.
chapter 1 clinical assessment of mental status T A B L E 1–4. Tests of Language Function Comprehension: single-/multiple-stage verbal and written commands, newspaper article Repetition: words, phrases, sentences Naming: colors, body parts, objects Reading: simple and complex words, phrases Writing: spontaneous and dictated sentences
Examination of Visuoperceptual/ Visuoconstructional Function and Calculation Visual and constructional impairments are often present with parieto-occipital lesions, particularly of the nondominant hemisphere, which, in combination with lesions of prefrontal regions, is important for spatially directed attention.124 When ventral occipitotemporal regions are affected, visual recognition is impaired, particularly for objects, written words (pure alexia), colors, or faces (prosopagnosia). Dorsal lesions result in impairment of visuospatial organization. A detailed exposition of disorders of visual perception may be found in Chapter 5. When a patient is unable to maintain attention to one side of his or her spatial field or body soma, visual and somatosensory neglect, respectively, are said to occur and are typically seen with nondominant parietal lesions. Lesions in the dominant parietal region may result in Gerstmann’s syndrome, which, in addition to agraphia, manifests with calculation dysfunction (acalculia), right/left disorientation, and naming inability for fingers (finger agnosia). A disorder of skilled movement, apraxia, occurs when lesions in a network that includes the inferior dominant parietal region result in the loss of the ability to perform the “formulas for movement” stored in this region of the brain (ideomotor apraxia) or the capacity to perform a series of actions such as putting a letter in an envelope, sealing it, and stamping it in the correct sequence (ideational apraxia). Visuospatial organization is commonly tested by tasks of figure drawing or copying, such as figure copying or clock drawing, although the latter taps into many cognitive functions and can be considered as a cognitive screening test in its own right.125 A gradient from simple to complex figures should be used, and patients can also be asked to spontaneously draw figures such as a house or a tree. Many different ways to conduct and score clock drawing tasks have been published, although most require subjects to correctly place all numbers on the clock and appropriately place hands demonstrating a time in response to command. Most constructional tests are sensitive for visual neglect, which can also be tested by line bisection tasks. Orobuccal and limb praxis should be tested separately because they are controlled by different neural pathways. Dominant and nondominant sides should be tested separately. Patients should be asked to demonstrate a movement such as using a comb and to imitate the examiner’s movements. The latter can be done in a systematized manner by using the interlocking finger test.126 Calculation should be specifically tested by means of simple arithmetic in addition to functional real-life examples but is often tapped by the serial sevens test (Table 1–5).123
13
T A B L E 1–5. Tests of Visuoconstructional Function, Prascis, and Calculation Spatial organization: figure copying and clock drawing Neglect: figure copying, clock drawing, somatosensory testing, line bisection Praxis: left and right limb demonstrations and imitations, orobuccal demonstrations, finger postures Calculation: simple arithmetic, shopping tasks
Examination of Memory “Memory disturbance” is most commonly used to refer to a disorder of episodic, declarative memory (memory for things that can be stated). This manifests as difficulty in recalling personally experienced material from the past and/or learning new information, and it is often found in dementing disorders such as Alzheimer’s disease and in amnestic disorders such as Korsakoff’s syndrome. Declarative memory has traditionally been divided into immediate, recent, and remote memory. Immediate memory is now more commonly described as working memory and refers to the very brief storage of the auditory and visual contents of current consciousness in the dominant perisylvian language areas of the cortex and the nondominant parietal cortex, respectively, and under frontal executive control. Recent memory is the term traditionally used by physicians to describe the capacity for new learning of verbal and visual material. The consolidation of recent memories is a function of the hippocampus, related structures in the medial temporal zones, and hippocampal outflow through the fornices to the mammillary bodies and thalamus. Remote memory is a time-based distinction, but the term may be used to imply that the relevant memories are consolidated and no longer hippocampally dependent. Remote memory is made up of autobiographical, episodic memory (memory for events) and semantic memory (memory for knowledge and words, dependent on anterior temporal neocortex). The nosology of the various memory systems and their disorders is covered in detail in Chapter 4. Working memory is usually tested by items such as digit span or by the immediate recall of a word list. Recent memory is generally tested with delayed recall of a word list, name and address, or a short story. Patients with a primary deficit in registration or encoding of memory (e.g., as in Alzheimer’s disease) demonstrate rapid forgetting and limited spontaneous recall and do not benefit from the provision of clues. Patients with lesions affecting dorsal prefrontal circuits have poor or inefficient retrieval of normally registered memory and show limited spontaneous recall but may benefit from cueing.127 Nonverbal memory should be tested through the reproduction of a visual figure after a delay. Ideally, these figures are constructions that do not lend themselves to a verbal description, as then patients can use intact verbal memory as a “workaround.” Testing for nonverbal recall is not included in the MMSE, but it is featured in other brief tools such as the Neuropsychiatry Unit Cognitive Screening Instrument (NUCOG)128 and is illustrated in Figure 1–2. Remote memory is tested by the patient’s recall of personal history and his or her general fund of knowledge. The latter may
14
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s ■
Drawing reproduction.
Figure 1–2. Testing for nonverbal recall.
Stimuli
Copies
Recall
T A B L E 1–6 Tests of Memory Function Working memory: digit span, immediate verbal recall Recent memory: recall of word list, name and address, short story, visual shapes (with cueing) Remote memory: autobiographical data, general knowledge, word meanings
be difficult to test in a standardized manner, inasmuch as commonly used questions about political leaders or historical events are strongly education- and culture-dependent (Table 1–6).
Examination of Executive Function Control of executive functions is commonly ascribed to the prefrontal lobes and related subcortical structures, although this involves a deliberate simplification. Executive dysfunction may be seen in focal prefrontal lesions, frontotemporal dementias, or neurobehavioral syndromes such as schizophrenia and major depression, among other disorders. The basal ganglia and thalamus are connected to the frontal lobes through defined circuits, and lesions of these structures or circuits can manifest with executive impairment.129 A fuller account of executive functioning and the various features of the dysexecutive syndrome can be found in Chapter 7. Set-shifting/sequencing is the ability of the patient to shift efficiently from one cognitive set to another and to inhibit no longer appropriate responses, and its impairment manifests as perseveration.130,131 The neural substrate for set-shifting involves the dorsolateral prefrontal cortex and its connections to basal ganglia and thalamus.132 The initiation of cognitive
strategies is an integral but often overlooked element of the cognitive examination and is often the core deficit underlying apathy syndromes, particularly after occurrence of medial frontal lesions that affect the anterior cingulate region.65 Abstract thinking appears to be a function of the lateral frontal zones, and impairment of abstract thinking manifests as concreteness of thinking. The orbitomedial frontal zones are involved in the processing of emotion and in judgment and planning; lesions to this region, particularly on the nondominant side, manifest as disinhibition and poor judgment.65 The capacity to integrate abstractive and emotional functions, perhaps best illustrated in the appreciation of humor, relates to right frontal regions.133 Although impairments in set shifting can be observed behaviorally, they can be directly tested with tasks of motor or written sequencing. Motor sequencing is tested with the fist-edge-palm task, which is particularly impaired in patients with dominant frontal lesions but also at the extremes of age.134 Written sequences of alternating letters or shapes can also be used.135 Initiation can be assessed with tests of verbal fluency by initial letter (words beginning with a particular letter) in a limited time span. Most adults score 16 to 18 ± 4 words in 1 minute. Although abstract thinking is commonly tested with proverbs, these are notoriously culturally, educationally, and age sensitive and are best replaced by questions regarding similarities (e.g., “What is the similarity between a desk and a chair?” or “What is the difference between a painting and poetry?”). Capacity to inhibit, as well as manage, interference can be tested with a “go–no-go” task where the patient is asked to provide a response to one particular examiner’s instruction, while not responding to a second, but related, instruction, such as “Tap on the table when I tap it once, but don’t tap the table when I tap it twice” (Table 1–7).
chapter 1 clinical assessment of mental status T A B L E 1–7. Tests of Executive Function Set-shifting: motor and written sequencing Initiation: verbal (category and word) fluency Abstraction: proverbs, similarities Inhibition: go–no-go task
Cortical Release Signs Although they are technically not a part of the mental status examination, a brief discussion of cortical release signs or primitive reflexes is warranted. These signs include the grasp, palmomental/pollicomental, snout, and pout reflexes.74 The presence and nature of such signs in schizophrenia may be an index of severity of neurodevelopmental disturbance and may aid in assessing prognosis, expected outcome, development of medication side effects such as tardive dyskinesia, and treatment planning.136,137 In geriatric psychiatry, cortical release signs are valuable aids to illness staging138,139 and outcome prediction140 and may be diagnostic aids in particular subtypes such as frontotemporal dementia.141,142 Although the palmomental reflex is relatively nonspecific, the grasp reflex is virtually never present in healthy elderly subjects143-147 and should be considered an indicator of CNS disease in this population.
STANDARDIZED COGNITIVE ASSESSMENT INSTRUMENTS Standardized cognitive assessment instruments are collections of cognitive testing items that have been validated against “gold standards” of neuropsychological testing or clinical or neuropathological diagnosis. These tools, which are designed to be rapidly administered during clinical assessments, are recommended in populations in which the rate and severity of impairment is relatively high—that is, in which a high prior probability maximizes positive predictive value. The ultimate goal of cognitive assessment has been to develop the ideal cognitive screening or assessment instrument, and this search is reflected in the plethora of published tools.
15
patients, with low to moderate correlations between scores on this task and those on standard neuropsychological tests of memory.148 The MMSE does not assess long-delay recall, which can result in false-negative findings in the evaluation of relatively mild memory disorder and may fail to reveal amnesia.149 The “WORLD backwards” and serial sevens forms are not equivalent, and it has been recommended that they be replaced by the “months backwards” task.150 A significant concern with the structure of the MMSE is the lack of specific items that test executive function and spatial recall, and the American Neuropsychiatric Association has recommended that clinicians “supplement it with specific measures of spatial functions, delayed memory, and executive abilities.”151 Finally, a patient’s age and level of education significantly affect MMSE scores, and this needs to be taken into account when scores are interpreted.152,153 In response to these limitations, the more comprehensive Modified Mini-Mental State Examination has been developed and is being increasingly used in epidemiological and community-based surveys.154
Neurobehavioral Cognitive Status Examination The Neurobehavioral Cognitive Status Examination (NCSE), now known as the Cognistat, was developed for use in neurosurgical patients and involves the “screen and metric” approach in 11 cognitive domains155: level of consciousness, orientation, attention, comprehension, repetition, naming, construction, memory, calculation, similarities, and judgment. The resultant profile provides a “pattern” of distribution of cognitive dysfunction across the relevant domains. The Cognistat has shown utility in a number of neurocognitive conditions, particularly dementias, but has proved less useful in populations with neurobehavioral or neuropsychiatric disorders. The Cognistat assesses some aspects of executive function but does not test sequencing, inhibition, or verbal fluency. It appears to be a reasonably sensitive tool for the detection of dementia, but at a significant cost to its specificity,156 and is subject to the same effects of age and education as is the MMSE.157 The screen and metric approach has been criticized for sacrificing sensitivity for expediency, resulting in false-negative results in some populations.158 The Cognistat takes significantly longer to complete than the MMSE.
Mini-Mental State Examination and the Modified Mini-Mental State Examination
Addenbrooke’s Cognitive Examination
The MMSE is the most widely used of a substantial number of available screening tests122 and is a popular clinical measure that has validated versions available in many languages. The MMSE consists of a variety of tasks, yields a summed score with a maximum of 30 points, and can generally be administered in less than 10 minutes. The tasks have been grouped into seven categories, each rationally representing a different function: orientation to time, orientation to place, registration, attention and calculation, spontaneous recall, language (naming, repetition, reading, and spontaneous writing), and visual construction. The traditional cutoff score for dementia in mixed samples is less than 24, but this requires adjustment depending on the desired sensitivity versus specificity (see Chapter 2). The MMSE has significant content limitations. There is substantial variability in the recall of three words in healthy elderly
Addenbrooke’s Cognitive Examination (ACE) was developed by Mathuranath and coworkers in Cambridge159 and was reported to be able to reliably differentiate frontotemporal from Alzheimer’s dementia, although this property has been questioned.160 It has shown utility in parkinsonian syndromes161 and in differentiating early dementia from affective disorders.162 Addenbrooke’s Cognitive Examination provides a total score out of 100 and includes all items from the MMSE, which allows the clinician to generate both scores. It provides unequal scores on scales of orientation, attention/concentration, verbal fluency, language, and visuospatial function. Calculating a ratio of scores in these areas may aid in the differentiation of dementia subtypes. A revised version of Addenbrooke’s Cognitive Examination is currently being developed by the Cambridge group.
16
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Frontal Assessment Battery In view of the generally low inclusion rates of executive function testing in most screening tools, a further option is to use a dedicated executive battery such as the Frontal Assessment Battery, which has shown good correlation with neuropsychological measures of cognitive function and discriminant validity for patients with frontal lobe disorders.163 The Frontal Assessment Battery may for be used to supplement the MMSE, because of its lack of executive function testing.
COGNITIVE ASSESSMENT BEYOND THE BEDSIDE The testing methods, items, and screening instruments described in this chapter are all bedside methods of ascertaining neurocognitive function. The “gold standard” of cognitive assessment is the “formal” neuropsychological assessment, in which validated tools backed by normative and illness data are used. Neuropsychological assessment is a valuable but scarce and time-intensive resource. Not all patients with cognitive impairment require or tolerate neuropsychological testing. Hence, although all neurological services should have access to appropriately trained neuropsychologists, it is up to the neurologist to determine which patients need formal assessment and the nature of the question asked of the neuropsychologist. A referral to “Please provide a cognitive assessment” is the equivalent of the inadequate “Please provide a neurological/ psychiatric opinion.” The more information made available and the more specific the referral question, the more relevant will be the opinion; for example, “How does this patient’s current function differ from their estimated baseline?”; “Can the pattern of this patient’s cognitive dysfunction differentiate between a developmental or acquired disorder?”; or “Is this patient’s pattern of impairment indicative of a frontotemporal rather than Alzheimer’s dementia?” Aspects of neuropsychological testing are covered in greater detail in the following chapter.
ASSESSING THE “UNASSESSABLE” PATIENT On occasion, a patient refuses to participate in cognitive testing. Such patients include the insightful patient with early dementia who becomes anxious and distraught and develops a “catastrophic reaction” if asked questions that are clearly probing his or her memory. In other situations, patients may berate the examiner for asking “silly questions”: “Do you think I’m stupid?” “What are you, a schoolteacher?” “Why don’t you ask that other doctor I saw before?” The clinical imperative for cognitive assessment may still be as relevant as it is for the compliant patient. It is in these situations that the skill and expertise of the clinician are paramount. When faced with such a situation, the junior clinician may give up and state that “the patient is not assessable.” The experienced clinician may be able to rescue the interview through gently reassuring the patient and moving on to more familiar and less threatening territory such as the patient’s family, his or her interests, or day-to-day activities. Through skillful questioning about a favorite football team’s recent fortunes or grandchildren’s names and ages, the clinician may build up a clear picture of memory difficulties. Similarly, asking the patient to draw the floor plan of his or her house may provide important cognitive information. The clinician’s inventiveness and flexibility can be developed only
through the experience of clinical contact with a variety of patients.
THE NEUROCOGNITIVE FORMULATION The aim of the neurocognitive formulation is to piece together a “story” from all the information available. Although this chapter has focused on the neurocognitive history and the mental status examination, the physical examination and the results of investigations must contribute to the formulation. The process of assembling the formulation allows the clinician to integrate the developmental, educational, social, and genetic aspects of the patient’s presentation into a framework that provides not only a diagnosis but also a comprehensive management and treatment plan.
Case Example Mr. Jones, a 50-year-old executive with two teenaged children, presented for neurological assessment after a recent minor head injury in a car accident, on a background of 18 months of personality and functional change. Mr. Jones’ major complaint was of feeling rundown and lethargic, which had led his local doctor to prescribe antidepressants. His wife had noted that, for the last 18 months, he had been lacking motivation, had been forgetful, and had been allocated work duties well below his level of seniority. The family history revealed that Mr. Jones’ father had recently received a diagnosis of Parkinson’s disease after a 10-year history of gradual cognitive decline. Mr. Jones had been educated to tertiary level. There was no medical, psychiatric, or substance use history. On mental state examination, he manifested psychomotor retardation with poor grooming and a relative lack of concern regarding the recent events in his life. He did not describe depressed mood or communicate a depressed affect. He was oriented and performed well on attentional and memory testing. There were no abnormalities of visuoconstruction, praxis, left/right orientation, or calculation. He performed normally on language tasks. He had difficulty with a three-step motor sequencing task, could name only five animals in 1 minute (Fig. 1–3) and gave concrete responses on a task of similarities. He scored 29 out of 30 on the MMSE. Neurological examination findings were normal except for bilateral grasp reflexes. The neurocognitive history revealed personality and functional change, decreased motivation, slowing, and blandness of affect in a man with a family history of a dementia. Bedside cognitive testing yielded a normal MMSE score, but he performed poorly on tasks of executive function. The neurological finding of bilateral grasp reflexes was considered abnormal. A provisional diagnosis of a frontotemporal dementia was made, and investigations were ordered. Magnetic resonance imaging showed bilateral frontal atrophy out of keeping with his age, together with mild enlargement of the frontal horns of the ventricles; cerebral single photon emission computed tomography revealed bilateral frontal hypoperfusion. Neuropsychological testing confirmed the executive deficits and provided a baseline of cognitive performance for future reference. Several significant issues needed to be addressed in the ensuing months, including the possibility of a genetic condition and its implications for his young family, his ability to work and drive, and the effect of an early dementia on his family.
chapter 1 clinical assessment of mental status ■
0 – 15
15 – 20
antelope
owl
30 – 45
45⫹
17
Figure 1–3. Verbal fluency by semantic category (animals) in 15-second epochs: impaired in a case of frontotemporal dementia.
hippo
eagle zebra
“I don’t know the names of many animals”.
CONCLUSION
Suggested Reading
The assessment of neurocognitive function extends far beyond the administration of cognitive tests and should include relevant aspects of history from a breadth of informants, as well as from the patient, and examination findings. A diagnosis is rarely made on the basis of a deficit in cognition alone. Even if the only positive finding is a single deficit in one cognitive domain, the clinician must always bear in mind Lishman’s “delicate balance”7 when discussing his or her formulation with the patients and caretakers and planning management and treatment appropriately.
Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience. New York: Oxford University Press, 2003. Mitchell AJ: Neuropsychiatry and Behavioral Neurology Explained. Philadelphia: Elsevier, 2004. Price BH, Adams RD, Coyle JT: Neurology and psychiatry. Closing the great divide. Neurology 2000; 54:8. Schiffer RB, Rao SM, Fogel BS: Neuropsychiatry, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2003. Yudovsky SC, Hales RE: American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. Washington, DC: American Psychiatric Publishing, 2003.
References
K E Y
P O I N T S
●
The assessment of a patient with suspected cognitive impairment incorporates information obtained from a variety of sources, including the mental status examination.
●
A neurocognitive history contains information from patients and informants regarding the evolution of illness, history, and associated functional and behavioral changes.
●
The mental status examination should cover a broad range of cognitive domains, including attention, memory, language, executive function, and visuospatial tasks. It should be informed by observation and assessment from first contact to the end of the interaction with the patient, and it includes the use of a structured assessment.
●
The neurocognitive formulation is the synthesis of the history and mental status examination findings with physical examination findings. Diagnosis is based on the overall clinical picture, and should not be made on the basis of test scores alone. The neurocognitive formulation informs diagnosis, further investigation, and management options.
1. Andrewes D: Neuropsychology: From Theory to Practice. East Sussex, UK: Psychology Press Ltd., 2001. 2. Mesulam M-M: Behavioral Neurology. Philadelphia: FA Davis, 1985. 3. Cummings J: Clinical Neuropsychiatry. Orlando, FL: Grune & Stratton, 1985. 4. Lishman WA: Organic Psychiatry: The Psychological Consequences of Cerebral Disorder. Oxford, UK: Blackwell Science, 1998. 5. Schiffer RB, Rao SM, Fogel BS: Neuropsychiatry. Philadelphia: Lippincott Williams & Wilkins, 2003. 6. Yudovsky SC, Hales RE: American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. Washington, DC: American Psychiatric Publishing, 2003. 7. Lishman AW: Neuropsychiatry: a delicate balance. Psychosomatics 1992; 33(1):4-9. 8. Price BH, Adams RD, Coyle JT: Neurology and psychiatry. Closing the great divide. Neurology 2000; 54:8. 9. Strub R, Black F: The Mental Status Examination in Neurology. Philadelphia: FA Davis, 2000. 10. Finkel S: Behavioral and psychological symptoms of dementia: a current focus for clinicians, researchers, and caregivers. J Clin Psychiatry 2001; 62(Suppl 21):3-6. 11. Marvel C, Paradiso S: Cognitive and neurological impairment in mood disorders. Psychiatr Clin North Am 2004; 27:19-36.
18
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
12. Flashman L, Green M: Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment. Psychiatr Clin North Am 2004; 27:1-18. 13. Chow T: Frontotemporal dementias: clinical features and management. Semin Clin Neuropsychiatry 2003; 8:58-70. 14. Schweitzer I, Tuckwell V, O’Brien J, et al: Is late onset depression a prodrome to dementia? Int J Geriatr Psychiatry 2002; 17:995-1005. 15. Tombaugh T, McIntyre N: The Mini-Mental State Examination: a comprehensive review. J Am Geriatr Soc 1992; 40: 922-935. 16. Nelson H, O’Connell A: Dementia: the estimation of premorbid intelligence levels using the new adult reading test. Cortex 1978; 14:234-244. 17. Cummings J, Houlihan J, Hill M: The pattern of reading deterioration in dementia of the Alzheimer type: observations and implications. Brain Lang 1986; 29:315-323. 18. Wilkinson G: WRAT3 Administration Manual. Wilmington, DE: Wide Range, 1993. 19. Beardsall L, Huppert F: Improvement in NART word reading in demented and normal older persons using the Cambridge contextual reading test. J Clin Exp Neuropsychol 1994; 16:232-242. 20. Alexander M, Benson D: The aphasias and related disturbances. In Joynt RJ, Griggs RC, eds: Clinical Neurology. Philadelphia, Lippincott: 1998, pp 1-58. 21. Shenal B, Harrison D, Demaree H: The neuropsychology of depression: a literature review and preliminary model. Neuropsychol Rev 2003; 13:33-42. 22. Rogers M, Kasai K, Koji M, et al: Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence. Neurosci Res 2004; 50:1-11. 23. Tandberg E, Larsen J, Aarsland D, et al: The occurrence of depression in Parkinson’s disease. A community-based study. Arch Neurol 1996; 53:175-179. 24. Folstein S, Abbott M, Chase G, et al: The association of affective disorder with Huntington’s disease in a case series and in families. Psychol Med 1983; 13:537-542. 25. Feinstein A: The Clinical Neuropsychiatry of Multiple Sclerosis. Cambridge, UK: Cambridge University Press, 1999. 26. Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561-571. 27. Hamilton MA: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56-62. 28. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press, 1994. 29. Castillo C, Schultz S, Robinson R: Clinical correlates of earlyonset and late-onset post-stroke generalized anxiety. Am J Psychiatry 1995; 152:1174-1179. 30. Paulsen J, Ready R, Hamilton J, et al: Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry 2001; 71:310-314. 31. Richard I, Schiffer R, Kurlan R: Anxiety and Parkinson’s disease. Mov Disord 1996; 8:501-506. 32. Young G, Chandarana P, Blume W, et al: Mesial temporal lobe seizures presenting as anxiety disorders. J Neuropsychiatry Clin Neurosci 1995; 7:352-357. 33. Simon N, Blacker D, Korbly N, et al: Hypothyroidism and hyperthyroidism in anxiety disorders revisited: new data and literature review. J Affect Disord 2002; 69:209-217. 34. George M, Trimble M, Ring H, et al: Obsessions in obsessivecompulsive disorder with and without Gilles de la Tourette’s syndrome. Am J Psychiatry 1993; 150:93-97. 35. Snider L, Swedo S: PANDAS: current status and directions for research. Mol Psychiatry 2004; 9:900-907. 36. Cummings J: Organic psychosis. Psychosomatics 1988; 29:16-26.
37. Cummings J: Organic delusions: phenomenology, anatomical correlates and review. Br J Psychiatry 1985; 146:184187. 38. Cutting J: The phenomenology of acute organic psychosis. Comparison with acute schizophrenia. Br J Psychiatry 1987; 151:324-332. 39. van Os J: Is there a continuum of psychotic experiences in the general population? Epidemiol Psichiatr Soc 2003; 12:242-252. 40. Bentall R, Slade P: Reality testing and auditory hallucinations: a signal detection analysis. Br J Clin Psychol 1985; 24:159-169. 41. Assad G, Shapiro B: Hallucinations: theoretical and clinical overview. Am J Psychiatry 1986; 143:1088-1097. 42. Santhouse AM, Howard RJ, Ffytche DH: Visual hallucinatory syndromes and the anatomy of the visual brain. Brain 2000; 123(Pt 10):2055-2064. 43. Goldberg D, Bridges K, Duncan-Jones P, et al: Dimensions of neuroses seen in primary-care settings. Psychol Med 1987; 17:461-470. 44. Harwood D, Sultzer D, Wheatley M: Impaired insight in Alzheimer’s disease: association with cognitive deficits, psychiatric symptoms, and behavioural disturbances. Neuropsychiatry Neuropsychol Behav Neurol 2000; 13:83-88. 45. Lacro J, Dunn L, Dolder C, et al: Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002; 63:892-909. 46. Johnson S, Orrell M: Insight, psychosis and ethnicity: a casenote study. Psychol Med 1996; 26:1081-1084. 47. David A: “To see ourselves as others see us.” Aubrey Lewis’ insight. Br J Psychiatry 1999; 175:210-216. 48. David A: Insight and psychosis. Br J Psychiatry 1990; 156: 798-808. 49. McGlashan T: Recovery from mental illness and long-term outcome. J Nerv Ment Dis 1987; 175:681-685. 50. Babinski J: Contribution à l’étude des troubles mentaux dans l’hémiplégie organique cérébrale (anosognosie). Revue Neurologique 1914; 22:845-848. 51. Vuilleumier P: Anosognosia: the neurology of beliefs and uncertainties. Cortex 2004; 40:9-17. 52. Heilman K, Watson R: Mechanisms underlying the unilateral neglect syndrome. Adv Neurol 1977; 18:93-105. 53. Hodges J, Miller B: Frontotemporal dementia (Pick’s disease). In Hodges J, ed: Early-Onset Dementia: A Multidisciplinary Approach. Oxford, UK: Oxford University Press, 2001, pp 284-303. 54. Marin R: Differential diagnosis and classification of apathy. Am J Psychiatry 1990; 147:22-30. 55. Mega M, Cummings J: Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci 1994; 6:358-370. 56. Burns A, Folstein S, Brandt J, et al: Clinical assessment of irritability, aggression and apathy in Huntington’s and Alzheimer’s disease. J Nerv Ment Dis 1990; 178:20-26. 57. Starkstein S, Mayberg H, Preziosi T, et al: Reliability, validity and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1992; 4:134-139. 58. Andersson S, Krogstad J, Finset A: Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med 1999; 29:447-456. 59. Roth R, Flashman L, Saykin A, et al: Apathy in schizophrenia: reduced frontal lobe volume and neuropsychological deficits. Am J Psychiatry 2004; 161:157-159. 60. Phillips S, Sangalang V, Sterns G: Basal forebrain infarction. A clinicopathologic correlation. Arch Neurol 1987; 44:11341138.
chapter 1 clinical assessment of mental status 61. Marin R, Fogel B, Hawkins J, et al: Apathy: a treatable syndrome. J Neuropsychiatry Clin Neurosci 1995; 7:23-30. 62. Hertel P, Nomikos G, Iurlo M, et al: Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain. Psychopharmacology (Berlin) 1996; 124:74-86. 63. Levy M, Cummings J, Fairbanks L, et al: Apathy is not depression. J Neuropsychiatry Clin Neurosci 1998; 10:314-319. 64. Aron A, Robbins T, Poldrack R: Inhibition and the right inferior frontal cortex. Trends Cogn Sci 2004; 8:170-177. 65. Starkstein S, Robinson R: Mechanism of disinhibition after brain lesions. J Nerv Ment Dis 1997; 185:108-114. 66. Starkstein S, Boston J, Robinson R: Mechanisms of mania after brain injury: 12 case reports and review of the literature. J Nerv Ment Dis 1988; 176:87-100. 67. Neary D, Snowden J, Northen B, et al: Dementia of frontal lobe type. J Neurol Neurosurg Psychiatry 1988; 51:353-361. 68. Cooper S, Dourish C: Neurobiology of Stereotyped Behaviour. London: Oxford University Press, 1990. 69. Lewis M, Gluck J, Bodfish J, et al: Neurobiological basis of stereotyped movement disorder in animals and humans. In Sprague R, Newell K, eds: Stereotypy: Brain-Behavior Relationships. Washington, DC, American Psychological Association Press, 1996, pp 37-67. 70. Stuss D, Benson D: Neuropsychological studies of the frontal lobes. Psychol Bull 1984; 95:3-24. 71. Grossman M: Frontotemporal dementia: a review. J Int Neuropsychol Soc 2002; 8:566-583. 72. Graybiel A, Canales J: The neurobiology of repetitive behaviors: clues to the neurobiology of Tourette syndrome. In Cohen D, Goetz C, Jankovic J, eds: Tourette Syndrome. Philadelphia: Williams & Wilkins, 2001, pp 123-131. 73. Cummings J: Anatomic and behavioral aspects of frontalsubcortical circuits. Ann N Y Acad Sci 1995; 769:1-13. 74. Walterfang M, Velakoulis D: Cortical release signs in psychiatry. Aust N Z J Psychiatry 2005; 39:317-327. 75. Lhermitte F: “Utilization behaviour” and its relation to lesion of the frontal lobes. Brain 1983; 106:237-255. 76. Rudd R, Maruff P, MacCuspie-Moore C, et al: Stimulus relevance in eliciting utilisation behaviour. Case study in a patient with a caudate lesion. Cogn Neuropsychiatry 1998; 3:287-298. 77. Harris JC: Developmental Neuropsychiatry. Assessment, Diagnosis and Treatment of Developmental Disorders. New York: Oxford University Press, 1998. 78. Coffey CE, Brumback RA, eds: Pediatric Neuropsychiatry. Washington, DC: American Psychiatric Press, 1998. 79. Tanner CM, Chamberland J: Latah in Jakarta, Indonesia. Move Disord 2001; 16:526-529. 80. Schuler A: Echolalia. Issues and clinical applications. J Speech Hear Disord 1979; 44:411-434. 81. Wint D, Okun M, Fernandez H: Psychosis in Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17:127-136. 82. Katzenschlager R, Sampaio C, Costa J, et al: Anticholinergics for symptomatic management of Parkinson’s disease. Cochrane Database Syst Rev 2003; (2):CD003735. 83. Loftis J, Hauser P: The phenomenology and treatment of interferon-induced depression. J Affect Disord 2004; 82:175190. 84. Brown E, Khan D, Nejtek V: The psychiatric side effects of corticosteroids. Ann Allergy Asthma Immunol 1999; 83:495503. 85. Inouye S: Prevention of delirium in hospitalized older patients: risk factors and targeted intervention strategies. Ann Med 2000; 32:257-263. 86. Lawson W, Waldman I, Weinberger D: Schizophrenic dementia. Clinical and computed axial tomography correlates. J Nerv Ment Dis 1988; 176:207-212.
19
87. Shulman K: Disinhibition syndromes, secondary mania and bipolar disorder in old age. J Affect Disord 1997; 46:175182. 88. Dobie D: Depression, dementia and pseudodementia. Semin Clin Neuropsychiatry 2002; 7:170-186. 89. Harris D, Batki S: Stimulant psychosis: symptom profile and acute clinical course. Am J Addict 2000; 9:28-37. 90. Kalant H: Adverse effects of cannabis on health: an update of the literature since 1996. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:849-863. 91. Westermeyer J: The psychiatrist and solvent-inhalant abuse: recognition, assessment and treatment. Am J Psychiatry 1987; 144:903-907. 92. Cummings J, Mega M, Gray K, et al: The Neuropsychiatric Inventory: a comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314. 93. Wood S, Cummings J, Hsu M, et al: The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 2000; 8:75-83. 94. Choi S, Na D, Kwon H: The Korean version of the Neuropsychiatric Inventory: a scoring tool for neuropsychiatric disturbance in dementia patients. J Korean Med Sci 2000; 15:609-615. 95. Leung V, Lam L, Chiu H: Validation study of the Chinese version of the Neuropsychiatric Inventory (CNPI). Int J Geriatr Psychiatry 2001; 16:789-793. 96. Vilalta-Franch J, Lozano-Gallego M, Hernandez-Ferrandiz M, et al: The Neuropsychiatric Inventory: psychometric properties of its adaptation into Spanish. Rev Neurol 1999; 29: 15-19. 97. Politis A, Mayer L, Passa M, et al: Validity and reliability of the newly translated Hellenic Neuropsychiatric Inventory (H-NPI) applied to Greek outpatients with Alzheimer’s disease: a study of disturbing behaviors among referrals to a memory clinic. Int J Geriatr Psychiatry 2004; 19:203208. 98. Reisberg B, Auer S, Monteiro I: Behavioral pathology in Alzheimer’s disease (BEHAVE-AD) rating scale. Int Psychogeriatr 1996; 8(Suppl 3):301-308. 99. Mega M, Cummings J, Fiorello T, et al: The spectrum of behavioural changes in Alzheimer’s disease. Neurology 1996; 46:130-135. 100. Aarsland D, Cummings J, Larsen J: Neuropsychiatric differences between Parkinson’s disease with dementia and Alzheimer’s disease. Int J Geriatr Psychiatry 2001; 16:184191. 101. Mourik J, Rosso S, Niermeijer M, et al: Frontotemporal dementia: behavioral symptoms and caregiver distress. Dement Geriatr Cogn Disord 2004; 18:299-306. 102. Litvan I, Mega M, Cummings J, et al: Neuropsychiatric aspects of progressive supranuclear palsy. Neurology 1996; 47:1184-1188. 103. Litvan I, Cummings J, Mega M: Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiatry 1998; 65:717-721. 104. Lyketsos C, Lopez O, Jones B, et al: Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002; 288:1475-1483. 105. Kulisevsky J, Litvan I, Berthier M, et al: Neuropsychiatric assessment of Gilles de la Tourette patients: comparative study with other hyperkinetic and hypokinetic movement disorders. Mov Disord 2001; 16:1098-1104. 106. Aharon-Peretz J, Kliot D, Tomer D: Behavioral differences between white matter lacunar dementia and Alzheimer’s disease: a comparison on the neuropsychiatric inventory. Dement Geriatr Cogn Disord 2000; 11:294-298.
20
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
107. Diaz-Olavarrieta C, Cummings J, Velazquez J, et al: Neuropsychiatric manifestations of multiple sclerosis. J Neuropsychiatry Clin Neurosci 1999; 11:51-57. 108. Holmes C, Wilkinson D, Dean C, et al: The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 2004; 63:214-219. 109. Monsch A, Giannakopoulos P: Effects of galantamine on behavioural and psychological disturbances and caregiver burden in patients with Alzheimer’s disease. Curr Med Res Opin 2004; 20:931-938. 110. Aupperle P, Koumaras B, Chen M, et al: Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer’s disease: results of a 52-week open-label study. Curr Med Res Opin 2004; 20:1605-1612. 111. Levin H, High W, Goethe K, et al: The Neurobehavioural Rating Scale: assessment of the behavioural sequelae of head injury by the clinician. J Neurol Neurosurg Psychiatry 1987; 50:183-193. 112. Overall J, Gorham D: The brief psychiatric rating scale. Psychol Reports 1962; 10:799-812. 113. Vanier M, Mazaux J, Lambert J, et al: Assessment of neuropsychologic impairments after head injury: interrater reliability and factorial and criterion validity of the Neurobehavioral Rating Scale–Revised. Arch Phys Med Rehabil 2000; 81:796-806. 114. Merchant R, Bullock M, Carmack C, et al: A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury. Ann N Y Acad Sci 1999; 890:42-50. 115. Rapoport M, McCauley S, Levin H, et al: The role of injury severity in neurobehavioral outcome 3 months after traumatic brain injury. Neuropsychiatry Neuropsychol Behav Neurol 2002; 15:123-132. 116. Vilkki J, Ahola K, Holst P, et al: Prediction of psychosocial recovery after head injury with cognitive tests and neurobehavioral ratings. J Clin Exp Neuropsychol 1994; 16:325338. 117. Sultzer D, Berisford M, Gunay I: The Neurobehavioral Rating Scale: reliability in patients with dementia. J Psychiatr Res 1995; 29:185-191. 118. Pollock B, Mulsant B, Rosen J, et al: Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry 2002; 159:460-465. 119. Mathias J: Neurobehavioral functioning of persons with Parkinson’s disease. Appl Neuropsychol 2003; 10:57-68. 120. Hilton G, Sisson R, Freeman E: The Neurobehavioral Rating Scale: an interrater reliability study in the HIV seropositive population. J Neurosci Nurs 1990; 22:36-42. 121. Rabee H, Saadani M, Iqbal K, et al: Neurobehavioral effects of carotid endarterectomy. Saudi Med J 2001; 22:433-437. 122. Folstein M, Folstein S, McHugh P: “Mini Mental State.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198. 123. Manning R: The serial sevens test. Arch Intern Med 1982; 142:1192. 124. Critchley M: The Parietal Lobes. New York: Hafner, 1966. 125. Shulman K: Clock drawing: is it the ideal cognitive test? Int J Geriatr Psychiatry 2000; 15:548-561. 126. Moo L, Slotnick S, Tesoro M, et al: Interlocking finger test: a bedside screen for parietal lobe dysfunction. J Neurol Neurosurg Psychiatry 2003; 74:530-532. 127. Tulving E, Kapur S, Craik F, et al: Hemispheric encoding/ retrieval asymmetry in episodic memory: positron emission tomography findings [Review]. Proc Natl Acad Sci U S A 1994; 91:2016-2020.
128. Walterfang M, Velakoulis D, Gibbs A, et al: The NUCOG: construction and piloting of a cognitive screening instrument in a neuropsychiatric unit. Australas Psychiatry 2003; 11: 325-329. 129. Marburg D: The effect of lesions in the centromedian nucleus of the thalamus on the monkey’s performance in delayed alternation and object reversal tasks. Int J Neurosci 1973; 5:207-214. 130. Ridley R: The psychology of perseverative and stereotyped behaviour. Prog Neurobiol 1994; 44:221-231. 131. Hotz G, Helm-Estabrooks N: Perseveration. Part I: a review. Brain Inj 1995; 9:151-159. 132. Nagahama Y, Okada T, Katsumi Y, et al: Dissociable mechanisms of attentional control within the human prefrontal cortex. Cereb Cortex 2001; 11:85-92. 133. Shammi P, Stuss D: Humour appreciation: a role of the right frontal lobe. Brain 1999; 122:657-666. 134. Luria A: The Working Brain. New York: Basic Books, 1973. 135. Luria A: Frontal lobe syndromes. In Vinken P, Bruyn G, eds: Handbook of Clinical Neurology, vol 2. New York: Elsevier, 1969, pp 725-757. 136. Barnes T, Crichton P, Nelson H, et al: Primitive (developmental) reflexes, tardive dyskinesia and intellectual impairment in schizophrenia. Schizophr Res 1995; 16:47-52. 137. Youssef H, Waddington J: Primitive (developmental) reflexes and diffuse cerebral dysfunction in schizophrenia and bipolar affective disorder: over-representation in patients with tardive dyskinesia. Biol Psychiatry 1988; 23:791-796. 138. Franssen E, Reisberg B, Kluger A, et al: Cognitionindependent neurologic symptoms in normal aging and probable Alzheimer’s disease. Arch Neurol 1991; 48:148154. 139. Benesch C, McDaniel K, Cox C, et al: End-stage Alzheimer’s disease: Glasgow Coma Scale and the neurologic examination. Arch Neurol 1993; 50:1309-1315. 140. Burns A, Jacoby R, Levy R: Neurological signs in Alzheimer’s disease. Age Ageing 1991; 20:45-51. 141. Gregory C, Orrell M, Sahakian B, et al: Can frontotemporal dementia and Alzheimer’s disease be differentiated using a brief battery of tests? Int J Geriatr Psychiatry 1997; 12:375383. 142. Sjögren M, Wallin A, Edman A: Symptomatological characteristics distinguish between frontotemporal dementia and vascular dementia with a dominant frontal lobe syndrome. Int J Geriatr Psychiatry 1997; 12:656-661. 143. Di Legge S, Di Piero V, Altieri M, et al: Usefulness of primitive reflexes in demented and non-demented cerebrovascular patients in daily clinical practice. Eur Neurol 2001; 45:104110. 144. Hogan D, Ebly E: Primitive reflexes and dementia: results from the Canadian Study of Health and Aging. Age Ageing 1995; 24:375-381. 145. Jacobs L, Gossman M: Three primitive reflexes in normal adults. Neurology 1980; 30:184-188. 146. Jenkyn L, Reeves A, Warren T, et al: Neurologic signs in senescence. Arch Neurol 1985; 42:1154-1157. 147. Kobayashi S, Yamaguchi S, Okada K, et al: Primitive reflexes and MRI findings, cerebral blood flow in normal elderly. Gerontology 1990; 36:199-205. 148. Cullum M, Thompson L, Smernoff E: Three word recall as a measure of memory. J Clin Exp Neuropsychol 1993; 15: 321-329. 149. Benedict R, Brandt J: Limitations of the Mini-Mental State Examination for the detection of amnesia. J Geriatr Psychiatry Neurol 1993; 5:233-237. 150. Galasko D, Klauber MR, Hofstetter CR, et al: The Mini-Mental State Examination in the early diagnosis of Alzheimer’s disease. Arch Neurol 1990; 47:49-52.
chapter 1 clinical assessment of mental status 151. Malloy P, Cummings J, Coffey C, et al: Cognitive screening instruments in neuropsychiatry: a report of the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 1997; 9:189-197. 152. O’Connor D, Pillott P: The influence of education, social class and sex on Mini-Mental State scores. Psychol Med 1989; 19:771-776. 153. Mungas D, Marshall S, Weldon M, et al: Age and education correction of Mini-Mental State Examination for English and Spanish speaking elderly. Neurology 1996; 46:700-706. 154. Teng EL, Chui H: The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987; 48:314-318. 155. Kiernan R, Mueller J, Langston J, et al: The Neurobehavioral Cognitive Status Examination: a brief but quantitative approach to cognitive assessment. Ann Intern Med 1987; 107:481-485. 156. Drane D, Osato S: Using the Neurobehavioral Cognitive Status Examination as a screening measure for older adults. Arch Clin Neuropsychol 1997; 12:139-143. 157. Drane DL, Yuspeh RL, Huthwaite JS, et al: Healthy older adult performance on a modified version of the Cognistat
158.
159. 160. 161. 162.
163.
21
(NCSE): demographic issues and preliminary normative data. J Clin Exp Neuropsychol 2003; 25:133-144. Oehlert M, Hass S, Freeman M, et al: The Neurobehavioral Cognitive Status Examination: accuracy of the “screenmetric” approach in a clinical sample. J Clin Psychol 1997; 53:733-737. Mathuranath P, Nestor P, Berrios G, et al: A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 2000; 55:1613-1620. Bier J, Ventura M, Donckels V, et al: Is the Addenbrooke’s Cognitive Examination effective to detect frontotemporal dementia? J Neurol 2004; 251:428-431. Bak T, Rogers T, Crawford L, et al: Cognitive bedside assessment in atypical parkinsonian syndromes. J Neurol Neurosurg Psychiatry 2005; 76:420-422. Dudas R, Berrios G, Hodges J: The Addenbrooke’s Cognitive Examination (ACE) in the differential diagnosis of early dementias versus affective disorder. Am J Geriatr Psychiatry 2005; 13:218-226. Dubois B, Slachevsky A, Litvan I, et al: The FAB: a frontal assessment battery at bedside. Neurology 2000; 55:16211626.
CHAPTER
PRINCIPLES
2
OF NEUROPSYCHOMETRIC ASSESSMENT ●
●
●
●
Elsdon Storey and Glynda Kinsella
It might legitimately be asked why this chapter was written by both a neurologist and a neuropsychologist. The answer, in part, is that a neurologist who has worked closely with neuropsychologists is perhaps in the best position to interpret the discipline to his or her colleagues; neuropsychology is often a “black box” to neurologists, to a greater extent than neuropsychologists themselves may realize. This can lead to uncritical acceptance of neuropsychologists’ conclusions without the productive interaction that characterizes, for example, neuroradiological review sessions. At the other extreme, the real added value of expert neuropsychological assessment may be discounted by those unconvinced of its validity. In any event, the value of neuropsychological assessment is considerably increased when the neurologist requesting it understands its strengths, limitations and pitfalls, and the sort of data on which its conclusions are based.
are pure tests of a single domain, and almost all can be performed poorly for several reasons. For example, inability to copy the Rey Complex Figure might result from impairments of volition, comprehension, planning, or praxis, as well as from some form of the most obvious cause of visual impairment. Assignment of particular tests to particular domains is therefore to some extent arbitrary; many tests are capable of being assigned to more than one domain. The interested reader is referred to Lezak and colleagues (2004) and Spreen and Strauss (1998) for details of individual tests. Multidimensional tests, such as the Mini-Mental State Examination (MMSE), may be subjected to factor analysis. This type of analysis identifies groupings of test items that correlate with each other and may well assess aspects of the same domain. In this way, the range of domains assessed by such a test may be identified.
COGNITIVE DOMAINS AND NEUROPSYCHOLOGICAL TESTS
Prerequisites for Meaningful Testing
Cognitive Domains Cognitive domains are constructs (intellectual conceptualizations to explain observed phenomena, such as gravity) invoked to provide a coherent framework for analysis and testing of cognitive functions. The various cognitive processes in each domain are more or less related and are more or less independent of processes in other domains. Although these domains do not have strict, entirely separable neuroanatomical substrates, they do each depend on particular (but potentially overlapping) neural networks.1 In view of the way in which cognitive domains are delineated, it is not surprising that there is some variation in their stated number and properties, but commonly recognized ones with their potential neural substrates are listed in Table 2–1.
Neuropsychological Assessment of Individual Cognitive Domains In practice, although many neuropsychological tests assess predominantly one domain, very few in routine clinical use
22
Adequate testing within some domains requires that some others are sufficiently intact. For example, a patient whose sustained, focused attention (concentration) is severely compromised by a delirium is unable to register a word list adequately. Consequently, delayed recall is impaired, even in the absence of a true amnesia or its usual structural correlates. A patient with sufficiently impaired comprehension may perform poorly on the Wisconsin Card Sorting Test because the instructions were not understood, rather than because hypothesis generation was compromised. These considerations give rise to the concept of a pyramid of cognitive domains, with valid testing at each level dependent on the adequacy of lower level performance2 (Fig. 2–1). In addition to intact attention and comprehension, patient performance may be compromised by poor motivation—for example, as a result of depression or in the setting of potential secondary gain—or by anxiety. Neurological impairments (e.g., poor vision, ataxia), psychiatric comorbid conditions, preexisting cognitive impairments (e.g., mental retardation), specific learning difficulties or lack of education (e.g., resulting in illiteracy), and lack of mastery of the testing language can all interfere with valid testing and must be carefully considered by the neuropsychologist in interpreting test results.3
chapter 2 principles of neuropsychometric assessment
23
T A B L E 2–1. Commonly Assessed Cognitive Domains and Their Potential Neural Substrate Domain
Main Neural Substrate
Attention
Ascending reticular activating system, superior colliculus, thalamus, parietal lobe, anterior cingulate cortex, and the frontal lobe Classical speech zones, typically in the left dominant hemisphere, including Wernicke’s and Broca’s areas, and the angular gyrus Hippocampal-entorhinal cortex complex Frontal regions Left parietal cortex Ventral visual system: occipital regions to anterior pole of temporal lobe
Language Memory Object recognition (visual) Spatial processing Executive functioning
Posterior parietal cortex, frontal eye fields, dorsal visual system Inferotemporal/midtemporal and polar temporal cortex Frontal-subcortical circuits, including dorsolateral prefrontal, orbital frontal, and anterior cingulate circuits
Executive function Memories (various types) Visuoperceptual function, Praxis Comprehension (language) Attention (Consciousness) ■
Figure 2–1. The pyramid of cognitive domains. An unconscious or inattentive patient is not able to comprehend test instructions, even though the relevant linguistic networks may be intact. A patient with severely impaired comprehension may not understand the test instructions for praxis, for example, and so forth.
BASIC PRINCIPLES OF PSYCHOMETRICS Test Reliability For a neuropsychological test (or any other test) to be clinically useful, it must be both reliable and valid. A reliable test is one for which differences in scores reflect true differences in what is being measured, rather than random variation (“noise”) or systematic bias (e.g., consistent differences between test scores at different centers). The reliability coefficient of a test is the proportion of total test result variability that is attributable to true differences in test results. It may also be conceptualized as the variability that would remain after multiple administrations of a test resulted in random variations that canceled each other out, with no systematic bias assumed. (An analogy familiar to neurologists would be electronic averaging in evoked potentials.) Reliability coefficients of standard neuropsychological tests typically vary from about 0.70 (acceptable) to 0.95 (high). Reliability may be assessed in a number of ways. Test-retest reliability accounts for both random variability resulting from the test itself and systematic bias resulting from practice effects, although it cannot enable the clinician to easily distinguish between the two. It presupposes a stable test popu-
lation, which may be an unattainable ideal over longer periods of time, inasmuch as acute pathological conditions such as results of strokes and traumatic injuries tend to improve and degenerative conditions tend to worsen. The internal consistency of a multi-item test can be gauged by split-half reliability, whereby scores from half the test items are compared with scores from the other half (but this leaves moot how the division is performed), or by calculating the mean reliability coefficient obtained from all possible split-half comparisons. The latter strategy generates a statistic called Cronbach’s a. Sometimes, alternative (parallel) versions of tests are constructed, often in order to facilitate serial testing in an effort to avoid practice effects. The reliabilities of the different versions can then be compared, in a process very similar to split-half reliability testing. The difficulty, of course, is in knowing whether the two versions really are equivalent, so that variance between the two represents unreliability rather than differences in difficulty or in the variable or variables actually being measured. Interrater reliability accounts for the variation in test scores resulting from administration by different testers. This is clearly important particularly in multicenter studies and is an essential property for semiquantitative clinical rating scales. The importance of test reliability underlies the importance of test administration with standardized materials in a standardized manner and a conducive environment, and by appropriately trained personnel (e.g., not by an intern in a noisy ward).
Test Validity A valid test measures what it is purported to measure. Whereas an unreliable test cannot be valid (as score variations reflecting true differences in the intended measured variable are concealed by noise or systematic bias), reliability itself is no guarantee of validity. Consideration of the following test of semantic knowledge illustrates this point: 1. 2. 3. 4.
What is 2 + 3? Which city is the capital of the USA? How many seconds are in a minute? What was the maiden name of Charcot’s maternal grandmother?
24
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
All readers presumably score 75% on this test, which is therefore absolutely reliable but quite invalid as a test of semantic knowledge. Validity can be gauged in a number of ways. Criterion validity reflects the utility of the test in decision making. Perhaps the ideal form of criterion validity is predictive validity, in which test results are used to make a decision or prediction, such as in which patients amnestic mild cognitive impairment will convert to Alzheimer’s disease, and the validity of the decision is subsequently established on follow-up. Such studies tend to be long and expensive, however, and so other methods of assessing validity are often required. Concurrent validity, another form of criterion validity often used instead, involves comparing test results with a nontest parameter of relevance, such as sustained, directed attention in children with their class disciplinary records. Ecological validity, a related concept, reflects the predictive value of the test for performance in real-world situations. For example, neuropsychological tests of visual attention and executive function, but not of other domains, have been found to have reasonable ecological validity for predicting driving safety, in comparison with the “gold standard” of on-road testing.4 Construct validity assesses whether, for example, a test purportedly of a particular cognitive domain is correlated with other established tests of that particular domain and functions as tests of that domain are expected to function. Content validity concerns checking the test items against the boundaries and content of the domain (or portion of the domain) to be assessed. Face validity exists when, to a layperson (such as the subject undergoing testing), a test seems to measure what it is purported to measure. Thus, a driving simulator has good face validity as a test of on-road safety, whereas an overlapping figures test of figure/ground discrimination may not, even though it may actually be relevant to perceptual tasks during driving. More detailed discussions of reliability and validity were given by Mitrushina and associates (2005), Halligan and colleagues (2003), or Murphy and Davidshofer (2004).
Symptom Validity Testing Symptom validity testing is rather different and is used as a method to reveal nonorganic deficits (e.g., malingering). It relies on the fact that patients with no residual ability in a domain, who are forced to respond to items randomly or by guessing, can nevertheless sometimes be correct by chance. Performance at statistically significantly worse than chance levels can be explained only by some retention of ability in that domain, with that ability being used (consciously or unconsciously) to produce incorrect answers. This forced-choice/ statistical analysis concept should already be familiar to neurologists, as it underlies much of psychophysically correct sensory testing. (A fine example is the University of Pennsylvania Smell Identification Test [UPSIT] for evaluation of olfaction.5) Other methods for detecting nonorganic deficits also exist; they depend on recognition of deviation from the usual patterns of cognitive impairment (e.g., recognition memory’s being worse than spontaneous recall) or discrepancy between scores on explicit tests of a domain and behavior or other tests implicitly dependent on that domain (e.g., dysfluency appearing only when “language” is tested). This subject is covered in more detail elsewhere.6
Ceiling and Floor Effects Two further difficulties may limit the use of neuropsychological measures: lack of discrimination across the range of abilities expected and practice effects on repeated testing. An ideal test would reveal a linear decline in ability in the tested domain, from the supremely gifted to the profoundly impaired. In practice, this is rarely, if ever, achieved. Some tests discriminate well between patients with different severities of obvious impairment but are problematic in attempts to detect subtle disorders and fail to stratify the normal population appropriately. This is known as a ceiling effect. On the other hand, some tests sensitive to subtle declines and capable of stratifying the normal population, are too difficult for patients with more profound deficits. Real differences in their residual abilities may be missed. This is a floor effect. Some tests have both ceiling and floor effects, leading to a sigmoid curve of scores versus ability. If patients with Alzheimer’s disease are assumed to decline at a constant rate, then on average, over time, the MMSE shows both ceiling and floor effects (Fig. 2–2).
Practice Effects Practice effects arise when the act of taking a test more than once results in an improvement in the subject’s true score. Repeated assessments over time are often desirable, to determine whether a deficit is static or declining or to monitor treatment or recovery. Such serial assessment is virtually impossible with some tests because of practice effects. For example, once the patient has been exposed to the Wisconsin Card Sorting Test and has learned that the examiner periodically changes the correct sorting rule without divulging this to the patient, much of the challenge and novelty of this test is lost. Repeated exposure to a test, particularly over a short period, may result in overt learning. This probably accounts for the initial rise in MMSE and Alzheimer’s Disease Assessment Scale, Cognitive subscale (ADAS-Cog) scores in the placebo recipients in trials of cholinesterase inhibitors in Alzheimer’s disease, for example (Fig. 2–3). The use of alternative forms, such as the Crawford version of the Rey Auditory Verbal Learning Test, may overcome some of these difficulties,7 but not all alternative versions of tests really are equivalent (e.g., the Taylor alternative version of the complex figure is easier to recall than the original Rey Complex Figure itself; see Chapter 12 in Mitrushina et al [2005]). Furthermore, learning may be implicit (procedural), in such a way that patients become more proficient at a type of test with practice in the absence of conscious remembering. This may improve scores even on true alternative versions.
Comparison with Appropriate Normative Data For tests to be useful in making clinical predictions about an individual, particularly on the first assessment, it is essential that individuals’ scores be compared with appropriate normative data. Many test scores in normal populations show systematic variation with demographic variables, such as age, years of education, and gender, and these must be accounted for before interpretation is possible. This may be done by using either stratified norms or regression equations with the
chapter 2 principles of neuropsychometric assessment
25
NATURAL HISTORY OF AD
Early diagnosis
Severe
Mild-moderate
30 Cognitive symptoms 25 Loss of functional independence
MMSE
20 15
Behavioral problems
10
Nursing home placements
5
Death
0
2
1
3
4
5
6
7
8
9
Years ■
Figure 2–2. The Mini-Mental State Examination (MMSE) shows both ceiling effects (flatter segment of
Mean (±SEM) change in ADAS-cog/11 from baseline
graph, upper left) and floor effects (flatter segment of graph, to right) in comparison with its sensitivity to change in the middle stages of Alzheimer’s disease (AD). (From Gauthier S, ed: Clinical Diagnosis and Management of Alzheimer’s Disease. London, UK: Martin Dunitz, 1996.)
Double-blind
Open-extension
Improvement
–4 –3 –2 –1 0 1 2 3 Deterioration Baseline
3
6 Time (months)
9
relevant variables factored in. It is essential that the “normal” population sampled to provide the normative data is relevant to the patient being tested. For example, a stratification category of native English speakers “>60 years” with an average of 16 years of education is hardly an appropriate normative population against which to compare an 89-year-old patient with only 5 years of education who learned English as an adult immigrant. The selection of appropriate norms is covered in detail in the handbook by Mitrushina and associates (2005). Testing patients whose language of preference is not that of the test (and the examiner) is particularly plagued with pitfalls: Direct translation on the spot introduces too much random variability. Versions in the target language must first be validated and norms established in that population, allowing for differences in word usage and familiarity. In the case of nonverbal tests, it must be shown that scores are equivalent in the different target groups. Even a carefully translated test may end up measuring something different from the original version.8
12
■
Figure 2–3. Alzheimer’s Disease Assessment Scale, Cognitive subscale (ADAS-Cog) scores in a trial of an acetylcholinesterase inhibitor in Alzheimer’s disease. Diamonds represent scores of patients receiving placebo in the double-blind phase and inhibitor in the extension phase; squares represent scores of patients taking the inhibitor. A drop in score (negative values) represents an improvement on this test on which 0/70 is a perfect score. Note the improvement of about −1/2 at 6 weeks in the placebo recipients’ scores. In large part, this probably represents a practice effect. (From Coyle J, Kershaw P: Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer’s disease. Biol Psychiatry 2001; 49: 289-299. Copyright 2001. Reprinted with permission from the Society of Biological Psychiatry.)
These considerations can considerably restrict test choice in assessment in these patients. The effects of culture are even more insidious. Even populations with a common language and broadly similar cultures, such as Americans and Australians, cannot always be directly compared. For example, the Boston Naming Test, a commonly used confrontational naming assessment instrument, contains pictures of a pretzel and a beaver. Older Australians, without experience of either, tend to call the first a snake and the second a platypus!
Reporting of Test Scores Once appropriate norms are identified, the test scores have to be reported in an intelligible manner. This is commonly done in terms of standard deviations from the mean for the appropriate normative sample, by using Z scores, T scores, or IQ scores. A Z score of −11/2 would indicate a score 11/2 standard
26
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
deviations (SD) below average, whereas one of +2 would indicate a score 2 SD above average. T scores have the mean set at 50 and 1 SD set at 10. Hence, a T score of 70 is 2 SD above average. IQ scores have the mean set at 100, and 1 SD set at 15. Hence, an IQ score of 85 is 1 SD below average. Of course, reporting scores in terms of SD assumes that the measured variable is normally distributed in the population. This is not the case with, for example, the Boston Naming Test or the Rey Complex Figure Test copy, for which results from the normal population are positively skewed (see Mitrushina et al [2005]). Reporting by percentiles—the percentage of the normative population whose scores fall below that score level—avoids this difficulty: If a score is below the second percentile, it would indicate impairment, regardless of the distribution of test scores. On the other hand, for tests with a normal distribution of scores, reporting by percentiles does tend to overemphasize unimportant differences near the mean and underemphasize more extreme deviations. For example, the real difference between the first and the 10th percentile levels is likely to be much more important (and larger) than the real difference between the 41st and 50th percentiles. However, other tests have their own idiosyncratic scoring systems (e.g., MMSE: maximum score 30/30; ADAS-Cog: maximum score 0/70). Neuropsychologists also frequently report scores by bands with descriptive labels (such as superior, above average, borderline, etc.). The relationship between some of these various scoring methods for a test with normally distributed scores is shown in Figure 2–4.
Low average
Borderline impaired
Impaired
11/3 2.5
2.0
1.5
2nd
The concepts of sensitivity, specificity, and, more particularly for decision making, positive and negative predictive value and likelihood ratio are as important for neuropsychological tests as for any other form of diagnostic testing in medicine. Their definitions are provided in Table 2–2. The important effect of base rate (prevalence) on these values must also be remembered. For example, the base rate of Alzheimer’s disease in 75year-old patients with memory complaints is much higher than that in 45-year-olds worried that they are not staying on top of their jobs, so that poor performance on a brief verbal memory test has a much higher positive predictive value in the older population.
Cutoffs and Receiver Operating Characteristic Curves When a test cutoff point is set (as is often done for the MMSE or the Modified Mini-Mental State Examination, to distinguish demented from nondemented subjects), there is a trade-off between sensitivity and specificity. This may be formalized as a receiver operating characteristic (ROC) curve, on which sensitivity is plotted against 1 − specificity for each proposed cutoff point. The optimal cutoff point for the purpose (e.g., individual diagnosis, requiring high specificity, or community screening, requiring high sensitivity) can then be ascertained from this
High average
Average
2/3
1.0
10
20
M
0.5
Standard deviations
25th
30
40
50
60
1.0
75th
70
Very superior
Superior
11/3
2/3
0.5
9th
1
Decision Theory
1.5 91st
80
2.0
2.5
98th
90
99
Percentiles
–2.5
–2.0
–1.5
–1.0
–0.5
M
0.5
1.0
1.5
2.0
2.5
55
60
65
70
75
137.5
Z-Score (SD)
25
30
35
40
45
50 T-Score
62.5
70
80
90
100
110
120
130
12
14
16
IQ Scores (WAIS III)
1
4
6
8
10 Subtest Scores (WAIS III)
■
Figure 2–4. The relationship between various ways of reporting test scores and the normal distribution. SD, standard deviation; WAIS III, Wechsler Adult Intelligent Scale–Third Edition. (Adapted from The Psychological Corporation. Methods of expressing test scores. Test Service Notebook, April 1955, No. 1 48. Reproduced with permission of publisher, Harcourt Assessment, Inc.)
–19
chapter 2 principles of neuropsychometric assessment 1.0
T A B L E 2–2. Definitions of Important Test Parameters
0.8
0.6 Sensitivity
a = true positive scores b = false positive scores c = false negative scores d = true negative scores Prevalence = (a + c)/(a + b + c + d) Sensitivity = a/(a + c) Specificity = d/(b + d) Positive predictive value = a/(a + b) Negative predictive value = d/(c + d) Likelihood ratio (positive) = posttest odds/pretest odds = sensitivity/{1 − specificity} = {a/(a + c)}/{1 − [d/(b + d)]}
27
0.4 AUC = 0.959, CSF-CBF index AUC = 0.850, CSF tau level
graph. For example, Monsch and colleagues (1995) used ROC analysis to determine that the optimal cutoff score for the MMSE in a geriatric outpatient service is 25/26.9 The utility of different measures of the same parameter can also be compared (e.g., see Fig. 2–5), or the effects of adding another test of the same parameter studied; the test or combination that has the greatest area under the ROC curve is the most accurate discriminator.
MEASURING DEFICITS AND CHANGES Methods of Establishing a Baseline Most patients have not previously undergone neuropsychological assessment when they are referred, and so there is no established personal baseline against which they can be compared when they are assessed. There are several approaches to this problem. Using demographically stratified norms (see section on Comparison with Appropriate Normative Data) is helpful, and there are even demographic formulas available in some countries, including the United States, to enable estimation of premorbid IQ.10 However, these still involve comparison with a group, which may not be completely appropriate for a given individual. A second approach is to estimate premorbid ability from performance on a cognitive task known to be (relatively) resistant to cognitive decline, such as semantic knowledge. The National Adult Reading Test (of pronunciation of irregularly spelled words)11 and its U.S. variants, as well as the vocabulary subtest of the Wechsler Adult Intelligence Scale and its successors, have been used for this purpose. A large variation between Z scores in different domains might suggest that the lower scores are the result of deterioration and that the higher scores (the patient’s best performance), qualified by all available qualitative information about the patient’s premorbid achievements and abilities, provide a reasonable estimate of the patient’s overall cognitive ability. For example, sometimes an individual’s occupational history is helpful: some otherwise normal older individuals may have difficulty copying a cube, but such difficulty in a former architect, draftsperson, or mathematics teacher would indeed be cause for concern. This best performance approach is discussed by Lezak and colleagues (2004, pp 97-99). The pitfalls in relying on the best test score in the absence of such further qualifying information have been illustrated by Mortensen and associates (1991).12
0.2
AUC = 0.871, CBF ratio in posterior cingulate AUC = 0.590, CBF ratio in temporoparietal region
0.0 0.0 ■
0.2
0.4 0.6 1 – specificity
0.8
1.0
Figure 2–5. Receiver operating characteristic curves of the power of four diagnostic indexes to discriminate between patients with mild cognitive impairment that did (in 22 patients) or did not (in 8 patients) progress to Alzheimer’s disease. AUC, area under the curve; CBF, cerebral blood flow; CSF, cerebrospinal fluid. (From Okamura N, Arai H, Maruyama M, et al: Combined analysis of CSF tau levels and [(123)I]iodoamphetamine SPECT in mild cognitive impairment: implications for a novel predictor of Alzheimer’s disease. Am J Psychiatry 2002; 159:474-476. Reprinted with permission from the American Journal of Psychiatry. Copyright 2002 American Psychiatric Association.)
Measuring Change Sometimes, despite the previously mentioned inferential methods for obtaining a baseline, there is still doubt as to whether deterioration has occurred. Repeated assessments can help to identify progressive deterioration in such circumstances, even if there was uncertainty about score interpretation at the initial assessment. However, this raises the question of how true deterioration can be distinguished from random fluctuations in test scores. One simple way of determining whether a change in test score is significant is the standard deviation method, in which it is assumed that any score change of more than 1 SD is significant. Although this often does reveal truly significant changes, it is less accurate in doing so than are a number of more sophisticated methods.13 In part, this potential inaccuracy arises from the random error component of the actual test scores themselves. Even if a test does not display practice effects, or if truly parallel (alternative) forms are available, only part of a patient’s actual test score consists of the true score, whereas part consists of random variability. The reliability coefficient (rxx) of a test is a measure of the proportion of the total variance of a test score that results from variance in the true score. If a subject took such a test multiple times, the average score would approximate the true score. The extent to which a single observed total score represents that patient’s true score can be estimated with the standard error of measurement (SEM), which increases as the total test variance (σx) increases and
28
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
decreases as the reliability coefficient (rxx) increases (indicating a decrease in that portion of the total variance due— to— random variance), according to the formula SEM − σx √1 − rxx . This means that confidence intervals (e.g., 95%) can be placed on an individual score, or two scores obtained on separate occasions can be compared to determine whether they are likely to represent a true change. Reliable change indices (RCIs), calculated from data on normal subjects or—better—from populations containing individuals identified as undergoing significant change according to an external “gold standard” (e.g., reaching criterion for diagnosis of dementia) have been devised that account for measurement error, practice effects, and regression to the mean.13 Regression equation-based measures have also been developed.13 Overall, these perform more satisfactorily, although none is ideal.
STRATEGIES IN NEUROPSYCHOLOGICAL ASSESSMENT Neuropsychological assessment would be extremely protracted and exhausting (and thereby inaccurate) for both tester and patient, not to mention prohibitively expensive, if all domains were assessed in all possible detail. Some strategy for keeping time and costs to acceptable levels is therefore required. One possibility is to use a standard battery, such as the HalsteadReitan or Luria-Nebraska battery.14,15 The difficulty with this approach is that testing may occupy several hours, but the particular referral problems are still insufficiently clarified at the end. Another approach is hypothesis driven, on the basis of referral details and the history from the patient. This makes intrinsic sense to physicians: a patient complaining of diplopia and unsteadiness of gait will rightly be given a more thorough neurological examination than will a patient complaining of dyspnea, pleuritic chest pain, and productive cough. Many assessors use a combination of screening tests across the range of cognitive domains, concentrating on those that seem most relevant (e.g., episodic memory in Alzheimer’s disease). This flexible approach may be modified in midsession: As pointed out in the Cognitive Domains and Neuropsychological Tests section, an abnormal performance may well have a number of possible causes, each of which must then be assessed. Often, the Wechsler Adult Intelligence Scale–Third Edition and the Wechsler Memory Scale–Third Edition, or a selection of items from these, are used for screening. Although the Wechsler Adult Intelligence Scale was designed to assess the range of abilities in the normal population rather than to investigate patients with particular cognitive deficits, test administration is very well standardized, and the normative data are extensive (although not stratified by educational level); therefore, these tests are an attractive option for this purpose. Their merits and pitfalls are discussed by Lezak and colleagues (2004, pp 648-660). Some multidomain bedside screening mental status tests used by nonneuropsychologists, such as the Mattis Dementia Rating Scale16 and the Cognistat (formerly called the Neurobehavioral Cognitive State Examination),17 are designed on a “tripwire” (“screen + metric”) basis, with a challenging item given first and, only if the screening item is failed, easier ones then given to establish the degree of impairment in that domain. This approach can save time for both examiner and patient.
Computerized versions of some individual tests are in widespread use (e.g., the Continuous Performance Test and the Wisconsin Card Sorting Test). In view of the duration and expense of neuropsychological assessment, however, it is not surprising that attempts have been made to computerize the entire testing process. An example is the Cambridge Neuropsychological Test Automated Battery.18 The drawbacks of this approach, however, include not only the loss of flexibility, and therefore the ability to perform hypothesis-generated testing, but also the loss of the potentially very valuable information derived from consideration of referral details, the history from patient and informant, and observation during the test procedure. Consideration of all these features by a trained practitioner is the basis of neuropsychological assessment, as distinct from the more limited neuropsychological testing. An experienced neuropsychologist is able to detect evidence of impulsivity, poor or fluctuating attention, poor planning, and so forth. These observations are particularly important when assessing patients with the dysexecutive syndrome (see Chapter 7: Executive Function and its Assessment), in whom the manner of test performance is often more revealing than the result. Furthermore, anxiety, fatigue, and depression adversely affect performance on many neuropsychological tests; detection of and allowance for or minimization of these process factors are important parts of the neuropsychologist-patient interaction. In interpreting neuropsychological test results, as with any other collection of test results, the neuropsychologist must remember that if abnormality is defined statistically, and if enough tests are performed, some are expected to yield “abnormal” results by chance. Formal adjustment of the statistical threshold of abnormality (a Bonferroni correction) is possible but cannot be applied blindly in a situation in which the tests are not necessarily fully independent. Conversely, even mild abnormalities on several different measures of a particular domain greatly increase the likelihood that function is impaired in that domain. The corollary is that reliance on a single test to define abnormality within a domain is unsound.
OPTIMAL USE OF NEUROPSYCHOLOGY In earlier years in the field of neuropsychology, much effort was devoted to separating “organic” from “nonorganic” causes of deficit. With the enormous advances in neuroimaging since the 1970s, the emphasis has shifted somewhat. Neuropsychology is supremely useful for determining whether a patient is impaired in a particular domain or domains (e.g., “Does my HIV [human immunodeficiency virus]–positive patient have early features of AIDS [acquired immunodeficiency syndrome]–dementia complex?”). It may identify mild impairments in the absence of obvious neuroimaging changes (e.g., after traumatic brain injury or in some patients with mild cognitive impairment). It is also useful for determining the pattern of involvement across cognitive domains. The latter information can suggest particular diagnoses or refine the differential diagnosis (e.g., “This pattern of deficits is most consistent with semantic dementia”), and can also suggest likely problem areas—and, as important, areas of retained strength—that can be used to inform rehabilitation and compensatory strategies. Although neuropsychological tests are typically not tests of decision-making capacity per se, useful inferences regarding the possible or likely presence of problems in this area can be
chapter 2 principles of neuropsychometric assessment drawn. Neuropsychological assessment can be employed preoperatively (e.g., for epilepsy or tumor surgery) to document the extent of cognitive problems and again postoperatively to determine whether worsening (or new deficits) have resulted from the procedure. Serial assessments can be performed to monitor the progression of a condition (e.g., mild cognitive impairment) or the effectiveness of treatment (e.g., central nervous system vasculitis). Lastly, through variations of symptom validity testing, and by studying the pattern of failures on easier versus harder tasks, conscious or unconscious simulation of deficit can be detected. For a neuropsychology referral to yield the most useful information, the right question must be asked, accompanied by the appropriate background information. A note such as “?Dementia—please do the needful” is hardly adequate! The relevant symptoms with their duration, a list of past medical and psychiatric problems (especially substance abuse, anxiety, depression, and sleep apnea), and a full list of current medications are required. The neuropsychologist starts by taking an extensive history, but ready availability of documented background information saves time and false starts.
SUMMARY Psychometric testing, as a component of neuropsychological assessment, is a rigorous, scientifically based discipline. For results to be valid and useful, however, the most suitable tests and normative data must be selected. Administration by experienced clinicians trained to note qualitative as well as quantitative abnormalities, and to detect interference from process factors, contributes greatly to the value of such testing. Resources are often scarce, but careful selection of patients for referral and proper referral information ensures their optimal use.
K E Y
P O I N T S
●
Neuropsychological assessment involves consideration of referral information, history from the patient and (if possible) informant, observed personality, behavioral and emotional features, and quantitative and qualitative aspects of neuropsychological testing.
●
As with any test, neuropsychological tests must be reliable; that is, random variability must be low. This requirement underlines the importance of training and standardization in test administration.
●
Neuropsychological tests must also be valid; that is, they must actually measure what they are purported to measure.
●
Appropriate normative data are an essential prerequisite for test interpretation. Correction for the effects of demographic variables (e.g., age, education) is often necessary. Translation of tests across languages or cultures is potentially problematic.
●
Although individual tests are often considered as measures of one cognitive domain, poor performance on almost all tests in current routine clinical practice can occur for
29
multiple reasons. Conversely, poor performance on multiple tests of a single domain increases the reliability of a judgment that there is impairment within that domain. ●
Neuropsychological assessment is particularly useful in detecting mild cognitive changes in the absence of obvious neuroimaging abnormalities or other neurological features and in determining whether these are likely to have an organic basis, in the differential diagnosis (based on the pattern of deficits) of conditions causing cognitive impairment, in identifying cognitive strengths and weaknesses to guide rehabilitation and compensatory strategies, in providing inferential information on competency and employability issues, and in following changes in cognition as a result of disease or its treatment.
Suggested Reading Halligan PW, Kischka U, Marshall JC. Handbook of Clinical Neuropsychology. Oxford, UK: Oxford University Press, 2003. Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment, 4th ed. New York: Oxford University Press, 2004. Mitrushina M, Boone KB, Razani J, et al. Handbook of Normative Data for Neuropsychological Assessment, 2nd ed. New York: Oxford University Press, 2005. Murphy KR, Davidshofer CO. Psychological Testing: Principles and Applications, 6th ed. Englewood Cliffs, NJ: Prentice Hall, 2004. Spreen O, Strauss E. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary, 2nd ed. New York: Oxford University Press, 1998.
References 1. Mesulam MM: From sensation to cognition. Brain 1998; 121:1013-1052. 2. Crowe SF: Neuropsychological Effects of the Psychiatric Disorders. Amsterdam: Harwood Press, 1998, p 11. 3. Groth-Marnat G: Neuropsychological Assessment in Clinical Practice. New York: John Wiley & Sons, 2000, p 95. 4. Whelihan WM, DiCarlo M, Paul RH: The relationship of neuropsychological functioning to driving competence in older persons with early cognitive decline. Arch Clin Neuropsychol 2005; 20:217-228. 5. Doty RL, Shaman P, Kimmelman CP, et al: University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984; 94:176-178. 6. Rodgers R, ed: Clinical Assessment of Malingering and Deception, 2nd ed. New York: Guilford Press, 1997. 7. Crawford JR, Steward LE, Moore JW: Demonstration of savings on the AVLT and development of a parallel form. J Clin Exp Neuropsychol 1989; 11:975-981. 8. Ferraro FR, ed: Minority and Cross-Cultural Aspects of Neuropsychological Assessment. Studies on Neuropsychology, Development, and Cognition. Lisse, The Netherlands: Swets and Zeitlinger, 2002. 9. Monsch AU, Fold NS, Ermini-Fünfschilling DE, et al: Improving the diagnostic accuracy of the Mini-Mental State Examination. Acta Neurol Scand 1995; 92:145-150. 10. Barona A, Chastain R: An improved estimate of premorbid IQ for blacks and whites on the WAIS-R. Int J Clin Neuropsychol 1986; 8:169-173.
30
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
11. Nelson HE, Willison JR: The National Adult Reading Test (NART): Test Manual, 2nd ed. Windsor, UK: NEFR Nelson, 1991. 12. Mortensen EL, Gade A, Reinisch JM: “Best Performance Method” in clinical neuropsychology. J Clin Exp Neuropsychol 1991; 13:361-371. 13. Frerichs RJ, Tuokko HA: A comparison of methods for measuring cognitive change in older adults. Arch Clin Neuropsychol 2005; 20:321-333. 14. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Applications, 2nd ed. Tucson: Neuropsychology Press, 1993.
15. Golden CJ, Purisch AD, Hammeke TA: Luria-Nebraska Neuropsychological Battery: Forms I and II. Los Angeles: Western Psychological Press, 1991. 16. Mattis S: Dementia Rating Scale (DRS). Odessa, FL: Psychological Assessment Resources, 1988. 17. Kiernan RJ, Mueller J, Langston JW: Cognistat (Neurobehavioral Cognitive Status Examination). Lutz, FL: Psychological Assessment Resources, 1995. 18. Robbins TW, James M, Owen AM, et al: Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 1994; 5:266-281.
CHAPTER
DISORDERS ●
OF ●
●
3
LANGUAGE ●
Michael M. Saling
There are two main schools of thought in the history of neurogenic language disorders, both of which have relevance to modern aphasiology. The first, the Wernicke-LichtheimGeschwind tradition, emphasized that primary language functions are represented in discrete regions of cortex (“centers”) and that the activities of these loci are integrated through connecting fiber tracts. The Wernicke-Lichtheim scheme consisted of a center for motor images of words, located in the posterior third of the inferior frontal convolution (Broca’s area), as well as a center for acoustic images of words (Wernicke’s area). A fiber tract (arcuate fasciculus) joined the two centers, with the flow of information running from posterior to anterior. A third center for concepts was located in the extrasylvian cortex, with an outflow to Broca’s area and input from Wernicke’s area. There was an output from Broca’s area to the motor cortex and an input to Wernicke’s area from the auditory cortex. This simple scheme systematized the main perisylvian and transcortical aphasia syndromes observed before 1885 and predicted the existence of a syndrome as yet unobserved at that time: conduction aphasia. The WernickeLichtheim model was later refined by members of the Boston School, principally Frank Benson and Norman Geschwind, with the addition of three new syndromes, and the inclusion of the inferior parietal lobule as language cortex (see Benson and Ardila, 1996). The second main stream is represented by neurologists such as Hughlings Jackson, Sigmund Freud, and Aleksandr Luria who conceived of language as represented in broader hierarchical cortical zones or gradients, organized around the centers of the Wernicke-Lichtheim model. The role of connecting tracts was deemphasized. Luria’s aphasiology preserves the anteroposterior schema of the Wernicke-Lichtheim model but redefines localization of language as hierarchical and distributed. Modern clinical aphasiology is based on the classical syndromes described in the Wernicke-Lichtheim tradition and their modifications. Concepts of their localization, however, have come to be shaped further by ongoing clinicopathological observation and functional neuroimaging, and current views on the localization of language are not too distant from those of the Jackson-Freud-Luria tradition. Linguistic ideas have also become part and parcel of modern aphasiology. A glossary of important linguistic terms and concepts is given in Table 3–1.
LANGUAGE PRODUCTION At a clinical level, language disorders are more easily recognized and identified in language production, either spoken or written, than in disturbances of comprehension. Production consists of three broad stages: conceptualization, formulation, and overt execution. The first two of these stages are described in detail in the following sections. From a neuroanatomical perspective, conceptualization (the development of an intention to speak, and a decision about what will be said) depends on the dorsolateral prefrontal cortex. Formulation (the conversion of ideas into the structure of spoken language) depends on Broca’s region. Execution is the production of physical speech and depends on all of the motor mechanisms associated with speech (see Duffy, 2005).
Conceptualization This is a largely prelinguistic phase that involves the development of an intention to speak and a decision as to what will be said. Development of an intention and a decision about the message to be conveyed is often referred to as macroplanning. From that point on, the message must be reshaped into a particular set of logical relationships (propositions) that can be expressed in terms of the syntactic and semantic structure of language. This is often referred to as microplanning. Propositions form a link between thought and its expression in language. It is noteworthy that this concept was anticipated by the British neurologist Hughlings Jackson, who regarded it as essential for understanding the relationship between thought and speech in aphasia. Conceptualization depends on connectivity between extrasylvian association cortex and the classical perisylvian language axis, a concept borne out by functional neuroimaging (see Blank, Scott, Murphy, et al, 2002).
Formulation This phase deals with the conversion of propositions into actual sentences (sentence encoding). It is governed directly by the rules of syntax and semantics and consists of two important components. The first involves the selection of appropriate open class of lexical items (see Table 3–1) to convey the
31
32
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 3–1. Essential Linguistics Concepts Phonological
Lexical
Morphological
Phonology is the study of the structure and patterning of the sounds of language. Many of the clinical features of language disorders are phonological. The units of analysis are phonemes, which can be defined as the basic meaningdistinguishing sounds (essentially consonant and vowel sounds) of the language. Whereas phonology is concerned with the patterning of sounds within a word, and is therefore a sublexical discipline, lexicology is concerned with the whole word as a single entity. At a lexical level, there is a dichotomy that is fundamental to the understanding of aphasic disorders, because aphasic variants affect the two classes of words differentially. The open class, so-called because it is conceptually unlimited and new items are steadily added as vocabularies increase, consists principally of nouns, verbs, adverbs, and adjectives—that is, words that refer to specific objects, actions, and attributes and that convey substantive content. The closed class, which is conceptually limited and does not increase in size as vocabularies increase, consists of articles (e.g., “a,” “the,” “that”), conjunctions (e.g., “and,” “but”), pronouns (e.g., “you,” “they”), and prepositions (e.g., “up,” “along,” “below”). The distinction between open- and closed-class words parallels the distinction between the meaning of a sentence (semantics) and the form or sequential structure of a sentence (syntax). Morphology concerns the internal structure of words. The aspect of morphology that is most important for understanding language disturbances is word formation, or the construction of a new word from an existing word by adding an affix. This can be derivational, whereby an adjective such as “good” is converted to a noun such as “goodness,” or inflectional, whereby a word is changed to suit the grammar of a sentence; for example, “run” might become “running,” or “pencil” might become “pencils.” Because the suffixes “-ing” and “-s” cannot stand alone, they are referred to as bound morphemes.
intended meaning. The linguistic concept of selection is of central importance in aphasic disorders. Selection implies the possibility of choice among alternatives, and errors in selection manifest clinically as paraphasias. A paraphasia has two essential features: (1) It is an error of selection resulting in the substitution of a word or part of a word with a frequently incorrect or inappropriate alternative, and (2) it is unintended. Selection processes occur at the phonemic and the semantic levels (see Table 3–1). In neuroanatomical terms, selection processes are heavily, but not exclusively, dependent on posterior perisylvian association cortices. The second component of formulation involves the genesis of correctly ordered positional slots into which the words of the sentence are inserted. These sequentially ordered schemas are often called sentence frames, and their construction is contributed to and defined by closed class (function) words and bound morphemes (see Table 3–1) Sentence frames are constructed according to the rules of syntax (see Table 3–1). The functional neuroanatomy of syntactic processing is complex, involving a network of left perisylvian structures, and it appears that Broca’s area is a key nodal structure within this network. Disorders of syntax, including Broca’s
T A B L E 3–2. The Fluent-Nonfluent Distinction
Anatomical Fundamental disorder Syndrome
Nonfluent Production
Fluent Production
Anterior (prerolandic) language areas Sequential organization (conceptualization, formulation) Perisylvian Aphemia Broca’s aphasia Extrasylvian Transcortical motor aphasia
Posterior (postrolandic) language areas Selection Perisylvian Pure word deafness Wernicke’s aphasia Conduction aphasia Extrasylvian Transcortical sensory aphasia Anomic aphasia
Note: Mixed transcortical aphasia and global aphasia are associated with clinically nonfluent production but also involve an underlying selection disorder.
aphasia, occur most prominently with lesions involving the anterior aspects of the perisylvian language zone.
Fluency The division of language disturbances into fluent and nonfluent is the most fundamental and clinically appreciable dichotomy in diagnostic aphasiology. The major aphasia syndromes are encompassed within the distinction of fluent versus nonfluent (see Table 3–2). Fluent language output in an aphasic patient is defined by the use of sentences that are syntactically intact but are semantically compromised because of a selection disorder. The following example, taken from a description of a severe form of fluent dysphasia, namely jargonaphasia (a variant of Wernicke’s aphasia), illustrates this point:1 “This guy has got to this thing, this thing made out in order to slash immediately to all of the windpails. . . . This is going right over me from there, that’s up to is 5 station stuff from manatime, and with that put it all in and build it all up so it will all be spent with him conversing his condessing.” The sequential relationships between grammatical entities in the passage are preserved. It is the closed class entities that are primarily affected by errors in selection, resulting in phrases that are devoid of meaning, and jargonistic substitutions (neologistic paraphasias) such as “manatime,” and “condessing.” Prosodic features are characteristically retained. Prosodic features are rhythmic and emphatic aspects of language production that allow the listener to appreciate whether the speaker is, for example, asking a question or making a statement. Nonfluent aphasic output, in contrast, is characterized by a dissolution of syntactic structure; in particular, the production of closed class words is affected. The following are examples of nonfluent language: 1. A soldier talking about a bullet wound to his head on the battlefront: “Well . . . well . . . front . . . well . . . advance . . . well . . . bullet . . . well . . . nothing much . . . hospital . . . operation . . . well . . . speech . . . speech . . . speech. . . .”2
chapter 3 disorders of language 2. In response to the question “Have you played no games?”: “Played games, yes, played one, daytime, garden.”3 3. Explaining a readmission to hospital: “Ah . . . Monday . . . ah, Dad and Paul and Dad . . . hospital. Two . . . ah, doctors . . . and ah . . . thirty minutes.”4 In contrast to the fluent output, these utterances are devoid of syntactic structure, exemplified by the lack of closed class words, and the relative excess of open class words. This pattern constitutes agrammatism. Nevertheless, there is appropriate selection of open class words (nouns and verbs), and as a consequence nonfluent output does not entirely have the “empty” character of fluent output. The length of phrases is heavily reduced in agrammatic disorders.
33
Unintended substitutions also occur in writing (paragraphias). Like paraphasias, they can be literal or they can involve semantic substitutions (see Table 3–3).
Circumlocutions Circumlocutions are compensatory phenomena, produced in response to a word retrieval failure. Patients with fluent aphasias, particularly anomic aphasia, use an expanded expression or phrase as a substitute for the intended word. For example, “eyelashes” may be expressed as “eye butterflies,” or “skiing” as “walking on water.” Circumlocutory language produces a rambling, wordy quality to the patient’s conversation.
Empty Speech Paraphasia and Other Deviations Paraphasias Paraphasias are defined as unintended utterances. In essence, there is a failure of selection at the phonemic level, producing a phonemic (literal) paraphasia (e.g., “I drove home in my lar”) or at a word (lexical) level (e.g., “I drove home in my wagon”), producing a verbal paraphasia (Table 3–3). Paraphasias are said to be neologistic when the unintended word is heavily contaminated with extraneous phonemes and, as a result, contains juxtapositions of sublexical fragments that are not characteristic of the language (phonemic neologisms) and are nonsensical in context. For example:5 EXAMINER: Are you feeling better than this morning? PATIENT: Not too melsise, I don’t think. EXAMINER: Pardon me? PATIENT: I motsumsirs, orie. Morphemic neologisms occur when valid morphemes are assembled in a manner that does not produce an acceptable word (e.g., “man-a-time”).
T A B L E 3–3. Paraphasias and Other Selection Errors Type
Examples
Phonemic (literal)
“glear” instead of “clear” “spink” instead of “sphinx” “gedrees” instead of “degrees” “tums” instead of “tongs” “trep”→“tretz”→“fretful”→“pretzel”
Conduit d’approche (successive phonemic approximations to a target word) Verbal Formal (similar form, different meaning) Morphemic (assembled from legal morphemes) Semantic (substituted word belongs to the same general category) Circumlocutions (word substituted with a phrase of the same meaning)
“dare” instead of “pear” “man-a-time,”* “summer-ly” “train” instead of “car” “Taj Mahal” instead of “pyramid” “cloth” instead of “blanket” “seahorse” instead of “unicorn” “drinking container” instead of “cup”
*Morphemic assemblies that do not produce acceptable words are called neologisms.
When lengthy sentences with very few open class (substantive) words are produced, the output is devoid of content and is referred to as “empty.” For example: “Well you know . . . that thing . . . that thing we were going to do . . . well, okay, then. . . . and that’s it.”
Paragrammatism Paragrammatism consists of errors in grammatical usage, such as unusual word order or juxtaposition of function words. It is observed in fluent aphasias and is not to be confused with agrammatism (described previously), which occurs in nonfluent aphasia. For example: “I couldn’t is that where I went.”
APHASIA SYNDROMES Contrary to earlier views, more recent tractography findings indicate that the arcuate fasciculus consists of two components. The first is a direct tract connecting the posterior segments of the inferior and middle temporal gyri with Broca’s area (Brodmann’s areas 44 and 45), as well as with parts of the middle frontal gyrus and inferior precentral gyrus. The second component is an indirect tract with anterior and posterior segments. The posterior segment connects Wernicke’s area with the inferior parietal lobule (Brodmann’s areas 39 and 40), whereas the anterior segment connects the inferior parietal lobule with frontal language cortex (see Catani et al, 2005). Structures connected by the arcuate fasciculus are somewhat more extensive than classical views suggested, and this broader concept of the perisylvian region accommodates the clinicopathological studies of fundamental language disorders since the 1950s more successfully. Furthermore, it suggests that the arcuate fasciculus might be important in uniting perisylvian and extrasylvian language regions. Aphasias caused by anterior (prerolandic) lesions are associated with nonfluent language production, whereas those caused by posterior lesions (postrolandic) are associated with fluent disorders. There are two major nonfluent aphasias: Broca’s aphasia, in which repetition is disturbed, and transcortical motor aphasia (TMA), in which repetition is normal. The fluent aphasias are Wernicke’s and conduction aphasias, in which repetition is disturbed, and anomic and transcortical sensory aphasias (TSA), in which repetition is preserved (Table 3–4) (see LaPointe, 2005). In addition, there are two aphasias in which the dysfluency typical of anterior dysphasias is combined with the impaired comprehension typical of posterior dysphasias: global aphasia and mixed transcortical aphasia.
34
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 3–4. Classification of Aphasia by Fluency and Comprehension Impaired Repetition
Normal Repetition
Nonfluent Broca’s* Global†
Transcortical motor Mixed transcortical
Fluent Conduction* Wernicke’s†
Anomic Transcortical sensory
*Comprehension preserved. † Comprehension impaired.
Nonfluent Production with Impaired Repetition: Speech Dyspraxia and Broca’s Aphasia Speech Dyspraxia (Aphemia) The syndrome of speech dyspraxia occurs quite separately from the other anterior aphasias. There is, however, a widely recognized dictum in aphasiology that lesions restricted to Broca’s area do not necessarily cause Broca’s aphasia. Embolic infarctions of Brodmann’s areas 44 and 45, often involving subjacent white matter and extension into the anterior insula, cause a wide spectrum of acute effects ranging from subtle hesitancy to mutism. Recovery is rapid—within days, weeks, or months— and in some cases, minimal residual dysfluency may be the only detectable language feature. Dyspraxia of facial, oropharyngeal, lingual, and respiratory functions is an associated feature that might persist beyond the resolution of language deficits, manifesting, in many cases, with some features reminiscent of the syndrome of speech dyspraxia. The chronic picture is “deficits in the smoothness with which vocalization of one phoneme in a series can be ceased and changed to the next, in precise control of the respiratory component of vocalization, and/or in precise positioning of the oral cavity to produce desired phonemes . . . better explained by inadequacy in skilled execution of movements, an apraxia in speaking . . . but not an associated disorder in language usage.”6 This resembles Luria’s idea of efferent motor aphasia, in which the primary disorder relates to skilled sequential movements or kinetic melodies in which the patient is able to position the articulators correctly but is not capable of moving smoothly from one articulatory position to the next.7 Originally, Pierre Paul Broca used the term aphemia to refer to this condition. There appears to be a revival in the use of this term in relation to progressive speech disturbances. Michael Alexander’s group at Boston University has taken the view that aphemia is a distinctive syndrome arising from small lesions in the left inferior frontal gyrus (pars opercularis), inferior precentral gyrus, and underlying white matter.8 The main features of speech dyspraxia are shown in Table 3–5.
Functional neuroanatomy of speech dyspraxia It is now recognized that articulatory function depends on a hierarchically organized network of structures involving cerebellum, thalamus, striatum, anterior insula, and sensorimotor cortex. Current concepts of Broca’s area, particularly the
T A B L E 3–5. Main Features of Speech Dyspraxia (Aphemia) Effortful articulatory approximations and attempts at self-correction Dysprosody Articulatory inconsistency Difficulty initiating speech, sometimes with unproductive articulatory groping Often preserved articulation of automatic speech Preserved syntax and semantics
posterior portion (Brodmann’s area 44) abutting on the precentral sulcus (Brodmann’s area 6), include the view that it mediates the encoding of phonological word forms into articulatory plans. This places it at the apex of the articulatory hierarchy. Broca’s area also shows increased activity during syntactic processing, although lesions restricted to this area cause impairments in speaking rather than language,6 a view dramatically foreshadowed by the neurologist Pierre Marie in 1906 with a paper titled “The Third Frontal Convolution Does Not Play Any Special Role in the Function of Language” (see Harrington). Functional neuroimaging findings have raised the possibility that Broca’s area represents a bridge between articulation and language production.
The Syndrome of Broca’s Aphasia The term Broca’s aphasia is applied to a syndrome that occurs after more extensive infarction in the territory of the superior division of the middle cerebral artery. A core clinical feature is the production of sentences that lack syntactic structure. In its milder forms, affected patients produce simplified phrase structures, with a loss of the prosodic (melodic) aspects of speech. In its more severe forms, speech becomes telegraphic with strikingly effortful articulation. The effort involved in articulation results in highly economical phrases, usually restricted to nouns and verbs (e.g., “money. . . . send”). Loss of fluency in Broca’s syndrome is the combined effect of an impairment at the linguistic level (agrammatism) and an impairment of articulatory programming (speech dyspraxia). Agrammatism, or a dissolution of grammatical form, is characterized by greatly reduced use of open class words (articles, conjunctions, prepositions) and of morphemic structure (affixes), with relative preservation of words that convey substantive content (open class words such as nouns and verbs). The writing disturbance in Broca’s aphasia parallels spoken language in that it is sparse, effortful, clumsy, agrammatic, and paragraphic. Repetition is impaired and reflects essentially the same pattern of nonfluency as is that in spontaneous language. Written language is also agrammatic, with graphemic and graphomotor errors. Comprehension in Broca’s aphasia is not unscathed, but it nevertheless serves the patient comparatively well in daily life, and comprehension deficits are not a particularly noticeable feature of the clinical encounter. Some authorities have argued that there is a unitary impairment that produces both expressive agrammatism and syntactic comprehension deficits. There are cases, however, in which expressive agrammatism and comprehension dissociate, which suggests that there are separate mechanisms for elaborating syntactic form in language production and for appreciating syntactic
chapter 3 disorders of language form in heard or read language and that these mechanisms can be separately impaired. Gesture and communicative pragmatics (i.e., all of the nonverbal behaviors that accompany language appropriate the communicative context) are usually preserved. The syndrome of Broca’s aphasia can be observed as a later consequence of infarction. The initial clinical picture resembles a global aphasia. After weeks or months, there is a gradual emergence of the dyspraxic and agrammatic features, and these evolve slowly toward the long-standing features of the syndrome of Broca’s aphasia (see Mohr,6 page 230).
Functional neuroanatomy of Broca’s aphasia Broca’s aphasia is typically produced by fairly large lesions in the territory of the superior division of the left middle cerebral artery. Right hemiparesis, particularly involving the face and arm, is typically present as a neighborhood sign. Broca’s area, the anterior insula, and the basal ganglia are often all damaged, and the lesion usually also includes the middle frontal gyrus and the anterior parietal lobe. Involvement of Broca’s area alone is not a sufficient condition for the emergence of the syndrome of Broca’s aphasia. Neuroimaging findings have suggested that damage to Broca’s area impairs the production of all forms of speech (propositional and nonpropositional; see Blank et al, 2002). Propositional speech refers to newly formulated language output that conveys an idea, as opposed to nonpropositional speech, which is more automatic in nature and conveys nonideational content such as feeling states. At a clinical level, it is well accepted that propositional speech is most severely affected and that automatic nonpropositional aspects of speech are often preserved. Grammatical output depends on the interaction between Broca’s area and other cortical regions. Functional neuroimaging in normal subjects demonstrates that the middle frontal gyrus is commonly activated by language tasks that activate Broca’s area, which suggests that this region should also be included in a language production network (see Blank et al., 2002). Tractography of the arcuate fasciculus suggest that this pathway terminates in the middle frontal and inferior precentral gyri (Fig. 3–1), as well as in classically defined Broca’s area (see Catani et al., 2005).
Anterior segment
Geschwind's territory
Broca's territory
Posterior segment Long segment
35
Nonfluent Production with Normal Repetition: Transcortical Motor Aphasia Like all actions, language output, whether in the form of speech or writing, must be planned. Planning is a complex and multilevel process, ranging from the intention to produce propositional output (conceptualization) to the specification of appropriate syntactic structure and semantic forms (formulation) and then to the specification of phonology and articulatory patterns (overt execution). Cognitive capacity for planning is limited and dependent on normal frontal lobe function. The cardinal clinical manifestations of TMA can be conceptualized as a pathological disruption in planning of language output.
The Syndrome of Transcortical Motor Aphasia TMA is a nonfluent aphasia. The quantity and complexity of speech and of written output are reduced, but repetition, writing in response to dictation, reading, confrontation naming, and comprehension are well preserved. This pattern reflects the notion that TMA is a disorder of spontaneous, selfinitiated language output, with facilitation of output when external supports are provided. There is general agreement that there are two variants of TMA.10 The first often manifests initially as mutism, which resolves to poorly initiated and nonfluent output, characterized more by an articulatory disturbance than by a language disturbance. Output is normal during repetition. Comprehension and naming are also well preserved. There is some debate as to whether this form of TMA is a true aphasia. It occurs with infarcts in the territory of the left anterior cerebral artery, particularly with involvement of the supplementary motor area. It also occurs after resection of the left supplementary motor area. This variant of TMA has been ascribed to isolation of the supplementary motor area from frontal perisylvian language mechanisms. In this view, isolation of the supplementary motor area results in impaired motor programming before the overt execution of language output.11 The second variant of TMA is characterized by very sparse language production, which gives the impression of a reduced intention or motivation to speak. What speech is produced is well articulated but with impoverished syntax and narrative. Nevertheless, repetition is normal, even for long and complex sentences. Although patients with this form of TMA do not initiate routine series (e.g., naming the months of the year, nursery rhymes) on request, they freely complete the series after the examiner has provided the first few elements. Similarly, they are able to fill in sentence frames provided by the examiner (e.g., and the sun is ”). Luria “the day is referred to this condition as dynamic aphasia.7 He believed that the underlying impairment was an inability to elaborate the linear scheme of sentences or, in current terms, an inability to elaborate propositions. Luria’s description of the production difficulties of this group of patients is instructive:12 “As a rule, these patients answer simple questions relatively easily, frequently prefacing their reply with an echolalic*
Wernicke's territory ■
Figure 3–1. Terminations of the arcuate fasciculus suggested by tractography. (From Catani M, Jones DK, Ffytche DH: Perisylvian language networks of the human brain. Ann Neurol 2005; 57:8-16, Fig. 3. Copyright © 2006 Wiley-Liss, Inc., A Wiley Company. Reprinted with permission of John Wiley & Sons, Inc.)
*Echolalia is the patient’s tendency to echo what the examiner says but to change the grammar to suit himself or herself. For example, in response to the examiner’s question “How are you feeling?” the patient may reply, “How am I feeling?” Logoclonia is the tendency to repeat the final syllable of a word. For example, “telephone . . . phone . . . phone.”
36
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
repetition of the question, but they have difficulty as soon as they are asked to read a text and relate it to the examiner, or to compose a story from a picture given to them, and they are completely helpless if they have to write an essay on any freely chosen subject. In these cases they state that their thoughts will not move, that nothing enters their head, and they usually abandon the task or do nothing more than reproduce some habitual verbal stereotype, usually taken from their past experience.” The dynamic variant of TMA occurs with damage to the left frontal cortex anterior or superior to Broca’s area, involving the middle or superior frontal gyrus or both.
Fluent Production with Impaired Repetition and Comprehension: Wernicke’s Aphasia and Pure Word Deafness The Syndrome of Wernicke’s Aphasia The disturbance associated with Karl Wernicke’s name is perhaps the prototypic fluent aphasia. Nevertheless, disagreements about the exact features of Wernicke’s aphasia continue, and it should be recognized that there are a number of variants, which range from a lexical agnosia (pure word deafness) to jargonaphasia. From a diagnostic perspective, this condition is sometimes confused with psychiatric disturbances or even delirium in a busy emergency room. The following is a list of core features accepted in current practice: ■ Output is fluent, often empty of substantive meaning, with ■
■
■
■
an excess of closed class words and circumlocutions. Paraphasias are common. These may be phonemic (literal) or semantic, but the former is held to be the most frequent type. Paraphasias may be so severe that jargon is produced (jargonaphasia). Similar output features are seen in writing, which, however, displays preserved penmanship. Patients appear to be unaware of or unconcerned about their highly disturbed and often nonsensical output, in contrast to the frustration shown by those with Broca’s aphasia. Comprehension is severely impaired, predominantly because of a difficulty in discriminating between phonemes. The profundity of the comprehension impairment makes this the most disabling feature of Wernicke’s aphasia. As a consequence of the comprehension difficulty, output during attempts at conversation is seldom related to the conversational context. Some patients respond on the basis of incidental nonlinguistic cues. Repetition of words and sentences is impaired.
The following is an example of the fluent output disorder of a patient with severe Wernicke’s aphasia, illustrating runs of paragrammatism:13 I feel very well. My hearing, writing been doing very well; things that I couldn’t hear from; in other words, I used to be able to work cigarettes I didn’t know how. The pay I didn’t know how. I can write, cheesterfeela for over twenty years I can write it. Chesterfeel, I know all about it, I can write it.
Neuroanatomy of Wernicke’s Aphasia Wernicke’s aphasia is caused by lesions in the posterior segment of the superior temporal gyrus. Persistent and very severe forms, such as jargonaphasia, involve the supramarginal gyrus as well. Because Wernicke’s area falls within the territory of the inferior division of the middle cerebral artery, it is seldom accompanied by hemiparesis as a neighborhood sign. It may, however, be accompanied by a right superior quadrantanopia as a result of damage to the temporal portion of the optic radiation in subjacent white matter.
Pure Word Deafness The hallmark of this condition is an inability to recognize the phonology of language, despite normal hearing and normal ability to recognize nonlanguage sounds. The fundamental disturbance is at a phonemic rather than a lexical level, as evidenced by normal comprehension of written language. Repetition and writing in response to dictation are impossible. Spontaneous writing, however, is intact. Pure word deafness is, in effect, a phonemic agnosia. Pure word deafness is caused by damage to the region of the posterior insula and temporal isthmus. The condition is also encountered in epileptic aphasia (Landau-Kleffner syndrome).
Fluent Production with Normal Comprehension and Impaired Repetition: Conduction Aphasia The syndrome of conduction aphasia is perhaps the most controversial of the aphasias. It was postulated as a theoretical possibility from the Wernicke-Lichtheim model. In essence, Wernicke assumed that if the pathway connecting Broca’s and Wernicke’s areas were to be interrupted, speech would be fluent but paraphasic, and comprehension would be preserved, but the patient would be unable to repeat what he or she heard. This disconnection concept was challenged, principally by Sigmund Freud, who held that conduction aphasia, to the extent that this syndrome actually existed, was more likely to be the result of cortical damage and that its exact character would depend on the proximity of the lesion to either Broca’s or Wernicke’s areas. This notion has been revisited in light of tractography studies of the arcuate fasciculus (see Catani et al, 2005). Conduction aphasia is fundamentally a disorder of repetition. The breakdown in repetition has two underlying causes, giving rise to two variants of the syndrome: reproduction conduction aphasia and repetition conduction aphasia. Reproduction conduction aphasia is a specific disorder of phonological processing in which the processes by which the perceived phonemic representation of a word is converted into articulatory sequences are impaired. Repetition conduction aphasia, or acousticomnestic aphasia in Luria’s classification,7 is considered to be a disorder in a particular aspect of short-term memory: namely, reduced capacity to pass information from a short-term acoustic store to the output system. From a cognitive perspective, both forms of the syndrome involve a breakdown in a privileged communication channel. From a neuroanatomical perspective, the notion that this channel is necessarily the arcuate fasciculus, a deep white matter pathway
chapter 3 disorders of language that was initially thought to connect Broca’s and Wernicke’s areas, has been remarkably persistent in neurological thinking, but the clinicoanatomical literature indicates that there is no reason to believe that arcuate fasciculus interruption is a more feasible explanation for conduction aphasia than are lesions in the perisylvian language cortex.
The Syndrome of Conduction Aphasia The core clinical features of reproduction conduction aphasia are as follows: ■ Output is fluent, with phonemic paraphasias and with
normal or near normal comprehension. ■ Against this background, repetition of words, phrases, and
sentences, as well as writing in response to dictation, is very impaired and is hampered by prominent phonemic paraphasias. Phonemic paraphasias are also seen in naming and reading. ■ Characteristic attempts are made to correct the phonemic selection errors by successive approximations, or conduit d’approche (see Table 3–3). This phenomenon suggests that the representation of phonological knowledge is intact in conduction aphasia and that the impairment lies in the integration of phonology with articulatory processing. Repetition conduction aphasia is easily recognized on neuropsychological evaluation from a severe inability to repeat sentences, against a background of fluent spontaneous output and normal comprehension. Because of the absence of overt language symptoms, these cases rarely come to medical attention. In contrast to reproduction conduction aphasia, language is devoid of paraphasic errors. Affected patients usually exhibit a severely reduced digit span. The following example of fluent output in a conduction aphasic illustrates the profuse phonemic paraphasias and conduit d’approche:13 EXAMINER: Tell me what’s going on in this picture. PATIENT: Oh . . . he’s on top o’ the ss . . . ss . . . swirl . . . it’s a . . . ss . . . sss . . . ss . . . sweel . . . sstool . . . stool.
Neuroanatomy of Conduction Aphasia Most cases with conduction aphasia have lesions centered on the supramarginal gyrus. The lesion can include white matter deep to the supramarginal gyrus, involving the posterior end of the arcuate fasciculus. Whether involvement of the posterior arcuate fasciculus is a necessary condition is debatable. Anterior transection of the arcuate fasciculus does not produce conduction aphasia. Lesions in the insular cortex, including subinsular white matter, are also an important cause of conduction aphasia. It is recognized that conduction aphasia can occur with pure suprasylvian or pure subsylvian lesions (see Benson and Ardila, 1996).
Fluent Production with Normal Repetition and Impaired Comprehension: Transcortical Sensory Aphasia TSA is a rather controversial condition. It is similar to all posterior aphasias in the sense that it manifests as a fluent language disturbance, which ranges from severely paraphasic and
37
circumlocutory speech to relatively normal output with occasional semantic paraphasias. The hallmark of TSA is impaired comprehension but well-preserved repetition. Patients with TSA are able to repeat long and complex sentences that they cannot comprehend. The pattern of cognitive breakdown in TSA is variable, which suggests that this is not a single entity. Location of the causative lesion is also not certain and might be more widely distributed than classical aphasiologists suspected. Computed tomographic evidence suggests that lesions producing TSA tend to overlap in the inferior region of the temporo-parieto-occipital junctional cortex, as well as occipitotemporal cortex and underlying white matter. This inferior and medial distribution implicates the posterior cerebral artery.14 Other affected patients have lesions that are more superolateral, lying in the posterior watershed region between the posterior and middle cerebral arteries.14 TSA is also associated with degenerative conditions, such as the posterior cortical atrophy variant of Alzheimer’s disease.15 TSA is noted for its frequent association with other posterior focal neighborhood signs, such as Gerstmann’s syndrome, agnosia, alexia, constructional impairments, and ideational apraxia, in both focal and degenerative etiologies.
Fluent Production, Normal Repetition, and Preserved Comprehension: Anomic Aphasia The main feature of anomic aphasia is a supramodal wordfinding difficulty, with little effect on comprehension. Supramodal implies that the anomia is present regardless of the sense modality through which the item to be named is presented. Language production is fluent, but it is devoid of substantive content, circumlocutory, and paraphasic. Repetition is normal, which means that anomic aphasia is a transcortical disorder, and it has been suggested that it is on a continuum with TSA. Norman Geschwind’s adaptation of the Wernicke-Lichtheim model attributed the role of name retrieval to the angular gyrus, which is widely recognized as a zone of convergence for visual, auditory, and tactile information and a repository for semantic information. It is anatomically well placed as a nodal structure for the activation of semantically specified concepts. It is richly interconnected with the posterior temporal region, where activated concepts are converted to phonemic form. Angular gyrus lesions produce the features of anomic aphasia, but it is recognized that dysnomic features can arise from multiple loci and are therefore poorly localizing. In the author’s own experience, however, extra-angular lesions seldom produce the prominent fluent and circumlocutory output disturbance of anomic aphasia. For example (in which the patient attempts to convey that he suffered a stroke after aortic surgery):13 EXAMINER: Can you tell me about your illness? PATIENT: I had a. . . . I had a one or two three . . . There’s one . . . I had a . . . a . . . I know the exact part of it. EXAMINER: And it was after the operation? PATIENT: Right, about a day later, while I was under whatchmacall. . . . EXAMINER: Anesthesia? PATIENT: Under where they put you, just two or three people, an’ you stay in there for a couple o’ days.
38
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Nonfluent Production, Normal Repetition, and Impaired Comprehension: Mixed Transcortical Aphasia The syndrome of mixed transcortical aphasia was initially described in 1948 by Kurt Goldstein, although the condition had been anticipated by the classical aphasiologists. There is a severe reduction in the quantity of spontaneous output; comprehension is also severely impaired, but repetition remains intact. This pattern of impairment was ascribed to isolation of the speech area, a concept that was later to be confirmed by Geschwind in his classic study of a case of carbon monoxide poisoning. Repetition is made possible by the integrity of the perisylvian language axis: namely, Broca’s and Wernicke’s areas and the connections between them. Broca’s and Wernicke’s areas are, however, disconnected from anterior and posterior association cortices that mediate the ideational basis of language. Functional neuroimaging findings support the notion of a widely distributed left-lateralized extrasylvian neocortical system involved in the formulation of propositional language before its conversion to articulated speech (see Blank et al., 2002). Echolalia is a prominent component of mixed transcortical aphasia and, like intact repetition, can be thought of as reflecting the preservation of the automatic aspects of language, devoid of an ideational context. The lesions producing mixed transcortical aphasia tend to be multifocal or diffuse and include hypoxic insults, large watershed infarctions or a combination of focal watershed and pial infarction, and degenerative processes. The mixed transcortical aphasia syndrome also occurs in thalamic infarction.
PRIMARY PROGRESSIVE APHASIA Primary progressive aphasia refers to a gradually evolving aphasia, in the absence of other cognitive disorders. It is often the first symptom of neurodegenerative conditions such as one of the forms of frontotemporal dementia (see Chapter 73). The term primary progressive aphasia is applied when the speech and language symptoms have progressed for about 2 years in the absence of any other cognitive or behavioral changes.16 Even when the underlying dementia begins to manifest, the aphasic disturbance remains the most prominent and disabling symptom. Although some studies suggest that 50% to 60% of primary progressive aphasia cases have a fluent disturbance, at least two variants (fluent and nonfluent forms) are currently acknowledged. A third logopenic variant (characterized by slow and halting word production in the context of highly simplified but grammatically correct sentences) has also been proposed. Mesulam16 estimated that the underlying neuropathology in about 60% of patients with primary progressive aphasia is neuronal loss, gliosis, and spongiform change. Some cases are caused by frontotemporal dementia with parkinsonism linked to chromosome 17 (see Chapter 74), a genetic tauopathy. A further 20% have Pick’s disease, and fewer than 20% have Alzheimer’s disease.
Fluent Progressive Aphasia: Semantic Dementia In semantic dementia, spontaneous language is fluent, dysnomic, and possibly circumlocutory, but production and
comprehension of syntax are normal. The hallmark feature is a loss of word meaning, underpinned by a degradation of semantic function. On confrontation testing, for example, patients not only are anomic but also are unable to give any of the attributes of the object. The intended word is often replaced by a superordinate category (e.g., “flower” instead of “daisy”), which reflects an early loss of subordinate knowledge. Speech itself is normal in terms of rate of production and articulation. Published consensus criteria for the diagnosis of frontotemporal dementia link semantic dementia with disorders of object and face recognition (visual agnosia and prosopagnosia, respectively) as additional manifestations of semantic loss.17 This is controversial with regard to the definition of primary progressive aphasia mentioned previously.16 The earliest cerebral change in this variant is left anterolateral temporal atrophy. Semantic dementia is considered to be one of the clinical variants of frontotemporal dementia.
Nonfluent Progressive Aphasia The nonfluent progressive aphasia variant manifests with nonfluent speech, agrammatism, and difficulties in comprehending complex syntactic structures but also with preserved semantic function, at least at a single-word level. Articulation is labored. Cases of progressive aphemia or of speech apraxia but without a true aphasia have also been described. The distinction between nonfluent progressive aphasia and progressive aphemia parallels the distinction between Broca’s aphasia and aphemia. Most patients with nonfluent progressive aphasia and pure progressive aphemia have been shown to have Pick’s disease, with more restricted atrophy in the latter group.18 Both conditions are regarded as frontotemporal dementia variants17 and may represent a clinical spectrum reflecting varying degrees of damage to the anterior insular, inferior premotor cortex, and pars opercularis.
An Intermediate Variant: Logopenic Progressive Aphasia The logopenic progressive aphasia variant does not meet the criteria for semantic dementia or nonfluent progressive aphasia. Rate of speech output is reduced, with hesitancies suggestive of a word-finding difficulty and with impaired repetition. Articulation is normal. Grammar is simplified but correct. Semantic function is preserved, but syntactic comprehension is impaired. Logopenic progressive aphasia is associated with left temporoparietal atrophy. Together with a high frequency of the apolipoprotein E ε4 haplotype in this group, this anatomical distribution of atrophy suggests that logopenic progressive aphasia might be an atypical-onset form of Alzheimer’s disease. Further definition of primary progressive aphasia variants is likely to continue (see Grossman, 2002). Because primary progressive aphasia is an evolving language disorder, distinctions between the variants might be stage related. On the basis of a longitudinal study, Kertesz and colleagues suggested that although the aphemic, logopenic, agrammatic, and semantic distinctions are useful, there is some tendency for outcomes to converge as the dementia progresses.19
chapter 3 disorders of language ACQUIRED DISORDERS OF READING: THE ALEXIAS Fundamental Concepts: The Dual-Route Model In nonideographic writing systems—in which individual symbols do not themselves stand for concepts or ideas—all phonemes of the language have corresponding written representations, known as graphemes. Learning to read depends on acquiring knowledge of the phonemic equivalents of the graphemic system: that is, the rules of grapheme-phoneme correspondence. In sensory terms, this involves an integration between visual and auditory processing systems. Beginning and unskilled readers depend heavily on grapheme-phoneme correspondence and therefore on phonological pathways. This gives rise to the phenomenon of letter-by-letter synthesis: reading by sounding out each grapheme in turn before synthesizing the individual sounds into the word itself. This approach is considered to be sublexical because it depends on sequential identification of individual components of the word. It allows the individual to read any string that conforms to the phonological structure of the language and can therefore be “sounded out.” This would include all words with regular grapheme-phoneme correspondence, such as “cat,” “glint,” and “slap,” as well as pseudowords such as “rint,” “glaint,” or “lume.” But this does not allow the individual to read orthographically irregular words (written differently from the way they sound) such as “yacht,” “psalm,” or “thyme.” Words such as these can be read correctly only through a purely visual route; an attempt at using a phonological (grapheme-to-phoneme conversion) pathway would result in a mispronunciation. With increasing reading proficiency, all words come to be recognized visually (lexical or whole-word reading), but the sublexical route must still be recruited for pseudowords. This dual-route model is fundamental to understanding the acquired alexias.
The Dual-Route Model and Reading Disorders: Deep and Surface Alexias Deep alexia and surface alexia are psycholinguistic “syndromes.” They do not necessarily correspond to particular loci of cerebral damage, but they are useful in systematizing patterns of reading impairment and relating these patterns to putative mechanisms of disruption.
Deep Alexia The main features of deep alexia are as follows: ■ Normal reading of familiar and highly imageable words,
regardless of whether they have regular (“desk”) or irregular (“yacht”) grapheme-phoneme correspondence. ■ Inability to read pseudowords correctly according to the usual grapheme-phoneme conversion rules of the language. ■ Visual reading errors (e.g., “patience” for “patients”) and semantic reading errors (e.g., “ship” for “boat,” “cash” for “money”) are common. This pattern is brought about by a loss of the phonological or grapheme-phoneme conversion route. The patient is left with a residual ability to recognize familiar words but cannot recruit a phonological strategy to tackle unfamiliar words or pseudowords, which are, in effect, profoundly unfamiliar.
39
T A B L E 3–6. Central Alexia Syndromes Psycholinguistic Syndrome Deep alexia Surface alexia
Deficit Loss of grapheme-tophoneme conversion Loss of visual word form access to semantic system
Closest Equivalent Neurological Syndrome, or Lesion Location Alexia with agraphia Aphasic alexia Left temporoparietal Generalized atrophy Primary progressive aphasias
Deep alexia is seen in patients with severe aphasias and with widespread damage in a frontoparietal distribution.
Surface Alexia Patients with surface alexia are able to read orthographically regular words (“rush,” “tint,” “same”) and pseudowords (“glant,” “sint,” “glame”) but are unable to read irregular words (“gaoled,” “subtle,” “colonel”). Pronunciation is regularized (e.g., “denni” for “deny”). This feature cannot be detected in languages with uniform, unambiguous grapheme-phoneme conversion rules (e.g., Spanish), but it is readily demonstrable in English. Reading is effortful, taking appreciably more time for long words than short words (word length effect). There is inability to recognize words at a glance. Word meaning is accessed only after the word has been pronounced. If an error in pronunciation occurs, the meaning is deemed to be that of the unintended word. For example, if the word “pretty” is read as “pity,” its meaning is judged to be “compassion.” This constellation of features implies preservation of the phonological route but loss of visual access to the semantic system. Deep alexia and surface alexia are regarded as central alexias, because they represent a loss of access by visual representations of word forms to central phonemic and semantic mechanisms (Table 3–6).
Neurological Classification of Alexias There is an alternative, nonpsycholinguistic classification system for the alexias. Although some syndromes are essentially the same in both (e.g., pure alexia), there really is no equivalent syndrome in the other classification system for others (see Benson and Ardila, 1996, for suggested correlations between the two classification systems).
Alexia without Agraphia (Pure Alexia) Patients with pure alexia read by sequentially identifying the letters of the word (letter by letter reading). This is a slow and laborious process, and at least in the subacute phase, silent reading is not possible. Speed of reading depends on the number of letters in the word (word length effect); therefore, wholeword recognition is not possible. All other language functions are well preserved, giving rise to the term pure alexia. Writing is also intact, but the patient is not able to read what he or she has written. The classical lesion in pure alexia is infarction of
40
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
the medial surface of the left occipital lobe and splenium of the corpus callosum. It is now accepted that splenial involvement is not a necessary condition for the emergence of pure alexia. Pure alexia tends to evolve acutely from an inability to identify individual letters to recovery of letter identification and letter-by-letter reading and, in some cases, recovery of silent reading. Alexia without agraphia is regarded as a peripheral alexia because the deficit occurs at the level of visual processing without involving the more central mechanisms of grapheme-phoneme conversion or semantic processing.
Alexia with Agraphia Strictly speaking, alexia with agraphia is diagnosed when reading and writing are impaired against a background of otherwise normal language functions. This pattern, however, is rare. The nature of the reading and writing impairment is variable. Alexia with agraphia is caused by lesions in the temporoparietal cortex and is often accompanied by mild features of Wernicke’s aphasia. In pure forms of alexia with agraphia, residual reading depends on whole-word recognition, and it therefore resembles the psycholinguistic syndrome of deep alexia.
Aphasic Alexia (Co-occurring with Broca’s or Wernicke’s Aphasia) With severe Broca’s aphasia there is a profound disruption of grapheme-to-phoneme conversion, and residual reading occurs at the level of whole-word reading. This brings about a striking impairment of reading comprehension despite relatively wellpreserved comprehension of speech. Like alexia with agraphia, alexia in Broca’s aphasia resembles the psycholinguistic syndrome of deep alexia. It is sometimes referred to in the neurological classification of alexias as the third alexia. Wernicke’s aphasia causes impairments for spoken and written language. The comprehension impairment for speech tends to recover more rapidly than does reading comprehension, and the evolving clinical picture is one of alexia with agraphia.
ACQUIRED NEUROGENIC AGRAPHIA Speech and writing are the two major output modalities for language. It is often assumed that language disorders in speech are paralleled by an equivalent pattern in writing, and, as a consequence, the agraphias have come to be overshadowed by the aphasias. Aphasic agraphias certainly can reflect the production disorder of the aphasic syndrome, but this is not always the case, and there is often overlap between writing disorders in fluent and nonfluent aphasias. Classical agraphic syndromology is therefore somewhat less satisfactory than classical aphasiology. Most classifications have recognized agraphias associated with aphasic syndromes (aphasic agraphias), those associated with fundamental visuospatial disorders (e.g., neglect), and those associated with upper limb motor disorders and dyspraxic disorders. Benson and Ardila (1996) proposed a dichotomous classification, into aphasic and mechanical agraphias (Table 3–7). The mechanical agraphias raise the question as to whether writing impairments of nonsymbolic origin (such as dystonic, paretic, or apractic forms) should be regarded as true agraphias, which is, again, reminiscent of the question of whether speech dyspraxia should be regarded as aphasic or dysarthric. Perhaps
T A B L E 3–7. Classification of the Agraphias Aphasic Agraphias Agraphia in Broca’s aphasia Agraphia in Wernicke’s aphasia Agraphia in conduction aphasia Agraphia in other aphasias Mechanical Agraphias Motor agraphia Paretic agraphia Dyskinetic agraphia Hypokinetic agraphia Hyperkinetic agraphia Dystonic agraphia Pure agraphia Apractic agraphia Spatial agraphia Based on Benson DF, Ardila A: Aphasia: A Clinical Perspective. New York: Oxford University Press, 1996, p 214, Table 12.1.
the term agraphia should be reserved for language-based disturbances in writing and graphomotor impairment for nonlinguistic disturbances. Table 3–8 lists the main characteristics of some of the aphasic agraphias, and Table 3–9 lists characteristics of the higher-level mechanical agraphias.
Neurocognitive Classification of Agraphias Neuropsychological studies have resulted in an alternative classification of the agraphias, analogous to the psycholinguistic classification of the alexias. The distinction is made between central and peripheral agraphias, with matching of the concepts of central and peripheral alexias. Spatial and apractic agraphia can be regarded as peripheral because they do not involve fundamental language mechanisms. Table 3–10 summarizes the central agraphias.
T A B L E 3–8. Characteristics of Aphasic Agraphia: Comparison with Spoken Output Spoken Output
Written Output
Agraphia in Broca’s Aphasia Sparse output Effortful Poor articulation Short phrase length Dysprosody Agrammatism (lack of closed class words) Poor spelling
Sparse output Effortful Clumsy calligraphy Abbreviated output (No written equivalent) Agrammatism (lack of closed class words) Poor spelling
Agraphia in Wernicke’s Aphasia Normal vocal characteristics Noneffortful speech Good articulation Normal phrase length Normal prosody Lack of open class (substantive) words Paraphasias
Normal graphic characteristics Noneffortful writing Well-formed letters Normal sentence length (No written equivalent) Lack of open class (substantive) words Paragraphias
Adapted from Benson DF, Ardila A: Aphasia: A Clinical Perspective. New York: Oxford University Press, 1996, pp 218-219, Tables 12.3 and 12.4.
chapter 3 disorders of language
41
T A B L E 3–9. Apractic and Spatial Agraphias Apractic Agraphia Fundamentally, a loss of ability to form normal graphemes Profuse written spelling errors, despite a retained ability to spell orally Profuse iterations, repairs, and other distortions Writing difficulty evident in spontaneous writing, writing in response to dictation, and copying Can occur in isolation from speech difficulties or upper limb apraxia and can therefore be regarded as a “pure” apraxia; this, however, is rare Usually occurs in association with ideomotor dyspraxia or other inferior parietal signs Spatial Agraphia Loss of ability to utilize spatial constraints and organization in writing Letters are reiterated Spatial delimiters between words are not used correctly (“Th esunis shi ning” instead of “The sun is shining”) Progressive enlargement of margins, heavily slanted writing, and other forms of malpositioning of writing Impairments seen in automatized (for example, signature) and nonautomatized forms of writing Occurs in association with other spatial impairments, typically in right hemisphere lesions
T A B L E 3–10. Central Agraphias Syndrome
Linguistic Impairment
Neuroanatomy
Lexical agraphia (analogous to surface dyslexia)
Loss of whole word processing Inability to spell irregular or ambiguous words, with preserved spelling of regular words and graphemically legal nonwords Graphemic regularization (for example, “grayshus” instead of “gracious”) Loss of sublexical processing Impairment of phoneme-to-grapheme conversion Inability to spell nonwords, with preserved ability to spell regular and irregular familiar words Inability to write nonwords or words with low imageability Semantic paragraphias with no visual similarity to the target (for example, “travel” instead of “car”)
Dominant angular gyrus, with sparing of immediate perisylvian region
Phonological agraphia (analogous to phonological dyslexia) Deep agraphia (analogous to deep dyslexia)
Dominant supramarginal gyrus and insula
Large supramarginal or insula lesions
Suggested Reading
K E Y
P O I N T S
●
Aphasias can be divided into fluent and nonfluent types. This basic dichotomy can be refined further, depending on whether repetition and comprehension are impaired, to describe eight basic aphasic syndromes.
●
Several types of focal degenerative pathologies can manifest as primary progressive aphasias, without significant involvement of other cognitive domains over at least the first 2 years of the illness. These are of two broad types: fluent primary progressive aphasia (a feature of the syndrome of semantic dementia) and nonfluent primary progressive aphasia.
●
Two different classification systems for acquired dyslexias are in current use: one based on the two-pathway (wholeword and phonetic) psycholinguistic model and the other based on classical lesional behavioral neurological observations. Although there is no direct correspondence, both systems account for a distinction between central disorders (of language) and peripheral disorders (of visual processing of letters and words).
Benson DF, Ardila A: Aphasia: A Clinical Perspective. New York: Oxford University Press, 1996. Blank SC, Scott SK, Murphy K, et al: Speech production: Wernicke, Broca, and beyond. Brain 2002; 125:1829-1838. Catani M, Jones DK, Ffytche DH: Perisylvian language networks of the human brain. Ann Neurol 2005; 57:8-16. Duffy JR: Motor Speech Disorders: Substrates, Differential Diagnoses, and Management. 2nd ed. St. Louis: Mosby, 2005. Grossman M: Progressive aphasic syndromes: clinical and theoretical advances. Curr Opin Neurol 2002; 15:409-413. LaPointe LL, ed: Aphasia and Related Neurogenic Language Disorders, 3rd ed. New York: Thieme, 2005.
References 1. Brown JW: Case reports of semantic jargon. In Brown JW, ed: Jargonaphasia. New York: Academic Press, 1981, p 171. 2. Luria AR: Language and Cognition. New York: Wiley & Sons, 1982, p 224. 3. Head H: Aphasia and Kindred Disorders of Speech, vol 2. London: Cambridge University Press, 1926, p 229. 4. Goodglass H: Agrammatism. In Whitaker H, ed: Studies in Neurolinguistics, vol 2. New York: Academic Press, 1976, p 238.
42
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
5. Kertesz A: The anatomy of jargon. In Brown JW, ed: Jargonaphasia. New York: Academic Press, 1981, p 91. 6. Mohr JP: Broca’s area and Broca’s aphasia. In Whitaker H, ed: Studies in Neurolinguistics, vol 1. New York: Academic Press, 1976, p 221. 7. Kagan A, Saling MM: An Introduction to Luria’s Aphasiology: Theory and Application. Baltimore: Paul H. Brookes, 1992. 8. Schiff HB, Alexander MP, Naeser MA, Galaburda AM: Aphemia: Clinical-anatomic correlations. Arch Neurol 1983; 40:720727. 9. Harrington A: Medicine, Mind, and the Double Brain. Princeton, NJ: Princeton University Press, 1987, p 261. 10. Ardila A, Lopez MV: Transcortical motor aphasia: one or two aphasias? Brain Lang 1984; 22:350-353. 11. Cimino-Knight AM, Hollingsworth AL, Gonzalez-Rothi LJ: The transcortical aphasias. In LaPointe LL, ed: Aphasia and Related Neurogenic Language Disorders 3rd ed. New York: Thieme, 2004, pp 169–185. 12. Luria AR: Human Brain and Psychological Processes. New York: Harper & Row, 1966, pp 358-359.
13. Goodglass H, Wingfield A: Word-finding deficits in aphasia: brain-behavior relations and clinical symptomatology. In Goodglass H, Wingfield A, eds: Anomia: Neuroanatomical and Cognitive Correlates. San Diego, CA: Academic Press, 1997, p 7. 14. Kertesz A, Sheppard A, McKenzie R: Localization in transcortical sensory aphasia. Arch Neurol 1982; 39:475-478. 15. Benson DF, Davis RJ, Snyder BD: Posterior cortical atrophy. Arch Neurol 1988; 45:789-793. 16. Mesulam MM: Primary progressive aphasia. Ann Neurol 2001; 49:425-432. 17. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546-1554. 18. Hodges JR, Davies RR, Xuereb JH, et al: Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004; 56:399-406. 19. Kertesz A, Davidson W, McCabe P, et al: Primary progressive aphasia: diagnosis, varieties, evolution. J Int Neuropsychol Soc 2003; 9:710-719.
CHAPTER
DISORDERS ●
●
OF ●
4
MEMORY ●
Peter J. Nestor
DEFINITIONS AND TERMINOLOGY Declarative and Nondeclarative Memory In general, when patients speak of memory complaints, they are referring to the recollection of information for which there is conscious awareness. In neuropsychological terminology, this is called declarative, or explicit, memory. The corollary is nondeclarative, or implicit, memory, which refers to phenomena such as motor skill learning, priming and classical conditioning (Table 4–1). For instance, with appropriate training, a tennis player can be seen to “learn,” as evidenced by improved performance; however, in the course of a rally, the player is not consciously recollecting the motor sequence required to execute each shot. Priming refers to a situation in which prior exposure leads to altered performance and can be shown experimentally in language tasks such as naming and lexical decision making. For example, imagine being presented with words on a computer screen and being asked to read them as soon as they appear; the latency between exposure and response (reaction time) is shorter if a related, as opposed to a nonrelated, item is presented immediately before the test item (e.g., a subject will respond faster to the word tiger if it is preceded by lion rather than house). Highlighting the dissociation between declarative and nondeclarative memory is the fact that patients with Alzheimer’s disease have marked declarative deficits and yet may respond even faster with priming (hyperpriming) than control subjects. Although nondeclarative memory is crucial for many functions, it is not what patients usually mean when they report memory symptoms and is not discussed further.
Episodic and Semantic Memory Declarative memory is further subdivided into context-specific and non–context-specific types known as episodic and semantic memory, respectively. Episodic memories are unique in that they are recollections of an individual’s own past experiences, and therefore each is specific in time and space. In contrast, semantic memory refers to knowledge of universal facts and does not require evocation of the circumstances in which such information was acquired. Furthermore, factual knowledge is typically not learned from a single episode but rather is encoun-
tered in many contexts over time. To illustrate these definitions, an individual is retrieving semantic memories when he or she recalls that Paris is the capital of France and is home to the Louvre and Eiffel Tower. When the individual recollects specific events from his or her own visit to Paris, this virtual reconstruction of the event constitutes an episodic memory—regardless of how fragmentary the events recalled may have become. This ability to travel mentally in time is sometimes referred to as autonoetic (self-understanding) consciousness, which emphasizes the critical position of self-awareness in the recollective process. It is characteristically multimodal (e.g., visual scenes, sounds, verbal narrative). Declarative memory is also considered in terms of encoding, storage, and retrieval. In other words, a neurophysiological change takes place during learning (encoding); this change must leave some enduring trace (storage), and there must be a mechanism by which this trace can be reactivated, at will, to lead to the subjective experience of remembering (retrieval). Often, these processes cannot be disentangled in the clinic; for instance, a patient with no recall of new information on formal neuropsychological testing may have a deficit at any or all of these stages. Nevertheless, neuropsychological tests can, to some extent, tease these stages apart by varying task demands. For example, a patient who requires an excessive number of learning trials to reach a criterion and yet retains a lot of this information after a delay can be considered as having an encoding problem. This profile is often indicative of an attention disorder rather than a true amnesic syndrome. Storage problems may be suggested by an accelerated decay in recall performance between two time points (e.g., immediately and 30 minutes after encoding). However, it is important to realize that a degree of decay is seen under normal circumstances; therefore, interpretation requires comparison with demographically matched norms. Retrieval deficits can be investigated by comparing free recall (“What did I ask you to remember?”) with recognition memory (“Which of these did I show you earlier?”). Recognition is typically tested by either forced-choice questions—in which target answers and foils (incorrect alternatives) are presented simultaneously in pairs and the patient has to choose those that he or she has seen before—or by asking for yes/no responses as targets and foils are presented in a random sequence. Because the patient is presented the previously studied material, retrieval demands are minimized, and
43
44
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
hence a retrieval deficit is suggested where there is disproportionate impairment of free recall in comparison with recognition memory. Recognition is, however, an easier task than is free recall, and so this dissociation also needs to be assessed by comparison with control norms. It is likely that the neural systems responsible for these processes partially overlap, in that some brain areas such as the hippocampus may be necessary for all aspects, whereas other areas may be differentially engaged at a specific stage. For example, functional activation studies of changes in cerebral blood flow suggest greater engagement of the left and right prefrontal cortices during encoding and retrieval, respectively.1
Amnesia Amnesia is the generic term for loss of memory. An inability to establish new memories after the pathological event is called anterograde amnesia, whereas the inability to recall memories that had been established before the pathological event is called retrograde amnesia (Fig. 4–1). The fact that the distinction
T A B L E 4–1. Classification of Memory Types
Memory performance
Nondeclarative (implicit) memory Motor skill learning Priming Classical conditioning Working memory Declarative (explicit) memory Episodic memory Semantic memory
between anterograde and retrograde is referenced to the pathological insult is important. Students often think erroneously that retrograde amnesia refers to memory loss for past events, whereby “past” is loosely defined as any time before the clinical consultation. This leads to the absurd situation of testing for retrograde deficits by asking the patient what they did “yesterday,” which makes the distinction from anterograde deficits meaningless, as it becomes referenced to the everchanging present. Patients with dense amnesia, especially in the acute phase, may confabulate: that is, fill in memory gaps with false statements. The episodic/semantic memory distinction is inconsistently defined with regard to the term amnesia. In popular usage, the term amnesic syndrome denotes severe loss of episodic memory with preservation of working memory and general semantic memory (i.e., word meanings, object knowledge). The most sensitive marker is loss of autonoetic awareness. A patient may produce what sounds like a specific episodic memory (e.g., “When I was ten, I fell off a horse and broke my arm”) but, when asked to elaborate, is unable to do so in a manner that offers convincing evidence of mental time travel, rather than mere repetition of an overlearned statement. The situation becomes more ambiguous with regard to factual semantic knowledge (public events, famous people), including personal semantic facts (e.g., names of schools attended, name of employers). Variable degrees of impairment in factual semantic knowledge are usual in amnesia, and this information can be objectively dated in time (in contrast to an individual’s episodic recollections, which are more difficult to date or verify). As a consequence, evidence for temporal gradients in memory impairment is typically compiled from these datable facts. For instance, a patient with a new-onset pathological process who knows that the Berlin Wall was pulled
Key Anterograde, with temporally graded retrograde, amnesia Focal anterograde amnesia Focal (organic) retrograde amnesia Focal (non-organic) retrograde amnesia Global amnesia
Time Remote past
Present Pathological insult Retrograde amnesia
■
Anterograde amnesia
Figure 4–1. Schematic representation of different profiles of amnesia.
chapter 4 disorders of memory down, that apartheid ended, and that Iraq invaded Kuwait but does not remember a tsunami killing hundreds of thousands, the World Trade Center being destroyed, or Princess Diana dying has evidence for a retrograde amnesia extending back to the early to mid-1990s. It should be noted that the distinction between episodic and semantic memory—the degree of “semanticization”—becomes blurred at this point, inasmuch as some facts may be recalled from the specific context in which they were encountered—as so-called “flashbulb” memories. In addition, the frequency of exposure to particular facts varies between individuals. For example, the average American has most likely had many more encounters with stories about the World Trade Center than with stories about the Berlin Wall, and this will bias successful recollection towards the more recent, semantically reinforced event.
Working Memory An important concept to distinguish from both episodic and semantic memory is working memory, frequently referred to by experimental psychologists as short-term memory. This refers to information that, at any given moment, is held “online” by the brain—that is, in consciousness—and that is not recollected after a distraction period (unless incidental episodic encoding of the material has also taken place). This faculty is exemplified by the ability to keep a telephone number in the mind in the interval between looking it up the telephone directory and dialing the number. Models of working memory posit auditory-verbal and visuospatial components that are coordinated and manipulated by a central executive system.2 A highly distributed network of cortical and subcortical areas supports working memory, although the dorsolateral prefrontal cortex appears to be particularly important for the executive component. It is therefore unsurprising that working memory is most vulnerable to diffuse insults such as those found in metabolic encephalopathies and closed head injury. It can be dissociated from the long-term declarative memory systems described previously; patients with even the densest amnesia can still have intact working memory. It is important for clinicians to understand the difference between this true short-term memory system and what patients (and many clinicians) may colloquially refer to as short-term memory. The latter, incorrect usage indicates memory for recently experienced events or exposures and therefore actually refers to recently acquired episodic memory.
NEUROBIOLOGY OF LEARNING AND MEMORY Cellular Mechanisms From a theoretical perspective, a neural system responsible for learning must be adaptive; in its most elementary form, a sensory event leads to an alteration in behavior at a later time. Put another way, biological events corresponding to learning must take place at the initial experience, and some outcome from these events must remain stable over time. In everyday experience, evidence for this adaptation is illustrated through the sense of familiarity experienced when a related sensory stimulus is subsequently encountered. However, in neurobiological terms, this process can be generalized to any alteration
45
of behavior that is a consequence of a prior experience. Therefore, learning and memory in the broadest sense can encompass phenomena that are far removed from the recollection of an individual’s previous life events, such as the habituation of a blink reflex in response to a recurring visual stimulus. The relevance of this to the neurobiology of memory is that these more fundamental phenomena—forms of nondeclarative memory—are much more accessible to direct experimentation, not least because they can be studied in organisms with much simpler nervous systems. Important insights into the neural basis of learning and memory have been gleaned from studies in organisms as diverse as invertebrates, such as the Drosophila fruit fly and the Aplysia sea slug, and mammalian species, including nonhuman primates. These models indicate that activity-dependent changes can occur in the efficacy of synaptic transmission; in other words, certain physiological stimuli can give rise to synaptic plasticity. This plasticity is often referred to as a Hebbian synapse, after Donald Hebb, who postulated in 1949 that if a given neuron is repeatedly involved in provoking a second neuron to fire, then the efficiency with which this process takes place will increase. Support for Hebb’s postulate was subsequently explored and developed in a large body of neurophysiological experimentation. The basic observation is that after a brief repetitive stimulation, the amplitude of the excitatory postsynaptic potential is enhanced, and this enhancement can be shown to persist for hours or days. This phenomenon is referred to as long-term potentiation (LTP) and is initially facilitated through modifications to existing proteins at the synapse. A further level of complexity in the dynamics of synaptic transmission is that with certain neurons and stimulation protocols, the converse process, long-term depression (LTD), may occur. Clearly, long-term memory as it is known in humans requires neural changes that persist over much longer periods. By studying very simple nervous systems such as that of Aplysia, neuroscientists have demonstrated, in behaving organisms, that synaptic plasticity in response to classical conditioning gives rise to changes in gene expression and consequently to alterations in protein synthesis. Glutamate is the principal excitatory neurotransmitter in the central nervous system, and LTP has been demonstrated to occur through agonism of ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. LTP can be induced by agonism of NMDA receptors, whereas maintenance of LTP, including modulation of gene expression, occurs through AMPA receptors. The relevance of this to clinical practice is that perturbation of glutamate transmission has become a target for pharmacological intervention to enhance mnemonic function. It is already recognized that certain manipulations can impair function; for instance, the NMDA antagonist, ketamine, causes dosedependent impairments in episodic memory. Another excitatory neurotransmitter implicated in some forms of LTP is acetylcholine. Loss of cholinergic neurons in the basal forebrain is a recognized feature of Alzheimer’s disease, in which memory impairment is the most salient feature. Cholinesterase inhibitor therapy for Alzheimer’s disease is now standard; unfortunately, although these agents offer some symptomatic benefit for attention deficits and behavioral disturbances, their ability to improve memory performance is, at best, modest. These observations suggest that the transmission properties of existing synapses can be modified by usage, but it is notable that the “hard wiring” of the nervous system is also dynamic.
46
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
The dendritic spines, the sites of synaptic connections in the neuronal dendritic arbor, also display plasticity over time, which suggests that the neural networks themselves may be adaptive.3 Technical developments, enabling dendritic spines to be labeled and studied in real time, have shown that changes in structure, including the generation of new dendritic spine protrusions, can be triggered by LTP-inducing activity. Conversely, some LTD-inducing stimuli have been shown to cause loss of dendritic spines. It must be acknowledged, however, that although these morphological and physiological findings suggest mechanisms by which learning and memory may be supported, the precise relevance of these specific processes to memory in vivo is far from established in the mature brain. For further reading on these topics and other current issues in the neuroscience of memory, the excellent essays by Dudai (2002) are recommended.
The Topography of Memory Experimental manipulations of individual synapses are also considerably removed from an understanding of what constitutes a “memory trace”; this shorthand term is often used to indicate the neural representation of an individual memory. Lesions studies indicate that several brain regions have a critical role in supporting declarative memory. Amnesia characteristically arises with lesions to limbic areas that are subsumed within the anatomical network, often referred to as either the circuit of Papez or the Delay and Brion system. This network includes the mesial temporal lobe (including hippocampus and adjacent entorhinal cortex), the fornix, the diencephalon, and the posterior cingulate region (see Fixed Memory Disorders section, Strategic Lesions subsection). Between synaptic plasticity and the topographical anatomy of regions implicated in amnesia, the precise nature of the memory trace remains difficult to delineate. As already discussed, the information that constitutes episodic memory comprises multiple sensory modalities. The prevailing hypothesis is that structures such as the hippocampus do not “store” this information, but rather act to bind the disparate components that constitute a memory trace. To illustrate this model,
consider an episodic memory of a specific conversation comprising, for simplicity, an auditory component (the dialogue) and a visual component (the scene). At the time of encoding, visual and auditory inputs contemporaneously activate a neural network in the isocortex, including auditory and visual association cortex, as well as the mesial temporal lobe. The temporospatial firing pattern that represents the memory trace can then be subsequently re-activated via the hippocampus. The traditional view (Fig. 4–2) is that with time, this neural representation gradually becomes independent of the hippocampus: so-called consolidation. This is the explanation for the Ribot effect, a temporal gradient in retrograde amnesia in which amnesia is most dense for the time immediately before the pathological insult and is progressively less dense for earlier periods. This view is almost certainly an oversimplification; many amnesic patients do not exhibit a Ribot effect but, rather, a flat profile of memory loss extending back over their whole life. Furthermore, when it is found, the temporal gradient often extends back over several decades, which suggests that consolidation is an implausible entity in evolutionary terms, inasmuch as it implies that in old age, the brain is still consolidating memories from early adult life.4 Another hotly debated topic is whether the distinction between semantic and episodic memory is meaningful in biological terms. Evidence for two separable memory systems comes from the observation that individuals with episodic memory amnesia have preservation of general semantic knowledge. Furthermore, neuropsychological studies have shown that patients with hippocampal amnesia, including those with damage sustained in infancy,5 can acquire new semantic knowledge in spite of the amnesia. This suggests that semantic memory, including its acquisition, can be supported independently of the hippocampus. The opposing view is that the acquisition of both semantic and episodic memory is dependent on a unitary system. Evidence for this comes from the observation that although acquisition of semantic knowledge may occur in patients with hippocampal amnesia, it is not completely normal.6 Whereas each episodic memory is unique in time and space, semantic facts are experienced in multiple contexts. This means that there is an enormous encoding advantage for the latter, which may explain the dissociation.
Isocortical neural network
Hippocampus
Encoding
Retrieval (Early
■
Years
Remote)
Figure 4–2. Schematic representation of the “classical” model of memory consolidation. At encoding, the sensory percept activates a network of isocortical neurons in concert with the hippocampus. Reactivation of this “memory trace” (corresponding to conscious retrieval of the memory) initially requires hippocampal input; however, in time, the memory trace maybe be reactivated independently of the hippocampus. Although this model can account for some features of the amnesic syndrome in some cases, there are many inconsistencies and controversies. In summary, the concept of memory consolidation remains a hotly debated subject.
chapter 4 disorders of memory In addition to the interaction of the hippocampus and isocortical sensory association areas in sustaining declarative memory, the amygdala and prefrontal cortex merit mention. The amygdala is involved in emotional processes, such as recognition of fear in other’s faces, but with regard to memory, it is thought to reinforce encoding of emotionally salient events. Clearly, people do not recollect their entire life experience as a bland, continuous narrative. The fact that some experiences are forgotten but others are remembered is related in part to their differing emotional significance, and it is thought that encoding of emotionally significant events is facilitated by an interaction of the amygdala with other mesial temporal structures.7 The prefrontal cortex is thought to have a “meta” role in mnemonic processing, being involved in focusing attention for encoding, forming retrieval strategies, and monitoring output.8 For instance, when a person is asked to produce a list of animals, performance is enhanced if the list is clustered into semantic categories (“category clustering”) such as zoo animals, farm animals, and domestic animals. The prefrontal cortex is specifically engaged in this type of processing, but not in storing the memories per se. Consequently, frontal lesions can cause deficits in free recall with relative preservation of recognition, because the latter does not require an active retrieval strategy.
ASSESSMENT OF MEMORY Clinical Assessment Wherever possible, a history should be obtained from a close relative of the patient to cross-reference to the patient’s account. After the clinician explains the procedure to the patient and obtains his or her consent, the informant should be seen alone, to allow frank discussion without fear of embarrassment. A common mistake in assessing patients with memory symptoms is failure to examine memory adequately. There is often insufficient time in a general clinic to test delayed recall over a long interval; however, new learning can be informally assessed by giving the patient some material to encode and then testing recall and recognition after a 5-minute distraction period filled with other elements of the examination. A seven-item name and address recall can be assessed without any special equipment; this test yields indices of encoding, recall, and recognition (Fig. 4–3). Asking the patient to copy abstract designs, followed by testing of spontaneous recall and recognition, can help assess nonverbal memory.
47
Remote autobiographical memory is best evaluated in the clinic by probing for facts about the patient’s life, such as place of birth, schools attended, occupational history, residences, marriages, children, and grandchildren. This provides personal semantic facts that can be checked against the informant’s account. Remote episodic memory can be assessed by asking for specific anecdotes from different life periods (e.g., “Tell me something that happened to you at secondary school”). This, of course, raises the problem of how the veracity of these memories is confirmed, particularly as even a spouse may be unable to confirm some events. When possible, prompts to events that include the informant can circumvent this problem (e.g., “Tell me something that happened on your wedding day”; “Tell me about a family holiday when the children were young”). In pragmatic terms, false memories seldom pose a problem because the usual response with organic memory impairment is failure to produce any memory (real or otherwise). In a clinical setting, in contrast, memory impairment in confabulators is typically apparent without the use of such probes. Semantic memory for facts can be tested by knowledge of famous people and events, but these must be tailored to the expected knowledge of the local population. For instance, in a U.K. clinic, the clinician might ask, “Who is the prime minister?” “Who was the woman prime minister?” “Which member of the Royal family died in a car accident in Paris?” “Which members of the Beatles are still alive and which are not?” and so forth. Family informants offer a ready-made, reasonably well-matched source for gauging control performance. General semantic knowledge can be assessed by category fluency tasks (naming as many animals as possible in 1 minute), picture naming, definition (“What is a caterpillar?”), naming according to definition (“What is the large gray animal with a trunk called?”), object knowledge (asking patient to demonstrate use of a stethoscope, corkscrew, stapler, and so forth). The important detail in testing general semantic memory is to ensure that a range of low-frequency items is included; asking the patient to name a “watch” and a “pen,” as in the Mini-Mental State Examination, will only identify very advanced impairments.
Neuropsychological Assessment The neuropsychologist also documents the patient’s history, including the demographic information necessary for test interpretation (age, education, handedness). Memory performance also needs to be interpreted in the context of general cog■
Figure 4–3. Bedside test of name and address recall. Scoring: Each encoding trial (T1 to T3) is scored on a 7-point scale (1 point for each item). Delayed recall (DR) is tested after five minutes. Recognition can be assessed by presenting the name and address on paper with two foils of similar structure. (See Mathuranath PS, Nestor PJ, Berrios GE, et al: A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 2000; 55:1613-1620.)
48
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 4–2. Selected Neuropsychological Tests of Memory Test New Learning Rey Auditory Verbal Learning Test (RAVLT) California Verbal Learning Test (CVLT) Story Recall (Logical Memory) Recognition Memory Test (RMT) Doors and People Test
Description
Word list encoding, free recall, and recognition Word list semantic clustering, encoding, free recall and recognition Story free recall ± recognition Face and word recognition
Rey-Osterrieth Complex Figure*
Verbal and nonverbal recall and recognition Nonverbal recall ± recognition
Paired Associates Learning (PAL)
Object/spatial location recall
Rivermead Behavioural Memory Test (RBMT)
Various tests including some “real-life” memory tasks
Remote Memory Autobiographical Memory Interview (AMI) Galton-Crovitz cue-word test
General Semantic Memory Category fluency
Personal semantics and episodes from childhood, early adulthood, and recent past Specific autobiographical episodes generated to word prompts
Boston Naming Test
Generation of exemplars to a target category Picture naming
Graded Naming Test
Picture naming
Pyramids and Palm Trees Test
Word and picture forced-choice associative knowledge
Reference or Source
Rey A: L’Examen Clinique en Psychologie. Paris: Presses Universitaires de France, 1964 Delis DC, Kaplan E, Kramer J, et al: California Verbal Learning Test (CVLT-II) Second Edition—Adult Version. San Antonio, TX: The Psychological Corporation, 2000 Wechsler D: Wechsler Memory Scale—Revised. San Antonio, TX: The Psychological Corporation, 1987. Warrington, EK: Recognition Memory Test. Windsor, UK: NFER-Nelson, 1984 Baddeley A, Emslie H, Nimmo-Smith I: Doors and people. Oxford, UK: Thames Valley Test Company, 1994 Osterrieth PA: Le Test de Copie d’Une Figure Complex [Complex Figure Copy Test]. Arch Psychol 1944; 30:206-356. Cambridge Neuropsychological Test Automated Battery. Cambridge, UK: Cambridge Cognition, Ltd. Wilson BA, Cockburn J, Baddeley A: Rivermead Behavioural Memory Test (RBMT-II). Oxford, UK: Thames Valley Test Company, 2003 Kopelman M, Wilson B, Baddeley A: The Autobiographical Memory Interview (AMI). Oxford, UK: Thames Valley Test Company, 1990 Crovitz HF, Schiffman H: Frequency of episodic memories as a function of their age. Bull Psychonom Soc 1974; 4:517-518
Kaplan E, Goodglass H, Weintraub S: Boston Naming Test. Philadelphia: Lea & Febiger (Also published by Psychcorp and LWW.), 1983 McKenna P, Warrington EK: The Graded Naming Test. Windsor, UK: NFER-Nelson, 1993 Howard D, Patterson K: Pyramids and Palm Trees Test. Oxford, UK: Thames Valley Test Company, 1992
Factual Semantic Memory Variations on tests of famous people, news events, etc.† *See Figure 4-9 † These tests are typically used to assess the temporal extent of amnesia; however, because knowledge of such events varies greatly between communities, these tests are typically devised by individual neuropsychology laboratories.
nitive abilities; thus, the assessment is never restricted to memory alone. A vast array of tests are available that probe various aspects of memory: encoding, retrieval, and recognition; verbal and nonverbal memory; remote memory; and so on. Some of the memory tests in common usage are listed in Table 4–2. Reliable interpretation of neuropsychological performance requires that the tests be administered under standardized conditions by an appropriately trained examiner. Ad hoc incorporation of neuropsychological tests into the bedside examination is therefore best avoided.
SYNDROMES OF MEMORY DISTURBANCE Transient Memory Disorders Transient Global Amnesia Transient global amnesia (TGA) is a syndrome of sudden onset, occurring in late middle or old age. An affected patient is
characteristically densely amnesic and appears confused, repeatedly asking questions such as “Where am I?” or “What are we doing?” The event typically lasts for several hours, and during this time there is both anterograde and retrograde amnesia, although knowledge of personal identity is maintained. After the acute attack resolves, the patient is left with a period of amnesia for the time of the episode. The cause is uncertain, with suggested possibilities including a vascular transient ischemic attack, a seizure, or migraine. In single photon emission computed tomography images, transient perfusion defects in the mesial temporal lobe are evident during the episode,9 which highlights the presence of hippocampal dysfunction even if not identifying the underlying cause. Although TGA has an acute onset, it is seldom confused with more dangerous causes of acute amnesia such as viral limbic encephalitis, because the patient is otherwise alert, well and, more often than not, already in the recovery phase by the time of assessment. TGA typically occurs only once, and although cases of recurrent TGA are described, repeated episodes should alert the clinician to the possibility of transient epileptic amnesia (TEA).
chapter 4 disorders of memory
49
Transient Epileptic Amnesia
Trauma
Temporal lobe epilepsy is an increasingly recognized cause of transient memory impairment in middle-aged and elderly persons. The diagnosis is most secure when amnesic attacks are associated with a history of temporal lobe epilepsy or electroencephalographic evidence of temporal lobe discharges— which may be evident only on a during-sleep recording—and when the frequency of episodes is unequivocally improved by anticonvulsant therapy. Typical attacks of TEA differ in several ways from those of TGA, although the syndromes may be impossible to differentiate on the basis of the retrospective clinical account of an individual episode. The most useful distinguishing features of TEA are that the amnesic attacks are often briefer than those of TGA (less than 1 hour) and may occur on waking from sleep.10 In contrast to TGA, the patient may remember that he or she was unable to remember during the episode. It is not clear whether TEA results from an ictal or postictal state. In addition to discrete attacks of TEA, some patients with temporal lobe epilepsy appear to have accelerated forgetting of new episodic memories. These patients do not have evidence of an anterograde amnesia over the half-hour period usually employed to test delayed recall during neuropsychological assessment. However, episodic memory recall over longer periods appears to be impaired.11 Typically, the problem becomes apparent to the patient when the patient is discussing specific events with family members, such as the details of a particular outing, or while he or she is looking at holiday photographs. Although the family members confirm that the patient appeared normal at the time the particular event took place, the patient subsequently claims no recollection of the episode. It is speculated that subclinical temporal spike activity—particularly during sleep—may interfere with longterm consolidation of these memories.
After regaining consciousness from severe closed head injury, patients typically have a variable retrograde amnesia in combination with anterograde amnesia, called post-traumatic amnesia. This type of amnesia is conventionally defined as the period from regaining consciousness to when a continuous memory record is reestablished. If the period of amnesia is brief (hours), the prognosis for a full recovery is generally good. Although those with prolonged post-traumatic amnesia appear to have significant memory impairment, they do not have a pure amnesic syndrome in the strict sense, inasmuch as there are also deficits in attention and concentration. The marked distractibility seen in such cases is more akin to that seen with a diffuse encephalopathy.
Migraine On occasion, migraine sufferers present with memory symptoms similar to those described in the previous section on TEA, but no evidence can be found to support a diagnosis of epilepsy. In such circumstances, it is impossible to be certain of a causal relationship, but a speculative trial of migraine prophylaxis may be worthwhile.
Drugs Severe alcohol intoxication is a well-known cause of brief amnesic periods. However, in this author’s experience, these “alcoholic blackouts” never come to specialists’ attention as a diagnostic problem. More relevant to clinical practice is that a multitude of prescribed drugs are associated with symptoms of memory impairment. Patients affected by these medications do not have amnesia as such, but they complain of poor memory in the context of feeling “spaced out,” “like a zombie,” or “unable to think”; these symptoms are indicative of an attention deficit. Commonly implicated agents include benzodiazepines, antidepressants, anticonvulsants, neuroleptics, and anticholinergics. Obtaining a detailed drug history is especially important for patients with organic memory impairment, particularly in the context of a degenerative etiology such as Alzheimer’s disease, because these compounds exacerbate the existing deficits.
Electroconvulsive Therapy Electroconvulsive therapy for treatment of severe depression is associated with a brief retrograde and anterograde amnesia but is not generally thought to cause ongoing memory impairment after the event. The severity of memory impairment is minimized by applying a unilateral, as opposed to bilateral, stimulus.
Fixed Memory Disorders Strategic Lesions Mesial temporal lobe Lesions that damage the hippocampus and adjacent areas provide the archetypal substrate for amnesia. Possibly the most famous (or notorious, depending on one’s perspective) case in 20th century neuropsychology is that of H.M., a man who underwent bilateral mesial temporal lobectomy to control intractable epilepsy in the 1950s and was found postoperatively to have profound episodic memory impairment.12 Since H.M., numerous cases of hippocampal amnesia have been studied. Such cases typically have dense anterograde amnesia with variable retrograde amnesia. The degree of retrograde amnesia is approximately proportional to the extent of mesial temporal lobe lesions, whereas damage restricted to the cornu ammonis 1 field of the hippocampus may be associated with an almost pure anterograde amnesia.13 The hippocampus is particularly susceptible to anoxic damage; hence, bilateral focal hippocampal lesions are typically seen after resuscitation from cardiac arrest, carbon monoxide poisoning, and other states of hypoxemia or hypotension that cause inadequate cerebral perfusion. The blood supply of the hippocampus is predominantly via temporal branches of the posterior cerebral artery and, consequently, emboli to the vertebrobasilar system can also cause bilateral infarction. Unilateral infarcts (Fig. 4–4) from the same source tend to cause material-specific deficits; left- and right-sided lesions cause disproportionate verbal and visual memory deficits, respectively. The latter are usually evident in spatial memory tasks, although there is controversy regarding whether a lesion restricted to the right hippocampus is sufficient to cause the deficit. There is evidence to suggest that right parahippocampal damage may play a crucial role.14 Unilateral infarcts of the hippocampal head can also arise from anterior choroidal artery
50
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s Retrosplenial cortex
Diencephalon (Thalamus and mamiliary body)
Fornix
Basal forebrain
Mesial temporal lobe (Hippocampus and entorhinal cortex) ■
Figure 4–5. Lesion sites associated with amnesia in humans.
Basal forebrain
■
Figure 4–4. Right-sided mesial temporal lobe infarct (related to atrial fibrillation) in a patient with a material-specific nonverbal memory deficit.
occlusion. Aside from vascular disease, the other major causes of focal mesial temporal lobe damage are viral and immune system–mediated limbic encephalitides (see sections on Immune System–Mediated Limbic Encephalitis and Viral Limbic Encephalitis).
Fornix The fornix is the principal projection from the mesial temporal lobe to the mamillary body and thalamus. Most reports describe a relatively pure, anterograde amnesia. Iatrogenic lesions caused by surgical division in the course of removing colloid cysts from the third ventricle,15 as well as tumors and trauma, are recognized causes.
Diencephalon The fornix, both directly and via the mamillary body, projects to the rostral thalamic nuclei and particularly to the anterior thalamic nucleus. Lesions in this region can cause dense anterograde and retrograde amnesia. Posteromedial central branches from the posterior cerebral arteries supply the anterior nuclei, and hence infarction caused by emboli in the vertebrobasilar system can cause bilateral lesions. This bilateral vulnerability is further increased because the central artery of Percheron, which arises from one or other posterior cerebral artery, divides to supply both mesial thalami; thus, a single vessel occlusion can lead to bilateral infarction. Bilateral lesions can also result from anoxic damage (deep watershed infarcts). As with mesial temporal lesions, unilateral thalamic lesions are associated with material-specific deficits. It is difficult to prove that amnesia may be caused by focal mamillary body lesions, but this seems the most parsimonious explanation in some cases.16 Patients with diencephalic amnesia may also have a degree of executive impairment, caused by disruption of frontostriatal networks.
Cases in which lesions in the region of the septal nuclei, the diagonal band of Broca, the nucleus basalis of Meynert, the substantia innominata, and the nucleus accumbens are associated with amnesia have been described. It is speculated that this may be a consequence of damage to cholinergic projections originating in the diagonal band of Broca and projecting to the hippocampus,17 although the specific anatomical mechanism is far from certain. Although this area lies in close proximity to the diencephalon, several reports indicate that the latter may be spared in such cases. The typical pathological process is rupture of an aneurysm in the anterior communicating artery.
Retrosplenial cortex As the name suggests, the retrosplenial cortex lies immediately adjacent to the splenium of the corpus callosum (Fig. 4–5). This cause of amnesia is rare, because focal lesions of the retrosplenial cortex are seldom encountered. Nevertheless, there have been several case reports in which amnesia was associated with damage to this area. Material-specific deficits are typical with unilateral lesions.18 Interestingly, the neural connections of the retrosplenial cortex are to the mesial temporal lobe and the dorsolateral prefrontal cortex, which place it in what is potentially a pivotal point in relation to structures involved in episodic memory processing. The usual pathological process is hemorrhage related to an underlying vascular malformation. Tumors of the splenium itself have also been reported to cause amnesia,19 and it may be that this is a consequence of retrosplenial cortex compression; however, the fornix lies subjacent to the ventrorostral surface of the splenium, so that damage to this structure may also be relevant to the genesis of the amnesic syndrome.
Korsakoff’s Psychosis Korsakoff’s psychosis (or syndrome) is a severe, diencephalic amnesia caused by thiamine deficiency. It is typically seen in alcoholic patients with very poor diets, but it is important to remember that the critical factor is the dietary deficiency, rather than the alcohol. Thus, Korsakoff’s psychosis may occur in any disorder in which there is failure to maintain thiamine intake, such as gastrointestinal disorders (including gastric
chapter 4 disorders of memory T A B L E 4–3. Checklist of Emergency Management of Management and Investigation of Acute Amnesia 1. Start thiamine (>400 mg daily) with multi–vitamin B supplement and IV acyclovir. 2. Check blood biochemistry (including Mg) and hematology, and arrange cerebral imaging (MRI if possible). Is there: Temporal lobe hemorrhagic necrosis? (HSVE) High signal in hippocampi? (autoimmune and paraneoplastic limbic encephalitis) 3. CSF for biochemistry, cell counts, and HSV PCR assay Is there evidence of HSVE? 4. Is there evidence of EEG? Nonconvulsive status epilepticus Period complexes (HSVE) 5. Antineuronal antibody, VGKC-Ab, paraneoplastic screen (including FDG-PET if standard test results negative). 6. Trial of immunomodulation therapy if HSVE and Korsakoff’s psychosis are definitely ruled out. CSF, cerebrospinal fluid; EEG, electroencephalogram; FDG-PET, fluorodeoxyglucose–positron emission tomography; HSV, herpes simplex virus; HSVE, herpes simplex virus encephalitis; IV, intravenous; Mg, magnesium; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; VGKC-Ab, voltagegated potassium channel antibodies.
restriction surgery) and hyperemesis gravidarum. It usually follows from Wernicke’s encephalopathy, which consists of the classic triad of ataxia, ophthalmoplegia, and delirium, although presentation with delirium alone is common. It is therefore also referred to as Wernicke-Korsakoff syndrome. Korsakoff’s psychosis can be prevented at this encephalopathic stage by highdose parenteral thiamine (given in combination with empirical multi–vitamin B group supplements, because multiple deficiencies may be present). Thiamine levels can be assessed by assay of erythrocyte transketolase activity, but this is seldom appropriate, because empirical therapy is straightforward and should not be delayed. Wernicke’s encephalopathy can be precipitated by glucose infusion in incipient thiamine deficiency. Of importance is that Mg2+ is a cofactor for thiamine activity, and patients may be resistant to thiamine therapy until concomitant magnesium deficiency is corrected.20 Unfortunately, if the patient has amnesia without delirium, which suggests that Korsakoff’s psychosis has already ensued, the prognosis for recovery is very poor. Nevertheless, suspected Korsakoff’s psychosis and limbic encephalitides (see next section) represent the most urgent management problems among the memory disorders, and thiamine deficiency should always be considered in cases with acute or subacute amnesia (Table 4–3). Korsakoff’s psychosis typically causes a severe global amnesia. Anterograde amnesia is profound and accompanied by a severe retrograde amnesia. If the retrograde amnesia is temporally graded (worse for more recent retrograde memories) rather than complete, it usually spares only very remote memory. Typically, there is an associated dysexecutive syndrome. Neuronal loss is found in the mamillary body, the mediodorsal nucleus, and anterior thalamic nucleus; damage to the anterior thalamic nucleus appears most specific for Korsakoff’s psychosis–related amnesia.21
Immune System–Mediated Limbic Encephalitis Paraneoplastic limbic encephalitis causes the subacute onset of amnesia, typically over days to weeks. Like other paraneo-
51
plastic neurological syndromes, antibodies raised in response to the tumor are thought to cross-react with neuronal epitopes. Patients typically present with memory impairment in association with confusion and, not infrequently, seizures. Because of these additional features, it is difficult to make appropriate generalizations about the type of memory deficit, but marked impairment of free recall of new information is typical. The electroencephalogram may show focal temporal lobe discharges. Magnetic resonance imaging (MRI) in the acute phase may reveal high signal in the hippocampi on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. The presence of antineuronal antibodies in serum—most commonly anti-Hu—is supportive, but a negative result should not deter a search for malignancy if suspicion is high, particularly if there is a cerebrospinal fluid (CSF) pleocytosis.22 A twopronged management strategy offers the best chance of improvement: treatment of the acute neurological disorder and definitive management of the tumor. Anecdotal reports suggest that immunomodulatory therapy (steroids, gamma globulin, or plasmapheresis) may be helpful in some cases and should be tried. The most commonly associated malignancy is small-cell lung cancer, with gonad, breast, and non-Hodgkin lymphoma also likely possibilities. Imaging of chest, abdomen, pelvis, and breasts should be performed. Paraneoplastic phenomena are often associated with very early tumors; therefore, if these investigations yield negative results, a full-body fluorodeoxyglucose positron emission tomographic scan to look for metabolic hot spots can increase yield. Cases in which hippocampal atrophy ensues have a poor prognosis for recovery. However, some patients with hippocampi that appear preserved on MRI may recover memory, although prognosis for such recovery is unpredictable (Fig. 4–6).23 Nonparaneoplastic limbic encephalitis has a clinical onset and memory symptoms that may be indistinguishable from those of paraneoplastic limbic encephalitis.24 Temporal lobe seizures and confusion may also occur. The key feature is the presence of voltage-gated potassium channel antibodies (VGKC-Ab) in the serum, as are found in neuromyotonia, a condition that may coexist with the limbic encephalitis. Imaging studies indicate abnormal signal in the hippocampus on MRI scanning (Fig. 4–7), whereas the CSF is usually acellular.22 Anecdotal reports suggest that immunomodulatory therapy can improve amnesia and that the VGKC-Ab titer may be correlated with disease activity.
Viral Limbic Encephalitis Limbic encephalitis also occurs with herpes simplex virus encephalitis (HSVE); typically, herpes simplex virus (HSV) type 1 is the causative organism, although HSV type 2 can produce the same illness. The clinical features are similar to those of immune system–mediated limbic encephalitis, with memory impairment, confusion, and seizures, although the presentation is typically more fulminant. There is a significant mortality rate, and memory sequelae are common in survivors. HSVE is a medical emergency, in that the best chance for full recovery is with early treatment. Empirical acyclovir should be commenced in all suspected cases as first-line management (i.e., before the diagnostic workup is started; see Table 4–3). Cerebral imaging with MRI, to look for signal changes and hemorrhage in the rostral temporal lobes, often provides supportive evidence. If MRI is unavailable, computed tomography can be
52
■
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Figure 4–6. Two cases of limbic encephalitis and underlying small cell lung cancer—one with preserved hippocampi (left) whose amnesia responded to therapy and the other with severe hippocampal destruction (right) whose amnesia persisted. (From Bak TH, Antoun N, Balan KK, et al: Memory lost, memory regained: neuropsychological findings and neuroimaging in two cases of paraneoplastic limbic encephalitis with radically different outcomes. J Neurol Neurosurg Psychiatry 2001; 71:40-47. Reproduced by permission from the BMJ Publishing Group.)
■
Figure 4–7. High signal intensity (arrows) in hippocampi on coronal magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery (FLAIR) in voltage-gated potassium channel antibodies (VGKC-Ab)–associated limbic encephalitis. (From Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody– associated encephalopathy: a potentially immunotherapy response form of limbic encephalitis. Brain 2004; 127(3):701-712. Reproduced by permission of Oxford University Press.)
utilized, although it is considerably less sensitive.25 Periodic temporal lobe discharges on electroencephalography also provide good supportive evidence. The CSF study shows a lymphocytic pleocytosis, but a very high erythrocyte count— suggestive of a traumatic tap—may also result from cortical hemorrhagic necrosis. Definitive diagnosis is usually established by demonstration of a positive CSF polymerase chain reaction assay for HSV. In the acute phase, memory assessment is usually superfluous because patients are typically delirious, often requiring sedation and mechanical ventilation. Various combinations of semantic and episodic memory impairments are seen in survivors, depending on the precise location and extent of cerebral damage. Mesial temporal damage is associated with anterograde amnesia, and because the distribution of pathological process is often asymmetrical, material-specific deficits are common. Variable degrees of retrograde amnesia may occur in association with the anterograde memory deficit, and HSVE can occasionally give rise to a relatively focal retrograde amnesia.26 This phenomenon appears to occur when there is disproportionate temporal isocortical damage (as opposed to hippocampal and entorhinal lesions). Temporal isocortical damage can also cause semantic memory impairments. Unlike semantic dementia (see later discussion), these are often quite patchy, giving rise to what are referred to as category-specific deficits.27 Semantic knowledge can be considered in categories defined by their semantic relatedness. For instance, varieties of land animals, breeds of dogs, varieties of birds, body parts, tools, and musical instruments can all be considered as belonging to definable semantic categories and tested for accordingly. The commonest reported category-specific deficit is the dissociation of synthetic artifacts from living creatures, but various other
chapter 4 disorders of memory permutations are also described. Category-specific deficits are of research interest because they offer insights into the neural structuring of semantic memory. The basic principle is that as the degree of similarity between semantic exemplars increases, so too does the overlap in the neural networks that represent the items. The attributes of an item give rise to a stable neural representation—or “attractor” in computational models—that identifies it as a specific, nameable entity. For semantically related items (e.g., land animals), these attractors share common features and thus may share common vulnerability if part of the network is damaged. See Rogers and Plaut (2002) for a detailed review of lesion evidence, computational models and proposed theories of category-specific deficits.28
Progressive Memory Disorders Alzheimer’s Disease Alzheimer’s disease is the commonest cause of memory impairment. In established Alzheimer’s disease, the diagnosis is usually straightforward: Patients have severe impairment of episodic memory with variable degrees of impairment in other cognitive domains, including semantic and working memory. However, the insidious onset and slowly progressive nature of the impairment make early diagnosis more difficult because, in contrast to the disorders already discussed, patients do not start out with a dense amnesia. It is increasingly recognized that relatively isolated episodic memory impairment can precede full-blown dementia by several years.29 Because the clinical diagnostic criteria for Alzheimer’s disease include impairment in multiple cognitive domains, early symptomatic cases that have not crossed this threshold cannot be labeled “Alzheimer’s disease” if the consensus diagnostic criteria are strictly applied.30 This had led to the introduction of the term amnestic mild cognitive impairment (MCIa) to describe isolated impairment of episodic memory.31 In spite of the current vogue for “diagnosing” MCIa, it must be emphasized that this term does not denote a pathological entity but rather a degree of severity. If symptomatic Alzheimer’s disease begins with isolated episodic memory impairment, why not revise the diagnostic criteria so that MCIa is called Alzheimer’s disease? The problem is that in the clinic, the more subtle the cognitive impairment, the less certain it is that symptoms will progress. Many patients with what appears to be isolated memory impairment may have a psychiatric illness or simply have “a bad memory” that will not worsen over time. Annual progression rates from the MCIa stage to probable Alzheimer’s disease are usually reported to be in the vicinity of 15% per annum. However, there is considerable variability in progression rates between cohorts, which most likely relates to differences in clinical features at baseline; within the designation of MCIa, there is scope for inclusion of cases that vary from minimal impairment to being on the cusp of a consensus classification of Alzheimer’s disease. Therefore, it is not surprising that MCIa patients who exhibit features suggestive of Alzheimer’s disease—such as subtle non-mnestic cognitive deficits, hippocampal atrophy visible on MRI, and temporoparietal hypometabolism evident on positron emission tomography—are at highest risk of early deterioration to dementia. The key to clinical assessment is to disentangle “sinister” memory symptoms from more benign lapses. To this end, three factors in the clinical assessment are essential. The first is
53
always to document history from an informant who knows the patient well. Although the patient usually acknowledges memory lapses, sinister lapses are particularly evident to the informant. In contrast, patients with nonsinister memory symptoms often complain vociferously of the problem, but an informant states that the symptoms have little or no effect. The second is to note the quality of the symptoms. Attention lapses, which can be exacerbated by stress or depression, occur in the normal population and cause people to misplace their keys, forget why they just opened the refrigerator (the “fridge door” effect), miss prearranged appointments, and so on. On the other hand, forgetting an appointment or passing on a phone message but then subsequently having no clear recollection of the appointment’s being made or the conversation’s occurring in the first place is a far more ominous symptom. Likewise, getting temporarily lost in an unfamiliar place is of little significance, whereas forgetting how to get about in one’s usual neighborhood is a more serious matter. Another helpful way to examine these issues objectively is to take a detailed autobiographical history. Many patients with early Alzheimer’s disease present very well if allowed to take the lead in the consultation. However, patients can be taken out of their “comfort zone” by being asked for specific details of major life events (e.g., schools attended, full employment history, residences, marriages, birth details of children and grandchildren), and their answers can often expose major problems that would otherwise be missed. The final assessment is to examine memory formally, both in the clinic and with formal neuropsychological measures. In the early stages, patients with organic memory impairment resulting from Alzheimer’s disease exhibit good registration of new information but profound deficits in delayed free recall. Of note is that the widely used Mini-Mental State Examination contains little to expose this deficit. The only delayed-recall task is threeitem word recall, which is usually conducted after a delay of only a few seconds. Intelligent patients can often hold this information in working memory; hence, a perfect score on the Mini-Mental State Examination does not exclude the possibility of a significant episodic memory deficit. The cause of the episodic memory deficit in Alzheimer’s disease is complex. Early neurofibrillary tangle deposition (one of the hallmarks of Alzheimer’s disease) in the mesial temporal lobe suggests that memory impairment may be underpinned by damage to this area. However, although structural imaging may reveal hippocampal atrophy in many individuals (Fig. 4–8), there is considerable overlap in this feature between Alzheimer’s disease and healthy aging. Likewise, although cholinergic depletion is well recognized in Alzheimer’s disease, pathological32 and cholinergic ligand-based functional imaging studies33 suggest that this is not a major feature of the very early stage of the disease. Positron emission tomography suggests that the deficit may result from the combined effect of a degeneration of the functional network, including the mesial temporal lobe, diencephalon, and retrosplenial/posterior cingulate cortex.34
Dementia with Lewy Bodies Dementia with Lewy bodies (DLB) is probably the second commonest cause of dementia in elderly persons, after Alzheimer’s disease. It is characterized by fluctuating confusion, hallucinations (typically of the formed visual type), spontaneous extrapyramidal features, and a neuropsychological profile of prominent working memory and visuoperceptual deficits.35
54
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
■ ■
Figure 4–8. Hippocampal atrophy (arrows) in a man with mild
Figure 4–9. Rey-Osterrieth Complex Figure Copy Test.
Alzheimer’s disease (Mini-Mental State Examination score = 22/30).
Nevertheless, the presenting complaint is often stated to be “memory problems.” The key difference from Alzheimer’s disease is that for the degree of episodic memory impairment, there is disproportionate impairment of the aforementioned domains. The memory impairment itself is also qualitatively different from that seen in Alzheimer’s disease and, indeed, from amnesic syndromes in general. In keeping with the working memory deficit, patients have marked deficits in encoding. For instance, in three-trial learning of a sevenelement name and address, many patients with very mild Alzheimer’s disease can repeat all seven elements after the first trial and, if not, performance generally improves over the subsequent trials. In contrast, DLB patients tend to have marked impairment of registration after the first trial and little or no improvement over subsequent trials. However, whereas delayed recall in early Alzheimer’s disease is markedly impaired in spite of good registration (e.g., learning trial scores are 6/7, 7/7, and 7/7; delayed-recall score is 0/7), many patients with DLB recall a large proportion of what they managed to encode (e.g., learning trial scores are 3/7, 4/7, and 4/7; delayed-recall score is 3/7). DLB is associated with a marked cholinergic deficit and, although cholinesterase inhibitors were introduced primarily for Alzheimer’s disease, it appears from anecdotal reports and small trials that they are more useful in improving cognition in DLB.36 In addition to the positive effects that these drugs have on the neuropsychiatric features of DLB, they seem particularly helpful in improving working memory and the related encoding deficit.
Frontotemporal Dementia There are three clinical presentations of frontotemporal dementia: a neuropsychiatric syndrome, nonfluent progressive aphasia, and semantic dementia.37 Of these, semantic dementia is of most interest with respect to impainment of declarative memory.38 As the name suggests, these patients have progressive semantic memory impairment (factual knowledge, word meanings, and object knowledge), which gives rise to
comprehension deficits and fluent aphasia. Unlike post-HSVE cases, significant category-specific deficits in semantic knowledge are rarely encountered, possibly because HSVE is more likely to result in a patchy distribution of cortical damage. In fascinating contrast to amnesic syndromes, patients with semantic dementia have relative preservation of episodic memory, as evinced by their often remarkably rich ability to recount anecdotes from the recent past. An important caveat for the neuropsychological assessment of episodic memory in semantic dementia is that the semantic knowledge deficit confounds performance on verbal memory tasks. Word-list learning or story recall is aided under normal circumstances by the ability to make semantic associations; if semantic knowledge is degraded, then word-list learning is analogous to normal subjects’ learning a list of unfamiliar foreign-language words. Nevertheless, because degeneration is usually maximal in the left temporal lobe, a degree of verbal episodic memory impairment is difficult to rule out. However, on nonverbal tests that minimize semantic associative knowledge (e.g., the Rey-Osterrieth Complex Figure Copy Test [Fig. 4–9]), delayed recall scores are often within the normal range. The remote memory profile also provides an interesting contrast to that seen in classic amnesic syndromes. Recent episodic memory (dating back weeks to months) is relatively preserved in comparison with memory from more remote time periods,39 a finding that is also true of semantic facts that can be dated to a specific time period (such as knowledge of famous people and events).40 These findings suggest that remote autobiographical memories may actually be supported by similar mechanisms to those involved in semantic memory. The distribution of degenerative change in semantic dementia is typically asymmetrical and involves the anterior temporal lobes (especially the poles and inferior surfaces) (Fig. 4–10). The preservation of episodic memory was initially thought result from sparing of the hippocampi; however, volumetric MRI has shown that hippocampal atrophy in semantic dementia is at least as severe as that seen in Alzheimer’s disease, which suggests that the amnesia in the latter may be more a consequence of damage to other areas. A final contentious issue in semantic dementia is whether the asymmetrical atrophy of the
chapter 4 disorders of memory
55
antidepressant therapy may be indicated, but longitudinal follow-up is the only way to reach a definitive diagnosis.
Hysterical Amnesia
■
Figure 4–10. Focal atrophy of the temporal lobe (arrow) in semantic dementia.
temporal lobes can give rise to material-specific semantic memory deficits. Some authors have suggested that patients with greater right-sided atrophy have more problems with nonverbal semantics41 (such as prosopagnosia for famous faces). The alternative view is that semantic knowledge is bilaterally distributed but naming is lateralized to the left. Consequently, verbal semantics are more impaired with greater degrees of left temporal atrophy, because this weights word-processing ability.
Memory Impairment in Psychiatric Disorders Anxiety and Depression Symptoms of episodic memory impairment are very common with anxiety and depression, and disentangling these from early Alzheimer’s disease represents one the greatest diagnostic challenges in the assessment of memory disorders. This is further compounded by the fact that the anxiety itself may be driven by fear of Alzheimer’s disease in a patient with a positive family history. As already discussed in the Alzheimer’s disease section, the quality of memory symptoms can be a helpful discriminator. Exacerbation of normal attention lapses (the already mentioned “fridge door” effect) is typical in anxiety and depression. A discrepancy between the severity of self-rated versus informant-related memory deficits and a discrepancy between selfreported memory deficits and retained functional abilities are also useful for diagnosis. Normal neuropsychological performance is also reassuring; however, many patients in this category have impairments in free recall, which may be related to both compromised attention at encoding and anxiety-induced interference with retrieval strategies. Independent evidence of anxiety or affective symptoms offers only circumstantial evidence to support the diagnosis of “nonorganic” memory symptoms, because there is also an increased prevalence of anxiety and depression among patients with incipient dementia. In summary, it is sometimes impossible to discriminate between the memory impairment of anxiety or depression and that of incipient Alzheimer’s disease. In such circumstances, a trial of
Neuropsychological performance is only a semiobjective measure, inasmuch as valid results depend on the motivation and cooperation of the patient. Thus, there is scope for patients to elaborate their deficits, if that is their wont. As with any deficit in which elaboration of the signs is suspected, the examiner must be alert to the possibility that the patient may be exaggerating a truly organic deficit for fear of not being taken seriously. Nevertheless, a few profiles should alert the examiner that test performance may not necessarily be indicative of an organic disorder. For instance, apparent marked impairment on encoding, with no learning curve over successive learning trials but followed by good recall after delay, raises suspicions. Likewise, clinicians occasionally encounter patients who display reasonable free recall and yet perform far worse when the same material is presented in a recognition memory format. In such circumstances, the remainder of the neuropsychological assessment can offer further clues; many tests (e.g., naming) are graded in difficulty, and therefore finding that a patient is struggling with easy items but managing difficult items may be helpful. True hysterical amnesia is a fairly uncommon disorder but one that most commonly manifests with a characteristic profile: focal retrograde amnesia. The patient presents with a dense amnesia for a discrete period, with apparently normal memory for events from before and after the amnesic period and normal performance on tests of new learning. Alternatively, there may be a complete retrograde amnesia, including loss of personal identity. Psychological precipitants for this so-called psychogenic fugue state, such as marital problems, criminal fraud, and bereavement, are often reported. One caveat is that cases of organic focal retrograde amnesia are also described, particularly in connection with focal temporal isocortical damage (such as after HSVE or severe head injury).42 Nevertheless, in organic cases, the border zone between preservation and loss in remote memory is often rather blurred. Furthermore, in organic cases, anterograde memory is usually not entirely normal, particular in the early stages. In other words, focal retrograde amnesia tends to be relative in organic disorders but appears absolute in hysterical amnesia.43
K E Y
P O I N T S
●
Conscious long-term memory in humans is divided into memory for specific events (episodic memory) and memory for general knowledge and facts (semantic memory).
●
Working memory is a short-term memory system that allows the mind to keep information in continuous consciousness (“on line”). It is important for clinicians to understand how this system differs from long-term memory in order to accurately classify deficits.
●
The term amnesia refers to a severe inability to establish and/or recall long-term memories, with preservation of working memory.
56
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
●
Most patients who seek medical advice for symptoms of memory failure do not have frank amnesia but, nevertheless, may have organic impairment in long-term memory. Accurate diagnosis in such cases is facilitated by (1) taking a corroborative history from an informant and (2) having a problem-oriented, structured plan for memory examination.
●
Acute or rapidly evolving amnesia is a medical emergency for which the clinician must have a clear understanding of the differential diagnosis, because immediate empirical therapy offers the best hope of avoiding long-term disability.
Suggested Reading Dudai Y: Memory from A to Z. Keywords, Concepts and Beyond. Oxford, UK: Oxford University Press, 2002. Kopelman MD: Disorders of memory. Brain 2002; 125:2152-2190. Nestor PJ, Scheltens P, Hodges JR: Advances in the early detection of Alzheimer’s disease. Nat Med 2004; 5:S34-S41. Rogers TT, Plaut DC: Connectionist perspectives on categoryspecific deficits. In Forde E, Humphreys G, eds: Category Specificity in Brain and Mind. Brighton, UK: Psychology Press, 2002, pp 251-289. Squire LR, Zola SM: Episodic memory, semantic memory, and amnesia. Hippocampus 1998; 8:205-211. Tulving E, Craik FM, eds: The Oxford Handbook of Memory. New York: Oxford University Press, 2000.
References 1. Tulving E, Kapur S, Craik FI, et al: Hemispheric encoding/retrieval asymmetry in episodic memory: positron emission tomography findings. Proc Natl Acad Sci U S A 1994; 91:2016-2020. 2. Baddeley A: Working memory. Science 1992; 255:556-559. 3. Hayashi Y, Majewska AK: Dendritic spine geometry: functional implication and regulation. Neuron 2005; 46:529-532. 4. Nadel L, Moscovitch M: Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 1997; 7:217-227. 5. Vargha-Khadem F, Gadian DG, Watkins KE, et al: Differential effects of early hippocampal pathology on episodic and semantic memory. Science 1997; 277:376-380. 6. Manns JR, Hopkins RO, Squire LR: Semantic memory and the human hippocampus. Neuron 2003; 38:127-133. 7. Kensinger EA, Schacter DL: Emotional content and realitymonitoring ability: fMRI evidence for the influences of encoding processes. Neuropsychologia 2005; 43:1429-1443. 8. Moscovitch M: Memory and working-with-memory: a component process model based on modules and central systems. J Cogn Neurosci 1992; 4:257-267. 9. Jovin TG, Vitti RA, McCluskey LF: Evolution of temporal lobe hypoperfusion in transient global amnesia: a serial single photon emission computed tomography study. J Neuroimaging 2000; 10:238-241. 10. Zeman AZ, Boniface SJ, Hodges JR: Transient epileptic amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatry 1998; 64:435-443. 11. Blake RV, Wroe SJ, Breen EK, et al: Accelerated forgetting in patients with epilepsy: evidence for an impairment in memory consolidation. Brain 2000; 123(Pt 3):472-483.
12. Scoville WB, Milner B: Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957; 20:11-21. 13. Zola-Morgan S, Squire LR, Amaral DG: Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 1986; 6:2950-2967. 14. Bohbot VD, Kalina M, Stepankova K, et al: Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex. Neuropsychologia 1998; 36:1217-1238. 15. Hodges JR, Carpenter K: Anterograde amnesia with fornix damage following removal of IIIrd ventricle colloid cyst. J Neurol Neurosurg Psychiatry 1991; 54:633-638. 16. Dusoir H, Kapur N, Byrnes DP, et al: The role of diencephalic pathology in human memory disorder. Evidence from a penetrating paranasal brain injury. Brain 1990; 113(Pt 6):16951706. 17. Abe K, Inokawa M, Kashiwagi A, et al: Amnesia after a discrete basal forebrain lesion. J Neurol Neurosurg Psychiatry 1998; 65:126-130. 18. McDonald CR, Crosson B, Valenstein E, et al: Verbal encoding deficits in a patient with a left retrosplenial lesion. Neurocase 2001; 7:407-417. 19. Rudge P, Warrington EK: Selective impairment of memory and visual perception in splenial tumours. Brain 1991; 114:349360. 20. McLean J, Manchip S: Wernicke’s encephalopathy induced by magnesium depletion. Lancet 1999; 353:1768. 21. Harding A, Halliday G, Caine D, et al: Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 2000; 123(Pt 1):141-154. 22. Darnell RB, Posner JB: A new cause of limbic encephalopathy. Brain 2005; 128:1745-1746. 23. Bak TH, Antoun N, Balan KK, et al: Memory lost, memory regained: neuropsychological findings and neuroimaging in two cases of paraneoplastic limbic encephalitis with radically different outcomes. J Neurol Neurosurg Psychiatry 2001; 71:40-47. 24. Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody–associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127:701-712. 25. Jha S, Patel R, Yadav RK, et al: Clinical spectrum, pitfalls in diagnosis and therapeutic implications in herpes simplex encephalitis. J Assoc Physicians India 2004; 52:24-26. 26. O’Connor M, Butters N, Miliotis P, et al: The dissociation of anterograde and retrograde amnesia in a patient with herpes encephalitis. J Clin Exp Neuropsychol 1992; 14:159178. 27. Warrington EK, Shallice T: Category specific semantic impairments. Brain 1984; 107:829-854. 28. Rogers TT, Plaut DC: Connectionist perspectives on categoryspecific deficits. In Forde E, Humphreys G, eds: Category Specificity in Brain and Mind. Brighton, UK: Psychology Press, 2002, pp 251-289. 29. Amieva H, Jacqmin-Gadda H, Orgogozo JM, et al: The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study. Brain 2005; 128:10931101. 30. McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease. Neurology 1984; 34:939944. 31. Petersen RC, Stevens JC, Ganguli M, et al: Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1133-1142.
chapter 4 disorders of memory 32. DeKosky ST, Ikonomovic MD, Styren SD, et al: Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002; 51:145-155. 33. Rinne JO, Kaasinen V, Jarvenpaa T, et al: Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003; 74:113-115. 34. Nestor PJ, Fryer TD, Smielewski P, et al: Limbic hypometabolism in Alzheimer’s disease and mild cognitive impairment. Ann Neurol 2003; 54:343-351. 35. McKeith IG, Galasko D, Kosaka K, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:1113-1124. 36. Grace J, Daniel S, Stevens T, et al: Long-Term use of rivastigmine in patients with dementia with Lewy bodies: an open-label trial. Int Psychogeriatr 2001; 13:199205. 37. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546-1554.
57
38. Hodges JR, Patterson K, Oxbury S, et al: Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain 1992; 115:1783-1806. 39. Nestor PJ, Graham KS, Bozeat S, et al: Memory consolidation and the hippocampus: further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia. Neuropsychologia 2002; 40:633654. 40. Hodges JR, Graham KS: A reversal of the temporal gradient for famous person knowledge in semantic dementia: implications for the neural organisation of long-term memory. Neuropsychologia 1998; 36:803-825. 41. Snowden JS, Thompson JC, Neary D: Knowledge of famous faces and names in semantic dementia. Brain 2004; 127:860872. 42. Kapur N, Ellison D, Smith MP, et al: Focal retrograde amnesia following bilateral temporal lobe pathology. A neuropsychological and magnetic resonance study. Brain 1992; 115(Pt 1): 73-85. 43. Kopelman MD: Focal retrograde amnesia and the attribution of causality: An exceptional critical view. Cogn Neuropsychol 2000; 17:585-621.
CHAPTER
5
HIGHER VISUOPERCEPTUAL DISORDERS AND DISORDERS OF SPATIAL COGNITION ●
●
●
●
Zoë Terpening and John D. G. Watson
At least one third of the primate brain is devoted to visual perception and visual processing.1 A vast amount has been learned about the visual system in the past 100 years or so, from both laboratory studies and studies of clinical and healthy populations. This research has identified multiple areas in the cerebral cortex (not just the occipital lobe) that receive visual input (Figs. 5–1 through 5–3). There is both parallel and distributed processing of visual stimuli. One of the most famous depictions are the diagrams of Van Essen and colleagues,2 which map the macaque cerebral cortex (Fig. 5–1). The term higher visuoperceptual disorders carries the implication of abnormalities at the level of the thalamus and above, with the majority of cases arising from diseases of the cerebral hemispheres. Many disorders of higher visuoperceptual function have been described, some of them in syndromic fashion, and include Balint’s syndrome, cerebral akinetopsia (rare), cerebral dyschromatopsia (somewhat more common), disorders of face recognition (prosopagnosia), environmental disorientation (which overlaps with spatial disorientation: see also Chapter 6), and visual agnosias. Even one of the rarer language disorders may be thought of as a primary visual disturbance: alexia without agraphia (see Chapter 3). Higher-order visual complaints are often one of the first indications of a number of other neurological illnesses such as prion diseases. All these entities are of interest in their own right and may lead to significant morbidity. They are commonly not initially recognized, which causes further distress and difficulty for the patients, their families, and those who interact with them on a daily basis, such as work colleagues and health professionals.
EPIDEMIOLOGY Many of the diseases that underlie these abnormalities are age related—in particular, the dementias and cerebrovascular disease—so these entities are more frequent in older persons and are increasingly commonly encountered as the population ages. Within the neurodegenerative disorders, using Alzheimer’s disease as the prototype, estimates for the prevalence of higher-order visual disturbances are as high as 57%,
mainly because of a high prevalence of visual agnosia. The severity of the dementia is strongly correlated with the complexity of the presenting visual disturbance.3 The effects of these higher visuoperceptual disorders are amplified by other disorders of perception that may be present in older people, including visual loss because of anterior visual pathway disease (e.g., cataract, macular degeneration) and impairments of hearing and mobility. Studies have suggested that of people between the ages of 75 and 79, at least 12% have some visual impairment, rising to 23% in the 85- to 89-yearold age range.4 By 90 years of age, at least one in three people will have some visual deficit.4,5
THE TWO-SYSTEMS APPROACH TO HIGHER VISUOSPATIAL FUNCTIONING Higher visual processing attempts to achieve two primary objectives: the identification of visual stimuli and their localization in space. These two goals of visual analysis are often abbreviated as “what” and “where” (Fig. 5–4). Research has demonstrated that these two goals are achieved relatively independently through two anatomically separated systems known as the ventral (what) and dorsal (where) visual processing pathways.6-8 The fundamental concept is that there is a dorsal stream of information concerned with an object’s location and a ventral stream concerned with its identity. Because this distinction is so widespread in the literature, it must be considered, but even the proponents of this dualistic model freely admit that it is an oversimplification of the true situation, given that strong interactions occur between the two networks. We use this dichotomy in the current chapter to help distinguish higher visual disorders that are primarily deficits of visuoperception from those that are largely visuospatial in nature.
ANATOMY AND PHYSIOLOGY In general, higher visuoperceptual and visuospatial disorders reflect damage to one or several multiple brain regions includ-
59
60
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s Medial prefrontal 25
32 24
PSd 23 29
SMA MEF Motor
PO
4
MIP 5 PIP
VIP LIP
14
9 46
30 MDP
V2d V3
10
Somatosensory
6 FEF 45
3a 2 1 3b
Pall
Lateral prefrontal 12 11
13 SII Id G Pro Pall 7a PA Ig AI V3A DP MSTd CM RL Orbitofrontal L V4t M PIR T MSTi Auditory STPP FST Pac PITd STPa Olfactory CITd PITv ER AITd VOT 35 CITv AITv V4v VP 36 TF V2v ER Subicular TH 7b
Ri
V1
PSv
Disorders of the Temporal Vision–Related Cortex (Ventral Processing Stream) Damage to the cortical regions of the ventral processing stream results in a variety of disturbances of visual form and color perception (Table 5–1). These can include dyschromatopsia and alexia without agraphia. Most commonly, however, damage to these regions results in a form of visual agnosia, a clinical syndrome characterized by an inability to recognize a visually presented object despite the presence of adequate cognition, visual acuity, attention, and language skills.11,12 Agnosias are commonly subdivided on the basis of a distinction made by Lissauer,13 who posited in 1890 that the process of recognition has two distinct stages: apperception and association. Apperception is the ability to form a conscious percept of a sensory impression (e.g., an object), which can be thought of as the construction of different visual attributes of
Figure 5–1. Flattened map of cortical areas in the macaque. The locations of multiple visual areas are shown in colors that indicate whether they are in the occipital lobe (purple, blue, and reddish hues), parietal lobe (yellow, orange, and light brown hues), temporal lobe (green hues) or frontal lobe (dark brown hues). Note how much of the cerebral cortex is devoted to processing of visual information. The scale applies only to the flattened map; the brain drawings are much smaller. The abbreviations and numbers refer to discrete areas of cortex—refer to the original publication for a full explanation. (From Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1991; 1(1): 1-47. Reproduced by permission of Oxford University Press.)
CA3 CA1
ing (but not restricted to) the occipital lobes, temporal lobes, parietal lobes, and underlying white matter. In many of the described syndromes, the right hemisphere appears to be more affected than the left, with many investigators proposing that much of the bilateral activation on higher visual tasks results from the transcallosal influence of the right hemisphere.9,10 The precise nature of the damage for each particular disorder is discussed in the following sections.
■
1 cm
the stimulus into a whole percept. Patients who present with these difficulties are said to have the syndrome of apperceptive agnosia, sometimes referred to as apperceptive visual object agnosia.12 Association, on the other hand, refers to the imparting of meaning to the percept, achieved through the use of matching or linking the percept to a previous experience or knowledge.13 Patients with association difficulties, who are said to have the syndrome of associative visual agnosia, often have difficulty accessing the memory of an object’s name or its meaning from the visual stimulus, despite a more or less correctly perceived visual percept, and demonstrably intact knowledge (if accessed via other modalities) of the object’s name and semantic attributes. Visual agnosias are often further classified on the basis of the categorical impairment such as prosopagnosia (agnosia for faces), environmental agnosia (agnosia for topographical orientation), and color agnosia.
Dyschromatopsia and Color Anomia Dyschromatopsia is a rare acquired inability to discriminate colors by hue.14 Dyschromatopsia is most often associated with damage to the inferior part of the occipital lobes, in the fusiform gyrus. This corresponds to the area identified in functional experiments as the human color area (V4).15,16 Patients usually have difficulty in tasks such as sorting sets of colored
chapter 5 higher visuoperceptual disorders ■
HC ER TF
46
36
TH
STPa 7a
7b
VIP
FEF
LIP
MSTl
MSTd
STPp
CITo
FST
PITd
VO
DP
MDP
PO
MIP
V4t
MT
PIP
61
Figure 5–2. Hierarchy of visual areas in the macaque. This diagram shows over 30 visual cortical areas, shaded similarly to Figure 5–1, two subcortical visual stages— the retinal ganglion cell layer (RGC) and the lateral geniculate nucleus (LGN), plus several non-visual areas such as area 7b of the somatosensory cortex, area 36 and the hippocampal complex (HC). These areas are connected by extensive linkages, most of which have been demonstrated to be reciprocal pathways. The patterns of connections help to illustrate two fundamental principles of organization: hierarchical connections and parallel processing. (From Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1991; 1:1-47.)
V4
V3A
V3
VP M
V2
P-B P-I
M
V2
P-B P-I
M
P
LGN
M
P
RGC
T A B L E 5–1. Summary of Clinical Presentation and Location of Lesion in the Temporo-Occipital Vision Disorders Condition
Description
Location of Lesion
Dyschromatopsia Color agnosia (and anomia)
Inability to distinguish colors by hue Inability to name colors despite being able to match and sort items by color Inability to read despite preserved ability to write
Inferior occipital lobe, occipitotemporal lobe
Inability to recognize familiar objects despite intact visual acuity, contrast sensitivity, and often color perception and stereopsis Sensory percept stripped of meaning Inability to recognize familiar faces Inability to recognize familiar environments
Bilateral occiptotemporal lobes
Alexia without agraphia or pure alexia Apperceptive (object) Associative agnosia Prosopagnosia Environmental agnosia
counters. Hemidyschromatopsia may be more common; reflecting the location of damage, there is often an associated superior quadrantanopia on the same side. Color anomia is a disorder in which patients present with an inability to name colors but are still able to sort colored counters and differentiate between colors despite failure to name them.17
Occipitotemporal lobes
Bilateral occiptotemporal lobes Bilateral (but right > left) occipitotemporal lobes Right occipitotemporal lobes
Alexia Without Agraphia Alexia without agraphia (or pure alexia) is an acquired reading disorder in which the patient is unable to read, despite preservation of other aspects of language such as spelling and writing.18 Pure alexia is usually caused by an occlusion of distal
62
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s monly manifests as an inability to separate the object from a confounding background (figure-ground discrimination) or to interpolate the contours of a fragmented object (visual closure). Patients with severe visual object agnosia are normally unable to name objects presented to them visually, such as an empty glass, but can usually do so with the assistance of additional cues such as being allowed to hold it or hearing the noise when a spoon is tapped on the side of the glass. Causative lesions are typically bilateral, in the occipitotemporal lobes. Isolated, severe cases of visual object agnosia are rare, and almost all have followed carbon monoxide or mercury poisoning. However, lesser degrees of visual object agnosia are commonly encountered, particularly in Alzheimer’s disease, and may also result from tumors, hypoxic/hypotensive brain damage, or stroke, usually in the posterior cerebral artery territory.
Associative Agnosia
■
Figure 5–3. Borders of multiple visual areas in humans revealed by functional magnetic resonance imaging. Several functionally defined visual areas (V1, V2, etc.) are displayed on the flattened cortex of the right hemisphere, viewed from behind. The positive sign denotes areas that correspond with the upper visual field, and the negative sign the lower visual field (although there is controversy relating to the properties of the ventrally placed color area, V4). The brightness of the areas represents the significance of the responses. Note that there are many visually responding areas that are not yet further typified. (From Sereno MI, Dale AM, Reppas JB, et al: Borders of multiple visual areas in human revealed by functional magnetic resonance imaging. Science 1995; 268:889-893.)
(posterior) branches of the left posterior cerebral artery. The resultant damage is believed to interrupt the transfer of neural information from the visual cortex to the language cortex. Stroke is one of the most common causes of pure alexia, but more rarely it may result from closed head injury, tumor, occipital lobectomy, arteriovenous malformations, and Alzheimer’s disease. Further details are given in Chapter 3, Disorders of Language.
Apperceptive Visual Agnosia: Visual Object Agnosia Visual object agnosia is an inability to recognize familiar objects from their visual shape attributes despite preservation of visual acuity, contrast sensitivity, and often color perception and stereopsis. This failure of object recognition can be attributed to impaired perception, which may be severe enough to prevent matching or copying of simple shapes, but more com-
Those patients with associative agnosia have apparently preserved sensory capability and may retain the ability to match and copy common objects but still fail to recognize them. Such cases led Teuber19 in 1968 to describe this as “a normal percept that has somehow been stripped of its meaning.” Some patients may have their problem limited to a specific class of objects, of which the best known is prosopagnosia—the failure to discriminate and recognize faces. Other object classes with which specific difficulties have been reported include animals or animal species, plants, foods, clothing, makes of cars, colors, or places. Some examples are discussed in the following paragraphs. The cerebral lesions are in areas similar to those causing apperceptive agnosia but have occasionally been linked to more diffuse cerebral damage such as hypoxic/ischemic brain damage or carbon monoxide poisoning and progressive multifocal leukoencephalopathy.
Associative Visual Agnosia for Familiar Faces: Prosopagnosia Prosopagnosia is characterized by an inability to identify familiar faces. Patients may correctly identify the emotion but still fail to identify the face. Given that differences between faces are subtle, the patient with prosopagnosia has difficulty telling them apart but might be able to do so if there is a highly salient feature such as a birthmark or beard. The patient is often able to recognize familiar people from other attributes, such as gait, clothes, or voice. The particular attributes of faces and the task of their recognition are much debated in the literature, but it seems likely that face recognition requires some abilities that do not overlap with other visual recognition abilities. A number of studies have been made of the ability to recognize faces in the normal, upright orientation in a type of gestalt perception, compared with recognizing faces that are upside-down. The latter is a very much harder task for normal subjects and involves different (feature-by-feature rather than whole-object) visual processing. It is intriguing that some prosopagnosics do not have this face inversion effect and, paradoxically, may perform better with inverted faces, suggesting a specific deficit in whole-object processing.20 Prosopagnosia is usually caused by more anterior lesions in the inferior occipitotemporal cortex (the anterior aspects of the lingual and fusiform gyri).21,22 In most cases, bilateral damage
chapter 5 higher visuoperceptual disorders ■
63
Figure 5–4. Network analysis of cortical visual pathways represented graphically for object and spatial visual networks in the right hemisphere. The magnitude of the direct effect (which can vary between −1 and +1) is proportional to the arrow width for each path, with values given in the scale below. Positive path coefficients are shown in solid arrows, and negative in dashed arrows. Paths where the coefficient was at or near zero are shown as dotted lines. The relative location of the brain regions is distorted somewhat to maintain figure clarity. (From McIntosh AR, Grady CL, Ungerleider LG, et al: Network analysis of cortical visual pathways mapped with PET. J Neurosci 1994; 14:655666.)
is described, but some cases have occurred with just a rightsided lesion. This damage is most commonly a result of stroke, tumors, demyelination, or degenerative atrophy. Many face recognition studies on normal subjects have been carried out using functional brain imaging techniques. Haxby and colleagues8 provided some of the key experiments, initially with positron emission topography and then with functional magnetic resonance imaging. Figure 5–5 is an example of the type of stimulus used for these experiments. Figure 5–6 shows the activation along the inferior occipitotemporal cortex in such a face-matching experiment.23
Associative Visual Agnosia: Environmental or Topographical Agnosia Environmental agnosia, also referred to as topographical disorientation, is an inability to recognize the features or landmarks of a familiar place or region, such as one’s town or even one’s home. Environmental agnosia is associated with lesions in the right medial occipitotemporal region. Unlike the other agnosias, formal testing is not usually required for diagnosis; although disorders such as visual hemineglect may affect navigational tasks, they rarely manifest the profound disorientation observed in this disorder (see Table 5–1).
Disorders of the Parietal Vision–Related Cortex (Dorsal Processing Stream) Damage to the parietal vision–related cortex commonly results in impairments of the perception, location, and manipulation of items in space (Table 5–2). These can include hemispatial neglect, Balint’s syndrome, impaired spatial relations, and akinetopsia.
Hemispatial Neglect Hemispatial neglect is said to be present when patients fail to respond, report, or act on meaningful stimuli that are presented to the side contralateral to a brain lesion. This deficit cannot be attributed to sensory or motor deficits and usually
■
Figure 5–5. Stimuli used in the prior positron emission tomography study and current functional magnetic resonance imaging study. A sample stimulus item used in the face-matching task is shown at left; the sensorimotor control stimulus is shown at right. For the face-matching task, the subject indicated whether the right or left test face was the same individual as shown in the upper sample stimulus (right in this case). For the sensorimotor control condition, the subject responded to the left or right, in alternating order, on each presentation of this stimulus. (From Haxby JV, Horwitz B, Ungerleider LG, et al: The functional organization of human extrastriate cortex: a PET-rCBF study of selective attention to faces and locations. J Neurosci 1994; 14:6336-6353.)
results from unilateral lesions of the posterior parietal region, although other critical regions have also been identified. This disorder is discussed in detail in Chapter 6.
Balint’s Syndrome Patients with Balint’s syndrome usually present with a triad of features—optic ataxia, oculomotor gaze apraxia, and simultanagnosia/visual inattention—as a result of bilateral damage to the parieto-occipital regions. Causes include strokes, tumor, trauma, Creutzfeldt-Jakob disease, diffuse cerebral hypotension/hypoxia, Alzheimer’s disease (especially its posterior cortical atrophy variant),24-26 and human immunodeficiency
64
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 5–2. Summary of Clinical Presentation and Location of Lesions in Parieto-occipital Vision Disorders Condition
Description
Location of Lesion
Hemispheric neglect
Patients fail to respond to, report, or act on meaningful stimuli that are presented to the side opposite a brain lesion Triad of symptoms of optic ataxia, oculomotor apraxia, and visuospatial inattention (simultanagnosia) Inability to guide limbs visually Inability to execute purposeful eye movements Inability to perceive entire picture or integrate separate parts Impaired spatial relations in which patients misestimate size, distance, shape, and orientation. Inability to detect motion
Unilateral parietal lobe (usually greater on right)
Balint’s syndrome Optic ataxia Oculomotor apraxia Simultanagnosia Impaired spatial relations Akinetopsia
Bilateral damage to the parieto-occipital region Bilateral parieto-occipital region Bilateral parieto-occipital region Bilateral parieto-occipital region Bilateral parieto-occipital region Damage to the human visual motion area (V5/MT)
arm’s length). The second component of Balint’s syndrome is oculomotor gaze apraxia, also called psychic paresis of gaze, which is a defect of volitional pursuit movements and saccadic movements to visual targets, not attributable to visual inattention, in the presence of preserved spontaneous and reflexive saccades. Completing the triad is visual inattention (or simultanagnosia), which is a reduced ability to detect more than one visual object at the same time, regardless of size. The most common complaints that might flag such a diagnosis included persistent complaints of bumping into things, “tunnel vision,” and reading difficulties. Impaired spatial relations are also found in this syndrome, including difficulty in estimating the size, distance, orientation, and shape of objects.
Environmentally Impaired Spatial Relations Commonly a result of biparieto-occipital lesions, these patients present with a disordered perception of spatial relations. They often report walking into furniture and misreaching for objects because they cannot judge the distance to the item.
■
Figure 5–6. Whole-head reconstruction of S5 showing right sagittal cut-away view with statistical results reconstructed from posterior coronal EPI images. Regions with larger signal intensities during the face-matching task relative to control are shown. The focal signal increase in the ventral pathway is located in the inferior occipital sulcus and the fusiform gyrus. (From Clark VP, Keil K, Maisog JM, et al: Functional magnetic resonance imaging of human visual cortex during face matching: a comparison with positron emission tomography. Neuroimage 1996; 4:1-15.)
virus–associated encephalitis. Optic ataxia refers to the inaccurate reaching for a stationary object in extrapersonal space, and although it usually manifests concurrently with oculomotor gaze apraxia and simultanagnosia, it may exist independently. The differential diagnosis includes cerebellar ataxia and proprioceptive deficits. The distinction can usually be made by comparing the reaching inaccuracy to an object in the patient’s own space (e.g., his or her nose) with that to an item that is specifically extrapersonal (e.g., the examiner’s finger held at
Akinetopsia Akinetopsia is an inability to detect motion, so that a moving object such as a car will appear to “jump” from one stationary position to another. Compared with the other higher visuospatial disorders, cases of cerebral akinetopsia are very rare. The human visual motion area (V5/MT) has been identified to lie in the lateral cortex at the junction of the occipital, parietal, and temporal lobes (Fig. 5–7).27 The only two cases of akinetopsia from bilateral lesions have been well described in the literature.28,29
DIAGNOSIS As with much of clinical medicine, and in particular clinical neurology, a detailed history is of paramount importance in achieving an accurate diagnosis of higher visuoperceptual and visuospatial spatial disorders. Indeed, despite the descriptions of the classical, “pure” syndromes in the previous section, such isolated deficits are distinctly uncommon, and patients more usually present with elements of two or more of these syn-
chapter 5 higher visuoperceptual disorders
■
65
Figure 5–7. The human visual motion area (V5/MT) has been identified to lie in the lateral cortex at the junction of the occipital, parietal, and temporal lobes. (From Watson JDG, Myers R, Frackowiak RSJ, et al: Area V5 of the human brain: evidence from a combined study using positron emission tomography and magnetic resonance imaging. Cereb Cortex 1993; 3(1):79-94. Reproduced by premission of Oxford University Press.)
dromes. Many patients may be dismissed as having psychiatric conditions. A number of patients in our experience have been seen by optometrists and ophthalmologists and have been told that there was nothing wrong with their eyes, without the possibility of an organic process affecting the brain being considered. A clinical neurological examination should be performed, particularly directed at the visual system. With a little time and care, confrontation visual field testing can be most informative about the nature of any visual field defect, particularly in cases of quadrantanopia or hemianopia. (It is worth noting that standard implementations of automatic computerized visual field testing may not be very helpful in some instances.) Color recognition and naming are easy to test. Object recognition (describing visually presented objects, matching objects in arrays, copying drawings of objects, identifying overlapping or fragmented objects, displaying verbal knowledge of objects, naming by tactile or auditory information) can be tested at the bedside
or in the clinic, and one can also attempt a simple but systematic assessment of prosopagnosia (descriptions of faces, recognition and naming of faces, facial matching, verbal knowledge of familiar and famous people, identifying people through other modalities such as voice, gait, or perfume smell). With access to a clinical neuropsychology service, especially with research facilities, such patients can be more readily assessed in greater detail (see screening battery in the following section for more specific tests for each disorder). Cerebral imaging may be useful, including computed tomography and particularly magnetic resonance imaging. This may show generalized or focal atrophy, evidence of nonfocal and/or discrete cerebral ischemic changes, space occupying lesions such as tumors or abscesses, or even the characteristic appearances of Creutzfeldt-Jakob disease (especially on diffusion-weighted images). Other forms of cerebral imaging that may help include single-photon emission computed tomography and positron emission tomography scans,
66
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 5–3. Neuropsychological Tests Used to Assess Visuoperceptual, Visuospatial, and Visuoconstructional Abilities Visuoperceptual
Visuospatial
Visuoconstructional
Benton Visual Form Discrimination Test Hooper Visual Organization Test Embedded Figures Test Visual Object and Space Perception Battery Benton Facial Recognition Test
Line Bisection Test Mesulam’s Cancellation Test Benton Judgment of Line Orientation Visual Object and Space Perception Battery
Clock drawing test (Addenbrooke’s Cognitive Examination) Rey-Osterrieth Complex Figure Test Block Design Test (Wechsler Adult Intellegence Scale)
although the latter are often not as accessible or affordable. Patients with such disorders may from time to time also undergo electroencephalograms and visual evoked responses, but in our experience these are not often helpful.
Diagnostic Pitfalls It is always helpful to bear in mind a hierarchy of neurological function when testing perception. An integrative higher visual disorder is difficult to diagnose reliably unless attention, cognition, language, and elementary vision are reasonably intact. Delirious patients often present with false localizing cortical signs (easy to recognize when the delirium is florid but much harder when there is a “quiet delirium”). If a patient presents with concurrent depression or advanced dementia, it may be difficult to diagnose an agnosia reliably without careful consideration of the potential confounding effects of these disorders on visuoperceptual testing. It is also important to remember that many of these disorders should be demonstrably limited to the visual sensory modality. For example, a patient presenting with visual object agnosia should be unable to recognize an object by sight but able to recognize the object when other cues such as touch or sound are introduced. If the clinician fails to assess this second step in diagnosis when the patient is unable to name visually presented objects, it might be incorrectly concluded that the patient has an anomia, resulting in the underlying problem being missed. In our experience, a common pitfall in diagnosis, perhaps surprising given the importance of visual function in day-today life, is that a patient’s complaints and/or disability may not be immediately recognized as essentially visuospatial in nature. This is compounded by the commonly observed fact that patients with visual field deficits may be unaware of them. For example, in the history taking, difficulties with dressing are often mentioned by the patient, family members, or nursing staff. This loosely named “dressing apraxia” may also be observed as a sign if the patient is in the hospital. Dressing difficulties may be sought by asking the patient to put on an item of clothing for the upper body, such as a shirt, blouse, or pullover, that has been turned inside out. Such difficulties are often not apraxic at all but instead arise from visuospatial impairments such as neglect.
variety of normed tests. These can be classified according to whether they focus on visuoperceptional, visuospatial, or visuoconstructional impairments (Tables 5–3 and 5–4).
Assessment Strategies for the Non–neuropsychologist While a neurologist frequently requests a neuropsychological assessment to assess visual impairments formally, in the context usually of a dementia, there are simple ways to screen for suspected disorders within the course of a neurological examination.30 The commonly used screening instrument for dementia, the Folstein Mini-Mental State Examination (MMSE), is inadequate for an assessment of this type. The only test items in this or in similar screening examinations that are especially relevant to higher visuoperceptual and visuospatial disorders are the copying of the interlocking pentagons and cube, the drawing of a clock face, the naming of objects such as the watch and pencil, the reading and subsequent carrying out of a simple command, and the writing of a sentence (although the last is more relevant to language testing). One can also examine for neglect phenomena (see Chapter 6) by asking the patient to copy diagrams, bisect lines, draw and copy a clock, and search for a target or targets in an array of shapes or letters (Fig. 5–8). The more complex copying of the Rey-Osterrieth figure is extremely sensitive to higher visuoperceptual and visuospatial disorders (Figs. 5–9 and 5–10). It has the advantage of a scoring system, with norms being widely available. Object recognition can be tested by having people name and describe visually presented objects, match objects out of an array, and copy and spontaneously draw objects. The patient’s verbal knowledge of named objects and ability to name objects by touch or other sensory inputs rather than sight should also be checked, to ensure that difficulties with visual recognition are not merely manifestations of a broader dissolution of semantic knowledge about the objects, rather than a visual agnosia. These functions can be more formally assessed by a number of neuropsychological tests.
TREATMENT AND ASSISTANCE A Screening Battery for Detecting and Diagnosing Disorders of Higher Visual Function Neuropsychologists have a wide range of specialized tools for assessing particular aspects of higher visual disorders, with a
The first important task of the clinician in this situation is to make a diagnosis or institute steps that will lead to a diagnosis; the condition must be recognized for what it is, delineated, labeled appropriately, and explained to the patient, family members, and others. If investigations demonstrate a
chapter 5 higher visuoperceptual disorders
67
T A B L E 5–4. Screening Battery for Higher Visual Disorders for the Neurologist Disorder
Practical Screening Batteries for the Differential Diagnosis
Dyschromatopsia
Ask the patient to name colors presented to them. Those with dyschromatopsia will fail this task. Ask the patient to read Ishihara color plates. Patients with the more severe cases of dyschromatopsia will have difficulty on this task. Ask the patient to match colored counters (Farnsworth tests). Patients will generally have difficulty with this task if they have dyschromatopsia. Ask the patient to name colors presented to them. They should be unable to do this. Ask the patient to match colored counters. Unlike patients with dyschromatopsia, they will be able to complete the task. Ask the patient “What color is the sky?” and similar questions. The patient will be able to give the correct answer. Ask the patient to color in a picture giving them colored pens. If the patient colors with appropriate colors (e.g., a tree trunk as brown) he is more likely suffering from color anomia. If unable to do so, the differential diagnosis includes color agnosia. Ask the patient to read a paragraph from a magazine or newspaper, progressing down to single words and letters; if impaired, proceed to Step 2. Ask the patient to trace the letters and try to identify each of them. Someone with alexia without agraphia should be able to identify them by tracing. Hold up an object such as glasses or a stopwatch and ask patients to name the object. Those with visual agnosia will be unable to do so. Ask the patient to mime an object’s use (e.g., a toothbrush or hammer). He will generally be unable to mime the object’s use. Give the object to the patient to hold, and ask the patient to name it. Those with visual agnosia will be able to name the object with the help of perceptual cues. Formal neuropsychological testing is usually required to determine the specific type of visual agnosia. Ask the patient to identify pictures of famous people from a magazine or other pictures. A patient with prosopagnosia will have difficulty naming famous people. If the patient is able to name family members, ask a spouse or family member to wear an unusual item such as large glasses and a hat and return to the room without speaking. Failure to identify the family member is strongly suggestive of prosopagnosia. Family members report disorientation and confusion in familiar places or areas. Exclude hemispatial neglect. Ask the patient to copy a simple drawing of a house or tree. A patient with true hemispatial neglect will generally fail to draw a particular side of the picture or will only draw one part of the object. Ask the patient to search for a target or targets in an array of shapes or letters. Patients with hemispatial neglect will miss targets in the affected part of their visual field. Simultagnosia: Ask the patient to describe what is going on in a complex picture or copy a complex drawing (such as the Rey figure). A person with simultagnosia will tend to focus on one small area and is generally unable to integrate the parts of the picture into the whole. Optic ataxia: Ask the patient to reach out or point to a target object in space. A patient with optic ataxia will be unable to do this accurately, a form of visual disorientation. Oculomotor apraxia: Observe the patient’s gaze while the patient is asked to make voluntary eye movements in different directions. Ask the patient to draw a clock face with the hands at a particular time. A patient with impaired spatial relations will have difficulty arranging the hands, circle, and numbers. One must always remember impaired semantic function (such as in Alzheimer disease or focal lobar atrophy of the temporal lobes) can affect such tasks as drawing a clock in a similar way. Ask the patient to complete a simple maze task. Patients with impaired spatial relations will have trouble staying within the lines and completing the task. Patient reports seeing the world in “snapshots” or as if strobe lighting is present. Ask the patient about difficulties in crossing the road, anticipating speeds of cars, and so on.
Color anomia/color agnosia Color agnosia
Alexia without agraphia
Visual agnosia
Prosopagnosia
Environmental agnosia Hemispatial neglect
Balint’s syndrome
Impaired spatial relations
Akinetopsia
treatable cause (e.g., a tumor), then correct treatment should be implemented.
Driving The next responsibility is to arrange appropriate driving assessment. Driving may already be quite dangerous for such people, and early recognition of this is very important. Unfortunately, advice to cease driving is often met by considerable resistance from patients, including the elderly (and sometimes their non-driving partners). Being able to drive is a
badge of independent adulthood and a central part of modern life, particularly in Western countries. In our experience the patient and/or spouse or other close relative may report problems such as not being able to reverse properly, hitting objects such as other cars when parking or driving into and out of garages, failing to stop at the end of the garage, and more general spatial difficulties while driving. In cases of doubt or dispute, an on-road driving test (where available), conducted by a specially trained occupational therapist in a dual control car, may be useful in identifying and documenting such difficulties.
68
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
A
C
B ■
Figure 5–8. A copy of pentagons (A) and a cube (B) and drawings of a clock face (C) by a 59-year-old man with moderate Alzheimer’s disease and posterior cortical atrophy.
Compensatory Techniques for Patients With Visual Agnosias Patients with visual object agnosia benefit by complementing visual with tactile/auditory stimuli where possible. For patients with prosopagnosia, strategies for helping the individual to identify people by nonfacial cues such as presence or lack of a beard, the voice, clothing, and environment combined with instructions to family and hospital staff to identify themselves in conversation can be particularly helpful for the patient. Agnosia for more specific items, such as clothing or cars, can be overcome to some extent by simple practical strategies such as labeling all the patient’s clothes or getting them to memorize the car’s location or license plate. These strategies may help patients remain independent. Topographical disorientation can be more difficult to ameliorate, but helping the patient to understand the safety issues involved, such as trying not to travel or drive alone and using verbal instructions for travel, and practical solutions, such as marking
routes that are commonly traveled around the house using colored dots, can often help. Agencies that help and train or retrain the blind and vision impaired may offer practical assistance and should always be involved in the care of such patients.
CONCLUSIONS The identification and diagnosis of higher visuoperceptual and visuospatial disorders can be challenging and arduous tasks, given the overlapping symptomatology of many of the entities. “Pure” (classical) cases are rarely seen, and it is more important to untangle the myriad of complaints reported by such patients to establish the range of impaired and preserved functions than it is to attempt to pigeonhole them into a particular syndrome. This allows the clinician to implement compensatory strategies or contact with support agencies that can improve the patient’s quality of life.
chapter 5 higher visuoperceptual disorders
B
A ■
Figure 5–9. A copy of the Rey complex figure (A) and drawing of a house (B) by a patient with simultagnosia. He is unable to combine the parts to form the whole and produces a segmented drawing, unable to locate and integrate each part in space. In B the parts of the house are, from left to right, a wall, the roof, a door, another roof with a driveway immediately below.
69
70
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s ●
One of the most important issues in Western society in general and for the aging population in particular is early recognition of difficulties in driving.
●
Many patients with higher visuoperceptual disorders and disorders of spatial cognition, even those with apparently relatively mild problems, are probably not safe drivers.
Suggested Reading Farah MJ: Visual Agnosia, 2nd ed. Cambridge: MIT Press/Bradford Books, 2004. Heilman KM, Valenstein E (eds): Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003. Barton JJS, Rizzo M (eds): Vision and the Brain, Parts 1 and 2. Neurologic Clinics, Vol. 21, parts 2 and 3. Philadelphia: WB Saunders, 2003.
References
■
Figure 5–10 A copy of the Rey complex figure in a patient presenting with higher visual impairments who produces what appears to be an almost mirror image of the original figure.
K E Y
P O I N T S
●
These disorders are not as uncommon as is commonly believed, and they lead to intriguing cognitive difficulties and practical problems, although pure, classical cases are rare.
●
These disorders may not be recognized initially for what they are, and they are often misdiagnosed by primary care practitioners, optometrists, and ophthalmologists. People with such disorders may be referred to psychiatrists before the final diagnosis is reached.
●
Underlying diseases include dementias (particularly of the Alzheimer and Lewy body types), cerebrovascular disease, tumors, and encephalitis.
●
Apart from treating the underlying condition (e.g., tumor), there are not many specific therapies available. Often, one must resort to teaching the patient compensatory strategies, but even these can sometimes be unhelpful.
1. Sereno MI, Dale AM, Reppas JB, et al: Borders of multiple visual areas in human revealed by functional magnetic resonance imaging. Science 1995; 268:889-893. 2. Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1991; 1:1-47. 3. Mendez MF, Mendez MA, Martin R, et al: Complex visual disturbances in Alzheimer’s disease. Neurology 1990; 40:439-443. 4. Evans R, Fletcher AE, Wormald RPL, et al: Prevalence of visual impairment in people aged 75 years and older in Britain: results from the MRC trial of assessment and management of older people in the community. Br J Ophthalmol 2002; 86:795800. 5. Taylor HR, Keeffe JE, Vu HT, et al: Vision loss in Australia. Med J Aust 2005; 182:565-568. 6. Ungerleider LG, Haxby JV: “What” and “where” in the human brain. Curr Opin Neurobiol 1994; 4:157-165. 7. Haxby JV, Grady CL, Horwitz B, et al: Dissociation of object and spatial visual processing pathways in human extrastriate cortex. Proc Natl Acad Sci U S A 1991; 88:1621-1625. 8. Haxby, J. V, Horwitz, B, Ungerleider, L. G, et al: The functional organization of human extrastriate cortex: a PET-rCBF study of selective attention to faces and locations. J Neurosci 1994; 14:6336-6353. 9. Horwitz B, Soncrant TT, Haxby JV: Covariance analysis of functional interactions in the brain using metabolic and blood flow data. In Gonzalez-Lima F, Finkenstaedt T, Scheich H (eds): Advances in Metabolic Mapping Techniques for Brain Imaging of Behavioral and Learning Functions. Dordrecht: Kluwer, 1992, pp 189-217. 10. McIntosh AR, Grady CL, Ungerleider LG, et al: Network analysis of cortical visual pathways mapped with PET. J Neurosci 1994; 14:655-666. 11. Bauer RM, Demery JA: Agnosia. In Heilman KM, Valenstein E (eds): Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 236-295. 12. Farah MJ: Visual Agnosia: Disorders of Object Recognition and What They Tell Us About Normal Vision. Cambridge: MIT Press, 1990. 13. Lissauer H: Ein fall von seelenblindheit nebst einem Beitrage zur Theori derselben [A case of visual agnosia with a contribution to theory]. Arch Psychiatr Nervenkrankheiten 1890; 21:222-270.
chapter 5 higher visuoperceptual disorders 14. Heilman KM, Valenstein E: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003. 15. Lueck CJ, Zeki S, Friston KJ, et al: The colour centre in the cerebral cortex of man. Nature 1989; 340:386-389. 16. Zeki S, Watson JDG, Lueck CJ, et al: A direct demonstration of functional specialization in human visual cortex. J Neurosci 1991; 11:641-649. 17. Denes G, Semenza C, Stoppa E, et al: Unilateral spatial neglect and recovery from hemiplegia: a follow-up study. Brain 1982; 105:543-552. 18. Warrington EK, Shallice T: Word-form dyslexia. Brain 1980; 103:99-112. 19. Teuber HL: Alteration of perception and memory in man. In Weiskrantz L (ed): Analysis of Behavioral Change. New York: Harper and Row, 1968. 20. Farah MJ, Tanaka JW, Drain HM: What causes the face inversion effect? J Exp Psychol Hum Percept Perform 1995; 21:628634. 21. Damasio AR, Damasio H, Van Hoesen GW: Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology 1982; 32:331-341. 22. Farah M, Levinson KL, Klein KL: Face perception and withincategory discrimination in prosopagnosia. Neuropsychologia 1995; 33:661-674.
71
23. Clark VP, Keil K, Maisog JM, et al: Functional magnetic resonance imaging (fMRI) of human visual cortex during face matching: a comparison with positron emission tomography (PET), Neuroimage 1996; 4:1-15. 24. Mendez MF, Ghajarania M, Perryman KM: Posterior cortical atrophy: clinical characteristics and differences compared to Alzheimer’s disease. Dementia Geriatr Cogn Disord 2002; 14:33-40. 25. Benson DF, Davis RJ: Snyder BD. Posterior cortical atrophy. Arch Neurol 1988; 45:789-793. 26. Caine D: Posterior cortical atrophy: a review of the literature. Neurocase 2004; 10:382-385. 27. Watson JDG, Myers R, Frackowiak RSJ, et al: Area V5 of the human brain: evidence from a combined study using positron emission tomography and magnetic resonance imaging. Cereb Cortex 1993; 3:79-94. 28. Zihl J, von Cramon D, Mai N: Selective disturbance of movement vision after bilateral brain damage. Brain 1983; 106:313340. 29. Vaina LM: Functional segregation of color and motion processing in the human visual cortex: clinical evidence. Cereb Cortex 1994; 45:555-572. 30. Hodges JR: Cognitive Assessment for Clinicians. Oxford: Oxford University Press, 1994.
6
CHAPTER
THE NEGLECT SYNDROME ●
●
●
●
Elsdon Storey
There are few more dramatic sights in clinical neurology than a patient ignoring one half of his or her environment, including one half of a meal, or insisting that a paretic left arm is entirely normal, while that held by the examiner must belong to someone else. These examples of severe neglect syndromes, manifest by spatial neglect, and personal neglect with anosognosia (denial of deficit), respectively, are uncommon and a suitable subject for medical literature.1 However, lesser degrees of the neglect syndrome are common, especially in right hemisphere stroke, and have an adverse effect on prospects for rehabilitation and function. Therefore, any practicing neurologist likely to encounter patients with acute or subacute hemispherical lesions—the typical cause of the neglect syndrome— must be aware of its possible manifestations and must be able to confirm their presence at the patient’s bedside. The neglect syndrome is a constellation of related lateralized deficits, including neglect of sensory stimuli; extinction of awareness of one sensory stimulus by another when both are delivered simultaneously; neglect of one half of an object or of space (recognizing that different reference points for “left” exist in this context); neglect of part of a person’s own body; failure to move a (nonparetic) body part as rapidly or persistently as its contralateral equivalent; and failure to recognize that the function of one part of the body is, indeed impaired.2 Although many of these features tend to occur together in individual patients, they are potentially dissociable, and each patient must have his or her own distinctive pattern of impaired and retained abilities elucidated and documented, to facilitate further monitoring, care, and rehabilitation. The neglect syndrome has proved to be a fruitful field for experimental neuropsychology and neuroimaging, and there has been considerable interest in practical techniques to ameliorate its effects, such as prism adaptation. This chapter attempts a broad overview of the area, concentrating on the clinical importance, phenomenology, and examination of neglect.
TERMINOLOGY AND PHENOMENOLOGY The various components of the neglect syndrome each have their own descriptive terms; because patients may exhibit a wide range of combinations of these individual deficits, it would be as inappropriate to lump these together as “neglect” as it would be to refer to all disorders of central language processes
as “aphasia” without further qualification. The reader interested in a more detailed exposition of each of the elements of the neglect syndrome is referred to Heilman and colleagues (2003). The following classification is somewhat arbitrary—for example, neglect dyslexia might conceivably also be regarded as a motor disorder, and spatial neglect might legitimately be considered “sensory”—but some form of organization, even imperfect, is probably useful in considering the wide range of deficits subsumed under “neglect”.
Sensory Aspects of the Neglect Syndrome Sensory Neglect Sensory neglect is said to exist when the patient is not consciously aware of or able to respond to a sensory stimulus contralateral to the lesion, in the absence of a deficit in the relevant sensory pathways or its cortical projections sufficient to prevent apprehension of the stimulus. This defect can be unimodal, but it may affect vision, touch, hearing, and even olfaction together. It can, of course, be difficult to determine whether a patient has neglect or a primary sensory disturbance. However, as pointed out by Heilman and colleagues (2003),2 the bilateral nature of the central auditory pathways makes the diagnosis of auditory neglect easy: A patient with unilateral deafness will hear a sound applied to their deaf side in their good ear if the sound is loud enough, and unilateral cortical lesions typically do not cause deafness. Complete hemianesthesia is uncommon with hemispherical lesions, apart from those involving the thalamus. A patient with a thalamus-sparing cortical lesion who has hemianesthesia probably actually has sensory neglect. The olfactory pathways are uncrossed. Hemianopia, particularly hemianopia plus neglect, is the most difficult to distinguish from hemineglect alone.2,3 Patients with hemianopia without neglect are often aware of and compensate for their deficit, deliberately scanning into their area of field loss, but even the use of examination techniques such as supramaximal stimuli (e.g., bright torch in a dark room) may leave room for doubt.
Extinction Extinction (or sensory extinction to double simultaneous stimulation) is said to be present when the patient does respond to sensory stimulation on the contralesional side but then fails to
73
74
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
do so when another stimulus is applied simultaneously. The extinguishing stimulus is typically similar to that being extinguished and is usually applied to the corresponding contralateral area, but transmodal extinction (e.g., of a left-sided tactile stimulus by a right-sided visual stimulus) can occur, as can extinction of one stimulus by a second ipsilateral stimulus. When this occurs, the rightward stimulus typically extinguishes that further to the left: this allocentric effect can be seen in the ipsilesional as well as the contralesional receptive field. Extinction, too, may be unimodal or multimodal.
point). For example, patients with neglect of somatocentric hemispace who turn their heads and eyes to the right bring their left visual field into the right side of space, as defined in relation to a somatocentric reference point. This improves their detection of left-sided visual stimuli (defined in relation to a retinocentric reference point) and may help the clinical distinction from hemianopia. A patient with left environmentalcentered neglect who lies on his or her left side would neglect stimuli toward the feet. Spatial neglect also occurs for only peripersonal (near) space (i.e., what can be reached) and, less commonly, for far space, or for both together. A related concept is that of spatial neglect for object-centered (allocentric) space. This refers to a tendency to ignore the left sides of objects, regardless of where they are in retinocentric, somatocentric, or environmental space (Fig. 6–1).4 In addition to neglecting half their environment, such patients may also display neglect dyslexia, in which there is a tendency to ignore the left parts of words (e.g., misreading “consequence” as “sequence”) or of lines. This is an unlikely occurrence in hemianopia without neglect.
Allesthesia Allesthesia refers to the tendency of a patient, without other evidence of right-left confusion, to report contralesional (leftsided) stimuli as having occurred on the ipsilesional (right) side. Thus, when the examiner stimulates the left leg, the patient may be able to point to and move the left leg correctly when asked but reports that the right leg was touched.
Spatial Aspects of the Neglect Syndrome
Representational Neglect
Spatial Neglect
Representational neglect refers to the neglect of the left side of mental images. This disorder first became widely recognized as a result of a thought experiment in which patients imagined themselves standing in the Piazza del Duomo in Milan.5 If they imagined themselves standing on the steps of the cathedral, they could recall the buildings on their right in greater detail than those on the left. If they then imagined themselves standing at the opposite end of the square looking back at the cathedral, they could now recall those buildings previously on their
Spatial neglect refers to decreased awareness of contralesional hemispace. However, what constitutes “hemispace” depends on the frame of reference. Patients may neglect the left side of retinocentric space (i.e., the left side of wherever they are looking), the left side of cephalocentric or somatocentric space (referable to the direction of the head or body), or the left side of environmental space (in relation to an environmental fixed
a.
b.
A ■
B
Figure 6–1. Left, A patient with object-centered neglect fails to copy the left side of the upright tower (A). When the tower is tilted so that some of the left side of the tower now lies on the right side of the picture (and vice versa), the patient still copies only the left side of the tower (B). Right, A patient with left spatial neglect does not cancel lines to the left of the array (a). When the array is separated into two, the patient fails to cancel lines to the left of each array (b), although those to the left of the right-sided array were previously detected before the array was split. (Left, A and B, from Halligan PW, Marshall JC: Towards a principled explanation of unilateral neglect. Cogn Neuropsychol 1994; 11:167-206. Right, a and b, from Driver J, Halligan PW: Can visual neglect operate in object-centered coordinates? An affirmative single case study. Cogn Neuropsychol 1991; 8:475-496.)
chapter 6 the neglect syndrome left (but now on their right) in greater detail than those previously on their right (but now on their left).
Body Image Aspects of the Neglect Syndrome Personal Neglect Personal neglect (or hemiasomatognosia), in its severest form, refers to a patient’s failure to recognize that the contralesional portion of the body belongs to him or her. Such patients may fail to dress, apply makeup to, or shave one side. Milder forms of personal neglect may be suspected when a patient refers to the affected limb in the third person: “It doesn’t work” rather than “my arm doesn’t work.”
Anosognosia and Anosodiaphoria The reader might intuitively suspect that anosognosia (denial of deficit, such as hemiparesis), or the less severe but similar anosodiaphoria (lack of appropriate concern regarding an admitted deficit) is related to personal neglect; however, anosognosia can certainly exist in the absence of personal neglect.6 Of course, neither anosognosia alone nor anisodiaphoria alone is necessarily part of a neglect syndrome: both can occur in other circumstances (e.g., denial of cortical blindness in Anton’s syndrome, la belle indifference in conversion disorders).
Motor Aspects of the Neglect Syndrome Motor neglect, in a broad sense, refers to a situation in which patients fail to perform an appropriate movement, despite awareness of the imperative stimulus and preservation of the requisite power. It is usually implicit that the disorder does not just affect skilled movements, inasmuch as this could then be classed as an apraxia. Heilman and colleagues classified these deficits as action-intentional disorders and recognize four types: akinesia, motor extinction, hypokinesia, and motor impersistence.2 Akinesia refers to failure of initiation of movement. If this failure of initiation is in response to an external stimulus, it may be also be termed motor neglect (in a narrower sense). Akinesia may vary, depending on in which part of peripersonal space the movement occurs and on in which direction the movement is made. For example, akinesia of the left hand may be less severe if movements are attempted in right hemispace (e.g., with the hands crossed), and the ipsilesional (right) hand may move less freely to the left side. Ingenious experiments, designed to separate motor from sensory/hemispatial neglect, have been reported. Perhaps one of the simplest is the crossed response task, in which a stimulus in the right hemifield requires movement of the left arm, and that in the left hemifield requires movement of the right arm.2 Motor extinction is analogous to sensory extinction: a limb that can move normally in isolation moves less well when the opposite limb is moved at the same time. Hypokinesia refers to a normally executed movement with an abnormally long delay from stimulus to movement onset (reaction time). This delay may be long enough to be obvious clinically. Inability to sustain a motor act constitutes motor impersistence. This may be directional (e.g., inability to keep looking in the contralesional but not ipsilesional direction) or may affect the contralesional arm or whichever arm is in contralesional hemispace.
75
How Separable Are the Various Components of the Neglect Syndrome? The neglect syndrome has long been recognized to consist of various combinations of the constituent deficits outlined previously. Formal double dissociations have been recorded between a number of the components (e.g., different measures of hemispatial neglect; hemispatial neglect and extinction).7,8 The best evidence for the heterogeneity of the syndrome probably comes from the large study of Buxbaum and coworkers, who found most possible combinations of personal neglect, peripersonal spatial neglect, sensory neglect/extinction (“perceptual neglect”), and motor neglect in their sample of 166 patients with right hemisphere stroke.9 Pure personal neglect was rare, but pure peripersonal spatial neglect, pure sensory neglect, and pure motor neglect were each not uncommon. Of course, their “purity” depends on which tests are chosen for each, together with their psychometric characteristics, but the double dissociations observed still stand.
EXAMINATION FOR THE NEGLECT SYNDROME It is apparent from the preceding section that no one test is adequate for ruling out the neglect syndrome. At the same time, a relatively brief bedside assessment readily detects most clinically significant neglect syndromes. Several batteries of appropriate tests have been developed.10,11 The following outline is condensed predominantly from Heilman and colleagues (2003), to which the reader is referred for further details.
Sensory Aspects The patient should be stimulated on the left side, right side, and on both sides together, in random order, with visual, tactile, and auditory stimuli and asked to state or indicate on which side or sides the stimulus occurred. Verbal misreporting of left as right, despite absence of left-right confusion on other measures (e.g., the patient can point to and/or move the appropriate side as requested), suggests allesthesia. As pointed out previously, auditory neglect or extinction is clearly separable from unilateral deafness, or unilateral involvement of auditory cortex, and nonthalamic lesions typically do not cause complete hemianesthesia, but it can be more difficult to separate visual hemineglect from hemianopia. Confrontational field testing should then be performed with the head turned to the right and to the left: a true hemianopic defect should remain retinocentric, but visual neglect may improve with the head’s turning to the right. Stronger stimuli should also be employed (e.g., a torch, the spot of a laser pointer on the wall in a darkened room, or, at least, targets larger than a hat pin). Sometimes, however, it is difficult to be certain of with what the clinician is dealing.3 Visual extinction of the more central stimulus by that further to the right may be demonstrable in the intact field.3
Spatial Aspects Gross degrees of spatial neglect are evident on observation: the patient disregards the left side of the environment. Asking the patient to report 10 objects around their room (provided that
76
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s ■
A
B
Figure 6–2. Patients with left-sided neglect may omit elements to their left when drawing or copying (A, B), although this method is less sensitive than other methods such as object cancellation (C) or line bisection (D). As a practical test of environmental neglect, patients may be asked to list 10 items around them, while the examiner plots their location from the perspective of the patient (E). (From Parton A, Malhotra P, Husain M: Hemispatial neglect. J Neurol Neurosurg Psychiatry 2004; 75:13-21.)
C
D E
the bed is not against the left wall) and marking these with regard to a patient-centered reference frame can be a useful measure of less severe spatial neglect (Fig. 6–2E).3 Persistent head and/or eye deviation to the right may also offer a clue to lesser degrees of neglect, which may be elicited by a number of pencil and paper tests. Object drawing/copying tests (see Fig. 6–2A and B) are traditionally used but are not particularly sensitive by themselves,12 are difficult to quantify, and may be confounded by other visuoconstructional problems. A number of cancellation tests have been devised. Those with dense, random arrays with many different types of distractor items, such as the Bells Test,13 or Mesulam’s shape cancellation test (Fig. 6–3; see also Fig. 6–2C),14 seem to be the most sensitive.2,3 A starting point toward the right of the array is probably the most sensitive measure,12 and the location of the first item canceled should be noted. The left-minus-right omission score is also noted: a cutoff point of greater than 2 has been used on the Bells Test, for example.12 Line bisection tests are also easily carried out at the bedside; normal subjects tend to bisect a 20-cm line slightly toward the left, whereas those with left spatial neglect tend to bisect toward the right (see Fig. 6–2D). (They bisect short lines [e.g., 2 to 5 cm] toward the left—the so-called crossover effect—but although this is of great theoretical interest, it is not of practical importance to the clinician, provided that these short lines are avoided.) If the average rightward deviation from the true center points of two successively centrally presented horizontal 20-cm lines is used, a cutoff point of greater than 6.5 mm has been suggested.12 Occasional patients (actually almost 25% in the study of Azouvi et al)12 bisect even the longer lines toward the left: so-called ipsilateral neglect. Although line bisection tasks are less sensitive than cancellation tasks, patients with neglect may show abnormalities on just one or the other, which makes assessment with both necessary. In fact, line bisection may be more related to extinction than to the form of neglect elicited by cancellation tasks, and they may have different anatomical substrates (see “Anatomy of the Neglect Syndrome” section).15
Representational neglect, which does not depend on visuomotor control, may be elicited by asking the patient to describe the landmarks that he or she would see while walking down a well-known thoroughfare—familiar to both the patient and the examiner—in one direction and then in the other.
Body Image Aspects Personal neglect, if severe, may be evident in the patient’s failure to dress or groom one side, in fact, or after they are asked
■
Figure 6–3. Mesulam’s object cancellation task, an example of a dense, random array cancellation task with distractors. The subject is shown a separate drawing of the target object (the open “sun” crossed by a diagonal slash). The sheet is aligned with the patient’s midline. The position of the first target circled should be noted. (From Mesulam M-M: Principles of Behavioral Neurology: Tests of Directed Attention and Memory. Philadelphia: FA Davis, 1985.)
chapter 6 the neglect syndrome to demonstrate how they would do so. This has been formalized as the comb and razor/compact test.16 Personal neglect may also be detected by asking the patient to reach his or her left arm with the right arm. This may be rated from 0 (normal) to 3 (no attempt to reach the left arm) according to a published scale.17 Another graded test (the Fluff Test) involves placement of Velcro-backed stickers or cotton balls on a blindfolded patient, and asking the patient to find and remove them.9,18 In the author’s opinion, severe directional akinesia might confound these tests, and should be ruled out separately. Severe anosognosia may be evident in general conversation with the patient, but milder forms are best detected with simple structured scales. In one such test,2 the hemiparetic patient is first asked, “Why did you come to the hospital?” If the patient does not mention the hemiparesis, he or she is asked whether he or she has any other problems. Failure to mention hemiparesis at this stage constitutes grade 1. Such patients are then asked, “Are you weak anywhere?” Failure to acknowledge their hemiparesis at this stage constitutes grade 2. The examiner then picks up the hemiparetic arm and moves it into the ipsilesional space. Denial of weakness when the patient is asked constitutes grade 3. Such a patient is then asked to move the arm. Continued denial of weakness under these circumstances constitutes grade 4.2 Other scales are similar in concept.9
Motor Aspects Spontaneous (endokinetic) akinesia of the contralesional side, out of proportion to weakness, may be evident on observation. The oculomotor equivalent—a gaze preference toward the ipsilesional side—should also be noted if present. Testing arm movements with the patient’s arms crossed and uncrossed, in response to visual cues in the right hemifield (e.g., downward movement of the examiner’s finger triggers movement of the patient’s limb on the left; upward movement, of that on the right) allows distinction of sensory from motor neglect and differentiation of hemispatial from contralateral exogenously evoked akinesia. Visual saccades toward or away from the examiner’s finger in the right hemifield may be tested similarly. Marked hypokinesia, if present, can be observed during this testing as well. Motor extinction can be elicited with an adaptation of the sensory extinction test, in which the patient has to report which side was stimulated and must move that side. Patients with motor extinction, unlike those with sensory extinction, are able to report simultaneous bilateral stimulation but are able to move appropriately after only a unilateral stimulus. Motor impersistence can be tested by asking the patient to hold a limb posture for 20 seconds. This should be checked in both arms, each tested in both contralesional and ipsilesional space. A more formalized motor impersistence battery is available, if required.19
ANATOMICAL SUBSTRATE, AND THEORIES OF CAUSATION Anatomy of the Neglect Syndrome It is well known that in right-handed individuals, left-sided neglect is more frequent and severe with right hemisphere lesions than is right-sided neglect with left hemisphere lesions. Most left-handed patients also display this pattern; only rare left-
■
77
Figure 6–4. Traditional lesion localization in the neglect syndrome. The computed tomography–defined lesions of 10 patients with the neglect syndrome are superimposed. Note the concentration at the temporoparietal junction. (From Heilman KM, Watson RT, Valenstein E: Neglect and related disorders. In Heilman KM, Valenstein E, eds: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 296-346.)
handed patients showing severe right-sided neglect with left hemisphere lesions: so-called crossed neglect. However, severe right-sided neglect may also occur with bilateral lesions.20 In keeping with this, the author has encountered right-sided neglect in patients with probable Alzheimer’s disease. Neglect has traditionally been considered to arise from right parietal damage, and lesions of the inferior parietal lobule and the adjacent section of the superior temporal gyrus are indeed most commonly implicated in modern imaging studies (Fig. 6–4).8 However, it is now clear from both animal and human studies that neglect can arise from lesions of the inferolateral frontal lobe, cingulate gyrus, thalamus, neostriatum, (unilateral) mesencephalic reticular formation,2,21 and even the posterior limb of the internal capsule or the parahippocampal gyrus8 on occasions. It is reasonable to consider these areas as forming an attentional network, disruption of any component of which might result in the neglect syndrome (see Heilman et al, 2003, and Mesulam, 2000, for detailed discussions). Because the neglect syndrome has a number of possible component deficits, some of which have been shown to be doubly dissociable (able to occur independently of each other), the question arises as to whether the various components might have different anatomical substrates. This issue remains unsettled, but there is at least some evidence that visual extinction (and the possibly related impairment of line bisection) is correlated with damage to the inferior parietal lobule or even the parieto-occipital junction, whereas spatial neglect as defined by abnormal performance on cancellation tasks correlated with more anterior lesions, involving the posterior portion of the superior temporal gyrus, or the parietotemporal junction (Fig. 6–5).7,8 Studies of transcranial magnetic stimulation to produce transient focal deficits in normal subjects have supported this view (see Milner and McIntosh, 2005). It is also, at first sight, appealing to speculate that motor aspects of the neglect syndrome, such as hypokinesia, might relate to damage to frontal or striatal components of the
78
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s ■
Rightward shift in line bisection
Figure 6–5. Lesion overlap in 13 patients with neglect (defined by behavioral findings of hemispatial neglect and confirmed on a cancellation task) who also showed rightward deviation on a line bisection task, in comparison with that on 9 otherwise similar patients with neglect who did not show deviation on line bisection. The lesions in those with abnormal line bisection extend further posteriorly. (From Rorden C, Fruhmann Berger M, Karnath H-O: Disturbed line bisection is associated with posterior brain lesions. Brain Res Cogn Brain Res 2005 [ePublication ahead of print].)
Unbiased line bisection
attentional network, whereas sensory aspects, such as sensory neglect and extinction, might arise particularly from parietotemporal damage. However, patients with neglect caused by frontal lesions may be indistinguishable from those with parietal lesions on standard tests of sensory neglect,22 and one transcranial magnetic stimulation study confirmed the importance of sensory aspects to the neglect syndrome observed with frontal damage.23 As both areas are strongly reciprocally connected, and subserve sensory-motor integration, it is not surprising that a strict sensory/motor dichotomy has not been confirmed and that attempts to separate frontal from parietal neglect syndromes on the basis of clinical phenomena at the bedside are likely to be unavailing.
A
Pathophysiology of Sensory Neglect As pointed out previously, the neglect syndrome has multiple, potentially dissociable components and has been a fertile area for cognitive and experimental neuropsychologists. This brief discussion of potential pathomechanisms covers only sensory neglect: readers are referred to the Suggested Readings list for detailed expositions of possible mechanisms underlying these and other components of the syndrome. An obvious suggestion is that sensory neglect actually arises from impaired sensory input. However, patients with obviously impaired sensory input (e.g., hemianesthesia) are often only too well aware of their deficit, whereas unattended stimuli in patients with sensory neglect still elucidate cortical evoked potentials. Perhaps most convincingly, there is now overwhelming evidence for preconscious (implicit) sensory processing of the neglected stimuli. For example, a subject asked to count four indented circles could see only the two on the right, unless the indentations were oriented to form an implied rectangle, in which case all four were reported (Fig. 6–6).24 Furthermore, patients with visual neglect are still able to use left-sided visual information at a preconscious level to guide reaching and grasping movements (see Milner and McIntosh, 2005).
B ■
Figure 6–6. Preconscious processing in visual neglect. When asked to count the number of incomplete circles, a patient with left neglect reported 4 for A and two for B. The implied rectangle (Kanisza’s figure) in A was presumably processed as a single stimulus; although incidental to the task, this preconscious processing demonstrates that the two circles on the left in B were not missed because of sensory impairment. (From Mattingley JB, Davis G, Driver J: Preattentive filling-in of visual surfaces in parietal extinction. Science 1997; 275:671-674. Copyright 1997. AAAS. Reprinted with permission from AAAS.)
Another explanation relates to the role of attention in determining which of the many stimuli with which humans are constantly bombarded are noticed and which are deemed irrelevant and screened out before they reach consciousness. Mesulam proposed that the left hemisphere tends to endow the right side
chapter 6 the neglect syndrome of the environment, or the right side of whatever is being attended (i.e., egocentric or object-centered right), with salience and is biased toward producing rightward-directed attentional shifts, whereas the effects of the unopposed right hemisphere are larger and more symmetrical (slightly favoring the left side).21 Posner and associates had emphasized the role of the right parietal region in disengaging attention from rightsided objects to enable a subsequent leftward shift.25 There is no fundamental conflict between the directional bias and impaired disengagement hypotheses, although there is some evidence that impaired disengagement is not solely responsible for the observed deficits.26 More recently, the attentional network concept has been elaborated to encompass different roles for roles of a ventral network—composed of the temporoparietal junction and ventrolateral frontal lobe—whose role is to detect novel sensory stimuli, and a dorsal network— composed of the superior parietal lobule and the frontal eye fields—that is responsible for goal-directed stimulus and response selection. Only lesions of the ventral network typically result in neglect, elaborated in part through functional disruption of the dorsal network (Fig. 6–7). Recovery is associated with increased activity in the dorsal network, suggesting a “topdown” rather than “bottom-up” compensatory strategy (i.e., a redirection of attention rather than a recapturing of attention by exogenous stimuli).27
THE FREQUENCY AND IMPORTANCE OF NEGLECT The neglect syndrome is typically a result of a focal, lateralized brain lesion. Such lesions are typically structural and acute or subacute (e.g., strokes or rapidly growing tumors), but the syndrome may also occur with focal epilepsy. Diffuse processes, such as those occurring with toxic-metabolic encephalopathies or diffuse axonal injury from trauma, rarely cause neglect.21 In view of the heterogeneity of stroke topographies, the multifaceted nature of the neglect syndrome, the varying methods (with varying sensitivities) used for its detection, and the varying times after stroke at which studies have been conducted, it is not surprising that the literature contains widely differing estimates of the prevalence of the neglect syndrome in stroke. Indeed, a systematic review in 1999 concluded that although the greater frequency of the neglect syndrome after right than after left hemisphere lesions was supported, an accurate estimate of the frequency and recovery rates of the neglect syndrome could not be reached.28 Since then, several large studies have addressed these issues. Using a standardized (but not exhaustive) test battery, Azouvi and associates found moderate to severe behavioral neglect in 25 (36%) of 69 subacute patients (an average of about 3 months after right hemisphere stroke onset), whereas 177 (86%) of 206 such patients displayed some degree of neglect on at least one pencil and paper measure.12 A study by the same group of 78 additional patients with subacute left hemisphere lesions (but without major impairment of comprehension) showed that for each test in the battery, right-sided neglect was less severe. Than was left-sided neglect after right-sided lesions, and only 25-50% as frequent.29 Patients with left hemisphere lesions also tended to show abnormalities on fewer tests within the battery; 44% displayed abnormalities on at least one measure.29 One report of 1281 patients with acute stroke, who
FEF
IPS-SPL
79
Ventral cortex damaged
Visual cortex TPJ (IPL-STG)
A
VFC (IFg-MFg)
Top-down control L FEF
Structural damage
R FEF
Stimulusresponse selection
L VFC
R VFC
Circuit breaker
Dynamic imbalance L TPJ
LIPS
R IPS
Visual areas
Relative decrease
B ■
RTPJ
Stimulus-driven control Functional damage
Relative increase
Figure 6–7. A, Anatomical regions involved in the dorsal attentional network (blue) involved in goal-directed stimulus and response selection (“top-down”), and in the ventral attentional network (orange) involved in detection of salient sensory events, and in the reorienting of the dorsal network to these, especially if unattended (“bottom-up”). The darkened area represents a hypothetical cortical lesion causing neglect. FEF, frontal eye field; IFg-MFg, inferior frontal gyrus–middle frontal gyrus; IPL-STG, inferior parietal lobule–superior temporal gyrus; IPS-SPL, intraparietal sulcus–superior parietal lobule; TPJ, temporoparietal junction; VFC, ventral frontal cortex. B, A hypothesis for the involvement of both attentional networks in neglect, given a lesion only affecting the ventral network, based on functional magnetic resonance imaging data. Damage to the right ventral circuit (either to the ventral frontal cortex, as shown here, or to the ventral temporoparietal junction) leads to impaired ability to redirect the right dorsal network to new targets (i.e., the “circuit breaker” or disengagement signal function of the ventral network on the dorsal is lost). This decreased activity in structurally intact areas sets up an imbalance between the left and right dorsal systems, as well as the left and right ventral systems, with decreased activity on the right and increased on the left, leading to neglect. Functional improvement in the chronic stage correlates with increased activity of the (intact) dorsal parietal cortex on the right, with decreased activity of that on the left (not shown). L FEF, left frontal eye field; L IPS, left intraparietal sulcus; L TPJ, left temporoparietal junction; L VFC, left ventral frontal cortex; R FEF, right frontal eye field; R IPS, right intraparietal sulcus; R TPJ, right temporoparietal junction; R VFC, right ventral frontal cortex. (From Corbetta M, Kincade MJ, Lewis C, et al: Neural basis and recovery of spatial attention deficits in spatial neglect. Nat Neurosci 2005; 8:1603-1610. Copyright 2005. Reprinted by permission of Macmillan Publishers Ltd.)
80
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
were assessed only for tactile extinction and “visual inattention” on describing a standard scene (the Cookie Theft picture from the Boston Diagnostic Aphasia Examination) revealed that 43% of patients with right hemisphere lesions and 20% of those with left hemisphere lesions displayed abnormalities on one or both measures.30 Subacutely (at 3 months), the respective figures were 17% and 5%. (These percentages are doubtless lower than those reported by the other cited studies as a result of the limited assessment of the neglect syndrome in this study.) Further analysis showed that cortical involvement, right-sided involvement, and increasing age were associated with lesser degrees of improvement by 3 months, whereas handedness and gender had no effect.30 A similar estimate of recovery was derived from an earlier study employing life table analyses, which showed that only 7 (21%) of 34 patients with obvious behavioral neglect in the acute period still displayed such neglect at 3 months.31 The median duration of obvious leftsided sensory neglect was 9 weeks; less florid features such as extinction (median, 43 weeks) and motor impersistence (median, 54 weeks) improved more gradually.31 The presence of the neglect syndrome is an adverse factor for recovery. Patients with right hemisphere strokes recover more slowly than those with left hemisphere strokes; the difference appears to relate to the presence of neglect rather than to poorer motor strength recovery.32 Although this study did not demonstrate the intuitively expected correlation of outcome with anosognosia, others have done so since.33,34 Indeed, one of the study groups found that limited recovery and failure to regain functional independence were correlated with the severity of neglect and the presence of anosognosia in the acute period, as well as with increasing age,34 whereas the other group found no effect of hemispatial neglect (defined on a cancellation task) and personal neglect once anosognosia was allowed for.33 The adverse effect of anosognosia is hardly surprising: It is difficult for patients to cooperate enthusiastically with a rehabilitation program or use strategies to overcome a deficit that they do not believe they have. Chronic neglect increases burden of care; one study of 80 patients with subacute or chronic right hemisphere lesions showed that 37 (48%) displayed neglect on at least one of five measures and that neglect severity rather than lesion size was predictive of increased functional impairment and caregiver burden.9 Neglect can also pose safety concerns, such as in crossing roads or standing next to a hot stove in the kitchen. Education of caregivers is therefore an important aspect of rehabilitation for persistent neglect.
studies reported improvements, whereas others reported worsening of neglect. It has been postulated that the effects of dopaminergic agonists depend on whether the lesion includes damage to the striatum, with the unintended effect of increased disparity in striatal activation in such patients, resulting in increased neglect. (See also Heilman et al, 2003, for additional discussion of dopaminergic agonist treatment.)
Cognitive Training for Remediation of Visual Attention Deficits Remediation of visual attention deficits through a cognitive training (“top-down”) approach has resulted in improvement in some aspects of the neglect syndrome. For example, subjects may be taught to scan back to a red line at the left margin of a text, in order not to ignore the start of each line. Unfortunately, the benefits do not seem to generalize readily to other activities, and maintenance of improvement has not been adequately addressed.35
Treatment of Spatial Representation Deficits
Various rehabilitation strategies have been tried for the neglect syndrome, and the existing literature has been the subject of two 2002 reviews.35,36 Treatment strategies may be divided into those targeting arousal deficits, those directed at deficient visual attention, and those seeking to improve spatial representation deficits.35 (See Pierce and Buxbaum, 2002, for further details of the treatments outlined as follows, together with their outcomes.)
Treatments targeting spatial representation deficits include hemispherical activation approaches (e.g., moving the contralesional limb) and constraint approaches (e.g., immobilizing the unaffected ipsilesional limb or obscuring the ipsilesional visual field in each eye with hemifield patches on glasses). There is some evidence in favor of these approaches, but it is hardly overwhelming.35 A number of other “bottom-up” approaches, aimed at inducing preconscious shifts in spatial representations, have also been explored. An example is leftward trunk rotation therapy, in which more of the left visual field is brought within right-sided peripersonal space. Application of vibration to the left posterior side of the neck produces a similar illusion. Cold water caloric irrigation of the contralesional ear might be thought to act by producing the illusion of head rotation to the right (with compensatory slow eye movement to the left and nystagmus toward the right) but may actually act through the vestibular system’s contribution to spatial representations. Unfortunately, the treatment is uncomfortable, and the effects last only 10 to 15 minutes. Similarly, opticokinetic nystagmus with quick phases induced to the right (i.e., stripes moving to the left) might be considered to produce the illusion of rightward movement. The benefits, however, are reported not to outlast the stimulus. Perhaps the most exciting therapy is prism adaptation, a cheap and noninvasive treatment in which the patient wears Fresnel prisms, which cause a 10-degree apparent rightward shift of viewed objects (Fig. 6–8).37 The benefits generalize to nonvisual aspects of the neglect syndrome, such as tactile extinction38 and, in an initial study, were apparently long-lasting (at least weeks).39 The effects may also extend to patients with chronic neglect syndromes.40 This is potentially an exciting advance in neurorehabilitation, and the results of the first randomized controlled trials should be available in the near future.15
Treatment of Arousal Deficits
CONCLUSION
Dopaminergic agonists (e.g., bromocriptine) have been used to overcome arousal deficits, with contradictory results: Some
The neglect syndrome is common, readily detectable at the patient’s bedside, and has an important effect on rehabilitation
TREATMENT OF THE NEGLECT SYNDROME
chapter 6 the neglect syndrome Optical effect of rightward prism induced shift
■
Start of prism adaptation period
End of prism adaptation period
Post-adaptation (after effect)
Prisms on
Prisms on
Prisms off
81
Figure 6–8. Adaptation to a rightward displacement in subject’s vision produced by a prism. The adaptation process requires the subject to reach repeatedly for the target. Although error caused by the apparent object placement (second panel) quickly diminishes (third panel), about 50 repetitions have to be performed for full adaptation. After removal of the prisms, the after effect (fourth panel) disappears after a few minutes in normal subjects. The effects on the neglect syndrome, however, persist for longer. (From Parton A, Malhotra P, Husain M: Hemispatial neglect. J Neurol Neurosurg Psychiatry 2004; 75:13-21.)
and recovery of function. However, it is probably underrecognized, at least in its less florid forms, partly because of its diverse manifestations. Examination for these disorders should form part of the assessment of any patient with an acute or subacute hemispherical lesion, especially if it is right-sided. An impressive body of experimental work is now beginning to generate ideas for rationally based rehabilitative therapies, of which prism adaptation shows considerable early promise.
K E Y
P O I N T S
●
The neglect syndrome is most typically observed with acute or subacute hemispherical lesions, particularly those affecting the right hemisphere. Disruption anywhere within the attentional network may be responsible, but lesions of the temporoparietal junction and inferolateral frontal lobe are particularly likely to produce neglect.
●
The neglect syndrome consists of various combinations of deficits affecting the patient’s conscious detection of contralesional sensory stimuli, awareness of contralesional space (hemispace), whether imagined or real; awareness of the patient’s own body parts contralateral to the lesion; and ability to move contralesional body parts or within contralesional space, not adequately explained by elementary sensory or motor deficits such as hemianopia, hemianesthesia, or hemiparesis.
●
These various component deficits can usually be identified at the bedside with a limited range of simple examination techniques, although no one test alone is adequate for this purpose.
●
The neglect syndrome has an important adverse effect on rehabilitation and recovery from stroke, and although its most florid manifestations more usually than not resolve within 3 months, it may persist.
●
A number of hypotheses have been advanced to explain aspects of the neglect syndrome. Although the resulting debates continue, several rational therapeutic approaches have been suggested as a result. Of these, prism adaptation has shown the greatest initial promise.
Suggested Reading Heilman KM., Watson RT, Valenstein E: Neglect and related disorders. In Heilman KM, Valenstein E, eds: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 296-346. Mesulam M-M: Attentional networks, confusional states and neglect syndromes. In Mesulam M-M, ed: Principles of Behavioral and Cognitive Neurology, 2nd ed. New York: Oxford University Press, 2000, pp 193-256. Milner AD, McIntosh RD: The neurological basis of visual neglect. Curr Opin Neurol 2005; 18:748-753.
82
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Parton A, Malhotra P, Husain M: Hemispatial neglect [Review]. J Neurol Neurosurg Psychiatry 2004; 75:13-21. Pierce SR, Buxbaum LJ: Treatments of unilateral neglect: A review. Arch Phys Med Rehabil 2002; 83:256-268.
References 1. Sacks O: The Man Who Mistook His Wife for a Hat. London: Duckworth, 1985. 2. Heilman KM, Watson RT, Valenstein E: Neglect and related disorders. In Heilman KM, Valenstein E, eds: Clinical Neuropsychology, 4th ed. New York: Oxford University Press, 2003, pp 296-346. 3. Parton A, Malhotra P, Husain M: Hemispatial neglect [Review]. J Neurol Neurosurg Psychiatry 2004; 75:13-21. 4. Driver J, Halligan PW: Can visual neglect operate in objectcentered coordinates? An affirmative single case study. Cogn Neuropsychol 1991; 8:475-496. 5. Bisiach E, Luzzatti C: Unilateral neglect of representational space. Cortex 1978; 14:129-133. 6. Adair JC, Na DL, Schwartz RL, et al: Anosognosia for hemiplegia: test of the personal neglect hypothesis. Neurology 1995; 45:2195-199. 7. Mort DJ, Malhotra P, Mannan SK, et al: The anatomy of visual neglect. Brain 2003; 126:1986-1997. 8. Rorden C, Fruhmann Berger M, Karnath H-O. Disturbed line bisection is associated with posterior brain lesions. Brain Res Cogn Brain Res 2005 [ePublication available ahead of print]. 9. Buxbaum LJ, Ferraro MK, Veramonti T, et al: Hemispatial neglect: subtypes, neuroanatomy and disability. Neurology 2004; 62:749-756. 10. Azouvi P, Marchal F, Samuel C, et al: Functional consequences and awareness of unilateral neglect: study of an evaluation scale. Neuropsychol Rehab 1996; 6:133-150. 11. Wilson B, Cockburn J, Halligan P: Behavioural Inattention Test. Bury St. Edmunds, UK: Thames Valley Test Co., 1987. 12. Azouvi P, Samuel C, Louis-Dreyfus A, et al: Sensitivity of clinical and behavioral tests of spatial neglect after right hemisphere stroke. J Neurol Neurosurg Psychiatry 2002; 73: 160-166. 13. Gauthier L, Dehaut F, Joanette Y: The Bells Test: a quantitative and qualitative test for visual neglect. Int J Clin Neuropsychol 1989; 11:49-54. 14. Mesulam M-M: Principles of Behavioral Neurology: Tests of Directed Attention and Memory. Philadelphia: FA Davis, 1985. 15. Milner AD, McIntosh RD: The neurological basis of visual neglect. Curr Opin Neurol 2005; 18:748-753. 16. Breschin N, Robertson IH: Personal versus extrapersonal neglect: a group study of their dissociation using a reliable clinical test. Cortex 1997; 33:379-384. 17. Bisiach E, Perani D, Vallar G, et al: Unilateral neglect: personal and extra-personal. Neuropsychologia 1986; 24:759-767. 18. Cocchini G, Beschin N, Jehkonen M: The Fluff Test: a simple task to assess body representational neglect. Neuropsychol Rehab 2001; 11:17-31. 19. Benton AL, Sivan AB, Hamsher K deS, et al: Contributions to Neuropsychological Assessment: A Clinical Manual, 2nd ed. New York: Oxford University Press, 1994. 20. Weintraub S, Daffner KR, Ahern G, et al: Right-sided hemispatial neglect and bilateral cerebral lesions. J Neurol Neurosurg Psychiatry 1996; 60:342-344.
21. Mesulam M-M: Attentional networks, confusional states and neglect syndromes. In Mesulam M-M, ed: Principles of Behavioral and Cognitive Neurology, 2nd ed. New York: Oxford University Press, 2000. 22. Husain M, Mattingley JB, Rorden C, et al: Distinguishing sensory and motor biases in parietal and frontal neglect. Brain 2000; 123:1643-1659. 23. Brighina F, Bisiach E, Piazza A, et al: Perceptual and response bias in visuospatial neglect due to frontal and parietal repetitive transcranial magnetic stimulation in normal subjects. Neuroreport 2002; 13:2571-2575. 24. Mattingley JB, Davis G, Driver J: Preattentive filling-in of visual surfaces in parietal extinction. Science 1997; 275:671674. 25. Posner MI, Walker JA, Friedrich JF, et al: Effects of parietal injury on covert orienting of attention. J Neurosci 1984; 4: 1863-1874. 26. Mark VW, Kooistra CA, Heilman KM: Hemispatial neglect affected by non-neglected stimuli. Neurology 1988; 38:12071211. 27. Corbetta M, Kincade MJ, Lewis C, et al: Neural basis and recovery of spatial attention deficits in spatial neglect. Nat Neurosci 2005; 8:1603-1610. 28. Bowen A, McKenna K, Tallis RC: Reasons for variability in the reported rate of occurrence of unilateral spatial neglect after stroke. Stroke 1999; 30:1196-1202. 29. Beis J-M, Keller C, Morin ST, et al: Right spatial neglect after left hemisphere stroke: qualitative and quantitative study. Neurology 2004; 63:1600-1605. 30. Ringman JM, Saver JL, Woolson RF, et al: Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort. Neurology 2004; 63:468-474. 31. Hier DB, Mondlock J, Caplan LR: Recovery of behavioral abnormalities after right hemisphere stroke. Neurology 1983; 33:345-350. 32. Denes G, Semenza C, Stoppa E, et al: Unilateral spatial neglect and recovery from hemiplegia. Brain 1982; 105:543-552. 33. Pedersen PM, Jørgenson HS, Nakayama H, et al: Hemineglect in acute stroke—incidence and prognostic implications: the Copenhagen Stroke Study. Am J Phys Med Rehab 1997; 76:122127. 34. Stone SP, Patel P, Greenwood RJ, et al: Measuring visual neglect in acute stroke and predicting its recovery: the visual neglect recovery index. J Neurol Neurosurg Psychiatry 1992; 55:431-436. 35. Pierce SR, Buxbaum LJ: Treatments of unilateral neglect: a review. Arch Phys Med Rehabil 2002; 83:256-268. 36. Bowen A, Lincoln NB, Dewey M: Cognitive rehabilitation for spatial neglect following stroke. Cochrane Database Syst Rev 2002; (2):CD003586. 37. Rossetti Y, Rode G, Pisella L, et al: Prism adaptation to a rightward optical deviation rehabilitates left hemispatial neglect. Nature 1998; 395:166-169. 38. Maravita A, McNeil J, Malhotra P, et al: Prism adaptation can improve contralesional tactile perception in neglect. Neurology 2003; 60:1829-1831. 39. Frassinetti F, Angeli V, Meneghello F, et al: Long-lasting amelioration of visuospatial neglect by prism adaptation. Brain 2002; 125:608-623. 40. McIntosh RD, Rossetti Y, Milner AD: Prism adaptation improves chronic visual and haptic neglect: a single case study. Cortex 2002; 38:309-320.
CHAPTER
7
EXECUTIVE FUNCTION ITS ASSESSMENT ●
●
●
AND
●
Glynda Kinsella, Elsdon Storey, and John R. Crawford
EXECUTIVE FUNCTION The dysexecutive syndrome has long been exemplified by the classic case of Phineas Gage, whose prefrontal damage from a railway construction accident in 1848 completely altered his personality and work performance.1 A more contemporary exemplar, with the advantage of modern neuroimaging and neuropsychological assessment, is that of E.V.R., reported by Eslinger and Damasio.2 E.V.R. was a successful young accountant who underwent surgical removal of a large orbitofrontal meningioma. His postoperative course illustrates the potentially far-reaching and devastating consequences of executive function impairment: “Post-operatively, E.V.R. was assessed to be in the ‘above average’ range on the Wechsler Adult Intelligence Scale, and at 3 months post-surgery he returned to accounting. However . . . he needed prompting to get up and go to work. He lost all sense of a schedule and employers complained about tardiness and disorganization, although basic skills, manners, and temper were appropriate. Similar difficulties led to a deterioration of his marital life . . . . Unable to hold a job and separated from his family . . . . Employment problems continued . . . . Deciding where to dine might take hours . . . . He would drive to each restaurant to see how busy it was . . . .” This case example provides many of the hallmark features of executive dysfunction and graphically demonstrates the dissonance between preservation of basic cognitive and behavioral skills and grossly impaired regulation of these skills: this is the essence of executive dysfunction.
Characterization of Executive Function Executive function can be understood as the skills that allow humans to solve problems; adapt effectively and flexibly to their environment; and plan, perform, and evaluate goal-directed intentions, such as making a timely financial investment. Correspondingly, executive dysfunction can lead to deficits in the generation and initiation of appropriate behavior, limitations in cognitive flexibility and reasoning skills, and impairments in social judgement.3-10 The breadth of coverage in these descriptions immediately signals the complexity of the processes involved and, not surprisingly, the difficulty that researchers
have encountered in formulating adequate and comprehensive explanatory models of these behaviors. Notwithstanding this challenge, executive function continues to be a focus of interest for both researchers and clinicians, because the concept provides a description of humans’ adaptability to their environment and assistance in developing expectations and predictions of relevance to (1) differential diagnosis in clinical evaluations (for example, in delineating the syndromes of the frontotemporal dementias; see Chapter 74); (2) anticipating dysfunctional behavior of patients in everyday settings11; and (3) estimating decision-making capacity in everyday roles (for example, capacity for handling financial responsibilities12). Understandably, assessment of executive function has become a core component of most neuropsychological assessments.13
Neuropsychological Models of Executive Function Neuropsychological approaches to conceptualizing a model of executive function are varied. Banich4 provided a helpful roadmap to several of the approaches, including working memory, the supervisory attentional system, script knowledge, and goal-directed behavior. A brief description of two of the major theories follows.
Working Memory Baddeley’s working memory model14 (Fig. 7–1) consists of multiple specialized and interlinked components of cognition that allow humans to (1) mentally represent their immediate environment, (2) retain information on-line (available in consciousness in an on-going manner) to enable acquisition of new knowledge, and (3) formulate and act on current goals, through both an attentional control system—the central executive— and several specialized temporary storage systems, which are slave systems to the central executive, such as the articulatory loop and the visuospatial scratch pad.15 Working memory provides on-line cognition (manipulation of data in consciousness) that allows a reasoned response to complex tasks. Research since the 1990s has consistently supported the proposition that the central executive can be fractionated, or, as Baddeley persuasively commented, skills can be governed by an “executive committee” rather than a “homunculus.”16 There have been various attempts at defining the breadth and nature
83
84
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s ■
(simultaneous) Dual tasking (divided attention)
Attentional switching
Figure 7–1. Diagram of the working memory model of executive functioning. LTM, long-term memory.
Central executive
Fluid systems
Crystalized systems
Visuospatial sketch pad
Visual semantics
Episodic buffer
Phonological loop
Episodic LTM
Language
of executive functions.16-18 However, most taxonomies include focusing attention and inhibiting distraction, coordinating and dividing attention, switching attention, planning, and activating and generating representations drawn from long-term memory via an episodic buffer. Impairments in working memory can result in many of the core features of executive dysfunction, such as inability to maintain task focus as a result of susceptibility to distraction, or inability to perform two or more tasks simultaneously (multitasking). (An example of such multitasking would be simultaneously monitoring young children playing in a swimming pool and cooking a meal, while speaking on a mobile phone.) Working memory, therefore, can provide a comprehensive account of many features of executive dysfunction. Furthermore, the executive aspects of working memory have been closely associated with the prefrontal regions, especially the dorsolateral prefrontal cortex.19
attentional system was conceptualized as a unitary construct, but more recently, Stuss and Alexander argued for a multicomponent supervisory attentional system within which specific processes interlink with specific neural substrates of the frontal cortical-subcortical neural network.10 Furthermore, Stuss and Alexander cautioned against a simple conceptualization of supervisory attentional control. They emphasized that there are many types and levels of attentional control of behavior (e.g., Fig. 7–2) and that the concept of a simple frontal/ posterior dissociation related to control/automatic processes would not adequately capture the complexity of linkage of the system to particular neural substrates. They thereby concurred with other authorities that executive function fractionates into various subordinate roles important for goal-directed behavior. Although varied, existing theories of executive function are not necessarily mutually exclusive. Within most models, there is recognition of a multicomponent executive function system
Supervisory Attentional System Within this model, the emphasis is on the role of attentional control (executive function) in everyday actions. Shallice20,21 provided a two-layer model of an attention system that influences behavior: contention scheduling (automatic processing) and the supervisory attentional system (controlled processing). Contention scheduling allows fast automatic execution of welllearned action sequences. This may be sufficient for many everyday tasks, but it is also prone to error as it operates under minimal conscious supervision. For example, making a cup of coffee can become relatively automatic, but sometimes when a person is tired or distracted, he or she may unintentionally pour milk into the coffee pot instead of into the cup. In contrast, the supervisory attentional system is activated when conscious effort is required: for example, in situations of novelty or crisis or when new skills are learned. An impaired supervisory attentional system and an unmonitored contention scheduling system can account for many of the qualitative features of executive dysfunction, such as perseveration (failing to cease an ongoing behavior when it is no longer appropriate). Contention scheduling and the supervisory attentional system have been proposed to be operated by distinct neural substrates. Specifically, the supervisory attentional system is associated with the prefrontal cortex.22 Initially, the supervisory
Stuss and Benson—prefrontal hierarchies
Level 3
Self-awareness/metacognition (frontopolar) Social integration through principles and values (orbital)
Goal selection Level 2
Planning and anticipation Monitoring of current behavior (dorsolateral)
Sequencing (dorsolateral) Level 1 ■
Drive (medial frontal)
Figure 7–2. Diagrammatic representation of model of executive function. (From: Stuss DT, Alexander MP, Benson DF. Frontal Lobe Functions. In Trimble MR, Cummings JL, eds: Contemporary Behavioral Neurology. Boston: Butterworth Heinemann, 1996, pp 169-187.)
chapter 7 executive function and its assessment ■
Dorsolateral prefrontal cortex
Lateral orbital cortex
Anterior cingulate cortex
Caudate (dorsolateral)
Caudate (ventromedial)
Nucleus accumbens
Globus pallidus (lateral dorsomedial)
Globus pallidus (medial dorsomedial)
Globus pallidus (rostrolateral)
Thalamus (VA and MD)
Thalamus (VA and MD)
Thalamus (MD)
subserving multiple roles. Furthermore, although executive function disorders are more commonly observed with frontal system dysfunction, most researchers argue that it would be overly simplistic to reduce executive function to a concept of frontal lobe disorder; instead, executive skills undoubtedly rely on networks of interactive systems.10
Neuroanatomical Substrates of Executive Functioning Functional imaging studies have confirmed that complex behaviors such as executive functions are subserved by networks of interconnected brain regions rather than by discrete cortical areas (Fig. 7–3), and a series of parallel frontalsubcortical circuits that link specific regions of the frontal cortex to the striatum, globus pallidus, and thalamus have been described.23,24 Miller and Cummings provided an extensive model of five defined frontal-subcortical circuits,25 of which the dorsolateral prefrontal, orbital frontal, and anterior cingulate circuits are purported to subserve cognitive and behavioral aspects of executive function.26 A corollary of this network structure is that interruption of such circuits outside the frontal cortex leads to many of the classic features of “frontal” dysfunction. For example, infarcts in the caudate head may disturb planning and sequencing, with disinhibition or apathy, depending on which part of the caudate—and therefore which circuit—is disrupted (e.g., see Mendez et al27). Progressive supranuclear palsy is another example of a disorder whose pathological effect is subcortical rather than on the prefrontal cortex and yet that is characterized by a prominent dysexecutive syndrome on the basis of disruption of these circuits.28
Orbitofrontal Circuit The orbitofrontal circuit is important for inhibition, and changes in this control mechanism can, in a variety of ways, affect the behavioral response to environmental and social demands.24,26 Affected patients have been described as acting impulsively, exhibiting emotional and socially inappropriate behavior, and being liable to increased distractibility.29 In severe instances, dysfunction can result in the phenomenon of utilization behavior, in which patients become devastatingly stimulus-bound to environmental cues.30 The orbitofrontal
85
Figure 7–3. Diagram of the three principal circuits involving prefrontal cortex: organization of three frontal subcortical circuits in which lesions produce alterations of cognition and emotion. MD, medial dorsal; VA, ventral anterior. (From Baddeley A: Fractionating the central executive. In Stuss DT, Knight RT, eds: Principles of Frontal Lobe Function. New York: Oxford University Press, 2002, pp 246-260.)
network serves as a braking mechanism to stop automatic responding and allows for a flexible approach to environmental manipulation.
Anterior Cingulate Circuit The anterior cingulate circuit is medial in location and has been implicated in resistance to interference (including cognitive inhibition of automatic responses) and in response initiation.31 Cummings24 described the characteristic syndrome as that of apathy, the most extreme form being of akinetic mutism: a profound indifference to the environment in which patients lack any internally generated activity or behavior (see Chapter 9).
Dorsolateral Prefrontal Circuit Impairment of the dorsolateral prefrontal circuit is argued to contribute to many of the observed cognitive features of executive dysfunction that affect cognitive flexibility or attentional switching and the formulation of novel ideas and responses. Deficits include impairments in self-generated behavioral (motor or cognitive) planning, maintenance of cognitive set and set switching,9 and manipulation of working memory information on-line.32 Patients with dorsolateral lesions are frequently described as displaying impaired mental flexibility and poor reasoning.
Information Flow to the Frontal Cortex A complementary view of executive functioning and the prefrontal cortex is that the dorsolateral prefrontal cortex sits at the apex of information flow from the external milieu (the subject’s interaction with the external environment), after that information has been processed through unimodal and then multimodal association cortices, and is able to modulate and select responses to this information. The orbitofrontal and mesial prefrontal cortices, in contrast, receive information on the subject’s internal milieu, including needs and drives, and modulate and select responses to these stimuli.33,34 Therefore, although there is continuing debate on a comprehensive taxonomy of executive processes, most researchers
86
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
agree that executive function is a fractionated functional system that relies on differentiated underlying neural regions and pathways.
FORMAL ASSESSMENT OF EXECUTIVE FUNCTION Common Problems Affecting Executive Function Tests Most clinicians are familiar with the frustrating situation in which patients with executive dysfunction have a significant discrepancy between the reasonably average results of formal testing procedures and major difficulties in real-life behavior.6 Sometimes this may relate to the following aspects of the testing process.
Clinical Tests Can Be Multifactorial Many traditional measures of executive function (e.g., the Wisconsin Card Sorting Test [WCST]) are multifactorial (i.e., they assess a number of different aspects of executive function and other cognitive domains), which renders them liable to be sensitive to executive dysfunction but poor in isolating why failure occurs. That is, test specificity is low, and a patient may fail the test for multiple reasons.
Repeated Testing Can Lead to Marked Practice Effects All executive function tests suffer from practice effects. Although parallel test versions may be available to obviate direct learning effects of the test material (for example, alternate letters in verbal fluency), procedural learning (implicit learning that can improve performance simply by performance of a task more than once) is common in executive function tests. This may reflect the fact that the tasks are designed to be novel and cognitively engaging and the fact that the participant will actively attempt to rehearse strategies to make the task easier. With repeated exposure, a previously novel task therefore becomes automatic.35 This represents a major difficulty in longitudinal studies.
Testing in the Office Is Not the Same as Real-Life Situations In formal testing procedures, most typically conducted within a quiet office environment, distractions are minimized, and tasks are often carefully structured to increase the reliability of the test. However, these artificial constraints may substitute for the patient’s defective executive system.36 Furthermore, test procedures can be relatively brief episodes, so that persistent and sustained attention to a task is rarely assessed thoroughly, and demand for multitasking is low.6,13,37 Unfortunately, these constraints of office testing can prevent the demonstration of the essential features of executive dysfunction. To improve the ecological validity of the assessment, formalized versions of real-world activities in which patients are assessed in naturalistic settings (e.g., Shallice and Burgess’s shopping center
task9) have been devised; although these approaches have yielded highly informative results for guiding rehabilitation,38 they are generally impractical for a busy hospital-based assessment clinic.
Assessment of the Affective, Social, and Judgmental Changes of Executive Dysfunction Are Not Well Covered by Existing Tests Alterations in emotional and social behavior are important components of the executive syndrome, to the extent that Stuss and Alexander argued that social behavioral changes represent the most disabling aspect of the disorder.10 Performance on many tests can be undermined by apathy, disinhibition, or other features of lack of emotional control. However, formalized approaches to the documentation of these key characteristics are limited, although research measures of social cognition, such as the faux pas test,39 or of judgment, such as the gambling game,40 show promise.
Level of Premorbid Ability Is Important when Executive Function Is Assessed It is important to evaluate executive function within the context of the estimated overall premorbid ability of the individual; that is, a below-average score on a test of executive function may be significant if the patient was of above-average premorbid ability, but it would be less suspect if previous general ability was estimated to lie in the below-average range. Furthermore, researchers41,42 have noted that tests of executive function are frequently correlated with general cognitive ability in healthy populations, and this should be considered when individual performances in tests of executive skills are evaluated. In response to these various criticisms, the examiner using executive function tests must carefully observe the quality of performance on the selected tests as much as record the overall level of performance achieved on the outcome measures.
Standard Neuropsychological Tests Commonly Used in Assessing Executive Function Test Batteries or Individual Tests for Executive Function? There are now several test batteries of executive function, including the Behavioural Assessment of the Dysexecutive Syndrome (BADS),43 the Behavioral Dyscontrol Scale,44 and the Delis-Kaplan Executive Function Scale (D-KEFS).45 The DKEFS is especially useful because of its reasonably large normative sample and the provision of multiple standardized tests in which the same outcome scale is used for comparison purposes. These batteries should be considered for use, because they allow comprehensive assessment of executive function; however, in many clinical examinations, time is limited and administration of a full test battery cannot be easily accommodated. Consequently, the neuropsychologist is faced with the decision of individual test selection. Consideration of the cognitive and neural models of executive function, and of reports of the patient’s particular difficul-
chapter 7 executive function and its assessment ties, is essential to guide the examiner in determining which aspects of the fractionated roles of executive function are critical in the assessment. The following sections summarize some of the neuropsychological tests commonly used to assess executive function. The listing is by no means exhaustive, and for more information on these and other related tests, the reader is referred to Lezak and colleagues (2004). The listing of the tests within separate domains of executive function is also debatable16,17 and is provided simply as a guide to the reader. As stated earlier, neuropsychological tests of executive function tend to be multifactorial, which precludes a simple description of the underlying properties of the tests.
Focusing Attention and Inhibiting Distraction An important feature of executive function is the ability to maintain attention on task and to resist interference from distracting events or thoughts. The Stroop Test46-49 provides a classic paradigm for assessing capacity to resist interference from an automatic process (in this instance, reading words: the names of colors) on a more effortful process (identifying the colors of the ink in which the words are printed). There are multiple versions of this test (including the Color-Word interference subtest from the D-KEFS), but in the basic task, participants are timed in (1) reading aloud words that are the names of colors; (2) naming ink patches of color; and (3) naming the color of the ink in which incongruent-color words are printed: for example, stating “blue” when the word “red” is printed in blue letters.46 The increased time taken to complete this final interference trial provides an index of the capacities to focus attention on the appropriate stimulus and to inhibit distraction from the more automatic response of reading the color word (cognitive inhibition). Excessive slowing or an increase in errors on the interference trial provides indication of diminished ability to inhibit inappropriate responses (Fig. 7–4). The test is relatively quick to administer (most versions take approximately 8 minutes), and scoring is by time or error on each trial. A substantial amount of cognitive neuropsychological research50 and a number of neuroimaging studies have confirmed the role of executive function and of the prefrontal
blue yellow red green
blue yellow
green
red
red yellow red ■
green red
blue yellow
green yellow blue red
green
blue
blue yellow green
Figure 7–4. Interference trial of the Stroop test (Victoria version). (From Spreen O, Strauss E: A Compendium of Neuropsychological Tests: Administration, Norms and Commentary, 2nd ed. New York: Oxford University Press, 1998.)
87
regions of the brain—specifically, the anterior cingulate/ mesiofrontal circuit—in task performance.51,52 Satisfactory test-retest reliability has been reported for different test versions;6,53 for example, Houx and associates reported high test-retest reliability (r = .80) within a multicenter study of 5804 older adults.35 However, practice effects, as observed in most executive measures, are apparent. Houx and associates reported that speed of performance on the interference trial improved by approximately 5 seconds between baseline and reassessment 2 weeks later, and they argued that procedural learning in the Stroop test has to be taken into account when the course of executive function in patients is monitored over time. Impaired visual acuity or severe color blindness precludes use of the test, but it has been found to be sensitive to executive dysfunction in a range of clinical populations, including patients with traumatic brain injury54 and mildly and moderately demented patients.55 In both of these populations and in patients with Huntington’s disease,56 however, increasing severity of disorder results in increased generalized slowing of response, so that the specific Stroop effect diminishes.55,57 More recent versions of the test have increased its complexity by adding an additional switching trial to the basic color naming, word reading, and color-word interference trials.54,5845,54 In the switching trial, participants are required to name the color of the ink as per the traditional color-word interference trial but to switch to reading the color word of any items enclosed by a rectangle, randomly positioned throughout the trial. This addition provides increased sensitivity for the identification of mild impairment in executive function.
Set-Shifting and Cognitive Flexibility The ability to shift attention readily between different cognitive tasks (cognitive flexibility) is an important feature of adaptive behavior.16,58 One of the most popular tests of set-shifting is the Trail Making Test (TMT)59,60 which consists of two parts: the Trail Making Test Part A (TMT-A) and the Trail Making Test Part B (TMT-B). The TMT-A is a timed trial that requires participants to draw lines to interconnect 25 consecutively numbered circles. The TMT-B is also timed and requires participants to interconnect consecutive numbers and letters, alternating between the two sequences (i.e., 1-A-2-B-3-C-4-D . . . . L-13). Scoring is based on time to complete each trial (errors being reflected in the time score) and derived scores of (1) the difference in time to complete the two sections (TMT-B score minus TMT-A score) and (2) the ratio of TMT-B score to TMTA score. The derived scores provide the advantage of removing the individual variance in speed of response before set-shifting capacity is calculated. These derived scores, as well as time taken to complete TMT-B, have frequently been used as indices of cognitive flexibility or set-shifting.61-66 The derived scores have been shown in some reports of TMT performance to provide better correlations with other measures of cognitive flexibility,61 and neuroimaging research has provided support for the critical role of the dorsolateral and medial frontal cortices in the regulation of cognitive flexibility and set-shifting, as required in the TMT.67 The TMT is quick to administer (approximately 4 to 6 minutes), but additional difficulties in visual scanning and motor control can compromise performance. To address this, the TMT subtest in the D-KEFS includes three extra conditions
88
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
that allow the contributions of visual sequencing and motor speed to be evaluated more thoroughly.45 Because the TMT is predicated on familiarity with the English alphabet, the Color Trails Test68 was developed to provide a nonalphabetical parallel form for use in cross-cultural studies or clinical settings, although only limited normative data are available.69,70 Satisfactory test-retest reliability is reported for the TMT, with many reported coefficients higher than .80 and all exceeding .60.6,53 However, practice effects are again noticeable, especially on the TMT-A, and need to be considered when performance over time is evaluated. A large normative study of 911 participants aged 18 to 89 years has provided useful information on the TMT-A and TMT-B and on the effects of age and education on test performance,71 and this can be supplemented by normative information on the derived scores from a smaller study.72 The TMT has been demonstrated to be sensitive to cognitive impairment in a range of clinical conditions, including Parkinson’s disease,73,74 Alzheimer’s disease,75,76 and other dementias.77-81 The WCST82,83 is the most extensively characterized test of executive function. Although multifactorial, it is frequently described as a task of attentional set-shifting.17,84 The test requires the client to sort a set of cards on the basis of several different characteristics: color, form, and number. Clients are not given instructions on how to sort the cards but must infer the correct method of sorting from the examiner’s mention of “Correct” or “Incorrect” in response to their previous sorting attempts (Fig. 7–5). After a series of consecutive successful sorts, the sorting principle changes without notice, and the participant must both discern that the rule has changed and discover the new criterion for sorting. Scoring includes the
number of correct categories achieved and the number of perseverative errors (an error of sorting within a category that was formerly correct but is no longer appropriate: that is, a failure in ability to switch response according to task demands). The WCST has a number of drawbacks for consideration in the clinic.85 First, administration time is lengthy (approximately 30 to 45 minutes). In response to this limitation, a short form of the WCST has been developed (Modified Wisconsin Card Sorting Test86). A further limitation is that although the WCST was initially reported to be sensitive to dysfunction of the dorsolateral prefrontal cortex, especially on the left,87,88 researchers have more recently criticized the test for failing to discriminate between frontal and nonfrontal brain injury patients.89-91 This lack of specificity may result from the complexity of the task; failure on the WCST can arise as a result of a range of different deficits.29 A further problem for clinical use of the WCST is that performance is particularly prone to practice effects once the subject gains an appreciation of its principles; on the basis of results from a 3-year study of cognitive disorder in Huntington’s disease, Snowden and colleagues suggested that the WCST has limited use in longitudinal studies, although its use in cross-sectional studies remains important.56 Nevertheless, the WCST has been found to be a modest predictor of everyday functional ability after discharge from acute rehabilitation.92
Coordinating the Performance of Multiple Tasks (Dual Tasking) Performing two tasks simultaneously requires dividing attention between the two tasks, coordination of attention, and
■
A
Figure 7–5. The Wisconsin Card Sorting Test (WCST). A. Matching by shape, but not number or color. B. Matching by color, but not number or shape.
red blue green yellow
B
chapter 7 executive function and its assessment ongoing monitoring of the effectiveness of performance.93 This skill, termed dual-tasking, provides another avenue to assessment of executive attention.14,17 A commonly used paradigm in dual-task research requires verbal performance of digit span at the same time as a paper and pencil tracking task; dual-task capacity is indexed by comparing performance level in each single task with performance of both tasks under dual-task conditions.93 Within such a paradigm, dual-task impairment has distinguished normal older adults from those with early Alzheimers’s disease94 and from older adults with nonspecific cognitive impairment.95 In a study of patients with severe head injury, Alderman found that a large dualtask decrement was associated with a poor response to behavioral intervention.96 However, as yet, dual-task paradigms have been restricted to clinical research procedures, and their adoption into routine clinical assessment will be dependent on the development of standardized tests and normative databases. In this regard, a new battery of dual-task measures may prove useful.97
Strategically Activating Information from Long-Term Memory and Manipulating Information Online Extensive neuropsychological research has linked verbal fluency performance to executive functioning.98 Verbal fluency tasks require generation of words, usually for 60 to 90 seconds, based on either phonemic (letter fluency) or semantic (category fluency) criteria. A nonverbal analog, design fluency, has been developed and is included in the D-KEFS battery.44 Probably the best known verbal fluency task is the Controlled Oral Word Association test,99 consisting of three 1-minute trials of generating words beginning with the letters F, A, and S (or C, F, and L or with P, R and W). Scoring is based on total words generated within the time limit and is adjusted for age, gender, and education. Phonemic fluency has been argued to be an effortful task, requiring recruitment of executive function, because retrieving words on the basis of orthographic criteria (spelling) is unusual: People normally retrieve words on the basis of their meaning.100 In contrast, semantic fluency is considered less effortful, although patients with early Alzheimer’s disease have been reported to demonstrate more difficulty with semantic fluency than with phonemic fluency, presumably as a function of impaired semantic memory caused by early involvement of the temporal neocortex.101 However, contrary to early conceptualizations concerning differential performance on phonemic and semantic fluency,102 Henry and Crawford demonstrated through meta-analysis that both forms of fluency are equivalent in sensitivity to frontal lesions, which suggests that both draw on resources of executive processes, including initiation, efficient organization of verbal retrieval and recall, and selfmonitoring.103 However, semantic fluency is also sensitive to temporal lobe lesions, which suggests that impaired semantic fluency may be a result of either executive or temporal dysfunction. Research has also confirmed that set-shifting ability contributes to verbal fluency by allowing active strategic search of relevant retrieval cues for generating words (e.g., “ship, sailor, sea . . .”; “soap, shower, shampoo . . .”),104-106 and this has pro-
89
moted additional scoring measures: the number of subcategory switches and the cluster size of individual groups of words. Qualitative aspects, such as production of socially inappropriate words or rule breaking by producing proper nouns despite being able to state that these are not allowed, are important additional observations. (The latter is an example of what Walsh termed “the curious dichotomy between knowing and doing” that typifies dysexecutive behavior.107) Neuroimaging studies identify significant activation of the left dorsolateral prefrontal cortex (or its associated network) and the left thalamic nucleus during verbal fluency tasks.108,109 A variety of populations with frontal damage, including patients with many varieties of cortical and subcortical dementia, demonstrate reduced fluency,110 although the underlying neuropsychological impairment causing the reduced fluency varies.111 An advantage of verbal fluency tests is that they are quick to administer (approximately 3 to 8 minutes). However, several variables need to be considered when performance on verbal fluency tasks is interpreted, including (1) the presence of aphasia and (2) premorbid verbal ability112 and educational and vocational achievements,46 which are correlated with fluency performance.
Planning and Hypothesis Generation A further group of tests, such as the Zoo Map test from the BADS,43 require planning and capacity for maintaining goaldirected behavior through dependence on rule adherence. Another of a number of such instruments is the Tower of London task, which requires participants to solve increasingly more difficult spatial problems by planning several moves ahead to resolve the problems in the minimum number of moves.20 The participant is provided with a starting array of different colored beads placed on three pegs (initial position). The task is to move the beads, according to certain rules, across the pegs to achieve a target configuration; the target configurations become increasingly complex, requiring an increasing number of bead moves (Fig. 7–6). Performance is measured in accuracy, latency to initial move, and total time to completion. A computerized version of the task also exists.113 Patients with frontostriatal dysfunction tend to make more rule-breaking errors and perform poorly on the task, often being unable to find solutions to the more complex problems.9,114,115 Although the Tower of London task has been used frequently in research on executive dysfunction, concerns about its reliability116 may limit its use in clinical settings. However, there is some evidence that difficulty in thinking ahead (forming plans of action/goaldirected behavior) during the test may reflect everyday behavioral problems.9
Self-Reports and Informant Reports of Everyday and Emotional Behavior Collateral information in the assessment of executive functioning is vital, because significant executive dysfunction invariably impairs the capacity of affected patients to gauge the effects of their actions on other people, and awareness of social performance in everyday life is frequently observed to be diminished.13 Systematic reports gathered from friends and relatives
90
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
( 2 moves)
Initial position
( 4 moves)
( 5 moves)
Goal position
Goal position
Goal position
(No. 2)
(No. 6)
(No. 10)
■
Figure 7–6. The Tower of London Test.
Tower of London Test
assist in clarifying the impact of executive dysfunction on everyday functioning and behavior. To this end, the Dysexecutive Questionnaire43 has been developed as a 20-item self-report and informant report on the difficulties related to executive dysfunction in everyday life. Preliminary analysis identified three factors in the questionnaire (behavior, cognition, and emotion), and a moderately high correlation was established between tests of executive functions (BADS43) and the factor scores derived from informant (family) ratings. Although some other groups were unable to replicate these relationships,117,118 Chan subsequently identified a five-factor structure within a healthy community sample and reported correlations between these Dysexecutive Questionnaire factors and tests of executive function.119 These results were supported and extended in a later study of patients with traumatic brain injury.120 The Dysexecutive Questionnaire, when completed by a health professional, has also been reported to be sensitive to executive dysfunction that follows traumatic brain injury (although it is less accurate when completed by family or patient rating), and it has been suggested that it can be used effectively as a screening instrument to identify executive disorder, through this method of administration.121 Another assessment based on a structured interview of an informant is the Neuropsychiatric Inventory.122 This 10-domain scale was initially developed to fractionate and quantify psychopathology in dementia, but it includes areas of behavior that are relevant to executive dysfunction. The Neuropsychiatric Inventory domains concern delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior. Its originators reported that the inventory was both reliable and valid.122 A self-administered informant-report version (Neuropsychiatric Inventory -Q123) is available. Two recent caregiver-rated questionnaires, designed specifically to assess frontal behavioral change, are the 24-item Frontal Behavioral Inventory124 and the 46-item Frontal Systems Behavioral Scale.125 The items in the Frontal Behavioral Inventory were selected to reflect the core symptoms of frontal lobe–related dementias, whereas the Frontal Systems Behavioral Scale covers the three principal frontal behavioral syndromes: apathy (mesial), disinhibition (orbitofrontal), and (cognitive) executive dysfunction (dorsolateral). Good reliability has been reported for both scales, although an advantage of the Frontal Systems Behavioral Scale is availability of large-scale norms (436 persons; age range, 18 to 95 years), and the availability of self- and family informant–rating versions.125
QUALITATIVE OBSERVATIONS AND BEDSIDE TESTS Qualitative Observations The non-neuropsychologically trained clinician can nevertheless make important qualitative observations about patients with the dysexecutive syndrome. Social inappropriateness in the form of intrusiveness or suggestive comments may be evident. In the dementia clinic in which one of the authors works, this is often displayed or evident only to an examiner of the opposite gender; thus, there is an advantage in the team approach. Apathy is often confused with depression, but it lacks the transmitted affect of despair. A related phenomenon is decreased verbal output, characterized by minimally elaborated answers to questions, with associated lack of spontaneous propositional speech. Apparent indifference (blunted unconcern) displayed while family informants relate a torrid tale of deterioration in behavior, performance, and interpersonal relationships is an important observation, although it is also wise to interview informants separately from the patient. Stereotyped motor behavior or purposeless motor activity may also be evident. Utilization behavior, as a manifestation of stimulus boundedness, may be evident spontaneously or specifically sought.
Bedside Testing Individual Bedside Tests A range of behaviors characteristic of frontal system disorders can provide insight into the features of executive dysfunction. Motor perseveration may be evident in copying drawings of repeating patterns (e.g., “+ 0 + + 0 + + + 0 . . .”), and motor impersistence—often initially evident as a failure to keep eyes closed during sensory testing—can be quantitated.126 Impairment of sequencing can be sought through motor control tests such as Luria’s fist/edge/palm test.127 Sometimes patients may even say the correct sequence aloud while performing it incorrectly: another example of the “curious dichotomy between knowing and doing.”107 Cognitive inhibition may be demonstrated on the antisaccade test,128 as well as on the conflicting tapping test (“tap once when I tap twice, and tap twice when I tap once”) and the go–no-go test (“tap once when I tap once, but don’t tap at all when I tap twice”).127 In each case, the patient should be
chapter 7 executive function and its assessment able to repeat the instructions correctly after having performed the maneuvers incorrectly, to ensure that failure was not attributable merely to impairments of comprehension or memory. It is traditional to test “abstraction” using proverb interpretation. Although this has been formalized as the Gorham proverb test,129 it is problematic because known proverbs may well elicit known interpretations (i.e., they may actually test semantic memory), whereas unknown proverbs may have a number of possible interpretations, which inhibits response. The California Proverbs test45 was intended to overcome this through the use of a multiple-choice format with proverbs of graded unfamiliarity, but tests of word similarities (e.g., “clock”/“thermometer,” “bicycle”/“train,” “poem”/“statue,” and “bridge”/“tunnel”) and differences (“dwarf”/“child,” “river”/ “canal,” “laziness”/“idleness,” “character”/“reputation”)6 are easier to apply in the clinic or at the bedside. Judgment is sometimes assessed by asking patients what they would do in a hypothetical situation, such as if they found water flooding into their kitchen. The difficulty with this approach is that patients may know and give the “correct” answer but do something quite different in practice. An informal adaptation of Shallice’s and Evans’s Cognitive Estimation test,130 which also has several American versions,6 is an examination of practical judgment. For example, patients might be asked how fast a racehorse can gallop (any answer of more than 40 miles/65 km per hour is incorrect), how tall the tallest building in the city is, how many slices are in a loaf of bread, or what the length of the average man’s spine is.
ably always abnormal.134,135 Release signs are more likely to be significant (if still nonlocalizing) in younger patients (younger than 50 years). This subject has been reviewed in depth.135
CONCLUSION Executive function fractionates into subskills, and different executive tests measure different components of executive function. Therefore, within any clinical assessment, more than one test of executive function is required, and the choice of tests must be guided not only by the cognitive and neural model to be used to interpret executive function but also by the presenting complaint of the patient. In many cases, qualitative features of test performance may be critical in the delineation of executive disorder. The challenge for clinical assessment of executive dysfunction in office-based settings continues to be finding a relationship between office-based test performance and performance in everyday activities.
K E Y
Executive function refers to components of cognition that allow humans to form relevant goals, plan how to achieve them, and successfully carry out the intended actions.
●
Executive function is a complex cognitive domain, consisting of a number of subcomponents. Several theories successfully account for many aspects of executive dysfunction: prominent theories include those of working memory, developed by Baddeley, and the supervisory attentional system, originally set out by Shallice. Such theories are not mutually exclusive, however.
●
Although the terms prefrontal or frontal function and executive function are often used interchangeably, executive functions depend on the integrity of neural networks encompassing structures beyond the prefrontal cortex. Damage to these other structures (e.g., caudate nuclei) can also result in executive dysfunction.
●
At least three such networks that include prefrontal cortex have been identified, involving dorsolateral, orbitofrontal, and mesial frontal cortices. Disruption of these networks results in major deficits in planning/sequencing/set-shifting, response inhibition/impulse control, and motivation/drive, respectively. Patients frequently exhibit a combination of two or more of these syndromes.
●
Standard neuropsychological assessment in a managed environment can often be surprisingly unrevealing, and even classic “executive” tasks can be insensitive to orbitofrontal or mesial frontal damage. Informant history and behavioral observations form an important part of the assessment in patients with dysexecutive syndromes.
●
Non-neuropsychologically trained clinicians can make important behavioral observations and use various bedside techniques to qualitatively examine aspects of executive functioning.
Release Signs (Primitive Reflexes) Release signs, or primitive reflexes (e.g., palmomental, glabellar tap, snout and grasp reflexes), are sometimes sought as evidence of “frontal” involvement. They are thought to represent reappearance of infantile reflexes as a result of loss of inhibition from higher centers, but they have relatively poor localizing value,132 although asymmetrical release signs (palmomental/grasp) are more likely in asymmetrical disease (e.g., strokes) than in diffuse degenerations. Also, about 16% of normal elderly persons have at least one primitive reflex; the palmomental is the least specific for dementia and a grasp response the most specific.133 Even normal elderly individuals do not have three or more, however, and a grasp reflex is prob-
P O I N T S
●
The Frontal Assessment Battery A number of such bedside tests, comprising similarities, phonemic verbal fluency (generation of words beginning with “S”), Luria’s fist/edge/palm test, conflicting tapping, and the grasp response have been assembled into the Frontal Assessment Battery.131 This takes less than 10 minutes to perform, and instructions and scoring details are given in the appendix to the original article. The Frontal Assessment Battery demonstrated high interrater reliability of .87, good internal consistency, good concurrent validity against other measures thought to be sensitive to (but not specific for) executive dysfunction (including the WCST), and 89% accuracy in distinguishing patients with “frontal” disorders from controls. Its specificity for patients with executive dysfunction as distinct from other types of cognitive deficits has not, however, yet been established.
91
92
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Suggested Reading Crawford JR, Henry JD: Assessment of executive dysfunction. In Halligan PW, Wade N, eds: The Effectiveness of Rehabilitation for Cognitive Deficits. London: Oxford University Press. 2005, 233-245. Lezak MD, Howieson DB, Loring DW: Neuropsychological Assessment, 4th ed. Oxford, UK: Oxford University Press, 2004. Miller BL, Cummings JL, eds: The Human Frontal Lobes— Functions and Disorders. New York: Guilford Press, 1999. Stuss DT, Knight RT, eds: Principles of Frontal Lobe Function. New York: Oxford University Press, 2002.
References 1. Macmillan M: An Odd Kind of Fame: Stories of Phineas Gage. Cambridge, MA: MIT Press, 2000. 2. Eslinger PJ, Damasio AR: Severe disturbance of higher cognition following bilateral frontal lobe ablation. Neurology 1985; 35:1731-1741. 3. Andrewes DG: Neuropsychology: From Theory to Practice. East Sussex, UK: Psychology Press, 2001. 4. Banich M: Cognitive Neuroscience and Neuropsychology, 2nd ed. Boston: Houghton Mifflin, 2004, pp 365-392. 5. Bechara A, Damasio H, Damasio AR: Emotion, Decision Making and the Orbitofrontal Cortex. Cereb Cortex 2000; 10:295-307. 6. Lezak MD, Howieson DB, Loring DW: Neuropsychological Assessment, 4th ed. Oxford, UK: Oxford University Press, 2004. 7. Luria AR: The Working Brain. Harmondsworth, UK: Harper & Row, 1973. 8. Robbins TW: Dissociating executive functions of the prefrontal cortex. Phil Trans R Soc Lond B 1996; 351:1463-1471. 9. Shallice T, Burgess P: Deficits in strategy application following frontal lobe damage in man. Brain 1991; 114:727-741. 10. Stuss DT, Alexander MP: Executive functions and the frontal lobes: a conceptual view. Psychol Res 2000; 63:289-298. 11. Cahn-Weiner DA, Ready RE, Malloy PF: Neuropsychological predictors of everyday memory and everyday functioning in patients with mild Alzheimer’s disease. J Geriatr Psychiatry Neurol 2003; 16:84-89. 12. Griffith HR, Belue K, Sicola A, et al: Impaired financial abilities in mild cognitive impairment. Neurology 2003; 60:449457. 13. Manchester D, Priestley N, Jackson H: The assessment of executive functions: coming out of the office (a review). Brain Injury 2004; 18:1067-1081. 14. Baddeley AD: Is working memory still working? Am Psychol 2001; 56:849-864. 15. Baddeley AD, Logie R: Working memory: the multiplecomponent model. In Miyake A, Shah P, eds: Models of Working Memory. New York: Cambridge University Press, 1999, pp 28-61. 16. Baddeley AD: Exploring the central executive. Q J Exp Psychol A 1996; 49:5-28. 17. Miyake A, Friedman NP, Emerson MJ, et al: The unity and diversity of executive functions and their contributions to complex “frontal lobe” tasks: a latent variable analysis. Cogn Psychol 2000; 41:49-100. 18. Rabbitt PMA, ed: Methodology of Frontal and Executive Functions. Hove, UK: Psychology Press, 1997. 19. D’Esposito M, Postle BR: The Neural Baiss of Working Memory Storage, Rehearsal, and Contral Processes: Evidence from Patient and Functional Magnetic Resonance Imaging Studies. In Squire L, Schacter D, eds: Neuropsychology of Memory 3rd edn. New York: Guilford Press, 2002, pp 215-224.
20. Shallice T: Specific impairments of planning. Philos Trans R Soc Lond B 1982; 298:199-209. 21. Cooper R, Shallice T: Contention scheduling and the control of routine activities. Cogn Neuropsychol 2000; 17:297338. 22. Stuss DT, Shallice T, Alexander MP, et al: A multidisciplinary approach to anterior attentional functions. Ann N Y Acad Sci 1995; 769:191-212. 23. Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986; 9:357-381. 24. Cummings JL: Fronto-subcortical circuits and human behaviour. Arch Neurol 1993; 50:873-880. 25. Miller BL, Cummings JL: The Human Frontal Lobes: Functions and Disorders. New York: Guilford Press, 1998. 26. Tekin S, Cummings JL: Frontal-subcortical neuronal circuits and clinical neuropsychiatry. An update. J Psychosom Res 2002; 53:647-654. 27. Mendez MF, Adams NL, Lewandowski KS: Neurobehavioral changes associated with caudate lesions. Neurology 1989; 39:349-354. 28. Zakzanis KK, Leach L, Kaplan E: Neuropsychological Differential Diagnosis. Lisse, The Netherlands: Swets & Zeitlinger, 1999, pp 73-82 and 173-193. 29. Royall DR, Lauterbach EC, Cummings JL, et al: Executive control function: a review of its promise and challenges for clinical research. J Neuropsychiatry Clin Neurosci 2002; 14:377-405. 30. Lhermitte F, Pillon B, Serdaru M: Human autonomy and the frontal lobes. Part I: Imitation and utilization behavior: a neuropsychological study of 75 patients. Ann Neurol 1986; 19:326-334. 31. Nathaniel-James DA, Fletcher P, et al: The functional anatomy of verbal initiation and suppression using the Hayling test. Neuropsychologia 1997; 35:559-566. 32. D’Esposito M, Postle BR, Rypma B: Prefrontal cortical contributions to working memory: evidence from event related fMRI studies. Exp Brain Res 2000; 133:3-11. 33. Damasio AR: Descartes’ Error: Emotion, Reason, and the Human Brain. New York: GP Putnam, 1994. 34. Gilbert SJ, Frith CD, Burgess PW: Involvement of rostral prefrontal cortex in selection between stimulus-oriented and stimulus-independent thought. Eur J Neurosci 2005; 21:1423-1431. 35. Houx PJ, Shepherd J, Blauw G-J, et al: Testing cognitive function in elderly populations: the PROSPER study. J Neurol Neurosurg Psychiatry 2005; 73:385-389. 36. Lezak M: The problem of assessing executive functions. Int J Psychol 1982; 17:281-297. 37. Burgess PW: Theory and methodology in executive function and research. In Rabbitt P, ed: Methodology of Frontal and Executive Function. Hove, UK: Psychology Press, 1997, pp 81-116. 38. Alderman N, Burgess PW, Knight C, et al: Ecological validity of a simplified version of the multiple errands shopping test. J Int Neuropsychol Soc 2003; 9:31-44. 39. Stone VE, Baron-Cohen S, Knight RT: Frontal lobe contributions to theory of mind. J Cogn Neurosci 1998; 10:640656. 40. Rahman S, Sahakian BJ, Hodges JR, et al: Specific cognitive deficits in mild frontal variant frontotemporal dementia. Brain 1999; 122:1469-1493. 41. Crawford JR, Obonsawin MC, Bremner M: Frontal lobe impairment in schizophrenia: Relationship to intellectual functioning. Psychol Med 1993; 23:787-790. 42. Obonsawin MC, Crawford JR, Page J, et al: Performance on tests of frontal lobe function reflect general intellectual ability. Neuropsychologia 2002; 40:970-977.
chapter 7 executive function and its assessment 43. Wilson BA, Alderman N, Burgess P, et al: Behavioural Assessment of the Dysexecutive Syndrome. Bury St. Edmunds, UK: Thames Valley Test Company, 1996. 44. Grigsby J, Kaye K, Shetterly SM, et al: Prevalence of disorders of executive cognitive functioning among the elderly: findings from the San Luis Valley Health and Aging Study. Neuroepidemiology 2002; 21:213-220. 45. Delis D, Kaplan E, Kramer J: Delis-Kaplan Executive Function Scale. San Antonio, TX: Psychological Corporation, 2001. 46. Stroop JR: Studies of interference in serial verbal reaction. J Exp Psychol 1935; 18:643-662. 47. Dodrill CB: A neuropsychological battery for epilepsy. Epilepsia 1978; 19:611-623. 48. Golden C: Stroop Color and Word Test Manual (Cat. 30150M). Chicago: Stoelting, 1978. 49. Trennery MR, Crosson B, DeBoe J, et al: Stroop Neuropsychological Screening Test. Tampa, FL: Psychological Assessment Resources, 1989. 50. Stuss DT, Floden D, Alexander MP, et al: Stroop performance in focal lesion patients: dissociation of processes and frontal lobe lesion location. Neuropsychologia 2001; 39:771-786. 51. Cabeza R, Nyberg L: Imaging cognition II: an empirical review of 275 PET and fMRI studies. J Cogn Neurosci 2000; 12:1-47. 52. Peterson BS, Skudlarski P, Getenby JC, et al: An fMRI study of Stroop Word-Color Interference: evidence for anterior cingulate subregions subserving multiple distributed attentional systems. Biol Psychiatry 1999; 45:1237-1258. 53. Spreen O, Strauss E: A Compendium of Neuropsychological Tests: Administration, Norms and Commentary, 2nd ed. New York: Oxford University Press, 1998. 54. Bohnen N, Jolles J, Twijnstra A: Modification of the Stroop Color Word Test improves differentiation between patients with mild head injury and matched controls. Clin Neuropsychol 1992; 6:178-184. 55. Bondi MW, Serody AB, Chan AS, et al: Cognitive and neuropathologic correlates of Stroop Color-Word Test Performance in Alzheimer’s disease. Neuropsychology 2002; 16:335-343. 56. Snowden J, Craufurd D, Griffiths H, et al: Longitudinal evaluation of cognitive disorder in Huntington’s disease. J Int Neuropsychol Soc 2001; 7:33-44. 57. Ponsford J, Kinsella G: Attentional deficits following closed head injury. J Clin Exp Neuropsychol 1992; 14:822838. 58. Burgess PW, Veitch EJ, Costello AdeL, et al: The cognitive and neuroanatomical correlates of multitasking. Neuropsychologia 2000; 38:848-863. 59. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation, 2nd ed. Tucson, AZ: Neuropsychology Press, 1993. 60. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery: research findings and clinical application. In Kaufman AS, ed: Specific Learning Disabilities and Difficulties in Children and Adolescents: Psychological Assessment and Evaluation. New York: Cambridge University Press, 2001, pp 309-346. 61. Arbuthnott K, Frank J: Trail Making Test Part B as a measure of executive control: validation using a set-switching paradigm. J Clin Exp Neuropsychol 2000; 22:518-528. 62. Korrte KB, Horner MD, Windham WK: The Trail Making Test Part B: cognitive flexibility or ability to maintain set? Appl Neuropsychol 2002; 9:106-109. 63. Crowe SF: The differential contribution of mental tracking, cognitive flexibility, visual search, and motor speed to performance on Parts A and B of the Trail Making Test. J Clin Psychol 1998; 54:585-591.
93
64. Lamberty GJ, Putnam SH, Chatel DM, et al: Derived Trail Making Test indices: a preliminary report. Neuropsychiatry Neuropsychol Behav Neurol 1994; 7:230-234. 65. Ratti MT, Bo P, Giardini A, et al: Chronic alcoholism and the frontal lobe: which executive functions are impaired? Acta Neurol Scand 2002; 105:276-281. 66. Stuss DT, Bisschop SM, Alexander MP, et al: The Trail Making Test: a study in focal lesion patients. Psychol Assess 2001; 13:230-239. 67. Moll J, De Oliveiro-Souza R, Moll FT, et al: The cerebral correlates of set-shifting. An fMRI study of the Trail Making Test. Arq Neuropsiquiatr 2002; 60:900-905. 68. Maj M, D’Elia L, Satz P, et al: Evaluation of two new neuropsychological tests designed to minimise cultural bias in the assessment of HIV-1 seropositive persons: a WHO study. Arch Clin Neuropsychol 1993; 8:123-135. 69. Ponton MO, Gonzalez JJ, Hernandez I, et al: Factor analysis of the Neuropsychological Screening Battery for Hispanics (NeSBHIS). Appl Neuropsychol 2000; 7:32-39. 70. Lee TM, Chan CC: Are trail making and color trails tests of equivalent constructs? J Clin Exp Neuropsychol 2000; 22:529534. 71. Tombaugh TN: Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol 2004; 19:203-214. 72. Hester RL, Kinsella GJ, Ong B, et al: 2005 Demographic influences on baseline and derived scores from the Trail Making Test in healthy older Australian adults. Clin Neuropsychol 19:45-54. 73. Goldman WP, Baty JD, Buckles VD, et al: Cognitive and motor functioning in Parkinson disease: subjects with and without questionable dementia. Arch Neurol 1998; 55:674680. 74. Pillon B, Gouider-Khouja N, Deweer B, et al: Neuropsychological pattern of striatonigral degeneration: comparison with Parkinson’s disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1995; 58:174-179. 75. Chen P, Ratcliffe G, Belle SH, et al: Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology 2000; 55:1847-1853. 76. Chen P, Ratcliffe G, Belle SH, et al: Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001; 58:853858. 77. Hestad K, Aukrust P, Ellertsen B, et al: Neuropsychological deficits in HIV-1 seropositive and seronegative intravenous drug users (IVDUs): a follow-up study. J Int Neuropsychol Soc 1996; 2:126-133. 78. Heun R, Papassotiropoulos A, Jennssen F: The validity of psychometric instruments for detection of dementia in the elderly general population. Int J Geriatr Psychiatry 1998; 13:368-380. 79. Lunn S, Skydsbjerg M, Schulsinger H, et al: A preliminary report on the neuropsychologic sequelae of human immunodeficiency virus. Arch Gen Psychiatry 1991; 48:139-142. 80. Paul R, Moser D, Cohen R, et al: Dementia severity and pattern of cognitive performance in vascular dementia. Appl Neuropsychol 2001; 8:211-217. 81. Selnes OA, Jacobson L, Machado AM, et al: Normative data for a brief neuropsychological screening battery. Multicenter AIDS Cohort Study. Percept Mot Skills 1991; 73:539-550. 82. Grant DA, Berg EA: A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. J Exp Psychol 1948; 38:404411. 83. Heaton RK, Chelune GJ, Talley JL, et al: Wisconsin Card Sorting Test. Manual Revised and Expanded. Odessa, FL: Psychological Assessment Resources, 1993.
94
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
84. Perry RJ, Hodges JR: Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer’s disease. Neurology 2000; 54:2277-2284. 85. Parker DM, Crawford JR: Assessment of frontal lobe function. In Crawford JR, Parker DM, McKinlay WW, eds: A Handbook of Neuropsychological Assessment. London: Erlbaum, 1992, pp 267-291. 86. Nelson HE: A modified card sorting test sensitive to frontal lobe damage. Cortex 1976; 12:313-324. 87. Drewe EA: The effect of type and area of brain lesions on Wisconsin Card Sorting Test performance. Cortex 1974; 10:159170. 88. Milner B: Effects of different brain lesions on card sorting. Arch Neurol 1963; 9:90-100. 89. Anderson CV, Bigler ED, Blatter DD: Frontal lobe lesions, diffuse damage, and neuropsychological functioning in traumatically brain-injured patients. J Clin Exp Neuropsychol 1995; 17:900-908. 90. Axelrod BN, Goldman RS, Heaton RK, et al: Discriminability of the Wisconsin Card Sorting Test using the standardization sample. J Clin Exp Neuropsychol 1996; 18:338-342. 91. Mountain MA, Snow WG: Wisconsin Card Sorting Test as a measure of frontal pathology: a review. Clin Neuropsychol 1993; 7:108-118. 92. Hanks RA, Rapport LJ, Millis SR, et al: Measures of executive functioning as predictors of functional ability and social integration in a rehabilitation sample. Arch Phys Med Rehabil 1999; 80:1030-1037. 93. Logie RH, Cocchini G, Della Sala S, et al: Is there a specific executive capacity for dual task coordination? Evidence from Alzheimer’s disease. Neuropsychology 2004; 18:504-513. 94. Baddeley AD, Baddeley HA, Bucks RS, et al: Attentional control in Alzheimer’s disease. Brain 2001; 124:1492-1508. 95. Holtzer R, Burright RG, Donovick PJ: The sensitivity of dualtask performance to cognitive status in aging. J Int Neuropsychol Soc 2004; 10:230-238. 96. Alderman N: Central executive deficit and response to operant conditioning methods. Neuropsychol Rehabil 1996; 6:161186. 97. Wilson BA, Evans JJ, Greenfield E, et al: Test of Divided Attention. London: Thames Valley Test Company, 2005. 98. Henry JD, Crawford JR: A meta-analytic review of verbal fluency performance following focal cortical lesions. Neuropsychology 2004; 18:284-295. 99. Benton AL, Hamsher KdeS: Multilingual Aphasia Examination. Iowa City: AJA Associates, 1989. 100. Crowe SF: Dissociation of two frontal lobe syndromes by a test of verbal fluency. J Clin Exp Neuropsychol 1992; 14:327339. 101. Salmon DP, Heindel WC, Lange KL: Differential decline in word generation from phonemic and semantic categories during the course of Alzheimer’s disease: implications for the integrity of semantic memory. J Int Neuropsychol Soc 1999; 5:692-703. 102. Perret E: The left frontal lobe of man and the suppression of habitual responses in verbal categorical behaviour. Neuropsychologia 1974; 12:323-330. 103. Henry JD, Crawford JR: Verbal fluency deficits in Parkinson’s disease: a meta-analysis. J Int Neuropsychol Soc 2004; 10:608-622. 104. Baldo J, Shimamura AP, Delis DC, et al: Verbal and design fluency in patients with frontal lobe lesions. J Int Neuropsychol Soc 2001; 7:586-596. 105. Rende B, Ramsberger G, Miyake A: Commonalities and differences in the working memory components underlying letter and category fluency tasks: a dual-task investigation. Neuropsychology 2002; 16:309-321.
106. Troyer AK, Moscovitch M, Winocur G: Clustering and switching as two components of verbal fluency: evidence from younger and older healthy adults. Neuropsychology 1997; 11:138-146. 107. Walsh K: Understanding Brain Damage, 2nd ed. Edinburgh: Churchill Livingstone, 1991. 108. Brannen JH, Badie B, Moritz CH, et al: Reliability of functional MR imaging with word-generation tasks for mapping Broca’s area. AJNR Am J Neuroradiol 2001; 22:1711-1718. 109. Paulescu E, Goldacre B, Scifo P, et al: Functional heterogeneity of left inferior frontal cortex as revealed by fMRI. Neuroreport 1997; 8:2011-2016. 110. Stuss DT, Alexander MP, Hamer LP, et al: The effects of focal anterior and posterior brain lesions on verbal fluency. J Int Neuropsychol Soc 1998; 4:265-278. 111. Henry JD, Crawford JR, Phillips LH: Verbal fluency performance in dementia of the Alzheimer’s type: a meta-analysis. Neuropsychologia 2004; 42:1212-1222. 112. Crawford JR, Moore JW, Cameron IM: Verbal fluency: a NARTbased equation for the estimation of premorbid performance. Br J Clin Psychol 1992; 31:327-329. 113. Robbins TW, James M, Owen AM, et al: A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. J Int Neuropsychol Soc 1998; 4:474-490. 114. Lewis SJ, Cools R, Robbins TW, et al: Using executive heterogeneity to explore the nature of working memory deficits in Parkinson’s disease. Neuropsychologia 2003; 41:645654. 115. Owen AM: Cognitive dysfunction in Parkinson’s disease: the role of fronto-striatal circuitry. Neuroscientist 2004; 10:525557. 116. Humes G, Welsh MC, Retzlaff P, et al: Towers of Hanoi and London: reliability and validity of two executive function tasks. Assessment 1997; 4:249-257. 117. Bogod NM, Mateer CA, McDonald SWS: Self-awareness after traumatic brain injury: a comparison of measures and their relationship to executive functions. J Int Neuropsychol Soc 2003; 9:450-458. 118. Norris G, Tate RL: The Behavioural Assessment of the Dysexecutive Syndrome (BADS): ecological, concurrent, and construct validity. Neuropsychol Rehabil 2000; 10:33-45. 119. Chan RC: Dysexecutive symptoms among a non-clinical sample: a study with the use of the Dysexecutive Questionnaire. Br J Psychol 2001; 92:551-565. 120. Chan RCK, Manly T: The application of “dysexecutive syndrome” measures across cultures: performance and checklist assessment in neurologically healthy and traumatically braininjured Hong Kong Chinese volunteers. J Int Neuropsychol Soc 2002; 8:771-780. 121. Bennett PC, Ong B, Ponsford J: Measuring executive dysfunction in an acute rehabilitation setting: Using the Dysexecutive Questionnaire (DEX). J Int Neuropsychol Soc 2005; 11:376-385. 122. Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314. 123. Kaufer DI, Cummings JL, Ketchel P, et al: Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci 2000; 12:233239. 124. Kertesz A, Nadkarni N, Davidson W, et al: The Frontal Behavioral Inventory in the differential diagnosis of frontotemporal dementia. J Int Neuropsychol Soc 2000; 6:460-468. 125. Grace J, Malloy PF: Frontal Systems Behavior Scale. Professional manual. Odessa, FL: Psychological Assessment Resources, 2001.
chapter 7 executive function and its assessment 126. Benton AL, Sivan AB, Hamsher KdeS, et al: Contributions to Neuropsychological Assessment, 2nd ed. New York: Oxford University Press, 1994, pp 137-149. 127. Christensen A-L: Luria’s Neuropsychological Investigation, 2nd ed. Copenhagen: Munksgaard, 1979, p 44. 128. Currie J, Ramsden B, McArthur C, et al: Validation of a clinical antisaccade eye movement test in the assessment of dementia. Arch Neurol 1991; 48:644-648. 129. Gorham DR: A proverbs test for clinical and experimental use. Psychol Rep Monogr 1956; 2:1-12. 130. Shallice T, Evans ME: The involvement of the frontal lobes in cognitive estimation. Cortex 1978; 14:294-303. 131. Dubois B, Slachevsky A, Litvan I, et al: The FAB: a frontal assessment battery at bedside. Neurology 2000; 55:16211626.
95
132. Jenkyn L, Walsh D, Culver C, et al: Clinical signs in diffuse cerebral dysfunction. J Neurol Neurosurg Psychiatry 1977; 40:956-966. 133. Hogan DB, Ebly EM: Primitive reflexes and dementia: results from the Canadian Study of Health and Aging. Age Ageing 1995; 24:375-381. 134. Di Legge S, Di Piero V, Altieri M, et al: Usefulness of primitive reflexes in demented and non-demented cerebrovascular patients in daily clinical practice. Eur Neurol 2000; 45:104110. 135. Walterfang M, Velakoulis D: Cortical release signs in psychiatry. Aust N Z J Psychiatry 2005; 39:317-327.
CHAPTER
COMA
BRAIN DEATH
AND ●
8
●
●
●
Jeffrey V. Rosenfeld and Peter J. Lennarson
Assessing the level of consciousness and diagnosing the cause of coma are fundamental aspects of medical practice. Consciousness consists of two main components: the level of alertness or arousal and the content of thought. Impairment of arousal is a continuum from drowsiness to stupor and then to coma. In stupor, the patient awakens briefly in response to stimulation and then slips back into a sleeplike state. There is no verbal response. Coma is the inability of the patient to be aroused (i.e., to obey commands, speak, or open the eyes in response to painful stimuli). This is obviously different from a sleep state from which the individual can be aroused. Stupor and coma of recent onset are medical emergencies. Speedy diagnosis and treatment are imperative for achieving the optimal outcome; however, a discussion of the treatment of the many causes of coma is beyond the scope of this chapter. The term brain death implies that the functions of the human brain have irreversibly ceased while other body organ functions continue. Brain death is an important diagnosis because, when made, life support can be validly terminated, allowing the reassignment of resources to patients who can benefit from them. Second, establishing a diagnosis of brain death might expand the number of organs available for transplantation, inasmuch as families of brain-dead patients could be approached with regard to their interest in organ donation. Raising this possibility of organ donation with a family is critical, because even if a patient has declared his or her intentions regarding organ donation before death, the final decision rests with the next of kin in many jurisdictions. The many important ethical issues surrounding brain death are also explored in this chapter; the physician should be cognizant of these so as to offer appropriate advice to the family and to treat the patient with dignity.
CONSCIOUSNESS An appreciation of the phenomenon of consciousness should precede a discussion of coma or “unconsciousness.” Many aspects of consciousness still remain a cardinal mystery of the human being. The essence of consciousness is an awareness of the environment and of the self. This awareness at least involves perception and memory, but the prerequisites for consciousness are alertness and attention. Primary consciousness is the state of having mental images of the present (the “remembered present”). Higher order consciousness is the ability to be aware of being conscious and is accompanied by memories of
the past and the ability to plan for the future. It requires semantic ability, which is the ability to attach meaning to a symbol, and also the ability to manipulate those symbols. Higher order primates may have higher order consciousness to a limited degree. Qualia are the high-order perceptions of qualities, such as the warmth of warm or the redness of red, that are experienced in the normal conscious state.1 Free will, conscience, metamemory (knowledge and beliefs about the functioning of one’s own memory systems), the analysis of one’s own thoughts, and imagination are all integral components of human higher order consciousness that remain mysterious. Much of the planning and execution that humans perform is unconscious or preconscious in the “zombie mode.” An example is sensory processing and gating. The automatisms of complex partial seizures are an extended pathological example of this. Penfield (1937) showed that electrical stimulation of the cortex could alter the content of consciousness and produce “experiential responses” that the patient usually realized were unreal. The “déjà vu” phenomenon is a natural example of this. The neural correlates of consciousness are slowly yielding to the study of individual and group neuronal electrical activity, through the use of surface cortical electrodes and implanted microelectrodes, and to functional brain imaging. Although there is a modularity to brain function, it is the integration of all the modules that is necessary for consciousness. There also seems to be competition between different cortical areas and neurons to choose the best fit for a set of perceptual inputs. There are “essential nodes” for particular perceptions such as face recognition or color perception. Clearly, multiple nodes and regions of the brain, functioning in concert, are necessary for consciousness to exist.2,3 Both the cerebral cortex and subcortical structures such as the thalamus are involved in consciousness. Dandy described temporary loss of consciousness after removal of both frontal lobes with sacrifice of the anterior cerebral arteries at the genu of the corpus callosum and speculated that the striatal damage was responsible for the coma.4 The reticular nucleus that surrounds the thalamus acts as a switch or “gate” to particular thalamic nuclei. It results in different patterns of activity of the thalamic nuclei and therefore in different weighting of sensory input. The intralaminar nucleus of the thalamus sets thresholds for the cortical response to the thalamic input. Thalamic gating is also influenced by feedback from the prefrontal
97
98
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
cortex.5 The filtering of sensory information is done at a preconscious level so that attention is selectively directed, although it can also be altered at will. Moruzzi and Magoun6 in 1949 produced electroencephalographic arousal by stimulating the brainstem reticular formation rostral to the mid-pons. They termed this system, including its rostral projection, the ascending reticular activating system (ARAS). This is an alerting or arousal system that also indirectly influences sensory processing in the cerebral cortex. It projects rostrally through the midline, intralaminar nucleus, and other nuclei of the thalamus, and via these structures to the cerebral cortex. Attention enables an awake and alert individual to select a task or a stimulus to process from a number of alternatives and to select a cognitive strategy to carry it out.5 The ARAS is thought to facilitate this process by enhancing the perception of differences between competing stimuli. The anterior cingulate gyrus is involved in a wide range of attentional and discriminatory activity and is involved in higher order motor control of many tasks. The parietal cortex is involved in attention in the visual field and the pulvinar of the thalamus is involved in selecting information for attention. The dorsolateral prefrontal cortex is also involved in attention, intention, and working memory; working memory is the term applied to the holding and manipulation of the current content of consciousness. The hippocampal system—including the fornices, the mammillary bodies and mammillothalamic tracts, the amygdala, the anterior thalamic nuclei, the medial dorsal thalamic nuclei, and the entorhinal cortex—are all involved with establishing new anterograde episodic memory. The amygdala, hippocampus, and associated limbic and nonlimbic structures are involved in the generation of internal feelings, emotions, and motivation.5 Various brainstem and basal nuclei form ascending and descending neural systems that influence large areas of the brain by releasing particular neurotransmitters. The cholinergic nuclei, such as the basal forebrain nuclei, the pedunculopontine nucleus, and the laterodorsal tegmental nuclei, play a role in alertness and arousal. Acetylcholine is probably an important neurotransmitter for memory function. The noradrenergic locus ceruleus and lateral tegmental nuclei of the pons assist in responding to sudden contrasting or adverse stimuli, and the locus ceruleus projection to the forebrain and visual cortex is involved in attention. The majority of the cell bodies of the dopaminergic system are in the ventral brainstem tegmentum and are involved in motor function and cognition. The dopaminergic nigrostriatal projection is also involved in motor function and attention. The serotonergic system of the midline raphe nuclei of the tegmentum, largely inhibitory in nature, has a stabilizing effect on information processing, is involved in sleep, and modulates the sleep-wake cycle. The g -amino butyric acid (GABA) inhibitory neurons are widely dispersed throughout the central nervous system and are involved with the selection of sensory information. Barbiturates increase GABAergic activity in the ARAS. Glutamate and aspartate are the excitatory neurotransmitters that play a key role in cortical interplay.5 The N-methyl-D-aspartate (NMDA) receptor may be the main target for the action of general anesthetic agents that produce a pharmacological coma. The corollary, that the NMDA receptor is essential for consciousness, constitutes the Flohr hypothesis, about which there is considerable debate.7 Clearly, many other peptides and receptors are also involved in cortical function and consciousness.
Single neurons in the human entorhinal cortex have very specific responses (e.g., only to faces or only to different types of animal), and some temporal lobe neurons function at a different hierarchical level by responding to the extensively processed perception or imagining of an object and not to the raw retinal input.2 Different components of consciousness therefore seem to exist from the level of individual neurons to that of different brain regions and, indeed, that of the whole brain. Edelman (2004) proposed a theory called neural Darwinism, or neuronal group selection, to explain consciousness, as opposed to an instructive model in which the brain has computer-like properties with a set of programs and algorithms. The three tenets of neural Darwinism are that (1) developmental selection leads to a highly diverse group of circuits, (2) experiential selection leads to changes in the connection strength of synapses, and (3) reentrant mapping occurs, in which brain maps are coordinated in space and time through reentrant signaling across reciprocal connections. This coordination leads to widespread synchronization of widely dispersed neuronal groups, which integrates information such as the color and orientation of visual objects and which Edelman proposed is central to the understanding of consciousness. This is a possible solution to the binding problem, which is the seamless reintegration of separately processed aspects of a sensory percept at a preconscious level. According to neural Darwinism, the brain is a selectional system. Other examples of such systems in nature are evolution and the immune system. Another important characteristic of the brain is degeneracy, in which different elements of the brain can perform the same function and one element can carry out different functions in different neuronal networks at different times. This creates great diversity of brain function. There is no need in the theory of neural Darwinism for a homunculus in the head directing the brain and being the seat of consciousness.1 The principal neural structures of consciousness according to Edelman’s (2004) theory are the cerebral cortex, the thalamus, and the reentrant loops between the two, which he called the dynamic thalamocortical core. He proposed that this neural activity generates the qualia of consciousness. The gamma, or 40-Hz, rhythm of the electroencephalogram (EEG) is believed to be produced by thalamocortical circuits during attention and sensory processing tasks. Attention is directed partly by the reticular nucleus of the thalamus and partly by the relationship of the basal ganglia to the frontal and parietal cortices. Higher order consciousness is based in part on episodic memory, which depends on the hippocampi, and in part on semantic and linguistic ability, which depend on the language cortices of Broca and Wernicke and associated areas (for further reading, see Edelman, 2004; Jasper et al, 1998; John, 2002; Metzinger, 2002; Young et al, 1998; Zeman, 2001).
COMA The Etiology of Coma The fundamental causes of coma are structural, including the mechanical deformation or disruption of neural tissue and ischemia, and metabolic or toxic derangement of neural tissue, inducing hypoxia. A detailed list of the causes is presented in
chapter 8 coma and brain death
99
T A B L E 8–1. Etiology of Coma Toxic/Metabolic Causes Metabolic and endocrine derangements Hypothermia or hyperthermia Hypoglycemia Diabetic ketoacidosis Hyperosmolar nonketotic coma Renal failure: uremia Hepatic failure: hyperammonemia Reye’s syndrome Hyponatremia/hypernatremia Hypocalcemia Panhypopituitarism Myxedema Adrenal cortical failure (addisonian crisis) Porphyria Hypertensive encephalopathy Nutritional Wernicke’s encephalopathy (thiamine deficiency) Vitamin B12 deficiency Burn encephalopathy Septicemic/toxic shock Hypoxic brain injury Asphyxiation Drowning Anoxemic anoxia (low PaO2) (e.g., as in cardiac arrest) Anemic anoxia (e.g., as in hemorrhagic shock) Toxic brain damage Alcohol, carbon monoxide, cyclosporine, etc. Drug overdose Opiates, barbiturates, benzodiazepines, etc. Inflammatory: vasculitis/infectious processes Meningitis (bacterial) Encephalitis Postinfectious encephalomyelitis (ADEM) Lupus cerebritis and other vasculitides Neurosarcoidosis Neoplastic Leptomeningeal carcinomatosis Dementing processes (end-stage, although PVS is more usual) Epilepsy Status epilepticus (including nonconvulsive status epilepticus) Postictal state Structural Causes Traumatic brain injury Diffuse axonal injury Epidural hematoma Subdural hematoma Intracerebral hematoma Penetrating brain injury Intracranial hemorrhage Subarachnoid hemorrhage Subarachnoid hemorrhage (spontaneous) Aneurysm rupture Arteriovenous malformation rupture Tumor hemorrhage Hemorrhage (spontaneous) Intracerebral, cerebellar, or brainstem Infarction Cerebral, cerebellar, or brainstem Intracranial infection Subdural empyema Focal encephalitis (herpes simplex) Cerebral abscess Brain tumor Primary neoplasm Secondary neoplasm Hydrocephalus Obstructive Communicating ADEM, acute disseminated encephalomyelitis; PaO2, partial pressure of arterial oxygen; PVS, persistent vegetative state.
■
Figure 8–1. Computed tomographic scan showing the trajectory of small metal shrapnel fragments across both thalami and internal capsules of a young man who was a victim of a bomb blast. The entry point was just above and behind the right ear, and one fragment was lodged beneath the temporal bone on the left side. He remained deeply comatose after this injury, breathing spontaneously but with minimal response of his limbs to pain and with no eye opening.
Table 8–1. A detailed history from bystanders or relatives is vital in determining the cause of the coma.
The Anatomy and Pathophysiology of Coma Diffuse lesions of both cerebral hemispheres (cortical and subcortical white matter) may cause coma. Bilateral diencephalic damage (especially to the paramedian dorsal thalamus) may also cause coma (Fig. 8–1). The extension of the thalamic lesions into the midbrain tegmentum has an even greater propensity for causing coma or severe neurological deficit, apathy, and impaired attention. Damage to the paramedian gray matter anywhere from the posterior hypothalamus to the tegmentum of the lower pons causes coma.8,9 When the respiratory centers in the lower medulla are damaged, apnea ensues. The testing of brainstem reflexes and for apnea is the clinical means of confirming the destruction of theses critical areas. The irreversible destruction of critical brainstem areas usually follows catastrophic supratentorial events that cause brain herniation and subsequent compression and ischemia of the brainstem. The sequence of cardiovascular changes resulting from progressive mechanical compression and/or ischemia of the brainstem begins with vagal stimulation, which causes decreases in heart rate, mean arterial pressure, and cardiac output. As the pons becomes ischemic, sympathetic stimulation occurs, which results in hypertension with persistence of the bradycardia (Cushing’s reflex). As the medulla becomes ischemic, there
100
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
is unopposed sympathetic stimulation with tachycardia, increased mean arterial pressure, and increased cardiac output. This sequence has been called an “autonomic storm” and has not been well recognized in intensive care unit patients, partly because it may have occurred by the time the patient is admitted to intensive care unit and may be affected by treatment or the presence of other injuries.10
Clinical Assessment of the Comatose Patient A full neurological and general examination of the patient must be undertaken. Some of the pertinent components of the examination are described as follows.5,9
Assessment of the Conscious State The Glasgow Coma Scale (GCS) was devised to provide a simple, reliable, and reproducible method of assessment of conscious state so as to avoid misinterpretation and blurring of terms such as stupor, semicoma, and confusion.11 It has become a universally accepted scale for neurological observation, prognostication, and grading severity and has been found to have good interrater reliability. It was originally a 14-point scale but has been extended to 15 points by splitting limb flexion into two tiers: flexion-withdrawal and flexion-abnormal. Abnormal flexion is defined as any two elements of stereotyped flexion posture, extreme wrist flexion, adduction of the upper arm, and fisting of the fingers over the thumb.12,13 The 15-point scale is the preferred scale for research studies. The GCS is scored on the best response in each of the three categories: eye opening, vocalization, and limb movement (Table 8–2). Testing nail bed pressure with a pencil is the recommended method of applying a painful stimulus. Patients who do not open their eyes, do not speak, and are not obeying commands are said to be comatose. Many clinicians regard a maximum GCS score of 8 as the cutoff for coma. Some limitations to the usefulness of the GCS do exist, however. For example, periorbital swelling and endotracheal intubation, both common conditions in the trauma patient, prevent the accurate assessment of eye opening and verbal response, respectively. Some centers record a “T” next to the score when the patient is intubated and the verbal score cannot be assessed. The GCS is commonly used to monitor neurological progress, and a drop in the GCS of 2 points or more is a sensitive measure of neurological deterioration and necessitates action to halt the progression. Age and depth of coma are the principal predictors of poor outcome or death after traumatic brain injury. Repeated GCS assessments and the recognition of confounding factors are required for any confidence in prediction of outcome. The conscious state is more difficult to assess in infants and young children, and special pediatric coma scales have been devised.14 The Paediatric Glasgow Coma Scale is a simple system based on the GCS with age-related norms for verbal and motor responses (see Table 8–2).15 A rapid and simple assessment of conscious state is the “AVPU” system, in which the examiner assesses the level of response on a four-tiered scale: A is alertness, V is any response to vocal stimuli (what response? opens eyes? moves? vocalizes? any of the above?), P is response only to painful stimuli, and U is unresponsiveness to all stimuli. This scale is used in the primary survey of trauma patients as taught on the Advanced
T A B L E 8–2. Glasgow Coma Scale and Paediatric Glasgow Coma Scale Glasgow Coma Scale (Adult): 15 Points (Teasdale and Jennett14) Response
Paediatric Glasgow Coma Scale: 14 Points (Simpson and Reilly16) Score
Response
Score
Eye Opening Spontaneous To sound To pain Nil
4 3 2 1
Eye Opening Spontaneous To sound To pain Nil
4 3 2 1
Best Verbal Response Oriented Confused conversation Inappropriate words Incomprehensible sounds Nil
5 4 3 2 1
Best Verbal Response Oriented Words Vocal sounds Cries Nil
5 4 3 2 1
Best Motor Response* Obeys commands Localizes pain Flexion-withdrawal Flexion-abnormal Extension None
6 5 4 3 2 1
Best Motor Response Obeys commands Localizes pain Flexion Extension Nil
5 4 3 2 1
Maximum Score
15
Maximum Score
14
*Teasdale and Jennett’s 14-point scale, which was described in 1974,11 has a total of 5 points for the best motor score because there is only one tier for flexion, rather than two tiers, as in the 15-point scale, which is currently used in most centers.
Trauma Life Support Course of the American College of Surgeons. The GCS may also be used in the primary survey and is used in the secondary trauma survey, which includes a comprehensive general examination.
Respiratory Pattern 1. Normal pattern. 2. Cheyne-Stokes: periodic increase and decrease of rate and depth, followed by an expiratory pause and then a repeated pattern; seen with diencephalic pathology and bilateral hemisphere dysfunction (nonspecific). 3. Hyperventilation: raises suspicion of hypoxia or metabolic coma with acidosis, such as with ethylene glycol, methanol, salicylates, and lactic acidosis. Central neurogenic hyperventilation may occur with midbrain damage. 4. Cluster breathing: periods of rapid irregular breathing separated by periods of apnea; is similar to Cheyne-Stokes respiration but without the crescendo/decrescendo pattern or regularity of the latter. This is seen with high medullary or low pontine lesions. 5. Apneustic breathing: deep inspiration followed by breath holding, then long slow expiration at a rate of 6 breaths per minute; implies pontine damage (e.g., basilar artery occlusion). It is a rare pattern. 6. Ataxic (Biot’s) breathing: irregular and disorganized breathing; occurs with medullary dysfunction and is usually preterminal.
chapter 8 coma and brain death Vital Signs
101
1.
The blood pressure, pulse, capillary return, core temperature, and the state of hydration should all be ascertained. Eyes deviate to the side of lesion • Left frontal lobe lesion
Pupil Examination Pupillary size, shape, and reaction are integral components of the assessment of conscious state. The light reflex is the most useful in distinguishing metabolic from structural causes of coma. 1. Equal-sized and reactive pupils in a comatose patient indicate a metabolic or toxic cause, with the exceptions of anoxia, anticholinergics, glutethimide, and botulinum toxin, which cause fixed, dilated pupils. Narcotics cause small pupils (miosis) that react sluggishly. 2. Unequal-sized pupils imply a structural lesion of the brain or cranial nerves. One caveat is that direct ocular trauma may produce a mydriasis. A pupil that dilates after a cerebral insult is indicative of changing intracranial pathology with increasing tension on the ipsilateral oculomotor nerve resulting from uncal herniation through the tentorial hiatus. Dilated nonreactive pupils from the time of an injury imply irreparable brain damage or bilateral optic nerve injury. The miosis of Horner’s syndrome implies disruption of the sympathetic nervous system input to the pupil and may follow carotid occlusion or dissection, among other causes. 3. Bilateral pinpoint pupils occur with pontine lesions that leave the parasympathetic nerves unopposed. 4. Bilaterally fixed and dilated pupils (7 to 10 mm) occurs with medullary injury, with post-tonsillar or central herniation, after anoxia, or with hypothermia (<32° C). 5. Bilateral nonreactive pupils at the midposition(4 to 6 mm) occurs with an extensive midbrain lesion.
2.
Eyes deviate away from the lesion • Left pontine lesion • Left medial thalamic lesion
3.
Eyes deviate downward • Midbrain pretectal lesion • Thalamic lesion • Metabolic/toxic cause 4.
Left III nerve palsy • Patient looking straight ahead 5.
Right VI nerve palsy • Patient looking to the right side 6.
Eye Motion: Extraocular Muscle Function
(Fig. 8–2)
Deviation of the Ocular Axes
Left hypertropia • III or IV nuclear or nerve injury • Lesion of medial longitudinal fasciculus
Bilateral conjugate deviation ■ Frontal lobe lesion (frontal center for contralateral gaze):
■
Figure 8–2. Eye motion: extraocular muscle dysfunction.
the eyes look toward the side of the lesion. ■ Pontine lesion: the eyes look away from the side of the lesion. ■ Medial thalamic lesion: the eyes look away from the side of the lesion. ■ Downward deviation: thalamic or midbrain pretectal lesions, metabolic cause (especially barbiturates).
second and a pause of 2 to 3 seconds in each direction. This may indicate bilateral cerebral dysfunction.
Unilateral outward deviation with dilated pupil (nerve III palsy) Unilateral inward deviation (nerve VI palsy) Skew deviation: nerve III or IV nuclear or nerve injury, or an infratentorial lesion, especially of the dorsal midbrain.
Internuclear ophthalmoplegia is caused by a lesion of the medial longitudinal fasciculus. The eye on the side of the lesion does not adduct on spontaneous or reflex-induced eye movement.
Spontaneous Eye Movement
Reflex Eye Movement
Ocular bobbing with rapid downward movement of the eyes and a slow return occurs with pontine lesions. Random conjugate eye movements are nonspecific for lesion location. In the uncommon periodic alternating gaze (“ping-pong gaze”), the eyes deviate side to side with a frequency of three to five per
Internuclear Ophthalmoplegia
Oculocephalic reflex (doll’s-eye reflex) In the awake patient, the eyes follow the movement of the head or, if the movement is performed slowly, there is contraversive conjugate eye movement if the eyes fixate on a stationary
102
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
target. In the comatose patient with intact brainstem and cranial nerves, the reflex is preserved and the eyes move in the opposite direction when the head is turned laterally or the neck flexed and extended; that is, the conjugate eye movement is contraversive. When the brainstem is damaged, the reflex is lost, and the eyes follow the head movement. Cervical spine injury should be ruled out before this test is performed.
1
Oculovestibular reflex (iced water calorics) The head of the bed is elevated 30 degrees (to place the “horizontal” semicircular canals in the true vertical position), and one ear is irrigated with 50 to 100 mL of iced water. A comatose patient with an intact brainstem has tonic conjugate eye movement to the side of the cold stimulus which may be delayed up to one minute or more. There is no fast component (the nystagmus), which is present in the conscious subject. Absence of response results from brain death, neuromuscular blockade, metabolic causes, and massive infratentorial pathology. Nystagmus without tonic deviation occurs in psychogenic coma. Tympanic membrane rupture or external auditory canal obstruction by blood or debris should be ruled out before this test is performed.
2 3
5 4
Optokinetic nystagmus Optokinetic nystagmus is a rhythmic involuntary conjugate ocular movement in response to the movement of full visual field images, either rotation of an image before the subject, such as a drum with vertical black stripes on a white background, or rocking of a mirror back and forth in front of the patient’s eyes. There is a biphasic response with an initial slow phase provoked by, and in the direction of, the stimulus. This is followed by a fast corrective phase. Optokinetic nystagmus may be elicited in patients feigning coma.
Motor Examination Decorticate posturing is abnormal flexion of the upper limbs (adduction of the arm and slow flexion of the elbow, wrist, and fingers) and extensor posturing of the lower limbs (extension, internal rotation, and plantar flexion). It occurs with large cortical or subcortical lesions. The corticospinal pathway is interrupted above the level of the midbrain. Decerebrate posturing occurs with a brainstem injury at the level of the midbrain or below. There is said to be disinhibition of the vestibulospinal tract and pontine reticular formation by removal of inhibition of the medullary reticular formation (i.e., the “transection” is at the intercollicular level between the red nuclei and the vestibular nuclei in the classical lesion). There is abnormal extension of the upper and lower limbs with extended adducted and hyperpronated arms and extended and internally rotated legs, plantar-flexed and inverted feet, plantarflexed toes, variably clenched teeth, and opisthotonos. Flexed arms with flaccid legs may occur with a lesion in the pontine tegmentum. Flaccid arms with appropriate leg movements may occur after anoxic brain injury.
■
Figure 8–3. Schematic diagram showing the various types of brain herniation. 1, Subfalcine or cingulate herniation, in this case caused by an adjacent tumor. Note the midline shift of the septum pellucidum resulting from the mass lesion in the adjacent portion of the brain. 2, Transtentorial uncal herniation with midbrain compression, in this case caused by an acute epidural hematoma. 3, Central herniation with vertical descent of the brainstem. 4, Cerebellar tonsillar herniation through the foramen magnum with compression of the medulla. 5, Upward cerebellar herniation with upper brainstem compression.
disturb the conscious state by direct or indirect pressure on the diencephalon and brainstem. Indirect pressure means displacement of tissue at a distance from the mass. Coning is the name given to progressive cerebral herniation with secondary compression of the brainstem and resultant deepening coma. Computed tomography (CT) and magnetic resonance imaging have helped significantly to elucidate the anatomy of herniation. Plum and Posner (1982) in their classic treatise described progressive and predictable stages of herniation with cephalad-caudal progression. There are five types of supratentorial and infratentorial herniation (Fig. 8–3), described as follows.
Supratentorial Herniation Central (Transtentorial) Herniation
Herniation Syndromes (Coning) Cerebral herniation is the displacement of cerebral tissue as a result of intracranial mass lesions. This displacement may
The classic description is of a sequential rostral-caudal failure from diencephalon to the midbrain, the pons, and finally the medulla. Central herniation is often caused by a tumor in the frontal, parietal, or occipital lobes that reaches the point of
chapter 8 coma and brain death
103
T A B L E 8–3. Stages of Central Herniation Diencephalon Stage Consciousness
Respiration Pupils Oculomotor
Motor
Midbrain–Upper Pons Stage Respiration Pupils Oculomotor
Motor Lower Pons–Medulla Stage Respiration Pupils Oculomotor Motor
May be caused by displacement or ischemia of the diencephalon This stage is reversible Altered alertness is first sign Usually lethargy is present Some patients have agitation Later stupor, then coma Sighs, yawns, occasional pauses Small (1-3 mm), reacting Conjugate or slightly divergent roving eyes Doll’s-eye reflex present Parinaud’s syndrome with impaired upward gaze may be present Conjugate ipsilateral response to cold water calorics Early: appropriate response to painful stimulus Contralateral hemiparesis may worsen Bilateral Babinski reflex; later, grasp reflexes Decorticate (contralateral to the lesion initially) Prognosis is very poor when midbrain signs have developed; <5% having a good outcome if treatment is undertaken Cheyne-Stokes respiration → sustained tachypnea Moderately dilated: midposition (3-5 mm), fixed Doll’s-eye reflex impaired May be disconjugate May be internuclear ophthalmoplegia with medial moving eye moving less than the laterally moving eye) Response to calorics impaired Decorticate → bilaterally decerebrate Regular, shallow, and rapid (20-40/minute) Midposition (3-5 mm), fixed No doll’s-eye reflex Response to calorics absent Flaccid, bilateral Babinski reflex May be lower limb flexion in response to pain
Medullary Stage (Terminal Stage) Respiration Slow, irregular; sighs, gasps, occasional hyperpnea alternating with apnea Pupils Widely dilated and fixed Adapted from Greenberg MS: Coma. In Greenberg MS, ed: Handbook of Neurosurgery, 5th ed. New York: Thieme, 2001, pp 118-127. Also see Plum and Posner (1982).
decompensation. The diencephalon may herniate through the tentorial incisura, damaging the pituitary stalk and causing diabetes insipidus. Vertical downward shift of the brainstem may be a critical factor in the development of the features of central herniation.16 The brainstem may become ischemic as a consequence of shearing of perforating arteries from the basilar artery. Resultant hemorrhages in brainstem are called Duret hemorrhages. CT may show a downward displacement of the pineal gland and effacement of the perimesencephalic (ambient) cisterns. The posterior cerebral arteries may be kinked at the tentorial edge as they pass onto the inferior surface of the occipital lobe, which results in occipital infarction and cortical blindness. This may further increase the intracranial pressure. The clinical stages of central herniation are outlined in Table 8–3. It is difficult to discern these various stages (and those of the other types of coning) in many patients because of the speed of deterioration, the tendency of the stages to merge, and the mixed and complex pathology that may affect the supratentorial and infratentorial compartments, and because patients often receive early intervention with paralysis, endotracheal intubation, and ventilation that obscures or retards the clinical progression. Nevertheless, it is useful to think conceptually in these terms in contemplating the patient’s condition and the appropriate treatment.
Uncal herniation The uncus of the temporal lobe herniates over the free edge of the tentorium, compressing the midbrain and the oculomotor nerve. This is usually caused by a rapidly expanding middle cranial fossa epidural, subdural, or intratemporal lobe hematoma. The earliest sign of uncal herniation is the ipsilateral dilation of the pupil. A depressed state of consciousness is not a reliable early sign, but the patient may be confused or agitated. Once the brainstem is compromised, the conscious state may deteriorate rapidly to a deep coma. The mass lesion causing the uncal herniation usually causes a contralateral hemiparesis, but as the pressure increases, the opposite cerebral peduncle is compressed against the tentorium, which causes an ipsilateral hemiparesis (Kernohan’s sign). This is recognized at autopsy as Kernohan’s notch. As in central herniation, the posterior cerebral arteries may be compressed against the edge of the tentorium, which may cause occipital lobe infarcts. The early CT findings of uncal herniation are early unilateral encroachment on the suprasellar cistern and later brainstem displacement and flattening, flattening of the contralateral cerebral peduncle, and rotation of the midbrain. Contralateral hydrocephalus may occur. The clinical stages of uncal herniation are outlined in Table 8–4. The distinction between uncal and central herniation is difficult when the compression has reached the midbrain and
104
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 8–4. The Stages of Uncal Herniation Early Third Nerve Stage Pupils Unilateral dilating pupil, ipsilateral to lesion in 85% of patients; often sluggish Oculomotor Doll’s-eye reflex normal or disconjugate (failure of adduction of ipsilateral eye) Caloric reflex may be disconjugate Respiration Normal Motor Appropriate response to pain Contralateral Babinski reflex may be present Late Third Nerve Stage Consciousness Stupor → coma Pupil Fully dilated (unilateral) Oculomotor Complete third nerve palsy with pupil dilatation (>6 mm) and ophthalmoplegia Respiration Hyperventilation sustained; in rare cases, Cheyne-Stokes respiration Motor Usually contralateral weakness If opposite cerebral peduncle is compressed against the tent, an ipsilateral hemiparesis (Kernohan’s sign) and then bilateral decerebrate posture develop Midbrain–Upper Pons Stage Pupils Contralateral pupil dilates initially to midposition (5-6 mm) Oculomotor Palsy Respirations Sustained hyperpnea Motor Bilateral decerebrate rigidity Adapted from Greenberg MS: Coma. In Greenberg MS, ed: Handbook of Neurosurgery, 5th ed. New York: Thieme, 2001, pp 118-127. Also see Plum and Posner (1982).
below. Prediction of the location of the pathology on the basis of the type of herniation syndrome is unreliable, inasmuch as central and uncal herniation may occur together. Decrease in consciousness occurs early in the sequence of central herniation but later in the sequence of uncal herniation. Cushing’s reflex, consisting of hypertension, bradycardia, and respiratory irregularity, which is a feature of medullary compression, is often absent with slowly progressive supratentorial mass lesions. The cause of the coma and the third nerve palsy in cases of presumed uncal herniation is not always uncal compression, because the degree of uncal herniation on imaging or at autopsy may not be correlated with clinical state. The anatomy varies among patients, and in some cases, there is no uncal herniation or it is the contralateral pupil that dilates first, so that the mechanism of the third nerve palsy is likely to be central (i.e., intrinsic to the midbrain) in these cases. Horizontal displacement of the central supratentorial structures may also contribute to or cause the depressed conscious state (see Investigation of Coma).17
Cingulate or subfalcine herniation The cingulate gyrus herniates beneath the falcine edge. This is usually asymptomatic but may be a prelude to transtentorial herniation. Anterior cerebral artery territory infarction may occur if the anterior cerebral arteries are displaced and kinked by the subfalcine herniation.
as a prelude to tumor excision. The superior cerebellar arteries may be occluded, which causes cerebellar infarction; the cerebral aqueduct may be compressed, which causes hydrocephalus; and cortical blindness may result from kinking of the posterior cerebral arteries. Failure of upward gaze or conjugate downward deviation of the eyes may occur.
Tonsillar herniation The tonsils of the cerebellum herniate, or “cone,” through the foramen magnum with compression of the medulla. Respiratory arrest and death may follow. It is caused by supratentorial and infratentorial mass lesions and may be precipitated by lumbar puncture in a patient with noncommunicating (obstructive) hydrocephalus, because of the increasing pressure differential between the intracranial and intraspinal compartments. Patients who present with initial symptoms of occipital headache, diplopia, vertigo, bilateral limb weakness, and ataxia have a posterior fossa lesion and are likely to deteriorate rapidly. Bilateral motor signs at the onset, small pupils, ophthalmoplegia, multiple cranial nerve palsies, and abnormal breathing patterns are other features. Direct pontine compression by a posterior fossa mass lesion contributes to the clinical features of infratentorial herniation to a variable degree with signs such as loss of eye movements, loss of corneal reflexes, miosis, and decerebrate posturing.
Differential Diagnosis of Coma Infratentorial Herniation Upward cerebellar herniation In this type of herniation, the cerebellar vermis ascends through the tentorial incisura. This is sometimes seen with large cerebellar mass lesions and is exacerbated or precipitated by supratentorial ventricular drainage or shunting performed
The differential diagnosis of coma includes (1) the “locked-in” syndrome, which may occur with ventral pontine infarction (see Chapter 9); (2) psychiatric disorder with catatonia or hysterical conversion reaction; (3) neuromuscular weakness with unreversed neuromuscular blockade, which may be encountered in the intensive care unit; (4) myasthenia gravis; and (5) Guillain-Barré syndrome.
chapter 8 coma and brain death The Investigation of Coma The order and scope of the investigation of the patient in coma depends on the likely cause, the urgency of the situation, and the resources available. A detailed description is beyond the scope of this chapter. Some of the relevant investigations are electrolyte measurements, liver function tests, toxicology screen, blood glucose measurement, blood gas measurement, and full blood examination. CT should be performed urgently to establish the presence of a structural lesion, determine whether there are any radiological signs of brain herniation or midline shift, and determine whether urgent neurosurgical intervention is required. Midline shift is the degree of horizontal shift of midline cerebral structures as seen on axial images and is correlated with the conscious state. Anteriorly, the midline is the septum pellucidum between the two frontal horns of the lateral ventricles. Posteriorly, it is the pineal gland, which can be identified on CT if it is calcified. A patient with midline shift is generally alert with 0- to 3-mm shift, drowsy with 3- to 4-mm shift, stuporous with 6- to 8-mm shift, and comatose with 8- to 13-mm shift (Fig. 8–4).17 This correlation of the extent of midline shift with level of consciousness is variable and also depends on the rapidity over which the shift occurred. In our experience, the rapid development of a large midline shift (>2 cm) usually results in a poor outcome or death. A slowly enlarging mass may produce
105
marked midline shift without disturbing the conscious state. The location, as well as the size, of the mass lesion is also an important factor. A large frontal tumor may not cause significant shift, whereas a smaller temporal lobe mass might. Magnetic resonance imaging is also very helpful when the patient is more stable, because more information about the cause of the coma can be obtained. Other investigations that directly concern the neurologist are as follows:
Lumbar Puncture If papilledema is present, a CT scan should always be obtained before lumbar puncture is performed. The finding of an intracranial mass lesion and/or obstructive hydrocephalus is a contraindication to lumbar puncture, because of the risk of cerebellar tonsillar herniation. Absence of papilledema, however, does not rule out the presence of hydrocephalus, inasmuch as papilledema may take 6 to 24 hours or longer to develop. Signs of brain herniation and coagulopathy are also contraindications. Lumbar puncture, when feasible, is an important diagnostic tool for detection of central nervous system infection, inflammation, subarachnoid hemorrhage, and free tumor cells. Patients with communicating hydrocephalus may undergo lumbar puncture without undue risk.
Electroencephalogram The EEG slows in traumatic coma; the amount of slowing is proportional to the depth of coma. There may be some lag before the slowing occurs. There is also a loss of electroencephalographic reactivity to external stimuli, such as noise or eye opening, and a loss of spontaneous variability of the EEG patterns. The prognosis may be better when this reactivity is not completely lost and when there are periodic sleep patterns (“spindle pattern coma”). Burst suppression is the worst pattern short of electrical silence and, unless it is drug induced (e.g., by barbiturates), it is a preterminal finding.18 Alpha coma is widespread alpha (8- to 12-Hz) activity in the presence of coma. This is present over the entire scalp and does not vary with external stimuli. This is in contrast to normal alpha rhythm, which is seen over the occipital lobes of relaxed subjects with their eyes closed and is abolished by their becoming alert. Patients with alpha coma usually have a poor prognosis. The grades of electroencephalographic abnormality have been correlated with prognosis.19,20 The use of phase and coherence data improves the accuracy of the EEG. The EEG is easily perturbed by drugs, and so the clinician must be very careful in interpreting the EEG findings in the intensive care environment.18 Subclinical seizure activity may continue after the cessation of clinical seizures and is a possible cause of persistent coma. This seizure activity may be identified through continuous electroencephalographic monitoring with a single channel with two electrodes, one of which is usually a reference electrode. Repeated or continuous multiple-lead EEGs are obtained routinely in some intensive care units. ■
Figure 8–4. Computed tomographic scan showing a severe
Power Spectral Analysis
degree of midline shift caused by a small acute subdural hematoma and underlying severe hemisphere swelling after a traumatic brain injury. The patient was deeply comatose with dilated and fixed pupils.
Real-time power spectral analysis of the EEG is achieved with a fast Fourier transform algorithm, resolves the EEG into its individual frequency components, and can be displayed over
106
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
time.21 Power spectral analysis simplifies the interpretation of the EEG, but a display of the EEG is still necessary to detect seizures. Power spectral analysis has some predictive value; variable spectral patterns are associated with a better prognosis. An unvarying pattern with the frequency component in the delta range (1 to 3 Hz) carries a poor prognosis.22,23 The overall trend in background frequency mirrors the course of the patient over a number of days. Evoked potentials have less variability over time than does power spectral analysis and therefore are more useful.
Evoked Potentials Evoked potentials measure the response of the cerebral hemispheres or brainstem to a sensory stimulus. Signal-averaging techniques are necessary to eliminate the background and preserve the repeated stimuli at fixed intervals. They have some value in prognostication after brain injury. Loss of wave I of the brainstem auditory evoked potentials (BAEPs) after head injury occurs if the inner ear is damaged, and therefore this loss cannot be used for prognostication in these cases. The absence of BAEPs is predictive of a poor outcome. However, the BAEPs may be normal and the outcome poor after traumatic brain injury because the integrity of the cerebral hemispheres is not measured by BAEPs. Somatosensory evoked potentials (SSEPs) have better prognostic value than BAEPs because they test the integrity of the brainstem and the cerebral hemispheres. The absence of any activity beyond wave P15 is highly predictive of death. P15 is the SSEP wave thought to arise from the caudal medulla. N20 is the first cortical peak and is thought to arise from the postcentral gyrus. The presence of SSEP activity beyond 50 to 70 milliseconds appears essential for functional survival. Activity occurring beyond 70 milliseconds has particular prognostic value for quality outcome after anoxic or traumatic brain injury. However, elderly patients may do poorly despite the prediction for a good outcome on the basis of the SSEP. The SSEPs often deteriorate over time after traumatic brain injury and may be absent with high doses of barbiturates.18 Testing for visual evoked responses is not often performed in the comatose patient but may be used to assess the integrity of the visual pathways.
BRAIN DEATH Concepts of human death have evolved over the centuries. The ancient Greeks believed the heart was the essence of life and that absence of the heartbeat was the principal sign of death. Maimonides, the famous Jewish physician and philosopher in the 12th century, believed that breathing, not heartbeat, was the essence of life and that cessation of breathing defined death. He recognized that the decapitated body was dead: Even though there were muscle spasms, there was no central control. He believed the central control of locomotion was also as essential to life as breathing.24 The modern concept of brain death was developed in the 1950s with the advent of mechanical ventilation because patients with irreparable brain damage and apnea could have their heartbeat temporarily sustained. Mollaret and Goulon25 used the term le coma dépassé (a “state beyond coma”) to describe patients in profound coma, although they did not assert that those patients were dead. There were further reports of the same condition with varying causes, and in 1968
an ad hoc committee of the Harvard Medical School formulated criteria asserting that patients with irreversible apnea, areflexia, and complete unresponsiveness from devastating brain injury were legally dead.26 These concepts and the tests for brain death were further refined over two decades, and the declaration of brain death became a widely accepted practice in industrialized nations by the mid-1990s.24 Current opinion holds that death is a process rather than a single event and that the time of death is an arbitrary point on a continuum. Organs and tissues cease to function and eventually die at different times, depending on the cause of death. Most commonly, the death of the patient follows a cardiac arrest, with the brain dying subsequently: first the cortex and then the brainstem. Less commonly, respiratory arrest comes first, followed by brain death and then cardiac arrest within 15 to 30 minutes. Sometimes the brain dies first, followed by respiratory arrest and eventually by anoxic cardiac arrest. The arrest may be postponed many days by maintaining the patient’s oxygenation, ventilation, fluid input, and blood pressure by artificial means, but these patients are accepted as being already dead because there is brainstem death. This seemingly ambiguous state of having a patient with a beating heart, circulation, urine output, and metabolism but with a dead brain is a technological artifact that lengthens the completed process of death of the entire body. Cardiac arrest is not enough, in its own right, to declare death of the patient, because a person can be resuscitated or the heartbeat recommenced during cardiac surgery. It is the death of the brainstem in this situation that determines the death of the patient.
The Whole Brain Formulation Bernat24 defined death as the permanent cessation of function of the “organism as a whole,” which includes the coordination and integration of organ subsystems, the generation of vital functions, and the set of physiological homeostatic mechanisms. It is the “whole brain” that subserves all the clinical functions of the organism. The cerebral cortex directs higher mental function, the diencephalon is responsible for gating and initial processing of sensory input, the hypothalamus regulates homeostatic functions, and vital functions such as heart rate and respiratory drive are controlled by the brainstem. Therefore, permanent cessation of function of the whole brain is required for this formulation. Some subsystems may still be functioning under this definition of death, but they are uncoordinated and meaningless to that individual. Likewise, pockets of functioning neurons after death do not contribute to overall brain function or to the person’s function as a whole. This whole brain definition is favored by the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research and is accepted by the Law Reform Commission of Canada, many states of the United States, and several European countries.24 Machado27 proposed a new standard of human death that was based on the concept that consciousness is the key human attribute and provides the highest level of control in the hierarchy of integrating functions in the human being. There must be an irreversible destruction of the anatomical and functional substrata of consciousness throughout the whole brain to diagnose brain death in this formulation. There should be unresponsiveness, no arousal to any stimuli, and no cognitive and affective functions. This definition subtly distinguishes it from
chapter 8 coma and brain death
107
the standard whole brain formulation.27 This concept has not replaced the current formulation.
some people and cultures do not recognize the concept of brain death.32
The Higher Brain Formulation
The Legal or Statutory Definition of Brain Death
The neocortex is essential for consciousness and cognition, which are essential human attributes. The cerebral cortex, not the lower centers or brainstem, subserves awareness, memory, and personal identity. Permanent loss of the neocortex is necessary and sufficient to determine death in the higher brain formulation of death. Continued functioning of the brainstem and diencephalon are irrelevant to the determination of brain death by this definition. This concept was first proposed in 1975 by Veatch28,29 and supported by others.30 According to this definition, patients in a permanent vegetative state (permanent postcoma unresponsiveness) and anencephalic infants are dead. However, there are major conceptual and practical problems with this definition. Patients with loss of neocortex are still breathing spontaneously, and most societies would therefore not declare these individuals dead. There is a “slippery slope” argument to neocortical death in that there are various degrees of cortical and subcortical death, and patients with advanced dementias may manifest a similar situation, although no one would argue that these individuals are brain dead. How would the clinician distinguish these cases? The established diagnosis of permanent vegetative state requires several assessments over a considerable time, but a diagnosis of death cannot be made in this way. The higher brain formulation determines a loss of personhood, not death. Personhood has a spiritual and psychosocial dimension, in contradistinction to the biological dimension of death.24
In 1970, Kansas became the first state to incorporate brain death in a statutory definition of death. By 1993, more than 90% of states in the United States and the majority of industrialized nations had enacted legislation recognizing brain death. The American Bar Association drafted a model statute that stated in 1975, “For all legal purposes, a human body with irreversible cessation of total brain function, according to the usual and customary standards of medical practice, shall be considered dead.”24 This statute does not specify that death can be determined by the irreversible cessation of spontaneous respiratory and circulatory functions in the majority of cases. In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research developed a model statute called the Uniform Determination of Death Act: “An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions or (2) irreversible cessation of all functions of the entire brain, including the brainstem, is dead. A determination of death must be made in accordance with acceptable medical standards.”33 Bernat and associates34 proposed a modification to this statement so that the primary definition was that an individual who has sustained irreversible cessation of all functions of the entire brain, including the brainstem, is dead and that this can be determined (1) in the absence of cardiopulmonary support by prolonged absence of respiratory and circulatory function or (2) in the presence of artificial cardiopulmonary support by the tests of brain function.34
The Brainstem Formulation Brain death in the United Kingdom requires the determination of permanent cessation of brainstem function. This concept was developed in the United Kingdom by Pallis8 (see also Pallis, 1983). He recognized that most of the bedside tests for brain death were tests of brainstem function. The term brainstem death indicates that the whole brain is dead, because even if the cortex or basal ganglia, were alive they would not be able to function without a functioning reticular activating system and the body’s vital functions could not be maintained. In other words, brainstem death is equivalent to brain death. This concept is stated in the U.K. Royal Colleges memorandum of 1979.31 The one conceptual flaw in this determination is the rare possibility of a patient’s being “locked-in” with a functioning cerebral cortex and no clinical evidence of brainstem function, which is not an issue with the whole brain formulation. Typically, patients locked because of pontine tegmental pathology differ from patients with brainstem death in that they still have respiratory movements and often have preserved eye opening or vertical eye movements to command. The EEG may also identify this condition, which is discussed further in Chapter 9. (For further reading, see Pallis, 1983.)
The Circulatory Formulation It held by some conservative theologians, and has been stated by authorities in Japan, Israel, Denmark, and the Islamic countries, that death occurs only when the circulation ceases. Thus,
The Diagnosis of Brain Death From a philosophical standpoint, the development of diagnostic bedside tests for death is dependent on the acceptance of the definition of what constitutes death, followed by the development of criteria for the determination of death. These tests then must be validated.
The United Kingdom Guidelines for Brain Death The criteria for the diagnosis of brain death were published by the U.K. Conference of the Medical Royal Colleges in 197635,36 and were further confirmed in a memorandum of the U.K. Conference of the Medical Royal Colleges in 1979,31 in which it was stated that death could be declared once the criteria were satisfied. The diagnosis of brain death is clinical and does not require any confirmatory laboratory or imaging tests. Four preconditions must be met in order to proceed with the clinical tests to confirm brainstem death: 1. The patient is in deep coma. 2. The patient is apneic and therefore on a ventilator. 3. There is irrecoverable structural brain damage. Traumatic brain injury and massive intracranial hemorrhage are the common causes, but anoxic brain injury, intracranial infection, and brain tumor are other causes. Some time may be required to correct physiological derangements such as hypotension, hypoxia, and raised intracranial pressure (if possible) before this criterion can be established.
108
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
4. Reversible causes of brainstem depression or a state mimicking it must be ruled out. Examples of these are neuromuscular blocking agents, depressant drugs such as barbiturates, hypothermia, and gross metabolic derangement.
the diagnostic criteria for clinical diagnosis of brain death. These are outlined in detail in Table 8–6.
The diagnosis of brain death is not usually made for at least 6 hours or, when the cause is anoxic damage or drug overdose, for at least 24 hours. Our practice has been to wait for at least 24 hours in many cases of traumatic brain injury, partly to give the patient’s relatives a chance to accept the diagnosis and the consequences. The confirmatory tests for brainstem death are simple to perform and should be carried out by two independent senior medical practitioners no less than half an hour apart. (The Australia and New Zealand Intensive Care Society recommends that the two examinations be done at least 2 hours apart.37) The U.K. criteria specify that one examiner be a consultant and the other a senior registrar or consultant. These tests are outlined in Table 8–5. They are essentially tests of brainstem reflexes and are entirely clinical. The time of death is arbitrarily determined at the completion of the second examination. The Royal College of Physicians reviewed the U.K. criteria in 1995 and endorsed the original recommendations.38 Physicians in Australia follow the U.K. criteria.
1. Clinical and neuroimaging evidence of an acute central nervous system catastrophe that is compatible with the clinical diagnosis of brain death. 2. Exclusion of complicating medical conditions that may confound clinical assessment (no severe electrolyte, acid base, or endocrine disturbance). 3. No drug intoxication or poisoning. 4. Core temperature = 32° C (90° F).
The United States Guidelines for Brain Death The U.S. guidelines for brain death were presented by the medical consultants on the diagnosis of death to the President’s Commission for the Study of the Ethical Problems in Medicine and Biomedical and Behavioral Research in 1981.33,39 These guidelines were updated and clarified in 1995 by the Quality Standards Committee of the American Academy of Neurology40 and have achieved wide acceptance in the United States. Brain death is defined as the irreversible loss of function of the brain, including the brainstem. In summary, there are three parts to
Prerequisites
Cardinal Findings The three cardinal findings in brain death are coma, absence of brainstem reflexes, and apnea. The examination of brainstem reflexes and testing for apnea are similar to the U.K. criteria, but the guidelines in Table 8–6 should be referred to for the details.
Apnea Testing Pitfalls in the diagnosis of brain death in the U.S. guidelines are stated as follows: 1. 2. 3. 4.
Severe facial trauma. Preexisting pupil abnormalities. Drug toxicity. Sleep apnea or severe pulmonary disease resulting in chronic retention of CO2.
Clinical Observations Compatible with the Diagnosis of Brain Death The U.S. guidelines state that the following manifestations are occasionally seen and should not be misinterpreted as evidence for brainstem function:
T A B L E 8–5. Confirmatory Tests for Brainstem Death: The United Kingdom Guidelines The Five United Kingdom Criteria No pupillary reflex; pupils fixed and fully dilated No corneal reflex No facial muscle movement in response to facial or peripheral pain (e.g., supraorbital margin pressure over the supraorbital nerve) and no coughing or gag on movement of the endotracheal tube or to suction of the trachea (carinal reflex) Absent caloric vestibulo-ocular reflex; the external auditory canals are clear of wax; when at least 20 mL of ice-cold water is administered by syringe into the external canal on each side, no nystagmus results Apnea test* is performed when the other test results are confirmed: There is no respiratory effort after achieving a PaCO2 of 50 mm Hg (6.65 kPa). In practice, 6 to 8 minutes is often enough even to get above 50 mm Hg. The American Codes recommend 60 mm Hg (8.0 kPa), as does the Australia and New Zealand Intensive Care Society, which also requires a pH of <7.3.37 Additional Criteria Absent oculocephalic (doll’s-eye) reflex. The unconscious patient with an intact brainstem probably has an intact oculocephalic reflex. Cervical fracture or instability should be excluded. The head is turned slowly from side to side, and the axis of the eyes remains pointing straight ahead. This reflex is absent if there is brainstem death and the axis of the eyes follows the position of the head. This reflex can also be elicited with a flexion/extension movement of the head. (Author comment: this test is a less powerful vestibular stimulus than ice-cold calorics, and although a positive result rules out brain death, a negative result cannot substitute for a test with ice-cold calorics.) *Apnea Test It is important that this test be done carefully and according to the instructions so that an attempt is made to maintain the blood oxygen level. The PaCO2 should be ≥40 mm Hg (5.3 kPa) before the ventilator is stopped, because the rise of CO2 is often slow. The patient should be preoxygenated with 100% oxygen for 10 minutes before disconnection, and >6 L/minute of oxygen flow should continue to pass down the endotracheal tube via a catheter while the ventilator is disconnected. Special advice may be required for patients with chronic respiratory disease who are less responsive to raised PaCO2 and depend on hypoxia for their respiratory drive.31,35,36 PaCO2, arterial partial pressure of carbon dioxide.
chapter 8 coma and brain death T A B L E 8–6.
109
Diagnostic Criteria for Clinical Diagnosis of Brain Death: The United States Guidelines
1. Spontaneous movements of the limbs other than pathologic flexion or extension responses. 2. Respiration-like movements (shoulder elevation and adduction, back arching, intercostal expansion without significant tidal volumes). 3. Sweating, blushing, tachycardia. 4. Normal blood pressure without pressor support or sudden increases in blood pressure. 5. Absence of diabetes insipidus. 6. Deep tendon reflexes, superficial abdominal reflexes. 7. The Babinski reflex.40 Spinal reflexes may persist after brainstem death is diagnosed and may include movements of the body in response to light peripheral stimulation or to flexion of the neck or rotation of the body. These tend to occur at the time of the apnea test, during preparation for transport, at the time of abdominal incision for organ transplantation, and in the morgue. These movements involve withdrawal of the lower limbs, raising of
the arms independently of each other, abduction or adduction of the arms, head rotation, back arching, and even attempts to sit to 40 to 60 degrees. These are called Lazarus signs and are usually single events. Deep tendon reflexes, abdominal reflexes, and the Babinski sign may persist. There may also be skin flushing, shivering, sweating, and myoclonic twitching of limb muscles (see Wijdicks, 2001). There is also the maintenance of blood pressure and even some hypertensive response during donor nephrectomy, which may in part result from adrenal medullary stimulation by a reflex spinal arc.37,41 Patients with brain death develop gross vascular regulatory disturbance and a diffuse metabolic cellular injury that leads inexorably to organ failure and eventual cardiac arrest.10 The vascular regulatory disturbance results initially from extreme sympathetic stimulation and, in a second phase, from a failure of sympathetic outflow, which leads to hypotension and reduced cardiac output. This results in impaired autoregulation with vasodilation at the organ level. The cellular injury with a global mitochondrial dysfunction may result part from the
110
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
A ■
B Figure 8–5. Cerebral angiography of a patient with brain death. Note the filling of the external carotid arterial branches (B) but the cutoff of the internal carotid artery at the level of the skull base (A).
hormonal deficiency (e.g., triiodothyronine) from loss of hypothalamic control.10 Myocardial and renal ischemia commonly result. Neurogenic pulmonary edema and coagulopathy may also occur. Patients with a high chance of proceeding to brain death frequently develop hypotension, and cardiac arrest may occur despite active support.10 However, brain death does not always rapidly lead to somatic death. If hemodynamic parameters in patients with brain death are maintained with norepinephrine/epinephrine, cardiac standstill usually occurs within 48 hours, but this period can be extended to a mean of 23 days with the addition of arginine vasopressin.42 Anterior pituitary dysfunction occurs variably after brain death with falls in triiodothyronine, thyroxine, cortisol, prolactin and folliclestimulating hormone levels. However, thyroid-stimulating hormone and adrenocorticotropic hormone levels may remain normal. Posterior pituitary failure causing diabetes insipidus is common after brain death.10 Hypothalamic failure results in hypothermia. What is the validity of the criteria for the diagnosis of brain death? There has never been a case reported in which a person has recovered when the U.K. criteria were satisfied.43 Some intensive care staff and relatives are confused by the presence of spinal reflexes in the patient who is brain dead. These may increase as the brain-dead patient is maintained on mechanical ventilation. Some explanation to these staff and relatives is required. The diagnosis of brain death is now widely accepted in industrialized countries by both hospital staff and the lay public.
The Confirmatory Laboratory Tests for Brain Death These investigations are not a substitute for clinical examination except if the full clinical examination cannot be carried
out, as in gross facial trauma, and should not precede it. They are used to confirm the diagnosis. The U.S. guidelines state that these confirmatory laboratory tests are desirable for patients in whom specific components of the clinical testing cannot be reliably performed or evaluated. In order of sensitivity, these tests as stated in the U.S. guidelines are conventional angiography, electroencephalography, transcranial Doppler ultrasonography, radionuclide brain scan, and SSEPs.40
Cerebral angiography and radionuclide brain scan (Figs. 8–5 and 8–6) Blood flow tests such as angiography or radionuclide brain scans show no entry of contrast material or isotope into the brain when either is injected systemically into the brain-dead patient. These tests can usually be performed rapidly and are being used in some centers, in cases in which the clinical diagnosis cannot be confirmed, and in some children. Blood flow studies obviate the need for awaiting the elimination of sedatives such as barbiturates, which can linger for days and delay the diagnosis of brain death, and can be performed in patients with metabolic causes of brain death, in whom the etiology of brain death is unclear.44 The confirmation of diagnosis with imaging is of value in optimizing the timing of organ harvesting, but the use of these confirmatory tests is somewhat controversial and is not universally practiced. Cerebral angiography has been considered the final determinant for confirming the diagnosis of brain death. Blood flow must be absent from the anterior and posterior circulations. The blood flow in the internal carotid stops abruptly in the petrous carotid at the skull base. The carotid siphon does not fill. The vertebral artery flow stops at the atlanto-occipital junction. The external carotid flow remains patent and fills early. A
chapter 8 coma and brain death
■
111
Figure 8–6. Technetium-99m hexamethyl–propylene amine oxime radionuclide scan of a patient with brain death. Note the absence of radionuclide uptake in the cerebral hemispheres and in the posterior fossa.
criticism of the technique is that a subintimal injection may produce a false block to the artery, but this is unlikely in more than one vessel and should not alter a diagnosis made on the basis of a four-vessel angiogram. Correct positioning of the head and correct rate of contrast material injection are important points of technique that, if not adhered to, may introduce some contrast material into cerebral vessels, producing artifactual cerebral blood flow. The contrast material may injure transplantable organs or may reduce remaining cerebral blood flow. The angiogram should be obtained twice at an interval of 20 minutes to make sure the first result is not artifactual. Intracranial blood flow may still be present if the study is done very early after the diagnosis of brain death, particularly if the mechanism did not involve raised intracranial pressure. In cases in which the supratentorial intracranial pressure is raised, the posterior circulation may be present but the carotid flow is absent, because the pressure from the supratentorial compartment has not yet been completely transmitted to the infratentorial compartment.44-46 A radionuclide brain scan showing the brainstem and supratentorial circulation is an alternative to cerebral angiography in diagnosis of brain death.47 The radionuclide test for brain death is reliable, safe, and rapid. Intravenous injection of technetium 99m (Tc-99m) hexamethylpropylene-amine oxime or iodine 123 iodoamphetamine, which cross the blood-brain barrier, results in their accumulation by functioning brain cells, in which they are held for several hours. There is no uptake of these agents when there is widespread neuronal death. These agents are preferred to the blood pool radionuclides (Tc-99m pertechnetate, Tc-99m diethylenetriaminepentaacetic acid, and Tc-99m glucoheptonate), which do not cross the blood-brain barrier, may not demonstrate the state of blood
flow in the posterior fossa on standard scans, and appear to produce more artifact. However, the addition of single photon emission computed tomography can give precise regional information and show whether there is any preservation of posterior fossa blood flow.44 Absence of uptake produces a characteristic “hollow skull” or “empty light bulb” appearance (see Wijdicks, 2001).
Electroencephalography An EEG is not necessary for making the diagnosis of brain death. It is optional39 but is still used in many countries as a confirmatory test of brain death. A 16- to 18- channel instrument should be used for at least 30 minutes of recording. Electrical activity above 2 μV is absent at a sensitivity of 2 μV/mm with the low filter setting at less than 1 Hz and the high filter setting at 70 Hz. The sensitivity and specificity are about 90%. However, if brainstem death is used for diagnosis of brain death, the absence of electrical activity on an EEG is not very helpful because it reflects cortical activity rather than brainstem activity and may show some activity even though all the criteria for brainstem death have been met. The electroencephalographic findings are therefore irrelevant when brainstem death is used to signify brain death8 (see Wijdicks, 2001). It can also be difficult to achieve a flat trace with all the electronic devices around the patient and if high-gain amplification is used. Nonetheless, a flat trace may help the patient’s relatives accept the diagnosis of brain death.
Evoked potentials Both BAEPs and SSEPs can be used as confirmatory tests for brain death, but they have a rather poor predictive value. An
112
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
intact auditory nerve (wave I) is required for BAEP interpretation. In addition, BAEPs are not well correlated with the severity of brain injury. Absence of waves II to V indicates profound brainstem dysfunction; however, some waves may be present in patients who are brain dead, with absence of brainstem reflexes (see Wijdicks, 2001). The median nerve SSEP cortical wave (N20) is typically absent bilaterally in brain death, but it is also absent in 15% to 20% of patients who are comatose but not brain dead. Nevertheless, bilaterally absent SSEPs have an extremely high positive predictive value for failure to recover beyond permanent vegetative state (see Chapter 9). Similar uncertainties arise from the absence of the N18 wave, which is possibly generated in the cuneate nucleus (see Wijdicks, 2001). A single-wave SSEP with a mean latency of 9 milliseconds may be recorded at the level of C2 in patients with brain death. This potential may arise near the cervicomedullary junction and may indicate residual medullary function, but this does not negate the diagnosis of brain death. Erb’s point potentials must be present for the absence of cortical potentials to be interpretable. The evoked potentials may also be contaminated by potentials that are time locked to the stimulus but generated by extracranial sources.
vessels in brain-dead patients. Magnetic resonance spectroscopy reveals high lactate and choline levels and decreased N-acetyl aspartate levels44 (also see Wijdicks, 2001).
Ultrasonography
The tests for brain death in young children and neonates have not been as thoroughly validated as in adults. The diagnosis of brain death in children should not be made in the first 7 days after birth. Confirmatory tests, in addition to the clinical tests, are required in children up to 12 months of age. From 7 days to 2 months of age, two isoelectric EEGs or two radionuclide studies showing absence of intracranial uptake, 48 hours apart, are recommended. From 2 to 12 months of age, this interval need be only 24 hours. In children older than 12 months, the adult criteria can be used with up to 12 hours of observation without the need for electroencephalographic confirmation.50,51 There remains controversy in determination of brain death in the infant younger than 2 months because the clinical test results are difficult to interpret: the blood pressure and the duration and severity of the insult are often uncertain, and the degree of brain damage is difficult to determine on imaging.52 The determination of brain death in the infant is of relevance only for organ donation. Cessation of treatment for the neonate or infant with irreparable brain damage and ahopeless prognosis is common practice. There is controversy as to whether anencephalic newborns are brain dead and can proceed to multiple-organ donation.24 These infants have no cerebral hemispheres but do have a variably functioning brainstem and therefore, according to the definitions and concepts of brain death described previously, are technically not brain dead. Approximately 65% of anencephalic fetuses die in utero, and most anencephalic liveborn infants die in the first few days. Only about 5% are still alive at 1 week.53 Few of these infants die of brain death; most succumb to respiratory failure, cardiac arrhythmia, or sepsis. Our opinion (and that of Bernat24) is that it is not ethically acceptable to take the organs if these infants are still alive. These infants should be declared dead before their organs can be procured.
Transcranial Doppler ultrasonography is a noninvasive, quick bedside test. The characteristic features of brain death on transcranial Doppler ultrasonography are an oscillating movement of the blood column within arteries, short systolic spikes, and an absence of signal in patients in whom it was previously found to be present. Specificity and sensitivity have been found to be as high as 100% and 90% to 99%, respectively. The anterior and posterior circulations and the extracranial vessels must be studied on both sides to minimize false-positive findings. Patients with a large craniotomy or ventricular drains do not undergo this evaluation44 (also see Wijdicks, 2001). The World Federation of Neurology published a consensus opinion for the use of ultrasonography for the diagnosis of brain death.49
Computed tomography CT is performed with and without contrast material and may show the cause of the coma. After injection of contrast material, there is no increase in brain attenuation in the brain parenchyma of patients with brain death, nor is there any significant opacification of the vessels of the circle of Willis. Identification of contrast material in the extracranial soft tissue, the cervical great vessels, or the kidneys should be seen in order to confirm that enough contrast material has been administered. CT angiography can be used to show an absence of flow in the intracranial vessels. Xenon inhalation has been added to CT to detect cerebral blood flow; in the patient with brain death, there is minimal (<1 to 5 mL/100 g/minute) or no cerebral blood flow.44
Magnetic resonance imaging It is not often practicable to obtain magnetic resonance imaging in patients with brain death. Such imaging reveals transtentorial and tonsillar herniation, lack of intracranial flow void, poor gray-white differentiation, and marked contrast enhancement of the nose and scalp. Magnetic resonance angiography, similar to conventional angiography, shows no flow in the intracranial
The Differential Diagnosis of Brain Death Disorders that mimic brain death include hypothermia, acute poisoning, and acute metabolic encephalopathies. It should be possible to rule out these conditions after a detailed assessment of the patient. In rare cases, the coning process or pathology such as hemorrhage spares the medulla, and there is retained respiratory and cardiovascular function in the absence of other brainstem reflexes. Such patients have “isolated medulla oblongata” and do not meet criteria for brain death (see Wijdicks, 2001). The related neurological disorders akinetic mutism, persistent or permanent vegetative state (postcoma unresponsiveness), and the “locked-in” syndrome caused by pontine tegmental disruption have some of the features of brain death, but respiration is preserved. These conditions are discussed further in Chapter 9.
Brain Death in Neonates and Children
Maternal Brain Death and Live Birth It is possible to keep a brain-dead pregnant women alive on a ventilator many weeks until her fetus is mature enough for
chapter 8 coma and brain death delivery. Is it ethically acceptable to do this in order to save the child? In this situation, there is a conflict of interest between the mother and the fetus. Usually the mother’s interests are placed before those of the fetus, so that abortion is permitted if the mother’s health is in jeopardy. However, in this case, the mother is dead; therefore, even though there is indignity to the mother, delay in determination of maternal death and burial, prolonged emotional trauma for the family, and financial costs, it is ethically justified for the interests of the fetus to be placed first. This applies only if the obstetrician believes there is a reasonable chance that the fetus will reach maturity. The closer to term the fetus is, the more likely there will be a healthy delivery. The father should be able make the final decision on the basis of all the information provided. The mother’s wishes, if stated in advance, also need to be considered.24
Research and Teaching with Brain-Dead Patients Brain-dead patients provide an opportunity for clinicians to perform potentially toxic or injurious experiments or for trainees to practice invasive procedures such as intubation or central venous cannulation. Is it ethically acceptable to do this? The procedures or experiments should not interfere with organ donation or autopsy. The trainees may be helping others by improving their skills, and this may outweigh any disadvantage. Although these procedures have often been done without consent in the past, this practice, on balance, is not ethically acceptable. Consent should be obtained for any procedures, even on a brain-dead patient. The research team should not be involved in the brain death determination. LaPuma54 has formulated ethical guidelines for experimentation that, in summary, are as follows: The dignity and humanity of the body should not be violated. The experiment should be well designed and brief. The patient must be declared brain dead. Voluntary and knowledgeable consent must be given by the next of kin. There should be a clear medical importance to the experiment that will yield valuable information, such as a safe or efficacious treatment for a lethal disease. The institutional ethics review board must sanction the research. The investigators pay for the extra time that the patient spends in the intensive care unit.24,54
Religious and Family Attitudes toward Brain Death Although a religious definition of death may depend on the loss of the soul from the body, this concept is not suitable for medical purposes.24 Judeo-Christian religions have generally accepted the concept of brain death. However, some Catholic and Orthodox Jewish scholars have not accepted it, arguing that brain death is not equivalent to death determined by cardiopulmonary criteria because brain life is not equivalent to human life.24 There is differing opinion among rabbis; some say that according to ancient Jewish law (the Halachah), death can be determined only by prolonged cessation of the breathing and heartbeat, which represent life itself, the only exception being decapitation. Other rabbis have argued that brain death is consistent with Halachic law because brain death is the functional equivalent of decapitation.24 Muslims assert that they do not have the right to determine the timing of death— that is, when to terminate support. The Third International
113
Conference of Islamic Jurists considered brain death to be death of a person. Legal death and Sharia principles apply when the following signs are established (see Wijdicks, 2001, page 136): 1. Complete stoppage of the heart and breathing that doctors decide is irretrievable. 2. Complete stoppage of all the vital functions of the brain that the doctors decide is irreversible. It is clearly challenging for religious scholars to apply religious beliefs, precepts, and ancient laws to the modern medical environment, in which technological advance has created artificial and unique conditions. The family may firmly believe that, on religious grounds, brain death is not the true death of their relative and that the ventilator should not be turned off. If this objection is not based on emotional or psychological difficulty in accepting the diagnosis and prognosis, the physician should accept the family’s objections. This does not exclude the withdrawal of some support, such as vasopressor agents, in which case asystole will occur within hours or days. Some states, such as New Jersey, have enacted laws to provide personal religious exemption for the family that does not accept the diagnosis of brain death and desires that ventilation be continued.24 Conflicts between intensive care medical and nursing staff and the family of the brain-dead patient about when to stop artificial ventilation or extubate are common. It is difficult for many families to accept the death of their relative while ventilation and the heartbeat continue. The physicians and nursing staff have an ethical duty to explain clearly to the family what brain death indicates and how it is determined. The facts to emphasize are that cardiorespiratory arrest would have occurred if the ventilator had not been continued, that the patient is legally and biologically dead, and that no patient has ever survived after a diagnosis of brain death. Some families still object because of lack of understanding or a belief that the doctors are wrong. This situation is clearly delicate, but the physician should remain sensitive and compassionate in this situation and allow the ventilator to continue, but the physician can withdraw other aggressive support such as vasopressor drugs.
The Management of Brain Death The family must be fully informed of the likely outcome, and the doctor should try to establish that the relatives are making decisions on the basis of the patient’s wishes rather than their own. It is best if the patient has made known a directive about brain death, as well as his or her wishes regarding organ donation, before death, but this does not often happen.55
Diabetes Insipidus The development of diabetes insipidus often precedes brain death. The hypothalamopituitary axis fails, resulting in a deficiency of antidiuretic hormone secretion. There is polyuria (>250 mL/hour), hypernatremia, hyperosmolality, and dilute urine (urine specific gravity <1.005). 1-Deamino(8-D-arginine) vasopressin, 2 to 4 μg, can be given intravenously regularly or as an infusion to correct diabetes insipidus it if organ donation is contemplated.
114
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Organ Procurement The demand for organ donors has been a main driver for the acceptance and legalization of brain death. Families consenting to organ donation may derive considerable benefit in knowing that some good has come from the tragedy of the death of their loved one. However, there is a common fear held by family members that the diagnosis of brain death will be made prematurely and that organs will be procured while the patient is still alive. There should be no perception by the family of a conflict of interest by the staff. The family should be given sufficient time to accept the diagnosis of brain death before any discussion of organ donation. It is essential that the staff members who raise the issue of organ donation with the family are independent of the physicians treating the patient and that they not approach the family until the diagnosis of brain death is made by the treating physicians. The next of kin has the right to refuse the organ donation even if the patient has declared previously that he or she wishes to be a donor. It must be made very clear to the family that there can be no organ donation procedure unless the diagnosis of brain death is absolutely confirmed and that even if the family chooses not to proceed with organ donation, the ventilation and support will still cease. If the organ donation does not proceed, the patient is extubated after the second set of brain death tests. It is considered ethically acceptable to continue intravenous fluids and to maintain the blood pressure and ventilation of the patient who is declared brain dead until the organs are procured, as long as the delay is not excessive. A model policy on organ donation has been developed by the Australia and New Zealand Intensive Care Society.37
K E Y
P O I N T S
●
Consciousness is an awareness of the environment and of the self. The components of consciousness are alertness and thought content, which consists of primary consciousness, which is the “remembered present,” and higher order consciousness, which is an awareness of the self.
●
Coma is the inability of the patient to be aroused—that is, to obey commands, speak, or open the eyes in response to painful stimulus—and is generally represented by a Glasgow Coma Scale (GCS) score of 8 or less.
●
Coma is caused by mechanical deformation or disruption of neural tissue, ischemia and/or hypoxia of neural tissue, and metabolic or toxic derangement of neural tissue. Central and uncal herniation, vertical descent of the diencephalon and brainstem, horizontal shift of midline supratentorial structures, and direct compression of the brainstem are the mechanical deformations that cause coma.
●
The “whole brain” or brainstem formulations of brain death are the usually accepted clinical and philosophical concepts of brain death in the many countries that permit this diagnosis to be made.
●
The diagnosis of brain death is clinical and does not require any confirmatory laboratory tests. The four necessary preconditions that must be met in order to proceed with
confirmation of brainstem death are that the patient be in deep coma, that the patient be apneic and therefore on a ventilator, that there be irrecoverable structural brain damage, and that reversible causes of brainstem depression have been excluded. ●
The clinician should be aware of the legal and ethical dimensions of brain death and organ transplantation so that the patient is treated with dignity and the patient’s family is treated with respect.
Suggested Reading Edelman GM: Wider than the Sky. The Phenomenal Gift of Consciousness. New Haven, CT: Yale University Press, 2004. Jasper HH, Descarries L, Castellucci VF, et al, eds: Advances in Neurology, Vol 77: Consciousness: At the Frontiers of Neuroscience. Philadelphia, Lippincott Raven, 1998. John ER: The neurophysics of consciousness. Brain Res Rev 2002; 39:1-28. Metzinger T, ed: Neural Correlates of Consciousness. Empirical and Conceptual Questions. A Bradford Book. Cambridge, MA: MIT Press, 2002. Pallis C: ABC of Brainstem Death. London: British Medical Journal Publishers, 1983. Penfield W: The cerebral cortex and consciousness. The Harvey Lectures 1937, 35-39. In: Wilkins RH (Ed). Neurosurgical Classics. 1992. pp 226-241. American Association of Neurological Surgeons. Plum F, Posner JB: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia: FA Davis, 1982. Wijdicks EFM: Brain Death. Philadelphia: Lippincott, Williams & Wilkins, 2001. Young GB, Ropper AH, Bolton CF: Coma and Impaired Consciousness. A Clinical Perspective. New York: McGraw-Hill, 1998. Zeman A: Consciousness [Invited review]. Brain 2001; 124:12631289.
References 1. Edelman GM: Wider than the Sky. The Phenomenal Gift of Consciousness. New Haven, CT: Yale University Press, 2004. 2. Crick F, Koch C, Kreiman G, Fried I: Consciousness and neurosurgery. Neurosurgery 2004; 55:273-282. 3. Valatx JL: Disorders of consciousness: anatomical and physiological mechanisms. Adv Tech Standards Neurosurg 2004; 29:3-22. 4. Dandy W: The location of the conscious center in the brain: The corpus striatum. Bull Johns Hopkins Hosp 1946; 79:3458. 5. Young GB: Consciousness. In Young GB, Ropper AH, Bolton CF, eds: Coma and Impaired Consciousness. A Clinical Perspective. New York: McGraw-Hill, 1998, pp 3-37. 6. Moruzzi G, Magoun HW: Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949; 1:455. 7. Franks NP, Lieb WR: The role of NMDA receptors in consciousness: what can we learn from anesthetic mechanisms? In Metzinger T, ed: Neural Correlates of Consciousness. Empirical and Conceptual Questions. A Bradford Book. Cambridge, MA: MIT Press, 2002, pp 265-269.
chapter 8 coma and brain death 8. Pallis C: Further thoughts on brainstem death. Anaesth Intensive Care 1995; 23:20-23. 9. Plum F, Posner JB: The Diagnosis of Stupor and coma, 3rd ed. Philadelphia: FA Davis, 1982. 10. Power BM, Van Heerden PV: The physiological changes associated with brain death—current concepts and implications for treatment of the brain dead donor. Anaesth Intensive Care 1995; 23:26-36. 11. Teasdale G, Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2:81-84. 12. Jennett B, Teasdale G, Galbraith J, et al: Severe head injuries in three countries. J Neurol Neurosurg Psychiatry 1977; 40:291-298. 13. Teasdale G, Jennett B: Assessment and prognosis of coma after head injury. Acta Neurochir (Vienna) 1976; 34:45-55. 14. Simpson DA, Cockington, RA, Hanieh A, et al: Head injuries in young children: the value of the Paediatric Coma Scale. Review of literature and report on a study. Childs Nerv Syst 1991; 7:183-190. 15. Simpson DA, Reilly PL: Paediatric Coma Scale [Letter]. Lancet 1982; 2:450. 16. Ropper AH: Transtentorial herniation. In Young GB, Ropper AH, Bolton CF, eds: Coma and Impaired Consciousness. A Clinical Perspective. New York: McGraw-Hill, 1998, pp 119-129. 17. Ropper AH: Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. N Engl J Med 1986; 314:953-958. 18. Moulton RJ: Electrical function monitoring. In Reilly PL, Bullock R, eds: Head Injury. Pathophysiology and Management of Severe Closed Head Injury. London: Chapman & Hall, 1997, pp 229-240. 19. Synek VM: EEG abnormality grades and subdivisions of prognostic importance in traumatic and anoxic coma in adults. Clin Electroencephalogr 1988; 19:160-166. 20. Synek VM: Revised EEG coma scale in diffuse acute head injuries in adults. Clin Exp Neurol 1990; 27:99-111. 21. Bickford RG: Computer analysis of background activity. In Remond A, ed: Electroencephalography Informatics: A Didactic Review of Methods and Applications of Electroencephalography Data Processing. Amsterdam: Elsevier, 1977, pp 215-232. 22. Bricolo A, Turazzi S, Faccioli F, et al: Clinical application of compressed spectral array in long-term EEG monitoring of comatose patients. Electroencephalogr Clin Neurophysiol 1978; 45:211-225. 23. Sironi VA, Ravagnati L, Signoroni G, et al: Diagnostic and prognostic value of EEG compressed spectral analysis in post-traumatic coma. In Villani RJ, Papo I, Giovanelli M et al, eds: Advances in Neurotraumatology. Amsterdam: Excerpta Medica, 1982, pp 328-330. 24. Bernat JL: Brain death. In Bernat JL, ed: Ethical Issues in Neurology. Newton, MA: Butterworth-Heinemann, 1994, pp 113143. 25. Mollaret P, Goulon M: Le coma dépassé. Rev Neurol 1959; 101:3-15. 26. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. J Am Med Assoc 1968; 205:337340. 27. Machado C: Is the concept of brain death secure? In Zeman A, Emanuel L, eds: Ethical Dilemmas in Neurology. London: WB Saunders, 2000, pp 193-212. 28. Veatch RM: Defining death: the role of brain function [Editorial]. JAMA 1979; 242:2001-2002. 29. Veatch RM: The whole-brain oriented concept of death: an outmoded philosophical formulation. J Thanatol 1975; 3:13-30. 30. Shann F: A personal comment: whole brain death versus cortical death. Anaesth Intensive Care 1995; 23:14-15.
115
31. Conference of Medical Royal Colleges and their Faculties in the UK: Memorandum on the diagnosis of death. BMJ 1979; 1:322. 32. Pallis C: The position in the USA and elsewhere. ABC of brain stem death. BMJ 1983; 286:209-210. 33. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Defining Death. Medical, Ethical and Legal Issues in the Determination of Death. Washington, DC: U.S. Government Printing Office, 1981, p 160. 34. Bernat JL, Culver CM, Gert B: On the definition and criterion of death. Ann Intern Med 1981; 94:389-394. 35. Conference of Medical Royal Colleges and their Faculties of the UK: Diagnosis of death. Statement issued by the honorary secretary of the Conference of Medical Royal Colleges and their Faculties in the United Kingdom on 11 Oct 1976. BMJ 1976; 1:322. 36. Conference of Medical Royal Colleges and their Faculties of the UK: Diagnosis of brain death. BMJ 1976; 2:1187-1188. 37. Pearson IY: Australia and New Zealand Intensive Care Society Statement and Guidelines on brain death and model policy on organ donation. Anaesth Intensive Care 1995; 23:104-108. 38. Royal College of Physicians. Criteria for the diagnosis of brainstem death. J R Coll Physicians 1995; 29:381-382. 39. Guidelines for the determination of death. Report of the medical consultants on the diagnosis of death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. JAMA 1981; 246:2184-2186. 40. Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommittee the American Academy of Neurology. Neurology 1995; 45:1012-1014. 41. Wetzel R, Setzer N, Stiff JL, et al: Hemodynamic responses in brain dead organ donor patients. Anesth Analg 1985; 64:125128. 42. Yoshioka T, Sugimoto H, Uenishi M, et al: Prolonged hemodynamic maintenance by the combined administration of vasopressin and epinephrine in brain death. Neurosurgery 1986; 18:565-567. 43. Pallis C: Brain stem death. In Braakman R, ed: Handbook of Clinical Neurology, Volume 13: Head Injury. Amsterdam: Elsevier, 1990, pp 441-496. 44. Monsein LH: The imaging of brain death. Anaesth Intensive Care 1995; 23:44-50. 45. Rosenklint A Jorgensen PB: Evaluation of angiographic methods in the diagnosis of brain death. Correlation with local and systemic blood pressure and intracranial pressure. Neuroradiology 1974; 7:215-219. 46. Vatne K, Nakstad P, Lundar T: Digital subtraction angiography (DSA) in the diagnosis of brain death. A comparison of conventional cerebral angiography with intravenous and intraarterial DSA. Neuroradiology 27:155-157, 1985. 47. Reid RH, Gulenchyn KY, Ballinger JR: Clinical use of technetium-99m HM-PAO for determination of brain death. J Nucl Med 1989; 30:1621-1626. 48. Chatrian GE: Electrophysiological evaluation of brain death: a critical appraisal. In Aminoff MJ, ed: Electrodiagnosis in Clinical Neurology. Edinburgh: Churchill Livingstone, 1980, chapter 7. 49. Durocq X, Hassler W, Moritake K, et al: Consensus opinion on the diagnosis of cerebral circulatory arrest using Dopplersonography: Task Force Group on Cerebral Death of the Neurosonology Research Group of the World Federation of Neurology. J Neurol Sci 1998; 159:145-150. 50. Conference of Medical Royal Colleges and their Faculties in the UK: Report of the Working Party on Organ Transplantation in
116
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Neonates. London: Department of Health and Social Security, 1988. 51. Task Force for the Determination of Brain Death in Children: Guidelines for the determination of brain death in children. Arch Neurol 1987; 44:587-588. 52. Volpe JJ: Brain death determination in the newborn. Pediatrics 1987; 80:293-297.
53. Medical Task Force on Anencephaly: The infant with anencephaly. N Engl J Med 1990; 322:669-674. 54. La Puma J: Discovery and disquiet: research on the brain dead. Ann Intern Med 1989; 109:606-608. 55. Emanuel LL, Barry MI, Stoeckle JD, et al: Advance directives for medical care: a case for greater use. N Engl J Med 1991; 324:889-895.
CHAPTER
9
THE PERSISTENT VEGETATIVE STATE (PROLONGED POSTCOMA UNRESPONSIVENESS) AND POSTHYPOXIC BRAIN INJURY ●
●
●
●
Bruce Day Prolonged survival in a vegetative state is one of the most harrowing events encountered in modern medicine. Although the condition provides intellectual challenges to the expertise of medical ethicists, legal practitioners, and legislators, the patient’s family members and others intimately involved in the daily care of the patient are usually caught in a web of despair, unresolved grief, anger, a pervading sense of futility, and fading hope. Adversarial relationships between medical staff and family may arise, especially if iatrogenic issues such as anesthetic catastrophes are present. Family members may clutch at slim hopes offered by media reports of recovery after prolonged coma or vegetative states. Physicians may be torn by the conflict between limited resources and the pressure to persevere with intensive support, potentially restricting access to patients with substantially better chances of recovery. Decisions to continue or withdraw support are often charged with ethical and medicolegal implications, inasmuch as either course of action can be construed to be contrary to the “best interests” of the patient. The various terms vegetative state (persistent and permanent) and postcoma unresponsiveness are used to describe the clinical emergence of the patient from deep coma to a state in which the sleep-wake cycle is reestablished but the patient shows no clinical evidence of cognitive interaction with the world around him or her. When the state is deemed to be unremitting (more than 3 months after anoxic brain damage* or more than 12 months after traumatic brain injury) the term permanent vegetative state is recommended. Expert groups in the United States1 and Europe have suggested using only the terms vegetative state and permanent vegetative state because the term persistent has become shrouded with ambiguity. The terms vegetative state and persistent vegetative state do not
*Some authorities, such as the Royal College of Physicians of London,2 recommend that a 6-month period for nontraumatic etiologies elapse before the declaration of permanence. However, Jennett3 (2002, p 61) states that “the Task Force concluded from analysis of the 754 cases reviewed that the vegetative state could reasonably be declared permanent 3 months after nontraumatic damage and 12 months after head injury in both children and adults.” He further stated (p 64) that “given the interest in late recoveries provoked by the time limits proposed by the Task Force for declaring permanence, it might have been expected that most exceptions to these since then would have been reported, but only two have been.”
imply irreversibility; however, the term permanent vegetative state carries prognostic implications. For the situation in which some minimal level of purposeful response to environmental stimuli is observed, the term minimally conscious state has been advocated.4 The terminological uses vary, and some authors5 have advocated avoiding the term vegetative in view of its potentially pejorative connotations, but the original description6 remains widely accepted.
CRITERIA Vegetative State The salient features of the vegetative state† are as follows: 1. Long periods of wakefulness (spontaneous eye opening) without clinical evidence of purposeful responsiveness. Reflex responses and withdrawal to noxious stimulation may occur. 2. Roving eye movements but no sustained tracking of visual stimuli. 3. No response to verbal command. 4. No articulation or mouthing of words. 5. No bladder or bowel control. Movements such as yawning, grunting, grimacing, startle myoclonus, chewing, swallowing, bruxism, posturing, tearing, and even brief visual fixation may occur, but evidence of a purposeful act clearly linked to a stimulus is lacking. Such patients usually have varying degrees of spastic quadriparesis or decerebrate rigidity, often with preserved brainstem reflexes, including autonomic reflexes that control respiration and, occasionally, swallowing. There is usually a release (disinhibition) of primitive reflexes such as grasp reflexes and pouting reflexes. Joint contractures tend to develop with time. Rudimentary evidence of cognitive function such as response to command, consistent visual fixation or orientation to and tracking of a visual stimulus, smiling at jokes, or vocalizing recognizable words are inconsistent with the diagnosis.
†
For a full description of the various diagnostic criteria used internationally, see Jennett (2002).3
117
118
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
The Minimally Conscious/Responsive State Patients may improve from the vegetative state to demonstrate clearly discernible evidence of self or environmental awareness. The term minimally conscious state4 or minimally responsive state7 has been proposed to describe the condition of such patients. Minimal criteria such as the ability to follow a simple command, the presence of intelligible verbalization, or sustained visual following have been proposed to identify this state. Such responses may be intermittent and more easily evoked by family than by medical staff. Repeated observations may be necessary to distinguish this state from the vegetative state. Such purposeful responses clearly exclude a diagnosis of vegetative state, but difficulties defining the level of cognitive function sufficient to exceed a diagnosis of the minimally conscious state have limited widespread application of the term. The reestablishment of interactive communication, including orientation to place, the ability to give accurate autobiographical information, and the appropriate use of objects, are generally considered to indicate that the patient is functioning at a level higher than the minimally conscious state. It is important to note that the lack of behavioral manifestations of self or external awareness cannot by themselves prove the absence of a residual or rudimentary subjective awareness. It may not be possible clinically to distinguish a minimally responsive patient with residual cognitive function from one who lacks adequate afferent processing or efferent control to reliably demonstrate understanding or performance of a requested task. Indeed, Owen and colleagues8 reported three patients with clinical diagnoses of persistent vegetative state who demonstrated “covert cognitive processing” in positron emission tomographic scanning with a facial recognition task. It is also conceivable that patients may satisfy the criteria for the minimally conscious state on a “good” day and, perhaps as a consequence of infection, electrolyte disturbance, or fatigue, show no sign of awareness on a “bad” day.9 Because of such patients, the boundary between the vegetative state and the minimally conscious state may not be as discontinuous as the definitions suggest.
Locked-In Syndrome The locked-in syndrome refers to a state in which cognitive processing is clearly evident but severe paralysis prevents articulation or gestural expression of awareness. Communication may be achieved by encoding eyelid or ocular movement. In severe cases, the diagnosis may depend on the demonstration of a normal reactive alpha rhythm on the electroencephalogram (EEG).10 Such patients usually have isolated lesions of the ventral pons with preserved cerebral hemispheres. Locked-in syndrome may also occur as a consequence of severe peripheral nerve or muscle disease.
Akinetic Mutism The term akinetic mutism has been used to describe a range of cases in which varying degrees of consciousness, paralysis, and mutism may be present. Various pathological findings have been described,11 including infarction of the anterior cingulate gyrus.12 Cairns and associates13 described an adolescent with a craniopharyngioma who developed repeated episodes of “silent
immobility” with open and apparently attentive eyes and occasional whispered monosyllables whose state was reversed on several occasions by aspiration of the tumor. A similar case with improvement after shunting has been described more recently.14 Akinetic mutism has been divided into frontal and mesencephalic types, the latter distinguished by the presence of vertical gaze palsy or ophthalmoplegia. Cyclosporine neurotoxicity15 and baclofen toxicity16 may each cause a reversible state of akinetic mutism. Severe frontal abulia (for example, caused by bilateral anterior cerebral artery infarction or a ruptured anterior communicating aneurysm) may be impossible to distinguish on clinical criteria from either akinetic mutism or the minimally conscious state.
EPIDEMIOLOGY The incidence and prevalence of vegetative state in the community vary widely in accordance with the sources of the data. A comprehensive review3 of the epidemiology of vegetative state revealed prevalence rates in the United States ranging from 24 to 168 per million of the population in studies dating from 1990 to 1994. The Multi-Society Task Force on Persistent Vegetative State (1994) accepted an estimate from Ashwal and colleagues17 of 56 to 140 per million. The incidence of vegetative survivors after all acute causes at 1, 3, and 6 months has been estimated for the United Kingdom, the United States, and France.3 The incidence falls with time as patients either die or attain higher levels of function and is also heavily influenced by the level of head injury in the community. At 1 month after injury, the incidence ranges from 14 per million in the United Kingdom to 67 per million in France. By 6 months after the cerebral insult, the incidence of survival in a vegetative state is 5 per million in the United Kingdom, 17 per million in the United States, and 25 per million in France. The relative contribution of traumatic to nontraumatic causes of vegetative state also varies considerably, depending on the source of the data. Studies have shown the contribution of head injury ranging from 24%18 to 72%.1 Some studies include patients who decline into a vegetative state as a consequence of progressive neurodegenerative disorders, as opposed to progressing to a vegetative state from coma caused by an acute cerebral insult. This and other case ascertainment issues continue to complicate the epidemiological data.
PATHOLOGY Hypoxic/ischemic cerebral injury, cerebrovascular disease, and traumatic brain injury are the major causes of the vegetative state. Although patients with advanced neurodegenerative disorders (e.g., Alzheimer’s disease) may enter a state clinically indistinguishable from the vegetative state, this chapter is restricted to discussion of patients in a state of postcoma unresponsiveness. Patients may also recover to a state of postcoma unresponsiveness after severe bacterial meningitis, viral encephalomyelitis, or acute disseminated encephalomyelitis. In the setting of cerebral anoxia or diffuse ischemia, there is usually extensive neocortical laminar necrosis and bilateral hippocampal, amygdalar, and thalamic damage.19,20 The Purkinje cell layer of the cerebellum is similarly vulnerable to
chapter 9 the persistent vegetative state and posthypoxic brain injury diffuse ischemic injury. A second pattern of brain damage occurs after a short episode of profound hypotension, in which the ischemic damage is confined to the arterial boundary zones. This produces wedge-shaped zones of ischemia with additional bilateral thalamic damage and varying involvement of the hippocampus. After severe traumatic brain injury, the brunt of the pathology is subcortical and conforms to the diffuse shearing injuries now known as diffuse axonal injury (DAI), as described by Strich in 195621 and 1961.22 DAI is graded into types I to III; grade I is defined as diffuse subcortical shearing injury without callosal or brainstem involvement, grade II indicates additional focal lesions in the corpus callosum, and grade III indicates additional lesions in both the corpus callosum and the dorsolateral region of the rostral brainstem. Patients with DAI grade I are unlikely to remain in a prolonged vegetative state unless there is coexisting evidence of a hypoxic/ischemic insult. Coexisting evidence of hypoxic/ischemic damage in post-traumatic cases is not an uncommon finding.20 It is thought to reflect respiratory or circulatory failure at the time of head injury, although disturbances of cerebral autoregulation may also play a role. On the other hand, significant brainstem damage is a rare finding in prolonged survival in a vegetative state, which explains the recovery of sleep-wake function and autonomic cardiorespiratory control in this state. It appears that thalamic damage may play a critical role in the genesis of prolonged postcoma unresponsiveness, as cases with relatively little cortical damage are well described. Adams and associates20 published detailed studies of the pathological findings in both nontraumatic and traumatic cases and compared the latter group with 35 traumatic cases in which patients recovered to a state better than vegetative state before death. In summary, patients who remained in a vegetative state generally had more extensive DAI, thalamic damage, or both. Patients with lesser degrees of subcortical damage nearly always had extensive thalamic damage. Higher functioning patients rarely had both bilateral thalamic damage and extensive DAI, and if thalamic damage was present, it was considered to be of a lesser degree. Thus, extensive bilateral damage to the thalamus appears to be critical for the development of the vegetative state, especially if damage elsewhere is minimal.
DIAGNOSIS Misdiagnoses of the vegetative state and the minimally conscious state appear to be common.23 Repeated clinical assessments are necessary to clearly establish whether reliable evidence of cognitive function is present in a severely braindamaged patient. Patients are often in an intensive care environment when the diagnosis is first considered, and varying levels of potentially sedating medications may complicate the assessment. Similarly, metabolic manifestations of other major organ involvement may confound the clinical picture. Neurologists and intensive care physicians may disagree as to whether visual fixation or tracking is present or whether a particular movement is purposeful or reflexive. Nursing staff are often particularly helpful in determining whether an orienting or purposeful response can be consistently linked to a particular stimulus, especially if there is some fluctuation caused by extraneous factors such as seizures or bolus doses of anticonvulsants.
119
NEUROPHYSIOLOGICAL ASSESSMENT Clinical neurophysiological evaluation of the comatose patient has long been recognized to play an important role in determining both diagnosis and prognosis. In the modern intensive care environment, patients who remain in a coma after anoxic cerebral injury typically undergo electroencephalographic testing and somatosensory evoked potential (SSEP) testing, in view of the powerful prognostic information that these tests can provide. Usually these tests have been undertaken well before the patient has “emerged” to a vegetative state, and the results, if gravely abnormal, assist in the decision to withdraw cardiopulmonary support. Conversely, unexpectedly favorable electrophysiological findings lead the clinician to reassess the prognosis.
Electroencephalography Certain electroencephalographic patterns are known to be associated with extremely grave outcomes. Care must be taken to ensure that sedative medications, hypothermia, and severe metabolic disturbances are not confounding the interpretation of the record. In the setting of anoxic/ischemic cerebral injury, several electroencephalographic patterns have been associated with either a fatal outcome or, at best, survival with severe neurological sequelae.24 Of these patterns, the isoelectric or “flat” EEG after the first 24 hours is invariably associated with a poor outcome. The burst-suppression pattern (Fig. 9–1), especially if accompanied by generalized (typically facial and axial) myoclonic status25; the continuous bilateral periodic EEG or generalized epileptiform EEG (Fig. 9–2); and alpha (Fig. 9–3) and theta coma (Fig. 9–4) patterns usually but not invariably indicate a poor prognosis. Serial EEGs are sometimes necessary to identify a deteriorating trend. The isoelectric EEG is used in many countries as a confirmatory test for brain death, and the technique has been standardized.26 The recording must be undertaken for a minimum of 30 minutes at a sensitivity of 2 μV/mm using a minimum of eight channels with double-distance (>10 cm) electrodes in the 10-to-20 montage with filters set at less than 1 Hz and at 70 Hz. At these sensitivities, artifact is common, and the technician must take great care to identify all sources of artifact. ECG artifact is usually present in all channels, and this can usually be readily distinguished from activity of cerebral origin. The burst-suppression EEG pattern is usually readily identified; however, this pattern is also seen with the use of anesthetic agents—in particular, propofol and midazolam—and careful documentation of the use of such agents is necessary to avoid incorrect interpretation of the EEG. Even short-acting barbiturates can saturate adipose tissue after prolonged use, resulting in very prolonged excretion times. The continuous bilateral periodic EEG and generalized epileptiform records can be confused with nonconvulsive electrographic status epilepticus. The distinction may well be semantic. In general, patients who develop clinically subtle or nonconvulsive status epilepticus after anoxic cerebral injury do not do well, and aggressive trials of anticonvulsants are typically futile. If doubts remain on clinical grounds (e.g., a known epileptic patient who suffers a near-drowning event), a suitable trial of an anticonvulsant therapy is prudent, and SSEPs can be used as a more reliable guide to prognosis.
120
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Fp1–F3 F3–C3 C3–P3 P3–O1 Fz–Cz Cz–Pz Fp2–F4 F4–C4 C4–P4 P4–O2 150 V 1sec ■
Figure 9–1. Burst suppression electroencephalographic pattern two days after prolonged cardiac arrest. (Reproduced with permission from the American Journal of EEG Technology. Drury I.: The EEG in hypoxic-ischemic encephalopathy. Am J EEG Technol 1988; 28:129-137.)
Periodic complexes are also characteristic of advanced renal and hepatic failure, but these are readily ruled out by appropriate biochemical investigations. Alpha and theta coma patterns are rare electroencephalographic findings. The salient features of alpha coma pattern are widespread monorhythmic alpha frequency activity, devoid of the typical waxing and waning amplitude of normal alpha waves, and unreactive to eye opening. The alpha frequency activity in alpha coma pattern is often anterior predominant, as opposed to true alpha activity with its occipital predominance. Theta coma pattern tends to be seen more frequently in elderly patients and usually shows some degree of low-amplitude burst suppression. Although alpha and theta coma patterns are considered grave, rare patients have made a satisfactory recovery. The evolution from alpha or theta coma pattern to a burstsuppression pattern in the first week indicates a hopeless prognosis. In contrast, patients who develop continuous mixed frequencies or some degree of reactivity might be expected to show further gains. Alternatively, more benign electroencephalographic findings are sometimes very helpful in the decision to continue intensive support. In general, near normal EEGs or EEGs with mixed frequencies and some degree of reactivity to auditory, visual, or noxious stimulation indicate a more favorable prognosis, although varying proportions of such patients are left with neurological disability. Similarly, the rare comatose patients who manifest sleeplike changes (vertex waves, K complexes, and spindles on EEG) usually have a good prognosis. Apart from the technical difficulties often experienced in obtaining good-quality EEGs in patients with severe traumatic brain injury, prognostication for this group based on electroencephalographic findings is recognized to be less reliable. The presence of reactivity to auditory, visual, or noxious stimulation, which may be either “attenuation” or “paradoxical” (decrease or increase in background amplitude after stimulation), implies a better outcome.27 Such a finding suggests that the patient is very unlikely to remain in merely a permanent
vegetative state after emerging from coma. Electroencephalographic reactivity has been demonstrated in the cat to depend on an intact reticular activating system and preserved thalamocortical pathways.28 Head-injured patients with less favorable electroencephalographic findings may still do well, however, and in this group the additional use of other neurophysiological parameters—in particular, SSEPs—may help refine prognostication.
SOMATOSENSORY EVOKED POTENTIALS The bilateral absence of thalamocortical waveforms (N19/P22 or N1) in comatose patients after either anoxic cerebral injury or severe head injury29 indicates an extremely bleak prognostic outcome. If the study is performed with appropriate care, this is the most robust electrophysiological finding in the intensive care environment. In the setting of coma after anoxia, patients with this finding do not improve beyond the vegetative state. Repeated studies30 have shown this finding to have 100% specificity when the SSEPs are performed after 24 hours of coma. In patients with traumatic brain injury, care should be taken to rule out significant cervical trauma or brainstem pathology that may interrupt large fiber sensory pathways at that level and hence may complicate SSEP interpretation. Access and technical factors such as prominent scalp edema or hematoma can also make results of SSEP studies more difficult to interpret in head injury. In addition, the use of barbiturateinduced coma in severely head-injured patients may attenuate low-amplitude waveforms (B. Day, personal observation, 2003); therefore, SSEP studies for prognostication in these patients should be delayed until the barbiturate-induced coma therapy is withdrawn. Well-formed, normal-latency Erb’s point potentials and cervical potentials are important quality assurance requirements before prognostication can be made without thalamocortical waveforms (Fig. 9–5). Although higher stimulus intensities can be used in comatose patients, the stimulus frequency should be less than 5 Hz. If these technical issues do not
chapter 9 the persistent vegetative state and posthypoxic brain injury Fp1–A1 Fp2–A2 F2–A1 F4–A2 C3–A1 C4–A2 P3–A1 P4–A2 O1–A1 O2–A2 EKG 30 V 1sec ■
Figure 9–2. Continuous periodic anterior predominant sharp waves on electroencephalography after prolonged cardiac arrest. (Reproduced with permission from the American Journal of EEG Technology.)
Fp1–A1 Fp2–A2 F3–A1 F4–A2 C3–A1 C4–A2 P3–A1 P4–A2 O1–A1 O2–A2 F7–A1 F8–A2 T3–A1 T4–A2 T5–A1 T6–A2 70 V 1 sec ■
Figure 9–3. Diffuse unreactive alpha frequency activity on electroencephalography after cardiac arrest. (Reproduced with permission from the American Journal of EEG Technology.)
121
122
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
FP2–F4 PARIETAL
F4–C4 C4–P4 I
Fp1 Fp2
V
P4–O4
F3 F4 VI
FP1–F3
II
C3 C4
VII
III
P4 O1 O2
P3
VIII
F3–C3
IV
PARIETAL
C3–P3 P3–O1 TEMPORAL
FP2–F8 F8–T4 I
V
T4–T6 VI
T6–O2
Fp1 Fp2 F8 F7 T4
T3 VII
FP1–F7 VIII
T5
II III
T6
P1 P2
IV
TEMPORAL
F7–T3 T3–T5 T5–O2 50 V
1 sec ■
Figure 9–4. Diffuse unreactive theta slowing on EEG in an elderly patient after prolonged cardiac arrest.
complicate interpretation, bilateral absence of cortical SSEP responses is also 100% specific for an outcome no better than vegetative state in patients with traumatic brain injury. The high specificity of the bilateral absence of cortical waveforms is, however, accompanied by a low sensitivity (28% to 73%).30 Many patients with preserved but abnormal cortical waveforms nonetheless have very poor neurological outcomes, and the finding of normal cortical responses is not necessarily predictive of a favorable outcome. Unilateral delayed or lowamplitude cortical responses tend to be associated with a more severe residual neurological deficit in the stimulated limb, whereas a well-formed normal-latency cortical waveform is suggestive of a higher level of function in the corresponding limb, but the positive predictive value of such findings varies sufficiently between studies that their clinical utility is limited. For patients in whom the cortical waveforms (N19/P22 or N1) are present, some attempt to improve the sensitivity of SSEP studies has been undertaken by examining later waveforms, particularly the N70 (also called N3)31,32 (Fig. 9–6). No patient with bilaterally absent N19/P22 or N70 potentials “awakened” (“awakening” being defined as following commands or having comprehensible speech). No patient with absent N19/P22 potentials had preserved N70 waveforms. Patients in whom the N70 waveforms were present but prolonged beyond 176 milliseconds did not “awaken.” When the absence of the N70 or an N70 latency of more than 176 milliseconds was used instead of bilaterally absent N19/
P22 potentials for predicting nonawakening, the sensitivity of SSEP testing increased from 55% to 67%, and the specificity remained at 100%. Identification of the N70 waveform and determination of its peak latency can be technically more difficult, however, and it is more sensitive to the effects of anesthetic medications than is the N19/P22 waveform.
5 V 5 ms
Erb’s point 5 V Cervical
5 ms 1 V 5 ms
C4–Fz C3–Fz C4'–Fz C3'–Fz
1 V 5 ms ■
Figure 9–5. Bilateral (superimposed) absence of cortical waveforms with normal-latency, well-defined Erb’s point and cervical waveforms in a patient after prolonged anoxic cerebral injury. C3, C4′ are each 2 cm posterior to C3, C4.
chapter 9 the persistent vegetative state and posthypoxic brain injury 5 V
9.9
10 ms 1 8.4 12.9 N13
1 7.4
Erb’s
5 V 10 ms Cervical
18.6 N1
58.5 N3 (N70)
34.4 N2
2 V 10 ms
P1 21.8
P3 72.6
C4' –ear
P2 44.0 ■
Figure 9–6. Normal-latency, well-defined N70 waveform.
BIOCHEMICAL MARKERS Cerebrospinal Fluid Creatine Kinase BB activity Elevated creatine kinase BB (205 U/L) isoenzyme activity measured in the cerebrospinal fluid 48 to 72 hours after cardiopulmonary arrest has been reported to have 100% specificity and 48% sensitivity for never awakening33 (as defined previously). Using a lower cutoff increases the sensitivity but lowers the specificity. Using this parameter in conjunction with SSEP studies further increases sensitivity to 78% without sacrificing the 100% specificity required for making decisions about withdrawal of life support.31
Serum Astroglial S-100 Protein The calcium-binding modulator protein S-100 is an established biochemical marker of central nervous system injury.34 Increased serum levels (0.2 μg/L) in comatose patients 24 to 48 hours after out-of-hospital cardiopulmonary arrest were invariably associated with a fatal outcome within 14 days.35
Serum Neuron-Specific Enolase Serum concentrations of neuron-specific enolase exceeding 33 ng/mL were also predictive of a poor prognostic outcome in comatose patients, with a high degree of specificity (100%), when measured within 72 hours after out-of-hospital cardiopulmonary arrest.36 The role of biochemical markers, especially when used in conjunction with neurophysiological tests, is likely to become increasingly important in establishing the early prediction of outcome from coma caused by anoxic ischemic injury or severe head injury.30
IMAGING STUDIES Although computed tomographic and magnetic resonance imaging (MRI) studies are often routinely performed in patients with prolonged postcoma unresponsiveness after hypoxic brain
123
injury, these studies only rarely provide useful prognostic information. Diffusion-weighted MRI in the acute stage when the patient is still comatose may show diffuse cortical enhancement that is consistent with laminar infarction (Fig. 9–7A-D). Late imaging usually shows diffuse cortical atrophy (see Fig. 9–7E and F), but correlation between the degree of atrophy and outcome is imprecise. In one notable case, a 60-year-old academician was able to resume his career after emerging from a vegetative state of 8 weeks’ duration, despite generalized cerebral atrophy evident on the computed tomographic head scan.37 For patients in a post-traumatic vegetative state, more extensive MRI changes of DAI involving the corpus callosum and dorsolateral brainstem are correlated with continuing postcoma unresponsiveness.38 Magnetic resonance spectroscopy and diffusion tensor imaging have yet to be subjected to prospective longitudinal randomized studies in patients with prolonged postcoma unresponsiveness after anoxic cerebral injury or head injury, although early studies39 suggest that such techniques hold promise. Measurements of cerebral metabolism and brain activation with positron emission tomographic scanning and functional MRI studies after sensory stimulation are providing important insights into the pathophysiology of the vegetative state (see Laureys et al, 2004).40 These techniques are methodologically complex and careful interpretation is required, but important differences between the vegetative state and the minimally conscious state are beginning to emerge. Overall, patients who remain in a vegetative state have cerebral metabolic rates of the order of 30% to 40% of normal41 (Fig. 9–8), marginally lower than those in minimally conscious patients. A notable finding in the vegetative state is the extent of the metabolic impairment in the polymodal association cortices. These regions are important for higher order processing of incoming afferent information necessary for orientation, attention, recognition, memory, and language42 (Fig. 9–9). Such studies will potentially provide important new insights into prognostic and ethical issues, such as the presence of “covert cognitive processing”; however, current methodological complexities and problems with analysis and interpretation limit their clinical application.
PROGNOSTIC, MANAGEMENT, AND ETHICAL CONSIDERATIONS The phenomenon of prolonged survival in a vegetative state after coma is a direct consequence of advances in modern medical practice, particularly of the popular promotion of techniques such as cardiopulmonary resuscitation and highly expeditious emergency rescue and retrieval systems, coupled with access to sophisticated intensive care facilities. As a consequence, many busy intensive care units are faced on a daily basis with acutely comatose patients with potentially very poor but ultimately uncertain prognoses for independent recovery. Although ethical concerns dictate that economic considerations be set aside in the management of such patients, many intensive care services in large tertiary hospitals have problems with both significant access and cost containment. Ongoing futile management represents a serious misallocation of limited health care resources, as well as an unnecessary addition to the family’s distress. There is little doubt that prolonged survival in
124
Section
■
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Figure 9–7. Magnetic resonance imaging (MRI) findings in a 50-year-old patient who suffered a severe anoxic injury, emerging from coma to a vegetative state after 2 weeks to remain in a permanent vegetative state for 6 months before death. A, Sagittal T1-weighted MRI performed on day 6 after anoxic injury. B, Axial T1-weighted MRI on day 6 after anoxic injury. C and D, Diffusionweighted images performed on day 6 after the anoxic event, showing diffuse cortical enhancement. E and F, Sagittal and axial T1-weighted images from the same patient 3 months after the anoxic event showing diffuse cortical atrophy and ex vacuo dilatation of the ventricles.
chapter 9 the persistent vegetative state and posthypoxic brain injury 100 90 Cerebral metabolism (%)
80 70 60 50 40 30 20 10 at h in
de
st at e Br a
e eg
tv en
m Pe
rm
an
fro y er ov
et at iv
e ta tiv ge
ve
ed ck Lo R
ec
st at e
e ro nd sy
-in
ci ns co
ly al
in
im
m
st at e ou
e
s
st at e
om C
et at iv Ve g
an al er
G
en
a
a si th e es
sl p ee D
M
N
or
m
al
co
ns
ci
ou
sn
ee
es
p
s
0
■
Figure 9–8. Cerebral metabolism in various states. (From Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537-546. Copyright 2004. Reprinted with permission from the American Academy of Opthalmology.)
■
Figure 9–9. Resting cerebral metabolism in a healthy individual (“Conscious control”) and patients in the vegetative state, with locked-in syndrome, and in the minimally conscious state. Sagittal images showing reduced activity in the medial posterior cortex (precuneus and adjacent cingulate cortex). (From Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537-546. Copyright 2004. Reprinted with permission from the American Academy of Opthalmology.)
125
126
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
a vegetative state represents a disastrous outcome, particularly if it results from overly zealous application of intensive care support of comatose patients in the presence of extremely grave prognostic indicators. There is therefore an urgent need to refine neurophysiological, biochemical, and cerebral metabolic activity imaging studies further as early prognostic indicators to assist clinicians and families make the painful decisions regarding ongoing support. Once the patient has emerged from coma into a vegetative state with autonomous respiratory function, the ethical issues regarding support become much more vexed. As indicated previously, the vegetative state, especially in its early phase, cannot be considered irreversible. The significant difference in the chances for recovery from the vegetative state that arise as a consequence of anoxic cerebral injury as distinct from that caused by head injury is reflected in the difference in elapsed time before the vegetative state can be considered permanent (Fig. 9–10). Even after these times have elapsed, there are occasional single case reports of late recovery. Review of many of these cases reveals a small error rate for declaring permanence.3 Since the Multi-Society Task Force review of late recovery cases in 1994, only two cases of late recovery have been reported,43,44 which perhaps reflects more widespread acceptance of the
■
definitional criteria and time constraints on the determination of permanence. There are few useful data to guide clinicians in predicting recovery from a vegetative state once the diagnosis is established. It is generally considered that the prognosis for emergence is better after trauma than after hypoxia and that younger patients have a better chance of recovery. A short duration of coma before eye opening has been postulated to indicate an improved likelihood of further gains in function beyond a vegetative state.5 Recovery of visual pursuit or of a blink response to visual threat are often the first signs of recovery beyond vegetative state, and the early finding of such signs may suggest a better chance of further gains. Evidence on the quality of recovery from vegetative state is also very limited. A large study from France of 522 patients who were vegetative 1 month after head injury showed that although 61% had regained consciousness after 1 year of follow-up, only 14% had become independent. The statistics were markedly affected by age: only 5% of adults became independent, whereas 24% of those younger than 20 years reached this level.45 In the nontraumatic vegetative state, only 1% of patients who remained vegetative at 3 months and none who remained vegetative at 6 months achieved an independent outcome by 1 year.1
Figure 9–10. Outcome for patients in a persistent vegetative state after traumatic or nontraumatic injury. Note that after nontraumatic causes of persistent vegetative state (PVS) in both children and adults, if consciousness has not been achieved by 3 months, no further recovery can be anticipated. (From Multi-Society Task Force on Persistent Vegetative State: Medical aspects of the persistent vegetative state. Parts 1 and 2. N Engl J Med 1994; 330:1499-1508 and 1572-1579. Copyright 1994 Massachusetts Medical Society. All rights reserved.)
chapter 9 the persistent vegetative state and posthypoxic brain injury Conversely, very prolonged survival in the vegetative state is also unusual, although survival (up to 41 years)46 has been described. In the Multi-Society Task Force review, mean survival in a vegetative state after acute cerebral injury ranged from 2 to 5 years1 with a 70% rate of mortality by 3 years and an 84% rate of mortality by 5 years. However, long-term survival figures are likely to be heavily influenced by decisions to limit treatment. The decision to withdraw or withhold support (usually only artificial hydration and nutritional support, but occasionally antibiotics for intercurrent infections) from a patient in the permanent vegetative state is an emotional, ethical, and medicolegal challenge. The relevant legal protocols vary between jurisdictions. The ethical considerations hinge on the concepts of patient autonomy, the presence of advance directives, the wishes of family or other proxies, and the ability of a surrogate to act on behalf of an incompetent patient. A full discussion of the ethical and legal issues involved is beyond the scope of this chapter but is well covered in several monographs.3,47
K E Y
P O I N T S
●
Diagnosis of a vegetative state (postcoma unresponsiveness) depends on careful and repeated clinical assessment for the absence of evidence of a purposeful response to environmental stimuli.
●
Diagnosis of a vegetative or persistent vegetative state does not necessarily indicate irreversibility. Diagnosis of permanent vegetative state is reasonably appropriate for patients remaining in a vegetative state for 3 months after anoxic cerebral injury and 12 months after severe head injury. According to these criteria, a diagnosis of permanent vegetative state carries an extremely high likelihood that this state will continue indefinitely.
●
Certain neurophysiological and biochemical investigations undertaken early in the course of comatose patients after anoxic cerebral injury and severe head injury can provide highly predictive indicators that a patient will not recover to a state better than vegetative.
●
Further studies of neurophysiological and biochemical markers of cerebral injury, both alone and in combination, are likely to refine further the ability to predict such a devastating outcome and thus help prevent ongoing futile interventions.
Suggested Reading Jennett B: The Vegetative State: Medical Facts, Ethical and Legal Dilemmas. Cambridge, UK: Cambridge University Press, 2002. Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537-546. The Multi-Society Task Force on Persistent Vegetative State: Medical aspects of the persistent vegetative state. Parts 1 and 2. N Engl J Med 1994; 330:1499-1508 and 1572-1579.
127
References 1. Multi-Society Task Force on Persistent Vegetative State: Medical aspects of the persistent vegetative state. Parts 1 and 2. N Engl J Med 1994; 330:1499-1508 and 1572-1579. 2. Royal College of Physicians of London: The Vegetative State, Guidance on Diagnosis and Management. Clin Med 2003; 3:249-254. 3. Jennett B: The Vegetative State: Medical Facts, Ethical and Legal Dilemmas. Cambridge, UK: Cambridge University Press, 2002. 4. Giacino JT, Ashwal S, Childs N, et al: The minimally conscious state: definition and diagnostic criteria. Neurology 2002; 58:349-353. 5. National Health and Medical Research Council: Post-coma unresponsiveness (vegetative state): a clinical frame work for diagnosis. Canberra, Australia: National Health and Medical Research Council, 2004. 6. Jennett B, Plum F: Persistent vegetative state after brain damage: a syndrome in search of a name. Lancet 1972; 299:734-737. 7. American Congress of Rehabilitation Medicine: Recommendations for use of uniform nomenclature pertinent to patients with severe alterations in consciousness. Arch Phys Med Rehabil 1995; 76205-76209. 8. Owen AM, Menon DK, Johnsrude IS, et al: Detecting residual cognitive function in persistent vegetative state. Neurocase 2002; 8:394-403. 9. Thomasma DC, Brumlik J: Ethical issues in the treatment of patients with a remitting vegetative state. Am J Med 1984; 77:373-377. 10. Bauer G, Gerstenbrand F, Rumpl E: Varieties in locked-in syndrome. J Neurol 1971; 221:77-91. 11. Plum F, Posner JB: The Diagnosis of Stupor and Coma, 2nd ed. Philadelphia: FA Davis, 1972, pp 24-25. 12. Freeman FR: Akinetic mutism and bilateral anterior cerebral artery occlusion. J Neurol Neurosurg Psychiatry 1971; 34:693698. 13. Cairns H, Oldfield RC, Pennybaker JP, et al: Akinetic mutism with an epidermoid cyst of the third ventricle. Brain 1941; 64:237-290. 14. Abekura M: Akinetic mutism and magnetic resonance imaging in obstructive hydrocephalus: case illustration. J Neurosurg 1998; 88:161. 15. Bird GL, Meadows J, Goka J, et al: Cyclosporin associated akinetic mutism and extrapyramidal syndrome after liver transplantation. J Neurol Neurosurg Psychiatry 1990; 53: 1068-1071. 16. Rubin DI, So EL: Reversible akinetic mutism possibly induced by baclofen. Pharmacotherapy 1999; 19:468-470. 17. Ashwal S, Bale JF, Coulter DL, et al: The persistent vegetative state in children: report of the Child Neurology Society Ethics Committee. Ann Neurol 1992; 32:570-576. 18. Sato S, Imamura H, Ueki K, et al: Epidemiological survey of vegetative state patients in the Tokohu District, Japan. Neurol Med Chir (Tokyo) 1979; 8:327-333. 19. Kinney HC, Samuels MA: Neuropathology of the persistent vegetative state—a review. J Neuropathol Exp Neurol 1994; 53:548-558. 20. Adams JH, Graham DI, Jennett B: The neuropathology of the vegetative state after an acute brain insult. Brain 2000; 123:1327-1338. 21. Strich SJ: Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neurosurg Psychiatry 1956; 19:163-185. 22. Strich SJ: Shearing of nerve fibres as a cause of brain damage due to head injury. Lancet 1961; 278:443-448.
128
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
23. Andrews K: International Working Party on the Management of the Vegetative State: summary report. Brain Injury 1996; 10:797-806. 24. Young GB: The EEG in coma. J Clin Neurophysiol 2000; 17:473-485. 25. Wijdicks EF, Parisi JE, Sharbrough FW: Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol 1994; 35:239-243. 26. Silverman D, Saunders MG, Schwab RS, et al: Cerebral death and the electroencephalogram: Report of the ad hoc committee of the American Electroencephalographic Society on EEG Criteria for determination of cerebral death. JAMA 1969; 209:1505-1510. 27. Gutling E, Gonser A, Imhof HG, et al: EEG reactivity in the prognosis of severe head injury. Neurology 1995; 45:915918. 28. Moruzzi G, Magoun HW: Brainstem reticular formation and activation of the EEG. 1949. J Neuropsychiatry Clin Neurosci 1995; 7:251-267. 29. Carter BG, Butt W: Review of the use of somatosensory evoked potentials in the prediction of outcome after severe brain injury. Crit Care Med 2001; 29:178-186. 30. Zandbergen EGJ, de Haan RJ, Stoutenbeek CP, et al: Systematic review of early prediction of poor outcome in anoxicischaemic coma. Lancet 1998; 352:1808-1812. 31. Sherman AL, Tirschwell DL, Micklesen PJ, et al: Somatosensory potentials, CSF creatine kinase BB activity and awakening after cardiac arrest. Neurology 2000; 54:889-894. 32. Madl C, Kramer L, Yeganehfar W, et al: Detection of nontraumatic comatose patients with no benefit of intensive care treatment by recording of sensory evoked potentials. Arch Neurol 1996; 53:512-516. 33. Tirshwell DL, Longstreth WT Jr, Rauch-Matthews ME, et al: Cerebrospinal fluid creatine kinase BB isoenzyme activity and neurological prognosis after cardiac arrest. Neurology 1997; 48:352-357.
34. Raabe A, Grolms C, Sorge O, et al: Serum S-100B protein in severe head injury. Neurosurgery 1999; 45:477-483. 35. Rosen H, Rosengren L, Herlitz J, et al: Increased serum levels of the S-100 protein are associated with hypoxic brain damage after cardiac arrest. Stroke 1998; 29:473-477. 36. Fogel W, Krieger D, Veith M, et al: Serum neuron-specific enolase as early predictor of outcome after cardiac arrest. Crit Care Med 1997; 25:1133-1138. 37. Falk RH: Physical and intellectual recovery following prolonged hypoxic coma. Postgrad Med J 1990; 66:384-386. 38. Kampfl A, Schmutzhard E, Franz G, et al: Prediction of recovery from post traumatic vegetative state with cerebral magnetic-resonance imaging. Lancet 1998; 351:1763-1767. 39. Ricci R, Barbarella G, Musi P, et al: Localised proton MR spectroscopy of brain metabolism in vegetative patients. Neuroradiology 1997; 39:313-319. 40. Laureys S, Owen AM, Schiff ND: Brain function in coma, vegetative state and related disorders. Lancet Neurol 2004; 3:537546. 41. Tommasino C, Grana C, Lucignani G, et al: Regional cerebral metabolism of glucose in comatose and vegetative state patients. J Neurosurg Anesthesiol 1995; 7:109-116. 42. Baars B, Ramsøy T, Laureys S: Brain, conscious experience and the observing self. Trends Neurosci 2003; 26:671-675. 43. Childs NL, Mercer WN: Brief report: late improvement in consciousness after post-traumatic vegetative state. N Engl J Med 1996; 334:24-25. 44. Dyer C: Hillsborough survivor emerges from permanent vegetative state. BMJ 1997; 314:996. 45. Danze F, Veys B, Lebrun T, et al: Prognostic factors of posttraumatic vegetative states: 522 cases. Neurochirurgie 1994; 40:348-357. 46. Sibbison JB: USA: right to live, or right to die? Lancet 1991; 337:102-103. 47. Bernat JL: Ethical Issues in Neurology, 2nd ed. Boston: Butterworth Heinemann, 2002.
CHAPTER
10
AUTISM AND ATTENTION DEFICIT/ HYPERACTIVITY DISORDER ●
●
●
●
Bruce J. Tonge and Nicole J. Rinehart
Autism and attention deficit hyperactivity disorder (ADHD) are the two main classes of neurodevelopmental disorders that begin in early childhood. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)1 specifies that the diagnosis of ADHD cannot be made if the symptoms occur in a child with autism. However, symptoms of attention deficit and hyperactivity are common problems in children with autism, which points toward some neuropathophysiological characteristics shared between these two groups of neurodevelopmental disorders. Autism is a generic term referring to a group of related conditions defined in the DSM-IV-TR1 and the International Classification of Diseases, Tenth Revision (ICD10),2 as pervasive developmental disorders. The term autistic spectrum disorders is frequently used but lacks any international agreement regarding its definition.3 The term is sometimes used to refer to a group of related conditions similar to pervasive developmental disorders. It is also used to describe the range of intellectual abilities, from severe disability to normal ability, found in children with autism. The concept of a spectrum has also been applied to describe developmental changes, such as improvement in language ability, which might occur over time in an individual with autism. In this chapter, autism refers to the pervasive developmental disorders, which share the core features of severe and pervasive impairment in social and communication skills, together with the presence of restricted and repetitive patterns of behavior and interests. The onset of these disorders occurs within the first 3 years of life, but the clinical picture may change with development. In DSM-IV-TR1 the pervasive developmental disorders comprise the categories of Autistic Disorder, Asperger Disorder, Rett’s Disorder, Childhood Disintegrative Disorder, and Pervasive Developmental Disorder–Not Otherwise Specified (PDD-NOS). Autism was first described by Leo Kanner in 1943 for a group of 11 children who had the distinctive core features of social, language, and communication disturbance and an obsessive desire for sameness.4 In the following year, Hans Asperger described a group of 16 children and adolescents who had deficits in communication and social skills together with obsessional interest, intolerance of change, and motor clumsiness.5 Unlike the children described by Kanner, these young people were of normal intellectual ability and did not have any delay or abnormality in their language development. This has become the differentiating feature of Asperger’s disorder from autistic disorder. This review focuses on the assessment, pathophysiologic aspects, and treatment of the
two main pervasive developmental disorders, autistic disorder and Asperger’s disorder. The problem of excessive hyperactive, inattentive, and impulsive behavior in children has been described in the medical literature from the 19th century.6 Current theories regarding the etiology of developmentally excessive inattentiveness and hyperactivity encompass an interaction of genetic predisposition, central nervous system dysfunction resulting from prenatal and early postnatal traumatic or toxic events, and environmental and social influences. The concept of minimal brain damage with associated soft neurological signs led to theories of dysfunction of the thalamus and prefrontal circuits to account for the hyperactivity and inattention, respectively. Current interest is focused on deficiencies of executive function and inhibition of attention resulting from such dysfunction, particularly affecting the right prefrontal cortex and associated basal ganglia structures.7 These primary deficits affect the development of working memory, emotional regulation, motivation, and the development of language and morality.7 Historically, the approach to the diagnosis of ADHD has differed between North America and Europe. Clinicians in Europe have sought for evidence of neurological dysfunction and pervasive symptoms of inattention and hyperactivity in all contexts. Clinicians in North America have taken a more qualitative approach to diagnosis, acknowledging that symptoms may vary in different settings and subdividing the diagnosis into the number of symptoms in each of the dimensions of inattention or hyperactivity/impulsiveness. Thus, a child may receive a diagnosis of ADHD predominantly hyperactive type or predominantly inattentive type. There has been an attempt to bring the diagnostic criteria for ADHD in the DSM-IV-TR into line with the criteria for hyperkinetic disorder in the ICD-10.2 Although the criteria used in both classification systems are now virtually identical, there are still differences regarding the number of criteria required and the pervasiveness of symptoms. As a consequence, application of ICD-10 criteria is more restrictive and conservative, which has implications for studies of epidemiology and etiology. The discovery in 1937 of the therapeutic effect of dextroamphetamine on concentration and hyperactivity in children with disruptive behavior has also influenced approaches to diagnosis and the interest taken by society in these behavioral problems.8 Regardless of an element of social determinism inherent in the diagnosis of ADHD, there is no doubt that young people
129
130
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
with pervasive difficulties with attention, impulsiveness, and motor hyperactivity are at great risk of suffering educational, social, emotional, and behavioral problems during childhood and subsequent mental health, relationship, occupational, forensic, and substance abuse problems in adult life. This chapter focuses on advances in the understanding of the neuropathophysiology and treatment of ADHD.
EPIDEMIOLOGY Autism There is evidence that the prevalence of autism is increasing. More than 23 prevalence studies of autism have been reported in the literature from 1966 to 1997. In most studies before 1990, investigators reported prevalence rates of 4 to 5 per 10,000. In more recent studies in which rigorous diagnostic criteria and standardized diagnostic assessment were used, investigators have found rates of approximately 10 to 12 per 10,000.9 Since the mid-1990s in a number of countries, specialist children’s services have reported an increasing demand for services for children with autism. For example, in Iceland, the prevalence of autism and the demand for services are reported to have doubled.10 Reviews indicate that the apparent increase in prevalence is probably a result of differences in ascertainment and diagnosis and an increasing awareness of autism by the general public.9 At least 14 different approaches to diagnosis have been used in prevalence studies. For example, when DSMIV-TR or ICD-10 diagnostic criteria are used, the prevalence of autism is two to three times higher than that found with the application of the earlier criteria of Kanner.9 The inclusion of subcategory diagnoses of pervasive developmental disorders such as PDD-NOS or atypical autism leads to further increases of prevalence to approximately 27 to 30 per 10,000.9 In several longitudinal studies, researchers using equivalent methods of diagnosis over time, but with relatively small sample sizes, have not found significant changes in prevalence rates in subsequent birth cohorts.9,11 There is no evidence that prevalence varies between countries or racial groups, and social class and level of parental education are not associated with autism.9 Autistic disorder is more common in boys than in girls (ratio, 4:1), and the gender distribution is even more marked for Asperger’s disorder (ratio, 10:1 to 13:1). This gender distribution might point to the possibility of an X-linked element to the disorder, but research has failed to confirm this explanation.
Attention Deficit/Hyperactivity Disorder Estimates of the prevalence of ADHD vary widely according to the diagnostic criteria, measures used, ascertainment methods, and demographics of the population. For example, in a populationwide study in the United States in which parent- and selfreport screening questionnaires were used, a prevalence of ADHD of up to 20% was identified.12 Population rates of 1% to 2% are found if prevalence is based on the application of the restrictive ICD-10 criteria2 without the presence of comorbid conditions.13 Prevalence rates of 5% to 10% are found in studies in which the more inclusive DSM-IV-TR criteria, which allow
some variability of symptoms and the presence of comorbidity, are used.14 Studies with DSM-IV-TR criteria reveal that the combined inattentive-hyperactive subtype of ADHD is the most common manifestation. For example, a clinic study demonstrated that 60% of young people with a diagnosis of ADHD had the combined subtype, 30% had the inattentive subtype, and 10% had the hyperactive-impulsive subtype.15 Note that the subtypes are designated on the basis of symptom predominance; meeting criteria for one subtype, such as inattentive subtype, does not preclude the presence of some symptoms from another subtype, such as hyperactive symptoms. Community studies reveal that the childhood prevalence of ADHD is approximately three times higher in boys than in girls but is more likely to decrease over time in male patients while remaining stable into adulthood in female patients.16 Symptoms usually reduce with maturation, but at least 30% of children with ADHD continue to suffer from the disorder in adulthood.17 Because of differences in diagnostic criteria and methods of ascertainment, the prevalence of ADHD in adults varies between 0.3% and 5%.17 Approximately a third of these adults are likely to suffer from a comorbid affective disorder as well, and the majority have associated social, marital, employment, and legal problems.18
CLINICAL FEATURES Autism Autism manifests with delays and abnormalities in the development of language and social skills, and the presence of rigid, repetitive, stereotyped play and behavior, often in association with intellectual disability and a variety of neurological conditions such as epilepsy. Therefore, the assessment and diagnosis is multifaceted, involving medical, cognitive, language, developmental, and mental state assessments.19 A reliable diagnosis can be made in patients aged 2 years and older. In view of the value of early intervention, early diagnosis is important and can be facilitated with the use of screening tools completed by parents (e.g., the Developmental Behavior Checklist),20 and clinician-completed checklists (e.g., the Checklist for Autism in Toddlers).21 Diagnosis is enhanced by the use of a structured, reliable, and valid parental interview and child observation schedule,22 such as the Autism Diagnostic Interview/Revised23 and the Autism Diagnostic Observation Schedule.24 All children with autism have impaired social interactions, which may change as they develop. Infants with autism do not anticipate social interactions, such as being picked up, or seek physical comfort or parental attention. Preschool children with autism usually avoid eye contact and do not engage in social imitation such as waving goodbye. They are unresponsive to the feelings and emotions of others. They are aloof and unable to engage effectively with other children or understand reciprocal social interactions. As such children grow older, there may be an increased interest in other people, but social skills are often stilted and learned in an inflexible manner, leading the children to appear odd and socially clumsy. Parents usually first seek help because their children have language delay and a lack of nonverbal communication and easily becomes frustrated. About 50% of children with autism fail to develop functional
chapter 10 autism and attention deficit/hyperactivity disorder speech and learn only slowly to compensate with gesture. Language development is often abnormal in the remainder, with echolalia, self-directed jargon, and the repetition of irrelevant phrases (for example, from a television show). The correct use of pronouns and the related development of a sense of self and others are delayed. Poor comprehension, problems expressing needs by words and gesture, and difficulty in social understanding are frequently the causes of frustration and disturbed behavior. Children who do develop functional language usually have difficulty in using language socially and in initiating or sustaining a reciprocal conversation. For example, the child may talk at others in a socially inappropriate manner. In contrast to children with autistic disorder, young people with Asperger’s disorder have no delay in the development of normal expressive and receptive language, including the use of communicative phrases by the age of 3 years. However, children with Asperger’s disorder have problems in their social use of language, such as being verbose and preoccupied with a favorite topic. Their speech may appear odd because of the use of an unusual accent or because of the presence of abnormalities in pitch and volume; for example, delivery may be flat and monotonous. The play, behavior, and daily life of children with autism are usually rigid and repetitive. Younger autistic children may line up toys or objects or may be preoccupied with special objects such as stones, and they become distressed if these activities are interrupted. Their ritualistic play lacks imagination and social imitation. With development, play may become more complex, such as reenacting scenes from a favorite video story, but is usually still repetitive. Older autistic children may develop preoccupations with themes such as train timetables or dinosaurs, and this is the focus of their play, drawing, and conversation. They may have a number of rituals associated with daily life, such as a fixed order for bathing and dressing or an insistence on wearing the same clothes or taking the same route to a familiar place. Change or unexpected events, such as the arrival of a new student in the classroom, can be distressing. There may be a number of perceptual or sensory abnormalities such as hyperacusis or tactile sensitivity, manifesting, for example, as an aversion to having their hair brushed. Some children with autism have a remarkable lack of sensitivity to pain. Children with autism are usually visually attentive; for example, they may study the detail in a picture book or closely observe spinning wheels, the edges of objects, or reflections in water. There are usually some motor mannerisms, such as hand flapping, tiptoe walking, and gait abnormality. Approximately 80% of children with autism also have intellectual disability, and other emotional and behavioral disturbances are common. Children with autistic disorder who have intellectual abilities within the normal range are referred to as high functioning. The individual cognitive profiles of children with autism usually show a wide scatter of abilities, with deficits in verbal and social comprehension tasks and more ability with visuomotor performance skills. In contrast, children with Asperger’s disorder have overall normal intellectual abilities but usually have relative deficits in visuomotor tasks and motor skills in comparison with their verbal performance. Children with autism often have a range of disruptive behaviors such as stubbornness, self-injury, and aggression, which place a high burden of care on parents and teachers. These disruptive behaviors are the main cause of failure in school and community activities and lead to more restrictive care. High
131
levels of anxiety are common and prevent these children from learning, coping with change, and participating in family and community activities. The anxiety associated with autism is likely to persist into adult life.25 Children with autism are also likely to suffer from depression, particularly during adolescence. This may manifest as mood disturbance and irritability, sleep and appetite disturbance, and thoughts of suicide, which may be enacted.26 The increased vulnerability to depression during adolescence may be associated with self-awareness of the disability, but pubertal brain development and a family history of depression may also contribute. At least 13% of children with autism also meet diagnostic criteria for ADHD,27 but the DSM-IV-TR specifically precludes the diagnosis of ADHD “during the course of a Pervasive Developmental Disorder” (p. 93).1 Nevertheless, symptoms of attention deficit and hyperactivity in children with autism impede and disrupt their learning, school adjustment, and family life. These symptoms of ADHD are responsive to educational, behavioral, and pharmacological managements used for children with ADHD, although not always as successfully.26 Children with autism also have an increased risk of suffering tic disorder or Gilles de la Tourette syndrome, with the tics becoming more prevalent during times of stress and anxiety, such as a change in school placement.26 Epilepsy occurs in approximately 20% of young people with autism, emerging most commonly in early childhood or during adolescence. It is seen more frequently in children with more severe levels of intellectual disability.26 Young people with Asperger’s disorder also suffer from a similar range of mental health problems but are even more likely to have higher levels of disruptive and antisocial behavior and to suffer from anxiety and depression.28 They may also have an increased risk of developing psychosis during adolescence or early adult life.
Attention Deficit/Hyperactivity Disorder The diagnosis of ADHD is based on a clinical judgment that there are sufficient symptoms of inattention and hyperactivity/impulsivity, together with the decision that these symptoms cause significant impairment in daily functioning in at least two settings and are not consistent with the developmental level of the child.1 Therefore, the diagnosis requires a careful and comprehensive history of the child’s development and behavior from the parents and other informants such as the teacher, together with observation of the child during both structured and unstructured activities. A structured cognitive assessment, apart from providing information on specific learning difficulties and related problems such as deficits in short-term auditory memory, also reveals problems with concentration and distractibility—that is, with sustained, directed attention. The use of structured behavior rating scales, such as the Conner’s Parent and Teacher Rating Scales,29 may be useful for screening and as a measure of response to treatment. Apart from high levels of distractibility and inattention, children with ADHD are disorganized and are usually unable to follow routine or complete tasks.1 They have difficulty monitoring their behavior and therefore often interrupt others, have difficulty following rules, and display inappropriate and impulsive behavior.1 Those who also suffer from hyperactivity are constantly restless and fidgety, have difficulty remaining seated, and behave as if they are driven by a motor. These behaviors are
132
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
influenced by aspects of the environment, such as the degree of external stimulation and sensory complexity. Therefore, observers may report differences in behavior, depending on the context. For example, a teacher in a busy, noisy classroom setting is more likely to observe inattention than is a teacher’s aide who has the child for individual teaching in a quiet library environment. However, the symptoms and impairments are usually observed, at least to some extent, in all aspects of the child’s daily life. Young people with ADHD have a range of associated problems. Their primary symptoms often lead to hostile interactions with other children, who may reject them. ADHD is frequently complicated by the presence of other psychopathological conditions: in particular, conduct disorder (25%), oppositional defiant disorder (35%), depression (15%), and anxiety disorder (25%).30 The majority of children with ADHD have various learning difficulties and poor school performance in relation to their intellectual abilities.31 Approximately 25% of individuals with ADHD have intellectual disability, including delayed language development.31 Children with ADHD have difficulty falling asleep and wake early, and their sleep is often unsettled and complicated by breathing and snoring difficulties.32 Adolescents with ADHD are at risk for delinquent behavior and abuse of nicotine, alcohol, and other substances, perhaps as a means of self-medication.33 Young people who are treated with stimulant medication for ADHD are less likely to use substances than are adolescents with ADHD who are not receiving treatment.33 There is also an association between the use of alcohol, tobacco, and other substances during pregnancy and the birth of a child with ADHD, but the mechanisms for these associations are likely to reflect the complex interaction of genes and environment.33 The assessment and diagnosis of ADHD for the first time in adults is difficult.34 Such an adult may not be living in a situation in which others can report on behaviors and symptoms to help the clinician reach a judgment on the severity of symptoms and the degree of disability. The presence of other comorbid psychiatric illnesses complicates the presentation. Adults are not able to reliably remember their childhood; therefore, if possible, a history of the manifestation of the disorder throughout childhood should be obtained from other persons or from school reports.34 Adults with ADHD are usually less disruptive and hyperactive than are children with ADHD, but they usually remain impulsive, disorganized, inattentive, and restless.34
ETIOLOGY AND PATHOPHYSIOLOGY Autism Neurocognitive Theories There are three main cognitive theories of autism: the “theoryof-mind,”35 the “executive dysfunction” theory,36 and the theory of “weak central coherence.”37 Deficiencies in theory-of-mind— that is, the ability to understand that other people have unique perspectives and thoughts that are sometimes contextually independent—are thought to be linked to the social-communicative deficits associated with autism.35 Weak central coherence, a deficit in the ability to integrate details into a coherent global perception, is thought to be linked to the tendency of
individuals with autism to be preoccupied with parts of objects and to miss the “bigger picture.”37 Executive functioning refers to the role of the frontostriatal circuits in coordinating cognitive-motor output so that behavior is well timed, planned, adaptable, appropriate, and relevant38 (and see Chapter 7). The repetitive, stereotyped, and restricted behaviors seen in autism are thought to result, in part, from deficient executive functioning.39 Poor performance on tests of executive functioning “. . . is found more consistently in autism than in any other form of childhood psychopathology” (p. 103).40 It is not clear which, if any, of these cognitive deficits is central to the psychiatric and neurological symptoms that characterize autism.41 Volkmar and colleagues42 argued that the main criticism leveled at theory-of-mind is that it cannot account for the clinical phenomenology of autism, because the social deficits characteristic of autism appear at a point in development before normally developing children demonstrate the acquisition of a theory-of-mind. Furthermore, children with autism and normal intelligence are reported to perform at an age-appropriate level on theory-of-mind tasks,43 although some authors disagree with this conclusion.44,45 Other, more primary deficits reflect problems with “weak central coherence.” Studies suggest that problems in moving attentional focus away from the detail of an object may better account for why individuals with autism appear to get “stuck” on detail and have a poor ability to appreciate the object’s gestalt.46,47 The broader executive dysfunction theory of autism (including attentional dysfunction) is perhaps the most appealing theory from a cognitive neuroscience perspective, inasmuch as it enables the linking of more specific cognitive deficits to possible impairments in specific neurological circuitries. Contemporary cognitive research has focused on uncovering distinct executive functioning profiles48 that might distinguish children with autism from those with other neurodevelopmental disorders: for example, ADHD, obsessive compulsive disorder, Gilles de la Tourette disorder, schizophrenia, and depression.49 Standardized neuropsychological tests—for example, the Wisconsin Card Sort Test, the Tower of Hanoi, and the Stroop Color-Word Test—have demonstrated that the profile of autism is characterized primarily by deficient cognitive flexibility and planning,48 with intact sustained and directed attention50 and intact cognitive inhibition.48 However, results of attempts to measure impairment of cognitive inhibition in autism with novel approaches that align more closely to a child’s everyday experiences—for example, generating novel verbal utterances, ideas, and drawings—challenge the view that this area of cognition is intact in autism.51,52 Some studies suggest that measures of “motor” functioning in autism may provide a more useful neurobiological probe than do more complex cognitive-social measures, which do not define discrete neural pathways.53,54 Motor studies of young people with autism (3 to 21 years of age) demonstrate movement anomalies commensurate with basal ganglia dysfunction.55-57 For example, atypical upper-body motor preparation with intact execution,58 reduced motor evoked potentials,59 and postural abnormalities60 have been reported. Studies of gait in autism also suggest a cerebellar contribution to motor dysfunction: for example,61 gait variability60,61 and difficulty with straight-line walking, which are consistent with a cerebellar ataxic gait disturbance.62 An important issue in the cognitive description of autism is the question of so-called “knock-on” effects: that is, how one
chapter 10 autism and attention deficit/hyperactivity disorder potentially primary cognitive deficit may have downstream effects on other emerging skills.41 A neurocognitive comparison of normally intelligent individuals with autism and those with Asperger’s disorder can be used to illustrate the potential “knock on” effects of disordered and delayed language, because this is the clearest point of neurological departure between these disorders in the first 3 years of life. Neurocognitive comparisons of individuals with autism and those with Asperger’s disorder have revealed quantitative and qualitative differences in executive functioning,63,64 which potentially represent downstream neural and environmental consequences of language deficits in autism. For example, executive functioning anomalies show a lateralization pattern consistent with left-hemisphere dysfunction for autism, but not in Asperger’s disorder.65 A better understanding of the primacy of cognitive deficits and how they unfold and link to the psychiatric and neurological symptoms of autism is likely to come from detailed prospective studies of the newborn siblings of autistic children, who are themselves at higher genetic risk of developing autism than are unrelated newborns.
Neuroanatomical and Neuroimaging Studies There is no consistent neuroimaging marker that has been identified for autism. Structural changes in the brains of individuals with autism include slightly increased average brain volume, decreased gray matter volumes in the limbic system (an area important for social cognition), reduced neuron numbers in the vermis of the cerebellum, and gross structural changes in cerebellum66,67 and the parietal lobes68 (areas important for efficient attention). A reduction in neuronal integrity in prefrontal areas and concurrent abnormalities in the frontal cortex and cerebellum67 possibly underlie the repetitive behavioral symptoms that characterize autism.69 Several imaging studies have uncovered left hemisphere impairment in autism.70 One review71 concluded that although many structural abnormalities have been identified in individuals with autism, the findings are inconsistent and not specific. Functional magnetic resonance imaging (fMRI) has the potential to more clearly elucidate the neurobiological substrates that underpin faulty cognitive-motor processes in autism. There have been several attempts to link the socialcommunicative deficits with particular neural regions using neuroimaging techniques,72-74 but there have been relatively few attempts to study frontal regions associated with executive functioning. A study of the application of fMRI during a mental rotation task75 revealed that individuals with autism and Asperger’s disorder showed decreased activation in the highly interconnected cortical and subcortical frontal structures, including lateral and medial premotor cortex, frontal eye fields, caudate, dorsolateral prefrontal cortex, and anterior cingulate cortex, suggestive of disruption to multiple frontostriatal circuits. Although advances in the cognitive neuroscience of executive function and attention enable investigators to more clearly study the component processes and anatomical substrates of autism,76 a more comprehensive understanding of the brainbehavior disruption that characterizes autism is likely to come from a larger systematic examination of cognitive processing, in which the cognitive and anatomical specificity afforded by fMRI and event-related methods are used.
133
Genetic Theories In fewer than 10% of cases, autism is associated with defined environmental causes, such as rubella and cytomegalovirus, fetal infections, perinatal brain injury, toxins, and specific genetic abnormalities such as tuberous sclerosis and fragile X syndrome.77 A suggested link between measles, mumps, and rubella vaccination and the use of thimerosal in vaccines as a cause of the increased prevalence of autism has been discounted by several comprehensive studies.78 Thimerosal has not been in vaccines in North America and Japan since the mid-1990s, during the time of reported increases in prevalence. The cause of the majority of cases remains unknown, but they are almost certain to have a multifactorial and complex genetic basis. The 3:1 predominance of autism in boys is probably not X-linked but might be accounted for by a malespecific excess of linkage peaks at the chromosomal locus 17q11.79 If an older sibling has autism, the risk that a subsequent full sibling will have autism is 2% to 8%. The concordance for autism in monozygotic twins is 60% for autistic disorder and 92% for the spectrum of pervasive developmental disorder. For dizygotic twins, the concordance for either diagnosis is up to 10%.7 Studies of individuals with autism suggest that chromosome 15q11-q13 is a candidate region for genetic risk factors.80 There is also an increased frequency of the chromosome 4B null allele and of variant serotonin transporter gene alleles at chromosomal locus 17q11-q12.77 Studies of multiplex families (those with more than one case of autism) also suggest linkage at chromosomal loci 7q31-q33, 2q31-q33, and 3p25-p26 sites.77,81 These family studies point to the possible involvement of multiple genetic risk factors.
Attention Deficit/Hyperactivity Disorder Neurocognitive Theories DSM-IV-TR criteria preclude a comorbid diagnosis of ADHD and autism.1 However, this is at odds with the frontostriatal model of developmental dysfunction proposed by Bradshaw,38 which links these disorders by virtue of shared neural circuitry. The frontostriatal model of developmental dysfunction also predicts that the two disorders are likely to share “common heritability factors” (p. 262).38 In addition, both disorders share a number of neurotransmitter abnormalities, including of dopamine, noradrenaline, acetylcholine, γ-amino butyric acid, and serotonin.38 The likelihood of comorbidity between these two conditions is confirmed by study findings that indicate that at least 13% of children with autism also meet criteria for ADHD.27 In contrast to autism, the executive frontostriatal profile of ADHD is characterized by inhibitory deficits82 and problems with sustained attention.83,84 The classic neuropsychological paradigms used to measure these inhibitory deficits include the Stop Signal Task and the Stroop Color-Word Task. Children with ADHD are generally slower to inhibit their responses on the Stop Signal Task and exhibit more false alarms; these abnormalities have been associated with decreased orbitofrontal and anterior cingulate cortex activation.85 On the Stroop task, children with ADHD are typically slower at calling out the color in which the incongruent words are printed, because of problems with inhibiting the more automatic word-reading response. Deficien-
134
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
cies of sustained attention in children with ADHD have been demonstrated on the Continuous Performance Task, a measure of sustained attention that requires participants to identify a target stimuli interspersed within a series of irrelevant distractor stimuli,83 and on the Test of Everyday Attention, a standardized test that analyzes component attentional deficits.86 Whereas planning and cognitive flexibility deficits are prominent in the cognitive profiles of children with autism, these areas of cognition are relatively intact in children with ADHD.48 Brain lateralization is potentially another point of neurocognitive difference between children with ADHD and those with autism. Whereas children with autism have been shown to display deficiencies in right hemispace performance on executive function tasks, implicating left hemisphere dysfunction,65 there is evidence that the performance of nonmedicated children with ADHD on a line-bisection task is consistent with right hemisphere dysfunction.87
Neuroanatomical and Neuroimaging Studies As is the case with autism, no consistent structural abnormalities have been recorded for individuals affected by ADHD. Whereas autism has been associated with larger whole-brain volumes and left hemisphere anomalies, ADHD has been associated in some but not all studies with smaller whole-brain volumes,88 and right, rather than left, prefrontal anomalies.87 As with autism, structural anomalies have been reported in the basal ganglia, cerebellum, and corpus callosum.88,89 Neural regions that subserve key attentional and inhibitory functions—for example, the dorsolateral prefrontal, lateral temporal, and posterior parietal regions—have been shown to be dysfunctional in fMRI studies of individuals with ADHD.90 Children with ADHD also show decreased left caudate activation when engaged in a response inhibition task, which is potentially linked to the core symptoms of hyperactivity, disinhibition, and inattention.91 A separate fMRI study in which the same mental rotation task was used for a group of normally intelligent adolescents with ADHD (mean age 14.6 years)92 and a group with autism (mean age 14.7 years)75 revealed similar patterns of reduced prefrontal activation for both disorders, which is consistent with the frontostriatal model of neurodevelopmental disorders.38 Therefore, inherited or environmentally determined developmental dysfunction of frontostriatal circuits may manifest predominantly as autism or as ADHD, depending on the particular regions that are defective.
Genetic Theories Evidence from twin studies and molecular genetic studies points to an inherited basis for ADHD in approximately 80% of cases, with perinatal brain injury responsible for the remainder.93 The cause in the inherited cases is likely to be a complex interaction of multiple genes; in some individuals, there is also an interaction with perinatal brain injury or other environmental traumas such as fetal alcohol exposure or postnatal malnutrition. There have been a large number of candidate gene and linkage studies of ADHD, using a variety of case-control and multiplex family methods, as well as dimensional or categorical definitions of ADHD. As a consequence, they have produced conflicting results. The most consistent findings implicate dopamine D4 and D5 receptors and the dopamine transporter and the serotonin
transporter genes as candidate risk factor genes in ADHD.94,95 Genetic screening for ADHD is not yet possible, and recognition of the complex gene-environment interaction associated with each individual with ADHD is central to clinical management.95
TREATMENT Autism There is a wide range of approaches to the treatment and management of autism but relatively little empirical evidence to support claims of effectiveness. In view of the devastating and persistent nature of the disorder, parents understandably try interventions that promise cure, regardless of a lack of scientific evidence.96 The U.S. National Academy of Sciences concluded that there is no single intervention or treatment that is effective for all individuals with autism.97 The best outcomes are produced by a combination of educational, behavioral, communication, and social skills training approaches, together with medication if indicated, designed to target the specific needs of each child and also to provide education, support, and skills training for the parents.
Behavioral Management Difficult behaviors such as self-injury can be eliminated, and competent behaviors such as remaining seated with other children can be taught, after an identification of the antecedents and consequences of the target behaviors. New skills can be taught with the use of positive reinforcement, physical and verbal prompts, and incrementally shaping behavior, by breaking a desired outcome into small steps (chaining). An analysis of the communicative function of a negative behavior may facilitate the development of more positive behaviors that achieve the same communicative outcome. Time out, the withdrawal of attention, and the use of a loss of favorite activities or privileges may help immediately to decrease undesirable behaviors but should be used in conjunction with approaches that then teach appropriate behaviors. Aversive, cruel, and abusive responses to negative behaviors create further adverse consequences and are unethical. There is some evidence that the application of an intensive 40-hour-per-week behavioral program (applied behavior analysis) might be associated with significant and sustained improvement, particularly in cognitive skills.98 Some parents may report satisfaction with applied behavior analysis programs, but the costs of therapy can be prohibitive, and replication of the initial study in a randomized controlled trial with comprehensive outcome measures is required.
Education The provision of a structured and consistent educational program individually designed for the child with autism facilitates development and learning. The level of the child’s intellectual and language impairment must be taken into account, and techniques that entail use of visual means of communication and learning are usually necessary. Integration into mainstream classrooms is desirable but depends on the provision of adequate education aide support and classroom resources. Children with autism who become isolated and unoccupied in class usually become increasingly disruptive or withdraw into ritualistic, nonfunctional behaviors.
chapter 10 autism and attention deficit/hyperactivity disorder Communication Skills Improving the capacity of a child with autism to more effectively communicate reduces inappropriate behavior and distress. The augmentation of spoken communication with visual and nonverbal communication, such as the use of pictures and line drawings, helps improve communication skills. Social skills may also be improved through the use of cartoons or social stories that teach appropriate social behavior, such as catching a bus to school.99
Parent Training Effective management involves collaboration between parents, teachers, and clinicians. The involvement of parents of preschool children with autism in a structured education and skills training program is associated with reduced parental stress and a sustained improvement in parental mental health, and it also facilitates developmental progress and behavioral improvement in the child.100
Pharmacotherapy Evidence for the effectiveness of medication in the treatment of disturbed emotions and behaviors in individuals with autism is derived mostly from studies of adults with intellectual disability. Drugs should be prescribed only after an assessment has defined the specific symptoms or disorder, such as depression, that is the focus of treatment. Before the implementation of medication, it is necessary to record a baseline measure of target symptoms—for example, with a behavior checklist—in order to follow response to treatment and monitor side effects.20 Compliance is improved when the parents and individual with autism are involved in regular review. There is some evidence that neuroleptic medication (e.g., haloperidol, risperidone) reduces aggressive, disruptive, and stereotypical behaviors and anxiety.101 However, it may produce side effects, including sedation, dystonic reactions, and increased weight gain. Tricyclic antidepressants (e.g., imipramine, clomipramine) are effective anxiolytics and may also reduce repetitive behaviors.102 Caution should be exercised, because of the potential cardiotoxic effects of tricyclic antidepressants. Case reports indicate that the selective serotoninreuptake inhibitors such as fluoxetine may reduce anxiety and associated obsessive-compulsive behaviors, although the side effects (excitation, nausea, and headache) can be troublesome. Lithium and other mood stabilizers may reduce episodes of disruptive, aggressive, and self-injurious behavior, particularly if there is a family history of bipolar disorder. Other drugs such as stimulant medication, clonidine, and naltrexone are used to treat disruptive behaviors and symptoms of attention deficit and hyperactivity, but evidence of their efficacy is lacking.
Attention Deficit/Hyperactivity Disorder A multimodal approach to management, including medication, special education, behavior modification, and parent education and skills training, is likely to lead to the greatest treatment response.103 Medication is the most important aspect of treatment, but multimodal treatments that account for the complex learning, behavioral, and social problems of the child improve outcomes.104 An elimination diet is effective for children in
135
whom the specific provocative food, such as those containing tartrazine, can be identified, but it is of benefit to fewer children than is medication.105 Stimulants (methylphenidate and dexamphetamine) are the most frequently used medications. They are indirect catecholamine agonists, which facilitate the action of dopamine and noradrenaline agonists by inhibiting reuptake and facilitating release, as well as antagonizing α2-adrenergic receptors.106 There have been many randomized placebo-controlled trials of the efficacy of stimulant medication. These have clearly demonstrated immediate improvement in inattention, impulsivity, and hyperactivity and a reduction in aggression.104,105 The longer term effects on learning and academic achievement are less clear, and there is a lack of good long-term evidence for the effectiveness of stimulant medication.105 Anorexia, insomnia, irritability, and emotional distress are significant side effects that may necessitate cessation of treatment. The use of long-acting preparations may reduce some side effects and improve compliance. There is some evidence that prolonged treatment does not increase the risk of subsequent drug abuse.103,107 Stimulant medication is less effective in preschool children and young people with intellectual disability, including those with autism, and these groups are more likely to suffer adverse side effects.108 The presence of comorbid anxiety disorder also militates against the effectiveness of stimulant medication. Children who have side effects, or who are unresponsive to stimulant medication, may benefit from treatment with tricyclic antidepressants (imipramine) or perhaps clonidine. These agents reduce hyperactivity and improve behavior but are less effective for inattention and learning. In view of the potential cardiotoxic effects of tricyclic antidepressants, review of the cardiovascular system is indicated.105 The combination of stimulant medication and nighttime clonidine is used to overcome insomnia, and neuroleptic medication may be added to control aggressive behavior, but there are no long-term studies regarding the safety or efficacy of combination treatments. Atomoxetine, an inhibitor of the presynaptic norepinephrine transporter, has been shown in several randomized controlled trials to be at least as effective as methylphenidate in the treatment of inattention, impulsiveness, and hyperactivity.109,110 Reported side effects include decreased appetite, somnolence, fatigue, irritability, and some increase in pulse rate and blood pressure. A single morning dose produces a therapeutic effect throughout the day, and insomnia is not a side effect. Parents are understandably apprehensive regarding the use of medication, but compliance is improved with regular review of response and monitoring of side effects.
CONCLUSIONS AND RECOMMENDATIONS Both pervasive developmental disorders and ADHD are serious neurodevelopmental conditions that cause profound distress, impairment, and disability for the individual child, stress and burden for the parents and family, and long-term cumulative costs for the community. Diagnosis depends on the careful and systematic gathering of a developmental history and on observation of behavior in a variety of settings, supplemented by a comprehensive cognitive assessment. The management of autism relies on a multimodal program of structured and targeted behavioral and educational interventions supplemented, when indicated, by pharmacotherapy. Effective medications are
136
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
available for the treatment of ADHD but should be prescribed in the setting of a comprehensive educational and behavioral management program. The active involvement of parents as partners in management, together with the provision of education and skills training, further helps to consolidate treatment response, relieve family stress, and improve parental mental health. Current research into the neuropsychological features of these conditions, together with advances in understanding of central nervous system abnormalities and contributory genetic factors, is likely to lead to the elucidation of more specific neurobiological markers that will aid in the specificity of the diagnosis and the elucidation of subtypes of these disorders, with implications for treatment.
Suggested Reading Barkley RA: Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment, 2nd ed. New York: Guilford Press, 1998. Bock G, Goode J: Autism: Neural Basis and Treatment Possibilities. Novartis Foundation Symposium, No. 251. London: Wiley, 2003. Bradshaw JL: Developmental Disorders of the Frontostriatal System: Neuropsychological, Neuropsychiatric and Evolutionary Perspectives. Hove, UK: Psychological Press, 2001. Brereton AV, Tonge BJ: Preschoolers with Autism: An Education and Skills Training Program for Parents. London: Jessica Kingsley, 2005. Cohen DJ, Volkmar FR, eds: Handbook of Autism and Pervasive Developmental Disorders, 2nd ed. New York: John Wiley, 1997.
References
K E Y
P O I N T S
●
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) specifies that the diagnosis of attention deficit/hyperactivity disorder (ADHD) cannot be made if the symptoms occur in a child with autism. However, symptoms of attention deficit and hyperactivity are a common problem in children with autism, which points toward some neuropathophysiological characteristics shared between these two groups of neurodevelopmental disorders.
●
The frontostriatal model of developmental dysfunction links autism and ADHD by virtue of shared neural circuitry and predicts that the two disorders are likely to share common heritability factors. In addition, both disorders share a number of neurotransmitters, including dopamine, noradrenaline, acetylcholine, γ-amino butyric acid, and serotonin.
●
Children with autism have an increased risk of suffering tic disorder or Gilles de la Tourette syndrome, with the tics becoming more prevalent during times of stress and anxiety, such as a change in school placement.
●
Epilepsy occurs in approximately 20% of young people with autism, emerging most commonly in early childhood or during adolescence and more frequently in children with more severe levels of intellectual disability.
●
Standardized neuropsychological tests have demonstrated that the profile of autism is characterized primarily by deficiencies in cognitive flexibility and planning, whereas the neuropsychological profile of ADHD is characterized predominately by inhibitory deficits and problems with sustained attention.
●
The management of autism relies on a multimodal program of structured and targeted behavioral and educational interventions supplemented, when indicated, by pharmacotherapy.
●
Effective medications are available for the treatment of ADHD but should be prescribed in the setting of a comprehensive educational and behavioral management program.
1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association, 2000. 2. World Health Organization: International Statistical Classification of Diseases and Related Health Problems, 10th Revision. Geneva: World Health Organization, 1992. 3. Tonge BJ: Autism: time for a national approach to early assessment and management [Editorial]. Med J Aust 1996; 165:244-245. 4. Kanner L: Autistic disturbances of affective contact. Nervous Child 1943; 2:217-250. 5. Asperger H: Die “autistichen psychopathen” in kindersalter. Arch Psychiatrie Nervenkrankheiten 1944; 117:76-136. 6. Sandberg S, Barton J: Historical development. In Sandberg S, ed: Hyperactivity Disorders of Childhood. Cambridge, UK: Cambridge University Press, 1996, pp 1-25. 7. Barkley RA: Behavioural inhibition, sustained attention, and executive functions: constructing a unified theory of ADHD. Psychol Bull 1997; 121:65-94. 8. Bradley C: The behavior of children receiving Benzedrine. Am J Psychiatry 1937; 94:577-585. 9. Fombonne P: Epidemiological surveys of autism and other pervasive developmental disorders. J Autism Dev Disord 2003; 33:365-382. 10. Magnusson P, Saemundsen E: Prevalence of autism in Iceland. J Autism Dev Disord 2001; 31:153-163. 11. Fombonne P, Du Mazaubrunc C, Cans C, et al: Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997; 36:15611569. 12. Wolraich ML, Hannah JN, Baumgaertel A, et al: Examination of DSM-IV criteria for attention deficit/hyperactivity disorder in a country wide sample. J Dev Behav Pediatr 1998; 19:162168. 13. Swanson JM, Sargeant JA, Taylor E, et al: Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 1998; 351:429-433. 14. Bird HR, Gould MS, Staghezza BM: Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Am Acad Child Adolesc Psychiatry 1993; 32:361-368. 15. Faraone SV, Biederman J, Weber W, et al: Psychiatric, neuropsychological and psychosocial features of DSM IV subtypes of attention-deficit/hyperactivity disorder: results from a clinically referred sample. J Am Acad Child Adolesc Psychiatry 1998; 37:185-193. 16. Szatmari P, Offord DR, Boyle MH: Correlates, associated impairments and patterns of service utilization of children
chapter 10 autism and attention deficit/hyperactivity disorder
17. 18. 19. 20.
21. 22. 23. 24.
25. 26. 27. 28. 29. 30. 31. 32. 33.
34. 35. 36. 37. 38.
with attention deficit disorder: findings from the Ontario Child Health Study. J Child Psychol Psychiatry Allied Disciplines 1989; 30:205-217. Mannuzza S, Klein RG, Bessler A, et al: Adult psychiatric status of hyperactive boys grown up. Am J Psychiatry 1998; 155:493-498. McCann S, Roy-Byrne P: Screening and diagnostic utility of self report attention deficit hyperactivity disorder scales in adults. Compr Psychiatry 2004; 45:175-183. Filipek PA, Accardo PJ, Ashwal S, et al: Practice parameter: screening and diagnosis of autism. Neurology 2000; 55:468479. Einfeld SL, Tonge BJ: Manual for the Developmental Behaviour Checklist (Edition 2). Melbourne, Australia: Monash University Centre for Developmental Psychiatry and Psychology and School of Psychiatry, University of New South Wales, 2002. Baron-Cohen S, Allen J, Gillberg C: Can autism be detected at 18 months? The needle, and the CHAT. Br J Psychiatry 1992; 161:839-934. Pipek PA, Accardo PJ, Baranek GT, et al: The screening and diagnosis of autistic spectrum disorders. J Autism Dev Disord 1999; 29:437-482. LeCouteur A, Rutter M, Lord C, et al: Autism Diagnostic Interview: a standardized investigator based instrument. J Autism Dev Disord 1989; 19:363-387. Lord C, Rutter M, Goode S, et al: Autism Diagnostic Observation Schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 1989; 19:185-212. Tonge BJ, Einfeld SL: Psychopathology and intellectual disability: the Australian Child to Adult Longitudinal Study. Int Rev Res Ment Retard 2003; 26:61-91. Tonge BJ: Autism: time for a national approach to early assessment and management [Editorial]. Med J Aust 1996; 165:244-245. Keen D, Ward S: Autistic spectrum disorder: a child population profile. Autism 2004; 8:39-48. Tonge BJ, Brereton AV, Gray KM, et al: Behavioural and emotional disturbance in high functioning autism and Asperger disorder. Autism Int J Res Pract 1999; 2:117-130. Conners CK: Rating scales in attention-deficit/hyperactivity disorder: use in assessment and treatment monitoring. J Clin Psychiatry 1998; 59:24-30. Jensen PS, Martin D, Cantwell DP: Comorbidity in ADHD: implications for research, practice and DSM-V. J Am Acad Child Adolesc Psychiatry 1997; 36:1065-1079. Mannuzza S, Klein RG, Bessler A, et al: Educational and occupational outcome of hyperactive boys grown up. J Am Acad Child Adolesc Psychiatry 1997; 36:1222-1227. Corkum P, Tannock R, Moldofsky H: Sleep disturbances in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1998; 37:637-646. Whalen CK, Jamner LD, Henker B, et al: The ADHD spectrum and everyday life: experience sampling of adolescent moods, activities, smoking and drinking. Child Dev 2002; 73:209227. Toone B: Attention deficit hyperactivity disorder in adulthood. J Neurol Neurosurg Psychiatry 2004; 75:523-525. Baron-Cohen S, Leslie AM, Frith U: Does the autistic child have a “theory of mind”? Cognition 1985; 21:37-46. Russell J: Autism as an Executive Disorder. New York: Oxford University Press, 1997. Frith U, Happe F: Autism: beyond “theory of mind.” Cognition 1994; 50:115-132. Bradshaw JL: Developmental Disorders of the Frontostriatal System: Neuropsychological, Neuropsychiatric and Evolutionary Perspectives. Hove, UK: Psychology Press, 2001.
137
39. Turner M: Annotation: repetitive behavior in autism: a review of psychological research. J Child Psychol Psychiatry 1999; 40:839-849. 40. Russell J, Jarrold C, Hood B: Two intact executive capacities in children with autism: implications for the core executive dysfunctions in the disorder. J Autism Dev Disord 1999; 29: 103-112. 41. Happe F: Cognition in autism: one deficit or many ? In Novartis Foundation Symposium: Autism: Neural Basis and Treatment Possibilities. London: Wiley, 2003, pp 198-212. 42. Volkmar FR, Klin A, Pauls D: Nosological and genetic aspects of Asperger syndrome. J Autism Dev Disord 1998; 28:457461. 43. Dahlgren SO, Trillingsgaard A: Theory of mind in nonretarded children with autism and Asperger’s syndrome: a research note. J Child Psychol Psychiatry Allied Disciplines 1996; 37:759-763. 44. Baron-Cohen S, O’Riordan M, Stone V, et al: Recognition of faux pas by normally developing children and children with Asperger syndrome or high-functioning autism. J Autism Dev Disord 1999; 29:407-415. 45. Baron-Cohen S, Jolliffe T, Mortimore C, et al: Another advanced test of theory of mind: evidence from very high functioning adults with autism or Asperger syndrome. J Child Psychol Psychiatry 1997; 38:813-822. 46. Rinehart NJ, Bradshaw JL, Moss SA, et al: A deficit in shifting attention present in high functioning autism but not Asperger’s disorder. Autism Int J Res Pract 2001; 5:67-80. 47. Rinehart NJ, Bradshaw JL, Moss SA, et al: Atypical interference of local detail on global processing in high functioning autism and Asperger’s disorder. J Child Psychol Psychiatry 2000; 41:796-778. 48. Ozonoff S, Jensen J: Brief report: specific executive function profiles in three neurodevelopmental disorders. J Autism Dev Disord 1999; 29:171-177. 49. Sheppard DM, Bradshaw JL, Purcell R, et al: Tourette’s and comorbid syndromes: Obsessive compulsive and attention deficit hyperactivity disorder. A common etiology? Clin Psychol Rev 1999; 19:531-552. 50. Noterdaeme M, Amorosa H, Mildenberger K, et al: Evaluation of attention problems in children with autism and children with a specific language disorder. Eur Child Adolesc Psychiatry 2001; 10:58-66. 51. Turner MA: Generating novel ideas: fluency performance in high-functioning and learning disabled individuals with autism. J Child Psychol Psychiatry 1999; 40:189-201. 52. Rinehart NJ, Bradshaw JA, Moss SA, et al: Pseudo-random number generation in children with high-functioning autism and Asperger’s disorder: further evidence for a dissociation in executive functioning? Autism J Res Pract. 2006; 10:70-85. 53. Mari M, Castiello U, Marks D, et al: The reach-to-grasp movement in children with autism spectrum disorder. Philos Trans R Soc Lond B Biol Sci 2003; 358:393-403. 54. Minshew NJ, Sung K, Jones BL, et al: Underdevelopment of the postural control system in autism. Neurology 2004; 63:2056-2061. 55. Maurer RG, Damasio AG: Childhood autism from the point of view of behavioral neurology. J Autism Dev Disord 1982; 12:195-205. 56. Damasio AR, Maurer RG: A neurological model for childhood autism. Arch Neurol 1978; 35:777-786. 57. Vilensky JA, Damasio AR, Maurer RG: Gait disturbances in patients with autistic behavior. Arch Neurol 1981; 38:646649. 58. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: An examination of movement kinematics in young people with high-functioning autism and Asperger’s disorder: further evidence for a motor planning deficit. J Autism Dev Disord. In press.
138
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
59. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: Movement-relatedpotentials in autism and Asperger’s disorder. Dev Med Child Neurol. 2006; 48:272-277. 60. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: Kinematic gait function in children with high functioning autism and Asperger’s disorder. Eur Child Adolescent Psychiatry (In Press). 61. Hallet M, Lebiedowska MK, Thomas SL, et al: Locomotion of autistic adults. Arch Neurol 1993; 50:1304-1308. 62. Rinehart NJ, Tonge BJ, Bradshaw JL, et al: Kinematic gait function in newly diagnosed children with autism (3-5 years). Dev Med Child Neurol (In Press) 63. Rinehart NJ, Bradshaw JL, Brereton AV, et al: A clinical and neurobehavioural review of high-functioning autism and Asperger’s disorder. Aust N Z J Psychiatry 2002; 36:762-770 64. Rinehart NJ, Bradshaw JL, Tonge BJ, et al: A neurobehavioural examination of individuals with high-functioning autism and Asperger’s disorder using a fronto-striatal model of dysfunction. Behav Cogn Neurosci Rev 2002; 1(2):164-177. 65. Rinehart NJ, Bradshaw JL, Brereton AV, et al: Lateralization in individuals with high-functioning autism and Asperger’s disorder: a frontostriatal model. J Autism Dev Disord 2002; 32:321-332. 66. Abell F, Krams M, Ashburner J, et al: The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. Neuroreport 1999; 10:1647-1651. 67. Carper RA, Moses P, Tigue ZD, et al: Cerebral lobes in autism: early hyperplasia and abnormal age effects. Neuroimage 2002; 16:1038-1051. 68. Giedd JN, Castellanos FX: Developmental disorders. In Krishnan KRR, Doraiswamy PM, eds: Brain Imaging in Clinical Psychiatry. New York: Marcel Dekker, 1997, pp 121137. 69. Murphy DG, Critchley HD, Schmitz N, et al: Asperger syndrome: a proton magnetic resonance spectroscopy study of brain. Arch Gen Psychiatry 2002; 59:885-891. 70. Muller RA, Pierce K, Ambrose JB, et al: Atypical patterns of cerebral motor activation in autism: a functional magnetic resonance study. Biol Psychiatry 2001; 49:665-676. 71. Sokol DK: Neuroimaging in autistic spectrum disorder (ASD). J Neuroimaging 2004; 14:8-15. 72. Haznedar MM, Buchsbaum MS, Wei TC, et al: Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 2000; 157:1994-2001. 73. Happe F, Ehlers S, Fletcher P, et al: “Theory of mind” in the brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 1996; 8:197-201. 74. Haznedar MM, Buchsbaum MS, Metzger M, et al: Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry 1997; 154:1047-1050. 75. Silk TJ, Rinehart NJ, Bradshaw JL, et al: Visuospatial processing and the function of prefrontal-parietal networks in autism spectrum disorder: a functional MRI study. Am J Psychiatry. (In Press). 76. Fan J, McCandliss BD, Sommer T, et al: Testing the efficiency and independence of attentional networks. J Cogn Neurosci 2002; 14:340-347. 77. Muhle R, Trentacost SV, Rapin I: The genetics of autism. Pediatrics 2004; 113:472-486. 78. Tidmarsh F, Volkmar F: Diagnosis and epidemiology of autism spectrum disorders. Can J Psychiatry, 2003; 48:517523. 79. Stone JL, Merrimon B, Cantor RM, et al: Evidence for sexspecific risk alleles in autism spectrum disorder. Am J Hum Genet 2004; 75:1117-1123. 80. McCauley JL, Olson LM, Delahanty R, et al: A linkage disequilibrium map of the 1-Mb 15g12 GABA(A) receptor subunit
81. 82. 83. 84. 85. 86.
87.
88.
89. 90. 91.
92.
93. 94. 95. 96. 97. 98.
99. 100.
cluster and association to autism. Am J Med Genet B Neuropsychiatr Genet 2004; 131:51-59. Rabionet R, Jaworski JM, Ashley-Kock AE, et al: Analysis of the autism chromosome 2 linkage region: GAD1 and other candidate genes. Neurosci Lett 2004; 382:209-214. Barkley RA: Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 1997; 121:65-94. Barkley RA: The executive function and self-regulation: an evolutionary neuropsychological perspective. Neuropsychol Rev 2001; 11:1-29. Nichols SL, Waschbusch DA; A Review of the Validity of laboratory cognitive tasks used to assess symptoms of ADHD. Child Psychiatry Hum Dev 2004; 34:297-315. Casey J, Trainor RJ, Orendi JL, et al: A developmental functional MRI study of prefrontal activation during performance of a go–no-go task. J Cogn Neurosci 1997; 9:835-847. Manly T, Anderson V, Nimmo-Smith I, et al: The differential assessment of children’s attention: the Test of Everyday Attention for Children (TEA-Ch), normative sample and ADHD performance. J Child Psychol Psychiatry 2001; 42:1065-1081. Sheppard DM, Bradshaw JL, Mattingley JB, et al: Effects of stimulant medication on the lateralisation of line bisection judgements of ADHD children. J Neurol Neurosurg Psychiatry 1999; 66:57-63. Castellanos FX, Giedd JN, Marsh JL, et al: Quantitative brain magnetic resonance imaging in attention deficit hyperactivity disorder. Arch Gen Psychiatry 1996; 53:607616. Hill DE, Yeo RA, Campbell RA, et al: Magnetic resonance imaging correlates of attention-deficit/hyperactivity disorder in children. Neuropsychology 2003; 17:496-506. Sowell ER, Thompson PM, Welcome SE, et al: Cortical abnormalities in children and adolescents with attention deficit hyperactivity disorder. Lancet 2003; 362:1699-1707. Rubia K, Overmeyer S, Taylor E, et al: Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatry 1999; 156:891-896. Silk T, Vance A, Rinehart NJ, et al: Fronto-parietal activation in attention deficit hyperactivity disorder, combined type: functional magnetic resonance imaging study. Br J Psychiatry. 2005; 187:282-283. Voeller KKS: Attention deficit hyperactivity disorder (ADHD). J Child Neurol 2004; 19:798-814. Bobb AJ, Castellanos FX, Addington AM, et al: Molecular genetic studies of ADHD: 1991 to 2004. Am J Med Genet B Neuropsychiatr Genet 2005; 132:109-125. Yeh M, Morley KI, Hall WD: The policy and ethical implications of genetic research on attention deficit hyperactivity disorder. Aust N Z J Psychiatry 2004; 38(1-2):10-19. Volkmar F, Lord C, Bailey A, et al: Autism and pervasive developmental disorders. J Child Psychol Psychiatry 2004; 45:135170. National Research Council: Educating Young Children with Autism. Washington, DC: National Academies Press, 2001. Lovaas I, Calouri K, Jada J: The nature of behavioral treatment and research with young autistic persons. In Gillberg C, ed: Diagnosis and Treatment of Autism. New York: Plenum Press, 1989, pp 285-305. Gray CA, Garand JD: Social stories: improving responses of students with autism with accurate social information. Focus Autistic Behav 1993; 8:1-10. Brereton AV, Tonge BJ: Preschoolers with Autism: An Education and Skills Training Program for Parents. London: Jessica Kingsley, 2005.
chapter 10 autism and attention deficit/hyperactivity disorder 101. Aman MG: A double-blind, placebo-controlled trial of risperidone in children with autistic disorder. N Engl J Med 2002; 347:314-321. 102. Gordon CT, State RC, Nelson JE, et al: A double blind comparison clomipramine, desipramine and placebo in the treatment of autistic disorder. Archs Gen Psychiatry 1993; 50:441-447. 103. Zametkin AJ, Ernst M: Problems in the management of attention-deficit/hyperactivity disorder. N Engl J Med 1999; 340:40-46. 104. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999; 56:1073-1086. 105. Hill P: Attention deficit hyperactivity disorder. Arch Dis Child 1998; 79:381-386. 106. Solanto MV: Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity dis-
107.
108. 109.
110.
139
order: a review and integration. Behav Brain Res 1998; 94:127-152. Hechtman L, Weiss G: Controlled prospective 15 year follow up of hyperactives as adults: non medical drug and alcohol use and antisocial behaviour. Can J Psychiatry 1986; 31:557567. Mayes SD, Crites DL, Bixler EO, et al: Methylphenidate and ADHD: influence of age, IQ and neurodevelopmental status. Dev Med Child Neurol 1994; 36:1099-1107. Kratochvil CJ, Heiligenstein MD, Dittmann R, et al: Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry 2002; 41:776-784. Kelsey DK, Sumner CR, Casat CD, et al: Once-daily atomoxetine treatment for children with attention deficit/hyperactivity disorder, including an assessment in the evening and morning behavior: a double-blind placebo-controlled trial. Pediatrics 2004; 114:111-118.
CHAPTER
11
DELIRIUM ●
●
●
●
Kim Jeffs and Pe¯teris Da¯rzinsˇ
The key features of delirium are acute change in cognitive status, fluctuation in consciousness, deficits in attention, and perceptual disturbances.1 Nonarbitrary definitions of these features, especially consciousness and attention, are lacking, and this limits the ability to define delirium precisely.
Delirium may be caused by specific brain injury (e.g., herpes simplex encephalitis), but more often, delirium is a nonspecific response of the brain to challenges from systemic illness or medications. Delirium can occur in otherwise normal brains with extreme physiological challenge (e.g., intensive care admission), but in diseased brains (e.g., Alzheimer’s dementia), even apparently trivial challenges, such as a urinary tract infection or constipation, may trigger delirium. Delirium may be caused by just one factor (e.g., recreational drug use) but commonly appears to result from a combination of harmful factors. In most cases, delirium is easy to recognize once it is considered and an adequate history has been obtained. Although a diagnostic workup—and therapy, if indicated—for specific brain injury is always important, this situation is rare. More commonly, multiple possible etiological factors are identified, and attention needs to be directed to each of these. Masterful delirium management seldom requires a single clever diagnosis; more commonly, management requires insightful clinical practice that can detect multiple potential contributors and ameliorate each of these. A collaborative team approach is the key to success. Truly outstanding clinicians manage this well, through attention to systems issues aimed at the prevention and optimal management of delirium. Delirium is common and is associated with a higher risk of death, persistent cognitive impairment, institutionalization, and prolonged hospitalization. There is some evidence that prevention of delirium is often possible, but prevention strategies remain underused. Because delirium treatments have limited efficacy, and because neuropathological insights are of limited clinical relevance, the emphasis of any discussion of delirium must be on prevention.
Delirium is common (Table 11–1). The prevalence of delirium in hospitalized older patients is 14% to 60%; the rates are higher in surgical patients (particularly those with hip fracture or requiring emergency surgery).2-6 Approximately 1 per 10 elderly patients presenting to hospital are delirious, and a further 10% to 40% develop delirium while hospitalized.7 Delirium occurs in up to 45% of hospitalized patients with preexisting cognitive impairment.8 Delirium is even more common in patients nearing the end of life, occurring in up to four fifths of such patients.9,10 Delirium occurs in 10% of patients presenting to emergency departments and is almost universal in intensive care units.11-16 Of patients admitted to post–acute care facilities, 16% have a diagnosis of delirium, and a further 23% to 53% have symptoms of delirium at the time of admission.17,18 Despite the high incidence and prevalence of delirium, it remains underrecognized by clinicians—up to 90% of cases in in-patients are missed.13,19-26 Furthermore, patients are discharged home from the emergency department without delirium being recognized, and this has been linked to increased mortality.12,13,23
DEFINITION
Clinical Syndromes
Many terms have been used to describe the delirious state, including acute organic brain syndrome, acute confusional state, toxic psychosis, intensive care unit (ICU) syndrome, and postoperative psychosis. This variation reflects the difficulty in describing the syndrome or syndromes that are now most commonly called delirium. The most common definition used in delirium research is that of the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (Fig. 11–1).1
Delirium is not a homogenous disorder; rather, it is a complex clinical syndrome with diverse etiologies and presentations. Delirium tremens is the classic picture of delirium with which most clinicians are familiar. Agitation; being out of touch with reality, with visual, tactile, and auditory hallucinations; obvious fear; and suspicion and mistrust of others typify the hyperactive form of delirium. The hypoactive form of delirium is recognized from apathy in patients with marked cognitive impairment. Hypoactive delirium is easily missed, inasmuch as
EPIDEMIOLOGY Prevalence and Incidence
141
142
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s ■
Figure 11–1. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for delirium. Washington DC: American Psychiatric Association, 1994.
T A B L E 11–1. Delirium in Various Settings Setting
Age
Method of Detecting Delirium
Rate
Study
Mixed* Post–acute care facilities Post–acute care facilities Critical care unit Critical care unit§ Critical care unit§ Critical care unit Emergency department Emergency department Medical inpatients Medical inpatients Medical inpatients Patients with hip fracture Patients with hip fracture¶¶ Patients with hip fracture¶ Patients with hip fracture¶ Major abdominal surgery** Patients undergoing elective orthopedic or urological surgery
>75 >65 >65 All >65 >65 >18 >65 >70 >65 >70 >65 >65 >65 >65 >50 >65 >65
Organic Brain Syndrome Scale Confusion Assessment Method Minimum Data Set—Post Acute Care‡ Confusion Assessment Method Confusion Assessment Method Confusion Assessment Method Intensive Care Delirium Screening Checklist Confusion Assessment Method Confusion Assessment Method Confusion Assessment Method Psychiatric interview Confusion Assessment Method DSM-III criteria Confusion Assessment Method Organic Brain Syndrome Scale Confusion Assessment Method Confusion Assessment Method Screening tool based on DSM-IV criteria
43.9% 15.6%† 23% 7.3% 70% 83% 45% 9.6%¶ 10.1% 12.0% 20.4% 21.3% 44-66% 14.6% 48.5% 28% 34.5% 5.1%
Sandberg et al, 19993 Kiely et al, 200317 Marcantonio et al, 200318 Rincon et al, 200114 McNicoll et al, 200315 Ely et al, 200194 Roberts et al, 200595 Elie et al, 200019 Hustey and Meldon, 200213 Cole et al, 20024 Johnson et al, 199296 Jeffs et al, 200440 Gustafson et al, 199120 Marcantonio et al, 199897 Edlund et al, 200198 Zakriya et al, 200299 Shigeta et al, 2001100 Dai et al, 2000101
*Hospital patients, patients in residential aged care facilities, and patients receiving home medical care. † A further 12.6% had two symptoms of delirium, and 39.5% had one symptom of delirium. ‡ Delirium is defined as the presence of one or more symptoms of delirium on the Minimum Data Set—Post Acute Care. § Cumulative incidence of delirium. ¶ Includes definite and probable delirium. ¶¶ Patients interviewed by telephone and face to face 1 month after repair of hip fracture. **Study of 29 patients in whom melatonin levels were investigated. DSM, Diagnostic and Statistical Manual of Mental Disorders.
chapter 11 delirium there are no behavioral disturbances that bring attention to the patients and the patients seldom volunteer that they are experiencing psychotic thoughts or bizarre sensations. About 25% of cases of delirium are of the hyperactive form, another 25% are of the hypoactive form, and the remainder of patients with delirium have both hyperactive and hypoactive features.3,27,28 The cause of delirium cannot be reliably diagnosed from the subtype observed, although drug withdrawal states more commonly manifest with the hyperactive form and metabolic encephalopathies with the hypoactive form.28,29 Infection may manifest with either form of delirium.30,31 Patients who have some of the key features of delirium but do not fully satisfy the DSM-IV criteria experience adverse events similar to those who do meet the criteria. This “subsyndromal delirium” has been associated with poor outcomes, and there is probably a relationship between the number of features present and the risk of adverse outcomes.32,33
Course Delirium often lasts for a few days or a week, but some patients experience prolonged delirium. One study showed that only approximately one fifth of patients have complete resolution of delirium at 6 months.34 Symptoms of memory impairment, inattention, and disorientation may still be present 12 months after an episode of delirium.35 Prolonged delirium leads to diagnostic difficulty, especially when the precipitating event has apparently resolved, and it may be difficult to distinguish delirium from dementia. Dementia with Lewy bodies, with its characteristic attentional fluctuations causes particular difficulty (see Chapter 71). Nearly one in five patients has a new diagnosis of dementia in the year after an episode of delirium.36 The existence of prolonged delirium also makes it difficult to predict recovery of individual patients and complicates decisions about rehabilitation potential and long-term care.
143
burden for health care systems as a result of increased duration of hospitalization and increased postdischarge costs.44-46
RISK FACTORS Baseline Vulnerability Factors that increase vulnerability to delirium include preexisting cognitive impairment, comorbid illness, and sensory deficits (Table 11–2).11,45,47,48 A delirium risk prediction model based on the presence or absence of cognitive impairment, severe illness, visual impairment, and dehydration at the time of admission to hospital shows that when one or two risk factors are present, the rate of incident delirium is 16% to 23%, whereas when three or four risk factors are present, the rate of delirium is 32% to 83%.48 The magnitude of the noxious event or events necessary to produce a delirious episode is inversely proportional to the degree of baseline vulnerability. In vulnerable people, delirium acts as a sensitive, but not specific, indicator of illness.
Precipitating Factors The study of precipitating factors is plagued by confounding variables. The confounding variables (in this case, putative risk factors for delirium, such as prescription of new medications or insertion of a urinary catheter) are related to both the study factor (sickness that necessitates hospitalization and in turn may necessitate the new medications or catheterization) and the outcome factor (delirium that may be caused by the sickness, the interventions, or both). Confounding cannot be adjusted for statistically. Because it would be unethical to subject healthy people to medications, procedures, or hospitalization to test these as independent risk factors for delirium, the evidence
Sequelae Physical Delirium is associated with major morbidity and mortality. Patients suffering from delirium have an initial mortality rate of up to 26%.37 Twelve months after an episode of delirium, patients are twice as likely to have died than are similar patients who have not had delirium.36,38 Mortality rates as high as 75% three years after an episode of delirium have been reported.39 Complications attributable to delirium include malnutrition, dehydration, pneumonia, pressure sores, and falls. Patients with delirium suffer greater functional decline in hospital, and are more likely to require rehabilitation or long-term residential care.34,40-43 Patients with hyperactive delirium are more likely to fall while hospitalized.30 Patients with hypoactive delirium are generally sicker, remain hospitalized longer, and are more likely to develop pressure sores.30
Social and Economic Delirium often imposes a heavy burden on the families of those affected as they come to terms with a serious condition that substantially alters the behavior of their family member and that has an uncertain prognosis. It also creates an economic
T A B L E 11–2. Baseline Vulnerability and Precipitating Factors for Delirium Risk Factor* Cognitive impairment/dementia11,45,47,48 Number of major diagnostic categories45 Depression11,45 Alcoholism11,45 Severe medical illness11,58 Male gender11 Abnormal sodium11,47 Hearing impairment11 Visual impairment11,48 Diminished ADL11 Fever or hypothermia47 Psychoactive drug use47 Azotemia/dehydration47 Use of physical restraints52 Malnutrition52 More than three medications added in 24 hours52 Use of indwelling urinary catheter52 Any iatrogenic event52 *References cited as superscripts. ADL, activities of daily living.
Adjusted Relative Risk 2.1-5.3 1.7 1.9-3.2 3.3-5.7 3.5-5.9 1.9 2.2-6.2 1.9 1.7-3.5 2.5 5.0 3.9 2.0-2.9 4.4 4.0 2.9 2.4 1.9
144
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
regarding precipitating factors comes from descriptive studies. Nonetheless, the weight of evidence shows that many events may precipitate delirium. Delirium is a syndrome with multifactorial etiologies; therefore, in any one patient, it is usual for a number of factors to contribute to delirium.49-51 Five independent risk factors associated with the hospitalization process that appear to increase the risk of developing delirium are (1) the addition of more than three medications in any 24-hour period, (2) the use of physical restraints, (3) the presence of malnutrition, (4) the insertion of an indwelling urinary catheter,
and (5) any iatrogenic adverse event.52 The risk of delirium rises proportionately with the number of risk factors. Of importance is that these precipitating factors are potentially avoidable. Patients with three or more precipitating factors have an 8% per day risk of developing delirium.52 Other environmental factors, such as frequent room changes, absence of a clock, or absence of reading glasses, are associated with increased “severity” of delirium.53 Figure 11–2A depicts a hospital environment likely to produce delirium, whereas Figure 11–2C depicts a hospital environment likely to decrease the risk of delirium.
A 1. Bed at "orthopedic height" 2. Cot sides up—hence bed at "neurosurgical height" 3. Treatment given via indwelling intravenous line 4. Urinary continence managed by indwelling urinary catheter 5. Physical restraint 6. Spectacles not on (out of reach) 7. Hearing aids not in (on the floor) 8. Drink not accessible 9. Call bell out of reach 10. Polypharmacy (pills on the table) 11. Bright light on despite it being night time 12. Music despite it being night time 13. No clock 14. No orienting information
B ■
Figure 11–2. A, Example of suboptimally managed illness in an older patient. B, Fourteen aspects of care that increase the risk of delirium.
Continued
chapter 11 delirium
145
C 1. Patient sitting out of bed 2. Patient dressed in normal day attire rather than pajamas 3. Spectacles are on and clean 4. Hearing aids are in and ears have been cleared of wax 5. A drink is within easy reach 6. Call bell is within easy reach 7. Orienting information is available, including a clock 8. The bed is at an appropriate height 9. The patient is engaged in cognitively stimulating activities 10. No unnecessary indwelling devices 11. No polypharmacy
D ■
Figure 11–2, cont’d. C, Example of a well-managed illness in an older patient. D, Eleven aspects of care that decrease the risk of delirium.
PATHOPHYSIOLOGY It is not surprising, in view of the myriad of etiologies and manifestations of delirium, that there is no one satisfactory unifying pathophysiological explanation. In addition, the neural mechanisms by which delirium is produced are poorly understood. To date, proposed pathophysiological mechanisms remain excessively simplistic or, when detailed, cannot explain adequately the various manifestations of delirium. It is not clear whether delirium is the final common pathway for a broad range of insults or whether the different causes of delirium have different pathophysiological processes that are clinically indis-
tinguishable. Delirium is believed to occur as a result of perturbation to systems that have little reserve, and this fits well with the clinical risk prediction tools. A number of neurotransmitter systems have been implicated in the pathophysiology of delirium. Abnormalities of the cholinergic system are the best studied. The notion that a central cholinergic deficiency leads to delirium is supported clinically by the observation that anticholinergic medications are potent causes of delirium.54,55 Investigators measuring serum anticholinergic activity have reported increased levels associated with the presence of delirium, with levels falling after resolution of delirium.56 Physostigmine, a reversible
146
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
anticholinesterase inhibitor, has been used to treat anticholinergic delirium with some success.57 Cholinesterase inhibitors have been proposed as a means of treating delirium, with some case reports of success, but, conversely, tacrine has been reported to cause delirium.58,59 Excess dopamine has been implicated in the pathogenesis of delirium, and dopamine antagonists are used to treat delirium.60,61 Both serotonin excess and deficiency have been implicated; serotonin excess appears more likely to be associated with medication-related delirium.55 There is no conclusive evidence to relate either dopamine or γ-amino butyric acid to medical or surgical delirium, but perturbation of its activity has been linked with hepatic encephalopathy and benzodiazepine intoxication or withdrawal states.62,63 Hypercortisolism, such as that occurring in Cushing’s syndrome, is known to have effects on cognition, as well as on mood and sleep, but no decisive link with delirium has been established.55 Animal models such as stressed rats show changes in steroid sensitive hypothalamic neurones that can be prevented by adrenalectomy.64
CLINICAL FEATURES Symptoms, Signs, and Corroborative History Many delirious patients do not volunteer any symptoms. Patients’ families or involved health professionals might report changed cognition, fluctuations in alertness, sleep-wake cycle disturbance, or psychotic features. Nursing staff members commonly report nocturnal agitation. Delirium may manifest only as a “failure to thrive.” When patients fail to improve as clinically expected a high level of suspicion for underlying delirium is warranted. A corroborative history that provides information about patients’ baseline cognitive function and the rate of deterioration of cognition may help the clinician identify possible etiologies for delirium, such as changes to medications, constipation, other recent illnesses, and substance abuse.
may yield evidence of a concomitant neurological disorder or a preexisting condition that has increased the vulnerability to delirium. The most common neurological signs in patients with delirium are signs of Alzheimer’s disease (including frontal lobe release signs and apraxia) and vascular-type dementias (including subtle bradykinesia, hypertonicity [gegenhalten], and extensor plantar responses). There may also be evidence of other neurodegenerative disorders such as Parkinson’s disease or a prior focal cerebral lesion such as a stroke or tumor. Patients with small infarcts that result in Wernicke’s aphasia without other focal signs sometimes receive misdiagnoses of delirium. The lack of disturbance of sustained directed attention helps rule out delirium, and the characteristic language disturbance helps make a positive diagnosis of Wernicke’s syndrome (see Chapter 3). There is a wide range of cerebral pathological processes that increase the risk of delirium; the neurological examination may yield evidence of these. Nystagmus and ataxia may be present in medication toxicity, and cranial nerve palsies may be present in Wernicke’s encephalopathy. Asterixis is observed in renal and hepatic failure. Meningism suggests meningitis. The presence of herpes simplex encephalopathy is suggested by fever, meningism, and rapid onset of recent memory loss, together with drowsiness. Differentiation of delirium from depression can be particularly challenging; depressive features such as apathy and complaints of depressed mood are common in delirium. Up to one half of the patients referred for psychiatric consultation for depressive symptoms in hospital actually have delirium.68-70 The differentiation of the disorders is especially important because many antidepressants have anticholinergic properties that have a marked potential to aggravate delirium. Conversely, when depression is misdiagnosed as chronic delirium, the opportunity for antidepressant therapy is lost. Table 11–3 outlines useful features for the differentiation of delirium from other common conditions.
General Physical Examination Cognitive Examination Fluctuating impairment of sustained directed attention is a key feature of delirium and may become apparent when patients have difficulty attending to questions in the medical interview or are easily distracted during conversation. Attention may be formally assessed by such items such as the Digit Span Memory Test or Trail Making Test.65 Restlessness or picking at the bedclothes may indicate underlying psychotic features. Patients should be questioned with regard to worrying thoughts or unusual sensory experiences in order to elicit the presence of hallucinations or delusions. Incorporating a screening test for cognition, such as the Mini Mental State Examination, in the initial assessment of hospitalized older patients could substantially improve the detection of delirium.66,67 Poor test performance would prompt clinicians to seek other evidence of delirium.
Neurological Examination Other than fluctuating attention and disordered thought, there are no specific signs of delirium. The neurological examination
The presence of delirium should prompt a thorough physical examination, with a focus on potential causes for delirium, particularly for evidence of occult infection. Chest and urinary sepsis should be sought. The patient should be examined for the presence of dehydration and constipation. The examination should include a search for signs of renal, respiratory, or hepatic failure. Review of the medication chart is a crucial part of the examination.
Diagnostic Instruments There is no single diagnostic test for the presence of delirium; the reference standard instrument is a formal psychiatric assessment. The Confusion Assessment Method (Fig. 11–3) is relatively short, and nonmedical staff can be trained to administer it.71 However, this test is not valid when administered by nurses involved in the routine care of patients unless they also perform the Mini Mental State Examination.72
chapter 11 delirium ■
CONFUSION ASSESSMENT METHOD (SHORT FORM) 1. Acute onset and fluctuating course a. Is there evidence of an acute change in mental status from the patient’s baseline? b. Did the (abnormal) behavior fluctuate during the day (i.e., tend to come and go or increase and decrease in severity)?
147
Figure 11–3. The Confusion Assessment Method (Short Form). From Inouye SK et al: Annals of Internal Medicine 1990; 113:941-948.
2. Inattention Did the patient have difficulty focusing attention (e.g., was easily distractible or had difficulty keeping track of what was being said)? 3. Disorganized thinking Was the patient’s thinking disorganized or incoherent (e.g., engaged in rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject)? 4. Altered level of consciousness Alert Vigilant (hyperalert) Lethargic (drowsy, easily roused) Stupor (difficult to rouse) Coma (unrousable)
Do any ticks appear in the box?
If either 1a or 1b AND 2 are present AND EITHER 3 or 4 are present, then a diagnosis of delirium is suggested.
T A B L E 11–3. Differential Diagnosis of Delirium Diagnosis Feature
Delirium
Dementia*
Depression
Onset
Acute (hours to days)
Insidious (generally more than 6 months)
Variable
Course
Fluctuating (both within a 24-hour period and from day to day) Clouded Impaired Difficulty maintaining and shifting attention Poor short-term memory
Progressive decline
Diurnal variation in symptoms Clear Not impaired May be impaired
Consciousness Orientation Attention Memory Psychotic symptoms Response to repeated questions
Hallucinations and delusions common Little or no change
Clear until end stage Increasing impairment with duration Generally intact until late stages Poor short-term memory Uncommon
Memory intact (may have some difficulty with registration) Not common (mood congruent)
Patient will try again but is likely to provide incorrect response
“Don’t know,” followed by correct answer
*Exceptions include Dementia with Lewy bodies, which has a fluctuating course and is manifested by attentional disturbance and hallucinations (see Chapter 70).
MANAGEMENT Aims of Management The best available evidence suggests that prevention of delirium is more effective than its treatment.37,73,74 Useful principles for the treatment of established delirium focus on investigation of possible causes, prevention of complications, and the management of behavioral disturbance.
Prevention With rare exceptions, hospital design and budgets are incompatible with truly optimal patient-centered care. Patients are
managed for the comfort and convenience of the system rather than in a way that is optimal for them. For example, patients are left dressed in pajamas rather than being dressed in daytime attire. Mobilization is discouraged by the delivery of meals to patients, instead of their being served in dining rooms. Sometimes patients are expected to remain in or near their beds for the nurses’ convenience (to facilitate medication administration and recording of nursing observations) and for the physicians’ convenience (to ensure that patients can be easily found during ward rounds). Patients are required to fit into hospital time frames (for example, early morning surgical ward rounds) rather than being allowed to follow normal daily routines. Hospitals are often noisy and are brightly lit, day and night. These environmental factors are disorienting and can contribute to delirium, especially in patients with dementia, as do invasive devices and polypharmacy.
148
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Addressing the known risk factors for delirium can prevent the occurrence of delirium while the patient is hospitalized.75 One multidisciplinary intervention reduced the rate of incident delirium by one third in medical patients at intermediate to high risk.75 This program aimed to ameliorate the delirium risk factors of cognitive impairment, dehydration, immobility, sensory impairment, and sleep disturbance.76 Education programs or clinical guidelines for hospital staff that were aimed at the prevention of delirium have yielded mixed results.77,78 Perioperative interventions that have reduced delirium incidence include the provision of continuous supplementary lowflow oxygen, the use of analgesic protocols, and a geriatric consultation service to elderly patients with hip fracture.33,79,80
ogy but is often unhelpful in elucidating the etiology of delirium. Only rarely is delirium the result of a primary neurological event.6,81 Focal neurological signs or a history of head trauma would prompt urgent cerebral computed tomography or magnetic resonance imaging. The electroencephalogram characteristically shows generalized background slowing and only rarely helps establish the cause of delirium. However, the excessive frontal beta activity of benzodiazepine or barbiturate intoxication can be a helpful diagnostic pointer. The electroencephalogram can rule out nonconvulsive status epilepticus, which can at times be indistinguishable from hypoactive delirium, and it may also assist in the differentiation of delirium from functional psychoses (the end stage of Wernicke’s encephalopathy).82
Investigating the Cause of Delirium Investigation is directed toward the likely cause. In children, the emphasis is on the search for infection. In young adults, investigations focus on drug intoxication/withdrawal and central nervous system infections, including the human immunodeficiency virus, and rare encephalopathies (arteritis, disseminated neoplasm). In older people, the causes of delirium are the causes of acute illness in older people; medication side effects, metabolic derangement, and occult infections are the most common. Investigations are directed at these and at ruling out less common etiological factors (Table 11–4). Medications are responsible for 22% to 39% of cases, and thus a medication review, including over-the-counter drugs, often identifies a potential cause (Table 11–5).6 In addition to obvious candidates (e.g., sedatives or hypnotics, anticonvulsants, and antidepressants), many common medications (e.g., frusemide, digoxin, and prednisolone) have significant anticholinergic activity and may contribute to the development of delirium.56 In up to 62% of cases, more than one etiological factor is involved.49-51 Figure 11–4 provides a suggested algorithm for the investigation of the cause of delirium. No clear cause can be found in some cases.6 The search for potential causes for delirium is complicated by the frequently atypical disease manifestations in elderly patients, in addition to the obvious practical difficulties of documenting histories from confused patients. The investigation of delirium must be considered in view of the patients’ own constellation of illnesses, and any algorithm can act only as a guide. Neuroimaging such as computed tomography of the brain commonly reveals underlying pathol-
T A B L E 11–4. Important Causes of Delirium Drugs Intoxication Withdrawal Interactions with other drugs Interactions with disease Infections Metabolic derangement Surgery Environmental Disorienting environment (no clock, frequent room changes) Physical restraints Bladder catheter Iatrogenic events
Treatment Wernicke’s encephalopathy is more common than usually realized, and 1% to 5% of postmortem specimens show evidence of Korsakoff’s pathology in two Australian coronial series.83 Most patients present with only a delirium, rather than with the classic triad of memory loss, ocular signs, and confabulation. For this reason, all patients presenting with delirium for which another cause is not immediately apparent should receive thiamine. It is disappointing that for as common and as serious a condition as delirium, there are few well-conducted trials. There is no specific therapy for delirium. Management centers on the diagnosis and elimination of any underlying etiological factors, the prevention of further harm or injury to patients, and the provision of support while natural recovery is awaited. There seems no reason to abandon the doctrine of “first do no harm” in the management of delirium and, in the absence of good evidence of benefit for particular therapies, plenty of reason to choose therapy with minimal potential for harm.
Nonpharmacological Measures With the exception of physical restraints, which worsen delirium and cause serious injuries and deaths, the use of nonpharmacological measures in the treatment of established delirium is not associated with harm and hence should be used exhaustively as the mainstay of management.52,53,72,84-89 Nonpharmacological management focuses on providing prompts to assist orientation, an environment conducive to appropriate rest, and activities to maintain cognitive stimulation and physical activity. Providing verbal and visual reminders of the date, time, place, and the daily schedule helps. When appropriate, clean spectacles and functioning hearing aids help this orient-
T A B L E 11–5. Drugs Commonly Implicated in Delirium Anticholinergic agents (many commonly used drugs have anticholinergic properties) Antidepressants Antiparkinsonian Benzodiazepines Histamine (H2) receptor antagonists Opioid analgesics Steroidal and nonsteroidal anti-inflammatory drugs
chapter 11 delirium
149
GUIDELINES FOR THE MANAGEMENT OF A PERSON WITH DELIRIUM Patient appears “off color” Relatives/caregivers concerned
Cognitive assessment: Confusion Assessment Method or DSM-IV
No features of delirium present
Features of delirium present
Supportive care: • Adequate nutrition and hydration • Avoid restraints, IDC • Mobilize • Quiet room, adequate lighting • Appropriate sensory aids • Orientation and reassurance • Education for family/caregivers
Investigations for the cause of delirium: • History (especially corroborative) • Physical examination • Medication review • Laboratory parameters: FBE, CU, glucose, CRP, calcium, urinalysis, pulse oximetry, EKG, drug levels if appropriate • CXR
Is behavior unsafe or impeding care? Bedside aids: • Bed that can be lowered to floor level • Secure ward with activities available
Potential cause for delirium found (n.b. may be >1)
Treat infection, discontinue drug, rehydrate, etc.
Commence low-dose neuroleptic (e.g., haloperidol 0.25–0.5 mg every 30 minutes until behavior settles, then give total amount split into 2 equal doses over the day)
History of trauma/fall Focal neurology on anticoagulants
Computed tomography of the brain
Cause of delirium remains unclear
Consider: • TFTs • EEG • Lumbar puncture • Cerebral MRI • B12/folate
Monitor for efficacy and side effects OK Wean once behavior settled or cause of delirium treated
Not OK Try another agent (e.g., risperidone or shortacting benzodiazepine)
Delirium improves
Discharge with appropriate supports or to rehabilitation Follow up cognitive assessment to assess for resolution of delirium or for presence of undetected dementia ■
Figure 11–4. Guidelines for the management of a person with delirium. CRP, C-reactive protein; CU, creatinine and urea; CXR, chest radiograph; ECG, electrocardiogram; EEG, electroencephalography; FBE, full blood examination; IDC, indwelling (urinary) catheter; MRI, magnetic resonance imaging; n.b., nota bene; TFT, thyroid function test.
ing process. Nursing provided by a small number of nurses (primary nursing) is less disorienting than team nursing. For agitated patients, a person who sits with the patient can improve safety. Equipment that immobilizes patients, such as indwelling urinary and intravenous catheters, should be
avoided. Patients should ambulate at least three times daily; participation in self-care tasks helps achieve this. Sensitive involvement of patients in normal daily activities helps them maintain mobility and adequate nutrition and minimizes constipation and urine retention. It is preferable to care
150
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
for delirious patients in single rooms, where noise and distractions can be kept to a minimum, and a few objects brought from home can provide a sense of familiarity.38 Some institutions have designed rooms specifically to manage delirious patients, but these have yet to be prospectively evaluated.90 Restless patients who are at great risk of falling and yet do not reliably stay in bed can be managed by a combination of close supervision while they are ambulant, together with nursing in an electronic bed that can be lowered almost to ground level. The bed is raised when nursing care is provided or to assist the patient in rising to walk, and then it is lowered to ground level when it is time to sleep. If patients then fall out of bed, they are unlikely to injure themselves, and they cannot readily get up to walk unsupervised if they attempt to do this alone. Patients must be examined for dehydration, pressure sores, and pneumonia at least daily. An alternating pressure air mattress may help to nurse patients with (hypoactive) delirium. Supportive care is also required for the patients’ families, who need explanation of the disease process, strategies to deal with often disturbing behavior, and frank discussion regarding the guarded prognosis.
Ethical Issues and Decision-Making Capacity Many patients with delirium lose the capacity to make healthrelated or other decisions during the delirium. Some may never regain this capacity, whereas for others, this incapacity is temporary and may fluctuate from hour to hour and day to day. Therefore, this capacity must be assessed whenever decisions are to be made. Adequate assessments are seldom performed, and the use of surrogate decision makers is suboptimal.27 A formal capacity assessment process may help provide valid assessments.93
CONCLUSION Delirium is a challenging disorder, but it is one of the neurological disorders in which clinicians can genuinely improve their patients’ well-being, principally through the provision of good general medical and nursing care. There remains scandalously little evidence to support therapeutic recommendations. The profession must rise to the challenge of designing and implementing trials to guide management of this common and potentially devastating condition.
Pharmacological Measures There is a paucity of research into the pharmacological management of delirium, and there is no evidence to suggest that the use of antipsychotic or other medications alters the natural history of delirium or improves outcome.91 Mainly, there is no evidence of benefit, but there is also evidence of little or no benefit. Antipsychotic drugs are often employed, but they can have unwanted side effects. The aim of treatment must be to relieve suffering or to ensure the safety of patients. Chemical restraint should be avoided, because oversedation leads to falls, pneumonia, and pressure sores. Agitation in delirium may be caused by fear from misperceptions, hallucinations, or delusions. Antipsychotic agents may relieve some of the symptoms. Some patients without obvious agitation experience marked delusional thoughts that might lead them to refuse food, fluids, or medications. The aim of pharmacotherapy for patients with nonspecific delirium is to treat the symptoms. The aim is not to sedate patients, not to make them less mobile, or not to make them less disruptive to nursing staff or family members, but to decrease inner turmoil. Most evidence regarding pharmacotherapy in delirium comes from case reports or small, uncontrolled series.91 Haloperidol at a low dosage (e.g., starting at 0.5 to 1 mg) can be effective in controlling psychotic symptoms and is probably superior to benzodiazepines.60 Care must be taken to avoid oversedation, and patients must be monitored for adverse effects such as postural hypotension, extrapyramidal side effects, and neuroleptic malignant syndrome. If a psychoactive agent fails, it seems prudent to discontinue it rather than continuing it and adding to it. If it is still believed to be required, another agent could be commenced in place of the first. Delirium tremens is a different situation and is best treated with benzodiazepines.92 See Chapter 117 for a withdrawal management protocol. Figure 11–4 provides a guide to the management of patients with delirium.
K E Y
P O I N T S
●
Delirium is an extremely important disorder.
●
Delirium may account for as much inpatient morbidity and mortality as all other neurological syndromes combined; however, it is often not recognized.
●
Delirium (1) is common in sick people; (2) is frequently undetected; (3) is associated with major adverse outcomes, including death and functional decline, leading to increased health care costs; (4) is potentially preventable in hospitalized patients, through the use of a systems approach; and (5) is most likely the final clinical manifestation of multiple, as yet poorly understood, pathological processes.
●
Clinicians should have a high index of suspicion for delirium when a patient appears to be nonspecifically unwell.
●
There is no specific therapy for delirium.
●
There is scant evidence to guide clinicians in the use of potentially harmful medications for the management of delirium.
●
The greatest advance physicians could make at this stage is to improve systems of care to reduce the incidence of delirium, to increase its recognition, and to optimize its management.
Suggested Reading Darzins P, Molloy D, Strang D: Who can decide? The six step capacity assessment process. Adelaide, Australia: Memory Australia Press, 2000, p 144. Inouye SK: Delirium: A Barometer for Quality of Hospital Care. Hosp Pract (Minneap) 2001; 36(2):15-16, 18. Lindesay J, Rockwood K, Macdonald A: Delirium in Old Age. Oxford, UK: Oxford University Press, 2002, p 238.
chapter 11 delirium Rockwood K, Bhat R: Should We Think Before We Treat Delirium? Intern Med J 2004; 34:76-78. Weber JB, Coverdale JH, Kunik ME: Delirium: Current Trends in Prevention and Treatment. Intern Med J 2004; 34:115-121.
References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. 2. Rockwood K: Acute confusion in elderly medical patients. J Am Geriatr Soc 1989; 37:150-154. 3. Sandberg O, Gustafson Y, Brannstrom B, et al: Clinical profile of delirium in older patients. J Am Geriatr Soc 1999; 47:13001306. 4. Cole MG, McCusker J, Dendukuri N, et al: Symptoms of delirium among elderly medical inpatients with or without dementia. J Neuropsychiatry Clin Neurosci 2002; 14:167-175. 5. Fick D, Foreman M: Consequences of not recognizing delirium superimposed on dementia in hospitalized elderly individuals. J Gerontol Nurs 2000; 26:30-40. 6. Inouye SK: The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients. Am J Med 1994; 97:278-288. 7. Roche V: Southwestern Internal Medicine Conference. Etiology and management of delirium. Am J Med Sci 2003; 325:2030. 8. Rockwood K: The occurrence and duration of symptoms in elderly patients with delirium. J Gerontol 1993; 48:M162M166. 9. Caraceni A, Nanni O, Maltoni M, et al: Impact of delirium on the short term prognosis of advanced cancer patients. Italian Multicenter Study Group on Palliative Care. Cancer 2000; 89:1145-1149. 10. Casarett DJ, Inouye SK: Diagnosis and management of delirium near the end of life. Ann Intern Med 2001; 135:32-40. 11. Elie M, Cole MG, Primeau FJ, et al: Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 1998; 13:204212. 12. Naughton BJ, Moran MB, Kadah H, et al: Delirium and other cognitive impairment in older adults in an emergency department. Ann Emerg Med 1995; 25:751-755. 13. Hustey FM, Meldon SW: The prevalence and documentation of impaired mental status in elderly emergency department patients. Ann Emerg Med 2002; 39:248-253. 14. Rincon HG, Granados M, Unutzer J, et al: Prevalence, detection and treatment of anxiety, depression, and delirium in the adult critical care unit. Psychosomatics 2001; 42:391396. 15. McNicoll L, Pisani MA, Zhang Y, et al: Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003; 51:591-598. 16. Bergeron N, Skrobik Y, Dubois MJ: Delirium in critically ill patients. Crit Care 2002; 6:181-182. 17. Kiely DK, Bergmann MA, Murphy KM, et al: Delirium among newly admitted postacute facility patients: prevalence, symptoms, and severity. J Gerontol A Biol Sci Med Sci 2003; 58:M441-M445. 18. Marcantonio ER, Simon SE, Bergmann MA, et al: Delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery. J Am Geriatr Soc 2003; 51:4-9. 19. Elie M, Rousseau F, Cole M, et al: Prevalence and detection of delirium in elderly emergency department patients. CMAJ 2000; 163:977-981.
151
20. Gustafson Y, Brannstrom B, Norberg A, et al: Underdiagnosis and poor documentation of acute confusional states in elderly hip fracture patients. J Am Geriatr Soc 1991; 39:760-765. 21. Inouye SK: The recognition of delirium. Hosp Pract (Off Ed) 1991; 26(4A):61-62. 22. Johnson J: Identifying and recognizing delirium. Dement Geriatr Cogn Disord 1999; 10:353-358. 23. Kakuma R, du Fort GG, Arsenault L, et al: Delirium in older emergency department patients discharged home: effect on survival. J Am Geriatr Soc 2003; 51:443-450. 24. Cameron DJ, Thomas RI, Mulvihill M, et al: Delirium: a test of the Diagnostic and Statistical Manual III criteria on medical inpatients. J Am Geriatr Soc 1987; 35:1007-1010. 25. Milisen K, Foreman MD, Wouters B, et al: Documentation of delirium in elderly patients with hip fracture. J Gerontol Nurs 2002; 28:23-29. 26. Rockwood K, Cosway S, Stolee P, et al: Increasing the recognition of delirium in elderly patients. J Am Geriatr Soc 1994; 42:252-256. 27. Auerswald KB, Charpentier PA, Inouye SK: The informed consent process in older patients who developed delirium: a clinical epidemiologic study. Am J Med 1997; 103:410-418. 28. Meagher DJ, O’Hanlon D, O’Mahony E, et al: Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci 2000; 12:51-56. 29. Camus V, Gonthier R, Dubos G, et al: Etiologic and outcome profiles in hypoactive and hyperactive subtypes of delirium. J Geriatr Psychiatry Neurol 2000; 13:38-42. 30. O’Keeffe ST, Lavan JN: Clinical significance of delirium subtypes in older people. Age Ageing 1999; 28:115-119. 31. Ross CA, Peyser CE, Shapiro I, et al: Delirium: phenomenologic and etiologic subtypes. Int Psychogeriatr 1991; 3:135147. 32. Cole MG: Delirium: effectiveness of systematic interventions. Dement Geriatr Cogn Disord 1999; 10:406-411. 33. Marcantonio E, Ta T, Duthie E, et al: Delirium severity and psychomotor types: their relationship with outcomes after hip fracture repair. J Am Geriatr Soc 2002; 50:850-857. 34. Levkoff SE, Evans DA, Liptzin B, et al: Delirium. The occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med 1992; 152:334-340. 35. McCusker J, Cole M, Dendukuri N, et al: The course of delirium in older medical inpatients: a prospective study. J Gen Intern Med 2003; 18:696-704. 36. Rockwood K, Cosway S, Carver D, et al: The risk of dementia and death after delirium. Age Ageing 1999; 28:551-556. 37. Cole MG, Primeau FJ, Elie LM: Delirium: prevention, treatment, and outcome studies. J Geriatr Psychiatry Neurol 1998; 11:126-137. 38. Meagher DJ: Delirium: optimising management. BMJ 2001; 322:144-149. 39. Curyto KJ, Johnson J, TenHave T, et al: Survival of hospitalized elderly patients with delirium: a prospective study. Am J Geriatr Psychiatry 2001; 9:141-147. 40. Jeffs K, Lim W, Berlowitz D, et al: Delirium in a culturally diverse medical inpatient population. Poster 4 presented at the Annual Scientific Meeting—Australian Society for Geriatric Medicine, Fremantle, Western Australia, April 2004. 41. Francis J: Outcomes of delirium: can systems of care make a difference? J Am Geriatr Soc 1997; 45:247-248. 42. Inouye SK, Rushing JT, Foreman MD, et al: Does delirium contribute to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med 1998; 13:234-242. 43. O’Keeffe S, Lavan J: The prognostic significance of delirium in older hospital patients. J Am Geriatr Soc 1997; 45:174-178. 44. McCusker J, Cole MG, Dendukuri N, et al: Does delirium increase hospital stay? J Am Geriatr Soc 2003; 51:1539-1546.
152
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
45. Pompei P, Foreman M, Rudberg MA, et al: Delirium in hospitalized older persons: outcomes and predictors. J Am Geriatr Soc 1994; 42:809-815. 46. Stevens LE, de Moore GM, Simpson JM: Delirium in hospital: does it increase length of stay? Aust N Z J Psychiatry 1998; 32:805-808. 47. Francis J, Martin D, Kapoor WN: A prospective study of delirium in hospitalized elderly. JAMA 1990; 263:1097-1101. 48. Inouye SK, Viscoli CM, Horwitz RI, et al: A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119:474481. 49. Brauer C, Morrison RS, Silberzweig SB, et al: The cause of delirium in patients with hip fracture. Arch Intern Med 2000; 160:1856-1860. 50. Rudberg MA, Pompei P, Foreman MD, et al: The natural history of delirium in older hospitalized patients: a syndrome of heterogeneity. Age Ageing 1997; 26:169-174. 51. Webster R, Holroyd S: Prevalence of psychotic symptoms in delirium. Psychosomatics 2000; 41:519-522. 52. Inouye SK, Charpentier PA: Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275:852857. 53. McCusker J, Cole M, Abrahamowicz M, et al: Environmental risk factors for delirium in hospitalized older people. J Am Geriatr Soc 2001; 49:1327-1334. 54. Clary G, Ranga Krishnan K: Delirium: diagnosis, neuropathogenesis, and treatment. J Psychiatr Pract 2001; 7:310323. 55. Flacker JM, Lipsitz LA: Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol A Biol Sci Med Sci 1999; 54:B239-B246. 56. Tune L, Carr S, Cooper T, et al: Association of anticholinergic activity of prescribed medications with postoperative delirium. J Neuropsychiatry Clin Neurosci 1993; 5:208-210. 57. Granacher RP, Baldessarini RJ, Messner E: Physostigmine treatment of delirium induced by anticholinergics. Am Fam Physician 1976; 13:99-103. 58. Trzepacz PT, Ho V, Mallavarapu H: Cholinergic delirium and neurotoxicity associated with tacrine for Alzheimer’s dementia. Psychosomatics 1996; 37:299-301. 59. Fischer P: Successful treatment of nonanticholinergic delirium with a cholinesterase inhibitor. J Clin Psychopharmacol 2001; 21:118. 60. Breitbart W, Marotta R, Platt MM, et al: A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153:231-237. 61. Platt MM, Breitbart W, Smith M, et al: Efficacy of neuroleptics for hypoactive delirium. J Neuropsychiatry Clin Neurosci 1994; 6:66-67. 62. Basile AS, Jones EA, Skolnick P: The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991; 43:27-71. 63. Jones EA, Skolnick P, Gammal SH, et al: NIH conference. The gamma-aminobutyric acid A (GABAA) receptor complex and hepatic encephalopathy. Some recent advances. Ann Intern Med 1989; 110:532-546. 64. Olsson T: Activity in the hypothalamic-pituitary-adrenal axis and delirium. Dement Geriatr Cogn Disord 1999; 10:345-349. 65. Hodges J: Cognitive Assessment for Clinicians. Oxford, UK: Oxford University Press, 1999. 66. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198.
67. Rockwood K, Bhat R: Should we think before we treat delirium? Intern Med J 2004; 34:76-78. 68. Armstrong SC, Cozza KL, Watanabe KS: The misdiagnosis of delirium. Psychosomatics 1997; 38:433-439. 69. Farrell KR, Ganzini L: Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med 1995; 155:2459-2464. 70. Nicholas LM, Lindsey BA: Delirium presenting with symptoms of depression. Psychosomatics 1995; 36:471-479. 71. Inouye SK, van Dyck CH, Alessi CA, et al: Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Int Med 1990; 113:941-948. 72. Inouye SK, Foreman MD, Mion LC, et al: Nurses’ recognition of delirium and its symptoms: comparison of nurse and researcher ratings. Arch Intern Med 2001; 161:2467-2473. 73. Britton A, Russell R: Multidisciplinary team interventions for delirium in patients with chronic cognitive impairment. Cochrane Database Syst Rev 2004; (2):CD000395. 74. Cole MG, Primeau F, McCusker J: Effectiveness of interventions to prevent delirium in hospitalized patients: a systematic review. CMAJ 1996; 155:1263-1268. 75. Inouye SK, Bogardus ST Jr, Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669-676. 76. Inouye SK, Bogardus ST Jr, Baker DI, et al: The Hospital Elder Life Program: a model of care to prevent cognitive and functional decline in older hospitalized patients. Hospital Elder Life Program. J Am Geriatr Soc 2000; 48:1697-1706. 77. Young LJ, George J: Do guidelines improve the process and outcomes of care in delirium? Age Ageing 2003; 32:525-528. 78. Tabet N, Hudson S, Sweeney V, et al: An educational intervention can prevent delirium on acute medical wards. Age Ageing 2005; 34:152-156. 79. Seibert CP: Recognition, management, and prevention of neuropsychological dysfunction after operation. Int Anesthesiol Clin 1986; 24:39-58. 80. Gustafson Y, Brannstrom B, Berggren D, et al: A geriatricanesthesiologic program to reduce acute confusional states in elderly patients treated for femoral neck fractures. J Am Geriatr Soc 1991; 39:655-662. 81. Flacker JM, Marcantonio ER: Delirium in the elderly. Optimal management. Drugs Aging 1998; 13:119-130. 82. Ebersole J, Pedley T: Current Practice of Clinical Electroencephalography, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2003. 83. Harper C, Sheedy D, Lara A, et al: Prevalence of WernickeKorsakoff syndrome in Australia: has thiamine fortification made a difference? Med J Austr 1998; 168:542-545. 84. Cole MG, McCusker J, Bellavance F, et al: Systematic detection and multidisciplinary care of delirium in older medical inpatients: a randomized trial. CMAJ 2002; 167(7):753-759. 85. Cole MG, Primeau FJ, Bailey RF, et al: Systematic intervention for elderly inpatients with delirium: a randomized trial. CMAJ 1994; 151:965-970. 86. Weber JB, Coverdale JH, Kunik ME: Delirium: current trends in prevention and treatment. Intern Med J 2004; 34:115121. 87. Webster JR, Chew R, Mailliard L, et al: Improving clinical and cost outcomes in delirium: use of practice guidelines and a delirium care team. Ann Long Term Care 1999; 7:128-134. 88. Lundstrom M, Edlund A, Karlsson S, et al: A multifactorial intervention program reduces the duration of delirium, length of hospitalization, and mortality in delirious patients. J Am Geriatr Soc 2005; 53:622-628. 89. Naughton BJ, Saltzman S, Ramadan F, et al: A multifactorial intervention to reduce prevalence of delirium and shorten hospital length of stay. J Am Geriatr Soc 2005; 53:18-23.
chapter 11 delirium 90. Flaherty JH, Tariq SH, Raghavan S, et al: A model for managing delirious older inpatients. J Am Geriatr Soc 2003; 51:1031-1035. 91. American Psychiatric Association: Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999; 156(5, Suppl):1-20. 92. Mayo-Smith MF, Beecher LH, Fischer TL, et al: Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004; 164:1405-1412. 93. Darzins P, Molloy D, Strang D: Who can decide? The six step capacity assessment process. Adelaide, Australia: Memory Australia Press, 2000. 94. Ely EW, Inouye SK, Bernard GR, et al: Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001; 286:2703-2710. 95. Roberts B, Rickard C, Rajbhandari D, et al: Multicentre study of delirium in ICU patients using a simple screening tool. Aust Crit Care 2005; 18:6-14.
153
96. Johnson JC, Kerse NM, Gottlieb G, et al: Prospective versus retrospective methods of identifying patients with delirium. J Am Geriatr Soc 1992; 40:316-319. 97. Marcantonio ER, Michaels M, Resnick NM: Diagnosing delirium by telephone. J Gen Intern Med 1998; 13:621-623. 98. Edlund A, Lundstrom M, Brannstrom B, et al: Delirium before and after operation for femoral neck fracture. J Am Geriatr Soc 2001; 49:1335-1340. 99. Zakriya KJ, Christmas C, Wenz JF Sr, et al: Preoperative factors associated with postoperative change in confusion assessment method score in hip fracture patients. Anesth Analg 2002; 94:1628-1632. 100. Shigeta H, Yasui A, Nimura Y, et al: Postoperative delirium and melatonin levels in elderly patients. Am J Surg 2001; 182:449-454. 101. Dai YT, Lou MF, Yip PK, et al: Risk factors and incidence of postoperative delirium in elderly Chinese patients. Gerontology 2000; 46:28-35.
CHAPTER
12
MOTOR SPEECH AND SWALLOWING DISORDERS ●
●
●
●
Richard A. L. Macdonell and Rhonda Holmes
Motor speech relies on a complex interaction of the resonatory, respiratory, articulatory, and laryngeal neuromuscular systems.1 Coordination of the neuromuscular components of the latter three systems is also essential for the execution of swallowing. Different neurological disorders affecting motor speech production may give it particular features that aid in anatomically localizing the disorders; there is, frequently, also an associated abnormality of the swallow mechanism.2
ANATOMY Corticobulbar Tract Upper motor neuron (UMN) pathways responsible for motor speech and swallowing originate in the motor cortex in each cerebral hemisphere and descend through the genu and posterior limb of the internal capsule, via the cerebral peduncle, to the pons and medulla (and upper cervical cord for the spinal nucleus of cranial nerve XI). At these levels, they synapse with the various lower motor nuclei responsible for supplying the bulbar muscles: cranial nerves V, VII, IX, and X; the cranial portion of cranial nerve XI (which contributes to the motor component of the vagus nerve [cranial nerve X]); and cranial nerve XII. The UMN pathways are known as the corticobulbar tracts, and are generally bilateral (contralateral and ipsilateral). There are, however, important exceptions, such as cranial nerve XII and the lower facial muscles, which receive their upper motor connection predominantly from contralateral corticobulbar fibers (Fig. 12–1). Emotional involuntary movements and voluntary facial movements may at times be clinically dissociated, which suggests that a separate supranuclear pathway for control of involuntary facial movements probably also exists. These fibers do not pass through the internal capsule, and it appears that the right cerebral hemisphere is dominant for expression of facial emotion.3
Lower Cranial Nerves Assessment of the bulbar cranial nerves and their function is extremely important when disorders of motor speech and swallowing are considered. These cranial nerves exit the brainstem at the level of the pons or medulla and leave the cranium
through the skull base, traveling either through the retropharynx or across the angle of the mandible to innervate the muscles of the face, mouth, soft palate, pharynx, and larynx (Fig. 12–2). The trigeminal nerve (V) innervates the muscles of mastication and the tensor veli palatini and communicates sensation from the face, mouth, teeth, mucosal lining, and anterior two thirds of the tongue (via the lingual nerve). The facial nerve (VII) supplies the muscles of facial expression and conveys taste from the anterior two thirds of the tongue (via the chorda tympani and lingual nerve). The glossopharyngeal nerve (IX) conveys taste from the posterior one third of the tongue, as well as sensation from this portion of the tongue, the fauces, the pharynx to about the level of the epiglottis, and the eustachian tube. It also provides the motor supply to the stylopharyngeus and, in part, to the superior and middle pharyngeal constrictor muscles through a contribution to the pharyngeal plexus. The vagus nerve (X) conveys sensation from the tympanic membrane, pharynx, larynx, and esophagus. One of its branches, the recurrent laryngeal nerve, innervates all the intrinsic muscles of the larynx other than the cricothyroideus, whereas the superior laryngeal nerve innervates the cricothyroideus and conveys sensation from the larynx and the base of the tongue. The vagus also contributes to the innervation of the pharyngeal constrictors through the pharyngeal plexus. The hypoglossal nerve (XII) innervates the muscles of the tongue, with the exception of the palatoglossus, which is supplied by the vagus nerve.4
Bulbar and Pseudobulbar Palsies UMN lesions affecting the corticobulbar tracts can be distinguished from disorders of the lower cranial nerves or their nuclei by the distinctive changes to speech that are associated with damage to these tracts, described in the next sections. The features of such corticobulbar tract lesions are collectively known as pseudobulbar palsy, a term used to distinguish them from the true bulbar palsy, which results from pathology affecting the lower cranial nerves or their nuclei. There may, in addition to speech, be other distinguishing features on examination, typical of all UMN disorders, such as increased muscle tone (as evidenced by slow side-to-side movement of the tongue) and exaggerated reflexes (gag or jaw reflex), without signs of muscle wasting, atrophy, or fasciculations. A patient
155
156
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s Motor cortex Internal capsule
Corticobulbar tract
Cranial nerve (motor) nuclei III
Midbrain
IV
Medial lemniscus Corticospinal tract Midbrain-pons
Corticobulbar tract
V
Pons-medulla
VI VII
Pyramid
Medial lemniscus Medulla
X Solitary (IX) XII Ambiguus (IX) Medulla
Pyramid
XI Medulla ■
pathway have been classified as aphasia, apraxia of speech (AOS), and dysarthria, each of which may then be subclassified further, depending on the nature of the dysfunction and its cause. Dysarthria and AOS are termed disorders of motor speech because they exist at the output level of the motor system and disrupt only sound output, sparing semantics and syntax. The patient has a full knowledge of words they are finding difficult to articulate. This serves to distinguish these disorders from aphasia, which is defined as “a disorder of linguistic processing characterized by a disturbance in the comprehension and formulation of language caused by dysfunction in specific brain regions.”5,6 Aphasia is discussed in detail in Chapter 3 and is not considered further here.
Figure 12–1. Corticobulbar tract. The fiber bundle originates primarily from the motor and premotor cortices and descends in the basilar region of the brainstem to supply cranial nerves V to XI bilaterally and, mainly contralaterally, nerve XII and a portion of nerve VII. (Adapted from Curtis BA, Jacobson S, Marcus EM, eds: An Introduction to Neurosciences. Philadelphia: WB Saunders, 1972.)
with bulbar palsy, in contrast, has the hallmarks of a lower motor neuron (LMN) disorder: namely, muscle weakness, wasting, and fasciculations.
DISORDERS OF MOTOR SPEECH Verbal communication involves a sequence of processes culminating in the motor execution of a cortically determined set of instructions to produce speech. Disorders of this complex
Apraxia of Speech Abnormalities of speech after neurological insult were subdivided into aphasias and dysarthrias before the contribution of Darley, who with colleagues delivered an unpublished paper on the topic in 1969.7 In this lecture, Darley was the first to use the term apraxia of speech and to attribute a specific disorder of speech—interposed between aphasia and dysarthria—to impaired motor programming,8,9 The term apraxia had long been used in other contexts to describe the inability to carry out a motor command despite normal comprehension and the normal ability to carry out the motor act in another context, such as by imitation or with use of a real object.10 This three-level model of sound-level speech production disorders survived without challenge until the late 1990s. In 1997, van der Merwe10 proposed a four-stage model in which there was an explicit division between “speech motor planning” and “speech motor programming.” Previously, these terms had been used interchangeably. In this model, speech motor planning involves two stages (linguistic-symbolic planning and motor planning) and refers to the planning of the temporal and spatial goals of the articulators. This is followed by a third stage, speech motor programming, which refers to the selection and sequencing of motor programs for the movements of the individual muscles of these articulators (including the vocal cords). The final stage is the execution stage, which refers to the actual realization of speech on an articulatory level. This model makes a clear assignment of AOS to the motor level of impairment as a disorder of speech motor programming.6 Aphasias are disorders of the stages of linguistic-symbolic and motor planning in this system, and dysarthrias are disorders of the execution stage. AOS is a syndrome in which a sequence of single sounds (phonemes), especially consonant sounds, are disrupted and inconsistently misarticulated, in contrast to the consistently abnormal articulation of dysarthria. A further identifying feature of AOS is that comprehension and automatic or reactive speech are normal, but volitional or purposive speech contains substitutions, additions, prolongations, and reversal of phonemes.9 The sufferer repeats incorrect initial phonemes, words, or phrases, which results in a labored, perseverative speech pattern. This may superficially resemble stuttering, but the effortful blocking on a correct initial phoneme typical of stuttering is not seen. AOS, according to this definition, is commonly encountered during attempted speech production in the aphasias, and the sites of lesions that produce a nonfluent
chapter 12 motor speech and swallowing disorders ■
Tensor veli palatini muscle
157
Figure 12–2. Anatomy of the lower cranial nerves and muscles involved in motor speech and swallowing.
Mandibular nerve Lateral pterygoid plate Middle meningeal artery Pterygomaxillary fissure
Levator veli palatini muscle Superior constrictor muscle
Maxillary artery
Styloglossus muscle Stylopharyngeus muscle Glossopharngeal nerve Hypoglossal nerve
Buccinator muscle Lingual nerve
Digastric tendon Internal laryngeal nerve
Hyoglossus muscle Mylohyoid muscle
Vagus nerve Stylohyoid muscle Thyroid membrane Thyroid lamina Inferior constrictor muscle
External laryngeal nerve Cricothyroid muscle
Esophagus
Recurrent laryngeal nerve Trachea
aphasia and AOS may overlap.6 One literature review suggests that cortical-subcortical lesions in the lower part of the left precentral gyrus in most right-handed persons, and a lesion of the corresponding region in the right hemisphere in some left-handed individuals, are the most likely to produce AOS.11 A lesion in Broca’s area may cause a combined syndrome of AOS, orobuccal dyspraxia, and nonfluent aphasia. This symptom complex is frequently referred to as Broca’s aphasia. Patients with AOS frequently have a co-occurring limb dyspraxia and/or orobuccal dyspraxia, which makes it difficult for them to execute simple motor commands accurately, although strength and sensation are intact. In response to requests to point to their own body parts, affected patients provide a head nod; in response to requests to perform specific facial movements such as blowing out a match, licking a stamp, or blowing a kiss, patients may perform groping movements or an approximation of the requested movements. Such responses may mistakenly be interpreted as a comprehension deficit. Patients frequently find it easier to perform these tasks when asked to imitate the examiner. In contrast, a patient with dysarthria always demonstrates the same level of difficulty when using orobuccal muscles, regardless of whether the task is mime or imitation, and during volitional movement and the semivolitional response to emotion.
Dysarthria Dysarthria is defined as a group of speech disorders resulting from disturbance in the control of speech mechanisms that, in turn, results from damage to the central or peripheral nervous systems, including muscles and neuromuscular junctions.12 There is consistently abnormal articulation of phonemes during both automatic and volitional speech. It is caused by the impaired functioning of one or several of the components of the motor speech subsystems (respiration, phonation, resonation, and articulation). Dysphonia is a subset of dysarthria, and the term refers specifically to a disruption of phonation, resulting in an abnormal voice sound without disturbance of articulation. The definition encompasses all disorders of voice sound, both organic and psychogenic. Speech is produced by co-coordinated contraction of the muscles of the larynx, pharynx, and tongue, linked to the expiration phase of respiration. At a cortical level, articulation requires the coordinated bilateral movements of the muscles concerned, which is effected by fibers passing from the inferior region of the left lateral frontal lobe to the corresponding region of the right hemisphere via the corpus callosum.13 The motor speech system relies on the normal function of the various elements of the nervous system involved in the control of motor speech: namely, UMNs and LMNs; the
158
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
coordinating and regulating influence of extrapyramidal, cerebellar, and sensory pathways; and the final output through neuromuscular junctions and muscles.14 Disorders affecting each part of this extensive control, effector, and feedback network have distinct effects on speech, which can be identified through the clinical examination. The nature of the change in speech therefore has localizing significance, which can be used to classify the motor speech disorder as AOS or a particular type of dysarthria.
Upper Motor Neuron Lesions In view of the bilateral nature of the majority of the UMN input to the cranial nerves responsible for speech, unilateral UMN lesions produce a relatively mild dysarthria that reflects primarily weakness and some loss of skilled movement. Bilateral UMN lesions have a much more severe effect that reflects both bilateral weakness and loss of skilled movement, as well as an increase in muscle tone (spasticity).15 The dysarthria accompanying such pathology is known as spastic dysarthria and is one of the features of pseudobulbar palsy. The speech changes characteristic of this condition include slow rate of speech, imprecise consonants, distorted vowels, hypernasality, monotone pitch, short phrases, and a strained-strangled quality to the voice. A number of neurological conditions can affect these pathways and cause a spastic dysarthria (Table 12–1).
Lower Motor Neuron Lesions LMN lesions affecting the cranial nerves involved in speech production, their neuromuscular junctions, or the muscles that the LMNs innervate cause weakness without change in muscle tone. A unilateral LMN lesion has more severe effects than does a unilateral UMN lesion. The dysarthria resulting from unilateral or bilateral LMN palsies is called a flaccid dysarthria and is one of the components of bulbar palsy. Which exact speech disorder accompanies a LMN lesion depends on the nerve or nerves involved. A brainstem stroke, for example, may affect several cranial nerves, whereas a mediastinal mass may affect only the left recurrent laryngeal nerve. Patients are usually able to compensate if damage is unilateral, whereas a bilateral lesion usually results in a severe impairment. The principal causes of flaccid dysarthria are listed in Table 12–1. The output of the direct pathway (UMN and LMN) is controlled by feedback loops involving auditory and somatosensory pathways and extrapyramidal and cerebellar systems. Disorders of each pathway may have a specific effect on speech. Reduced auditory acuity caused by sensorineural deafness, for example, usually causes an increase in vocal loudness, in order to provide feedback to enable the subject to monitor the output.
Cerebellar Disorders Disorders involving cerebellar pathways cause loss of the normal coordination and timing of speech output. This can lead to random breaks between words and syllables, vowel distortions, prolongations of sounds, and the use of equal stress on each syllable, thereby creating a “rambling” or “scanning” quality to the speech (ataxic dysarthria) (see Table 12–1). The
T A B L E 12–1. Examples of Neurological Conditions Causing Dysarthria or Neurogenic Dysphagia Reduced Awareness* Dementias, including Alzheimer’s disease Delirium Cerebral neoplasms and other mass lesions (e.g., subdural, abscess) Upper Motor Neuron–Pseudobulbar Palsy (Spastic Dysarthria) Stroke Cortical: uncommon cause of dysphagia, usually bilateral lesions Subcortical and midbrain: usually bilateral lesions, more common cause than cortical stroke Multiple sclerosis Motor neuron disease: amyotrophic lateral sclerosis (ALS) Traumatic brain injury (increases in severity and likelihood with increasing grade of injury) Central pontine myelinolysis Hypoxic encephalopathy Cerebral palsy Extrapyramidal Disorders (Hyperkinetic or Hypokinetic Dysarthria) Parkinson’s disease Progressive supranuclear palsy Huntington’s disease Multiple system atrophy (MSA) Wilson’s disease Torticollis Cerebellar Disorders (Ataxic Dysarthria) Inherited: e.g., spinocerebellar ataxias, Friedrich’s ataxia, vitamin E deficiency Acquired: e.g., stroke, neoplasm, paraneoplastic syndromes (anti-Yo, anti-Ma, anti-Hu antibodies), toxicity (alcohol), multiple sclerosis, hypothyroidism, vasculitis (systemic lupus erythematosus), MSA Lower Motor Neuron–Bulbar Palsy (Flaccid Dysarthria) Motor neuron diseases Inherited: bulbospinal muscular atrophy (Kennedy’s syndrome), FALS Acquired: ALS, progressive muscular atrophy/progressive bulbar palsy Stroke: infarct or hemorrhage in pons or medulla Multiple sclerosis Mass lesions Neoplasm: intra-axial: brainstem (glioma); extra-axial (meningioma); nasopharynx (nasopharyngeal carcinoma, metastasis) Brainstem abscess (e.g., caused by Listeria) After radiotherapy to head and neck Paraneoplastic syndromes (anti-Ma antibodies) Infectious disorders: diphtheria, polio Neuropathy Inherited: dHMN-VII, HMSN-IIC (vocal cord paralysis) Acquired: Guillain-Barré syndrome, diabetes Syringobulbia Neuromuscular Junction Myasthenia gravis, botulism, Lambert-Eaton myasthenic syndrome Muscle Inherited: oculopharyngeal dystrophy, myotonic dystrophy Acquired: inflammatory myopathies (polymyositis, dermatomyositis, inclusion body myositis), hypothyroidism, critical care neuromyopathy Traumatic Includes iatrogenic injury: trauma to cranial nerve XII during carotid endarterectomy, oral/pharyngeal dysphagia after tracheostomy or after intubation Psychogenic Psychogenic aphonia, psychogenic spasmodic dysphonia, psychogenic dysphagia *These are uncommon causes of dysarthria; they more commonly cause dysphagia. dHMN-VII, distal hereditary motor neuropathy type VII; FALS, familial amyotrophic lateral sclerosis ; HMSN-IIC, hereditary motor sensory neuropathy type IIC.
chapter 12 motor speech and swallowing disorders dysarthria accompanying focal cerebellar lesions tends to occur particularly with lesions of the vermal and (usually) left dorsal intermediate zone of the cerebellum, whereas it is typically not seen with lateral neocerebellar lesions.13
Extrapyramidal Disorders Extrapyramidal disorders, such as Parkinson’s disease or Huntington’s disease, result in hyperkinetic or hypokinetic dysarthria. The most common dysarthria accompanying Parkinson’s disease is a hypokinetic dysarthria, characterized by rapid speech rate (festination), slurring of words and syllables, and trailing off at the end of sentences. The voice is soft and monotonous, without the usual inflections. The speech disorder accompanying Huntington’s disease is hyperkinetic dysarthria, which results in an uncontrolled loud, harsh voice, poorly coordinated with breathing. Chorea and myoclonus may cause abrupt interruption between or within words by the superimposition of abnormal respiratory, phonatory, or articulatory movements.15
Mixed Dysarthrias In some situations, more than one type of dysarthria may be present, giving rise to a mixed dysarthria. An example is motor neuron disease, in which there may be a pseudobulbar palsy resulting from involvement of UMN pathways and a true bulbar palsy resulting from loss of anterior horn cells from the cranial nerve nuclei of the brainstem. The resultant speech exhibits features of a mixed spastic and flaccid dysarthria. Similarly, a patient with multiple sclerosis may exhibit a mixed spastic and ataxic dysarthria as a result of combined UMN and cerebellar damage by the disease process.
Dysphonia A circumscribed lesion affecting the vagus nerve or one of its branches, which supply the muscles of the larynx, may cause dysphonia in isolation. In the case of unilateral damage, the voice is usually breathy and soft. The voice may become harsh as the patient attempts to compensate for the soft voice and strains to increase vocal loudness. In some instances, a patient may produce two distinct vocal pitches (diplophonia) as a result of the differing masses and vibratory capacities of the two vocal folds. If the vagus lesion is high, there may also be a nasal quality resulting from the associated weakness of the soft palate and inability to prevent air from escaping through the nose during phonation. If the damage is bilateral, the vocal folds may be either abducted or adducted. If the vocal folds are adducted, the patient may present with inspiratory stridor, inasmuch as the vocal cords normally abduct during inspiration. Dysphonia may also be produced by conditions that cause weakness of the respiratory muscles—such as Guillain-Barré syndrome or a high cervical spinal cord lesion—because insufficient airflow is produced for phonation.15 Abnormalities of phonation become more apparent the longer the subject speaks, and asking the patient to read aloud from a magazine is a good means of bringing out these features.
159
Spasmodic Dysphonia Spasmodic dysphonia appears to result from a dystonia restricted to the phonatory apparatus, but it can occasionally co-occur with other dystonias, such as writer’s cramp and blepharospasm. More sufferers are women, and speaking gradually becomes more of an effort. Usually, attempts to speak result in co-contraction (adduction) of the vocal folds, causing a strained, strangled-sounding voice. In rare cases, the problem may be a breathy, soft voice; in these patients, the dystonia causes abduction of the vocal cords. In either instance, other activities involving use of the same muscles, such as swallowing and singing, are usually unimpeded.15
Nonorganic Disorders of Voice Voice disorders may have a psychological basis, rather than being the result of pathology affecting neural pathways or muscular control. The most common psychogenic speech disorders affect voice, fluency, or prosody. Prosody is the term used to describe all the variations in time, pitch, and loudness that accomplish emphasis, lend interest to speech, and characterize individual and dialectical modes of expression.16 Psychogenic speech disorders are not unusual and can account for up to 5% of acquired communication disorders.15 The most common is aphonia (hoarseness), but psychogenic spasmodic dysphonia, particularly adductor spasm, is also encountered.
Psychogenic Aphonia Aphonia is a common conversion symptom. Patients with conversion aphonia involuntarily whisper. The sharpness of the whisper, which often appears strained, contrasts with the weak, breathy whisper of a patient with vocal fold paralysis. The cough is usually normal, illustrating the retained ability to produce normal vocal fold adduction, and there is no inspiratory stridor, inasmuch as the involuntary ability to abduct the vocal folds during inspiration is unimpaired.
Psychogenic Spasmodic Dysphonia Establishing the diagnosis of this condition is very difficult in some cases, and distinction from an organic disorder such as a focal dystonia (see previous discussion) can be challenging. Symptom reversibility in some patients may be the only way to confirm the diagnosis. The adductor form is the most common and is characterized by a continuous or intermittent strained, jerky, grunting, squeezed, groaning, and effortful quality to the voice.15 The nature of the voice disorder is very similar to that in neurogenic spasmodic (adductor) dysphonia, although underlying voice tremor or evidence of laryngeal dystonia (e.g., adduction of the vocal cords during inspiration seen during laryngoscopy) (Fig. 12–3) is not ordinarily encountered in psychogenic etiologies unless a combination of causes is present.
CLINICAL ASSESSMENT OF SPEECH Clinical examination of speech requires the assessment of three aspects of speech production:15
160
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Base of tongue
Epiglottis
Vestibular folds (false vocal cords) Trachea
Vocal folds (true vocal cords)
Arytenoid cartilage Cuneiform cartilage
Corniculate cartilage
A
■
B
Figure 12–3. A, Illustration of vocal cords viewed from above, showing their relationship to the paired cartilages of the larynx and epiglottis. B, Endoscopic view of the vocal cords. (From Seeley RR, Stephens TD, Tate P: Anatomy and Physiology. St. Louis: Mosby–Year Book, 1992.)
1. Samples of contextual speech (e.g., reading a standard paragraph aloud) and of spontaneous speech. The latter is best assessed during the documentation of the history, when the patient’s speech is at its most natural. 2. Vowel prolongation (sustained “aah. . . .”). 3. Alternate motion of the lips, tongue, and jaw, tested by having the patient repeat “puh” (labial), “tuh” (anterior lingual) and “kuh” (posterior lingual) rapidly and evenly: “puh-tuh-kuh-puh-tuh-kuh . . .” A full neurological examination must be completed in any patient with dysarthria or dysphonia, with particular attention to the function of cranial nerves V to XII. During the acute stage of a unilateral UMN lesion, the tongue may deviate toward the weak side (i.e., toward the side opposite the lesion) on protrusion, and the palate moves toward the lesion side on elevation. There may also be facial weakness contralateral to the lesion side, affecting the muscles of the lower face. A pseudobulbar palsy is typically accompanied by an exaggerated jaw jerk, a brisk gag response, and slow, stiff, repetitive tongue movements. In addition to the cranial nerve examination, there may be other confirmatory findings in the limbs indicating unilateral or bilateral UMN pathology, such as increased tone, increased reflexes, and extensor plantar responses. A flaccid dysarthria is usually accompanied by other signs of bulbar weakness, such as a wasted appearance of or fasciculations in the tongue, unilateral or bilateral palatal weakness (tested by asking the patient to say “ah”), and a reduced or absent gag reflex. The acute phase of an UMN lesion such as stroke may also impair or abolish the gag reflex before the onset of spasticity but does not produce other LMN features such as muscle wasting or fasciculation. There may be other features of anterior horn cell loss on examination, such as muscle wasting, weakness, and fasciculations in the limbs, which point to a diagnosis of motor neuron disease. Myasthenia gravis may also manifest with symptoms of a flaccid dysarthria. The dysarthria accompanying this disease
typically becomes more severe the longer the patient talks, and speech recovers after rest. There should be no UMN signs and no signs of muscle wasting or fasciculation. There may be evidence of fatigability in other muscle groups, such as ptosis that increases with prolonged upward gaze, ocular movement weakness, or declining proximal limb girdle strength during sustained exercise. An ataxic dysarthria is usually accompanied by other signs of cerebellar dysfunction (see Chapter 7), particularly a widebased gait and, often, incoordination of the limbs and abnormalities in eye movement. Patients with Parkinson’s disease and a hypokinetic dysarthria ordinarily have other features of the disease, such as masklike, expressionless facies, bradykinesia, rigidity, and tremor, whereas a patient with a hyperkinetic dysarthria may exhibit other features of a movement disorder, such as choreiform movements or myoclonic jerks. The nature of the dysarthria and the findings on examination should indicate which further investigations, such as magnetic resonance imaging, nerve conduction study/ electromyography, repetitive stimulation studies, or blood tests, are likely to lead to the correct diagnosis. An assessment by a speech pathologist is often helpful in clarifying the type and nature of the dysarthria, when this is unclear, and in arranging speech rehabilitation. This assessment may involve formal instrumental speech analysis and fiberoptic stroboscopic laryngoscopy, which are available in some centers.
MANAGEMENT OF MOTOR SPEECH DISORDERS Treatment options for the dysarthric patient depend on the etiology of the speech defect. Recovery of function may be a realistic goal for a patient with a mild dysarthria as a result of a stroke, but is not a possibility for a patient with a progressive neurological disease such as motor neuron disease.15 In this case, compensation of function is more appropriate. Compensation may involve speech strategies such as overarticulation, alternative communication devices, management of the environment, or prosthetic devices.
chapter 12 motor speech and swallowing disorders Management approaches can be separated into three broad areas: medical, prosthetic, and behavioral.15 Because of the heterogeneous nature of the dysarthric population, a single approach is very rarely adequate; often, all three approaches are used in conjunction.
Medical Management Pharmacological The first consideration in the management of any motor speech disorder is to ensure that any underlying neurological problem receives appropriate pharmacological treatment. This can have a dramatic positive effect on speech: For example, acetylcholinesterase antagonists for the treatment of myasthenia gravis can improve or restore speech,17 and botulinum toxin has been shown to reduce vocal fold spasm in cases of spasmodic dysphonia.18 There are inconsistent reports of the effects of dopaminergic agents on speech intelligibility in Parkinson’s disease: Some investigators have reported a trend for improvement of speech,19 whereas others have reported no difference.20,21 Some drugs—for example, benzodiazepines and anticonvulsants—may have a negative effect on speech, and this may result in a worsening of the dysarthria.17
Surgical Surgery may be the treatment of choice for patients who have severe hypernasality as the result of velopharyngeal incompetence.22 Pharyngoplasties and construction of pharyngeal flaps can be performed by otolaryngologists to rectify such speech defects. Patients with unilateral vocal fold paralysis may be referred for medialization procedures such as thyroplasty23,24 or vocal fold augmentation techniques.25,26
Prosthetic Management Numerous available appliances can improve the communication of dysarthric speakers. Palatal lifts may be used for hypernasal patients who have a hyporeflexive gag.27 Voice amplifiers allow patients with reduced modal loudness to increase their speech volume. Other devices, such as pacing boards and delayed auditory feedback, are used during behavioral therapy to slow speech production rate.19 Patients who are severely dysarthric or anarthric may need to use augmentative or alternative communication devices.28 These range from simple devices such as picture or alphabet boards to more advanced devices such as computers with voice synthesizers. Assessment and decision making about the appropriateness of prosthetic devices is the realm of the speech pathologist.
Behavioral Management When providing behavioral treatment, the speech pathologist analyzes the severity of the patient’s dysarthria and identifies the cluster of deviant speech symptoms. In the case of a mildto-moderate dysarthria, patients usually receive direct therapy aimed at recovering as much speech function as possible; the goal is to improve intelligibility while maintaining speech naturalness.15,29 Direct therapy approaches that are supported
161
by the literature include use of various biofeedback devices aimed at improving respiratory support30 and improving respiratory/phonatory coordination and control.31,32 Effortful closure techniques to increase adduction of vocal folds in cases of hypoadduction33,34 and tension-reducing strategies to reduce hyperadduction are also supported.35 A large body of research has demonstrated the efficacy of an intensive treatment program, which focuses on increased vocal loudness, in mild to moderate cases of Parkinson’s disease.27 Various studies have shown benefits of rate-control techniques, such as pacing and delayed auditory feedback, to slow speech rate.36-39 In cases of severe dysarthria, indirect therapy may be used; this is aimed at optimizing the communication environment, and training caretakers to repair communication breakdowns.40 Behavioral management is the foundation of treatment for AOS. Unlike treatment for dysarthria, in which the aim is to improve physiological support for speech that is appropriately planned and programmed, the treatment of AOS focuses on reorganizing the disturbed programs for speech movements, which are then able to be implemented by an intact neuromuscular speech system. Most treatment goals for AOS are aimed at improving articulation and prosody through the use of imitation and cuing in a progressive hierarchy of intensive drills.15
NEUROGENIC DYSPHAGIA Neuromuscular Control of Swallowing Normal swallowing is a complex sensorimotor behavior involving the coordinated contraction and inhibition of the muscles around the mouth and the tongue, larynx, pharynx, and esophagus bilaterally (Fig. 12–4).41 The act of swallowing has been subdivided into three phases: oral, pharyngeal, and esophageal, after Magendie’s classic description (Fig. 12–5).42 The initial (oral) phase is voluntary, whereas the latter two phases are semiautonomous reflex responses. The motor events of swallowing, however, are best described as occurring in two stages: the first (“oropharyngeal”) stage, which incorporates the first two phases of swallowing, and the subsequent (“esophageal”) stage or phase.43,44
Oral Phase of Swallowing The act of swallowing commences before food or fluid is actually placed in the mouth. The anticipation, smell, or presence of food stimulates saliva production in the mouth, which is necessary to commence the digestive processes and lubricate the bolus of food for the swallow. Once the bolus enters the mouth, the duration of the oral phase is highly variable, depending on the taste, texture, and consistency of the food and on the hunger, motivation, and consciousness of the subject.43 The motor events accompanying this phase involve lip closure, tension within the buccinator muscles, downward movement of the soft palate (allowing breathing during mastication), and actual chewing of the food. The final step generally takes place with the positioning of the adequately chewed and mixed bolus of manageable size, usually on the mid-dorsum of the tongue. The tongue subsequently sweeps the bolus posteriorly, forming a rolling wave of contact stripping against the hard palate, pushing the bolus toward the posterior tongue surface and into
162
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Tubal eminence Jugular bulb Sigmoid sinus Inferior alveolar nerve Lingual nerve Tensor palati Digastric muscle Medial pterygoid muscle Palatopharyngeus muscle Stylohyoid muscle Mylohyoid nerve and muscle Internal laryngeal nerve Thyrohyoid muscle Thyroid gland Parathyroid gland
Dorsum sellae Basilar sinus Mastoid air cells Salpingopharyngeal muscle Superior construictor muscle Glossopharyngeal nerve Hypoglossal nerve Greater cornu of hyoid Inferior constrictor muscle Cricopharyngeus muscle
Recurrent laryngeal nerve Longitudinal muscle Esophagus Circular muscle
A
Pharyngeal palate
Orifice of eustachian tube
Oral palate
Salpingopharyngeal fold
Uvula Superior constrictor muscle Genioglossus muscle
Middle constrictor muscle Epiglottis
Geniohyoid muscle Hyoid bone Ventricular fold (false cord) Laryngeal ventricle Vocal fold (true cord)
Laryngeal aditus Thyropharyngeus muscle Interarytenoid muscle Cricoid cartilage
Thyroid cartilage Trachea
Esophagus
Thyroid gland
B ■
Figure 12–4. The nasopharynx opened to view the soft palate from behind (A) and in midline section (B). (A from Last RJ: Anatomy: Regional and Applied, 7th ed. Edinburgh: Churchill Livingstone, 1984. B from Groher ME: Dysphagia: Diagnosis and Management, 2nd ed. Boston: ButterworthHeinemann, 1992.)
chapter 12 motor speech and swallowing disorders ■
Superior constrictor muscle
Epiglottis Middle constrictor muscle Inferior constrictor muscle Pharyngoesophageal constrictor Esophagus
A
B
C
D
E
F
163
Figure 12–5. The three phases of swallowing. A, Oral phase: A bolus of food (yellow) is pushed against the hard palate and posteriorly toward the oropharynx by a stripping action of the tongue against the palate. (Black arrows indicate movement of the bolus). B to E, Pharyngeal phase: The soft palate is elevated, closing off the nasopharynx, and the pharynx is elevated by the palatopharyngeal and salpingopharyngeal muscles. Successive contractions of the pharyngeal constrictors (C and D) force the bolus through the pharynx and into the esophagus. As this occurs, the epiglottis is bent down over the opening of the larynx, largely by the force of the bolus pressing against it. (Red arrows indicate muscle movement). E, The tonically active pharyngoesophageal constrictor relaxes (outward direction red arrows), allowing the bolus to enter the esophagus. F, During the esophageal phase, the bolus is moved by successive contractions of the esophagus toward the stomach. (From Seeley RR, Stephens TD, Tate P: Anatomy and Physiology. St. Louis: Mosby–Year Book, 1992.)
164
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
the oropharynx.1 The oral phase may be disrupted by disorders of the motor nerves responsible for muscle function in this area (cranial nerves V, VII, IX, X, and XII) or by disorders of their central control, impairing coordinated mastication and posterior bolus movement (e.g., Huntington’s disease.)
it is actively closed in the resting state. It is opened by a complex series of actions, including laryngeal elevation.39 There is no voluntary control of the lower esophageal sphincter.
Assessment of Patients with Dysphagia Pharyngeal Phase of Swallowing The oral and pharyngeal phases are highly interrelated, and the distinction between them is often unclear. All of the events, from the initiation of the swallowing reflex until the esophageal phase, are probably under the control of a central pattern generator in the brainstem.44,45 As the bolus enters the pharynx, it triggers the swallow reflex. The nature of the triggering is not known.43 It is assumed that the afferent pathway is conveyed through the trigeminal, glossopharyngeal, and vagus nerves from sensory fibers innervating the pharynx. These fibers converge in the brainstem in the tractus solitarius and synapse in the nucleus tractus solitarius. Cortical descending inputs reach similar areas of the nucleus tractus solitarius. There is also sensory input to cortical regions involved in initiating swallowing.46,47 The initiation or triggering of swallowing is probably more complex than a simple brainstem reflex and may depend on structures above the brainstem. The swallow reflex consists of several movements (see Fig. 12–5):48 1. Elevation and retraction of the velum and complete closure of the velopharyngeal port to prevent material from entering the nasal cavity. 2. Elevation and anterior movement of the hyoid and larynx. 3. Closure of the larynx at the level of the true vocal folds, false vocal folds, and aryepiglottic folds, and by the epiglottis, to prevent food from entering the airway. 4. Opening of the cricopharyngeal sphincter to allow material to pass from the pharynx to the esophagus. The normally tonically active cricopharyngeus muscle relaxes and opens as the larynx moves anterosuperiorly. 5. Ramping of the base of the tongue to deliver the bolus to the pharynx, followed by tongue base contraction to contact the anteriorly bulging posterior pharyngeal wall. 6. Progressive top-to-bottom contraction of the pharyngeal constrictors. These oral and pharyngeal movements rely on the coordinated bilateral contraction and relaxation of muscles innervated by the lower cranial nerves.
Clinicians should be alert to the clinical signs of swallowing disorders (dysphagia), which may suggest that oral feeding is not safe. Eating is a demanding cognitive process requiring planning and judgment, intact bulbar musculature, and neural control systems.49 Patients presenting with confusion after any cause of neurological impairment may not be mentally able to eat safely. All patients presenting with dysarthria should also be suspected of having dysphagia, because of shared neuroanatomical pathways. However, dysphagia may also occur independently of dysarthria. Dysphagia is potentially lifethreatening and must be evaluated promptly. During history taking, patients may complain of difficulties during the act of swallowing, such as food sticking in the back of the throat, regurgitation, or dribbling. Others may not report dysphagia at all and present with complications such as recurrent chest infections caused by “silent” aspiration. Other manifestations that may warrant a dysphagia examination include wetsounding voice, coughing on saliva or food, pain on swallowing (odynophagia), slowed eating rate, unexplained weight loss, and difficulty chewing. Neurogenic dysphagia may result from UMN or LMN disorders, including those affecting neuromuscular junctions or muscle (see Table 12–1).
Medical History A standard medical history should include details regarding any history of pneumonia, reflux, or swallowing problems. The patient should be asked about complaints, including duration and frequency of the swallowing difficulty; associated symptoms such as pain, choking, coughing during meals; nasal regurgitation; weight loss; and the length of time taken to eat meals. Although patients often reliably report the presence of a problem affecting deglutition (oral-pharyngeal transfer), their reports of the level at which a bolus is arrested after entering the pharynx are notoriously inaccurate; pharyngeal and upper and lower esophageal difficulties are often perceived as a problem “in the throat.” A list of current medications should be analyzed for use and possible side effects. Drugs that have anticholinergic side effects, such as tricyclic antidepressants, reduce saliva production and thereby reduce the ability to lubricate the bolus in preparation for swallowing.
Esophageal Phase of Swallowing The esophageal phase starts from the time the bolus enters the esophagus at the upper esophageal sphincter until it passes through the lower esophageal sphincter and enters the stomach. This transit time ranges between 8 and 20 seconds. A peristaltic wave begins at the top of the esophagus and pushes the bolus ahead of it as it travels toward the stomach. The upper esophageal sphincter is formed by the cricopharyngeus muscle and the cricoid cartilage and, as such, can be affected by disorders of voluntary skeletal muscle, whereas the lower esophageal sphincter is formed by smooth muscle. Opening of the upper esophageal sphincter is partially under voluntary control, and
Oral Peripheral Examination Impaired dentition and any dryness or inflammation of the oral mucosa should be particularly noted. The cranial nerve examination should include the assessment of taste. Sweet, sour, salty, bitter, and, possibly, umami (the taste of the glutamate moiety in monosodium L-glutamate, a compound that occurs naturally in protein-rich and other foods50) constitute the basic taste qualities; all others are flavors, their appreciation depending on an intact sense of smell. Taste is tested on the anterior two thirds of the tongue (enervated by the facial nerve) with sugar, salt, vinegar, quinine, and, if required, monosodium L-
chapter 12 motor speech and swallowing disorders glutamate, in that order. The patient sticks out the tongue to one side, keeps it out through the test, and does not talk. The four or five possible tastes are written on a card. The tip of the tongue is held gently with a piece of gauze, and the side of the tongue is moistened about one inch from the tip with a little of the test substance. The patient indicates the taste by pointing to the appropriate line on the card. Between tests, the patient rinses out the mouth with water. Alternatively, an electrical device (Rion Electrogustometer, Sensonics, Inc.) can be used, but this is expensive and a little cumbersome for easy bedside use. Testing taste on the posterior one third of the tongue (glossopharyngeal nerve) is so difficult by conventional means that it is hardly worth attempting. An electrogustometer is needed to acquire the information. Olfaction should also be tested by a smell identification test, such as those produced by Sensonics, Inc. (see Chapter 13). Hyposmia or anosmia may impede swallowing by impairing anticipatory salivation.
Oral Trials Patients with oral and pharyngeal dysphagia as a result of bulbar impairment are generally referred for speech pathology assessment. Speech pathologists provide oral trials, usually starting with the consistency that would be easiest for the patient to manage. In a neurologically impaired patient, the safest consistency is generally a thickened fluid rather than a thin fluid.51 This is because weak or uncoordinated swallowing mechanisms render it difficult to initiate reflexes rapidly enough to protect the airway and do not have the precise, welltimed movements necessary to move boluses of thin fluids, which tend to fragment, safely through the hypopharynx. The examiner palpates the patient’s thyroid notch between the
165
hyoid bone and larynx and feels for the anterosuperior excursion of the larynx during swallowing trials (Fig. 12–6).51 In cases of severe brainstem stroke, the swallow reflex may be absent. This palpation position also gives an indication of tongue movement during the oral phase and may reveal repetitive tongue pumping, as is frequently observed in patients with Parkinson’s disease. Examiners should make note of any delay between tongue movement and laryngeal excursion, because this may be correlated with delayed initiation of the swallow reflex. Patients should be asked to phonate after oral trials, as an indication of laryngeal protection. If the voice sounds wet after swallow, it may indicate either laryngeal penetration or aspiration. Laryngeal penetration occurs when foreign material enters the laryngeal vestibule to the level of the vocal folds. Aspiration occurs when foreign material enters the larynx below the level of the vocal folds (see Fig. 12–3). When material is aspirated in the absence of the protective cough reflex, as may be indicated by a wet-sounding voice, it is referred to as silent aspiration. This is a common phenomenon, occurring in up to two thirds of patients in the acute poststroke phase.52 Extreme caution is needed when oral trials are initiated in patients with illnesses often associated with neurogenic dysphagia, because there is the potential to cause serious negative health consequences, including aspiration pneumonia, malnutrition, and death.53-55 Ice chips are frequently used when cautious testing is required, because very small amounts are able to be presented, and the cold provides heightened sensory input that may help to stimulate a swallow in some patients.56,57 Some clinicians use cervical auscultation to listen to laryngeal and pharyngeal noises during swallowing, to determine whether pooling or aspiration has occurred,57,58 although the reliability of this technique is not yet established. Pulse oximetry may be
Epiglottis Superior thyroid notch Hyoid bone
Cuneiform cartilage
Thyrohyoid ligament
Corniculate cartilage Arytenoid cartilage
Thyroid cartilage
Cricothyroid ligament Cricoid cartilage Thyroid gland Parathyroid gland Tracheal cartilage
A ■
Trachea
Anterior
Membranous part of trachea
B
Posterior
Figure 12–6. Anatomy of the larynx. A, Anterior view. B, Posterior view. (From Seeley RR, Stephens TD, Tate P: Anatomy and Physiology. St. Louis: Mosby–Year Book, 1992.)
166
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
used to observe drops in oxygen saturation levels. It has been suggested that a decline of more than 4% during swallowing may be indicative of episodes of penetration or aspiration.59,60 Other clinical signs of aspiration include gurgling breath sounds, wet-sounding voice, and dyspnea. Fatigue is a factor that affects patients with neurogenic dysphagia; several boluses should therefore be tried before a decision regarding oral feeding is made. The cough is the most important protective mechanism preventing aspiration, and patients who are unable to produce a volitional cough at the clinical examination may be unable to expectorate material from their upper airway, should the need arise. The bedside clinical examination has been shown to miss up to 40% of cases of silent aspiration,51 and patients without adequate airway protection, as provided by a volitional cough, may benefit from more objective assessments such as videofluoroscopic swallowing studies (VFSS) or fiberoptic endoscopic evaluation of swallowing (FEES). These procedures, described later, enable clinicians to perform conservative swallowing examinations of the dysphagic patient and more objectively determine the risks associated with oral feeding. The presence of a tracheostomy tube, as may be encountered in patients with brainstem strokes or patients with motor neuron disease, necessitates a specific dysphagia assessment approach.61 It has been shown that tracheostomy tubes anchor the larynx and that cuffed tubes splint open the airway, thereby impeding the protective laryngeal closure mechanism. In addition, the upper airway sensory characteristics are altered, and the pressure gradients within the larynx, which help prevent penetration by foreign material, are reduced. It is generally accepted that tracheostomy cuffs should be deflated during oral trials. It has also been suggested that a one-way speaking valve may help normalize the upper airway characteristics and therefore possibly improve swallowing safety and function.61,62
■
Figure 12–7. Videofluoroscopic swallowing study (VFSS) demonstrating aspiration of the barium-laced puree into the trachea (arrow).
Fiberoptic Endoscopic Evaluation of Swallowing FEES, first described in 1988,63 involves insertion of a fiberoptic nasoendoscope into the nasopharynx to obtain a view of the hypopharynx and larynx. The image is displayed on a video monitor, allowing the patient and health professionals to view the patient’s swallow clearly as foods and fluids of different consistencies are provided. Direct images of the mucosa, secretion management, and the biomechanical relationships of the structures crucial in swallowing are obtained. Because of the lack of radioactive exposure in this procedure, in comparison with VFSS, FEES is a useful biofeedback and therapy tool (Fig. 12–8).
Instrumental Assessment After a comprehensive clinical dysphagia examination, further and more objective assessments may be necessary to assist the diagnostic and management processes. These include videofluoroscopic and endoscopic swallowing studies and manometry.
Videofluoroscopic Swallowing Study VFSS is a dynamic radiographic study used to evaluate the oral and pharyngeal phases of the swallow. The patient is provided with foods and fluids of differing consistencies that are mixed with a radiopaque substance such as barium. Moving images provide an indication of the interrelationships between the swallowing structures during transit of the bolus. These images allow observation of any pooled material in the pharynx and help delineate the timing and quantity of aspiration in real time. VFSS may aid in clarifying the physiological basis of the patient’s dysphagia. If possible, it is beneficial to include a full esophageal view in each VFSS to provide further information about possible retrograde aspiration and reflux, as well as esophageal causes of dysphagia. Although the procedure is usually performed in the lateral plane, an anteroposterior view may be useful for highlighting asymmetrical dysphagia (e.g., with unilateral stroke) and assist in implementing appropriate swallowing strategies (Fig. 12–7).
Manometry Manometric studies are used to assess peristalsis of the pharynx and esophagus. Pharyngeal manometry requires pressure sensors that are sensitive enough to detect the rapid changes in pressure that occur during the swallow reflex. These studies usually need to be combined with VFSS in order to make accurate judgments regarding the causes of pressure changes49 and are not commonly used in clinical practice.
Management of Patients with Neurogenic Dysphagia One of the primary considerations in treating patients with neurogenic dysphagia is their potential for safe oral intake. If oral intake is not an option, then enteral nutrition must be considered.
Oral Feeding Patients with neurological swallowing disorders who are able to tolerate oral intake may require modifications to the consistency of their diet. Patients with oral-stage problems affecting tongue and lip function often benefit from pureed food.48
chapter 12 motor speech and swallowing disorders
167
A Median glossoepiglottic fold
Pharyngeal surface of tongue Epiglottic vallecula Epiglottis Hyoid bone
Lateral glossoepiglottic fold Tubercle of epiglottis
Aryepiglottic fold Vocal fold
Ventricle of larynx
Rima glottidis
Cuneiform tubercle
Piriform recess
Pharyngeal wall (cut)
Corniculate tubercle
Mucous membrane on back of cricoid cartilage
B ■
Figure 12–8. A, Fiberoptic endoscopic evaluation of swallowing (FEES) with residual puree around the epiglottic rim, valleculae, and piriform fossae. B, The larynx as seen from above (inverted compared with A).
However, some of these patients require increased sensory input to stimulate saliva flow, mastication, and triggering of the swallowing reflex and may respond better to semisolid textures or foods of different temperatures and strong flavors.64 Patients with delay of the swallow reflex may need fluids to be thickened so that they pass slowly as a cohesive bolus in a more controlled manner through the pharynx. In patients with weak pharyngeal musculature, in which pharyngeal dysmotility and pooling are a problem, fluids may need to be of a slightly thickened nectarlike consistency, making pharyngeal pooling less likely. Flaky textures and foods consisting of dual consistencies (e.g., cereal
flakes with milk) are notoriously difficult for patients with neurogenic dysphagia to manage, because of the level of swallowing coordination necessary to maintain these textures in a cohesive bolus. In cases in which some recovery of swallowing function is expected, such as stroke, traumatic brain injury, and neurosurgery, a modified diet should be only a temporary measure while swallowing rehabilitation takes place. The ultimate aim is to return the patient to as normal a diet as possible. In progressive neurological diseases, diet modification may be a precursor to enteral nutrition.
168
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
Nonoral Feeding When patients are unable to eat an oral diet sufficient to sustain their nutritional needs, they require enteral feeding. Enteral feeding may accompany oral intake or, in cases of severe dysphagia, may be the only means of nutrition. If recovery of swallowing function to full quantities of oral diet is expected in the short term, a nasogastric tube is appropriate. For long-term nutrition, an endoscopic or radiographic percutaneous gastrostomy may be performed; in patients with gastroesophageal reflux, a jejunostomy may be a more appropriate option.64,65
may enable a patient to visualize and perform vocal fold closure techniques, thereby increasing airway protection during swallowing. Surface electromyography has been used to demonstrate effort behind swallowing.71 Investigators have reported the use of electrical stimulation techniques as a therapeutic tool to improve swallowing.73,74 The use of such devices is not well supported; many questions regarding the type and degree of stimulation, the placement of electrodes, and patients who may gain the most benefit from the technique remain unanswered.
Swallowing Therapy Rehabilitation of neurogenic dysphagia requires treatment programs individually tailored with regard to the underlying etiology and clinical manifestation. Patients within the same diagnostic category can have very different clinical manifestations of dysphagia, requiring different treatment approaches. The following are some general therapy approaches used by speech pathologists when treating patients with neurogenic dysphagia.
Swallowing Strategies/Maneuvers Altered swallowing postures may increase safety during oral intake. Postures include chin tuck, in which the chin is placed on the chest to provide more airway protection66; supraglottic swallow, which closes the airway at the level of the vocal folds, thereby affording more control in protecting the airway during the swallow67; and head turn to the side of pharyngeal weakness, to move the bolus through the stronger side.68 There is some preliminary evidence that the following techniques may also strengthen weakened pharyngeal musculature: effortful swallow to improve pharyngeal clearance69 and the Mendelsohn maneuver, a prolonged laryngeal elevation that helps in opening the upper esophageal sphincter.70
Education of Patients/Caregivers Successful dysphagia management depends on patients and caregivers’ being fully informed and cognizant of the implications of the dysphagia diagnosis. Some clinicians find that patients respond well to education with FEES or VFSS, either to support rationales for their recommendations or as a therapy tool to educate patients in swallowing techniques. Other advice may be appropriate for the patient, including initiating small boluses, taking small meals frequently, using double swallows to clear oral or pharyngeal pooling, minimizing distractions such as conversation during eating, alternating solids with fluids to clear pharyngeal residue, and ensuring that meals are taken in an upright position. A number of illnesses causing neurogenic dysphagia also affect executive function (e.g., progressive supranuclear palsy, pseudobulbar palsy resulting from bilateral strokes), thereby reducing the ability to self-monitor the cognitively demanding process of swallowing and making the adoption of safe swallowing strategies difficult. In such cases, it is wise to educate family and caregivers in providing direct assistance, to ensure that the feeding process is a safe one.
Biofeedback Positive results have been obtained with different types of biofeedback to instruct patients on expected targets.71,72 FEES
K E Y
P O I N T S
●
Motor speech disorders and aphasias should be differentiated by careful bedside assessment, with particular note of comprehension and formulation of language, consistency of articulation, and sound.
●
The clinical examination should be used to look for signs that help to localize pathology affecting motor speech or swallowing to UMNs or LMNs, neuromuscular junctions, or muscle.
●
The presence of dysarthria should always raise suspicion about the possibility of concomitant neurogenic dysphagia.
●
Bedside clinical examination misses up to 40% of cases of silent aspiration. Patients without evidence of adequate airway protection, as provided by a strong, volitional cough, may benefit from more objective assessments such as VFSS or FEES.
●
Fatigue is a factor that affects patients with neurogenic dysphagia; several boluses should be tried before a decision regarding oral feeding is made.
Suggested Reading Duffy JR: Motor Speech Disorders. Substrates, Differential Diagnosis and Management. St. Louis: Mosby, 1995. Freed DB: Motor Speech Disorders: Diagnosis and Treatment. San Diego, CA: Singular Publishing Group, 2000. Groher ME, ed: Dysphagia: Diagnosis and Management, 3rd ed. Boston: Butterworth-Heinemann, 1997, pp 223-243. Logemann JA: Evaluation and treatment of swallowing disorders, 2nd ed. Austin, TX: Pro-Ed, 1998.
References 1. Rosenfield DB, Barroso AO: Difficulties with speech and swallowing. In Bradley WG, Daroff RB, Fenichel JM, et al, eds: Neurology in Clinical Practice, 3rd ed. New York: ButterworthHeinemann, 2000. 2. Brazis PW, Masdeu JC, Biller J: Localization in Clinical Neurology, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2001. 3. Borod JC, Koff E, Lorch MP, et al: Emotional and nonemotional facial behaviour in patients with unilateral brain damage. J Neurol Neurosurg Psychiatry 1988; 51:826-832. 4. Seikel JA, King DW, Drumright DG: Anatomy and physiology for speech and language. San Diego, CA: Singular Publishing Group, 1997.
chapter 12 motor speech and swallowing disorders 5. Damasio AR: Aphasia. N Engl J Med 1992; 326:531-539. 6. Maassen B, Kent RD, Peters HFM, et al, eds: Speech Motor Control in Normal and Disordered Speech. Oxford, UK: Oxford University Press, 2004. 7. Darley FL, Aronson AE, Brown JR: Audio Seminars in Speech Pathology—Motor Speech Disorders. Philadelphia: WB Saunders, 1975. 8. Darley FL, Aronson AE, Brown JR: Motor Speech Disorders. Philadelphia: WB Saunders, 1975, pp 250-269. 9. Kirshner HS: Aphasia. In Bradley WG, Daroff RB, Fenichel JM, et al, eds: Neurology in Clinical Practice, 3rd ed. New York: Butterworth-Heinemann, 2000, pp 141-169. 10. van der Merwe A: A theoretical framework for the characterization of pathological speech sensorimotor control. In McNeil MR, ed: Clinical Management of Sensorimotor Speech Disorders. New York: Thieme, 1997, pp 1-25. 11. Sugishita M, Konno K, Kabe S, et al: Electropalatographic analysis of apraxia of speech in a left hander and in a right hander. Brain 1987; 110:1393-1417. 12. Pryse Phillips W: Companion to Clinical Neurology, 2nd ed. Oxford, UK: Oxford University Press, 2003. 13. Brain R: Speech Disorders—Aphasia, Apraxia and Agnosia. London: Butterworths, 1965. 14. Guenther FH: Neural control of speech movements. In Meyer A, Schiller N, eds: Phonetics and Phonology in Language Comprehension and Production: Differences and Similarities. Berlin, Mouton de Gruyter, 2002. 15. Duffy JR: Motor Speech Disorders. Substrates, Differential Diagnosis and Management. St. Louis: Mosby, 1995. 16. Monrad-Krohn GH: Dysprosody or altered “melody of language.” Brain 1947; 70:405-415. 17. Vogel D, Carter JE: The Effects of Drugs on Communication Disorders. San Diego, CA: Singular Publishing Group, 1995. 18. Duffy JR, Yorkston KM, Buekelman DR, et al: Medical interventions for spasmodic dysphonia and some related conditions [Technical Report 2]. Minneapolis, MN: Academy of Neurological Communication Disorders and Sciences, 2001. 19. Rigrodsky S, Morrison EB: Speech changes in parkinsonism during L-dopa therapy: preliminary findings. J Am Geriatr Soc 1970; 18:142-151. 20. Larson KK, Ramig LO, Scherer RC: Acoustic and glottographic voice analysis during drug-related fluctuations in Parkinson’s disease. J Med Speech Pathol 1994; 2:227-239. 21. Poluha PC, Teulings HL, Brookshire RH: Handwriting and speech changes across the levodopa cycle in Parkinson’s disease. Acta Psychol (Amsterdam) 1998; 100:71-84. 22. Johns DF: Surgical and prosthetic management of neurogenic velopharyngeal incompetency in dysarthria. In Johns DF, ed: Clinical Management of Neurogenic Communicative Disorders, 2nd ed. Boston: Little, Brown, 1995, pp 168-173. 23. Isshiki N, Okamura H, Ishikawa T: Thyroplasty type 1 (lateral compression) for dysphonia due to vocal cord paralysis or atrophy. Acta Otolaryngol 1975; 80:465. 24. Sasaki CT, Leder SB, Petcu L: Longitudinal voice quality changes following Isshiki thyroplasty type I: the Yale experience. Laryngoscope 1990; 100:849-852. 25. Ford CN, Bless DM: Clinical experience with injectable collagen for vocal fold augmentation. Laryngoscope 1986; 96:863869. 26. Mikaelian DO, Lowry LD, Sataloff RT: Lipoinjection for unilateral vocal cord paralysis. Laryngoscope 1991; 101:465-468. 27. Bedwinek AP, O’Brian RL: A patient selection profile for the use of speech prosthesis in adult disorders. J Commun Disord 1985;18:169-182. 28. Beukelman DR, Mirenda P: Augmentative and Alternative Communication, 2nd ed. Baltimore: Paul H. Brooks, 1998. 29. Brookshire RH: An Introduction to Neurogenic Communication Disorders, 4th ed. St. Louis: Mosby–Year Book, 1992.
169
30. Yorkston KM, Spencer MS, Duffy J: Behavioral management of respiratory/phonatory dysfunction from dysarthria: a systematic review of the evidence. J Med Speech Lang Pathol 2003; 11(2):13-38. 31. Murdoch BE, Pitt G, Theodoros DG, et al: Real-time continuous visual biofeedback in the treatment of speech breathing disorders following childhood traumatic brain injury: report of one case. Pediatr Rehabil 1999; 3(1):5-20. 32. Thompson-Ward EC, Murdoch BE, Stokes PD: Biofeedback rehabilitation of speech breathing for an individual with dysarthria. J Med Speech Lang Pathol 1997; 5:277-290. 33. Dworkin J, Meleca R: Vocal pathologies: diagnosis, treatment and case studies. San Diego, CA: Singular Publishing Group, 1997. 34. Yamaguchi H, Yotsukura T, Sata H, et al: Pushing exercise program to correct glottal incompetence. J Voice 1993; 7:250256. 35. Murry T, Woodson G: Combined-modality treatment of adductor spasmodic dysphonia with Botulinum toxin and voice therapy. J Voice 1995; 9:460-465. 36. Ramig LO, Pawlas AA, Countryman S: The Lee Silverman Voice Treatment. Iowa City, IA: National Center for Voice and Speech, 1995. 37. Yorkston KM, Hammen VL, Beukelman DR, et al: The effect of rate control on the intelligibility and naturalness of dysarthric speech. J Speech Hear Disord 1990; 55:550-560. 38. Thomas-Stonell N, Leeper HA, Young P: Evaluation of a computer-based program for training speech rate with children and adolescents with dysarthria. J Med Speech Lang Pathol 2001; 9:17-29. 39. Downie AW, Low JM, Lindsay DD: Speech disorder in parkinsonism: usefulness of delayed auditory feedback in selected cases. Br J Disord Commun 1981; 16:135-139. 40. Berry WR, Sanders SB: Environmental education: the universal management approach for adults with dysarthria. In Berry WR, ed: Clinical Dysarthria. Boston: College-Hill, 1983. 41. Ropper A, Victor M: Disorders of speech and language. In Victor M, Ropper A, eds: Adam’s and Victor’s Principles of Neurology. New York: McGraw-Hill, 2001. 42. Magendie F: Précis Elémentaire de Physiologie, vol 2. Paris: Mequignon-Marvis, 1836, p 628. 43. Ertekin C, Aydogdu I: Neurophysiology of swallowing. Clin Neurophysiol. 2003; 114:2226-2244. 44. Miller AJ: Deglutition. Physiol Rev 1982; 62:129-184. 45. Jean A, Amri M, Calas A: Connections between the medullary swallowing area and the trigeminal motor nucleus of the sheep studied by tracing methods. J Auton Nerv Syst 1983; 7:8796. 46. Miller AJ: The Neuroscientific Principles of Swallowing and Dysphagia. San Diego, CA: Singular Publication Group, 1999. 47. Jean A: Brainstem control of swallowing: neuronal network and cellular mechanisms. Physiol Rev 2001; 81:929-969. 48. Logemann JA: Evaluation and Treatment of Swallowing Disorders, 2nd ed. Austin, TX: Pro-Ed, 1998. 49. Miller RM: Clinical examination for dysphagia. In Groher ME, ed: Dysphagia: Diagnosis and Management, 3rd ed. Boston: Butterworth-Heinemann, 1997, pp 223-243. 50. Chaudhari N, Landin MA, Roper SD: A metabotropic glutamate receptor variant functions as a taste receptor. Nature Neurosci 2000; 3:113-119. 51. Linden P, Siebens AA: Dysphagia: predicting laryngeal penetration. Arch Phys Med Rehabil 1983; 64:28. 52. Ramsey DJ, Smithard DG, Kalra L: Early assessments of dysphagia and aspiration risk in acute stroke patients. Stroke 2003; 34:1252-1257. 53. Langmore SE, Terpenning MS, Schork A, et al: Predictors of aspiration pneumonia; how important is dysphagia? Dysphagia, 1998; 13:69-81.
170
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
54. Odderson R, Keaton JC, McKenna BS: Swallow management in patients on an acute stroke pathway: quality is cost effective. Arch Phys Med Rehabil 1995; 76:1130-1133. 55. Smithard DG, O’Neill PA, Park C, et al: Complications and outcome after acute stroke: Does dysphagia matter? Stroke 1996; 27:1200-1204. 56. Lazzara G, Lazarus C, Logemann JA: Impact of thermal stimulation on the triggering of the swallowing reflex. Dysphagia 1986; 1:73-77. 57. Hamlet SL, Penney DG, Formolo J: Stethoscope acoustics cervical auscultation of swallowing. Dysphagia, 1994; 9:63-68. 58. Takahashi K, Groher ME, Mihi K: Methodology for detecting swallowing sounds. Dysphagia 1994; 9:54-62. 59. Sellars C, Dunnet C, Carter R: A preliminary comparison of videofluoroscopy of swallow and pulse oximetry in the identification of aspiration in dysphagic patients. Dysphagia 1998; 13:82-86. 60. Sherman B, Nisenboum JM, Jesberger BL, et al: Assessment of dysphagia with the use of pulse oximetry. Dysphagia 1999; 14:152-156. 61. Dikeman KJ, Kazandjian MS: Communication and Swallowing Management of Tracheostomized and Ventilator-Dependent Adults, 2nd ed. San Diego, CA: Singular Publishing Group, 2003. 62. Elpern EH, Scott MG, Petro L, et al: Pulmonary aspiration in mechanically ventilated patients with tracheostomies. Chest 1994; 105:563-566. 63. Langmore SE, Schatz K, Olsen N: Fiberoptic endoscopic examination of swallowing safety: a new procedure. Dysphagia 1988; 2:216-219. 64. Miller RM, Groher ME: General treatment of neurologic swallowing disorders. In Groher ME, ed: Dysphagia: Diagnosis and
65. 66. 67. 68. 69. 70. 71. 72. 73. 74.
Management, 3rd ed. Boston: Butterworth-Heinemann, 1997, pp 223-243. Workman JR, Pillsbury HC III, Hulka G: Surgical intervention in dysphagia. In Groher ME, ed: Dysphagia: Diagnosis and Management, 3rd ed. Boston: Butterworth-Heinemann, 1997. Welch MV, Logemann JA, Rademaker AW, et al: Changes in pharyngeal dimensions effected by chin tuck. Arch Phys Med Rehabil 1993; 74:178-181. Martin BJW, Logemann JA, Shaker R, et al: Normal laryngeal valving patterns during three breath-hold maneuvers: a pilot investigation. Dysphagia 1993; 8:11-20. Logemann J, Kahrilas P, Kobara M, et al: The benefit of head rotation on pharyngesophageal dysphagia. Arch Phys Med Rehabil 1989; 70:767-771. Crary MA: A direct intervention program for chronic neurogenic dysphagia secondary to brainstem stroke. Dysphagia 1995; 10:6-18. Jacob P, Kahrilas PJ, Logemann JA, et al: Upper esophageal sphincter opening and modulation during swallowing. Gastroenterology 1989; 97:1469-1478. Huckabee ML, Cannito M: Outcomes of swallowing rehabilitation in chronic brainstem dysphagia: a retrospective evaluation. Dysphagia 1999; 14:93-109. Pouderoux P, Kahrilas PJ: Eglutitive tongue force modulation by volition, volume, and viscosity in humans. Gastroenterology 1995; 108:1418-1426. Freed ML, Freed L, Chatburn RL, et al: Electrical stimulation for swallowing disorders caused by stroke. Respir Care 2001; 46:466-474. Leelamanit V, Limsakul C, Geater A: Synchronized electrical stimulation in treating pharyngeal dysphagia. Laryngoscope 2002; 112:2204-2210.
CHAPTER
DISORDERS
OF ●
13
SMELL ●
●
AND TASTE
●
Graeme M. Gonzales and Mark J. Cook
The “chemical” senses of smell and taste are the human organism’s means of qualitatively analyzing the chemical composition of its immediate environment. Although impairment of smell or taste is not generally perceived to be as disabling as impairment of sight or hearing, hyposmia (impaired olfaction) or hypogeusia (impaired taste) may nevertheless cause substantial loss in quality of the esthetic and hedonistic aspects of the individual’s life, may contribute to comorbid conditions such as poor nutritional intake in the elderly, and, uncommonly, may be an early sign of a serious underlying disorder.1 Unpleasant smells or tastes may trigger recognition of toxins in food or the environment not otherwise detectable by the other senses. Smell via pheromones is an important component of courtship and mating in the life cycles of other species but to a far lesser extent in Homo sapiens, which is not known to possess a vomeronasal organ or a discrete pheromonal system.2 Loss of olfaction or gustation may go relatively unnoticed by the patient; in other cases, a perceived hypersensitivity of the chemical senses or inappropriate activation of sensory pathways may be the cause of symptoms.
within glomeruli, with second-order afferent neurons. Considerable convergence and information processing occur within the olfactory bulb and tract.5 Significant inhibitory and interglomerular innervation occurs within the bulb3 and is believed to modulate afferent excitatory transmission even at this level. Significant bilateral communication occurs at multiple levels within the olfactory pathways, beginning from the anterior olfactory nuclei (which are collections of neuronal bodies lying posteriorly within the olfactory tracts) and extending to the thalami and cortical olfactory areas. In humans, neurons of the olfactory tracts terminate, without synapse in the thalami, in regions collectively termed the primary olfactory cortex (lateral olfactory gyrus, piriform cortex, and periamygdaloid areas). These sites subsequently project to the hypothalamus, limbic structures, entorhinal cortex, and other areas. A minority of relays project through the dorsomedial nucleus of the thalamus. Olfactory and other areas of cortex in turn project centrifugally back to the olfactory bulbs and may modulate feedback inhibition or facilitation of afferent stimuli. Finally, the trigeminal nerve is also important in the perception of smell, mediating tactile, noxious, and pain stimuli in the nasopharynx and associated structures.6
DISORDERS OF SMELL Clinical Approach to Olfactory Disorders Aspects of the Anatomy and Physiology of Olfaction The primary sensory neurons of the olfactory pathway continuously die and are continuously replaced, being generated from the basal cells of the olfactory epithelium.3 The ciliated olfactory neurons have a lifespan of between 30 and 60 days3 and can be regenerated after damage or loss.4 The olfactory epithelium secretes mucus, which bathes the sensory dendritic surface of the olfactory neurons and provides a medium to dissolve odorants. Odorant signal transduction occurs through binding to G protein–coupled olfactory receptors, of which about 350 forms occur in humans. As might be expected, congenital genetically based specific anosmias (for certain odorants) have been reported, analogous to various forms of color blindness (see Hawkes, 2002). The bipolar olfactory neurons constituting the first cranial nerve pass through the cribriform plate of the ethmoid bone and synapse in the olfactory bulb,
Neurological disorders of olfaction can be conveniently approached according to symptom presentation (anosmia or hyposmia; hyperosmia or dysosmia), anatomical site of dysfunction (Table 13–1), or etiology (Table 13–2).7 A careful history and examination usually allow the clinician to make a provisional diagnosis and target subsequent investigations. Upper respiratory tract infection is the most common cause of neural olfactory dysfunction, accounting for up to 33% of cases. However, in up to 40% of patients with olfactory dysfunction, no cause for their symptoms is found.8
History The nature of the olfactory abnormality, its temporal course, and its variation with differing stimuli should be clarified as precisely as the patient’s recall, cognitive state, and descriptive abilities allow. Dysosmia refers to a general distortion of smell
171
172
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 13–1. Potential Anatomical Sites of Olfactory Disturbance Anatomical Site of Damage
Typical Cranial Nerve I Finding
Other Neurological and Medical Findings
Common Etiologies
Sensory receptors and primary neuron
Hyposmia or anosmia Dysosmia Can be unilateral
With trauma, rare nasal leaks of CSF
Head trauma Upper respiratory infections Nasal or sinus disease Toxic exposure
Secondary neurons Olfactory bulb cells Anterior olfactory nucleus Medial and lateral striae
Hyposmia or anosmia Dysosmia Can be unilateral
Foster Kennedy syndrome Disinhibition, change in personality Gait dyspraxia, disinhibition, change in personality
Meningioma Neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease) Frontal lobe tumors Pituitary tumors Aneurysms
Medial dorsal nucleus the of thalamus
Decreased odor identification Normal or increased odor thresholds*
Signs of Wernicke-Korsakoff syndrome: ataxia, extraocular paresis, nystagmus, memory problems including confabulations
Wernicke-Korsakoff syndrome Infarctions
Primary and secondary olfactory cortices
Decreased odor identification Normal or increased odor thresholds*
Lip smacking, automatisms during seizures Dementia, memory loss Tremor, bradykinesia Chorea, dementia Contralateral weakness, aphasia, homonymous quadrant visual field defects
Epilepsy Neurodegenerative disorders Alzheimer’s disease Parkinson’s disease Huntington’s disease Tumors or infarcts
From Doty RL: Cranial nerve I: olfactory nerve. In Goetz CG, ed: Textbook of Clinical Neurology, 2nd ed. Philadelphia: WB Saunders, 2003, p 101, Table 7-1. *Because of bilateral cortical and subcortical representation of olfactory function, unilateral lesions at this level generally do not cause clinically meaningful olfactory dysfunction. CSF, cerebrospinal fluid.
T A B L E 13–2. Causes of Olfactory Disturbance Mechanical Cause Craniofacial trauma Surgery Frontal or intracranial mass lesion (e.g., malignancy, aneurysm) Environmental Cause Radiation treatment Tobacco smoking Environmental toxin (e.g., benzene, chlorine, formaldehyde, acetone, lead) Inhaled cocaine Neurologic or Psychiatric Disorder Epilepsy or seizure disorder Psychotic disorder (e.g., schizophrenia) Depression or other affective disorder Neurodegenerative disorders (especially Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s disease) Migraine Stroke Korsakoff’s syndrome Infections Viral respiratory tract infection Systemic viral infections (influenza, HIV/AIDS) Acute bacterial sinusitis AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.
Chronic or recurrent sinusitis Meningitis, encephalitis Metabolic Organ Dysfunction Hepatic failure Renal failure Vitamin deficiency states (A, B6, B12) Zinc, copper deficiency states Drugs (see Table 13–3) Disseminated malignancy/cachexia Vasculitic disorders Endocrine Thyroid dysfunction Diabetes mellitus Pituitary adenoma Cushing’s syndrome Menopause Pseudohypoparathyroidism Miscellaneous Allergic rhinitis/sinusitis Pregnancy Aging Kallman’s syndrome and other cilia dysfunction syndromes Turner’s syndrome
chapter 13 disorders of smell and taste
173
T A B L E 13–3. Drugs That May Impair Olfaction or Gustation* Antianxiety Agents Alprazolam (Xanax) Buspirone (BuSpar)
Gold (Myochrysine) Hydrocortisone Penicillamine (Cuprimine)
Antibiotics Ampicillin Azithromycin (Zithromax) Ciprofloxacin (Cipro) Clarithromycin (Biaxin) Enalapril (Vaseretic) Griseofulvin (Grisactin) Metronidazole (Flagyl) Ofloxacin (Floxin) Terbinafine (Lamisil) Ticarcillin (Timentin) Tetracycline
Antimanic Drugs Lithium
Anticonvulsants Carbamazepine (Tegretol) Phenytoin (Dilantin) Antidepressants Amitriptyline (Elavil) Clomipramine (Anafranil) Desipramine (Norpramin) Doxepin (Sinequan) Imipramine (Tofranil) Nortriptyline (Pamelor) Antihistamines and Decongestants Acetazolamide (Diamox) Amiloride (Midamor) Amiodarone (Cordarone, Pacerone) Betaxolol (Betoptic) Captopril (Capoten) Diltiazem (Cardizem) Enalapril (Lexxel, Vasotec, Vaseretic) Hydrochlorothiazide (Esidrix) Nifedipine (Procardia) Nitroglycerin Propafenone (Rythmol) Propranolol (Inderal) Spironolactone (Aldactone) Tocainide (Tonocard) Anti-inflammatory Agents Auranofin (Ridaura) Beclomethasone (Beclovent, Beconase) Budesonide (Rhinocort) Colchicine Dexamethasone (Decadron) Flunisolide (Nasalide, Aerobid) Fluticasone (Flonase)
Antimigraine Agents Dihydroergotamine (Migranal) Naratriptan (Amerge) Rizatriptan (Maxalt) Sumatriptan (Imitrex) Antineoplastics Cisplatin (Platinol) Doxorubicin (Adriamycin) Levamisole (Ergamisol) Methotrexate (Rheumatrex) Vincristine (Oncovin) Antiparkinsonian Agents Levodopa (Larodopa; with carbidopa: Sinemet) Antipsychotics Clozapine (Clozaril) Trifluoperazine (Stelazine) Antithyroid Agents Methimazole (Tapazole) Propylthiouracil Antiviral Agents Ganciclovir (Cytovene) Interferon (Roferon-A) Zalcitabine (HIVID) Bronchodilators Bitolterol (Tornalate) Pirbuterol (Maxair) Lipid-Lowering Agents Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Pravastatin (Pravachol) Muscle Relaxants Baclofen (Lioresal) Dantrolene (Dantrium) Pancreatic Enzyme Preparations Pancrelipase (Cotazym) Smoking Cessation Aids Nicotine (Nicotrol)
From Doty RL, Bromley SM: Effect of drugs on olfaction and taste. Otolaryngol Clin North Am 2004; 37:1231, Box 1. *Most of these agents are noted in the Physician’s Desk Reference as having adverse effects on the olfactory system.
sense, whereas troposmia refers to distortion in quality of a particular normal smell stimulus. Whether the smell concerned is pleasant, unpleasant, or excessively unpleasant (cacosmia) may be important. Complaints of nasal discharge or unilateral epistaxis are suggestive of an upper airway abnormality. Traumatic head injury is an important cause of smell and taste disorders and may account for up to 23% of cases of documented hyposmia.9 Intracranial surgery likewise may cause hyposmia. Any variation of intensity with a particular stimulus or scent, particular hyperosmia, should be noted. The possibility of preg-
nancy should be considered in the female patient of childbearing potential with hyperosmia or dysosmia.10 The medical history and drug history may reveal use of agents known to impair olfaction (Table 13–3). A history of smoking, alcohol consumption, and recreational drug use should be documented.11 The medical history may be notable for sinusitis or other rhinal disease,12 thyroid or other endocrine disease, hepatic or renal impairment, Parkinson’s disease13 or other neurodegenerative conditions,14 stroke, or features such as deafness or diabetes that are suggestive of a mitochondrial dis-
174
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 13–4. Office Tests Commonly Used in Olfactory Assessment University of Pennsylvania Smell Identification Test (UPSIT) Pocket Smell Test Brief Smell Identification Test (B-SIT) Connecticut Clinical Research Center Test (CCCRC) Smell Threshold Test Sniffin’ Sticks
order. Association of a smell, particularly a strongly unpleasant or noxious one, with a period of amnesia, loss of awareness, or other suggestive symptoms, can indicate a focal seizure disorder.15 The patient may perceive an odor when no stimulus is present (phantosmia). A history from an observer can prove invaluable in this circumstance. Olfactory hallucinations are an uncommon manifestation of schizophrenia, being noted in approximately 6% of patients.16 A family history may also yield clues in regard to any of these conditions. Other important points include occupational or other exposure to toxins or fumes, past treatment with radiation, the psychiatric history, and past intracranial or systemic infection, including human immunodeficiency virus infection.17 Congenital hyposmia is known to be associated with immotility or absence of olfactory epithelial cilia, most commonly in association with hypogonadotropic hypogonadism (Kallman’s syndrome).18 Headache or other symptoms suggestive of an enlarging intracranial mass or of frontal region dysfunction may herald a progressive frontal, temporal, or anterior fossa tumor. It should be remembered that a significant decline in olfactory acuity is seen with aging, particularly in the sixth and seventh decades.19 Quality-of-life questionnaires have been developed to try to reproduce reliably the largely subjective perception of olfactory dysfunction.1
Examination Office assessment of olfactory dysfunction by the general neurologist includes targeted neurological examination and a general medical examination, including ears and oropharynx; both examinations are guided by the history. Unilateral olfactory acuity can be assessed by sequential nasal occlusion, and a number of formal office tests of olfactory dysfunction are available (Table 13–4). The four-alternative forced-choice structure of the 40-item University of Pennsylvania Smell Identification Test (UPSIT) odor identification test may enable malingering to be detected on the basis of a performance significantly worse than that expected by chance alone, which may be useful in medicolegal cases involving trauma or toxic exposure. Formal gustatory examination should also be performed, because many causes of olfactory and taste impairment may also affect taste and smell, respectively. Endoscopic examination of the upper respiratory tract, performed by a suitably skilled and experienced clinician with appropriate equipment, should be considered, especially if a tumor or other rhinological cause is suspected.8 A Mini Mental State Examination, neuropsychological, or formal psychiatric evaluation may be indicated.
Investigation of Olfactory Disorders Computed tomography of the head, orbits, and nasopharynx is the initial imaging modality of choice.7 Lesions causing bony destruction or infiltration are readily visualized, as are most collections or intracranial masses large enough to cause neural distortion or compression. Magnetic resonance imaging and angiography with paramagnetic contrast material remain the “gold standards” for detecting subtle neuraxial lesions, small anterior fossa masses, and other nonbony structural abnormalities, such as caudate atrophy in early Huntington’s disease or focal frontal or temporal cortical epileptogenic foci. Blood and other body fluid analyses are useful for screening for specific etiologies such as infection or vitamin B12 deficiency. Electroencephalography is useful in diagnosing seizure disorders. Cerebrospinal fluid analysis and measurement of the intrathecal pressure should be performed if basal meningitis is suspected. Biopsy and histological or other examinations may be performed on suspect mass lesions. More extensive psychophysical investigation of olfactory disturbances may include threshold determination, odor discrimination, and odor memory tests, as well as odor identification tests such as the UPSIT. Odor event–related potentials and electro-olfactography are techniques generally confined to specialized clinical or research centers (see Hawkes, 2002).
Principles of Management of Olfactory Disorders Therapy for olfactory disorders is most usefully directed at the underlying cause of dysosmia.11 Rhinological causes of olfactory dysfunction are most easily accessible. Specific treatment may include topical or systemic antihistamines or antiallergy agents, antimicrobial therapy, or invasive interventions for recurrent sinusitis, obstruction, or malignancy. Neurological causes of olfactory dysfunction often resolve if the primary site of dysfunction is at the olfactory nerve, because of regeneration of bipolar neurons from the basal layer. However, avoidance of environmental agents or cessation of medications known to induce dysosmia may not fully reverse the deficit.20 Likewise, olfactory disturbance caused by chemotherapy or radiotherapy for malignancy may or may not improve after conclusion of treatment. Smoking cessation is medically advisable for many reasons, and normosmia usually is successfully restored if the hyposmia was attributable to this cause. Treatment of intracranial causes of sensorineural dysosmia has varying success. A focal epileptogenic lesion may respond to anticonvulsants or be amenable to surgical excision, as may a frontal meningioma or other surgically accessible mass. However, deficits may be irreversible if tissue damage is permanent. Most neurodegenerative illnesses associated with olfactory disturbance are incurable. As mentioned previously, olfaction is vital to the appreciation of drink, food, and other pleasurable aspects of normal life and is important in the detection of dangerous or unpleasant odorants such as household cooking gas or spoiled food. Elderly persons especially may develop unrecognized hyposmia. They are therefore at increased risk of not recognizing such threats. Loss of smell may also be misinterpreted as anhedonia or depression. Loss of taste, too, is important in the elderly (see later discussion). Age-related hyposmia is not reversible. Counseling, heightened awareness, and physical safety measures
chapter 13 disorders of smell and taste such as gas and smoke detectors are useful interventions. An acute sense of smell is important in many professions and trades (plumber, parfumier, chef or baker, winemaker, physician), and occupational compensation may be warranted. This should always be considered in managing the patient whose sense of smell affects his or her livelihood, according to the individual laws in the state or country concerned.7 Because many cases of olfactory disturbance are not amenable to treatment or, at best, are only partially treatable, a supportive and sympathetic attitude toward the patient is always important. Appropriate education of the patient about the disorder can help greatly toward the patient’s understanding and coping with the disability.
175
routes of these pathways are less well delineated. Many fibers decussate at this level, and unilateral lesions of the medulla oblongata are not well described as causing taste disturbances. The pathways then ascend, largely via the central tegmental tract (not the medial lemniscus as previously thought) to the ventral posterior median nucleus of the thalamus and from there to the anteroinferior sensory and motor cortex, superior temporal gyrus, frontal operculum, and anterior insula. These pathways are, again, separate from somatosensory cortical representations of the tongue and palatal structures. Other pathways may synapse with the hypothalamus and limbic structures to mediate autonomic and emotional aspects of taste.6
Clinical Approach DISORDERS OF TASTE Aspects of the Anatomy and Physiology of Gustation The five currently recognized tastes are salty, sour, bitter, sweet, and umami (conveniently described as the taste of glutamate).21 Smell, texture, other somatosensory perceptions (such as those elicited by menthol or chili), as well as taste, collectively contribute to the perception of flavor of ingested substances. Taste receptors are found within taste buds on the tongue, soft palate, pharynx, larynx, and upper esophagus. Individual taste receptors are responsive to all tastants with varying sensitivity, and each taste bud appears to exhibit one preferential sensitivity. The popular notion that a particular taste is “localized” onto any one area of the tongue is therefore largely inaccurate.3 Taste receptors, like olfactory bipolar cells, continuously regenerate from basal cells, being replaced approximately every 10 to 20 days. Like odorants, tastants need to be dissolved to interact with receptors, in this case in saliva. Salty (Na+) and sour (H+) tastants appear to evoke taste receptor depolarization through direct interaction with apical ion channels. Bitter and sweet tastants evoke depolarization via G protein–mediated secondmessenger mechanisms, largely involving cyclic adenosine monophosphate and inositol 1,4,5-triphosphate, respectively. Taste receptors synapse with high convergence onto primary afferent neurons, which are unipolar neurons with cell bodies in the genicular ganglion of the facial nerve and the petrosal and nodose (inferior) ganglia of the glossopharyngeal and vagal nerves, respectively. Afferent fibers from the anterior two thirds of the tongue travel proximally via the chorda tympani. Afferent fibers from the posterior third of the tongue and other posterior structures travel proximally in the greater petrosal nerve branch of the facial nerve (inferior soft palate) and the lingual branch of the glossopharyngeal nerve, together with the internal laryngeal branch of the vagus nerve (epiglottis and extreme pharyngeal part of tongue). Somatosensory afferent fibers are also believed to travel proximally along similar routes, except that somatosensory fibers from the anterior two thirds of the tongue remain with the lingual branch of the mandibular nerve (V3), rather than departing with the chorda tympani. The afferent cranial nerves synapse, in descending order, caudally, ipsilaterally in the medulla of brainstem, and in the rostral third of the nucleus of the tractus solitarius with secondary gustatory neurons. At this level, taste afferent fibers are organized separately from somatosensory information. The subsequent
The complaint of “loss of taste” (ageusia or hypogeusia) in food discrimination is related more often to an olfactory deficit (described previously) than to true impairment of gustation.22 Again, a careful history usually allows the clinician to interpret the patient’s symptom correctly. The evaluation of taste dysfunction is directed toward establishing which modalities (sweet, salty, bitter, sour umami) are preferentially impaired; whether the impairment can be localized anatomically within the sensorineural gustatory pathways as described previously; and whether a cause, treatable or otherwise, can be identified. Isolated disorders of taste caused by central nervous system lesions are rare.21 Abnormal taste (dysgeusia) is usually unpleasant; it may be strongly revolting (cacogeusia), and it may be hallucinatory (phantogeusia), as in a seizure or psychotic disorder, or real, as with a purulent nasopharyngeal infection. Hypergeusia is difficult to quantify and, more rarely, is a symptom prompting medical attention.
History Common causes of taste dysfunction are listed in Table 13–5. They can be conveniently grouped into peripheral, central, and systemic causes. However, the anatomical site sometimes cannot be well localized. The clinician should attempt to gain as clear a description as possible of the exact nature of the patient’s taste disturbance, of any associated symptoms that may localize a lesion or suggest an underlying cause, and of recent respiratory infection. The clinician should also obtain medical and surgical histories23,24; a family history; and a careful history of prescription drug, tobacco, alcohol, and recreational drug use. Inquiry should be made into possible olfactory dysfunction. Important symptoms include xerostomia (dry mouth) or dry eyes; oral, head, facial, or neck pain; facial rash; balance difficulty, oscillopsia, or tinnitus; mouth ulcers or oral thrush; headache; and evidence of oculomotor weakness, facial weakness, or speech disturbance. Mechanical trauma causes isolated dysgeusia less frequently than it does olfactory dysfunction.9 Drugs known to be associated with taste dysfunction are listed in Table 13–3. Prior neck manipulation or trauma should prompt consideration of cervical cerebral arterial dissection.21 Symptoms suggestive of a seizure disorder in association with a powerful, intrusive, clearly abnormal taste in the absence of a tastant (phantogeusia) should prompt consideration of a focal seizure disorder. Unilaterality of taste dysfunction strongly suggests a cause below the level of the thalamus. Anhedonia should prompt consideration of a thalamic lesion or depression. Atten-
176
Section
I
C o n s c i o u s n e s s, C o g n i t i o n, a n d S p e c i a l S e n s e s
T A B L E 13–5. Common Causes of Sensorineural Taste Disturbance Peripheral (Facial Nerve) Bell’s palsy Trauma Surgical procedures (e.g., uvulopalatopharyngoplasty) Herpetic or other facial neuritis Meningitis, mastoiditis Basal skull mass lesions (e.g., meningioma, cholesteatoma) Vestibular schwannoma Parotid malignancy Sarcoidosis Central Intra-axial tumor or other mass lesion Ischemic or hemorrhagic stroke Neurodegenerative disease Multiple sclerosis Epilepsy or seizure disorder Systemic Disease Vasculitis Poorly Localizable Migraine Psychiatric disease Dysautonomic disorders Guillain-Barré syndrome Drug or environmental toxin related Idiopathic Age-related hypogeusia
tion should be paid to the patient’s nutritional state, body mass index, and history of recent weight loss. Again, it should be remembered that an age-related decline in taste acuity may be seen in the normal individual.19
be established by serial dilutions of the tastants down to the lowest recognizable concentration. Standardized “test strips” and other kits are commercially available with specific stimulus concentrations. It should be noted whether the deficit is unilateral or bilateral and whether the abnormality occurs on the anterior two thirds or posterior one third of the tongue. Taste examination of palatopharyngeal structures seldom adds additional useful information. Differentiation between phantom and real tastes can be made by applying topical anesthesia to the tongue. Phantogeusia can intensify after this. Formal magnitude-matching tests can be performed through comparison with another, normal, sensory modality in the patient, such as with a controlled frequency-specific aural stimulus. However, these are usually performed in specialized referral centers for taste disorders.
Investigation of Gustatory Disorders The broad principles of investigation for taste disorders are similar to those for olfactory disorders. If a peripheral cause or localized central lesion is suspected, computed tomography and magnetic resonance imaging of the head, brain and brainstem, anterior cranial structures, internal acoustic meatus, and skull are required. Analyses of blood and body fluids, including cerebrospinal fluid analysis, are useful for a few specific causes such as infection, diabetes, or metabolic organ dysfunction. Suspect or abnormal masses should be subjected to biopsy where accessible. Directed investigation of suspected underlying causes of gustatory dysfunction is dictated by the clinical findings. Electrogustometry can be used to quantify dysgeusia objectively and assist with anatomical localization in difficult cases.26 Electrogustometry can also be used to assess glossopharyngeal nerve dysfunction. However, its use is more common in specialized otolaryngological and chemosensory disturbance clinics.
Principles of Management of Gustatory Disorders Examination Office assessment of gustatory dysfunction includes examination of modality and lingual site of taste dysfunction, targeted neurological examination, and a general medical examination including nose, ears, and oropharynx. Formal otorhinolaryngological endoscopy may be necessary. Height and weight should be recorded, body mass index calculated, and attention paid to signs of protein or micronutrient malnutrition. The aims of neurological examination should be primarily to localize the anatomical site of taste disturbance if possible, and to seek evidence of a generalized process—such as sarcoidosis— that could be selectively affecting taste pathways. On oral examination, particular note should be taken of xerostomia, leukoplakia, ulcers, salivary gland enlargement, and oral hygiene. Dentures or other oral prostheses may interfere with palatal taste sensations. Psychiatric assessment may be warranted if depression or psychosis is suspected. Various methods of taste examination are described. A simple office spatial taste test is performed to assess tastant recognition of the four basic tastes (excluding umami); cotton-tipped swabs are used to apply strong sour, sweet, salty, or bitter solutions to separate areas of the patient’s tongue.25 A crude sensitivity threshold can
Specific therapy for taste disturbance should be directed at the underlying cause when possible. In certain circumstances, taste disturbance may be self-limited and recover with time. Drug cessation in cases of drug-induced dysgeusia does not always reverse the disturbance, and many patients who do recover take months to years to do so.20 Prediction of dysgeusia when drug treatment begins is difficult in the individual patient. Although zinc and other micronutrient or vitamin supplementation are advocated by some authorities, it has not been shown to be of great benefit in the treatment of taste disorders outside of true deficiency states.21 The specific therapy for taste dysfunction is otherwise unsatisfactory, and many patients are left with permanent dysgeusia. Many patients with taste abnormalities, particularly elderly patients, have diabetes, congestive cardiac failure, or hypertension. Hypogeusia may prompt patients to add inordinate amounts of sugar or salt to their food, thereby potentially exacerbating these medical disorders.25 Patient education and counseling are therefore particularly important in supportive treatment of taste abnormalities in these patients. Consultation with a nutritionist may be of value. Finally, the intractable nature of these disabilities means that a supportive and sympathetic attitude toward the patient must always constitute an integral part of his or her care.
chapter 13 disorders of smell and taste
K E Y
P O I N T S
●
Smell and taste disorders are seldom the initial manifestation of serious illness, but they may cause significant morbidity and may be overlooked unless specifically sought by the clinician.
●
Smell and taste disorders are usually related either to agerelated sensory loss or to an identifiable underlying cause. A broad diagnostic approach usually identifies potential causes of olfactory or gustatory dysfunction, including local and central (e.g., neurodegenerative) disorders.
●
Otorhinolaryngological disorders are frequently the cause of olfactory or gustatory dysfunction, and assessment of the patient with a smell or taste disorder may need to be performed in coordination with an otorhinolaryngology specialist.
●
Causes of smell and taste dysfunction are often related, and impairments of both sensory modalities may therefore be present.
●
Primary treatment of smell and taste dysfunction often yields unsatisfactory results. Therapy for smell and taste disorders is best directed at the underlying cause, when that is treatable. Patient education and supportive measures are also important in minimizing the morbidity associated with these disorders.
Suggested Reading Buck LB: Smell and taste: the chemical senses. In Kandel ER, Schwartz JH, Jessell TM, eds: Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000. Hawkes CH: Smell and Taste Complaints. Boston: ButterworthHeinemann, 2002. Heckmann JG, Heckmann SM, Lang CJG, et al: Neurological aspects of taste disorders. Arch Neurol 2003; 60:667-671. Hummel T, Nordin S: Olfactory disorders and their consequences for quality of life. Acta Otolaryngologica 2005; 125:116-121. Mann N: Management of smell and taste problems. Cleve Clin J Med 2002; 69:329-336. Wrobel BB, Leopold DA: Clinical assessment of patients with smell and taste disorders. Otolaryngol Clin North Am 2004; 37:11271142.
References 1. Hummel T, Nordin S: Olfactory disorders and their consequences for quality of life. Acta Otolaryngologica 2005; 125:116-121. 2. Keverne EB: Brain evolution, chemosensory processing, and behavior. Nutr Rev 2004; 62(11): S218-S223.
177
3. Buck LB: Smell and taste: the chemical senses. In Kandel ER, Schwartz JH, Jessell TM, eds: Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000. 4. Upadhyay UD, Holbrook EH: Olfactory loss as a result of toxic exposure. Otolaryngol Clin North Am 2004; 37:1185-1207. 5. Buck LB: Olfactory receptors and odor coding in mammals. Nutr Rev 2004; 62(11):S184-S188. 6. Williams PL, Warwick R, Dyson M, et al, eds: Gray’s Anatomy, 37th ed. New York: Churchill Livingstone, 1989. 7. Doty RL: Cranial nerve I: olfactory nerve. In Goetz CG, ed: Textbook of Clinical Neurology, 2nd ed. Philadelphia: WB Saunders, 2003, pp 99-110. 8. Wrobel BB, Leopold DA: Clinical assessment of patients with smell and taste disorders. Otolaryngol Clin North Am 2004; 37:1127-1142. 9. Reiter ER, DiNardo LJ, Costanzo RM: Effects of head injury on olfaction and taste. Otolaryngol Clin North Am 2004; 37:11671184. 10. Nordin S, Broman DA, Olofsson JK, et al: A longitudinal descriptive study of self reported abnormal smell and taste perception in pregnant women. Chem Senses 2004; 29:391-402. 11. Mann N: Management of smell and taste problems. Cleve Clin J Med 2002; 69:329-336. 12. Raviv JR, Kern RC: Chronic sinusitis and olfactory dysfunction. Otolaryngol Clin North Am 2004; 37:1143-1157. 13. Katzenschlager R, Lees AJ: Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr Opin Neurol 2004; 17:417-423. 14. Hawkes C: Olfaction in neurodegenerative disorder. Mov Disord 2003; 18:364-372. 15. Acharya V, Acharya J, Luders H: Olfactory epileptic auras. Neurology 1998; 51:56-61. 16. Sadock BJ, Sadock VA. Schizophrenia. In Sadock, BJ, Kaplan HI, Sadock VA, eds: Kaplan & Sadock’s Synopsis of Psychiatry. Lippincott Williams & Wilkins, 2003, pp 471-504. 17. Heald AE, Pieper CF, Schiffman SS: Taste and smell complaints in HIV infected patients. AIDS 1998; 12:1667-1674. 18. Afzelius BA: Cilia related diseases. J Pathol 2004; 204:470-477. 19. Seiberling KA, Conley DB: Aging and olfactory and taste function. Otolaryngol Clin North Am 2004; 37:1209-1228. 20. Doty RL, Bromley SM: Effects of drugs on olfaction and taste. Otolaryngol Clin North Am 2004; 37:1229-1254. 21. Heckmann JG, Heckmann SM, Lang CJG, et al: Neurological Aspects of Taste Disorders. Arch Neurol 2003; 60:667-671. 22. Pribitkin E, Rosenthal MD, Cowart BJ: Prevalence and causes of severe taste loss in a chemosensory clinic population. Ann Otol Rhinol Laryngol 2003; 112:971-978. 23. Kamel UF: Hypogeusia as a complication of uvulopalatopharyngoplasty and use of taste strips as a practical tool for quantifying hypogeusia. Acta Otolaryngol 2004; 124:12351236. 24. Collet S, Eloy P, Rombaux P, et al: Taste disorders after tonsillectomy: case report and literature review. Ann Otol Rhinol Laryngol 2005; 114:233-236. 25. Brackmann DE, Fetterman BL: Cranial nerve VII: facial nerve. In Goetz CG, ed: Textbook of Clinical Neurology, 2nd ed. Philadelphia: WB Saunders, 2003, pp 181-194. 26. Tomita H, Ikeda M: Clinical use of electrogustometry: strengths and limitations. Acta Otolaryngol Suppl 2002; (546):27-38.
SECTION II Anthony H. V. Schapira
SLEEP AND SLEEP DISORDERS ✺
✺
✺
CHAPTER
14
THE PHYSIOLOGY ●
●
●
OF
SLEEP
●
Timothy A. Roehrs and Thomas Roth
Sleep is an essential and appetitive behavior characterized by minimal movement; reduced responsiveness to stimuli; reversibility; and species-specific diurnal timing, duration, and preferred posture.1 The appetitive and essential nature of sleep is clearly evident in the human’s inability to maintain continuous wakefulness for more than 2 to 3 days. As a state of sleep need progressively increases with attempts at prolonged wakefulness, sleep begins to intrude into wakefulness as brief microsleeps occurring during ongoing behavior and as longer episodes of unintended sleep during periods of inactivity.2 The inability to completely deprive oneself of sleep after 2 to 3 days, in contrast to one’s ability to avoid food or fluids and thereby deprive oneself to death, demonstrates the compulsory nature of sleep. In fact, the compulsory nature of sleep accounts for much of the morbidity associated with sleep loss (e.g., car accidents). Sleep in humans is recognized behaviorally by its recumbence and eye closure, but some mammals sleep with open eyes (e.g., cattle) or while standing (e.g., horse, elephant).1 The immobility of the sleep state is relative in that sleep walking and talking occur in some human sleep disorders and, among animals, some fish swim in place and mammals move about periodically. The two characteristics of arousability and rapid reversibility differentiate sleep from death, coma, and hibernation. Nonvisual sensory monitoring of both exogenous and endogenous stimuli continues during the sleep state. For example, a vital stimulus, hypoxemia, readily arouses even a severely sleep-deprived individual; similarly, a parent is easily aroused by the cry of his or her baby. In fact, sensory discrimination continues during sleep, inasmuch as a parent does not arouse to the cry of another baby, corrected for stimulus intensity differences. Average daily sleep time varies from 2 to 20 hours among mammals, typically being 8 hours for humans.3 The single best correlate of variation in sleep length among mammals appears to be metabolic rate.3 Whereas the major sleep period in humans typically occurs as a single bout during the dark hours, for some mammals sleep is linked to the daylight period and occurs in multiple bouts.
NATURE OF SLEEP Because sleep would be disrupted if it were assessed behaviorally (e.g., testing arousal threshold), sleep scientists measure
180
sleep electrophysiologically, which is less obtrusive and more precise.4 The simultaneous recording of the electroencephalogram (EEG), the electro-oculogram, and the electromyogram are the accepted standard measures of sleep and waking, a standardized procedure termed polysomnography. The polysomnogram correlates well with behavioral observations. But it also reveals further subtleties not apparent behaviorally or subjectively. Sleep is an active, complex, and highly organized process composed of two distinct brain states of sleep: rapid eye movement (REM) and non-rapid eye movement (NREM).
Electrophysiology of NREM and REM sleep In contrast to the electroencephalographic low voltage (10 to 30 μV) and fast frequency (16 to 35 Hz) of activated wakefulness, the cortical EEG (C3/4 to A1/2) of relaxed, eyes-closed wakefulness is characterized by increased voltage (20 to 40 μV) and an 8- to 12-Hz frequency. During the transition to sleep, sometimes called drowsy sleep or transitional sleep, the electroencephalographic frequency becomes mixed, whereas the voltage remains at the level of relaxed wakefulness. In NREM sleep, electroencephalographic voltage is further increased and frequency is further slowed. When arousal threshold is highest, the EEG of NREM sleep has a 0.5- to 2-Hz frequency with voltages of 75 μV and higher, which is termed slow-wave sleep. The electromyographic activity, highest in wakefulness, is gradually reduced during NREM sleep, although limb and body movements occur aperiodically during NREM and there is voluntary control of musculature. The electro-oculograms of wakefulness reveal rapid eye movements, which, during the transition to NREM sleep, become slow and rolling. Of importance is that the rolling eye movements mark the onset of the functional blindness all humans experience during sleep. The electrooculogram becomes quiescent during slow-wave sleep. After 90 to 120 minutes of NREM sleep, the healthy normal person enters REM sleep. The electro-oculogram of REM sleep is characterized by rapid conjugate eye movements (hence the name of this sleep state). The cortical EEG of REM sleep reverts to the low-voltage, mixed-frequency pattern of drowsy sleep. The second defining characteristic of REM sleep is its skeletal muscle atonia, which is reflected in the electromyogram achieving its lowest level of the night. The muscle atonia of REM sleep occurs through a
chapter 14 the physiology of sleep process of postsynaptic inhibition of motor neurons at the dorsal horn of the spinal cord. Another important feature of REM sleep is its tonic and phasic components. The tonic components of REM sleep are the persistent muscle atonia and the desynchronized EEG. The phasic components are intermittent and include bursts of eye movements occurring against a background of electro-oculographic quiescence. Coupled with the eye movement bursts are muscle twitches, typically involving peripheral muscles. These twitches are superimposed on the tonic muscle atonia of REM and probably reflect sympathetic drive breaking through the postsynaptic inhibition (see the following discussion of the autonomic nervous system during sleep).
Physiological Function during Sleep Autonomic Nervous System The activity of the autonomic nervous system varies between the two sleep states (NREM and REM) and the wakefulness state.5 Parasympathetic activity increases during NREM sleep in relation to wakefulness. It remains relatively increased during both tonic and phasic REM sleep. Sympathetic activity remains constant during wakefulness and NREM sleep and is slightly reduced during tonic REM sleep. Consequently, parasympathetic activity predominates during sleep with the exception of phasic REM sleep. Sympathetic drive is dramatically increased during phasic REM sleep, and it predominates despite the increased parasympathetic activity of phasic REM sleep.
Respiratory System Breathing patterns and the control of respiration are different in sleep and wakefulness.6 Minute ventilation is decreased from waking levels by 13% to 15% during NREM sleep. Two factors are responsible: First, the nonmetabolic drive to breathe in wakefulness is removed with the onset of NREM sleep; second, airflow resistance is enhanced, as a result of a reduction of upper airway dilator muscle tone that occurs in conjunction with the general reduction of skeletal muscle tone of sleep. During the tonic skeletal muscle atonia of REM sleep, airway resistance is further increased in comparison with that of NREM sleep, resulting in a twofold increase in relation to that of wakefulness. This heightened airway resistance, coupled with the autonomic nervous system sympathetic activation, particularly in phasic REM sleep, leads to irregular breathing patterns and even respiratory pauses during REM sleep. Metabolic control of breathing is also altered by the NREM and REM sleep states. Hypoxic ventilatory drive is reduced in NREM sleep and declines further in REM sleep. Hypercapnic drive, although also reduced in NREM sleep in relation to wakefulness, is virtually absent in REM sleep. Breathing during NREM sleep is controlled primarily by arterial levels of CO2; thus, when levels of CO2 are below the elevated threshold of NREM sleep, the effort to breathe ceases. Consequently, at transitions from wakefulness to sleep, breathing often becomes periodic as a result of this shifting of the hypercapnic set point. Individuals with fragmented sleep characterized by frequent wake-sleep transitions often have frequent central apnea events. For example, many elderly persons have central apnea,
181
which results from fragmented sleep and itself further fragments sleep. On the other hand, in view of the absence of hypercapnic drive in REM sleep, obstructive apneas that occur during REM sleep are prolonged relative to NREM apneas.
Thermal Regulation Altered thermoregulation is also displayed in the NREM and REM sleep states.7 The thermal set point is reduced in NREM sleep in relation to the wakefulness state. Consequently, sweating and shivering occur at lower temperatures during NREM sleep than during wakefulness. Again, REM sleep is unique in that there is no temperature regulation during REM sleep and sweating and shivering cease during REM sleep. If a person remained in REM sleep long enough, body temperature would equilibrate to the ambient temperature. However, REM episodes are never much longer than 30 minutes, and thus noticeable body temperature fluctuations do not occur during REM sleep.
REGULATION OF SLEEP AND WAKEFULNESS Wakefulness, sleep, and its constituent REM and NREM states are regulated by three hypothesized processes: a homeostatic process that is driven by the prior amount of sleep and wakefulness, a circadian process that organizes sleep and wakefulness episodes across the 24-hour day, and an ultradian process that controls the expressions of REM and NREM within the sleep period. The NREM and REM states are interdependent, whereas both the homeostatic and circadian systems are independent but interacting. Knowledge about the neurobiology of the circadian system, although far from complete, is more advanced than that of the homeostatic system. Little is known yet about the ultradian system, and how these three processes interact to produce REM or NREM sleep at a given time of day.
Homeostatic Regulation Homeostatic regulation of sleep has been inferred from measurement of the amount of electroencephalographic slow-wave activity during the sleep period, the auditory arousal threshold during sleep, the total amount and continuity of sleep, and the speed of falling asleep at night and during the day.8 Reductions of sleep time yield increases in these various measures, whereas increases in sleep time yield reductions in these measures, with two exceptions: sleep continuity and arousal threshold, which behave conversely. For example, computer-assisted quantification of slow-wave activity during sleep shows an increased amount of slow-wave activity during recovery sleep after total or partial sleep deprivation. During normal sleep, in the absence of prior deprivation, the amount of slow-wave activity diminishes in each successive NREM sleep cycle across the night. Measuring the speed of falling asleep throughout the day on a standard measure, the Multiple Sleep Latency Test, also suggests the existence of an underlying homeostatic process for sleep.4 A single night in which sleep time is reduced by 2 to 8 hours produces a linear increase in the speed of falling asleep on the Multiple Sleep Latency Test the following day, and nightly sleep durations reduced by as little as 1 to 2 hours across successive nights accumulate to increase speed of falling asleep the following day. Conversely, extension of sleep
182
Section
II
Sleep and Sleep Disorders
duration beyond 8 hours, or a compensatory nap, produces a reduction in the speed of falling asleep on the Multiple Sleep Latency Test.9
Circadian Regulation In addition to, and independent of, the homeostatic process is a circadian process that organizes sleep and wakefulness according to the 24-hour day and in phase with the light-dark cycle. The suprachiasmatic nucleus is the biological clock.10 It receives input from the retinohypothalamic tract that serves to synchronize the suprachiasmatic nucleus to the light-dark cycle. The suprachiasmatic nucleus efferent fibers then convey circadian timing signals that regulate a variety of physiological rhythms. Circadian phase typically is documented in humans by recording body temperature and in animals by recording wheel running. The daily human body temperature nadir occurs between 3:00 and 5:00 AM; a secondary decline in body temperature appears at about midday and peaks between 5:00 and 8:00 PM. The speed of falling asleep and the duration of sleep episodes parallel the body temperature rhythm; rapid sleep onsets and long durations occur over the temperature nadirs, whereas long onsets and short durations occur over temperature peaks. Hormonal and metabolic rhythms also are driven by the suprachiasmatic nucleus. For example, thyroid-stimulating hormone, cortisol, prolactin, growth hormone, and melatonin all show a circadian rhythm. Some of these hormones are linked to sleep (i.e., prolactin and growth hormone); that is, their release is delayed when sleep is delayed, at least acutely. Other hormones (e.g., cortisol) are directly linked to the lightdark cycle with their basal circadian rhythm remaining regardless of the timing of sleep. Melatonin is considered to be the internal hormonal signal that communicates the light-dark cycle throughout the body.11 Its production and release are controlled by the suprachiasmatic nucleus, and it is expressed during darkness and suppressed during light. The release of melatonin attenuates the alerting pulse of the suprachiasmatic nucleus, thereby facilitating sleep onset in the dark. A brief pulse of light interrupting darkness produces a rapid decline in melatonin levels, which continues for the duration of the light pulse. Its hypnotic capacity, beyond its chronobiotic characteristic, is unclear.
Homeostatic and Circadian Interaction Models that conceptualize the interaction of the homeostatic and circadian processes have been developed; the most widely cited model is the two-process of Borbely and colleagues.12 In this model, the sleep process (process S) builds during wakefulness and decreases during sleep. The circadian process (process C) promotes wakefulness and gates the expression of sleep at the appropriate circadian phase, if process S has reached its threshold. Another model, the opponent-process model, assigns the role of actively promoting wakefulness to the suprachiasmatic nucleus, the circadian pacemaker, which opposes an accumulating sleep drive.13 The alerting signal of the suprachiasmatic nucleus has a circadian rhythm, which, when absent or low, allows the expression of the sleep drive. When present at its peak, the alerting signal opposes the expression of sleep even when the sleep drive approaches its
peak level. Although these models clearly have heuristic value, several critical questions remain. The biochemical or molecular substrates of process S, or the “sleep drive,” are not known, and the neurobiological pathways by which process C interacts with sleep mechanisms have not been identified. On the other hand, an understanding of the neurobiological controls of wakefulness and sleep is emerging, which is discussed as follows.
NEUROBIOLOGICAL CONTROLS OF WAKE AND SLEEP Wake Giuseppe Moruzzi and Horace Winchell Magoun in 1949 identified an ascending arousal system, which they termed the reticular activating system, that regulates the level of forebrain wakefulness, but its origins were not characterized until 2001.15 The system consists of two main pathways: one innervating the thalamus and the other extending into the hypothalamus.15 The thalamic path originates from cholinergic pedunculopontine and laterodorsal tegmental (PPT-LDT) nuclei, and the hypothalamic path consists of noradrenergic locus ceruleus and serotoninergic dorsal and median raphe nuclei projections, which are joined at the hypothalamus by histaminergic tuberomammillary nucleus projections. These all project diffusely to the cortex. Electrophysiological recordings have verified the role of these nuclei in wakefulness.14 The locus ceruleus, dorsal and median raphe, and tuberomammillary nuclei fire at their fastest rate during wakefulness, are slowed in slow-wave sleep, and silent in REM sleep. In contrast, the PPT-LDT nuclei fire at their fastest rate during REM sleep, also fire during wakefulness, and are silent during slow-wave sleep.
Sleep The critical element in initiating sleep is inhibitory pulses generated by neurons in the ventrolateral preoptic (VLPO) nucleus, which project to the tuberomammillary, locus ceruleus, and dorsal and median raphe nuclei and to the PPT-LDT nuclei.14 The majority of these projections are γ-amino butyric acid mediated (GABAergic) and galaninergic and appear to inhibit the monoaminergic and cholinergic arousal systems. Electrophysiological recordings of neurons in the VLPO nucleus have shown that they fire at highest rates during sleep and are silent during wakefulness. The relation of the VLPO nucleus to monoaminergic and cholinergic arousal systems is reciprocal. The VLPO nucleus receives input from these systems that, during wakefulness, inhibit the VLPO nucleus’s sleep-promoting effect. The VLPO nucleus also receives input from the retina and the suprachiasmatic nucleus, which may provide the circadian signal for sleep initiation. But this step has not been verified.
Bistable Flip-Flop The reciprocal relation of the VLPO nucleus to monoaminergic and cholinergic arousal systems was characterized as a bistable flip-flop by Saper and colleagues.15 Rapid firing of the VLPO
chapter 14 the physiology of sleep nucleus inhibits the arousal system, which in turn disinhibits its own firing. Similarly, rapid firing of the arousal systems inhibits the VLPO nucleus, which thereby disinhibits the firing of these systems. Such a model, derived from electrical engineering, provides for stability of sleep and wakefulness states, no intermediate states, and rapid transitions between states. Once the sleep or wakefulness threshold is reached, a rapid reversal of firing patterns occurs. Because circadian signals and homeostatic sleep drive change slowly and continuously, a bistable system ensures rapid transitions and no entry into intermediate states. Saper and colleagues incorporated the recently discovered orexin/hypocretin peptides into the model in the role of stabilizing behavioral state.14 Orexin/hypocretin peptides were discovered in 1998 by two different investigating groups as neurotransmitters synthesized in the lateral hypothalamus. Orexin/hypocretin neurons were found to innervate all the ascending arousal systems and, furthermore, to project to the VLPO nucleus. On the basis of gene knockout studies in mice and genetic studies of humans with narcolepsy, both which show that the absence of orexin/hypocretin signaling via the type 2 receptor leads to intrusions of sleep into wakefulness, it appears that these neurons have an important role in maintaining wakefulness and further stabilizing sleep-wake state.14
SUMMARY Sleep is a vital, active, and highly organized behavior that has a dramatic effect on many aspects of physiology. It is controlled by two independent but interacting systems: a homeostatic and a circadian system. An additional system, an ultradian process, organizes the expression of two distinct states of sleep, REM and NREM, into 90- to 120-minute cycles. The neurobiological control of sleep and wakefulness involves cholinergic and monoaminergic substrates that promote arousal and GABAergic and galaninergic neurons that promote sleep. These two systems interact in a reciprocal inhibitory manner to maintain stable sleep and wakefulness. Control of sleep and wakefulness through these systems has been modeled as a bistable flip-flop switch. Behavioral state is further stabilized by the recently identified orexin/hypocretin peptides that affect both sides of the flip-flop circuit.
K E Y
P O I N T S
●
Sleep is a behavioral state that is characterized by minimal movement, reduced responsiveness to stimuli, reversibility, and species-specific diurnal timing, duration, and posture.
●
Electrophysiological assessment of sleep has revealed that it is an active, complex, and highly organized process composed of two distinct brain states of sleep: REM and NREM.
●
The REM and NREM states of sleep are associated with differing physiological characteristics and regulation.
●
Wakefulness and the constituent states of sleep are regulated by three hypothesized processes—homeostatic, circadian, and ultradian—that are independent but interactive.
●
183
Neurobiological control of sleep and wakefulness involves cholinergic and monoaminergic substrates that promote arousal and GABAergic and galaninergic neurons that promote sleep.
Suggested Reading Borbely AA, Achermann PA: Sleep homeostasis and models of sleep regulation. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 405-417. Carskadon MA, Dement WC: Normal human sleep: an overview. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 13-23. Czeisler CA, Turek FW: Melatonin, sleep and circadian rhythms: current progress and controversies [Special Issue]. J Biol Rhythms 1997; 12:485-708. Roth T, Roehrs T: An overview of normal sleep and sleep disorders. Eur J Neurol 2000; 7(Suppl 4):3-8. Saper CB, Chou TC, Scammell TE: The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24:726731.
References 1. Tobler I: Is sleep fundamentally different between mammalian species? Behav Brain Res 1995; 69:35-54. 2. Roehrs T, Carskadon MA, Dement WC, et al: Daytime sleepiness and alertness. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 39-50. 3. Zepelin H, Siegel JM, Tobler I: Mammalian sleep. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 91-100. 4. Rechtschaffen A, Kales A: A Manual of Standardized Techniques and Scoring System for Sleep Stages of Human Sleep. Los Angeles: Brain Information Service/Brain Research Institute, University of California at Los Angeles, 1968. 5. Roth T, Roehrs T: An overview of normal sleep and sleep disorders. Eur J Neurol 2000; 7(Suppl 4):3-8. 6. Issa FG, Suratt PM, Remmers JE, eds: Sleep and Respiration. New York: John Wiley, 1990. 7. Heller HC: Temperature, thermoregulation, and sleep. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 292-304. 8. Borbely AA, Achermann PA: Sleep homeostasis and models of sleep regulation. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 405-417. 9. Roehrs T, Shore E, Papineau K, et al: A two-week sleep extension in sleepy normals. Sleep 1996; 19:576-582. 10. Turek FW, Dugovic C, Laposky AD: Master circadian clock, master circadian rhythm. In Kryger MH, Roth T, Dement WC, eds: Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: WB Saunders, 2005, pp 318320. 11. Czeisler CA, Turek FW: Melatonin, sleep and circadian rhythms: current progress and controversies [Special Issue]. J Biol Rhythms 1997; 12:485-708.
184
Section
II
Sleep and Sleep Disorders
12. Achermannn P, Dijk DJ, Brunner DP, et al: A model of human sleep homeostasis based on EEG slow-wave activity: quantitative comparison of data and simulations. Brain Res Bull 1993; 31:97-113. 13. Egar DM, Dement WC, Fuller CA: Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci 1993; 13:1065-1079.
14. Moruzzi G, Magoun H: Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949; 1:455-473. 15. Saper CB, Chou TC, Scammell TE: The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24:726-731.
CHAPTER
15
PRIMARY DISORDERS ●
●
●
OF
SLEEP
●
John W. Winkelman and Milena Pavlova
Difficulty with the regulation of sleep and wake states is present in up to 25% of the general population on a chronic basis and in up to one half of all individuals on occasion. For some, the primary concern is difficulty falling asleep, whereas for others it may be maintaining sleep or awakening feeling unrefreshed, even after a full night’s rest. Other individuals report excess daytime sleepiness, having difficulty maintaining alertness at inopportune or embarrassing times, or interference of sleepiness at times with productivity or even safety. The evaluation and treatment of such patients are the domains of sleep disorders medicine, a field that combines elements of neurology, psychiatry, pulmonary medicine, and otolaryngology. One of the most important motivations to the development of the field of sleep disorders has been the recognition of the effect of these conditions on multiple aspects of health. For instance, insomnia, the most common sleep disorder, has been hypothesized to account for $10 billion to $15 billion in direct and indirect costs to society, is associated with substantial decrements in quality of life, has been hypothesized to predispose sufferers to a variety of medical disorders, and has been clearly documented to be associated with substantial incident risks of major depression and other psychiatric disorders. Similarly, obstructive sleep apnea is clearly associated with excessive daytime sleepiness and an increase in motor vehicle accidents and is believed to contribute to hypertension and, potentially, premature mortality. A nosology of sleep disorders, the International Classification of Sleep Disorders, now in its second edition (ICSD-2),1 developed by the American Academy of Sleep Medicine (Table 15–1), has existed for more than 20 years. Its codes are consistent with the existing codes of the International Classification of Disease, 10th edition. The ICSD-2 organizes sleep disorders in eight categories on the basis of their predominant manifesting symptom and/or etiological basis: the insomnias; the sleep-related breathing disorders; hypersomnia not caused by a sleep-related breathing disorder; the circadian rhythm disorders; the parasomnias; the sleep-related movement disorders; and two miscellaneous categories comprising normal variants, isolated symptoms, and other sleep disorders. Readers are referred to Chapters 16 and 37 for detailed descriptions of obstructive sleep apnea and restless legs syndrome (RLS).
INSOMNIA Insomnia is defined as a difficulty in falling asleep, a difficulty in staying asleep, or nonrestorative sleep (awakening feeling unrefreshed). It is usually classified as transient, short-term, or chronic, according to the duration of symptoms, although many affected individuals describe recurrent episodes of short-term insomnia, which complicates classification. It may also be classified, on the basis of the predominant insomnia complaint, as initial insomnia, sleep maintenance insomnia, or insomnia with premature terminal awakening. This division, however, is also overly simplistic, inasmuch as many patients with chronic or recurrent short-term insomnia have an evolution of symptoms over time: Initial insomnia may develop into frequent or prolonged nocturnal awakenings or a mixture of the two. Thus, etiological inferences based on the type of manifesting symptom are bound to be confounded by these symptomatic fluctuations.
Epidemiology, Consequences, and Diagnosis of Insomnia Insomnia has also traditionally been characterized as primary or secondary on the basis of its presumed etiology. Insomnia is referred to as secondary when it is believed to be a symptom of an underlying medical, psychiatric, or sleep disorder, or when it follows medication use. This diagnosis is based on a plausible mechanism by which the underlying disorder causes insomnia (e.g., pain, shortness of breath), the occurrence of insomnia after that of the underlying condition, and a course that follows the severity of the underlying condition. According to this schema, treatment of the underlying cause should resolve the insomnia symptom. In contrast, primary insomnia is considered to be caused by physiological and cognitive hyperarousal, both within the sleep environment and during the day. The distinctions between primary and secondary insomnia have more recently been questioned, however, because of the difficulties in making this distinction, the recognition that secondary insomnia may evolve into primary insomnia, and the fact that some insomnia vulnerability factors may predispose persons with medical disorders to develop insomnia. The point prevalence of insomnia that lasts more than a few weeks is approximately 10% to 15% of the general population.2
185
186
Section
II
Sleep and Sleep Disorders
T A B L E 15–1. International Classification of Sleep Disorders, 2nd Edition Insomnia ADJUSTMENT Insomnia (Acute Insomnia) Psychophysiological Insomnia Paradoxical Insomnia Idiopathic Insomnia Insomnia Due to Mental Disorder Inadequate Sleep Hygiene Behavioral Insomnia of Childhood Insomnia Due to Drug or Substance Insomnia Due to Medical Condition Insomnia Not Due to Substance or Known Physiological Condition, Unspecified (Nonorganic Insomnia [NOS]) Physiological (Organic) Insomnia, Unspecified Sleep-Related Breathing Disorders Central Sleep Apnea Syndromes Primary Central Sleep Apnea Central Sleep Apnea Due to Cheyne-Stokes Breathing Pattern Central Sleep Apnea Due to High-Altitude Periodic Breathing Central Sleep Apnea Due to Medical Condition Not Cheyne-Stokes Central Sleep Apnea Due to Drug or Substance Primary Sleep Apnea of Infancy (formerly “Primary Sleep Apnea of Newborn”) Obstructive Sleep Apnea Syndromes Obstructive Sleep Apnea, Adult Obstructive Sleep Apnea, Pediatric Sleep-Related Hypoventilation/Hypoxemic Syndromes Sleep Related Nonobstructive Alveolar Hypoventilation, Idiopathic Congenital Central Alveolar Hypoventilation Syndrome Sleep-Related Hypoventilation/Hypoxemia Due to Medical Condition Sleep-Related Hypoventilation/Hypoxemia Due to Pulmonary Parenchymal or Vascular Pathology Sleep-Related Hypoventilation/Hypoxemia Due to Lower Airway Obstruction Sleep-Related Hypoventilation/Hypoxemia Due to Neuromuscular and Chest Wall Disorders Other Sleep-Related Breathing Disorder Sleep Apnea/Sleep Related Breathing Disorder, Unspecified Hypersomnias of Central Origin Not Due to a Circadian Rhythm Sleep Disorder, Sleep-Related Breathing Disorder, or Other Cause of Disturbed Nocturnal Sleep Narcolepsy with Cataplexy Narcolepsy without Cataplexy Narcolepsy Due to Medical Condition Narcolepsy, Unspecified Recurrent Hypersomnia Kleine-Levin Syndrome Menstrual-Related Hypersomnia Idiopathic Hypersomnia with Long Sleep Time Idiopathic Hypersomnia without Long Sleep Time Behaviorally Induced Insufficient Sleep Syndrome Hypersomnia Due to Medical Condition Hypersomnia Due to Drug or Substance Hypersomnia Not Due to Substance or Known Physiological Condition (Nonorganic Hypersomnia [NOS]) Physiological (Organic) Hypersomnia, Unspecified (Organic Hypersomnia, NOS) Circadian Rhythm Sleep Disorders Circadian Rhythm Sleep Disorder, Delayed Sleep Phase Type (Delayed Sleep Phase Disorder) Circadian Rhythm Sleep Disorder, Advanced Sleep Phase Type (Advanced Sleep Phase Disorder) Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type (Irregular Sleep-Wake Rhythm) Circadian Rhythm Sleep Disorder, Free-Running Type (Nonentrained Type) Circadian Rhythm Sleep Disorder, Jet Lag Type (Jet Lag Disorder) Circadian Rhythm Sleep Disorder, Shift Work Type (Shift Work Disorder) Circadian Rhythm Sleep Disorder Due to Medical Condition Other Circadian Rhythm Sleep Disorder (Circadian Rhythm Disorder, NOS) Other Circadian Rhythm Sleep Disorder Due to Drug or Substance Parasomnias Disorders of Arousal (from NREM Sleep) Confusional Arousals Sleepwalking Night Terrors Parasomnias Usually Associated with REM Sleep REM Sleep Behavior Disorder (Including Parasomnia Overlap Disorder and Status Dissociatus) Recurrent Isolated Sleep Paralysis Nightmare Disorder Reprinted from American Academy of Sleep Medicine: International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd ed. Rochester, MN: American Academy of Sleep Medicine, 2005.
chapter 15 primary disorders of sleep
187
T A B L E 15–1. International Classification of Sleep Disorders, 2nd Edition—cont’d Other Parasomnias Sleep-Related Dissociative Disorders Sleep Enuresis Sleep-Related Groaning (Catathrenia) Exploding Head Syndrome Sleep-Related Hallucinations Sleep-Related Eating Disorder Parasomnia, Unspecified Parasomnia Due to Drug or Substance Parasomnia Due to Medical Condition Sleep Related Movement Disorders Restless Legs Syndrome Periodic Limb Movement Disorder Sleep-Related Leg Cramps Sleep-Related Bruxism Sleep-Related Rhythmic Movement Disorder Sleep-Related Movement Disorder, Unspecified Sleep-Related Movement Disorder Due to Drug or Substance Sleep-Related Movement Disorder Due to Medical Condition Isolated Symptoms, Apparently Normal Variants, and Unresolved Issues Long Sleeper Short Sleeper Snoring Sleep Talking Sleep Starts (Hypnic Jerks) Benign Sleep Myoclonus of Infancy Hypnagogic Foot Tremor and Alternating Leg Muscle Activation During Sleep Propriospinal Myoclonus at Sleep Onset Excessive Fragmentary Myoclonus Other Sleep Disorders Other Physiological (Organic) Sleep Disorder Other Sleep Disorder Not Due to Substance or Known Physiological Condition Environmental Sleep Disorder NREM, non–rapid eye movement; REM, rapid eye movement.
However, because of its association with medical and psychiatric illnesses, up to 50% of individuals seen in medical practices report at least mild insomnia.3 Results of studies in individuals older than 65 suggest a 5% incidence and a 5% to 15% yearly rate of remission of insomnia.4,5 Female gender, increasing age, psychiatric and medical illnesses, substance use, low income, unemployment, and being single are all risk factors for having insomnia, although some of these may be consequences of insomnia rather than vulnerability factors.6-8 There is increasing recognition of the adverse consequences of insomnia. Multiple studies have demonstrated that persistent insomnia is associated with a substantial increased risk of incident depression.9 Insomnia is also associated with globally worsened quality of life, even when psychiatric illness10 or medical comorbidity3 is accounted for. The decrements in physical functioning, general health perception, and vitality are as substantial as, or more so than, those observed with congestive heart failure.3 Furthermore, there are suggestions that insomnia is associated with an increased risk of work-related and motor vehicle accidents, as well as falls by elderly persons.11 Finally, health costs in individuals with insomnia are elevated, even when comorbid medical and psychiatric illnesses are accounted for.12 The concept of hyperarousal is being used to unify the understanding of the pathophysiology of primary insomnia.13-15 From a physiological perspective, individuals with insomnia
have elevated evening cortisol levels,16 increased 24-hour whole body metabolic rate,17 increases in both waking and sleeprelated global cerebral glucose metabolism (Fig. 15–1),18 and high-frequency electroencephalographic (EEG) activity during sleep.19 It is unclear which neural circuits are responsible for
Ascending reticular activating system ■
Figure 15–1. Areas in which metabolism did not decrease from sleep to wakefulness in insomniac patients. (From Nofzinger EA, Buysse DJ, Germain A, et al: Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161:2126-2168.)
188
Section
II
Sleep and Sleep Disorders
these disparate findings. Similarly, cognitive arousal is considered to be central to the generation and maintenance of insomnia. It is hypothesized that cognitive and physiological hyperarousal become paired with the sleep environment, which gradually worsens sleep and increases these arousal processes in that setting, creating a vicious cycle of insomnia.15,20 Maladaptive compensatory strategies, such as spending excess time in bed, daytime napping, and alcohol and caffeine intake can then exacerbate this process. The evaluation of patients with insomnia involves identifying the scope and duration of the complaint, including its effects on daytime functioning, and searching for potential etiologies. Behaviors and cognitions relevant to sleep during both daytime and evening should be solicited from the patient. In particular, explicit focus on the period in bed both before sleep and at nocturnal awakenings may assist with determining physical or mental events that interfere with sleep. Sleep diaries may help in elucidating predictable changes in sleep quality that are based on day of the week and/or work schedules. Factors that worsen or improve sleep quality longitudinally should also be identified. Life events that have a temporal relationship to the onset of sleep problems can frequently assist in identifying potential causes of insomnia, particularly in individuals with insomnias of shorter duration. In individuals with chronic insomnia, such events may have occurred many years in the past and may not be clear, or the insomnia may have a more insidious waxing course of severity. Identification of potential medical, sleep-related, and psychiatric causes of insomnia is essential for optimal treatment, because treatment of such causes may at times eliminate the insomnia complaint. Insomnia in elderly persons, in whom frequent nocturnal awakenings are the most common complaint, is particularly related to medical illness,21 and careful attention to patients’ medical problems may provide guides to the etiology of insomnia in this group. The most common medical disorders associated with insomnia are listed in Table 15–2. In addition, all psychiatric disorders can and frequently do cause insomnia, and assessments for depression and anxiety disorders are an essential feature of the insomnia evaluation. However, it should be made clear that approximately 40% of individuals with insomnia do not have a psychiatric disorder,22 and thus the assumption that insomnia is necessarily caused by psychiatric illness is ill founded. Polysomnography can also assist with the assessment of insomnia in some cases. This diagnostic procedure is not recommended for most individuals with insomnia23; however, when the clinician suspects sleep apnea or periodic limb movements of sleep (PLMSs), or when the patient reports frequent brief awakenings, polysomnography is indicated for further evaluation.
Treatment of Insomnia The treatment of insomnia is best achieved by addressing all possible underlying contributing factors, whether they are related to medical or psychiatric causes, poor sleep habits, or counterproductive sleep-related cognitions. A combination of approaches is generally recommended. For individuals with insomnia of recent onset, an identifiable precipitant (a physical or emotional stressor) is usually present, and the duration of
T A B L E 15–2. Medical Disorders or Conditions Commonly Associated with Insomnia Cardiovascular Congestive heart failure with paroxysmal nocturnal dyspnea and/or Cheyne-Stokes respiration Nocturnal angina Pulmonary Chronic obstructive pulmonary disease Asthma Nocturnal cough Gastrointestinal Gastroesophageal reflux disease Irritable bowel syndrome Musculoskeletal Arthritis Fibromyalgia Traumatic injury Endocrine Perimenopause or menopause Diabetes Thyroid disease Renal Insufficiency or Failure
the complaint is often short. If, in such individuals, the insomnia is associated with substantial concern or daytime dysfunction, short-term use of a hypnotic agent is recommended so as to minimize the immediate effect of the insomnia and to prevent the development of a more chronic conditioned insomnia. In individuals with chronic primary insomnia, and in some individuals with secondary insomnia, first-line treatments are modification of sleep-related behaviors and attitudes, called cognitive-behavioral therapy. Cognitive-behavioral therapy has a number of components: (1) limitation of time in bed (sleep restriction and stimulus control), which produces mild sleep deprivation, thus allowing shorter sleep onset and reduction in the number and duration of awakenings, and reduces the duration of time awake in bed, limiting negative associations to the sleep environment; (2) relaxation techniques, which reduce physiological and cognitive arousal in the sleep setting by use of yoga, meditation, and/or biofeedback; (3) cognitive restructuring, which addresses catastrophic beliefs and attitudes regarding sleeplessness, replacing them with more rational expectations of sleep and effects of insomnia; and (4) sleep hygiene, which refers to a variety of habits that promote good sleep such as regular bedtimes and waking times, daily exercise, avoidance of napping, careful use of alcohol and caffeine, and reduction in behaviors that promote nocturnal emotional and physical arousal (e.g., work, emotional stimulation, nighttime exercise). Cognitive-behavioral therapy has been shown to produce consistent reduction in sleep onset latency and wake time during the night, as well as smaller increases in total sleep time.24,25 These gains have generally been maintained over periods of up to 24 months. Pharmacological therapies for insomnia have evolved since the 1950s from barbiturates to long-acting benzodiazepines, then to shorter acting benzodiazepines, and, since the
chapter 15 primary disorders of sleep α1
T A B L E 15–3. Benzodiazepine Receptor Agonists Commonly Used for the Treatment of Insomnia Agent (Brand Name) *
α2
α3
α4
■
Figure 15–2. γ-Amino butyric acid A (GABAA) receptor subtypes, localization and function in mouse brain. (From Mohler H, Fritschy J, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300:2-8.)
mid-1990s, to non-benzodiazepine receptor agonists (BzRAs). In addition, there has been a trend away from these approved medications for insomnia and toward the use of sedating medications with original indications for other disorders (e.g., antidepressants, anticonvulsants, antipsychotics), to the point at which antidepressants constitute more than 50% of all prescription medications for insomnia.26 Recommendations as to the appropriate use of hypnotics in the treatment of insomnia are evolving, and this and other treatment issues in insomnia were reviewed in a state-of-the-science National Institute of Mental Health consensus statement.27 Benzodiazepines and BzRAs bind at an allosteric site on the γ-amino butyric acid A (GABAA) receptor complex, influencing GABA binding and chloride flux. The BzRAs demonstrate relatively selective binding for GABAA receptors that contain α1 subunits. The α1 subunits mediate the sedative, amnestic, and anticonvulsant properties of these agents but few of the muscle relaxant and anxiolytic aspects (Fig. 15–2).28 However, it is unclear whether the relative receptor selectivity of the BzRAs have clinical significance in terms of efficacy or short- or longterm tolerability. More important than the receptor-binding characteristics of these agents are the major differences between the half-lives of these agents, which, when combined with dosage, determine the duration of the medication’s effects. Half-lives of hypnotics in this class vary from 1 to more than 100 hours (Table 15–3). Because of the variability of sleep complaints, medication choices in this class are usually based on matching the patient’s sleep complaint with an appropriate half-life agent, so as to maximize the opportunity for sleep but minimize waking hangover effects. Meta-analyses have demonstrated the efficacy of benzodiazepines and BzRAs in reducing sleep onset latency, decreasing
189
Flurazepam (Dalmane) Estazolam (Prosom)* Temazepam (Restoril)* Triazolam (Halcion)* Eszopiclone (Lunesta) Zolpidem (Ambien) Zaleplon (Sonata)
Dosage Range
Half-Life
15-30 mg 1.0-2.0 mg 7.5-30 mg 0.125-0.25 mg 1-3 mg 5-10 mg 5-10 mg
50-100 hours 10-20 hours 4-18 hours 2-3 hours 5.5-8 hours 2-3 hours 1-2 hours
Benzodiazepines.
the amount of wakefulness after sleep onset, and in increasing total sleep time in patients with primary insomnia.29 However, when a meta-analysis of benzodiazepines alone was performed, the absolute size of this effect for sleep onset latency was not dramatic: a reduction of 4.2 minutes when assessed by polysomnography and of 14.3 minutes by self-report. On the other hand, total sleep time was increased by a mean of 61.8 minutes.30 The majority of these efficacy data come from shortduration studies. For instance, the median duration of the studies in the benzodiazepine and BzRA meta-analysis was 7 days; the common duration of insomnia complaints, in contrast, is often months to years. Studies addressing the longer term efficacy of these medications in continuous and intermittent use have been performed. Eszopiclone, the S-isomer of the commonly prescribed hypnotic zopiclone, has been shown to produce persistent benefits for sleep onset latency, wakefulness after sleep onset, total sleep time, and daytime functioning for 6 months of nightly use in comparison with placebo in patients with primary insomnia.31
PERIODIC LIMB MOVEMENT DISORDER PLMSs are commonly recorded movements during sleep consisting of repetitive dorsiflexion of the foot and/or lower leg. Movements are generally subtle and may not be recognized by a bed partner, although in more severe forms, they are more obvious. PLMS may or may not be associated with arousals from sleep, and indices of the number of movements with and without arousal per hour of sleep are derived. The term periodic limb movement of sleep is derived from the strict periodicity of movements, which occur at 15- to 30-second intervals during sleep. Movements are roughly 2 seconds in duration (Fig. 15–3). When a sleep complaint occurs in the presence of PLMS, in the absence of other known causes of sleep disruption, a diagnosis of periodic limb movement disorder is given. PLMSs are commonly recorded on overnight polysomnography, and population estimates of the prevalence of PLMSs exceeding five per hour range from 11% to 58%.32 PLMSs are more commonly recorded in elderly persons, in patients taking antidepressants, and in a number of medical conditions (end-stage renal disease, congestive heart failure, diabetes) and neurological or sleep disorders (obstructive sleep apnea, narcolepsy, Parkinson’s disease, multiple sclerosis). Although approximately 80% of individuals with RLS demonstrate PLMS, only a small proportion of those with PLMS describe symptoms
190
Section
II
Sleep and Sleep Disorders
EEG
Chin EMG Heart rate R.A.T. EMG L.A.T. EMG
30 sec. ■
Figure 15–3. Periodic limb movements of sleep (PLMS) as recorded on polysomnography. EEG, electroencephalogram; EMG, electromyogram; L.A.T., left anterior tibialis; R.A.T., right anterior tibialis.
of RLS. Controversy exists regarding the clinical importance of PLMS for sleep quality or daytime alertness; some studies show a lack of correlation between PLMS index and subjective or objective sleep quality or daytime sleepiness, and others show some mild associations.33 There is substantial evidence that PLMSs are associated with dopaminergic dysregulation at either spinal or higher central nervous system levels. Dopaminergic antagonists can produce PLMS,34 whereas dopaminergic agonists are extremely effective in reducing PLMS.35 Disorders characterized by dopaminergic deficiency (e.g., narcolepsy, rapid eye movement [REM] sleep behavior disorder [RBD]) are accompanied by high rates of PLMS. Functional imaging of the brain has demonstrated small but consistent reductions in dopaminergic function in PLMS. Finally, dopaminergic metabolites have been observed to be correlated with the number of PLMSs.36 The presence of PLMS in quadriplegic patients suggests that the motor programs for these movements exist in the spinal cord and are somehow disinhibited in patients with excessive movements during sleep. Clinically, periodic limb movement disorder should be suspected when an individual (or his or her bed partner) reports kicking or jerking of his or her legs during sleep and has a complaint of sleep disruption or excess daytime sleepiness that cannot be accounted for by another cause. Polysomnography is necessary to make the diagnosis of periodic limb movement disorder, both to document the PLMS but also to exclude other causes of repetitive leg movements—most prominently, obstructive sleep apnea. The differential diagnosis of nocturnal leg movements in the sleep period includes RLS (in which leg restlessness is reported before sleep onset), anxiety (in which leg movements are observed during wakefulness, not sleep), nocturnal seizures (which produce abnormal EEG changes), obstructive sleep apnea (in which characteristic respiratory abnormalities are observed), or RBD (in which movements are dream enactments, occur during REM sleep, and are not periodic). Treatment of periodic limb movement disorder begins with an accurate diagnosis and proceeds to consideration of eliminating potential precipitating or exacerbating agents (e.g., antidepressants). PLMS can be dramatically reduced with the addition of dopaminergic agents, at least within the context of RLS. However, there is some suggestion that EEG arousals may persist even with elimination of the manifest motor activity. For
this reason, coadministration of substitution of a benzodiazepine has also been advocated. Although studies of triazolam in patients with PLMS did not reveal a reduction in the periodic limb movement index, improvements in leg movements associated with arousal, sleep architecture, and daytime alertness were all demonstrated,37 even after 12 weeks of nightly use.38 Use of clonazepam in small numbers of patients was effective in reducing the number of PLMs, as well as improving scores on sleep continuity measures.39
EXCESS DAYTIME SLEEPINESS Excess daytime sleepiness has numerous causes. Clinical diagnostic algorithms proceed from a determination of sleep quantity to an evaluation of sleep quality and then to assessment of potential contributors to an intrinsic excess sleep drive. Insufficient sleep is the most common cause of excess daytime sleepiness among both adults and children. Because of its pervasiveness, careful attention to sleep times is required in individuals with a description of excess daytime sleepiness. Sleep quantity is determined by history, sleep logs, and if necessary, polysomnography. Any cause of poor sleep quality can produce excess daytime sleepiness, although the most common are sleep apnea, neurological, pulmonary and cardiac diseases, and environmental sleep disruption. The underlying cause of sleep disruption is commonly discernible from the history and/or physical examination, although polysomnography may be required for some disorders (e.g., sleep apnea). Finally, if excessive daytime sleepiness is present, and if sleep quantity and quality appear to be sufficient, a primary disorder of sleepiness or a medication effect should be suspected. These are discussed as follows.
Excess Daytime Sleepiness as a Result of Medical and Neurological Diseases Multiple neurological diseases can cause sleepiness: either by disrupting the mechanisms involved in sleep homeostasis or by simply disrupting nighttime sleep. For example, cerebral traumatic injury or thalamic lesions (such as bilateral medial thalamic infarcts) can impair the central mechanisms of sleep-wake regulation, while pain from diabetic neuropathy of multiple
chapter 15 primary disorders of sleep sclerosis can cause sleep fragmentation and thus result in excessive sleepiness. Some specific examples are described as follows.
Stroke Common Comorbid Conditions One common cause of excessive sleepiness in the general population is sleep apnea. This condition is also quite common in patients with stroke.40 Symptoms of sleepiness and snoring may in fact be associated with higher risk of first-ever stroke.41,42 Prevalence after stroke may be even higher: Harbison and associates42 reported that up to 94% of patients had a respiratory disturbance index of 10 or above on polysomnography, performed in the 2 weeks after a stroke. Patients more likely to have more severe sleep apnea were older and more likely to have lacunar infarcts and greater prestroke disability. Sleepdisordered breathing improved over time, but about 72% of the patients had clinically important sleep apnea 6 weeks later. As good-quality sleep may improve recovery from illness, treatment of sleep apnea can also hasten recovery from stroke. Patients with sleep apnea may have more residual symptoms of stroke after rehabilitation,43 whereas treatment of sleep apnea, when present in a patient with stroke, may hasten the rehabilitation process.44
Role of Specific Vascular Lesions Sleepiness after stroke is common.45-47 Hemispheric stroke can result in insomnia, hypersomnia, or sleep disruption, but most EEG changes are transient.46,48,49 There can be alterations of sleep architecture, including REM sleep, especially within the first 3 days after the event.49 Increased slow-wave activity may be seen in the contralateral hemisphere.46 Consolidated sleep and high sleep efficiency are likely to herald a good clinical outcome.48,49 Rare alterations of sleep architecture include REM sleep abnormalities. For example, there are reports of dream loss with bilateral posterior cerebral artery infarcts50 and lesions of the pontine tegmentum can lead to absence of REM sleep,51 as well as to hypersomnia.52 Additional sleep disruption in patients who have had a stroke may be secondary to bulbar involvement, as well as to discomfort from pain and spasticity. Therefore, treatment is generally targeted at the cause and can include continuous positive airway pressure, bilevel positive airway pressure, or conservative measures for treatment of sleep apnea, if present. Treatment of spasticity can include higher doses of muscle relaxants (typically baclofen), especially in the evening, inasmuch as most have sedating properties.
Multiple Sclerosis Patients with multiple sclerosis frequently complain of sleepiness, fatigue, and cognitive problems, as well as sleep disruption. Common causes for impairment of sleep and resulting sleepiness are described as follows.
Impaired Sleep as a Result of Pain, Spasticity, or Nocturia Spasticity may be associated with nocturnal pain and consequently sleep fragmentation. Muscle relaxants can effectively
191
improve sleep. Because urinary symptoms are common in multiple sclerosis, nocturia can also fragment sleep. Treatment with desmopressin may be effective in reducing the nocturnal voids by 31% to 54% and, in one study, increased the initial sleep period or mean maximum period of uninterrupted sleep by approximately 2 hours.53
Associated Psychiatric Disorders Many patients with multiple sclerosis have associated depressive or other psychiatric symptoms.54-56 These symptoms may vary in intensity, depending on the short-term risk of disability or wheelchair dependence.56 Because both depression and anxiety are associated with sleep disturbance, they can contribute to sleep impairments in patients with multiple sclerosis.
Immunological Factors Immunological factors, which are involved in the pathogenesis of multiple sclerosis, may also have somnogenic effects. These include interleukin-1,57 which is known to be associated with sleepiness. Fatigue may be more prominent in patients who have markers of immune activation, including inductors of lymphocyte B cells, increase in helper T cells, interleukin-2 receptor cells, or other markers.54
Impaired Sleep-Wake Regulation as a Result of Plaques Because demyelination can involve various pathways involved in the regulation of sleep and wakefulness, it would be logical to expect an independent effect of the focal dysfunction, depending on the location of the multiple sclerosis plaques. Indeed, case reports have suggested some such effects. For example, Oka and colleagues58 reported signs of narcolepsy associated with multiple sclerosis. Plazzi and Montagna59 reported RBD as a first symptom of multiple sclerosis. However, plaque location and burden are variable, and most sleep problems are multifactorial.
Medication Effect Most muscle relaxants have sedating properties. Although their use at night improves sleep continuity, daytime use may be associated with undesirable sleepiness. This effect is more pronounced at the beginning of treatment, and some tolerance may develop over time. Pain management, when necessary, may lead to further sedation. Steroid treatment may be associated with decreased slow-wave sleep, increased sleep onset latency, and increased wakefulness after sleep onset.60 Certain sleep architecture abnormalities, resembling the ones seen in depression (shorter REM latency and increase in REM density), have also been reported.61 Interferon treatment may also be associated with increased somnolence.62,63
Treatment In most cases, treatment should be targeted to the cause of sleep disruption. For example, treatment of the urinary frequency will probably improve sleep continuity as a result of fewer episodes of nocturia. Relief of spasticity and pain with gabapentin or baclofen may improve sleep as well.64 Most muscle relaxants can help additionally with sleep onset and continuity through their sedating properties.
192
Section
II
Sleep and Sleep Disorders
When sleepiness continues despite optimal treatment of the underlying symptoms, the addition of modafinil can safely and effectively improve vigilance.65,66
Parkinson’s Disease Patients with Parkinson’s disease frequently report sleepiness. This is reported on standardized instruments67,68 and also confirmed in standardized laboratory tests of sleepiness (i.e., a multiple sleep latency test), as well as a maintenance of wakefulness test. These impairments are correlated with poor sleep.69 Sleepiness should be distinguished from fatigue, which is also prevalent among patients with Parkinson’s disease.70,71 Longer disease duration, as well as anticholinergic medications, are associated with especially impaired sleep.72
Sleep Disruption from Parkinson’s Disease Itself One cause of sleep fragmentation in Parkinson’s disease is the degeneration of dopaminergic neurons in the central nervous system. Because dopamine is involved in the regulation of the sleep-wake cycle, dopamine depletion, as well as dopaminergic stimulation in a dopamine-depleted state, may lead to sleepiness. In addition, alterations of levels of the hypothalamic peptide hypocretin, which have been reported to be extremely low or absent in narcolepsy, have been implicated in the pathogenesis of sleepiness in Parkinson’s disease, because hypocretin may have a role in the dopamine release mechanism.73,74 In addition, reports have implicated genetic polymorphism in D2 receptors in sleep attacks.75 Sleep in patients with Parkinson’s disease can be additionally disrupted by pathological motor phenomena. Patients may have nocturnal akinesia, tremor and rigidity, freezing, and motor restlessness, as well as motor behavior during REM sleep or PLMS. Other causes include nocturia, which is common in these patients.
Vivid Dreams Vivid dreams are another potential cause of sleep disruption. This phenomenon may be more prevalent with the use of dopamine agonists and may be more likely to occur in patients who also have hallucinations. In a 6-year prospective study, patients with hallucinations had similar sleep patterns as did those without hallucinations, but vivid dreams were associated with significantly poorer sleep.76
Effects of Medications Sleepiness, as well as arousal, can be increased by levodopa, as well as by dopamine agonists. For example, irresistible sleep attacks (“sudden onset of sleep”) have been reported with all of the dopamine agonists, although some patients experience insomnia. Medications that have stimulant metabolites (selegiline, amantadine) may lead to sleep fragmentation.
RBD Sleep Behavior Disorder RBD is common in patients with Parkinson’s disease. For example, Schenck and associates77 reported that 38% of the patients with Parkinson’s disease develop RBD. Possible causes in both disorders include loss of striatal dopamine transporters78 and resulting abnormal muscle tone, including loss of REM atonia.
Treatment The first step of treatment is control of sleep-disrupting factors. In patients with refractory sleepiness, modafinil can be helpful to control residual sleepiness with minimal side effects.79 Counseling about driving may be appropriate as well, because episodes of irresistible sleepiness may occur, not preceded by obvious warning.
Other Neurological Diseases Multisystem Atrophy Multisystem atrophy may be associated with a high prevalence of apnea, mainly central.80,81 In addition, patients may have laryngeal stridor, which may lead to vocal cord paralysis and risk for sudden death.82-84 Depending on the clinical circumstances, the patients may require assisted ventilation or surgical procedures.
Dystonia Sleep alterations with cervical dystonia are correlated with the severity of the disease, especially frequency of spasms.85,86 Spasms can persist in sleep even in the absence of EEG arousals but become progressively less severe with sleep depth.
Cerebellar Atrophy Among patients with spinocerebellar ataxia, sleep complaints seem most common in spinocerebellar ataxia type 3.87 Contributing factors include higher frequencies of neuropathy and RLS with this form. Thus, treatment includes pain relief in the case of neuropathy and dopamine agonists or gabapentin if RLS is present.
Poliomyelitis and Postpolio Syndrome Among patients with postpolio syndrome, the incidence of both obstructive and central apneas during sleep is higher than that in the general population. These disturbances are more prominent in patients who have had respiratory involvement during the initial illness.88 Thus, treatment is targeted at treatment of the sleep breathing disorder.
Cervical Myelopathy Patients with cervical myelopathy have a higher prevalence of respiratory disturbances during sleep. In a study of 50 randomly selected tetraplegic patients, 55% of the men and 20% of the women had a respiratory disturbance index of 5 or higher.89 Mid- and low cervical lesions may also lead to delayed apneas, and these can sometimes be very severe.90 In an isolated case, anterior spinal artery syndrome led to continuous central apneas during sleep.91 Additional problems may include bradycardia, with or without hypotension.91 Thus, treatment should involve careful evaluation and treatment of sleep breathing disturbance (e.g., with continuous positive airway pressure). Other causes of sleep impairment in these patients involve neurological deficits, pain, spasticity, and injury to the pathways involved in melatonin secretion. A study of patients with tetraplegia caused by cervical and upper thoracic injuries demonstrated near absence of melatonin in the patients with cervical lesions.92 To date, however, there are no reports of successful treatment with exogenous melatonin in these patients.
chapter 15 primary disorders of sleep Dementia Dementia can be the result of various conditions, including neurodegenerative, vascular, infectious, and other causes. The most common form is Alzheimer’s disease. Patients may have reduced sleep efficiency and increased number of arousals, and the severity of these findings tends to parallel that of the dementia itself. Abnormalities of sleep architecture, such as increased REM latency and decreased slow-wave sleep, have also been reported, but these findings are less consistent. Circadian rhythm abnormalities are also seen, discussed in more detail in the section “Circadian Rhythm Disorders.” Treatment of sleep disturbances is challenging in patients with dementia. Because poor sleep can negatively affect cognition, evaluation early in the course for common sleep disorders, such as sleep apnea and RLS, is warranted. As dementia patients may have more severe cognitive impairments, as well as paradoxical agitation with benzodiazepines, nonbenzodiazepine hypnotics are generally preferred.
Epilepsy Effects of Seizures on Sleep Sleepiness is common among patients with epilepsy. As in other neurological conditions, sleepiness is multifactorial, secondary to the effects of sleep fragmentation from the disorder itself, as well as from effects of antiepileptic medications, most of which have sedative properties (Table 15–4). Nocturnal seizures can be associated with sleep fragmentation, and arousal or awakening may occur before or after the event. Frequently, temporal lobe seizures occur after awakening, and frontal lobe seizures occur during sleep. However, the causal relationship is still debated. Sleep is also disrupted in patients with localized epilepsy, independently from any seizures. Patients with temporal lobe epilepsy (TLE) report multiple awakenings, even on the nights when they have not had a seizure.
Diurnal and nocturnal variations in seizure rate have led to examinations of the relationship of seizures to sleep. In two prospective studies, researchers examined the distribution of seizures in relation to sleep stage and depth. Both Herman and colleagues in 200193 and Minecan and coworkers in 200294 reported that of all sleep stages, non-REM sleep, especially stage 2 sleep, is associated with the highest proportion of seizures. T A B L E 15–4. Medications Associated with Sleepiness and Insomnia
Anticonvulsants Dopamine agonists or precursors Interferons SSRIs
Occurrence of seizures during sleep (versus wakefulness) may depend on epileptogenic region. A study of intracranial recordings in patients with TLE revealed a tendency toward arousal before a seizure in almost all of the patients.95 However, patients with frontal lobe epilepsy tended to have seizures during sleep, and these were usually not associated with abrupt arousal from sleep.93,96
Effects of Sleep on Interictal Discharges Interictal discharges distinguish patients with epilepsy from healthy individuals. Interictal discharges are not evenly distributed through all sleep stages. Multiple studies have reported a higher rate of interictal discharges during stages 3 and 4 sleep than in stages 1 and 2 sleep in patients with TLE97,98 and those with generalized epilepsy.99,100 The effect of sleep stage on interictal discharges in patients with TLE was robust: most patients had a higher interictal discharge rate in deep non-REM sleep, and this rate was up to nine times higher than the interictal discharge rate during wakefulness. A caveat to this interpretation is that sleep preferentially occurs at specific circadian times; therefore, it is possible that these sleep-related effects are at least partially caused by an underlying circadian rhythm in interictal discharge propensity.
Seizures and Circadian Rhythm Pavlova and associates101 analyzed data from 26 consecutive patients with confirmed TLE or other localization-related epilepsy. To test for any systematic day/night pattern in seizure frequency, they divided the 24-hour period into six 4-hour “bins” and compared the proportion of seizures across bins. In the TLE group, there was a clear peak in the time of occurrence of seizures: 50% occurred between the hours of 15:00 and 19:00 (see Fig. 15–1). In the patients with other localization-related epilepsies, there was a peak in seizure frequency between the hours of 19:00 and 23:00.
NARCOLEPSY
Effects of Sleep on Seizures
Medications Associated with Sleepiness
193
Medications Associated with Insomnia β Blockers Steroids SSRIs Antimigraine medications (especially ones containing caffeine)
Tricyclic antidepressants Opiates SSRI, selective serotonin reuptake inhibitor.
Although narcolepsy is relatively rare, its features are so distinctive that it remains the most commonly discussed and researched of the primary disorders of sleepiness. Dramatic advances in the biology of this disorder have furthered the understanding of the disease process, as well as of sleep-wake regulation. Narcolepsy is characterized by excess daytime sleepiness and dysregulation of REM processes. The first of these is assessed clinically and verified by the multiple sleep latency test, in which the patient is allowed five nap opportunities, each 2 hours apart, beginning 2 hours after awakening. An average latency to sleep onset of less than 5 minutes across the five naps is indicative of pathological daytime sleepiness. The REM dysregulation is verified by the appearance of more than one REM period during the multiple sleep latency test nap, with or without an early appearance of REM during the overnight polysomnography. Ironically, most narcoleptic patients also demonstrate poor nocturnal sleep quality, describing frequent nighttime awakenings. Clinically, REM dysregulation in narcolepsy is characterized by the inappropriate appearance of the REM phenomena muscle paralysis and dreams during wakefulness or at the sleep-wake transition. Cataplexy is a sudden onset of muscle atonia in the antigravity and facial muscles, resulting in falls,
194
Section
II
Sleep and Sleep Disorders
difficulty holding objects, or twitching of agonist and antagonist muscles in these areas. Cataplexy is usually stimulated by laughter, telling a joke, anger, surprise, or other emotional processes. Sleep paralysis is the appearance of REM atonia in wakefulness, leading to brief (seconds to minutes), usually frightening inability to move voluntary musculature in the presence of full alertness, either on awakening or at the transition from wakefulness to sleep. Concomitant paralysis of the accessory muscles of inspiration may result in the sensations of dyspnea. Hypnogogic (at sleep onset) or hypnopompic (at awakening) hallucinations is the appearance of the hallucinatory phenomena of dreams during wakefulness. Usually these are fragmentary and brief (hearing the telephone or one’s name being called) or seeing a shadow of a person, although in rare cases they may be more elaborate. Although these REM phenomena are occasionally reported in isolation by individuals without narcolepsy, they are common, and frequently observed as a group, in this disorder. Narcolepsy is currently classified as existing with or without cataplexy. The exact percentage of individuals with the excess daytime sleepiness of narcolepsy who also have cataplexy is unclear but is thought to be 50% to 80% of cases. Narcolepsy is present in 0.05% of adults. Its onset occurs most commonly in the second decade of life, but initial appearance of symptoms in the 30s is not uncommon. The mean time between symptom onset and diagnosis is frequently prolonged, because of the misdiagnosis of narcolepsy as a psychiatric disorder or a manifestation of laziness. Narcolepsy is a chronic but nonprogressive disorder. However, some individuals experience the onset of cataplexy a number of years after the onset of daytime sleepiness. Equal numbers of men and women are affected, and no clear ethnic variations have been reported. Major progress in the understanding of the pathophysiology of narcolepsy has been made since the mid-1990s, stimulated by findings derived from molecular biology. A mutation in the gene that codes for the receptor for the hypothalamic peptide hypocretin was determined to be responsible for the Doberman pinscher model of narcolepsy.102 At the same time, Chemelli and associates103 found that when the gene for the same peptide (which they called orexin) was knocked out in mice, the mice exhibited behavioral states consistent with narcolepsy. In humans, the dramatic reduction in hypothalamic neurons responsible for the production of hypocretin (orexin)104 and the absence of this ligand in the cerebrospinal fluid105 of narcoleptic patients have confirmed the importance of hypocretin (orexin) in human narcolepsy with cataplexy. The excess expression of the specific human leukocyte antigen genotype DQB1*0602 in individuals with narcolepsy (85% of narcoleptics versus 25% of the general population) is suggestive of an immunological etiology of narcolepsy. However, neither immunological abnormalities nor antigenic targets have been identified in human narcolepsy. Treatment of narcolepsy is directed independently for the daytime sleepiness and REM dysregulation (Table 15–5). It is essential to stress the importance of adequate nocturnal sleep and the value of daytime napping, if feasible, as means of minimizing excess daytime sleepiness in narcolepsy. Stimulant medications, which have been available since the 1950s, have been the traditional mainstay of narcolepsy pharmacological treatment. These medications both release the catecholamines norepinephrine and dopamine and block their reuptake into their releasing neurons, enhancing their effects. They are effec-
T A B L E 15–5. Medications Used for the Treatment of Narcolepsy Medication Modafinil (Provigil) Dextroamphetamine (Dexedrine and others) Methylphenidate (Ritalin and others)
T1/2 (Hours)
Tmax
FDA Schedule
15 5-10
2-4 3
IV II
3
1.9
II
FDA, U.S. Food and Drug Administration; T1/2, half-life; Tmax, time to maximal serum concentration.
tive in promoting wakefulness in narcolepsy, allowing a more normal level of professional and social functioning. In addition, controlled-release preparations of methylphenidate and amphetamines have been developed, allowing once- to twiceper-day dosing. However, there are persistent concerns regarding their potential for abuse and the not uncommon side effects of headache, anorexia, mood alterations, and blood pressure and pulse elevations. First-line treatment of excess daytime sleepiness has become modafinil, a long-acting agent that only partially acts on the dopaminergic system, and thus has substantially less risk of abuse, and that has fewer sympathomimetic side effects. Treatment of the REM dysregulation–related symptoms (principally cataplexy) is achieved with REM suppressants. Tricyclic antidepressants, which once had a primary role in treatment, have been replaced by the better tolerated and safer selective serotonin reuptake inhibitors (Tables 15–6 and 15–7). Both of these classes of medications suppress cataplexy, sleep paralysis, and hynogogic hallucinations. Cataplexy, which does not respond to these agents, may be successfully treated with γ-hydroxybutyrate, a short-acting sedating medication that is given twice during the night and has demonstrated benefit in reducing daytime cataplectic attacks, as well as daytime sleepiness.
T A B L E 15–6. Overview of Parasomnias Non-REM Parasomnias
REM-Related Parasomnias
Stage of arousal Time of night EEG with event
II, III, IV First third N.A.
EMG with event Relative unresponsiveness during event Autonomic activity
Low Yes
REM Any time Characteristic of REM High, variable Yes
Amnesia Confusion after episode Family history of parasomnias
Low (confusional arousal) High (sleep terror) Yes Yes Yes
High No No No
EEG, electroencephalography; EMG, electromyography; N.A., not applicable; REM, rapid eye movement.
chapter 15 primary disorders of sleep T A B L E 15–7. Pharmacological Treatment of Parasomnias Drug
Dosage
Non-REM Parasomnias Triazolam Zolpidem Lorazepam Clonazepam
0.125-0.5 mg 5-10 mg 1-2 mg 0.5-2.0 mg
REM-Related Parasomnias Clonazepam Lorazepam Melatonin Pramipexole
0.5-2.0 mg 1.0-2.0 mg 3-15 mg 0.5-1.0 mg
195
toxic, or structural abnormalities. Electroencephalograms can be characterized by fast (14- to 16-Hz), nonreactive background activity.111 Plasma and cerebrospinal fluid may show a marked increase in a benzodiazepine-like endogenous substance, endozepine-4.111,112 Flumazenil, a benzodiazepine receptor antagonist, may promptly resolve the syndrome.
CIRCADIAN RHYTHM DISORDERS
REM, rapid eye movement.
IDIOPATHIC HYPERSOMNIA A number of less common causes of excess daytime sleepiness are recognized. Principal among these is idiopathic hypersomnolence; patients experience the excess daytime sleepiness of narcolepsy but do not have any of the REM-related symptoms. Individuals report normal nocturnal sleep (in contrast to narcolepsy) but severe difficulty arousing from sleep in the morning or from daytime naps. These naps are longer than the ones in patients with narcolepsy and may take 2 to 3 hours. Even after these long naps, patients are only partially refreshed. Diagnosis is made by polysomnography and results of the multiple sleep latency test. Overnight polysomnography demonstrates high sleep efficiency, and the multiple sleep latency test reveals pathologically shortened sleep latency (similar to narcolepsy), but without the appearance of REM periods during daytime naps. Because medical and neurological disorders (described previously) can lead to excess daytime sleepiness, this is generally a diagnosis of exclusion. As suggested by its name, the cause of idiopathic hypersomnolence is unknown. Treatment is targeted to symptomatic relief of the daytime somnolence. Modafinil (at dosages of 200 to 400 mg/day) can be used, as can conventional stimulants (e.g., amphetamines, methylphenidate).
KLEINE-LEVIN SYNDROME The Kleine-Levin syndrome is characterized by periodic, sudden-onset episodes of hypersomnia, compulsive hyperphagia, and hypersexuality, lasting from a few days to a few weeks, with complete remission in between. Various other behavioral disturbances may occur during the episodes. The cause and pathogenesis of Kleine-Levin syndrome remain unknown. It is more common in men, but female patients have been described as well, and the ratio is probably 4:1.106-108 When seen in young women, it can have a catamenial pattern.108 Diagnosis is made on the presence of the classic triad after other causes of excessive sleepiness are ruled out. Treatment can include stimulants or modafinil for hypersomnolence and possibly lithium salts.109,110
IDIOPATHIC RECURRENT STUPOR Idiopathic recurring stupor is a syndrome of spontaneous stupor or coma that is not associated with known metabolic,
Circadian Rhythm Effects on Normal and Abnormal Neurophysiological Functions Normal neurophysiological functions are affected by the circadian system independently of sleep or wakefulness state and time awake. Subjective alertness, cognitive performance, and short-term memory are lowest close to the time of the temperature minimum, or the “biological night” (e.g., see Johnson et al,74 and Dijk et al113). Mood in healthy subjects is also modulated by a nonadditive interaction between the sleep-wake cycle and the circadian phase, and this modulation may be implicated in mood disorders.114 Multiple neurological conditions have a circadian pattern. Patients with various forms of dementia may have transient changes in mental status, including agitation, hallucinations, and delusions. These are especially prominent in the evening hours, and this situation thus has been termed sundowning. Patients with epilepsy may also have specific exacerbations related to circadian rhythms (see “Epilepsy” section).
Disorders of the Circadian Rhythm Delayed Sleep Phase Syndrome Delayed sleep phase syndrome (DSPS) is a disorder of the phase relationships between the desired sleep times and the circadian system manifesting as a tendency to fall asleep much later than desired and awakening later than the desired time. As a result, these patients frequently come to medical attention with complaints of insomnia. DSPS is an especially frequent cause of insomnia in the young adult.115
Diagnosis The International Classification of Sleep Disorders1 has established the following “minimal criteria” for diagnosis: (1) The patient is unable to initiate sleep at the desired time and difficulty awakening; (2) timing of the habitual sleep episode is delayed (late); (3) symptoms are present for 1 month or more; (4) when constraints permit (e.g., when not working or attending classes), the patient opts for delayed timing of the major sleep episode, which is believed to be of good quality and quantity, and can awaken from this sleep episode without difficulty and remains on this delayed sleep-wake schedule without difficulty; and (5) subjective sleep data (e.g., sleep-wake diary) for 2 weeks or more verify the presence of the delayed, habitual sleep-wake schedule. In most cases, the diagnosis can be made from the history, in addition to a sleep-wake diary. In some instances, documenting sleep-wake times through wrist actigraphy can be helpful as well.
196
Section
II
Sleep and Sleep Disorders
Treatment
Non–24-Hour Rhythm Disturbance
The most powerful factors that entrain the circadian rhythm are (1) light, which provides information about the time of the “day,” and (2) melatonin, which provides information about the time of “night.” On the basis of these, several major approaches have been proposed:
Light is the primary stimulus that synchronizes the endogenous circadian rhythm with the environmental conditions. It is perceived by the retinal cells, and the signal is transmitted to the circadian pacemaker, the suprachiasmatic nucleus, via the retinohypothalamic tract. Because the circadian period tends to be close to but slightly longer than 24 hours, daily exposure to light ensures that sleep occurs during the night time for most people. Impairment or absence of light perception can lead to disruption or lack of synchronization between the circadian sleep promoting mechanisms and the scheduled time to sleep. This can occur in blind people. Klein and colleagues129 described such a cause of insomnia in a blind person, confirming that sleep was most likely to occur close to the subject’s temperature minimum.
1. Chronotherapy was proposed by Czeisler and colleagues,116 on the basis of the assumption that the patient’s schedule cannot be advanced. Thus, the patient is advised to delay his or her wake sleep times by 3 hours every 24 hours until the desired sleep time is reached. 2. Phototherapy (light treatment) is considered useful because bright light can shift the “biological night” of individuals (as measured by major physiological parameters, such as core body temperature) in experimental conditions.117-120 The rapidity and degree of change depend on the intensity of the stimulus and its timing in relation to the subject’s core body temperature minimum at the start of the treatment. Empirical use of bright light can be used for treatment of DSPS, administered in the hours between 6:00 and 9:00 AM at 2000 to 2500 lux with reasonable success. The optimal duration of therapy is not established, although a treatment for 2 weeks for 2 hours every morning has been reported as successful.121,122 3. Melatonin can be used to shift the circadian rhythm and can be a reasonable alternative treatment. Administration of 5 mg at 10:00 P.M. has been reported successful in two studies123,124 and well tolerated. Unlike the use of some hypnotics, treatment is not associated with a “hangover effect,” but some patients have reported morning fatigue.124 Because the effects on the reproductive system development are not fully known, caution has been advised for younger patients. Other reported treatment options include vitamin B12 supplementation. In a two-patient report of an adolescent who did not have a vitamin B12 deficiency, administration of high-doses vitamin B12 was successful. However, no randomized studies have been performed. None of these approaches has been compared head to head, and thus none is established as superior to the others. In additional, patients vary widely with regard to compliance, and thus any one of these methods or a combination can be used, depending on the clinical circumstances.
Advanced Sleep Phase Syndrome In advanced sleep phase syndrome, as in DSPS, the “biological night” of the patient is believed to be “locked” in an adverse time in relation to the desired bedtime but occurs hours earlier rather than later. This disturbance is more frequent among older individuals. Occasional familial forms exist as well.125-127 Like that of DSPS, diagnosis is based on clinical history and can be confirmed by sleep diary or objective measures, such as wrist actigraphy. Treatment options are similar to those for DSPS. Phototherapy, as evening bright light, at 2000 to 2500 lux in the hours between 8:00 and 11:00 P.M. for 2 to 3 hours, can be used.123 However, the effectiveness of bright light has been questioned in one study.128
Jet Lag A similar desynchronization between the environmental night and the “biological night” occurs during travel across time zones in a short period of time; this desynchronization is commonly known as jet lag. Like non–24-hour rhythm disturbance, it can manifest as insomnia, difficulty with concentration, or sleepiness and could be logically expected to modify disorders that have a circadian pattern. Typically, adjustment to eastbound travel is found to be more difficult. Treatment can include phase advance before travel,130,131 use of bright light, or use of melatonin.132,133
PARASOMNIAS The term parasomnia is derived from the Latin para, meaning “next to,” and somnus, referring to sleep. In the International Classification of Sleep Disorders, 2nd edition, parasomnias are defined as “undesirable physical or experiential events that accompany sleep.”1 Parasomnias are traditionally divided into those arising from non-REM sleep (also known as confusional arousals) and those occurring during REM sleep. These two types of parasomnias can often be distinguished by their distinctive time of night occurrence, type of mentation during the event, mental status on awakening, duration, degree of amnesia for the event, and associated autonomic activation. Thus, with a few simple questions, parasomnias can often be correctly classified by the clinician.
Non-REM Parasomnias The understanding of non-REM parasomnias is based on the concept that arousal from sleep is not an all-or-none phenomenon but rather a continuum of alertness, judgment, and control over behavior. Behaviors or affective expression can occur during full or partial sleep states, which are at least partially divorced from full awareness, both during the event and on awakening. Most commonly, such behaviors are dissociated motor activities (walking, eating, sexual behavior) or emotional responses (fear, anger, sexual excitement).134 They are distinct from waking behavior in that complex mentation is usually not present, feedback from the environment is usually given less
chapter 15 primary disorders of sleep salience, and sound judgment is usually not present. It is unclear to what extent these behaviors or emotional states are related to waking motivation, psychological state, or psychopathology. It is clear that these behaviors run in families.135 Phenotypically, they share many features: They are commonly brief, are more frequently expressed in children, are associated with amnesia, and occur in the first 1 to 2 hours of sleep, usually arising during slow-wave sleep. Non-REM parasomnias are best conceptualized along a continuum of emotional/motoric/ autonomic arousal, in which confusional arousals have the least arousal and sleep terrors the most. Confusional arousals are usually brief, simple, motor behaviors, which usually occur without substantial affective expression. Mental confusion with automatic behavior, indistinct speech, and relative unresponsiveness to the environment are hallmarks of a confusional arousal.136 Sitting up in bed with simple vocalization or picking at bedclothes are common examples. If interrupted by family members, responses may be absent, incomplete, or inappropriate. Sleepwalking involves more elaborate behavior than simple confusional arousals, but it forms a continuum with the latter. Simple motivations without substantial emotional involvement, such as attempts to use the bathroom, go to the kitchen, or, in some cases, leave the home, are usually pursued. Although the walker’s eyes are open, behavior may be clumsy.137,138 Dreaming is usually not present, and individuals (if awakened) report only simple mentation. As in confusional arousals, sleepwalkers usually return to sleep, but if aroused by family members or as a result of their inappropriate behavior, sleep inertia may be present. In rare cases, individuals may become agitated if sleepwalking episodes are interrupted. Sleep terrors have many of the properties of other non-REM parasomnias but are characterized by more intense autonomic, motor, and affective expression (and experience). In children, sleep terrors are classically heralded by a piercing scream, with extreme fear, crying, and inconsolability.139 In adults, agitation is common, frequently with the belief that there is an imminent threat, with the requirement of escape or defense.140 For this reason, sleep terror sufferers may cause injury to themselves, to others, or to property in their highly agitated state. As in sleepwalking, dreaming is usually not reported, but simple thoughts are present (“The room is on fire” or “I am being attacked”), which can be difficult to dispel, even after the sufferer has awakened. They may incorporate an individual into the threatening scenario if they are interfered with, potentially harming that individual. For this reason, it is recommended that individuals experiencing a sleep terror be gently redirected in an attempt to raise their level of consciousness. Non-REM parasomnia variants have also been identified in adults: excessive sleep inertia (or “sleep drunkenness”),141 abnormal sleep-related sexual behavior (“sexsomnia”),142 and sleep-related violence.143 Amnesia for non-REM parasomnias is often so dense that without a bed partner’s or parent’s report, or evidence from the episode, these episodes might go unnoticed. Epidemiological information is therefore unreliable. In view of this caveat, approximately 10% to 20% of children and 2% to 5% of adults report a history of confusional arousals.136 Sleepwalking occurs in 10% to 20% of children and 1% to 4% of adults.136,144 Sleep terrors are less common than sleepwalking; approximately 5% of children and 1% to 2% of adults report a history of such
197
events.136 In approximately 80% of adults with sleepwalking, this parasomnia is a continuation of a childhood behavior, although many such persons do not come to medical attention until their 20s or 30s. There is a wide range of sleepwalking frequency; most sleepwalkers present with only occasional episodes, although those who frequently sleepwalk are the ones who usually come to medical attention. The expression of all non-REM parasomnias appears to depend on a genetic predisposition combined with a precipitating event, which may be endogenous (e.g., respiratory obstructive event, pain, leg movement of sleep) or exogenous (e.g., forced awakening or environmental disruption).144,145 In predisposed individuals, sleep deprivation, medications, sleep disorders, stress, and circadian misalignment may all aggravate or expose this underlying parasomnia. It is unclear why such partial arousals are more common in children. Nevertheless, genetic factors in non-REM parasomnias are evidenced by both epidemiological studies and studies of twins.145,146 Risk of sleepwalking is approximately doubled if one parent has a sleepwalking history and tripled when both parents have such a history. There do not appear to be gender or racial differences in the prevalence rates of these parasomnias. Even in individuals with frequent episodes, parasomnia episodes are often not observed in the sleep laboratory.147 Sleep studies, however, are often performed in such patients (particularly in an adult with new-onset sleepwalking) to determine whether there are potential precipitating events occurring during sleep, such as a sleep-related breathing disorder, PLMSs, nocturnal seizures, or RBD. When they are observed, the electroencephalogram may show delta waves (characteristic of slow-wave sleep), theta or alpha activity, or alternation between sleep and waking activity.148 There is an unclear relationship between psychiatric disorders and non-REM parasomnias.134 Although childhood sleepwalking does not appear to be associated with psychiatric disorders, a variety of psychiatric disorders may increase the risk of persistent sleepwalking into adulthood.136,149 However, it is not believed that sleepwalking represents latent psychopathology.150 Nonetheless, psychiatric medications may raise the risk of sleepwalking, because of their sleep-disruptive or sleep-enhancing properties.151 Similarly, stress, sleep deprivation,152 and chaotic sleep schedules may increase the risk of sleepwalking, and each of these precipitants may be more common in the psychiatric patient. When seeing a patient with abnormal nocturnal behavior, the clinician needs to consider a number of disorders. These include nocturnal panic attacks, nocturnal dissociative episodes, frontal or temporal lobe seizures, delirium associated with medical or neurological disorders, and RBD. A daytime history of behaviors similar to the nocturnal behaviors (e.g., panic or dissociative episode) would certainly direct the diagnosis away from a non-REM parasomnia. Similarly, overnight polysomnography might assist in the diagnosis of RBD or a seizure disorder.
Treatment of Non-REM Parasomnias The decision to treat non-REM parasomnias is based on the frequency of the event, the risk of associated injury to self or others, and the distress the behavior is causing the patient or family members.136 Fortunately, for the majority of adult
198
Section
II
Sleep and Sleep Disorders
sufferers, parasomnias occur infrequently, but unfortunately, their appearance is unpredictable. Therefore, the decision to treat must be carefully considered, particularly when the sleepwalker engages in high-risk behaviors. For most children, parasomnias do not necessitate treatment, unless there is risk of harm, and although the parents’ sleep may be disrupted, the child is usually unaware of the events. Regularization of the sleep-wake cycle and avoidance of sleep deprivation reduce the frequency of events. For those children and young adults who do sleepwalk, enhancing the safety of the sleeping environment, such as locking doors and windows and keeping hallways and stairs well lit, is essential. When treatment of sleepwalking or sleep terrors in an adult is warranted, a three-step approach is used: modification of predisposing and precipitating factors, enhancing safety of the sleeping environment, and, when these are not successful, pharmacotherapy. Sleep disorders (e.g., sleep apnea, PLMSs), symptoms of medical disorders (pain, nocturia, dyspnea), or medications that are thought to be contributing to sleep instability should be modified to the extent possible. As described previously, the safety of the environment should be maximized. The majority of data on the treatment of non-REM parasomnias exist for clonazepam (0.5 to 1.0 mg one hour before bed), which has been used successfully for sleepwalking and sleep terrors for extended periods without the development of tolerance in most patients.153 However, if the parasomnia occurs within the first half of the sleep period, short-acting benzodiazepine receptor agonists such as triazolam (0.125 to 0.25 mg) or zolpidem (5 to 10 mg) are recommended, to minimize daytime carryover effects. It is unclear whether these medications work by suppressing arousals during sleep or decreasing slow-wave sleep, and no controlled trials testing their efficacy have been performed. However, because of favorable clinical experience, they are first-line agents in the treatment of these disorders.
An animal model of RBD, in which lesions around the locus ceruleus produced “REM sleep without atonia” was developed well before the discovery of RBD and implicates these brainstem areas in the control of motor activity in REM sleep.157 In patients with RBD, dopamine transporter abnormalities in the nigrostriatal system have been demonstrated.158 Similarly, a reduction in neurons around the locus ceruleus has been seen.159 However, more widespread central nervous system dysfunction is suggested by data showing slowing of the EEG pattern during wakefulness as well as subtle neuropsychological dysfunction in patients with idiopathic RBD.160 The diagnosis of RBD is made by polysomnography, which demonstrates elevated muscle tone or excessive phasic muscle activity in the submental and anterior tibialis electromyogram during REM sleep.1 At times, body movements are manifest during REM on sleep study. Excess PLMSs may also be observed during both REM and non-REM sleep. Otherwise, polysomnography findings are generally normal. First-line treatment of RBD consists of benzodiazepine receptor agonists. The most commonly used agent is clonazepam (0.5 to 1.0 mg), which has been shown to substantially decrease the number and extent of pathological dream-enacting behaviors.153 In general, the medication is well tolerated for this indication; however, because of the age of most of the patients with RBD and the long half-life of clonazepam, excess daytime sleepiness and/or cognitive impairments may occur. In this case, shorter acting benzodiazepines (e.g., lorazepam, 1 to 2 mg) may be used. Other medications, particularly melatonin (3 to 15 mg one hour before bed)161 and pramipexole (0.5 to 1.0 mg one hour before bed), have also been used with some success.162 These alternatives are appropriate for patients for whom a benzodiazepine is associated with cognitive or motor side effects or is contraindicated because of substance abuse. Certainly, removal of potentially offending medications, such as antidepressants, should be attempted if clinically possible. In addition, as with the non-REM parasomnias, safety of the sleeping environment for both the patient and the bed partner is essential.
REM Sleep Behavior Disorder RBD is characterized by pathological appearance of the normal features of REM sleep. In RBD, the usual atonia of REM sleep is absent; this allows the sleeper to enact dreams, which, when agitated or violent, can result in injury to the sleeper or bed partner.154 During such episodes, the sleeper’s eyes are closed, and the sleeper is unresponsive to the environment until awakened, at which point he or she achieves rapid and full alertness and reports a dream that usually corresponds to the exhibited behavior. It is this agitation and/or injury that bring the patient to medical attention, usually at the behest of the bed partner. Episodes of full-blown RBD are intermittent, but sleeptalking, shouting, vivid dreams, or fragmentary motor activity may commonly occur between such events. RBD is a chronic disorder, usually observed in men older than 50 and in individuals with certain neurological disorders. In particular, RBD is often present in individuals with αsynucleinopathies (Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy).155 RBD may also be a heralding symptom of neurological illness: In one study, twothirds of patients with RBD monitored for 10 years developed Parkinson’s disease.156 RBD may also be precipitated by treatment with serotonergic antidepressants.
K E Y
P O I N T S
●
Sleep disorders can be classified into the insomnias, the hypersomnias, circadian rhythm disorders, and the parasomnias.
●
Chronic insomnia, which is present in approximately 10% of adults, has substantial consequences for daytime functioning and has been associated with an increased incidence of major depression.
●
Both cognitive behavioral therapy and pharmacotherapy have roles in the treatment of insomnia.
●
Excess daytime sleepiness can be the result of multiple neurological disorders, and treatments can either be empirical or directed to the underlying disorders.
●
Parasomnias, when frequent or associated with risk of injury, are usually treated with benzodiazepine-receptor agonists.
chapter 15 primary disorders of sleep Suggested Reading Krystal AD, Walsh JK, Laska E, et al: Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26:793-799. Peyron C, Faraco J, Rogers W, et al: A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6:991-997. Riemann D, Voderholzer U: Primary insomnia: a risk factor to develop depression? J Affect Disord 2003; 76:255-259. Ripley B, Overeem S, Fujiki N, et al: CSF. hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001; 57:2253-2258. Schenck CH, Bundlie SR, Mahowold MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996; 46:388-393.
References 1. American Academy of Sleep Medicine: International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd ed. Rochester, MN: American Academy of Sleep Medicine, 2005. 2. Ohayon MM: Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002; 6:97-111. 3. Katz DA, McHorney CA: The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract 2002; 51:229-235. 4. Foley DJ, Monjan A, Simonsick EM, et al: Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6800 persons over three years. Sleep 1999; 22:S366-S372. 5. Dodge R, Cline MG, Quan SF: The natural history of insomnia and its relationship to respiratory symptoms. Arch Intern Med 1995; 155:1797-1800. 6. Klink ME, Quan SF, Kaltenborn WT, et al: Risk factors associated with complaints of insomnia in a general adult population. Influence of previous complaints of insomnia. Arch Intern Med 1992; 152:1634-1637. 7. Foley DJ, Monjan AA, Brown SL, et al: Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995; 18:425-432. 8. Ohayon MM, Roth T: What are the contributing factors for insomnia in the general population? J Psychosom Res 2001; 51:745-755. 9. Riemann D, Voderholzer U: Primary insomnia: a risk factor to develop depression? J Affect Disord 2003; 76:255-259. 10. Léger D, Scheuermaier K, Philip P, et al: SF-36: evaluation of quality of life in severe and mild insomniacs compared with good sleepers. Psychosom Med 2001; 63:49-55. 11. Avidan AY, Fries BE, James ML, et al: Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005; 53:955-962. 12. Simon GE, VonKorff M: Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry 1997; 154:14171423. 13. Bonnet MH, Arand DL: Hyperarousal and insomnia. Sleep Med Rev 1997; 1:97-108. 14. Drake C, Richardson G, Roehrs T, et al: Vulnerability to stressrelated sleep disturbance and hyperarousal. Sleep 2004; 27:285-291. 15. Tang NK, Harvey AG: Effects of cognitive arousal and physiological arousal on sleep perception. Sleep 2004; 27: 69-78.
199
16. Vgontzas AN, Bixler EO, Lin HM, et al: Chronic insomnia is associated with nyctohemeral activation of the hypothalamicpituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 2001; 86:3787-3794. 17. Bonnet MH, Arand DL: Situational insomnia: consistency, predictors, and outcomes. Sleep 2003; 26:1029-1036. 18. Nofzinger EA, Buysse DJ, Germain A, et al: Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161:2126-2128. 19. Krystal AD, Edinger JD, Wohlgemuth WK, et al: NREM sleep EEG frequency spectral correlates of sleep complaints in primary insomnia subtypes. Sleep 2002; 25:630640. 20. Perlis ML, Giles DE, Mendelson WB, et al: Psychophysiological insomnia: the behavioural model and a neurocognitive perspective. J Sleep Res 1997; 6:179-188. 21. Vitiello MV, Moe KE, Prinz PN: Sleep complaints cosegregate with illness in older adults: clinical research informed by and informing epidemiological studies of sleep. J Psychosom Res 2002; 53:555-559. 22. Ford DE, Kamerow DB: Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989; 262:1479-1484. 23. Sateia MJ, Doghramji K, Hauri PJ, et al: Evaluation of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 2000; 23:243-308. 24. Morin CM, Culbert JP, Schwartz SM: Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry 1994; 151:1172-1180. 25. Edinger JD, Glenn DM, Bastian LA, et al: Sleep in the laboratory and sleep at home II: comparisons of middle-aged insomnia sufferers and normal sleepers. Sleep 2001; 24:761770. 26. Walsh JK: Pharmacologic management of insomnia [Review]. J Clin Psychiatry 2004; 65(Suppl 16):41-45. 27. National Institutes of Health: State-of-the-science conference statement: manifestations and management on chronic insomnia in adults. Available at: http://consensus.nih.gov/ta/ 026/InsomniaDraftStatement061505.pdf (accessed March 9, 2006). 28. Mohler H, Fritschy J, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300:2-8. 29. Nowell PD, Mazumdar S, Buysse DJ, et al: Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997; 278:2170-2177. 30. Holbrook AM, Crowther R, Lotter A, et al: Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000; 162:225-233. 31. Krystal AD, Walsh JK, Laska E, et al: Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26:793-799. 32. Morrish E, King MA, Pilsworth SN, et al: Periodic limb movement in a community population detected by a new actigraphy technique. Sleep Med 2002; 3:489-495. 33. Carrier J, Frenette S, Montplaisir J, et al: Effects of periodic leg movements during sleep in middle-aged subjects without sleep complaints. Mov Disord 2005; 20:1127-1132. 34. Cohrs S, Rodenbeck A, Guan Z, et al: Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berl) 2004; 174:421-429. 35. Montplaisir J, Nicolas A, Denesle R, et al: Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999; 52:938-943. 36. Cohrs S, Guan Z, Pohlmann K, et al: Nocturnal urinary dopamine excretion is reduced in otherwise healthy subjects with periodic leg movements in sleep. Neurosci Lett 2004; 360:161-164.
200
Section
II
Sleep and Sleep Disorders
37. Doghramji K, Browman CP, Gaddy JR, et al: Triazolam diminishes daytime sleepiness and sleep fragmentation in patients with periodic leg movements in sleep. J Clin Psychopharmacol 1991; 11:284-290. 38. Bonnet MH, Arand DL: Chronic use of triazolam in patients with periodic leg movements, fragmented sleep and daytime sleepiness. Aging (Milano) 1991; 3:313-324. 39. Peled R, Lavie P: Double-blind evaluation of clonazepam on periodic leg movements in sleep. J Neurol Neurosurg Psychiatry 1987; 50:1679-1681. 40. Parish JM, Somers VK: Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc 2004; 79:1036-1046. 41. Davies DP, Rodgers H, Walshaw D, et al: Snoring, daytime sleepiness and stroke: a case-control study of first-ever stroke. J Sleep Res 2003; 12:313-318. 42. Harbison J, Ford GA, James OF, et al: Sleep-disordered breathing following acute stroke. Q J Med 2002; 95:741-747. 43. Cherkassky T, Oksenberg A, Froom P, et al: Sleep-related breathing disorders and rehabilitation outcome of stroke patients: a prospective study. Am J Phys Med Rehabil 2003; 82:452-455. 44. Kaneko Y, Hajek VE, Zivanovic V, et al: Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep 2003; 26:293-297. 45. De Groot MH, Phillips SJ, Eskes GA: Fatigue associated with stroke and other neurologic conditions: implications for stroke rehabilitation. Arch Phys Med Rehabil 2003; 84:17141720. 46. Muller C, Achermann P, Bischof M, et al: Visual and spectral analysis of sleep EEG in acute hemispheric stroke. Eur Neurol 2002; 48:164-171. 47. Bliwise DL, Rye DB, Dihenia B, et al: Greater daytime sleepiness in subcortical stroke relative to Parkinson’s disease and Alzheimer’s disease. J Geriatr Psychiatry Neurol 2002; 15:6167. 48. Vock J, Achermann P, Bischof M, et al: Evolution of sleep and sleep EEG after hemispheric stroke. J Sleep Res 2002; 11:331338. 49. Bassetti CL, Aldrich MS: Sleep electroencephalogram changes in acute hemispheric stroke. Sleep Med 2001; 2:185194. 50. Bischof M, Bassetti CL: Total dream loss: a distinct neuropsychological dysfunction after bilateral PCA stroke. Ann Neurol 2004; 56:583-586. 51. Gironell A, de la Calzada MD, Sagales T, et al: Absence of REM sleep and altered non-REM sleep caused by a haematoma in the pontine tegmentum. J Neurol Neurosurg Psychiatry 1995; 59:195-196. 52. Arpa J, Rodriguez-Albarino A, Izal E, et al: Hypersomnia after tegmental pontine hematoma: case report. Neurologia 1995; 10:140-144. 53. Cvetkovic RS, Plosker GL: Desmopressin: in adults with nocturia. Drugs 2005; 65:99-107. 54. Irarte J, Subira M, Castro PL Modalities of fatigue in multiple sclerosis: correlation with clinical and biologic factors. Mult Scler 2000; 6:124-130. 55. Janssens AC, van Doorn PA, de Boer JB, et al: Impact of recently diagnosed multiple sclerosis on quality of life, anxiety, depression and distress of patients and partners. Acta Neurol Scand 2003; 108:389-395. 56. Janssens AC, van Doorn PA, de Boer JB, et al: Perception of prognostic risk in patients with multiple sclerosis: the relationship with anxiety, depression, and disease-related distress. J Clin Epidemiol 2004; 57:180-186. 57. Rothwell NJ, Luheshi GN: Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 2000; 23:618-625.
58. Oka Y, Kanbayashi T, Mezaki T, et al: Low CSF hypocretin1/orexin-A associated with hypersomnia secondary to hypothalamic lesion in a case of multiple sclerosis. J Neurol 2004; 251:885-886. 59. Plazzi G, Montagna P: Remitting REM sleep behavior disorder as the initial sign of multiple sclerosis. Sleep Med 2002; 3:437-439. 60. Vgontzas AN, Chrousos GP: Sleep, the hypothalamicpituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol Metab Clin North Am 2002; 31:15-36. 61. Antonijevic IA, Steiger A: Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis. Psychoneuroendocrinology 2003; 28:780-795. 62. Kimura M, Majde JA, Toth LA, et al: Somnogenic effects of rabbit and recombinant human interferons in rabbits. Am J Physiol 1994; 267:R53-R61. 63. Munschauer FE 3rd, Kinkel RP: Managing side effects of interferon-beta in patients with relapsing-remitting multiple sclerosis. Clin Ther 1997; 19:883-893. 64. Mueller ME, Gruenthal M, Olson WL, et al: Gabapentin for relief of upper motor neuron symptoms in multiple sclerosis. Arch Phys Med Rehabil 1997; 78:521-524. 65. Zifko UA, Rupp M, Schwarz S, et al: Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002; 249:983-987. 66. Rammohan KW, Rosenberg JH, Lynn DJ, et al: Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72:150. 67. Johns M: Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth sleepiness scale. Chest 1993; 103:30-36. 68. Tan EK, Lum SY, Fook-Chong SMC, et al: Evaluation of somnolence in Parkinson’s disease: comparison with age- and sex-matched controls. Neurology 2002; 58:465-468. 69. Stevens S, Cormella CL, Stepanski EJ: Daytime sleepiness and alertness in patients with Parkinson disease. Sleep 2004; 27:967-972. 70. Alves G, Wentzel-Larsen T, Larsen JP: Is fatigue an independent and persistent symptom in patients with Parkinson disease? Neurology 2004; 63:1908-1911. 71. Serrano C, Garcia-Borreguero D: Fluctuations in cognition and alertness in Parkinson’s disease and dementia. Neurology 2004; 63:S31-S34. 72. Nausieda PA, Weiner WJ, Kaplan LR, et al: Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis. Clin Neuropharmacol 1982; 5:183194. 73. Ripley B, Overeem S, Fujiki N, et al: CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001; 57:2253-2258. 74. Johnson MP, Duffy JF, Dijk DJ, et al: Short-term memory, alertness and performance: a reappraisal of their relationship to body temperature. J Sleep Res 1992; 1:24-29. 75. Rissling I, Geller F, Brandmann O, et al: Dopamine receptor gene polymorphisms in Parkinson’s disease patients reporting “sleep attacks.” Mov Disord 2004; 19:1279-1284. 76. Goetz CG, Wuu J, Curgian LM, et al: Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 2005; 64:81-86. 77. Schenck CH, Bundlie SR, Mahowold MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996; 46:388-393. 78. Eisensehr I, Linke R, Tatsch K, et al: Increased muscle activity during rapid eye movement sleep correlates with decrease
chapter 15 primary disorders of sleep
79.
80. 81.
82. 83.
84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96.
97. 98.
of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003; 26:507-512. Hogl B, Saletu M, Brandauer E, et al: Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a doubleblind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002; 25:905-909. Guilleminault C, Lehrman K, Forno L, et al: Sleep apnoea syndrome: states of sleep and autonomic dysfunction. J Neurol Neurosurg Psychiatry 1977; 40:718-725. Castaigne P, Laplane D, Autret A, et al: [Shy-Drager syndrome with disturbances of the respiratory rhythm and consciousness. A propos of an anatomo-clinical case]. Rev Neurol 1977; 113:455-466. Munschauer FE, Loh L, Bannister R, et al: Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology 1990; 40:677-679. Isozaki E, Hayashi M, Hayashida T, et al: [Vocal cord abductor in multiple system atrophy—paradoxical movement of vocal cords during sleep]. Rinsho Shinkeigaku 1996; 36:52933. Sadaoka T, Kakitsuba N, Fujiwara Y, et al: Sleep-related breathing disorders in patients with multiple system atrophy and vocal fold palsy. Sleep 1996; 19:479-484. Sforza E, Montagna P, Defazio G, Lugaresi E. Sleep and cranial dystonia. Electroencephalogr Clin Neurophysiol 1991; 79:166-169. Silvestri R, De Domenico P, Di Rosa AE, et al: The effect of nocturnal physiological sleep on various movement disorders. Mov Disord 1990; 5:8-14. Schols L, Haan J, Riess O, et al: Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? Neurology 1998; 51:1603-1607. Steljes DG, Kryger MH, Kirk BW, et al: Sleep in postpolio syndrome. Chest 1990; 98:133-140. Stockhammer E, Tobon A, Michel F, et al: Characteristics of sleep apnea syndrome in tetraplegic patients. Spinal Cord 2002; 40:286-294. Lu K, Lee TC, Liang CL, et al: Delayed apnea in patients with mid- to lower cervical spinal cord injury. Spine 2000; 25:1332-1338. Manconi M, Mondini S, Fabiani A, et al: Anterior spinal artery syndrome complicated by the Ondine curse. Arch Neurol 2003; 60:1787-1790. Kneisley LW, Moskowitz MA, Lynch HG: Cervical spinal cord lesions disrupt the rhythm in human melatonin excretion. J Neural Transm Suppl 1978; 13:311-323. Herman ST, Walczak TS, Bazil CW: Distribution of partial seizures during the sleep-wake cycle: differences by seizure onset site. Neurology 2001; 56:1453-1459. Minecan D, Natarajan A, Marzec M, et al: Relationship of epileptic seizures to sleep stage and sleep depth. Sleep 2002; 25:899-904. Malow BA, Kushwala R, Lin X, et al: Relationship of interictal epileptiform discharges to sleep depth in partial epilepsy. Electroencephalogr Clin Neurophysiol 1997; 102:20-26. Crespel A, Baldy-Moulinier M, Coubes P: The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. Epilepsia 1998; 39:150-157. Malow BA, Lin X, Kushwaha R, et al: Interictal spiking increases with sleep depth in temporal lobe epilepsy. Epilepsia 1998; 39:1309-1316. Sammaritano M, Gigli GL, Gotman J: Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 1991; 41:290-297.
201
99. Ross JJ, Johnson LC, Walter RD: Spike and wave discharges during stages of sleep. Arch Neurol 1966; 14:399-407. 100. Sato S, Dreifus FE, Penry JK: The effect of sleep on spikewave discharges in absence seizures. Neurology 1973; 23:1335-1345. 101. Pavlova MK, Shea SA, Bromfield EB: Day/night patterns of focal seizures. Epilepsy Behav 2004; 5:44-49. 102. Lin L, Faraco J, Li R, et al: The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98:365-376. 103. Chemelli RM, Willie JT, Sinton CM, et al: Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98:437-451. 104. Peyron C, Faraco J, Rogers W, et al: A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6:991-997. 105. Nishino S, Ripley B, Overeem S, et al: Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001; 50:381-388. 106. Mayer G, Leonhard E, Krieg J, et al: Endocrinological and polysomnographic findings in Kleine-Levin syndrome: no evidence for hypothalamic and circadian dysfunction. Sleep 1998; 21:278-284. 107. Billiard M, Guilleminault C, Dement WC: A menstruationlinked periodic hypersomnia. Kleine-Levin syndrome or new clinical entity? Neurology 1975; 25:436-443. 108. Kesler A, Gadoth N, Vainstein G, et al: Kleine-Levin syndrome (KLS) in young females. Sleep 2000; 23:1-5. 109. Muratori F, Bertini N, Masi G: Efficacy of lithium treatment in Kleine-Levin syndrome. Eur Psychiatry 2002; 17:232-233. 110. Visscher F, Smit LM, Smith F, et al: The Kleine-Levin syndrome. Tijdschr Kindergeneeskd 1989; 57:218-221. 111. Tinuper P, Montagna P, Plazzi G, et al: Idiopathic recurring stupor. Neurology 1994; 44:621-625. 112. Rothstein JD, Guidotti A, Tinuper P, et al: Endogenous benzodiazepine receptor ligands in idiopathic recurring stupor. Lancet 1992; 340:1002-1004. 113. Dijk DJ, Duffy JF, Czeisler CA: Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance. J Sleep Res 1992; 1:112-117. 114. Boivin D: Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. J Psychiatry Neurosci 2000; 25:446-458. 115. Okawa M, Uchiyama M, Ozaki S, et al: Circadian rhythm sleep disorders in adolescents: clinical trials of combined treatments based on chronobiology. Psychiatry Clin Neurosci 1998; 52:483-490. 116. Czeisler CA, Richardson GS, Coleman RM, et al: Chronotherapy: resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep 1981; 4:1-21. 117. Dijk DJ, Beersma DG, Daan S, et al: Bright morning light advances the human circadian systems without affecting the NREM sleep homeostasis. Am J Physiol 1989; 256:R100-R111. 118. Czeisler CA, Kronauer RE, Allan JS, et al: Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 1989; 244:1328-1333. 119. Minors DS, Waterhouse JM, Wirz-Justice A: A human phaseresponse curve to light. Neurosci Lett 1991; 133:36-40. 120. Morris M, Lack L, Dawson D: Sleep-onset insomniacs have delayed temperature rhythms. Sleep 1990; 13:1-14. 121. Rosenthal NE, Joseph-Vanderpool JR, Levendosky AA, et al: Phase-shifting effects of bright morning light as treatment for delayed sleep phase syndrome. Sleep 1990; 13:354-361. 122. Chesson AL Jr, Littner M, Davila D, et al: Practice parameters for the use of light therapy in the treatment of sleep disorders. Sleep 1999; 22:641-660.
202
Section
II
Sleep and Sleep Disorders
123. Dahlitz M, Alvarez B, Vignau J, et al: Delayed sleep phase syndrome response to melatonin. Lancet 1991; 337:1121-1124. 124. Dagan Y, Yovel I, Hallis D, et al: Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS). Chronobiol Int 1998; 15:181-190. 125. Reid KJ, Chang AM, Dubocovich ML, et al: Familial advanced sleep phase syndrome. Arch Neurol 2001; 58:1089-1094. 126. Zucconi M: Familial advanced sleep phase syndrome. Sleep Med 2002; 3:177-178. 127. Satoh K, Mishima K, Inoue Y, et al: Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 2003; 26:416417. 128. Palmer CR, Kripke DF, Savage HC Jr, et al: Efficacy of enhanced evening light for advanced sleep phase syndrome. Behav Sleep Med 2003; 1:213-226. 129. Klein T, Martens H, Dijk DJ, et al: Circadian sleep regulation in the absence of light perception: chronic non–24-hour circadian rhythm sleep disorder in a blind man with a regular 24-hour sleep-wake schedule. Sleep 1993; 16:333-343. 130. Eastman CI, Gazda CJ, Burgess HJ, et al: Advancing circadian rhythms before eastward flight: a strategy to prevent or reduce jet lag. Sleep 2005; 28:33-44. 131. Burgess HJ, Crowley SJ, Gazda CJ, et al: Preflight adjustment to eastward travel: 3 days of advancing sleep with and without morning bright light. J Biol Rhythms 2003; 18:318-328. 132. Oxenkrug GF, Requintina PJ: Melatonin and jet lag syndrome: experimental model and clinical implications. CNS Spectr 2003; 8:139-148. 133. Herxheimer A, Waterhouse J: The prevention and treatment of jet lag. BMJ 2003; 326:296-297. 134. Schenck CH, Mahowald MW: Parasomnias. Managing bizarre sleep-related behavior disorders. Postgrad Med 2000; 107: 145-156. 135. Mahowald MW: Parasomnias. Med Clin North Am 2004; 88:669-678. 136. Ohayon MM, Guilleminault C, Priest RG: Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry 1999; 60:268-276. 137. Kavey NB, Whyte J, Resor SR Jr, et al: Somnambulism in adults. Neurology 1990; 40:749-752. 138. Crisp AH: The sleepwalking/night terrors syndrome in adults. Postgrad Med J 1996; 72:599-604. 139. Mehlenbeck R, Spirito A, Owens J, et al: The clinical presentation of childhood partial arousal parasomnias. Sleep Med 2000; 1:307-312. 140. Schenck CH, Boyd JL, Mahowald MW: A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases. Sleep 1997; 20:972-981. 141. Roth B, Nevsimalova S, Rechtschaffen A: Hypersomnia with “sleep drunkenness.” Arch Gen Psychiatry 1972; 26:456-462. 142. Shapiro CM, Trajanovic NN, Fedoroff JP: Sexsomnia—a new parasomnia? Can J Psychiatry 2003; 48:311-317. 143. Cartwright R: Sleepwalking violence: a sleep disorder, a legal dilemma, and a psychological challenge [Review]. Am J Psychiatry 2004; 161:1149-1158. 144. Laberge L, Tremblay RE, Vitaro F, et al: Development of parasomnias from childhood to early adolescence. Pediatrics 2000; 106:67-74.
145. Hublin C, Kaprio J, Partinen M, et al: Parasomnias: cooccurrence and genetics. Psychiatr Genet 2001; 11:65-70. 146. Hublin C, Kaprio J, Partinen M, et al: Prevalence and genetics of sleepwalking: a population-based twin study. Neurology 1997; 48:177-181. 147. Broughton RJ: Sleep disorders: disorders of arousal? Enuresis, somnambulism, and nightmares occur in confusional states of arousal, not in “dreaming sleep.” Science 1968; 159:1070-1078. 148. Gaudreau H, Joncas S, Zadra A, et al: Dynamics of slow-wave activity during the NREM sleep of sleepwalkers and control subjects. Sleep 2000; 23:755-760. 149. Gau SF, Soong WT: Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: a case-control study. Aust N Z J Psychiatry 1999; 33:734-739. 150. Hartman D, Crisp AH, Sedgwick P, et al: Is there a dissociative process in sleepwalking and night terrors? Postgrad Med J 2001; 77:244-249. 151. Landry P, Warnes H, Nielsen T, et al: Somnambulistic-like behaviour in patients attending a lithium clinic. Int Clin Psychopharmacol 1999; 14:173-175. 152. Joncas S, Zadra A, Paquet J, et al: The value of sleep deprivation as a diagnostic tool in adult sleepwalkers. Neurology 2002; 58:936-940. 153. Schenck CH, Mahowald MW: REM sleep parasomnias. Neurol Clin 1996; 14:697-720. 154. Schenck CH, Mahowald MW: REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002; 25:120-138. 155. Boeve BF, Silber MH, Parisi JE, et al: Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003; 61:40-45. 156. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 1996; 46:388-393. 157. Hendricks JC, Morrison AR, Farnbach GL, et al: A disorder of rapid eye movement sleep in a cat. J Am Vet Med Assoc 1981; 178:55-57. 158. Eisensehr I, Linke R, Noachtar S, et al: Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson’s disease and controls. Brain 2000.123:1155-1160. 159. Turner RS, D’Amato CJ, Chervin RD, et al: The pathology of REM sleep behavior disorder with comorbid Lewy body dementia. Neurology 2000; 55:1730-1732. 160. Gagnon JF, Fantini ML, Bedard MA, et al: Association between waking EEG slowing and REM sleep behavior disorder in PD without dementia. Neurology 2004; 62:401-406. 161. Boeve BF, Silber MH, Ferman TJ: Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4:281-284. 162. Fantini ML, Gagnon JF, Filipini D, et al: The effects of pramipexole in REM sleep behavior disorder. Neurology 2003; 61:1418-1420.
CHAPTER
16
SLEEP APNEA ●
●
●
●
Adrian J. Williams
The sleeping patient is still a patient. His disease may progress differently in sleep, or disease may originate in sleep. (Eugene Robin, 1958) Sleep-disordered breathing is the broad term used to describe the endpoint of a number of conditions of diverse etiology that can disrupt breathing during sleep. Apnea is defined as the cessation of breathing for more than 10 seconds. Hypopnea refers to a reduction in tidal volume without total cessation of respiration. Degrees of hypopnea are recognized: either substantial (>50% reduction in airflow) or moderate (<50% reduction in airflow with desaturations of >3%, or electroencephalographic evidence of arousal). Episodes of apnea and hypopnea often, if not always, coexist; apnea represents the more severe end of the spectrum of reduction in tidal volume (Fig. 16–1). Apneas and hypopneas may develop as a result of lack of drive to breathe, which is a central phenomenon, or as a result of narrowing of the upper airway, which is an obstructive phenomenon. These are considered separately. Brief episodes of apnea or hypopnea are a feature of normal sleep, occurring most commonly during the transition from wakefulness to sleep when the level of arterial carbon dioxide tension in the body is reset to a level that is higher by approximately 5 mm Hg (0.7 kPa). Such transitional apneas occur in most individuals but can be very pronounced in patients with frequent arousals during sleep. In an attempt to differentiate between normal and abnormal frequencies of apneic or hypopneic levels, the apnea-hypopnea index, referring to the number of episodes of apnea and hypopnea per hour of sleep, is used. The upper limit of normal has traditionally been considered to be five events per hour, but some authors have suggested a higher cutoff level, 10 events per hour. Sleep-disordered breathing is common, and its prevalence increases with age. It is often accompanied by hypoxemia, changes in heart rate and blood pressure, and arousals that may fragment sleep and lead to daytime fatigue and somnolence, as well as cognitive and cardiovascular changes, known as the sleep apnea syndrome. Despite this, most cases remain undiagnosed and untreated.
OBSTRUCTIVE SLEEP APNEA-HYPOPNEA Epidemiology Obstructive sleep apnea-hypopnea (OSAH) is an increasingly important disease with numerous clinically relevant consequences, including neurocognitive and cardiovascular sequelae.1-3 The prevalence of this disease varies, depending on the definitions (of hypopnea) used. Young and colleagues4,5 showed that 4% of men and 2% of women in a middle-aged North American population had symptoms of OSAH and an apneahypopnea index exceeding 5. However, 24% of men aged 30 to 60 and 9% of women had an abnormal apnea-hypopnea index but without excessive sleepiness, which had been used to define the former statistics. Cardiovascular risk assessments, however, have shown a dose-response relationship between the apneahypopnea index and various sequelae; thus, the definition and epidemiology are still evolving (Young, Peppard, Gottlieb 2002).
Pathophysiology Considerable progress has been made in understanding the genesis of obstructive events. The upper airway is anatomically small, and augmented pharyngeal dilator muscle activation maintains airway patency while the patient is awake but not while asleep, when an increase in upper airway resistance is found. Snoring, an important marker of increased upper airway resistance, is in part genetically determined,6 which perhaps reflects anatomical contributions such as a degree of retrognathia or overbite. Racial differences may be explained by this (apnea is more frequent among African Americans).7 Airway muscle tone insufficient for the airway size may allow intraluminal negative pressure to collapse the pharyngeal “tube.” Additional anatomical factors include enlarged tonsils or adenoids, vascular perfusion, the posture of the individual (supine versus lateral) and, of importance, fat accumulated in the pads in the lateral pharyngeal wall (Fig. 16–1).8 During wakefulness, augmented pharyngeal dilator muscle activity maintains airway potency. At sleep onset and/or during
203
204
Section
II
Sleep and Sleep Disorders NORMAL
APNEIC
Clinical Manifestations/Sequelae OSAH should be suspected in patients who snore intrusively and who are obese (body mass index > 30) and/or in whom apneas have been witnessed. However, more subtle manifestations can occur (e.g., in the 30% who are not obese); therefore, questioning with regard to daytime sleepiness and sleep quality is mandatory. Poor sleep quality and daytime sleepiness are largely the results of sleep fragmentation by repetitive arousals. The neurocognitive sequelae of recurrent arousals also include reduced performance in neuropsychological tests, lengthened reaction times, altered quality of life, and an increased risk of vehicular accidents and work-related accidents.1,8 A causal relationship to all is supported by the response to treatment with continuous positive airway pressure (CPAP), which improves these sequelae.11-13 Because of its practical importance, more should be said about sleep apnea and driving. Human error is a major determinant in automobile accidents; inattention, improper lookout, and other perceptual and cognitive errors account for up to 40% of cases. Progressive daytime sleepiness can enhance inattention and thereby increase the risk of accidents in such patients. OSAH is an important cause of daytime sleepiness, along with cognitive impairment, and consequently contributes to the problem of drowsy driving. Sleep-related vehicular accidents are not only more common than is generally realized (Maycock found that 29% of 4600 respondents in a U.K. survey admitted to having felt close to falling asleep at the wheel in the previous year, and 18% had accidents in the previous 3 years) but are also more liable to result in death or serious injury as a result of the relatively high speed of the vehicles on impact. The financial and human costs can be considerable. The determination that sleeping at the wheel is the cause of an accident is based on the following: ■ The absence of skid marks. ■ The fact that for 7 seconds, the driver could have clearly seen
at the point of runoff or the object hit (which implies prolonged inattention rather than momentary distraction). ■ Other causes such as mechanical failure are eliminated. ■
Figure 16–1. Restriction of the airway during an apneic event.
rapid-eye-movement sleep (with active inhibition of muscles), this reflex activity is diminished, and if airway anatomy is abnormal, the airway is compromised, which leads to hypopneas and/or apneas. As a result, hypoxia and hypercapnia occur; ventilation is stimulated, often with arousal from sleep; and airway patency is reestablished. With the return to sleep, the cycle is repeated. It is possible, then, to conceive of a continuum of disordered breathing from snoring alone to an inability to breathe and sleep at the same time. Additional risk factors for OSAH are obesity, male gender, and increasing age. Of patients with OSAH, 70% are obese (pharyngeal size is diminished); sleep laboratories report a fivefold or sixfold increased risk of OSAH in men in comparison with women; and the prevalence increases with age.9 An evolving literature10 also suggests an important concept of snoring-induced traumas causing sensory and/or motor neuronal damage, as well as actual damage to the muscle (Boyd, Petrof, and Hamid, 2004).
It is appreciated that drivers who are able to respond after these accidents seldom acknowledge having fallen asleep. A strong association between sleep apnea and the risk of traffic accidents is now well documented. A Spanish study revealed that 102 drivers received emergency treatment after vehicular accidents and were more likely by a factor of 6 to have OSAH. Results of a French study suggested that approximately one half of drivers involved in sleep-related vehicular accidents have sleep disorders and that 31% have clear indications of OSAH. In addition, patients with OSAH in many other studies have been shown to have an increased rate of accidents. It is important to stress, however, that although patients with OSAH as a group are at increased risk, not all patients are at the same risk; results of the largest study to date suggested that increased automobile accidents may be restricted to patients with more severe apnea [age > 40], although sleep-related vehicular accidents are recognized to be multifactorial in origin. Driver performance can be measured by simulators of varying degrees of sophistication, and some patients with OSAH perform as poorly as subjects intoxicated with alcohol. Beneficial effects of treatment, including CPAP and surgery, have also been shown with these simulators. The U.K. Driver and Vehicle
chapter 16 sleep apnea
■
205
Figure 16–2. A composite of: abdominal and thoracic respiband (respiratory inductance plethysmography) set-up; overnight oximetry demonstrating repetitive desaturations typical of obstructive apnoeas; a 30 sec epoch of the polysomnogram with electroocculogram and electroencephalogram showing sleep onset and a mixed apnoea with initial absence of effort (sleep onset induced) followed by paradoxical movement of the abdomen and thoracic bands indicating effort.
Licensing Agency (DVLA) has a guide for medical practitioners in which it is pointed out that it is the duty of the license holder to notify the DVLA of any medical condition that may affect safe driving. There are some circumstances in which the license holder cannot, or will not, do this. Under these circumstances, the General Medical Council has issued clear guidelines: Make sure that the patients understand that the condition may impair their ability to drive and explain to the patients they have a legal duty to inform the DVLA. If the patient continues to drive but is not fit to do so, the physician should make every reasonable effort to persuade them to stop. This may include telling their next of kin. If the individuals cannot be persuaded to stop driving, the practitioner should disclose relevant medical information immediately in confidence to the medical adviser of the DVLA, informing the patient of the decision to do so. Sleep disorders are specifically mentioned under the Respiratory Disorders Section where the Group 1 entitlement states, “driving must cease if continuing to cause excessive awake time sleepiness, but driving will be permitted when satisfactory control of symptoms is achieved,” whilst for Group 2 entitlement, “cease driving on diagnosis. When it is confirmed by specialist assessment that the condition is
adequately controlled, driving may be resumed subject to review.” Readers should consult their national driving agencies for local recommendations or regulations as these may vary between countries. The cardiovascular sequelae are best considered as immediate and delayed. The immediate response to the obstructed breathing is an increase in negative intrapleural pressure with increased venous return (and increased output of atrial natriuretic peptide and resulting nocturia) and reduced cardiac output (due to the increased afterload). At the same time, the associated hypoxemia promotes sympathetic activation and circulatory vasoconstriction. With the return of airflow, the augmented preload leads to increases in stroke volume and in systemic blood pressure. This occurs repeatedly, and the normal nocturnal fall in blood pressure may be lost. A delayed effect on diurnal blood pressure may then follow. Indeed, it is appreciated that as much as one third of “essential” hypertension is associated with OSAH.14,15 A causal relationship is, again, supported by the response to treatment (with CPAP)16 (Pepperell, 2002). The combination of immediate and delayed hemodynamic effects in OSAH have been associated with increased risk of myocardial infarction and
206
Section
II
Sleep and Sleep Disorders
congestive heart failure, and there is evidence of a link between these and stroke.17 Additional links have been demonstrated with insulin resistance.18 The combination of obesity, insulin resistance (with or without diabetes), hypertension, and cardiovascular disease is typical of the metabolic syndrome, or syndrome X. Because these may all be associated with OSAH also, OSAH should obviously be considered as well; some authorities refer to it as syndrome Z.19 Finally, consideration might be given to the role of chronic hypercapnia in the setting of OSAH. Obesity is complicated in 10% of patients with OSAH by CO2 retention (in part caused by the increased load on the respiratory system), but OSAH alone may produce this through repeated bouts of CO2 retention at night, compensatory bicarbonate retention, and a daytime metabolic alkalosis that necessitates compensation. Evidence for this comes, again, from response to treatment with CPAP. One clinical variant of this is the pickwickian syndrome, so named after the “fat boy,” Joe, in Charles Dickens’ “Posthumous Papers of the Pickwick Club” who was, like the patient reported, obese, a snorer, sleepy, and in heart failure (dropsy). All these patients also have CO2 retention and sleep apnea, usually obstructive. In the example shown in Figure 16–2, a sleep-onset central apnea is followed by a hypopnea associated with efforts to breathe, registered by abdominal and thoracic impedance plethysmography. The hypopnea in this instance, however, resulted from ineffectual diaphragm contraction, evidenced by the paradoxical inward movement of the abdomen, presumably caused by the excessive abdominal load.
Diagnosis The initial evaluation of the patient with suspected OSAH is based on identification of disease markers by history and, to a lesser extent, physical examination. The physician may then choose to proceed with a relatively simple and inexpensive investigation such as overnight oximetry to confirm the presence of sleep-disordered breathing before other investigations such as nocturnal polysomnography.
History Although not every patient with OSAH is a middle-aged obese snorer with hypersomnolence, disease markers—which may be associations, risk factors, or disease effects—greatly contribute to the diagnosis of OSAH. As previously noted, it is well established that male gender and high body mass index are important risk factors for the development of OSAH. The prevalence of the disease also increases with age. Snoring is common (70% to 95%) and in some cases, it may even be the only symptom. Excessive daytime somnolence is highly correlated with the presence of OSAH. It is, however, important to rule out other causes of hypersomnolence, especially sleep deprivation. Cognitive effects of sleep apnea such as memory loss have previously been described. A history of alcohol ingestion, as well as a complete drug history, should be obtained. The interview should be extended to include questioning of the bed partner. This can yield invaluable information regarding important features of the disease of which the patient may be unaware, such as snoring, gasping, apnea, cyanosis, pathological somnolence, and changes in cognition.
Finally, it is important to note whether the patient has a history suggestive of other respiratory or cardiovascular disease that could be exacerbated by the presence of OSAH.
Physical Examination A thorough physical examination should be performed. The relationship between weight and height, as well as neck size, should be noted. The astute clinician looks for evidence of uncommon conditions associated with obstructive apnea, such as Marfan syndrome and acromegaly. General examination should include examination of thyroid status. The clinician should also look for the presence of oropharyngeal crowding, micrognathia, or macroglossia. An examination of the cardiovascular and respiratory systems should follow. It is particularly important to note the patient’s blood pressure, signs of right or left ventricular impairment, and evidence of associated obstructive or restrictive lung disease.
Investigations Overnight oximetry is a useful screening test for patients suspected of having OSAH. It is highly specific and relatively inexpensive. It is simple to perform and noninvasive, and it can be performed reliably in the community. Its sensitivity has been reported to be as high as 70%, but its specificity is closer to 90%.20 A number of automated devices have been used in an attempt to improve the specificity of oximetry without resorting to polysomnography. These devices may include sound recorders for assessment of snoring, thermistors for detection of airflow, transducers for measurement of chest and abdominal wall movement with breathing, and accelerometers or other sensors for detecting limb movement. Several reports have confirmed that both sensitivity and specificity can be quite high, but these monitors tend to be expensive and generally inferior to full polysomnography equipment. Polysomnography remains the “gold standard” for the diagnosis of OSAH, even though it requires expensive equipment in a dedicated sleep laboratory and highly trained personnel. During polysomnography, continuous and simultaneous recordings are made: electrocardiography; electroencephalography, with at least three channels; chin and leg electromyography; electro-oculography; oxygen saturation measurement, with finger or ear oximetry; airflow measurement, with nasal pressure; measurement of chest and abdominal wall movement, with inductance bands; and snoring evaluation, with a microphone and sound recorder. The patient is, ideally, supervised throughout the study, and although unsupervised studies can be performed, the technician’s observations often prove very useful. The recording is digitized and recorded on a computer before analysis. With polysomnography, apneas and hypopneas can be recognized with relative ease and classified into obstructive, central, and mixed events. Changes in sleep stage and arousals are noted on the basis of electroencephalographic, electro-oculographic, and electromyographic features and are related to respiratory events. The severity of sleep apnea is indicated by the apnea-hypopnea index and indices of oxygen desaturation.
chapter 16 sleep apnea
207
Treatment
Oral Appliances
When the primary problem is an abnormally small upper airway, treatment is aimed at rectifying this. Cures may be potentially effected with surgical removal of obstructing tonsils and adenoids, substantial weight loss, and, in rare cases, prevention of supine sleep. There currently exist no drugs that increase further upper airway dilator activity. Medical treatment then relies on devices to produce dilatation of the pharyngeal airway: nasal CPAP, which acts as a pneumatic splint, and oral appliances, which advance the mandible and hence the tongue.
Oral appliances are generally less effective but often preferred by patients and have an evidence base to support their use.
Nasal Continuous Positive Airway Pressure This remains the treatment of choice with substantial grade A evidence summarized by a Cochrane Review. Important immediate benefits are seen in sleepiness, cognition, quality of life, accidents, and blood pressure reduction, and reduced cardiovascular events are anticipated. However, compliance with CPAP is imperfect; approximately 20% of patients do not adhere to the CPAP regimen. Remedial, if imperfect, strategies include heated humidification, use of nasal decongestants, and intensive follow-up (cognitive behavioral therapy). Bilevel positive airway pressure is no better tolerated (Fig. 16–3).
Pragmatic Approach The author believes that thinner, younger patients with the primary complaint (needing remedying) of snoring are likely to use and benefit from an oral appliance, whereas older, heavier patients with the primary complaint of sleepiness require CPAP. Oral appliances can be considered also for those who refuse CPAP or in whom it fails. For completeness, surgical treatment must be mentioned. The most common surgical procedure is uvulopalatopharyngoplasty, in which the uvula and redundant soft tissue of the soft palate are resected. The reduction in apnea-hypopnea index is, however, small; only 41% of patients who undergo this procedure have an apnea-hypopnea index of less than 20.21 Results of newer techniques such as radiofrequency ablation have also been disappointing. However, for the patient with the primary complaint of snoring with little or no apnea, these procedures may be considered.
CENTRAL SLEEP APNEA Unlike obstructive apnea, in which there is marked respiratory effort against a closed upper airway, central sleep apnea (CSA) involves repetitive cessation of airflow in the absence of respiratory effort (Fig. 16–4).
Etiology and Pathogenesis
■
Figure 16–3. Continuous positive airway pressure (CPAP) mask.
CSA is a heterogeneous disease entity. In general, patients can be classified into two broad groups based on wakefulness levels of arterial carbon dioxide tension (PaCO2) and their ventilatory response to carbon dioxide. The first group consists of patients who tend to hypoventilate, have high levels of PaCO2 in the absence of intrinsic lung disease, and have a blunted ventilatory response to carbon dioxide. They tend to have recurrent episodes of respiratory failure. Patients within this group often have a clinical picture that merges into the spectrum of primary alveolar hypoventilation. Many of them are obese and have features of the obesity-hypoventilation syndrome. At the other end of the spectrum of CSA is the second group of patients, who either ventilate normally or hyperventilate and have normal or low wakefulness PaCO2 levels and a normal or exaggerated ventilatory response to carbon dioxide. These patients often present with clinical features typical of sleep apnea. Many of them have Cheyne-Stokes respiration (CSR). Even though the clinical and physiological differences between the two groups are marked, the two groups may have similar nocturnal apneic events and sleep architecture. CSR is characterized by alternating periods of hyperventilation and hypoventilation or apnea. It was first described by Hippocrates, but the classic descriptions were made by John Cheyne and William Stokes in the 19th century. The etiology and pathogenesis of CSR have been argued since the description by John Cheyne of a patient with both enlarged cerebral
208
Section
II
Sleep and Sleep Disorders
■
Figure 16–4. Central apnea. bpm, beats per minute; SpO2, pulse oximetry.
ventricles and heart disease who had periodic breathing. Autopsy studies have shown that most subjects with CSR have structural abnormalities of the brain. The disease is, however, seen frequently in patients with cardiovascular disease, particularly heart failure. Therefore, theories suggesting both neurological and cardiovascular mechanisms in the pathogenesis of the disease have been postulated. Proposed neurological abnormalities include cyclical medullary depression or medullary hyperexcitability alternating with periods of depression. Described cardiovascular abnormalities involve a circulatory delay related to heart failure. It is now known that both neurological and cardiovascular factors contribute to the pathogenesis of the disease and that if the relationship between these cardiac and neurological components is altered, the stability of the respiratory control system is lost. Such disturbance in the control system may arise by prolongation of the circulation time or by the system’s becoming more dependent on the arterial partial pressure of oxygen rather than carbon dioxide. Patients with heart failure and CSR often hyperventilate. They have lower PaCO2 both when awake and during sleep than do control subjects with heart failure but no CSR or CSA. Circulatory delay is a well-known feature of heart failure, and animal models suggest that circulatory delay can indeed lead to periodic breathing. Whether the changes observed in animal models of CSR are also valid in humans with heart failure remains controversial, because the magnitude of circulatory delay necessary to produce CSR in animals is rarely if ever seen in humans. Nonetheless, a strong correlation has been noted between circulation time and CSR-CSA cycle length in humans. Arousal and apnea termination are associated with the hyperventilation stage of CSR. Termination of apnea in patients with periodic breathing appears to be related largely to
chemoreceptor input, which is in contrast to the proposed mechanism for apnea termination in OSAH, in which mechanoreceptor input from the lungs is believed to be of primary importance. Arousals disrupt sleep and are associated with lack of slow-wave sleep but surprisingly little daytime hypersomnolence (Cormican, Williams 2005).
Prevalence The exact prevalence of CSA remains unclear. It does, however, appear to be particularly high in patients with neurological disease, including structural brainstem and cerebrovascular disease, as well as in patients with cardiac dysfunction. Several studies have shown that significant left ventricular impairment is associated with sleep-disordered breathing, CSA, and CSR. Sleep-disordered breathing has been reported to occur in up to 50% of patients with stable congestive heart failure, and left ventricular systolic dysfunction may be an independent risk factor for sleep apnea in these patients.22 One small study showed that approximately 40% of patients on a heart transplantation waiting list had periodic breathing and CSA. In another study, patients with left ventricular impairment caused by ischemic heart disease were found to have cyclical oxygen desaturations with a frequency 10 times higher than those observed in healthy controls.23 Similar results suggesting a very high prevalence of CSR and central apnea have been reported in patients with dilated cardiomyopathy.
Morbidity and Mortality In one relatively small study designed to determine the effect of CSA with or without CSR on morbidity and mortality, CSR was found in 60% of patients with CSA. Patients with severe
chapter 16 sleep apnea CSR had more central apneas, more but shorter desaturations, and more awakenings and spent more time awake during the night. Heart failure was associated with CSR. Even though patients with severe CSR were at almost twice the risk of dying than were those with no apnea, CSR was not found to be an independent risk factor for increased mortality risk. On the basis of the limited information available, it appears that even though CSA is associated with significant morbidity, the prognosis in patients with CSA is largely dependent on the underlying disease and not on the presence of sleep apnea per se.
Diagnosis A history of cardiac dysfunction, cerebrovascular disease, or structural brainstem disease should alert the clinician to the possibility of CSA. Obese patients may have central apnea as part of the obesity-hypoventilation syndrome. Daytime hypercapnia in the absence of structural lung disease may be an indicator of worsening hypoventilation during sleep. Most patients with CSA, however, have normal or exaggerated ventilation during wakefulness. Most patients with cardiac failure belong to this group. The bed partner may note apneic episodes in the absence of respiratory effort. Screening tests such as overnight oximetry and some more sophisticated techniques are often useful, but their sensitivity and specificity in patients with CSA have not been established. The diagnosis relies ultimately on demonstration of repetitive apnea or hypopnea in the absence of respiratory effort during polysomnography.
Treatment In patients with CSA, treatment of the underlying cause, whenever possible, is of paramount importance. In patients with heart failure, angiotensin-converting enzyme inhibition with captopril increases the proportion of sleep spent in slow-wave and rapid-eye-movement sleep. Apneic episodes, arousals, and episodes of desaturation are also reduced. In patients with advanced heart failure, CSR has been cured by heart transplantation.
1. Drugs Respiratory stimulants such as methylxanthines appear to be a logical treatment for CSA, but large controlled studies have not been performed. In two small studies that included patients with heart failure, administration of theophylline resulted in a reduction in CSR and an improvement in oxygen desaturation events and sleep disruption.24,25 Aminophylline has also been reported to ameliorate CSA caused by structural brainstem disease. The tricyclic antidepressant imipramine may also reduce the number of apneic episodes and improve both nocturnal and diurnal symptoms in patients with CSA. Oxygen administration appears to be beneficial for the patients with heart failure and CSA. Oxygen may not only relieve hypoxemia but may also reduce apneic episodes and arousals and may improve sleep duration and quality. Oxygen may also be beneficial in patients with primary alveolar hypoventilation and CSA, again not only by relieving hypoxia and its cardiovascular complications but also by reducing the number and duration of apneic events.
209
2. Noninvasive Continuous Positive Airway Pressure Use of nasal CPAP is a relatively well-described form of treatment for CSA. Its mechanism of action remains unclear, but CPAP administration may raise the level of PaCO2 above the apneic threshold in patients with CSA who have CSR. The acute hemodynamic effects of nasal CPAP administration in patients with heart failure remain highly controversial; authors of a number of small studies have reported conflicting results. Some investigators have reported adverse hemodynamic effects, including a fall in cardiac index and a rise in systemic vascular resistance, and acute left ventricular failure occurring shortly after initiation of treatment has been described.26 Conversely, other studies have reported that CPAP either does not change or may improve the cardiac index in patients with left ventricular dysfunction and elevated pulmonary arterial wedge pressure.27 Regardless of these findings, long-term administration of nasal CPAP to patients with advanced cardiac failure and CSR appears to reduce the number of apneic events and to improve symptoms of sleep apnea and oxygen saturation. Left ventricular function and inspiratory muscle strength may also improve, and daytime breathlessness and fatigue may be ameliorated. Moreover, nasal CPAP is known to improve the imbalance between sympathetic and parasympathetic tone in heart failure, as evidenced by reductions in both nocturnal and daytime catecholamine levels and an increase in heart rate variability. Nasal CPAP also appears to be effective in reducing hypoventilation and hypoxemia in patients with primary and central alveolar hypoventilation.
3. Noninvasive and Invasive PositivePressure Ventilation Although positive-pressure ventilation, including nasal bilevel positive airway pressure, seems to be a logical treatment for CSA, and although it has been used fairly extensively, little evidence regarding its use is available from controlled studies. It has, nonetheless, been shown to be effective in patients with CSA, including primary alveolar hypoventilation, in whom apneic events are reduced and hypercapnia and hypoxemia are corrected. It may be particularly useful in patients unresponsive to treatment with nasal CPAP or in those who hypoventilate.
CONCLUSIONS Sleep apnea is a common disturbance with many effects on sleep and daytime functioning. Obstructive sleep apnea is linked to many important adverse daytime consequences such as poor performance, accidents, hypertension, heart disease, stroke, and insulin resistance. The close association with obesity and the current epidemic of obesity mean that in the future, these disorders will become more prevalent, and thus clinicians need to remain alert to them and to be proactive in their evaluation of sleep. To this end, sleep-related questions should be routine and include those about snoring, daytime sleepiness (with the Epworth Sleepiness Scale [Table 16–1]), witnessed apneic events, nocturia, sleep duration, and sleep quality. Other parts of this book point out additional questions
210
Section
II
Sleep and Sleep Disorders
T A B L E 16–1. The Epworth Sleepiness Scale How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Use the following scale to choose the most appropriate number for each situation: 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing Situation Sitting and reading Watching TV Sitting inactive in a public place (e.g., a theater or a meeting) As a passenger in a car for an hour without a break Lying down to rest in the afternoon when circumstances permit Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in traffic
Chance of Dozing –––––––––– –––––––––– –––––––––– –––––––––– –––––––––– –––––––––– –––––––––– ––––––––––
Scoring Total the points from all situations. If your score is 1-6, you are getting enough sleep. A score of 7-8 is average. If your score is 9 and up, seek the advice of a sleep specialist in your area without delay.
of importance, such as those aimed at identifying cataplexy and restless legs syndrome and injury in sleep. Simple approaches to diagnosis through nocturnal oximetry are encouraged, and referral for more complex studies should be contemplated if results are equivocal.
K E Y
P O I N T S
●
Obstructive sleep apnea is a disease of increasing importance because of its neurocognitive and cardiovascular consequences, not least stroke and hypertension.
●
A characteristic history is found with snoring and sleepiness, and obesity is common among affected patients.
●
Diagnosis is often possible through the use of overnight pulse oximetry, which is recommended as the first diagnostic approach.
●
Nasal CPAP is unequivocally effective, particularly in substantially lowering blood pressure and relieving sleepiness.
Suggested Reading Boyd J, Petrof B, Hamid Q, et al: Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170:541-546. Cormican L, Williams AJ: Sleep disordered breathing in congestive heart failure. Br J Cardiol 2005; 12:171-172. Pepperell J, Ramdassingh-Dow S, Crosthwaite N, et al: Ambulatory blood pressure after therapeutic and subtherapeutic nasal con-
tinuous positive airway pressure for obstructive sleep apnea: a randomised parallel trial. Lancet 2002; 359:204-210. Young T, Peppard P, Gottlieb D: The epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165:1217-1239.
References 1. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J: The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999; 340:847-851. 2. Shahar E, Whitney CW, Redline S, et al: Sleep disordered breathing and cardiovascular disease: cross sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163:19-25. 3. Peppard P, Young T, Palta M, et al: Prospective study of the association between sleep disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384. 4. Young T, Palta M, Dempsey J, et al: The occurrence of sleepdisordered breathing among middle-aged adults. N Engl J Med 1993; 32:1230-1235. 5. Young T, Peppard P, Gottlieb D: The epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165:1217-1239. 6. Desai A, Cherkas L, Spector T, et al: Genetic influences in self reported symptoms of OSA—a Twin Study. Twin Res 2004; 7:589-595. 7. Redline S, Tishler PV, Hans MG, et al: Racial differences in sleep-disordered breathing in African-Americans. Am J Respir Crit Care Med 1997; 155:186-192. 8. Schwab RJ, Gupta KB, Gefter WB, et al: Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing: significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995; 152:1673-1689. 9. Bixler EO, Vgontzas AN, Ten Have T, et al: Effects of age on sleep apnea in men: prevalence and severity. Am J Respir Crit Care Med 1998; 157:144-148. 10. Boyd J, Petrof B, Hamid Q, et al: Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170:541-546. 11. Jenkinson C, Davies RJ, Mullins R, et al: Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 1999; 353:2100-2105. 12. Engleman HM, Martin SE, Kingshott RN, et al: Randomised placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome. Thorax 1998; 53:341-345. 13. Jenkinson C, Stradling J, Petersen S: Comparison of three measures of quality of life outcome in the evaluation of continuous positive airways pressure therapy for sleep apnea. J Sleep Res 1997; 6:199-204. 14. Berry RB, Gleeson K: Respiratory arousal from sleep: mechanisms and significance. Sleep 1997; 20:654-675. 15. Williams AJ, Houston D, Finberg S: Sleep apnea and essential hypertension. Am J Cardiol 1985; 55:1019-1022. 16. Pepperell J, Ramdassingh-Dow S, Crosthwaite N, et al: Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnea: a randomised parallel trial. Lancet 2002; 359: 204-210. 17. Yaggi HK, Concato J, Kernan WN, et al: Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353:2034-2041. 18. Ip M, Lam B, Ng M, et al: Obstructive sleep apnea is independently associated with insulin resistance. Am J Res Crit Care 2002; 165:670-676.
chapter 16 sleep apnea 19. Wilcox I, McNamara SG, Collins F, et al: Syndrome Z: the interaction of sleep apnea, vascular risk factors and heart disease. Thorax 1998; 53:S5-S28. 20. Williams AJ, Yu G, Santiago S, et al: Screening for sleep apnea using pulse oximetry. Chest 1991; 100:631-635. 21. Hudgel DW: Availability of a meta-analysis of the surgical treatment of obstructive sleep apnea. Chest 1997; 111:265-266. 22. Markides V, Williams AJ: Detection of sleep apnea in the cardiac care unit. In Mohsenifar Z, Shah PK, eds: Practical Critical Care Cardiology. New York: Marcel Dekker, 1998, pp 90-124. 23. Rasche K, Hoffarth HP, Marek W, et al: Nocturnal oxygen saturation in patients with coronary heart disease dependent on degree of left ventricular functional impairment. Pneumonologie 1991; 45:261-264.
211
24. Dowdell WT, Javaheri S, McGinnis W: Cheyne Stokes respiration presenting as sleep apnea syndrome. Am Rev Respir Dis 1990; 141:871-879. 25. Tomcsanyi J, Karlocai K: Effect of theophylline on periodic breathing in congestive heart failure measured by transcutaneous oxygen monitoring. Eur J Clin Pharmacol 1994; 46:173174. 26. Liston R, Deegan PC, McCreery C, et al: Haemodynamic effects of nasal continuous positive pressure in severe congestive heart failure. Eur Respir J 1995; 8:430-435. 27. Naughton MT, Rahman MA, Hara K, et al: Effect of continuous airway pressure on left ventricular transmural pressure in patients with congestive cardiac failure. Circulation 1995; 91:1725-1731.
CHAPTER
17
TOURETTE’S SYNDROME, TICS AND OBSESSIVE-COMPULSIVE DISORDERS ●
●
●
●
Anette Schrag and Mary M. Robertson
TICS AND GILLES DE LA TOURETTE SYNDROME Once considered a rarity, Gilles de la Tourette syndrome is now recognized to be a relatively common disorder, which may be associated with considerable psychiatric comorbidity and impaired psychosocial functioning. Gilles de la Tourette syndrome is defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) as a combination of multiple motor tics and at least one vocal tic that cannot be explained by another cause and has persisted for at least 1 year.1,2 The current criteria no longer require that these tics produce significant distress or impairment, and a large proportion of people who fulfill these criteria are not aware of their tics or are not disturbed by them. However, in the tertiary referral setting and in patients with more severe or frequent tics or with associated comorbidity, there are both considerable psychosocial impairment and reduced quality of life.3 Gilles de la Tourette syndrome is frequently undiagnosed; tics may be misinterpreted as a “nervous habits” or, particularly in children, as inattention or inability to sit still. On occasion, tics are mistaken for another movement disorder or a psychiatric disease. In addition to Gilles de la Tourette syndrome, tics can occur in chronic tic disorders that are purely motor or verbal and in transient tic disorders that do not last more than 1 year. The latter are common phenomena in childhood. Tics may also occur as a side effect of drugs or toxins and may be a manifestation of an underlying neurological disorder, usually associated with other phenomena but occasionally as the first or only manifesting symptom (see later discussion).
Characteristics of Tics Tics are abrupt, recurrent, and stereotyped but nonrhythmic movements. They can affect any body part, can be simple or complex, and manifest with motor or vocal actions. Examples of simple motor tics are eye blinking, nose twitching, eye rolling, and head nodding, and simple verbal tics include sniffing, throat clearing, or coughing. Examples of complex motor tics are jumping, touching, or twirling, and complex verbal tics include barking or uttering a string of words. Many patients experience a premonitory sensation before a tic, which can be localized or generalized. Characteristically, tics increase with stress and anxiety, but also with relaxation, and can be sup-
214
pressed for a period of time by concentration. However, this typically leads to a buildup of tension, and there is often a rebound after the suppression of tics. In Gilles de la Tourette syndrome, tics wax and wane over time, moving from one body part to another or changing characteristics. In addition to tics, other phenomena in this syndrome include echolalia (copying what other people say), echopraxia (copying what other people do), palilalia (repeating the last word or part of a sentence) and palipraxia (repeating the last action). Coprolalia (inappropriate, involuntary swearing) and copropraxia (inappropriate, involuntary obscene gestures) occur only in about 10% to 15% of patients with Gilles de la Tourette syndrome and are frequently disguised (e.g., by coughing or transformation of the word). The onset of motor tics in this syndrome is in childhood and occurs between ages 2 and 21 years; on average, onset occurs at ages 5 to 7 years. Verbal tics typically manifest a few years later, and coprolalia has a mean onset at age 15 years.
Differential Diagnosis of Tics Other brief movement disorders may be difficult to distinguish from tics. Tics may particularly resemble dystonia, tremor, myoclonus, chorea, and akathisia (for a review of hyperkinetic movement disorders, see Chapters 33 to 37). They also need to be distinguished from mannerisms (bizarre execution of purposeful acts), stereotypies (purposeless, repetitive movements often over long periods of time, as in a learning disability), and other medical conditions, such as coughing or sniffing in upper respiratory tract infections or eye blinking in allergy or blepharospasm. Particularly difficult may be the distinction between tics and other features of Gilles de la Tourette syndrome, such as obsessive-compulsive behaviors (OCBs), attention deficit/hyperactivity disorder (ADHD), antisocial behaviors and movement disorders associated with treatment.4 These differentiations are particularly important for appropriate pharmacological management.
Epidemiology Tics occur in 3% to 22% of children at some stage during their development5 but are transient in the majority. The more severe Gilles de la Tourette syndrome affects approximately 1% of chil-
chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders dren, and prevalence rates range from 0.4 to 1.8%.6-13 However, although the disorder typically starts in childhood, on average between the ages of 5 and 7 years,14,15 and typically increases until the age of 13 years, it often improves in adolescence so that by the age of 18 years, 50% of those affected are virtually free of tics.16 The prevalence rate is higher in special educational populations, such as those with learning difficulties17 or autism.18 About three to four times as many boys as girls are affected.14 Prevalence rates and clinical characteristics are broadly similar across countries.14 In rare cases, tic disorders with both motor tics and verbalizations begin in adulthood. Some of these patients have been described to have had compulsive tendencies in childhood or a family history of tics or OCB. In comparison with patients with Gilles de la Tourette syndrome that started in childhood, patients with adult-onset tic disorder more often had a potential trigger event, have more severe symptoms and greater social morbidity, and increased sensitivity and poorer response to neuroleptics.19
Diagnosis Tics and Gilles de la Tourette syndrome are clinical diagnoses. In cases of classic Gilles de la Tourette syndrome, no diagnostic tests are required. However, atypical cases, such as those without waxing and waning over time, those with adult onset, and particularly those with abnormalities on neurological examination, should be further investigated, including measurements of copper and ceruloplasmin for Wilson’s disease, full blood count for acanthocytes, and magnetic resonance imaging of the brain. Neuroimaging has also provided insight in the pathophysiology of Gilles de la Tourette syndrome: reduced volumes and abnormal asymmetry as well as altered dopamine metabolism of the basal ganglia, particularly the caudate20,21, and frontal lobe abnormalities,22 all of which implicate the frontal-striatal-thalamic-frontal circuitry.
215
A genes have been implicated,34,36 and linkage to chromosome 17 has been demonstrated.37 However, despite many years of research by a number of groups worldwide, no single genetic cause has been found for Gilles de la Tourette syndrome. This suggests that other factors also play a role in the etiology of this disorder. An increasingly popular hypothesis suggests that Gilles de la Tourette syndrome is the product of an interaction between a genetic vulnerability and environmental factors. Stressors at various times of the life cycle have been implicated, particularly perinatal injury, but also stressors during pregnancy, such as severe nausea, vomiting, and antiemetic medication, which may alter dopaminergic receptors.16,38-41 Particularly intriguing has been the association of group A β-hemolytic streptococcal infections with a syndrome of sudden-onset neuropsychiatric disturbances, including OCD, tics, and other psychopathology in children. This syndrome has been termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).42 More recently, laboratory evidence of streptococcal infection in patients with Gilles de la Tourette syndrome has been reported, including elevated antistreptolysin O titers and anti–basal ganglia antibodies in up to 25% of patients with Gilles de la Tourette syndrome.43,44 An autoimmune mechanism has therefore been suggested as a contributor to the development of tics in this syndrome.44,45 Although the majority of studies have supported this notion,43-46 others have disputed this association,47,48 and whether anti–basal ganglia antibodies play a role in the development of Gilles de la Tourette syndrome currently remains a controversy.17 Although it seems clear that there is a strong genetic component in the etiology of Gilles de la Tourette syndrome and it seems that streptococcal infection causes the syndrome, it may be that individuals inherit a susceptibility to this syndrome and that environmental factors such as perinatal injury or an autoimmune response to streptococcal infections trigger the development of this syndrome in some individuals.
Etiology Tics can be symptomatic; for example, in neurodegenerative conditions, such as Huntington’s disease, they can be the first manifesting symptom. They can also represent a sequela of trauma or encephalitis, or they can represent extrapyramidal side effects of neuroleptic medication or cocaine abuse. However, the most common cause for chronic tic disorders is Gilles de la Tourette syndrome; this applies to adults, with childhood tics that have recurred or in whom previous tics may have been unnoticed or forgotten until an increase in tic severity brought them to medical attention. Suggestions for the etiology of Gilles de la Tourette syndrome have included genetic influences, infections, and perinatal difficulties. There is a wealth of evidence pointing toward genetic causes, including family studies, which suggested an autosomal dominant inheritance pattern with variable expression and penetrance.23-25 There is also growing evidence for bilineal transmission, with the father typically affected by childhood tics and the mother by symptoms of obsessive-compulsive disorder (OCD).26-28 Genetic studies have led to the identification of several regions of interest on chromosomes 2, 4, 8, and 1129-32 and, more recently regions of interest on the chromosomes 5, 10, 13,33 7,34 and 18.35 In addition, the DRD4 and MOA-
Psychopathology Gilles de la Tourette syndrome is associated with increased rates of a number of comorbid psychiatric conditions (see Robertson, 200049 and 200350). Although some of these are likely to represent a manifestation of or be integral to Gilles de la Tourette syndrome, others may be the consequence of the social and emotional consequences of this disorder. An investigation of 3500 patients with Gilles de la Tourette syndrome worldwide demonstrated that across all ages, 88% of individuals had associated psychiatric comorbidity, and male patients were more likely to have comorbid disorders.14 Only those with comorbid disorders had more severe behavioral problems such as anger control problems and self-injurious behavior, as well as sleep difficulties and coprolalia. The presence of such behavioral problems should therefore alert the clinician to the possible presence of comorbidity, the management of which is often at least as important as tic reduction. The spectrum of comorbid disorders includes OCD, other anxiety disorders, mood disorders, ADHD, and other behavior disorders, including self-injurious behavior.51 Although the exact relationship of these to Gilles de la Tourette syndrome is unclear, a strong association exists between Gilles de la Tourette
216
Section
III
Neuropsychiatry
syndrome and OCD and OCB, and a number of studies have suggested that these reflect the variable expression of a single disorder.24,26,27,50 OCD in patients with Gilles de la Tourette syndrome has, however, been found to differ in clinical manifestation from primary OCD, with predominant checking, counting, and symmetry obsessions and less frequent obsessions with contamination and violence.52-57 The rate of ADHD is also increased in patients with Gilles de la Tourette syndrome, and although the relationship between Gilles de la Tourette syndrome and ADHD is less clear, it has been suggested that some types are related genetically to Gilles de la Tourette syndrome. Depending on whether or not the International Classification of Diseases and Health-Related Problems, 10th Revision, or DSM-IV-TR criteria are used, the prevalence of ADHD in youngsters is between 1% and 9%.58 In patients with Gilles de la Tourette syndrome, the prevalence of ADHD is much greater and may be as high as 60%.14 This is not confined to chronic populations: Even in an epidemiological study conducted on members of the Israeli Defense Force, the prevalence of ADHD in Gilles de la Tourette syndrome was 8%, in comparison with 4% in the population without Gilles de la Tourette syndrome, a difference that was statistically significant.59 Personality disorders in adulthood in patients with Gilles de la Tourette syndrome are likely to be related to comorbid ADHD in childhood rather than to the syndrome itself. Whether other psychiatric comorbid conditions such as conduct disorder, oppositionaldefiant disorder, personality disorder, rage, and impulsivity are clearly more prevalent in patients with Gilles de la Tourette syndrome or their apparent prevalence is a result of referral bias in Gilles de la Tourette syndrome clinics is currently unknown. The multiple medications used for Gilles de la Tourette syndrome (see later discussion) may lead to increase. Anxiety and cognitive disorders, and anxiety may occur as a result of having Gilles de la Tourette syndrome and its social and personal consequences. The rate of depression, on the other hand, is clearly increased among patients with Gilles de la Tourette syndrome and is likely to be multifactorial in origin.60-63
Prognosis Clearly, for symptomatic tics in the context of another neurological disorder or as a drug effect, the prognosis is associated with the underlying disorder. The prognosis of individuals with Gilles de la Tourette syndrome varies widely; whereas those with mild tics without coprolalia or associated comorbidity mostly do not suffer impairment of social or personal function, those at the other end of the spectrum can be severely disabled. Children may be disadvantaged in school, particularly if comorbidity is present,64,65 but, as mentioned previously, tics often improve in adolescence.15,57 When the affected individuals and their environments receive appropriate explanation of this disorder and understand it, most do not need regular follow-up. Adult-onset cases appear to have worse morbidity and worse response to treatment, but this is rare. Overall, health-related quality of life has been shown to be worse in patients with Gilles de la Tourette syndrome than in controls, although it is better than in patients with intractable epilepsy.3 Factors associated with poorer health-related quality of life in this study in a tertiary referral center were employment status, tic severity, obsessive-compulsive symptoms, anxiety, and depression.
Management Many individuals with mild Gilles de la Tourette syndrome are not aware of their tics or do not find them bothersome and may never come to medical attention. For those who have come to medical attention, a diagnosis of their condition, explanation, and reassurance are often all that is required. When medication is considered in more severe cases, patient and physician should take into account the severity, frequency, and interference of tics; the presence and severity of comorbid conditions; the patient’s life style, requirements, expectations, and attitudes; and the long-term nature of pharmacological treatments, which may have reversible or irreversible side effects. Ideally, treatment should be multidisciplinary.
Nonpharmacological Treatment Supportive psychotherapy and psychological education are very important for all patients and their families, particularly if the patients are young. More specific behavioral treatment has been shown to produce better results than psychotherapy in adult patients with Gilles de la Tourette syndrome and include habit reversal training, graded exposure, social skills training, imaginal exposure, massed negative practice, contingency management, relaxation training, and biofeedback.66,67
Pharmacological Treatment Pharmacological treatment is based primarily on neuroleptic medication, and the individual’s response is idiosyncratic. Thus, an individual may respond to one particular neuroleptic agent but not another. Haloperidol, pimozide, sulpiride, and tiapride have all been shown to be more effective than placebo, and the doses required for tics in Gilles de la Tourette syndrome are much lower than those used for schizophrenia or mania. Although side effects at these doses are less common, all these agents carry the risk of extrapyramidal side effects, including acute dystonic reactions, parkinsonism, and tardive dyskinesia. In addition, sedation, cognitive side effects, depression, and social phobias can be dose limiting. Pimozide also must be used with caution because it has a higher rate of cardiac side effects than do other neuroleptic medications. In addition, an increase in prolactin levels with these drugs may necessitate discontinuation. The newer “atypical” antipsychotic agents have been demonstrated to be useful in treating patients with Gilles de la Tourette syndrome. Their chief advantage is the lower risk of extrapyramidal side effects. The main side effect is weight gain and, in some individuals, the precipitation of diabetes mellitus. It is therefore recommended that fasting glucose levels be checked in patients, particularly if they have put on weight. The atypical antipsychotic agents successfully used for treatment of Gilles de la Tourette syndrome have included risperidone,68 olanzapine,69 quetiapine,70 aripiprazole,71 and ziprasidone.72 It has also been suggested that quetiapine does not lead to hyperprolactinemia73 and may therefore merit further studies in patients with Gilles de la Tourette syndrome. In patients with severe vocal tics, which may not respond well to oral pharmacological treatment, botulinum toxin injections may be useful.74 Other suggested alternatives for the treatment of Gilles de la Tourette syndrome have included the neuroleptics amisulpride, aripiprazole, ziprasidone, fluphenazine, metoclopramide,
chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders piquindone, and tetrabenazine and agents from other substance groups, such as clonazepam, calcium channel antagonists, celecoxib, dopamine agonists, and selegiline. In severe, medically intractable cases, various surgical approaches have been tried with little success.75 However, in a literature review, Rauch and associates76 suggested that there is no compelling evidence that any neurosurgical procedure is superior to all others, and such surgery is not recommended outside specialist centers. Deep brain stimulation of the thalamus, which is largely reversible, is currently being explored as a treatment option for severe tics and OCD.77 The treatment of comorbid conditions requires additional drug choices. OCD and OCB often respond to selective serotonin reuptake inhibitors or the tricyclic antidepressant clomipramine, which inhibits both serotonin and noradrenaline uptake. In some countries, the use of some of these agents (e.g., paroxetine) is contraindicated in children. When ADHD exists comorbidly, the α2-adrenergic agonist clonidine and, in the United States, guanfacine can be useful for tics, impulse control, and ADHD, but electrocardiography and blood pressure control are recommended for patients taking these drugs. These agents must not be discontinued suddenly, because of rebound hypertension. Children with ADHD may require the addition of a psychostimulant such as methylphenidate. Previous concerns about exacerbation of tics with this medication have not been substantiated, and the management of ADHD may be more important than that of tics. An alternative may be the nonstimulant selective norepinephrine reuptake inhibitor atomoxetine.78,79 Depression in Gilles de la Tourette syndrome should be treated like primary depression or, for depression associated with other chronic disorders, by using cognitivebehavioral approaches, education, psychotherapeutic treatments, and pharmacotherapy.
217
OBSESSIVE-COMPULSIVE DISORDER Obsessions are intrusive and recurrent thoughts, which include intrusive doubts, images, impulses, or ruminations (continuous pondering). They are recognized by affected individuals as their own thoughts, but they are characteristically egodystonic—that is, unwelcome and uncomfortable—to the individual, who usually tries to avoid or suppress them.52 Common obsessions are concerned with contamination, violence, sex, blasphemy, and numbers. Rarer obsessions are arithmomania (obsession with counting), onomatomania (the desire to utter a forbidden word), and folie de pourquoi (irresistible habit of repetitively asking the same banal question). Compulsions are carried out in response to these obsessions in a stereotyped manner, with reluctance, in order to neutralize or prevent a dreaded event. However, they are often not realistically related to the obsession, are considered unreasonable by the individual, and are excessive and time consuming. If the compulsion is suppressed, anxiety results until the compulsive behavior is performed. Common compulsive behaviors include washing, checking, arranging, counting, or mental rituals. Patients try to avoid situations that may provoke obsessions. Although obsessions and compulsions are common in the general population, a diagnosis of OCD according to DSMIV-TR requires that obsessions and compulsions cause marked distress or significantly interfere with a person’s functioning and do not occur in the context of a medical illness. There is considerable phenotypic variability of obsessions and compulsions, and the existence of specific subtypes has therefore been postulated: for example, familial and related to tic disorders, familial and unrelated to tics, and sporadic OCD.80 However, the existence of these different subtypes has been controversial.81
Conclusions and Recommendations
Epidemiology
Tics and Gilles de la Tourette syndrome occur more frequently than previously believed but are frequently unrecognized. The diagnoses of tics and Gilles de la Tourette syndrome are clinical, but diagnostic differentiation of tics from other movement disorders, associated phenomena in Gilles de la Tourette syndrome, and side effects of medication can be difficult. Tics may also occur in the context of other neurological conditions and as a consequence of neuroleptic treatment or drug abuse. In adults and those presenting with atypical features, these differential diagnoses should be explored. However, only in patients with atypical features are investigations required. In Gilles de la Tourette syndrome, there is no doubt that genetic factors play an important role in its etiology, but no single gene has been identified, and environmental factors such as infection or perinatal injury may also play a role. Tics in Gilles de la Tourette syndrome are often associated with significant psychiatric comorbidity and impaired psychosocial functioning and quality of life. Although tics in Gilles de la Tourette syndrome often improve in adolescence, patients with a more severe tic disorder that interferes with their lives and those with associated psychiatric comorbid conditions often require long-term treatment with pharmacological or nonpharmacological approaches. These should be tailored to the individual’s needs, with consideration of comorbid conditions and the context of the individual’s life.
OCD has a lifetime prevalence of 1.8% to 3.5% in the population with an onset in childhood or adolescence and a slight preponderance among girls.82-84 OCBs are much more common and may be part of the spectrum of normal behavior. OCD occurs worldwide with similar core features, but the content of the obsessions appears to be related to cultural context.85
Diagnosis Obsessions and compulsions are diagnosed clinically. Obsessions and compulsions should be distinguished from psychosis, in which voices or thoughts are experienced as coming from outside; from impulsive thoughts, which are egosyntonic (i.e., not uncomfortable or alien); and from rituals, which are purposeful actions, often with a cultural significance. Tics and compulsions can be difficult to distinguish, and they overlap. However, compulsions are typically preceded by obsessions and cognitions, and suppression of compulsions is typically followed by anxiety, whereas tics are typically preceded premonitory sensations and an urge to perform the tic, with no anxiety after suppression but physical discomfort and frequent rebound of tics afterward. Obsessions and compulsions are also common in other psychiatric disorders, including depression, schizophrenia, and
218
Section
III
Neuropsychiatry
obsessional (anankastic) personality disorder, and they overlap with Gilles de la Tourette syndrome, as discussed previously. Segregation analysis in families with Gilles de la Tourette syndrome and OCD suggested that OCD and Gilles de la Tourette syndrome are variant expressions of the same syndrome. A concurrent obsessional (anankastic) personality is present in about 70% of cases.52 They may also occur in generalized anxiety disorder, puerperal illness (as a fear of harming the baby), anorexia nervosa, Huntington’s disease, encephalitis lethargica, PANDAS, manganese poisoning and after head injury. In these psychiatric and neurological disorders, other features are present, but even in pure OCD, soft neurological signs such as astereognosia or agraphesthesia may be present.52
Etiology Obsessions were originally believed to be rooted in repressed impulses or in an aggressive or sexual nature,86 and other explanations have included obsessions as a result of aberrant learning.87 An increase in severity of OCD is also often seen when depression or stressful life events occur. However, obsessions and compulsions are seen in the context of a number of neurological disorders, such as Huntington’s disease or encephalitis lethargica, implicating underlying brain abnormalities, particularly in the frontal cortex and basal ganglia. Functional imaging studies and neuropsychological testing also provide increasing evidence that OCD is associated with abnormal functioning of the orbitofrontal cortex, the cingulate, and the caudate, and biochemical abnormalities, especially involving serotonin, are believed to be important in the pathophysiology of OCD.88 Increased rates of obsessions and compulsions in families of patients with OCD suggest that genetic factors play a role in the etiology of OCD, and twin studies with higher concordance rates in monozygous twins than in dizygous twins have supported the importance of genetic factors. In addition, abrupt onset or exacerbations of OCD or tics or both have been described after streptococcal infections (see previous discussion), suggestive of environmental causes. Neuroimaging studies reveal increased basal ganglia volumes, and the proposed cause involves the cross-reaction of streptococcal antibodies with basal ganglia tissue. A genetic susceptibility to PANDAS has been postulated.89
Prognosis Mild cases of obsessions and compulsions are often self-limited within 1 year. OCD is a chronic disorder but typically runs a fluctuating course with periods of long remissions and the greatest prevalence in mid-adult life. A meta-analysis of studies with up to 16 years’ follow-up revealed persistence rates of 41% for full OCD and 60% for full or subthreshold OCD.90 Comorbid psychiatric illness and poor initial treatment response were poor prognostic factors. Depression and abuse of alcohol and anxiolytics is common. Quality of life has been found to be significantly related to severity of obsessions, whereas the severity of compulsive rituals did not affect quality-of-life ratings. However, the single greatest predictor of poor quality of life was comorbid depression severity,91 and suicide rates are increased, particularly in
patients with comorbid depression. This is contrary to previous notions that suicide is uncommon in patients with OCD.
Management In many cases, obsessions and compulsions do not necessitate treatment, and the fluctuating course needs to be considered before treatment starts. In cases in which treatment is required, cognitive-behavioral therapy has been successful, including exposure and response prevention for compulsions, and habituation training and thought-stopping for obsessions.92 Psychoeducation can also be a valuable source. Pharmacological treatment is often effective, although up to 50% of patients may require more than one treatment trial. Effect medication includes the serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), and the tricyclic antidepressant clomipramine (which has a less favorable side effect profile). Of importance is that the doses of these medications required for treatment of OCD are often higher than those for depression. In addition, in severe cases, augmentation with neuroleptic medication, including risperidone and olanzapine, has been suggested. In cases in which all other classic treatments have failed after a minimum of 5 years, psychosurgery is occasionally considered. Capsulotomy, cingulotomy, subcaudate tractotomy, and limbic leukotomy, performed by radiofrequency thermolesions or radiosurgery,93-96 and the largely reversible deep brain stimulation97 have all been used. These surgical approaches are aimed at altering the neural circuits between the frontal lobes and different structures of the limbic system, but they are used very rarely.
Conclusions and Recommendations OCD is a common disorder with a wide phenotype, and it overlaps with Gilles de la Tourette syndrome. There may be different subtypes of OCD, and although streptococcal infection has been associated with OCD and with symptoms of Gilles de la Tourette syndrome, genetic factors are clearly implicated in OCD. OCD can also occur in the context of other psychiatric or neurological syndromes and is then associated with greater morbidity and worse quality of life. Management comprises cognitive-behavioral treatment and a number of pharmacological treatment options; in extremely rare cases of intractable and disabling OCD, patients may undergo surgery. Future research will address the etiological questions relating to genetic and environmental causes of OCD, its overlap with other psychiatric conditions, and improved management options.
K E Y
P O I N T S
●
Gilles de la Tourette syndrome affects approximately 0.5% to 1% of all school-aged children, but severity of tics often improves in adolescence.
●
Tics also occur in other neurological disorders and as a result of neuroleptic medication or drug abuse, particularly in adults.
chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders ●
There is a strong genetic component in the etiology of Gilles de la Tourette syndrome, but no single gene has been identified; it is likely to be multifactorial, including possible infectious or perinatal factors.
●
Gilles de la Tourette syndrome is frequently associated with obsessive-compulsive symptoms and other psychopathology, including depression and ADHD; these affective and behavioral disorders are major contributors to impaired psychosocial functioning.
●
Management of Gilles de la Tourette syndrome focuses on the aspects of the syndrome that are individually most important, including tics and the behavioral and affective disorders.
●
OCD affect approximately 1.9% to 3.5% of the population, but milder obsessive-compulsive symptoms are more common.
●
Obsessions are repetitive, intrusive thoughts that are unpleasant to the individual but are recognized as the individual’s own; compulsive behaviors are carried out to neutralize or prevent obsessions.
●
Treatment of obsessive-compulsive symptoms includes cognitive-behavioral therapy, supportive therapy, and pharmacotherapy, including selective serotonin reuptake inhibitors and clomipramine.
Suggested Reading Husted DS, Shapira NA: A review of the treatment for refractory obsessive-compulsive disorder: from medicine to deep brain stimulation. CNS Spectr 2004; 9:833-847. Leckman JF: Phenomenology of tics and natural history of tic disorders. Brain Dev 2003; 25(Suppl 1):S24-S28. Pauls DL: An update on the genetics of Gilles de la Tourette syndrome. Psychosom Res 2003; 55:7-12. Robertson MM: Tourette syndrome, associated conditions and the complexities of treatment. Brain 2000; 123(Pt 3):425-462. Singer HS: Tourette’s syndrome: from behaviour to biology. Lancet Neurol 2005; 4:149-159.
References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC: American Psychiatric Association, 2000. 2. World Health Organization: Internation Classification of Diseases and Health-Related Problems, 10th revision. Geneva: World Health Organization, 1992. 3. Elstner K, Selai CE, Trimble MR, et al: Quality of life (QOL) of patients with Gilles de la Tourette’s syndrome. Acta Psychiatr Scand 2001; 103:52-59. 4. Kompoliti K, Goetz CG: Hyperkinetic movement disorders misdiagnosed as tics in Gilles de la Tourette syndrome. Mov Disord 1998; 13:477-480. 5. Gadow KD, Nolan EE, Sprafkin J, et al: Tics and psychiatric comorbidity in children and adolescents. Dev Med Child Neurol 2002; 44:330-338. 6. Kurlan R, McDermott MP, Deeley C, et al: Prevalence of tics in school children and association with placement in special education. Neurology 2001; 57:1383-1388.
219
7. Hornsey H, Banerjee S, Zeitlin H, et al: The prevalence of Tourette syndrome in 13–14-year-olds in mainstream schools. J Child Psychol Psychiatry 2001; 42:1035-1039. 8. Kadesjo B, Gillberg C: Tourette’s disorder: epidemiology and comorbidity in primary school children. J Am Acad Child Adolesc Psychiatry 2000; 39:548-555. 9. Khalifa N, von Knorring AL: Prevalence of tic disorders and Tourette syndrome in a Swedish school population. Dev Med Child Neurol 2003; 45:315-319. 10. Lanzi G, Zambrino CA, Termine C, et al: Prevalence of tic disorders among primary school students in the city of Pavia, Italy. Arch Dis Child 2004; 89:45-47. 11. Wang HS, Kuo MF: Tourette’s syndrome in Taiwan: an epidemiological study of tic disorders in an elementary school at Taipei County. Brain Dev 2003; 25(Suppl 1):S29-S31. 12. Jin R, Zheng RY, Huang WW, et al: [Study on the prevalence of Tourette syndrome in children and juveniles aged 7-16 years in Wenzhou area]. Zhonghua Liu Xing Bing Xue Za Zhi 2004; 25:131-133. 13. Mason A, Banerjee S, Eapen V, et al: The prevalence of Tourette syndrome in a mainstream school population. Dev Med Child Neurol 1998; 40:292-296. 14. Freeman RD, Fast DK, Burd L, et al: An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries. Dev Med Child Neurol 2000; 42:436-447. 15. Leckman JF, Zhang H, Vitale A, et al: Course of tic severity in Tourette syndrome: the first two decades. Pediatrics 1998; 102:14-19. 16. Leckman JF, Dolnansky ES, Hardin MT, et al: Perinatal factors in the expression of Tourette’s syndrome: an exploratory study. J Am Acad Child Adolesc Psychiatry 1990; 29:220-226. 17. Eapen V, Robertson MM, Zeitlin H, et al: Gilles de la Tourette’s syndrome in special education schools: a United Kingdom study. J Neurol 1997; 244:378-382. 18. Baron-Cohen S, Scahill VL, Izaguirre J, et al: The prevalence of Gilles de la Tourette syndrome in children and adolescents with autism: a large scale study. Psychol Med 1999; 29:11511159. 19. Eapen V, Lees AJ, Lakke JP, et al: Adult-onset tic disorders. Mov Disord 2002; 17:735-740. 20. Peterson BS, Thomas P, Kane MJ, et al: Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry 2003; 60:415-424. 21. Singer HS, Szymanski S, Giuliano J, et al: Elevated intrasynaptic dopamine release in Tourette’s syndrome measured by PET. Am J Psychiatry 2002; 159:1329-1336. 22. Kates WR, Frederikse M, Mostofsky SH, et al: MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome. Psychiatry Res 2002; 116:6381. 23. Curtis D, Robertson MM, Gurling HM: Autosomal dominant gene transmission in a large kindred with Gilles de la Tourette syndrome. Br J Psychiatry 1992; 160:845-849. 24. Eapen V, Pauls DL, Robertson MM: Evidence for autosomal dominant transmission in Tourette’s syndrome. United Kingdom cohort study. Br J Psychiatry 1993; 162:593-596. 25. Pauls DL, Leckman JF: The inheritance of Gilles de la Tourette’s syndrome and associated behaviors. Evidence for autosomal dominant transmission. N Engl J Med 1986; 315: 993-997. 26. Kurlan R, Eapen V, Stern J, et al: Bilineal transmission in Tourette’s syndrome families. Neurology 1994; 44:23362342. 27. McMahon WM, van de Wetering BJ, Filloux F, et al: Bilineal transmission and phenotypic variation of Tourette’s disorder in a large pedigree. J Am Acad Child Adolesc Psychiatry 1996; 35:672-680.
220
Section
III
Neuropsychiatry
28. Hanna PA, Janjua FN, Contant CF, et al: Bilineal transmission in Tourette syndrome. Neurology 1999; 53:813-818. 29. Simonic I, Nyholt DR, Gericke GS, et al: Further evidence for linkage of Gilles de la Tourette syndrome (GTS) susceptibility loci on chromosomes 2p11, 8q22 and 11q23-24 in South African Afrikaners. Am J Med Genet 2001; 105:163-167. 30. Simonic I, Gericke GS, Ott J, et al: Identification of genetic markers associated with Gilles de la Tourette syndrome in an Afrikaner population. Am J Hum Genet 1998; 63:839-846. 31. A complete genome screen in sib pairs affected by Gilles de la Tourette syndrome. The Tourette Syndrome Association International Consortium for Genetics. Am J Hum Genet 1999; 65:1428-1436. 32. Merette C, Brassard A, Potvin A, et al: Significant linkage for Tourette syndrome in a large French Canadian family. Am J Hum Genet 2000; 67:1008-1013. 33. Curtis D, Brett P, Dearlove AM, et al: Genome scan of Tourette syndrome in a single large pedigree shows some support for linkage to regions of chromosomes 5, 10 and 13. Psychiatr Genet 2004; 14:83-87. 34. Diaz-Anzaldua A, Joober R, Riviere JB, et al: Association between 7q31 markers and Tourette syndrome. Am J Med Genet A 2004; 127:17-20. 35. Cuker A, State MW, King RA, et al: Candidate locus for Gilles de la Tourette syndrome/obsessive compulsive disorder/ chronic tic disorder at 18q22. Am J Med Genet A 2004; 130: 37-39. 36. Diaz-Anzaldua A, Joober R, Riviere JB, et al: Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population. Mol Psychiatry 2004; 9:272-277. 37. Paschou P, Feng Y, Pakstis AJ, et al: Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples: 17q25 is a putative susceptibility region. Am J Hum Genet 2004; 75:545-560. 38. Santangelo SL, Pauls DL, Goldstein JM, et al: Tourette’s syndrome: what are the influences of gender and comorbid obsessive-compulsive disorder? J Am Acad Child Adolesc Psychiatry 1994; 33:795-804. 39. Lees AJ, Robertson M, Trimble MR, et al: A clinical study of Gilles de la Tourette syndrome in the United Kingdom. J Neurol Neurosurg Psychiatry 1984; 47:1-8. 40. Burd L, Severud R, Klug MG, et al: Prenatal and perinatal risk factors for Tourette disorder. J Perinat Med 1999; 27:295-302. 41. Burnstein MH: Tourette’s syndrome and neonatal anoxia: further evidence of an organic etiology. J Psychiatry Neurosci 1992; 17:89-93. 42. Swedo SE, Leonard HL, Garvey M, et al: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998; 155:264-271. 43. Cardona F, Orefici G: Group A streptococcal infections and tic disorders in an Italian pediatric population. J Pediatr 2001; 138:71-75. 44. Church AJ, Dale RC, Lees AJ, et al: Tourette’s syndrome: a cross sectional study to examine the PANDAS hypothesis. J Neurol Neurosurg Psychiatry 2003; 74:602-607. 45. Muller N, Riedel M, Straube A, et al: Increased antistreptococcal antibodies in patients with Tourette’s syndrome. Psychiatry Res 2000; 94:43-49. 46. Pavone P, Bianchini R, Parano E, et al: Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol 2004; 30:107-110. 47. Singer HS, Loiselle CR, Lee O, et al: Anti-basal ganglia antibodies in PANDAS. Mov Disord 2004; 19:406-415. 48. Singer HS: PANDAS and immunomodulatory therapy. Lancet 1999; 354:1137-1138.
49. Robertson MM: Tourette syndrome, associated conditions and the complexities of treatment. Brain 2000; 123(Pt 3):425462. 50. Robertson MM: The heterogeneous psychopathology of Tourette syndrome. In Bedard MA, Agid Y, Chouinard S, et al, eds: Mental and Behavioral Dysfunction in Movement Disorders. Totowa, NJ: Humana Press, 2003, pp 433-466. 51. Kurlan R, Como PG, Miller B, et al: The behavioral spectrum of tic disorders: a community-based study. Neurology 2002; 59:414-420. 52. Katona C, Robertson MM: Gilles de la Tourette Syndrome. Psychiatry at a Glance, 3rd ed. Oxford, UK: Blackwell Science, 2005. 53. Eapen V, Robertson MM, Alsobrook JP, et al: Obsessive compulsive symptoms in Gilles de la Tourette syndrome and obsessive compulsive disorder: differences by diagnosis and family history. Am J Med Genet 1997; 74:432-438. 54. Frankel M, Cummings JL, Robertson MM, et al: Obsessions and compulsions in Gilles de la Tourette’s syndrome. Neurology 1986; 36:378-382. 55. Leckman JF, Pauls DL, Zhang H, et al: Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome. Am J Med Genet B Neuropsychiatr Genet 2003; 116:60-68. 56. Miguel EC, Leckman JF, Rauch S, et al: Obsessive-compulsive disorder phenotypes: implications for genetic studies. Mol Psychiatry 2004; 10:258-275. 57. Coffey BJ, Miguel EC, Biederman J, et al: Tourette’s disorder with and without obsessive-compulsive disorder in adults: are they different? J Nerv Ment Dis 1998; 186:201-206. 58. Swanson JM, Sergeant JA, Taylor E, et al: Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 1998; 351:429-433. 59. Apter A, Pauls DL, Bleich A, et al: An epidemiologic study of Gilles de la Tourette’s syndrome in Israel. Arch Gen Psychiatry 1993; 50:734-738. 60. Robertson MM, Trimble MR, Lees AJ: The psychopathology of the Gilles de la Tourette syndrome. A phenomenological analysis. Br J Psychiatry 1988; 152:383-390. 61. Robertson MM, Channon S, Baker J, et al: The psychopathology of Gilles de la Tourette’s syndrome. A controlled study. Br J Psychiatry 1993; 162:114-117. 62. Robertson MM, Banerjee S, Hiley PJ, et al: Personality disorder and psychopathology in Tourette’s syndrome: a controlled study. Br J Psychiatry 1997; 171:283-286. 63. Rickards H, Robertson M: A controlled study of psychopathology and associated symptoms in Tourette syndrome. World J Biol Psychiatry 2003; 4:64-68. 64. Carter AS, O’Donnell DA, Schultz RT, et al: Social and emotional adjustment in children affected with Gilles de la Tourette’s syndrome: associations with ADHD and family functioning. Attention Deficit Hyperactivity Disorder. J Child Psychol Psychiatry 2000; 41:215-223. 65. Brand N, Geenen R, Oudenhoven M, et al: Brief report: cognitive functioning in children with Tourette’s syndrome with and without comorbid ADHD. J Pediatr Psychol 2002; 27:203208. 66. Wilhelm S, Deckersbach T, Coffey BJ, et al: Habit reversal versus supportive psychotherapy for Tourette’s disorder: a randomized controlled trial. Am J Psychiatry 2003; 160:11751177. 67. Piacentini J, Chang S: Behavioral treatments for Tourette syndrome and tic disorders: state of the art. Adv Neurol 2001; 85:319-331. 68. Scahill L, Leckman JF, Schultz RT, et al: A placebo-controlled trial of risperidone in Tourette syndrome. Neurology 2003; 60:1130-1135.
chapter 17 tourette’s syndrome, tics and obsessive-compulsive disorders 69. Budman CL, Gayer A, Lesser M, et al: An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry 2001; 62:290-294. 70. Parraga HC, Parraga MI, Woodward RL, et al: Quetiapine treatment of children with Tourette’s syndrome: report of two cases. J Child Adolesc Psychopharmacol 2001; 11:187-191. 71. Kastrup A, Schlotter W, Plewnia C, et al: Treatment of tics in Tourette syndrome with aripiprazole. J Clin Psychopharmacol 2005; 25:94-96. 72. Sallee FR, Kurlan R, Goetz CG, et al: Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 2000; 39:292-299. 73. Kunwar AR, Megna JL: Resolution of risperidone-induced hyperprolactinemia with substitution of quetiapine. Ann Pharmacother 2003; 37:206-208. 74. Porta M, Maggioni G, Ottaviani F, et al: Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci 2004; 24:420-423. 75. Robertson M, Doran M, Trimble M, et al: The treatment of Gilles de la Tourette syndrome by limbic leucotomy. J Neurol Neurosurg Psychiatry 1990; 53:691-694. 76. Rauch SL, Baer L, Cosgrove GR, et al: Neurosurgical treatment of Tourette’s syndrome: a critical review. Compr Psychiatry 1995; 36:141-156. 77. Temel Y, Visser-Vandewalle V: Surgery in Tourette syndrome. Mov Disord 2004; 19:3-14. 78. Newcorn JH, Spencer TJ, Biederman J, et al: Atomoxetine treatment in children and adolescents with attention-deficit/ hyperactivity disorder and comorbid oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry 2005; 44:240-248. 79. Castellanos FX, Acosta MT: [Tourette syndrome: an analysis of its comorbidity and specific treatment]. Rev Neurol 2004; 38(Suppl 1):S124-S130. 80. Pauls DL, Alsobrook JP, Goodman W, et al: A family study of obsessive-compulsive disorder. Am J Psychiatry 1995; 152:7684. 81. McKay D, Abramowitz JS, Calamari JE, et al: A critical evaluation of obsessive-compulsive disorder subtypes: symptoms versus mechanisms. Clin Psychol Rev 2004; 24:283-313. 82. Angst J, Gamma A, Endrass J, et al: Obsessive-compulsive severity spectrum in the community: prevalence, comorbidity, and course. Eur Arch Psychiatry Clin Neurosci 2004; 254:156164. 83. Mohammadi MR, Ghanizadeh A, Rahgozar M, et al: Prevalence of obsessive-compulsive disorder in Iran. BMC Psychiatry 2004; 4:2.
221
84. Cillicilli AS, Telcioglu M, Askin R, et al: Twelve-month prevalence of obsessive-compulsive disorder in Konya, Turkey. Compr Psychiatry 2004; 45:367-374. 85. Fontenelle LF, Mendlowicz MV, Marques C, et al: Trans-cultural aspects of obsessive-compulsive disorder: a description of a Brazilian sample and a systematic review of international clinical studies. J Psychiatr Res 2004; 38:403-411. 86. Freud S: Obsessions and phobias, their psychical mechanisms and their aetiology. In Strachey J, ed: The Standard Edition of the Complete Psychological Works. London: Hogarth Press, 1895. 87. Rachman S, Hodgson RJ: Obsessions and Compulsions. Englewood Cliffs, NJ: Prentice-Hall, 1980. 88. Evans DW, Lewis MD, Iobst E: The role of the orbitofrontal cortex in normally developing compulsive-like behaviors and obsessive-compulsive disorder. Brain Cogn 2004; 55:220234. 89. Arnold PD, Richter MA: Is obsessive-compulsive disorder an autoimmune disease? CMAJ 2001; 165:1353-1358. 90. Stewart SE, Geller DA, Jenike M, et al: Long-term outcome of pediatric obsessive-compulsive disorder: a meta-analysis and qualitative review of the literature. Acta Psychiatr Scand 2004; 110:4-13. 91. Masellis M, Rector NA, Richter MA: Quality of life in OCD: differential impact of obsessions, compulsions, and depression comorbidity. Can J Psychiatry 2003; 48:72-77. 92. Geffken GR, Storch EA, Gelfand KM, et al: Cognitive-behavioral therapy for obsessive-compulsive disorder: review of treatment techniques. J Psychosoc Nurs Ment Health Serv 2004; 42:44-51. 93. Kim MC, Lee TK, Choi CR: Review of long-term results of stereotactic psychosurgery. Neurol Med Chir (Tokyo) 2002; 42:365-371. 94. Lippitz BE, Mindus P, Meyerson BA, et al: Lesion topography and outcome after thermocapsulotomy or Gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere. Neurosurgery 1999; 44:452-458. 95. Mindus, Jenike MA: Neurosurgical treatment of malignant obsessive compulsive disorder. Psychiatr Clin North Am 1992; 15:921-938. 96. Mindus P, Rasmussen SA, Lindquist C: Neurosurgical treatment for refractory obsessive-compulsive disorder: implications for understanding frontal lobe function. J Neuropsychiatry Clin Neurosci 1994; 6:467-477. 97. Kopell BH, Greenberg B, Rezai AR: Deep brain stimulation for psychiatric disorders. J Clin Neurophysiol 2004; 21:51-67.
CHAPTER
18
SCHIZOPHRENIA AND SCHIZOPHRENIA-LIKE PSYCHOSIS ●
●
●
●
Gary Price and Maria A. Ron
The first part of this chapter deals with schizophrenia as a primary illness, and the second describes schizophrenia-like features that appear in the context of other neurological illness.
SCHIZOPHRENIA Schizophrenia is a brain disease as common as multiple sclerosis that impairs the ability to work, independent living, and interpersonal relationships. The effect of schizophrenia on health care budgets is substantial and accounts for 1.5% to 3% of total national health care expenditure.1 Kraeplin2 introduced the term dementia praecox to refer to a cluster of symptoms that included catatonia and paranoia and carried a poor prognosis. The term schizophrenia was first used by Bleuler,3 who believed that certain “fundamental symptoms” were present in all affected patients. Current diagnostic classifications, such as the International Classification of Mental and Behavioural Disorders, 10th revision (ICD-10)4 and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV),5 still require the presence of a cluster of symptoms, in the absence of drug abuse or other organic brain disease, to establish the diagnosis (Table 18–1).
Epidemiology The incidence of schizophrenia is rather similar across different countries, with rates between 0.16 to 0.42 per 1000 and with a prevalence around 1% when narrow diagnostic criteria are used.6 There are some remote populations with an increased incidence and prevalence, such as the Afro-Caribbean population in the United Kingdom (incidence ratios above 7),7 and others with reduced rates, such as the Hutterites of South Dakota (ratio of observed to predicted mean rates, 0.48),8 and genetic and environmental factors probably contribute to this variability. Schizophrenia is common in men and women equally, and its onset may occur at any age, although it often starts between the ages of 15 and 45, with an earlier onset in men.9
Clinical Features and Natural History Schizophrenia is characterized by a multitude of symptoms that vary between patients and encompass a variety of mental
functions such as perception, emotion, and language (see Table 18–1). The symptoms of schizophrenia are often categorized as positive and negative. Positive symptoms include delusions, passivity phenomena, and hallucinations. Negative symptoms include apathy and social withdrawal. Functional imaging studies (positron emission tomography) have suggested that auditory hallucinations are accompanied by increased blood flow10 in subcortical nuclei, limbic structures, and paralimbic regions, and functional magnetic resonance imaging (MRI) demonstrates increased activation in the inferior frontal and temporal cortex.11 The neural correlates of other symptoms are less well understood. Psychotic symptoms usually start in late adolescence or early adulthood,12 tend to persist throughout the illness,13 and are often associated with poor psychosocial functioning.14 For many patients, schizophrenia starts with a prodromal period lasting from months to years. The symptoms of the prodromal stage may include depression, anxiety, dysphoria, social withdrawal, and cognitive underfunctioning, as well as attenuated psychotic symptoms.15 The outcome of schizophrenia is variable. Harrison and Eastwood16 found that one third of patients had recovered at follow-up 15 or 25 years later and that for many patients, schizophrenia is a relapsing-remitting disorder. The study also showed that lack of improvement early in the illness is predictive of persistence of symptoms and long-term disability. Other studies have revealed that an early onset of psychosis is associated with a more severe illness, irrespective of duration of illness.17
Cognitive Deficits Cognitive impairment is an integral feature of schizophrenia. Attention, executive function, and memory are most commonly impaired.18 Cognitive deficits are already present at the onset of psychosis19,20 and are present irrespective of medication.21 Some patients appear to undergo a decline in general intellectual function in the prodromal stages of the illness or during the onset of psychosis.22,23 After the onset of psychosis, cognitive impairments do not generally deteriorate further, which suggests that they are independent of clinical symptoms and the effects of medication.24 Large-scale studies have found that schizophrenic patients perform worse than healthy controls
223
224
Section
III
Neuropsychiatry
T A B L E 18–1. Key Symptoms of Schizophrenia with Exclusion Criteria
across a range of cognitive tasks,25,26 that cognitive impairment in a given function is predictive of impairment in all others,27 and that this impairment is global, variation between patients being a matter of degree. Other studies have found evidence for a subgroup of patients with isolated executive dysfunction.22,28 Deficits in executive function may be related to an increased genetic susceptibility to schizophrenia29 and may be part of the schizophrenia endophenotype.30 Similarly episodic memory deficits may be associated with an earlier age at onset,29 and this may suggest that early brain insults (e.g., hypoxia) that constitute a risk factor for young age at onset may, through their action on the amygdala and hippocampus, may also be responsible for the memory deficits. Functional imaging studies have shown reduced blood flow (positron emission tomography31,32) and reduced activation (functional MRI33) in the dorsolateral and other prefrontal areas of the cortex in schizophrenic patients in comparison with normal controls in response to executive function tasks. The neural correlates of other cognitive deficits are less well understood. The effect of typical neuroleptics on cognition is still controversial, although the blockade of dopamine D2 receptors achieved by these drugs may have a negative effect on cognition.34 In contrast, atypical neuroleptics, with antipsychotic effects not mediated by D2 blockade, may preserve or enhance cognition.35
Genetics Twin studies in schizophrenia have shown concordance rates of 41% to 65% in monozygotic pairs and 0% to 28% in dizygotic pairs and a heritability rate of 80% of 85%,36 which are suggestive of an important genetic contribution. The genetic risk for an individual increases with the degree of relation to the
affected relative: 40.8% if there is an affected monozygotic twin, 5.3% in siblings of affected patients,37 and a lifetime risk ranging from 3.1% to 16.9% in first-degree relatives of schizophrenic probands.38 A younger age at onset is associated with a higher familial risk for schizophrenia.39 A polygenic model—that is, the combined effects of multiple susceptibility genes—is the more likely pattern of inheritance. The way these susceptibility genes operate remains to be determined, but the clusters of genes operating in different individuals are likely to be heterogeneous, and they may be influenced by environmental factors. Of the susceptibility genes possibly associated with schizophrenia, catechol-O-methyl-transferase (COMT) is the most likely. COMT is predominantly expressed in prefrontal and hippocampal neurons and implicated in interneuronal monoaminergic signaling, especially dopamine. Hemideletion of chromosome 22q11, where COMT maps, results in the velocardiofacial syndrome40 with a greatly increased risk (24% in a study sample of patients with velocardiofacial syndrome) of schizophrenia-like psychosis.41 Other possible susceptibility genes, suggested by association studies, are DISC1 (“disrupted in schizophrenia”), a complex gene with effects on cytoskeletal proteins, cell migration, and membrane trafficking of receptors likely to influence hippocampal structure and function42; neuregulin 1 (NRG1) with effects in signaling and hence in neuronal development and plasticity; dysbindin (DTNBP1), widely expressed in neurons, including those in the dorsolateral prefrontal cortex, hippocampus, and substantia nigra, with effects on trafficking and tethering of receptors N-methyl-D-aspartate [NMDA], nicotinic acid, and γ-amino butyric acid A [GABAA]), and likely to contribute to glutamatergic hippocampal pathology; the regulator of G protein signaling 4, expressed in the dorsolateral prefrontal cortex involved in signaling; and the metabotropic glutamate receptor gene (GRM3), expressed presynaptically in neurons, astrocytes, and oligodendrocytes and likely to affect glutamatergic neurotransmission in the hippocampus and prefrontal cortex. Other genes associated with glutamatergic transmission and implicated in schizophrenia include G72 and D-amino acid oxidase (DAAO), which appear to directly affect NMDA receptors, and proline dehydrogenase (PRODH), which affects glutamatergic synapses by several mechanisms (Fig. 18–1).43,44 Most of the susceptibility genes so far identified have an effect on the molecular biology of the synapse, particularly glutamatergic synapses, but also influence the dopaminergic and GABAergic systems, thus causing malfunction of cortical microcircuits, which probably explains the pattern of symptoms and cognitive deficits that characterize schizophrenia.44
Neuropathology Imaging studies have demonstrated loss of brain volume in schizophrenic patients in comparison with controls45,46 and have highlighted pathological changes in the hippocampus and prefrontal cortext47 and in the superior temporal cortex and thalamus.46 More recent studies with magnetization transfer imaging, a technique sensitive to subtle neuropathological changes (e.g., changes in cell membranes and myelin) have demonstrated diffuse cortical abnormalities in patients with chronic schizophrenia.48 In patients with first episodes,49 these
chapter 18 schizophrenia and schizophrenia-like psychosis ■
PRODH Presynaptic neuron
DTNBP1 Glutamate
P5C
Proline
Glial cell NRG1 Synapse
Glutamate
KAR DAAO
Postsynaptic neuron
mGluR
ErbB4 NMDAR
Gq
PSD
G72
D-senne
225
Figure 18–1. Schizophrenia susceptibility genes and synaptic plasticity. Hypothetical scenario in which genes (in italics) may have shared effect on synapses, through influences on their formation, plasticity, or signaling properties. Only glutamatergic synapse is shown, but γ-amino butyric acid–mediated (GABAergic), cholinergic, and monoaminergic synapses (especially relevant to catechol-Omethyl-transferase [COMT]) are also probably involved. Also omitted is the issue of localization of pathology. Solid arrows indicate direct interactions; dotted arrows indicate indirect interactions. ErbB4, NRG7 receptor; Gq, subtype of guanosine triphosphate–binding proteins, KAR, kainate receptor; mGluR, metabotropic glutamate receptor; NMDAR, Nmethyl-D-aspartate receptor; P5C, pyrroline-5carboxylate; PSD, postsynaptic density proteins. (From Harrison PJ, Owen MJ: Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361:417-419.)
RGS4
abnormalities are limited to the medial prefrontal cortex, insula, and fasciculus uncinatus in the absence of atrophy. Imaging abnormalities are already evident before or at the time of the first episode of illness (Fig. 18–2)50 and may be present in unaffected relatives,51 which suggests that these abnormalities may be related to the genetic predisposition or early environmental factors, rather than to the illness itself. These changes, modest and often nonspecific, are not diagnostic of schizophrenia and may be present in other psychoses. The most consistent histological findings are decreases in neuronal size in the hippocampus and neocortex with reduced dendritic arborization and synaptic abnormalities.52 Levels of N-acetyl aspartate, a marker of neuronal integrity, measured in vivo with magnetic resonance spectroscopy, are reduced in the hippocampus53 and prefrontal cortex,54 which is in keeping with these findings. Neuronal loss in the dorsomedial nucleus of the thalamus and pulvinar have been less consistently reported.55 Reduction in the number of oligodendrocytes, important in myelination and synaptic integrity, whether primary or secondary to these neuronal changes, have also been reported.56 These quantitative alterations of the normal neural circuitry may result in subtle loss of cortical volume and thickness.16 Longitudinal imaging studies have not provided clear evidence of progression of brain abnormalities (see Shenton et al [2001]46 for a review), although loss of cortical volume may occur in the early stages of the illness in subgroups of patients with early onset and severe symptoms.57 Other investigators, using diffusion tensor imaging, have described axonal and myelin abnormalities in the corpus callosum of patients with chronic schizophrenia,58 which are absent at the onset of schizophrenia.59 Neuropathologically, astrogliosis and neurodegenerative changes, including those of Alzheimer’s disease, are not overrepresented in schizophrenia, which suggests that apparent clinical deterioration may be difficult to explain as a result of a neurodegenerative process.60-62 In contrast, abnormalities of neuronal migration, evidenced by aberrantly located
neurons in the lamina II of the entorhinal cortex and neocortical white matter, are strongly suggestive of disruption of normal brain development (for a review, see Harrison [1999]63). Further evidence for schizophrenia as a disorder of normal brain development is found in epidemiological studies that suggest early environmental factors that increase the risk for schizophrenia in later life. Evidence points toward a small winter-spring excess of births among patients with schizophrenia,64 as well as exposure to the influenza virus prenatally.65,66 Obstetrical complications are also linked to this risk, although the mechanisms are uncertain.67
Neurochemistry The dopamine hypothesis has been the chief neurochemical hypothesis in schizophrenia since the early 1960s68 and is supported by observations that dopamine D2 receptor blocking is common to all antipsychotic drugs.69 The mechanism and exact location of dopaminergic abnormalities in schizophrenia still remain unclear, and the dopamine hypothesis has undergone some revision since its initial inception. According to the hypothesis as it stands now, there exists a dopaminergic imbalance between the hyperactive subcortical, mesolimbic dopamine pathways (resulting in positive symptoms), and the hypoactive mesocortical dopaminergic connections to the prefrontal cortex (resulting in negative symptoms and cognitive impairment).70 The alternative glutamate hypothesis is based on the observation that the NMDA glutamate receptor antagonist phencyclidine causes psychosis that resembles both the positive and negative symptoms of schizophrenia.71 The glutamate hypothesis in its most simplified form is that a reduction in glutamate neurotransmission at the NMDA receptor results in symptoms of schizophrenia.72 However, the dopamine and glutamate hypotheses are not mutually exclusive, inasmuch as reciprocal synaptic relations between forebrain dopaminergic projections and glutamatergic systems have been described.73
226
Section
III
Neuropsychiatry
A
B
C
B
D ■
Figure 18–2. Magnetization transfer ratio reductions in patients with first-episode schizophrenia in comparison with controls, demonstrating bilateral reductions in (A) Prefrontal cortex, sagittal section, (B) Subcortical white matter and prefrontal cortex axial section, (C) Insula, sagittal section, (D) Subcortical white matter, coronal section. (From Bagary MS, Symms MR, Barker GJ, et al: Gray and white matter brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Arch Gen Psychiatry 2003; 60:779-788. Copyright © 2003 American Medical Association. All rights reserved.)
There is also evidence of dysfunction of the GABAergic system in schizophrenia (see Benes and Berretta74): namely, the reduction of specific GABAergic interneurons (paralbuminimmunoreactive cells) in the prefrontal cortex and hippocampus.75 Various subtypes of GABA neurons provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits believed to be involved in schizophrenia. The evidence for the role of the serotonergic system in schizophrenia is unclear, although there are serotonergic hallucinogens that block 5-hydroxytryptamine 2 receptors,76 and 5-hydroxytryptamine 2A receptor antagonism may contribute to the efficacy of atypical neuroleptics.77
The Pathophysiology of Schizophrenia One of the greatest challenges facing psychiatry today is to propose an explanatory theory that encompasses the often disparate facts known about schizophrenia and is able to accommodate emerging knowledge. There is evidence for a genetic predisposition, and a number of possible candidate genes with effects on the molecular biology of the synapse, as well as on the dopaminergic and GABAergic systems, have been identified.44 Histological findings such as aberrant neuronal clusters in the entorhinal cortex and an absence of gliosis also imply a neurodevelopmental etiology. Early environmental insults are
chapter 18 schizophrenia and schizophrenia-like psychosis additionally implicated, and these include complications of pregnancy and delivery.67 Abnormalities in cortical circuitry, induced by developmental and environmental factors, may limit neuronal information-processing capacity, and demands made on this malfunctioning system later in life may result in the emergence of psychotic symptoms and cognitive deterioration. The neurodevelopmental theory presupposes that pathological changes are not progressive and that changes in brain volume detected during the illness may be the consequence of disease-related changes in neuroplasticity (e.g., unstimulating environments, medication).78
Treatment of Schizophrenia Drug Treatment Neuroleptics have been used in the treatment of acute and chronic psychosis since the 1950s. The antipsychotic effect of the first-generation typical neuroleptics such as haloperidol and chlorpromazine depends on their action on the dopamine D2 receptors, and hallucinations are blocked when about 70% of the D2 receptors are occupied by neuroleptic drugs.79 Dopamine D3 and D4 receptor antagonism does not appear to be as important for antipsychotic effects.79 Antipsychotic agents may also affect brain structure directly: There are reports, albeit with a small sample size, of reversal of the superior temporal gyrus volume loss with neuroleptic treatment in a 1-year follow-up.80 Although typical antipsychotics have beneficial effects on positive symptoms, they are less effective in treating negative symptoms and cognitive impairment.81 They also have serious unwanted effects, such as extrapyramidal side effects (EPSEs), tardive dyskinesia, and neuroleptic malignant syndrome (NMS). Clinical EPSEs include acute dystonia, subjective feelings of restlessness (akathisia), and parkinsonism. Positron emission tomographic studies suggest that EPSEs are related to dopamine D2 occupancy in the range of 75% to 80%,82 but D1 antagonism has also been implicated.83 Although traditional neuroleptics do not necessarily lead to EPSEs, the therapeutic window between therapeutic effect and EPSE is small, and thus many patients receiving these medications have EPSEs. Tardive dyskinesia is a potentially irreversible side effect of long-term treatment with neuroleptic drugs and is characterized by abnormal involuntary hyperkinetic movements such as grimacing, lip smacking, tongue protrusion, and rapid eye blinking. Involuntary rapid movements of the fingers, arms, legs, and trunk may also occur. Various hypotheses, including overactivity in the striatal dopamine system,84 abnormal GABA-related striatal neurons,85 and free radical production73 have been proposed as pathophysiological mechanisms. Epidemiological data indicate that increasing age86 and female gender are risk factors for tardive dyskinesia.87 The outcome of tardive dyskinesia is more favorable in younger patients.87 Discontinuation of neuroleptic drugs or the use of a drug with fewer EPSEs (e.g., clozapine) is the first action of treatment. NMS is a life-threatening syndrome characterized by fever, muscular rigidity, and raised serum creatine kinase concentration. The incidence has been estimated to be between 0.07 and
227
0.9,88,89 and onset can occur within hours but is usually 4 to 14 days after starting neuroleptic therapy. The mechanism of NMS is uncertain, but the most widely accepted mechanism is of blockage of dopamine receptors in the nigrostriatal tracts.90 An alternative hypothesis suggests an imbalance between serotonin and dopamine.91 Risk factors for developing NMS include dehydration, male gender, the presence of organic brain disease or mental retardation, and rapid escalation of ingestion of neuroleptic drugs.92,93 The mortality rate has been reported at 8%,94 but most patients recover within 14 days.93 In NMS, antipsychotics should be discontinued, and, in general, intensive care treatment is required. Drugs that have been used in the treatment of NMS include dopamine agonists such as bromocriptine and apomorphine. If restarting a neuroleptic is deemed necessary, it is worth switching to a neuroleptic in a different chemical class and with a lower D2 affinity than the drug that produced the NMS.95 Other side effects of neuroleptics include weight gain, diabetes, sedation, sexual dysfunction, postural hypotension, and cardiac conduction problems, including sudden cardiac death. Gastric complications can be varied and paralytic ileus has been reported. Maintenance treatment with antipsychotic medication decreases relapse rates96; however, a substantial proportion of patients suffer relapse despite taking medication, and poor compliance is also a problem. A second generation of so-called atypical neuroleptics (e.g., clozapine, risperidone, quetiapine, olanzapine) has been developed with a spectrum of receptor effects different from those of typical neuroleptics and less severe side effects, resulting in better compliance and improved therapeutic outcome.97 Clozapine is the prototype of this class of neuroleptic. Kane and colleagues98 established the antipsychotic efficacy of clozapine in previously treatment-resistant patients without side effects, and this has been confirmed in other studies.99,100 Clozapine also has an effect on negative symptoms and cognitive functioning.100 One of the properties of clozapine is its high dissociation constant at the D2 receptor, which results in fewer EPSEs.101 Clozapine also has affinities for other nondopamine receptors such as 5-hydroxytryptamine 2, and its α2-adrenoceptor antagonism is believed to contribute to the freedom from EPSEs (see Reynolds102 for review). Clozapine may cause potentially fatal agranulocytosis, and regular blood monitoring is required. Other unwanted effects include hypersalivation, weight gain, and a lowering of the seizure threshold. The increased risk of stroke in older adults with dementia has also been linked to atypical antipsychotics.103 Recent developments in understanding the mechanism of action of antipsychotic medications has led to the development of the partial D2 and 5-hydroxytryptamine 1A receptor agonist aripiprazole,104 which is antipsychotic and possibly without EPSEs.105 Future drug treatments may continue to focus on partial agonism to improve antipsychotic symptoms or focus on NMDA-glutamatergic modulators.106 In the United Kingdom, the guidelines of the National Institute of Clinical Excellence recommend the use of atypical neuroleptics as first-line treatment, because of fewer side effects and efficacy comparable with those of typical neuroleptics, and the use of clozapine in treatment-resistant patients. Early treatment is recommended because of the possible association between a longer duration of untreated psychosis and poor outcome.107
228
Section
III
Neuropsychiatry
Psychological Treatments The use of psychological treatments has been shown to improve the outcome of schizophrenia when they are integrated with pharmacological treatments. Promising results have been reported with cognitive-behavioral therapy. A meta-analysis by Gould and associates108 showed it to be effective for positive symptoms. By challenging the patient’s interpretation of psychotic phenomena, this therapy reduces the frequency of relapse and the degree of distress. There is also evidence to suggest that cognitivebehavioral therapy may ameliorate negative symptoms.109 Cognitive-behavioral therapy has also been used in the prodromal phase of the illness in an attempt to delay or avoid the development of florid symptoms, with promising results.110 Family therapy has also been helpful as an adjuvant to pharmacological treatment in patients exposed to home environments with high levels of criticism, hostility, or emotional over-involvement.111,112 Supported employment programs are also promising.113
SCHIZOPHRENIA-LIKE PSYCHOSIS IN NEUROLOGICAL ILLNESS The association of epilepsy with schizophrenia-like symptoms was described in the 1960s,114 and similar symptoms have been described in association with other neurological diseases. These psychoses are included in the DSM-IV under the category of “Psychotic Disorder due to a General Medical Condition.” Initially, diseases involving the temporal lobes were believed to be more likely to cause psychotic symptoms,115 but more recent studies have described this association with extratemporal or diffuse pathology,116 and it has been suggested that damage to the dopaminergic limbic projections may be the common mechanism.117 The symptoms are similar to those of schizophrenia, although visual hallucinations, flat affect, passivity feelings, and catatonia may be commoner in patients with neurological disease,118,119 as are complex and specific delusional symptoms (e.g., morbid jealousy, erotomania, delusional parasitosis). Treatment follows the same protocol as that of schizophrenia, but the choice of medication may be dictated by the underlying neurological disease (e.g., danger of aggravating symptoms in patients with Parkinson’s disease). Features and treatment of schizophrenia-like psychosis associated with some neurological diseases are discussed in the following sections. Conditions in which psychotic symptoms are common (e.g., epilepsy, Parkinson’s disease, diffuse Lewy body disease) or where the mechanisms leading to psychosis shed some light onto schizophrenia research are included here.
Epilepsy The classification of psychotic symptoms in epilepsy is based on their temporal relationship to seizures: ictal, postictal, and interictal (see Sachdev120 for review). The combined prevalence of these syndromes is around 2% to 7%.121 In ictal psychosis, the psychotic episode may be an expression of nonconvulsive status epilepticus (i.e., absence status epilepticus, simple partial status epilepticus, and partial complex status epilepticus). Patients may experience delusions and hallucinations while in
a state of altered consciousness.122 Ictal psychoses usually last hours or days, and electroencephalographic (EEG) abnormalities help establish the diagnosis.120 Postictal psychoses account for 25% of psychotic episodes of epilepsy.123 They are usually brief and follow clusters of seizures or an increase in seizure frequency, usually after a lucid period of up to 1 week.124 EEG abnormalities may persist during the psychosis, and consciousness may be normal or impaired.121 The psychotic symptoms include paranoid delusions and hallucinations, and mood abnormalities are common.125 When psychotic symptoms develop gradually and in parallel to increases in seizure activity, the term peri-ictal psychosis may be used, in distinction to postictal psychosis.121 In peri-ictal psychosis, consciousness is usually impaired, and the EEG recording reflects increased epileptic activity.121 Interictal psychoses are not related to ictal activity and can develop when seizures are infrequent or fully controlled.120 They are the commonest psychoses and occur in 4% to 18% of epileptic patients, mostly in those with temporal lobe epilepsy.121 They can last from days to weeks but, once established, may follow a chronic course. Paranoid delusions, auditory hallucinations, and affective symptoms are common,120 and cognitive deficits are similar to those of schizophrenia.126 In some patients, the emergence of psychotic symptoms is accompanied by a normalization of the EEG recording127 or coincides with the use of some anticonvulsants such as vigabatrin and zonisamide, and recurrence of seizure activity ameliorates the psychosis.128 Schizophrenia-like psychosis can also appear after temporal lobe surgery for epilepsy, and it remains to be determined whether surgery is incidental and psychosis would have eventually emerged or whether surgery is a risk factor. If the latter is correct, a mechanism similar to forced normalization127 may also operate in these patients. Of postsurgical psychoses, 85% follow right temporal lobectomies and are usually short-lived, although they may follow a chronic course.129 The pathophysiology of the interictal psychosis is uncertain, but the lack of correlation with seizure frequency and the increased incidence in patients with mesial temporal sclerosis suggest that the epilepsy and the psychotic symptoms may be manifestations of a common pathology, rather than that the epileptic activity causes psychosis, although it is possible that stimulation of temporolimbic circuits may predispose to psychosis.120 Interictal psychoses have been considered a contraindication to temporal lobe surgery for the control of epilepsy, but this opinion has been revised,130 and some patients appear to benefit from surgery.131 Antipsychotic medication is usually needed to treat interictal psychosis, and atypical neuroleptics at low doses to avoid increased seizure activity are the best choice.
Parkinson’s Disease and Diffuse Lewy Body Disease Psychotic symptoms occur in 50% of patients at some time during the illness and increase with age and severity of the disease. Paranoid ideas and visual hallucinations are the most common psychiatric symptoms, occurring in 10% to 40% of patients.132 Visual hallucinations are usually complex and may be accompanied by auditory and tactile hallucinations.133 Vivid
chapter 18 schizophrenia and schizophrenia-like psychosis nightmares and reduction of rapid eye movement sleep have been observed in 80% of those who experienced psychotic symptoms.132 The pathophysiology of psychosis in Parkinson’s disease is complex. Dopaminergic medication plays a role in treatment, although psychotic symptoms are not related to the dose of medication,134 and they have even been reported in Parkinson’s disease before the introduction of levodopa therapy.134 In young patients, receptor hypersensitivity in the mesolimbic system may be relevant to psychiatric symptoms whereas in elderly patients, serotonergic hyperactivity caused by dopaminergic agonists (i.e., bromocriptine, lisuride, pergolide, cabergoline, ropinirole, and pramipexole) may be more relevant.135 In elderly patients, diffuse Lewy body disease or coexisting pathological processes such as cerebrovascular and Alzheimer’s disease may also play a role. In diffuse Lewy body disease, complex and vivid visual hallucinations occur in up to 80% of patients. Children and animals figure prominently in these hallucinations, and abnormalities of visual perception are common. Auditory hallucinations and paranoid delusions are less frequent (20% to 30%). Depression, apathy, irritability, and nocturnal confusion are also common, together with cognitive impairment involving executive functions, memory, and visuospatial functions. Fluctuations in psychiatric symptoms and cognition are the hallmarks of the disease. Deficits in presynaptic cholinergic transmission in the diencephalon and brainstem, in addition to deficits of dopaminergic transmission, may predispose to psychosis. In Parkinson’s disease, treatment strategies involve fostering good sleep habits and avoiding sensory overload.135 Progressive reduction of anticholinergic medication and dopamine agonists should be attempted, followed by reduction of the levodopa dosage, but in many patients, mobility reduction may become intolerable before psychotic symptoms are controlled, and antipsychotic medication is often required. Atypical antipsychotics should be tried; clozapine, with its low incidence of EPSEs may be the drug of choice.136 Other atypical neuroleptics (quetiapine, olanzapine, risperidone, and aripiprazole) can also be used in these patients, and the treatment may need to be long term. In diffuse Lewy body disease, reduction of dopaminergic medication should also be attempted. Frequent adverse reactions to neuroleptics has made their use problematic. Anticholinesterase inhibitors may be the drugs of choice, and their use can also be extended to patients with Parkinson’s disease.135
Psychosis in Traumatic Brain Injury The prevalence of schizophrenia-like symptoms is increased with traumatic brain injury.115,137 In head injuries of moderate severity, damage to the left temporal lobe appears to be a risk factor for psychosis.138 In subjects with a genetic vulnerability, minor trauma may be the trigger, rather than the cause of psychosis.139 Psychotic symptoms tend to appear 4 or 5 years after the injury, but their appearance could be delayed by many years. Psychotic symptoms that appear immediately after the injury are usually part of a confusional state and tend to be mild and transient. As in other schizophrenia-like psychosis, symptoms may follow a prodrome characterized by social isolation and nonspecific symptoms. Mood changes and agitation are
229
common, and negative symptoms infrequent. Diffuse cognitive deterioration often accompanies psychotic symptoms in these patients.138 Chronicity is the rule, and treatment with neuroleptics is often required, although comprehensive studies of outcome are not available.
Demyelinating Diseases Schizophrenia-like psychosis is uncommon in multiple sclerosis. Psychotic symptoms tend to appear when muscular sclerosis is well established, usually in patients with lesions in temporal lobe white matter, and usually respond to antipsychotic medication.140 In contrast, psychotic symptoms are far more frequent in metachromatic leukodystrophy, an autosomal recessive disease resulting from a mutation on chromosome 22q that leads to a deficit of the enzyme arylsulfatase A and accumulation of metachromatic material (sulfatides) in the brain and peripheral nervous system, which causes demyelination.141 Patients with the juvenile- and adult-onset forms of metachromatic leukodystrophy have higher arylsulfatase A activity and have a more protracted course than do those with the late infantile forms, and they often present with a schizophrenia-like illness.141 Usually it is only when neurological symptoms, progressive cognitive decline leading to dementia, or white matter MRI abnormalities become apparent that metachromatic leukodystrophy is diagnosed.142 Myelin abnormalities in the prefrontal white matter and frontotemporal connections, detectable by MRI, are likely to play a role in the emergence of psychosis. The high prevalence of psychosis in this age group is in contrast to the low prevalence in multiple sclerosis,143 which suggests that age may determine the psychiatric manifestations of demyelination.31 Treatment of symptoms is based on isolated case reports that indicate that psychosis in patients with metachromatic leukodystrophy improves with neuroleptic treatment.31
K E Y
P O I N T S
●
Schizophrenia has a prevalence of approximately 1% and may result in significant functional disability.
●
The symptoms of schizophrenia are often categorized as positive and negative. Positive symptoms include delusions, passivity phenomena, and hallucinations. Negative symptoms include apathy and social withdrawal.
●
Cognitive impairment is an integral feature of the illness.
●
Drug treatment should be in the form of newer (atypical) antipsychotics.
●
Symptoms similar to schizophrenia have been described in association with other neurological diseases.
Suggested Reading Harrison PJ: The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122:593624. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10:40-68.
230
Section
III
Neuropsychiatry
Joyce E, Huddy V: Defining the cognitive impairment in schizophrenia. Psychol Med 2004; 34:1151-1155. Shenton ME, Dickey CC, Frumin M, et al: A review of MRI findings in schizophrenia. Schizophr Res 2001; 49:1-52. Rapoport JL, Giedd JN, Blumenthal J, et al: Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999; 56:649-654.
References 1. Knapp M, Mangalore R, Simon J: The global costs of schizophrenia. Schizophr Bull 2004; 30:279-293. 2. Kraeplin E: Psychiatrie. Ein Lehrbuch für Studirende und Aerzte. Fünfte, vollständig umgearbeitete Auflage. Leipzig: Barth Verlag, 1896. 3. Bleuler E: Dementia praecox oder die Gruppe der Schizofrenien. In Aschaffenburg G, ed: Handbuch der Psychiatrie. Leipzig: G. Aschaffenburg, 1911-1928. 4. World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization, 1992. 5. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. 6. Jablensky A, Sartorius N, Ernberg G, et al: Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 1992; 20:1-97. 7. Harrison G, Glazebrook C, Brewin J, et al: Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom. Psychol Med 1997; 27:799-806. 8. Nimgaonkar VL, Fujiwara TM, Dutta M, et al: Low prevalence of psychoses among the Hutterites, an isolated religious community. Am J Psychiatry 2000; 157:1065-1070. 9. Hafner H, Hambrecht M, Loffler W, et al: Is schizophrenia a disorder of all ages? A comparison of first episodes and early course across the life-cycle. Psychol Med 1998; 28:351365. 10. Silbersweig DA, Stern E, Frith C, et al: A functional neuroanatomy of hallucinations in schizophrenia. Nature 1995; 378:176-179. 11. Shergill SS, Brammer MJ, Williams SC, et al: Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry 2000; 57:1033-1038. 12. Hafner H, Maurer K, Loffler W, et al: The influence of age and sex on the onset and early course of schizophrenia. Br J Psychiatry 1993; 162:80-86. 13. Arndt S, Andreasen NC, Flaum M, et al: A longitudinal study of symptom dimensions in schizophrenia. Prediction and patterns of change. Arch Gen Psychiatry 1995; 52:352-360. 14. Fenton WS, McGlashan TH: Testing systems for assessment of negative symptoms in schizophrenia. Arch Gen Psychiatry 1992; 49:179-184. 15. Davidson L, McGlashan TH: The varied outcomes of schizophrenia. Can J Psychiatry 1997; 42:34-43. 16. Harrison PJ, Eastwood SL: Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 2001; 11:508-519. 17. Suvisaari JM, Haukka J, Tanskanen A, et al: Age at onset and outcome in schizophrenia are related to the degree of familial loading. Br J Psychiatry 1998; 173:494-500. 18. Gold S, Arndt S, Nopoulos P, et al: Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia. Am J Psychiatry 1999; 156:1342-1348.
19. Bilder RM, Lipschutz-Broch L, Reiter G, et al: Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration. Schizophr Bull 1992; 18:437-448. 20. Hoff AL, Riordan H, O’Donnell DW, et al: Neuropsychological functioning of first-episode schizophreniform patients. Am J Psychiatry 1992; 149:898-903. 21. Joyce E, Hutton S, Mutsatsa S, et al: Executive dysfunction in first-episode schizophrenia and relationship to duration of untreated psychosis: the West London Study. Br J Psychiatry Suppl 2002; 43:s38-s44. 22. Weickert TW, Goldberg TE, Gold JM, et al: Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 2000; 57:907-913. 23. Fuller R, Nopoulos P, Arndt S, et al: Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. Am J Psychiatry 2002; 159:1183-1189. 24. Joyce E, Huddy V: Defining the cognitive impairment in schizophrenia. Psychol Med 2004; 34:1151-1155. 25. Townsend LA, Malla AK, Norman RM: Cognitive functioning in stabilized first-episode psychosis patients. Psychiatry Res 2001; 104:119-131. 26. Addington J, Brooks BL, Addington D: Cognitive functioning in first episode psychosis: initial presentation. Schizophr Res 2003; 62:59-64. 27. Dickinson D, Iannone VN, Wilk CM, et al: General and specific cognitive deficits in schizophrenia. Biol Psychiatry 2004; 55:826-833. 28. Goldstein G, Shemansky WJ: Influences on cognitive heterogeneity in schizophrenia. Schizophr Res 1995; 18:59-69. 29. Tuulio-Henriksson A, Partonen T, Suvisaari J, et al: Age at onset and cognitive functioning in schizophrenia. Br J Psychiatry 2004; 185:215-219. 30. Glahn DC, Therman S, Manninen M, et al: Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry 2003; 53:624-626. 31. Weinberger DR, Lipska BK: Cortical maldevelopment, antipsychotic drugs, and schizophrenia: a search for common ground. Schizophr Res 1995; 16:87-110. 32. Meyer-Lindenberg A, Miletich RS, Kohn PD, et al: Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002; 5:267271. 33. Volz HP, Gaser C, Hager F, et al: Brain activation during cognitive stimulation with the Wisconsin Card Sorting Test—a functional MRI study on healthy volunteers and schizophrenics. Psychiatry Res 1997; 75:145-157. 34. Gallhofer B, Lis S, Meyer-Lindenberg A, et al: Cognitive dysfunction in schizophrenia: a new set of tools for the assessment of cognition and drug effects. Acta Psychiatr Scand Suppl 1999; 395:118-128. 35. Keefe RS, Silva SG, Perkins DO, et al: The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 1999; 25:201-222. 36. Cardno AG, Gottesman II: Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics. Am J Med Genet 2000; 97:12-17. 37. Cardno AG, Marshall EJ, Coid B, et al: Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999; 56:162-168. 38. Gershon ES, DeLisi LE, Hamovit J, et al: A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 1988; 45:328-336. 39. Kendler KS, MacLean CJ: Estimating familial effects on age at onset and liability to schizophrenia. I. Results of a large sample family study. Genet Epidemiol 1990; 7:409-417.
chapter 18 schizophrenia and schizophrenia-like psychosis 40. Driscoll DA, Spinner NB, Budarf ML, et al: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 1992; 44:261-268. 41. Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56:940-945. 42. Hodgkinson CA, Goldman D, Jaeger J, et al: Disrupted in schizophrenia 1: association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75:862-872. 43. Harrison PJ, Owen MJ: Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361:417-419. 44. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10:40-68. 45. Lawrie SM, Whalley H, Kestelman JN, et al: Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 1999; 353:30-33. 46. Shenton ME, Dickey CC, Frumin M, et al: A review of MRI findings in schizophrenia. Schizophr Res 2001; 49:152. 47. Wright IC, Rabe-Hesketh S, Woodruff PW, et al: Metaanalysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000; 157:16-25. 48. Foong J, Symms MR, Barker GJ, et al: Neuropathological abnormalities in schizophrenia: evidence from magnetization transfer imaging. Brain 2001; 124:882-892. 49. Bagary MS, Symms MR, Barker GJ, et al: Gray and white matter brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Arch Gen Psychiatry 2003; 60:779-788. 50. Gur RE, Turetsky BI, Cowell PE, et al: Temporolimbic volume reductions in schizophrenia. Arch Gen Psychiatry 2000; 57:769-775. 51. McIntosh AM, Job DE, Moorhead TW, et al: Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives. Biol Psychiatry 2004; 56:544552. 52. Blennow K, Davidsson P, Gottfries C-G, et al: Synaptic degeneration in thalamus in schizophrenia [Letter]. Lancet 1996; 348:692-693. 53. Maier M, Ron MA, Barker GJ, et al: Proton magnetic resonance spectroscopy: an in vivo method of estimating hippocampal neuronal depletion in schizophrenia. Psychol Med 1995; 25:1201-1209. 54. Bertolino A, Roffman JL, Lipska BK, et al: Reduced Nacetylaspartate in prefrontal cortex of adult rats with neonatal hippocampal damage. Cereb Cortex 2002; 12:983-990. 55. Byne W, Buchsbaum MS, Kemether E, et al: Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder. Arch Gen Psychiatry 2001; 58:133-140. 56. Uranova NA, Vostrikov VM, Orlovskaya DD, et al: Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 2004; 67:269-275. 57. Rapoport JL, Giedd JN, Blumenthal J, et al: Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999; 56:649-654. 58. Foong J, Maier M, Clark CA, et al: Neuropathological abnormalities of the corpus callosum in schizophrenia: a diffusion tensor imaging study. J Neurol Neurosurg Psychiatry 2000; 68:242-244. 59. Price G, Bagary MS, Cercignani M, et al: The corpus callosum in first episode schizophrenia: a diffusion tensor imaging study. J Neurol Neurosurg Psychiatry 2005; 76:585-587.
231
60. Arnold SE, Trojanowski JQ, Gur RE, et al: Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998; 55:225-232. 61. Purohit DP, Perl DP, Haroutunian V, et al: Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry 1998; 55:205-211. 62. Falke E, Han LY, Arnold SE: Absence of neurodegeneration in the thalamus and caudate of elderly patients with schizophrenia. Psychiatry Res 2000; 93:103-110. 63. Harrison PJ: The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122:593-624. 64. Torrey EF, Miller J, Rawlings R, et al: Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 1997; 28:1-38. 65. Wright P, Takei N, Rifkin L, et al: Maternal influenza, obstetric complications, and schizophrenia. Am J Psychiatry 1995; 152:1714-1720. 66. Brown AS, Begg MD, Gravenstein S, et al: Serologic evidence of prenatal influenza in the etiology of schizophrenia. Obstet Gynecol Surv 2005; 60:77-78. 67. Cannon M, Jones PB, Murray RM: Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002; 159:1080-1092. 68. Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963; 20:140-144. 69. Creese I, Burt DR, Snyder SH: Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192:481-483. 70. Davis KL, Kahn RS, Ko G, et al: Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148:1474-1486. 71. Luby ED, Cohen BD, Rosenbaum G, et al: Study of a new schizophrenomimetic drug: sernyl. AMA Arch Neurol Psychiatry 1959; 81:363-369. 72. Javitt DC, Zukin SR: Recent advances in the phencyclidine model of schizophrenia [Review]. Am J Psychiatry 1991; 148:1301-1308. 73. Carlsson M, Carlsson A: Interactions between glutamatergic and monoaminergic systems within the basal ganglia— implications for schizophrenia and Parkinson’s disease. Trends Neurosci 1990; 13: 272-274. 74. Benes FM, Berretta S: GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25:1-27. 75. Reynolds GP, Beasley CL, Zhang ZJ: Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons. J Neural Transm 2002; 109:881-889. 76. Gouzoulis-Mayfrank E, Hermle L, Thelen B, et al: History, rationale and potential of human experimental hallucinogenic drug research in psychiatry. Pharmacopsychiatry 1998; 31(Suppl 2):63-68. 77. Meltzer HY, Matsubara S, Lee JC: Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D2 and serotonin 2 pKi values. J Pharmacol Exp Ther 1989; 251:238-246. 78. Weinberger DR, McClure RK: Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry 2002; 59:553-558. 79. Seeman P: Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 1992; 7:261-284.
232
Section
III
Neuropsychiatry
80. Keshavan MS, Haas GL, Kahn CE, et al: Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? J Psychiatr Res 1998; 32:161-167. 81. Hawkins KA, Mohamed S, Woods SW: Will the novel antipsychotics significantly ameliorate neuropsychological deficits and improve adaptive functioning in schizophrenia? Psychol Med 1999; 29:1-8. 82. Farde L, Nordstrom AL, Wiesel FA, et al: Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992; 49:538-544. 83. Casey DE: Dopamine D1 (and D2 [haloperidol]) antagonists in drug-naïve monkeys. Psychopharmacology (Berl) 1992; 107:18-22. 84. Klawans HL Jr, Rubovits R: An experimental model of tardive dyskinesia. J Neural Transm 1972; 33:235-246. 85. Gunne LM, Haggstrom JE: Pathophysiology of tardive dyskinesia. Psychopharmacology Suppl 1985; 2:191-193. 86. Jeste DV, Caligiuri MP, Paulsen JS, et al: Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients. Arch Gen Psychiatry 1995; 52:756-765. 87. Kane JM, Jeste DV, Barnes TRE, et al: Tardive Dyskinesia: A Task Force Report of the American Psychiatric Association. Washington, DC: American Psychiatric Association, 1992. 88. Gelenberg AJ, Bellinghausen B, Wojcik JD, et al: A prospective survey of neuroleptic malignant syndrome in a shortterm psychiatric hospital. Am J Psychiatry 1988; 145:517-518. 89. Keck PE, Sebastianelli J, Pope HG, et al: Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 1989; 50:352-355. 90. Adnet P, Lesteval P, Krivosic-Horber R: Neuroleptic malignant syndrome. Br J Anaesth 2000; 85:129-135. 91. Ames D, Wirshing W: Ecstasy, the serotonin syndrome and neuroleptic malignant syndrome: a possible link? JAMA 1993; 269:869. 92. Sachdev P, Mason C, Hadzi-Pavlovic D: Case-control study of neuroleptic malignant syndrome. Am J Psychiatry 1997; 154:1156-1158. 93. Addonizio G, Susman VL, Roth SD: Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 1987; 22:1004-1020. 94. Levinson DF, Simpson GM: Neuroleptic-induced extrapyramidal symptoms with fever: heterogeneity of the “neuroleptic malignant syndrome.” Arch Gen Psychiatry 1986; 43: 839-848. 95. Pelonero AL, Levenson JL, Pandurangi AK: Neuroleptic malignant syndrome: a review. Psychiatr Serv 1998; 49:11631172. 96. Gilbert P, Harris MJ, McAdams LA: Neuroleptic withdrawal in schizophrenic patients: a review of the literature. Arch Gen Psychiatry 1995; 52:173-188. 97. Leucht S, Barnes TR, Kissling W, et al: Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 2003; 160:1209-1222. 98. Kane J, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789-796. 99. Simpson GM, Josiassen RC, Stanilla JK, et al: Double-blind study of clozapine dose response in chronic schizophrenia. Am J Psychiatry 1999; 156:1744-1750. 100. Wahlbeck K, Cheine M, A Essali, et al: Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and metaanalysis of randomized trials. Am J Psychiatry 1999; 156:990999. 101. Seeman P, Tallerico T: Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to
102. 103. 104.
105. 106. 107. 108. 109.
110.
111.
112. 113. 114. 115.
116. 117. 118. 119. 120. 121. 122. 123.
brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998; 3:123-134. Reynolds GP: Receptor mechanisms in the treatment of schizophrenia. J Psychopharmacol 2004; 18:340-345. Wooltorton E: Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ 2002; 167:12691270. Lawler CP, Prioleau C, Lewis MM, et al: Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999; 20:612-627. Taylor DM: Aripiprazole: a review of its pharmacology and clinical use. Int J Clin Pract 2003; 57:49-54. Heresco-Levy U: N-Methyl-D-aspartate (NMDA) receptor– based treatment approaches in schizophrenia: the first decade. Int J Neuropsychopharmacol 2000; 3:243-258. Wyatt RJ, Henter ID: The effects of early and sustained intervention on the long-term morbidity of schizophrenia. J Psychiatr Res 1998; 3:169-177. Gould RA, Mueser KT, Bolton E, et al: Cognitive therapy for psychosis in schizophrenia: an effect size analysis. Schizophr Res 2001; 48:335-342. Sensky T, Turkington D, Kingdon D, et al: A randomized controlled trial of cognitive-behavioral therapy for persistent symptoms in schizophrenia resistant to medication. Arch Gen Psychiatry 2000; 57:165-172. McGorry P, Yung AR, Phillips LJ, et al: Randomized controlled trial of interventions designed to reduce the risk of progression to first episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry 2002; 59:921-928. Vaughn CE, Leff JP: The influence of family and social factors on the course of psychiatric illness. A comparison of schizophrenic and depressed neurotic patients. Br J Psychiatry 1976; 129:125-137. Pitschel-Walz G, Leucht S, Bauml J, et al: The effect of family interventions on relapse and rehospitalization in schizophrenia—a meta-analysis. Schizophr Bull 2001; 27:73-92. Bond GR, Becker DR, Drake RE, et al: Implementing supported employment as an evidence-based practice. Psychiatr Serv 2001; 52:313-322. Slater E, Beard AW, Glithero E: The schizophrenia-like psychosis of epilepsy. Br J Psychiatry 1963; 109:95-105. Davidson K, Bagley CR: Schizophrenia-like psychosis associated with organic disorders of the central nervous system: a review of the literature. In Herrington RN, ed: Current Problems in Neuropsychiatry. British Journal of Psychiatry Special Publication No. 4. Ashford, Kent, UK: Hedley Brothers, 1969. Feinstein A, Ron MA: Psychosis associated with demonstrable brain disease. Psychol Med 1990; 20:793-803. Cummings JL: Organic psychosis [Review]. Psychosomatics 1988; 29:16-26. Johnstone EC, Cooling NJ, Frith CD, et al: Phenomenology of organic and functional psychoses and the overlap between them. Br J Psychiatry 1988; 153:770-776. Toone BK, Garralda EM, Ron MA: The psychosis of epilepsy and the functional psychosis. A clinical and phenomenological evaluation. Br J Psychiatry 1982; 141:256-261. Sachdev P: Schizophrenia-like psychosis and epilepsy: the status of the association. Am J Psychiatry 1998; 155:325336. Gaitatzis A, Trimble MR, Sander JW: The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004; 110:207-220. Wolf P, Trimble MR: Biological antagonism and epileptic psychosis. Br J Psychiatry 1985; 146:272-276. Dongier S: Statistical study of clinical and electroencephalographic manifestations of 536 psychotic episodes occurring in 516 epileptics between clinical seizures. Epilepsia 1959; 1:117-142.
chapter 18 schizophrenia and schizophrenia-like psychosis 124. Torta R, Keller R: Behavioral, psychotic, and anxiety disorders in epilepsy: etiology, clinical features, and therapeutic implications. Epilepsia 1999; 40(Suppl 10):S2-S20. 125. Logsdail SJ, Toone BK: Post-ictal psychoses. A clinical and phenomenological description. Br J Psychiatry 1988; 152: 246-252. 126. Nathaniel-James DA, Brown RG, Maier M, et al: Cognitive abnormalities in schizophrenia and schizophrenia-like psychosis of epilepsy. J Neuropsychiatry Clin Neurosci 2004; 16:472-479. 127. Landolt H: Some clinical EEG correlations in epileptic psychoses (twilight states). EEG Clin Neurophysiol 1953; 5:121. 128. Kanner AM: Psychosis of epilepsy: a neurologist’s perspective. Epilepsy Behav 2000; 1:219-227. 129. Trimble MR: The Psychoses of Epilepsy. New York: Raven Press, 1991. 130. Toone BK: The psychoses of epilepsy. J Neurol Neurosurg Psychiatry 2000; 69:1-4. 131. Reutens DC, Savard G, Andermann F, et al: Results of surgical treatment in temporal lobe epilepsy with chronic psychosis. Brain 1997; 120:1929-1936. 132. Sánchez-Ramos JR, Ortoll R, Paulson GW: Visual hallucinations associated with Parkinson’s disease. Arch Neurol 1996; 53:1265-1268. 133. Fenelon G, Mahieux F, Huon R, et al: Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000; 123:733-745.
233
134. Burn DJ, Troster AI: Neuropsychiatric complications of medical and surgical therapies for Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17:172-180. 135. Wint DP, Okun MS, Fernandez HH: Psychosis in Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17:127-136. 136. Friedman JH, Factor SA: Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord 2000; 15:201-211. 137. Wilcox JA, Nasrallah HA: Childhood head trauma and psychosis. Psychiatry Res 1987; 21:303-306. 138. Sachdev P, Smith JS, Cathcart S: Schizophrenia-like psychosis following traumatic brain injury: a chart-based descriptive and case-control study. Psychol Med 2001; 31:231-239. 139. Fujii DE, Ahmed I: Risk factors in psychosis secondary to traumatic brain injury. J Neuropsychiatry Clin Neurosci 2001; 13:61-69. 140. Feinstein A, du Boulay G, Ron MA: Psychotic illness in multiple sclerosis. A clinical and magnetic resonance imaging study. Br J Psychiatry 1992; 161:680-685. 141. Black DN, Taber KH, Hurley RA: Metachromatic leukodystrophy: a model for the study of psychosis. J Neuropsychiatry Clin Neurosci 2003; 15:289-293. 142. Hyde TM, Ziegler JC, Weinberger DR: Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992; 49:401-406. 143. Ron MA, Feinstein A: Multiple sclerosis and the mind. J Neurol Neurosurg Psychiatry 1992; 55:1-3.
CHAPTER
19
AFFECTIVE DISORDERS ●
●
●
●
Gad A. Marshall and Jeffrey L. Cummings
Affect refers to the external expression of emotions, whereas mood refers to the internal expression or feeling of emotions. Typically, affect and mood are congruent.1 However, in some conditions, they may be dissociated: Individuals with pseudobulbar palsy may have bursts of laughter or crying, which do not reflect how they feel at the time, whereas individuals with parkinsonism who do not have a depressed mood may appear depressed because of limited facial expressions. Mood has many manifestations, ranging from depression to euphoria. Neuropsychiatric manifestations, such as changes in mood and affect, are very common in neurological conditions such as neurodegenerative diseases (Alzheimer’s disease: apathy, agitation, depression, irritability, anxiety, psychosis; Parkinson’s disease: depression, anxiety, psychosis; frontotemporal dementia: disinhibition, apathy), cerebrovascular disease (depression, apathy, psychosis), epilepsy (depression, psychosis), and multiple sclerosis (depression, eutonia, irritability, anxiety).2 These manifestations have a significant effect on individuals’ quality of life and caregiver burden. This chapter focuses on dysphoria (sadness) as the main feature of depression and elevated mood (exaggerated feeling of happiness) and expansive mood (expression of feelings without restraint and exaggerated sense of self-importance) as aspects of mania.1 We also discuss the personality change seen with apathy (lack of motivation). We provide information about prevalence, characteristics, course, and precipitating factors of mood changes in neurological conditions. The neuroanatomical localization of mood changes—commonly involving the basal ganglia and the frontal and anterior temporal regions— is reviewed. Finally, issues concerning treatment of mood changes in neurological conditions are discussed, and practical treatment algorithms are offered. A discussion of primary mood disorders and miscellaneous neurological conditions with mood changes, such as pseudobulbar palsy, Klüver-Bucy syndrome, ictal affect, hypothalamic lesions, and catastrophic reactions, is beyond the scope of this chapter.
DEPRESSION Depression is a common feature of many neurological conditions, but it is often underdiagnosed and undertreated. It can manifest as a symptom or as a syndrome complex such as a
major depressive episode. Mood changes in depression consist of sadness and inability to experience pleasure (anhedonia), putatively mediated by the limbic system. They are often accompanied by feelings of worthlessness and hopelessness (mediated by the dorsolateral prefrontal cortex), guilt, helplessness, and, in extreme situations, suicidal ideation. Affective changes in depression include changes in facial expressions (reduced or immobile expression [hypomimia], sad expression, or furrowed brow), crying, and avoidance of eye contact. Reduced interest in or reduced initiation of new activities is often present (mediated by the anterior cingulate cortex and related structures). Cognitive changes include reduced associations and executive and visuospatial dysfunction. Changes in verbal expression include increased speech latency, slow rate and reduced volume of speech, decreased spontaneous speech, and lack of emotional inflection (dysprosody). Neurovegetative changes mediated by the hypothalamus include appetite alterations, sleep disturbances, libido loss, and diurnal mood variations. Motor changes include slumped shoulders and head, decreased gestures, slowing of movements and gait, and catatonia (mediated by the basal ganglia).3,4 Depression in neurological conditions occurs most commonly with the involvement of the frontal region (orbitofrontal and dorsolateral prefrontal cortices), temporal region (anterior temporal and paralimbic cortices), and basal ganglia (usually the caudate), mediated by the frontal-subcortical circuits. Lesions of the left hemisphere more commonly cause depression than do lesions of the right hemisphere (Fig. 19–1).2,5,6 Neurological conditions often can mask depression. Aphasic patients may not be able to voice their depressive feelings, whereas patients with dysprosody caused by basal ganglia or right hemisphere involvement may not be able to inflect their voice to convey their mood. In contrast, there are conditions that can imitate depression. Apathy, which is a common symptom in many neurological conditions, is commonly mistaken for depression. Patients with pseudobulbar palsy, parkinsonism, multiple sclerosis, and lesions causing emotional facial paresis may appear depressed without being so.3,7 The diagnosis of depression in neurological conditions is usually based on the criteria proposed for primary depression in the Diagnostic and Statistical Manual of Mental Disorders1 and is often classified as major depression or minor depression (according to the criteria for dysthymic disorder). Alternatively, the presence of depression is assessed with specific rating scales
235
236
Section
III
Neuropsychiatry
A
C
B ■
Figure 19–1. Brain regions associated with depression in neurological conditions. A, Coronal section through the corpus striatum. B, Left lateral view. C, Bottom view. The caudate (A, in red), orbitofrontal region (B and C, in purple), and anterior temporal regions (B and C, in pink), with a left-sided predominance, are highlighted in these illustrative maps. The localization of lesions associated with depression is often not as definitive as suggested here (see text).
such as the Neuropsychiatric Inventory8 or the Geriatric Depression Scale.9 Depression can herald the onset or occur during the course of neurological conditions as a neurobiological component of those conditions or simply as a psychiatric comorbid condition. Cognitive changes seen in primary depression may sometimes imitate dementia, whereas depressive symptoms seen in dementia may sometimes imitate primary depression.3 The different presentations of depression in neurological conditions are described in the following sections and are summarized in Table 19–1. Table 19–2 lists neurological agents and psychotropic medications associated with depression.
Alzheimer’s Disease Alzheimer’s disease is the most common form of dementia and produces cognitive impairment, functional deterioration, and behavioral changes. Among patients with Alzheimer’s disease, the prevalence of major depression has been reported as 1.1% to 23%10-15; that of minor depression, 13.9% to 34%10,13-15; and that of general depressive symptoms, 20.1% to 54.9%.16-20 As demonstrated, the reported rates of depression in Alzheimer’s disease have a wide range because of the different measures and criteria used. The criteria in the National Institute of Mental Health Provisional Diagnostic Criteria for Depression in
chapter 19 affective disorders
237
T A B L E 19–1. Neurological Conditions Manifesting with Depression Condition
Prevalence of Depression
Specific Features and Localization
Alzheimer’s disease
MaD: 1%-23% MiD: 14%-34% DS: 20%-55% MaD: 8%-38% MiD: 10%-32% DS: 34%-47% MaD: 8%-34%
Milder depression and irritability greater functional deficits; depression heralds diagnosis of Alzheimer’s disease; frontal and parietal involvement
Parkinson’s disease Stroke Vascular dementia Epilepsy Multiple sclerosis Traumatic brain injury115,116 Huntington’s disease94,117 Frontotemporal lobar degeneration107 Wilson’s disease94
MaD: 29%-45% DS: 30%-34% MaD: 6%-30% MaD: 16% (lifetime, 50%) DS: 79%-85% MaD: 17%-33% MaD: 22% DS: 30% MaD: 20%
Anxiety, greater motor fluctuations, greater cognitive impairment, akinetic-rigid variant; frontal (left) involvement More common in women than in men; depression associated with larger lesions; frontal, temporal, caudate involvement Increases with time, lower education level, and greater functional deficits Increased suicide rate among patients with ictal and interictal forms; temporal (left), frontal involvement Irritability, frustration, increased suicide rate; arcuate fasciculus (left) involvement Anxiety, aggressive behavior, lower education level, alcohol abuse, executive dysfunction; frontal (left) involvement Increased suicide rate; medial caudate, orbitofrontal involvement Depression in semantic dementia is worse than in frontal variant of frontotemporal dementia Lenticular nuclei
DS, general depressive symptoms; MaD, major depression; MiD, minor depression.
Alzheimer’s Disease reflect the generally more mild depression in Alzheimer’s disease, requiring the presence of only 3 (of 11) depressive symptoms (rather than 5 as in primary major depression), including irritability and social withdrawal as symptoms, and not requiring the presence of symptoms to be nearly daily over 2 weeks.21,22 Depression in Alzheimer’s disease is associated with greater functional deficits, wandering behavior, agitation, anxiety,
T A B L E 19–2. Neurological Agents and Psychotropic Medications Associated with Depression3,78,82 Antiparkinsonian drugs Anticonvulsants
Sedative-hypnotics
Neuroleptics Psychostimulants
Miscellaneous
Amantadine Bromocriptine Levodopa Phenobarbital Primidone Tiagabine Vigabatrin Felbamate Topiramate Benzodiazepines Chloral hydrate Clomethiazole Clorazepate Butyrophenones Phenothiazines Amphetamines Diethylpropion Fenfluramine Phenmetrazine Acetazolamide Azathioprine Baclofen Cholinesterase inhibitors Corticosteroids Interferon-β1b/interferon-βa (possibly)
apathy, disinhibition, and irritability.14,18,23-25 Depressed Alzheimer’s disease patients often complain more about difficulties in thinking and concentration than about depressed mood and neurovegetative changes.26,27 Depressive symptoms tend to be episodic and recur frequently in Alzheimer’s disease.28,29 Frequency of mild depressive symptoms is correlated with severity of cognitive impairment15,30,31 but is not related to self-awareness of cognitive deficits.32 Depressive symptoms tend to occur early in the course of Alzheimer’s disease and may precede the diagnosis.15,33-35 Risk factors for developing depression in Alzheimer’s disease include female gender, lower education level, early-onset disease, family history of depression, and possibly premorbid history of depression.15,25,31,33,36,37 Depression in Alzheimer’s disease has been correlated mostly with frontal and parietal dysfunction. Functional imaging studies showed localization of associated lesions to the bilateral superior frontal and left anterior cingulate cortices38 or the parietal lobe,39 and quantified electroencephalographic recording pointed toward abnormalities of the parietal lobes.40 Pathological and neurochemical studies of patients with Alzheimer’s disease and depression demonstrated greater involvement of the locus ceruleus (noradrenergic system) and, to a lesser degree, the substantia nigra (dopaminergic system) and dorsal raphe nucleus (serotonergic system), with relative preservation of the nucleus basalis of Meynert (cholinergic system).41-44 Mild cognitive impairment is often a transitional stage between normal aging and dementia. The prevalence of depressive symptoms among patients with mild cognitive impairment has been reported as 9.3% to 47%.16,17,45-47 One study reported that 85% of depressed patients with mild cognitive impairment went on to develop dementia, which again emphasizes the importance of depression in heralding the diagnosis of Alzheimer’s disease.46
238
Section
III
Neuropsychiatry
Parkinson’s Disease and Parkinsonian Syndromes Parkinson’s disease is the second most common neurodegenerative disease (after Alzheimer’s disease) and has a range of motor manifestations, cognitive impairment, and behavioral disturbances. Among patients with Parkinson’s disease, the prevalence of major depression has been reported as 7.7% to 38%48-50; that of minor depression, 10% to 32%48,50; and that of general depressive symptoms, 34% to 47%.49,51-55 Depression in Parkinson’s disease is associated with less self-punitive ideation, more anxiety, dysautonomia, and greater motor fluctuations (“on-off” phenomenon). It is correlated with advanced stage of disease and greater cognitive impairment.49-51,54,56-59 Depression is more common in the akinetic-rigid Parkinson’s disease variant than the classic tremor-predominant type.48,51 Risk factors for depression in Parkinson’s disease include premorbid history of depression, greater functional deficits, lower cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, early-onset Parkinson’s disease, more left hemisphere involvement, and, possibly, female gender.50,51,57 Depression in Parkinson’s disease is associated with frontal lobe dysfunction, often of the left hemisphere, and is correlated with involvement of the dopaminergic, noradrenergic, and serotonergic systems.50,51,60 Neuropsychological studies show a relationship with disruption of frontal-lobe related tasks.61 Functional imaging studies show a localization of depressionrelated dysfunction in the bilateral medial prefrontal and anterior cingulate cortices62 or caudate and inferior orbitofrontal cortex.63 Depression has been reported in other parkinsonian syndromes. Among patients with dementia with Lewy bodies, the prevalence of major depression has been reported as 19% to 33.3%12,64 and that of general depressive symptoms, 47.5%.12 Among patients with progressive supranuclear palsy, the prevalence of general depressive symptoms has been reported as 18% to 25%,53,65 whereas that among patients with corticobasal degeneration has been reported as 73%.65
Cerebrovascular Disease Depression in cerebrovascular disease has been described in the context of vascular depression, discrete strokes, and vascular dementia. Patients with vascular depression have clinical or imaging evidence of cerebrovascular disease, as well as vascular risk factors.66 In comparison with patients with primary depression, patients with vascular depression are older at onset of mood changes and have greater functional disability and cognitive impairment (mostly in verbal fluency and naming), greater psychomotor retardation, greater anhedonia, less agitation, lesser feelings of guilt, less insight, and less family history of depression.66,67 Vascular depression is associated with single or multiple lesions that disrupt the striatopallidothalamocortical (prefrontal) pathways.66,68 The prevalence of major depression among patients who have suffered strokes has been reported as 8.3% to 33.6%.69-71 Poststroke major depression is more common in women (23.6%), in whom it is associated with more left hemisphere lesions and a history of psychiatric disorder and cognitive impairment, whereas in men (12.3%), it is associated with greater functional deficits.72 Depression has been shown to be more common with larger lesion volumes.71 Lesions in the frontal and temporal lobes, basal ganglia (especially the head of
the caudate), and ventral brainstem circuitry are associated with depression.70,73 However, there is a tendency for depression after the acute poststroke period to be related to lesions of the left frontal region, whereas depression in the chronic poststroke period is associated with lesions of the right posterior region.4,74 Vascular dementia is the second most common dementia and is associated with executive dysfunction, motor symptoms, and significant behavioral changes. Among patients with vascular dementia, the prevalence of major depression has been reported as 29% to 45%,64,75 and that of general depressive symptoms, 29.7% to 34.2%.19,75,76 Depressive symptoms in vascular dementia tend to increase with time and are related to lower education level and greater functional deficits.25,76
Epilepsy Epilepsy is common and is associated with significant behavioral disturbances. The prevalence of major depression among patients with epilepsy has been reported as 6% to 30%.77,78 Depression in epilepsy is associated with decreased quality of life and increased suicide rate (5 to 10 times higher than in the general population).77-79 Ictal and interictal forms of depression have been reported in epilepsy: The “interictal dysphoric disorder” resembles dysthymia and consists of depressed mood, low energy, pain, insomnia, irritability, euphoria, fear, and anxiety, whereas ictal depression usually occurs as an “aura” for a seizure and consists of guilt, anhedonia, and suicidal ideation.77 Depression is more common in patients with temporal (often left) and frontal seizure foci, and the hippocampus and amygdala appear to play a role as well.77,80,81
Multiple Sclerosis Multiple sclerosis is an autoimmune disease with widespread physical, cognitive, and behavioral changes. Among patients with multiple sclerosis, the prevalence of major depression has been reported as 15.7% (lifetime prevalence, 50%)82,83 and that of general depressive symptoms, 79% to 85%.84,85 Depression in multiple sclerosis is associated with discouragement, irritability, frustration, higher rate of suicide (seven times higher than in the general population), and greater volume of lesions and cerebral atrophy.82 Depression in multiple sclerosis has been associated with lesions of the arcuate fasciculus, more so on the left.86
Treatment of Depression Few controlled clinical trials have addressed depression in neurological conditions, and no medications have been approved by the U.S. Food and Drug Administration (FDA) specifically for this indication. For most conditions, clinicians have used medications studied in primary depression, which are often not as well tolerated and not as effective in neurological conditions. Therefore, a good adage is “Start low and go slow.” Direct treatment of the neurological condition may be helpful in treating the secondary depression. In dementias with cholinergic deficits, the use of cholinesterase inhibitors has proved helpful in the treatment of neuropsychiatric manifestations,87 as
chapter 19 affective disorders well as in depression specifically.88 There is also some evidence that memantine, an N-methyl-D-aspartate antagonist approved by the FDA for the treatment of Alzheimer’s disease, may have similar effects.89 In Parkinson’s disease, selegiline, a monoamine oxidase type B inhibitor, and D3 receptor agonists, such as pramipexole and ropinirole, have shown antidepressant effects.90,91 The first-line antidepressants in most neurological conditions are the selective serotonin reuptake inhibitors, because of their tolerability, safety, and apparent efficacy (especially sertraline and citalopram in Alzheimer’s disease and epilepsy). Serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and mirtazapine, appear to be good alternative firstline agents because of their tolerability, but they are newer agents and have not been studied adequately. Tricyclic antidepressants and monoamine oxidase inhibitors have been shown to be effective but often are not tolerated as well, especially by elderly patients, and therefore are considered second-line agents. If the patient’s depression resolves, the antidepressant should be continued for 3 to 6 months and then gradually tapered, while the patient is monitored closely for recurrence of depression.4,78,92 In patients with severe depression that is refractory to medical treatment, electroconvulsive therapy and repetitive transcranial magnetic stimulation may be effective (especially in Parkinson’s disease).90 Electroconvulsive therapy should not be performed in patients with elevated intracranial pressure, headache, or focal neurological deficits. Figure 19–2 provides an algorithm for the treatment of depression in neurological conditions.
Depression
Treat neurological condition
Mania has been reported in multiple neurological conditions and as a consequence of medication use. It consists of elevated or expansive mood, irritability (often associated with aggressiveness), accelerated and/or disorganized thought or speech, distractibility, poor judgment, psychomotor agitation, expansive gestures and facial expressions, and neurovegetative changes (decreased need for sleep, hypersexuality, and increased energy). Mania may be accompanied by moodcongruent hallucinations or delusions. Hypomania is similar to mania but milder and is not accompanied by psychosis. Many patients with secondary mania caused by a focal lesion have a family history of psychiatric morbidity. Certain neurological conditions, such as pseudobulbar palsy, may imitate mania.1,3 Mania in neurological conditions has been correlated with lesions of the frontal region (especially the orbitofrontal area), basal ganglia (especially the inferior caudate), thalamus, and inferior temporal region, usually lateralized to the right, which possibly reflects overactivity of the paleocortical limbic division (Fig. 19–3).2,5 The different manifestations of mania in neurological conditions are described and summarized in Table 19–3. Table 19–4 lists neurological agents and psychotropic medications associated with mania.
Cerebrovascular Disease Mania has been described in patients with focal strokes. It is often associated with hyperkinetic movement disorders (hemi-
If symptoms relapse, restart effective agent; if response is inadequate, reenter algorithm
SSRI
Another SSRI or SNRI
TCA or MAO-I
ECT or rTMS
Symptom resolution
Continue treatment for 3–6 months; slowly withdraw and follow closely ■
MANIA
239
Figure 19–2. Algorithm for the treatment of depression in neurological conditions. Nonsolid arrows indreate next step if response to treatment is adequate. Solid arrows indicate next step if response to previous treatment is inadequate. ECT, electroconvulsive therapy; MAOI, monoamine oxidase inhibitor; rTMS, repetitive transcranial magnetic stimulation; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. (Adapted from Cummings JL: The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London: Martin Dunitz, 2003.)
ballismus, chorea, postural tremor, hemidystonia).93 Lesions are usually right-sided and involve subcortical and midline structures (especially the thalamus), damaging the frontalbasal ganglia-thalamocortical circuits.93
Extrapyramidal Disorders Although not as common as depression, mania is seen in patients with Huntington’s disease. Among such patients, the prevalence of mania and hypomania has been reported as 4.8% and 10%, respectively. Mania in Huntington’s disease consists of euphoria or irritability, grandiosity, overactivity, impulsiveness, and decreased need for sleep.94 Patients with Parkinson’s disease treated with dopaminergic agents or surgically (deep brain stimulation, pallidotomy, or thalamotomy) may develop mania. Among patients with medically treated Parkinson’s disease, the prevalence of mania has been reported as 1% (euphoria, 10%).3,95
240
Section
III
Neuropsychiatry
A ■
B Figure 19–3. Brain regions associated with mania and elevated mood in neurological conditions. A, Bottom view. B, Coronal section through the mammillary bodies. The orbitofrontal (A, in purple) and inferior temporal regions (A, in pink), caudate (B, in red), and thalamus (B, in green), with a right-sided predominance, are highlighted in these illustrative maps.
T A B L E 19–3. Neurological Conditions Manifesting with Mania and Elevated Mood
T A B L E 19–4. Neurological Agents and Psychotropic Medications Associated with Mania and Elevated Mood
Condition
Prevalence of Mania
Specific Features and Localization
Antiparkinsonian drugs
Stroke
Rare
Huntington’s disease
5% (hypomania, 10%) 9%
Hyperkinetic movement disorders; right thalamus (frontal, basal ganglia) involvement Euphoria or irritability, grandiosity, overactivity, impulsiveness, insomnia Irritability, aggressiveness; brief duration; family history; post-traumatic seizures; right thalamus, caudate, orbitofrontal, and inferior temporal involvement Late-onset presentation usually without family history and with dementia Eutonia; possible genetic predisposition in women
Traumatic brain injury
Human immunodeficiency virus118 Multiple sclerosis82
Alzheimer’s disease119 Miscellaneous98
8% Twice more common than in general population 2.2%
May precede cognitive decline Frontotemporal dementia, neurosyphilis, CreutzfeldtJakob disease, tumors (hypothalamic involvement)
Anticonvulsants
Sedative-hypnotics
Antidepressants
Antipsychotics Miscellaneous
Amantadine Bromocriptine Levodopa Lisuride Piribedil Procyclidine Selegiline Carbamazepine Phenytoin Barbiturates Ethosuximide Clonazepam Phenacemide Alprazolam Triazolam Buspirone Meprobamate Bupropion SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) TCAs (phenelzine) MAOIs (clomipramine imipramine, desipramine, amitriptyline) Mirtazapine Nefazodone Trazodone Olanzapine Risperidone Baclofen Psychostimulants Corticosteroids
MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.3,120,121
chapter 19 affective disorders Traumatic Brain Injury Mania has been observed after traumatic brain injury. The prevalence of such mania has been reported as 9%. In traumatic brain injury, mania is associated with irritability and aggressiveness and is usually short-lasting (about 2 months). Risk factors for developing mania in TBI include family history of mood disorders, post-traumatic seizures, and premorbid diencephalic and frontal subcortical atrophy. Mania in traumatic brain injury is related to lesions localized in the right hemisphere, particularly the thalamus, caudate, and orbitofrontal and inferior temporal regions.96,97
241
ued for 3 to 6 months and then gradually tapered, while the patient is monitored closely for recurrence of mania. In the acute stages of mania or in mania with mood-congruent delusions and hallucinations, an atypical antipsychotic may be added. Atypical antipsychotics may be the best choice for management of mania in some patients. If sedation is desired, a benzodiazepine may be added. If patients are resistant to mood stabilizers, electroconvulsive therapy may be considered.3,82,94,99 Figure 19–4 provides an algorithm for the treatment of mania in neurological conditions.
APATHY Treatment of Mania Essentially no clinical trials have addressed mania in neurological conditions, and no medications have been approved by the FDA for this indication. For most conditions, clinicians have used medications studied in primary bipolar illness. However, before mood stabilizer treatment is initiated, the underlying condition should be treated or, in the case of medication-induced mania, the offending agent discontinued.98 The commonly used mood stabilizers include lithium, valproate, carbamazepine, and atypical antipsychotics. Patients with mania in some neurological conditions, such as Huntington’s disease or human immunodeficiency virus infection, do not respond as well to lithium and are more vulnerable to its toxic effects. Lamotrigine and gabapentin are newer anticonvulsants that may have a role as mood stabilizers as well. If the patient’s mania resolves, the mood stabilizer should be contin-
Apathy is a common neuropsychiatric symptom in neurological conditions, especially in neurodegenerative diseases. It consists of loss of interest, emotions, or motivation, and in extreme situations, patients become akinetic and mute. Apathy may resemble depression and may coexist with a mood disorder, but it has been shown to be a separate entity. The decreased motivation seen in apathy (mediated by the anterior cingulate cortex) is associated with lack of concern (mediated by the parietal lobe), impaired cognition (mediated by the neocortex), placidity and impaired emotional memory (mediated by the medial temporal lobe), inattention (mediated by the dorsolateral prefrontal cortex), decreased experience of emotion (mediated by the limbic system), and decreased perception and expression of emotion (mediated by the right hemisphere).3-5,100,101 As just mentioned, apathy in neurological conditions has been related to lesions localized to the anterior cingulate gyrus, nucleus accumbens, globus pallidus, substantia nigra, and
■
Mania
and elevated mood in neurological conditions. Nonsolid arrows indicate next step if response to treatment is adequate. Solid arrows indicate next step if response to previous treatment is inadequate. ECT, electroconvulsive therapy.
Treat underlying condition Add atypical antipsychotic for acute mania or mania with psychosis
Add benzodiazepines for sedation
Lithium, valproate, carbamazepine, atypical antipsychotics
If symptoms relapse, restart effective agent; if response is inadequate, reenter algorithm
Lamotrigine, gabapentin
ECT
Figure 19–4. Algorithm for the treatment of mania
Symptom resolution
Continue treatment for 3–6 months; slowly withdraw and follow closely
242
Section
III
Neuropsychiatry
A
C
B ■
Figure 19–5. Brain regions associated with apathy in neurological conditions. A, Left midsagittal view. B, Coronal section through the anterior commissure. C, Coronal section through the midbrain and pons. The anterior cingulate gyrus (A, in yellow), nucleus accumbens (B, in pink), globus pallidus (B, in turquoise), substantia nigra (C, in blue), and thalamus (C, in green) are highlighted in these illustrative maps.
thalamus, which make up the anterior cingulate-subcortical circuit, responsible for mediating motivation (Fig. 19–5).2,4-6 The different manifestations of apathy in neurological conditions are listed in Table 19–5.
Alzheimer’s Disease Apathy is the most common neuropsychiatric symptom in Alzheimer’s disease. Among patients with Alzheimer’s disease, the prevalence of apathy has been reported as 28.5% to 70%.4,16,17,19,102 It has been shown to be associated with executive dysfunction and severity of cognitive impairment but
remaining distinct from depression.30,102 Apathy often heralds the diagnosis of Alzheimer’s disease or becomes apparent early in its course.33,103 Apathy has been reported among patients with mild cognitive impairment with a prevalence of 11.1% to 39%.16,17,47 Apathy in Alzheimer’s disease is associated in most cases with lesions of the anterior cingulate gyrus. Functional imaging studies showed localization to the anterior cingulate bilaterally104 or the prefrontal and anterior temporal regions.105 One pathological study showed increased pathological burden in the anterior cingulate gyrus of patients with Alzheimer’s disease and apathy.106
chapter 19 affective disorders Frontotemporal Dementia Frontotemporal dementia is a degenerative dementia in which prominent behavioral changes manifest early in its course. The prevalence of apathy among patients with frontotemporal dementia has been reported as 68% to 90%.4,107,108 Apathy occurs early in the course of frontotemporal dementia, is associated with loss of emotions and loss of interest, and is more common in the frontal variant of frontotemporal dementia.107,108
Parkinson’s Disease and Parkinsonian Syndromes Apathy has been reported in the various parkinsonian syndromes. The prevalence of apathy among patients with Parkinson’s disease has been reported as 16.5% to 20%.4,53,54 Apathy in Parkinson’s disease is correlated with advanced stage of disease, greater cognitive impairment, and executive dysfunction.54,109 The prevalence of apathy among patients with progressive supranuclear palsy has been reported as 84% to 90%,4,53 and apathy has been associated with lesions of the orbitofrontal and medial frontal circuits.53 Among patients who have dementia with Lewy bodies and corticobasal degeneration, the prevalence of apathy has been reported as 90% and 40%, respectively.4
Cerebrovascular Disease Apathy in cerebrovascular disease has been described in the context of stroke and vascular dementia. The prevalence of apathy among stroke patients has been reported as 56.7% and
has been associated with predominantly right hemisphere lesions and decreased heart rate reactivity to mental stress.110 The prevalence of apathy among patients with vascular dementia has been reported as 22.6% to 47%.19,108
Treatment of Apathy No clinical trials have addressed apathy in neurological conditions, and no medications have been approved by the FDA for this indication. Direct treatment of the neurological condition may be helpful in treating the associated apathy. The use of cholinesterase inhibitors in dementias with cholinergic deficits (Alzheimer’s disease, vascular dementia, dementia with Lewy bodies) has been shown to improve neuropsychiatric symptoms and apathy (and visual hallucinations) in particular.87,88,111,112 Psychostimulants and related agents have been commonly used to treat severe apathy in neurological conditions. These drugs, which include methylphenidate, dextroamphetamine, atomoxetine, and modafinil, have been used successfully in patients with dementia and stroke.113,114 Some antidepressants with activating properties (fluoxetine and desipramine) and dopaminergeric agents (amantadine and bromocriptine) have been used successfully in patients with Huntington’s disease and akinetic mutism.2,94 If treatment is successful, the medication should be continued for 3 to 6 months and then gradually tapered, while the patient is monitored closely for recurrence of apathy (this does not apply to cholinesterase inhibitors). Figure 19–6 provides an algorithm for the treatment of apathy in neurological conditions.
Apathy
T A B L E 19–5. Neurological Conditions Manifesting with Apathy Condition
Prevalence of Apathy
Specific Features and Localization
Alzheimer’s disease
29%-70%
Associated with executive dysfunction and severity of cognitive impairment; distinct from depression; apathy heralds diagnosis of Alzhermer’s disease; anterior cingulate involvement Occurs early in the course of disease, more common in frontal variant Occurs in advanced stage of disease; greater cognitive impairment and executive dysfunction Orbitofrontal and medial frontal circuit involvement Decreased heart rate reactivity to mental stress; right hemisphere lesions Right hemisphere lesions
Frontotemporal dementia
68%-90%
Parkinson’s disease
17%-20%
Progressive supranuclear palsy Stroke
84%-90%
Traumatic brain injury110 Huntington’s disease94 Multiple sclerosis85
46%
57%
48% 20%
Disregard for appearance and personal hygiene Variable correlations with imaging changes
243
Treat neurological condition If symptoms relapse, restart effective agent; if response is inadequate, reenter algorithm
Psychostimulant
Antidepressant or dopaminergic agent
Symptom resolution
Continue treatment for 3–6 months; slowly withdraw and follow closely ■
Figure 19–6. Treatment of apathy in neurological conditions. Nonsolid arrows indicates next step if responce to treatment is adequate. Solid arrow indicates next step if response to previous treatment is inadequate.
244
Section
III
K E Y
Neuropsychiatry
P O I N T S
●
Mood symptoms and syndromes are common in neurological conditions.
●
Mood symptoms are most prevalent among patients with neurodegenerative diseases, cerebrovascular disease, traumatic brain injury, and multiple sclerosis.
●
Depression and apathy are common, whereas mania is rare, in neurological conditions.
●
Mood symptoms in neurological conditions are associated with lesions of the basal ganglia and the frontal and temporal regions.
●
In treatment, the neurological condition should be targeted first (e.g., cholinesterase inhibitors for dementia).
●
Conventional treatments used in primary psychiatric disorders are used in patients with neurological conditions with mood symptoms despite little evidence of their efficacy in these conditions.
●
The adage “Start low and go slow” applies to patients with neurological conditions, who are more sensitive to conventional medications.
Acknowledgment Figures 19-1, 19-3, and 19-5 were created with the assistance of Dr. Liana G. Apostolova.
Suggested Reading Aarsland D, Litvan I, Larsen JP: Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:42-49. Cummings JL: Principles of neuropsychiatry: towards a neuropsychiatric epistemology. Neurocase 1999; 5:181-188. Cummings JL: Cognitive and behavioral heterogeneity in Alzheimer’s disease: seeking the neurobiological basis. Neurobiol Aging 2000; 21:845-861. Cummings JL: The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London: Martin Dunitz, 2003. Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience. New York: Oxford University Press, 2003.
References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC: American Psychiatric Association, 2000. 2. Cummings JL: Principles of neuropsychiatry: towards a neuropsychiatric epistemology. Neurocase 1999; 5:181-188. 3. Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience. New York: Oxford University Press, 2003. 4. Cummings JL: The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London: Martin Dunitz, 2003. 5. Mega MS, Cummings JL, Salloway S, et al: The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci 1997; 9:315-330.
6. Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol 1993; 50:873-880. 7. Hopf HC, Muller-Forell W, Hopf NJ: Localization of emotional and volitional facial paresis. Neurology 1992; 42:19181923. 8. Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314. 9. Yesavage JA, Brink TL, Rose TL, et al: Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982; 17:37-49. 10. Gilley DW, Wilson RS, Bienias JL, et al: Predictors of depressive symptoms in persons with Alzheimer’s disease. J Gerontol B Psychol Sci Soc Sci 2004; 59:P75-P83. 11. Weiner MF, Doody RS, Sairam R, et al: Prevalence and incidence of major depressive disorder in Alzheimer’s disease: findings from two databases. Dement Geriatr Cogn Disord 2002; 13:8-12. 12. Ballard C, Holmes C, McKeith I, et al: Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry 1999; 156:1039-1045. 13. Starkstein SE, Chemerinski E, Sabe L, et al: Prospective longitudinal study of depression and anosognosia in Alzheimer’s disease. Br J Psychiatry 1997; 171:47-52. 14. Lyketsos CG, Steele C, Baker L, et al: Major and minor depression in Alzheimer’s disease: prevalence and impact. J Neuropsychiatry Clin Neurosci 1997; 9:556-561. 15. Migliorelli R, Teson A, Sabe L, et al: Prevalence and correlates of dysthymia and major depression among patients with Alzheimer’s disease. Am J Psychiatry 1995; 152:37-44. 16. Geda YE, Smith GE, Knopman DS, et al: De novo genesis of neuropsychiatric symptoms in mild cognitive impairment (MCI). Int Psychogeriatr 2004; 16:51-60. 17. Hwang TJ, Masterman DL, Ortiz F, et al: Mild cognitive impairment is associated with characteristic neuropsychiatric symptoms. Alzheimer Dis Assoc Disord 2004; 18:17-21. 18. Cummings JL: The impact of depressive symptoms on patients with Alzheimer disease [Comment]. Alzheimer Dis Assoc Disord 2003; 17:61-62. 19. Lyketsos CG, Steinberg M, Tschanz JT, et al: Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry 2000; 157:708-714. 20. Frisoni GB, Rozzini L, Gozzetti A, et al: Behavioral syndromes in Alzheimer’s disease: description and correlates. Dement Geriatr Cogn Disord 1999; 10:130-138. 21. Olin JT, Schneider LS, Katz IR, et al: Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry 2002; 10:125-128. 22. Olin JT, Katz IR, Meyers BS, et al: Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am J Geriatr Psychiatry 2002; 10:129-141 [Erratum in Am J Geriatr Psychiatry 2002; 10:264]. 23. Espiritu DA, Rashid H, Mast BT, et al: Depression, cognitive impairment and function in Alzheimer’s disease. Int J Geriatr Psychiatry 2001; 16:1098-1103. 24. Fitz AG, Teri L: Depression, cognition, and functional ability in patients with Alzheimer’s disease. J Am Geriatr Soc 1994; 42:186-191. 25. Hargrave R, Reed B, Mungas D: Depressive syndromes and functional disability in dementia. J Geriatr Psychiatry Neurol 2000; 13:72-77. 26. Heun R, Kockler M, Ptok U: Lifetime symptoms of depression in Alzheimer’s disease. Eur Psychiatry 2003; 18:63-69. 27. Devanand DP, Jacobs DM, Tang MX, et al: The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry 1997; 54:257-263.
chapter 19 affective disorders 28. Marin DB, Green CR, Schmeidler J, et al: Noncognitive disturbances in Alzheimer’s disease: frequency, longitudinal course, and relationship to cognitive symptoms. J Am Geriatr Soc 1997; 45:1331-1338. 29. Levy ML, Cummings JL, Fairbanks LA, et al: Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer’s disease. Am J Psychiatry 1996; 153:1438-1443. 30. Mega MS, Cummings JL, Fiorello T, et al: The spectrum of behavioral changes in Alzheimer’s disease. Neurology 1996; 46:130-135. 31. Devanand DP, Sano M, Tang MX, et al: Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Arch Gen Psychiatry 1996; 53:175-182. 32. Cummings JL, Ross W, Absher J, et al: Depressive symptoms in Alzheimer disease: assessment and determinants. Alzheimer Dis Assoc Disord 1995; 9:87-93. 33. Jost BC, Grossberg GT: The evolution of psychiatric symptoms in Alzheimer’s disease: a natural history study. J Am Geriatr Soc 1996; 44:1078-1081. 34. Berger AK, Fratiglioni L, Forsell Y, et al: The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study. Neurology 1999; 53:1998-2002. 35. Chen P, Ganguli M, Mulsant BH, et al: The temporal relationship between depressive symptoms and dementia: a community-based prospective study. Arch Gen Psychiatry 1999; 56:261-266. 36. Harwood DG, Barker WW, Ownby RL, et al: Association between premorbid history of depression and current depression in Alzheimer’s disease. J Geriatr Psychiatry Neurol 1999; 12:72-75. 37. Strauss ME, Ogrocki PK: Confirmation of an association between family history of affective disorder and the depressive syndrome in Alzheimer’s disease. Am J Psychiatry 1996; 153:1340-1342. 38. Hirono N, Mori E, Ishii K, et al: Frontal lobe hypometabolism and depression in Alzheimer’s disease. Neurology 1998; 50:380-383. 39. Sultzer DL, Mahler ME, Mandelkern MA, et al: The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:476-484. 40. Pozzi D, Golimstock A, Petracchi M, et al: Quantified electroencephalographic changes in depressed patients with and without dementia. Biol Psychiatry 1995; 38:677683. 41. Zubenko GS: Clinicopathologic and neurochemical correlates of major depression and psychosis in primary dementia. Int Psychogeriatr 1996; 8(Suppl 3):219-223; discussion, Int Psychogeriatr 1996; 8(Suppl 3):269-272. 42. Forstl H, Burns A, Luthert P, et al: Clinical and neuropathological correlates of depression in Alzheimer’s disease. Psychol Med 1992; 22:877-884. 43. Zubenko GS, Moossy J, Kopp U: Neurochemical correlates of major depression in primary dementia. Arch Neurol 1990; 47:209-214. 44. Zubenko GS, Moossy J: Major depression in primary dementia. Clinical and neuropathologic correlates. Arch Neurol 1988; 45:1182-1186. 45. Feldman H, Scheltens P, Scarpini E, et al: Behavioral symptoms in mild cognitive impairment. Neurology 2004; 62:1199-1201. 46. Modrego PJ, Ferrandez J: Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurol 2004; 61:1290-1293. 47. Lyketsos CG, Lopez O, Jones B, et al: Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impair-
48. 49. 50. 51. 52. 53.
54. 55. 56. 57. 58. 59. 60. 61. 62. 63.
64. 65. 66. 67. 68. 69.
245
ment: results from the cardiovascular health study. JAMA 2002; 288:1475-1483. Starkstein SE, Petracca G, Chemerinski E, et al: Depression in classic versus akinetic-rigid Parkinson’s disease. Mov Disord 1998; 13:29-33. Tandberg E, Larsen JP, Aarsland D, et al: The occurrence of depression in Parkinson’s disease. A community-based study. Arch Neurol 1996; 53:175-179. Cole SA, Woodard JL, Juncos JL, et al: Depression and disability in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1996; 8:20-25. Cummings JL: Depression and Parkinson’s disease: a review. Am J Psychiatry 1992; 149:443-454. Shulman LM, Taback RL, Rabinstein AA, et al: Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002; 8:193-197. Aarsland D, Litvan I, Larsen JP: Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:4249. Aarsland D, Larsen JP, Lim NG, et al: Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 67:492-496. Dooneief G, Mirabello E, Bell K, et al: An estimate of the incidence of depression in idiopathic Parkinson’s disease. Arch Neurol 1992; 49:305-307. Norman S, Troster AI, Fields JA, et al: Effects of depression and Parkinson’s disease on cognitive functioning. J Neuropsychiatry Clin Neurosci 2002; 14:31-36. Tandberg E, Larsen JP, Aarsland D, et al: Risk factors for depression in Parkinson disease. Arch Neurol 1997; 54:625630. Berrios GE, Campbell C, Politynska BE: Autonomic failure, depression and anxiety in Parkinson’s disease. Br J Psychiatry 1995; 166:789-792. Richard IH, Justus AW, Kurlan R: Relationship between mood and motor fluctuations in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:35-41. Mayeux R, Stern Y, Cote L, et al: Altered serotonin metabolism in depressed patients with Parkinson’s disease. Neurology 1984; 34:642-646. Kuzis G, Sabe L, Tiberti C, et al: Cognitive functions in major depression and Parkinson disease. Arch Neurol 1997; 54:982986. Ring HA, Bench CJ, Trimble MR, et al: Depression in Parkinson’s disease. A positron emission study. Br J Psychiatry 1994; 165:333-339. Mayberg HS, Starkstein SE, Sadzot B, et al: Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson’s disease. Ann Neurol 1990; 28:5764. Ballard C, Bannister C, Solis M, et al: The prevalence, associations and symptoms of depression amongst dementia sufferers. J Affect Disord 1996; 36:135-144. Litvan I, Cummings JL, Mega M: Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiatry 1998; 65:717-721. Alexopoulos GS, Meyers BS, Young RC, et al: Clinically defined vascular depression. Am J Psychiatry 1997; 154:562565. Krishnan KR, Hays JC, Blazer DG: MRI-defined vascular depression. Am J Psychiatry 1997; 154:497-501. Alexopoulos GS, Meyers BS, Young RC, et al: “Vascular depression” hypothesis. Arch Gen Psychiatry 1997; 54:915922. Toso V, Gandolfo C, Paolucci S, et al: Post-stroke depression: research methodology of a large multicentre observational study (DESTRO). Neurol Sci 2004; 25:138-144.
246
Section
III
Neuropsychiatry
70. Kim JS, Choi-Kwon S: Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000; 54:1805-1810. 71. Sharpe M, Hawton K, House A, et al: Mood disorders in longterm survivors of stroke: associations with brain lesion location and volume. Psychol Med 1990; 20:815-828. 72. Paradiso S, Robinson RG: Gender differences in poststroke depression. J Neuropsychiatry Clin Neurosci 1998; 10:41-47. 73. Starkstein SE, Robinson RG, Berthier ML, et al: Differential mood changes following basal ganglia vs thalamic lesions. Arch Neurol 1988; 45:725-730. 74. Shimoda K, Robinson RG: The relationship between poststroke depression and lesion location in long-term follow-up. Biol Psychiatry 1999; 45:187-192. 75. Reichman WE, Coyne AC: Depressive symptoms in Alzheimer’s disease and multi-infarct dementia. J Geriatr Psychiatry Neurol 1995; 8:96-99. 76. Li YS, Meyer JS, Thornby J: Longitudinal follow-up of depressive symptoms among normal versus cognitively impaired elderly. Int J Geriatr Psychiatry 2001; 16:718-727. 77. Kanner AM: Depression in epilepsy: a frequently neglected multifaceted disorder. Epilepsy Behav 2003; 4(Suppl 4):1119. 78. Kanner AM: Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry 2003; 54:388-398. 79. Johnson EK, Jones JE, Seidenberg M, et al: The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia 2004; 45:544-550. 80. Hecimovic H, Goldstein JD, Sheline YI, et al: Mechanisms of depression in epilepsy from a clinical perspective. Epilepsy Behav 2003; 4(Suppl 3):S25-S30. 81. Victoroff JI, Benson F, Grafton ST, et al: Depression in complex partial seizures. Electroencephalography and cerebral metabolic correlates. Arch Neurol 1994; 51:155-163. 82. Feinstein A: The neuropsychiatry of multiple sclerosis. Can J Psychiatry 2004; 49:157-163. 83. Patten SB, Beck CA, Williams JV, et al: Major depression in multiple sclerosis: a population-based perspective. Neurology 2003; 61:1524-1527. 84. Zephir H, De Seze J, Stojkovic T, et al: Multiple sclerosis and depression: influence of interferon beta therapy. Mult Scler 2003; 9:284-288. 85. Diaz-Olavarrieta C, Cummings JL, Velazquez J, et al: Neuropsychiatric manifestations of multiple sclerosis. J Neuropsychiatry Clin Neurosci 1999; 11:51-57. 86. Pujol J, Bello J, Deus J, et al: Lesions in the left arcuate fasciculus region and depressive symptoms in multiple sclerosis. Neurology 1997; 49:1105-1110. 87. Wynn ZJ, Cummings JL: Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer’s disease. Dement Geriatr Cogn Disord 2004; 17:100-108. 88. Feldman H, Gauthier S, Hecker J, et al, Donepezil MSAD Study Investigators Group: A 24-week, randomized, doubleblind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001; 57:613-620 [Erratum in Neurology 2001; 57:2153]. 89. Tariot PN, Farlow MR, Grossberg GT, et al, Memantine Study Group: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291:317-324. 90. Tom T, Cummings JL: Depression in Parkinson’s disease. Pharmacological characteristics and treatment. Drugs Aging 1998; 12:55-74. 91. Cummings JL: D-3 receptor agonists: combined action neurologic and neuropsychiatric agents [Comment]. J Neurol Sci 1999; 163:2-3.
92. Lyketsos CG, Olin J: Depression in Alzheimer’s disease: overview and treatment. Biol Psychiatry 2002; 52:243-252. 93. Berthier ML, Kulisevsky J, Gironell A, et al: Poststroke bipolar affective disorder: clinical subtypes, concurrent movement disorders, and anatomical correlates. J Neuropsychiatry Clin Neurosci 1996; 8:160-167. 94. Rosenblatt A, Leroi I: Neuropsychiatry of Huntington’s disease and other basal ganglia disorders. Psychosomatics 2000; 41:24-30. 95. Cummings JL: Behavioral complications of drug treatment of Parkinson’s disease. J Am Geriatr Soc 1991; 39:708-716. 96. Wright MT, Cummings JL, Mendez MF, et al: Bipolar syndromes following brain trauma. Neurocase 1997; 3:111-118. 97. Jorge RE, Robinson RG, Starkstein SE, et al: Secondary mania following traumatic brain injury. Am J Psychiatry 1993; 150:916-921. 98. Mendez MF: Mania in neurologic disorders. Curr Psychiatry Rep 2000; 2:440-445. 99. Dunn RT, Frye MS, Kimbrell TA, et al: The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol 1998; 21:215-235. 100. Marin RS: Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991; 3:243-254. 101. Levy ML, Cummings JL, Fairbanks LA, et al: Apathy is not depression. J Neuropsychiatry Clin Neurosci 1998; 10:314319. 102. McPherson S, Fairbanks L, Tiken S, et al: Apathy and executive function in Alzheimer’s disease. J Int Neuropsychol Soc 2002; 8:373-381. 103. Cummings JL: Cognitive and behavioral heterogeneity in Alzheimer’s disease: seeking the neurobiological basis. Neurobiol Aging 2000; 21:845-861. 104. Migneco O, Benoit M, Koulibaly PM, et al: Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer’s disease and nondemented patients. Neuroimage 2001; 13:896-902. 105. Craig AH, Cummings JL, Fairbanks L, et al: Cerebral blood flow correlates of apathy in Alzheimer disease. Arch Neurol 1996; 53:1116-1120. 106. Tekin S, Mega MS, Masterman DM, et al: Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol 2001; 49:355-361. 107. Bozeat S, Gregory CA, Ralph MA, et al: Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 2000; 69:178-186. 108. Bathgate D, Snowden JS, Varma A, et al: Behaviour in frontotemporal dementia, Alzheimer’s disease and vascular dementia. Acta Neurol Scand 2001; 103:367-378. 109. Pluck GC, Brown RG: Apathy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002; 73:636-642. 110. Andersson S, Krogstad JM, Finset A: Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med 1999; 29:447-456. 111. Erkinjuntti T, Kurz A, Gauthier S, et al: Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet 2002; 359:1283-1290. 112. McKeith I, Del Ser T, Spano P, et al: Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356: 2031-2036. 113. Galynker I, Ieronimo C, Miner C, et al: Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci 1997; 9:231-239.
chapter 19 affective disorders 114. Watanabe MD, Martin EM, DeLeon OA, et al: Successful methylphenidate treatment of apathy after subcortical infarcts. J Neuropsychiatry Clin Neurosci 1995; 7:502-504. 115. Dikmen SS, Bombardier CH, Machamer JE, et al: Natural history of depression in traumatic brain injury. Arch Phys Med Rehabil 2004; 85:1457-1464. 116. Jorge RE, Robinson RG, Moser D, et al: Major depression following traumatic brain injury. Arch Gen Psychiatry 2004; 61:42-50. 117. Mayberg HS, Starkstein SE, Peyser CE, et al: Paralimbic frontal lobe hypometabolism in depression associated with Huntington’s disease. Neurology 1992; 42:1791-1797.
247
118. Lyketsos CG, Hanson AL, Fishman M, et al: Manic syndrome early and late in the course of HIV. Am J Psychiatry 1993; 150:326-327. 119. Lyketsos CG, Corazzini K, Steele C: Mania in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:350-352. 120. Aubry JM, Simon AE, Bertschy G: Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. J Clin Psychiatry 2000; 61:649-655. 121. Sultzer Dl, Cummings JL: Drug-induced mania—causative agents, clinical characteristics and management: a restrospective analysis of the literature. Med Toxicol Adverse Drug Exp 1989; 4:127-143.
CHAPTER
20
CONVERSION AND DISSOCIATION SYNDROMES ●
●
●
●
Christopher Bass
Social historians have confidently asserted that conversion hysteria has disappeared from clinical practice, to be replaced by syndromes characterized by fatigue and other medically unexplained disorders.1,2 Although the florid manifestations of hysteria seen in the days of Pierre Janet are less common in the 21st century, the evidence from clinical practice is that patients with conversion disorders are not infrequently encountered by neurologists in both outpatient and inpatient settings.3 Indeed, it has been shown that symptoms considered “functional,” “psychogenic,” “medically unexplained,” or “hysterical” account for up to one third of new referrals to neurology outpatient departments.3,4 In a German survey, Rief and colleagues5 found a 2% base rate of unexplained paralysis or localized weakness in the population and a 5% base rate for “impaired coordination or balance” and “unpleasant numbness or tingling sensations.” In this chapter, the diverse manifestations of conversion and dissociation disorders are described, and the advances in approaches to treatment are outlined.
PROBLEMS WITH DEFINITION There are a number of problems with the definition of the conversion disorder. First, physical disorder must be excluded, but the rate of neurological comorbidity is known to be high in patients with conversion disorder,6 and distinguishing which symptoms are accounted for by organic disease and which are not can be difficult. Second, it is stated that6a a temporal association between a psychological stressor and the onset on the disorder should be identified, but in practice, this is often impossible to establish, and doing so depends to a large extent on the skill of the interviewing physician. Finally, by definition, the process should be unconsciously mediated, but in practice it is difficult (some authorities would say impossible) to distinguish between symptoms that are not consciously produced and those that are intentionally manufactured. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition,6a provides no criteria for distinguishing conscious from unconscious intent, and many authors have argued that the criteria of whether the patients are consciously aware of producing these symptoms should be excluded from the diagnosis of conversion disorder.7 A question often asked by neurologists, when confronted with a patient with unexplained loss of function of the limb, is
“How do I distinguish between conversion disorder, factitious disorder, and malingering?” For the reasons just described, it is difficult to answer this question, because a patient’s “awareness” or “motivations” are not knowable. Various attempts have been made to provide adequate definitions, but all have their limitations (Table 20–1). Attempts to “demedicalize” this complex diagnostic field have introduced the concepts of “free will” and patient choice,8 and motor symptoms of hysteria have been discussed as “disorders of willed action.”9 Neurologists require considerable skills to diagnose and manage these conditions, which can be among the most taxing in the speciality.10 The term conversion is conventionally applied to somatic symptoms, whereas if the symptom is psychological (e.g., a loss of memory or an external hallucination) rather than physical (e.g., a loss of power), it is regarded as dissociative. Dissociation has attracted considerable interest, and in a major review of the topic, Holmes and colleagues (2005)11 drew a distinction between two qualitatively distinct, clinically relevant forms of dissociation, labeled compartmentalization (type 1) and detachment (type 2)12 (Table 20–2). Compartmentalization phenomena are characterized by impairment in the inability to control processes or actions that would usually be amenable to such control and that are otherwise functioning normally. This category encompasses unexplained neurological symptoms (including dissociative amnesia) and benign phenomena such as those produced by hypnotic suggestion. In contrast, detachment phenomena are characterized by an altered state of consciousness associated with a sense of separation from the self, the body, or the world. Depersonalization, derealization, and out-of-body experiences constitute archetypal examples of detachment in this account. Evidence suggests that these phenomena are generated by a common pathophysiological mechanism involving the top-down inhibition of limbic emotional processing by frontal brain systems. Although these two types of dissociation are typically conflated, evidence suggests that different pathological mechanisms may be operating in each case. Support for the compartmentalization model comes from psychophysiological research, which suggests that psychogenic illness is associated with a deficit in attentional, conscious processing and the preservation of preattentive, preconscious processes. According to Brown,13 there is very little difference between “negative” symptoms, such as sensory loss and paralysis, and “positive” symptoms, such as tremor and dystonia, in
249
250
Section
III
Neuropsychiatry
T A B L E 20–1. Relationships between Conversion Hysteria, Factitious Disorder, and Malingering Subject Insight Aware Hysterical conversion Factitious disorder Malingering
Target of Deception
Unaware
Conscious Self
+
+
+ +
Other + +
Perceived Outcome
Motivation/Reason
Sick and disabled role Sick and disabled role Sick and disabled role
Care/dependency Care/dependency Personal benefit (e.g., financial, avoiding prison)
From Halligan P, Bass C, Oakley D: Willful deception as illness behaviour. In Halligan P, Bass C, Oakley D, eds: Malingering and Illness Deception. Oxford, UK: Oxford University Press, 2003, pp 3-28.
EPIDEMIOLOGY
T A B L E 20–2. Classification of Two Types of Pathological Dissociation Type 1 Dissociation (Compartmentalization)
Type 2 Dissociation (Detachment)
Conversion disorders Dissociative amnesia Dissociative fugue Dissociative identity disorder
Depersonalization/derealization Peritraumatic dissociation Out-of-body experiences Autoscopy (?)
From Brown RJ: The cognitive psychology of dissociative states. Cogn Neuropsychiatry 2002; 7:221-235.
terms of basic underlying mechanisms. According to this view, all symptoms result from a loss of normal high-level attentional control over low-level processing systems; in this sense, all symptoms can be viewed as involving a form of compartmentalization. In each case, the “dissociation” between high- and low-level control results from the repetitive reallocation of high-level attention onto “rogue representations” in memory, causing low-level attention to misinterpret this stored information as an account of current rather than past processing activity. The model is shown diagrammatically in Figure 20–1.
In 1976, an editorial in the British Medical Journal suggested that hysteria was “virtually a historical curiosity in Britain.”14 Despite this assertion, the published evidence suggests that it is as common as other disabling conditions such as multiple sclerosis and schizophrenia.15 In a comprehensive review of the literature, Akagi and House15 concluded that the lowest prevalence data suggested a rate of about 50 per 100,000 for cases of conversion disorder known to health services at any one time, with perhaps twice that number affected over a 1-year period. These prevalence studies suggest that the burden of disability associated with chronic hysteria is far higher than a typical practicing psychiatrist might expect or than is reflected in standard textbooks of psychiatry or clinical neurology.
CLINICAL FEATURES Conversion Disorder Motor Symptoms The most typical motor symptoms are paralyses, functional weakness, gait disturbances, seizures resembling epilepsy, and abnormal movements. ■
Operation perceived as effortful and deliberate: associated with self-awareness.
Secondary attentional system
Operation perceived as intuitive, effortless, and self-evident.
Primary attentional system
Spread of activation in perceptual and memorial systems
Activation of perceptual hypotheses
Creation of primary representations
Experience
Figure 20–1. The generation of experience and control of action by the cognitive system. This model suggests that the management of behavior is governed by systems that operate without direct volitional control. This is important in that it allows for functional dissociations between the experience of volition and the control of thought and action. (From Brown RJ: Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model. Psychol Bull 2004; 130:793-812.)
Activation of thought and action schemata
Behavior
chapter 20 conversion and dissociation syndromes The Clinical Approach The physician must not only rule out neurological disorder with the usual methods of history taking, examination, and investigation, but at the same time seek the “positive signs” of hysteria and establish that there is an appropriate psychosocial background for the emergence of medically unexplained symptoms. Since the mid-1990s, diagnostic procedures have improved, and the availability of noninvasive, accurate imaging has drastically reduced the rates of organic pathology that remains undetected in patients with diagnoses of hysteria. Indeed, several studies have reported rates of misdiagnosis of between 0% and 4% in regional and tertiary neurological centers,16 which suggests that a diagnosis of conversion disorder can be made relatively confidently and accurately. In the following section, the process of diagnosis is briefly outlined through the history, examination, and investigation.
The History The onset, temporal sequence, and character of the presenting complaint may not be typical of a neurological disorder, and a number of other features may emerge, especially after an interview with a family member or a review of the hospital and general practitioner notes. Previous Unexplained Symptoms. There is accumulating evidence that the more unexplained symptoms the patient has, the more likely the primary symptom is to be unexplained.17 In one study of patients with medically unexplained motor symptoms, additional unexplained symptoms, including paresthesia (65%), pseudo-epileptic seizures (23%), and memory impairment (20%), were reported.18 It is, therefore, often useful when conversion disorder is being considered as a diagnosis to obtain a printout of the patient’s history from the primary care physician. This may reveal repeated presentations to different specialists, as well as a history of repeated surgical procedures, particularly without clear evidence of pathology. Psychiatric Comorbidity. Rates of depression (38% to 50%) and anxiety (10% to 16%) have been identified in a number of studies. In one small prospective controlled study, there was a fourfold increase in depression among patients with conversion disorder in comparison with matched controls with similar organic disability.19 Recent Life Events or Difficulties. An increased number of life events in the year preceding symptom onset have been recorded in small controlled studies of unexplained motor symptoms20 and pseudoseizures.21 More recent evidence suggests that when patients are interviewed carefully, some report symptoms of panic just before the onset of, for example, functional weakness (J. Stone, personal communication, 10.2.2006). Judicious questions about sensations of sweating, dizziness, and breathing difficulty may reveal these somatic symptoms of anxiety, which may also be reported before the onset of sensory symptoms (see later section on sensory symptoms). Secondary Gain/Litigation. This is a complex issue, but impending litigation has been described in a number of studies of patients with unexplained motor symptoms and tremor.18,21 Neurological Comorbidity. In one study in the United Kingdom, 42% of patients with unexplained motor symptoms had a comorbid neurological disease and, interestingly, one half of these had a peripheral origin.18 Epilepsy is believed to coexist in a significant percentage of patients with nonepileptic seizures.22
251
History from Relative/Informant. There is a considerable amount of evidence to suggest that the observations and attitudes of caretakers may be important in the perpetuation of medically unexplained symptoms, especially motor conversion symptoms. For example, Davison and associates23 found caretakers to be ill informed and dissatisfied with the advice they had received from doctors about their relatives’ diagnosis and disabilities.
The Examination and Diagnostic Discrepancies There is often a discrepancy between the patient’s concept of the symptoms and the physician’s knowledge of the anatomy and physiology. The way in which a patient moves or undresses may indicate a global affectation that is incompatible with a specific nerve lesion or with a hemiplegia. Give-way weakness is often used as a diagnostic test of hysterical paralyses, but it is unreliable. Unilateral functional weakness of a leg, if severe, tends to produce a characteristic gait in which the leg is dragged behind the body as a single unit, like a sack of potatoes. The hip is either held in external or internal rotation so that the foot points inward or outward. The most impressive quantitative discrimination to date between hysterical and neurological weakness is reported in a study of Hoover’s sign—the involuntary extension of hysterically paralyzed leg when the “good leg” is flexing against resistance. Ziv and colleagues24 demonstrated a clear difference in the pattern of response between neurological and psychogenic patient groups. It should be borne in mind, however, that the patient may have both a functional disorder and an organic disorder.25
Individual Symptoms Paralyses Paralyses may affect one or more limbs or one side of the face. They may be flaccid or occur with contractures. In a hysterical spasm, both arm and leg are contracted on the same side of the body, the hand is closed tightly, the knee is flexed, and perhaps the leg and the foot are drawn up. Paralysis with contractures is one of the most extreme examples of disability caused by hysterical illness. Hysterical paraplegia has been described,26 and both spinal and orthopedic surgeons, as well as rehabilitation specialists and neurologists, should be alert to the development of this disorder in their patients.27 These patients have the potential to use considerable health care resources.28
Abnormal Movements Psychogenic movement disorders are believed to account for 1 per 30 patients attending a movement disorder clinic21 and have been the subject of a book.29 Since the mid-1980s, a number of case series of patients with psychogenic dystonia have been reported. Fahn and Williams30 described 21 cases in 1988, and Lang31 subsequently described 18 more. Clinical features that suggest a psychogenic movement disorder are shown in Table 20–3. In a systematic study of 103 patients with fixed dystonia, Schrag and associates (2004)32 found that 37% fulfilled criteria for psychogenic dystonia and 29% fulfilled criteria for somatization disorder, which is characterized by chronic, multiple,
252
Section
III
Neuropsychiatry
T A B L E 20–3. Features Suggestive of a Psychogenic Movement Disorder Abrupt onset Inconsistent movements (changing characteristics over time) Incongruous movements (movements do not fit with recognized patterns or with normal physiological patterns) Presence of additional types of abnormal movements that are not consistent with the basic abnormal movement pattern or are not congruous with a known movement disorder, particularly: Rhythmical shaking Bizarre gait Deliberate slowness in carrying out the requested voluntary movement Bursts of verbal gibberish Excessive startle (bizarre movements in response to sudden, unexpected noise or threatening movement) Entrainment of the psychogenic tremor to the rate of the requested rapid successive movement the patient is asked to perform Demonstrating exhaustion and fatigue Spontaneous remissions Movements disappear with distraction Response to placebo, suggestion, or psychotherapy Presence as a paroxysmal disorder Dystonia beginning as a fixed posture Adapted from Fahn S: Psychogenic movement disorders. In Marsden CD, Fahn S, eds: Movement Disorders: 3. Oxford, UK: Butterworth-Heinemann, 1995, pp 359-372.
persistent, medically unexplained symptoms. Although many patients fulfilled strict criteria for a somatoform disorder/ psychogenic dystonia, the diagnosis remained uncertain in a proportion of patients, and whether the disorder was primarily neurological or psychiatric remains an open question. Such patients require the services of a multidisciplinary team.
Seizures (Psychogenic Nonepileptic Seizures) It is estimated that more than 25% of patients receiving a diagnosis of refractory epilepsy in a chronic epilepsy clinic do not have epilepsy.33 Although the population incidence of psychogenic nonepileptic seizures (PNESs) may be only 4% that of epilepsy, PNES constitutes a large share of the workload of neurologists and of emergency and general physicians. A number of details in the patient’s history may suggest a diagnosis of PNES rather than epileptic seizures (Table 20–4). PNESs can be distinguished from epileptic seizures: PNESs generally occur in the presence of an audience or when another person is close by. They may be precipitated by stress but more often seem to occur in response to the social setting. The fall to the ground is not usually abrupt, and movements may follow the fall with clutching, but the characteristic regular tonicclonic sequence of epilepsy is not found. Tongue biting and incontinence of urine are rare in hysterical seizures, the corneal reflexes are preserved, and the plantar muscles are flexed, unless previously abnormal. Firm handling and pressure on the supraorbital nerves to the point of pain may arouse the patient. PNESs occur most often among epileptic patients or among others who have seen epileptic seizures. A few epileptic patients learn how to induce ictal discharges and can produce extra seizures. Although rarely available during a seizure, the
T A B L E 20–4. Details in Patients’ History That May Suggest a Diagnosis of Psychogenic Nonepileptic Seizures Rather Than Epileptic Seizures Feature in History Manifestation at age <10 years Change in symptoms Aggravation by AEDs Seizures in presence of physicians Recurrent “status epilepticus” Multiple unexplained physical symptoms Multiple operations/ invasive tests Psychiatric treatment Sexual and physical abuse
Psychogenic Nonepileptic Seizures
Epileptic Seizures
Unusual
Common
Occasional Occasional Common
Rare Rare Unusual
Common
Rare
Common
Rare
Common
Rare
Common Common
Rare Rare
Adapted from Reuber M, Elger C: Psychogenic non epileptic seizures: review and update. Epilepsy Behav 2003; 4:205-216. AED, antiepileptic drug.
electroencephalogram is generally abnormal in epilepsy and normal during hysterical seizures.22 It usually takes several years to arrive at the diagnosis of PNES, and 75% of patients (with no additional epilepsy) are treated with anticonvulsants initially. If PNES is not diagnosed and managed early, significant iatrogenic harm may occur. The outcome is not always favorable in these patients: in one study carried out at a mean of 11.9 years after manifestation and 4.1 years after diagnosis of PNES, 71% of patients continued to have seizures and 56% were dependent on Social Security. Outcome was better in patients with greater educational attainments, younger age at onset and diagnosis, attacks with less dramatic features, and fewer additional medically unexplained complaints.34 It has been reported that patients with PNES have a consistently different psychosocial profile from patients with motor conversion symptoms. In a prospective study of consecutive neurological inpatients with either motor conversion or pseudoseizures of recent onset, patients with PNES were younger, more likely to have both an emotionally unstable personality disorder and a worse perception of parental care, more likely to report incest, and more likely to have reported more life events in the 12 months before symptom onset than were patients with motor conversion symptoms.20
Sensory Symptoms Sensory Disturbance The clinical detection and localization of sensory dysfunction is probably one of the least reliable areas of the neurological examination. Sensory loss may involve one half of the entire body from head to toe or from right to left. It may affect the whole of a limb and characteristically has a glove or stocking distribution on the arms or legs or both. The sensory loss generally fails to fit in with known anatomical boundaries but conforms more with the patient’s concept of physiology and anatomy. Thus, hysterical sensory loss is likely to stop sharply at the midline, whereas nonhysterical sensory change only
chapter 20 conversion and dissociation syndromes approaches the midline, inasmuch as at this point segmental nerves overlap by one or two centimeters on each side. Unfortunately, these classic signs are often unreliable. Gould and coworkers35 found “psychogenic” features on sensory examination in more than one half of their neurological patient group, and diminished vibration sense over the affected part of the forehead was noted in 69 of 80 patients with neurological disorders.36 This study also revealed that “midline splitting” of sensory function was not helpful in determining whether there was an underlying neurological disorder. These clinical findings should clearly be interpreted with circumspection. Hemisensory disturbances can often manifest as emergencies; sometimes the patient ascribes the symptoms to “a stroke,” in association with anxiety and panic and other physical symptoms of anxiety.37 These symptoms may be provoked by hyperventilation38 or hypnotic suggestion.39 The pathophysiological mechanisms underlying these changes are not as yet understood. Toth40 described 34 patients with the “hemisensory syndrome,” in which patients present with hemisensory disturbance and intermittent blurring of vision in the ipsilateral eye (asthenopia) and sometimes ipisilateral hearing problems as well. Hemisensory symptoms are increasingly recognized in patients with chronic pain and in patients with reflex sympathetic dystrophy.
Visual Disturbances Ophthalmologists have estimated that psychogenic visual disorders account for up to 5% of their practice.41 Simple observation of visually guided behavior sometimes reveals telling inconsistencies, particularly in the case of severe apparent visual loss. A number of reliable optometric techniques are available to support bedside tests and the diagnosis of psychogenic visual loss, field disturbance, or gaze abnormality (for more details, see Stone and Zeman16). Disabling hysterical blindness presents more difficulties. Evoked potential studies help demonstrate intact visual pathways.
253
There is little chance of improvement once the symptoms have become chronic and enduring.42 The etiological implications accruing from follow-up studies43,44 are that a short history and young age are predictors of good outcome, whereas the presence of a personality disorder, chronicity of symptoms, receipt of disability benefits, and involvement with litigation predict poor recovery. Ron42 wrote an excellent recent review of this topic. Patients with chronic motor symptoms (e.g., unilateral functional weakness), as well as those with sensory symptoms, appear to do particularly poorly. In particular, patients with unexplained motor symptoms who are referred to tertiary care centers continue to do very poorly after discharge. Despite the stability of the diagnosis, a pattern of multiple hospital referrals continues for many of these patients once they have been discharged from the tertiary care center. Interviews of patients conducted an average of 6 years after their original admission to a tertiary care center revealed that many continued to be referred to neurologists and other specialists but that subsequent psychiatric referral was rare.43 Many changed their primary care physician after discharge from the hospital, and a disproportionate number of repeated referrals was made by primary care physicians who had known their patients for less than 6 months. Psychological attribution of symptoms was rare, and many patients felt dissatisfied with the treatment they had received. Many were exposed to unnecessary iatrogenic harm. These consistent findings of very poor outcome after discharge from neurological outpatient and inpatient services in patients with both unexplained motor disorders and PNES suggest that every neurological service should have access to referral to specialist liaison psychiatry services. Such patients are often very difficult to treat and, because of their poor prognosis, should have a reasonable chance of obtaining early and appropriate management for their primary disorder.44,45 Without appropriate treatment, the prognosis is poor (Table 20–5).
MANAGEMENT
PROGNOSIS Outcome in published studies depends to some degree on the setting: tertiary referral centers tend to attract patients with chronic or intractable symptoms. Better outcomes appear to be associated with short or acute onset and early improvement.
Resources Before any discussion of treatment, it is important to consider the resources available to the neurologist to manage these
T A B L E 20–5. Follow-up Studies (1998 to 2003) of Patients with Unexplained Motor Symptoms Sample Size
Mean Follow-up (Years)
Axis I
Axis II
Outcome/Disability at Follow-up
Crimlisk et al, 199818
64
6.0
75%*
53%*
Binzer and Kullgren, 199860 Feinstein et al, 200161
30
1.0
33%*
50%*
50% either had retired on grounds of ill health or were on sick leave 43% not working at 1 year
42‡
3.2
95%†
45%†
§
12.5
—
—
Study/Year
Stone et al, 2003
44
47
Persistence of abnormal movements in >90%; 57% disabled 83% reported weakness or sensory symptoms; 30% had taken medical retirement
Axis I: mental illness; axis II: personality disorder. All patients presented to secondary or tertiary care centers, which contributes to the poor prognosis. *Diagnoses at baseline. † Diagnoses at follow-up. ‡ All patients had hyperkinetic movement disorder (i.e., tremor, dystonia, myoclonus). § 55% manifested weakness; 45% manifested only sensory symptoms.
254
Section
III
Neuropsychiatry
patients. In contrast to disorders such as multiple sclerosis and schizophrenia, which have similar prevalences, there are no designated resources for patients with psychogenic disorders. Some neurologists may have no access whatsoever to mental health resources, whereas others may have close collaborative links with either clinical psychology or psychiatry services. There is no doubt that the successful management of these patients requires the cooperation of a number of clinical specialties, including psychologists, nurses, physiotherapists, and occupational therapists. Some patients may be so disturbed or disabled (or both) that they may require inpatient admission to a specialized unit with access to both mental health and medical nurses, as well as to physiotherapists and occupational therapists. In the opinion of this writer, every neurology service should have access to a specialist liaison psychiatry service.46
Management Strategies for the Neurologist First, the diagnosis has to be established by a neurologist after relevant organic disease has been ruled out. Second, the neurologist not only must explain to the patient that there is no serious underlying organic disease but also must provide an explanation for the symptoms that is comprehensible to the patient. During the initial assessment, it is important for the neurologist to inquire about a number of psychosocial problems as part of the general interview. Key questions include the following: 1. “Have you experienced any distressing setbacks or reversals in the last 6-9 months?” (life events) 2. “How have you been feeling in your mood? Have you been feeling low; or tense or wound up; or panicky?” (anxiety and depression) 3. “What do you think is causing the symptoms? What is your worst fear?” (illness beliefs) 4. “What impact are the symptoms having on your life?” (functional impairment) Armed with this information, the neurologist may be able to make some kind of initial formulation, such as the following: We have completed our tests, and I am pleased to say that all results are normal, and we have not found any evidence of disease. However, I know that your symptoms are distressing, and they are certainly real. I recall your telling me that the weakness in your left leg began 9 months ago with altered sensation in your left toes. You also said that you became tense and upset at work around this time, with problems with your sleep and memory and feeling panicky in crowds. I am struck by the fact that these symptoms came on soon after your disagreement with your manager and failure to get a promotion, and life has been difficult for you since then. Have you thought about it like that? After this, the neurologist may wish to help the patient establish mind-body links by saying something like the following: You have what we call functional weakness: All the parts of the nervous system are there but are just not working properly, so that when you try to move your leg, it doesn’t do it as well as it should. Sometimes stress can cause these symptoms, which are often accompanied by feelings of frustration, worry, and sadness but these are not the cause of the
problem. Stress is a common problem and can lead to hypertension and duodenal ulcers, as well as what we call functional weakness. This explanation can be supplemented by giving the patient a fact sheet containing information about functional weakness, which contains information about how to become involved with rehabilitation (J. Stone, personal communication, 2006). It is worth noting at this stage that patients prefer the term functional rather than hysterical, when their unexplained weakness, seizures, and other symptoms are being referred to.46 The neurologist can supplement this interview by using rating scales, which provide useful baseline pretreatment information. They include the Hopkins Symptom Checklist somatization scale to measure somatic symptoms47; the Hospital Anxiety and Depression Scale to measure anxiety and depression48 (the Beck Depression and Anxiety scales are also useful); and the Illness Perception Questionnaire, which provides a rating of illness attitudes and concerns.49 There are several measures of functional impairment, including the Dartmouth Primary Care Cooperative Information Project50 and the Barthel index.51
Referral to Psychiatrist/Psychologist Discussing referral to a mental health specialist with the patient is a skilled process requiring the neurologist to provide a rationale for the referral without alienating the patient. Neurologists in training are not routinely taught these skills. One suggested method might be to use the following explanations: ■ “You have a number of physical and psychological (stress)
symptoms at present.” ■ “The physical symptoms are real but do not reflect any
underlying damage.” ■ “In our experience, it is as important to deal with the psy-
chological as well as the physical symptoms in problems like this (such as functional weakness).” ■ “Would you like me to organize a referral to a psychiatrist/ psychologist who has a specific interest in your problems?” ■ [If relevant] “This person works in the general hospital and has had a lot of experience dealing with patients with similar problems.”
Further Management Traditional behavioral approaches to treatment are based on the premise that the symptoms reported by the patient are interpreted as physical but are amenable to recovery. The aim of treatment is to bring about a gradual increase in function through a combination of physical and occupational therapies. The patient receives rewards and praise for improvement of function, and reinforcement is withdrawn for continuing signs of disability. Avoiding direct confrontation of psychological problems and providing “face-saving” techniques are also regarded as key components.52 More recently, the approach to patients has changed from a predominantly medical one to one in which psychological and sociocultural aspects are equally important, and the need for organized specialist rehabilitation services involving a multi-disciplinary team is recognized as essential.
chapter 20 conversion and dissociation syndromes What Is the Evidence? With one or two exceptions,53 there are no large, randomized, controlled studies of treatment in patients with conversion disorders. Nor is there any good evidence to support the use of one specific intervention, such as biofeedback, hypnosis, or psychotherapy. Although repeated case series have documented the effectiveness of multidisciplinary inpatient behavioral treatment, there is little controlled research. In an innovative approach, a “strategic behavioral intervention” was shown to be superior to standard behavioral treatment for chronic nonorganic motor disorders.7 In this method, patients and their families were told that full recovery constituted proof of an organic etiology, whereas failure to recover was definite proof of psychiatric etiology. This approach clearly requires special facilities and trained personnel.
A Framework for Rehabilitation
Cognitive-behavioral therapy is concerned mainly with helping the patients overcome identified problems and ascertain specified goals. It discourages “maintaining factors” such as repeated body self-checking and excessive bed rest, and challenges patients’ negative or false beliefs about symptoms. Chalder described specific cognitive-behavioral therapy–based treatment for patients with conversion disorders.58 A cognitivebehavioral approach may also help with the formulation. An example is given in Figure 20–2.
Pharmacological Treatments There is evidence from randomized controlled trials and systematic reviews that antidepressants (both tricyclic antidepressants and selective serotonin reuptake inhibitors) can be useful in the treatment of patients with medically unexplained symptoms (such as poor sleep and pain), whether depression is present or not.59
In the absence of good experimental evidence, a possible framework for future research has been developed; it is based on published evidence and described in the World Health Organization’s International Clarification of Functioning, Disability and Health,54 which is particularly useful for patients in whom there is a disability that is out of proportion to known disease and signs. The model provides opportunities for intervention and is well suited to the kind of multidisciplinary approach that is likely to be successful in these patients. The model emphasizes that whatever the primary cause of an illness, many factors have an influence on its manifestations. It has been pointed out that patients experience a sense of control and influence over their behavior by choosing (whenever possible) between different courses of action.55,56 The notions of free will and personal responsibility remain a core belief for most democratic and legal conceptions of human nature, and they may help explain illness not produced by disease, injury, psychopathology, or psychosocial factors. For example, a 44-year-old woman with a long history of irritable bowel syndrome and facial pain developed a sudden loss of sensation and weakness of both legs soon after a traumatic separation from her husband. All neurological investigations yielded normal results, and despite attempts made by the medical staff to link her symptoms to distressing life events, she retired to a wheelchair and endorsed a “medical” view of her illness, joining the local multiple sclerosis society. This state was reinforced by the family and medical services, which provided sick notes and disability aids.
A
Previous experience (My father died of a brain tumor.)
B Formation of dysfunctional assumptions (I should always be able to explain my symptoms; symptoms always mean there is something wrong.)
C
Critical incident (My best friend died of cancer last month; I’m having a lot of headaches.)
D Activation of assumptions
Psychological Treatments Because patients with conversion disorders share features in common with patients with other medically unexplained syndromes, treatments that have been used in these latter disorders may have potential. Most of the evidence-based treatments in this field involve cognitive-behavioral therapy (see Kroenke and Swindle57) or interpersonal therapy. These usually have to be undertaken by trained clinical psychologists or other clinicians. However, increasing numbers of specialist nurses are being trained to deliver these treatments; therefore, they should become more widely available.
255
E
Negative automatic thoughts/images (I could have a brain tumor; this will get worse.)
• Behavior • Mood ■
• Thoughts • Physiology
Figure 20–2. Example of a cognitive behavioral formulation in a patient with headaches.
256
Section
III
K E Y
Neuropsychiatry
P O I N T S
●
Clinical assessment supported by appropriate imaging and other paraclinical tests should allow the neurologist to establish a confident diagnosis of conversion disorder.
●
It is often difficult for the clinician to differentiate between symptoms attributable to conversion disorder, fabricated illness, and malingering. In cases in which the diagnosis is unclear, a psychiatric opinion should be sought.
●
Before the clinical examination of the patient in whom conversion disorder is suspected, the neurology team should attempt to obtain (and document in the medical file) as much medical history from the primary care physician and other medical records as possible. These records may reveal extensive histories of medically unexplained symptoms and/or unnecessary surgery.
●
It is important for the neurologist to establish an early diagnosis of conversion disorder. This is easier if, at an early stage in the interview with the patient, psychosocial factors are discussed. Early diagnosis and referral prevent iatrogenic harm, which is particularly likely to occur in patients with PNES and functional weakness.
●
Neurology services should have access to a designated liaison psychiatry service. This is essential because conversion disorders and PNES have poor prognoses if they are not treated. Neurology services without access to liaison psychiatry should lobby their managers to provide one.
Suggested Reading Hallett M, Fahn S, Jancovic J, et al, eds: Psychogenic Movement Disorders: Psychobiology and Treatment of a Functional Disorder. New York: Lippincott Williams & Wilkins, 2005. Halligan P, Bass C, Marshall J, eds: Contemporary Approaches to the Study of Hysteria. Clinical and Theoretical Perspectives. Oxford, UK: Oxford University Press, 2001. Holmes EA, Brown R, Mansell W, et al: Are there two qualitatively distinct forms of dissociation? A review and some clinical implications. Clin Psychol Rev 2005; 25:1-23. Reuber M, Elger CE: Psychogenic non-epileptic seizures: review and update. Epilepsy Behav 2003; 4:205-216. Schrag A, Trimble M, Quinn N, et al: The syndrome of fixed dystonia: an evaluation of 103 patients. Brain 2004; 127:2360-2372.
References 1. Micale M: Approaching hysteria. Princeton, NJ: Princeton University Press, 1994. 2. Showalter E: Hystories. Hysterical Epidemics and Modern Culture. New York: Columbia University Press, 1997. 3. Carson A, Ringbauer B, Stone J, et al: Do medically unexplained symptoms matter? A prospective cohort study of 300 new referrals to neurology outpatient clinics. J Neurol Neurosurg Psychiatry 2000; 68:207-211. 4. Fink P, Hansen MS, Sondergaard L, et al: Mental illness in new neurological patients. J Neurol Neurosurg Psychiatry 2003; 74:817-819.
5. Rief W, Hessel A, Braehler E: Somatisation symptoms and hypochondriacal features in the general population. Psychosomat Med 2001; 63:595-602. 6. Eames P: Hysteria following brain injury. J Neurol Neurosurg Psychiatry 1992; 55:1046-1051. 6a. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. 7. Shapiro A, Teasell RW: Behavioural interventions in the rehabilitation of acute v chronic non-organic (conversion/factitious) motor disorders. Br J Psychiatry 2004; 185:140-146. 8. Halligan P, Bass C, Oakley D: Willful deception as illness behaviour. In Halligan P, Bass C, Oakley D, eds: Malingering and Illness Deception. Oxford, UK: Oxford University Press, 2003, pp 3-28. 9. Spence S: Hysterical paralyses as disorders of action. Cogn Neuropsychiatry 1999; 4:203-226. 10. Fahn S: Psychogenic movement disorders. In Marsden CD, Fahn S, eds: Movement Disorders: 3. Oxford, UK: Butterworth Heinemann, 1995, pp 359-372. 11. Holmes E, Brown R, Mansell W, et al: Are there two qualitatively distinct forms of dissociation? A review and some clinical implications. Clin Psychol Rev 2005; 25:1-25. 12. Brown RJ: The cognitive psychology of dissociative states. Cogn Neuropsychiatry 2002; 7:221-235. 13. Brown RJ: Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model. Psychol Bull 2004; 130:793-812. 14. The search for a psychiatric Esperanto [Editorial]. BMJ 1976; 2:600-601. 15. Akagi H, House A: The clinical epidemiology of hysteria: vanishingly rare, or just vanishing? Psychol Med 2002;32:191-194. 16. Stone J, Zeman A: Hysterical conversion—a view from clinical neurology. In Halligan P, Bass C, Marshall J (eds): Contemporany Approaches to the study of Hysteria. Oxford, UK: Oxford University Press, 2001, pp 102-125. 17. Wessely S, Nimnuan C, Sharpe M: Functional somatic syndromes: one or many? Lancet 1999; 354:936-939. 18. Crimlisk H, Bhatia K, Cope H, et al: Slater revisited: 6 year follow up study of patients with medically unexplained motor symptoms. BMJ 1998; 316:582-586. 19. Binzer M, Andersen P, Kullgren G: Clinical characteristics of patients with motor disability due to conversion disorder: a prospective control group study. J Neurol Neurosurg Psychiat 1997; 63:83-88. 20. Stone J, Sharpe M, Binzer M: Motor conversion symptoms and pseudoseizures: a comparison of clinical characteristics. Psychosomatics 2004; 45:492-499. 21. Factor S, Podskalny R, Molho E: Psychogenic movement disorders: frequency, clinical profile and characteristics. J Neurol Neurosurg Psychiatry 1995; 59:406-412. 22. Reuber M, Elger C: Psychogenic non epileptic seizures: review and update. Epilepsy Behav 2003; 4:205-216. 23. Davison P, Sharpe M, Wade D, et al: “Wheelchair” patients with non-organic disease: a psychological enquiry. J Psychosom Res 1999; 47:93-103. 24. Ziv I, Djaldetti R, Zoldan Y, et al: Diagnosis of “non-organic” limb paresis by a novel objective motor assessment: the quantitative Hoover’s test. J Neurol 1998; 245:797-802. 25. Stone J, Zeman A, Sharpe M: Functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2002; 73:241-245. 26. Baker J, Silver J: Hysterical paraplegia. J Neurol Neurosurg Psychiatry 1987; 50:375-382. 27. Heruti R, Reznik J, Adunski A, et al: Conversion motor paralysis disorder: analysis of 34 consecutive referrals. Spinal Cord 2002; 430:335-340. 28. Allanson J, Wade D, Bass C: Characteristics of patients with persistent severe disability and medically unexplained neuro-
chapter 20 conversion and dissociation syndromes
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.
43. 44. 45. 46.
logical symptoms: a pilot study. J Neurol Neurosurg Psychiatry 2002; 73:307-309. Hallett M, Fahn S, Jankovic J, et al, eds: Psychogenic Movement Disorders: Psychobiology and Treatment of a Functional Disorder. New York: Lippincott Williams & Wilkins, 2005. Fahn S, Williams D: Psychogenic dystonia. Adv Neurol 1988; 50:431-455. Lang AE: Psychogenic dystonia: a review of 18 cases. Can J Neurol Sci 1995;22:136-143. Schrag A, Trimble M, Quinn N, et al: The syndrome of fixed dystonia: an evaluation of 103 patients. Brain 2004; 127:23602372. Smith D, Defalla B, Chadwick D: The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. Q J Med 1999; 92:15-23. Reuber M, Pukrop R, Bauer J, et al: Outcome in psychogenic nonepileptic seizures: 1 to 10 year follow up in 164 patients. Ann Neurol 2003; 53:305-311. Gould R, Miller B, Goldberg M, et al: The validity of hysterical signs and symptoms. J Nerv Ment Dis 1986; 174:593-597. Rolak L: Psychogenic sensory loss. J Nerv Ment Dis 1988; 176:686-687. Blau N, Wiles M, Solomon F: Unilateral somatic symptoms due to hyperventilation. BMJ 1983; 286:1108. O’Sullivan G, Harvey I, Bass C, et al: Psychophysiological investigations of patients with unilateral symptoms in the hyperventilation syndrome. Br J Psychiatry 1992; 160:664-667. Fleminger J, McClure G, Dalton R: Lateral response to suggestion in relation to handedness and the side of psychogenic symptoms. Br J Psychiatry 1098; 136:562-566. Toth C: Hemisensory syndrome is associated with a low diagnostic yield and a nearly uniform benign prognosis. J Neurol Neurosurg Psychiatry 2003; 74:1113-1116. Kathol R, Cox T, Corbett J, et al: Functional visual loss: I. A true psychiatric disorder? Psychol Med 1983; 13:307-314. Ron M: The prognosis of hysteria/somatisation disorder. In Halligan P, Bass C, Marshall J, eds: Contemporary Approaches to the Study of Hysteria. Oxford, UK: Oxford University Press, 2001, pp 271-283. Crimlisk H, Bhatia K, Cope H, et al: Patterns of referral in patients with medically unexplained motor symptoms. J Psychosom Res 2000;49: 217-219. Stone J, Sharpe M, Rothwell P, et al: The 12-year prognosis of unilateral functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2003; 74:591-596. Gotz M, House A: Prognosis of symptoms that are medically unexplained. BMJ 1998; 317:536. Stone J, Wojcik W, Durrance D, et al: What should we say to patients with symptoms unexplained by disease? The “number needed to offend.” BMJ 2002; 325:1449-1450.
257
47. Derogatis L, Melisaratos N: The Brief Symptom Inventory: an introductory report. Psychol Med 1983; 13:595-605. 48. Zigmond A, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983; 67:361-370. 49. Weinman J, Petrie K, Moss-Morris R, et al: The Illness Perception Questionnaire: a new method for assessing the cognitive representation of illness. Psychol Health 1996; 11:431445. 50. Jenkinson C, Mayou R, Day A, et al: Evaluation of the Dartmouth COOP charts in a large-scale community survey in the United Kingdom. J Public Health Med 2002; 24:106-111. 51. Wade D, Collin C: The Barthel ADL Index: a standard measure of physical disability? Int Disabil Stud 1988; 10:64-67. 52. Teasell R, Shapiro A: Rehabilitation of chronic motor conversion disorder. Crit Rev Phys Rehabil Med 1993; 5:1-13. 53. Moene F, Spinhoven P, Hoogduin K, et al: A randomised controlled clinical trial on the additional effect of hypnosis in a comprehensive treatment programme for inpatients with conversion disorder of the motor type. Psychother Psychosom 2002; 71:66-76. 54. World Health Organization: International Clarification of Functioning, Disability and Health. Geneva: World Health Organization, 2001. Available at: http://www3.who.int/ icficftemplate.cfm. 55. Wade D, Halligan P: New wine in old bottles: the WHO ICF as an explanatory model of human behaviour. Clin Rehabil 2003; 17:349-354. 56. Wade D: Medically unexplained disability—a misnomer, and an opportunity for rehabilitation. Clin Rehabil 2001; 15:343-347. 57. Kroenke K, Swindle R: Cognitive behavioural therapy for somatisation and symptom syndromes: a critical review of controlled clinical trials. Psychother Psychosom 2000; 69:205-215. 58. Chalder T: Cognitive behavioural therapy as a a treatment for conversion disorders. In Halligan P, Bass C, Marshall J, eds: Contemporary Approaches to the Study of Hysteria: Clinical and Theoretical Perspectives. Oxford, UK: Oxford University Press, 2001, pp 298-311. 59. O’Malley P, Jackson J, Santoro J, et al: Antidepressant therapy for unexplained symptoms and symptom syndromes. Fam Pract 1999; 48:980-990. 60. Binzer M, Kullgren G: Motor conversion disorder. A prospective 2- to 5-year follow-up study. Psychosomatics 1998; 39:519527. 61. Feinstein A, Stergiopoulos V, Fine J, et al: Psychiatric outcome in patients with a psychogenic movement disorder: a prospective study. Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:169-176.
CHAPTER
EXAMINATION
21
OF THE VISUAL ●
●
●
SYSTEM
●
Desmond Kidd
VISUAL ACUITY A sizeable minority of patients who are referred to a neuroophthalmology clinic have a refractive error as the only cause for the visual symptoms. It is thus essential to assess visual acuity only after having ensured that any refractive error has been corrected. The patient should be assessed with spectacles on, and if the acuity is abnormal, the clinician should add a pinhole to the lens and repeat the assessment. A standard distance acuity should be assessed using a Snellen 6 m Chart placed 6 m from the patient in a brightly illuminated position. Low luminance reduces visual acuity because foveal ganglion cells have high light thresholds. LogMAR charts are similar but allow comparison of repeated measurements in a statistical way. Near acuity can be assessed using Jaeger charts held by the patient at whatever distance is comfortable. Patients with refractive, corneal, or lens problems may have better near than distance acuity, and patients with accommodative and convergence disorders may have better distance acuity than those with near acuity. A more sensitive assessment of visual acuity involves the use of contrast sensitivity threshold measurements using wall charts or computer programs. These measure the sensitivity of minimum spatial resolution of gratings. In patients with amblyopia, a neutral density filter placed in front of the affected eye will not cause a substantial further loss of visual acuity (a 2.0 log filter reduces acuity in normal people by a factor of 2.0), whereas patients with reduced acuity due to a problem causing delayed optic nerve conduction demonstrate a much greater fall in visual acuity such as 6/9 to 6/60). Color vision is assessed using pseudo-isochromatic plates such as Ishihara, Hardy-Rand-Ritter, and Dvorine plates. These are all easy and quick to use, although they cannot be used to assess the severity of the loss of color vision and they do not provide an adequate assessment of blue-green disorders. More complicated measurements such as the Farnsworth Munsell 100 hue test and others are better but much more time consuming. These tests are useful in the assessment of visual loss due to optic nerve and macular problems. Congenital color blindness occurs in 8% of males and is symmetrical; an asymmetrical loss of color vision is always acquired. The prevalence of color blindness is as follows: Red-green males Red-green females Blue-yellow Achromacy
260
8% 0.4% 0.005% 0.003%
Köllner’s rule states that loss of red-green discrimination occurs in optic nerve disorders and loss of blue/yellow discrimination arises in macular problems. There are exceptions to this rule, however, because optic neuropathies that involve disruption of the papillomacular bundle (e.g., optic neuritis) will cause red-green color deficits, whereas those that disrupt fibers arising from the perifoveal fields (e.g., glaucoma and papilloedema) will cause blue-yellow deficits (as well as a proportionately smaller reduction in visual acuity).
VISUAL FIELD EXAMINATION The assessment of the visual field is of crucial importance to the examination of the visual system because it is the most helpful aspect of the examination in determining the anatomical substrate of the visual symptom. Confrontation methods are adequate only if carried out very carefully indeed. Wiggling fingers only detect field defects that are absolute; that is, there is no vision within that field, and some may have no vision within a hemianopic field but are nonetheless able to perceive movement. Finger counting is better; the patient must focus on the examiner’s eye and say or copy the number of fingers presented to the four quadrants and the central field. Use of a small target such as a hat pin is more accurate; a white hat pin plots out the peripheral field and the red is used for central defects, particularly optic nerve disorders in which, as noted earlier, red-green color deficits arise. The principle behind dynamic perimetric methods of field analysis such as the Goldman is that the examiner is identifying successive boundaries of vision known as differential light sensitivities (DLSs). These are the thresholds within which it is possible for that part of the retina to identify when a light projected is more bright than the background. The fovea is most sensitive, and this reduces with distance from the fovea. The temporal field changes slowly with distance from the fovea, whereas the DLS on the nasal side reduces abruptly. A normal Goldman field is shown in Figure 21−1. The advantage of this method of field assessment is that the skilled examiner can plot very carefully visual field abnormalities and can return over and over again to check the boundaries of the field. Automated static perimetry is available in all ophthalmic departments, can be carried out in around 10 minutes, is easy to administer, and does not require so much skill to perform. It is less sensitive a measure than the Goldman when the exam-
chapter 21 Examination of the Visual System ■
261
Figure 21–1. Normal Goldman field.
iner is highly skilled in use of the latter. Automated static field tests identify the threshold of accurate vision within the four visual quadrants within a 10-, 24-, 30-, or 70-degree field. Fields can be recorded for comparison with subsequent examinations; reliability can be assessed by noting fixation losses and falsepositive and -negative errors. The gray scale indices note the mean or pattern deviation of the patient’s responses to those of age-matched normal controls (Fig. 21−2).
Factors that influence the precision of these field examinations include cognitive function and tiredness, refractive errors, and ophthalmic disorders such as cataract. The field is plotted at a certain level of background illumination because the threshold varies with background luminance up to a certain point and then increases in a linear way with suprathreshold background luminance. Examples of common field defects that are seen are shown in Figures 21−3 to 21−8.
262
Section
IV
Neuro-Ophthalmology
■
Figure 21–2. Normal Humphrey field, left, upper field; right, lower field.
chapter 21 Examination of the Visual System
■
Figure 21–3. Upper quadrantinopia due to a left temporal infarction, left, upper field; right, lower field.
263
264
Section
■
IV
Neuro-Ophthalmology
Figure 21–4. Congruous but incomplete hemianopia due to an infarction of the left occipital lobe, left, upper field; right, lower field.
chapter 21 Examination of the Visual System
■
Figure 21–5. Bitemporal hemianopia due to a craniopharyngioma, left, upper field; right, lower field.
265
266
Section
IV
Neuro-Ophthalmology
■
Figure 21–6. Centrocecal scotoma due to toxic amblyopia.
chapter 21 Examination of the Visual System
■
Figure 21–7. Arcuate scotoma due to glaucoma.
267
268
Section
IV
Neuro-Ophthalmology
■
Figure 21–8. Enlarged blind spots due to bilateral papilloedema.
chapter 21 Examination of the Visual System
269
The examination involves inspection of pupil size and shape at rest. Each should be round and of the same size. Pupil size can be measured using a ruler or more easily using a pupil gauge such as that seen on a hand-held pinhole occluder. The pupils should then be inspected in light and dark—particularly if there is inequality in room lighting. Physiological anisocoria is detectable in 20% of young people and increases in prevalence with age to 33% of people over the age of 60 years. The inequality increases in dark in the case of physiological anisocoria and to a greater degree in the case of Horner’s syndrome. It may also be affected by anxiety, which increases sympathetic drive, and by fatigue.
Pupillary Reaction to Light The pupil should be assessed by a bright (but not too bright) light source such as a fully charged ophthalmoscope light source with low background illumination (just enough to see the pupil in darkness). The patient will be looking into the distance in order to prevent meiosis in accommodation. The light source is applied to the pupil for 2 or 3 seconds, and the response amplitude and reaction speed are noted. This should be repeated several times. The latency of redilatation should also be observed; early pupillary escape, in which redilation occurs earlier on one side and sometimes even before the light source is removed, implies a mild afferent pupillary defect.
Consensual Response When light is applied to one eye, the pupillary response in the other should be equal in amplitude and synchronous because the decussation of pupillary fibers in the midbrain is 50%.
Near Response ■
Figure 21–9. Amsler grid with central field defect due to agerelated macular dystrophy.
The Amsler grid is useful for plotting central field distortions, such as macular disorders, but also very small central field abnormalities due to, for example, optic neuropathy. The patient plots out the abnormality on the grid himself (Fig. 21−9). Tangent screen testing is also easy and rapid; a 1-m screen can be attached to the wall of a clinic room, and a light source with varying target size and luminance can be used very accurately to plot out a visual field. The contour of light sensitivity to the target of the same size and luminance is termed an isopter. Different target sizes and luminances give rise to different isopters, and so the field is plotted.
The patient is instructed to look into the distance and then at a target held at the nearest point of distinct vision (25 cm in emmetropic people). A brisk and symmetrical meiosis should follow as convergence occurs. The speed and amplitude of the near response are noted and compared with the direct light response; light-near dissociation may arise in upper midbrain lesions due to compressive, infiltrative, or inflammatory causes (including, of course, neurosyphilis), severe bilateral optic neuropathies, and isolated parasympathetic nerve disorders.
Pupillary Dilatation The pupil returns to its size appropriate for low levels of background illumination 12 to 15 seconds after a bright light source is removed from the eye. In patients with Horner’s syndrome, there is a dilatation lag, in which the affected side dilates more slowly than the normal side, and an increase in anisocoria is seen.
PUPILS
Relative Afferent Pupillary Defect
Patients with recent-onset pupillary mydriasis may complain of blurring of vision and photophobia, but most patients have no symptoms.
Everyone knows about this test and medical students believe that they should also perform it, but it is very complicated and requires skill and experience in order to perform it well. The
270
Section
IV
Neuro-Ophthalmology
eyes may be covered and uncovered in turn or the swinging light test may be applied. In the latter, the light source is applied in turn to each eye for 3 to 5 seconds repeatedly. The trick is to vary the time taken to move from one eye to the other; often, the relative afferent pupillary defect (RAPD) can be brought out thus. Great care should be taken to not apply the light source to one eye for longer than the other, to apply the light source to the same amount of retina in each eye (this is particularly important if there is ocular misalignment), and to ensure that there is no accommodative meiosis. Provided the test is performed properly, the examiner is able to see that there is pupillary dilatation on the side of a unilateral optic neuropathy when the light source returns to that side. Neutral density filters can be used, first, to measure the severity of the RAPD and, second, to bring it out if by regular testing the result is equivocal. The grading of RAPD is as follows:
A
B
Grade 1: weak initial contraction followed by a greater redilatation 0.4 log unit Grade 2: a slight stall in movement followed by dilatation 0.7 log unit Grade 3: immediate pupillary dilatation 1.1 log units Grade 4: pupillary dilatation during prolonged illumination of the good eye for 6 seconds 2.0 log units Grade 5: no signs of constriction no light transmission Pupillography, in which infrared cameras are used to measure pupil size and shape in darkness and light, can be used to measure pupillary reaction times, amplitude, and latency.
C
D ■
Figure 21–10. Pupillary responses in Horner’s syndrome (A) in light, (B) in dark, (C) following instillation of 10% cocaine, and (D) following instillation of 1% hydroxamphetamine; the lesion is postganglionic.
Pharmacological Testing Horner’s syndrome consists of meiosis and ipsilateral partial ptosis, apparent enophthalmos, and absence of sweating of the face ipsilaterally. The anisocoria is more evident in dark than in the light. The direct responses are normal. There is a failure of the affected pupil to dilate with 10% cocaine solution. Hydroxyamphetamine 1% dilates the affected pupil if the lesion is central or preganglionic, and no response occurs if the lesion is postganglionic (Fig. 21-10). Holmes-Adie syndrome consists of subacute severe mydriasis, which partially resolves over many months. It is associated with absent reflexes and rarely autonomic failure (Ross syndrome). The anisocoria is more marked in light than in dark. Pupils are tonic; denervation is rarely complete so vermiform movements (movements of the parts of the iris that have not been denervated) can be seen on slit lamp examination. Pilocarpine 0.1% constricts the affected pupil more than the normal owing to denervation supersensitivity (Fig. 21−11). Tonic pupils also occur following damage due to trauma and more commonly to inflammation due to viral infections and uveitis. A partial third nerve palsy manifested only as mydriasis does not show denervation hypersensitivity and so does not constrict with 0.1% pilocarpine but does with 1.0%. Finally, a pharmacologically mediated mydriasis will fail to constrict with 1% pilocarpine. In essential anisocoria, the pupils are usually the same size in light and dark; this may be more apparent in dark but not to the same degree as with Horner’s syndrome. There are normal responses to cocaine (Fig. 21−12).
A
B
C ■
Figure 21–11. Pupillary responses in tonic pupil (A) in light, (B) in dark, and (C) following instillation of 0.1% pilocarpine solution.
chapter 21 Examination of the Visual System
271
mesencephalic dysfunction. When entirely lone, they may be associated with Cogan’s twitch.
A
Oculomotor Fascicle or Nerve Lesions Fascicle lesions occur with other central signs such as contralateral hemiparesis or cerebellar signs. Pupils are often but not always affected. Nerve lesions usually but not always are associated with other signs, although these may be minimal even when aneurysm or pituitary adenoma is the cause.
B
Lesions of the Oculosympathetic Pathway These lesions cause ipsilateral Horner’s syndrome.
Neuromuscular Ptosis C ■
Figure 21–12. Pupillary responses in essential anisocoria (A) in
Examples include myasthenia gravis and, much less frequently, Eaton-Lambert syndrome.
light, (B) in dark, and (C) following instillation of 10% cocaine.
Myopathic Ptosis EYELIDS The eyelids are held open predominantly by levator palpebrae superioris, innervated by fibers of the superior division of the oculomotor nerve, which arise in the dorsocaudal nucleus in the midbrain. Hence, lid function may be spared or, alternately, the only presenting manifestation of differently situated midbrain lesions; a lesion of the dorsocaudal nucleus itself causes bilateral complete ptosis. Müller’s muscle is a thin sheet of smooth muscle fibers that attaches the levator to the upper tarsus and is innervated by the sympathetic nerve. The two eyelids are yoked, resulting in synkinetic and symmetrical movement alongside change in gaze, although compensatory lid retraction on the nondiseased side is not common. When the patient is looking forward, the palpebral fissures should be the same and 12 to 15 mm in vertical length. Levator function is assessed by asking the patient to look into extreme downgaze and then extreme upgaze, and the excursion of the eyelid is measured; normal levator function is 12 to 17 mm of movement. Diminished levator function is not due to levator disinsertion or an acquired aponeurotic defect of eyelid control but only to neurogenic or myopathic processes. In aponeurotic ptosis, the levator function is normal and the height of the lid crease is often noticeably greater on the ptotic side. The severity of the ptosis tends to increase in downgaze. It is common in the elderly and in patients following ophthalmic surgery such as cataract extraction, glaucoma procedures, and orbital or eyelid surgery.
Neurogenic Ptosis Central Lesions Cortical lesions are usually unilateral and contralateral, usually temporal and frontal lesions, and occasionally bilateral. Midbrain lesions of the dorsocaudal nucleus are usually bilateral and complete and are associated with other signs of
Congenital myopathic ptosis is only rarely neurogenic and is more often associated with a developmental abnormality of the levator muscle. There is a family history in 15% of cases and 20% of cases are bilateral. Often, there are other ocular problems, particularly superior rectus underaction. Acquired myopathic ptosis includes chronic progressive external ophthalmoplegia (CPEO), myotonic dystrophy, and oculopharyngeal dystrophy. Exophalmos, arising, for example, due to dysthyroid eye disease or to an orbital mass, can be assessed by comparing the supraorbital ridges of the patient from above and more precisely using an exophthalmometer.
OCULOMOTOR SYSTEM Fixation The patient is asked to fixate on a target such as the top letter of the Snellen chart and the efficiency of fixation with both eyes open; then each eye is observed with the other covered. Latent nystagmus and a change of fixation due to phoria can also be seen thus. Further examination of the eyes with fixation eliminated using Frenzel goggles is helpful because vestibular nystagmus is always accentuated under these circumstances. Standard clinical tests of vestibular function such as Hallpike’s maneuver and caloric testing are also important.
Smooth Pursuit The patient is asked to fix on a target such as a pen top or hat pin while it is moved slowly and at steady speed from side to side. Those with abnormalities of smooth pursuit show corrective “catch up” saccades and the pursuit becomes fragmented. An optokinetic drum also shows up abnormalities on one side (there will be fewer corrective saccades on that side). In patients with nystagmus, pursuit can be tested by testing for suppres-
272
Section
IV
Neuro-Ophthalmology
sion of the vestibulo-ocular reflex; the patient is asked to fixate on the thumb with the arm outstretched while he rotates the head. With abnormalities, there are corrective saccades because the eyes will be taken off track by the slow phase of the vestibulo-ocular reflex.
Vestibulo-ocular Reflex Vigorous head shaking from side to side and then up and down with Frenzel goggles shows abnormalities were there to be a unilateral peripheral vestibular disorder; there may be a brief run of jerk nystagmus with the slow phase in the direction of the abnormality. This may not arise in acute lesions in which complete canal paresis occurs or in bilateral disorders or in central disorders. In central disorders, horizontal head shaking may induce vertical nystagmus. The vestibulo-ocular reflex may be tested at the bedside when the patient fixes on a target and the examiner moves the head rapidly in one or another sideway direction. When the vestibulo-ocular reflex is normal, gaze is held steadily; with a lesion on one side, a corrective saccade arises at the end of the head movement. Visual symptoms due to vestibular problems can also be tested by asking the patient to fix on a Snellen chart while the head is moved from side to side and then up and down at a steady state at about 2 cycles per second: with abnormalities of vestibular gain, a deterioration in acuity of several lines ensues.
Examination of Saccades The patient is asked to fix alternately on two objects (a finger and a nose, a finger and a thumb) placed in horizontal and then vertical planes. The examiner initiates the movement with a command. Attention is made to the character of the movement and its conjugacy, velocity, and accuracy. Slowing can readily be appreciated in this setting or when using a hand-held optokinetic drum. Saccadic latency (the time taken after instruction to initiating the saccade) may be abnormal in reduced levels of consciousness or disorders of attention. It also occurs in Huntington’s disease, Parkinson’s disease, ocular motor apraxia, conditions such as Balint’s syndrome, or the congenital type. Saccadic dysmetria occurs when there is inaccuracy in fixation; hypermetria occurs when there is an overshoot; and hypometria occurs when there is an undershoot. Dysmetric saccades are usually followed by a corrective saccade. Saccadic dysmetria arises in brainstem and cerebellar pathologies, in drowsiness and drug-induced states, and in field defects due to visual pathway lesions.
Saccadic Intrusions Square-wave jerks are involuntary saccades in which the eye moves from its position of fixation and then returns to the correct position after a normal intersaccadic interval (of 130 to 200 milliseconds). When these are small, they are not abnormal, but larger squarewave jerks (of 1 to 5 degrees) are more frequent and are readily seen during a clinical examination of fixation. These arise in cerebellar disorders, progressive supranuclear palsy, and Huntington’s disease. Much larger intrusions, so-called macrosquare wave jerks (of 10 to 40
degrees), have an intersaccadic latency of 100 milliseconds. These arise most commonly in the cerebellar form of multiple system atrophy (MSA-C) and multiple sclerosis. When large saccadic intrusions occur back-to-back in multiples (three to five), without an intersaccadic interval, a condition known as ocular flutter arises; if the condition is manifest as a series of saccadic intrusions in all directions, it is known as opsoclonus. These conditions occur in a variety of brainstem lesions and are due to abnormalities of the pause cells within the pons.
EXAMINATION OF DIPLOPIA The patient is asked to follow a target through its range of movements in the nine directions of gaze. One eye is tested at a time (ductions) and then both are tested together (versions). The patient is asked to comment on the presence and severity of diplopia during version testing, and the eyes are examined for evidence for paresis. The patient notes that the diplopic image is displaced in the direction of the paresis when the direction of gaze is that of the paresis. Covering one eye with a red filter often helps to determine which image is which. Orthoptists use other tests such as the Maddox rod or the Hess chart.
Alternate Cover Test This is most helpful in subtle abnormalities of vergence because when one eye and then the other eye are covered, the patient fixing on a target, the uncovered eye will be required to perform a corrective saccade in order to regain fixation, and so small movements in both horizontal and vertical directions may be seen. Esotropia and exotropia refer to outward and inward movements of the uncovered eye, respectively, when there is a horizontal deviation and hypotropia and hypertropia when there is a vertical one. When the eyes appear not to be misaligned but nonetheless a refixation movement occurs at the alternate cover test, the movement is termed a phoria. The extent of the tropia can be measured in diopters using a prism to correct the diplopia.
Bielschowsky’s Head-Tilt Test This test is undertaken in four stages: 1. Identification of the site of the hyperphoria 2. Identification of whether the deviation is greater in the right or left gaze 3. Identification of whether the deviation is greater in the up or down gaze 4. Measurement of the size of the deviation with the head tilted to the right or to the left In the first stage, the patient is examined with the alternate cover test in the primary position of gaze and this reveals a right-over-left hyperphoria; either the depressors of the right (superior oblique and inferior rectus) or the elevators of the left (inferior oblique and superior rectus) are weak (Fig. 21-13). The second stage, in which the patient is examined again with the alternate cover test but in the left and then right gaze, the right-over-left deviation increases on the left gaze. Hence, the oblique muscles, which exert a greater influence on vertical eye movements in adduction, and the recti, which exert a
chapter 21 Examination of the Visual System ■
273
Figure 21–13. Diagram of the Bielschowsky maneuver. This patient has a right IV neuropathy.
greater influence in abduction, can be differentiated. In this case, the right hyperphoria increases in left gaze, so either the right superior oblique or the left superior rectus must be weak. In the third stage, the patient is asked to look up then down in left gaze. If the hyperphoria increases in downgaze, then the oblique is weak; if the hyperphoria increases in upgaze, the rectus must be weak. In this case, the diagnosis is a right superior oblique palsy. The fourth stage measures its severity, the degree of head tilt to the left required to correct the vertical diplopia. This works well for acute palsies, but in longstanding cases, changes in the tone of the reciprocally innervated muscles may give differing abnormalities.
K E Y
P O I N T S
●
The neuro-ophthalmological examination is intricate and requires care and practice to perform it well.
●
All of the examination can readily be performed at the bedside or in the office with only a few pieces of equipment.
The neurological examination of the visual system begins only after the ophthalmic examination of the visual system has been completed. Corneal abnormalities, lens opacities, and retinal problems can all cause blurring or distortion of vision, which are entirely unrelated to the structure and function of those parts of the nervous system that are responsible for the appreciation of vision.
Suggested Reading Digre KB: Principles and techniques of examination of the pupils, accommodation and the lacrimal system. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-ophthalmology, 5th ed. Baltimore: Williams and Wilkins, 1998, pp 933-961. Johnson CA, Keltner JL: Principles and techniques of examination of the visual sensory system. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-ophthalmology, 5th ed. Baltimore: Williams and Wilkins, 1998, pp 153-237. Leigh RJ, Zee DS: The Neurology of Eye Movements, 2nd ed. Philadelphia: FA Davis, 1991.
CHAPTER
GENETIC CAUSES ●
●
22
OF ●
BLINDNESS
●
John B. Kerrison and Nancy J. Newman
The study of genetic diseases offers an opportunity to understand the pathophysiology at the molecular level. Identification of genetic defects that lead to clinical syndromes and how a syndrome can be caused by a variety of genetic defects offer powerful insight. In addition, such insights offer a rationale for therapeutic target development. The visual sensory system has been an area of genetic investigation by well-known pioneers including Horner, Leber, Nettleship, Sorsby, Tay, Usher, and Waardenberg. Many basic genetic mechanisms were initially demonstrated in ocular diseases, including X-linked recessive inheritance for color blindness, cytoplasmic inheritance of optic atrophy, inactivation of a single X chromosome in the mosaic pigmentary pattern in females heterozygous for ocular albinism, the two-hit hypothesis of hereditary retinoblastoma, and triallelic inheritance in Usher’s syndrome. A variety of genetic diseases may lead to blindness by affecting the entire globe, primarily the anterior segment (cornea and lens), or primarily the posterior segment (retina and optic nerve) of the eye. Disorders of the globe are often caused by abnormal closure of the fetal fissure resulting in colobomatous malformations and microphthalmia. Nanophthalmos refers to a small but normally formed eye. Anophthalmia, or absence of the eye, results from failure of outgrowth of the primary optic vesicle. Congenital genetic blinding disorders of the anterior segment include congenital cataracts; the Axenfeld-Riger spectrum, which encompasses a variety of anterior segment malformations involving the cornea, anterior chamber angle, and the iris; and Peter’s anomaly, consisting of a central corneal leukoma with varying amounts of iris and lens attachments. Progressive genetic disorders affecting the anterior segment include a variety of corneal dystrophies with gradual deposition of amyloid, mucopolysaccharide, or other components into the cornea. Neural genetic blindness arises from disorders affecting the retina and optic nerve. To a lesser extent, retrogeniculate genetic disorders may affect the vision but often have other neurological manifestations as well. Retina and optic nerve disorders are the focus of this chapter. A highly recommended and thorough discussion of ophthalmic genetics is available in Traboulsi (1998).
274
HOW DO PATIENTS WITH NEURAL GENETIC BLINDNESS PRESENT? Genetic blinding diseases may manifest with isolated visual loss or with vision loss as the most prominent manifestation. For example, a patient with bilateral progressive vision loss and a clinical picture of retinitis pigmentosa may, on further questioning, complain of weakness and ataxia leading to a diagnosis of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa). Such patients with primarily visual symptoms generally present to the ophthalmologist, although other features commonly require neurological consultation. In some patients with slowly progressive vision loss with an onset in childhood or early adulthood, ophthalmological findings may be subclinical. Such patients may discover reduced visual acuity on a vision screening test, whether at school or when obtaining a driver’s license. Such patients are then referred for ophthalmological investigation. In other cases, patients with primarily neurological complaints of weakness, numbness, or ataxia may present to the neurologist with a peripheral neuropathy and not be aware of any significant visual loss. An ophthalmological examination might demonstrate a mild bilateral optic neuropathy and suggests Charçot-Marie-Tooth syndrome. Whether patients with a genetically blinding disease present to the ophthalmologist or the neurologist, it is important that patients in whom a genetically blinding disease is suspected undergo a complete evaluation.
CLASSIFICATION OF GENETIC DISEASE Genetically blinding disorders may be classified by localization of vision loss, age of onset, pattern of inheritance, or presence of other symptoms. No single classification is entirely satisfactory. From a clinical point of view, all of these parameters are essential to establishing the diagnosis. We have organized this discussion based on whether the disease primarily affects the retina or optic nerve and the age of onset. Those disorders with prominent neurological or systemic involvement are considered separately.
chapter 22 genetic causes of blindness LOCALIZATION IN THE VISUAL SENSORY SYSTEM Vision loss may occur anywhere in the neural visual sensory system including the retina, optic nerve, chiasm, optic tract, lateral geniculate nucleus, visual radiations, or visual cortex. Most genetic causes of blindness affect the retina or optic nerve. Localization to the retina or optic nerve can usually be confirmed by a comprehensive ophthalmological evaluation but may require ancillary testing. These disorders are typically bilateral and associated with multiple parameters of decreased visual function: visual acuity, color vision, and visual field. The primary distinction between retinal and optic nerve disease is made on ophthalmoscopy with direct observation of the pathology. In several instances, there may no visible abnormalities on ophthalmoscopy, and electrophysiological evaluation with electroretinography (ERG) and visual evoked potential (VEP) is critically important for correct localization.
AGE AT ONSET AND COURSE From a diagnostic point of view, it is useful to consider the age at onset of vision loss. The presence of nystagmus is critical in determining the onset of a potentially blinding genetic disease. Bilateral congenital loss of vision is associated with nystagmus. Nystagmus develops whether the vision loss is caused by genetic or nongenetic mechanisms. Furthermore, nystagmus develops whether the vision loss is due to corneal, lens, retinal, or optic nerve abnormalities. Thus, the nystagmus is thought to arise from abnormal ocular motor adaptation to impaired sensory input. The reason for the development of nystagmus is not understood. Congenital nystagmus most often is caused by Leber’s congenital amaurosis, optic nerve hypoplasia, and ocular albinism. Approximately 10% of patients with congenital nystagmus have no apparent abnormality of the visual sensory system and are referred to as congenital idiopathic or congenital motor nystagmus. The vision in such patients is generally much better than those patients in whom nystagmus is caused by congenital diseases of the retina or optic nerve, probably because the visual loss in the former group of patients is secondary to the nystagmus itself, rather than its cause. Although many well-recognized genetic disorders have their onset and clinical presentation in infancy, others may not be recognized until childhood or early adulthood. Such patients may have subclinical disease or only notice difficulty seeing at night. These disorders are typically slowly progressive and can lead to diagnostic confusion in the early stages when findings are mild. A variety of ancillary testing including electrophysiology and fluorescein angiography can be useful in making a diagnosis. Most genetic diseases are characterized by slowly progressive vision loss. A notable exception to this is Leber’s hereditary optic neuropathy (LHON), which has an acute presentation and may be confused with optic neuritis.
EVALUATION Patients should undergo a complete ophthalmic examination. Refractive errors should be noted as patients with congenital stationary night blindness (CSNB) are myopic whereas patients with Leber’s congenital amaurosis (LCA) are hyperopic. The
275
pupil reaction is of interest. Although loss of vision is commonly associated with a reduction in the pupil light reflex and sluggish pupils, the pupils in some congenitally blinding disorders actually constrict in darkness rather than dilate. This finding, referred to as paradoxical pupils, occurs in LCA and CSNB. Color vision testing is abnormal in patients with achromatopsia and cone dystrophy. Additionally, the pattern of visual field loss is often characteristic of the underlying abnormalities. Retinitis pigmentosa tends to produce progressive peripheral constriction of visual fields, whereas cone dystrophy and optic nerve disorders tend to produce central scotomas. Slit lamp biomicroscopy is used to examine for iris transillumination defects by shining a beam of light through the pupil and observing to see if it is reflected through defects in the iris due to lack of pigmentation, as seen in ocular albinism. Ophthalmoscopic examination may reveal a pigmentary retinopathy in patients with retinitis pigmentosa or bilateral optic atrophy in a patient with dominant optic atrophy. In other cases, ophthalmoscopic findings are mild. Many patients with LCA who present in infancy have a normal fundus. Adults with CNSB often have a normal-appearing fundus. ERG is critical in distinguishing these disorders. In macular disease, a multifocal ERG, which can detect focal retinal defects, is more sensitive than a full-field ERG.
RETINAL DISEASES—CONGENITAL Many of the congenital blinding disorders of the retina involve proteins that are members of the phototransduction cascade, primarily affecting photoreceptors. Other disorders affect the structural relationship between the neural retina and the vitreous. LCA is an autosomal recessive syndrome characterized by significantly reduced vision before age one, nystagmus, paradoxical pupillary reactivity, and retinal degeneration. This syndrome has a prevalence of 3:100,000 children and is a common cause of congenital nystagmus. Six LCA-causing genes have been identified, which account for approximately one half of the cases.1 These genes are expressed preferentially in the retina or the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). The clinical appearance is varying with fundus findings ranging from a retinitis pigmentosa picture with bony spicules to a salt and pepper appearance (Fig. 22−1). Electroretinography (ERG) demonstrates a markedly reduced or nonrecordable scotopic and photopic response, confirming the diagnosis. Although no therapy is presently available, promising gene-based interventions have demonstrated long-term rescue of vision as assessed by psychophysical, behavioral, and molecular biology studies. In a naturally occurring LCA animal model, the RPE65−/− dog, recombinant adenoassociated virus carrying wild-type RPE65 successfully restored visual function.2 Achromatopsia is a rare retinal disorder characterized by a complete absence of cone photoreceptor function. In accordance with the trichromatic theory of vision, individuals with normal color vision can match any color with a combination of three primary colors: red, green, and blue. Dichromats who are missing either the red (protanopes) or green (deuteranopes),
276
■
Section
IV
Neuro-Ophthalmology
Figure 22–1. Ophthalmoscopic appearance of the retina in a patient with Leber’s congenital amaurosis caused by mutations in CRB1. (Courtesy of I. H. Maumenee.)
but retain the blue cone function, can only match colors with two primary colors. The red (OPN1LW, opsin 1, long wave sensitive) and green (OPN1MW, opsin 1 medium wave sensitive) photopigments are encoded on the long arm of the X chromosome and, as such, these disorders are transmitted in a pattern of X-linked inheritance. The blue (OPN1SW, opsin 1, short wave sensitive) photopigment is encoded on chromosome 7. Achromats present in infancy with reduced vision, photophobia, total color blindness, nystagmus, and a normal-appearing retina. Achromatopsia refers to a spectrum of disease encompassing complete achromatopsia (rod monochromacy), in which there are no cones; atypical rod monochromacy, in which there are some functioning cones; and blue cone monochromacy, where the red and green photopigments are absent but the blue photopigment is functional. Psychophysical testing in such patients must be performed after age 10 in order to get reproducible results. Genes associated with achromatopsia include CNGA33 and CNGB3,4 encoding the α and β subunits of the cone cyclic nucleotide−gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A third gene identified in achromatopsia is GNAT2,5 encoding the cone specific α unit of transducin, a G protein of the phototransduction cascade. Aniridia is a syndrome in which the most prominent manifestation is absence or hypoplasia of the iris. Importantly, visual acuity is reduced due to hypoplasia of the fovea, macula, or
optic nerve. Patients present with reduced visual acuity, elevated intraocular pressure, and nystagmus and may develop cataract, glaucoma, keratopathy, strabismus, and amblyopia. Aniridia is caused by mutations in PAX6, a homeobox gene on chromosome 11.6 The homeobox encodes the homeodomain, a protein domain that binds DNA and regulates the transcription of other genes. Aniridia is inherited as an autosomal dominant disorder. WAGR syndrome consists of Wilm’s tumor, aniridia, genitourinary abnormalities, and retardation, resulting from a deletion on chromosome 11p. Albinism is traditionally divided into oculocutaneous albinism and ocular albinism. Oculocutaneous albinism is autosomal recessive and has been divided into tyrosinasepositive and -negative forms. Tyrosinase catalyzes three steps in a series of reactions in the melanosome that lead to the formation of melanin from its precursor tyrosine. Major oculocutaneous albinism syndromes include HermanskyPudlak syndrome and Chediak-Higashi syndrome, which are inherited in autosomal recessive manner. Nettleship-Falls ocular albinism is an X-linked recessive disorder characterized by reduced visual acuity, congenital nystagmus, transillumination defects of the iris (Fig. 22−2), hypopigmentation of the uveal tract and retinal pigment epithelium, hypoplasia of the fovea, and abnormal decussation of optic nerve fibers through the chiasm. Strabismus and refractive abnormalities are common. Ocular albinism is caused by mutations in OA1, a member of the G protein−coupled receptor superfamily.7 Hereditary vitreoretinopathies are characterized by degenerative changes involving the vitreous and retina. These include familial exudative vitreoretinopathy, Goldmann-Favre syndrome, Stickler’s syndrome, Knobloch’s syndrome, and Norrie disease. Familial exudative vitreoretinopathy (FEVR) has features similar to retinopathy of prematurity but without premature birth or supplemental oxygen. This autosomal dominant disorder is caused by mutations in the frizzled-4 gene (FZD4)8 and is characterized by peripheral retinal vascular nonperfusion, exudative retinal detachment, and proliferative, cicatricial vitreoretinopathy. With severe loss of vision, patients develop nystagmus and strabismus. Goldmann-Favre syndrome is an autosomal recessive disorder caused by mutations in the nuclear receptor gene NR2E3 with characteristic features of retinitis pigmentosa along with central and peripheral retinoschisis, a splitting of the retina. Stickler’s syndrome, a progressive hereditary arthro-ophthalmopathy, is characterized by high myopia, vitreous degeneration, and retinal detachment (Fig. 22−3) in association with orofacial abnormalities such as Pierre-Robin sequence and musculoskeletal abnormalities such
■
Figure 22–2. In a patient with albinism, transillumination of the globe demonstrates the absence of pigment in the iris (left). On ophthalmoscopic examination of the retina, the lack of pigmentation in the retinal pigment epithelium allows easy visualization of the choroidal vessels (right). (Courtesy of I. H. Maumenee.)
chapter 22 genetic causes of blindness
■
Figure 22–3. Fundus appearance of a total retinal detachment in a patient with Stickler’s syndrome. (Courtesy of I. H. Maumenee.)
as arthritis, scoliosis, and arachnodactyly. It is inherited as an autosomal dominant disorder and caused by mutations in type II collagen (COL2A1). Knobloch’s syndrome is characterized by high myopia, vitroretinal degeneration with retinal detachment, and occipital encephalocele and is caused by a mutation in collagen XVIII (COL18A1). Norrie’s disease is characterized by mental retardation and bilateral retinal detachment presenting early in life. It is inherited as an X-linked disorder caused by mutations in the Norrie gene, which is thought to interact with the FZD4 gene.
RETINAL DISEASES—ONSET IN CHILDHOOD AND ADULTHOOD Retinitis pigmentosa (RP) encompasses a variety of disorders that primarily affect rod photoreceptors. Although a pigmentary retinopathy may occur as a feature of a variety of multisystem diseases discussed at the end of the chapter, it may also occur as an isolated disorder of the retina. Initial vision loss in RP occurs in the midperipheral visual field and initial retinal pathology in the postequatorial fundus. In contrast, cone dystrophies refer to those photoreceptor disorders primarily affecting cones and initially involving the macula. There is considerable overlap between these entities. Inability to see as clearly in dim light as in bright light (nyctalopia) is the initial symptom of the rod dystrophies, followed by loss of peripheral vision. The fundus initially has a gray discoloration at the level of the retinal pigment epithelium (RPE) in areas corresponding to vision loss. With time, pigmented cells migrate into the retina aggregating around blood vessels leading to the characteristic bone spicule appearance and a “waxy” pallor of the optic nerve. The most common hereditary form of RP is autosomal recessive (60%), followed by autosomal dominant (10% to 25%) and X-linked (5% to 18%). The X-linked and recessive forms are more severe than autosomal dominant RP. The first gene
277
determined to be mutated in RP was rhodopsin.9 Other genes include peripherin, tissue inhibitor of metalloproteinase, and geronyl-geronyl transferase. More than 20 genes causing RP have been identified. In contrast to retinitis pigmentosa, patients with cone dystrophies present with symptoms of blurred vision and inability to see as clearly in bright light as in dim light (hemeralopia). On examination, patients have central loss of vision which manifests as a reduction in visual acuity or a central scotoma on visual field testing and loss of color vision due to degenerative disease of the cone photoreceptors. In early stages, it may be difficult to diagnose because of a normal appearing ophthalmoscopic examination. Patients eventually develop a pigmentary degeneration of the macula, often described as a bull’s eye maculopathy. In many instances, optic pallor develops, leading one to suspect optic nerve disease rather than retinal disease. The ability to diagnose cone dystrophies in the early stages prior to ophthalmoscopically evident retinal pathology has been advanced by the use of multifocal ERG. Well-known toxicities associated with degenerative cone disease include chloroquine and digoxin. Cone degenerations may be inherited in an autosomal or Xlinked pattern. Genes identified as causing cone degenerations include guanylate cyclase activator-1A (GUCA1A), retinitis pigmentosa GTPase regulator (RPGR), and the CRX gene, a homeobox gene expressed in photoreceptors. Juvenile retinoschisis is an X-linked recessive disorder that manifests in childhood with reduction in visual acuity. The characteristic macular abnormality is a cystlike appearance with spoke like extensions from the fovea. It is highly penetrant in males, whereas carrier females rarely show macular pathology. It is caused by mutations that lead to the pathological development of a schisis or splitting of the retina in the nerve fiber layer. The RS gene is implicated in cell-cell adhesion and phospholipid binding.10 Stargardt’s disease is a storage disease of the retinal pigment epithelium that leads to bilateral progressive loss of central visual acuity. Stargardt’s disease is an autosomal recessive disorder caused by mutations in the ABCR4 gene, encoding an ATP-binding cassette (ABC) transporter.11 Patients often present in the second decade of life with unexplained reduction in visual acuity. Features include subretinal yellow pisiform flecks, referred to as fundus flavimaculatus, and macular changes including increased granularity and a “beaten metal” appearance. ERG shows a moderately reduced photopic response and a nearly normal scotopic response. Fluorescein angiography is important in establishing the diagnosis, demonstrating a “silent choroid sign,” which refers to the darkened appearance of the choroid due to blockage by diffuse storage of material at the RPE (Fig. 22−4). Best’s vitelliform macular dystrophy is an autosomal dominant disease characterized by the development of an eggyellow, slightly raised lesion in the macula that is usually 1 to 3 disc diameters in size. Patients may experience blurred central vision and metamorphopsia. Although the fundus appearance is often dramatic, the visual acuity is often better than 20/40. An abnormal electro-oculogram, which measures the electrical potential across the retinal pigment epithelium, is particularly helpful in the diagnosis of patients. The macular abnormality evolves with time from an “egg yolk” appearance to a “scrambled egg” appearance to a late cicatricial stage. Mutations in VMD2, a gene encoding the bestrophin protein,
278
Section
■
IV
Neuro-Ophthalmology
Figure 22–4. Fluorescein angiogram is performed by injecting fluorescein dye into the vein of a patient and taking a series of photographs as the dye passes through the retinal and choroidal vasculature. In a normal ocular fundus, a “background” of fluorescence emanating form the choroid is observed (left). In a patient with Stargardt’s disease (right), fluorescence is “blocked” by deposits in the RPE and referred to as a “dark choroid.” The arrowhead in the right photograph indicates an area of early and late central hyperfluorescence in a bull’s-eye pattern. (Right, reprinted with permission from Margalit E, Sunness JS, Green WR, et al. Stargardt disease in a patient with retinoblastoma. Arch Ophthalmol 2003; 121:1643-1646. Copyright 2003 American Medical Association. All rights reserved.)
have been associated with Best’s disease. Bestrophin localizes to the basolateral plasma membrane of RPE cells12 and is likely involved in chloride ion conductance. Congenital stationary night blindness (CSNB) describes a group of retinal diseases characterized by nyctalopia without progressive retinal degeneration. CSNB may be inherited in an autosomal dominant or X-linked pattern. Two types of ERG abnormalities that may be observed in different subtypes of CSNB are (1) a reduced scotopic ERG waveform in the dark adapted ERG or (2) absence of the b-wave on a dark-adapted bright-flash ERG referred to as a “negative” waveform. Autosomal dominant CSNB has been associated with mutations in either the α or β subunit of rod cGMP phosphodiesterase as well as the rhodopsin gene. X-linked CSNB patients have a myopic tigroid-appearing fundus and congenital nystagmus. The visual acuity is typically better than 20/40. It is caused by mutations in NYX, encoding nyctalopin, and a retina-specific calcium channel α1 subunit gene (CACNA1F).13 Although the typical CSNB fundus doe not have any significant pathologicalfeatures, two types of CSNB stand out. Fundus albipunctatus is a type of CSNB inherited in an autosomal recessive pattern that shows distinct, impressive white, round flecks scattered throughout the fundus. Oguchi’s disease is inherited as an autosomal recessive disorder in which the macular retina has an abnormally dark appearance compared with the rest of the fundus, an appearance that disappears with dark adaptation. It is caused by mutations in the arrestin gene. Choroideremia is an X-linked progressive chorioretinal degeneration characterized by progressive nyctalopia and peripheral vision loss. The fundus undergoes progressive atrophy of the choriocapillaris, the retinal pigment epithelium, and photoreceptors that gradually encroaches on the macula. The appearance is very similar to gyrate atrophy of the retina and choroid. Choroideremia is caused by a mutation in the Rab escort protein-1 gene (REP-1) of geranylgeranyl transferase. This enzyme catalyzes the addition of 20 carbon groups to two cysteines at the carboxyl terminus of Rab proteins.
OPTIC NERVE DISEASES—CONGENITAL Optic nerve hypoplasia may be observed with normal visual acuity in association with a subtle visual field defect or manifest with profound visual loss (Fig. 22−5). In childhood, optic nerve hypoplasia may manifest as a unilateral decrease in vision diagnosed initially as amblyopia or bilateral decreased vision in infancy diagnosed initially as congenital nystagmus. In these instances, it is important to recognize its association with midline forebrain abnormalities, which can result in pituitary hormone deficiencies and even sudden death. Both teratogenic and genetic etiologies have been described. Recognized teratogens associated with optic nerve hypoplasia include alcohol, quinine, and anticonvulsants. Maternal insulin-dependent diabetes mellitus is associated with superior segmental optic nerve hypoplasia as well. Optic nerve hypoplasia has also been observed in association with many ocular and systemic syndromes including chromosomal duplications and deletions. Septo-optic dysplasia (de Morsier’s syndrome) refers to the association of hypoplasia of the anterior visual pathways, absence of the septum pellucidum, and thinning or agenesis of the corpus callosum. Although familial cases have been reported, most cases are sporadic. Mutations in the homeobox containing transcription factor, HESX1, have been implicated with homozygous inheritance, causing the more severe phenotype, and heterozygous inheritance, causing a mild phenotype.14,15 Mutations in PAX6 have been observed with a variety of optic nerve abnormalities including coloboma, morning glory disc anomaly, optic-nerve hypoplasia/aplasia, and persistent hyperplastic primary vitreous.16 Papillorenal syndrome (renal-coloboma syndrome) is a primary dysgenesis that causes vascular abnormalities predominantly affecting the eye, kidney, and urinary tract. The characteristic optic nerve finding in papillorenal syndrome is an absence or attenuation of the central retinal vessels within the optic nerves, with multiple compensatory cilioretinal vessels. Although the abnormality in these patients has been
chapter 22 genetic causes of blindness
■
279
Figure 22–5. The optic nerve on the left is hypoplastic. For comparison, a normal optic nerve is shown on the right. Both optic nerves are from the right eye.
■
Figure 22–6. A 10-year-old boy presents with a visual acuity of 20/40, bilateral central scotomas, and bilateral temporal optic atrophy (right and left eyes). His father has similar findings. Genetic testing revealed a mutation in OPA1.
referred to as a coloboma, it is not a true coloboma arising from failure of closure of the optic nerve fissure with superonasal displacement of the central retinal vessels.17,18 Papillorenal syndrome is inherited in an autosomal dominant pattern. Mutations in PAX2 have been identified in papillorenal syndrome,19 but it is a heterogeneous disease. Patients should undergo renal function testing including serum creatinine and urea nitrogen measurements, urinalysis to test for microalbuminuria, and renal ultrasound.
OPTIC NERVE—ONSET IN CHILDHOOD AND ADULTHOOD Autosomal dominant optic atrophy is characterized by bilateral insidious vision loss often manifesting in the first or second decade of life. It is inherited in an autosomal dominant pattern
with high penetrance. OPA1, located on the long arm of chromosome 3, accounts for the majority of cases, although there is evidence of genetic heterogeneity. The protein is a dynamin-related GTPase targeted to mitochondria, further demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.20,21 At presentation, the visual acuity is typically 20/40 to 20/60, bilateral, and symmetrical. There is an insidious progression of vision loss, although final visual acuity may vary from 20/20 to no light perception. Most individuals retain a visual acuity of 20/40 to 20/200. Color vision testing has demonstrated a characteristic tritanopic-type deficiency, although a generalized dyschromatopsia is most common. Visual field defects include central and cecocentral scotomas. Optic atrophy is present, often localized to the temporal portion of the optic nerve (Fig. 22−6). Other than sensineural hearing loss, neurological or systemic findings are uncommon.
280
Section
IV
Neuro-Ophthalmology
The differential diagnosis includes nutritional deficiency, toxic optic neuropathy, and macular dystrophy. Diagnosis is based on family history and clinical examination. Genetic testing has not become widely available for this disorder. Unfortunately, no treatments are available at the present time to prevent vision loss, arrest the progression of vision loss, or restore vision. Wolfram’s disease is an autosomal recessive disease caused by mutations in WFS1 which encodes an integral membrane glycoprotein that localizes primarily in the endoplasmic reticulum.22 The most consistent criteria for diagnosis of this syndrome are juvenile-onset diabetes mellitus and optic atrophy. However, other findings include diabetes insipidus and sensory neural hearing loss. The constellation of findings has led to the acronym DIDMOAD: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness. Less commonly recognized features include central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure, startle myoclonus, axial rigidity, and Parinaud’s syndrome.23 Behr’s disease is an autosomal recessive syndrome of optic atrophy, beginning in the first decade of life, associated with pyramidal tract signs, ataxia, mental retardation, nystagmus, urinary incontinence, and pes cavus. Behr’s disease may represent a phenotype that is common to several genetic disorders that are likely metabolic in origin. Methylglutaconic aciduria, diagnosed by increased amounts of 3-methylglutaconic and 3methylglutaric acid in urine, may manifest with this constellation of findings.24 X-linked optic atrophy patients present with vision loss in early childhood, which may be progressive. This rare disease is often associated with other neurological findings, including ataxia, tremor, sensineural deafness, and polyneuropathy.25 Leber’s hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy with bilateral vision loss, typically occurring in young men. LHON is caused by point mutations in the mitochondrial genome at nucleotide positions 3460,26 11778,27,28 and 1448429 in genes encoding subunits of complex I of the respiratory chain, with the 11778 mutation accounting for the majority of cases. As mitochondria are only transmitted by the mother to all offspring, the typical rules of mendelian inheritance do not apply. All children of maternal carriers are at risk of vision loss, although male children are at greater risk of vision loss than their female siblings. The offspring of male carriers are not at risk for vision loss. Vision loss typically begins painlessly in one eye, progressively worsening over a few weeks. Although some individuals subjectively describe visual loss as sudden and complete, others describe progression over the course of a few weeks. Almost all patients develop vision loss in the fellow eye, usually within 6 months of the vision loss in the first eye. Typically, no other symptoms occur at the time of vision loss. Visual acuity is commonly worse than 20/200 in each eye with bilateral central scotomas. On ophthalmoscopy, the optic nerve may appear normal or have a characteristic abnormality that has been described as a triad of circumpapillary telangiectasia (Fig. 22−7), swelling of the nerve fiber layer around the disc, and absence of leakage on fluorescein angiography. The optic nerve progresses to optic atrophy with nonglaucomatous cupping, pallor, and arteriole attenuation. In rare individuals, associated neurological abnormalities may be present such as pathological reflexes, mild cerebellar
■
Figure 22–7. The right optic nerve from a patient with Leber’s hereditary optic neuropathy demonstrates circumpapillary telangiectasia and a prominent peripapillary nerve fiber layer.
ataxia, tremor, movement disorders, muscle wasting, and distal sensory neuropathy. In a few pedigrees, more severe neurological deficits may be present such as dystonia, spasticity, and encephalopathic episodes. In addition to neurological abnormalities, some patients may have cardiac conduction defects, and patients should undergo electrocardiography. Patients generally present with unilateral acute or subacute vision loss. The differential diagnosis includes optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, and neoplasm. Definitive diagnosis is made by genetic testing. The prognosis for restoration of vision is typically poor for these individuals. Nevertheless, some individuals may recover vision spontaneously, even years later. Unfortunately, no treatments are available at the present time to prevent vision loss, arrest the progression of vision loss, or restore vision.
RETINOPATHY AND OPTIC NEUROPATHY ASSOCIATED WITH SYSTEMIC AND NEURODEGENERATIVE DISEASE A variety of genetic disorders lead to vision loss in addition to other systemic and neurological symptoms. These include metabolic defects of amino acid, protein, and lipoprotein metabolism; lysosomal storage diseases; lipid metabolic disorders; peroxisomal diseases; mitochondrial genetic disease; neuronal ceroid lipofuscinosis; other neurodegenerative disorders; and a variety of disorders with prominent systemic manifestations. Disorders of amino acid, protein, and lipoprotein metabolism may lead to blindness from retinal degeneration. Gyrate
chapter 22 genetic causes of blindness
■
Figure 22–8. Corneal clouding is a prominent feature of many lysosomal storage diseases, particularly mucopolysaccharidoses. The picture is from a patient with Maroteaux-Lamy syndrome. (Courtesy of I. H. Maumenee).
atrophy of the retina and choroid is an autosomal recessive disease due to a defect in ornithine aminotransferase leading to serum hyperornithemia. It leads to geographic and roundshaped areas of chorioretinal atrophy that begin peripherally and progress centrally. Cystinosis is an autosomal recessive disease characterized by progressive renal failure, pigmentary retinopathy, and growth retardation due to a deposition of cysteine crystals throughout the body. It is caused by a lysosomal defect preventing transport of cysteine crystals from the lysosome to the cytosol. Cysteine crystals are also deposited in the cornea leading to significant photophobia. Methylmalonic aciduria and homocystinuria result in a pigmentary retinopathy and optic nerve pallor due to an abnormality in cobalamin metabolism. Abetalipoproteinemia is an autosomal recessive disorder associated with a pigmentary retinopathy in which patients have fat malabsorption, progressive ataxia, and abnormal plasma lipids due to deficient beta lipoproteins and chylomicons. Lysosomal storage diseases are caused by enzymatic defects that lead to an accumulation of partially degraded intermediates in cells, tissues, and organs leading to dysfunction. They are generally inherited in an autosomal recessive manner. Mucopolysaccharidoses are caused by defects in specific lysosomal enzymes involved in the degradation of glycosaminoglycans or mucopolysaccharides. General features include facial dysmorphic changes, mental retardation, corneal clouding (Fig. 22−8), and retinal degeneration. Optic disc swelling and optic atrophy are also features of mucopolysaccharidoses. Mucopolysaccharidoses associated with ophthalmological features include Hurler’s syndrome, Scheie’s syndrome, Hunter’s syndrome, Sanfilippo’s syndrome, and Maroteaux-Lamy syndrome. Sialadoses are characterized by the progressive lysosomal storage of sialidated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. There is a progressive accumulation and excretion of sialic acid. Patients develop corneal clouding and a cherry-red spot in the macula. Mucolipidoses have similar features to mucopolysaccharidoses but without mucopolysacchariduria. Patients have a Hurler-like facies, hepatosplenomegaly, and a thickened skull. Major subtypes of mucolipidoses include mucolipidosis II (I cell disease),
281
mucolipidosis III, and mucolipidosis IV. Mucolipidosis IV has the most prominent ocular features including corneal clouding and retinal degeneration in addition to hypotonia and psychomotor retardation. Sphingolipidoses are due to an accumulation of glycosphingolipids, an abundant component of neurons. These disorders include the gangliosidoses (GM2 gangliosidoses [type 1: Tay-Sachs disease; type 2: Sandhoff’s disease] and GM1 gangliosidoses [Gaucher’s disease, Farber’s disease, Fabry’s disease, and Neimann-Pick disease]). Tay-Sachs and Sandhoff diseases are notable for the development of a cherry-red spot in the macula in which there is a deep red spot in the fovea surrounded by a ring of opacified retina. In addition, patients have hepatosplenomegaly and skeletal dysostosis. Metachromatic leukodystrophy (MLD) is a lipid metabolic disorder caused by mutations in the arylsulfatase A gene. There are five allelic forms, including late infantile, adult partial cerebroside sulfate deficiency, and pseudo-arylsulfatase deficiency.30 On histopathological staining, there is a metachromatic staining of abnormally stored galactosphingosulfatides in central nervous system white matter. The late infantile form is the most common form of MLD, manifesting in the second year of life with gait disturbance and muscle rigidity. This is followed by progressive mental deterioration and convulsions. A cherry-red spot may be present in the macula and optic atrophy may develop. Peroxisomal disorders are rare disorders affecting multiple tissues, including the eye. These diseases have overlapping clinical manifestations and are classified into two categories. In peroxisome biogenesis disorders, peroxisomal assembly is defective due to abnormal localization of proteins normally targeted to the peroxisomes. This results in severe diseases that commonly affect the retina: Zellweger’s syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum’s disease (IRD). Although these three diseases were described as separate entities before the underlying peroxisomal defect was defined, identification of the underlying molecular defects and better understanding of the resulting biochemical defects, suggest that all three are parts of one spectrum in which ZS represents the more severe form, NALD an intermediate severity, and IRD the least severe. In the most severe form of ZS, children present with seizures, hypotonia, and developmental delay. Ophthalmological abnormalities include cataracts, glaucoma, corneal clouding, pigmentary retinal degeneration, and optic atrophy. In IRD, patients have reduced cognition, hearing loss, and a pigmentary retinopathy. As in classic Refsum’s disease, they have elevated phytanic acid and cholesterol but differ because of the elevation of very-long-chain fatty acids. A second group of peroxisomal disorders are due to gene defects that result in abnormal peroxisome function without affecting its assembly. This group includes entities such as Xlinked adrenoleukodystrophy, primary hyperoxaluria type 1, and classic Refsum’s disease. XLA is characterized by an accumulation of very-long-chain fatty acids of 22 to 30 carbons. Xlinked adrenoleukodystrophy may manifest in childhood with gait disturbance and intellectual deterioration between the ages of 5 and 8. There is impressive inflammation of white matter and demyelination. In latter stages of the disease, patients develop vision loss with optic atrophy. The adult-onset variety of X-linked adrenoleukodystrophy is referred to as adrenomyeloneuropathy. X-linked adrenoleukodystrophy is caused by mutations in ABCD1, a member of the ATP-binding cassette (ABC) transporter superfamily that contains membrane
282
■
Section
IV
Neuro-Ophthalmology
Figure 22–9. The nasal fundus of the left eye from a patient with NARP syndrome demonstrates diffuse peripheral bone spicule formation. (Reprinted with permission from Kerrison JB, Biousse V, Newman NJ: Retinopathy of NARP syndrome. Arch Ophthalmol 2000; 118:298. Copyright © 2000 American Medical Association. All rights reserved.)
proteins that translocate a wide variety of substrates across extracellular and intracellular membranes. Primary hyperoxaluria type 1 is an autosomal recessive disorder caused by a defect in the enzyme alanine glyoxylate aminotransferase and characterized by renal failure and elevated intracranial pressure. Patients develop a hyperplasia of the retinal pigment epithelium due to deposition of calcium oxalate crystals. Classic Refsum’s disease is characterized by a pigmentary retinopathy, polyneuropathy, hearing loss, icthyosis, and ataxia due to a defect in phytanoyl-CoA hydroxylase (PAHX) or peroxin-7 (PEX7), which impair the degradation of phytanic acid. Mitochondrial disorders in addition to LHON include NARP, MELAS, and Kearns-Sayre syndrome. NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) is caused by a T-to-G point mutation in nucleotide 8993 of mtDNA, which results in a substitution of a highly conserved leucine by an arginine residue in the mitochondrial ATPase 6 gene.31 As the acronym implies, clinical features include migraine, sensory neuropathy, proximal muscle weakness, ataxia, seizures, dementia, and pigmentary retinopathy (Fig. 22−9). The retinal degeneration in NARP may manifest as a cone-rod dystrophy, a progressive cone dystrophy, a bull’s eye maculopathy, or rodcone type of retinal dystrophy. The severity of NARP appears to correlate with the burden of mutated mitochondria within the population of mitochondria in the cell. The 8993 mutation also causes maternally inherited Leigh disease.32 MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) is caused by a mutation at nucleotide position 3243 affecting the mitochondrial encoded gene for leucine tRNA. Although vision loss in mitochondrial genetic disorders more commonly occurs from retinal degeneration or optic nerve disease, in MELAS, vision loss can occur from damage to the retrochiasmal visual pathways. Other features included diabetes mellitus and deafness. Of note, the A3243G mutation may also be associated with a pigmentary retinopathy or optic neuropathy as well as chronic progressive external ophthalmoplegia (CPEO). Kearns-Sayre syndrome (KSS) is characterized by the triad of external ophthalmoplegia (CPEO), pigmentary retinopathy,
and heart block. Onset is in the first or second decades of life. CPEO is characterized by a bilateral symmetrical ptosis associated with ophthalmoplegia and orbicularis oculi weakness. The pigmentary retinopathy of KSS differs from RP in that the macula is often the first part of the retina to be affected, followed by the retinal periphery. Visual acuity, visual fields, and ERG are usually only mildly affected. Neurological manifestations in KSS may include cerebellar ataxia, hearing loss, dementia, and weakness of facial, pharyngeal, trunk, and extremity muscles. Heart block is a characteristic finding. Skeletal muscle biopsy demonstrates ragged-red fibers. KSS is caused by mitochondrial DNA deletions, usually 1.3 to 7.6 kb in size, affecting 45% to 75% of total mtDNA.33 KSS may be maternally inherited or sporadic. Leigh disease is a subacute necrotizing encephalomyopathy frequently ascribed to mitochondrial respiratory chain deficiency. Patients usually develop an acute or progressive decline in neurological function with characteristic magnetic resonance imaging consisting of symmetrical lesions scattered from the basal ganglia to the brainstem. A pigmentary retinopathy may be present. Although progression of symptoms is expected, some patients may improve. Mutations have been found in many nuclear and mitochondrial encoded genes involved in energy metabolism, specifically oxidative phosphorylation and the generation of ATP. Neuron ceroid lipofuscinoses (NCLs) are a group of typically autosomal recessive disorders characterized by abnormal accumulation of ceroid and lipofuscin in neuronal cells. Six major clinical forms of NCL have been described differing in their age of onset, clinical course, and neuropathological findings. Patients develop progressive psychomotor findings with vision loss being a prominent manifestation. Vision loss in neuronal ceroid lipofuscinosis occurs from both cortical and photoreceptor disease with development of a pigmentary retinopathy, attenuation of blood vessels, and optic atrophy. Diagnosis is made by observation of characteristic inclusions in skin, conjunctival, or rectal biopsy Cerebroretinal neurodegenerative diseases in addition to those discussed can affect the retina and optic nerve to varying degrees. Neurodegenerative disorders that may have pigmentary retinopathy or optic atrophy as a feature include spinocerebellar ataxia, Friedreich’s ataxia, familial dysautonomia, various familial forms of motor and sensory neuropathies, Pelizaeus-Merzbacher disease, Krabbe’s disease, and Hallervorden-Spatz disease.
RETINOPATHY AND OPTIC NEUROPATHY ASSOCIATED WITH DERMATOLOGICAL DISEASE, SKELETAL ANOMALIES, HEARING LOSS, OR RENAL DISEASE Incontinentia pigmenti is an X-linked disorder caused by mutations in a gene encoding necrosis factor-κB essential modulator (NEMO). It manifests in infancy with a bullous dermoid eruption that evolved into characteristic pigmented streaks. Vision loss occurs from retinal vascular occlusions and retinal detachment. Other findings include ischemic or hemorrhagic cerebrovascular events leading to seizures and mental retardation. Cockayne’s syndrome (CS) is an autosomal recessive disorder whose features include dwarfism, precociously senile
chapter 22 genetic causes of blindness appearance, pigmentary retinal degeneration, optic atrophy, deafness, marble epiphyses in some digits, photosensitivity, and mental retardation. Magnetic resonance imaging demonstrates hypomyelination, cerebellar atrophy, and basal ganglia calcification. CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. The CSA and CSB genes are involved with DNA repair. Bardet-Biedel syndrome (BBS) consists of obesity, postaxial polydactyly, hypogonadism, mental retardation, and renal abnormalities. Vision loss occurs due to a pigmentary retinopathy. It is a genetically heterogeneous disorder with linkage to eight loci. Although considered to be autosomal recessive, the discovery of three mutant alleles in single pedigrees led to the conclusion that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. The Laurence-Moon syndrome is differentiated from BBS by the presence of spastic paraplegia and the absence of polydactyly and obesity. Usher’s syndrome comprises a group of autosomal recessive disorders that are characterized by autosomal recessive inheritance, congenital sensorineural hearing loss, and retinitis pigmentosa. In some varieties, vestibular function is not significantly affected. Usher’s syndrome is caused by at least 12 loci with several identified genes: USH2A (encoding usherin), MYO7A (encoding myosin VIIa), CDH23 (encoding cadherin 23), PCDH15 (encoding protocadherin 15), USH1C (encoding harmonin), USH3A (encoding clarin 1), and USH1G (encoding SANS).34 Joubert’s syndrome is an autosomal recessive disorder characterized by psychomotor retardation, absence of the cerebellar vermis, nystagmus, and episodic hypernea. In addition, patients with renal cysts may develop retinal dystrophy.
K E Y
P O I N T S
●
Congenital loss of vision is associated with nystagmus, thought to develop as an abnormal ocular motor adaptation to impaired sensory input.
●
In several instances, there may be no visible abnormalities of the retina or optic nerve on ophthalmoscopy, and electrophysiological evaluation with electroretinography and visual evoked potentials (VEP) is critically important to correct localization.
●
Many blinding disorders of the retina involve proteins that are members of the phototransduction cascade.
●
Patients with slowly progressive vision loss may not be aware of their deficit. Ophthalmological examination should be considered in a patient with a progressive neurological syndrome that might be associated with retinal or optic nerve disease.
Suggested Reading Newman NJ: Hereditary optic neuropathies. In Miller NR, Newman NJ, Biousse V, Kerrison, JB (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed, Vol 1. Baltimore: Lippincott, Willians, and Wilkins, 2004, pp 465-502
283
Repka MX: Degenerative and metabolic diseases in infants and children: In Miller NR, Newman NJ, Biousse V, Kerriscn JB (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed, Vol 2. Baltmore: Lippincott, Willians, and Wilkins, 2004, pp 2469-2512. Traboulsi EI (eds): Genetic Diseases of the Eye. New York: Oxford University Press, 1998. Online Mendelian Inheritance in Man, available at http://www.ncbi.nlm.nih.gov
References 1. Cremers FP, van den Hurk JA, den Hollander AI: Molecular genetics of Leber congenital amaurosis. Hum Mol Genet 2002; 11:1169-1176. 2. Acland GM, Aguirre GD, Ray J, et al: Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001; 28:92-95. 3. Kohl S, Marx T, Giddings I, et al: Total colour blindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 1998; 19:257-259. 4. Sundin OH, Yang JM, Li Y, et al: Genetic basis of total colour blindness among the Pingelapese islanders. Nat Genet 2000; 25:289-293. 5. Kohl S, Baumann B, Rosenberg T, et al: Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet 2002; 71:422-425. 6. Davis A, Cowell JK: Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet 1993; 2:2093-2097. 7. Bassi MT, Schiaffino MV, Renieri A, et al: Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome. Nat Genet 1995; 10:13-19. 8. Robitaille J, MacDonald ML, Kaykas A, et al: Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 2002; 32:326-330. 9. Dryja TP, McGee TL, Hahn LB, et al: Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N Engl J Med 1990; 323:1302-1307. 10. Sauer CG, Gehrig A, Warneke-Wittstock R, et al: Positional cloning of the gene associated with X-linked juvenile retinoschisis. 1997; 17:164-170. 11. Allikmets R, Singh N, Sun H, et al: A photoreceptor cellspecific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997; 15:236-246. 12. Marmorstein AD, Marmorstein LY, Rayborn M, et al: Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci U S A 2000; 97:12758-12763. 13. Strom TM, Nyakatura G, Apfelstedt-Sylla E, et al: An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 1998; 19:260263. 14. Thomas PQ, Dattani MT, Brickman JM, et al: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001; 10:39-45. 15. Tajima T, Hattorri T, Nakajima T, et al: Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab 2003; 88:45-50. 16. Azuma N, Yamaguchi Y, Handa H, et al: Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am J Hum Genet 2003; 72:1565-1570. 17. Parsa CF, Goldberg MF, Hunter DG: Papillorenal syndrome in a Brazilian family. Arch Ophthalmol 2002; 120:1772-1773; author reply 1773.
284
Section
IV
Neuro-Ophthalmology
18. Parsa CF, Goldberg MF, Hunter DG: Papillorenal (“renal coloboma”) syndrome. Am J Ophthalmol 2002; 134:300-301; author reply 301. 19. Chung GW, Edwards AO, Schimmenti LA, et al: Renalcoloboma syndrome: report of a novel PAX2 gene mutation. Am J Ophthalmol 2001; 132:910-914. 20. Alexander C, Votruba M, Pesch UE, et al: OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000; 26:211-215. 21. Delettre C, Lenaers G, Griffoin JM, et al: Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 2000; 26:207-210. 22. Inoue H, Tanizawa Y, Wasson J, et al: A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 1998; 20:143-148. 23. Scolding NJ, Kellar-Wood HF, Shaw C, et al: Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy. Ann Neurol 1996; 39:352-360. 24. Sheffer RN, Zlotogora J, Elpeleg ON, et al: Behr’s syndrome and 3-methylglutaconic aciduria. Am J Ophthalmol 1992; 114:494-497. 25. Assink JJ, Tijmes NT, ten Brink JB, et al: A gene for Xlinked optic atrophy is closely linked to the Xp11.4-Xp11.2 region of the X chromosome. Am J Hum Genet 1997; 61:934939.
26. Johns DR, Smith KH, Miller NR: Leber’s hereditary optic neuropathy: clinical manifestations of the 3460 mutation. Arch Ophthalmol 1992; 110:1577-1581. 27. Wallace DC, Singh G, Lott MT, et al: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242:1427-1430. 28. Newman NJ, Lott MT, Wallace DC: The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991; 111:750-762. 29. Johns DR, Heher KL, Miller NR, et al: Leber’s hereditary optic neuropathy: clinical manifestations of the 14484 mutation. Arch Ophthalmol 1993; 111:495-498. 30. Polten A, Fluharty AL, Fluharty CB, et al: Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med 1991; 324:18-22. 31. Holt IJ, Harding AE, Petty RK, et al: A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990; 46:428-433. 32. Tatuch Y, Christodoulou J, Feigenbaum A, et al: Heteroplasmic mtDNA mutation (T-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 1992; 50:852-858. 33. Zeviani M, Moraes CT, DiMauro S, et al: Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346. 34. Ahmed Z, Riazuddin S, Wilcox E: The molecular genetics of Usher syndrome. Clin Genet 2003; 63:431-444.
CHAPTER
23
OPTIC NEUROPATHIES ●
●
●
●
Neil R. Miller
Virtually every pathological process that can damage an organ in the body can damage the optic nerve. Thus, optic neuropathies can be produced by ischemia, inflammation, infection, compression, infiltration, toxic exposure, metabolic dysfunction, and trauma. Unfortunately, regardless of the cause of an acute optic neuropathy, the optic disc—the only portion of the optic nerve that can be observed with an ophthalmoscope—has only two possible appearances: swollen or normal. Even more confusing is that with chronic damage to the optic nerve, the optic disc simply becomes pale. Thus, the determination of the cause of an optic neuropathy usually cannot be made from the appearance of the optic disc alone. It can, however, be made from a complete assessment, including a complete history, a complete examination, and, in many cases, appropriate ancillary studies. Damage to the optic nerve occurs in three main clinical settings: (1) optic disc swelling without visual loss; (2) acute visual loss with and without optic disc swelling; and (3) subacute or insidious visual loss with and without progression and with and without optic disc swelling. In this chapter, the common optic neuropathies within these settings are considered.
OPTIC DISC SWELLING WITHOUT VISUAL LOSS The most common cause of optic disc swelling without visual loss is papilledema. Papilledema is defined as optic disc swelling caused by increased intracranial pressure.1 It may be produced by an intracranial mass, by blockage of the arachnoid villi by blood or protein (e.g., after a subarachnoid hemorrhage or from a spinal cord tumor), by obstruction of flow of cerebrospinal fluid through the ventricles, and by decreased flow of venous blood through dural sinuses. The symptoms of patients with papilledema are mostly those of increased intracranial pressure (e.g., headache, nausea, vomiting). Visual symptoms are minor and include transient obscurations of vision and double vision. The transient obscurations that occur in patients with papilledema are binocular and simultaneous, and they are extremely brief, lasting only a few seconds. They may occur once a day or dozens of times a day; they may be unassociated with activity or they may occur primarily during a change in
posture, as in changing from lying down to sitting up or standing. This is in contrast to the transient visual obscurations that can occur in patients with emboli from the heart or internal carotid arteries. Those tend to be monocular, rarely have any relationship to activity, and tend to last at least 15 seconds and often many minutes. The presence of transient visual obscurations in patients with papilledema has no prognostic significance. Double vision in patients with papilledema is almost always caused by a unilateral or bilateral sixth nerve paresis. The paresis is almost always incomplete. In most cases, it is caused by the effects of the increased intracranial pressure on the abducens nerve and not by direct compression of the nerve by an intracranial mass lesion. Patients with acute papilledema usually do not complain of decreased or blurred vision unless there are hemorrhages or exudates in the macula or subretinal fluid beneath it or there is an intracranial mass that involves the optic nerve, optic chiasm, or both. The visual field in an eye with papilledema is usually initially normal; however, as disc swelling worsens, the physiological blind spot enlarges and may become noticed by the patient. When increased intracranial pressure causes death of axons, field defects similar to those that occur in patients with open-angle glaucoma (i.e., nasal steps and arcuate defects) occur. With continued damage, generalized field constriction occurs. Visual acuity is preserved until damage is very severe. The appearance of papilledema varies with its severity. Early papilledema is characterized by mild swelling and hyperemia of the optic discs (Fig. 23–1). There are often no hemorrhages, and the retinal veins are not dilated. Visual function is usually normal at this time. As papilledema worsens, the disc becomes increasingly swollen and hyperemic, the vessels on the surface of the disc become obscured by the swollen tissue, and peripapillary flame-shaped hemorrhages may appear (Fig. 23–2). Patients with this fully developed papilledema continue to have normal visual acuity and color vision; however, their blind spots are enlarged, and they may have some mild, nonspecific field defects. If intracranial pressure is not lowered, chronic papilledema develops, characterized by a rounding up of the discs, which begin to become pale (Fig. 23–3). During this time, the hemorrhages resolve. The visual acuity may be slightly
285
286
■
■
Section
Figure 23–1.
IV
Neuro-ophthalmology
Early papilledema. Note mild swelling of optic disc.
Figure 23–2.
Fully-developed papilledema. Note moderate swelling of optic disc with peripapillary hemorrhages and exudates.
decreased, but the main visual finding is significant constriction of the visual field. The final stage of papilledema—atrophic papilledema—occurs when the swelling resolves as nerve fibers die, and the optic discs become pallid (Fig. 23–4). At this point, the visual acuity is reduced, and the visual field is markedly constricted, often to only 5 degrees or less. Papilledema is an emergency. Patients in whom this condition is suspected require an immediate assessment, including neuroimaging and, if no mass is present, a lumbar puncture. Treatment is directed at the underlying process, the increased intracranial pressure, or both.
■
Figure 23–3.
Chronic papilledema. Note marked disc elevation and obscuration of disc vessels.
■
Figure 23–4.
Atrophic papilledema. Note pallor of optic disc.
SUDDEN VISUAL LOSS WITH AND WITHOUT OPTIC DISC SWELLING The most common causes of optic nerve–related acute visual loss are optic neuritis, ischemic optic neuropathy (ION), and Leber’s hereditary optic neuropathy (LHON).
Acute Optic Neuritis Most patients with optic neuritis are women between 25 and 45 years of age, although this condition can also develop in chil-
chapter 23 optic neuropathies
■
Figure 23–5.
Acute optic neuritis. Note swelling of optic disc associated with perivascular sheathing.
dren and older patients. Optic neuritis is characterized in more than 95% of cases by the sudden onset of pain, often quite severe, behind or around the eye, followed shortly thereafter by decreased central vision and, in many cases, by central field loss.2 The loss of central vision is variable. It may be extremely mild or quite severe; indeed, in some cases, all vision is lost.
■
Figure 23–6.
287
Affected patients have decreased color vision that may be worse than the acuity would suggest. A relative afferent pupillary defect is always present unless the patient has experienced a previous attack of optic neuritis or has some other optic neuropathy in the opposite eye or the acute process is bilateral. The affected optic disc appears normal in about two thirds of cases; in the other one third, it is swollen (Fig. 23–5). Most cases of optic neuritis are idiopathic or demyelinating in origin; however, rare cases are caused by such inflammatory or infectious conditions as sarcoid, syphilis, Lyme disease, and cat-scratch disease.2 The natural history of demyelinating or idiopathic optic neuritis is to improve vision to 20/20 or better without treatment. Although a 3-day course of high-dose (1 g/day) methylprednisolone followed by a 2-week course of low-dose (1 mg/kg/day) prednisone may speed recovery by several weeks to a month, this treatment does not affect the ultimate visual outcome. The use of low-dose steroids without first use of highdose steroids in a patient with acute optic neuritis increases the risk of recurrent optic neuritis in the affected eye and the risk of an attack of acute optic neuritis in the other eye. Patients who experience an attack of acute optic neuritis have an increased risk of developing multiple sclerosis, depending in large part on whether white-matter lesions are visible on magnetic resonance images at the time of the acute attack (Fig. 23–6). The presence of even one lesion doubles a patient’s risk of developing multiple sclerosis over the subsequent 10 years.3 Fortunately, there is evidence that the use of interferon β-1a reduces the risk of developing multiple sclerosis in these patients.4 Patients who experience an attack of optic neuritis in one eye have a 10% to 20% risk of developing a similar event in the opposite eye.2 Risk factors for second-eye involvement include
Magnetic resonance images are two different levels showing multiple white-matter lesions in a patient with isolated acute optic neuritis.
288
Section
IV
Neuro-ophthalmology
Ischemic Optic Neuropathy
■
Figure 23–7.
Acute neuroretinitis. Note swelling of optic disc associated with macular star appearance composed of lipid.
white-matter lesions on magnetic resonance images, a family history of multiple sclerosis, and neurological symptoms. A variant of optic neuritis that has a very different prognosis from the demyelinating or idiopathic form is neuroretinitis.5 This condition begins as an apparently straightforward anterior optic neuritis in which vitreous cells may or may not be present; however, within 1 to 3 weeks, a macular star develops that often persists after the optic disc swelling resolves (Fig. 23–7). Neuroretinitis may be caused by cat-scratch disease, sarcoid, syphilis, tuberculosis, or Lyme disease; however, it is never caused by multiple sclerosis.
■
Figure 23–8.
The second major cause of acute visual loss with and without optic disc swelling is ION.6 This condition occurs in three main settings: (1) as a complication of systemic noninflammatory vascular diseases, such as diabetes mellitus, hypertension, and hypercholesterolemia; (2) in the perioperative period, most often after cardiac surgery or back surgery in the prone position; and (3) as a complication of vasculitis, most often temporal (giant cell) arteritis. Nonarteritic ION usually occurs in patients older than 55; equal numbers of men and women are affected. At least one underlying systemic vasculopathy is usually present, but it may or may not have been identified at the time vision is lost. Nonarteritic ION is usually painless. When eye pain is present, it is usually mild, and pain on eye movement is very rare. As in the case of optic neuritis, the degree of visual loss in patients with nonarteritic ION is variable, ranging from 20/20 to hand motion vision or worse. Color vision usually mirrors acuity; the worse the central vision is, the worse the color vision is. The visual field usually shows an altitudinal or arcuate field defect. A relative afferent pupillary defect is always present if the condition is unilateral and there is no optic neuropathy in the opposite eye. Nonarteritic ION may be of the anterior or the retrobulbar variety.7 In anterior ION, which constitutes about 90% of all cases, the optic disc is usually hyperemic, and peripapillary flame-shaped hemorrhages are often present (Fig. 23–8); however, soft exudates (cotton-wool spots) are usually absent. The opposite optic disc is almost always small with little or no cup (see Fig. 23–8), and this morphological anomaly is believed to predispose the nerve to ischemia by causing crowding of the optic nerve axons. Patients with retrobulbar ION have a normal-appearing optic disc. Because this condition is rare in
Acute nonarteritic anterior ischemic optic neuropathy. Note hyperemic optic disc and flame-shaped hemorrhages (left). Opposite optic disc (right) is small and has no cup (disc at risk).
chapter 23 optic neuropathies comparison with anterior ION, retrobulbar ION should be considered a diagnosis of exclusion: that is, other causes of retrobulbar optic neuropathy, particularly an intracranial mass, should be considered. In about 40% of patients with nonarteritic ION, the condition improves spontaneously, although visual acuity is more likely to improve than is visual field.6 No treatment exists for patients whose vision does not recover. In addition, patients who experience an attack of nonarteritic ION are at risk for subsequent cerebrovascular and cardiovascular events, and such patients have an increased rate of mortality in comparison with age- and gender-matched control subjects. Patients who experience an attack of nonarteritic ION have a 10% to 20% risk of experiencing a similar attack in the opposite eye.8 Risk factors for opposite eye involvement include advanced age, severe vascular disease, and persistent poor visual acuity in the affected eye. Perioperative ION occurs most often after back surgery in the prone position and after cardiac surgery in which cardiopulmonary bypass is used. The rates vary from 0.06% to 0.1% after cardiac surgery and from 0.1% to 0.01% after back surgery in the prone position.9,10 The major factors leading to this complication appear to be operative and perioperative anemia and hypotension, although there are cases in which neither of these factors appears to be in evidence. Perioperative ION is often, although not invariably, bilateral; visual acuity in the affected eye is usually very poor, and the optic discs may be swollen or normal in appearance. Spontaneous improvement is rare. There is no proved treatment, but the author believes that anemia and hypotension should be corrected immediately, because there is indirect evidence from cases of nonsurgical anemia or hypotension that vision could improve with this treatment. Nevertheless, the author is unaware of any cases of perioperative ION in which vision has substantially improved after this treatment. Arteritic ION is the least common type of ION. It is usually associated with temporal (giant cell) arteritis,6 but other vasculitides can be responsible, such as periarteritis nodosa. Patients with this condition do not experience eye pain, but they may have headache, scalp tenderness, jaw pain, ear pain, or a combination of these manifestations. Thus, the physician evaluating a patient with possible arteritic ION must ask specifically about these symptoms. The visual manifestations of arteritic ION are typical. Many affected patients have experienced episodes of transient visual loss preceding permanent loss of vision. The episodes are identical with those experienced by patients with carotid artery disease, usually lasting between 15 seconds and one minute or two. The episodes are unilateral, but both eyes may be affected. Once an attack of arteritic ION occurs, the visual acuity loss is usually profound. Many patients become completely blind in the affected eye, and in almost all, vision is worse than 20/400. The condition is usually unilateral, but bilateral simultaneous ION is not uncommon, and bilateral sequential ION is the rule if the condition is not diagnosed correctly and treated within a short time. As with other unilateral optic neuropathies, patients with arteritic ION always have an ipsilateral relative afferent pupillary defect. The absence of this finding in a patient with presumed arteritic ION should raise concern regarding subclinical involvement of the contralateral eye.
■
289
Figure 23–9.
Arteritic anterior ischemic optic neuropathy. Note pallid swelling, indicating an infarction of the disc substance. Also note peripapillary soft exudate (cotton-wool spot).
As with nonarteritic and perioperative ION, arteritic ION may be of the anterior or retrobulbar variety. When the condition is of the anterior type, the optic disc usually shows pallid rather than hyperemic swelling, which indicates a true infarction of the nerve, and one or more soft exudates (cotton-wool spots) are often present (Fig. 23–9). Indeed, in the appropriate clinical setting, the presence of such exudates in a patient with an acute anterior optic neuropathy is almost pathognomonic of arteritic ION. In most patients, regardless of treatment, arteritic ION does not improve. Nevertheless, a small percentage do experience improvement; these are usually patients treated with high-dose systemic corticosteroids (methylprednisolone [Solu-Medrol], 1 g/day). Of more importance, perhaps, is that this treatment substantially reduces, although it does not eliminate, the risk of second-eye involvement and also may protect the patient against other complications of the vasculitis, including stroke, heart attack, and renal failure. Thus, it is crucial to diagnose and treat unilateral arteritic ION as soon as possible.
Leber’s Hereditary Optic Neuropathy LHON can occur at any age but typically manifests in young adults; about eight times more men than women are affected.11 Visual loss is bilateral and simultaneous in about one half the cases; in the remainder, one eye is affected initially, and the other eye becomes affected, in most cases, within 1 month. Whether unilateral or bilateral, the visual loss is always painless, and this distinguishes the condition from acute optic neuritis, which is almost always associated with pain behind or around the eye, often worsening with eye movement (see previous discussion). The rate of visual loss in LHON is slower than that caused by optic neuritis but faster than that caused by most compressive lesions. The nadir, typically about 20/400, is usually reached within 3 to 6 months. The visual loss is
290
■
Section
Figure 23–10.
IV
Neuro-ophthalmology
Leber’s hereditary optic neuropathy. Note dilated vessels on disc surface and in the peripapillary region in both
fundi.
associated with marked color vision loss; a central or cecocentral scotoma with preservation of the peripheral field in most but not all cases; and either a normal-appearing optic disc or the triad of hyperemic “pseudoedema” of disc, telangiectatic vessels on the disc and in the peripapillary region, and no evidence of leakage on fluorescein angiogram (Fig. 23–10). LHON is a mitochondriopathy. It is, therefore, maternally inherited; more than 90% of cases are caused by mutations at sites 11778 (the most common site), 14484, and 3460. There are a number of other sites at which mutations are responsible for small numbers of cases. Approximately 20% of patients with the pathogenic mutations that cause LHON become symptomatic, but it is not known which factors cause some patients but not others to lose vision. Alcohol abuse, tobacco abuse, and metabolic stress have all been postulated to play a role, but none has been proved to do so.12 The natural history of LHON varies with the site of the mutation.11 Patients with the 11778 mutation have the worst visual prognosis, with a 4% improvement rate, whereas 25% to 40% of patients with mutations at sites 14484 and 3460 experience improvement, often to 20/20 or better. Improvement is associated with breaking up of the central field defects. Unfortunately, there is no definitive treatment for LHON. Although it has been suggested that idebenone, a form of coenzyme Q, may be helpful, there are few data to support this contention, and other “cocktails” of various vitamins and enzymes have not been found to successfully treat or prevent the condition. The diagnosis of LHON should be considered in any patient, young or old, who experiences painless, relatively rapid (too slow for optic neuritis and too fast for most compressive lesions) visual loss in one or both eyes in association with normal-appearing optic discs what appears to be minimal disc swelling (i.e., hyperemic disc) without hemorrhages or exudates.
INSIDIOUS VISUAL LOSS WITH OR WITHOUT OPTIC DISC SWELLING The causes of optic nerve–related insidious visual loss depend in large part on whether the visual loss is unilateral or bilateral. If visual loss is unilateral, a compressive lesion is most likely to be the cause; if the loss is bilateral, a compressive process is still likely, but both toxic and metabolic causes must be considered, as must infiltrative processes.
Compressive Optic Neuropathy A compressive optic neuropathy may be unilateral or bilateral.13 When it is unilateral, the optic disc may be swollen or normal in appearance. When it is swollen, the mass is almost always located within the anterior or middle portion of the orbit (Fig. 23–11). When the disc appears normal, the lesion is located in the posterior orbit, in the optic canal, or intracranially. When the visual loss is bilateral, the lesion is almost always intracranial or in the paranasal sinuses, and the optic discs appear normal, at least initially. Regardless of their location, lesions that compress the optic nerve can produce any level of visual loss and any type of field defect. In most cases, color vision is diminished in the affected eye, and the severity of color deficit may be more than expected in comparison with the severity of visual loss. A relative afferent pupillary defect is present in every patient with a unilateral process. Patients suspected of having a compressive optic neuropathy require neuroimaging. When an orbital or paranasal sinus process is suspected, computed tomographic scanning is the optimum imaging modality, whereas intracranial lesions are best detected with magnetic resonance imaging. The treatment of a compressive lesion of the optic nerve depends on the nature
chapter 23 optic neuropathies
■
291
Figure 23–11.
Compressive anterior optic neuropathy. Left, Optic disc is moderately swollen. Note absence of hemorrhages. Right, Computed tomographic scan shows intraconal mass. Note compression and medial deviation of the optic nerve by the mass.
of the lesion, as well as its location. Whether a patient improves after successful elimination of the compression process depends in part on how long symptoms have been present and the severity of visual dysfunction before treatment.
toxicity, which can cause complete blindness. The visual loss in patients with toxic or deficiency optic neuropathies is virtually always accompanied by bilateral severe loss of color vision, bilateral central or cecocentral scotomas, and optic discs that appear normal or perhaps slightly swollen (Fig. 23–13).
Infiltrative Optic Neuropathy Like compressive optic neuropathies, infiltrative optic neuropathies may be unilateral or bilateral.13 Any level of visual loss can occur, and any type of visual field defect can be present. As with other optic neuropathies, a relative afferent pupillary defect is always present in unilateral cases. Patients with an infiltrative optic neuropathy may have an optic disc that is truly swollen, a disc that appears swollen but that is actually infiltrated with the underlying lesion, or a normal disc. Disorders most likely to produce an infiltrative optic neuropathy include reticuloendothelial disorders, such as leukemia and lymphoma; inflammatory conditions, such as sarcoidosis; and metastatic tumors, particularly carcinomas (Fig. 23–12). The diagnosis of an infiltrative optic neuropathy may be difficult; however, in many cases, magnetic resonance imaging reveals diffuse or focal enlargement and enhancement of the affected nerve. Both treatment and prognosis depend on the nature and severity of the process.
Toxic and Deficiency Optic Neuropathies These conditions are almost always bilateral, although one eye may be affected days to weeks before the other.14 The loss of vision occurs slowly, usually over one month or more. The eventual nadir is usually about 20/400, except with methanol
■
Figure 23–12.
Infiltrative optic neuropathy. Optic disc has a fluffy appearance, which is consistent with infiltration, rather than true swelling.
292
■
Section
IV
Neuro-ophthalmology
Figure 23–13.
Toxic optic neuropathy in a patient taking ethambutol and isoniazid for pulmonary tuberculosis. Both right (left) and left (right) optic discs appear slightly swollen.
Hemorrhages and exudates are almost never seen. Because of the bilaterality of the process, a relative afferent pupillary defect is almost never present. The substances that can cause a toxic optic neuropathy include both common and uncommon medications (Table 23–1). Nutritional optic neuropathies occur in a number of settings. The most common is chronic alcohol abuse; others include starvation, malabsorption syndromes, fad diets, incorrect vegetarianism, and depression (resulting in a poor diet).15 The diagnosis generally becomes apparent with a careful history of medications being taken, exposures to potential toxins, and eating habits. The treatment of toxic or nutritional optic neuropathies is to eliminate the toxin or replace the nutrient. Most, but not all, patients experience improvement; the degree of improvement is related to the duration of symptoms and the severity of visual loss before institution of treatment. The main differential diagnosis of toxic and nutritional optic neuropathies is LHON; however, LHON usually progresses more rapidly than most nutritional or toxic optic neuropathies and does not improve at all when toxic exposure is eliminated or the nutritional deficiency is corrected.
OTHER OPTIC NEUROPATHIES Traumatic Optic Neuropathy The diagnosis of traumatic optic neuropathy is usually quite easy to establish.16 It usually occurs in the setting of blunt head trauma, in which there is often a period of loss of consciousness. The majority of cases appear to result from damage to the optic nerve within the optic canal, where traumatic hemorrhage and swelling produce severe damage to the optic nerve
T A B L E 23–1. Some Reported Causes of Toxic Optic Neuropathy Alcohol Amiodarone Amoproxan Caramiphen Catha edulis (plant) Chlorambucil Chloramphenicol Chlorpropamide Cisplatin Clioquinol Clomiphene Cyclosporine Deferoxamine Dideoxyinosine Disulfiram Ethambutol Ethchlorvynol Ethylene glycol Toxic optic neuropathies
5-Fluorouracil Glue Hexachlorophene Hydroxyquinolones Isoniazid Methanol Methimazole Methylbromide Minoxidil Organophosphates Penicillamine Phenobarbital Streptomycin Tamoxifen Tobacco Tolbutamide Toluene Vincristine
and its blood supply. The severity of visual loss is variable, from mild loss of visual acuity to no light perception. Although some physicians advocate treatment with systemic corticosteroids and others advocate decompression of the optic nerve within the optic canal, there is no evidence that any intervention is better than the natural history of the process.
Radiation-Induced Optic Neuropathy This condition occurs in 10% to 15% of cases in which the optic nerves have received at least 5000 cGy.17 The only exceptions
chapter 23 optic neuropathies
K E Y
■
293
P O I N T S
●
Optic neuropathies can be categorized as those that are unassociated with visual loss, those that are associated with sudden visual loss, and those that are associated with subacute or chronic visual loss.
●
In patients with acute optic neuropathies, the optic discs are swollen or appear normal, regardless of the cause.
●
In patients with chronic optic neuropathies, the optic discs are pale, regardless of the cause.
●
Acute papilledema is never associated with visual loss unless the causative lesion damages the intracranial visual sensory pathway or there are associated hemorrhages, exudates, or edema in the macula.
●
The most common optic neuropathies that cause sudden visual loss are optic neuritis, ION, and LHON.
●
The most common optic neuropathies that cause subacute or chronic visual loss are compressive, toxic, and hereditary optic neuropathies.
Figure 23–14.
Neuroimaging of radiation-induced optic neuropathy. Magnetic resonance image shows enlargement and enhancement of the left optic nerve.
Suggested Reading
appear to be patients with diabetes mellitus and patients receiving chemotherapy for cancer at the time of the irradiation, in which case the condition can occur with smaller doses. A transient type of optic neuropathy can occur during the irradiation itself and is believed to be related to acute swelling of the nerve. This form of optic neuropathy is usually self-limited, and treatment consists of systemic corticosteroids. Most cases of radiation-induced optic neuropathy, however, occur 1 to 8 years after irradiation and consist of a relatively rapid progression of visual loss in one or both eyes, usually associated with an initially normal-appearing optic disc that gradually becomes pale. Neuroimaging in such cases may reveal enhancement and enlargement of one or both optic nerves, but this is not a universal finding (Fig. 23–14). There is no proved treatment for radiation-induced optic neuropathy. Corticosteroids, anticoagulants, and hyperbaric oxygen all have their supporters, but none of these treatments has proved successful in the majority of cases.
CONCLUSION The most important issues in dealing with a patient with an optic neuropathy are the onset of the visual loss; whether there has been any progression and, if so, the speed of the loss of vision; whether the process is unilateral or bilateral; and whether there is swelling of the optic disc. A complete history, a thorough examination, and appropriate ancillary studies help identify the cause of an optic neuropathy in almost 100% of cases.
Burde RM, Savino PJ, Trobe JD, eds: Optic neuropathies. In: Clinical Decisions in Neuro-ophthalmology, 3rd ed. St. Louis: CV Mosby, 2002, pp 27-58. Kline LB: Optic Nerve Disorders. San Francisco: American Academy of Ophthalmology, 1996. Miller NR, Newman NJ: The Essentials: Walsh & Hoyt’s Clinical Neuro-ophthalmology. Baltimore: Williams & Wilkins, 1999, pp 134-322. Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005.
References 1. Friedman DI: Papilledema. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 237-292. 2. Smith CH: Optic neuritis. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 293-348. 3. Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis. Arch Ophthalmol 2003; 121:944-949. 4. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000; 343:898-904. 5. Williams N, Miller NR: Neuroretinitis. In Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular Infection and Immunology. St. Louis: CV Mosby, 1996, pp 601-608. 6. Arnold A: Ischemic optic neuropathy. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuroophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 349-384.
294
Section
IV
Neuro-ophthalmology
7. Sadda SR, Nee M, Miller NR, et al: Clinical spectrum of posterior ischemic optic neuropathy. Am J Ophthalmol 2001; 132:743-750. 8. Newman NJ, Scherer R, Langenberg P, et al: The fellow eye in NAION: report from the ischemic optic neuropathy decompression trial follow-up study. Am J Ophthalmol 2002; 134:317-328. 9. Kalyani SD, Miller NR, Dong LM, et al: Incidence of and risk factors for perioperative optic neuropathy following cardiac surgery. Ann Thorac Surg 2004; 78:34-37. 10. Chang S-H, Miller NR: The incidence of visual loss due to perioperative ischemic optic neuropathy associated with spine surgery: The Johns Hopkins Hospital experience. Spine 2005; 30:1299-1302. 11. Newman NJ: Hereditary optic neuropathies. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 465-502. 12. Kerrison JB, Miller NR, Hsu F-C, et al: A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 2000; 130:803-812.
13. Volpe NJ: Compressive and infiltrative optic neuropathies. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 385-430. 14. Phillips PH: Toxic and deficiency optic neuropathies. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 447-464. 15. Hsu C, Miller NR, Wray M: Optic neuropathy from folic acid deficiency without alcohol abuse. Ophthalmologica 2002; 216:65-67. 16. Steinsapir K, Goldberg RA: Traumatic optic neuropathy. In Miller NR, Newman NJ, Biousse V, et al, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed, vol 1. Baltimore: Lippincott Williams & Wilkins, 2005, pp 431-446. 17. Lessell S: Friendly fire: neurogenic visual loss from radiation therapy. J Neuroophthalmol 2004; 24:243-250.
CHAPTER
24
RETINAL DISEASE ●
●
●
●
Eoin O’Sullivan and Elizabeth Graham
The retina reflects many of the pathophysiological processes that occur in the central nervous system (CNS). Indeed the retinal appearances may be diagnostic but, conversely, can be nonspecific; for example, pigmentary retinal changes are part of the diagnostic criteria for Kearns-Sayre syndrome but are also present in many other diseases. Furthermore, in other diseases, the retina may appear clinically normal, but psychophysical and electrophysiological testing reveal abnormalities. In this chapter, both neurological diseases with retinal involvement that patients would tend to present with to a neurologist, as well as diseases that patients would tend to present with to an ophthalmologist but that have neurological involvement, are discussed. Disorders of the choroid that might be apparent on funduscopy are also discussed. The following is a brief description of the embryology, anatomy, and physiology of the retina, highlighting its similarities to the CNS. There is also an explanation of some of the ophthalmological terms that are used in this chapter. The eyeball consists of three layers, which, starting from the outside, are a fibrous layer, a vascular pigmented layer, and a nervous layer. The fibrous layer consists of the sclera, which makes up the posterior five sixths of the eyeball and is opaque, and the cornea, which forms the anterior one sixth and is transparent. The vascular pigmented layer is also known as the uveal tract and consists of the choroid, which is a very vascular layer; the ciliary body; and the iris. The retina constitutes the nervous layer. The cavity behind the cornea and in front of the iris is the anterior chamber, and it is filled with aqueous humor. The vitreous humor fills the eyeball behind the lens. Embryologically, the ectoderm that is derived from the neural tube gives rise to the retina, the fibers of the optic nerve, and the smooth muscle of the iris. The choroid is derived from mesenchyme and is homologous in its embryonic origin with the pia mater and arachnoid tissue. The photoreceptors, consisting of rod and cone cells, are located near the outer surface of the retina. In the process of phototransduction, light energy is absorbed by specialized visual pigments within the outer segments of the photoreceptors, which results in hyperpolarization and the generation of an electrical signal. After photoreception, the signal is conducted to the bipolar cells in the inner nuclear layer, which in turn transmit their signals to the ganglion cells. The axons of
the ganglion cells are collected on the inner surface of the retina and form the optic nerve. There are many interneuronal connections and a variety of neurotransmitters and neuromodulators such as acetylcholine, γ-amino butyric acid (GABA), glutamate, and dopamine, which are involved in the signal processing. At the extreme outer layer of the retina is the retinal pigment epithelium, which is in contact with the outer segments of the photoreceptors. This layer is in contact with Bruch’s membrane, which is the inner layer of the choroid. The choroid provides the blood supply for the outer layers of the retina, including the photoreceptors, whereas the inner layers are supplied by branches of the central retinal artery. The macula lutea is a yellowish, oval area located at the center of the posterior part of the retina. It has a central depression, the fovea centralis. Uveitis, inflammation of the uveal tract, can occur in association with neurological disease. In this chapter, the classification recommended by the Standardization of Uveitis Nomenclature Working Group is used.1 In this classification, the primary site of inflammation in anterior uveitis is the anterior chamber. For intermediate uveitis, it is the vitreous humor. The primary site of inflammation in posterior uveitis can be the retina or choroid. Panuveitis is used when there is no predominant site of inflammation, but inflammation occurs in the anterior chamber, vitreous humor, and retina and/or choroid.
UVEOMENINGEAL SYNDROMES The uveomeningeal syndromes are a heterogeneous group of disorders that share involvement of the uveal tract (which comprises the iris, the ciliary body, and the choroid), retina, and meninges. Causes of this syndrome include infectious, inflammatory, and neoplastic disorders. The infectious and neoplastic causes are discussed elsewhere; in this section, syndromes caused by inflammatory disease are discussed.
Sarcoidosis Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can affect the eye and the CNS, as well as the lungs, skin, and other organs. Of all patients with sarcoidosis, 25% to 60% have ocular involvement, which may be
295
296
Section
IV
Neuro-ophthalmology
the manifesting sign. Sarcoidosis can affect most ocular tissues, but the most common ocular manifestations are uveitis and conjunctival nodules. Uveitis can occur in about 30% of patients before nonocular signs.2 A 10-year follow-up study of patients with uveitis caused by sarcoidosis or presumed sarcoidosis revealed that over this period, the disease spread most often to the CNS.3 Posterior segment involvement is frequently associated with neurological disease.4,5 It may be more common in white patients, especially elderly women,2 although this has not been confirmed by all studies.6 The optic nerve may become swollen because of intraocular inflammation, when visual acuity is usually preserved, or it may be involved either directly by granulomas or as a result of meningeal changes, when loss of visual acuity and field result from compressive optic neuropathy. The classic sign of retinal involvement by sarcoidosis is retinal periphlebitis (Fig. 24–1),7-9 which may be described as similar to candle wax dripping. Other vascular changes include retinal hemorrhages, vein occlusions, neovascularization, and possibly retinal arteriolitis with aneurysm or ectasia formation.10 Focal subretinal lesions have been described, but these do not appear to affect vision.9 Confluent choroidal infiltrates have been described.11 Appearances similar to that of a multifocal choroiditis (Fig. 24–2),12,13 and a serpiginous choroidopathy have been described.14 Multiple sclerosis may include a similar ocular inflammatory manifestation, but the choroid is not involved.
Behçet’s Disease Behçet’s disease is characterized by recurrent episodes of orogenital aphthae and by systemic and retinal venous thrombosis. It remains a clinical diagnosis, and diagnostic criteria have been published.15 The CNS manifestations of Behçet’s disease can be categorized into parenchymal and nonparenchymal involvement (neurovascular Behçet’s disease). Parenchymal CNS manifestations include brainstem and hemisphere
■
Figure 24–1. Retinal periphlebitis.
involvement, spinal cord lesions, and meningoencephalitis. Nonparenchymal involvement includes dural sinus thrombosis, arterial occlusion, and arterial aneurysms. These categories have different clinical and prognostic properties.16 The ocular manifestations in the parenchymal category include optic neuritis and ischemic optic neuropathy.17-19 Papilledema caused by intracranial hypertension secondary to dural sinus thrombosis occurs in neurovascular Behçet’s disease20,21 and can result in significant visual loss. Intracranial hypertension can, however, occur in the absence of venous sinus thrombosis or meningitis.18 Inflammatory eye disease occurs in approximately 70% of all patients who may have additional neurological or neuroophthalmological disease. The inflammation usually occurs after the onset of oral aphthosis, but the delay between the two may be as long as 14 years.22 In approximately 10% of patients, intraocular inflammation is the manifesting feature,23 and in rare cases, neither oral nor genital ulcers may occur at all.24 Usually the involvement is bilateral. The main ocular finding is panuveitis, although there may be differing degrees of anterior and posterior segment involvement. The anterior uveitis may be so severe that the inflammatory cells precipitate in the inferior portion of the anterior chamber, forming a hypopyon. Retinal vein occlusion is the most characteristic fundal sign, but others include retinal perivasculitis and retinal infiltrates. The perivasculitis involves mainly the veins and less frequently the arteries. The retinal infiltrates are collections of lymphocytes in the superficial retina and are pathognomonic of Behçet’s disease (Fig. 24–3). They resolve spontaneously and carry no visual morbidity. However, recurrent retinal vein occlusions can result in total attenuation of all vessels and consequent optic atrophy. Macular edema may also cause visual loss. Unfortunately, the visual prognosis is poor in spite of the development of new immunosuppressive therapies. Up to 15% of patients are unresponsive to these therapies,25 and the disease may remain active for many years.
■
Figure 24–2. Choroidal lesions in sarcoidosis.
chapter 24 retinal disease
■
Figure 24–3. A peripapillary retinal infiltrate and a vein
■
Vogt-Koyanagi-Harada (VKH) disease is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin of unknown etiology. VKH disease usually affects darkly pigmented Asian, American Indian, Hispanic, or African-American adults. Like Behçet’s disease, it is diagnosed on clinical findings. Diagnosis can be difficult because there are no specific tests and the clinical features are dependent on the stage of the disease at which the patient is examined. Diagnostic criteria have been published.26 One of the following neurological features has to be present for the diagnosis of VKH: meningismus, tinnitus or cerebrospinal pleocytosis. The ocular features have been divided into early and late manifestations of the disease. In the early manifestation, the retinal and choroidal features are mainly in the form of serous retinal detachments. In the late manifestations, choroidal depigmentation that results in a mottled “sunset glow” appearance, nummular chorioretinal depigmented scars, and retinal pigment epithelium clumping and/or migration26 may be present (Fig. 24–4). Recurrent or chronic uveitis also occurs in the late stage of VKH. The criteria include the presence of bilateral ocular involvement. The integumentary findings are alopecia, poliosis, or vitiligo. A further neurological association with VKH is Guillain-Barré syndrome. Three patients who developed VKH within 3 months of having Guillain-Barré syndrome have been reported.27
Figure 24–4. Pigmentary changes in Vogt-Koyanagi-Harada disease.
occlusion superior to the optic disc.
Vogt-Koyanagi-Harada Disease
In rare cases, venulitis develops. Choroidal involvement can also occur. A postmortem study of patients with systemic lupus erythematosus affecting the brain and eye demonstrated vasculitis in the brain and the choroidal vessels.30 A number of retinal arterioles were occluded with thrombus, but there was no evidence of inflammation of the retinal vessels. Emboli from a diseased heart valve or deposition of immune complexes may have caused the occlusion. A number of the vasculitides affect the retina. This, however, is not always caused primarily by the vasculitis, but it can result from other complications of the disease, such as hypertension. The diseases are discussed according to the size of vessel they affect.
RHEUMATOLOGICAL DISEASES AND THE SYSTEMIC VASCULITIDES Rheumatoid arthritis is associated with corneal and sclera changes but not usually retinal ones. Retinal involvement is, however, a common ocular feature of systemic lupus erythematosus. Indeed, the presence of ocular features may mirror disease activity elsewhere.28,29 Retinal arteriolar occlusion may occur, and multiple cotton-wool spots may be seen (Fig. 24–5).
297
■
Figure 24–5. Multiple cotton-wool spots in systemic lupus erythematosus.
298
Section
IV
Neuro-ophthalmology
Large Artery Giant cell arteritis is a necrotizing vasculitis targeting large and medium-sized arteries and affects mainly white patients older than 50 years. Anterior ischemic neuropathy is the most common cause of visual loss in giant cell arteritis, but patients can suffer from either central retinal artery occlusions or, less commonly, branch retinal artery occlusions. Compromised blood flow to the retina may result in signs of ischemia such as cotton-wool spots and hemorrhages. Posture can also affect the ischemia in that vision may be reduced in the upright position, in relation to lying down.31 Poor perfusion of the choroid may result in reduced vision, which can be reversible, but permanent infarction can occur (Fig. 24–6). Treatment is aimed primarily at preventing both visual loss in the second eye and the development of stroke. Takayasu’s disease is another disease of the large vessels. Retinal disease is present in fewer than 50% of patients with Takayasu’s disease.32 The retinal changes include vessel dilation, tortuosity of vessels, arteriovenous anastomoses, and hemorrhages. In many patients, hypertension is probably the major cause of retinal changes; in some patients, however, the changes may result from reduced flow to the retinal circulation (i.e., a hypotensive retinopathy).32
Medium-Sized Artery Ocular involvement occurs in 10% to 20% of patients with polyarteritis nodosa. Retinal artery occlusion, ischemic retinopathy, exudative retinal detachment,33 and choroidal infarcts have been described.34 Kawasaki’s disease tends not to affect the retina, although one postmortem study did yield evidence of retinal ischemia.35
Medium-Sized and Small Vessels Wegener’s granulomatosis is characterized by a systemic vasculitis and necrotizing granulomatous lesions that may be
■
Figure 24–6. Choroidal insufficiency in giant cell arteritis.
found in the respiratory tract, kidney, orbit, and brain. Between 30% and 50% of patients with Wegener’s granulomatosis have neurological involvement.36,37 The patterns of neurological involvement have been described as granulomatosis invasion of the orbit, granulomas of the brain and meninges, and vasculitis of the nervous system.36 The orbital involvement usually is from the extension of disease in the paranasal sinuses. Orbital involvement may be the initial sign of the disease, manifesting with orbital pain, rapidly progressing proptosis, and limited eye movements with associated granulomatosis infiltration of adjacent structures. Cranial nerves may also be involved; the optic nerve, the abducens nerve, and the facial nerve are the most commonly affected.37 Retinal and choroidal involvement is rare but may manifest as retinitis, vein occlusion, or an intermediate uveitis.38 Some of these changes, however, may have been secondary to hypertension or cytomegalovirus–associated retinitis. A number of patients taking cyclophosphamide for Wegener’s granulomatosis have developed cytomegalovirusassociated retinitis (Fig. 24–7).39-41 In patients with the limited form of Wegener’s granulomatosis, the neuro-opthalmological features may, again, be the earliest feature of the disease.42 A similar pattern of neuro-ophthalmological involvement is seen, the orbit being affected more frequently than the retina.43 Ocular involvement in the Churg-Strauss syndrome can be in the form of either chronic orbital pseudotumor or ischemic vasculitis. The retinal manifestations of the latter group include retinal artery occlusions.44 Cotton-wool spots in the retina have been described in a patient with microscopic polyangiitis. The patient also had a very severe uveitis that resulted in a hypopyon.45
MULTIPLE SCLEROSIS Manifestations of multiple sclerosis in the eye other than optic neuritis include uveitis and retinal changes, such as periphlebitis or sheathing or cuffing of the retinal veins by lymphocytes and plasma cells.46-49 This may occur in isolation or as part of an intermediate uveitis. Periphlebitis may occur in up
■
Figure 24–7. Cytomegalovirus-associated retinitis.
chapter 24 retinal disease
■
299
Figure 24–8. Vascular changes in multiple sclerosis seen on fluorescein angiography.
to 36% of patients with multiple sclerosis50,51 and is usually asymptomatic. These changes are often in the peripheral retina and so cannot be viewed through a direct ophthalmoscope trained on an undilated pupil. Indeed, the changes may be visible only on fluorescein angiography (Fig. 24–8).52 Focal perivenous hemorrhage can also occur. The presence of vascular changes and/or ocular inflammation in patients with optic neuritis is associated with a greater risk of developing multiple sclerosis.52,53 It has been suggested that periphlebitis is a marker for disease activity,50,54 but this has not been confirmed.55 Vascular sheathing can occur in other diseases such as sarcoidosis, systemic lupus erythematosus, Wegener’s granulomatosis, and Behçet’s disease.56 Multiple sclerosis can be differentiated from sarcoidosis inasmuch as it is not associated with choroidal lesions.
Uveitis Studies of records of patients at multiple sclerosis clinics have revealed that 1% to 2% have uveitis, which is a higher frequency than in the general population.57,58 Asymptomatic uveitis has been found in a range from none59 to 18%60 of patients with multiple sclerosis. This range probably reflects the difference in disease activity of the patients in the studies. All types of uveitis are observed; one form of intermediate uveitis, pars planitis, is probably the most common,57,61,62 but this has not been found in all studies.59 There does not seem to be any correlation between the type of multiple sclerosis and uveitis or between the degree of neurological disability and the type of uveitis,57,59 although the presence of optic atrophy may be protective against uveitis.60
■
Figure 24–9. Neuroretinitis.
culitis with associated neovascularization63,65 can also result in visual loss. The features that suggest a diagnosis of uveitis rather than optic neuritis include photophobia, floaters, redness of the eye, and the absence of a relative afferent pupillary deficit. Nevertheless, many patients with multiple sclerosis–associated uveitis retain useful vision if it is treated appropriately.62
Neuroretinitis Neuroretinitis is a descriptive term for optic disc swelling and macular exudates (Fig. 24–9) that classically results from infective causes (discussed in the next section). One study has suggested that the presence of neuroretinitis indicated that the patient did not have demyelinating disease.66 Thus, neuroretinitis should be differentiated from cases of optic neuritis that manifest with papillitis. However, in a retrospective review of 35 patients with neuroretinitis, 3 patients were found to have multiple sclerosis, although they also had received interferon β therapy.67
INFECTIONS A number of various infectious agents can cause both retinal and neurological disease. Some, however, usually do so only in the presence of immunosuppression, most often caused by human immunodeficiency virus (HIV) infection. This section therefore deals with infections both in immunocompetent individuals and in those with HIV infection.
Visual Loss In patients with multiple sclerosis and uveitis, visual loss cannot be assumed to result from optic neuritis, because the complications of uveitis such as macular edema63,64 and retinal vas-
Infectious Causes of Neuroretinitis As discussed, the presence of a swollen disc and macular exudates in a starlike pattern is known as neuroretinitis and is
300
Section
IV
Neuro-ophthalmology
classically caused by infection. However, other causes such as hypertension can result in the same clinical picture. A number of infections are classically associated with neuroretinitis and can have neurological associations. These include cat-scratch disease, Lyme disease, and syphilis. In very rare cases, toxoplasmosis manifests this appearance.68 The ocular features of these other conditions are discussed as follows, except for toxoplasmosis, which is discussed elsewhere. Cat scratch fever is caused by Bartonella henselae. There may be an associated uveitis, and the other fundal appearances include discrete retinal or choroidal lesions, which are more common than in classic neuroretinitis.69 Lyme disease is a spirochetal infection that results from tickborne transmission of Borrelia burgdorferi. Conjunctivitis is the most common ocular manifestation of early Lyme disease and occurs in approximately 10% of cases. Uveitis is a relatively rare manifestation of Lyme disease, but it may occur in the later stages. Vitritis, choroiditis optic neuritis, and motility problems have also been described.70-74 Exudative detachment associated with the choroiditis74 has been reported, as has a case of retinal vasculitis.75 Syphilis is caused by Treponema pallidum. Between 1995 and 2003, the increase in the incidence of syphilis in the United Kingdom has been more than 10-fold.76 Ocular disease typically occurs in secondary syphilis but is also observed in tertiary syphilis. Uveitis is the most common ocular manifestation in both these stages of the disease.77,78 The retinal changes are essentially similar in both secondary and tertiary syphilis. In keeping with its moniker, the “great imitator,” the disease can affect all structures of the eye. The combination of good visual acuity, reasonable visual fields, mild panuveitis, swollen disc, and afferent papillary defect is highly suggestive of syphilitic infection. In addition to neuroretinitis, the retinal findings include chorioretinitis, retinal vasculitis, serous retinal detachment, and necrotizing retinitis (Fig. 24–10). The necrotizing retinitis may be such that it is difficult to clinically distinguish from acute retinal necrosis (ARN) (discussed later in this chapter). The diagnosis is established by the presence of other systemic
■
Figure 24–10. Peripheral retinal changes in syphilis.
features.79 The association with HIV is discussed elsewhere in this chapter.
Tuberculosis Choroidal involvement is probably the most common form of ocular involvement in tuberculosis. Usually it is in the form of choroidal tubercles that are white, gray, or yellow lesions (Fig. 24–11). The patient neither has to be seriously unwell nor has to have miliary tuberculosis for ocular disease to be present.80,81 The ocular disease may manifest many years after the tuberculosis has been found and treated elsewhere in the body.82 Other manifestations include multifocal choroiditis or serpiginouslike choroiditis. Retinal involvement can result from either choroidal extension or bloodborne spread. Retinal involvement can be either as tubercles or as a diffuse retinitis. Neovascularization and retinal vasculitis can also occur.83,84
Whipple’s Disease Whipple’s disease is characterized by arthralgia, abdominal pain, and weight loss. The causative organism is Tropheryma whippelii. Oculomasticatory myorrhythmia is believed to be pathognomonic, but fundal changes also occur. These include vitreous opacities, diffuse chorioretinal inflammation with capillary involvement, and retinitis.85-89
Herpetic Infections Herpesviruses cause ARN. The clinical characteristics for the diagnosis are focal, well-demarcated areas of retinal necrosis, which progresses in a rapid and circumferential manner; occlusive vasculopathy; and a prominent inflammatory reaction (Fig. 24–12).90 ARN may occur in isolation or in association with other forms of herpes infection, such as herpes zoster ophthalmicus. ARN may also be present in association with either
■
Figure 24–11. Choroidal changes in tuberculosis.
chapter 24 retinal disease
301
An autopsy study of eyes from 235 patients with HIV infection revealed intraocular tuberculosis in only two eyes.98
Retinal Manifestations of HIV Infection
■
Figure 24–12. Areas of retinal necrosis in acute retinal
Microvasculopathy is the most common ocular manifestation of HIV infection, being present in 40% to 60% of patients,99 and appears to be inversely related to the CD4 count.100 In the retina, it is most frequently represented by cotton-wool spots, which are usually asymptomatic and resolve after about 6 weeks. Hemorrhages may occur, particularly in patients with low platelet counts or diabetes. They are a response to the HIV infection. Less commonly, patients may develop macular ischemia,101 which is also probably caused by the primary infection. Large retinal vessel disease has been described,102 but this is rare. Progressive visual loss has been described in a patient with HIV infection who had a clinically normal retina but abnormal photoreceptor function on electrophysiological testing.103 This process continued even when the viral load was undetectable.
necrosis.
Cytomegalovirus-Associated Retinitis meningitis or encephalitis. It appears that encephalitis, either concurrent or past, is more likely to be associated with herpes simplex virus type 1 infection, whereas herpes simplex virus type 2 is more likely to be involved in the presence of meningitis, whether past or concurrent.91 Genotypical analysis in two patients who had ARN after encephalitis revealed identical strains of herpes simplex virus type 1 in the brain and eye, suggestive of brain-to-eye transmission of the infection in these patients.92 ARN may occur concurrently with encephalitis or up to 20 years later.93 A case of cerebral vasculitis in which ARN was the only manifestation of any herpetic infection has been reported.94
Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis can occur months to years after measles infection. It usually affects children or young adults, but a case in a 49-year-old man has been described.95 Ocular involvement occurs in about 50% of cases and most often develops at the same time as neurological symptoms. Chorioretinitis with subsequent scarring is the most common retinal appearance. In rare cases, the ocular signs precede the neurological ones.96
Human Immunodeficiency Virus The retinal manifestations of HIV can be subdivided into those resulting primarily from the HIV infection, from associated infections, and from malignancies. The incidence of many of these conditions appears to have decreased since the introduction of highly active antiretroviral therapy.97 Diagnosis can be difficult because the ocular signs may differ from those in an immunocompetent individual, and there may be two concurrent infections. Also interesting is that although HIV has contributed to the increase in incidence of tuberculosis, this may not have been mirrored by an increase of ocular tuberculosis.
Cytomegalovirus-associated retinitis is the commonest ocular infection in patients with acquired immunodeficiency syndrome (Fig. 24–7). However, its incidence has dropped since the introduction of highly active antiretroviral therapy.104 It rarely occurs in patients with a CD4 count lower than 50.100 Cytomegalovirus-associated retinitis occurs mainly in patients with HIV infection but can occur in patients who are immunocompromised for other reasons.41,105 There are two main forms of clinical presentation: a fulminant form and an indolent form. The fulminant form is characterized by confluent retinal necrosis with hemorrhage that in most cases develops in the posterior retina, whereas the indolent form has a more granular form. Up to 15% of patients with cytomegalovirus-associated retinitis are asymptomatic; therefore, screening is required for patients with HIV infection who have low CD4 counts and positive cytomegalovirus serological profiles.
Herpetic Infections Associated with HIV Infection Necrotizing herpetic retinopathy represents a continuum of posterior segment inflammation caused by herpesviruses. The best recognized are ARN and progressive outer retinal necrosis. Usually ARN occurs in immunocompetent patients or in patients with HIV infection but minimal immune dysfunction; progressive outer retinal necrosis occurs in patients with HIV and significant immune compromise. Progressive outer retinal necrosis consists of a retinitis, often in the posterior pole, that is not usually associated with an inflammatory reaction. However, the two diseases can occur simultaneously, one eye having ARN and the other progressive outer retinal necrosis.106 Both necessitate intraocular and systemic antiviral treatment.
Syphilis in HIV Infection Ocular syphilis has been discussed elsewhere, but it has a number of significant features in relation to HIV infection. It can develop when CD4 counts are higher than 200 and can be the manifesting sign of HIV infection. The ocular findings are similar to those in patients without HIV infection, but a rare
302
Section
IV
Neuro-ophthalmology
appearance, believed to be more common in patients infected with both HIV and T. pallidum, has been described. This is a placoid chorioretinopathy, consisting of large, yellowish placoid lesions with faded centers in the region of the macula and optic disc.107 There are two important features about syphilis infections in HIV-seropositive individuals. First, it can mimic the appearance of other ocular conditions such as cytomegalovirusassociated retinitis, making diagnosis and treatment difficult. Second, ocular syphilis is associated with CNS involvement in 85% to 100% of patients with HIV infection, as opposed to 35% to 40% of HIV-seronegative patients.108,109
Toxoplasmosis in HIV Infection Toxoplasmosis retinitis can be similar to cytomegalovirus-associated retinitis, but there is usually more inflammation, and it is less likely to be associated with hemorrhage. The classic appearance in an immunocompetent patient is that of a fluffy white chorioretinal lesion in association with an area of scarring in one eye. However, in immunosuppressed patients, it can be bilateral, multifocal, and not associated with an old scar (Fig. 24–13). All of these features are suggestive of a primary infection rather than a reactivation of the condition. More than 50% of patients with ocular toxoplasmosis may have simultaneous toxoplasmosis cerebritis.99 Other fundal appearances include choroiditis, numerous scattered white lesions (a “miliary” pattern),110 a diffuse necrotizing retinitis,111,112 and punctate lesions in the outer retina.113
Malignancies Associated with HIV Infection In patients with HIV infection, ocular non-Hodgkin lymphoma is usually associated with CNS and systemic involvement. The fundal features include necrotizing retinitis, choroidal infiltrates, and vitritis, but these appearances can also be as a result of infection by syphilis, toxoplasmosis, or viruses.114-118 Therefore, the diagnosis must be considered if the retinitis is
unresponsive to antiviral, antisyphylis, and antitoxoplasmosis treatment.
Fungal Infections A number of fungi can affect the brain and the retina. These are most often present in patients who are immunocompromised. The incidence of ocular fungal infections, such as Pneumocystis and Cryptococcus organisms, in HIV-seropositive patients appears to have decreased since the introduction of highly active antiretroviral therapy.97
Mucormycosis Mucormycosis is an acute fungal infection that is rapidly invasive and carries a high mortality rate. Diabetes is a common predisposing factor. There are a number of clinical forms of mucormycosis, the most common being rhino-orbito-cerebral. This form affects the eye, and a necrotic eschar of the nose or hard palate is a characteristic sign. Although orbital cellulitis is the most common form of ocular involvement, serous retinal detachment and retinitis119 and choroidal ischemia have been described.120,121
Candida Albicans A fluffy white chorioretinal lesion with overlying vitreous haze is the typical lesion of C. albicans–related endophthalmitis. The infection may extend into the vitreous humor, causing cotton ball–like opacities characteristic of candidal infection. Progressive retinochoroiditis with satellite lesions may also occur.
Cryptococcus Cryptococcal infection occurs mainly in patients who are HIV-seropositive. Up to 25% of patients with cryptococcal meningitis have neuro-ophthalmological lesions, which makes it the most common cause of acquired immunodeficiency syndrome–related neuro-ophthalmological lesions.99 Cryptococcal choroiditis is, however, rare. It may be may be multifocal, solitary, or confluent (Fig. 24–14).122 The lesions may initially be asymptomatic. Progressive visual loss may occur as a result of papilledema and also fungal optic nerve sheath invasion.123
Pneumocystis Carinii One of the ocular features of P. carinii is choroiditis.124 It is classically bilateral and multifocal. The lesions are distinctive, being yellowish and well demarcated. They are slowly progressive, and usually vision is unaffected. There is not usually any associated ocular inflammation.124,125 In HIV-seropositive patients with presumed P. carinii choroidopathy, the majority had used inhaled pentamidine as prophylaxis against recurrent Pneumocystis-related pneumonia.125
MITOCHONDRIAL DISEASES ■
Figure 24–13. Toxoplasmosis in a patient with human immunodeficiency virus infection.
Pigmentary changes in the retina may occur in patients with mitochondrial disease. These can take a variety of forms and
chapter 24 retinal disease
■
Figure 24–14. Cryptococcal choroiditis with a swollen optic disc.
include appearances that have been described as pigment clumping, atrophy, salt-and-pepper retinopathy, and appearances of classic retinitis pigmentosa (Fig. 24–15). Involvement of the macula can occur, as can vascular attenuation. The most common appearance is that of a salt-and-pepper retinopathy. There does not, however, appear to be any link between the presence or type of retinal pigmentary change, the type of genetic defect, biochemical abnormality, and any clinical features. A pigmentary retinopathy is a major diagnostic criterion for the diagnosis of Kearns-Sayre syndrome (the other features being a chronic progressive external ophthalmoplegia; onset before the age of 20; and cardiac conduction abnormalities, elevated cerebrospinal fluid protein levels, or cerebellar dysfunction). Retinal pigmentary degeneration can also be present in patients with chronic progressive external ophthalmoplegia and no other neurological or systemic abnormalities, as well as in otherwise unaffected relatives.126
303
Pigmentary retinopathy is also a major diagnostic feature of the syndrome of neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP). However, patients who have no retinopathy, no subtle pigmentary retinopathy, and no severe bone spicule pattern have been identified with the same mutation.126 Furthermore, a patient in whom the retinal changes progressed from an initial salt-and-pepper retinopathy to typical retinitis pigmentosa over an 8-year period has been described.127 Other mitochondrial diseases in which retinal changes have been reported include the syndrome of myoclonic epilepsy and ragged red fibers and the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS). The retinal changes in MELAS are in the form of pigmentary changes in the macula.128,129 MELAS is associated with the 3243 mutation, which can also manifest as maternally inherited diabetes and deafness. Macular changes similar to those in MELAS have also been reported in these patients,130,131 which demonstrates the marked overlap between clinical syndromes. Funduscopic abnormalities may be present in patients with Leber’s hereditary optic neuropathy and in their asymptomatic maternal relatives. Especially during the acute phase of visual loss, there may be hyperemia of the optic nerve head, dilation and tortuosity of vessels, hemorrhages, circumpapillary telangiectatic microangiopathy, or circumpapillary nerve fiber layer swelling (pseudoedema). There may be cupping of the optic disc and arterial attenuation.126 In 2 of 20 patients with Leber’s hereditary optic neuropathy, pigmentary changes were noted at the retina.128
NEOPLASIA Metastatic Disease Metastases are probably the most common form of intraocular malignancy and can be associated with concurrent neurological involvement. They tend to involve the choroid but can affect the retina or vitreous humor (Fig. 24–16).132,133 Lung and breast carcinoma are the most common sources of ocular metastases and may be the manifesting sign of the disease.
Lymphoma
■
Figure 24–15. Retinitis pigmentosa.
Primary intraocular lymphoma may occur in isolation, without involvement of the CNS. However, because the ocular and the CNS components show identical cytological features and phenotypical expression, the two entities are often considered as one entity: primary CNS lymphoma. Involvement of the eyes in this condition has been reported to occur in 12% to 25% of cases,134-137 and 56% to 80% of patients with intraocular lymphoma eventually develop intracranial involvement.138-142 As yet, it is unknown whether lymphoma cells from the eye can invade the CNS or whether the disease arises multifocally, in the eye and CNS. Experimental data from an animal model suggest that invasion of the CNS from the eye does not occur.143 The clinical features are dependent on the site of lymphoma involvement. The only sign of the disease may be vitreous cellular infiltration with resulting floaters and reduction of acuity.
304
Section
IV
Neuro-ophthalmology adequately treated with only local therapy or requires treatment of the entire CNS presumptively.
Paraneoplastic Syndromes Paraneoplastic visual syndromes represent visual dysfunction in the setting of known or suspected malignancies, without direct involvement of the eye or nervous system by tumor, antineoplastic agent toxicity, or opportunistic infection. They are rare, and the fundus may appear normal on presentation. Furthermore, because some patients may present before the diagnosis of a neoplasm, diagnosis can be difficult. These syndromes are characterized by elevated serum levels of autoantibodies directed against tumor antigen that cross-react with retinal proteins, resulting in retinal dysfunction.
Carcinoma-Associated Retinopathy ■
Figure 24–16. Metastatic deposits with associated retinal detachment.
Because this is typically the appearance of a posterior uveitis, ocular lymphomas are described as being one of the masquerade syndromes. Diagnosis at this stage can therefore be difficult. The classic lesions are creamy yellow subretinal infiltrates (Fig. 24–17), with overlying retinal pigment epithelial detachments,142 but they may take on many forms, such as discrete white lesions, suggestive of ARN or toxoplasmosis144; branch retinal artery obstruction with coexistent multifocal chorioretinal scars145; and retinal vasculitis. If patients have combined CNS and eye involvement, therapy for the eyes is typically accomplished as part of the overall treatment plan, including the use of intravitreal methotrexate in some cases. An important question that has not been answered is whether apparently clinically isolated ocular disease is
Carcinoma-associated retinopathy (CAR) was first described in 1976.146 It is associated most commonly with small cell lung cancer and next most commonly with gynecological and breast cancers. Cases associated with other cancers such as non–small cell lung, colon, pancreatic, prostate, larynx, and bladder cancers and lymphoma have also been reported. Overall, the incidences among men and women are equal. Visual loss is usually subacute and bilateral, preceding tumor diagnosis in about 50% of cases. Patients may complain of positive visual phenomena, visual field loss, and night blindness. Initially there may be no retinal signs, but arteriolar narrowing and pigmentary retinal changes develop. Sheathing of the retinal vessels may develop. Electrophysiological testing demonstrates that both rods and cones are affected. The first antigen shown to represent the source of autoimmunity in patients with CAR was the 23-kD protein recoverin.147,148 This is a calcium-binding protein that regulates phosphorylation of the visual pigment rhodopsin during visual transduction. A number of other antigens have since been reported to be associated with CAR. The next most commonly found antigen is the 46-kD protein enolase,149 although a number have now been identified (see review by Chan150). However, the presence of neither anti-recoverin nor antienolase antibodies is diagnostic for CAR. A few patients with anti-recoverin antibodies but with no evidence of malignancy have been described.151,152 Up to two thirds of patients with antienolase antibody–associated retinopathy have no evidence of malignancy.153,154 Furthermore, in patients with anti-enolase antibodies, the retinopathy often develops after the detection of cancer, and the disease course is usually less severe than in patients with anti-recoverin antibodies.154
Melanoma-Associated Retinopathy
■
Figure 24–17. Ocular lymphoma. The hazy view is caused by vitreal inflammation.
Because of the relatively greater decrease in incidence of lung cancers in comparison with melanomas, it has been suggested that melanoma-associated retinopathy (MAR) is becoming more common than CAR.150 There are a number of differences between MAR and CAR. In MAR, the diagnosis of melanoma has often been made before the development of visual problems, and the incidence of MAR is higher in men. Patients tend to complain of shimmering vision and night blindness. The degree of visual loss is less severe than in CAR. As in CAR, the initial
chapter 24 retinal disease
305
retinal appearances may be normal, but retinal pigment epithelial irregularity, retinal arteriolar attenuation, and optic disc pallor are present in cases in which the symptoms have been present for some time. Vitritis and retinal periphlebitis have been reported.155 Autoantibodies from MAR sera were shown to stain rod bipolar cells in the human retina.156 The specific antigen responsible has not been identified. Retinal cells other than bipolar cells have implicated, and antibodies against a variety of antigens have been identified (see Chan150).
Paraneoplastic Optic Neuritis with Retinitis Paraneoplastic ophthalmological syndromes are usually retinopathies, but in rare cases, the optic nerve is affected. In some patients, both paraneoplastic optic neuritis and a retinopathy coexist. This has been described in patients with small cell lung carcinoma. None had anti-recoverin antibodies, but all had a distinct immunoglobulin G marker antibody to collapsing response-mediator protein-5.157
■
Figure 24–18. Macular changes in spinocerebellar ataxia type 7.
Bilateral Diffuse Uveal Melanocytic Proliferation This rare condition often precedes the diagnosis of cancer. Patients present with visual loss and are found to have many round or oval red patches at the level of retinal pigment epithelium and pigmented and nonpigmented melanocytic lesions of the uveal tract. An ultrasonogram reveals extremely thickened choroid. Retinal detachment and cataracts may develop.158 Approximately 25% of patients develop pigmentation of their skin or mucous membranes.159 The most commonly associated neoplasms are ovarian cancers in women and lung and pancreas cancers in men, although it has also been reported in kidney, colon, breast, and esophageal cancers.159,160
MOVEMENT DISORDERS AND ATAXIA Most often the neuro-ophthalmological findings in patients with movement disorders are those of the oculomotor system. Patients with Parkinson’s disease often complain of blurred vision. Retinal appearances are normal, however, but functional abnormalities are present on psychophysical and electrophysiological testing. Some of these are reversible with levodopa (see Jackson and Owsley161 for a review). Patients with Huntington’s disease also demonstrate abnormalities of retinal function on psychophysical testing.162 However, about 50% of patients with Guam amyotrophic lateral sclerosis–parkinsonism–dementia complex (Lytico-Bodig disease) do have retinal pigmentary changes.163 A number of rare movement disorders are associated with retinal changes. Pantothenate kinase–associated neurodegeneration (formerly known as Hallervorden-Spatz syndrome),164 which is caused by a mutation in the PANK2 gene, is characterized by dystonia, parkinsonism, iron accumulation in the brain, and occasionally retinopathy. Electrophysiological abnormalities have been observed in affected patients who have clinically normal eyes.165 The syndrome of hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration, which is also caused by a PANK2 mutation,166 also has a pigmentary retinopathy. Aceruloplasminemia is a rare condition that was first described in 1987.167 It also results in iron overload in the brain,
retina, and pancreas. The first patient described was Asian, and the retinal changes were noted in the midperipheral region.167 Subsequently a case was described in a white patient, but the changes were at the macula.168 In Wilson’s disease, there is also a deficiency of ceruloplasmin, but the biochemical problem relates to copper metabolism. Retinal changes have been reported in addition to the familiar Kayser-Fleischer rings in the cornea. However, it is unclear whether these were caused by long-term therapy with pencillamine.169 A number of the ataxias are also associated with retinal pigmentary changes. These include Bassen-Kornzweig disease,170 Refsum’s disease,171 and adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency.172 A deficiency of vitamin E may cause the initial retinopathy; the treatment of these conditions includes vitamin E supplementation.173 Although there are many forms of spinocerebellar ataxia with oculomotor abnormalities, spinocerebellar ataxia type 7 can be differentiated from the other forms by the associated retinal changes. These take the form of progressive macular changes with visual loss (Fig. 24–18).174 Electrophysiological studies have demonstrated that the functional defects are greater than expected from the clinical appearance.175
MUSCLE DISEASES Patients with facioscapulohumeral muscular dystrophy often have retinal telangiectasia. In rare cases, this can have significant visual consequences, such as exudative retinal detachment.176 Myotonic dystrophy is most frequently associated with cataract, but retinal pigmentary changes are also present. They can be peripheral or affect the macula and may slowly progress.177 The classic neuro-ophthalmological feature of dermatomyositis is the heliotrope rash of the eyelids, but a vasculitic retinopathy with retinal hemorrhages and cotton-wool spots may occur. With immunosuppression, visual recovery is usually but not always complete.178
306
Section
IV
Neuro-ophthalmology
PHACOMATOSES The phacomatoses are a group of disorders that feature multiple hamartomas of the nervous system, eye, skin, and viscera.
Neurofibromatosis Neurofibromatosis Type 1 The diagnostic criteria for neurofibromatosis type 1 include optic gliomas and Lisch nodules, which are hamartomas of the pigment epithelium. Nevertheless, retinal involvement is rare and generally nonspecific. The retinal lesions include a pigmentary retinopathy,179 retinal hamartomas,180,181 and capillary hemangiomas and combined hamartomas of the retina and pigment epithelium.181 Mild pigmentary changes that resemble cutaneous café au lait spots have been described.180 Myelinated fibers may be present more frequently than in the normal population,182 and vascular occlusions have also been reported,183 but it is unclear whether these are merely coincidental. Neurofibromas of the uveal tract can occur in up to 50% of patients.182,184-189 These are usually pale yellow nodules, but the entire uvea may be thickened by a diffuse neurofibroma. Choroidal nevi may occur more frequently in patients with neurofibromatosis type 1 than in the normal population.190
Neurofibromatosis Type 2 Cataracts and retinal changes are common in patients with neurofibromatosis type 2, whereas Lisch nodules are not as common as in neurofibromatosis type 1.191-196 Indeed, the ocular findings may be the first manifestation of the disease.194 The retinal changes can take the forms of epiretinal membranes,196-198 hamartomas of the retina,194,195 and combined pigment epithelial and retinal hamartomas.191,193,198 Retinal hamartomas are not exclusively associated with severe neurofibromatosis type 2, and neither the type nor the location of the germline neurofibromatosis type 2 mutation is the sole determinant of retinal abnormalities, which can be variably expressed in families with neurofibromatosis type 2.199
Tuberous Sclerosis Hamartomas of the retina are the most prominent ocular manifestation of tuberous sclerosis, present in about 50% of patients and bilateral in 25% of cases. They arise from the ganglion cell layers and infiltrate all layers of the retina. They do not tend to grow or interfere with vision. The appearances are varying, ranging form semitransparent structures to opaque multinodular lesions (Fig. 24–19). Although most lesions remain stable, becoming calcified over time, they can develop in areas of previously normal-appearing retina.200 A case of a patient with a giant cell astrocytoma of the retina with atypical histopathological features and local aggressive behavior has been reported.201 Depigmented pigment epithelial lesions may be present. These can have a shape similar to that of cutaneous mountain ash leaf spots.202-204
■
Figure 24–19. Astrocytic hamartoma.
Von Hippel-Lindau Disease The retinal capillary hemangioma is the most frequent and the earliest manifestation of von Hippel-Lindau disease (Fig. 24–20).205-209 The other systemic features include hemangiomas of the CNS; renal cell carcinoma; pheochromocytoma; and renal, pancreatic, and epididymal cysts. The retinal capillary hemangioma is usually an orange-red, circumscribed round lesion. It can enlarge and develop a feeder vessel, and fluid may extravasate, leading to a retinal detachment. Thus, patients should have an annual ophthalmological assessment with dilated funduscopy, because the lesions may be small and situated in the retinal periphery. Retinal capillary hemangiomas can also develop around the optic disc. A rare retinal feature of von Hippel-Lindau disease are retinal “twin vessels,”210 defined as a paired retinal arteriole and venule that are separated by less than the diameter of one venule. Twin vessels are of normal caliber and look like normal retinal vessels except for their course. Retinal capillary hemangiomas not associated with von Hippel-Lindau disease do occur but at a later age (48 years) than in patients with von Hippel-Lindau disease (25 years).211 Nevertheless, the systemic features of von Hippel-Lindau disease must be ruled out in patients presenting with a solitary capillary hemangioma. The presence of multiple retinal capillary hemangiomas (two or more) indicates the presence of underlying von Hippel-Lindau disease.212
Sturge-Weber Syndrome The chief components of the Sturge-Weber syndrome are a cutaneous hemifacial angioma and an ipsilateral angioma of the leptomeninges and brain. Glaucoma is the most common ocular association. Choroidal angiomas are also present; these can affect one or both eyes. Most commonly the angiomas are diffuse, obscuring the normal choroidal markings.213 More rarely, they are localized and may be associated with a serous retinal detachment.214 The retinal vasculature may be abnormal.215
chapter 24 retinal disease
■
■
Figure 24–20. Retinal capillary angioma.
Wyburn-Mason Syndrome The classic Wyburn-Mason syndrome consists of an intracranial arteriovenous malformation and a separate retinal one. The retinal arteriovenous malformation has also been described as an arteriovenous aneurysm or racemose angioma. It is usually unilateral and involves the posterior pole, thus affecting the vision. Often it is stable, but it may enlarge (Fig. 24–21).216,217
Other Phacomatoses The classic ophthalmological lesion of ataxia telangiectasia is telangiectasia of the conjunctiva, and the retina is spared. In Klippel-Trénaunay-Weber syndrome, varicosities of the retinal vasculature and choroidal angiomas have been described.218
CEREBROVASCULAR DISEASE Retinopathy The retinal and cerebral arterioles share common anatomy and physiology. Because the retina is readily visualized, it provides an opportunity to assess the retinal and, by inference, the cerebral circulation. Studies in people with hypertension have
307
Figure 24–21. Racemose angioma.
shown that signs of retinopathy are associated with both subclinical and clinical stroke.219-222 Retinal digital photography has been used in large population-based studies to investigate the relationship between retinal findings and systemic disease, including stroke. The images are analyzed in a standardized manner and are used to look for features of retinopathy such as microaneurysms, retinal hemorrhages, cotton-wool spots, arteriovenous nicking, and arteriolar narrowing. The studies include the Atherosclerosis Risk in Communities study, the Beaver Dam Eye Study, and the Blue Mountains Eye Study. The Atherosclerosis Risk in Communities study has demonstrated that after controlling of stroke risk factors such as diabetes and hypertension, the presence of retinopathy was predictive of an incident stroke.223 Retinopathy was also associated with cognitive decline224 and with magnetic resonance imaging findings such as white matter lesions225 and cerebral atrophy.226 The risk of stroke was higher in patients who had both retinopathy and changes noted on cerebral magnetic resonance imaging.225
Retinal Emboli and Arteriolar Occlusion Retinal emboli are usually present at the bifurcation of retinal arterioles and may be reflective or nonreflective. A variety of emboli have been described, but clinically a reliable distinction cannot always be made (Fig. 24–22).227 Emboli are also present in up to about 40% of central retinal artery occlusions (Fig. 24–23) and 70% of branch retinal artery occlusions.228,229 The emboli usually originate from the carotid arteries or a cardiac source. The carotid vessels are the commonest source of emboli in patients with amaurosis fugax or retinal artery occlusion and of asymptomatic emboli,230 but often no embolic source is found.230,231 In elderly patients, the absence of an embolus in a retinal artery occlusion necessitates the exclusion of giant cell arteritis as a diagnosis. Furthermore, the presence of an embolus that is asymptomatic232 or in association with a retinal artery occlusion233 is not a good predictor of carotid artery stenosis. This may be because the emboli result from plaques and are not associated with stenosis per se.232
308
Section
IV
Neuro-ophthalmology
Ocular Ischemic Syndrome and Other Ocular Associations with Carotid Artery Disease
■
Figure 24–22. Retinal embolus.
Emboli may be asymptomatic. It has been shown that for men with asymptomatic cholesterol emboli, there is an increased risk of stroke, but not myocardial infarction,234 and that patients with an embolus, symptomatic or not, have a reduced survival rate.228 Again, the analysis of digital photographs in large populations has added further information about emboli. The Beaver Dam Eye study found that for asymptomatic retinal emboli, the 10-year cumulative incidence was 1.5%.235 The incidence rose with age, from 1.0% in subjects aged 43 to 54 years to 2.2% in those aged 65 years or older at baseline. They are more common in men than in women. They appear to be transitory, and in approximately 30% of affected eyes, they are multiple. Bilateral ocular involvement is rare. The presence of asymptomatic retinal emboli is associated with carotid artery disease236 and an increased risk of death from stroke, independent of any other risk factors.235
Severe carotid stenosis is associated with venous stasis retinopathy. In this condition, there is an insidious onset of blurred vision in the affected eye. Patients may complain of episodes of transient monocular visual loss precipitated by exercise, eating, or bright lights. Examination reveals dilated and tortuous retinal veins, peripheral hemorrhages, and an easily induced pulsation of the central retinal artery with digital pressure.237,238 Venous stasis retinopathy may progress to ocular ischemic syndrome. This is a severe form of chronic ischemia caused by hypoperfusion of the eye, which affects both its anterior and posterior segments. Neovascularization of the iris, disc, and retina may occur. In patients with minimal or no neovascular changes, carotid endarterectomy appears to improve blood flow through the ophthalmic and central retinal arteries.239 It also appears to prevent progression of ocular ischemic syndrome, if not improve vision in all patients.239 Percutaneous angioplasty and stenting have also been used effectively in a number of patients who had lesions that were not amenable to endarterectomy.240 Patients with carotid occlusive disease may develop neurological symptoms at the same time as a central retinal artery occlusion.240 Carotid artery dissection is classically associated with a painful Horner’s syndrome, but both central and branch retinal artery occlusions can be present in this condition.241-243 Carotid artery disease is also associated with retinal vein occlusions.236
Retinal Vasculitis and Stroke One form of retinal vasculitis is localized to the eye, and fluorescin angiography demonstrates ischemic retinal changes. This condition, known as idiopathic ischemic retinal vasculitis, has a worse visual prognosis than does retinal vasculitis with no associated ischemia.244 Furthermore, after a minimum follow up of 5 years, almost one third of patients in one study had suffered a stroke and/or myocardial infarction.245
Secondary Causes of Stroke Coagulopathies that are associated with stroke, such as hyperhomocysteinemia and antiphospholipid syndrome, also have retinal manifestations such as retinal artery and vein occlusions.246,247
Cerebral Small-Vessel Disease The most common form of cerebral small-vessel disease is acquired degenerative small-vessel disease, and this usually is not clinically manifest before the sixth decade of life. There are, however, a number of other cerebral microangiopathies, several of which affect the eye. These include Susac’s syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and a number of hereditary diseases.
Susac’s Syndrome ■
Figure 24–23. Central retinal artery occlusion with the appearance of a cherry-red spot.
Susac’s syndrome consists of the triad of encephalopathy, branch retinal artery occlusions, and hearing loss, which
chapter 24 retinal disease
■
309
Figure 24–24. An area of focal leakage from a retinal arteriole on fluorescein angiography.
occurs most commonly in affected young women.248,249 The branch retinal artery occlusions are often bilateral and may be the manifesting features of the illness, or they may occur later in the clinical course. Fluorescein angiography may reveal focal leakage from retinal arterioles even in the absence of frank occlusion (Fig. 24–24). Such leakage can be used to measure disease activity. The encephalopathy manifests with headache, confusion, memory loss, behavioral changes, dysarthria, and occasional mutism. The hearing loss is usually bilateral and frequently associated with tinnitus and vertigo. Although the presence of encephalopathy, branch retinal artery occlusions, and hearing loss is pathognomonic for Susac’s syndrome, not all elements may be present initially. The condition usually stabilizes after a period of 2 to 4 years. On magnetic resonance images, lesions of the corpus callosum are often present.250
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy CADASIL is caused by mutations of the Notch3 gene, which is located on chromosome 19. In patients with CADASIL vision is usually preserved, although retinal findings such as peripapillary arteriolar sheathing, arteriolar narrowing, ateriovenous nicking,251 and cotton wool spots252 may be present. Visual loss may take the form of a hemianopic defect caused by stroke252 or anterior ischemic optic neuropathy.253 In asymptomatic patients, there may be electrophysiological evidence of retinal dysfunction.254 A histopathological study of four eyes from two patients with CADASIL demonstrated loss of vascular smooth muscle cells in the central retinal artery and its branches, as well as the optic disc. The choroidal circulation was spared, which demonstrated a differential involvement of small blood vessels.255
Other Hereditary Diseases of the Small Vessels There are other rare hereditary conditions that affect the retinal and cerebral circulation. Patients with autosomal dominant
■
Figure 24–25. Retinal hemorrhages in a patient with a subarachnoid hemorrhage.
vascular retinopathy, migraine, and Raynaud’s phenomenon may have a retinopathy that appears very similar to that of diabetic retinopathy. Indeed, a few patients may develop retinal neovascularization, which results in poor vision.256,257 Three other diseases with retinopathy have been linked to the same locus on chromosome 3p21. These are cerebroretinal vasculopathy; the syndrome of hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); and hereditary vascular retinopathy.258 The retinal vascular abnormality constitutes part of the disease title in the syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy.259 Fabry’s disease is also accompanied by retinal vascular changes.260 The practical implication of these findings is that all patients with small-vessel disease probably require ophthalmoscopy.261 Finally, of interest is that a high prevalence of migraine has been in reported in CADASIL; HERNS; hereditary vascular retinopathy; and the syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy.
Terson’s Syndrome Vitreous hemorrhage occurring in association with subarachnoid hemorrhage is known as Terson’s syndrome.262 However, intraocular hemorrhages of any type (retinal, subhyaloid, or vitreous) have been documented in 10% to 40% of individuals with subarachnoid hemorrhage,263 and reports have not always made a distinction between such types of hemorrhage (Fig. 24–25).264 Furthermore, preretinal hemorrhage may precede vitreous hemorrhage.263,265 Terson’s syndrome is present in between 3% and 13% of patients with a subarachnoid hemorrhage266 and carries an increased mortality rate in relation to patients who have had a subarachnoid hemorrhage but not vitreous hemorrhage.266 It has also been suggested that mild retinal hemorrhages are associated with a better prognosis than
310
Section
IV
Neuro-ophthalmology
are large preretinal hemorrhages or vitreous hemorrhages.267 An urgent vitrectomy may be required for visual rehabilitation in patients with bilateral vitreous hemorrhage.
METABOLIC DISEASES IN CHILDREN A variety of ophthalmological features may occur in these diseases, all of which may contribute to visual problems. Thus, it can be difficult to determine the precise cause of visual loss. For example, patients with Hunter’s syndrome may have corneal clouding, pigmentary retinal degeneration, and optic atrophy. Furthermore, there may also be mucopolysaccharide deposition in the occipital cortex. The most common retinal findings are the presence of a macular cherry-red spot (an appearance similar to that of a central retinal artery occlusion; see Fig. 24–23) and pigmentary retinopathy. The cherry-red spot is classically associated with Tay-Sachs disease. However, a form of this finding is present in many of the metabolic diseases, although not necessarily in all patients affected by them. Also, in other conditions it may have prognostic significance; for example, in Farber’s disease, its presence may be correlated with disease severity.268 Pigmentary retinopathy is also present in a number of conditions, although, again, not in all affected individuals. The clinical pattern of the retinopathy is variable. There are a few striking changes associated with the metabolic diseases, such as the absence of retinal pigmentation observed in phenylketonuria and the presence of bilateral parafoveal ringlets observed in hyperoxaluria type 1.269 The cherry-red spot tends to be present in the lysosomal storage diseases such as Tay-Sachs disease, Sandhoff’s disease, type 1 GM1 gangliosidosis, Farber’s disease, Niemann-Pick disease type A, and the sialidoses (namely types 1 and 2), as well as in metachromic leukodystrophy. Retinal pigmentary changes can be present in a number of the following conditions: 1. The mucopolysaccharidoses: namely, Hurler’s syndrome, Hunter’s syndrome, Scheie’s syndrome, and Sanfilippo’s syndrome. It is rarely present in Morquio’s syndrome and is not present in Maroteaux-Lamy or Sly’s syndrome. 2. The disorders of peroxisomes, such as Zellweger’s cerebrohepatorenal syndrome, neonatal adrenoleukodystrophy, infantile Refsum’s disease, and X-linked adrenoleukodystrophy. 3. The juvenile and infantile neuronal ceroid lipofuscinoses. 4. A few other conditions such as mucolipidosis type IV, GM1 gangliosidosis type 2 (in which a cherry-red spot is not present).
K E Y
P O I N T S
●
The brain and retina share much in terms of anatomy and physiology.
●
Retinal disease may be the primary manifestation of systemic disease, including inflammation, infection, and metabolic and degenerative disorders.
●
Retinal changes can be diagnostic of a wide range of neurological diseases, from demyelinating to neuromuscu-
Suggested Reading Albert DM, Jakobiec FA, eds: Principles and Practice of Ophthalmology. Philadelphia: WB Saunders, 2000. Gold DH, Weingeist TA, eds: Color Atlas of the Eye in Systemic Disease. Philadelphia: Lippincott Williams & Wilkins, 2001. Miller NR, Newman NJ, eds: Walsh and Hoyt’s Clinical NeuroOphthalmology. Baltimore: William & Wilkins 1998 Riordan-Eva P, Whitcher JP, eds: Vaughan & Asbury’s General Ophthalmology. New York: McGraw-Hill, 2004. Spalton DJ, Hitchings RA, Hunter P, eds: Atlas of Clinical Ophthalmology, 3rd ed. London: Elsevier, 2004.
References 1. Jabs DA, Nussenblatt RB, Rosenbaum JT: Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140:509-516. 2. Rothova A, Alberts C, Glasius E, et al: Risk factors for ocular sarcoidosis. Doc Ophthalmol 1989; 72:287-296. 3. Edelsten C, Pearson A, Joynes E, et al: The ocular and systemic prognosis of patients presenting with sarcoid uveitis. Eye 1999; 13(Pt 6):748-753. 4. Gould H, Kaufman HE: Sarcoid of the fundus. Arch Ophthalmol 1961; 65:453-456. 5. James DG, Neville E, Langley DA: Ocular sarcoidosis. Trans Ophthalmol Soc U K 1976; 96:133-139. 6. Stavrou P, Linton S, Young DW, et al: Clinical diagnosis of ocular sarcoidosis. Eye 1997; 11(Pt 3):365-370. 7. Walsh F: Ocular importance of sarcoid. Arch Ophthalmol 1939; 21:421-438. 8. Sanders MD, Shilling JS: Retinal, choroidal, and optic disc involvement in sarcoidosis. Trans Ophthalmol Soc U K 1976; 96:140-144. 9. Spalton DJ, Sanders MD: Fundus changes in histologically confirmed sarcoidosis. Br J Ophthalmol 1981; 65:348-358. 10. Rothova A, Lardenoye C: Arterial macroaneurysms in peripheral multifocal chorioretinitis associated with sarcoidosis. Ophthalmology 1998; 105:1393-1397. 11. Cook BE Jr., Robertson DM: Confluent choroidal infiltrates with sarcoidosis. Retina 2000; 20:1-7. 12. Lardenoye CW, Van der Lelij A, de Loos WS, et al: Peripheral multifocal chorioretinitis: a distinct clinical entity? Ophthalmology 1997; 104:1820-1826. 13. Thorne JE, Brucker AJ: Choroidal white lesions as an early manifestation of sarcoidosis. Retina 2000; 20:8-15. 14. Edelsten C, Stanford MR, Graham EM: Serpiginous choroiditis: an unusual presentation of ocular sarcoidosis. Br J Ophthalmol 1994; 78:70-71. 15. Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s Disease. Lancet 1990; 335:1078-1080. 16. Akman-Demir G, Serdaroglu P, Tasci B: Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. The Neuro-Behçet Study Group. Brain 1999; 122(Pt 11):2171-2182. 17. Kansu T, Kirkali P, Kansu E, et al: Optic neuropathy in Behçet’s disease. J Clin Neuroophthalmol 1989; 9:277-280. 18. Kidd D, Steuer A, Denman AM, et al: Neurological complications in Behçet’s syndrome. Brain 1999; 122(Pt 11):21832194. 19. Mitra S, Koul RL: Paediatric neuro-Behçet’s disease presenting with optic nerve head swelling. Br J Ophthalmol 1999; 83:1096. 20. Swerdlow RH, Hanna GR: Behçet’s disease: presentation with sagittal sinus thrombosis diagnosed noninvasively. Headache 1996; 36:115-118.
chapter 24 retinal disease 21. Wechsler B, Vidailhet M, Piette JC, et al: Cerebral venous thrombosis in Behçet’s disease: clinical study and long-term follow-up of 25 cases. Neurology 1992; 42:614-618. 22. Lee E-S, Hur W, Bang D, et al: Prognosis of recurrent oral ulceration in Behçet’s disease. In Godeau P, Wechsler B, eds: Behçet’s Disease. Paris: Elsevier, 1993, pp 291-294. 23. Dilsen N, Konice M, Aral O, et al: Risk factors for vital organ involvement in Behçet’s disease. In Godeau P, Wechsler B, eds: Behçet’s Disease. Paris: Elsevier, 1993, pp 165-169. 24. Lueck, CJ, Pires M, McCartney AC, et al: Ocular and neurological Behçet’s disease without orogenital ulceration? J Neurol Neurosurg Psychiatry 1993; 56:505-508. 25. Muhaya M, Lightman S, Ikeda E, et al: Behçet’s disease in Japan and in Great Britain: a comparative study. Ocul Immunol Inflamm 2000; 8:141-148. 26. Read RW, Holland GN, Rao NA, et al: Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001; 131:647-652. 27. Najman-Vainer J, Levinson RD, Graves MC, et al: An association between Vogt-Koyanagi-Harada disease and GuillainBarré syndrome. Am J Ophthalmol 2001; 131:615-619. 28. Klinkhoff AV, Beattie CW, Chalmers A: Retinopathy in systemic lupus erythematosus: relationship to disease activity. Arthritis Rheum 1986; 29:1152-1156. 29. Gold DH, Morris DA, Henkind P: Ocular findings in systemic lupus erythematosus. Br J Ophthalmol 1972; 56:800-804. 30. Graham EM, Spalton DJ, Barnard RO, et al: Cerebral and retinal vascular changes in systemic lupus erythematosus. Ophthalmology 1985; 92:444-448. 31. Hollenhorst RW: Effect of posture on retinal ischemia from temporal arteritis. Arch Ophthalmol 1967; 78:569-577. 32. Chun YS, Park SJ, Park IK, et al: The clinical and ocular manifestations of Takayasu arteritis. Retina 2001; 21:132140. 33. Galetta SL: Vasculitis. In Miller NR, Newman NJ, eds: Walsh and Hoyt’s Clinical Neuro-ophthalmology. Baltimore: Williams & Wilkins, 1998, pp 3725-3886. 34. Hsu CT, Kerrison JB, Miller NR, et al: Choroidal infarction, anterior ischemic optic neuropathy, and central retinal artery occlusion from polyarteritis nodosa. Retina 2001; 21:348351. 35. Font RL, Mehta RS, Streusand SB, et al: Bilateral retinal ischemia in Kawasaki disease: postmortem findings and electron microscopic observations. Ophthalmology 1983; 90:569577. 36. Drachman DA: Neurological complications of Wegener’s granulomatosis. Arch Neurol 1963; 8:145-155. 37. Nishino H, Rubino FA, DeRemee RA, et al: Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 1993; 33:4-9. 38. Bullen CL, Liesegang TJ, McDonald TJ, et al: Ocular complications of Wegener’s granulomatosis. Ophthalmology 1983; 90:279-290. 39. Riordan-Eva P, Williams CE, Wing AJ, et al: Retinal neovascularization secondary to cytomegalovirus retinitis in Wegener’s granulomatosis. J R Soc Med 1993; 86:301-302. 40. Tugal-Tutkun I, Kir N, Gul A, et al: Cytomegalovirus retinitis in a patient with Wegener’s granulomatosis. Ophthalmologica 2000; 214:149-152. 41. Agrawal A, Dick AD, Olson JA: Visual symptoms in patients on cyclophosphamide may herald sight threatening disease. Br J Ophthalmol 2003; 87:122-123. 42. Newman NJ, Slamovits TL, Friedland S, et al: Neuroophthalmic manifestations of meningocerebral inflammation from the limited form of Wegener’s granulomatosis. Am J Ophthalmol 1995; 120:613-621.
311
43. Spalton DJ, Graham EM, Page NG, et al: Ocular changes in limited forms of Wegener’s granulomatosis. Br J Ophthalmol 1981; 65:553-563. 44. Takanashi T, Uchida S, Arita M, et al: Orbital inflammatory pseudotumor and ischemic vasculitis in Churg-Strauss syndrome: report of two cases and review of the literature. Ophthalmology 2001; 108:1129-1133. 45. Mihara M, Hayasaka S, Watanabe K, et al: Ocular manifestations in patients with microscopic polyangiitis. Eur J Ophthalmol 2005; 15:138-142. 46. Arnold AC, Pepose JS, Hepler RS, et al: Retinal periphlebitis and retinitis in multiple sclerosis. I. Pathologic characteristics. Ophthalmology 1984; 91:255-262. 47. Hornstein G: The relation of retinal periphlebitis to multiple sclerosis and other neurological disorders. Acta Neurol Scand 1971; 47:413-425. 48. Rucker CW: Sheathing of the retinal veins in multiple sclerosis. Mayo Clin Proc 1944; 19:176-178. 49. Shaw PJ, Smith NM, Ince PG, et al: Chronic periphlebitis retinae in multiple sclerosis: a histopathological study. J Neurol Sci 1987; 77:147-152. 50. Tola MR, Granieri E, Casetta I, et al: Retinal periphlebitis in multiple sclerosis: a marker of disease activity? Eur Neurol 1993; 33:93-96. 51. Adams CW, Poston RN, Buk SJ, et al: Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 1985; 69:269-283. 52. Lightman S, McDonald WI, Bird AC, et al: Retinal venous sheathing in optic neuritis: its significance for the pathogenesis of multiple sclerosis. Brain 1987; 110(Pt 2):405-414. 53. Engell T, Sellebjerg F, Jensen C: Changes in the retinal veins in acute optic neuritis. Acta Neurol Scand 1999; 100:81-83. 54. Engell T: Neurological disease activity in multiple sclerosis patients with periphlebitis retinae. Acta Neurol Scand 1986; 73:168-172. 55. Birch MK, Barbosa S, Blumhardt LD, et al: Retinal venous sheathing and the blood-retinal barrier in multiple sclerosis. Arch Ophthalmol 1996; 114:34-39. 56. Graham EM, Stanford MR, Sanders MD, et al: A point prevalence study of 150 patients with idiopathic retinal vasculitis: 1. Diagnostic value of ophthalmological features. Br J Ophthalmol 1989; 73:714-721. 57. Biousse V, Trichet C, Bloch-Michel E, et al: Multiple sclerosis associated with uveitis in two large clinic-based series. Neurology 1999; 52:179-181. 58. Edwards LJ, Constantinescu CS: A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Mult Scler 2004; 10:575-581. 59. Schmidt S, Wessels L, Augustin A, et al: Patients with multiple sclerosis and concomitant uveitis/periphlebitis retinae are not distinct from those without intraocular inflammation. J Neurol Sci 2001; 187:49-53. 60. Graham EM, Francis DA, Sanders MD, et al: Ocular inflammatory changes in established multiple sclerosis. J Neurol Neurosurg Psychiatry 1989; 52:1360-1363. 61. Smith JR, Rosenbaum JT: Neurological concomitants of uveitis. Br J Ophthalmol 2004; 88:1498-1499. 62. Zein G, Berta A, Foster CS: Multiple sclerosis–associated uveitis. Ocul Immunol Inflamm 2004; 12:137-142. 63. Towler HM, Lightman S: Symptomatic intraocular inflammation in multiple sclerosis. Clin Exp Ophthalmol 2000; 28:97-102. 64. Wakefield D, Jennings A, McCluskey PJ: Intravenous pulse methylprednisolone in the treatment of uveitis associated with multiple sclerosis. Clin Exp Ophthalmol 2000; 28:103-106. 65. Vine AK: Severe periphlebitis, peripheral retinal ischemia, and preretinal neovascularization in patients with multiple sclerosis. Am J Ophthalmol 1992; 113:28-32.
312
Section
IV
Neuro-ophthalmology
66. Parmley VC, Schiffman JS, Maitland CG, et al: Does neuroretinitis rule out multiple sclerosis? Arch Neurol 1987; 44:1045-1048. 67. Williams KE, Johnson LN: Neuroretinitis in patients with multiple sclerosis. Ophthalmology 2004; 111:335-340; discussion, Ophthalmology 2004; 111:340-341. 68. Moreno RJ, Weisman J, Waller S: Neuroretinitis: an unusual presentation of ocular toxoplasmosis. Ann Ophthalmol 1992; 24:68-70. 69. Solley WA, Martin DF, Newman NJ, et al: Cat scratch disease: posterior segment manifestations. Ophthalmology 1999; 106:1546-1553. 70. Aaberg TM: The expanding ophthalmologic spectrum of Lyme disease. Am J Ophthalmol 1989; 107:77-80. 71. Balcer LJ, Winterkorn JM, Galetta SL: Neuro-ophthalmic manifestations of Lyme disease. J Neuroophthalmol 1997; 17:108-121. 72. Breeveld J, Kuiper H, Spanjaard L, et al: Uveitis and Lyme borreliosis. Br J Ophthalmol 1993; 77:480-481. 73. Kuiper H, Koelman JH, Hager MJ: Vitreous clouding associated with Lyme borreliosis. Am J Ophthalmol 1989; 108:453454. 74. Bialasiewicz AA, Ruprecht KW, Naumann GO, et al: Bilateral diffuse choroiditis and exudative retinal detachments with evidence of Lyme disease. Am J Ophthalmol 1988; 105:419420. 75. Smith JL, Winward KE, Nicholson DF, et al: Retinal vasculitis in Lyme borreliosis. J Clin Neuroophthalmol 1991; 11:7-15. 76. Trends in infectious syphilis; update on national data to 2003 and current epidemiological data from the London outbreak. Commun Dis Rep CDR Wkly 2004; 14(31):7-10. 77. Barile GR, Flynn TE: Syphilis exposure in patients with uveitis. Ophthalmology 1997; 104:1605-1609. 78. Deschenes J, Seamone CD, Baines MG: Acquired ocular syphilis: diagnosis and treatment. Ann Ophthalmol 1992; 24:134-138. 79. Cubillan LD, Cubillan EA, Berger TG, et al: Syphilitic uveitis and dermatitis. Arch Ophthalmol 1998; 116:696-697. 80. Jabbour NM, Faris B, Trempe CL: A case of pulmonary tuberculosis presenting with a choroidal tuberculoma. Ophthalmology 1985; 92:834-837. 81. Mansour AM, Haymond R: Choroidal tuberculomas without evidence of extraocular tuberculosis. Graefes Arch Clin Exp Ophthalmol 1990; 228:382-383. 82. Gur S, Silverstone BZ, Zylberman R, et al: Chorioretinitis and extrapulmonary tuberculosis. Ann Ophthalmol 1987; 19:112115. 83. Fountain JA, Werner RB: Tuberculous retinal vasculitis. Retina 1984; 4:48-50. 84. Shah SM, Howard RS, Sarkies NJ, et al: Tuberculosis presenting as retinal vasculitis. J R Soc Med 1988; 81:232-233. 85. Finelli PF, McEntee WJ, Lessell S, et al: Whipple’s disease with predominantly neuroophthalmic manifestations. Ann Neurol 1977; 1:247-252. 86. Avila MP, Jalkh AE, Feldman E, et al: Manifestations of Whipple’s disease in the posterior segment of the eye. Arch Ophthalmol 1984; 102:384-390. 87. Font RL, Rao NA, Issarescu S, et al: Ocular involvement in Whipple’s disease: light and electron microscopic observations. Arch Ophthalmol 1978; 96:1431-1436. 88. Leland TM, Chambers JK: Ocular findings in Whipple’s disease. South Med J 1978; 71:335-338. 89. Rickman LS, Freeman WR, Green WR, et al: Brief report: uveitis caused by Tropheryma whippelii (Whipple’s bacillus). N Engl J Med 1995; 332:363-366. 90. Holland GN: Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol 1994; 117:663-667.
91. Ganatra JB, Chandler D, Santos C, et al: Viral causes of the acute retinal necrosis syndrome. Am J Ophthalmol 2000; 129:166-172. 92. Maertzdorf J, Van der Lelij A, Baarsma GS, et al: Herpes simplex virus type 1 (HSV-1)–induced retinitis following herpes simplex encephalitis: indications for brain-to-eye transmission of HSV-1. Ann Neurol 2000; 48:936-939. 93. Kamel OR, Galloway GD, Trew DR: Delayed onset acute retinal necrosis 20 years following herpetic encephalitis. Eye 2000; 14(Pt 5):788-789. 94. Chung GW, Thulborn KR, Pulido JS, et al: Magnetic resonance imaging of diffuse cerebral vasculitis associated with acute retinal necrosis. Arch Ophthalmol 2004; 122:17191720. 95. Gagnon A, Bouchard RW: Fulminating adult-onset subacute sclerosing panencephalitis in a 49-year-old man. Arch Neurol 2003; 60:1160-1161. 96. Berker N, Batman C, Guven A, et al: Optic atrophy and macular degeneration as initial presentations of subacute sclerosing panencephalitis. Am J Ophthalmol 2004; 138:879881. 97. Goldberg DE, Smithen LM, Angelilli A, et al: HIV-associated retinopathy in the HAART era. Retina 2005; 25:633-649; quiz, Retina 2005; 25:682-683. 98. Morinelli EN, Dugel PU, Riffenburgh R, et al: Infectious multifocal choroiditis in patients with acquired immune deficiency syndrome. Ophthalmology 1993; 100:1014-1021. 99. Jabs DA: Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 1995; 93:623-683. 100. Kuppermann BD, Petty JG, Richman DD, et al: Correlation between CD4+ counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus–related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. Am J Ophthalmol 1993; 115:575-582. 101. Akduman L, Feiner MA, Olk RJ, et al: Macular ischemia as a cause of decreased vision in a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 1997; 124:699702. 102. Conway MD, Tong P, Olk RJ: Branch retinal artery occlusion (BRAO) combined with branch retinal vein occlusion (BRVO) and optic disc neovascularization associated with HIV and CMV retinitis. Int Ophthalmol 1995; 19:249-252. 103. Donahue SP: Human immunodeficiency virus–associated vision loss: electroretinogram attenuation. Am J Ophthalmol 1998; 126:729-731. 104. Holbrook JT, Jabs DA, Weinberg DV, et al: Visual loss in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome before widespread availability of highly active antiretroviral therapy. Arch Ophthalmol 2003; 121:99107. 105. Kuo IC, Kempen JH, Dunn JP, et al: Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004; 138:338-346. 106. Gariano RF, Berreen JP, Cooney EL: Progressive outer retinal necrosis and acute retinal necrosis in fellow eyes of a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 2001; 132:421-423. 107. Gass JD, Braunstein RA, Chenoweth RG: Acute syphilitic posterior placoid chorioretinitis. Ophthalmology 1990; 97:12881297. 108. Becerra LI, Ksiazek SM, Savino PJ, et al: Syphilitic uveitis in human immunodeficiency virus–infected and noninfected patients. Ophthalmology 1989; 96:1727-1730. 109. Levy JH, Liss RA, Maguire AM: Neurosyphilis and ocular syphilis in patients with concurrent human immunodeficiency virus infection. Retina 1989; 9:175-180.
chapter 24 retinal disease 110. Berger BB, Egwuagu CE, Freeman WR, et al: Miliary toxoplasmic retinitis in acquired immunodeficiency syndrome. Arch Ophthalmol 1993; 111:373-376. 111. Lee YF, Chen SJ, Chung YM, et al: Diffuse toxoplasmic retinochoroiditis as the initial manifestation of acquired immunodeficiency syndrome. J Formos Med Assoc 2000; 99:219-223. 112. Parke DW 2nd, Font RL: Diffuse toxoplasmic retinochoroiditis in a patient with AIDS. Arch Ophthalmol 1986; 104:571575. 113. Moraes HV Jr: Punctate outer retinal toxoplasmosis in an HIV-positive child. Ocul Immunol Inflamm 1999; 7:93-95. 114. Matzkin DC, Slamovits TL, Rosenbaum PS: Simultaneous intraocular and orbital non-Hodgkin lymphoma in the acquired immune deficiency syndrome. Ophthalmology 1994; 101:850-855. 115. Ormerod LD, Puklin JE: AIDS-associated intraocular lymphoma causing primary retinal vasculitis. Ocul Immunol Inflamm 1997; 5:271-278. 116. Rivero ME, Kuppermann BD, Wiley CA, et al: Acquired immunodeficiency syndrome–related intraocular B-cell lymphoma. Arch Ophthalmol 1999; 117:616-622. 117. Schanzer MC, Font RL, O’Malley RE: Primary ocular malignant lymphoma associated with the acquired immune deficiency syndrome. Ophthalmology 1991; 98:88-91. 118. Stanton CA, Sloan B 3rd, Slusher MM, et al: Acquired immunodeficiency syndrome–related primary intraocular lymphoma. Arch Ophthalmol 1992; 110:1614-1617. 119. Kim IT, Shim JY, Yung BY: Serous retinal detachment in a patient with rhino-orbital mucormycosis. Jpn J Ophthalmol 2001; 45:301-304. 120. Newman RM, Kline LB: Evolution of fundus changes in mucormycosis. J Neuroophthalmol 1997; 17:51-52. 121. Kadayifcilar S, Gedik S, Onerci M, et al: Chorioretinal alterations in mucormycosis. Eye 2001; 15:99-102. 122. Verma S, Graham EM: Cryptococcus presenting as cloudy choroiditis in an AIDS patient. Br J Ophthalmol 1995; 79:618619. 123. Garrity JA, Herman DC, Imes R, et al: Optic nerve sheath decompression for visual loss in patients with acquired immunodeficiency syndrome and cryptococcal meningitis with papilledema. Am J Ophthalmol 1993; 116:472-478. 124. Freeman WR, Gross JG, Labelle J, et al: Pneumocystis carinii choroidopathy: a new clinical entity. Arch Ophthalmol 1989; 107:863-867. 125. Shami MJ, Freeman W, Friedberg D, et al: A multicenter study of Pneumocystis choroidopathy. Am J Ophthalmol 1991; 112:15-22. 126. Biousse V, Newman NJ: Neuro-ophthalmology of mitochondrial diseases. Semin Neurol 2001; 21:275-291. 127. Kerrison JB, Biousse V, Newman NJ: Retinopathy of NARP syndrome. Arch Ophthalmol 2000; 118:298-299. 128. Isashiki Y, Nakagawa M, Ohba N, et al: Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand 1998; 76:6-13. 129. Latkany P, Ciulla TA, Cacchillo PF, et al: Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation. Am J Ophthalmol 1999; 128:112-114. 130. Smith PR, Bain SC, Good PA, et al: Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the mitochondrial DNA 3243 tRNA(Leu) A to G mutation. Ophthalmology 1999; 106:11011118. 131. Massin P, Virally-Monod M, Vialettes B, et al: Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group. Ophthalmology 1999; 106: 1821-1827.
313
132. Leys AM, Van Eyck LM, Nuttin BJ, et al: Metastatic carcinoma to the retina: clinicopathologic findings in two cases. Arch Ophthalmol 1990; 108:1448-1452. 133. Spraul CW, Martin DF, Hagler WS, et al: Cytology of metastatic cutaneous melanoma to the vitreous and retina. Retina 1996; 16:328-332. 134. DeAngelis LM, Yahalom J, Heinemann MH, et al: Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology 1990; 40:80-86. 135. Hochberg FH, Miller DC: Primary central nervous system lymphoma. J Neurosurg 1988; 68:835-853. 136. Peterson K, Gordon KB, Heinemann MH, et al: The clinical spectrum of ocular lymphoma. Cancer 1993; 72:843-849. 137. Verbraeken HE, Hanssens M, Priem H, et al: Ocular nonHodgkin’s lymphoma: a clinical study of nine cases. Br J Ophthalmol 1997; 81:31-36. 138. Merchant A, Foster CS: Primary intraocular lymphoma. Int Ophthalmol Clin 1997; 37:101-115. 139. Freeman LN, Schachat AP, Knox DL, et al: Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 1987; 94:1631-1639. 140. Chang TS, Byrne SF, Gass JD, et al: Echographic findings in benign reactive lymphoid hyperplasia of the choroid. Arch Ophthalmol 1996; 114:669-675. 141. Rockwood EJ, Zakov ZN, Bay JW: Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). Report of three cases. J Neurosurg 1984; 61:369-374. 142. Corriveau C, Easterbrook M, Payne D: Lymphoma simulating uveitis (masquerade syndrome). Can J Ophthalmol 1986; 21:144-149. 143. Assaf N, Hasson T, Hoch-Marchaim H, et al: An experimental model for infiltration of malignant lymphoma to the eye and brain. Virchows Arch 1997; 431:459-467. 144. Ridley ME, McDonald HR, Sternberg P Jr, et al: Retinal manifestations of ocular lymphoma (reticulum cell sarcoma). Ophthalmology 1992; 99:1153-1160; discussion, Ophthalmology 1992; 99:1160-1161. 145. Gass JD, Trattler HL: Retinal artery obstruction and atheromas associated with non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol 1991; 109:11341139. 146. Sawyer RA, Selhorst JB, Zimmerman LE, et al: Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol 1976; 81:606-613. 147. Thirkill CE, Tait RC, Tyler NK, et al: The cancer-associated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 1992; 33:2768-2772. 148. Polans AS, Burton MD, Haley TL, et al: Recoverin, but not visinin, is an autoantigen in the human retina identified with a cancer-associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34:81-90. 149. Adamus G, Aptsiauri N, Guy J, et al: The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Clin Immunol Immunopathol 1996; 78:120-129. 150. Chan JW: Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol 2003; 48:12-38. 151. Heckenlively JR, Fawzi AA, Oversier J, et al: Autoimmune retinopathy: patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol 2000; 118:1525-1533. 152. Whitcup SM, Vistica BP, Milam AH, et al: Recoverinassociated retinopathy: a clinically and immunologically distinctive disease. Am J Ophthalmol 1998; 126:230-237. 153. Adamus G, Ren G, Weleber RG: Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 2004; 4:5. 154. Weleber RG, Watzke RC, Shults WT, et al: Clinical and electrophysiologic characterization of paraneoplastic and
314
155.
156. 157. 158. 159.
160.
161. 162. 163. 164. 165.
166. 167. 168.
169. 170. 171.
172. 173. 174.
Section
IV
Neuro-ophthalmology
autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol 2005; 139:780-794. Keltner JL, Thirkill CE, Yip PT: Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol 2001; 21:173-187. Milam AH, Saari JC, Jacobson SG, et al: Autoantibodies against retinal bipolar cells in cutaneous melanoma–associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34:91-100. Cross SA, Salomao DR, Parisi JE, et al: Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5IgG. Ann Neurol 2003; 54:38-50. Gass JD, Gieser RG, Wilkinson CP, et al: Bilateral diffuse uveal melanocytic proliferation in patients with occult carcinoma. Arch Ophthalmol 1990; 108:527-533. O’Neal KD, Butnor KJ, Perkinson KR, et al: Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome. Surv Ophthalmol 2003; 48:613-625. Chahud F, Young RH, Remulla JF, et al: Bilateral diffuse uveal melanocytic proliferation associated with extraocular cancers: review of a process particularly associated with gynecologic cancers. Am J Surg Pathol 2001; 25:212-218. Jackson GR, Owsley C: Visual dysfunction, neurodegenerative diseases, and aging. Neurol Clin 2003; 21:709-728. Paulus W, Schwarz G, Werner A, et al: Impairment of retinal increment thresholds in Huntington’s disease. Ann Neurol 1993; 34:574-578. Cox TA, McDarby JV, Lavine L, et al: A retinopathy on Guam with high prevalence in Lytico-Bodig. Ophthalmology 1989; 96:1731-1735. Jankovic J, Kirkpatrick JB, Blomquist KA, et al: Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology 1985; 35:227-234. Egan RA, Weleber RG, Hogarth P, et al: Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). Am J Ophthalmol 2005; 140:267-274. Houlden H, Lincoln S, Farrer M, et al: Compound heterozygous PANK2 mutations confirm HARP and HallervordenSpatz syndromes are allelic. Neurology 2003; 61:1423-1426. Miyajima H, Nishimura Y, Mizoguchi K, et al: Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 1987; 37:761-767. Dunaief JL, Richa C, Franks EP, et al: Macular degeneration in a patient with aceruloplasminemia, a disease associated with retinal iron overload. Ophthalmology 2005; 112:10621065. Dingle J, Havener WH: Ophthalmoscopic changes in a patient with Wilson’s disease during long-term penicillamine therapy. Ann Ophthalmol 1978; 10:1227-1230. Bassen FA, Kornzweig AL: Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. Blood 1950; 5:381387. Refsum S: Heredopathia atactica polyneuritiformis: a familial syndrome not hitherto described. A contribution to the clinical study of the hereditary disorders of the nervous system. Acta Psychiatr Scand 1946; 38:1-303. Yokota T, Wada Y, Furukawa T, et al: Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol 1987; 22:84-87. Berger AS, Tychsen L, Rosenblum JL: Retinopathy in human vitamin E deficiency. Am J Ophthalmol 1991; 111: 774-775. Enevoldson TP, Sanders MD, Harding AE: Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy: a clinical and genetic study of eight families. Brain 1994; 117(Pt 3):445-460.
175. Ahn JK, Seo JM, Chung H, et al: Anatomical and functional characteristics in atrophic maculopathy associated with spinocerebellar ataxia type 7. Am J Ophthalmol 2005; 139:923-925. 176. Fitzsimons RB, Gurwin EB, Bird AC: Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy: a general association with genetic and therapeutic implications. Brain 1987; 110(Pt 3):631-648. 177. Kimizuka Y, Kiyosawa M, Tamai M, et al: Retinal changes in myotonic dystrophy: clinical and follow-up evaluation. Retina 1993; 13:129-135. 178. Backhouse O, Griffiths B, Henderson T, et al: Ophthalmic manifestations of dermatomyositis. Ann Rheum Dis 1998; 57:447-9. 179. La Piana FG: Sectoral retinal pigmentation in neurofibromatosis. Ann Ophthalmol 1977; 9:413-422. 180. Cotlier E: Café-au-lait spots of the fundus in neurofibromatosis. Arch Ophthalmol 1977; 95:1990-1992. 181. Destro M, D’Amico DJ, Gragoudas ES, et al: Retinal manifestations of neurofibromatosis: diagnosis and management. Arch Ophthalmol 1991; 109:662-666. 182. Font RL, Ferry AP: The phakomatoses. Int Ophthalmol Clin 1972; 12:1-50. 183. Moadel K, Yannuzzi LA, Ho AC, et al: Retinal vascular occlusive disease in a child with neurofibromatosis. Arch Ophthalmol 1994; 112:1021-1023. 184. Callender GR, Thigpen CA: Two neurofibromas in one eye. Am J Ophthalmol 1930; 13:121-124. 185. Freeman D: Neurofibroma of the choroid. Arch Ophthalmol 1934; 11:641-645. 186. Savino PJ, Glaser JS, Luxenberg MN: Pulsating enophthalmos and choroidal hamartomas: two rare stigmata of neurofibromatosis. Br J Ophthalmol 1977; 61:483-488. 187. Kobrin JL, Blodi FC, Weingeist TA: Ocular and orbital manifestations of neurofibromatosis. Surv Ophthalmol 1979; 24:45-51. 188. Lewis RA, Riccardi VM: Von Recklinghausen neurofibromatosis: incidence of iris hamartomata. Ophthalmology 1981; 88:348-354. 189. Huson S, Jones D, Beck L: Ophthalmic manifestations of neurofibromatosis. Br J Ophthalmol 1987; 71:235-238. 190. Green WR: The uveal tract. In Spencer WH, ed: Ophthalmic Pathology: An Atlas and Textbook. Philadelphia: WB Saunders, 1996, pp 1864-2099. 191. Landau K, Dossetor FM, Hoyt WF, et al: Retinal hamartoma in neurofibromatosis 2. Arch Ophthalmol 1990; 108:328-329. 192. Mautner VF, Lindenau M, Baser ME, et al: The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery 1996; 38:880-885; discussion, Neurosurgery 1996; 38:885886. 193. Rettele GA, Brodsky MC, Merin LM, et al: Blindness, deafness, quadriparesis, and a retinal malformation: the ravages of neurofibromatosis 2. Surv Ophthalmol 1996; 41:135-141. 194. Ragge NK, Baser ME, Riccardi VM, et al: The ocular presentation of neurofibromatosis 2. Eye 1997; 11(Pt 1):12-18. 195. Ragge NK, Baser ME, Klein J, et al: Ocular abnormalities in neurofibromatosis 2. Am J Ophthalmol 1995; 120:634-641. 196. Ragge NK: Clinical and genetic patterns of neurofibromatosis 1 and 2. Br J Ophthalmol 1993; 77:662-672. 197. Kaye LD, Rothner AD, Beauchamp GR, et al: Ocular findings associated with neurofibromatosis type II. Ophthalmology 1992; 99:1424-1429. 198. Meyers SM, Gutman FA, Kaye LD, et al: Retinal changes associated with neurofibromatosis 2. Trans Am Ophthalmol Soc 1995; 93:245-252; discussion, Trans Am Ophthalmol Soc 1995; 93:252-257. 199. Baser ME, Kluwe L, Mautner VF: Germ-line NF2 mutations and disease severity in neurofibromatosis type 2 patients with retinal abnormalities. Am J Hum Genet 1999; 64:1230-1233.
chapter 24 retinal disease 200. Zimmer-Galler IE, Robertson DM: Long-term observation of retinal lesions in tuberous sclerosis. Am J Ophthalmol 1995; 119:318-324. 201. Gunduz K, Eagle RC Jr, Shields CL, et al: Invasive giant cell astrocytoma of the retina in a patient with tuberous sclerosis. Ophthalmology 1999; 106:639-642. 202. Nyboer JH, Robertson DM, Gomez MR: Retinal lesions in tuberous sclerosis. Arch Ophthalmol 1976; 94:1277-1280. 203. Lucchese NJ, Goldberg MF: Iris and fundus pigmentary changes in tuberous sclerosis. J Pediatr Ophthalmol Strabismus 1981; 18:45-46. 204. Awan KJ: Leaf-shaped lesions of ocular fundus and white eyelashes in tuberous sclerosis. South Med J 1982; 75:227-228. 205. Green JS, Bowmer MI, Johnson GJ: Von Hippel-Lindau disease in a Newfoundland kindred. CMAJ 1986; 134:133-138, 146. 206. Hardwig P, Robertson DM: von Hippel-Lindau disease: a familial, often lethal, multi-system phakomatosis. Ophthalmology 1984; 91:263-270. 207. Lamiell JM, Salazar FG, Hsia YE: von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 1989; 68:1-29. 208. Maher ER, Yates JR, Harries R, et al: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990; 77:1151-1163. 209. Moore AT, Maher ER, Rosen P, et al: Ophthalmological screening for von Hippel-Lindau disease. Eye 1991; 5(Pt 6):723-728. 210. de Jong PT, Verkaart RJ, van de Vooren MJ, et al: Twin vessels in von Hippel-Lindau disease. Am J Ophthalmol 1988; 105:165-169. 211. Chang JH, Spraul CW, Lynn ML, et al: The two-stage mutation model in retinal hemangioblastoma. Ophthalmic Genet 1998; 19:123-130. 212. Neumann HP: Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 1987; 16:220-226. 213. Susac JO, Smith JL, Scelfo RJ: The “tomato-catsup” fundus in Sturge-Weber syndrome. Arch Ophthalmol 1974; 92:69-70. 214. Bacin F, Bonnet M, Caujolle JP, et al: [Choroidal angioma and Sturge-Weber syndrome.] J Fr Ophtalmol 1997; 20:405-407. 215. Shin GS, Demer JL: Retinal arteriovenous communications associated with features of the Sturge-Weber syndrome. Am J Ophthalmol 1994; 117:115-117. 216. Hopen G, Smith JL, Hoff JT, et al: The Wyburn-Mason syndrome: concomitant chiasmal and fundus vascular malformations. J Clin Neuroophthalmol 1983; 3:53-62. 217. Effron L, Zakov ZN, Tomsak RL: Neovascular glaucoma as a complication of the Wyburn-Mason syndrome. J Clin Neuroophthalmol 1985; 5:95-98. 218. Brod RD, Shields JA, Shields CL, et al: Unusual retinal and renal vascular lesions in the Klippel-Trénaunay-Weber syndrome. Retina 1992; 12:355-358. 219. Okada H, Horibe H, Yoshiyuki O, et al: A prospective study of cerebrovascular disease in Japanese rural communities, Akabane and Asahi. Part 1: evaluation of risk factors in the occurrence of cerebral hemorrhage and thrombosis. Stroke 1976; 7:599-607. 220. Svardsudd K, Wedel H, Aurell E, et al: Hypertensive eye ground changes: prevalence, relation to blood pressure and prognostic importance. The study of men born in 1913. Acta Med Scand 1978; 204:159-167. 221. Tanaka H, Hayashi M, Date C, et al: Epidemiologic studies of stroke in Shibata, a Japanese provincial city: preliminary report on risk factors for cerebral infarction. Stroke 1985; 16:773-780. 222. Nakayama T, Date C, Yokoyama T, et al: A 15.5-year follow-up study of stroke in a Japanese provincial city. The Shibata Study. Stroke 1997; 28:45-52.
315
223. Wong TY, Klein R, Couper DJ, et al: Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 2001; 358:1134-1140. 224. Wong TY, Klein R, Sharrett AR, et al: Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002; 33:1487-1492. 225. Wong TY, Klein R, Sharrett AR, et al: Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002; 288:67-74. 226. Wong TY, Mosley TH Jr, Klein R, et al: Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middleaged people. Neurology 2003; 61:806-811. 227. Sharma S, Pater JL, Lam M, et al: Can different types of retinal emboli be reliably differentiated from one another? An inter- and intraobserver agreement study. Can J Ophthalmol 1998; 33:144-148. 228. Savino PJ, Glaser JS, Cassady J: Retinal stroke: is the patient at risk? Arch Ophthalmol 1977; 95:1185-1189. 229. Wilson LA, Warlow CP, Russell RW: Cardiovascular disease in patients with retinal arterial occlusion. Lancet 1979; 1:292294. 230. Babikian V, Wijman CA, Koleini B, et al: Retinal ischemia and embolism: etiologies and outcomes based on a prospective study. Cerebrovasc Dis 2001; 12:108-113. 231. Smit RL, Baarsma GS, Koudstaal PJ: The source of embolism in amaurosis fugax and retinal artery occlusion. Int Ophthalmol 1994; 18:83-86. 232. McCullough HK, Reinert CG, Hynan LS, et al: Ocular findings as predictors of carotid artery occlusive disease: is carotid imaging justified? J Vasc Surg 2004; 40:279-286. 233. Sharma S, Brown GC, Pater JL, et al: Does a visible retinal embolus increase the likelihood of hemodynamically significant carotid artery stenosis in patients with acute retinal arterial occlusion? Arch Ophthalmol 1998; 116:16021606. 234. Bruno A, Jones WL, Austin JK, et al: Vascular outcome in men with asymptomatic retinal cholesterol emboli: a cohort study. Ann Intern Med 1995; 122:249-253. 235. Klein R, Klein BE, Moss SE, et al: Retinal emboli and cardiovascular disease: the Beaver Dam Eye Study. Arch Ophthalmol 2003; 121:1446-1451. 236. Wong TY, Larsen EK, Klein R, et al: Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities & Cardiovascular Health studies. Ophthalmology 2005; 112:540-547. 237. Hedges TR Jr: Ophthalmoscopic findings in internal carotid artery occlusion. Bull Johns Hopkins Hosp 1962; 111:8997. 238. Kearns TP, Hollenhorst RW: Venous-stasis retinopathy of occlusive disease of the carotid artery. Mayo Clin Proc 1963; 38:304-312. 239. Costa VP, Kuzniec S, Molnar LJ, et al: The effects of carotid endarterectomy on the retrobulbar circulation of patients with severe occlusive carotid artery disease: an investigation by color Doppler imaging. Ophthalmology 1999; 106:306310. 240. Wilson WB, Leavengood JM, Ringel SP, et al: Transient ocular motor paresis associated with acute internal carotid artery occlusion. Ann Neurol 1989; 25:286-290. 241. McDonough RL, Forteza AM, Flynn HWJ: Internal carotid artery dissection causing a branch retinal artery in a young adult. Am J Ophthalmol 1998; 125:706-708. 242. Newman NJ, Kline LB, Leifer D, et al: Ocular stroke and carotid artery dissection. Neurology 1989; 39:1462-1464. 243. Godfrey DG, Biousse V, Newman NJ: Delayed branch retinal artery occlusion following presumed blunt common carotid dissection. Arch Ophthalmol 1998; 116:1120-1121.
316
Section
IV
Neuro-ophthalmology
244. Palmer HE, Stanford MR, Sanders MD, et al: Visual outcome of patients with idiopathic ischaemic and non-ischaemic retinal vasculitis. Eye 1996; 10(Pt 3):343-348. 245. Palmer HE, Zaman AG, Edelsten CE, et al: Systemic morbidity in patients with isolated idiopathic retinal vasculitis. Lancet 1995; 346:505-506. 246. Cobo-Soriano R, Sanchez-Ramon S, Aparicio MJ, et al: Antiphospholipid antibodies and retinal thrombosis in patients without risk factors: a prospective case-control study. Am J Ophthalmol 1999; 128:725-732. 247. Cahill MT, Stinnett SS, Fekrat S: Meta-analysis of plasma homocysteine, serum folate, serum vitamin B(12), and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease. Am J Ophthalmol 2003; 136:1136-1150. 248. Susac JO, Hardman JM, Selhorst JB: Microangiopathy of the brain and retina. Neurology 1979; 29:313-316. 249. O’Halloran HS, Pearson PA, Lee WB, et al: Microangiopathy of the brain, retina, and cochlea (Susac’s syndrome): a report of five cases and a review of the literature. Ophthalmology 1998; 105:1038-1044. 250. Susac JO, Murtagh FR, Egan RA, et al: MRI findings in Susac’s syndrome. Neurology 2003; 61:1783-1787. 251. Haritoglou C, Rudolph G, Hoops JP, et al: Retinal vascular abnormalities in CADASIL. Neurology 2004; 62:1202-1205. 252. Cumurciuc R, Massin P, Paques M, et al: Retinal abnormalities in CADASIL: a retrospective study of 18 patients. J Neurol Neurosurg Psychiatry 2004; 75:1058-1060. 253. Rufa A, De Stefano N, Dotti MT, et al: Acute unilateral visual loss as the first symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Arch Neurol 2004; 61:577-580. 254. Parisi V, Pierelli F, Fattapposta F, et al: Early visual function impairment in CADASIL. Neurology 2003; 60:2008-2010. 255. Haritoglou C, Hoops JP, Stefani FH, et al: Histopathological abnormalities in ocular blood vessels of CADASIL patients. Am J Ophthalmol 2004; 138:302-305. 256. Storimans CW, Van Schooneveld MJ, Oosterhuis JA, et al: A new autosomal dominant vascular retinopathy syndrome. Eur J Ophthalmol 1991; 1:73-78.
257. Terwindt GM, Haan J, Ophoff RA, et al: Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud’s phenomenon. Brain 1998; 121(Pt 2):303-316. 258. Ophoff RA, DeYoung J, Service SK, et al: Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3. Am J Hum Genet 2001; 69:447-453. 259. Vahedi K, Massin P, Guichard JP, et al: Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy. Neurology 2003; 60:57-63. 260. Sher NA, Letson RD, Desnick RJ: The ocular manifestations in Fabry’s disease. Arch Ophthalmol 1979; 97:671-676. 261. Dichgans M: A new cause of hereditary small vessel disease: angiopathy of retina and brain. Neurology 2003; 60:8-9. 262. Terson A: De l’hémorrhagie dans le corps vitre au cours de l’hémorrhagie cerebrale. Clin Ophthalmol 1900; 6:309312. 263. Fahmy JA: Fundal haemorrhages in ruptured intracranial aneurysms. I. Material, frequency and morphology. Acta Ophthalmol (Copenh) 1973; 51:289-298. 264. Manschot WA: Subarachnoid hemorrhage: intraocular symptoms and their pathogenesis. Am J Ophthalmol 1954; 38:501505. 265. Shaw HE Jr, Landers MB, Sydnor CF: The significance of intraocular hemorrhages due to subarachnoid hemorrhage. Ann Ophthalmol 1977; 9:1403-1405. 266. McCarron MO, Alberts MJ, McCarron P: A systematic review of Terson’s syndrome: frequency and prognosis after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2004; 75:491-493. 267. Fahmy JA: Fundal haemorrhages in ruptured intracranial aneurysms. II. Correlation with the clinical course. Acta Ophthalmol (Copenh) 1973; 51:299-304. 268. Cogan DG: Ocular correlates of inborn metabolic defects. Can Med Assoc J 1966; 95:1055-1065. 269. Small KW, Letson R, Scheinman J: Ocular findings in primary hyperoxaluria. Arch Ophthalmol 1990; 108:89-93.
CHAPTER
25
EXAMINATION OF HEARING AND BALANCE ●
●
●
●
Brian C. Kung and Thomas O. Willcox, Jr.
Hearing loss and balance disorders are two of the most common reasons that patients visit their physicians. Varying degrees of hearing loss can affect patients at any age. One of every 1000 newborns is affected by some degree of hearing loss, and the prevalence of hearing loss rises with advancing age.1 By age 60, one of every three individuals is affected by hearing loss, and by age 85, one of every two is affected.1 Balance disorder, or “dizziness,” is the ninth most common complaint for which patients visit primary care physicians and the third most common complaint for 65- to 75-year-old patients.2-4 Hearing and balance disorders have a myriad of manifestations and etiologies, some of which are difficult to piece together. Treatment is often multidisciplinary, involving the neurologist, otolaryngologist, audiologist, neurosurgeon, and physical therapist, among others. It is important to recognize the signs and symptoms associated with specific types of hearing loss and balance disorders for the patient to receive proper referrals and proper treatment. The purpose of this chapter is to provide a better understanding of the otolaryngologist’s approach to the hearing and balance examination.
HEARING EXAMINATION There are three main forms of hearing loss: conductive, sensorineural, and mixed. Each can be caused by a wide variety of conditions, ranging from benign conditions, such as cerumen impaction, to potentially life-threatening diseases, such as squamous cell carcinoma of the temporal bone. Usually, conductive hearing loss is caused by a disorder in the external or middle ear, whereas a sensorineural hearing loss is caused by a disorder of the inner ear or neural structures leading from the inner ear to the central nervous system. Hearing loss can lead to speech and developmental delays in children and significant communication problems and decreased quality of life in both children and adults. Many of these conditions are treatable and early recognition is important. A structured hearing evaluation consists of a history, physical examination, and audiological testing; often radiological testing is necessary to lead to the proper diagnosis.
what to look for during the subsequent physical examination and audiological and/or radiographic tests in order to arrive at the correct diagnosis. The severity of the patient’s hearing loss can be assessed just by conversing with the patient in a normal or soft voice and observing whether the patient responds appropriately. If the patient speaks in a very loud voice, it may indicate a sensorineural cause of hearing loss, and if the patient speaks very softly, it may point to a conductive cause, as the patient’s voice may sound louder to the patient (just as a normal hearing person’s would if his or her ears were plugged). Sometimes, discrepancies between the patient’s behavior in conversation and during diagnostic tests can point to malingering as a possible diagnosis. When taking a history of present illness, specific points should be emphasized. These include the patient’s perception of the degree of hearing loss, whether the hearing loss is unilateral or bilateral, and the onset of the hearing loss (sudden within 3 days, rapidly progressive within 1 week, slowly progressive over weeks to years, fluctuating, or stable). The patient may have associated symptoms, such as aural fullness, tinnitus, vertigo, disequilibrium, otalgia, otorrhea, headache, visual problems, and other neurological complaints (facial numbness or weakness, ataxia, oscillopsia, etc.), that may help point to specific causes of hearing loss. The past medical history is also very helpful: cardiovascular, renal, rheumatological, hematological, endocrine, and neurological conditions can predispose a patient to certain types of hearing loss.5 Past surgical history should also be obtained, with special emphasis on head trauma and previous otological or neurological surgery. A history of noise exposure is also important, as excessive noise exposure, either suddenly or over a period of time, can lead to hearing loss. A full account of the patient’s recent medications, including potentially ototoxic medications, should be taken. It is very important to know whether there is a family history of hearing loss, as there is a genetic predisposition for many types of hearing loss, and many genes associated with deafness and predisposition to hearing loss have been identified.1,5
Physical Examination History A thorough history is one of the most important aspects of a hearing evaluation. Often, this gives the physician clues as to
318
A complete head and neck examination can give many clues to the cause of a patient’s hearing loss. The auricle and the postauricular area should be examined for deformities, surgical incisions, the presence of a hearing aid, and patency of the external
chapter 25 examination of hearing and balance auditory canal. Something as simple as cerumen impaction can be the cause of hearing loss in some patients, but other conditions, such as foreign bodies, exostoses, canal stenosis/atresia, and carcinoma of the external canal, can be more troublesome. Pneumatic otoscopy can then be used to examine the tympanic membrane and middle ear. Here, the presence of a tympanostomy tube, tympanosclerosis (scarring of the tympanic membrane), tympanic membrane perforation, retraction pocket, fluid in the middle ear, middle ear masses, or otorrhea can be assessed. It is important to obtain a good seal with the speculum in order to assess the mobility of the tympanic membrane. External and middle ear abnormalities usually point to a conductive component of hearing loss. Tuning fork testing is an essential part of the physical examination and can help determine if the cause of hearing loss is conductive, sensorineural, or mixed. The three types of tuning forks that can be used are 256 Hz (middle C), 512 Hz (octave above middle C), and 1024 Hz (two octaves above middle C). The Rinne test is useful in determining if there is a conductive hearing loss and is performed by striking the tuning fork and placing it on the mastoid bone (testing bone conduction). Once the patient stops hearing the sound, the tines of the tuning fork are then placed in front of the external canal (testing air conduction) with the tines oriented in the head-frontal plane, and the patient indicates whether he or she can hear the sound. If the patient can hear the sound, air conduction is greater than bone conduction, and the result is normal, or “positive.” If the patient cannot hear the sound, bone conduction is greater than air conduction, and the result is abnormal, or “negative.” The degree of conductive hearing loss can be estimated based on the results of the Rinne test. A test that is negative at 256 Hz and positive at 512 and 1024 Hz indicates a mild 20- to 30decibel (dB) conductive loss. A test that is negative at 256 and 512 Hz and positive at 1024 Hz indicates a moderate 30- to 45-dB conductive loss. A negative test at all three frequencies indicates a severe 45- to 60-dB conductive loss.6,7 The Weber test is a test used to lateralize the hearing loss. The tuning fork is struck and placed on the patient’s vertex, nasal bones, or maxillary teeth in the midline. The single most clinically useful fork used here is the 512-Hz variety, as the 256-Hz fork can be overly sensitive, leading to many false-positive results, and the 1024-Hz fork may not be sensitive enough.7-9 Lateralization of sound to one ear during the Weber test indicates either a conductive hearing loss in that ear or a greater sensorineural loss in the opposite ear.7 Simple tuning fork tests using only a few frequencies are far from comprehensive. If both ears are symmetrically affected by a sensorineural hearing loss, both the Rinne and Weber tests will be normal, provided the patient is able to hear the tuning fork at all. The physical examination should also include an assessment of any craniofacial deformities or stigmata that may be associated with hereditary causes of hearing loss or associated systemic diseases. Also, a full cranial nerve examination should be performed, as asymmetries in any of the cranial nerves may indicate that hearing loss is just one component of more severe or extensive disease, such as a skull base neoplasm. A decreased corneal blink reflex and hypesthesia of the external auditory canal (Hitselberger’s sign) can be suspicious for an acoustic neuroma. Finally, attention to the nose, nasopharynx, oral cavity, oropharynx, larynx, and hypopharynx can reveal other causes of hearing loss (e.g., the presence of nasopharyngeal carcinoma as the cause of serous otitis media).
319
Audiological Testing Audiological testing has been available for decades, but developments over the years have advanced the field of audiology to include tests and procedures that can determine the site of lesion with far greater accuracy than before. Otolaryngologists and audiologists often need to rely on one another to diagnose accurately the cause of a patient’s hearing loss using a combination of the history, physical examination, and results of various audiological tests. The audiological test battery includes audiometry (pure tone and speech), acoustic immittance testing (tympanometry and acoustic reflex testing), electrophysiological testing (auditory brainstem response and electrocochleography), and otoacoustic emission testing.
Pure-Tone Audiometry Pure-tone audiometry is the most commonly used test to measure auditory sensitivity. Pure-tone signals are delivered to the ear via air conduction and bone conduction at a variety of frequencies, and the patient responds to the sound by signaling the examiner with a button or by raising a hand. The response can be modified for pediatric patients or patients who lack the capacity to respond in the conventional manner. Although the entire range of human hearing is from 20 to 20,000 Hz, the typical range of frequencies tested runs from 250 to 8000 Hz, which is the range necessary to understand speech.10 The intensity of a sound presented is represented by a ratio of its sound pressure to a reference sound pressure, defined as the amount of pressure that can just be sensed by a normal human ear at its most sensitive frequency (0.0002 dyne/cm2).11 As the pressure level of a presented sound is often many times the reference sound pressure, the simplest way to present this ratio is to use the decibel, a logarithmic unit: dB = 20 log10(P2/P1)
where P2 is the presented sound pressure and P1 is the reference sound pressure. A sound referenced to the reference sound pressure is known as the absolute sound level, presented as decibels sound pressure level (dB SPL). The normal human ear is variably sensitive to different frequencies throughout its range, so clinically, the easiest reference level to use is the sound pressure level for each tested frequency that can be heard by a normal ear. The sound level is presented as decibels hearing loss, or dB HL.11 For example, if a normal hearing patient responds to a sound P2 that is equal to P1 (what another normal person would hear), then that patient has 20 log10 1 = 20(0) = 0 dB HL. If a patient with hearing loss responds to a sound P2 that is 100 times what a normal person would hear, then that patient has 20 log10 (100/1) = 20(2) = 40 dB HL. If a patient with hyperacusis (supersensitive hearing) responds to a sound P2 that is 1/10 what a normal person would hear, then that patient has 20 log10 (1/10) = 20(−1) = −20 dB HL. These examples help to illustrate that dB is indeed a comparison between sound levels and that 0 dB or negative dB does not mean that there is no sound⎯it just means that the sound is the same as or lower than the reference sound level, respectively. Auditory threshold is defined as the lowest signal intensity at which the signal can be identified 50% of the time.12 Air
320
Section
V
Neuro-Otology
conduction thresholds are determined by presenting sound to the ears via headphones or insert earphones, and bone conduction thresholds are determined by vibrating the mastoid directly. Air conduction thresholds measure the sensitivity of the entire auditory system from the external ear to the auditory cortex. When analyzed alone, they do not provide much information regarding the etiology of hearing loss. However, when they are analyzed together with bone conduction thresholds, which measure the degree of sensorineural hearing loss, they can provide valuable information regarding both the type and severity of the hearing loss.12 When air conduction thresholds are elevated relative to bone conduction thresholds, an “air-bone gap” exists, indicating a conductive hearing loss. Air conduction and bone conduction thresholds showing the same amount of hearing loss indicate a sensorineural hearing loss. A mixed hearing loss is present when both air and bone conduction thresholds are elevated, but air conduction thresholds are more elevated than bone conduction thresholds. The normal region on the audiogram is from 0 to 20 dB HL for adults and from 0 to 15 dB HL for children. Mild hearing loss is 20 to 40 dB HL, moderate loss is 40 to 55 dB HL, moderately severe loss is 55 to 70 dB HL, severe loss is 70 to 90 dB HL, and profound loss is above 90 dB HL. Hearing sensitivity within the speech frequencies is known as the pure-tone average (PTA) and can be calculated by adding the thresholds obtained at 500, 1000, and 2000 Hz and dividing the result by 3.11 For audiometric results to be valid, the patient must respond to stimulation of the ear being tested. When noninsert earphones are used, sounds greater than 40 dB HL presented to one ear can cross over to the opposite ear, most likely with the vibration of the earphone against the skull acting as a bone conductor. The amount of sound needed for crossover to occur is known as the interaural attenuation, which for air conduction is about 50 dB HL for lower frequencies and 60 dB HL for higher frequencies. The interaural attenuation is considerably higher when insert earphones are used. For bone conduction, interaural attenuation is less than 10 dB HL.11 To correct for the presence of interaural attenuation when a true hearing loss is present, masking techniques are used. A narrow band “white” noise is presented to the nontest ear when the true stimulus is being given to the test ear, and with adequate masking, any sound crossing over to the nontest ear is masked by the noise. To work, the masking noise presented to the nontest must be greater than the threshold of hearing for the nontest ear.11 This can be a problem when bilateral hearing loss (especially conductive) exists, as masking presented to the nontest ear can cross back over to the test ear. This is known as a “masking dilemma.”10 In air conduction testing, masking should be used when there is a difference between the air conduction presentation level to the test ear and the bone conduction threshold of the nontest ear of greater than 40 dB for lower frequencies and greater than 60 dB for higher frequencies. In bone conduction testing, masking should be used whenever there is any difference in the air and bone conduction thresholds.10
softest level at which the patient can barely detect the presence of a speech signal 50% of the time.12 The SRT is the softest level at which the patient can repeat 50% of balanced disyllabic words, or spondees (e.g. “hot dog,” “baseball”), correctly.10,12 The SDT should correspond to the PTA, whereas the SRT is usually about 8 to 9 dB higher than the PTA.12 Both SDT and SRT can be measured with bone conduction testing and can be masked if necessary. Discrepancies between the PTA and the SDT or SRT can indicate malingering. The speech discrimination score is a test of the patient’s ability to identify monosyllabic words, or phonemes, at a suprathreshold level, usually about 40 dB above the SRT.10 The speech discrimination score is important in that it helps assess the patient’s ability to understand speech, to communicate effectively, and to benefit from amplification. It also provides some information regarding the patient’s central auditory function.12 In general, patients with conductive hearing loss tend to have excellent speech discrimination scores when presented with sounds loud enough for them to hear. Patients with cochlear sensorineural loss tend to have lower speech discrimination scores, and patients with retrocochlear sensorineural loss (from lesions of the eighth cranial nerve to the auditory cortex) have even lower speech discrimination scores. They may even have lower speech discrimination in the presence of normal pure-tone thresholds.12
Tympanometry Acoustic immittance refers to either acoustic admittance (the ease with which energy flows through a system) or acoustic impedance (the blockage of energy flow through a system).12 In tympanometry, acoustic immittance measures are used to determine the status of the tympanic membrane and middle ear. A probe is placed in the ear canal and an airtight seal is obtained. A tone is introduced into the ear canal and the pressure in the canal is varied. When the pressure in the ear canal is equal to the middle ear pressure, the tympanic membrane will be at its most compliant (highest admittance) and will absorb the sound. This results in a tympanometric peak.10 If eustachian tube function is normal, the middle ear pressure is equal to the atmospheric pressure and the peak occurs at 0 mm H2O⎯this corresponds to a type A tympanogram. If there is negative middle ear pressure, the peak occurs at a negative pressure, corresponding to a type C tympanogram. If there is no peak (flat or type B tympanogram), there is no compliance of the tympanic membrane (no admittance), indicating a middle ear effusion, tympanic membrane perforation, or patent tympanostomy tube. These can be distinguished using ear canal volume measurements, with higher volumes corresponding to a hole in the tympanic membrane. Other types of tympanograms include As (shallow peak and low compliance at 0 mm H2O), indicating ossicular chain fixation or middle ear effusion, and Ad (very high peak and high compliance at 0 mm H2O), indicating ossicular chain discontinuity or a monomeric tympanic membrane.10
Speech Audiometry Commonly measured speech tests include the speech detection threshold (SDT), the speech reception threshold (SRT), and speech discrimination or word recognition. The SDT is the
Acoustic Reflex In acoustic reflex testing, acoustic immittance measures are used to assess the neural pathway surrounding the stapedial
chapter 25 examination of hearing and balance reflex, which occurs in response to a loud sound (70 to 90 dB above threshold).10 The afferent limb of the stapedial reflex is the ipsilateral eighth nerve, which leads to the brainstem. Complex pathways in the brainstem involving the ipsilateral ventral cochlear nucleus, trapezoid body, and bilateral medial superior olives lead from the eighth nerve on the ipsilateral (stimulated) side to the motor nucleus of the facial nerve on both sides of the brainstem.7,10-12 The efferent limb is the ipsilateral and contralateral facial nerves, which innervate the stapedius muscles. When the stapedius muscle contracts, the ossicular chain stiffens, causing a small change in compliance in the middle ear system that is detected by the probe.11 Patients with mild to moderate cochlear sensorineural hearing loss have reflexes bilaterally at about the same intensity level as those with normal hearing, but patients with severe or profound hearing loss have absent reflexes when the affected ear is stimulated.10 A conductive hearing loss results in absent reflexes when the affected ear is stimulated, as sound will not be loud enough to stimulate the reflex. Even when the normal ear is stimulated, the ear with the conductive loss does not have a reflex, as the middle ear condition prevents the stapedius from contracting.10 A lesion of the eighth nerve should result in absent reflexes bilaterally when the affected ear is stimulated, but reflexes should be present bilaterally when the nonaffected ear is stimulated. This can be confused with the reflex result associated with profound unilateral hearing loss (>70 dB) of cochlear origin. Lesions of the brainstem affecting the central crossed pathways may result in present ipsilateral reflexes when each ear is stimulated but absent contralateral reflexes. A facial nerve lesion results in an absent reflex on the affected side, no matter which side is stimulated, provided the lesion is proximal to the branching of the nerve to the stapedius muscle.10
Auditory Brainstem Response The auditory brainstem response (ABR) is an electrophysiological recording of responses of the distal auditory pathway (eighth nerve and brainstem) to sounds.11 The ABR involves placement of electrodes on the patient’s head and presentation of sound to the ear. When sound is presented to a normal ear, either in click form or frequency-specific tones, five to seven peaks occurring within 10 milliseconds make up the ABR.12 Usually only the first five peaks are considered. Wave I represents the action potentials from the eighth nerve near the cochlea. Wave II comes from the eighth nerve near the cochlear nucleus in the brainstem. Waves I and II are the only waves generated by ipsilateral structures. All subsequent waves represent bilateral crossed pathways. Wave III comes from the caudal pons with contributions from the cochlear nucleus, trapezoid body, and superior olive. Wave IV probably comes from the lateral lemniscus. Wave V, the most prominent wave, comes from the lateral lemniscus as it approaches the inferior colliculus.11 For audiological purposes, the latencies and amplitudes of waves I, III, and V are analyzed, and comparisons between sides are made. In normal hearing, the latencies of waves I, III, and V are within normal ranges and the latencies between ears are within 0.2 to 0.4 milliseconds of each other. In conductive hearing loss, the absolute latency of wave I is prolonged, but the latencies between waves and the amplitudes are not
321
affected. In cochlear sensorineural loss, the wave I latency is slightly delayed and is small in amplitude, but the latencies between waves are not affected. In retrocochlear (neural) hearing loss, wave I tends to be normal, but latencies between waves I-III and I-IV are abnormally prolonged.10,11 In practice, the ABR is a good tool to definitively test hearing in uncooperative patients (newborns) and in suspected malingerers, and it can be used to evaluate the eighth nerve and brainstem structures in patients with suspected retrocochlear hearing loss. It is also used in neurotological surgical procedures, such as vestibular nerve section and acoustic neuroma removal.11
Electrocochleography Electrocochleography is a test of the electrical activity generated by the cochlea and eighth nerve. It is most often used to aid in the diagnosis of Ménière disease, but it can also be used for intraoperative monitoring of the cochlear and eighth nerve. An electrode is placed in the ear canal, on the tympanic membrane, or on the promontory of the cochlea in the middle ear. The three main signals detected by electrocochleography are the cochlear microphonic, the summating potential, and the action potential. The cochlear microphonic and summating potential reflect cochlear electrical activity, and the action potential reflects eighth nerve activity and is the same as wave I of the ABR. The calculation of interest is the summating potential/action potential ratio. An abnormally high ratio is suggestive of endolymphatic hydrops characteristic of Meniere’s disease.10,11
Otoacoustic Emissions Otoacoustic emissions (OAEs) represent auditory signals produced by the cochlear outer hair cells that can be picked up by a very sensitive microphone in the ear canal.12 Although they are a measure of cochlear function, abnormalities anywhere between the microphone and cochlea (e.g. middle ear) block any signals going from the cochlea to the microphone⎯they will not be detectable in the presence of conductive hearing loss.10 The three main types of OAEs are spontaneous, transient evoked, and distortion product. Spontaneous OAEs occur in the absence of a stimulus, but they only occur in less than one half to 60% of normal hearing individuals.10,11 Transient evoked OAEs (OAEs) are elicited by a brief click or tone burst. Distortion product OAEs (OAEs) are generated when two pure-tone stimuli of different frequencies are presented to the ear simultaneously. In response to these tones, the outer hair cells generate signals called distortion products that are related to the frequencies of the presented tones. Transient evoked OAEs are used to determine mainly if there is good cochlear function, whereas distortion product OAEs can be used to generate a curve resembling an audiogram based on frequency-specific responses of the cochlea.10-12 OAEs are useful in that they are specific to cochlear function. They are not present in conductive hearing loss or cochlear hearing loss greater than 25 to 30 dB HL. However, they can be present in retrocochlear (neural) hearing loss, which can help differentiate cochlear from retrocochlear lesions.10 OAEs are noninvasive and easy to perform⎯they can be used to screen hearing in infants, to confirm audiometric
322
Section
V
Neuro-Otology
testing in young children, to monitor the effects of ototoxic medications, to detect cochlear abnormalities in patients with tinnitus and normal audiograms, and to help detect malingerers.10,11
Radiographic Testing Radiographic testing is indicated in certain patients with either conductive or sensorineural hearing loss. A CT scan of the temporal bones can be useful to detect the presence of congenital inner ear malformations, middle ear masses, erosive skull base neoplasms, and temporal bone fractures. It is also important in assessing the patient’s surgical anatomy and in planning for procedures such as cholesteatoma removal or cochlear implantation. Magnetic resonance imaging (MRI) of the internal auditory canals is extremely useful in the diagnosis of unilateral or asymmetric sensorineural hearing loss. It is more sensitive and specific than ABR for the detection of acoustic neuromas and is the gold standard in the diagnosis of acoustic neuromas as a cause of retrocochlear (neural) hearing loss.5,13 MRI with gadolinium enhancement is able to detect small tumors less than 1 cm in diameter, which results in better facial and hearing function after tumor removal.13 MRI should also be heavily considered in the face of sudden sensorineural hearing loss, even if it resolves with steroids, because as many as 19% of patients with acoustic neuromas can present with sudden hearing loss.14 Some reports state that as many as 47.5% of cases of sudden hearing loss may be caused by an acoustic neuroma.14,15
BALANCE EXAMINATION The diagnosis and treatment of patients with “dizziness” can be very challenging and frustrating for the patient, the neurologist, the otolaryngologist, and the audiologist. A huge variety of disorders can cause the patient to have a sensation of dizziness, and a huge variety of terms can be used to describe it (lightheadedness, spinning, “swimming sensation,” “things not being right in the head”).16 Often, the diagnosis is made by piecing together many different pieces of information. It is important to realize that not every case of dizziness can be completely cured or diagnosed exactly. An organized, systematic approach is necessary in order to make a reasonably accurate diagnosis and to avoid confusion. Key components in the evaluation of dizziness include the history, physical examination, electronystagmography, rotary chair testing, and computerized dynamic posturography testing.
History Obtaining a careful history is probably the most important step in the diagnosis of dizziness, but it often requires patience. Symptoms are often vague and difficult for the patient to describe. It may seem faster to begin by asking a lot of leading questions, but the physician will actually save time by allowing the patient to describe what he or she is feeling in the patient’s own words. Especially important is the patient’s description of the first episode of dizziness, although this may be difficult to elicit in patients who are so consumed by their dizziness that they cannot focus on the initial event and in patients who have already seen multiple specialists and/or lawyers.16
When the patient describes his or her symptoms, it is important to distinguish whether the patient is experiencing a sensation of movement, such as a spinning sensation or a falling sensation. Vertigo, a false sensation of movement, should be distinguished from dizziness, which is any kind of altered sense of orientation.17 Lightheadedness refers to a sensation characteristic of presyncope, which may include temporary blurred vision and pale facial color. It should be distinguished from vertigo and is usually caused by nonvestibular problems such as the cardiac or vasovagal reflex, both of which can result in cerebral hypoxia.17 A sense of imbalance refers to the inability to maintain the center of gravity, which causes the patient to feel unsteady and as if he or she is going to fall.17 This can be caused by both vestibular and nonvestibular disorders. When the patient describes vertigo, further information must be gathered in order to differentiate whether it is caused by a peripheral or central lesion. Vertigo can be caused by lesions anywhere from the vestibular end organs (utricle, saccule, and semicircular canals), the vestibular nuclei, the cerebellum, brainstem pathways, and the cortex (rarely).17 An important characteristic to ascertain is whether the vertigo is episodic or continuous. If episodic, how long the attacks last, how often they occur, and whether they occur with head movement or positioning are important points to know. Associated auditory symptoms, such as hearing loss, aural fullness, and tinnitus, are all important to ask about. Also important are associated neurological symptoms, such as headache with or without aura, visual changes, oscillopsia, numbness, weakness, ataxia, seizure, and loss of consciousness. Asking if the vertigo is more intense with a Valsalva maneuver is also helpful. A full otological history including history of infection, otalgia, otorrhea, and previous otological surgery is essential. In addition, it is imperative to obtain a full past medical history, past surgical history, history of head trauma, recent medications (with attention to ototoxic medications, blood pressure medications, stimulants, depressants, and illegal drugs), diet, allergies, social history, and family history of hearing loss or vestibular problems.16 Sorting out the history is important in suggesting possible diagnoses as well as recognizing more extensive and complex conditions. Episodic intense vertigo lasting up to one minute associated with head positioning or movement and not associated with other auditory symptoms is characteristic of benign paroxysmal positional vertigo (BPPV),17 but brief 5- to 10second episodes associated with head movement may also be a sign of vascular compression of the eighth nerve complex.2 Episodic vertigo lasting minutes to hours sometimes associated with fluctuating hearing loss, tinnitus, and/or aural fullness is suggestive of Meniere’s disease, but vertigo lasting 2 to 20 minutes may be associated with transient ischemic attacks, especially when associated with visual changes, ataxia, and other neurological findings.17 An isolated attack of continuous vertigo lasting longer than 24 hours with a sudden onset is suggestive of vestibular neuronitis when not associated with hearing loss and with viral labyrinthitis when associated with hearing loss.17 However, sudden-onset vertigo associated with hearing loss and tinnitus can also represent a brainstem stroke.18 Vertigo brought about by straining or other Valsalvalike maneuvers are associated with perilymphatic fistula, Chiari malformation, and superior semicircular canal dehiscence.17 There is also vertigo induced by sound, which is known as the Tullio phenomenon. This can be associated with perilymph
chapter 25 examination of hearing and balance fistula, Meniere’s disease, congenital inner ear malformations, Lyme disease, and superior semicircular canal dehiscence.19 Taking the history of the dizzy patient may be the most difficult part of the balance examination, but when done in an organized fashion, sometimes with the help of a questionnaire or preprinted template, it can be extremely useful in knowing what to look for in subsequent tests and examinations.
Physical Examination The physical examination of a patient with a balance disorder should contain a complete head and neck examination, including a detailed neurotological examination specifically using oculomotor function testing, positional testing, and postural control testing.
Head and Neck Examination The head and neck examination is similar to that described previously. Additional information can be found by performing a fistula test, which can be done by either tragal pressure or pneumatic otoscopy. The patient is instructed to look straight ahead, and continuous positive and negative pressure is applied. Normally, the eyes will not drift, but a positive fistula test (Hennebert’s sign) is manifest by the eyes drifting away from the tested ear with positive pressure and toward the tested ear with negative pressure. A positive fistula test is associated with a perilymph fistula, Meniere’s disease, or superior semicircular canal dehiscence.17,19 The cranial nerve examination should be as thorough as possible, as every cranial nerve may be potentially affected in disease processes that cause vertigo. Oculomotor examination documenting the function of cranial nerves III, IV, and VI should be performed. Internuclear ophthalmoplegia produced by lesions in the medial longitudinal fasciculus of the lower midbrain and pons is important to recognize, as vertigo may be one of the manifesting signs of multiple sclerosis.16 Subtle abnormalities in cranial nerves V, VII, and VIII may indicate a retrocochlear lesion. These can be tested by closely examining facial symmetry at rest and during movement, performing the corneal blink reflex test, and performing tuning fork testing. Usually, though, patients with retrocochlear lesions will present with hearing loss rather than tinnitus or vertigo.16 Finally, cranial nerves IX, X, XI, and XII should be thoroughly examined.
Oculomotor Function Testing The basis for nystagmus and oculomotor testing revolves around the vestibulo-ocular reflex (VOR). The VOR is a pathway that associates the activity of paired semicircular canals to a set of extraocular muscles.20 There are two main types of VOR: the angular reflex associated with the semicircular canals and the linear reflex associated with the utricle and saccule. The purposes of the reflex are to maintain binocular vision and to stabilize images on the fovea during head movement.2 The pathway involves the vestibule, the vestibular nuclei, and the oculomotor nuclei with modulation between cerebellar centers. The easiest reflex pathway to test is the paired horizontal semicircular canals with cranial medial and lateral recti muscles. For example, in a normal individual, there is an equal tonic
323
firing rate of both vestibular nerves in the absence of head movement, but when the head turns to the left, the endolymph in the left horizontal canal moves to the right. This displaces the cupula and consequently the cilia toward the kinocilium, leading to an increased firing rate in the left superior vestibular nerve. The opposite effect occurs on the right side. Pathways in the brainstem then cause activation of the left medial rectus and the right lateral rectus, while the left lateral rectus and right medial rectus are inhibited. The eyes then move conjugately to the right in the exact opposing fashion to head rotation until they reach a limit. At this point, a saccade to the left brings the eyes back to the midline. When a patient has a unilateral left vestibular lesion, tonic input from the left vestibular nerve ceases, resulting in unopposed input from the right vestibular nerve. This leads to conjugate eye movements to the left (slow phase), followed by corrective saccades to the right (fast phase). The direction of nystagmus is defined by its fast phase. This is a right-beating spontaneous nystagmus. Right-beating torsional nystagmus would also occur from unopposed stimulation of the right superior and inferior canals. Upbeating or downbeating nystagmus is not characteristic of peripheral vestibular lesions and usually is caused by central lesions. Spontaneous peripheral nystagmus can be suppressed by visual fixation. The use of Frenzel lenses that do not allow visual fixation are useful to increase the examiner’s sensitivity to the patient’s nystagmus.2 Nystagmus can also be enhanced by having the patient look toward the intact side. Vestibular suppressants, alcohol, and antiepileptic medications decrease the amplitude of the nystagmus and can make evaluation difficult.16 Gaze nystagmus can be identified by having the patient look at the examiner’s index finger held at off-center positions. Gazeevoked nystagmus is often a side effect of drugs such as anticonvulsants, benzodiazepines, or alcohol, but when it is present in the absence of these drugs, it almost always indicates a central disorder involving the brainstem, cerebellum, or midbrain depending on its direction, and also tends to be direction changing.17,20 Head-shaking nystagmus is assessed by having the patient shake his or her head very rapidly back and forth in the horizontal plane while wearing Frenzel lenses. Shaking is abruptly stopped, and nystagmus is assessed. Normal individuals usually have just a beat or two of nystagmus, but individuals with a unilateral vestibular lesion show nystagmus with the fast phase toward the intact side.2 Patients with central lesions such as cerebellar dysfunction may also have post head-shaking nystagmus, often in the vertical direction.2 Nonlinearity testing, or head thrust testing, is performed by applying quick head thrusts about 15 degrees in the plane of each semicircular canal from the neutral position while the patient attempts to fix his gaze on the examiner’s nose. A normal patient is able to keep his or her gaze on the examiner’s nose, but a patient with a lesion affecting a semicircular canal demonstrates a corrective saccade after the head thrust toward the lesioned side.17
Positional Testing The first positional test that should be performed is the DixHallpike maneuver to detect the presence of benign paroxysmal positional vertigo of the posterior semicircular canal. In this
324
Section
V
Neuro-Otology
test, the patient is sitting upright on an examination table and the head is turned 45 degrees to the side in question. The head is brought quickly down to a position where the head hangs off the edge of the table and the patient is instructed to look straight ahead with the eyes open (the patient may also wear Frenzel lenses if desired).2,17 This position is held for 30 seconds, and in the presence of BPPV, classically the patient has horizontorotary nystagmus with the fast phase beating toward the down ear (geotropic), which is delayed in onset and fatigable. Almost all persons with BPPV have a sensation of spinning.16 Nystagmus of central origin may also manifest itself during the Dix-Hallpike maneuver, but it usually lasts indefinitely while the patient is in the supine position.16
then with the eyes closed. Failure of this test can indicate an abnormality in the vestibulospinal pathway.2,17
Electronystagmography Electronystagmography is a combination of tests based on the VOR that provides important information about the vestibular and ocular systems. Results of the electronystagmographic battery should be used in conjunction with findings from the history, the physical examination, and other studies to arrive at a diagnosis.22
Electro-oculography Postural Control Testing Postural control testing is based on the vestibulospinal reflex. These pathways work in conjunction with visual and proprioceptive pathways to help the patient maintain balance. For example, if your body leans to the left, the left leg extensors are activated to counteract a change in the patient’s new center of gravity. With a perceived forward motion, the body sways forward to maintain the center of gravity. A simple way to think of this is that balance in gravity depends on three peripheral components: vision, proprioception, and the vestibular system. These three components are bilateral peripheral inputs to the brain, which integrates balance, whereas the cerebellum is considered a central input. Taking away one of the inputs places the burden of maintaining balance on the other two inputs, and taking away two of the inputs places all of the burden on the one remaining input. This is analogous to a person standing in darkness having to rely on vestibular inputs and proprioception to maintain balance.16 The Romberg test was originally described for tabes dorsalis and primarily tests proprioception.16,21 In this test, the patient stands with both feet together with the arms either folded in front or down at the sides. Then the patient closes his or her eyes and attempts to keep balance. Patients with a unilateral vestibular lesion tend to fall toward the lesioned side. The tandem Romberg test is a variant that requires patients to stand with one foot directly in front of the other. This increases its sensitivity.16 The Fukuda stepping test is performed with the patient’s arms straight out in front and the eyes closed. The patient then marches in place. A vestibular lesion is indicated if the patient is turned more than 30 degrees from the original position after approximately 50 steps. Usually, patients turn toward the diseased side. Patients with a vestibular lesion with a positive Fukuda stepping test are usually surprised by the result, as they do not sense that they are rotating during the test.16 Another test of vestibulospinal function is the tandem gait test, in which the patient is asked to step heel-to-toe with his/her eyes closed. Normal individuals can do this for at least 10 steps, but patients with vestibular disorders fail this test.17 The past pointing test is done by having the patient and examiner stand facing each other with arms extended forward and their index fingers in contact with one another. The patient then raises his or her arms up and brings his or her fingers into contact again with the examiner’s, first with the eyes open and
Electro-oculography is used to record eye movements during electronystagmographic testing. It is based on the corneoretinal potential (difference in electrical charge between the cornea and the retina), with the long axis of the eye acting as a dipole. Movements of the eye relative to the surface electrodes placed around the eye produce an electrical signal that corresponds to eye position. Recordings of eye movement are accurate to about 0.5 degree, but it is still less sensitive than visual inspection, which can perceive movements of about 0.1 degree.2 Therefore, visual inspection with Frenzel lenses is sometimes still necessary to document nystagmus of low amplitude. Another limitation of electro-oculography is that torsional eye movements cannot be monitored. Again, visual inspection with Frenzel lenses is sometimes necessary to document torsional nystagmus.2 Fortunately, new techniques have been developed to provide greater accuracy and breadth for oculomotor testing. The most clinically useful technique that has been developed is the infrared video electronystagmographic system. Here, the patient wears goggles that illuminate the eyes with infrared light (invisible to the patient), allowing a small video camera to pick up and project an image of the eyes onto a monitor. This can also assess eye movement in horizontal, vertical, and torsional directions and is more accurate than electrooculography.22
Oculomotor Testing Oculomotor testing measures the accuracy, latency, and velocity of eye movements in response to a stimulus (usually an LED light). The tests performed include tests for saccades, smooth pursuit, and optokinetic nystagmus. Saccades are rapid eye movements that bring objects from the peripheral visual fields onto the fovea. They are controlled by the occipitoparietal cortex, the frontal lobe, the basal ganglia, the superior colliculus, the cerebellum, and the brainstem.17 During saccade testing, the patient follows the LED, which flashes sequentially in positions 15 to 20 degrees to the right or left of center. The test is repeated vertically. The latency, peak eye velocity, and accuracy are then calculated. The latency is the time lag between presentation of the stimulus and the beginning of a saccade. Prolonged or shortened latency, as well as differences in latency between eyes, are usually indicative of neurodegenerative disease. Abnormally slow peak velocities can be caused by sedative drugs, drowsiness, cerebellar disorders, basal ganglia disorders, and brainstem lesions. Abnormally fast
chapter 25 examination of hearing and balance velocities are found with calibration errors and eye muscle restrictions. Asymmetrical velocities are caused by internuclear ophthalmoplegia, eye muscle restriction, and cranial nerves III and VI palsies. Poor accuracy, described as overshoot or undershoot dysmetria, usually indicates cerebellar, brainstem, or basal ganglia abnormalities.17 Smooth pursuit describes eye movements that are generated when tracking moving objects. In smooth pursuit testing, the patient follows an LED moving back and forth between two points at a constant velocity. The gain and phase are then calculated. Gain is the ratio of the eye velocity to the target velocity. Abnormally low gain is suggestive of a central disorder (brainstem or cerebellum).17 Phase is the difference in time between eye movement and target movement. Abnormalities here also indicate central nervous system disorders.17 The morphology of the smooth pursuit tracing can be analyzed. A saccadic pattern of smooth pursuit is associated with a cerebellar disorder.22 Acute peripheral vestibular lesions can also impair smooth pursuit when the eyes are trying to move opposite the slow phase of spontaneous nystagmus.17 Optokinetic nystagmus is tested by having the patient look ahead while seated in a rotating drum with black and white stripes on it. When the patient tries to look straight ahead, there will be small involuntary excursions of the eye (stare nystagmus). When the patient follows a target, smooth pursuit is tested (look nystagmus). Both types of nystagmus are probably responsible for eye movement during stimulation. However, when the lights go out, the patient with an intact optokinetic system will continue to have nystagmus for about 25 seconds⎯optokinetic after nystagmus (OKAN).22 The optokinetic system is distributed widely throughout the brainstem and cerebellum, so abnormalities are difficult to localize. However, absence or asymmetry of OKAN can occur with peripheral vestibular lesions. Bilateral lesions tend to greatly reduce or eliminate OKAN, whereas unilateral lesions can result in asymmetrical OKAN with prolonged nystagmus directed at the site of lesion.22,23
Spontaneous and Gaze Nystagmus The electronystagmogram can record eye movements associated with spontaneous and gaze-evoked nystagmus similar to that described earlier (see Physical Examination). An advantage of electronystagmography over physical examination is that eye movements can be monitored with the eyes closed. If during any part of the test nystagmus is identified with the eyes closed, the patient is then told to open the eyes so that changes in nystagmus can be detected. Patients with peripheral causes of nystagmus and a normal central pathway are able to suppress the nystagmus with the eyes open. This is called fixation suppression. A central lesion is suggested when there is no fixation suppression and the nystagmus continues with the eyes open.22
Positional and Positioning Tests Positional tests measure the response to changes in the direction of gravitational force. With the eyes closed, the patient is moved slowly into a series of stationary positions, and the presence of nystagmus is assessed, which can be fixed or direction changing. Positional nystagmus from a peripheral lesion can fatigue with repeated testing, is usually fixed in direction, and
325
usually does not change independent of head movement. Nystagmus that changes in direction independent of head movement is suggestive of a central lesion.22 Positioning tests include the Dix-Hallpike maneuver, among others. The patient is positioned as described earlier (see Physical Examination), and the presence of nystagmus is noted. If the patient has nystagmus, the test is repeated to see if the response fatigues. If the response fatigues, it is suggestive of a peripheral disorder, but if it does not, it suggests a central lesion.22
Caloric Testing Caloric testing is a very important part of electronystagmography in that it is one of the few tests that allows one labyrinth to be examined independently of the other.2 Horizontal nystagmus is induced by stimulation of the horizontal semicircular canal using a cold and warm stimulus (air or water). The patient lies in the supine position with the head tilted 30 degrees upward to bring the horizontal canal into the vertical plane (direction of gravity), making it more sensitive to the flow of endolymph.17 The external canal is irrigated with 250 mL of water at 30ºC and 44ºC for about 30 seconds each. Alternatively, air at temperatures of 24ºC and 50ºC can be used. For example, a cold stimulus in the left ear causes the endolymph of the horizontal canal to fall (as if the head was turning right and the endolymph was moving left) and the cupula moves the cilia in an ampullofugal direction away from the kinocilium, causing a decreased firing rate in the left vestibular nerve and inhibition of the left medial rectus and the right lateral rectus via the VOR. The eyes then drift conjugately to the left (slow phase) and corrective saccades bring the eyes back to the right (fast phase)⎯this results in a right-beating nystagmus. The opposite occurs with warm stimulation. A mnemonic used to determine the direction of the fast phase of nystagmus in cold and warm stimulation is “COWS”: Cold Opposite, Warm Same. The measured value of the induced nystagmus for each stimulus is the peak slow-phase velocity averaged over a 10-second period.17 The difference between the sides is calculated, and any difference greater than 20% to 25% between sides is considered significant and indicates weakness of the vestibular labyrinth or nerve on the less active side. Directional preponderance, which compares the peak slow-phase velocities of eye movements to the right with the left, can also be calculated. A difference of 25% to 30% is considered significant and indicates an imbalance but is a nonlocalizing measure.16
Rotational Chair Testing Rotational chair testing measures the VOR response to small rotations of the body around an axis. It can be useful in monitoring changes in vestibular function over time (especially bilateral lesions or lesions from vestibulotoxic medications), monitoring compensation following acute injury, and identifying residual vestibular function in patients with no response during caloric testing.22 The easiest canal to test is the horizontal canal. The patient is fitted with electro-oculographic electrodes and rotated slowly around a vertical axis with the eyes covered. The patient then undergoes sinusoidal harmonic acceleration, during which the patient is rotated back and forth
326
Section
V
Neuro-Otology
at gradually increasing frequencies to a peak angular velocity of about 50 degrees per second.16 The three values analyzed are phase, gain, and symmetry. Phase measures the timing of eye movement relative to head movement. In individuals with an intact VOR, the direction of slow phase eye velocity is exactly opposite head velocity, but patients with a vestibular or cerebellar lesion have an abnormal phase, with either a phase lead or lag. Gain is the ratio of the slow phase eye velocity to the head velocity. Abnormally low gain may indicate bilateral peripheral vestibular weakness, whereas abnormally high gain may be seen in cerebellar lesions.17 Symmetry measures the difference between slow phase velocities associated with rightward and leftward rotation and can suggest involvement of the central pathways or peripheral vestibular dysfunction.17
Other Testing Additional tests that may be useful in the balance evaluation are audiometric tests, radiographic tests, and blood tests. Audiometric tests are extremely important in the evaluation of dizziness. Every patient should at least have an audiogram and immittance testing. A unilateral hearing loss supports a peripheral cause of vertigo, and reduced speech discrimination scores may prompt a search for a retrocochlear abnormality such as an acoustic neuroma.16 Radiographic tests such as an MRI will be able to detect acoustic neuromas, multiple sclerosis, and brainstem strokes. CT scans may detect middle and inner ear anomalies such as a cholesteatoma eroding into the semicircular canals or a superior semicircular canal dehiscence. Finally, blood tests looking for thyroid function, glucose tolerance, syphilis, rheumatoid factor, and ANA may also be useful in helping to diagnose a dizzy patient.
Computerized Dynamic Posturography Posturography is a quantitative test of the vestibulospinal reflex. It has the same basis as the Romberg test, where three peripheral inputs of vision, the labyrinth, and proprioception are integrated for a patient to maintain balance. If one of these inputs is taken away, the patient has to rely on the remaining inputs to maintain balance. No one input can be measured by itself. Patients with cerebellar lesions and certain cortical lesions are characteristically ataxic and will have poor results on posturography.16 There are two tests in posturography: the sensory organization test and the motor control test. In the sensory organization test, the patient is subjected to six conditions. In condition 1, the patient stands on a fixed platform with the eyes open and looks at a fixed visual surround. In condition 2, the platform is fixed, but the eyes are covered, forcing the patient to rely on proprioceptive and vestibular cues. In condition 3, the platform is fixed and the eyes are open, but the visual surround moves in reference to body sway, forcing the patient to ignore the visual stimulus and rely on proprioceptive and vestibular cues. In condition 4, the eyes are open and the visual surround is fixed, but the platform sways, taking away proprioception, which forces the patient to rely on visual and vestibular cues. Patients with vestibular dysfunction still tend to do well in condition 4. In condition 5, the platform sways and the eyes are covered, forcing the patient to rely on vestibular cues alone⎯patients with vestibular dysfunction tend to fall here. In condition 6, the eyes are open, but both the platform and visual surround move, forcing the patient to rely on vestibular cues while ignoring inaccurate proprioceptive and visual cues.2 Patients with vestibular dysfunction tend to fall here as well. The parameter measured is the patient’s anterior and posterior body sway, and is measured on a 0-to-100 scale (fall = 0, no sway = 100).22 Motor control tests evaluate the automatic postural responses to forward and backward horizontal movements of the platform. The main parameter tested here is latency. A prolonged latency in both directions suggests a central lesion, whereas a prolonged latency in only one direction suggests either a peripheral or central lesion.17 Although posturography results tend not to localize lesions, they are useful for planning vestibular rehabilitation. Posturography may also aid in the detection of malingerers, who tend to have inconsistent results and may do more poorly on conditions 1 and 2 than on conditions 5 and 6.2
K E Y
P O I N T S
●
Hearing loss and balance disorders are two of the most common reasons why patients visit their physicians.
●
There are three main forms of hearing loss: conductive, sensorineural, and mixed. Each can be caused by a wide variety of conditions, ranging from benign conditions, such as cerumen impaction, to potentially life-threatening diseases, such as squamous cell carcinoma of the temporal bone.
●
A thorough history is one of the most important aspects of a hearing evaluation.
●
A complete head and neck examination can give many clues to the cause of a patient’s hearing loss.
●
Audiological testing has been available for decades, but developments over the years have advanced the field of audiology to include tests and procedures that can determine the site of lesion with far greater accuracy than before. Otolaryngologists and audiologists often need to rely on one another to diagnose accurately the cause of a patient’s hearing loss using a combination of the history, physical examination, and results of various audiological tests.
●
The diagnosis and treatment of patients with “dizziness” can be very challenging and frustrating for the patient, the neurologist, the otolaryngologist, and the audiologist. A huge variety of disorders can cause the patient to have a sensation of dizziness, and a huge variety of terms can be used to describe it (lightheadedness, spinning, “swimming sensation,” “things not being right in the head”).
●
Often, the diagnosis is made by piecing together many different pieces of information. Not every case of dizziness can be completely cured or diagnosed exactly. An organized, systematic approach is necessary to make a reasonably accurate diagnosis and avoid confusion. Key components in the evaluation of dizziness include the history, physical examination, electronystagmography, rotary chair testing, and computerized dynamic posturography testing.
chapter 25 examination of hearing and balance Suggested Reading Chole RA, Cook GB: The Rinne test for conductive deafness. A clinical reappraisal. Arch Otolaryngol Head Neck Surg 1998; 114:399-403. Cueva RA: Auditory brainstem response versus magnetic resonance imaging for the evaluation of asymmetric sensorineural hearing loss. Laryngoscope 2004; 114:1686-1692. Kileny PR, Zwolan TA: Diagnostic and rehabilitative audiology. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3483-3502. Satar B: Vestibular testing. In Lalwani AK, ed: Current Diagnosis and Treatment in Otolaryngology⎯Head and Neck Surgery. New York: McGraw-Hill, 2004, pp 643-658.
References 1. McGee J, Walsh EJ: Cochlear transduction and the molecular basis of peripheral auditory pathology. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3402-3465. 2. Hullar TE, Minor LB, Zee DS: Evaluation of the patient with dizziness. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3160-3192. 3. Kroenke K, Arrington ME, Mangelsdorff AD: The prevalence of symptoms in medical outpatients and the adequacy of therapy. Arch Intern Med 1990; 150:1685-1689. 4. Kroenke K, Mangelsdorff AD: Common symptoms in ambulatory care: Incidence, evaluation, therapy, and outcome. Am J Med 1989; 86:262-266. 5. Arts HA: Sensorineural hearing loss: evaluation and management in adults. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3535-3561. 6. Diagnosis of ear disease. In Glasscock ME, Shambaugh GE, Johnson GD, eds: Surgery of the Ear. Philadelphia: WB Saunders, 1990. 7. Backous DD, Niparko JN: Evaluation and surgical management of conductive hearing loss. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3522-3534.
327
8. Miltenburg DM: The validity of tuning fork tests in diagnosing hearing loss. J Otolaryngol 1994; 23:254-259. 9. Chole RA, Cook GB: The Rinne test for conductive deafness. A clinical reappraisal. Arch Otolaryngol Head Neck Surg 1998; 114:399-403. 10. Sweetow RW, Bold JM: Audiologic testing. In Lalwani AK, ed: Current Diagnosis and Treatment in Otolaryngology⎯Head and Neck Surgery. New York: McGraw-Hill, 2004, pp 631-641. 11. Hall JW, Antonelli PJ: Assessment of peripheral and central auditory function. In Bailey BJ, ed: Head and Neck Surgery⎯Otolaryngology. Philadelphia: Lippincott Williams and Wilkins, 2001, pp 1659-1672. 12. Kileny PR, Zwolan TA: Diagnostic and rehabilitative audiology. In Lustig LR, Cummings CW, eds: Cummings Otolaryngology⎯Head and Neck Surgery. St Louis: Mosby Elsevier, 2004, pp 3483-3502. 13. Cueva RA: Auditory brainstem response versus magnetic resonance imaging for the evaluation of asymmetric sensorineural hearing loss. Laryngoscope 2004; 114:1686-1692. 14. Nageris BI, Popovtzer A: Acoustic neuroma in patients with completely resolved sudden hearing loss. Ann Otol Rhinol Laryngol 2003; 112:395-397. 15. Chaimoff M, et al: Sudden hearing loss as a presenting symptom of acoustic neuroma. Am J Otolaryngol 1999; 20:157160. 16. Linstrom CJ: Office management of the dizzy patient. Otolaryngol Clin North Am 1992; 25:745-780. 17. Satar B: Vestibular testing. In Lalwani AK, ed: Current Diagnosis and Treatment in Otolaryngology⎯Head and Neck Surgery. New York: McGraw-Hill, 2004, pp 643-658. 18. Lee H, et al: Sudden deafness and anterior inferior cerebellar artery infarction. Stroke 2002; 33:2807-2812. 19. Mong A, et al: Sound- and pressure-induced vertigo associated with dehiscence of the roof of the superior semicircular canal. AJNR Am J Neuroradiol 1999; 20:1973-1975. 20. Brandt T, Strupp M: General vestibular testing. Clin Neurophysiol 2005; 116:406-426. 21. Moffat DA, et al: Unterberger’s stepping test in acoustic neuroma. J Laryngol Otol 1989; 103:839-841. 22. Driscoll CL, Green JD: Balance function tests. In Bailey BJ, ed: Head and Neck Surgery⎯Otolaryngology. Philadelphia: Lippincott Williams and Wilkins, 2001, pp 1652-1658. 23. Hain TC, et al: Localizing value of optokinetic afternystagmus. Ann Otol Rhinol Laryngol 1994; 103:806-811.
chapter 26 auditory system disorders
CHAPTER
26
329
AUDITORY SYSTEM DISORDERS ●
●
●
●
Thomas O. Willcox and Gregory J. Artz
Hearing loss can be defined as an increase in the threshold of sound perception. Understanding speech and the general world around us depends on the accurate perception and processing of complex, multifrequency sounds. There are multiple areas along the auditory pathway for pathology to occur that can cause distorted, inefficient, or unperceived sound, resulting in hearing loss. Hearing loss affects nearly 28 million Americans, including 30% of adults over the age of 65 and 50% over the age of 85. Hearing loss is one of the most common chronic illnesses, and as the population ages and lives longer, it will increasingly affect the morbidity and quality of life of patients. Hearing loss is not just a disorder of adults. It also significantly affects children and their daily lives, as well as the lives of their parents and caregivers. Otitis media can cause a conductive hearing loss due to fluid accumulation that can take months to resolve. Otitis media is the most common reason for a child to visit the pediatrician. By 3 years of age, three of every four children will have had at least one episode of otitis media. This has a significant financial impact on the health care system, in addition to the financial impact on parents, who lose income when they miss work to care for their sick children. Children can also be afflicted with congenital causes of hearing loss; two or three of every 1000 children born today will be either deaf or hard of hearing. Hearing loss is a broad topic and first can be subdivided into hereditary and nonhereditary causes. Hereditary causes can be isolated genetic defects or associated with several childhood syndromes. Hereditary hearing impairment is not covered in depth in this chapter. Briefly, it is the cause of hearing impairment in more than 50% of children born with moderate to profound hearing loss. Of these children with genetic causes of their hearing loss, more than 75% will be determined to be nonsyndromic. More than 100 genetic loci have been implicated in causing nonsyndromic hereditary hearing loss, with defects in connexin 26 and connexin 30 being the most common. These causes are overwhelmingly autosomal recessive in approximately 75% of cases but also can be autosomal dominant or X-linked or even due to mitochondrial inheritance. Hereditary hearing loss usually manifests at birth, but some hearing disorders manifest as delayed onset or even adult onset in a nonprogressive or progressive fashion. Hearing loss can be subdivided into categories based on the site of pathology: conductive, sensorineural, or central hearing
loss. Conductive and sensorineural are the most common, whereas with central hearing loss is quite rare.
CONDUCTIVE HEARING LOSS Conductive hearing loss is caused by impairment in air transmission of sound waves to the inner ear. The impairment of function is due to pathology at the level of the external auditory canal, the tympanic membrane, or the ossicular chain, resulting in inefficient conversion of sound waves from air to the fluid medium of the endolymph in the membranous labyrinth. A rare cause of conductive hearing loss is the “third mobile window” of the inner ear, which is attributed to a dehiscent superior semicircular canal or an enlarged vestibular aqueduct. On bedside physical examination, a patient with a conductive hearing loss has a negative Rinne test, which means that the hearing threshold for bone conduction is less than air conduction in the tested ear. This test is performed by placing the 512-Hz tuning fork first on the mastoid tip, then approximately 2 to 3 inches from the entrance to the external auditory canal. Bone conduction surpasses air conduction when a conductive hearing loss reaches 25 to 30 decibels (dB). When performing the Weber test, the end of the tuning fork is placed in the middle of the patient’s forehead. If the patient has unilateral hearing loss, then the sound will lateralize to the bad ear, or the ear with the conductive hearing loss. The sensitivity of the Weber test can be increased by alternatively placing the tuning fork on the patient’s upper incisors.
SENSORINEURAL HEARING LOSS Sensorineural hearing loss is caused by damage to the cochlear sensory epithelium or, less commonly, the peripheral auditory neurons. The type of hearing loss a patient has can be quite different depending on whether the cochlea or the auditory nerve fibers are involved. When cochlear hair cell loss is the main reason for hearing difficulties, it often manifests as a sound threshold shift only. When the lesion involves the auditory nerve, or is called retrocochlear, a patient often has significant sound distortion that manifests as difficulty with word discrimination out of proportion to the associated hearing loss. On bedside evaluation, the Rinne test is positive, and if the
329
330
Section
V
Neuro-Otology
hearing loss is unilateral, the Weber test lateralizes away from the side with the hearing loss, or toward the good ear. Sensorineural hearing loss is a challenge to physicians, as it progresses with age and causes significant reductions in quality of life and there are no treatments to reverse its effects, other than sound amplification with the use of hearing aids or direct auditory nerve stimulation via cochlear implantation.
CENTRAL HEARING LOSS Central hearing loss is caused by a lesion in the central auditory pathway or in the auditory cortex. The auditory cortex processes and interprets the sounds amplified and received by the ossicles and cochlear hair cells. The auditory cortex is located on the transverse temporal gyri of Heschl. It is divided into the primary auditory cortex (Brodmann’s areas 41 and 42) and the auditory association cortex (Brodmann’s areas 22 and 52). Lesions such as brain tumors and ischemic or embolic strokes in the region of the transverse temporal gyri affect speech discrimination more than they affect hearing threshold levels, as patients with central hearing loss often have normal audiograms. Types of central hearing loss include aphasia (Wernicke’s aphasia), pure word deafness, auditory agnosia, cortical deafness, and auditory hallucinations. Another more common form of central hearing loss is associated with presbycusis, or age-related hearing loss. In the elderly, speech discrimination is often worse than would be expected based on their pure-tone hearing thresholds. It is believed that this may be due to a combination of cochlear hair cell loss, neuronal loss, and age-related central auditory processing changes.
CAUSES OF CONDUCTIVE HEARING LOSS Suboptimal air conduction of sound waves to the cochlea can cause a hearing loss. This is referred to as a conductive hearing loss. There are several places that a conductive hearing loss can occur: the external auditory canal, the tympanic membrane, the middle ear space, and the inner ear. Most of the causes of conductive hearing loss are due to anatomical obstruction or damping of the transmitted sound waves on their way toward the sensory epithelium of the cochlea. Almost all of these causes are amenable to surgical or medical correction and, by definition, all patients with purely conductive hearing losses have normal eighth nerve function and can achieve normal hearing thresholds through hearing aid amplification.
Treatment is atraumatic cerumen removal. Irrigation should be performed with caution, as irrigation in a patient with a tympanic membrane perforation can cause vertigo and subsequent otitis media.
Cholesteatoma Cholesteatoma is normally associated with the middle ear and mastoid, but it can occasionally occur in the external auditory canal. Through inflammation and associated infection, it can cause a conductive hearing loss. Cholesteatomas of the external canal are usually unilateral and have associated symptoms of otalgia and otorrhea. On examination, there is narrowing or occlusion of the external auditory canal, abundant keratin debris, and sometimes granulation tissue. Treatment includes resolution of the external otitis infection with topical antibiotic eardrops and occasional systemic antibiotics, followed by surgical debridement and excision of the cholesteatoma.1
External Auditory Canal Tumors Tumors of the external auditory canal, benign or malignant, can cause a conductive hearing loss. The two most common benign bony tumors are exostoses and osteomas.1 Exostoses are broadbased lesions that are often multiple and bilateral. Patients usually give a long history of cold water exposure, such as swimming, diving, or surfing. Exostoses are found in the medial portion of the bony external auditory canal near the annulus and often along the tympanomastoid and tympanosquamous suture lines. Osteomas are solitary and unilateral and are not associated with any significant history such as that of patients with exostosis. They are found in the lateral portion of the external auditory canal at the bony-cartilaginous junction. Treatment of exostoses and osteomas is based on symptoms, as they are benign lesions with no known malignant conversion. Chronic or recurrent acute otitis externa is the most common reason patients undergo surgical excision. Care must be taken not to injure the mastoid segment of the facial nerve when removing these lesions, particularly when operating in the posteromedial external auditory canal. The most common malignant tumor of the external auditory canal is squamous cell cancer. Fortunately, these are rare head and neck tumors. They can arise from anywhere within the external auditory canal, and patients often have symptoms of otorrhea, otalgia, and occasionally hearing loss. Treatment is surgical excision with postoperative chemoradiation therapy depending on the stage of the tumor.
Cerumen Impaction One of the most common causes of hearing loss is cerumen impaction. The external auditory canal is one third cartilaginous and two thirds bony. The lateral one third of the canal is cartilaginous and has overlying skin containing subcutaneous tissue, hair follicles, cerumen, and sebaceous glands. The medial two thirds of the canal are bony, has thin skin, and lacks hair follicles or glandular tissue that are adherent to the bone. A conductive hearing loss can occur if cerumen completely obstructs the lumen of the external auditory canal. This often occurs suddenly, often after cotton swab manipulation or water exposure. Symptoms can include aural fullness and tinnitus.
External Auditory Canal Stenosis or Absence A rare cause of conductive hearing loss is stenosis or absence of the external auditory canal, as in congenital aural atresia. The incidence of aural atresia is 1 in 10,000 to 20,000 births.2 Aural atresia is usually associated with a large conductive hearing loss or air-bone gap, assuming that the cochlear function is normal. Varying degrees of external ear malformations (microtia), temporal bone atresia, ossicular deformities, and facial nerve anomalies are seen. Surgical treatment to repair the external ear, external auditory canal, and middle ear
chapter 26 auditory system disorders abnormalities can restore hearing to normal levels in favorable candidates.
Tympanic Membrane Pathology of the tympanic membrane includes perforations, atelectasis, and tympanosclerosis. Aside from its role in protecting the middle ear, the tympanic membrane is critical in receiving sound waves and efficiently transmitting them through the ossicular chain to the endolymph of the cochlea. Any pathological process that compromises the mobility or efficiency of the tympanic membrane results in a conductive hearing loss. Tympanic membrane perforations can be caused by acute and chronic infections, head trauma, or iatrogenic causes, such as after tympanostomy tube extrusion. Tympanostomy tube placement is common in infants with otitis media and is one of the most common surgical procedures performed today. The reported rate of tympanic membrane perforation depends on the type of tube placed; however, routine grommet-type tubes have a 1% to 3% incidence.3 Most perforations from tympanostomy tubes are small, causing a 10-dB hearing loss or less, and usually heal with time. However, larger perforations and total perforations of the tympanic membrane, usually seen in patients with a history of chronic otitis media, can result in a significant conductive hearing loss of 30 dB or more. A thin, atrophic, atelectatic tympanic membrane can also cause a conductive hearing loss, particularly if there is associated ossicular erosion. A retracted, atelectatic tympanic membrane is caused by eustachian tube dysfunction and the resultant chronic negative middle ear pressure. Hearing loss can be further affected in these patients by chronic middle ear fluid. Initial treatments consist of tympanostomy tube placement, tympanoplasty, and medical therapy, including decongestants and nasal steroid sprays. A common finding on otoscopy during routine physical examination is tympanosclerosis, a white discoloration of the tympanic membrane. Tympanosclerosis can be due to a prior history of tympanostomy tube placement and/or an associated history of otitis media. Unless the tympanic membrane involvement is particularly severe, it is rare for tympanosclerosis to cause an appreciable conductive hearing loss. The ratio of the tympanic membrane area to the stapes footplate area results in an 18-fold amplification of sound under normal physiological conditions.4 Any disruption or fixation of the ossicular movements impairs this efficient sound transmission. Therefore, any abnormalities of the ossicular chain manifest as a conductive hearing loss. Otosclerosis is a common cause of conductive hearing loss due to stapes footplate fixation. Otosclerosis is a disease of bone limited to the otic capsule. Classically, it causes a conductive hearing loss, but it must be mentioned that otosclerosis can also affect the cochlea, causing a mixed or even a purely sensorineural hearing loss. It is inherited in an autosomal dominant fashion with incomplete penetrance and is more often seen in white populations at a histological incidence of 7% to 10%. Only approximately 10% of patients with histological evidence of otosclerosis present with clinical symptoms.5 Two thirds of patients with otosclerosis are women. The disorder is often bilateral and classically manifests in the third and fourth decades of life as a conductive hearing loss. Otosclerosis in women has always been believed to worsen during pregnancy; however, clinical data
331
have brought into question that premise.6 Treatment is often curative with stapedotomy or stapedectomy surgery. Middle ear and mastoid cholesteatoma is defined as an accumulation of keratin and desquamated debris from the squamous epithelial lining of the external auditory canal and lateral surface of the tympanic membrane. There are two types: congenital and acquired. Congenital cholesteatoma is an anteriorly based mass believed to be an embryological remnant. The more common type is the acquired cholesteatoma that results from otitis media. Squamous epithelium migrates into the middle ear and mastoid. Of the acquired type, cholesteatoma can occur in the setting of a tympanic membrane perforation or from chronic otitis media due to eustachian tube dysfunction causing persistent negative pressure and tympanic membrane retraction. Cholesteatoma manifests as a middle ear mass, often in close approximation to the ossicles, with or without bony erosion, and patients present with a conductive hearing loss. Other symptoms commonly include chronic otorrhea and rarely vertigo and facial nerve paresis or palsy. Treatment consists of treating any infection first and then surgical removal of the cholesteatoma with ossicular reconstruction if warranted. Ossicular reconstruction is sometimes delayed 6 to 12 months, during which time patients are observed for any signs of recurrence or recidivism. If the posterior external auditory canal wall is left intact, recurrence rates are slightly higher at 5% to 27% versus 2% to 10% when the posterior canal wall is removed.7 When treating cholesteatoma, the first priority is to create a dry, safe ear, as infectious complications of a cholesteatoma can have significant morbidity, such as meningitis and brain abscesses. Correcting the conductive hearing loss is a second priority only after antimicrobial and surgical treatments have been successful.
Otitis Media The most common cause of hearing loss in children is due to otitis media. Approximately 85% of children have at least one episode of acute otitis media. A decade ago, otitis media was estimated to cost the health care industry more than $5 billion annually.8 Factors that predispose children to otitis media include bottle feeding, crowded living conditions, day care, smoking at home, hereditary influences, and craniofacial abnormalities, such as cleft palate. Early treatment for children with chronic otitis media is critical to proper development. Lack of intervention can result in abnormal development of cognition, language, and general communicative skills.9 Otitis media with effusion or serous otitis media causes a conductive hearing loss by preventing normal mobility of the tympanic membrane as seen on pneumatic otoscopy and tympanometry examination. Audiometry in children with otitis media with effusion reveals an average air-conduction threshold of 28 dB.10 Guidelines from the Agency for Health Care Policy and Research (now called the Agency for Healthcare Research and Quality [AHRQ]) recommend treatment for chronic otitis media with effusion for any conductive hearing loss greater than 20 dB.11 Treatment for hearing loss from otitis media with effusion usually consists of tympanostomy tube placement. Antibiotic prophylaxis is generally not recommended due to the risk of promoting antimicrobial resistance. Other medications, such as antihistamines, decongestants, and corticosteroids, have not proved to be effective in clinical studies.
332
Section
V
Neuro-Otology
Middle Ear Fluid or Masses There are several other causes of middle ear fluid or masses that can cause a conductive hearing loss. Chronic eustachian tube dysfunction can cause a persistent middle ear effusion that often requires myringotomy with or without placement of a tympanostomy tube. However, when an adult presents with a unilateral conductive hearing and physical examination reveals a middle ear effusion, the physician must rule out more serious causes, such as a spontaneous cerebrospinal fluid leak of the temporal bone or a nasopharyngeal mass causing obstruction of the eustachian tube orifice. Patients with cerebrospinal fluid leaks can have a conductive hearing loss that is exacerbated by a meningoencephalocele impinging directly on the ossicular chain. Cerebrospinal fluid leaks must be repaired surgically and nasopharyngeal masses are most commonly squamous cell cancers and are treated with chemoradiation. Other middle ear masses, such as paragangliomas (glomus tympanicum, glomus jugulare) and hemangiomas, can also manifest as a conductive hearing loss.
Superior Canal Dehiscence Syndrome Pathology of the inner ear has always been associated with sensorineural hearing loss. However, in 1998 superior canal dehiscence syndrome was described.12 In this syndrome, the bone overlying the semicircular canal on the floor of the middle cranial fossa is found to be dehiscent on computed tomography. Signs and symptoms may include vertical-torsional eye movements in response to loud sounds or middle ear pressure changes, autophony, and chronic disequilibrium, all of which can be disabling when severe.13,14 The symptoms and signs in this syndrome have been described as the dehiscence being a third window into the inner ear, with the other two being the oval and round windows. Intracranial pressure differences can exert pressure on this third window, creating the characteristic signs and symptoms. Other symptoms of this syndrome have been air-bone gaps and suprathreshold bone conduction hearing levels believed to be due to sound wave escape through the dehiscent superior semicircular canal. The dehiscence provides a low resistance alternative pathway for sound waves, thereby increasing air-conduction thresholds. There are several reports of patients undergoing unsuccessful stapes surgery for a conductive hearing loss only to be later diagnosed with superior canal dehiscence15 (personal communication, Michael Teixido, MD, Wilmington, DE, 2005). There have also been cases of patients having air-bone threshold gaps on audiometry with enlarged vestibular aqueducts, a possible alternative site contributing to the third mobile window theory. Treatment for superior canal dehiscence is surgical in those patients with severe debilitating symptoms. Surgical approaches include middle fossa craniotomy or transmastoid with varying success rates16 (personal communication, Michael Teixido, MD, Wilmington, DE, 2005).
CAUSES OF SENSORINEURAL HEARING LOSS Age-related hearing loss, or presbycusis, is a common diagnosis in the aging population. By strict definition, presbycusis is hearing loss specifically caused by aging. However, it has been nearly impossible to filter out other causes that can contribute to age-related hearing loss, such as genetic factors, accumu-
lated noise injury, acoustic trauma, and vascular and metabolic factors. Strictly speaking, there are four main physiological mechanisms that contribute to presbycusis. There can be loss of cochlear hair cells, predominantly in the high-frequency range, and the speech discrimination is usually preserved. There can be auditory neuronal loss that results in a generalized loss in all pure-tone averages but a disproportionate impairment in speech discrimination. The stria vascularis, which produces the endocochlear potential of the endolymph, can atrophy, and the result is a flat hearing loss on pure-tone averages with preservation of speech discrimination. And last, the basilar membrane can stiffen with age, which results in less sensitivity to sound waves, causing a cochlear conductive hearing loss.17 Cochlear implantation is a technological advance that can restore hearing to those adults with severe-profound hearing loss who have limited benefit from hearing aids. Success rates are high and can dramatically improve patients’ quality of life, particular the elderly.
Noise-induced Hearing Loss Noise-induced hearing loss is one of the most common causes of adult hearing impairment in the United States, second only to presbycusis. It is estimated that over 10 million people have noise-induced hearing loss.18 Noise exposure can be in the workplace, at home, or during recreational activities. Even the ambient noise level that Americans are exposed to on a daily basis is significantly higher now than it was one or two centuries ago prior to modern industrialization, which probably exacerbates noise-induced hearing loss as the population ages. Noise exposure causes a sensorineural hearing loss that affects both the cochlear hair cells and the auditory neurons. Most exposures result in what is called a temporary threshold shift that is reversible and recovers over a 24- to 48-hour period. Repeat exposures eventually result in a permanent threshold shift and subsequent hearing loss that can be documented by audiometry. Continuous noise exposure has been shown to be more damaging than intermittent noise exposure, due to limited recovery time during continuous exposure. A single episode of severe noise exposure or what is called acoustic trauma, if loud enough, can result in an immediate, permanent threshold shift. Noise damage to the cochlea typically affects the outer hair cells and is temporary; however, if the exposure persists, the outer hair cell damage becomes permanent and proceeds to affect the inner hair cells as well.19 The classic hearing loss seen on audiometry is in the 2-, 4-, and 6-kHz frequency ranges. An increase in the sensorineural hearing threshold at the 4-kHz frequency has been historically called the boilermakers notch and is classic for occupational noiseinduced hearing loss.20 Only in the past few decades has noiseinduced hearing loss been recognized as one of the most common causes of occupation-induced disability. As a result, noise exposure is now regulated by the Occupational Health and Safety Administration (OSHA). Current OSHA regulations require hearing protection for workers exposed to 90-dBA noise based on an 8-hour-per-day time-weighted average. Most industries require hearing conservation programs when noise levels are greater than or equal to 85 dBA. Treatment of noise-induced hearing loss consists of early identification and prevention of harmful noise exposure to prevent further deterioration in hearing threshold levels.
chapter 26 auditory system disorders Ototoxicity Ototoxicity is another common cause of sensorineural hearing loss and, with few exceptions, is usually irreversible. Nearly 100 pharmacological agents have been implicated as having potential ototoxic side effects. Among the types of drugs implicated are antibiotics, diuretics, salicylates, nonsteroidal antiinflammatory drugs, and chemotherapeutic medications. Aminoglycoside antibiotics are potent medications against gram-negative infections, and all have been found to have ototoxic side effects. Because of their low cost, they are commonly used worldwide.21 Streptomycin, discovered in 1940, was the first aminoglycoside. It was originally used to treat tuberculosis and, with these early treatment trials, reports of ototoxicity surfaced. Streptomycin and gentamicin are generally more vestibulotoxic, whereas tobramycin, amikacin, and neomycin are more cochleotoxic. The cochleotoxic effects manifest with tinnitus and then proceed with damage to the outer hair cells in the basal turn of the cochlea, giving a high-frequency sensorineural hearing loss. This hearing loss is often believed to be irreversible, but some recovery of hearing has been seen weeks after cessation of therapy.22 The risk of ototoxicity with aminoglycoside use is believed to be 10% to 15%, and this is increased in combination with certain other medications, such as loop diuretics and cisplatin.23,24 Factors that increase the risk of aminoglycoside-induced ototoxicity include renal disease, prolonged duration of therapy, and elevated peak and/or trough levels on serum blood testing. Occasionally, the vestibulotoxic effects of aminoglycosides are used therapeutically, such as in patients with episodic vertigo from Meniere’s disease. When patients are refractory to conventional treatments, gentamicin can be administered topically into the middle ear space to induce a chemical labyrinthectomy and relieve the disabling vertigo many of these patients experience. There are scant data on most other antibiotics in regard to hearing loss; however, there have been some reports of macrolide and vancomycin ototoxicities. The mechanism of macrolide-induced hearing loss is unknown, and the effects are generally reversible.25 Vancomycin-related ototoxicity has been more difficult to quantify due to multiple other medications and confounding comorbidities in the majority of patients receiving vancomycin therapy. The incidence of vancomycin ototoxicity has been estimated to be 3% and does not correlate to serum levels.26 The two most commonly implicated diuretic medications causing ototoxicity are furosemide and ethacrynic acid. Ototoxicity with these medications manifests as sensorineural hearing loss, as well as tinnitus and vertigo. These loop diuretics cause ototoxicity by injuring the stria vascularis, which is responsible for producing endolymph, and the endocochlear potential that allows for sound perception.27 The risk of sensorineural hearing loss caused by these medications has been reported to be approximately 1% to 6% and can be both temporary and permanent.28,29 Renal failure and rapid infusion can increase the ototoxic risks of these loop diuretics. A well-known reversible cause of ototoxicity is treatment with salicylates and, less commonly, with nonsteroidal anti-inflammatory drugs. These medications are routinely prescribed for common problems such as arthritis. The mechanism is believed to be due to reduced cochlear blood flow and alterations of the outer hair cell motility.30 The effects are dose dependent and reverse with cessation of therapy.31 Tinnitus can
333
be consistently reproduced at doses of 6 to 8 g/day. Along with tinnitus, audiometric testing manifests a mild-to-moderate flat, bilateral sensorineural hearing loss that resolves in 48 to 72 hours after cessation of the medication.32 Other notable medications known for their ototoxic effects include the antimalarial medication quinine, which primarily causes transient hearing loss. Cisplatin, a common antineoplastic medication used to treat head and neck squamous cell cancers, is both ototoxic and nephrotoxic. The ototoxic effects are usually permanent and bilateral. At least some degree of hearing loss occurs in most treated patients. The effects are often dose dependent and affect the outer hair cells in the basal turn, yielding a highfrequency hearing loss.33
Sudden Sensorineural Hearing Loss Sudden sensorineural hearing loss (SSNHL) is a syndrome that has multiple etiologies. It is commonly defined as rapidly progressive hearing loss over 12 hours or less. Often these patients first present to their primary care physicians and the cause can be difficult to determine. The most common cause of SSNHL is believed to be a viral neuritis or cochleitis causing inflammation of the inner ear and subsequent hearing loss with or without vestibular symptoms. These patients are usually treated empirically with a high-dose prednisone steroid taper over 10 to 14 days. Antiviral therapy is also commonly prescribed, along with steroid therapy. The literature suggests that there is benefit with steroid therapy; however, the evidence supporting antiviral medication is less convincing. It is important for these patients to undergo evaluation by an otolaryngologist to monitor hearing levels through audiometry, as well as to rule out more serious etiologies such as an acoustic neuroma. Other causes of SSNHL include meningitis, syphilis, human immunodeficiency virus infection, autoimmune disorders, multiple sclerosis, and ischemic and thromboembolic events.
SUMMARY The initial differential diagnosis for hearing loss can be vast, ranging from cerumen impaction to cerebellar pontine angle tumors, such as acoustic neuromas. Based on history, physical examination, and audiometric testing, the clinician should be able to significantly narrow down the differential diagnosis. A conductive hearing loss is usually correctable with medical or surgical treatment to fix the anatomical obstruction to air conduction of sound waves. Sensorineural hearing loss, on the other hand, has proved to be more difficult to treat, and treatment is often in the form of prevention. Hearing aids are the mainstay for sound rehabilitation for patients with moderate degrees of hearing loss, although patients with severe-toprofound hearing losses and those with poor speech discrimination have had less success. Cochlear implantation has become the mainstay for those patients with severe-to-profound hearing losses who do not benefit from conventional hearing aid technology. Cochlear implants have a high success rate in postlingual adults and are a proved way to restore the sense of hearing and dramatically improve patient quality of life. Constant improvements in equipment, technology, and software enhance the perceptive experience of those who benefit from restoration of their sense of hearing.
334
Section
V
K E Y
Neuro-Otology
P O I N T S
●
Hearing loss can be defined as an increase in the threshold of sound perception. It can be subdivided into hereditary and nonhereditary causes.
●
Conductive hearing loss is caused by impairment in air transmission of sound waves to the inner ear. The impairment of function is due to pathology at the level of the external auditory canal, the tympanic membrane, or the ossicular chain, resulting in inefficient conversion of sound waves from air to the fluid medium of the endolymph in the membranous labyrinth.
●
Sensorineural hearing loss is caused by damage to the cochlear sensory epithelium or the peripheral auditory neurons. The type of hearing loss can be quite different depending on whether the cochlea or the auditory nerve fibers are involved.
●
Central hearing loss is caused by a lesion in the central auditory pathway or in the auditory cortex.
●
The most common cause of hearing loss in children is otitis media.
●
Age-related hearing loss, or presbycusis, is a common diagnosis in the aging population.
●
Noise-induced hearing loss is one of the most common causes of adult hearing impairment in the United States, second only to presbycusis.
●
When it comes to hearing loss, the initial differential diagnosis can be vast, ranging from cerumen impaction to cerebellar pontine angle tumors, such as acoustic neuromas. Based on history, physical examination, and audiometric testing, the clinician should be able to significantly narrow down the differential diagnosis.
Suggested Reading Gates GA: Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg 1996; 114:525. Minor LB: Labyrinthine fistulae: pathobiology and management. Curr Opin Otolaryngol Head Neck Surg 2003; 11:340-346. Mikulec AA, Poe DS, McKenna MJ: Operative management of superior semicircular canal dehiscence. Laryngoscope 2005; 115:501-507. Riggs LC, Brummett RE, Guitjens SK, et al: Ototoxicity resulting from combined administration of cisplatin and gentamycin. Laryngoscope 1996; 106:401-406.
References 1. Tran LP, Grundfast KM, Selesnick SH: Benign lesions of the external auditory canal. Otol Clin North Am 1996; 5:807-825. 2. Jahrsdoefer RA: Congenital atresia of the ear. Laryngoscope 1978; 88(Suppl 13):1-46. 3. McLelland CA: Incidence of complications from use of tympanostomy tubes. Arch Otolaryngol Head Neck Surg 1980; 106:97.
4. Wever EG, Lawerence M: Physiological Acoustics. Princeton: Princeton University Press, 1954. 5. Morrison AW, Bundey SE: The inheritance of otosclerosis. J Laryngol Otol 1970; 84:921. 6. Lippy WH: Otosclerosis and pregnancy. Presented at the Triological Society Annual Meeting, May 15, 2005, Boca Raton, FL. 7. Karmaker S, et al: Cholesteatoma surgery: the individualized technique. Ann Otol Rhinol Laryngol 1995; 104:591. 8. Gates GA: Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg 1996; 114:525. 9. Klein JO, et al: Otitis media with effusion during the first three years of life and development of speech and language. In Lim DL, et al, eds: Recent Advances in Otitis Media With Effusion. Philadelphia: Mosby, 1983. 10. Fria TJ, et al: Hearing acuity of children with otitis media with effusion. Arch Otolaryngol Head Neck Surg 1985; 111:10. 11. Stool SE, et al: Otitis Media With Effusion in Young Children. Rockville, MD: Agency for Health Care Policy and Research, U.S. Public Health Service, U.S. Department of Health and Human Services, 1994, Clinical Practice Guideline Technical Report No. 12, AHCPR Publication No. 94-0622. 12. Minor LB, Solomon D, Zinreich JS, et al: Sound- and/or pressure-induced vertigo due to bone dehiscence of the superior semicircular canal. Arch Otolaryngol Head Neck Surg 1998; 124:249. 13. Minor LB: Superior canal dehiscence syndrome. Am J Otol 2000; 21:9-19. 14. Minor LB: Labyrinthine fistulae: pathobiology and management. Curr Opin Otolaryngol Head Neck Surg 2003; 11:340346. 15. Minor LB: Dehiscence of bone overlying the superior canal as a cause of apparent conductive hearing loss. Otol Neurotol 2003; 24:270-278. 16. Mikulec AA, Poe DS, McKenna MJ: Operative management of superior semicircular canal dehiscence. Laryngoscope 2005; 115:501-507. 17. Schuknecht HF: Pathology of the Ear, 2nd ed. Philadelphia: Lea & Febiger, 1993. 18. Suter AH, Von Gierke HE: Noise and policy. Ear Hear 1987; 8:188. 19. Saunders JC, Cohen YE, Szymko YM: The structural and functional consequences of acoustic injury in the cochlea and peripheral auditory system: a five year update. J Acoust Soc Am 1991; 90:136. 20. Bunch CC: Nerve deafness of known pathology or etiology: the diagnosis of occupational or traumatic deafness; a historical an audiometric study. Laryngoscope 1937; 47:615. 21. Forge A, Schach J: Aminoglycoside antibiotics. Audiol Neurotol 2000; 5:3-22. 22. Matz GJ: Clinical perspectives on ototoxic drugs. Ann Otol Rhinol Laryngol Suppl 1990; 148:39. 23. Fee WE: Aminoglycoside ototoxicity in the human. Laryngoscope 1980; 90(Pt 2, Suppl 24):1-19. 24. Riggs LC, Brummett RE, Guitjens SK, et al: Ototoxicity resulting from combined administration of cisplatin and gentamycin. Laryngoscope 1996; 106:401-406. 25. Bizjak ED, Haug MT, Schilz RJ, et al: Intravenous azithromycin-induced ototoxicity. Pharmacotherapy 1999; 19:245-248. 26. Elting LS, Rubenstein EB, Kurtin D, et al: Mississippi mud in the 1990s. Risks and outcomes of vancomycin-associated toxicity in general oncology practice. Cancer 1998; 83;2597-2606. 27. Rybak LP: Pathophysiology of furosemide ototoxicity. J Otolaryngol 1982; 11:127. 28. Tuzel IJ: Comparison of adverse reactions to bumetanide and furosemide. J Clin Pharmacol 1981; 21:615. 29. Boston Collaborative Drug Surveillance Program: Druginduced deafness. JAMA 1973; 224:515.
chapter 26 auditory system disorders 30. Boettcher FA, Salvi RJ: Salicylate ototoxicity: review and synthesis. Am J Otolaryngol 1991; 12:33. 31. Jung TT, et al: Ototoxicity of salicylates, nonsteroidal antiinflammatory drugs, and quinine. Otolaryngol Clin North Am 1993; 26:791.
335
32. Myers EN, Bernstein JN, Fostiropolous G: Salicylate ototoxicity. N Engl J Med 1965; 273:587. 33. Laurell G: Ototoxicity of the anticancer drug cisplatin. Clinical and experimental aspects. Scand Audiol Suppl 1991; 33:147.
CHAPTER
27
VESTIBULAR SYSTEM DISORDERS ●
●
●
●
Linda M. Luxon and Doris-Eva Bamiou
Humans have developed a sophisticated and complex mechanism for maintaining balance that relies on the integration and modulation of sensory inputs from vision, the vestibular receptors within the labyrinth, and proprioception. Within the central nervous system, the cerebellum, the extrapyramidal system, the limbic system, and the cerebral cortex facilitate processing to enable the perception of head and body position in space, eye movement control, and appropriate static and dynamic postural function (Fig. 27–1). An alteration in any one of the three sensory inputs, or within the central vestibular pathways and their connections, may give rise to disordered eye movements, disequilibrium or instability, and the perception of dizziness or vertigo. The complexity of this system is such that pathology in almost all body systems may be associated with dizziness/disequilibrium; thus, affected patients present to many different specialist departments but most commonly to otology or neurology outpatient offices (Table 27–1). Despite these ubiquitous presentations, most clinicians do not have a clear diagnostic strategy, including knowledge of detailed neuro-otological examination, to enable them to accurately diagnose and appropriately manage vestibular symptoms. This chapter provides a broad overview of peripheral and central vestibular syndromes, together with an outline of an appropriate clinical assessment based on an understanding of vestibular pathophysiology, a discussion of management strategies, and specific points with regard to common vestibular disorders.
DEFINITIONS When the vestibular apparatus is damaged by any pathology, a number of typical clinical manifestations arise. Symptoms and signs of pathology are determined by the site of the lesion and not by the etiology. This in part compounds the diagnosis for the clinician. Nonetheless, the specific diagnosis is highly relevant in terms of appropriate management. The term peripheral vestibular disorders refers to pathology in the vestibular labyrinth and/or cranial nerve VIII, whereas pathology affecting the central nervous system pathways at or above the vestibular nuclei are referred to as central vestibular syndromes. For the purposes of this chapter, vertigo refers to an illusion of movement, whereas dizziness is a lay term variously covering a plethora of synonyms, including giddiness, light-
headedness, falling, “swimminess,” and mental disorientation. Ataxia is an inability to coordinate muscular movements; the terms falls and unsteadiness are self-explanatory. Oscillopsia refers to the rhythmic oscillation of the visual environment, often spontaneously as a consequence of a central eye movement disorder or in response to motion, as a consequence of bilateral vestibular failure.
EPIDEMIOLOGY Dizziness is an extremely common symptom, both in primary care and at the tertiary level. One in four healthy subjects in the community reports symptoms of dizziness, with significant effects on their daily living.1 By the age of 70, 36% of women and 29% of men have balance problems, whereas by the ages of 88 to 90, 45% to 50% of the population suffer symptoms of balance dysfunction.2 In the community, many cases of vestibular dysfunction resolve spontaneously, without recourse to medical care, although each year 5 per 1000 patients consult their general practitioners because of symptoms that are classified as vertigo, and a further 10 per 1000 are seen for dizziness or giddiness.3 In a tertiary setting, dizziness is associated with significant morbidity, and in the older population, falls and mortality are common sequelae.4 Vestibular symptoms after head/whiplash injury are the commonest cause of failure to return to work, and two thirds of patients in a tertiary neuro-otological clinic suffer psychiatric symptoms in association with vestibular pathology.5
VESTIBULAR ANATOMY AND PHYSIOLOGY The internal ear is a minute membranous structure within the bony labyrinth, buried in the temporal bone. Within the internal ear, the cochlea is the acoustic end-organ receptor, whereas, of the five vestibular end-organs, one lies within each of the three semicircular canals and one each in the utricle and saccule within the vestibule. The vestibular sensory epithelium is composed of type 1 and type 2 hair cells, covered with a gelatinous membrane that, in the saccule and utricle, contains calcium carbonate-rich crystals termed otoconia (Fig. 27–2). A force parallel to the surface of the sensory epithelium provides the maximal stimulus. Thus, the horizontal anterior and
337
338
Section
V
Neuro-otology
Cortex cerebellum Reticular formation Extra-pyramidal system
Cortical awareness of head/body/motion
Eye
Integrating/ data storage system Eye movement/ control of oculomotor activity
Joint position Proprioception Superficial sensation
posterior semicircular canals are stimulated by angular acceleration in the three planes of space but are insensitive to gravity or head position.6 The saccule, which lies approximately vertically, senses vertical linear head acceleration and gravity; the utricle, which is oriented approximately horizontally, senses horizontal linear head motion and head position in space. Physiologically, the vestibular apparatus can be considered in two halves, the right labyrinth and the left labyrinth, which are perfectly balanced and work in parallel. For example, when the head is turned to the right, the right horizontal semicircular canal increases its firing rate, whereas the left decreases its firing rate. This asymmetry in neural input is transmitted (1) to the vestibular nuclei and the cerebellum, which controls the amplitude and timing of movements, and (2) via the vestibular nuclei and the thalamus to the parietoinsular vestibular cortex. From birth, the vestibular, visual, and proprioceptive inputs associated with every type of movement are monitored, integrated, and stored in a “data bank,” which is considered to be the reticular formation of the brainstem.7 Subsequently, each movement generates signals that are then
Labyrinthine activity
Direction of view Control of posture Control of motor skills
■
Cupula movement generates nerve impulses
Cupula
Figure 27–1. Mechanisms of balance.
Crista
T A B L E 27–1. Causes of Disequilibrium General Medical Hematological Anemia Hyperviscosity Cardiovascular Mechanical (e.g., aortic stenosis) Postural hypotension Carotid sinus syndrome Dysrhythmia Metabolic Hypoglycemia Hyperventilation Otological Meniere’s syndrome Positional vertigo Viral Trauma Vascular Ototoxicity Tumor
Superior semicircular duct Lateral semicircular duct Utricle
Hair cell Supporting cells Nerve fibers
Ganglion of Sup. vestibular Inf. nerve Facial nerve Cochlear nerve
Posterior semicircular duct
Neurological Epilepsy Multiple sclerosis Vertebrobasilar insufficiency Infective disorders Degenerative disorders Tumors Foramen magnum anomalies Psychiatric disorders Miscellaneous Iatrogenic Cervical vertigo Visual vertigo Multisensory dizziness
Hair-like extensions
Ampullary crest
Otoliths
Sacculus
Otolithic membrane Hair process Hair cell Supporting cell
■
Macula
Figure 27–2. The vestibular end-organ and vestibular sensory epithelia.
chapter 27 vestibular system disorders
Corollary discharge
339
Expected afferences
Re-afferences
Central store
Voluntary motion
Habituation Comparison
Space constancy
Mismatch Vertigo
■
Figure 27–3. Visual-vestibular mismatch. An active movement leads to stimulation of the sensory organs whose messages are compared with a multisensory pattern of expectation calibrated by earlier experience of motions (central store-data bank). The pattern of expectation is prepared either by the efference copy signal, which is emitted parallel to and simultaneously with the motion impulse, or by vestibular excitation during passive transportation in vehicles. If concurrent sensory stimulation and the pattern of expectation are in agreement, self-motion is perceived while “space constancy” is maintained. If, for example, there is no appropriate visual report of motion, as a result of the field of view being filled with stationary environmental contrasts (reading in the car), a sensory mismatch occurs. With repeated stimulation, motion sickness is induced through summation; the repeated stimulation leads to a rearrangement of the stored pattern of expectation, however, so that a habituation to the initially challenging stimulation is attained within a few days. An acute unilateral labyrinthine loss causes vertigo, because the self-motion sensation induced by the vestibular tone imbalance is contradicted by vision and the somatosensors. (Reprinted from Brandt T: Vertigo: Its Multisensory Syndromes. London: Springer, 2002, p 5, Fig. 1.2. Reprinted with kind permission of Springer Science and Business Media.)
compared with the information in the “data bank.” Integration of movement-induced neural asymmetry with other sensory input and comparison with the “data bank” template allow for awareness of head and body position in space, together with the generation of compensatory oculomotor (vestibulo-ocular reflex) and motor (vestibulospinal) activity. In addition to the motor control, the extensive convergence of vestibular and autonomic afferent information in the brainstem and cerebellum allows for coordination of appropriate motor and autonomic responses during movement or changes in posture. Thus, if there is any mismatch of the sensory input to the existing template, the patient senses disorientation, may develop an abnormal eye movement, frequently feels off balance, and may develop nausea lvomiting and other autonomic symptoms (Fig. 27–3). The classic physiological example of such a mismatch is motion sickness.8 However, any pathological lesion that results in a change in, for example, vestibular input to the central
nervous system, as may occur in Meniere’s disease or vestibular neuritis, produces similar symptoms of disorientation, nausea, vomiting, and malaise as a consequence of the change in the vestibular signal, with no corresponding changes in visual and proprioceptive inputs. In addition, connections at various levels of the central vestibular system with the locus ceruleus, the limbic system, and other brain regions that control affective responses, mood, and arousal may underlie the observed overlap between psychiatric and vestibular disorders.9,10
AGING AND THE VESTIBULAR SYSTEM Histopathological age-related changes in the human vestibular sensory organs include progressive hair cell degeneration, otoconial degeneration in the otolith organs, and decreasing numbers of vestibular nerve fibers,11,12 and age-dependent
340
Section
V
Neuro-otology
changes in both caloric and rotational test responses have been demonstrated.13,14 These changes alone are unlikely to generate vestibular symptoms, as they are symmetrical, and dizziness in elderly people is probably more multifactorial in origin.15 Thus, although older patients may be subject to the same common balance disorders as are younger patients, they have more problems with chronic disequilibrium and falls, and vertigo has been reported to rise with advancing age in parallel with the incidence of hearing loss.13 Correct diagnosis, prevention, and rehabilitation are particularly important in treating this group of patients.16
T A B L E 27–3. Vestibular Compensation Adaptation/Habituation/Plasticity Recalibration of the gain of vestibular reflexes Substitution Other sensory inputs Visual Somatosensory Proprioceptive Intact labyrinthine input Motor responses Strategies
PERIPHERAL VESTIBULAR DISORDERS Acute Unilateral Vestibular Deafferentation Acute pathology of one labyrinth manifests as an acute clinical syndrome with profound motor and sensory abnormalities17 and with the same symptoms and signs irrespective of the cause. A patient with an acute total right vestibulopathy has the following signs (Table 27–2): 1. A partial or complete ocular tilt reaction to the right. 2. Spontaneous horizontal nystagmus, with the fast phases directed to the left; nystagmus is enhanced by removal of optic fixation (e.g., with Frenzel glasses). 3. Rotation to the right when marching on the spot with eyes closed, or drift to the right when performing gait with eyes closed. 4. A positive horizontal head impulse test result to the right that remains when all other symptoms and signs improve. In most cases, the characteristic symptoms and signs of vestibular deafferentation abate, and the patient is rendered asymptomatic over a period of 2 weeks to several months. In this regard, the vestibular system has been shown to be extremely adaptable.18 The processes, which bring about the resolution of vestibular symptoms, are collectively known as cerebral compensation and are attributed to cerebral plasticity (Fig. 27–4; Table 27–3). The structures subserving compensation for vestibular dysfunction are unknown, but it has been shown that brain-
stem, cerebellar, and cortical structures are involved; the cerebellum is key to this recovery phenomenon,17,19,20 in addition to the requirement for all sensory inputs, including vision, somatosensory afferents, and remaining labyrinthine input.21-23 Furthermore, integrity of both the vestibular nerve24 and the central vestibular connections25 is required. The physiological mechanisms on which compensation depends include physical activity26,27 and vision28 (Fig. 27–5). Moreover, Fetter and coworkers29 demonstrated that occipital
Cerebral compensation
Viral labyrinthitis Peripheral vestibular dysfunction and symptoms
Vascular event
Physical or psychological stress
Trauma
■
Asymptomatic state
Figure 27–4. Natural history of peripheral vestibular dysfunction and symptoms.
Unilateral vestibular neurotomy
T A B L E 27–2. Consequences of Unilateral Peripheral Vestibular Destruction
Otolith Destruction or Deafferentation (Right-Sided) Vertical diplopia Deviation of the subjective visual vertical and horizontal to the right Skewed eye deviation (right eye down) Right head tilt Clockwise conjugate eye torsion
Clinical state of recovery
Semicircular Canal Destruction or Deafferentation (Right-Sided) Vertigo Nausea Vomiting Left beat horizontal-torsional nystagmus (increases with absence of optic fixation) Head impulse test result: positive to the right Unterberger test result: to the right
4
Unrestrained Restrained
3
2
1 0
2
7
14
21
30
Post-operative time (d) ■
Figure 27–5. Graph of clinical state of recovery in restrained versus unrestrained animals after unilateral vestibular neurotomy.
chapter 27 vestibular system disorders
341
lobectomy before labyrinthectomy impaired compensational recovery, and Schaefer and Meyer in 197330 also demonstrated that transsection of the cervical cord that led to loss of proprioception delayed vestibular compensation.
congenital nystagmus32 and oculomotor palsies.33 In general, patients with bilateral vestibular function recover significantly, although a proportion remain handicapped by oscillopsia and instability.
Chronic Unilateral Vestibular Deafferentation
Compensation/Decompensation
This situation is seen clinically in the presence of a slowly growing tumor, such as a vestibular schwannoma. The patient may report merely some mild instability or no sense of imbalance, although a unilateral peripheral abnormality may be detected on formal vestibular function testing. This relative lack of symptoms may be explained on the basis of such slow loss that no significant acute vestibular asymmetry occurs. Alternatively, adaptation occurs simultaneously with the loss, so that symptoms do not manifest.
The majority of cases of a unilateral peripheral vestibular deficit recover by means of cerebral compensation. However, some patients do not recover spontaneously and require vestibular rehabilitation with physiotherapy. The basis of physical therapy intervention relies on a structured approach in promoting recovery with visual, proprioceptive, and vestibular stimulation by means of a standard or customized range of exercises. A number of factors that predispose to failure of compensation (Fig. 27–6) or decompensation from a previously recovered state (Fig. 27–7) have been identified. There is some evidence that there exists a critical period in which stimuli must be provided to the adaptive mechanisms and recalibration of the vestibular function must begin, or else the rate of recovery and
Bilateral Vestibular Hypofunction If there is sequential loss of unilateral function with a period of 1 week or more between each event, then the clinical presentation is that of two episodes of acute unilateral loss, as outlined previously. If, however, both vestibular labyrinths are lost together, there may be no acute vertiginous symptoms, in the absence of any vestibular asymmetry. The long-term effects of bilateral vestibular failure are the same, irrespective of whether the loss has been simultaneous or sequential. The clinical features include the following:
Inadequate/inappropriate CNS activity Psychological dysfunction
Pure eye/head stabilisation
■ Sense of imbalance when standing or walking, especially
on uneven surfaces (e.g., sand) or in the absence of vision (e.g., at night). ■ Bobbing oscillopsia: that is, vertical bouncing or blurring of vision when the patient walks, runs, or moves, with degradation of visual acuity as a result of loss of the vestibuloocular reflex. ■ An inability to stand or walk when both vision and proprioception are removed (e.g., when standing on a foam pad with eyes closed or when attempting to walk across a foam pad with eyes closed). In these cases, the cervico-ocular reflex has been implicated in recovery of function31; other authorities have suggested that slippage of the retinal image in bilateral vestibular failure may be compensated for by central visual mechanisms, as occurs in
Balance
Impaired/inadequate musculoskeletal functions
Poor compensation
Fluctuating vestibular activity
Impaired/inappropriate balance strategies
Impaired sensory inputs ■
Figure 27–6. Factors that predispose to failure of compensation. CNS, central nervous system.
Balance Decompensation days to weeks
(Normal) 100%
Disordered perception of stability
(Normal) 100%
Recovery Periods of freedom weeks to months
(Severe impairment) 0% Recovery
(Severe impairment) 0%
Time
Time Labyrinthine insult
6/52–6/12 Labyrinthine insult ■
Figure 27–7. Vestibular decompensation.
342
Section
V
Neuro-otology
perhaps the ultimate degree of recovery may decrease.34 However, Shepard and colleagues35 did not identify duration of symptoms, or age, as a negative prognostic factor of a vestibular rehabilitation program, although financial compensation, head injury, and severe postural control abnormalities have all been reported to indicate poor outcome. Failure of compensation may follow an acute episode of vertigo and vomiting leaving the patient constantly disorientated and disabled, so that he or she cannot function occupationally or socially in an effective manner. Decompensation is often seen in a patient who has had a single acute episode of vertigo and vomiting with recovery over a period of 6 weeks to 6 months and then subsequent relapses, episodes usually becoming progressively less severe and more infrequent with the passage of time. Notwithstanding this, for the nonexpert in the field, such a presentation may be misdiagnosed as a recurrent condition or a new illness, as opposed to a previous labyrinthine event with repeated decompensation.
DIAGNOSIS OF VESTIBULAR DISORDERS The diagnosis of vertigo is critically dependent on a clear history that includes the following: ■ The exact character of the symptom (dizziness, vertigo,
ataxia). ■ The duration of both the illness and individual episodes. ■ The presence of associated symptoms: cochlear, neurologi-
cal, or general medical (Fig. 27–8). Vertigo of less than 1 minute’s duration is most commonly associated with benign paroxysmal positional vertigo (BPPV), whereas acute rotational vertigo of several hours’ duration is most commonly associated with migraine and Meniere’s disease. Vertigo lasting several days is common in viral vestibular neuritis and in ischemic and brainstem labyrinthitis. Pathology involving the labyrinth and cranial nerve VIII is commonly associated with hearing loss and/or tinnitus, whereas vertigo arising in the central vestibular pathways is
Outline of Diagnostic Strategy History Character Duration • episode • constant Associated symptoms • cochlear • neurological • general medical
General medical disorder ■
Examination General Medical Neurological Otological Neuro-otological • eye movement range and conjugacy • smooth pursuit • saccades • spontaneous nystagmus • positional nystagmus • optokinetic nystagmus • gait and stance
Neurological disorder
Neuro-otological disorder
Figure 27–8. Diagnosis of vertigo.
most commonly associated with disordered eye movements. In order to make a correct neuro-otological diagnosis, a clinical examination of the vestibular and oculomotor systems is key and requires a clear understanding of vestibular and oculomotor pathology, together with regular clinical practice at examination.36
COMMON PERIPHERAL VESTIBULAR DISORDERS Acute Vestibular Neuritis Single episodes of acute rotational vertigo associated with nausea and vomiting, with or without cochlear symptoms, are a common occurrence in all age groups. The attacks are usually unprecipitated and are commonly ascribed to a viral infection, termed vestibular neuritis, vestibular neuronitis, labyrinthitis, or acute vestibulopathy.37,38 The signs and symptoms are as described earlier for an acute unilateral vestibular disorder, and the natural history is resolution of symptoms within a few days or weeks. The majority of patients recover spontaneously, but it appears that early mobilization and vestibular rehabilitation reduce the incidence of disability from chronic vestibular symptoms, which develops in about 20% of patients with acute vestibular neuritis.39 Most cases of vestibular neuritis affect the superior vestibular nerve, with a marked canal paresis on caloric testing, which shows progressive recovery in about 50% of patients on repeat testing.40,41 Frequently, it is possible to obtain a normal saccular response, as judged by the vestibular evoked myogenic potential, which depends on normal inferior vestibular nerve function. In 25% of the patients with vestibular neuritis,43 BPPV (described later) of the posterior canal variant may develop subsequently. The differential diagnosis of acute vestibular neuritis includes perilymph fistula; vestibular neuritis with repeated decompensation and migrainous vertigo; cerebellar infarction; occlusion of a branch of the internal auditory artery in an elderly atherosclerotic patient or in a patient with risk factors for embolization; early Meniere’s disease with isolated episodes of vertigo; and autoimmune inner ear disease, either as an isolated phenomenon or as part of a systemic autoimmune disorder.
Ramsay-Hunt Syndrome The Ramsay-Hunt syndrome is the clinical presentation of herpes zoster oticus with facial palsy, auricular rash, and hearing loss, which are often associated with acute vertigo. Abramovich and Prasher44 reported vertigo in 85% of their series; conversely, vestibular dysfunction has also been described with Bell’s palsy or idiopathic facial palsy,45,46 at an incidence of between 20% and 92%. A number of mechanisms of vestibular involvement in this latter condition have been postulated, including compression of cranial nerve VIII by the edematous cranial nerve VII and involvement of both cranial nerves VII and VIII in the same disease process. Vertigo, imbalance, ataxia, and nausea have all been reported in human immunodeficiency virus infection, although it remains unclear whether the pathology is central or peripheral in type, and vestibular dysfunction is less common than auditory involvement.47
chapter 27 vestibular system disorders
343
Meniere’s Disease Meniere’s disease remains a clinical diagnosis characterized by fluctuating hearing loss, tinnitus, and vertigo, often associated with sensation of fullness or blockage in the ear. In 60% of patients affected, both vestibular and cochlear symptoms have developed within 6 months of the onset of the disease. The literature abounds with controversy on all aspects of this condition, and the diagnosis should be based on the strict American Academy of Otolaryngology—Head and Neck Surgery Committee on Hearing and Equilibrium Guidelines.48 The vertigo attacks usually last between 1 and 8 hours, but the tinnitus, hearing loss, and sensation of fullness in the ear may last for several days. Attacks tend to occur in clusters, with attackfree intervals. Initially, both vestibular function and cochlear function recover, so that the caloric test and audiometry may be normal between attacks. Later there is a progressive lowfrequency hearing loss, which, in the older patient, may be superimposed on presbycusis to yield a tent-shaped audiogram, and with continuing progression, a plateau hearing loss emerges. Moreover, with progressive attacks, interval disorientation may accompany loss of vestibular function. Clinical examination may show spontaneous nystagmus directed toward the affected ear (i.e., an irritative response), followed by an ablative phase, in which the nystagmus beats away from the affected ear, and a recovery phase, in which the nystagmus may again beat toward the affected side.49 Late in the disease, patients may develop drop attacks called Tumarkin or otolithic crises.50 The natural history of Meniere’s disease is variable, but in general there are clusters of episodes (relapses) with attack-free periods that may last several years (remission). Other patients, however, have a progressive course, with ultimate loss of auditory and vestibular function. Bilateral involvement is reported in 20% to 50% of cases.51 Electrocochleography with transtympanic recording at the promontory is the most sensitive and specific test for Meniere’s disease. Characteristically, there is broadening of the summating potential/action potential ratio; this ratio is often greater than 35%, in comparison with approximately 20% in normal subjects (Fig. 27–9). The underlying pathophysiology of Meniere’s disease is generally attributed to endolymphatic hydrops. In 75% of cases, the condition is considered idiopathic, whereas in 25%, a variety of other pathological conditions, including syphilis, trauma, infection, and otosclerosis, are reported to underlie the development of the condition. The disease may occur at any age, but the first attack most commonly occurs between the ages of 30 and 60. It is rare but not unknown in children and is uncommon as a presenting condition after the age of 60 years. About 10% of affected patients have a family history of this disease.52 A number of mechanisms have been hypothesized to predispose to a disorder of endolymph homeostasis, including a defect in normal endolymph absorption by the endolymphatic system. There may be hormonal factors53 or a viral etiology.54,55 Other hypotheses have been based on ischemia,56 and more complex disorders associated with autoimmune disease have been proposed.57 The differential diagnosis of Meniere’s disease includes perilymph fistula, vestibular neuritis with repeated decompensation, and vestibular migraine, which is a particularly difficult diagnosis in that there is a clear increased incidence of
N2
■
SP
N2
AP
N1
N1
Normal
Meniere’s disease
Figure 27–9. Electrocochleography. Left, Normal traces; right, findings in Meniere’s disease, with characteristic broadening of the summating potential/action potential (SP/AP) ratio. N1 and N2, first and second negative peaks of the action potential.
Meniere’s disease per se in migrainous subjects.58 Brief acute spells of dizziness may also occur in progressive bilateral vestibular failure of unknown etiology.59
Migrainous Vertigo Migraine affects approximately 4% to 6% of men and 11% to 18% of women in both Europe and the United States. The incidence and frequency of disequilibrium in association with migraine are reported to range between 50% and 70%.60 Vertigo may occur independently of headache, particularly in children (benign paroxysmal vertigo of childhood).61 Normally, there is a personal or family history of migraine, with troublesome motion sickness in childhood.62 In association with the vertigo, there may be classic symptoms of sensory hyperexcitability, including photophobia, phonophobia, and osmophobia. Visual symptoms are the symptoms most commonly associated with migraine with aura, but somatosensory and vestibular symptoms also occur frequently. Within this category are basilar migraine and migraine aura without headache, which are of particular neuro-otological relevance, although episodic vertigo without headache can prove difficult to diagnose etiologically. Frequently, such conditions are referred to as migraine equivalents or migraine accompaniments. Vertigo, tinnitus, and hearing impairment are common symptoms with basilar migraine, making the differential diagnosis between this condition and Meniere’s syndrome particularly difficult. Overall, episodic vertigo occurs in about 25% of unselected patients with migraine.58 In one study, nonspecific dizziness occurred approximately equally in patients with migraine (N = 200) and patients with tension-type headaches (N = 166), but vertigo occurred in 27% of patients with migraine, as opposed to 8% of patients with tension-type headache (a significant difference at the level of P > 0.001).28 Young children exhibit multiple and diverse manifestations of migraine, with headache frequently being absent.61 Children may present with cyclical vomiting or attacks of abdominal pain. Basser63 described an episodic disorder that occurs in young children younger than 4 years, termed benign paroxysmal vertigo. The affected child suddenly becomes frightened, cries out, clings to the caregiver, staggers, becomes pale, and often vomits. Typically, the attack is brief, lasting only several
344
Section
V
Neuro-otology
minutes, the symptoms are exacerbated by head movement, and nystagmus and/or torticollis may be observed. The child’s condition rapidly returns to normal, and although the attacks may occur up to several times a month before the age of 4, they gradually decrease in number and disappear by the age of 7 or 8. Characteristically, these children develop migraine with aura in adult life.64 Benign recurrent vertigo in adults was described by both Slater in 197965 and Moretti and coworkers in 1980,66 but subsequent consideration of their patients, who complained of episodic vertigo, nausea, and vomiting, worse around menses in women, with no auditory symptoms nor interval symptoms and strong personal or family histories of migraine, suggests that this condition also represents migraine equivalents. Rassekh and Harker67 followed up 38 patients with the diagnosis of “vestibular Meniere’s syndrome.” Of these, 8 developed characteristic Meniere’s disease, 7 became asymptomatic, and the remaining 21 failed to develop the classic triad of Meniere’s disease. Of this latter group, 81% had migraine, which highlights the diagnostic difficulty between early Meniere’s disease and migraine. It is currently believed that a specific pathophysiology underlines the association between vestibular and migrainous symptoms, termed migraine-related dizziness.68 Researchers have aimed to provide a diagnostic framework for this disorder on the basis of a combination of the International Headache Society criteria for migraine, the presence of specific other symptoms, and the exclusion of other pathology.69,70 Numerous studies have documented the familial pattern of migraine, although genetic studies to date have failed to define genetic abnormalities in the common forms of migraine. Familial hemiplegic migraine, a rare subtype of migraine with aura and autosomal dominant inheritance, is characterized by headache attacks that are preceded or accompanied by episodes of hemiplegia, usually lasting days. In about 50% of patients with familial hemiplegic migraine, mutations in a brainspecific P/Q-type calcium channel gene, CACNA1A,71 located on chromosome 19p, have been shown to produce this condition. Although the exact nature of the mutation has not been elucidated, certain features of migraine are compatible with ion channel dysfunction, including triggers, such as stress and menstruation. Research evaluating calcium channel genes in this population continues.
Benign Positional Paroxysmal Vertigo BPPV was characterized by Dix and Hallpike72 in their seminal work on patients with vertigo in 1952. This condition is the most common cause of vertigo in adults in virtually all reported series. Schuknecht73 defined degenerative changes in the superior vestibular nerve, the utricle, and the horizontal and anterior semicircular canals in the temporal bones of patients with BPPV and postulated ischemia of the anterior vestibular artery. He further74 identified basophilic deposits on the cupulae of the posterior semicircular canals in two patients with BPPV before death. On the basis of these findings, he proposed the hypothesis of cupulolithiasis (i.e., a heavy cupula) as the mechanism giving rise to positional nystagmus of the paroxysmal type (Fig. 27–10A). However, later workers75 proposed the hypothesis of canalithiasis, with free-floating debris from the otolith organ moving within the posterior
T A B L E 27–4. Positional Nystagmus BPPV Nystagmus direction Latent period Adaptation Fatigability Vertigo Incidence
Rotational to undermost ear 2-20 seconds Disappears in <50 seconds Disappears on repetition Strongly present Common
Central Positional Nystagmus Variable None Persists Persists Typically absent Uncommon
BPPV, benign paroxysmal positional vertigo.
canal and acting as a plunger, thus dragging the cupula (see Fig. 27–10B). Diagnosis is made by the Dix-Hallpike positioning test or roll tests. The typical features of BPPV (Table 27–4)76 are explained by free-floating otoconial debris, moving under the influence of gravity (so-called canalithiasis). In the upright position, a clot of calcium carbonate crystals is established around the most dependent portion of the posterior canal. As the patient moves backward and to the side, in the plane of the posterior canal (the movement induced by the Dix-Hallpike positioning test), the clot moves, producing an ampullar-fugal displacement of the cupula, as a result of a plunger effect within the narrow canal. The fatigability, which is characteristic of benign positional nystagmus of paroxysmal type, is explained by dispersion of the clot, making the plunger effect less marked on repeated maneuvers. The induced vertigo and nystagmus are brief, because once the clot settles in the lowest portion of the canal with regard to gravity, the cupula moves back to the primary position. Latency before the onset of nystagmus is best explained by a delay in the initial motion of the clot. Thus, BPPV is not a disease but a clinical manifestation that may result from a variety of different inner ear pathological processes, most commonly labyrinthine concussion secondary to trauma and vestibular neuritis. The condition may affect any of the semicircular canals (Table 27–5), but the posterior canal variant is the most common.76 Characteristically, the patient complains of brief, severe spells of vertigo induced by turning over in bed, tipping the head backward to look at something in the sky, or reaching for something on a high shelf (i.e., “top shelf vertigo”). Treatment is by an appropriate particle repositioning procedure (described later). Approximately 50% of patients suffer recurrence after resolution, and 15% of patients require a second attempt at this technique to clear the condition. In a very small number of intractable cases, a section of the ampullary nerve from the posterior semicircular canal or plugging of the posterior semicircular canal with bone is required. The majority of patients with BPPV show no abnormality on standard caloric testing, but 25% may demonstrate a canal paresis.
Autoimmune Inner Ear Disease Autoimmune inner ear disease is an uncommon but important cause of progressive bilateral loss of auditory and vestibular function.77 The condition commonly manifests with sequential stepwise loss of auditory and vestibular function. The disorder may be associated with systemic autoimmune phenomena,
chapter 27 vestibular system disorders
A
B ■
Figure 27–10. A, Cupulolithiasis: Otoconial debris on the cupula gives rise to positional nystagmus of paroxysmal type. B, Canalithiasis: free-floating debris from the otolith organ, moving within the posterior canal and acting as a plunger, drags the cupula and gives rise to positional nystagmus of paroxysmal type. (A reprinted from Brandt T, Vertigo: Its Multisensory Syndromes. London: Springer, 2002, p 259, Fig. 16.8. B reprinted from Brandt T, Vertigo: Its Multisensory Syndromes. London: Springer, 2002, page 260, Fig. 16.9.)
345
346
Section
V
Neuro-otology
T A B L E 27–5. Diagnostic Characteristics of Benign Paroxysmal Positional Vertigo (BPPV)
History Vertigo Latency Duration Nystagmus
Reversal Adaptation Fatigability
Posterior Canal BPPV
Horizontal Canal BPPV*
Anterior Canal BPPV
Vertigo on sitting up from supine position, lying down, rolling in bed, extending/flexing neck Present on testing 2-20 seconds after head tilt <40 seconds Linear-rotatory, geotropic (toward affected undermost ear) or upward when gaze is directed to uppermost ear On return to sitting position Yes Yes
Vertigo on rolling from side to side in bed
Onset of symptoms may follow a liberatory maneuver
Present on testing <5 seconds >20-60 seconds Geotropic toward undermost ear: beats stronger to affected ear
Present on testing Similar to that of posterior canal BPPV Similar to that of posterior canal BPPV Torsional toward unaffected undermost ear
On rolling to other side Yes No
Similar to that of posterior canal BPPV Yes Yes
*Atypical horizontal canal BPPV may beat toward the uppermost ear and last for minutes when the precipitating position is maintained. NS, not studied.
such as polyarthritis, Wegener’s granulomatosis, or otosclerosis; or it may be part of Cogan’s syndrome with associated interstitial keratitis or may occur in isolation as an inner ear organ-specific disorder.78 Initial symptoms may be suggestive of Meniere’s disease, with fluctuation of hearing and ear pressure, but unlike symptoms of Meniere’s disease, these symptoms progress rapidly over weeks or months to involve the opposite ear. Treatment requires high-dose steroids (60 to 80 mg of prednisolone for 10 days, tapering off, with or without the addition of cytotoxic drugs); plasmapheresis has also been advocated as treatment.
Labyrinthine Trauma Damage to the vestibular apparatus can occur as a result of barotrauma, acoustic trauma, and physical trauma.79 Scuba diving and flying in unpressurized aircraft are the commonest causes of otitic barotrauma, which, if sufficiently severe, may give rise to a perilymph fistula, in which there is disruption of the oval or round window, with acute loss of hearing and vertigo as a result of leakage of perilymph. Clinically, there may be a positive fistula sign with vertigo and nystagmus induced by pressure change in the external canal or by coughing or straining. Characteristically, audiometry shows a sensorineural hearing loss, and electronystagmography reveals a canal paresis on caloric testing. Management may be conservative, with bed rest, head elevation, and symptomatic treatment or surgical exploration if symptoms persist or there is a clear relationship to trauma. Acoustic trauma of sufficient severity to rupture the tympanic membrane may give rise to perilymph fistula, but vertigo usually does not result from noise exposure, which gives rise to a sensorineural hearing loss with a characteristic 4-kHz notch. Physical trauma to the head commonly gives rise to vestibular symptoms in three different presentations: 1. BPPV (discussed previously). 2. Labyrinthine concussion. 3. Vestibular failure. Labyrinthine concussion with or without unilateral hearing loss is common after mild, moderate, and severe head injuries.80 Acute vertigo with evidence of a canal paresis on caloric testing and spontaneous nystagmus in the direction opposite the affected ear are common.79,80 The natural history of the condition
is characteristic of that for any acute unilateral vestibular disorder, unless there is additional central vestibular dysfunction as a consequence of trauma, in which case recovery may be delayed. BPPV may also occur as an isolated late sequela of labyrinthine concussion—an important medicolegal consideration. Dizziness is reported in 75% to 93% of patients with temporal bone fractures. When a patient has a significant head injury, it may not be possible to identify post-traumatic vertigo immediately, because other problems correctly take priority. Nonetheless, evidence of a skull fracture should be sought as soon as possible. Nystagmus has been reported in 22% to 57% of patients with temporal bone fractures, although it has been suggested that the vestibular system is not as vulnerable to damage as the auditory system. Transverse fractures involve the labyrinth or cranial nerve VIII, with profound, irrecoverable hearing loss and severe vertigo, nausea, and vomiting. With the passing of time, the latter symptoms improve as a result of cerebral compensation, if there is no impairment of cerebral compensation. This type of fracture is commonly associated with involvement of the facial nerve. Longitudinal fractures result in less severe vestibular symptoms but commonly traverse the middle ear, giving rise to a conductive hearing loss that may or may not be associated with sensorineural loss. Labyrinthine concussion commonly occurs in this situation, with associated vestibular symptoms, including positional vertigo.
BILATERAL VESTIBULAR FAILURE Bilateral vestibular failure may result from genetic derangements, meningitis, trauma, autoimmune disease, or, most commonly, ototoxicity.59 Aminoglycoside antibiotics are well recognized as giving rise to vestibular (and auditory) toxicity, and the effect of the drug on a bedridden patient may not manifest until the patient begins to ambulate, at which point he or she develops ataxia and bobbing oscillopsia. The different aminoglycoside antibiotics vary in their predilection for the auditory or vestibular system, but gentamicin is relatively specific for the vestibular apparatus. None of the aminoglycosides is metabolized; they are excreted by glomerular filtration. Thus, patients with renal impairment cannot excrete these drugs, which accumulate in the blood and inner ear fluids. The ototoxic effect is on the hair cells of the inner ear.
chapter 27 vestibular system disorders Clinically, there may be no nystagmus, as there is bilateral vestibular loss, but the patient has degradation of visual acuity with head motion, is unable to walk across a firm mat with the eyes closed, and has absent or severely reduced caloric and rotational responses. Intensive vestibular rehabilitation is of value in rehabilitation.
Neoplasia In rare cases, both primary benign and malignant primary and secondary tumors involve the middle ear and temporal bone, but more rarely do they give rise to vertigo. Tumors of the cerebellopontine angle are also rare, but they are an important diagnostic entity in patients presenting with disequilibrium. A characteristic history is of a slowly progressive unilateral hearing loss, with tinnitus and instability, whereas only 10% to 20% of patients report vertigo. Together with the characteristic of the cranial nerve VIII, examination frequently reveals involvement of cranial nerve VII, followed by cranial nerve V, then the cerebellum, and, late in the disease process, the lower cranial nerves. Acoustic neuromata account for more than 90% of tumors in this region, but other tumors include meningiomas, epidermoid cysts, facial nerve schwannomas, cholesterol granulomas, and, in rare instances, secondary malignancies. Characteristically, there may be unidirectional horizontal nystagmus away from the affected ear, unless the tumor is compressing the brainstem, in which case Bruns bidirectional nystagmus is observed. The diagnosis should be suspected in all cases of progressive unilateral hearing loss and tinnitus and in unilateral hearing loss with an abnormal ipsilateral brainstem evoked response. The “gold standard” for diagnosis is magnetic resonance imaging (MRI) scan. Management may include watchful waiting, surgery, or radiotherapy.81
Acute Middle Ear Disorders Serous otitis media in childhood is well recognized to give rise to symptoms of disequilibrium and vertigo, although the underlying mechanism is poorly understood.82 Infections of the ear and temporal bone may give rise to acute pain, hearing loss, and disequilibrium, and in all cases of vertigo, a detailed otological examination must be undertaken to rule out erosive middle ear disease with serious intracranial complications, including meningitis, brain abscess, subdural effusion, lateral sinus thrombosis, otitic hydrocephalus, and subdural empyema. Such disorders are more common in immunosuppressed or otherwise debilitated patients.
CENTRAL VESTIBULAR DISORDERS Central vestibular disorders are associated with demyelination, degeneration, vascular events, or trauma and are commonly accompanied by disequilibrium, nausea, and eye movement disorders. Vertigo is much more commonly associated with peripheral vestibular disorders than with central disorders. Notwithstanding this, there are a number of central vestibular syndromes that require consideration. Vertebrobasilar transient ischemic attacks are characterized by brief episodes of vertigo, usually of minutes’ duration, in association with one or more of the constellation of brainstem symptoms and signs characteristic of ischemia in the posterior
347
circulation.83 Recurrent vertigo that is not associated with additional neurological symptoms should not be diagnosed as ischemic events; however, in posterior circulation ischemia, vertigo is usually associated with additional neurological symptoms, although, in general, there are no neurological signs, and MRI scans are often normal. Nonetheless, vertigo in association with posterior circulation ischemia is common. The commonest cause is atherosclerosis of the subclavian, vertebral, and/or basilar arteries, but dissection, arteritis, emboli, polycythemia, and hyperviscosity syndromes may also manifest in this way. It should be emphasized that although cervical spondylosis is common in older patients, mechanical compression of the vertebral artery is extremely rare in this condition.84 Lateral medullary infarction (Wallenberg’s syndrome). This condition manifests with acute-onset vertigo, nausea, vomiting, imbalance, incoordination, facial numbness and weakness, diplopia, dysphagia, and dysphonia. This manifestation is commonly associated with ischemia of the posterior inferior cerebellar artery, although, in practice, it more commonly results from ipsilateral vertebral artery occlusion. Classic signs include ipsilateral Horner’s syndrome; ipsilateral paralysis of the palate, pharynx, and larynx; ipsilateral loss of pain and temperature sensation on the face with ipsilateral dysmetria, dysrhythmia, and dysdiadochokinesia; contralateral loss of pain and temperature sensation of the body; and spontaneous nystagmus. Classically, patients experience lateropulsion, a prominent, strong motor disturbance tending to push both the patient and the eyes to the side of the lesion. MRI reveals infarction in the dorsolateral medulla, with or without infarction of the posterior inferior cerebellum.85 Ischemia in the distribution of the anterior inferior cerebellar artery may result in infarction of the dorsolateral pontomedullary region and the anterior interior cerebellum.86 Because the labyrinthine artery arises from the anterior inferior cerebellar artery in about 85% of cases, there is commonly also infarction of the membranous labyrinth. This gives rise to a clinical syndrome characterized by both acute peripheral and central vestibular findings. Diagnosis of cerebellar infarction is crucial, because surgical decompression may be required if massive edema results. There is acute-onset vertigo with nausea and vomiting, together with severe imbalance and incoordination. Clinically, spontaneous or gaze-evoked nystagmus with truncal ataxia and limb dysmetria is common. MRI shows infarction in the territory of one of the cerebellar arteries or in the watershed area between territories. The condition must be differentiated from acute unilateral peripheral vestibular loss87; the key lies in the finding of spontaneous nystagmus that changes direction with gaze and profound ataxia. After a latent period of 24 to 96 hours, some patients develop progressive brainstem dysfunction caused by compression from a swollen cerebellum and hydrocephalus. Death is inevitable unless the compression is surgically relieved. Cerebellar hemorrhage is similar in presentation to cerebellar infarction, but frequently, in association with acute vertigo, nausea, and vomiting, there is headache and a complete inability to stand. In contrast to cerebellar infarction, in the early stages of examination there is frequently marked nuchal rigidity and prominent cerebellar signs, together with ipsilateral facial paralysis and ipsilateral gaze paralysis. Pupils are often small bilaterally but reactive. Approximately 50% of patients lose consciousness within 24 hours of the initial symptoms, and 75%
348
Section
V
Neuro-otology
become comatose within 1 week of onset. The condition is often fatal, unless surgical decompression is performed.88 In more than 50% of cases of brain tumors of the posterior fossa, vestibular and cochlear symptoms occur. In cerebellar tumors, positional vertigo, vomiting, headache, and gait imbalance are the norm. An MRI scan is diagnostic, and audiometry frequently shows normal pure-tone audiometry but abnormalities on brainstem evoked responses. Central gaze-evoked nystagmus with abnormalities of smooth pursuit, saccades, and visual-vestibular interaction are common.89 Such tumors are particularly common in children and adolescents when they are rapidly growing, whereas in adults, cerebellar secondary tumors are more common. Multiple sclerosis is characterized by plaques of demyelination disseminated in time and space, and it is commonly associated with disorientation and/or imbalance. Symptoms commonly include monocular visual loss, vertigo, diplopia, weakness, numbness, and ataxia. Both the auditory and vestibular systems may be involved. Acute vertigo may manifest in 5% of patients with multiple sclerosis, frequently mimicking an acute peripheral vestibular episode. However, careful oculomotor examination90 usually reveals central vestibular findings of gaze-evoked nystagmus, disconjugate vertical nystagmus, central positional nystagmus, and/or disorders of smooth pursuit; saccades; and visual-vestibular interactions. Brainstem evoked responses and otoacoustic emission suppression evaluations of efferent auditory function frequently identify central auditory disorders. As in the majority of central vestibular syndromes, however, MRI is the definitive investigation. Arnold-Chiari malformation is characterized by oscillopsia associated with downbeat nystagmus and gait unsteadiness. In addition to downbeat nystagmus, lower cranial nerve palsies and both gait and limb ataxia are typically noted on examination. Associated auditory disturbances caused by neural involvement may be present, and diagnosis is by means of MRI. Suboccipital decompression of the foramen magnum may alle-
viate progression of the neuro-otological abnormalities, but this procedure rarely brings about improvement.91
MANAGEMENT OF VESTIBULAR DISORDERS Successful management of the patient with vertigo depends on accurate diagnosis, an understanding of vestibular physiology and compensation, appropriate intervention strategies, and the physician’s awareness of the overlap between vestibular, autonomic, and psychological aspects of vestibular pathology (Fig. 27–11). The five main branches of management intervention are as follows:92 1. General medical evaluation with correction/amelioration of associated comorbid conditions. 2. Pharmacological intervention. 3. Vestibular rehabilitation with physiotherapy and specific physical maneuvers for the management of BPPV. 4. Psychological intervention. 5. Surgery. On the basis of the diagnosis, an appropriate rehabilitation plan (Table 27–6) should be constructed for each patient, and T A B L E 27–6. Rehabilitation Program Explanation to individual and family Correction of remediable problems General fitness program Physical exercise regimen Systematic Customized Psychological assessment Treatment for specific disorders Monitor progress Discharge
■
Vertigo
of vestibular disorders.
Full history and examination
Medical investigation
Neuro-otological investigation
Diagnosis and treatment
Specific diagnosis
Medical treatment
Neurological investigation
Diagnosis and treatment
Peripheral labyrinthine vertigo
Otological surgery
Medical treatment of acute attack
Medical treatment of chronic recurrent vertigo: • Physical exercise regimes or maneuvers • Psychological support • (Vestibular sedatives)
Therapeutic procedures Surgery Failure Destructive procedures
Figure 27–11. Management
chapter 27 vestibular system disorders it is important that the patient fully understands the aims and objectives of the rehabilitation package to ensure active compliance.
General Measures If appropriate treatment is not undertaken, systemic disorders such as hypertension, vascular disease, diabetes, autoimmune disorders, and psychological pathology may affect vestibular compensation in the dizzy patient. Specifically, ophthalmological and rheumatological/orthopedic problems should be addressed to ensure optimal visual and proprioceptive input and to enable optimal vestibular compensation.
Pharmacological Treatment Antiemetics and vestibular sedative drugs impair vestibular compensation and, therefore, should not be used in the longterm management of chronic vertigo of peripheral origin. Drug treatments of vestibular disorders include the following: 1. Treatment of acute vestibular symptoms. 2. Specific treatment of a condition that causes vestibular symptoms, such as migraine, epilepsy, or Meniere’s disease. 3. Nonspecific but empirical treatment of a chronic vestibular disorder, such as central vestibular dysfunction. Acute vestibular symptoms may be ameliorated by antiemetic and vestibular-suppressant drugs. Antiemetics may be administered intramuscularly, via the buccal membrane, or by suppository, if vomiting precludes oral administration. Hyoscine, prochlorperazine, promethazine, cyclizine, dimenhydrinate, and metoclopramide are the usual drugs of choice. Calcium channel antagonists, such as cinnarizine and funarizine, have vestibular suppressant effects, although both drugs may have extrapyramidal side effects and should be used cautiously by older patients. Diazepam has no specific action on the vestibular system, but it is widely used for its anxiolytic effect in acute vestibular crises. Specific treatment of vestibular disorders is appropriate for Meniere’s disease, migraine, and episodic ataxia. The treatment of Meniere’s disease remains controversial and empirical,93 with few double-blind randomized studies to assess treatment efficacy and an 80% placebo response in this condition. Medical treatment aims to influence the underlying pathology of endolymphatic hydrops or the postulated immunological pathogenesis of this disorder, whereas destructive procedures may be either medical (intratympanic injection of aminoglycosides) or surgical. A low-salt diet and diuretics (bendrofluazide, 10 mg/day), together with potassium supplements and regular serum potassium checks to avoid hypokalemia, appear to be highly effective. Betahistine, a histamine analog, is advocated for treatment of Meniere’s disease but is contraindicated in the presence of migraine. Steroids have been proposed both systematically and transtympanically, on the assumption of an autoimmune pathogenesis for Meniere’s disease. The treatment of migraine-associated dizziness parallels the treatment of migrainous headache. General measures, including dietary restriction, lifestyle adaptations, stress reduction techniques, and vestibular rehabilitation are of value in the presence of a fixed vestibular deficit. Treatment may include
349
over-the-counter analgesics, in addition to triptans, ergot derivatives, and acetazolamide. Prophylactic medication includes β blockers, calcium channel blockers, serotonin reuptake inhibitors, and amitriptyline. Episodic ataxia, which is rare in comparison with migraine, may manifest with acute vertigo and ataxia. Both acetazolamide and 4-aminopyridine are effective in episodic ataxia type 2.94,95 Standard antiemetics and vestibular sedative drugs may be tried in maximal dosages to alleviate acute vestibular symptoms. On an empirical basis, nausea and disequilibrium associated with central eye movement disorders have reportedly been improved by a variety of drugs, including clonazepam, gabapentin, baclofen, flunarizine, and barbiturates. Each drug should be titrated against known side effects to obtain optimal suppression of symptoms.92 Ondansetron, a potent highly selective 5-hydroxytryptamine-3 receptor antagonist, has been effective in combating nausea, particularly in association with vertigo caused by brainstem stroke.96
Vestibular Rehabilitation Management of peripheral vertigo hinges on the facilitation of compensation through physical exercise regimens, such as the Cawthorne-Cooksey exercises and customized regimens,97 together with appropriate psychological support for patients who develop the common sequelae of avoidance behavior, anxiety, and depression.5 Treatment of BPPV is particularly rewarding, because particle repositioning procedures have been shown to be highly effective.97 In 1980, Brandt and Daroff98 proposed specific repetitive positional exercises that were based on the hypothesis of cupulolithiasis, and they claimed a 98% success rate. More recent studies in which both the Epley and the Semont maneuvers, based on the hypothesis of canalithiasis, were used reported success rates of between 80% and 95% after the first maneuver. Repeated maneuvers improve the success rate so much that fewer than 5% of patients appear to continue suffering persistent symptoms despite these treatments. It may be appropriate to consider surgical intervention such as plugging the posterior canal to bring about resolution of positional vertigo in this small subset of patients in whom medical management fails. There is some evidence to support the use of physiotherapy in central vestibular syndromes, and gait-retraining strategies may prove valuable in restoring confidence and optimizing available function.
Psychological Intervention The interaction of psychological factors and vestibular symptoms in recovery from peripheral vestibular disorders cannot be overemphasized. Many studies have highlighted the association of agoraphobia, avoidance behavior, anxiety states, panic attacks, and depression with vestibular pathology.99 When a patient is not recovering with physiotherapy intervention, such factors should always be considered.
Surgical Intervention It is now widely recognized that surgical intervention for vertigo is needed only in life-threatening complications of
350
Section
V
Neuro-otology
chronic middle ear disease, neoplasia involving otological structures (e.g., vestibular schwannoma), or trauma to the middle or inner ear, as may be seen in association with a perilymph fistula. Interventions such as endolymphatic sac decompression for Meniere’s disease have not been proved effective, and destructive surgical procedures such as labyrinthectomy or vestibular nerve section should be considered with caution in view of the reported incidence of bilateral pathology in this condition. Medical destruction of the inner ear with the aminoglycosides, through intratympanic instillation of gentamicin, remains an unproved therapeutic intervention in that although the episodes of vertigo may abate, there is a significant occurrence of sensorineural hearing loss, and the possible long-term consequence of bilateral disease must again be borne in mind.
Successful management of the patient with vertigo depends on accurate diagnosis, an understanding of vestibular physiology and compensation, appropriate intervention strategies, and the physician’s awareness of the overlap between vestibular, autonomic, and psychological aspects of vestibular pathology.
●
Management intervention is based on general medical evaluation with correction/amelioration of associated comorbid conditions; pharmacological intervention; vestibular rehabilitation with physiotherapy and specific physical maneuvers for the management of BPPV; psychological intervention; and rarely surgery.
Suggested Reading
CONCLUSION Balance disorders are common, and although the majority of peripheral vestibular disorders may resolve spontaneously, a significant proportion do not. This latter group, together with central vestibular syndromes, carries significant social and occupational morbidity. A clear diagnostic strategy, allowing accurate diagnosis and appropriate intervention, frequently facilitates a significant improvement in both patients’ symptoms and quality of life.
K E Y
●
P O I N T S
●
Balance relies on integration of movement-induced neural asymmetry with other sensory (visual and somatosensory) input and comparison with information in a central “data bank” template. If there is any mismatch between the sensory input and the existing template, or if there is a pathological lesion, the patient senses disorientation, may develop an abnormal eye movement, frequently feels off balance, and may develop nausea/vomiting and other autonomic symptoms.
●
Dizziness/disequilibrium is an extremely common symptom that may be associated with pathology in almost all body systems.
●
The diagnosis of vertigo is critically dependent on a clear history of the character of the symptom (dizziness, vertigo, ataxia), the duration of both the illness and individual episodes, and the presence of associated symptoms, in order to enable appropriate management.
●
In most cases, the characteristic symptoms and signs of vestibular deafferentation abate over a period of weeks to months. The processes that bring about the resolution of vestibular symptoms are collectively known as cerebral compensation and are attributed to cerebral plasticity.
●
A percentage of patients with a peripheral vestibular deficit do not recover spontaneously and require vestibular rehabilitation with physiotherapy, which promotes recovery with visual, proprioceptive, and vestibular stimulation.
●
Vertigo is much more commonly associated with peripheral vestibular disorders than with central neurological disorders. Notwithstanding this, there are a number of central vestibular syndromes that must be considered.
Baloh RW, Halmagyi GM: Disorders of the Vestibular System. Oxford, UK: Oxford University Press, 1996. Brandt T: Vertigo: Its Multisensory Syndromes, 2nd ed. London: Springer, 2003. Furman JM, Cass SP: Balance Disorders: A Case-Study Approach, 2nd ed. Oxford, UK: Oxford University Press, 2003. Herdman SJ: Vestibular Rehabilitation. Philadelphia: FA Davis, 2005. Luxon LM, Furman JM, Martini A, et al, eds: Textbook of Audiological Medicine. Martin Duritz London, 2003.
References 1. Yardley L, Owen O, Nazareth I, et al: Prevalence and presentation of dizziness in a general practice community sample of working age people. Br J Gen Pract 1998; 48:1131-1135. 2. Jonsson R, Sixt E, Landahl S, et al: Prevalence of dizziness and vertigo in an urban elderly population. J Vestib Res 2004; 14:47-52. 3. Royal College of General Practitioners and Office of Population Census and Surveys: Morbidity Statistics from General Practice. London: HMSO, 1986. 4. Downton JH: Falls in the Elderly. London: Edward Arnold, 1993. 5. Eagger S, Luxon LM, Davies RA, et al: Psychiatric morbidity in patients with peripheral vestibular disorder: a clinical and neuro-otological study. J Neurol Neurosurg Psychiatry 1992; 55:383-387. 6. Wuyts F: Physiology of Equilibrium. In Gleeson M, ed: ScottBrown’s Otolaryngology: Head & Neck Surgery, 7th ed. London: Hodder Arnold. In press. 7. Roberts TDM: Neurophysiology of Postural Mechanisms, 2nd ed. London: Butterworths, 1978. 8. Watt DG: Sensory and motor conflict in motion sickness. Brain Behav Evol 1983; 23(1-2):32-35. 9. Balaban CD: Neural substrates linking balance control and anxiety. Physiol Behav 2002; 77:469-475. 10. Furman JM, Balaban CD, Jacob RG, et al: Migraine-anxiety related dizziness (MARD): a new disorder? J Neurol Neurosurg Psychiatry 2005; 76:1-8. 11. Rauch SD, Velazquez-Villasenor L, Dimitri PS, et al: Decreasing hair cell counts in aging humans. Ann N Y Acad Sci 2001; 942:220-227. 12. Nadol JB Jr, Schuknecht HF: Pathology of peripheral vestibular disorders in the elderly. Am J Otolaryngol 1990; 11:213227. 13. Enrietto JA, Jacobson KM, Baloh RW: Ageing effects of auditory and vestibular responses: a longitudinal study. Am J Otolaryngol 1999; 20:371-378.
chapter 27 vestibular system disorders 14. Kazmierczak H, Pawlak-Osinski P: Visuoocular reflexes in presbyvertigo. Int Tinnitus J 2001; 7:112-114. 15. Drachman DA, Hart C: A new approach to the dizzy patient. Neurology 1972; 22:323-334. 16. Konrad H, Girardi M, Helfert R: Balance and aging. Laryngoscope 1999; 109:1454-1460. 17. Curthoys IS, Halmagyi GM: Vestibular compensation: a review of the oculomotor, neural and clinical consequences of unilateral vestibular loss. J Vestib Res 1995; 5:67-107. 18. Gonshor A, Melvill Jones G: Extreme vestibule-ocular adaptation induced by prolonged optical reversion of vision. J Physiol 1976; 256:381-414. 19. Ito M: The Cerebellum and Neural Control. New York: Raven Press, 1984. 20. Smith PF, Curthoys IS: Mechanisms of recovery following unilateral labyrinthectomy: a review. Brain Res Rev 1989; 14:155180. 21. Lacour M, Xerri C: Lesion induced neuronal plasticity in sensorineural systems. In Flohr H, Precht W, eds: Vestibular Compensation: New Perspectives. Berlin: Springer-Verlag, 1981, pp 240-253. 22. Halmagyi GM, Cremer PD, Curthoys IS: Peripheral vestibular disorders and diseases in adults. In Luxon LM, Furman JM, Martini A, et al, eds: Textbook of Audiological Medicine. London: Taylor & Francis, 2003, pp 797-818. 23. Luxon LM: Vestibular compensation. In Luxon LM, Davies RA, eds: Handbook of Vestibular Rehabilitation. London: Whurr, 1997, pp 17-29. 24. Cass SP, Goshgarian HG: Vestibular compensation after labyrinthectomy and vestibular neurectomy in cats. Otolaryngol Head Neck Surg 1991; 104:14-19. 25. Petrone D, De Benedittis G, De Candia N: Experimental research on vestibular compensation using posturography. Boll Soc Ital Biol Sper 1991; 67:731-737. 26. Lacour M, Roll JP, Appaix M: Modifications and development of spinal reflexes in the alert baboon (Papio papio) following an unilateral vestibular neurotomy. Brain Res 1976; 113:255269. 27. Igarashi M, Levy JK, O-Uchi T, et al: Further study of physical exercise and locomotor balance compensation after unilateral vestibular neurotomy. Acta Otolaryngol 1981; 92:101-105. 28. Courjon JH, Jeannerod M, Ossuzio I, et al: The role of vision in compensation of vestibulo-ocular reflex after hemilabyrinthectomy in the cat. Exper Brain Res 1977; 28:235-248. 29. Fetter M, Zee DS, Proctor LR: Effect of lack of vision and of occipital lobectomy upon recovery from unilateral labyrinthectomy in rhesus monkey. J Neurophysiol 1988; 59:394-407. 30. Schaefer KP, Meyer DL: Compensatory mechanisms following labyrinthine lesions in the guinea pig. A simple model of learning. In Zippel HP, ed: Memory and Transfer of Information. New York: Plenum, 1973, pp 203-232. 31. Bronstein AM, Hood JD: Oscillopsia of peripheral vestibular origin. Central and cervical compensatory mechanisms. Acta Otolaryngol 1987; 104:207-214. 32. Buchele W, Brandt T, Degner D: Ataxia and oscillopsia in downbeat-nystagmus vertigo syndrome. Adv Otorhinolaryngol 1983; 30:291-297. 33. Wist ER, Brandt T, Krafczyk S: Oscillopsia and retinal slip. Evidence supporting a clinical case. Brain 1983; 106(Part 1):153168. 34. Lacour M: Relearning and critical postoperative period in the restoration of nerve function. Example of vestibular compensation and clinical implications. Ann Otolaryngol Chir Cervicofac 1984; 101:177-187. 35. Shepard NT, Telian SA, Smith-Wheelock M, et al: Vestibular and balance rehabilitation therapy. Ann Otol Rhinol Laryngol 1993; 102:198-205.
351
36. Luxon LM: Evaluation and management of the dizzy patient. J Neurol Neurosurg Psychiatry 2004; 75(Suppl 4):iv45iv52. 37. Strupp M, Brandt T: Vestibular neuritis. Adv Otorhinolaryngol 1999; 55:111-136. 38. Strupp M, Arbusow V: Acute vestibulopathy. Curr Opin Neurol 1999; 14:11-20. 39. Strupp M, Arbusow V, Maag KP, et al: Vestibular exercises improve central vestibulospinal compensation after vestibular neuritis. Neurology 1998; 51:838-844. 40. Herzog N, Allum JH, Probst R: [Follow-up of caloric test response after acute peripheral vestibular dysfunction]. HNO 1997; 45:123-127. 41. Schmid-Priscoveanu A, Bohmer A, Obzina H, et al: Caloric and search-coil head-impulse testing in patients after vestibular neuritis. J Assoc Res Otolaryngol 2001; 2:72-78. 42. Fetter M, Dichgans J: Vestibular neuritis spares the inferior division of the vestibular nerve. Brain 1996; 119:755-763. 43. Aw ST, Fetter M, Cremer PD, et al: Individual semicircular canal function in superior and inferior neuritis. Neurology 2001; 57:768-774. 44. Abramovich S, Prasher DK: Electrocochleography and brainstem potentials in Ramsay-Hunt syndrome. Arch Otolaryngol Head Neck Surg 1986; 112:925-928. 45. Koizuka I, Goto K, Okada M, et al: ENG findings in patients with Bell’s palsy. Relationship between visual suppression and clinical course. Acta Otolaryngol Suppl 1988; 446:85-92. 46. Yagi T, Yamaguchi J, Nonaka M: Neurotological findings in Bell’s palsy and Hunt’s syndrome. Acta Otolaryngol Suppl 1988; 446:97-100. 47. Pappas DG Jr, Roland JT Jr, Lim J, et al: Ultrastructural findings in the vestibular end-organs of AIDS cases. Am J Otol 1995; 16:140-145. 48. Committee on Hearing and Equilibrium, the American Academy of Ophthalmology and Otolaryngology: Committee on Hearing and Equilibrium guidelines for diagnosis and evaluation of therapy in Meniere’s disease. Otolaryngol Head Neck Surg 1995; 113:181-185. 49. Jacobson GP, Pearlstein R, Henderson J, et al: Recovery nystagmus revisited. J Am Acad Audiol 1998; 9:263-271. 50. Ishiyama G, Ishiyama A, Jacobson K, et al: Drop attacks in older patients secondary to an otologic cause. Neurology 2001; 57:1103-1106. 51. Conlon BJ, Gibson WP: Meniere’s disease: the incidence of hydrops in the contralateral asymptomatic ear. Laryngoscope 1999; 109:1800-1802. 52. Paparella MM, Djalilian HR: Etiology, pathophysiology of symptoms, and pathogenesis of Meniere’s disease. Otolaryngol Clin North Am 2002; 35:529-545, vi. 53. Brenner M, Hoistad DL, Hain TC: Prevalence of thyroid dysfunction in patients with Meniere’s disease. Arch Otolaryngol Head Neck Surg 2004; 130:226-228. 54. Pulec L, House WF: Meniere’s disease study: three-year progress report. Int J Equilib Res 1973; 3:156-165. 55. Selmani Z, Marttila T, Pyykko I: Incidence of virus infection as a cause of Meniere’s disease or endolymphatic hydrops assessed by electrocochleography. Eur Arch Otorhinolaryngol 2005; 262:331-334. 56. Friberg U, Rask-Andersen H: Vascular occlusion in the endolymphatic sac in Meniere’s disease. Ann Otorhinolaryngol 2002; 111:237-245. 57. Tomoda K, Suzuka Y, Iwai H, et al: Meniere’s disease and autoimmunity: clinical study and survey. Acta Otolaryngol Suppl 1993; 500:31-34. 58. Kayan A, Hood JD: Neuro-otological manifestations of migraine. Brain 1983; 107:1123-1142. 59. Bronstein A, Rinne T, Gresty M, et al: Bilateral loss of vestibular function. Acta Otolaryngol Suppl 1994; 520:247-250.
352
Section
V
Neuro-otology
60. Harker LA: Migraine associated vertigo. In Baloh RW, Halmagyi GM, eds: Disorders of the Vestibular System. Oxford, UK: Oxford University Press, 1996, pp 407-417. 61. Al-Twaijri WA. Shevell MI: Pediatric migraine equivalents: occurrence and clinical features in practice. Pediatr Neurol 2002; 26:365-368. 62. Cutrer FM, Baloh RW: Migraine associated dizziness. Headache 1992; 32:300-304. 63. Basser LS: Benign paroxysmal vertigo of childhood (a variety of vestibular neuronitis). Brain 1964; 87:141-152. 64. Lanzi G, Balottin U, Fazzi E, et al: Benign paroxysmal vertigo of childhood: a long-term follow-up. Cephalalgia 1994; 14:458460. 65. Slater R: Benign recurrent vertigo. J Neurol Neurosurg Psychiatry 1979; 42:363-367. 66. Moretti G, Manzoni GC, Caffarra P, et al: Benign recurrent vertigo and its connection with migraine. Headache 1980; 20:344-346. 67. Rassekh CH, Harker LA: The prevalence of migraine in Meniere’s disease. Laryngoscope 1992; 102:135-138. 68. Furman JM, Balaban CD, Jacob RG, et al: Migraine-anxiety related dizziness (MARD): a new disorder? J Neurol Neurosurg Psychiatry 2005; 76:1-8. 69. Furman JM, Marcus DA, Balaban CD: Migrainous vertigo: development of a pathogenetic model and structured diagnostic interview. Curr Opin Neurol 2003; 16:5-13. 70. Neuhauser H, Leopold M, von Brevern M, et al: The interrelations of migraine, vertigo and migrainous vertigo. Neurology 2001; 56:436-441. 71. Ophoff RA, Terwindt GM, Vergouwe MN, et al: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87:543-552. 72. Dix MR, Hallpike CS: Pathology, symptomatology and diagnosis of certain common disorders of the vestibular system. Proc R Soc Med 1952; 45:341-354. 73. Schuknecht HF: Positional vertigo: clinical and experimental observations. Trans Am Acad Ophthalmol Otolaryngol 1962; 66:319-331. 74. Schuknecht HF: Cupulolithiasis. Arch Otolaryngol 1969; 90:765-778. 75. Hall SF, Ruby RRF, McLure JA: The mechanics of benign paroxysmal vertigo. J Otolaryngol 1979; 8:151-158. 76. Honrubia V, Baloh RW, Harris MR, et al: Paroxysmal positional vertigo syndrome. Am J Otol 1999; 20:465-470. 77. Yu TJ, Yazawa Y: Immunology of cochlear and vestibular disorders. In Luxon LM, Furman JM, Martini A, et al, eds: Textbook of Audiological Medicine. London: Taylor & Francis, 2003, pp 61-88. 78. Agrup C, Luxon LM: Autoimmune inner ear disease. Curr Opin Neurol. 2006; 19(1):26-32. 79. Luxon LM: Post-traumatic vertigo. In Baloh RW, Halmagyi M, eds: Disorders of the Vestibular System. New York: Oxford University Press, 1996, pp 381-395. 80. Davies RA, Luxon LM: Dizziness following head injury: a neuro-otological study. J Neurol 1995; 242:222-230.
81. British Association of Otorhinolaryngologists—Head and Neck Surgeons: Clinical Effectiveness: Acoustic Neuroma (Vestibular Schwannoma) [Document 5]. London: ENT-UK, 2002. 82. Golz A, Netzer A, Angel-Yeger B, et al: Effects of middle ear effusion on the vestibular system in children. Otolaryngol Head Neck Surg 1998; 119:695-699. 83. Grad A, Baloh RW: Vertigo of vascular origin: clinical and electronystagmographic features in 84 cases. Arch Neurol 1989; 46:281-284. 84. Baloh RW, Honrubia V: Vascular disorders In Baloh RW, Honrubia V, eds: Clinical Neurophysiology of the Vestibular System, 3rd ed. New York: Oxford University Press, 2001, p 292. 85. Bjerner K, Silfverskold BJ: Lateropulsion and imbalance in Wallenberg’s syndrome. Acta Neurol Scand 1968; 44:91-98. 86. Osis JG, Baloh W: Vertigo and the anterior inferior cerebellar artery syndrome. Neurology 1992; 42:1274-1279. 87. Norrving B, Magnussen M, Holtas S: Isolated acute vertigo in the elderly: vestibular or vascular disease? Acta Neurol Scand 1995; 91:43-48. 88. Pollak L, Rabey JM, Gur R, et al: Indication to surgical management of cerebellar haemorrhage. Clin Neurol Neurosurg 1998; 100:99-103. 89. Hirose G, Halmagyi GM: Brain tumours and balance disorders. In Baloh RW, Halmagyi GM, eds: Disorders of the vestibular system. Oxford, UK: Oxford University Press, 1996, pp 446-460. 90. Williams NP, Roland PS, Yellin W: Vestibular evaluation in patients with early multiple sclerosis. Am J Otol 1997; 18:93100. 91. Crtistante L, Westphal M, Herrmann HD: Cranio-cervical decompression for Chiari I malformation: a retrospective evaluation of functional outcome with particular attention to the motor deficits. Acta Neurochir (Wien) 1994; 130(1-4):94-100. 92. Bamiou D-E, Luxon LM: Vertigo-clinical management and rehabilitation. In Gleeson M, Luxon LM, eds: Scott-Brown’s Otolaryngology: Head & Neck Surgery—Ear, Hearing and Balance, 7th ed, London: Hodder Arnold. In press. 93. Kim HH, Wiet RJ, Battista RA: Trends in the diagnosis and management of Meniere’s disease: results of a survey. Otolaryngol Head Neck Surg 2005; 132:722-726. 94. Jen J: Familial episodic ataxias and related ion channel disorders. Curr Treat Options Neurol 2000; 2:429-431. 95. Strupp M, Kalla R, Dichgans M, et al: Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 2004; 62:1623-1625. 96. Rice GP, Ebers GC: Ondansetron for intractable vertigo complicating acute brainstem disorders. Lancet 1995; 345:11821189. 97. Luxon LM, Davies RA, eds: Handbook of Vestibular Medicine. London: Whurr, 1997. 98. Brandt T, Daroff RB: Physical therapy for paroxysmal positional vertigo. Arch Otolaryngol 1980; 106:484-485. 99. Jacobs RG, Furman JM, Cass SP: Psychiatric consequences of vestibular dysfunction. In Luxon LM, Furman J, Martini A, et al, eds: Textbook of Audiological Medicine. London: Taylor & Francis, 2002, pp 869-887.
CHAPTER
28
ORTHOSTATIC HYPOTENSION ●
●
●
●
Horacio Kaufmann and Italo Biaggioni
Maintenance of upright posture is made possible by rapid cardiovascular adaptation that ensures blood flow to vital organs, including the brain, and depends primarily on an intact autonomic nervous system. When this system fails, as occurs in neurological disorders affecting autonomic neurons, orthostatic hypotension results. Severely affected patients are completely disabled, unable to stand for more than few seconds before syncope ensues. The incapacitating nature of orthostatic hypotension in autonomic failure underscores the importance of cardiovascular autonomic reflexes for normal life. Even though treatment remains suboptimal, orthostatic hypotension is arguably the symptom of autonomic impairment most amenable to treatment. These patients are hypersensitive to pressor agents because of baroreflex impairment and receptor upregulation, and clinicians can take advantage of these features in designing treatment.
PATHOPHYSIOLOGY When a normal individual stands, about 700 mL of blood pools in the legs and lower abdominal veins. Venous return decreases, resulting in a transient decline in cardiac output. The reduction in central blood volume and arterial pressure is sensed by pressure-sensitive cardiopulmonary volume receptors and arterial baroreceptors. This leads to baroreflex-mediated sympathetic activation with increases in stroke volume and peripheral vasoconstriction and parasympathetic withdrawal with increase in heart rate (Fig. 28–1). These rapid hemodynamic changes prevent blood pressure from falling; their failure causes orthostatic hypotension. When arterial blood pressure falls below a critical level, cerebral blood flow also decreases. When systolic blood pressure is around 50 mm Hg at brain level (which corresponds to a systolic blood pressure of approximately 70 mm Hg at cardiac level when a person is standing) (Fig. 28–1), the autoregulatory capacity of cerebral blood flow reaches maximum vasodilation and is unable to compensate for a further fall in blood pressure. In addition to these almost instantaneous changes in vascular tone and heart rate directly mediated by autonomic innervation, other longer term mechanisms that contribute to the maintenance of upright blood pressure are also influenced by the baroreflex. These mechanisms are impaired in patients with
354
autonomic failure and contribute to their orthostatic hypotension. Increased sympathetic renal nerve activity induces tubular sodium reabsorption directly1 and by stimulating the secretion of renin from the juxtaglomerular apparatus.2 Renin and converting enzyme convert circulating angiotensinogen into angiotensin II, which is a vasoconstrictor and secretagogue of aldosterone from the adrenal medulla. Aldosterone retains sodium in the kidney, increasing extracellular fluid volume. Patients with autonomic failure have low renin and low aldosterone levels. In addition, unloading of thoracic baroreceptors releases the antidiuretic hormone from the neurohypophysis into the systemic circulation.3,4 Acting on specific receptors in vascular smooth muscle cells,5 vasopressin produces vasoconstriction, and in the kidney it causes water retention and expands extracellular fluid volume.6 Baroreflexmediated vasopressin release is blunted in some patients with autonomic failure. Two other circulating vasoactive peptides, atrial natriuretic factor (ANF) and endothelin, are involved in the regulation of blood pressure and extracellular fluid volume, and their secretion may also be controlled, at least in part, by autonomic reflexes. ANF is secreted from atrial myocites7 when atrial pressure increases. ANF produces natriuresis, relaxation of vascular smooth muscle, and inhibition of renin and aldosterone secretions.8-10 When right atrial pressure decreases, as during the upright posture, circulating levels of ANF quickly fall, contributing to vasoconstriction and expansion of extracellular fluid volume. Whether ANF is released by the direct effect of pressure on the cardiocytes or by a centrally mediated autonomic reflex is still unclear. Kaufmann and colleagues found that the response of circulating ANF to changes in atrial pressure is preserved in patients with baroreflex impairment, which suggests that a local intracardiac reflex regulates the secretion of the peptide.11 Endothelin, a powerful vasoconstrictor synthesized by endothelial cells,12 has an important role in the local control of the circulation.13 In addition, however, endothelin is synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus14 and is co-released with vasopressin from the neurohypophysis into the bloodstream when thoracic baroreceptors are unloaded.15 The physiological function of the endothelin released into plasma during baroreflex activation remains to be defined, but it is likely that circulating endothelin contributes to the vasoconstriction that maintains blood pressure in the upright posture.15
chapter 28 orthostatic hypotension
355
T A B L E 28–1. Assessment of Autonomic Function: Bedside Physiological Tests Posture Test Measure blood pressure (BP) and heart rate (HR) after patient has been supine 15 minutes and standing 5 minutes. Express as supine – standing values. Normal response: systolic BP = 0-20 mm Hg, diastolic BP = 510 mm Hg, HR = 0-15 beats/minute. Sinus Arrhythmia (SA) Ratio Have patient breathe deeply 6 times/minute while HR is monitored. Measure longest R-R interval during expiration and shortest R-R interval during inspiration. Take average of R-R intervals in 6 breaths. SA ratio = R-Rexp/R-Rinsp; normal response: ≥1.2 (decreases with age). Valsalva Ratio Use 6- to 12-mL syringe barrel as mouthpiece connected to sphygmomanometer. Ask patient to blow mercury column to 40 mm Hg for 15 seconds while HR is monitored on continuous strip. Repeat four times. Make sure effort is barred by thorax and not mouth (e.g., by introducing a pin size leak in the mouthpiece). Measure shortest R-R interval during strain and longest R-R interval after release. Valsalva ratio = R-Rrelease/R-Rstrain; normal response: ≥1.4 (decreases with age). Cold Pressor Test Measure baseline BP and HR. Have patient place hand in ice water for 1 min. Measure BP and HR at end of minute. Normal response: rise in systolic BP > 15 mm Hg. R-R, R wave to R wave; R-Rexp, R-R interval during expiration; R-Rinsp, R-R interval during inspiration. ■
Figure 28–1. Effect of gravity on arterial and venous pressure in an upright posture. Below heart level, both arterial and venous pressures increase. Above heart level, pressures decrease. Within the cranium, the perfusion pressure (arterial-venous) remains relatively constant because of the subatmospheric pressure in cerebral sinuses. (From Hainsworth R: Pathophysiology of syncope. Clin Auton Res 2004; 14[Suppl 1]:18-24.)
DIAGNOSIS AND EVALUATION OF ORTHOSTATIC HYPOTENSION Orthostatic hypotension produces a characteristic clinical history. Symptoms of lightheadedness and tunnel vision occur on standing, never while the person is lying down, and are always relieved immediately on sitting or lying down, because cerebral blood flow is passively restored. Failure to meet these criteria suggests other causes of impaired consciousness (e.g., hypoglycemia, seizures, cardiac arrhythmias).16 In patients with diabetes or other peripheral neuropathies, proprioceptive abnormalities lead to feeling of unsteadiness that patients refer as dizziness, which may wrongly suggest orthostatic hypotension. In addition to the classic lightheadedness with blurred vision and syncope, symptoms of chronic orthostatic hypotension may include vague generalized weakness, fatigue, cognitive impairment, and pain in the shoulders and back of the neck (coat hanger pain). Many patients with chronic autonomic failure can tolerate very low orthostatic blood pressures with few symptoms of cerebral hypoperfusion, perhaps because their cerebral autoregulatory capacity is well preserved.17 However, physical
exercise, prolonged standing, the postprandial state, or mild volume depletion exacerbates orthostatic hypotension and invariably triggers symptoms of cerebral hypoperfusion, including presyncope or syncope. The diagnosis of orthostatic hypotension relies on simple measurements of blood pressure and heart rate after the patient has lain down for 5 to 10 minutes and after 1 to 3 minutes of standing. Orthostatic hypotension is arbitrarily defined as a decrease in systolic blood pressure of at least 20 mm Hg and in diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing, in association with symptoms of cerebral hypoperfusion.18 On occasion, the diagnosis of orthostatic hypotension may require repeated measurements of blood pressure throughout the day. In patients with autonomic impairment, the severity of orthostatic hypotension is worse early in the morning or about 30 minutes after a meal compared to the rest of the day. Concomitant measurements of heart rate are crucial for adequate interpretation of results. Side effects of medications are arguably the most common causes of orthostatic hypotension. The most common culprits are tricyclic antidepressants, diuretics, nitrates, and α blockers used to treat benign prostatic hypertrophy. In these cases, there is usually a compensatory increase in heart rate in association with orthostatic hypotension. In contrast, the presence of symptomatic orthostatic hypotension without an adequate compensatory increase in heart rate is sufficient clinical indication of autonomic failure (Fig. 28–3). The diagnosis can be easily confirmed with simple measurements of heart rate and blood pressure (Table 28–1). No single test completely differentiates patients with auto-
356
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s PVN
AVP
SON
NTS
NA Vagal outflow RVL
CVL
Baroreceptors IML Sympathetic outflow ■
Figure 28–2. Simplified outline of autonomic blood pressure regulation by the baroreflex. The baroreflex is a classic example of regulatory feedback control as exerted by the autonomic nervous system. Information is collected by pressure-sensitive receptors located in the walls of cardiopulmonary veins, the right atrium, and within almost every large artery of the neck and thorax, particularly within the carotid and aortic arteries. Venous and the aortic arch baroreceptors relay their information via fibers that course within the vagus nerve (cranial nerve X). Carotid sinus baroreceptor nerve activity is relayed centrally by the carotid sinus (Hering’s) nerve, then through the glossopharyngeal nerve (cranial nerve IX). Afferent fibers from baroreceptors have their first synapse in the nucleus tractus solitarii (NTS) of the medulla oblongata, a structure that also receives input from many other cardiovascular brain centers, such as the area postrema. The NTS provides excitatory input to the caudal ventrolateral (CVL) medulla, which in turn provides inhibitory influence on the rostral ventrolateral (RVL) medulla, where the pacemaker neurons that originate sympathetic tone are located. Axons from RVL neurons synapse with cell bodies of preganglionic sympathetic neurons in the intermediolateral column of the spinal cord, which send axons outside the central nervous system. These “preganglionic” axons synapse in peripheral ganglia with postganglionic efferent sympathetic neurons, which release norepinephrine at target organs; this results in an increase in heart rate and cardiac contractility, partial restoration of venous return and diastolic ventricular filling by venoconstriction, and an increase in peripheral resistance by arteriolar vasoconstriction. Parasympathetic activity is also modulated by the NTS, through projections to the nucleus ambiguus (NA), where preganglionic cardiac parasympathetic neurons are located. An increase in blood pressure stretches baroreceptors and increases firing of afferent fibers, which results in activation of the NTS and the caudal ventrolateral (CVL) medulla, which in turn inhibit the RVL to produce sympathetic withdrawal. Activation of the NTS also results in activation of the nucleus ambiguus, leading to parasympathetic activation. The end result is a decrease in vascular tone, myocardial contractility, and heart rate, which brings blood pressure back to “baseline” levels. In general, sympathetic activation is accompanied by parasympathetic withdrawal, and vice versa. This is probably explained by the central integration of both pathways, as exemplified by the role of the NTS in baroreflex responses. Sympathetic activation to the different organs is not homogeneously distributed and depends on the stimuli and afferent pathways involved. For example, mental stress induces sympathetic activation and increases blood pressure but causes vasodilation of the forearm vasculature. AVP, arginine vasopressin; IML, intermediolateral column; PVN, paraventricular nucleus; SON, supraoptic nucleus.
chapter 28 orthostatic hypotension
357
A
*
* 0.16
0.12 800 0.08 400 0.04
0
0
B 90
200
30
100 50 Sleep
Nocturnal
C
BP (mm Hg)
150
Diurnal
200
140
150
50
HR (bpm)
Nocturnal
HR (bpm)
Diurnal
BP (mm Hg)
Na+/crea (mmol/mg)
Uvolume (mL/12 h)
1200
100 50 Sleep 0
0 13 15 17 19 21 23 1 3 5 7 9 11 13 15 Time ■
14 15 16 18 19 21 23 1 4 7 9 11 13 14 Time
Figure 28–3. A, Patients with autonomic failure have reversal of the normal diurnal variation in natriuresis, with about twice as much urine volume (Uvolume) (dark bars) and sodium excretion (lighter bars) during the night as during the day. Crea, creatinine. B and C, Patients with autonomic failure have reversed circadian rhythm of blood pressure (BP) and heart rate (HR). B, subject with autonomic failure; C, normal subject. bpm, beats per minute.
nomic failure from age-matched control subjects, but together these tests provide a reliable indicator of the presence and severity of cardiovascular autonomic impairment.
CAUSES OF AUTONOMIC FAILURE The most common cause of autonomic failure is autonomic neuropathy secondary to diabetes mellitus. Any systemic illness that causes peripheral neuropathies that affect somatic nerves may also affect autonomic fibers. Citetreeman (2005) lancet from suggested reading list in general, the primary condition is clinically apparent. Primary forms of autonomic failure are rarely the result of congenital deficiency of the enzyme dopamine β-hydroxylase. Affected patients cannot synthesize norepinephrine in sympathetic nerves.19 Most cases of primary autonomic failure are caused by degeneration of autonomic neurons.20 Autonomic failure is a prominent feature of two of the most prevalent neurodegenerative diseases: the Lewy body syndromes and multiple-system atrophy (MSA). The Lewy body syndromes, so named because of characteristic cytoplasmic eosinophilic neuronal inclusions (Lewy body, Lewy neuritis) found in the brain and peripheral autonomic nerves of affected patients, manifest with three different but overlapping phenotypes: pure auto-
nomic failure, with neuronal degeneration restricted mostly to peripheral autonomic neurons and autonomic failure as the sole clinical finding; Parkinson’s disease, with prominent degeneration of the substantia nigra and other brainstem nuclei, in addition to peripheral autonomic neurons, and clinical findings dominated by motor abnormalities with varying degrees of autonomic failure; and dementia with Lewy bodies, a disorder with extensive cortical involvement, in addition to degeneration of brainstem nuclei and peripheral autonomic neurons and, clinically, severe cognitive impairment associated with parkinsonism and autonomic dysfunction. The second type of neurodegeneration with prominent autonomic failure, MSA, affects neurons in basal ganglia, cortex, and spinal cord, sparing peripheral autonomic neurons, with characteristic glial cytoplasmic inclusions but no Lewy bodies. MSA has two phenotypes: parkinsonian and cerebellar, named MSAp and MSAc according to the predominant motor abnormality. Severe autonomic failure is prominent in both phenotypes.21 The differential diagnosis between primary neurodegenerative autonomic disorders can be difficult. There are three common diagnostic challenges. First, it is often very difficult to distinguish, early on in the disease process, between pure autonomic failure and MSA because patients with MSA can present initially with isolated autonomic failure. It may be impossible to rule out MSA and make a definitive diagnosis of
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
pure autonomic failure during the first 1 to 2 years of disease onset. Follow-up may be required before a definitive diagnosis can be made. MSA has a more rapid progression, with disability resulting from worsening of the movement disorder, which commonly occurs 6 to 8 years after onset of symptoms. Another differential diagnosis challenge is that between MSA and Parkinson’s disease. Patients with otherwise classical Parkinson’s disease can have severe orthostatic hypotension. Patients with MSA rarely have the onset of unilateral resting tremor typical of Parkinson’s disease and, in general, respond poorly to levodopa. Third, studies suggest that autoimmune autonomic neuropathy can resemble pure autonomic failure clinically but with more prominent gastrointestinal abnormalities. Autonomic failure with an acute or subacute (less than 3 months) clinical onset is suggestive of an autoimmune autonomic neuropathy. In most cases, the precise cause is not known, but in some patients, ganglionic nicotinic acetylcholine receptor (nAChR) autoantibodies are found. Clinical autonomic impairment is more pronounced in patients with high antibody titers, which indicates a pathogenic role for the nAChR antibodies.22 In addition to orthostatic hypotension, patients have dry eyes and dry mouth, severe upper gastrointestinal motility impairment, large pupils that react poorly to light and accommodation, and neurogenic bladder.23 Autoimmune autonomic neuropathy with a subacute onset may also occur as a paraneoplastic syndrome.24 This is commonly associated with anti-Hu antibodies (also known as type 1 antineuronal nuclear antibody), most often in patients with small cell lung cancer but also in those with other malignancies.25 Other antibodies associated with paraneoplastic autonomic neuropathy include Purkinje cell cytoplasmic antibodies type 2 and antibodies to the neuron cytoplasmic protein collapsin response-mediator protein-5. The clinical onset is generally subacute; acute or chronic manifestations are unusual. As in autoimmune autonomic neuropathy, prominent clinical findings are orthostatic hypotension, bowel hypomotility, bladder dysfunction, pupillomotor and sudomotor dysfunction, and xerophthalmia.
T A B L E 28–2. Stepwise Approach to Management of Orthostatic Hypotension Aggravating Factors to Be Removed Volume depletion Prolonged bed rest/deconditioning Alcohol Diuretics Tricyclic antidepressants Venodilators (nitrates) Antihypertensives (α blockers, guanethidine) α Blockers used to treat prostatic hypertrophy Insulin in diabetic patients with autonomic neuropathy Medical Nonpharmacological Treatment Liberalize salt intake, salt supplements Head-up tilt during the night Waist-high support stockings Exercise as tolerated, preferable in a pool Pharmacological Treatment* Fludrocortisone Short-acting pressor agents *See Table 28–3.
150
mm Hg
358
100
50 SBP DBP 0 –15
0
15
30
45
60
Time (min) ■
MANAGEMENT In general, a stepwise approach to treatment according to the severity of the symptoms is preferable.26 Table 28–2 shows general management guidelines, but treatment should be individualized. Some recommendations may actually be contraindicated in a given patient. The initial approach is always to remove any of the conditions enumerated in Table 28–2 that may induce or aggravate orthostatic hypotension. The suggestions for management described as follows are relevant to patients with orthostatic hypotension caused by autonomic impairment.
Nonpharmacological Therapy In patients with persistent symptoms, conservative nonpharmacological therapy is indicated. Patients with autonomic failure are unable to conserve sodium, and liberalization of sodium intake is generally recommended. These patients have exaggerated nocturnal diuresis with relative hypovolemia and worsening of orthostatic hypotension early in the morning. Elevating the head of the bed with 6- to 9-inch blocks can
Figure 28–4. Example of the pressor response produced by 500 mL of tap water in a patient with multiple-system atrophy. DBP, diastolic blood pressure; SBP, systolic blood pressure.
reduce nocturnal diuresis by reducing nocturnal hypertension. This simple maneuver may ameliorate orthostatic hypotension the following morning. During the day, wearing waist-high custom-fitted elastic support stockings exerts pressure on the legs and reduces venous pooling. It is important to avoid wearing support stockings in the supine position because they may contribute to diuresis and supine hypertension. Support stockings, however, are difficult to wear, and compliance is low. Most of the pooling of blood, however, occurs in the abdomen.27 Therefore, patients can try using an abdominal binder as an alternative to support stockings (Table 28–3).28 It has been discovered that rapid intake of 500 mL of water results in an acute (within 30 minutes) and transient (lasting about 60 minutes) increase in blood pressure in patients with autonomic failure.29 This pressor effect can be substantial (Fig. 28–4) and can be used to alleviate orthostatic hypotension. It is commonly recommended that patients drink 500 mL of water
chapter 28 orthostatic hypotension
359
T A B L E 28–3. Pharmacological Agents for the Treatment of Orthostatic Hypotension Agent
Dosage
Side Effects
Sodium chloride Fludrocortisone (Florinef)
1 g/meal 0.1-0.3 mg/day
Midodrine (ProAmatine) Yohimbine (Yocon) Indomethacin (Indocin) † L-Dihydroxyphenyl serine (DOPS)
5-10 mg* 5.4 mg* 25 mg
Nausea, diarrhea Hypokalemia, congestive heart failure, supine hypertension Scalp itching, goose bumps Nervousness, tremor Gastrointestinal discomfort, peptic ulcer Supine hypertension
Please refer to more detailed sources for complete list of side effects and contraindications. *A dose of these short-acting pressor agents, given before exertion, improves orthostatic symptoms for 2-3 hours. In general, administration of >3 doses/day is discouraged, to avoid side effects and development of tolerance. † Available only in Japan.
about 15 minutes before getting out of bed in the morning, when symptoms are at their worst.
Pharmacological Therapy In addition to nonpharmacological therapy, severely affected patients usually require the use of drugs. The goal of treatment is to minimize symptoms rather than to normalize an upright blood pressure. Therapy is often initiated with fludrocortisone acetate at a low dose (0.1 mg/day) and increased slowly up to 0.3 mg/day if needed.30 As an indication that volume expansion has occurred, a weight gain of 1 to 2 kg and mild ankle edema may be desirable in these patients. However, hypokalemia, supine hypertension, and pulmonary edema may occur, and patients must be monitored carefully. Fludrocortisone is not effective unless it is given in conjunction with increased salt intake (e.g., sodium chloride tablets, 1 g with meals), because its pressor effect is dependent on its ability to enhance renal sodium retention. A common mistake is to increase the dose of fludrocortisone without ensuring that patients have adequate salt supplementation. Fludrocortisone worsens supine hypertension, and its long-term safety in patients suffering from supine hypertension is not known. Patients with autonomic failure who receive fludrocortisone have target organ damage in the form of left ventricular hypertrophy, similar to that in patients with chronic arterial hypertension.31 Most patients with severe autonomic impairment also require short-acting pressor agents also cite Jordan et al., (1998).32 The goal in prescribing these drugs is to provide patients with periods when they can remain upright, rather than to try to keep severely afflicted patients symptom free throughout the day. Most of the agents listed in Table 28–4, if effective in a given patient, increase blood pressure for 2 to 3 hours. In general, these agents are best given before periods of exertion as needed, rather than at fixed (e.g., three-times-a-day) intervals. This approach may reduce the likelihood of side effects and the development of tolerance that reduces their long-term efficacy.33 Patients should also avoid lying down for 4 to 5 hours after taking these drugs, to prevent supine hypertension. These drugs have negligible effects in healthy subjects; the increase in blood pressure seen in patients with autonomic failure is a reflection of their extreme hypersensitivity to most pressor and depressor agents.34 For this reason, treatment should be started at very small doses and should be individualized. This is best done by measuring blood pressure at intervals
T A B L E 28–4. Stepwise Approach to Treat Supine Hypertension Education and Avoidance Instruct the patient about over-the-counter medication with pressor effects Avoid fluid intake at bedtime Avoid using elastic stocking when supine Avoid the use of pressor agents before bedtime Nonpharmacological Measures Raise the head of the bed by 6-9 inches Recommend rest on a semirecumbent chair with feet on floor during the day Encourage snack consumption before bedtime Allow minimal alcohol consumption before bedtime Pharmacological Measures Nitrates, transdermal nitroglycerin (0.1-0.2 mg/hour) Hydralazine (50 mg) Short-acting calcium blocker, nifedipine (10-30 mg) Minoxidil (2.5 mg) Clonidine (0.1 mg), early in the evening
for 2 to 3 hours after administration of the first dose of each drug. L-Threo-dihydroxyphenyl serine (the biologically active stereoisomer of the amino acid 3,4-dihydroxyphenyl serine) is a precursor of norepinephrine that has shown promise in the treatment of orthostatic hypotension in small clinical trials.35
Treatment of Related Conditions Autonomic failure can be associated with low-production anemia and inappropriately low serum erythropoietin levels. If other causes of anemia are ruled out, patients can be treated with recombinant erythropoietin (25 to 50 U/kg subcutaneously three times per week). Erythropoietin has been shown to improve upright blood pressure,36,37 and its use may be warranted for this reason alone, rather than as a treatment for anemia. Many patients may also have supine hypertension resulting from preexisting essential hypertension or as part of autonomic failure.38 In occasional patients, significant hypertension may be present even in the seated position. During the day, supine hypertension is best managed by simply avoiding the supine position. At night, it is necessary for many patients to take vasodilators at bedtime, after which they should be advised against getting up during the night without assistance.
360
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
Hydralazine hydrochloride (25 to 100 mg) and low doses of nitrates as transdermal preparations (e.g., Nitro-Dur, 0.1 mg/hour, applied at bedtime and removed on arising) or short-acting calcium channel blockers (e.g., nifedipine, 10 mg) are often useful. A stepwise approach to the management of supine hypertension in the setting of orthostatic hypotension is included in Table 28–3 and discussed in detail elsewhere.39
K E Y
P O I N T S
●
The autonomic nervous system is crucial for the regulation of blood pressure in general and for maintaining orthostatic hemodynamics in particular. Disorders associated with autonomic impairment are often characterized by disabling orthostatic hypotension.
●
Systemic illnesses producing peripheral neuropathy can cause secondary autonomic failure. Primary autonomic failure is caused by neurodegenerative disorders with neuronal or glial deposits of α-synuclein, including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure, and multiple-system atrophy (Shy-Drager syndrome).
●
Subacute onset of autonomic failure and rapid progression can be caused by an autoimmune autonomic disorder or may be a paraneoplastic syndrome.
●
The hallmark of autonomic failure is profound orthostatic hypotension without an appropriate compensatory increase in heart rate. Autonomic function tests are usually confirmatory, but the differential diagnosis can be challenging.
●
There is currently no treatment to cure or delay the progression of disease. Symptomatic treatment of orthostatic hypotension is often successful and relies on a combination of nonpharmacological measures, blood and plasma volume enhancement, and short-acting pressor agents taken before upright activity rather than at fixed intervals.
●
About half of the patients with autonomic failure paradoxically develop supine hypertension, which is managed during the day by simply avoiding the supine posture but may necessitate pharmacological treatment during the night.
Suggested Reading Freeman R: Autonomic peripheral neuropathy. Lancet 2005; 365:1259-1270. Jordan J, Shannon JR, Biaggioni I, et al: Contrasting actions of pressor agents in severe autonomic failure. Am J Med 1998; 105:116-124. Jordan J, Shannon JR, Grogan E, et al: A potent pressor response elicited by drinking water. Lancet 1999; 353:723. Shibao C, Gamboa A, Diedrich A, et al: Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension 2005; 45:469-476. Wright RA, Kaufmann H, Perera R, et al: A double-blind, doseresponse study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124.
References 1. Zambrasky E, DiBona G, Kaloyanides G: Specificity of neural effect on renal tubular sodium reabsorption. Proc Soc Exp Biol Med 1976. 151:543-546. 2. Ganong W, Reid I: Role of the sympathetic nervous system and central alpha and beta adrenergic receptors in regulation of renin secretion. In Onesti G, ed: Regulation of Blood Pressure by Central Nervous System. New York: Grune & Stratton, 1976, pp 261-273. 3. Segar W, Moore W: The regulation of antidiuretic hormone release in man. Effects of change in position and ambient temperature on blood ADH levels. J Clin Invest 1968; 47:21432151. 4. Leimbach WN Jr, Schmid PG, Mark AL: Baroreflex control of plasma arginine vasopressin in humans. Am J Physiol 1984 Oct; 247(4 Pt 2):H638-44. 5. Altura BM, Altura BT: Vascular smooth muscle and neurohypophyseal hormones. Fed Proc 1977; 36:1853-1860. 6. Jard S: Vasopressin receptors. In Czernichow P, Robinson A, eds: Diabetes Insipidus in Man. Basel: S. Karger, 1985, pp 89104. 7. de Bold AJ, Borenstein HB, Veress AT, et al: A rapid and potent natriuretic response to intravenous injections of atrial myocardial extract in rats. Life Sci 1981; 28:89-94. 8. Ledsome J, Wilson N, Courneya CA, et al: Release of atrial natriuretic peptide by atrial distension. Can J Physiol Pharmacol 1985; 63:739-742. 9. Garcia J, Thibault G, Cantin M, et al: Effect of a purified atrial natriuretic factor on rat and rabbit vascular strips and vascular beds. Am J Physiol 1984; 247:R34-R39. 10. Atarashi K, Mulrow PJ, Franco-Saenz R, et al: Inhibition of aldosterone production by an atrial extract. Science 1984; 224:992-994. 11. Kaufmann H, Oribe E, Pierotti AR, et al: Atrial natriuretic factor in human autonomic failure. Neurology 1990; 40:11151119. 12. Yanagisawa M, Kurihara H, Kimura S: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332:411-415. 13. Vane JR, Anggard EE, Botting RM: Regulatory functions of the vascular endothelium. N Engl J Med 1990; 323:27-36. 14. Yoshizawa T, Shinmi O, Giaid A, et al: Endothelin: a novel peptide in the posterior pituitary system. Science 1990; 247:462-464. 15. Kaufmann H, Oribe E, Oliver JA: Plasma endothelin during upright tilt: relevance for orthostatic hypotension? Lancet 1991; 338:1542-1545. 16. Kaufmann H: Syncope. A neurologist’s viewpoint. Cardiol Clin 1997; 15:177-194. 17. Horowitz DR, Kaufmann H: Autoregulatory cerebral vasodilation occurs during orthostatic hypotension in patients with primary autonomic failure. Clin Auton Res 2001; 11:363-367. 18. Kaufmann H: Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res 1996; 6(2):125-126. 19. Robertson D, Haile V, Perry SE, et al: Dopamine betahydroxylase deficiency. A genetic disorder of cardiovascular regulation. Hypertension 1991; 18:1-8. 20. Kaufmann H, Biaggioni I: Autonomic failure in neurodegenerative disorders. Semin Neurol 2003; 23:351-363. 21. Gilman S, Low P, Quinn N, et al: Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res 1998; 8(6):359-362. 22. Vernino S, Adamski J, Kryzer TJ, et al: Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 1998; 50:1806-1813.
chapter 28 orthostatic hypotension 23. Klein CM, Vernino S, Lennon VA, et al: The spectrum of autoimmune autonomic neuropathies. Ann Neurol 2003; 53:752-758. 24. Freeman R: Autonomic peripheral neuropathy. Lancet 2005; 365:1259-1270. 25. Winkler AS, Dean A, Hu M, et al: Phenotypic and neuropathologic heterogeneity of anti-Hu antibody- related paraneoplastic syndrome presenting with progressive dysautonomia: report of two cases. Clin Auton Res 2001; 11(2):115-118. 26. Kaufmann H: Treatment of patients with orthostatic hypotension and syncope. Clin Neuropharmacol 2002; 25:133141. 27. Diedrich A, Biaggioni I: Segmental orthostatic fluid shifts. Clin Auton Res 2004; 14(3):146-147. 28. Smit AA, Wieling W, Fujimura J, et al: Use of lower abdominal compression to combat orthostatic hypotension in patients with autonomic dysfunction. Clin Auton Res 2004; 14(3):167175. 29. Jordan J, Shannon JR, Grogan E, et al: A potent pressor response elicited by drinking water [Letter]. Lancet 1999; 353:723. 30. Hickler R: Successful treatment of orthostatic hypotension with 9-alpha fluorohydrocortisone. N Eng J Med 1959; 261:788-791. 31. Vagaonescu TD, Saadia D, Tuhrim S, et al: Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet 2000; 355:725-726.
361
32. Kaufmann H, Brannan T, Krakoff L, et al: Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology 1988; 38:951-956. 33. Wright RA, Kaufmann HC, Perera R, et al: A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124. 34. Jordan J, Shannon JR, Biaggioni I, et al: Contrasting actions of pressor agents in severe autonomic failure. Am J Med 1998; 105:116-124. 35. Kaufmann H, Saadia D, Voustianiouk A, et al: Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 2003; 108:724-728. 36. Biaggioni I, Robertson D, Krantz S, et al: The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 1994; 121:181-186. 37. Perera R, Isola L, Kaufmann H: Erythropoietin improves orthostatic hypotension in primary autonomic failure. Neurology 1994; 44(Suppl 2):A363. 38. Shannon JR, Jordan J, Diedrich A, et al: Sympathetically mediated hypertension in autonomic failure. Circulation 2000; 101:2710-2715. 39. Shibao C, Gamboa A, Diedrich A, et al: Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension 2005; 45:469-476. 40. Hainsworth R: Pathophysiology of syncope. Clin Auton Res 2004; 14(Suppl 1):18-24.
CHAPTER
29
BLADDER
AND SEXUAL FUNCTION AND DYSFUNCTION ●
●
●
●
Ronald F. Pfeiffer
The autonomic nervous system is sometimes perceived by neurologists as a somewhat mysterious, even miasmic, component of the nervous system. Consequently, when autonomic dysfunction accompanies a neurological disease process, neurologists often are reluctant to discuss the autonomic symptoms with their patients or to initiate specific evaluation or treatment, preferring to cede this to specialists in other disciplines such as cardiology, gastroenterology, and urology. However, autonomic dysfunction is an integral component of a number of neurological disease processes routinely managed by neurologists, and if attention to and assessment of autonomic dysfunction are inadequate, treatment of the disease and management of the patient may be inadequate. In this chapter, bladder and sexual dysfunction are addressed with the intent of providing practical information for the practicing neurologist.
BLADDER FUNCTION At a basic level, the bladder has two primary functions. First, it serves as an expandable storage vessel, collecting urine produced by the kidneys. Most of its time is spent in this storage mode. The second function of the bladder is to actively contract and eliminate the stored urine, typically at socially acceptable times that are consciously determined by the individual. To achieve these functions, a fine-tuned and well-orchestrated symphony of actions involving the urethral sphincter, bladder, peripheral nerves, spinal cord, brainstem, and cerebral centers must take place. Damage to any portion of this interconnected system can result in urinary dysfunction.
Brainstem Direct motor control of bladder function resides in the pons. The pontine micturition center, identified by Barrington in 19258,9 and now bearing his name, lies in the medial dorsal pons. Stimulation of this nucleus has the dual effect of producing both contraction of the detrusor muscle and relaxation of the urethral sphincter, the latter via inhibition of Onuf’s nucleus in the sacral spinal cord, with consequent micturition.10 A second, more lateral pontine region appears to tonically stimulate Onuf’s nucleus and to thus prevent micturition by inhibiting detrusor contraction and urethral relaxation.11 Sensory information regarding the state of bladder filling does not appear to come directly to these two pontine centers; rather, its path is coordinated through neurons in the periaqueductal grey matter in the mesencephalon.2,12
Neuroanatomy and Neurophysiology
Spinal Cord and Peripheral Nerves
Cortex
Control of bladder function at the spinal cord level is dependent on both autonomic and somatic mechanisms. Parasympathetic signals reach the bladder detrusor smooth muscle via pelvic nerves that originate in the intermediolateral column of the sacral cord at the S2-S4 levels, whereas sympathetic input arises from T11-L2 spinal cord levels and arrives at the smooth muscle of the bladder neck and urethra through the hypogastric nerves. The striated muscle of the urethral sphincter is innervated by a specialized group of anterior horn cells at the S2-S4 cord levels, first described by Onufrowicz in 1899 and
There is a tendency to focus on the spinal cord and sacral nerves when bladder function is assessed, but cortical and brainstem centers play active and very important roles in the control of bladder function.1,2 Early information regarding cerebral control of voiding was collected in studies of individuals with structural brain lesions.3-5 These studies demonstrated that lesions in the anterior frontal lobe may produce disturbances in bladder control. Affected individuals were noted to experi-
362
ence severe, precipitous urgency without prior sensation of bladder fullness, but coordination of detrusor and sphincter muscle function during micturition remained normal. Studies of individuals after stroke have also implicated the anteromedial frontal lobe and its descending pathway, along with the basal ganglia in the production of urinary dysfunction.6 More recent elegant neuroimaging studies with single photon emission computed tomography (SPECT), positron emission tomography, and functional magnetic resonance imaging have revealed a more detailed pattern of a complex array of cortical centers involved with voluntary regulation and control of bladder function, including not only frontal cortex but also the cingulate cortex, parietal cortex, basal ganglia, hypothalamus, and even the cerebellum.2,7
chapter 29 bladder and sexual function and dysfunction now called Onuf’s nucleus.13 Their axons travel in the pudendal nerves to reach the sphincter. Parasympathetic stimulation results in contraction of the detrusor muscle (mediated by acetylcholine) and relaxation of urethral smooth muscle (mediated by nitric oxide) with the net result of micturition.14,15 Sympathetic stimulation has the opposite effect. Stimulation of Onuf’s nucleus produces contraction of the striated urethral sphincter.16 Sensory information from the bladder is transmitted by several different types of neurons.16,17 Small, unmyelinated, mechanosensitive Aδ fibers have a low activation threshold and are the principal conduit for transmitting information regarding the degree of bladder filling. Nociceptive, unmyelinated C fibers respond primarily to noxious stimuli rather than bladder distension. Finally, somatic afferents from the urethra transmit information regarding imminence of micturition.
BLADDER DYSFUNCTION A normally functioning bladder can expand to hold 400 to 500 mL of urine before detrusor contraction is triggered and bladder pressure increases, producing a sense of the need to void.14 Damage to the nervous system can produce three basic patterns of neurogenic bladder dysfunction, described in Table 29–1. As already noted, lesions affecting cerebral centers, both cortical and subcortical, may remove inhibitory influences on bladder function with consequent development of detrusor contractions at bladder volumes smaller than normal but without disturbing the coordinated contraction and relaxation of the detrusor and sphincter muscles. This has been labeled detrusor hyperreflexia, or neurogenic detrusor overactivity,18 and may prompt urinary frequency, often accompanied by a sense of urgency, that can lead to incontinence. In contrast, lesions involving neurons in the sacral cord or processes that damage the peripheral nerves emanating from this cord level result in reduced detrusor activity, with subsequent reduced urinary frequency and excessive bladder filling. The term hyporeflexic bladder is sometimes applied to this situation. This can also lead to incontinence, but of the overflow type. Lesions of the suprasacral spinal cord, by severing communication between pontine and sacral centers, may result in a loss of the normal coordinated reciprocal actions of the detrusor and sphincter muscles so that they contract simultaneously, producing a combination of increased pressure within the bladder and increased resistance to urine outflow from the bladder. This is called detrusor-sphincter dyssynergia. Obstruction of urine outflow from the bladder is usually caused by nonneurological processes (prostatic hypertrophy is an example), but on occasion, dystonic contractions of the urethral sphincter can cause similar difficulty in the setting of neurological disease. Symptoms of obstruction include hesitancy in initiating micturition, reduced urine flow, and dribbling.
T A B L E 29–1.
Patterns of Neurogenic Bladder Dysfunction
Detrusor overactivity (detrusor hyperreflexia) Detrusor underactivity (detrusor hyporeflexia) Detrusor-sphincter dyssynergia
363
Diagnostic Tests Although diagnostic testing of bladder function is usually performed by a urologist, it is important for neurologists to be familiar with the types of testing employed and the significance of the findings. Therefore, several of the most frequently used tests are discussed briefly as follows (Table 29–2).
Urodynamic Testing Urodynamic testing actually entails a battery of tests, the exact complement of which can vary from urologist to urologist. Uroflowmetry is a screening study in which the patient urinates into a receptacle that measures the rate at which urine is voided. A urine flow curve is generated, and a variety of measurements, including mean and maximum flow rates, can be calculated. The normal flow curve has an unbroken bell shape, whereas obstructive lesions produce flattening and elongation of the curve. The flow curve in individuals with detrusorsphincter dyssynergia is characterized by intermittent, discontinuous flow.19 Cystometry measures detrusor pressure during both bladder filling and voiding. After catheterization, the bladder is filled at a set rate, while intravesical pressure and rectal pressure (as a measure of abdominal pressure) are continuously recorded. This recording is called a cystometrogram. Detrusor pressure is calculated by subtracting the abdominal (rectal) pressure from the intravesical pressure. In a normally functioning bladder, detrusor compliance allows filling of the bladder without a significant rise in detrusor pressure. Hyperreflexic detrusor muscle contractions produce rises in pressure that occur suddenly and involuntarily as the bladder is filling. If the pressure produced by the hyperreflexic contraction is high enough, it can overcome the urethral sphincter muscles, and incontinence ensues. If the elastic properties of the detrusor muscle and bladder wall are decreased, compliance is reduced and detrusor pressure rises as the bladder fills, triggering the need for what might be called “premature urination” before bladder filling is complete. Detrusor hyperreflexia and diminished bladder compliance reflect suprasacral neurological injury.
Electromyography Electromyography of the pelvic floor can be performed with either surface or needle electrodes. Surface electrodes are less invasive but record lower amplitude signals and are more prone to artifacts.20 The normal electromyographic sphincter pattern consists of continuous activity that ceases before detrusor contraction initiates micturition. Failure of this coordinated sphincter relaxation and detrusor contraction to occur is what constitutes detrusor-sphincter dyssynergia. Concentric needle electromyography of the urethral sphincter can also demonstrate a pattern of denervation and reinnervation. Evidence of this can be seen in structural lesions of the
T A B L E 29–2. Urodynamic testing Electromyography Ultrasonography
Diagnostic Testing of Bladder Function
364
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
cauda equina and in degenerative processes that involve Onuf’s nucleus, such as multiple-system atrophy (MSA). Additional, more detailed, clinical neurophysiological testing can also be performed at specialized centers.20
Bladder Ultrasonography The measurement of the amount of urine remaining in the bladder after voiding can be accomplished noninvasively by means of ultrasonography. A postvoid residual amount of greater than 100 mL is considered abnormal.
Specific Neurological Diseases Stroke Bladder dysfunction after stroke is frequently described, although specific data about incidence are difficult to pinpoint.21 In a review of the topic of stroke and incontinence, Brittain and colleagues22 noted that in various studies, incontinence on hospital admission had been described in 32% to 79% of stroke patients and was still present in 25% to 28% at the time of discharge. Problems with incontinence persisted in 12% to 19% even months after discharge. The pattern of urinary difficulty differs between patients with hemispheric stroke and those with lesions in the brainstem. In individuals with hemispheric stroke, Sakakibara and colleagues6 documented nocturnal urinary frequency in 36%, urge incontinence in 29%, and difficulty voiding in 25%. Urinary symptoms were more frequent in persons with frontal lobe infarcts. Urodynamic testing in symptomatic patients demonstrated detrusor hyperreflexia in 68%, detrusorsphincter dyssynergia in 14%, and uninhibited sphincter relaxation in 36%. In a different group of patients after acute brainstem stroke, urodynamic studies showed detrusor hyperreflexia in 73%, low compliance bladder in 9%, atonic bladder in 27%, detrusorsphincter dyssynergia in 45%, and uninhibited sphincter relaxation in 27%.23 Lesions producing bladder dysfunction involved either the dorsolateral or medial pons. Thus, as expected, patients with stroke, whether hemispheric or brainstem, experience predominantly overactive or irritable bladder symptoms, although obstructive symptoms, including urinary retention, may also develop.23,24 Large infarct size, aphasia, cognitive impairment, and functional disability are associated with increased risk of urinary incontinence after stroke.25 Multiple infarcts, especially if bilateral, also predispose to urinary abnormalities after stroke.26 Because of the variability in urinary dysfunction that may appear after a stroke, urodynamic testing is invaluable in documenting the specific nature of the dysfunction. Specific treatment can then be tailored to the documented deficit.
Parkinson’s Disease Urinary symptoms are a frequent source of difficulty for individuals with Parkinson’s disease. Reported frequencies of urinary dysfunction in Parkinson’s disease show considerable variability, ranging from 36% to 90%.27-30 Hobson and colleagues,29 comparing a community-based sample of patients with Parkinson’s disease with a similar-aged healthy elderly control group,
discovered that the relative risk for bladder symptoms in the group with Parkinson’s disease was more than twice that of the control group. Some27,28,31-33 but not all29 studies have found a correlation between disease duration and severity and the presence of urinary symptoms. Irritative symptoms, such as frequency, urgency, and nocturia, are most common,27,28,30,34,35 but obstructive symptoms may also be reported. The most frequent finding on urodynamic testing in individuals with Parkinson’s disease is detrusor hyperreflexia. Studies have revealed detrusor hyperreflexia to be present in 45% to 100% of urologically symptomatic patients with Parkinson’s disease.33-36 It is important to remember, however, that obstructive uropathies, such as prostatic hypertrophy, can be superimposed on detrusor hyperreflexia. In these instances, urodynamic testing can be especially helpful. Urethral sphincter dysfunction may also develop in patients with Parkinson’s disease. Delayed relaxation of the sphincter on initiation of voiding, termed sphincter bradykinesia, has been reported in 11% to 42% of such patients.32,35,37 This phenomenon may create an obstructive pattern, characterized by a reduced flow rate. Inability to relax the perineal muscles on initiation of micturition has also been identified in the setting of Parkinson’s disease.38 The role of dopaminergic mechanisms in the production of urinary dysfunction in Parkinson’s disease has been the focus of research interest. In rats with unilateral 6-hydroxydopamine–induced lesions of the nigrostriatal pathway, bladder capacity was documented to be reduced and could be increased with administration of the dopamine D1/D5 receptor agonist SKF38393.39 In contrast, a D2/D3/D4 receptor agonist, quinpirole, reduced bladder capacity. In monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection, the same pattern was evident in that the D2 agonist bromocriptine excited the micturition reflex, whereas the mixed D1/D2 agonist pergolide inhibited the reflex.40 Improvement in urinary symptoms has also been reported in humans whose treatment switched from bromocriptine to pergolide.41
Multiple-System Atrophy Autonomic dysfunction is one of the basic clinical features of MSA. Orthostatic hypotension and genitourinary dysfunction are especially likely to develop. In contrast to Parkinson’s disease, urinary dysfunction in MSA tends to develop earlier in the course of the disease process, sometimes appearing even before the motor features31,42; it is also more pervasively present. In a study by Stocchi and colleagues,38 100% of patients with MSA demonstrated some abnormality on urodynamic testing, whereas abnormalities were noted in only 63% of subjects with Parkinson’s disease. Urodynamic studies can be very useful in characterizing the nature of bladder dysfunction in MSA.43 A combination of detrusor hyperreflexia and impaired urethral sphincter function often produces a pattern of prominent urinary frequency and urgency, often accompanied by urge incontinence. Although this can also occur in Parkinson’s disease, it is typically a feature of only advanced Parkinson’s disease, whereas it can develop much earlier in the course of MSA. Urinary retention is also considerably more common in MSA than in Parkinson’s disease.31,44 Differentiating individuals with MSA from those with Parkinson’s disease is of very practical importance from the
chapter 29 bladder and sexual function and dysfunction urological standpoint, because patients with MSA who undergo surgery for prostatic hypertrophy are at especially high risk for developing urinary incontinence as a complication of the procedure. Thus, medical management is preferable to surgical management of prostatic hypertrophy in individuals with MSA.31
Multiple Sclerosis Symptoms of autonomic dysfunction may be present in almost 80% of patients with multiple sclerosis.45 Urinary symptoms are the most common, present in 65% of the 63 patients evaluated by McDougall and McLeod. In their study, urgency and frequency were especially common, and urinary incontinence was reported by more than 30% of patients. Detrusor-sphincter dyssynergia, as a consequence of spinal cord involvement, is the most common urodynamic finding in multiple sclerosis, reported in 15% to 20% of affected individuals.46 However, because multiple sclerosis can affect all levels of the central nervous system, some patients show evidence of detrusor hyperreflexia as a result of involvement of suprapontine cerebral pathways.46 Impaired voiding with hesitancy, interrupted urinary flow, and incomplete voiding can also be present.47 Urinary symptoms increase in frequency and severity in tandem with disease severity and duration.48-50 They are most evident in individuals with secondary progressive multiple sclerosis.45
Spinal Cord Injury The characteristics of urinary dysfunction after spinal cord injury depend on the timing of the injury and its location. During the period of spinal shock immediately after the trauma, reflexes below the level of the lesion are lost, including those associated with micturition. Detrusor areflexia with urinary retention is typically present. The duration of the spinal shock phase is variable; it may be present for only hours or may persist for weeks or even months. As spinal shock resolves, urinary function evolves into a pattern that reflects the level of the spinal cord injury. Detrusor hyperreflexia develops in individuals with suprasacral cord lesions. Because spinal cord injuries are typically labeled by the level of the vertebral bodies injured, it is important to remember that the spinal cord actually ends at the L1-L2 vertebral level. Therefore, lesions above a T10 vertebral level evolve into a pattern of detrusor hyperreflexia or detrusorsphincter dyssynergia, whereas the detrusor remains hyporeflexic with lesions below L2. If the injury is at vertebral levels T10-L2, either hyperreflexic or hyporeflexic bladder function may develop.51 If the spinal cord injury is complete in lesions above the T10 vertebral level, detrusor-sphincter dyssynergia is almost always present; with incomplete lesions, a pattern of detrusor hyperreflexia with maintained coordination of sphincter function is typically seen.52,53 Urodynamic testing is particularly valuable in assessing bladder function in patients with spinal cord injury at the thoracolumbar junction.54 When the vertebral injury is at the level of L2 or below, detrusor areflexia persists even after resolution of the period of spinal shock. The absence of detrusor function can be coupled with either intact sphincter function or with sphincter nonrelaxation.52
365
Treatment of Urinary Dysfunction The treatment employed for urinary dysfunction depends on the character of the dysfunction that is present. Because treatment approaches to an overactive bladder are vastly different from those used in treating an areflexic bladder, it is vital that a correct assessment of the type of dysfunction present be made. This is not always readily apparent by clinical history and examination alone, inasmuch as incontinence can occur in both settings. Moreover, patients may display a combination of both types of dysfunction. Therefore, urodynamic testing can provide invaluable information and guidance in formulating treatment plans.
Neurogenic Detrusor Overactivity Anticholinergic drugs have long been, and still remain, the standard treatment for detrusor overactivity (Table 29–3). Their effects are mediated via blockade of muscarinic cholinergic receptors located on the detrusor muscle. Although muscarinic receptors in human detrusor muscle are primarily of the M2 and M3 subtypes, older anticholinergic drugs are generally nonselective and block all five muscarinic receptor subtypes.55 Numerous adverse effects of these drugs, such as dry mouth and cognitive impairment, are the consequence of this nonselective blockade. Although still older anticholinergic drugs, such as hyoscyamine, atropine, propantheline, and flavoxate, are still occasionally used, oxybutynin and tolterodine have been the mainstays of treatment for a number of years. Both immediate- and extended-release preparations of these two drugs are available; oxybutynin is also available in a transdermal patch preparation. Oxybutynin is reported to have a higher propensity to produce central nervous system toxicity than does tolterodine, presumably because it crosses the blood-brain barrier more readily.56 The antimuscarinic armamentarium has expanded considerably with the introduction of trospium,57 solifenacin,58,59 and darifenacin.60 Trospium binds to M1, M2, and
T A B L E 29–3. Treatment of Neurogenic Detrusor Overactivity Anticholinergic Drugs Older, nonselective Atropine Hyoscyamine Propantheline Flavoxate Newer, nonselective Oxybutynin Tolterodine Newer, selective Trospium Solifenacin Darifenacin Other Oral Drugs Gabapentin Desmopressin Other Approaches Capsaicin (intravesical) Resiniferatoxin (intravesical) Botulinum toxin (injection) Vesical pacing
366
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
M3 receptors but does not cross the blood-brain barrier, whereas solifenacin and darifenacin are selective M3 receptor antagonists. These characteristics should diminish toxicity, but at increased expense. In individuals who have not responded to or have been intolerant of antimuscarinic drugs, various other experimental treatment approaches have been tried. Gabapentin has been reported to improve symptoms of overactive bladder.61 Desmopressin has also been employed as a means to reduce nocturia in individuals in whom anticholinergic drugs alone have not been adequate.47,62 A more radical treatment approach has been the intravesical instillation of drugs. Both capsaicin and resiniferatoxin have been used in this manner.47 Resiniferatoxin is a capsaicin analogue, derived from the Euphorbia species (Euphorbia resinifera) of cactus found in Morocco, and is 1000 times more potent than capsaicin.63 These compounds are presumed to act by means of their toxic effects on nonmyelinated C fiber afferent nerves.47,63,64 Botulinum toxin injections into the detrusor muscle under cystoscopic guidance have also been used successfully in treating detrusor overactivity.65,66 Vesical pacing has also been reported to be useful.67 Surgical treatment is rarely indicated.
Detrusor-Sphincter Dyssynergia In individuals with detrusor-sphincter dyssynergia, two problems must be attacked simultaneously. Anticholinergic drugs can reduce detrusor overactivity, but the failure of the urethral sphincter to relax during voiding must be addressed by other means. Intermittent self-catheterization remains the standard treatment approach for this problem,47 although botulinum toxin injections into the urethral sphincter have also been used.66 Incontinence is a potential complication of sphincter injections, but its incidence is low.66
Acontractile or Hypoactive Detrusor There really is no effective medical treatment for incomplete bladder emptying that results from an underactive or acontractile detrusor muscle. Intermittent self-catheterization is the best treatment option in this situation.47 If selfcatheterization is not possible, an indwelling catheter can be placed, but this increases the risk for recurrent urinary tract infections, bladder calculi, and urethral injury.47
SEXUAL FUNCTION Sexual function is a complex activity in which physiological and psychological aspects are inextricably intertwined. The psychological sphere, encompassing libido, is largely uncharted territory from an anatomical and physiological standpoint, whereas the physiological components of sexual function, such as erection, lubrication, ejaculation, and orgasm, have been more readily amenable to scientific inquiry. Considerably more attention has been focused on sexual function and dysfunction in men than in women, at least in part because of the greater ease in observing and quantifying many aspects of sexual functioning in men. Most neurologists are loathe to discuss sexual dysfunction with their patients even more than to discuss bladder dysfunction, but as with bladder dysfunction, sexual dysfunction is an integral component of the clinical pattern of a
considerable number of neurological disease processes, and familiarity with the features of this dysfunction is important for optimal patient care.
Neuroanatomy and Neurophysiology Cerebrum Although the cerebral cortex is presumed to be active in the realm of sexual desire, or libido, little is known about actual cortical localization of sexual function. Parasagittal primary sensory cortex receives sensory input from the genitalia, and the limbic cortex appears to play a role in sexual desire and behavior.68 Right frontal lobe activation during ejaculation has been identified in one study in which SPECT imaging was used.69 Additional evidence for frontal lobe involvement in sexual function comes from alterations in behavior, including sexual behavior, that have been observed in individuals with frontal lobe lesions.68 Temporal lobe dysfunction, especially in the setting of epilepsy, has also been implicated as a source of sexual dysfunction in both male and female patients; hypersexuality is occasionally seen, but sexual apathy is much more common.70,71 Hypothalamic involvement in sexual function and behavior has been clearly delineated. Hypothalamic injury can lead to a loss of sexual desire, as can occur in persons with pituitary tumors.68,72,73
Spinal Cord and Peripheral Nerves As with many aspects of sexual function, more detailed information regarding neuroanatomical and neurophysiological pathways and function is available for male patients than for female patients. Two distinct pathways have been identified for erectile function: psychogenic and reflexogenic. Psychogenic erections are triggered by visual or auditory stimuli or by fantasy thinking, whereas reflexogenic erections are induced by genital stimulation.74 Intact spinal cord pathways are necessary for psychogenic erections, whereas reflexogenic erections are mediated through the sacral spinal cord at the S2-S4 levels. The afferent pathway for reflexogenic erection is via the pudendal nerve; the efferent limb, through pelvic parasympathetic fibers. Thus, parasympathetic pathways are operative primarily in the generation of penile erection, although sympathetic function plays a role in psychogenic erection and also in detumescence.74 Ejaculation is a phenomenon separate from erection and involves parasympathetic, sympathetic, and somatic contributions.74 Parasympathetic fibers produce secretion by accessory glands during arousal; sympathetic fibers are responsible for producing bladder neck closure and contraction of smooth muscle within the seminal vesicles; somatic fibers induce actual ejaculation by triggering contraction of the bulbocavernosus and ischiocavernosus muscles.74,75
Diagnostic Tests Diagnostic testing for sexual dysfunction is more limited than that available for urological dysfunction, and it is limited primarily to the evaluation of erectile dysfunction (Table 29–4). Tests of both neurogenic and vascular integrity have been developed; vascular testing is not discussed here.
chapter 29 bladder and sexual function and dysfunction T A B L E 29–4. Diagnostic Testing of Sexual Function Nocturnal penile tumescence testing Sacral reflex testing Pudendal evoked responses
Nocturnal Penile Tumescence Testing Nocturnal penile tumescence testing has been used in the past as a means of separating neurogenic from psychogenic erectile dysfunction.76 If an individual with erectile dysfunction was documented to attain a full erection while sleeping, a psychogenic basis for the erectile dysfunction was presumed to be present. However, it has been recognized more recently that such test results can be unreliable and even misleading.77,78
Sacral Reflex Testing The bulbocavernosus reflex is the most frequently used sacral reflex test and typically involves electrical stimulation of the dorsal penile nerve with recording of the subsequent motor response in the bulbocavernosus muscle.20 Both the afferent and efferent responses of this reflex travel via the pudendal nerve. In patients with sacral cord (S2-S4) lesions or pudendal nerve lesions, latency of this reflex may be prolonged, or the reflex may be absent altogether. However, the sensitivity of this test is less than optimal,77 and its value in evaluating erectile dysfunction has been questioned.79
Pudendal Evoked Responses The pudendal somatosensory evoked potential is elicited by electrically stimulating the dorsal penile nerve and recording from the cerebrum.20 Latency may be prolonged in persons with spinal cord abnormalities, but the sensitivity and specificity of the test have been questioned, and its usefulness beyond the more frequently employed tibial somatosensory evoked potential testing is uncertain.77
Specific Neurological Diseases
367
kibara and colleagues82 reported decreased libido in 84% of the women and 83% of the men; erectile dysfunction was present in 79% and impairment of ejaculation in 79% of the men. Other investigators have reported the presence of erectile dysfunction in 60% of individuals83 or a greater than twofold risk of developing erectile difficulty29 in men with Parkinson’s disease. Erectile dysfunction typically develops later in the course of Parkinson’s disease31; this is in sharp contrast with MSA, in which erectile dysfunction is often the initial clinical feature.84
Multiple Sclerosis Although it is rarely a presenting feature,85-87 sexual dysfunction eventually develops in the majority of persons with multiple sclerosis. More than 50% of women with multiple sclerosis experience impaired sexual functioning, including decreased libido, difficulty achieving orgasm, and reduced lubrication.88,89 Although erectile dysfunction was noted less frequently in older studies, more recent reports indicate that it is present in approximately 50% to 70% of men with multiple sclerosis.45,87 Impairment of ejaculation is also common in men with multiple sclerosis.90 Some86,91 but not all92 reports note a correlation between signs of pyramidal tract involvement in the legs and the presence of erectile dysfunction in men with multiple sclerosis. Sexual dysfunction in multiple sclerosis is closely associated with urinary dysfunction in both men and women.45,87
Spinal Cord Injury Erectile dysfunction can occur with both sacral and suprasacral spinal cord injury, but differences between the two manifestations are often evident. Men with clinically complete sacral cord injury are unable to achieve erection with genital stimulation but may be able to do so with psychogenic stimulation.74,93 In contrast, men with suprasacral cord injury can achieve erection with genital stimulation but are usually unable to do so with psychogenic stimulation if the spinal cord injury is at a cervical or thoracic level.74,93 Analogous abnormalities have been documented in women with spinal cord injuries. In women with complete upper motor neuron lesions, impaired vaginal lubrication during sexual excitation is typically evident, whereas vaginal lubrication may occur with psychogenic stimulation in women with sacral spinal cord injuries.94
Epilepsy Sexual dysfunction is more common in individuals with epilepsy than in the general population. However, studies have shown that it is not epilepsy itself but rather the location of the lesion responsible for the epilepsy that is the determining factor. Thus, individuals with focal temporal lobe epilepsy are more likely to experience sexual dysfunction than are persons with generalized epilepsy.1,70,71,80,81 Both hypersexuality and sexual apathy may occur, although the latter is much more frequent.1,68 Genital sensations or sexual behavior can also occur as ictal phenomena.68
Parkinson’s Disease Alterations in sexual function are common in patients with Parkinson’s disease. In a survey of 115 such patients, Saka-
Treatment of Sexual Dysfunction The treatment of sexual dysfunction in persons with neurological disease processes has largely centered on the treatment of erectile dysfunction in men; little attention has been devoted to the treatment of dysfunction in women. A discussion of treatment of the psychological aspects of sexual dysfunction is beyond the scope of this chapter. The emergence of orally administered drugs that can enhance erections has revolutionized the treatment of erectile dysfunction (Table 29–5). Sildenafil, now joined by tadalafil and vardenafil, has been shown to be effective in men with spinal cord injury, multiple sclerosis, and other neurological conditions.95-98 These drugs are inhibitors of type 5 cyclic guanosine monophosphate phosphodiesterase, which via nitric
368
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
T A B L E 29–5. Treatment of Erectile Dysfunction Cyclic Guanosine Monophosphate Phosphodiesterase Inhibitors Sildenafil Vardenafil Tadalafil Dopamine Agonists Apomorphine Intracavernosal Injections Alprostadil Moxisylyte
K E Y ●
Neurological diseases at all levels of the nervous system— from cortex to brainstem to spinal cord to peripheral nerves—can produce bladder and sexual dysfunction.
●
Lesions affecting cerebral centers produce overactivity of the detrusor muscle, but coordination between the detrusor and sphincter muscles is retained.
●
Lesions affecting the sacral cord produce reduction in detrusor activity, but coordination between the detrusor and sphincter muscles is still retained.
●
Lesions affecting the suprasacral spinal cord result in loss of coordination between detrusor and sphincter muscles; this is called detrusor-sphincter dyssynergia.
●
Various medications are useful in treating overactive bladder, but intermittent catheterization remains the most effective treatment for underactive or acontractile detrusor function; a combination of both may be necessary to treat detrusor-sphincter dyssynergia.
●
Treatment for sexual dysfunction has focused largely on erectile dysfunction, and a variety of therapeutic approaches are available.
Intraurethral Instillation Alprostadil Vacuum Devices
oxide–mediated mechanisms produces smooth muscle relaxation and increases corpora cavernosa blood flow, thus enhancing penile erection.14,99 Sildenafil and related drugs are generally well tolerated, but headache, flushing, gastrointestinal upset, changes in color vision, and rhinitis may occur. Lethal adverse reactions have occurred in individuals taking nitrates concomitantly, and these drugs should be used very cautiously by persons with neurological diseases, such as Parkinson’s disease, in which orthostatic hypotension may occur. In fact, use of these drugs by persons with MSA is probably ill advised. For individuals who cannot use or tolerate sildenafil and its analogues, other treatment approaches are available. Intracavernosal injections of alprostadil and moxisylyte are effective, but the requirement for injections, which are sometimes associated with significant pain, and the potential for development of fibrotic nodules within the corpora deter many individuals from using this form of treatment.94 Priapism may also occur. Intraurethral administration of alprostadil is also available. Vacuum devices, used in conjunction with constrictor bands, are also effective in inducing penile erection, but patient acceptance of the devices is low. Dopamine agonist drugs have been shown to induce penile erection in both animals100 and humans.14,101 There is evidence that this may be caused specifically by D4 receptor–mediated activation of oxytocinergic neurons within the paraventricular nucleus of the hypothalamus.100 A sublingual apomorphine preparation has been developed for use by humans.14,101
CONCLUSION The neurologist is neither a urologist nor a gynecologist and should not expect to be the primary source of treatment for urological and sexual dysfunction that may arise in the setting of neurological disease. However, familiarity with the nature and treatment of such problems and a willingness to discuss them with patients and family members are tremendously valuable and can immeasurably enhance patient care and satisfaction. Effective treatment measures are actually available for many of these problems, but they first must be identified, and it is in identification that the neurologist, who is often the primary treating physician for patients with chronic neurological diseases, must play a role.
P O I N T S
Suggested Reading Andersson KE: Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004; 3:46-53. Apostolidis AN, Fowler CJ: Evaluation and treatment of autonomic disorders of the urogenital system. Semin Neurol 2003; 23:443452. Fowler CJ: Neurological disorders of micturition and their treatment. Brain 1999; 122:1213-1231. Fowler CJ, ed: Neurology of Bladder, Bowel and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999. Singer C: Urinary dysfunction in Parkinson’s disease. In Ebadi M, Pfeiffer RF, eds: Parkinson’s Disease. Boca Raton, FL: CRC Press, 2005, pp 275-286.
References 1. Sakakibara R, Fowler CJ: Cerebral control of bladder, bowel, and sexual function and effects of brain disease. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 229-243. 2. Athwal BS, Berkley KJ, Hussain I, et al: Brain responses to changes in bladder volume and urge to void in healthy men. Brain 2001; 124:369-377. 3. Andrew J, Nathan PW: Lesions of the anterior frontal lobes and disturbances of micturition and defaecation. Brain 1964; 87:233-262. 4. Ueki K: Disturbances of micturition observed in some patients with brain tumor. Neurol Med Chir 1960; 2:2533. 5. Maurice-Williams RS: Micturition symptoms in frontal tumours. J Neurol Neurosurg Psychiatry 1974; 37:431-436. 6. Sakakibara R, Hattori T, Yasuda K, et al: Micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by CT and MRI. J Neurol Sci 1996; 137:47-56.
chapter 29 bladder and sexual function and dysfunction 7. Zhang H, Reitz A, Kollias S, et al: An fMRI study of the role of suprapontine brain structures in the voluntary voiding control induced by pelvic floor contraction. Neuroimage 2005; 24:174-180. 8. Barrington FJF: The relation of the hindbrain to micturition. Brain 1921; 44:23-53. 9. Barrington FJF: The effect of lesions of the hind and midbrain on micturition in the cat. Q J Exp Physiol 1925; 15:81102. 10. Holstege G, Griffiths D, de Wall H, et al: Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat. J Comp Neurol 1986; 250:449-461. 11. Griffiths D, Holstege G, Dalm E, et al: Control and coordination of bladder and urethral function in the brainstem of the cat. Neurourol Urodyn 1990; 9:63-82. 12. Taniguchi N, Miyata M, Yachiku S, et al: A study of micturition inducing sites in the periaqueductal gray of the mesencephalon. J Urol 2002; 168:1626-1631. 13. Onufrowicz B: Notes on the arrangement and function of the cell groups in the sacral region of the spinal cord. J Nerv Mental Dis 1899; 26:498-504. 14. Apostolidis AN, Fowler CJ: Evaluation and treatment of autonomic disorders of the urogenital system. Semin Neurol 2003; 23:443-452. 15. Lundberg JM: Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev 1996; 48:113-178. 16. Yoshimura N: Bladder afferent pathway and spinal cord injury: possible mechanisms inducing hyperreflexia of the urinary bladder. Prog Neurobiol 1999; 57:583-606. 17. Fowler CJ: Bladder afferents and their role in the overactive bladder. Urology 2002; 59(5, Suppl 1):37-42. 18. Abrams P, Cardozo L, Fall M, et al: The standardization of terminology in lower urinary tract function: report from the standardization sub-committee of the International Continence Society. Urology 2003; 61:37-49. 19. Swinn MJ: Urodynamics. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 97-107. 20. Vodusˇek DB, Fowler CJ: Clinical neurophysiology. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 109-143. 21. Korpelainen JT, Sotaniemi KA, Myllyla VV: Autonomic nervous system disorders in stroke. Clin Auton Res 1999; 9:325-333. 22. Brittain KR, Peet SM, Castleden CM: Stroke and incontinence. Stroke 1998; 29:524-528. 23. Sakakibara R, Hattori T, Yasuda K, et al: Micturitional disturbance and the pontine tegmental lesion: urodynamic and MRI analyses of vascular cases. J Neurol Sci 1996; 141:105110. 24. Kong KH, Young S: Incidence and outcome of poststroke urinary retention: a prospective study. Arch Phys Med Rehabil 2000; 81:1464-1467. 25. Gelber DA, Good DC, Laven LJ, et al: Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24:378382. 26. Arena MG, Di Rosa AE, Arcudi L, et al: Voiding disorders in patients with cerebrovascular disease. Funct Neurol 1992; 7:47-49. 27. Singer C: Urological dysfunction. In Pfeiffer RF, BodisWollner I, eds: Parkinson’s Disease and Nonmotor Dysfunction. Totowa, NJ: Humana Press, 2005, pp 139-148. 28. Singer C: Urinary dysfunction in Parkinson’s disease. In Ebadi M, Pfeiffer RF, eds: Parkinson’s Disease. Boca Raton, FL: CRC Press, 2005, pp 275-286.
369
29. Hobson P, Islam W, Roberts S, et al: The risk of bladder and autonomic dysfunction in a community cohort of Parkinson’s disease patients and normal controls. Parkinsonism Relat Disord 2003; 10:67-71. 30. Campos-Sousa RN, Quagliato E, da Silva BB, et al: Urinary symptoms in Parkinson’s disease. Prevalence and associated factors. Arq Neuropsiquiatr 2003; 61:359-363. 31. Chandiramani VA, Palace J, Fowler CJ: How to recognize patients with parkinsonism who should not have urological surgery. Br J Urol 1997; 80:100-104. 32. Chandiramani VA, Fowler CJ: Urogenital disorders in Parkinson’s disease and multiple system atrophy. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 245-254. 33. Araki I, Kitahara M, Oida T, et al: Voiding dysfunction in Parkinson’s disease: urodynamic abnormalities and urinary symptoms. J Urol 2000; 164:1640-1643. 34. Murnaghan GF: Neurogenic disorders of the bladder in parkinsonism. Br J Urol 1961; 33:403-409. 35. Pavlakis AJ, Siroky MB, Goldstein I, et al: Neurourologic findings in Parkinson’s disease. J Urol 1983; 129:80-83. 36. Fitzmaurice H, Fowler CJ, Rickards D, et al: Micturition disturbance in Parkinson’s disease. Br J Urol 1985; 57:652-656. 37. Galloway NTM: Urethral sphincter abnormalities in parkinsonism. Br J Urol 1983; 55:691-693. 38. Stocchi F, Carbone A, Inghilleri M, et al: Urodynamic and neurophysiological evaluation in Parkinson’s disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 1997; 62:507-511. 39. Yoshimura N, Kuno S, Chancellor MB, et al: Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Br J Pharmacol 2003; 139:1425-1432. 40. Yoshimura N, Mizuta E, Yoshida O, et al: Therapeutic effects of dopamine D1/D2 receptor agonists on detrusor hyperreflexia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine– lesioned parkinsonian cynomolgus monkeys. J Pharmacol Exp Ther 1998; 286:228-233. 41. Kuno S, Mizuta E, Yamasaki S, et al: Effects of pergolide on nocturia in Parkinson’s disease: three female cases selected from over 400 patients. Parkinsonism Relat Disord 2004; 10:181-187. 42. Wenning GK, Colosimo C, Geser F, et al: Multiple system atrophy. Lancet Neurol 2004; 3:93-103. 43. Kirby R, Fowler CJ, Gosling J, et al: Urethrovesical dysfunction in progressive autonomic failure with multiple system atrophy. J Neurol Neurosurg Psychiatry 1986; 49:554-562. 44. Bonnet AM, Pichon J, Vidailhet M, et al: Urinary disturbances in striatonigral degeneration and Parkinson’s disease: clinical and urodynamic aspects. Mov Disord 1997; 12:509513. 45. McDougall AJ, McLeod JG: Autonomic nervous system function in multiple sclerosis. J Neurol Sci 2003; 215:79-85. 46. Shah DK, Badlani GH: Urological symptoms. In Voltz R, Bernat JL, Borasio GD, et al, eds: Palliative Care in Neurology. Oxford, UK: Oxford University Press, 2004, pp 262-271. 47. Fowler CJ: Neurological disorders of micturition and their treatment. Brain 1999; 122:1213-1231. 48. Nortvedt MW, Riise T, Myhr KM, et al: Reduced quality of life among multiple sclerosis patients with sexual disturbance and bladder dysfunction. Mult Scler 2001; 7:231-235. 49. Giannantoni A, Scivoletto G, Di Stasi SM, et al: Lower urinary tract dysfunction and disability status in patients with multiple sclerosis. Arch Phys Med Rehabil 1999; 80:437441. 50. Barbalius GA, Nikiforidis G, Liatsikos EN: Vesicourethral dysfunction associated with multiple sclerosis: clinical and urodynamic perspectives. J Urol 1998; 160:106-111.
370
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
51. Wyndaele JJ: Correlation between clinical neurological data and urodynamic function in spinal cord injured patients. Spinal Cord 1997; 35:213-216. 52. Van Kerrebroeck PEV: Lower urinary tract dysfunction in spinal cord injury. In Corazziari E, ed: Neurogastroenterology. Berlin: Walter de Gruyter, 1996, pp 289-299. 53. Kaplan SA, Chancellor MB, Blaivas J: Bladder and sphincter behavior in patients with spinal cord lesions. J Urol 1991; 146:113-117. 54. Pesce F, Castellano V, Finazzi Agro E, et al: Voiding dysfunction in patients with spinal cord lesions at the thoracolumbar vertebral junction. Spinal Cord 1997; 35:37-39. 55. Andersson KE: Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004; 3:46-53. 56. Todorova A, Vonderheid-Guth B, Dimpfel W: Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J Clin Pharmacol 2001; 41:636-644. 57. Rovner ES: Trospium chloride in the management of overactive bladder. Drugs 2004; 64:2433-2446. 58. Chilman-Blair K, Bosch JL: Solifenacin: treatment of overactive bladder. Drugs Today (Barc) 2004; 40:343-353. 59. Brunton S, Kurtizky L: Recent developments in the management of overactive bladder: focus on the efficacy and tolerability of once daily solifenacin succinate 5 mg. Curr Med Res Opin 2005; 21:71-80. 60. Cardozo L, Dixon A: Increased warning time with darifenacin: a new concept in the management of urinary urgency. J Urol 2005; 173:1214-1218. 61. Kim YT, Kwon DD, Kim J, et al: Gabapentin for overactive bladder and nocturia after anticholinergic failure. Int Braz J Urol 2004; 30:275-278. 62. Dasgupta P, Haslam C: Treatment of neurogenic bladder dysfunction. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 163-183. 63. Palma PCR, Thiel M, Riccetto CLZ, et al: Resiniferatoxin for detrusor instability refractory to anticholinergics. Int Braz J Urol 2004; 30:53-58. 64. Kuo HC: Multiple intravesical instillation of low-dose resiniferatoxin is effective in the treatment of detrusor overactivity refractory to anticholinergics. BJU Int 2005; 95:10231027. 65. Hajebrahimi S, Altaweel W, Cadoret J, et al: Efficacy of botulinum-A toxin in adults with neurogenic overactive bladder: initial results. Can J Urol 2005; 12:2543-2546. 66. Smith CP, Nishiguchi J, O’Leary M, et al: Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 2005; 65:37-41. 67. Shafik A, El Sibai O, Shafik AA, et al: Vesical pacing: pacing parameters required for normalization of vesical electric activity in patients with overactive bladder. Front Biosci 2004; 9:995-999. 68. Lundberg PO: Physiology of female sexual function and effect of neurologic disease. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 33-46. 69. Tiihonen J, Kuikka J, Kupila J, et al: Increase in cerebral blood flow of right prefrontal cortex in man during orgasm. Neurosci Lett 1994; 170:241-243. 70. Shukla GD, Srivastava ON, Katiyar BC: Sexual disturbances in temporal lobe epilepsy: a controlled study. Br J Psychiatry 1979; 134:288-292. 71. Blumer D, Walker AE: Sexual behavior in temporal lobe epilepsy. A study of the effects of temporal lobectomy on sexual behavior. Arch Neurol 1967; 16:37-43. 72. Hulting AL, Muhr C, Lundberg PO, et al: Prolactinomas in men: clinical characteristics and the effect of bromocriptine treatment. Acta Med Scand 1985; 217:101-109.
73. Lundberg PO, Hulter B: Sexual dysfunction in patients with hypothalamo-pituitary disorders. Exp Clin Endocrinol 1991; 98:81-88. 74. Beck RO: Physiology of male sexual function and dysfunction in neurologic disease. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 47-56. 75. Hoyle CHV, Lincoln J, Burnstock G: Neural control of pelvic organs. In Rushton DN, ed: Handbook of Neuro-Urology. New York: Marcel Dekker, 1994, pp 1-54. 76. Karacan I, Williams RL, Thornby JI, et al: Sleep-related penile tumescence as a function of age. Am J Psychiatry 1975; 132:932-937. 77. Beck RO: Investigation of male erectile dysfunction. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 145-160. 78. Schmidt MH, Schmidt HS: Sleep-related erections: neural mechanisms and clinical significance. Curr Neurol Neurosci Rep 2004; 4:170-178. 79. Nogueira MC, Herbaut AG, Wespes E: Neurophysiological investigations of two hundred men with erectile dysfunction. Interest of bulbocavernosus reflex and pudendal evoked responses. Eur Urol 1990; 18:37-41. 80. Lundberg PO: Sexual dysfunction in patients with neurological disorders. Annu Rev Sex Res 1992; 3:121-150. 81. Lundberg PO, Brattberg A: Sexual dysfunction in selected neurologic disorders: hypothalamopituitary disorders, epilepsy, myelopathies, polyneuropathies, and sacral nerve lesions. Semin Neurol 1992; 12:115-119. 82. Sakakibara R, Shinotoh H, Uchiyama T, et al: Questionnairebased assessment of pelvic organ dysfunction in Parkinson’s disease. Auton Neurosci 2001; 92:76-85. 83. Singer C, Weiner WJ, Sanchez-Ramos JR: Autonomic dysfunction in men with Parkinson’s disease. Eur Neurol 1992; 32:134-140. 84. Beck RO, Betts CD, Fowler CJ: Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urol 1994; 151:1336-1341. 85. Müller R: Studies on disseminated multiple sclerosis. Acta Med Scand 1949; 222:67-71. 86. Betts CD, Jones SJ, Fowler CG, et al: Erectile dysfunction in multiple sclerosis. Associated neurological and neurophysiological deficits, and treatment of the condition. Brain 1994; 117:1303-1310. 87. Betts CD: Bladder and sexual dysfunction in multiple sclerosis. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 289308. 88. Lundberg PO: Sexual dysfunction in female patients with multiple sclerosis. Int Rehabil Med 1981; 3:32-34. 89. Hulter BM, Lundberg PO: Sexual function in women with advanced multiple sclerosis. J Neurol Neurosurg Psychiatry 1995; 59:83-86. 90. Zorzon M, Zivadinov R, Bosco A, et al: Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups. Mult Scler 1999; 5:418-427. 91. Valleroy ML, Kraft GH: Sexual dysfunction in multiple sclerosis. Arch Phys Med Rehabil 1984; 65:125-128. 92. Minderhoud JM, Leemhuis JG, Kremer J, et al: Sexual disturbances arising from multiple sclerosis. Acta Neurol Scand 1984; 70:299-306. 93. Bors E, Comarr AE: Neurological disturbance of sexual function with special reference to 529 patients with spinal cord injury. Urol Surv 1960; 10:191-222. 94. Hatzichristou DG: Treatment of sexual dysfunction and infertility in patients with neurologic diseases. In Fowler CJ, ed: Neurology of Bladder, Bowel, and Sexual Dysfunction. Boston: Butterworth Heinemann, 1999, pp 209-225.
chapter 29 bladder and sexual function and dysfunction 95. Derry F, Hultling C, Seftel AD, et al: Efficacy and safety of sildenafil citrate (Viagra) in men with erectile dysfunction and spinal cord injury: a review. Urology 2002; 60(2, Suppl 2):49-57. 96. Langtry HD, Markham A: Sildenafil: a review of its use in erectile dysfunction. Drugs 1999; 57:967-989. 97. Sanchez Ramos A, Vidal J, Jauregui ML, et al: Efficacy, safety and predictive factors of therapeutic success with sildenafil for erectile dysfunction in patients with different spinal cord injuries. Spinal Cord 2001; 39:637-643. 98. Doggrell SA: Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction. Expert Opin Pharmacother 2005; 6:75-84.
371
99. Hallén K, Gustafsson LE, Wiklund NP. Nerve-induced release of nitric oxide from the rabbit corpus cavernosum is modulated by cyclic guanosine 3′,5′-monophosphate. Neuroscience 2005; 133:169-174. 100. Melis MR, Succu S, Mascia MS, et al: PD-168077, a selective dopamine D4 receptor agonist, induces penile erection when injected into the paraventricular nucleus of male rats. Neurosci Lett 2005; 379:59-62. 101. Montorsi F, Salonia A, Dehò F, et al: Pharmacological management of erectile dysfunction. BJU Int 2003; 91:446454.
CHAPTER
30
PRIMARY AUTONOMIC FAILURE ●
●
●
●
Felix Geser and Gregor K. Wenning
CLASSIFICATION A convenient approach to the syndromes of autonomic failure is to distinguish those of the primary variety, in which there is no clear etiological factor or specific disease association, from those with secondary autonomic failure, in which the lesion is defined (anatomically, as in spinal cord injuries, or biochemically, as in dopamine β-hydroxylase deficiency) or is linked to specific disease processes (as in diabetes mellitus). Furthermore, drugs form a major cause of autonomic dysfunction and merit separate categorization. Moreover, another group that probably warrants a separate entity is neurally mediated syncope, in which, between episodic autonomic disturbances, usually no abnormalities can be detected.1 Primary autonomic failure syndromes can be divided into a chronic subgroup and into a rarer subgroup with acute or subacute dysautonomia (Table 30–1). Furthermore, the chronic syndromes can be subdivided into those without (i.e., pure autonomic failure [PAF]) and those with associated neurological deficits. Clinically, the latter belong to at least three categories: Parkinson’s disease associated with autonomic failure, dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). Patients with parkinsonian features may be responsive to chronic levodopa (L-dopa) therapy, probable as part of treatment for Parkinson’s disease with autonomic failure. Alternatively, there may be no or poorly (transiently) L-dopa– responsive parkinsonism, probable as part of the parkinsonian variant of MSA, i.e. MSA-P. Other patients may have cerebellar features as the predominant motor disorder and may therefore be diagnosed as the cerebellar variant of MSA, i.e., MSA-C. Some patients present initially with autonomic abnormalities, including urogenital and cardiovascular dysfunction, and only later develop the additional neurological manifestations of MSA. Eventually, some patients present with parkinsonian features accompanied by dementia within the first year of disease onset, which leads to a diagnosis of DLB. Actually, it is important to classify patients or assign them to these different disease entities for a number of reasons, including prognosis. Indeed, analyses of two large series in the United Kingdom and the United States indicate that patients with PAF have a substantially better prognosis than those with additional neurological deficits.2 There are differences within this latter group as well, inasmuch as patients with Ldopa–responsive Parkinson’s disease and autonomic failure
372
appear to live longer than do patients with MSA or DLB (personal observations). In this chapter, we discuss the clinical manifestation and its underlying neuropathological changes and the diagnostic workup and management of the primary autonomic failure disorders, including PAF, Parkinson’s disease with autonomic failure, MSA, and DLB. The rarer subgroups with acute or subacute primary autonomic failure are briefly considered. No further mention is made of the secondary forms, including drug-induced autonomic failure.
NEUROPATHOLOGY Degeneration of autonomic neurons with disabling dysautonomia is a prominent feature of the Lewy body syndromes and MSA. α-Synuclein is a major component of the Lewy bodies in Parkinson’s disease, DLB, and the glial and neuronal cytoplasmic inclusions of MSA. α-Synuclein also is a major component of Lewy bodies in the brain and peripheral autonomic ganglia in PAF.3 Therefore, these disorders are increasingly being referred to as “synucleinopathies.” Abnormalities in the expression or structure of α-synuclein or associated proteins may cause degeneration of catecholamine-containing neurons.4 However, the function of α-synuclein is not known, but interest in this protein derives from the finding that the gene encoding for α-synuclein is mutated in families with the autosomal-dominant form of Parkinson’s disease.5 To investigate the consequence of α-synuclein overexpression in glia, Stefanova and colleagues6 transfected U373 astrocytoma cells with vectors encoding wild-type human α-synuclein or C-terminally truncated synuclein fused to red fluorescent protein. α-Synuclein immunocytochemistry of transfected astroglial cells revealed diffuse cytoplasmic labeling associated with discrete inclusions within both cell bodies and processes. Susceptibility to oxidative stress was increased in astroglial cells overexpressing αsynuclein, particularly in the presence of cytoplasmic inclusions. However, whether the α-synuclein aggregation is induced by some other factor or factors or whether it is the primary trigger of MSA pathology is unknown. Impairment in the ability of oligodendrocytes to degrade α-synuclein, which they may normally produce at low levels, may promote abnormal subcellular aggregation in MSA.7 Alternatively, ectopic expression of oligodendroglial α-synuclein may result in glial
chapter 30 primary autonomic failure cytoplasmic inclusions. This scenario is supported by experimental studies demonstrating glial cytoplasmic inclusion–like inclusion pathology in transgenic mice overexpressing oligodendroglial α-synuclein.8 More work is necessary to elucidate the cascade of cell death in MSA and to determine exogenous and genetic susceptibility factors, both of which are likely to drive the disease process in this disorder. It is not known what determines whether α-synuclein precipitates in neurons (Parkinson’s disease, PAF) or glial cells (MSA) or on autonomic (PAF) or striatonigral neurons (Parkinson’s disease, MSA). Anyway, there are clear distinctions between the different αsynucleinopathies and little evidence of migration from one clinical form to the other.
Lewy Body Disorders The Lewy body syndromes are characterized by intracytoplasmic eosinophilic neuronal inclusions, so-called Lewy bodies or Lewy neurites, found in the brain, including brainstem, basal ganglia, and cortical neurons, and in the peripheral autonomic nerves of affected patients. Lewy bodies contain abnormally phosphorylated intermediate neurofilament proteins, αsynuclein, ubiquitin, and associated enzymes. There are three different but overlapping phenotypes. In PAF there is early and
T A B L E 3 0 – 1. Failure Disorders Acute/subacute primary autonomic failure disorders Chronic primary autonomic failure disorders
■
Classification of Primary Autonomic Pure pandysautonomia Pandysautonomia with neurological features Pure cholinergic dysautonomia Acute noradrenergic autonomic neuropathy Pure autonomic failure Parkinson’s disease with autonomic failure Dementia with Lewy bodies Multiple system atrophy
373
widespread neuronal degeneration restricted mostly to peripheral autonomic neurons; autonomic failure is the sole clinical finding.9 In fact, in patients with PAF, intracytoplasmic eosinophilic inclusion bodies with the histological appearance of Lewy bodies, similar to those found in Parkinson’s disease, are identified in neurons of the substantia nigra, locus ceruleus, thoracolumbar and sacral spinal cord, and sympathetic ganglia and in peripheral sympathetic and parasympathetic nerves.9,10 Neuropathological reports of patients with PAF showed αsynuclein–positive intraneuronal cytoplasmic inclusions (Lewy bodies) in brainstem nuclei and peripheral autonomic ganglia.3,9 In Parkinson’s disease, there is prominent degeneration of the substantia nigra (Fig. 30–1) and other brainstem nuclei, in addition to peripheral autonomic neurons; clinically, there are motor abnormalities with varying degrees of autonomic failure.11 In DLB there is extensive cortical involvement in addition to degeneration of brainstem nuclei and peripheral autonomic neurons; clinical findings are dominated by severe cognitive impairment in association with parkinsonism and autonomic dysfunction.12 It is likely that the clinical phenotype of Lewy body syndromes depends on the temporal formation and distribution of Lewy bodies and associated neurodegeneration. Individual differences in neuronal susceptibility may determine the manifesting phenotype. Patients with PAF, however, can progress to Parkinson’s disease or DLB, which suggests that phenotypes overlap and that neurodegeneration in the Lewy body syndromes may start in postganglionic autonomic neurons and later affect neurons in the central nervous system. As initially suggested by Oppenheimer,13 PAF may be a “forme fruste” of Parkinson’s disease, with early severe widespread degeneration of peripheral autonomic neurons.9,10
Multiple-System Atrophy The second type of neurodegeneration with prominent autonomic failure is MSA. The term multiple-system atrophy was introduced in 196914; however, cases of MSA were previously
Figure 30–1. Gross photograph of a coronal section through the midbrain of a normal person (left) and that of a patient with Parkinson’s disease (right). Note the pigmentation pattern of the substantia nigra in the normal specimen and the loss of pigmentation, resulting in a marked paleness, in the case of Parkinson’s disease.
374
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
reported under the rubrics of striatonigral degeneration (SND),15-17 olivopontocerebellar atrophy (OPCA),18,19 ShyDrager syndrome,20 and idiopathic orthostatic hypotension. MSA is a sporadic neurodegenerative disorder characterized clinically by various combinations of parkinsonian, autonomic, cerebellar, or pyramidal symptoms and signs and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in several brain and spinal cord structures. Indeed, this disorder affects neurons in the basal ganglia, cortex, and spinal cord, but spares peripheral autonomic neurons. Pathologically, cytoplasmic inclusions are located in glial cells and do not form Lewy bodies.21 Clinically, two major motor presentations can be distinguished. Parkinsonian features predominate in 66% of patients (MSA-P), and cerebellar ataxia is the major motor feature in 34% of patients (MSA-C), according to a European survey.22 Severe autonomic failure is prominent in both phenotypes.23 In MSA-P, the striatonigral system is the main site of pathology, but less severe degeneration can be widespread and usually includes the olivopontocerebellar system.24,25 The putamen is shrunken with gray-green discoloration. When putaminal pathology is severe, there may be a cribriform appearance. In early stages, the putaminal lesion shows a distinct topographical distribution with a predilection for the caudal and dorsolateral regions.24 Degeneration of pigmented nerve cells occurs in the substantia nigra pars compacta, whereas cells of the pars reticulata are reported as normal. The topographical patterns of neurodegeneration involving the motor neostriatum, efferent pathways, and nigral neurons reflect their anatomical relationship and suggest a common denominator or “linked” degeneration.24 In MSA-C, the brunt of pathology is borne by the olivopontocerebellar system; the involvement of striatum and substantia nigra is less severe. The basis pontis is atrophic, with loss of pontine neurons and transverse pontocerebellar fibers. In sections stained for myelin, the intact descending corticospinal tracts stand out against the degenerated transverse fibers and the atrophic middle cerebellar peduncles. There is a disproportionate depletion of fibers from the middle cerebellar peduncles in comparison with the loss of pontine neurons, an observation consistent with a “dying back” process. The location of the α-synuclein precipitates determines not only the presence or absence of movement disorders but also the characteristics of the autonomic cardiovascular abnormality. Autonomic failure in MSA is caused by dysfunction of (1) central and preganglionic efferent autonomic activity, (2) neuronal networks in the brainstem that control cardiovascular and respiratory function, and (3) the neuroendocrine component of the autonomic regulation via the hypothalamopituitary axis. In MSA, cell loss is reported in dorsal motor nucleus of the vagus.26 Catecholaminergic neurons in the rostral (C1 group) and caudal (A1 group) ventrolateral medulla, which are involved in the control of sympathetic outflow to the cardiovascular system and reflex control of vasopressin release, are also affected, as are neurons of the arcuate nucleus that are involved in cardiorespiratory interactions.27-30 Cell loss has also been described for the Edinger-Westphal nucleus and posterior hypothalamus,20 including the tuberomammillary nucleus.31 Papp and Lantos21 demonstrated marked involvement of brainstem pontomedullary reticular formation with glial cytoplasmic inclusions, which represented a supraspinal histological counterpart for impaired visceral function. Autonomic
neuronal degeneration affects the locus ceruleus, too.32 It is noteworthy that there is not always a strong correlation between nerve cell depletion or gliosis and the clinical degree of autonomic failure. It is estimated that more than 50% of cells within the intermediolateral column must decay before symptoms become evident.13 Degeneration of sympathetic preganglionic neurons in the intermediolateral column of the thoracolumbar spinal cord is considered contributory to orthostatic hypotension. On the basis of only the reports in which formal cell counts have been made, it is apparent, with very few exceptions, that all cases of MSA with predominant pathology in either the striatonigral or olivopontocerebellar system show loss of intermediolateral cells.33 Orthostatic hypotension in MSA is caused by blunted autonomic and neuroendocrine reflexes as a result of afferent and central neuronal loss; postganglionic autonomic fibers, however, are spared.34 Disordered bladder, rectal, and sexual function in MSA-P and MSA-C have been associated with cell loss in parasympathetic preganglionic nuclei of the spinal cord. These neurons are localized rostrally in Onuf’s nucleus between sacral segments S2 and S3 and more caudally in the inferior intermediolateral nucleus chiefly in the S3 to S4 segments.35 Loss of corticotrophin-releasing factor neurons in the pontine micturition area may contribute to neurogenic bladder dysfunction.30 In the peripheral component of the autonomic nervous system, Bannister and Oppenheimer36 described atrophy of the glossopharyngeal and vagus nerves. No pathology has been reported in the visceral enteric plexuses or in the innervation of glands, blood vessels, or smooth muscles. Sympathetic ganglia have not often been examined in pathological studies of autonomic failure and have seldom been described quantitatively. In MSA with autonomic failure, there are either no obvious or mild abnormalities in sympathetic ganglia. Any morphological changes reported in sympathetic ganglionic neurons in MSA have tended to be nonspecific,37 exhibiting the normal age-related range of appearances, and published micrographs and counts have indicated at least a moderate density, and sometimes quite a high density, of surviving neurons.38 Enteric and parasympathetic ganglia have been studied only in a few instances. A variety of other neuronal populations are noted to show cell depletion and gliosis with considerable differences in vulnerability from case to case. Varying degrees of abnormalities in the cerebral hemisphere, including Betz cell loss, were detected in pathologically proved MSA cases.32,33 Furthermore, anterior horn cells may show some depletion, but rarely to the same extent as that occurring in motor neuron disease.39
CLINICAL PRESENTATION Acute/Subacute Primary Autonomic Failure Disorders Pure Pandysautonomia and Pandysautonomia with Neurological Features There is a clinical spectrum of acute autonomic neuropathies. Acute panautonomic neuropathy (pandysautonomia), characterized by severe widespread sympathetic and parasympathetic failure, is at one extreme. Guillain-Barré syndrome is at the
chapter 30 primary autonomic failure other end of the spectrum, in which the brunt of the disorder is borne by the somatic nervous system. Pure acute panautonomic neuropathies are relatively rare. Actually, the majority of acute autonomic neuropathies have some minor somatic features. Dysautonomia may be restricted to the cholinergic system (acute cholinergic neuropathy), the adrenergic system, or other organ systems (e.g., motility disorders).40 In medical history, a definite entity of pure pandysautonomia involving both sympathetic and parasympathetic nervous systems with a subacute onset, monophasic course, and partial recovery without significant features of somatic peripheral neuropathy was first described by Young and colleagues in 1969. Actually, there had been some earlier reports of the condition in the literature, although it was not clearly defined.47 The disorder differs from other neurological causes of autonomic dysfunction in that normal function of the central nervous system is preserved. Furthermore, there are no or only minor features of peripheral somatic nervous system involvement. Since these first descriptions, a number of other cases of acute pandysautonomia have been reported, as well as some cases of pure cholinergic dysautonomia. Some cases of acute dysautonomia with significant sensory disturbances have been described; in some, but not all, there was electrophysiological and pathological evidence of loss of small-diameter myelinated and unmyelinated fibers.41 In 1994, Suarez and colleagues42 clarified the features of acute idiopathic autonomic neuropathy. Both sexes and all ages can be affected. The onset is acute or subacute. In approximately one half of affected patients, there is an antecedent viral infection. Several cases that followed EpsteinBarr virus infection have been described, in one of which Epstein-Barr virus DNA and antibody to the virus were found in the cerebrospinal fluid.43 The most common presenting features are symptomatic orthostatic hypotension (lightheadedness, dizziness, syncope) and symptoms of gastrointestinal dysfunction (nausea, vomiting, diarrhea, constipation, and postprandial bloating) or sudomotor dysfunction (failure to sweat, causing heat intolerance and flushing). Other symptoms include numbness, tingling, bladder disturbances, and impotence. Neurological examination findings are normal in about one half the patients; the remainder have depressed reflexes and distal sensory impairment. The clinical course is monophasic. Recovery tends to be gradual and frequently incomplete. The cerebrospinal fluid protein level may be mildly elevated. In rare cases, there may be evidence of sensory neuropathy with sensory symptoms of minimal intensity (mainly thermal and pain hypoesthesia in distal areas). In most cases, nerve conduction studies yield normal results. Sural nerve biopsy in some cases has demonstrated reduction of myelinated fiber density, predominantly of small fibers, and axonal degeneration. Actually, in some cases, there are minimal signs of distal denervation in electromyographic-electroneurographic studies.44 In some acute neuropathies, such as pandysautonomia, small-fiber impairment is relatively pure, but it may also appear in disorders with prominent somatic damage, such as Guillain-Barré syndrome, in which autonomic failure worsens the prognosis.45 The cause of the condition remains uncertain. Pathological features include the presence of a small inflammatory mononuclear cell infiltrate in the epineurium. It is probably a form of acute idiopathic polyneuritis restricted to autonomic nerves with an immune-mediated pathogenesis similar to that of the Guillain-Barré syndrome. Together, the acute onset, frequent
375
antecedent viral infection, selectivity of involvement by fiber type and autonomic level, and presence of perivascular mononuclear cell infiltration suggest that the underlying mechanism is likely to be immune mediated. The following differential diagnoses have to be kept in mind: botulism, acute autonomic neuropathy associated with Guillain-Barré syndrome, porphyria, diabetes, toxic causes, systemic lupus erythematosus, and other connective tissue diseases.41
Pure Cholinergic Dysautonomia In pure cholinergic dysautonomia, clinical and laboratory features indicate only a cholinergic failure. A number of cases of pure cholinergic dysautonomia have been described in children. Clinical features include blurred vision, impaired lacrimation, dry mouth, constipation, urinary retention and incontinence, and absence of sweating. There is no postural hypotension. Excessive salivation and sweat secretion have been described in early disease stages. Cerebrospinal fluid findings are normal.41
Chronic Primary Autonomic Failure Disorders Primary Autonomic Failure Bradbury and Eggleston46 were the first to describe PAF in 1925. They used the term idiopathic orthostatic hypotension. Actually, the name pure autonomic failure was introduced by Oppenheimer as one of the primary autonomic failure syndromes. It is a sporadic, adult-onset, slowly progressive, neurodegenerative disorder of the autonomic nervous system.92 Clinically, it is characterized by an isolated impairment of the autonomic nervous system with no other neurological deficits.47 PAF affects men slightly more often than women, usually in their sixth decade. Its onset is slow, and symptoms begin developing insidiously for years as minimal impairment (nonspecific weakness and orthostatic intolerance). The patient may recall that symptoms first manifested several years before he or she sought medical treatment. Common symptoms causing the patient to seek medical advice include unsteadiness, lightheadedness, or faintness on standing. Questioning often elicits descriptions of aching in the neck or occiput only when standing; lying down relieves all symptoms. In general, orthostatic symptoms are more prominent after prolonged recumbency, as in the morning hours. Moreover, postural hypotension is exacerbated after mealtimes and physical exertion. Other contributory factors are heat, alcohol ingestion, coughing, and defecation.48,49 In fact, straining during evacuation or micturition elevates intrathoracic pressure and may result in symptomatic hypotension. Mathias and colleagues50 investigated the frequency of symptoms associated with orthostatic hypotension in PAF and MSA and found that more patients with PAF had syncope (91% vs. 45%), visual disturbances (75% vs. 53%), and suboccipital/paracervical “coat hanger” neck pain (81 vs. 53%) than did the patients with MSA. The reasons for this are unclear. Patients with PAF may also develop supine hypertension. Moreover, a decreased ability to sweat may be apparent, particularly in hot climates. Men found to have PAF may have sought advice about urinary tract symptoms (hesitancy, urgency, dribbling, and occasional incontinence). Other signs of dysautonomia, including erectile and
376
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
ejaculatory dysfunction, an inability to appreciate orgasm, and retrograde ejaculation may be present, too. Women may experience urinary retention or incontinence as early symptoms. In patients with neurally mediated syncope, nausea and pallor, which are prominent signs of autonomic activation, occur before loss of consciousness. In contrast, in patients with PAF, these signs are noticeably absent, and consciousness is lost with little or no warning.51 Autonomic tests are abnormal: orthostatic hypotension, cardiovagal dysfunction, and hypo- or anhidrosis of the postganglionic type (see “Laboratory Assessment” section). A definitive diagnosis of orthostatic hypotension as the cause of symptoms is made when symptoms are reproduced while declines in systolic blood pressure of at least 20 mm Hg and diastolic pressure of at least 10 mm Hg are documented, within 3 minutes of standing. The diagnosis cannot be excluded with a single measurement of upright blood pressure that does not fulfill these criteria. Several measurements of orthostatic blood pressure, preferably early in the morning or after a meal, may be necessary. Patients with PAF also have decreased sinus arrhythmia and absent blood pressure overshoot during phase IV of the Valsalva maneuver, which indicates parasympathetic and sympathetic efferent dysfunction. PAF affects mainly efferent postganglionic neurons; afferent pathways and somatic neurons are not affected. Nevertheless, there is evidence of a preganglionic disorder in 22% of patients with PAF, which suggests that such patients actually may have some central component.44 In terms of differential diagnosis, PAF should be distinguished from other forms of neurogenic orthostatic hypotension, including peripheral somatic neuropathies with autonomic involvement (e.g., diabetes and amyloid), MSA, Parkinson’s disease, and DLB. There are no symptoms or signs of sensory, cerebellar, pyramidal, or extrapyramidal dysfunction in patients with PAF. In general, this allows a clinical distinction from other forms of neurogenic orthostatic hypotension. However, it cannot be determined whether a single patient with PAF will eventually develop more widespread, nonautonomic neuronal damage that leads to a diagnosis of MSA or, in rare cases, DLB. A number of warning signs, or “red flags,” for a clinical diagnosis of MSA have been operationally defined, and their frequency has been determined in a large cohort of European patients with MSA in a natural history study conducted by the European MSA-Study Group. Some of these features that are, if present, suggestive of MSA can be attributed, at least in part, to autonomic nervous system abnormalities. Abnormal respiration occurred in 42% to 60% of patients; its manifestations included inspiratory stridor (19% to 33%), involuntary deep sighs and/or gasps (34% to 37%), sleep apnea (13% to 18%), and excessive snoring (22% to 33%). Rapid eye movement (REM) sleep behavior disorder was present in 35% to 39%. Cold hands and/or feet were noted in 26% to 34%, whereas Raynaud’s phenomenon was recorded in only 6% to 7%.52,53 Although the specificity and positive predictive value of the red flags for a diagnosis of MSA have not been determined yet, they may serve as useful “soft signs” pointing toward a diagnosis of MSA. Because of the slow disease progression in PAF, most patients probably die before central nervous system involvement can become clinically evident. Apart from dysautonomia, these patients are otherwise normal and have a relatively good prognosis. Complications are usually related to falls and associated disorders.54
Parkinson’s Disease and Autonomic Failure In Parkinson’s disease, extrapyramidal motor problems are the presenting features. Later in the disease process, patients may also suffer severe autonomic failure, which makes the clinical distinction from MSA difficult. As in Parkinson’s disease, some patients with MSA display motor deficits before autonomic failure is apparent, which complicates the distinction further. However, dysautonomia in Parkinson’s disease is rarely as severe as that in MSA. The uncommonly encountered patients with both Parkinson’s disease and autonomic failure are usually older and are often responsive to L-dopa. Although in most cases autonomic failure occurs late, there is a subgroup of patients with Parkinson’s disease who have clinically significant autonomic failure early in the course of the disease. Orthostatic hypotension is often the key clinical feature suggestive of autonomic failure. However, there are many causes of orthostatic hypotension, including side effects of antiparkinsonian therapy (such as L-dopa or selegiline), coincidental disease causing autonomic dysfunction (e.g., diabetes mellitus), or concomitant administration of drugs for an allied condition (e.g., antihypertensives or α-adrenoceptor blockers).55 Studies on patients with Parkinson’s disease indicate that selegiline can cause orthostatic hypotension independently of autonomic failure through mechanisms that are not clearly defined.56 Together, the confounding effect of antiparkinsonian drugs that often worsens orthostatic hypotension and difficulties in the differential diagnosis (particularly between Parkinson’s disease and MSA) make it difficult to estimate accurately the prevalence of autonomic dysfunction in patients with Parkinson’s disease. Studies that mistakenly include patients with MSA-P may overestimate the frequency of autonomic dysfunction in Parkinson’s disease or underestimate it if patients with both Parkinson’s disease and autonomic dysfunction are diagnosed as MSA-P.54 In a retrospective study, almost one third of patients with Parkinson’s disease confirmed with post mortem examination had autonomic dysfunction documented in their clinical records.57 However, it has to be kept in mind that this retrospective method may underestimate the frequency of autonomic failure. Actually, bladder dysfunction (such as urgency, frequency, and incontinence) and decreased gastrointestinal motility represent the most frequent autonomic problems in Parkinson’s disease. Constipation is extremely common. Moreover, intestinal pseudo-obstruction and toxic megacolon may occur. Sexual dysfunction (loss of libido and erectile failure) is common in this disorder.54 In a study of patients whose Parkinson’s disease was diagnosed by means of clinical criteria, almost two thirds of subjects had orthostatic hypotension with symptoms of cerebral hypoperfusion, including syncope, when tested on a tilt table for 40 minutes or until symptoms developed.58 Because patients with normal responses and with orthostatic hypotension were taking similar drug regimens, antiparkinsonian medication was not the main cause of orthostatic hypotension. Senard and colleagues59 found a fall of at least 20 mm Hg of systolic blood pressure in almost 60% of patients with Parkinson’s disease. There was symptomatic orthostatic hypotension in 20% of the patients. It was related to duration and severity of the disorder, as well as with the use of higher daily L-dopa and bromocriptine dosages.59 A higher prevalence of symptomatic orthostatic hypotension (78%) was found in a retrospective study on
chapter 30 primary autonomic failure patients with neuropathologically confirmed Parkinson’s disease.60 In an earlier study, vagal control of the heart and hemodynamic response to standing were impaired and related to duration of the clinical features of Parkinson’s disease.61 Between 20% and 40% of patients with Parkinson’s disease become demented in the course of their illness.62 Operational criteria defining the clinical boundaries between Parkinson’s disease and Parkinson’s disease with dementia (PDD) are lacking, although this distinction may have profound clinical implications for prognosis and treatment strategies.63 The criteria in Diseases and Statistical Manual of Mental Disorders (Fourth Edition, DSM-IV™) are incomplete and descriptive and do not describe several core clinical features associated with dementia in Parkinson’s disease. Peralta and colleagues showed that orthostatic hypotension is more frequent and more severe in patients with PDD than in those with Parkinson’s disease. Attentional scores during tilt testing were also more reduced in patients with PDD in comparison with those with Parkinson’s disease, which suggests that orthostatic hypotension may exacerbate cognitive dysfunction in patients with PDD.64
Dementia with Lewy Bodies DLB is the most frequent cause of degenerative dementia after Alzheimer’s disease. Whether DLB and PDD are the same or different disorders is uncertain.65 Clinically, the central feature required for a diagnosis of DLB is progressive cognitive decline, severe enough to cause social and occupational functional impairment. Core features of DLB are fluctuating cognition, recurrent and persistent visual hallucinations, and extrapyramidal motor symptoms. Supportive features may increase diagnostic sensitivity. They include repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, systematized delusions, and hallucinations in other modalities. The two main differential diagnoses are Alzheimer’s disease and PDD. In order to improve the differential diagnosis of DLB, consensus criteria that establish possible and probable levels of diagnostic accuracy have been developed.12,66 In general, their sensitivity is variable and low, but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. With the use of operationally defined criteria, DLB can be clinically diagnosed with an accuracy similar to that achieved for Alzheimer’s disease or Parkinson’s disease. Autonomic failure is frequent in DLB. A retrospective analysis of autonomic symptoms in neuropathologically diagnosed DLB showed that 62% of affected patients had significant autonomic failure.67 Patients with DLB may suffer vocal cord palsy, which results in sudden death. However, autonomic function has not been well documented in patients with DLB. Some of the supportive features, including repeated falls, syncope, and transient loss of consciousness, can be attributed in part to autonomic nervous system abnormalities. Orthostasis, either asymptomatic or associated with syncope, may be observed in these patients, although symptomatic orthostatic hypotension has been found in a lower frequency (15%) than in other types of parkinsonism.60 Mean age at onset is 75 years; the age range is 50 to 80 years, with a slight male predominance.68 Although dementia is the
377
most frequent presenting feature, psychiatric symptoms or transient alterations of consciousness are other early features. Indeed, affected patients may present with recurrent visual hallucinations even without exposure to dopaminergic antiparkinsonian agents and may have marked diurnal fluctuations in cognitive performance, which have been the most difficult feature of the disease to define but are often conspicuous in the environment. Although parkinsonism is common in DLB, occurring at some point during the course of the illness in 75% to 80% of cases,69,70 a minority of patients present with parkinsonism alone. In general, autonomic features occur later in the course of the disease, but some cases have been described in which dysautonomia was the initial and prominent feature, leading to an initial misdiagnosis of MSA.71 Fluctuating cognition, probably related to fluctuations in attention, is characteristic of DLB, occurring in 58% of cases at the time of presentation and observed during the disease course in 75%.72 The natural history of the neuropsychological changes in DLB is not well characterized, although differences with Alzheimer’s disease appear particularly pronounced in the early stages and lessen as the disease progresses. A rapidly progressive dementia, accompanied by aphasia, dyspraxia, and spatial disorientation suggestive of temporoparietal dysfunction can be seen as the disease progresses. Disability in DLB progresses at a rate similar to that in Parkinson’s disease (approximately 10% decline per year) or even at a significantly faster rate. The latency to onset of orthostatic hypotension in a postmortem series of the National Institute of Neurologic Disorders and Stroke were short in MSA patients, intermediate in patients with DLB, corticobasal degeneration, and progressive supranuclear palsy (PSP) and long in those with Parkinson’s disease.60 These data underpin the rapidly progressive nature of the disease process in DLB in comparison with that of Parkinson’s disease. As a result, mean length of survival in a series of patients with DLB confirmed with post mortem examination has been less than 10 years. It is similar to that for Alzheimer’s disease, although some patients with DLB show rapid symptom progression and die within 1 to 2 years of onset. Risk factors for increased mortality in DLB that are present at disease onset include older age, dementia, fluctuating cognition, and hallucinations.73 Strikingly, patients with DLB with neuroleptic sensitivity reactions show a twofold to threefold increase in mortality.
Multiple-System Atrophy This disease affects both men and women, usually starts in the sixth decade, and progresses relentlessly, with a mean survival length of 6 to 9 years.74-77 There is considerable variation in disease progression, with survival lengths of more than 15 years in some instances. Clinically, cardinal features include autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in various combinations. Previous studies suggest that 29% to 33% of patients with isolated late-onset cerebellar ataxia and 8% of patients with parkinsonism eventually develop MSA.78-80 Of importance, both motor presentations of MSA are associated with similar survival times.76 However, patients with MSA-P have a more rapid functional deterioration than do patients with MSA-C.74 MSA-P associated parkinsonism is characterized by progressive akinesia and rigidity. Jerky postural tremor and, less
378
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
commonly, tremor at rest may be superimposed. Frequently, patients exhibit orofacial or craniocervical dystonia in association with a characteristic quivering, high-pitched dysarthria. Postural stability is compromised early on; however, recurrent falls at disease onset are unusual, in contrast to PSP. Differentiating between MSA-P and Parkinson’s disease may be exceedingly difficult in the early stages because of a number of overlapping features such as rest tremor or asymmetrical akinesia and rigidity. Furthermore, L-dopa–induced improvement of parkinsonism may be seen in 30% of MSA-P patients. However, the benefit is transient in most of these subjects, leaving 90% of the MSA-P patients unresponsive to L-dopa in the long term. L-Dopa–induced dyskinesias affecting orofacial and neck muscles occur in 50% of MSA-P patients, sometimes in the absence of motor benefit.81 In most instances, a fully developed clinical picture of MSA-P evolves within 5 years of disease onset, allowing a clinical diagnosis during follow-up.82 The cerebellar disorder of MSA-C comprises gait ataxia, limb kinetic ataxia, and scanning dysarthria, as well as cerebellar oculomotor disturbances. Patients with MSA-C usually develop additional noncerebellar symptoms and signs but, before doing so, may be indistinguishable from other patients with idiopathic late-onset cerebellar ataxia, many of whom have a disease restricted clinically to cerebellar signs and pathologically to degeneration of the cerebellum and olives.78 Dysautonomia is characteristic of both MSA motor presentations, comprising primarily urogenital and orthostatic dysfunction. During the early stages of MSA, autonomic deficits may be the sole clinical manifestation, thus resembling PAF, but after a variable period of time (sometimes 2 or 3 years, always less than 5), extrapyramidal or cerebellar deficits or both invariably develop. Early impotence (erectile dysfunction) is virtually universal in men with MSA, and urinary incontinence or retention, often early in the course or as presenting symptoms, are frequent.77 Disorders of micturition in MSA are caused by changes in the complex peripheral and central innervation of the bladder83 and generally occur more commonly, earlier, and to a more severe degree than in Parkinson’s disease. In fact, patients with MSA have early dysuria with or without chronic retention, frequently associated with a hypoactive detrusor muscle and low urethral pressure. In contrast, patients with Parkinson’s disease have urgency to void, with or without difficulty, but without chronic retention, in association with detrusor hyperreflexia and normal urethral sphincter function. Constipation occurs in equal percentages of patients in Parkinson’s disease and MSA. Symptomatic orthostatic hypotension is present in 68% of patients with clinical diagnoses of MSA, but recurrent syncope emerges in only 15%.77 LDopa or dopamine agonists may provoke or worsen orthostatic hypotension.
LABORATORY ASSESSMENTS In addition to the clinical presentation, several laboratory investigations have been used to distinguish among Parkinson’s disease, PAF, and MSA (Table 30–2). Basically, most of these tests exploit the anatomopathological distinction between Lewy body syndromes, which affect postganglionic autonomic neurons, and MSA, which affects preganglionic, central autonomic neurons.
Cardiovascular Function Testing A history of postural faintness or other evidence of orthostatic hypotension, such as neck ache on rising in the morning or posturally related changes of visual perception, should be sought in all patients in whom MSA is suspected. After a comprehensive history is documented, cardiovascular function should be tested according to consensus recommendations.47,84 A drop in systolic blood pressure of 20 mm Hg or more or in diastolic blood pressure of 10 mm Hg or more, in comparison with baseline within a standing time of 3 minutes, is defined as orthostatic hypotension and must lead to more specific assessment. This is based on continuous noninvasive measurements of blood pressure and heart rate during tilt-table testing.85-87 Although abnormal cardiovascular test results may provide evidence of sympathetic and/or parasympathetic failure, they do not differentiate autonomic failure associated with Parkinson’s disease from that associated with MSA.88 The autonomic abnormality of MSA can be distinguished biochemically from that of PAF. In MSA, during supine rest, norepinephrine (noradrenaline) levels (representing postganglionic sympathetic efferent activity) are normal,89,90 and there is no denervation hypersensitivity, which indicates a lack of increased expression of adrenergic receptors on peripheral neurons.90 In contrast to this normal or only slightly decreased plasma norepinephrine level during recumbency in MSA and varying levels in patients with Parkinson’s disease, patients with PAF have very low plasma norepinephrine levels when recumbent.90,91 On standing or tilt-table testing, patients with PAF, those with MSA, and some with Parkinson’s disease with autonomic failure do not have the expected increase in plasma norepinephrine levels, which indicates an inability to normally stimulate the release of catecholamines by baroreflex activation in all these disorders. When norepinephrine is infused into patients with PAF, there is an exaggerated increase in blood pressure. This reflects an excessive sensitivity of postsynaptic α-adrenergic receptors to exogenous catecholamines. In contrast, patients with MSA and Parkinson’s disease show only a mildly increased blood pressure response to infused norepinephrine, without leftward shift in the dose-response curve.92 Similarly, there is a greater degree of β-adrenergic receptor supersensitivity in PAF than in MSA, as shown by Baser and associates93 in a study with intravenous isoproterenol. Sympathetic cardiac innervation is selectively affected in Parkinson’s disease and PAF but is intact in MSA. Imaging studies that measure catecholamine uptake by cardiac sympathetic neurons have confirmed that peripheral sympathetic nerves are preserved in MSA but greatly reduced in PAF.94 Visualization of sympathetic cardiac neurons through scintigraphy with norepinephrine analogue iodine 123–meta-iodobenzylguanidine ([123I]MIBG) has revealed loss of binding in patients with Parkinson’s disease, regardless of disease severity, which reflects postganglionic sympathetic denervation; in comparison, cardiac binding is preserved in MSA95-100 and PSP.101 Pooled data from several studies showed that MIBG scintigraphy occurately discriminated a total of 246 cases of Parkinson’s disease from 45 of MSA with high sensitivity (90%) and specificity (95%).96 Similarly, (18F) fluorodopamine positron emission tomography (PET) is able to demonstrate cardiac sympathetic denervation in PAF and Parkinson’s disease in contrast with intact cardiac sympathetic innervation in MSA.94 6-[18F] Fluorodopamine is a catecholamine taken up by sympathetic post-
chapter 30 primary autonomic failure T A B L E 3 0 – 2. Examined Body Domain/Function Cardiovascular Physiological
Biochemical Pharmacological
Imaging Brain Imaging CSF studies Endocrine Sudomotor Gastrointestinal Renal function and urinary tract Sexual Respiratory Eye and lacrimal glands
379
Laboratory Investigations in Primary Autonomic Failure Parameters/Techniques Head-up tilt (60 degrees); standing; Valsalva maneuver Pressor stimuli (isometric exercise, cutaneous cold, mental arithmetic) Heart rate responses-deep breathing, hyperventilation, standing, head-up tilt, 30 : 15 R-R interval ratio Liquid meal challenge Modified exercise testing Carotid sinus massage Plasma noradrenaline: supine and head-up tilt or standing; urinary catecholamines; plasma renin activity, and aldosterone Noradrenaline: α-adrenoceptors, vascular Isoprenaline: β-adrenoceptors, vascular and cardiac Tyramine: pressor and noradrenaline responses Edrophonium: noradrenaline response Atropine: parasympathetic cardiac blockade Cardiac [123I]MIBG SPECT, 6-[18F] fluorodopamine PET MRI (1.5 Tesla), diffusion-weighted imaging, voxel-based morphometry, [(123)I]β-CIT, [123I]iodobenzamide SPECT, 18Ffluorodopa PET, [11C]diprenorphine PET, 18F-fluorodeoxyglucose PET, 99mTc-hexamethylpropyleneamine oxime, [123I]FPCIT Neurofilament protein levels Clonidine–α2-adrenoceptor agonist: noradrenaline suppression; growth hormone stimulation Thermoregulatory sweat test Sweat gland response to intradermal acetylcholine, QSART, localized sweat test Sympathetic skin response External anal sphincter EMG, video-cinefluoroscopy, barium studies, endoscopy, gastric emptying studies, transit time, lower gut studies Day and night urine volumes and sodium/potassium excretion measurements Urodynamic studies, intravenous urography, ultrasonographic examination, sphincter electromyography Penile plethysmography Intracavernosal papaverine Laryngoscopy Sleep studies to assess apnea and oxygen desaturation Pupillary function, pharmacological and physiological Schirmer’s test
Modified from Mathias CJ: Autonomic diseases: clinical features and laboratory evaluation. J Neurol Neurosurg Psychiatry 2003; 74(Suppl 3):iii31-iii41. 11 C, carbon 11; β-CIT, 2β-carboxymethoxy-3β-(4-iodophenyl)tropane; CSF, cerebrospinal fluid; EMG, electromyography; 18F, fluorine 18; 123I, iodine 123; FP-CIT, 2βcarbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane; MIBG, meta-iodobenzylguanedine; MRI, magnetic resonance imaging; PET, positron emission tomography; QSART, quantitative sudomotor axon reflex test; SPECT, single photon emission computed tomography.
ganglionic neurons and handled similarly to norepinephrine. Together, these types of imaging of sympathetic cardiac neurons may turn out to be useful diagnostic tests to distinguish between Parkinson’s disease and MSA because sympathetic innervation of the heart is impaired in Parkinson’s disease and not in MSA. Moreover, in a patient with apparent PAF, finding normal sympathetic cardiac innervation should indicate a likely development of MSA.4 A caveat of this approach to be kept in mind is that published studies have compared patients with established diagnoses of MSA and PAF and, therefore, probably in later disease stages. It is not known whether these differences are apparent in patients during earlier stages of the disorder, when a diagnostic method would be more useful in the workup of patients in clinical practice.92 DLB affects peripheral postganglionic autonomic neurons (as with the other Lewy body syndromes). Actually, neuropathological studies on DLB associated with severe autonomic failure demonstrated—besides numerous Lewy bodies in the cortex and brainstem—sparse Lewy bodies in the intermediolateral columns of the spinal cord, as well as numerous Lewy bodies in autonomic ganglia and sympathetic neurons.71 These results suggests that, as in Parkinson’s disease,102 autonomic
dysfunction in DLB is, at least in part, caused by degeneration of peripheral autonomic neurons. This is supported by single photon emission computed tomography (SPECT) imaging of postganglionic sympathetic cardiac innervation with 123I-MIBG, which showed that postganglionic sympathetic neurons were nonfunctional.54 Indeed, 123I-MIBG SPECT has been shown to discriminate DLB from Alzheimer’s disease with severe denervation in the former and preserved sympathetic MIBG binding in the latter disorder.103-105
Bladder Function Testing Assessment of bladder function is a mandatory part of the diagnostic workup of parkinsonian patients and usually provides evidence of involvement of the autonomic nervous system already at an early stage of the disease (when bladder function is still normal in most patients with Parkinson’s disease). Urinary symptoms and studies of bladder function may help to distinguish between MSA-P and Parkinson’s disease. After documentation of a careful history regarding frequency of voiding, difficulties in initiating or suppressing voiding, and the
380
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
presence of urinary incontinence, a standard urine analysis should be performed to rule out an infection. Postvoid residual volume needs to be determined sonographically or through catheterization to initiate intermittent self-catheterization in due course. In some patients, only cystometry can discriminate between hypocontractile detrusor function and hyperreflexic sphincter-detrusor dyssynergy. The nature of bladder dysfunction is different in MSA and Parkinson’s disease. Although frequency and urgency are common in both disorders, marked urge or stress incontinence with continuous leakage is not a feature of Parkinson’s disease, apart from very advanced cases. Urodynamic studies show a characteristic pattern of abnormality in patients with MSA.106 In the early stages, there is often detrusor hyperreflexia, often with bladder neck incompetence caused by abnormal urethral sphincter function, which results in early frequency and urgency, followed by urge incontinence. Later on, the ability to initiate a voluntary micturition reflex and the strength of the hyperreflexic detrusor contractions diminish, and the bladder may become atonic, which accounts for increasing postmicturition residual urine volumes.
Sphincter Electromyography As a matter of fact, the striated muscle of the external anal and urethral sphincter is innervated by fibers that originate in Onuf’s nucleus (see “Neuropathology” section). This nucleus is particularly vulnerable in MSA but not in Parkinson’s disease.54 Involvement of Onuf’s nucleus is much more frequent than that of anterior horn cells in the rest of the spinal cord in MSA, although there may be some depletion of anterior horn cells.39 Interestingly, the reverse occurs in patients with amyotrophic lateral sclerosis, in whom Onuf’s nucleus is selectively spared. On electromyography (EMG) of the anal and urethral sphincter muscle, neuronal loss in Onuf’s nucleus is reflected by signs of denervation and chronic reinnervation. An abnormal finding on sphincter EMG may be found in many patients with clinically definitive MSA, including those who as yet have no urological or anorectal problems. In at least 80% of patients with MSA, EMG of the external anal sphincter reveals signs of neuronal degeneration in Onuf’s nucleus with spontaneous activity and increased polyphasia.83,107,108 Schwarz and colleagues109 suggested that abnormal spontaneous activity on sphincter EMG, although difficult to detect, may be the most useful criterion for distinguishing between Parkinson’s disease and MSA. However, the prevalence of abnormalities in early stages of MSA remains unclear. These findings do not reliably differentiate between MSA and other forms of atypical parkinsonian disorders such as PSP.110 Furthermore, neurogenic changes of external anal sphincter muscle have also been demonstrated in advanced stages of Parkinson’s disease.111 Chronic constipation, previous pelvic surgery, or vaginal deliveries can also be confounding factors that induce nonspecific abnormalities.112 However, abnormalities on anal sphincter EMG appear to distinguish MSA from Parkinson’s disease in the first 5 years after disease onset and from PAF, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out.113
Neuroendocrine Testing In vivo studies in MSA, which involved testing of the endocrine component of the central autonomic nervous systems (the
hypothalamopituitary axis) with a variety of challenge procedures, provided evidence of impaired humoral responses of the anterior and the posterior parts of the pituitary gland with impaired secretion of adrenocorticotropic hormone,114 growth hormone,115 and vasopressin/antidiuretic hormone.34 Although these observations can be made in virtually all patients in an advanced stage of the disease, their prevalence during the early course of MSA is unknown. PAF selectively affects the efferent, mainly postganglionic autonomic neurons. Afferent pathways are not involved. Baroreceptor-mediated vasopressin release—a measurement of afferent baroreceptor function—is normal in patients with PAF, and presumably in those with Parkinson’s disease, but is blunted in patients suffering from MSA.34 Intravenous clonidine also tests the function of hypothalamic-pituitary pathways.92 Clonidine is a centrally active α2-adrenoceptor agonist that stimulates growth hormone secretion and lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. There is an ongoing debate about the diagnostic value of the growth-hormone response to clonidine, a neuropharmacological assessment of central adrenoceptor function, in Parkinson’s disease and MSA. In an early study, there was no increase in growth hormone levels after clonidine administration in patients with MSA in comparison with those with Parkinson’s disease or PAF.116 Kimber and colleagues115 confirmed a normal increase in serum growth hormone in response to clonidine in 14 patients with Parkinson’s disease (without autonomic failure) and in 19 patients with PAF, whereas there was no growth hormone rise in 31 patients with MSA. However, these findings were challenged subsequently.117-119 After clonidine administration, growth hormone rose in patients with PSP and controls, but not in patients with MSA.120 In patients with PSP, responses to both physiological and pharmacological tests provided evidence against widespread autonomic dysfunction; this differed markedly from patients with MSA. Stimulation of growth hormone release with growth hormone–releasing hormone plus arginine rather than clonidine may differentiate MSA from idiopathic Parkinson’s disease and idiopathic late-onset cerebellar ataxia,121 but this hypothesis would need to be confirmed by further investigations. In normal humans, clonidine reduces arginine-vasopressin secretion, probably by presynaptic inhibition of noradrenergic neuron terminals in the supraoptic nucleus. A lesion of noradrenergic pathways in animals abolishes this response to clonidine. Postmortem study in MSA reveals marked loss of hypothalamic noradrenergic innervation. After clonidine administration, there was a significantly greater fall of arginine-vasopressin levels in controls than in patients with MSA, which suggests that there is an abnormal arginine-vasopressin response to clonidine in MSA, which probably represents loss of functional noradrenergic innervation of the supraoptic nucleus.122 More studies in well-defined patient cohorts are needed before clonidine challenge tests can be recommended as helpful diagnostic tests in patients with suspected MSA. Neuroendocrine responses to hypotension or centrally acting adrenergic agonists are blunted in MSA but are preserved in Parkinson’s disease and PAF, inasmuch as brainstemhypothalamic-pituitary pathways are affected only in MSA.92 Hypothalamic dopaminergic pathways are involved in the regulation of growth hormone and prolactin release from the anterior pituitary. Neuroendocrine studies in patients with MSA, in whom there is a reported loss of hypothalamic
chapter 30 primary autonomic failure dopamine, are few and contradictory. In patients with MSA, the growth hormone–releasing hormone and growth hormone responses to L-dopa were preserved and were similar to responses in age-matched control subjects in a study by Kimber and colleagues.123 In contrast, there was impaired dopaminergic suppression of prolactin secretion. In patients with MSA, this may represent a selective dysfunction, rather than generalized loss, of tuberoinfundibular dopaminergic neurons. Besides orthostatic hypotension, supine hypertension, paradoxically, is present in about one half of patients with MSA or PAF.124 However, the mechanisms of supine hypertension differ between MSA and PAF. Eliminating residual sympathetic tone with the ganglionic blocker trimethaphan completely abolished hypertension in patients with MSA but not in those with PAF.125 Therefore, hypertension in MSA can be totally explained by the residual sympathetic tone unopposed by the absence of baroreflex mechanisms. However, patients with MSA are not able to engage and modulate sympathetic tone during upright posture. Therefore, they are suffering from orthostatic hypotension despite their supine hypertension. In patients with PAF, the cause of supine hypertension is not yet resolved.54
Brain Imaging Magnetic resonance imaging (MRI) of the brain and PET of the brain and heart (see previous discussion) may be helpful in the differential diagnosis of a patient with parkinsonism and autonomic failure, distinguishing among PAF, MSA, and Parkinson’s disease. In patients with PAF, MRI results of the brain are normal.92 In Parkinson’s disease, brain MRI reveals only mild putaminal abnormalities with few brainstem or cerebellar changes. In contrast, in patients with MSA, brain MRI shows severe putaminal abnormalities, frequently accompanied by brainstem and cerebellar changes. However, MRI abnormalities in MSA frequently occur late in the time course of the disorder, and the abnormalities reviewed in the following sections have been observed in patients with advanced rather than early disease. In these early disease stages, MRI is not very sensitive but has good specificity. The diagnosis of MSA still rests on the clinical history and findings of the neurological examination. According to the Consensus Conference on the Diagnosis of MSA,23 additional investigations such as neuroimaging (and autonomic function tests or sphincter EMG, described previously) may be used to support the diagnosis or to exclude other conditions. Therefore, the Consensus Conference considered it premature to incorporate the results of laboratory investigations into the diagnostic guidelines that were established.
Structural Imaging Routine 1.5-T MRI, including diffusion-weighted imaging, should be performed in all patients with suspected MSA, because basal ganglia and/or brainstem abnormalities suggestive of MSA may be observed even during early disease stages. These changes include an OPCA-like atrophy pattern indistinguishable from autosomal dominant cerebellar ataxia.126 MRI measures of basal ganglia pathology in MSA are less well established, and naked eye assessments are often unreliable. In advanced cases, putaminal atrophy may be detectable, and its extent may be correlated with severity of extrapyramidal symptoms.
381
Abnormalities on MRI may include not only OPCA126 or putaminal atrophy127 but also signal abnormalities on T2-weighted images. Signal hyperintensities within the pons and middle cerebellar peduncles are believed to reflect degeneration of pontocerebellar fibers; these changes occasionally produce an appearance resembling a hot cross bun.127 Nonspecific putaminal hypointensities in patients with atypical parkinsonism, including MSA, were first reported in 1986 by two groups who used 1.5-T T2-weighted images.128,129 This change has subsequently been confirmed by other authors in cases of pathologically proved MSA.130-132 Similar MRI abnormalities may occur in patients with classic Parkinson’s disease.133 However, Kraft and colleagues demonstrated that hypointense putaminal signal changes were more frequent in MSA than in Parkinson’s disease, by using T2*-weighted gradient echo instead of T2-weighted fast-spin echo images; this indicates that T2*-weighted gradient echo sequences are of better diagnostic value for patients with parkinsonism.134 Increased putaminal hypointensities may be associated with a slitlike hyperintense band lateral to the putamen.134,135 This finding appears to be more specific for MSA than is putaminal hypointensity127,136; however, further studies in larger cohorts of patients are needed to confirm this. The hyperintense slit signal was correlated with reactive microgliosis and astrogliosis in a case of pathologically proved MSA.132 Diffusion-weighted imaging may represent a useful diagnostic tool that can provide additional support for a diagnosis of MSA-P. Diffusion-weighted imaging is able to discriminate patients with MSA-P from both patients with Parkinson’s disease and healthy volunteers on the basis of putaminal regional apparent diffusion coefficients (rADC) values.137 The increased putaminal rADC values in MSA-P probably reflect ongoing striatal degeneration, whereas most neuropathological studies reveal intact striatum in Parkinson’s disease. However, because rADCs were also significantly increased in both putamen and globus pallidus in PSP in comparison with Parkinson’s disease,138 increased putaminal rADC values do not discriminate MSA-P from PSP. Schulz and associates139 found significant reductions in mean striatal and brainstem volumes in patients with MSA-P, MSA-C, and PSP, whereas patients with MSA-C and MSA-P also showed a reduction in cerebellar volume. More recently, voxel-based morphometry confirmed previous region of interest–based volumetric studies139 showing basal ganglia and infratentorial volume loss in MSA-P patients.140 These data also revealed prominent cortical volume loss in MSA-P, comprising mainly the cortical targets of striatal projections such as the primary sensorimotor cortices, lateral premotor cortices, and the prefrontal cortex. MRI-based volumetry is a helpful tool to investigate the progression of cortical and subcortical atrophy patterns in MSA in comparison with other disorders; however, it cannot be applied for routine diagnostic workups of individual patients. Structural brain imaging with MRI reveals a relative preservation of the medial temporal lobes and the hippocampus in 40% of patients with DLB, in contrast to Alzheimer’s disease.141 There is no difference from Alzheimer’s disease in terms of degree of ventricular enlargement or presence of white matter changes on MRI.142 MRI shows atrophy of the putamen in DLB but not in Alzheimer’s disease.143 Additional features such as generalized atrophy141 and rates of progression of whole-brain atrophy144 are not helpful in differential diagnosis. In volumetric studies, frontal brain atrophy was described in DLB patients,
382
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
which was correlated with increasing Lewy body densities.145 Voxel-based morphometry of gray matter revealed significant atrophy of the basal forebrain in DLB, which discriminates it from Alzheimer’s disease.146
Functional Imaging Functional imaging methods for the differential diagnosis of parkinsonian disorders can be divided into investigations of receptor binding and the investigation of glucose metabolism. In studies of receptor binding in disorders with parkinsonism, investigators examine the presynaptic nigrostriatal neurons by evaluating the dihydroxyphenylalanine decarboxylase activity and the dopamine transporter, and they examine postsynaptic dopaminergic function by evaluating the dopamine D2 receptor. Scintigraphic studies focus on the cardiac sympathetic innervation and are discussed previously. Despite the lack of comparative studies, iodobenzamide (IBZM) and MIBG SPECT, as well as fluorodeoxyglucose PET (when available), appear to be helpful functional imaging tools that may support an early clinical diagnosis of MSA. PET imaging in MSA reveals a generalized reduction in glucose utilization rate, which indicates hypometabolism, most prominently in the cerebellum, brainstem, striatum, and frontal and motor cortices. In contrast, none of these findings was present in PAF.92 In fact, the Hammersmith Cyclotron Unit, using PET, found that putaminal uptake of the presynaptic dopaminergic markers [18F]fluorodopa and S-[11C]nomifensine147,148 was similarly reduced in MSA and Parkinson’s disease; in approximately one half the patients with MSA, caudate uptake was also markedly reduced, as opposed to only moderate reduction in Parkinson’s disease. However, discriminant function analysis of striatal [18F]fluorodopa uptake distinguished patients with MSA from those with Parkinson’s disease poorly.149 Measurements of striatal dopamine D2 receptor densities with raclopride and PET failed to differentiate between Parkinson’s disease and atypical parkinsonian disorders, demonstrating a similar loss of densities in patients with advanced Parkinson’s disease, MSA, and PSP.150 PET studies with other ligands such as [11C]diprenorphine (nonselective opioid receptor antagonist)151 and [18F]fluorodeoxyglucose152-154 have proved more consistent in detecting striatal degeneration and in distinguishing patients with MSA-P from those with Parkinson’s disease, particularly when combined with a dopamine D2 receptor scan.155 Widespread functional abnormalities in MSA-C have been demonstrated through [18F]fluorodeoxyglucose and PET.156 Reduced metabolism was most marked in the brainstem and cerebellum, but other areas such as the basal ganglia and cerebral cortex were also involved, which is evidence of its nosological status as the cerebellar subtype of MSA. Furthermore, assessing nigrostriatal dopaminergic function with 18F-fluorodopa PET may be a useful diagnostic aid in cases of DLB, inasmuch as there is a pronounced reduction of striatal dopamine uptake.157 PET examination of the cerebral glucose metabolism with 18F-fluorodeoxyglucose demonstrated that among widespread cortical regions showing glucose hypometabolism in patients with DLB, the metabolic reduction was most pronounced in the visual association cortex, in comparison with that in patients with Alzheimer’s disease.158 Therefore, among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the
occipital cortex may be an informative diagnostic aid to distinguish DLB from Alzheimer’s disease.158,159 SPECT evaluation of the dopamine transporter with 2β-carboxymethoxy-3β-(4-iodophenyl)tropane ([123I]β-CIT) reflects the disruption of the nigrostriatal pathway, and therefore MSA and PSP cannot be distinguished from Parkinson’s disease with this method alone.160 However, dopamine transporter SPECT may be useful in differentiating parkinsonism from controls.161 In another SPECT study, striatal [123I]β-CIT uptake was markedly reduced in both the patients with Parkinson’s disease and those with MSA,162 but patients with MSA showed a more symmetrical dopamine transporter loss, consistent with the more symmetrical clinical motor dysfunction observed in this condition. SPECT studies using [123I]IBZM as D2 receptor ligand have revealed significant reductions of striatal IBZM binding in subjects with clinically probable MSA in comparison with patients with Parkinson’s disease or controls.163-165 However, striatal IBZM binding is also reduced in other atypical parkinsonian disorders such as PSP,164 which limits its predictive value for an early diagnosis of MSA. IBZM SPECT imaging in patients with early parkinsonism seems to distinguish between L-dopa–responsive and Ldopa–unresponsive parkinsonism in patients not previously treated with dopaminergic drugs.166 A good response to apomorphine challenge and subsequent benefit from chronic dopaminergic therapy was observed in subjects with normal IBZM binding, whereas subjects with reduced binding failed to respond. Some of these patients developed other atypical clinical features suggestive of MSA during follow-up.167 Functional neuroimaging with technetium 99m–hexamethylpropyleneamine oxime and SPECT reveals occipital hypoperfusion in DLB, differentiating it from Alzheimer’s disease.168,169 In DLB, as well as in PDD, bilateral temporal and parietal perfusion deficits have been reported. Dopamine transporter loss in the caudate and putamen, a marker of nigrostriatal degeneration, can be detected by dopaminergic SPECT.170 [123I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT) and SPECT reveal significant reduction in striatal uptake of a ligand for the presynaptic dopamine transporter site (FP-CIT) in DLB but not in Alzheimer’s disease, and this may prove to be a highly specific and widely applicable diagnostic test.171,172
THERAPY The complex manifestations of primary autonomic failure syndromes generate multiple therapeutic needs, many of which are still unmet. Unfortunately, there are no causal therapies available. Therefore, the therapeutic strategies are defined by clinical symptoms and impairment of health-related quality of life in these patients.
Acute/Subacute Primary Autonomic Failure Patient education is an important aspect of treatment. Sympathomimetic drugs and 9-α-fluorohydrocortisone have been of value in treating postural hypotension in cases of pandysautonomia. Correcting anemia improves orthostatic tolerance, if necessary by hemopoietin. Because the underlying mechanism is likely to be immune mediated, plasma exchange or other
chapter 30 primary autonomic failure immunosuppressive modalities as early therapeutic intervention in patients with progressive disability may be justified. In fact, corticosteroids are frequently used, and plasmapheresis and intravenous immunoglobulin may be effective.173-175 Carbachol may be helpful for the management of urinary retention and impaired gastrointestinal motility associated with acute cholinergic neuropathy.
Chronic Primary Autonomic Failure Because of the chronic or progressive course of primary autonomic failure syndromes, a regular review of treatment is mandatory to adjust measures according to clinical needs. Guidelines for the practical management of chronic PAF syndromes are shown in Table 30–3.
Motor Disorder Treatment of the motor abnormalities is fairly successful in Parkinson’s disease but remains dismal in MSA patients. These patients often do not respond to antiparkinsonian medications and fail to benefit from current surgical treatments for Parkinson’s disease. Although less effective than in Parkinson’s disease, L-dopa replacement represents the mainstay of antiparkinsonian therapy in MSA. However, a sufficiently powered double-blind controlled trial has never been performed. Results of open-label studies suggest that, in contrast to patients with Parkinson’s disease, most patients with MSA fail to benefit from treatment with L-dopa in the long run, although a transient response may occur in some cases. However, the assumption that patients with MSA are generally not responsive or poorly responsive to L-dopa is certainly misleading. L-Dopa responsiveness should be tested by administering escalating doses (with a peripheral decarboxylase inhibitor) over a 3-month period up to at least 1000 mg per day (if necessary and if tolerated).23 Reports of open-label L-dopa therapy in MSA have documented L-dopa efficacy in up to 80% of patients with clinical diagnoses.75,77,81,176-184 Data obtained from series with pathological confirmation are more variable, with rates of beneficial L-dopa response ranging between 30% and 70%.32,77,179,185-188 On occasion, a beneficial effect is evident only when seemingly unresponsive patients deteriorate after Ldopa withdrawal.179 Whatever response there is usually declines after a few years of treatment.189 The effectiveness of L-dopa on motor symptoms in DLB has not been established but is probably less than in uncomplicated Parkinson’s disease, possibly because there is additional intrinsic striatal pathology and dysfunction.190 But, although this limited L-dopa responsiveness has generally been reported in DLB, it may reflect either a failure to treat or underdosing, because of concerns about exacerbating psychotic symptoms. In fact, there are reports showing that 70% to 100% of patients with DLB do have a good response.191-193 In comparison with Parkinson’s disease, Ldopa–related motor complications appear to be less common in DLB. L-Dopa is the preferred antiparkinsonian drug in DLB because dopamine agonists may increase the occurrence of hallucinations.194 Reviews of the therapeutic values of both dopaminergic and nondopaminergic drugs for the management of the motor disorder in Parkinson’s disease, MSA, and DLB are covered in more detail elsewhere.195-198
383
Orthostatic Hypotension The concept to treat symptoms of orthostatic hypotension is based on the increase of intravasal volume and the reduction of volume shift to lower body parts when a patient changes to an upright position. The selection and combination of the following options, including both nonpharmacological and pharmacological measures, depend on the severity of symptoms and their practicability in the single patient, but not on the extent of blood pressure drop during the tilt-table test. Nonpharmacological options include sufficient fluid intake, high-salt diet, more frequent but smaller meals per day to reduce postprandial hypotension by spreading the total carbohydrate intake, and as the ultima ratio custom-made elastic body garments. During the night, head-up tilt increases intravasal volume up to 1 L within a week, which is particularly helpful in improving hypotension early in the morning. This is achieved by an increased secretion of renin as a result of reduced renal perfusion pressure and by reduced atrial natriuretic hormone levels because of lower atrial filling pressure. This approach is successful, particularly in combination with the mineralocorticoid fludrocortisone, which further supports sodium retention. Indeed, medical treatment begins with attempting to increase blood volume by increasing sodium intake unless the patient is at risk for congestive heart failure or has renal insufficiency. The next group of drugs to use is the sympathomimetics. They include ephedrine (with both direct and indirect effects), which is often valuable in central autonomic failure as occurs in MSA. In fact, ephedrine can be helpful through its peripheral vasoconstrictor effects. With high doses, side effects include tremulousness, loss of appetite, and in men, urinary retention. Orthostatic hypotension is often successfully treated with midodrine,199-202 an adrenergic agonist activating α1 receptors on arterioles and veins. Midodrine increases peripheral resistance, thereby significantly reducing orthostatic hypotension. Side effects are usually mild and only rarely lead to discontinuation of treatment because of urinary retention or pruritus predominantly on the scalp. Furthermore, L-threo-3,4-dihydroxyphenyl serine has been used with some success in short clinical trials.203 It represents a precursor of norepinephrine and has been used for this indication in Japan for years. Mathias and associates showed its efficacy in an open-label, dose-finding trial in patients with MSA and PAF.204 If the above drugs do not produce the desired effect, then selective targeting is needed. The somatostatin analogue octreotide is often beneficial in postprandial hypotension,205 presumably because it inhibits release of vasodilatory gastrointestinal peptides;206 of importance, it does not enhance nocturnal hypertension.205 The vasopressin analogue desmopressin, which acts on renal tubular vasopressin-2 receptors, reduces nocturnal polyuria and improves morning postural hypotension.207 Recombinant erythropoietin, used to reverse the anemia common in MSA, increases upright blood pressure and ameliorates symptoms of orthostatic hypotension208-211 by secondarily improving cerebral oxygenation.209,211,212
Supine Hypertension In more than one half of patients with PAF or MSA, supine hypertension is present, complicating their management. Actually, the treatment of patients with primary autonomic failure is aimed primarily at improving orthostatic hypotension, and
384
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
T A B L E 3 0 – 3.
Practical Management of Chronic Primary Autonomic Failure Syndromes
Feature
Pharmacological Measures
Nonpharmacological Measures
Orthostatic hypotension
Starter drug Fludrocortisone (0.1-0.3-0.4 mg/day) Sympathomimetics Ephedrine (15-45 mg t.i.d.) Midodrine (2.5-10 mg t.i.d.) L-Threo-DOPS (300 mg b.i.d.) Specific targeting For postprandial hypotension: Octreotide (25-50 μg subcutaneously, 30 min before a meal) For nocturnal polyuria: Desmopressin (spray: 10-40 μg/night or tablet: 100-400-600 μg/night) Increasing red cell mass: Erythropoietin (25-50 U/kg body weight subcutaneously three times a week) In individual cases Vasoconstriction: Phenylephrine, noradrenaline, clonidine, tyramine with monoamine oxidase inhibitors, yohimbine, dihydroergotamine, terlipressin Preventing vasodilatation: Indomethacin (cave: gastric ulceration and hemorrhage), flurbiprofen, metoclopramide, domperidone, propanolol, caffeine Increasing cardiac output: Pindolol (cave: cardiac failure), xamoterol, ibopamine Nitroglycerin (transdermal, 0.1-0.2 mg/hour) Short-acting calcium antagonists (e.g., nifedipine, 30 mg) Hydralazine (50-100 mg) For urinary incontinence Oxybutynin for detrusor hyperreflexia (2.5-5 mg b.i.d-t.i.d., or 5 to 10 mg at bedtime) Trospium chloride (15-20 mg b.i.d.-t.i.d.) Tolterodine (1-2-4 mg b.i.d) For incomplete bladder emptying Prazosin (1 mg t.i.d.) Moxisylyte (10 mg t.i.d.) Tamsulosine (0.4 mg o.i.d.) Alfuzosine (5 mg b.i.d) Erectile dysfunction Yohimbine (2.5-5 mg t.i.d.) Sildefanil (50-100 mg) Intracavernosal papaverine, prostaglandin E1 Bulk agents, laxatives, and suppositories Macrogol 3350/electrolyte Avoid Botulinum toxin A
To be avoided Sudden head-up postural change (especially on waking) Prolonged recumbency Straining during micturition and defecation High environmental temperature (including hot baths) “Severe” exertion Large meals (especially with refined carbohydrates) Alcohol Drugs with vasodepressor properties To be introduced Head-up tilt during sleep Small frequent meals High salt intake Judicious exercise (including swimming; delay physical exertion until the afternoon; exercise caution on arising in the morning and immediately after meals or physical exertion) Body position and maneuvers—elevation of the legs periodically during the day To be considered Elastic stockings or tights Abdominal binders Water ingestion Cardiac pacing
Supine hypertension
Urinary difficulties
Sexual dysfunction
Constipation Inspiratory stridor
REM sleep behavior disorder Sialorrhea
Clonazepam 0.5-1.5 mg shortly before bedtime (cave: lower initial dose in a patient older than 70 years) Anticholinergics Botulinum toxin A: Parotid gland: Botox®, 10-40 MU Submandibular gland: Botox®, 5-15 MU
Nocturnal snacks Head-up tilt at night Treatment of concurrent prostatism in men or pelvic floor muscle laxity in women Treatment of concurrent urinary tract infection Urinary acidification Intermittent (residual volume>100 mL) or permanent urethral or suprapubic catheterization Penile implant/prosthesis
Dietary fiber and liquid intake Physical activity Continuous positive airway pressure Tracheostomy Anchoring one vocal cord in abduction/cord lateralization procedures Laser cricoarytenoidectomy Nasotracheal intubation Tissues
Modified from Wenning GK, Geser F, Poewe W: Therapeutic strategies in multiple system atrophy. Mov Disord 2005; 20(Suppl 12):S67-S76. DOPS, dihydroxyphenyl serine; REM, rapid eye movement.
chapter 30 primary autonomic failure the need to treat supine hypertension in these patients is disputed. As a matter of fact, all antihypertensive agents may worsen orthostatic hypotension and trigger symptoms of cerebral hypoperfusion. However, the finding of left ventricular hypertrophy in hypertensive patients with primary autonomic failure suggests that this question should be reconsidered.213 Effective treatment of supine hypertension can be easily accomplished simply by avoiding the supine position, at least during daytime. Sleeping in the head-up tilt position reduces nocturnal sodium loss, which improves orthostatic hypotension in the morning (see previous discussion).214,215 Although head-up tilt may reduce hypertensive cerebral perfusion pressure, it is often not sufficient to treat supine hypertension. Theoretically, a result similar to that with head-up tilt at night could be obtained pharmacologically by reducing blood pressure with antihypertensive agents. An ideal agent would decrease blood pressure and natriuresis during the night. Furthermore, it would have a short half life, in order to avoid worsening of orthostatic hypotension in the morning.54 In any case, supine hypertension does not necessitate drug treatment if systolic blood pressure is below 200 mm Hg. Patients with primary autonomic failure are particularly sensitive to transdermal nitroglycerin.124 It can be applied at bedtime and removed on arising in the morning. Short-acting calcium antagonists216 such as nifedipine given at nighttime have also been used in PAF. However, nifedipine increased the nocturnal sodium loss in a study by Jordan and colleagues,217 and nifedipine but not nitroglycerin worsened orthostatic hypotension in the morning. Oral hydralazine can also be used.54
Bladder Dysfunction Nocturnal voiding frequency can be lessened by curtailing fluid intake after the evening meal. If this is not effective, and if there is no significant postmicturition residual, peripherally acting anticholinergics (oxybutynin, propantheline, or tolterodine) are the initial pharmacological therapeutics to be administered.54 Anticholinergic agents alleviate detrusor hyperreflexia or sphincter-detrusor dyssynergy, but commonly at the expense of inducing urinary retention.83 Muscarinic receptors of the detrusor muscle are the common target of anticholinergics, and their M1, M2, or M3 subreceptor profile seems to have little influence on their clinical efficacy. Several anticholinergics are available, but for most cases, clinical use is based on the results of open-label trials. Propantheline bromide is nonselective for muscarinic receptor subtypes and has low bioavailability. It was a first-choice agent for detrusor overactivity in the 1980s but has been largely supplanted by newer agents since. Trospium chloride is a very efficacious nonselective quaternary ammonium compound showing tissue selectivity for the bladder over the salivary glands. Oxybutynin has antimuscarinic, muscle relaxant, and local anesthetic actions. It has been demonstrated to have a higher affinity for muscarinic M1 and M3 receptors than for M2 receptor, but the clinical significance of this is unclear. Side effects are typically antimuscarinic, including dry mouth, constipation, blurred vision, and drowsiness. The administration of desmopressin at night may improve nocturia (see previous discussion). In patients with MSA and incomplete bladder emptying, clean intermittent catheterization three to four times per day is a widely accepted approach to prevent myogenic overdistension and secondary consequences from failure to micturate. In the advanced stages of MSA, a
385
permanent urethral or transcutaneous suprapubic catheter may become necessary, when motor symptoms of MSA or mechanical obstruction in the urethra prevent uncomplicated catheterization. Pharmacological options with cholinergic or adrenergic substances are usually not successful to adequately reduce postvoid residual volume in MSA. However, α-adrenergic receptor antagonists (prazosin and moxisylyte) have been shown to improve voiding with reduction of residual volumes in patients with MSA.218 Urological surgery must be avoided in these patients because worsening of bladder control postoperatively is most likely.83
Erectile Dysfunction The necessity of a specific treatment of sexual dysfunction needs to be evaluated individually in each MSA patient. Sildenafil is an orally active inhibitor of the type V cyclic guanosine monophosphate–specific phosphodiesterase (the predominant isoenzyme in the human corpus cavernosum) and has shown remarkable success in clinical trials.219-221 In fact, preliminary evidence in patients with Parkinson’s disease220 suggests that sildenafil citrate may also be successful in treating erectile failure in patients with MSA. A double-blind, placebo-controlled trial confirmed the efficacy of this compound in MSA but also suggested caution because of the frequent cardiovascular side effects.221 Erectile failure in MSA may also be improved by oral yohimbine, by intracavernosal injection of papaverine, or by a penile implant.83 Moreover, erectile dysfunction can be treated with intracavernosal injections or transurethral suppositories of alprostadil, a synthetic prostaglandin E1.222 Dopaminergic agents may also help with sexual dysfunction, probably by alleviating bradykinesia, as well as increasing desire. On high doses of antiparkinsonian medication, some patients may become hypersexual—even despite their inability to perform.54
Constipation Constipation affects overall well-being and can be managed with dietary changes, adequate liquid intake, exercise, and pharmacotherapy. In fact, at least two meals per day should include high-fiber raw vegetables. Furthermore, increasing physical activity can also be helpful. Constipation can be relieved by increasing the intraluminal volume, which may be achieved with a macrogol-water solution. Indeed, it is already shown that macrogol 3350 plus electrolytes improves constipation in Parkinson’s disease and MSA.223 Stool softeners given with meals can be helpful. Lactulose may be beneficial for some patients. Bowel motility may be increased by discontinuing anticholinergic agents.
REM Sleep Behavior Disorder In many patients, REM sleep behavior disorder is responsive to low-dose clonazepam. In patients with DLB, precipitation or aggravation of hallucinations with dopaminergic agents may occur. L-Dopa has less of a propensity to cause hallucinations and somnolence and is therefore preferred over dopamine agonists.54 Although clonazepam may be regarded as the treatment of choice for REM sleep behavior disorder, an alternative treatment is desirable for affected patients whose condition is refractory to clonazepam, who experience intolerable side effects with clonazepam, or in whom clonazepam precipitates
386
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
or aggravates obstructive sleep apnea. In a series by Boeve and colleagues,224 a persistent benefit with melatonin beyond 1 year of therapy occurred in most patients, which suggests that melatonin may be considered as a possible sole or add-on therapy in selected patients with REM sleep behavior disorder.
Cognitive and Psychiatric Problems In patients with DLB, cholinesterase inhibitor drugs are commonly used for the treatment of cognitive dysfunction. These drugs may reduce hallucinations and other neuropsychiatric symptoms of DLB, too. According to a Cochrane Database review,225 DLB patients who suffer from behavioral disturbances or psychiatric problems may benefit from rivastigmine if they tolerate it. However, the evidence is weak, and further trials with rivastigmine or other cholinesterase inhibitors in DLB are needed.54 Another important issue that has to be kept in mind is that about one third to one half of patients with DLB develop severe side effects when treated with typical or atypical neuroleptics.191,226,227 The reported side effects include increased rigidity, immobility, confusion, sedation, and postural falls.191,226-232 It is not possible to predict these neuroleptic sensitivity reactions in an individual patient before treatment starts. Severe neuroleptic sensitivity probably also occurs in about 25% of PDD patients, and caution in their use is also urged.233 Selective serotonin reuptake inhibitors have shown some effectiveness for the management of depression and for behavioral and psychological disorders in patients with dementia (particularly in Alzheimer’s disease).54
tive bladder drainage, it is not an ideal long-term solution. Erosion of the urethra may occur in both men and women, whereas men are also prone to developing urethral stricture disease. Most urologists agree that a suprapubic catheter is the preferred route for long-term bladder drainage if an indwelling catheter is required. A reduction in maximal detrusor pressure, improvement in bladder structure, and a resolution of reflux have been reported. Complications common to both urethral and suprapubic catheterization include urine bypassing the catheter, leading to incontinence, and recurrent infections and catheter blockage. Expert uroneurological advice is invaluable. Occupational therapy helps to limit the handicap resulting from the patient’s disabilities and should include a home visit. Gait training and timely provision of a walking aide or assistive devices to prevent falling help avoid further debilitation of the patient. Provision of a wheelchair is usually dictated by the liability to falls because of postural instability and gait ataxia but not by akinesia and rigidity per se. Psychological support for patients and partners needs to be stressed. Until primary autonomic failure can be effectively treated or prevented, it will continue to present neurologists with a major challenge: that of providing the rapport, empathy, trust, and compassion necessary to support patients and family in the presence of progressive and incurable disease.
K E Y ●
Pure autonomic failure (PAF) is a rare neurodegenerative disorder that is characterized by Lewy bodies in the autonomic nervous system.
●
PAF may evolve into Parkinson’s disease with autonomic failure, dementia with Lewy bodies (DLB), or multiplesystem atrophy (MSA)
●
In PAF, Parkinson’s disease with autonomic failure, and DLB, the Lewy bodies stain positive for a-synuclein, whereas in MSA, a-synuclein immunoreactivity is found in glial cytoplasmic inclusions.
●
Postganglionic lesions predominate in PAF, Parkinson’s disease with autonomic failure, and DLB, whereas preganglionic lesions predominate in MSA.
●
The practical management of these disorders is based on alleviating patients’ individual symptoms.
●
New neuroprotective or neurorestorative treatment concepts to slow down, halt, or reverse disease progression are urgently required.
Palliative Care Patients with PAF should be assured that their disease has a relatively benign nature. MSA patients continue to suffer from this malignant and distressing condition. Because the results of drug treatment for MSA are generally poor in the long term, other therapies are all the more important. Palliative management decisions should be based on careful clinical judgment, with the expectations of both patient and caregivers taken into account. It is most crucial that patients have maximum access to speech, occupational, and physical therapists; social workers; wheelchair clinics; and continence advisers. In fact, physiotherapy helps maintain mobility and prevent contractures. Speech therapy can improve speech and swallowing and provide communication aids. Dysphagia may necessitate feeding via a nasogastric tube or even percutaneous endoscopic gastrostomy. Continuous positive airway pressure may be helpful in some affected patients with inspiratory stridor.234,235 Tracheostomy, after all the ethical issues related to this procedure have been considered, is only rarely (about 4%) needed in mobile patients with inspiratory stridor; it should be avoided in preterminal stages of the disease. The advisability of either gastrostomy or tracheostomy should be approached on an individual basis with a realistic appraisal of the patient’s general quality of life. In advanced disease, long-term indwelling catheters become the mainstay of urinary control. Many factors, including neurological, urological, sexual, psychological, and social factors, may complicate or affect the choice of bladder management. Indeed, sometimes the preservation of quality of life for caretakers or lack of adequate nursing may dictate the use of indwelling catheters. Although urethral catheterization does provide effec-
P O I N T S
Suggested Reading Kaufmann H, Schatz IJ: Pure autonomic failure. In Robertson D, ed: Primer on the Autonomic Nervous System, 2nd ed. Amsterdam: Elsevier, 2004, pp 309-311. Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford, UK: Oxford University Press, 1999.
chapter 30 primary autonomic failure Mathias CJ, Polinsky RJ: Separating the primary autonomic failure syndromes, multiple system atrophy, and pure autonomic failure from Parkinson’s disease. Adv Neurol 1999; 80:353-361. Wenning GK, Colosimo C, Geser F, et al: Multiple system atrophy. Lancet Neurol 2004; 3:293-103. Wenning GK, Stampfer M: Dementia with Lewy Bodies. In Robertson D, ed: Primer on the Autonomic Nervous System, 2nd ed. Amsterdam: Elsevier, 2004, pp 293-294.
References 1. Mathias CJ: The classification and nomenclature of autonomic disorders—ending chaos, resolving conflict and hopefully achieving clarity. Clin Auton Res 1995; 5:307-310. 2. Bannister R, Mathias CJ, Polinsky R: Clinical features of autonomic failure. B. Autonomic failure: a comparison between UK and US experience. In Bannister R, ed: Autonomic Failure. A Textbook of Disorders of the Autonomic Nervous System, 2nd ed. Oxford: Oxford University Press, 1988, pp 281-288. 3. Kaufmann H, Hague K, Perl D: Accumulation of alphasynuclein in autonomic nerves in pure autonomic failure. Neurology 2001; 56:980-981. 4. Kaufmann H: Primary autonomic failure: three clinical presentations of one disease? Ann Intern Med 2000; 133:382-384. 5. Polymeropoulos MH, Lavedan C, Leroy E, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276:2045-2047. 6. Stefanova N, Klimaschewski L, Poewe W, et al: Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 2001; 65:432-438. 7. Tu PH, Galvin JE, Baba M, et al: Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998; 44:415-422. 8. Kahle PJ, Neumann M, Ozmen L, et al: Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 2002; 3:583-588. 9. Hague K, Lento P, Morgello S, et al: The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Acta Neuropathol (Berl) 1997; 94:192-196. 10. van Ingelghem E, van Zandijcke M, Lammens M: Pure autonomic failure: a new case with clinical, biochemical, and necropsy data. J Neurol Neurosurg Psychiatry 1994; 57:745747. 11. Hughes AJ, Daniel SE, Blankson S, et al: A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol 1993; 50:140-148. 12. McKeith IG, Galasko D, Kosaka K, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:1113-1124. 13. Oppenheimer DR: Lateral horn cells in progressive autonomic failure. J Neurol Sci 1980; 46:393-404. 14. Graham JG, Oppenheimer DR: Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 1969; 32:28-34. 15. van der Eecken H, Adams R, van Bogaert L: Striopallidalnigral degeneration: a hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 1960; 19:159-161. 16. Adams R, Van Bogaert L, Van der Eecken H: [Nigro-striate and cerebello-nigro-striate degeneration. Clinical uniqueness and pathological variability of presenile degeneration of the extrapyramidal rigidity type]. Psychiatr Neurol (Basel) 1961; 142:219-259. 17. Adams RD, Vanbogaert L, Van der Eecken H: Striatonigral degeneration. J Neuropathol Exp Neurol 1964; 23:584608.
387
18. Dejerine J, Thomas A. L’atrophie olivo-ponto-cerebelleuse. Nouv Iconogr Salpetr 1900; 13:330-370. 19. Stauffenberg W: Zur Kenntnis des extrapyramidalen motorischen Systems und Mitteilung eines Falles von sog. Atrophie olivo-pontocerbelleuse. Zeitschr Ges Neurol Psychiatrie 1918; 39:1-55. 20. Shy GM, Drager GA: A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. Arch Neurol 1960; 2:511-527. 21. Papp MI, Lantos PL: The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 1994; 117(Pt 2):235243. 22. Geser F, Stampfer-Kountchev M, Seppi K, et al: The clinical presentation of multiple system atrophy (MSA) in Europe: An interim analysis of the EMSA-SG (European MSA-Study Group) Registry. Mov Disord 2004; 19(Suppl 9):347. 23. Gilman S, Low P, Quinn N, et al: Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res 1998; 8:359-362. 24. Kume A, Takahashi A, Hashizume Y: Neuronal cell loss of the striatonigral system in multiple system atrophy. J Neurol Sci 1993; 117:33-40. 25. Wenning GK, Tison F, Elliott L, et al: Olivopontocerebellar pathology in multiple system atrophy. Mov Disord 1996; 11:157-162. 26. Sung JH, Mastri AR, Segal E: Pathology of Shy-Drager syndrome. J Neuropathol Exp Neurol 1979; 38:353-368. 27. Benarroch EE, Smithson IL, Low PA, et al: Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure. Ann Neurol 1998; 43:156-163. 28. Benarroch EE, Schmeichel AM, Parisi JE: Depletion of cholinergic neurons of the medullary arcuate nucleus in multiple system atrophy. Auton Neurosci 2001; 87:293-299. 29. Benarroch EE, Schmeichel AM, Parisi JE: Depletion of mesopontine cholinergic and sparing of raphe neurons in multiple system atrophy. Neurology 2002; 59:944946. 30. Benarroch EE: Brainstem in multiple system atrophy: clinicopathological correlations. Cell Mol Neurobiol 2003; 23:519526. 31. Nakamura S, Ohnishi K, Nishimura M, et al: Large neurons in the tuberomammillary nucleus in patients with Parkinson’s disease and multiple system atrophy. Neurology 1996; 46:1693-1696. 32. Wenning GK, Tison F, Ben Shlomo Y, et al: Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997; 12:133-147. 33. Daniel S: The neuropathology and neurochemistry of multiple system atrophy. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 321-328. 34. Kaufmann H, Oribe E, Miller M, et al: Hypotension-induced vasopressin release distinguishes between pure autonomic failure and multiple system atrophy with autonomic failure. Neurology 1992; 42:590-593. 35. Konno H, Yamamoto T, Iwasaki Y, et al: Shy-Drager syndrome and amyotrophic lateral sclerosis: cytoarchitectonic and morphometric studies of sacral autonomic neurons. J Neurol Sci 1986; 73:193-204. 36. Bannister R, Oppenheimer DR: Degenerative diseases of the nervous system associated with autonomic failure. Brain 1972; 95:457-474. 37. Spokes EG, Bannister R, Oppenheimer DR: Multiple system atrophy with autonomic failure: clinical, histological and
388
38.
39. 40. 41.
42.
43. 44.
45. 46. 47. 48. 49. 50.
51. 52.
53.
54. 55.
56.
57.
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
neurochemical observations on four cases. J Neurol Sci 1979; 43:59-82. Matthews M: Autonomic ganglia and preganglionic neurons in autonomic failure. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 329-339. Sima AA, Caplan M, D’Amato CJ, et al: Fulminant multiple system atrophy in a young adult presenting as motor neuron disease. Neurology 1993; 43:2031-2035. Low PA: Autonomic neuropathies. Curr Opin Neurol 1994; 7:402-406. McLeod JG: Autonomic dysfunction in peripheral nerve disease. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 367-377. Suarez GA, Fealey RD, Camilleri M, et al: Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology 1994; 44:16751682. Bennett JL, Mahalingam R, Wellish MC, et al: Epstein-Barr virus—associated acute autonomic neuropathy. Ann Neurol 1996; 40:453-455. Santiago S, Ferrer T, Espinosa ML: Neurophysiological studies of thin myelinated (A delta) and unmyelinated (C) fibers: application to peripheral neuropathies. Neurophysiol Clin 2000; 30:27-42. Santiago S, Espinosa ML, Perez-Conde MC, et al: Small fiber dysfunction in peripheral neuropathies. Rev Neurol 1999; 28:543-554. Bradbury S, Eggleston C: Postural hypotension: a report of three cases. Am Heart J 1925; 1:75-86. Kaufmann H: Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res 1996; 6:125-126. Mathias CJ: Orthostatic hypotension: causes, mechanisms, and influencing factors. Neurology 1995; 45:S6-S11. Robertson D, Davis TL: Recent advances in the treatment of orthostatic hypotension. Neurology 1995; 45:S26-S32. Mathias CJ, Mallipeddi R, Bleasdale-Barr K: Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy. J Neurol 1999; 246:893898. Schatz IJ: Orthostatic hypotension. I. Functional and neurogenic causes. Arch Intern Med 1984; 144:773-777. Geser F, Stampfer-Kountchev M, Seppi K, et al: Warning signs (“red flags”) in multiple system atrophy (MSA): a preliminary cross-sectional analysis of 79 European MSA-P patients. Mov Disord 2004; 19(Suppl 9):346-347. Geser F, Stampfer-Kountchev M, Seppi K, et al: Warning signs (“red flags”) in possible MSA: a preliminary cross-sectional analysis of the European MSA-Study Group (EMSA-SG). Funct Neurol 2004; 19:144. Kaufmann H, Biaggioni I: Autonomic failure in neurodegenerative disorders. Semin Neurol 2003; 23:351-363. Mathias CJ, Polinsky RJ: Separating the primary autonomic failure syndromes, multiple system atrophy, and pure autonomic failure from Parkinson’s disease. Adv Neurol 1999; 80:353-361. Churchyard A, Mathias CJ, Boonkongchuen P, et al: Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 63:228-234. Magalhaes M, Wenning GK, Daniel SE, et al: Autonomic dysfunction in pathologically confirmed multiple system atrophy and idiopathic Parkinson’s disease: a retrospective comparison. Acta Neurol Scand 1995; 91:98-102.
58. Kaufmann H, Nouri S, Olanow W, et al: Orthostatic intolerance in Parkinson’s disease. Neurology 1997; 48: 149. 59. Senard JM, Rai S, Lapeyre-Mestre M, et al: Prevalence of orthostatic hypotension in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 63:584-589. 60. Wenning GK, Scherfler C, Granata R, et al: Time course of symptomatic orthostatic hypotension and urinary incontinence in patients with postmortem confirmed parkinsonian syndromes: a clinicopathological study. J Neurol Neurosurg Psychiatry 1999; 67:620-623. 61. Orskov L, Jakobsen J, Dupont E, et al: Autonomic function in parkinsonian patients relates to duration of disease. Neurology 1987; 37:1173-1178. 62. Mayeux R, Denaro J, Hemenegildo N, et al: A populationbased investigation of Parkinson’s disease with and without dementia: relationship to age and gender. Arch Neurol 1992; 49:492-497. 63. Aarsland D, Larsen JP, Karlsen K, et al: Mental symptoms in Parkinson’s disease are important contributors to caregiver distress. Int J Geriatr Psychiatry 1999; 14:866-874. 64. Peralta CM, Stampfer M, Karner E, et al: Orthostatic hypotension and attention in Lewy body disorders. Mov Disord 2004; 19(Suppl 9):331-332. 65. Geser F, Wenning GK, Poewe W, et al: How to diagnose dementia with Lewy bodies: state of the art. Mov Disord 2005, 20(Suppl 12):S11-S20. 66. McKeith IG, Perry EK, Perry RH: Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology 1999; 53:902-905. 67. Horimoto Y, Matsumoto M, Akatsu H, et al: Autonomic dysfunctions in dementia with Lewy bodies. J Neurol 2003; 250:530-533. 68. Ransmayr G: Dementia with Lewy bodies: prevalence, clinical spectrum and natural history. J Neural Transm Suppl 2000; (60):303-314. 69. Del Ser T, McKeith I, Anand R, et al: Dementia with Lewy bodies: findings from an international multicentre study. Int J Geriatr Psychiatry 2000; 15:1034-1045. 70. Aarsland D, Ballard C, McKeith I, et al: Comparison of extrapyramidal signs in dementia with Lewy bodies and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13:374-379. 71. Pakiam AS, Bergeron C, Lang AE: Diffuse Lewy body disease presenting as multiple system atrophy. Can J Neurol Sci 1999; 26:127-131. 72. McKeith I, Burn D: Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. In DeKosky S, ed: Neurologic Clinics: Dementia. Philadelphia: WB Saunders, 2000, pp 865-883. 73. Wenning GK, Seppi K, Jellinger K, et al: Survival of patients with dementia with Lewy bodies: a meta-analysis of 236 postmortem confirmed cases. Neurology 2000; 54(Suppl 3):391392. 74. Watanabe H, Saito Y, Terao S, et al: Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 2002; 125:1070-1083. 75. Testa D, Monza D, Ferrarini M, et al: Comparison of natural histories of progressive supranuclear palsy and multiple system atrophy. Neurol Sci 2001; 22:247-251. 76. Ben-Shlomo Y, Wenning GK, Tison F, et al: Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology 1997; 48:384-393. 77. Wenning GK, Ben Shlomo Y, Magalhaes M, et al: Clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 1994; 117(Pt 4):835845.
chapter 30 primary autonomic failure 78. Abele M, Burk K, Schols L, et al: The aetiology of sporadic adult-onset ataxia. Brain 2002; 125:961-968. 79. Gilman S, Little R, Johanns J, et al: Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy. Neurology 2000; 55:527-532. 80. Schwarz J, Tatsch K, Gasser T, et al: 123I-IBZM binding compared with long-term clinical follow up in patients with de novo parkinsonism. Mov Disord 1998; 13:16-19. 81. Boesch SM, Wenning GK, Ransmayr G, et al: Dystonia in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002; 72:300-303. 82. Wenning GK, Ben-Shlomo Y, Hughes A, et al: What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000; 68:434-440. 83. Beck RO, Betts CD, Fowler CJ: Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urol 1994; 151:1336-1341. 84. Braune S, Elam M, Baron R, et al: Assessment of blood pressure regulation. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999; 52:287-291. 85. Bannister R, Mathias C: Investigation of autonomic disorders. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford University Press, 1999, pp 169195. 86. Braune S, Auer A, Schulte-Monting J, et al: Cardiovascular parameters: sensitivity to detect autonomic dysfunction and influence of age and sex in normal subjects. Clin Auton Res 1996; 6:3-15. 87. Braune S, Schulte-Monting J, Schwerbrock S, et al: Retest variation of cardiovascular parameters in autonomic testing. J Auton Nerv Syst 1996; 60:103-107. 88. Riley DE, Chelimsky TC: Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003; 74:56-60. 89. Ziegler MG, Lake CR, Kopin IJ. The sympathetic-nervoussystem defect in primary orthostatic hypotension. N Engl J Med 1977; 296:293-297. 90. Polinsky RJ, Kopin IJ, Ebert MH, et al: Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 1981; 31:1-7. 91. Goldstein DS, Polinsky RJ, Garty M, et al: Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol 1989; 26:558-563. 92. Kaufmann H, Schatz IJ: Pure autonomic failure. In Robertson D, ed: Primer on the Autonomic Nervous System. Amsterdam: Elsevier, 2004, pp 309-311. 93. Baser SM, Brown RT, Curras MT, et al: Beta-receptor sensitivity in autonomic failure. Neurology 1991; 41:11071112. 94. Goldstein DS, Holmes C, Cannon RO 3rd, et al: Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 1997; 336:696-702. 95. Braune S, Reinhardt M, Schnitzer R, et al: Cardiac uptake of [123I]MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 1999; 53:1020-1025. 96. Braune S: The role of cardiac metaiodobenzylguanidine uptake in the differential diagnosis of parkinsonian syndromes. Clin Auton Res 2001; 11:351-355. 97. Orimo S, Ozawa E, Nakade S, et al: 123I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 67:189-194. 98. Takatsu H, Nagashima K, Murase M, et al: Differentiating Parkinson disease from multiple-system atrophy by measuring cardiac iodine-123 metaiodobenzylguanidine accumulation. JAMA 2000; 284:44-45.
389
99. Taki J, Nakajima K, Hwang EH, et al: Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 2000; 27:566-573. 100. Hirayama M, Hakusui S, Koike Y, et al: A scintigraphical qualitative analysis of peripheral vascular sympathetic function with meta-[123I]iodobenzylguanidine in neurological patients with autonomic failure. J Auton Nerv Syst 1995; 53:230-234. 101. Yoshita M: Differentiation of idiopathic Parkinson’s disease from striatonigral degeneration and progressive supranuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. J Neurol Sci 1998; 155:60-67. 102. Goldstein DS, Holmes C, Li ST, et al: Cardiac sympathetic denervation in Parkinson’s disease. Ann Intern Med 2000; 133:338-347. 103. Watanabe H, Ieda T, Katayama T, et al: Cardiac123I-metaiodobenzylguanidine (MIBG) uptake in dementia with Lewy bodies: comparison with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2001; 70:781-783. 104. Yoshita M, Taki J, Yamada M: A clinical role for [123I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer’s-type and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2001; 71:583-588. 105. Oide T, Tokuda T, Momose M, et al: Usefulness of [123I]metaiodobenzylguanidine ([123I]MIBG) myocardial scintigraphy in differentiating between Alzheimer’s disease and dementia with Lewy bodies. Intern Med 2003; 42:686690. 106. Kirby R, Fowler C, Gosling J, et al: Urethro-vesical dysfunction in progressive autonomic failure with multiple system atrophy. J Neurol Neurosurg Psychiatry 1986; 49:554562. 107. Pramstaller PP, Wenning GK, Smith SJ, et al: Nerve conduction studies, skeletal muscle EMG, and sphincter EMG in multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:618-621. 108. Palace J, Chandiramani VA, Fowler CJ: Value of sphincter electromyography in the diagnosis of multiple system atrophy. Muscle Nerve 1997; 20:1396-1403. 109. Schwarz J, Kornhuber M, Bischoff C, et al: Electromyography of the external anal sphincter in patients with Parkinson’s disease and multiple system atrophy: frequency of abnormal spontaneous activity and polyphasic motor unit potentials. Muscle Nerve 1997; 20:1167-1172. 110. Valldeoriola F, Valls-Sole J, Tolosa ES, et al: Striated anal sphincter denervation in patients with progressive supranuclear palsy. Mov Disord 1995; 10:550-555. 111. Giladi N, Simon ES, Korczyn AD, et al: Anal sphincter EMG does not distinguish between multiple system atrophy and Parkinson’s disease. Muscle Nerve 2000; 23:731-734. 112. Colosimo C, Inghilleri M, Chaudhuri KR: Parkinson’s disease misdiagnosed as multiple system atrophy by sphincter electro-myography. J Neurol 2000; 247:559-561. 113. Vodusek DB: Sphincter EMG and differential diagnosis of multiple system atrophy. Mov Disord 2001; 16:600-607. 114. Polinsky RJ, Brown RT, Lee GK, et al: Beta-endorphin, ACTH, and catecholamine responses in chronic autonomic failure. Ann Neurol 1987; 21:573-577. 115. Kimber JR, Watson L, Mathias CJ: Distinction of idiopathic Parkinson’s disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine. Lancet 1997; 349:1877-1881. 116. Zoukos Y, Thomaides T, Pavitt DV, et al: Beta-adrenoceptor expression on circulating mononuclear cells of idiopathic Parkinson’s disease and autonomic failure patients before and after reduction of central sympathetic outflow by clonidine. Neurology 1993; 43:1181-1187.
390
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
117. Clarke CE, Ray PS, Speller JM: Failure of the clonidine growth hormone stimulation test to differentiate multiple system atrophy from early or advanced idiopathic Parkinson’s disease. Lancet 1999; 353:1329-1330. 118. Tranchant C, Guiraud-Chaumeil C, Echaniz-Laguna A, et al: Is clonidine growth hormone stimulation a good test to differentiate multiple system atrophy from idiopathic Parkinson’s disease? J Neurol 2000; 247:853-856. 119. Strijks E, van’t Hof M, Sweep F, et al: Stimulation of growth-hormone release with clonidine does not distinguish individual cases of idiopathic Parkinson’s disease from those with striatonigral degeneration. J Neurol 2002; 249:12061210. 120. Kimber J, Mathias CJ, Lees AJ, et al: Physiological, pharmacological and neurohormonal assessment of autonomic function in progressive supranuclear palsy. Brain 2000; 123(Pt 7):1422-1430. 121. Pellecchia MT, Salvatore E, Pivonello R, et al: Stimulation of growth hormone release in multiple system atrophy, Parkinson’s disease and idiopathic cerebellar ataxia. Neurol Sci 2001; 22:79-80. 122. Kimber J, Watson L, Mathias CJ: Abnormal suppression of arginine-vasopressin by clonidine in multiple system atrophy. Clin Auton Res 1999; 9:271-274. 123. Kimber J, Watson L, Mathias CJ: Neuroendocrine responses to levodopa in multiple system atrophy (MSA). Mov Disord 1999; 14:981-987. 124. Shannon J, Jordan J, Costa F, et al: The hypertension of autonomic failure and its treatment. Hypertension 1997; 30:10621067. 125. Shannon JR, Jordan J, Diedrich A, et al: Sympathetically mediated hypertension in autonomic failure. Circulation 2000; 101:2710-2715. 126. Wullner U, Klockgether T, Petersen D, et al: Magnetic resonance imaging in hereditary and idiopathic ataxia. Neurology 1993; 43:318-325. 127. Schrag A, Good CD, Miszkiel K, et al: Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology 2000; 54:697-702. 128. Drayer BP, Olanow W, Burger P, et al: Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 1986; 159:493-498. 129. Pastakia B, Polinsky R, Di Chiro G, et al: Multiple system atrophy (Shy-Drager syndrome): MR imaging. Radiology 1986; 159:499-502. 130. O’Brien C, Sung JH, McGeachie RE, et al: Striatonigral degeneration: clinical, MRI, and pathologic correlation. Neurology 1990; 40:710-711. 131. Lang AE, Curran T, Provias J, et al: Striatonigral degeneration: iron deposition in putamen correlates with the slit-like void signal of magnetic resonance imaging. Can J Neurol Sci 1994; 21:311-318. 132. Schwarz J, Weis S, Kraft E, et al: Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996; 60:98-101. 133. Schrag A, Kingsley D, Phatouros C, et al: Clinical usefulness of magnetic resonance imaging in multiple system atrophy. J Neurol Neurosurg Psychiatry 1998; 65:65-71. 134. Kraft E, Trenkwalder C, Auer DP: T2*-weighted MRI differentiates multiple system atrophy from Parkinson’s disease. Neurology 2002; 59:1265-1267. 135. Konagaya M, Konagaya Y, Iida M: Clinical and magnetic resonance imaging study of extrapyramidal symptoms in multiple system atrophy. J Neurol Neurosurg Psychiatry 1994; 57:1528-1531. 136. Kraft E, Schwarz J, Trenkwalder C, et al: The combination of hypointense and hyperintense signal changes on T2-weighted
137.
138.
139.
140.
141. 142.
143. 144. 145. 146. 147.
148.
149.
150.
151.
152. 153.
magnetic resonance imaging sequences: a specific marker of multiple system atrophy? Arch Neurol 1999; 56:225228. Schocke MF, Seppi K, Esterhammer R, et al: Diffusionweighted MRI differentiates the Parkinson variant of multiple system atrophy from PD. Neurology 2002; 58:575580. Seppi K, Schocke MF, Esterhammer R, et al: Diffusionweighted imaging discriminates progressive supranuclear palsy from PD, but not from the parkinson variant of multiple system atrophy. Neurology 2003; 60:922-927. Schulz JB, Skalej M, Wedekind D, et al: Magnetic resonance imaging-based volumetry differentiates idiopathic Parkinson’s syndrome from multiple system atrophy and progressive supranuclear palsy. Ann Neurol 1999; 45:6574. Brenneis C, Seppi K, Schocke MF, et al: Voxel-based morphometry detects cortical atrophy in the Parkinson variant of multiple system atrophy. Mov Disord 2003; 18:1132-1138. Barber R, Ballard C, McKeith IG, et al: MRI volumetric study of dementia with Lewy bodies: a comparison with AD and vascular dementia. Neurology 2000; 54:1304-1309. Barber R, Scheltens P, Gholkar A, et al: White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer’s disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry 1999; 67:66-72. Cousins DA, Burton EJ, Burn D, et al: Atrophy of the putamen in dementia with Lewy bodies but not Alzheimer’s disease: an MRI study. Neurology 2003; 61:1191-1195. O’Brien JT, Paling S, Barber R, et al: Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia. Neurology 2001; 56:1386-1388. Cordato NJ, Halliday GM, Harding AJ, et al: Regional brain atrophy in progressive supranuclear palsy and Lewy body disease. Ann Neurol 2000; 47:718-728. Brenneis C, Wenning GK, Egger KE, et al: Basal forebrain atrophy is a distinctive pattern in dementia with Lewy bodies. Neuroreport 2004; 15:1711-1714. Brooks DJ, Ibanez V, Sawle GV, et al: Differing patterns of striatal 18F-dopa uptake in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990; 28:547-555. Brooks DJ, Salmon EP, Mathias CJ, et al: The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson’s disease, studied with PET. Brain 1990; 113 (Pt 5):1539-1552. Burn DJ, Sawle GV, Brooks DJ: Differential diagnosis of Parkinson’s disease, multiple system atrophy, and SteeleRichardson-Olszewski syndrome: discriminant analysis of striatal 18F-dopa PET data. J Neurol Neurosurg Psychiatry 1994; 57:278-284. Brooks DJ, Ibanez V, Sawle GV, et al: Striatal D2 receptor status in patients with Parkinson’s disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann Neurol 1992; 31:184-192. Burn DJ, Rinne JO, Quinn NP, et al: Striatal opioid receptor binding in Parkinson’s disease, striatonigral degeneration and Steele-Richardson-Olszewski syndrome, a [11C]diprenorphine PET study. Brain 1995; 118(Pt 4):951-958. De Volder AG, Francart J, Laterre C, et al: Decreased glucose utilization in the striatum and frontal lobe in probable striatonigral degeneration. Ann Neurol 1989; 26:239-247. Perani D, Bressi S, Testa D, et al: Clinical/metabolic correlations in multiple system atrophy: a fluorodeoxyglucose F 18
chapter 30 primary autonomic failure
154. 155.
156.
157. 158. 159. 160. 161.
162.
163.
164.
165. 166. 167. 168.
169. 170. 171. 172.
positron emission tomographic study. Arch Neurol 1995; 52:179-185. Antonini A, Kazumata K, Feigin A, et al: Differential diagnosis of parkinsonism with [18F]fluorodeoxyglucose and PET. Mov Disord 1998; 13:268-274. Ghaemi M, Hilker R, Rudolf J, et al: Differentiating multiple system atrophy from Parkinson’s disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging. J Neurol Neurosurg Psychiatry 2002; 73:517523. Gilman S, Koeppe RA, Junck L, et al: Patterns of cerebral glucose metabolism detected with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy. Ann Neurol 1994; 36:166-175. Hu XS, Okamura N, Arai H, et al: 18F-fluorodopa PET study of striatal dopamine uptake in the diagnosis of dementia with Lewy bodies. Neurology 2000; 55:1575-1577. Higuchi M, Tashiro M, Arai H, et al: Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies. Exp Neurol 2000; 162:247-256. Ishii K, Imamura T, Sasaki M, et al: Regional cerebral glucose metabolism in dementia with Lewy bodies and Alzheimer’s disease. Neurology 1998; 51:125-130. Brucke T, Djamshidian S, Bencsits G, et al: SPECT and PET imaging of the dopaminergic system in Parkinson’s disease. J Neurol 2000; 247(Suppl 4):IV/2-7. Kim YJ, Ichise M, Ballinger JR, et al: Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP. Mov Disord 2002; 17:303-312. Varrone A, Marek KL, Jennings D, et al: [123I]Beta-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson’s disease and multiple system atrophy. Mov Disord 2001; 16:1023-1032. Schulz JB, Klockgether T, Petersen D, et al: Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psychiatry 1994; 57:1047-1056. van Royen E, Verhoeff NF, Speelman JD, et al: Multiple system atrophy and progressive supranuclear palsy: diminished striatal D2 dopamine receptor activity demonstrated by 123I-IBZM single photon emission computed tomography. Arch Neurol 1993; 50:513-516. Brucke T, Wenger S, Asenbaum S, et al: Dopamine D2 receptor imaging and measurement with SPECT. Adv Neurol 1993; 60:494-500. Schwarz J, Tatsch K, Arnold G, et al: 123I-iodobenzamideSPECT predicts dopaminergic responsiveness in patients with de novo parkinsonism. Neurology 1992; 42:556-561. Schwarz J, Tatsch K, Arnold G, et al: 123I-iodobenzamideSPECT in 83 patients with de novo parkinsonism. Neurology 1993; 43:S17-S20. Donnemiller E, Heilmann J, Wenning GK, et al: Brain perfusion scintigraphy with 99mTc-HMPAO or 99mTc-ECD and 123Ibeta-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body disease. Eur J Nucl Med 1997; 24:320-325. Lobotesis K, Fenwick JD, Phipps A, et al: Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 2001; 56:643-649. Ransmayr G, Seppi K, Donnemiller E, et al: Striatal dopamine transporter function in dementia with Lewy bodies and Parkinson’s disease. Eur J Nucl Med 2001; 28:1523-1528. Walker Z, Costa DC, Ince P, et al: In-vivo demonstration of dopaminergic degeneration in dementia with Lewy bodies. Lancet 1999; 354:646-647. Walker Z, Costa DC, Walker RW, et al: Differentiation of dementia with Lewy bodies from Alzheimer’s disease using a
173. 174. 175.
176. 177. 178.
179. 180. 181.
182. 183.
184. 185. 186. 187.
188. 189. 190. 191.
192. 193.
391
dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry 2002; 73:134-140. Heafield MT, Gammage MD, Nightingale S, et al: Idiopathic dysautonomia treated with intravenous gammaglobulin. Lancet 1996; 347:28-29. Smit AA, Vermeulen M, Koelman JH, et al: Unusual recovery from acute panautonomic neuropathy after immunoglobulin therapy. Mayo Clin Proc 1997; 72:333-335. Ramirez C, de Seze J, Stojkovic T, et al: Pure subacute pandysautonomia: an assessment of treatment with intravenous polyvalent immunoglobulins. Rev Neurol (Paris) 2004; 160:939-941. Goetz CG, Tanner CM, Klawans HL: The pharmacology of olivopontocerebellar atrophy. Adv Neurol 1984; 41:143-148. Hughes AJ, Lees AJ, Stern GM: Apomorphine test to predict dopaminergic responsiveness in parkinsonian syndromes. Lancet 1990; 336:32-34. Staal A, Meerwaldt JD, van Dongen KJ, et al: Non-familial degenerative disease and atrophy of brainstem and cerebellum: clinical and CT data in 47 patients. J Neurol Sci 1990; 95:259-269. Hughes AJ, Colosimo C, Kleedorfer B, et al: The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry 1992; 55:1009-1013. Parati EA, Fetoni V, Geminiani GC, et al: Response to L-DOPA in multiple system atrophy. Clin Neuropharmacol 1993; 16:139-144. Albanese A, Colosimo C, Bentivoglio AR, et al: Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria. J Neurol Neurosurg Psychiatry 1995; 59:144-151. Gouider-Khouja N, Vidailhet M, Bonnet AM, et al: “Pure” striatonigral degeneration and Parkinson’s disease: a comparative clinical study. Mov Disord 1995; 10:288-294. Fetoni V, Soliveri P, Monza D, et al: Affective symptoms in multiple system atrophy and Parkinson’s disease: response to levodopa therapy. J Neurol Neurosurg Psychiatry 1999; 66:541-544. Rossi P, Colosimo C, Moro E, et al: Acute challenge with apomorphine and levodopa in Parkinsonism. Eur Neurol 2000; 43:95-101. Fearnley JM, Lees AJ: Striatonigral degeneration: a clinicopathological study. Brain 1990; 113(Pt 6):1823-1842. Rajput AH, Rozdilsky B, Rajput A, et al: Levodopa efficacy and pathological basis of Parkinson syndrome. Clin Neuropharmacol 1990; 13:553-558. Colosimo C, Albanese A, Hughes AJ, et al: Some specific clinical features differentiate multiple system atrophy (striatonigral variety) from Parkinson’s disease. Arch Neurol 1995; 52:294-298. Wenning GK, Ben-Shlomo Y, Magalhaes M, et al: Clinicopathological study of 35 cases of multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 58:160-166. Quinn N: Multiple system atrophy. In Marsden CD, Fahn S, eds: Movement Disorders 3. London: Butterworth-Heinemann, 1994, pp 262-281. Duda JE, Giasson BI, Mabon ME, et al: Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 2002; 52:205-210. Gnanalingham KK, Byrne EJ, Thornton A, et al: Motor and cognitive function in Lewy body dementia: comparison with Alzheimer’s and Parkinson’s diseases. J Neurol Neurosurg Psychiatry 1997; 62:243-252. Louis ED, Goldman JE, Powers JM, et al: Parkinsonian features of eight pathologically diagnosed cases of diffuse Lewy body disease. Mov Disord 1995; 10:188-194. Louis ED, Klatka LA, Liu Y, et al: Comparison of extrapyramidal features in 31 pathologically confirmed cases of diffuse
392
194. 195.
196.
197. 198. 199.
200. 201.
202. 203. 204.
205.
206.
207.
208. 209. 210. 211.
Section
VI
Au to n o m i c N e rvo u s Syst e m D i s e as e s
Lewy body disease and 34 pathologically confirmed cases of Parkinson’s disease. Neurology 1997; 48:376-380. Zesiewicz TA, Baker MJ, Dunne PB, et al: Diffuse Lewy body disease. Curr Treat Options Neurol 2001; 3:507-518. Poewe W, Granata R, Geser F: Pharmacologic treatment of Parkinson’s disease. In Watts RL, Koller WC, eds: Movement Disorders: Neurological Principles and Practice, 2nd ed. New York: McGraw-Hill, 2004, pp 247-271. Lees A: The treatment of the motor disorder of multiple system atrophy. In Mathias C, Bannister R, eds: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. Oxford, UK: Oxford: Oxford University Press, 1999, pp 357-363. Wenning GK, Geser F, Poewe W: Therapeutic strategies in multiple system atrophy (MSA). Mov Disord 2005; 20(Suppl 12):S67-S76. Poewe W: Treatment of dementia with Lewy bodies and Parkinson’s disease dementia. Mov Disord 2005; 20(Suppl 12):S77-82. Kaufmann H, Brannan T, Krakoff L, et al: Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology 1988; 38:951-956. Wright RA, Kaufmann HC, Perera R, et al: A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124. Low PA, Gilden JL, Freeman R, et al: Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension: a randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997; 277:1046-1051. Jankovic J, Gilden JL, Hiner BC, et al: Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993; 95:38-48. Kaufmann H, Saadia D, Voustianiouk A, et al: Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 2003; 108:724-728. Mathias CJ, Senard JM, Braune S, et al: L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res 2001; 11:235242. Alam M, Smith G, Bleasdale-Barr K, et al: Effects of the peptide release inhibitor, octreotide, on daytime hypotension and on nocturnal hypertension in primary autonomic failure. J Hypertens 1995; 13:1664-1669. Raimbach SJ, Cortelli P, Kooner JS, et al: Prevention of glucose-induced hypotension by the somatostatin analogue octreotide (SMS 201-995) in chronic autonomic failure: haemodynamic and hormonal changes. Clin Sci (Lond) 1989; 77:623-628. Mathias CJ, Fosbraey P, da Costa DF, et al: The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br Med J (Clin Res Ed) 1986; 293:353-354. Perera R, Isola L, Kaufmann H: Erythropoietin improves orthostatic hypotension in primary autonomic failure. Neurology 1994; 44(Suppl):A363. Biaggioni I, Robertson D, Krantz S, et al: The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 1994; 121:181-186. Hoeldtke RD, Streeten DH: Treatment of orthostatic hypotension with erythropoietin. N Engl J Med 1993; 329:611-615. Perera R, Isola L, Kaufmann H: Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure. Clin Auton Res 1995; 5:211213.
212. Winkler AS, Marsden J, Parton M, et al: Erythropoietin deficiency and anaemia in multiple system atrophy. Mov Disord 2001; 16:233-239. 213. Vagaonescu TD, Saadia D, Tuhrim S, et al: Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet 2000; 355:725-726. 214. Maclean A, Allen E: Orthostatic hypotension and orthostatic tachycardia, treatment with the “head up” bed. JAMA 1940; 115:2162-2167. 215. Ten Harkel AD, Van Lieshout JJ, Wieling W: Treatment of orthostatic hypotension with sleeping in the head-up tilt position, alone and in combination with fludrocortisone. J Intern Med 1992; 232:139-145. 216. Wenning GK, Colosimo C, Geser F, et al: Multiple system atrophy. Lancet Neurol 2004; 3:93-103. 217. Jordan J, Shannon JR, Pohar B, et al: Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol 1999; 10:35-42. 218. Sakakibara R, Hattori T, Uchiyama T, et al: Are alphablockers involved in lower urinary tract dysfunction in multiple system atrophy? A comparison of prazosin and moxisylyte. J Auton Nerv Syst 2000; 79:191-195. 219. Goldstein I, Lue TF, Padma-Nathan H, et al: Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338:1397-1404. 220. Zesiewicz TA, Helal M, Hauser RA: Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men with Parkinson’s disease. Mov Disord 2000; 15:305308. 221. Hussain IF, Brady CM, Swinn MJ, et al: Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001; 71:371-374. 222. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al: Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997; 336:1-7. 223. Eichhorn TE, Oertel WH: Macrogol 3350/electrolyte improves constipation in Parkinson’s disease and multiple system atrophy. Mov Disord 2001; 16:1176-1177. 224. Boeve BF, Silber MH, Ferman TJ: Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4:281-284. 225. Wild R, Pettit T, Burns A: Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database Syst Rev 2003; (3):CD003672. 226. McKeith I, Fairbairn A, Perry R, et al: Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 1992; 305:673-678. 227. Ballard C, Grace J, McKeith I, et al: Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer’s disease. Lancet 1998; 351:1032-1033. 228. Sechi G, Agnetti V, Masuri R, et al: Risperidone, neuroleptic malignant syndrome and probable dementia with Lewy bodies. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24:1043-1051. 229. McKeith IG, Ballard CG, Harrison RW: Neuroleptic sensitivity to risperidone in Lewy body dementia. Lancet 1995; 346:699. 230. Rich SS, Friedman JH, Ott BR: Risperidone versus clozapine in the treatment of psychosis in six patients with Parkinson’s disease and other akinetic-rigid syndromes. J Clin Psychiatry 1995; 56:556-559. 231. Burke WJ, Pfeiffer RF, McComb RD: Neuroleptic sensitivity to clozapine in dementia with Lewy bodies. J Neuropsychiatry Clin Neurosci 1998; 10:227-229.
chapter 30 primary autonomic failure 232. Walker Z, Grace J, Overshot R, et al: Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychiatry 1999; 14:459-466. 233. Aarsland D, Ballard C, Larsen JP, et al: Marked neuroleptic sensitivity in dementia with Lewy bodies and Parkinson’s disease. Nord J Psychiatry 2003; 57:94. 234. Iranzo A, Santamaria J, Tolosa E: Continuous positive air pressure eliminates nocturnal stridor in multiple system
393
atrophy. Barcelona Multiple System Atrophy Study Group. Lancet 2000; 356:1329-1330. 235. Iranzo A, Santamaria J, Tolosa E, et al: Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy. Neurology 2004; 63:930-932.
CHAPTER
31
ORGANIZATION: PYRAMIDAL AND EXTRAPYRAMIDAL SYSTEM ●
●
●
●
Glenda M. Halliday and Simon C. Gandevia
The large brains of primates have afforded remarkable behavioral adaptability. In humans, this adaptability is manifested in many ways, including the capacity for movements generated volitionally or somewhat automatically. Such movements include those required for speech and communication, for independent hand use, and for locomotion. Furthermore, these movements can be engaged in simultaneously, a feat that requires extraordinary adaptive control of the motoneuronal outputs to muscles. This occurs, for example, when a person talks and uses a mobile phone when walking or bicycling. This performance of skilled and complex movements can be generated by all components of the body’s musculature. Motoneuronal output to generate movements under volitional control is achieved by descending neural drive from socalled motor cortical centers that generate corticospinal and corticobulbar outputs, as well as corticoreticulospinal outputs.1 Since work in the late 19th and early 20th centuries on stimulation of motor cortex to elicit movements and on sectioning of the pyramidal tract to impair them, the important role of motor cortical outputs with axons in the medullary pyramids has been recognized. This emphasis has fitted with observations of paralysis and weaknesses after development of lesions of this system and with evidence for evolution of the size and terminations of the corticospinal system in primates. There are corticospinal outputs not only to interneurons within the spinal cord but also directly to motoneurons (termed corticomotoneuronal connections). The pyramidal tract itself, so named from the pyramidal decussation in the medulla, contains the bulk of direct corticofugal outputs destined to recruit spinal motoneurons.1 A primary role for the motor cortex in movement control has been paralleled by recognition that subcortical nuclei are also critically involved. Two subcortical systems appear crucial for adequate volitional movement: cortical interactions with the motor thalamus and the integration of information through the basal ganglia.2 The basal ganglia comprise a large number of integrated regions (see later discussion) that affect the motor system at the level of the thalamus and brainstem. Just as lesion and stimulation studies show the importance of motor cortical outputs, comparable approaches to study of the basal ganglia and thalamus have revealed that they profoundly gate and modify movements. Depending on the location of lesions or stimulation, there can be extreme poverty of all movements, abnormal postures, and uncontrollable rhythmic motor outputs.3
396
THE EXTRAPYRAMIDAL MOTOR SYSTEMS The basal ganglia and thalamus comprise a number of anatomically integrated regions involved in motor control.4,5 They also play important roles in emotional, motivational, associative, and cognitive functions. Basal ganglia regions include the caudate nucleus, putamen, internal and external segments of the globus pallidus, subthalamic nucleus, and substantia nigra. These regions have complex anatomical interconnections that are not fully characterized electrophysiologically. Thalamic regions participating in motor control include specific ventral, posterior, and intralaminar nuclei.6 The understanding of how these regions integrate motor information is based largely on knowledge of their relationship to the corticospinal pyramidal system. There are three types of subcortical extrapyramidal regions to consider: those that receive direct information from pyramidal or cortical regions with major influences on pyramidal regions; those with projections to pyramidal or directly related regions; and those that perform internal monitoring and regulation of extrapyramidal regions.
Subcortical Regions Receiving Pyramidal Input and Their Influence on the Pyramidal System The largest subcortical extrapyramidal region receiving pyramidal input from both supragranular and infragranular regions of the motor cortices is the putamen (Figs. 31–1 and 31–2).4 Together with the caudate nucleus, this striatal area receives an information from all cortical regions. The putamen passes on processed information through both a direct activating and an indirect inactivating pathway to the basal ganglia output nuclei, the internal globus pallidus, and the substantia nigra pars reticulata.4 These basal ganglia regions are small in comparison with the striatum (100-fold fewer neurons) and contain large nonspiny γ-amino butyric acid–ergic (GABAergic) inhibitory projection neurons. Striatal neurons also receive excitatory thalamic input from the ventral anterior, ventrolateral nuclei, and caudal intralaminar nuclei; receive inhibitory input from the external globus pallidus; and are modulated by dopamine from the substantia nigra pars compacta and mesencephalic tegmentum.4,7 Overall dopamine enhances activity in the direct pathway and decreases activity in the indirect pathway.8 The striatum con-
chapter 31 organization: pyramidal and extrapyramidal system
397
Cortical-cortical Premotor Pre-SMC 1˚ motor
Internal circuits
Throughput circuits
Dopamine GABA Glutamate ■
Figure 31–1. Basal ganglia internal feedback circuits (left) and throughput circuits (right). Projections from pyramidal neurons in the motor cortex innervate the putamen (red), the subthalamic nucleus (green), and the ventrolateral (gray) and caudal intralaminar (brown) thalamic nuclei. The basal ganglia output nuclei, the substantia nigra pars reticulata, and the internal globus pallidus (yellow), project to the motor thalamus (gray/brown) with information passing through a hyperdirect pathway from the subthalamus (green) or a direct pathway from the putamen (red) or an indirect pathway from the putamen (red) through the external globus pallidus (orange). Several feedback systems exist with information regulated within the putamen by γamino butyric acid–ergic (GABAergic) and cholinergic interneurons, by dopamine from the substantia nigra pars compacta (gray), and by glutamate from the caudal intralaminar thalamus (mauve). The subthalamic nucleus (green) and external globus pallidus (yellow) are strongly coupled.
tains mainly GABAergic spiny projection neurons and a small population of GABAergic and cholinergic interneurons (≈3% of striatal neurons). Striatal spiny neurons project to the globus pallidus and substantia nigra, as well as giving rise to dense local arbors that contact other spiny neurons.4 They are usually silent and discharge only when cortical information is received. The GABAergic interneurons establish contacts with the dendritic shafts of neighboring spiny neurons and form the structural basis for feedforward striatal surround inhibition. Striatal cholinergic interneurons, in contrast, are tonically active and play a major role in the learning of reward behavior. The smallest subcortical extrapyramidal region receiving pyramidal input from layer V neurons of the motor cortices is the subthalamic nucleus.9 This is the only cortical input to this nucleus, and this hyperdirect pathway conveys powerful excitatory effects from the motor cortices to the globus pallidus and substantia nigra pars reticulata, bypassing the striatum, with shorter conduction times than in the direct striatal pathway.9 It also receives significant inhibitory input from the globus pallidus and striatum.10 The subthalamic nucleus contains nonspiny excitatory glutamatergic neurons that conduct shortlatency excitatory responses to the globus pallidus and substantia nigra after cortical excitation.
Corticothalamic
Thalamocortical
Fast transmission Slow transmission ■
Figure 31–2. Pyramidal input to the thalamus (left) and thalamocortical pathways (right). Some corticocortical pathways are also indicated. Information from the presupplementary motor cortex (or area) is relayed to the supplementary and premotor cortices through the ventrolateral anterior (purple) and caudal intralaminar (brown) nuclei, as well by direct corticocortical connections. Feedback from the premotor cortices to the pre-SMC occurs via the mediodorsal thalamus (blue), whereas reciprocal feedback between the primary (1°) motor cortex and the ventrolateral posterior thalamus (purple).
Specific regions of the thalamus also receive pyramidal input from motor cortices.5 There is a reciprocal excitatory component from small layer VI neurons to the ventrolateral thalamus and a fast-conducting nonreciprocal excitatory component from layer V neurons that allows the synchronization of thalamocortical oscillations and information flow across functionally related cortical fields. Cortical regions associated with executive function (such as dorsolateral prefrontal cortex) have nonreciprocal connections to thalamic regions that project to premotor cortices (ventral anterior thalamus), whereas premotor cortices have nonreciprocal connections with thalamic regions that project to the primary motor cortex (ventrolateral thalamus).11 The thalamus contains nonspiny excitatory glutamatergic neurons that conduct short-latency excitatory responses after appropriate cortical excitation. These interconnections between the cortex and thalamus largely determine cortical activity, facilitating information transfer from one cortical region to another through a feedforward mechanism. The output nuclei of the basal ganglia inhibit thalamocortical activity in the ventral anterior, anterior ventrolateral, and caudal intralaminar nuclei.11
398
Section
VII
Motor System and Motor Diseases
Subcortical Regions Participating in the Internal Regulation of Extrapyramidal Systems There is significant internal modulation of the hyperdirect, direct, and indirect basal ganglia pathways (see Fig. 31–1). One of the basal ganglia regions that most influence striatal processing is the dopaminergic substantia nigra pars compacta, as discussed previously, although pallidal and thalamic projections also significantly modify striatal output. The large, tonically active, nonspiny dopaminergic neurons of the substantia nigra pars compacta receive input directly from striatal spiny projection neurons, which modifies their firing rate and patterns.8 This reinforces wanted behaviors and suppresses unwanted behaviors. These dopaminergic neurons also receive significant innervation from cortical, limbic, and brainstem regions and play a role in shifting attentional sets. The basal ganglia region with the most internal connections is the external segment of the globus pallidus.4 These pallidal neurons receive most input from the striatum and the subthalamic nucleus, as well as a small dopaminergic projection from the substantia nigra. Individual neurons in the external globus pallidus innervate the output nuclei, the subthalamic nucleus, and the substantia nigra pars compacta.4 About 25% of them also innervate the striatal GABAergic spiny neurons. These neurons provide the anatomical substrate for the synaptic integration of functionally diverse cortical information within the basal ganglia and appear to work in parallel with the subthalamic nucleus and striatum to set up appropriate oscillatory activity within the basal ganglia.10 They are therefore in a position to provide level-setting control of the activity through virtually the whole of the extrapyramidal basal ganglia system.
corresponds to the lower part of Brodmann’s area 6 and may be functionally subdivided into two or three regions. An alternative nomenclature derived by Matelli and colleagues15 refers to these areas as F4 and F5, F1 being the traditional primary motor cortex. The ventral premotor cortex areas are likely to be involved in the transformation of information about peripersonal space and visual space into motor commands for movements, particularly of the upper limb. The dorsal premotor cortex corresponds to the superior part of area 6, which also can be subdivided on functional grounds (F2 and F7). The precise role of F2 is debated, but it is involved in reaching and visual signaling. The F7 area is involved in eye movement control and perhaps also in stimulus-response associations for movements.16 The mesial part of area 6, once considered to be a single area, the supplementary motor area, is now subdivided into the supplementary motor area proper (F3) and the presupplementary motor area (F6). The supplementary motor area was originally defined in humans by Penfield and Welch.17 The main supplementary motor area is involved in preparation and selection of movements and perhaps in the initial learning of motor sequences.18 Finally, there are motor cortical areas within the cingulate sulcus (Brodmann areas 23 and 24), termed the rostral, dorsal, and ventral cingulate motor areas. The motor function of these nonprimary motor cortical areas has been discerned by a mixture of methods, including electrical stimulation and neurophysiological mapping, neuroanatomical tracing, and functional neuroimaging in primates. These areas not only contain some somatotopic organization (e.g., face, arm, and leg separations) but also have some direct projections of varying strength to the primary motor cortex and to the brainstem and spinal cord.1,19,20
Primary Motor Cortex THE MOTOR CORTICES AND PYRAMIDAL SYSTEM Pyramidal neurons in the somatomotor cortices send corticospinal and corticobulbar axons through the pyramidal tract. The primary motor cortex is usually known as area 4, defined according to Brodmann’s classic analysis of the cytoarchitecture of the human brain.12 In addition to its own local circuitry, it contains a topographically organized motor output to the bulbar muscles and to the trunk and extremities. The precise borders of this and other areas have been disputed partly because it is difficult to depict the areas precisely on maps of the cortical surface, which cannot reveal the borders in the depths of sulci (for review, see Zilles13). The caudal border of the primary motor cortex is clearly demarcated in the fundus of the central sulcus with its rostral border close to the anterior of the central sulcus. Hence, laterally over the hemisphere, the main part of area 4 lies in the central sulcus rather than on the external cortical surface. This delineation of the rostral edge of the primary motor cortex varies between individuals and relies on several architectural and cytoarchitectural features (see later discussion), and its existence is supported by highresolution imaging and cytoarchitectonic mapping.14 Before some of the specific features of the primary motor cortex are described, other cortical areas that have a motor function must be recognized. Although several nomenclatures exist for these areas, there is broad agreement that the following cortical areas are involved. The ventral premotor cortex
Certain anatomical features are unusual for this cortical region. First, it has the greatest cortical thickness (≈3.8 mm, the adjacent sensory cortex being narrowest at ≈1.8 mm), and it has a relatively low density of neuronal cell bodies.13 Presumably this allows substantial synaptic integration for flexible selection of motor outputs. Second, the area is agranular, lacking an obvious layer IV, and it contains giant Betz cells. These pyramidal neurons are characterized by large and variable size and the presence of many dendrites originating from their cell bodies, in addition to their major apical and basal dendrites.21 Pyramidal cells with output to subcortical and cortical regions are distributed throughout layers II to VI, with the majority in layers III and V. Layer V has a low density of neuronal packing, and approximately 15% of cells have projections through the pyramidal tract and are thus corticospinal cells. Such projections probably make up about 30% of the descending pyramidal tract (see later discussion). The projecting axons are largely myelinated with a range of conduction velocities. The intrinsic connectivity of the primary motor cortex, as in most of the cortex, is arranged radially in columns. Intrinsic nonpyramidal neurons (including stellate and basket cells) have radially oriented dendrites and make largely local connections. Basket cells exert GABAergic inhibition of pyramidal cell output, part of a recurrent, laterally spreading inhibitory circuit from local corticofugal cells.22 About a third of local pairs of primary cortical cells show evidence of correlated drive during tasks, which indicates that they are receiving common inputs.23,24
chapter 31 organization: pyramidal and extrapyramidal system Cortical and Thalamic Input to the Pyramidal System According to findings with various neuroanatomical techniques and electrophysiological mapping, many cortical areas project directly to the primary motor cortex (see Fig. 31–2).15 These include the ventral and dorsal premotor areas (both subfields of area 6), supplementary motor areas, and cingulate (rostral, dorsal, and ventral) motor areas. Some degree of somatotopic organization is maintained in these projections to the primary motor cortex. Sensory information from parietal areas also project either directly or indirectly through sensory cortex to the motor cortex.25 Corticocortical projection neurons are usually derived from the small supragranular pyramidal neurons and provide excitatory drive to supragranular neurons in nearby cortical regions. Within the cortical columns, these supragranular neurons provide strong excitatory drive to the large layer V pyramidal output neurons, thus reinforcing the thalamic input to these neurons. As discussed previously, a number of thalamic nuclei assist in determining cortical activity by facilitating information transfer from one cortical region to another through a feedforward mechanism.11 In particular, the ventral anterior thalamus feeds forward executive information to premotor cortices
(under basal ganglia influence), the ventrolateral anterior thalamus feeds forward premotor information to the primary motor cortex (under basal ganglia and cerebellar influence), and the ventrolateral posterior thalamus provides feedback from primary motor cortex (under cerebellar influence). These reciprocal and nonreciprocal corticothalamocortical connections form cohesive integrated circuits for the control of movement.11
Corticospinal Outputs and Their Origin In addition to major corticofugal outputs to the medullary motor nuclei and the spinal cord from the lower part of layer V in the primary motor cortex, the upper part of its layer V has outputs to the striatum, red nucleus, pons, and reticular formation (Fig. 31–3). The focal outputs to the principal relay nuclei of the thalamus originate in layer VI, whereas corticocortical, corticostriate, and corticocallosal fibers arise from layer III.26,27 Evolution of mammals and ultimately primates appears to have shaped the outputs to the medulla and spinal cord similarly, with a progressive shift away from projections to sensory nuclei and toward the motor nuclei. The most direct projections—that is, monosynaptic corticomotoneuronal
■
Motor cortices Planning of voluntary movements
Motor cortical and other corticospinal outputs
Input from muscle and other afferents
Other supraand propriospinal outputs
Spinal cord α and γ motoneurons
Muscle
Corticospinal tract
399
Figure 31–3. Pyramidal pathway through the corticospinal tract (left) and the influences most directly affecting the motoneurons innervating muscle (right).
400
Section
VII
Motor System and Motor Diseases
connections—arise largely from the caudal part of area 4. These outputs diverge at the motoneuronal level in such a way that one corticospinal axon can supply more than one motoneuron pool monosynaptically, and it probably synapses on many motoneurons within each pool.28 The primary motor cortex is concerned not with contraction of single muscles but with the actions of whole groups of functionally related muscles. Its function is to bring them to action both in specific movements and when a more static posture is maintained.29 The divergence of primary motor cortical output and the presence of multiple motor cortical areas allows for parallel control of muscle activity. The densest projections to the motoneuron pools arise in the primary motor cortex.19
COMMENTS ON FUNCTION AND CONCLUSIONS The following points deal with some of the complications of pyramidal and extrapyramidal functional anatomy as discussed in this chapter: 1. There is no comprehensive model of the motor cortical system that takes into account the range of inputs reaching the primary motor cortex or its multiple output paths, many of which are effectively “upstream” of the final common path at the motoneuron pool. Although description of the anatomical complexity promotes physiological insight, the special microcircuitry of the primary motor cortex and its increasing monosynaptic projection to motoneurons in primates emphasize its pivotal role in volitional movement. At a more fine-grained level, defining the anatomical convergent and divergent projections of the major motor cortical area is only one step in generating a comprehensive model, because it will ultimately be necessary to incorporate synaptic function. 2. There is increasing recognition of the importance of the different cortical areas that project to the motoneuron pool. Many of these premotor and cingulate regions receive a specific dominant set of projections from the thalamus, prefrontal cortices, and parietal lobe, and they are thus likely to have a more specialized role in shaping the final motor output. This implies that any functional “units” of cortical control of movement must include both its sensory input (through parietal projections) and its higher order motor role (through prefrontal projections) relating to, for example, motivation, planning, and skill acquisition. However, studies based on clinical lesions, electrical stimulation, and neuroimaging reveal the capacity of the different motor cortical areas to “take over,” at least partially, the functions of others. Hence, properties of ipsilateral corticospinal projections are altered after a middle cerebral artery stroke or when one motor cortical region is temporally depressed.30 3. Although the human corticospinal system can exert its actions on the motoneuron pool through direct monosynaptic input, less direct routes are important and numerically predominant. The corticospinal system is heavily engaged in fine motor tasks, but some of this motor command reaches motoneurons via less direct routes, including an important set of propriospinal premotoneurons.31,32 One function for the corticospinal system is the appropriate recruitment of these spinal premotor circuits.
K E Y
P O I N T S
●
The corticospinal pyramidal system arises from frontal motor cortical regions, which differ in their organization and function. Corticospinal neurons from primary motor cortex directly innervate motoneurons; corticospinal neurons from other motor cortices largely innervate excitatory and inhibitory spinal interneurons.
●
Interconnections between the cortex and thalamus largely determine cortical activity, facilitating information transfer from one cortical region to another through feedforward and feedback mechanisms.
●
The basal ganglia extrapyramidal system consists of three intersecting pathways (hyperdirect, direct, and indirect) that innervate the inhibitory output nuclei of the basal ganglia and process cortical information that modulates thalamocortical motor activity and drive.
Suggested Reading 1. Matelli M, Luppino G, Geyer S, et al: Motor cortex. In Paxinos G, ed: The Human Nervous System. New York: Academic Press, 2004, pp 973-996. 2. Rizzolatti G, Luppino G: The cortical motor system. Neuron 2001; 31:889-901. 3. Porter R, Lemon RN: Corticospinal Function and Voluntary Movement. Oxford, UK: Clarendon, 1993. 4. Nambu A: A new dynamic model of the cortico-basal ganglia loop. Prog Brain Res 2004; 143:461-466. 5. Bolam JP, Hanley JJ, Booth PA, et al: Synaptic organization of the basal ganglia. J Anat 2000; 196:527-542.
References 1. Dum RP, Strick PL: Motor areas in the frontal lobe of the primate. Physiol Behav 2002; 77:677-682. 2. Sherman SM, Guillery RW: On the actions that one nerve cell can have on another: distinguishing “drivers” from “modulators.” Proc Natl Acad Sci U S A 1998; 95:7121-7126. 3. Vilensky JA, Gilman S: Integrating the work of D. DennyBrown and some of his contemporaries into current studies of the primate motor cortex. J Neurol Sci 2001; 182:83-87. 4. Bolam JP, Hanley JJ, Booth PA, et al: Synaptic organisation of the basal ganglia. J Anat 2000; 196:527-542. 5. Guillery RW, Sherman SM: The thalamus as a monitor of motor outputs. Philos Trans R Soc Lond B Biol Sci 2002; 357:1809-1821. 6. Darian-Smith C, Darian-Smith I: Thalamic projections to areas 3a, 3b, and 4 in the sensorimotor cortex of the mature and infant macaque monkey. J Comp Neurol 1993; 335:173199. 7. Smith Y, Raju DV, Pare JF, et al: The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 2004; 27:520-527. 8. Onn SP, West AR, Grace AA: Dopamine-mediated regulation of striatal neuronal and network interactions. Trends Neurosci 2000; 23:S48-S56. 9. Hamani C, Saint-Cyr JA, Fraser J, et al: The subthalamic nucleus in the context of movement disorders. Brain 2004; 127:4-20.
chapter 31 organization: pyramidal and extrapyramidal system 10. Bevan MD, Magill PJ, Terman D, et al: Move to the rhythm: oscillations in the subthalamic nucleus–external globus pallidus network. Trends Neurosci 2002; 25:525-531. 11. Haber S, McFarland NR: The place of the thalamus in frontal cortical-basal ganglia circuits. Neuroscientist 2001; 7:315-324. 12. Brodmann K: Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth, 1909, p 324. 13. Zilles K: Architecture of the human cerebral cortex: regional and laminar organization. In Paxinos G, ed: The Human Nervous System. New York: Academic Press, 2004, pp 9971055. 14. Geyer S, Ledberg A, Schleicher A, et al: Two different areas within the primary motor cortex of man. Nature 1996; 382:805-807. 15. Matelli M, Luppino G, Geyer S, et al: Motor cortex. In Paxinos G, ed: The Human Nervous System. New York: Academic Press, 2004, pp 973-996. 16. Passingham RE: The Frontal Lobe and Voluntary Action. Oxford, UK: Oxford University Press, 1993. 17. Penfield W, Welch K: The supplementary motor area of the cerebral cortex; a clinical and experimental study. AMA Arch Neurol Psychiatry 1951; 66:289-317. 18. Tanji J: New concepts of the supplementary motor area. Curr Opin Neurobiol 1996; 6:782-787. 19. Lemon RN, Maier MA, Armand J, et al: Functional differences in corticospinal projections from macaque primary motor cortex and supplementary motor area. Adv Exp Med Biol 2002; 508:425-434. 20. Miyachi S, Lu X, Inoue S, et al: Organization of multisynaptic inputs from prefrontal cortex to primary motor cortex as revealed by retrograde transneuronal transport of rabies virus. J Neurosci 2005; 25:2547-2556. 21. Scheibel ME, Scheibel AB: The dendritic structures of the human Betz cell. In Braxier AAB, Pets H, eds: Architectonics
22. 23. 24. 25. 26. 27. 28. 29. 30.
31. 32.
401
of the Cerebral Cortex. New York: Raven Press, 1978, pp 4357. Hendry SH, Houser CR, Jones EG, et al: Synaptic organization of immunocytochemically identified GABA neurons in the monkey sensory-motor cortex. J Neurocytol 1983; 12:639-660. Fetz EE, Shupe LE: Neural network models of the primate motor system. In Eckmiller R, ed: Advanced Neural Computers. Amsterdam: Elsevier, 1991, pp 43-50. Baker SN, Olivier E, Lemon RN: An investigation of the intrinsic circuitry of the motor cortex of the monkey using intracortical microstimulation. Exp Brain Res 1998; 123:397-411. Jones EG: Ascending inputs to, and internal organization of, cortical motor areas. Ciba Found Symp 1987; 132:21-39. Jones EG, Wise SP: Size, laminar and columnar distribution of efferent cells in the sensory-motor cortex of monkeys. J Comp Neurol 1977; 175:391-438. Jones EG: Laminar distribution of cortical efferent cells. In Peters A, Jones EG, eds: Cerebral Cortex. New York: Plenum Press, 1984. Lemon RN, Baker SN, Davis JA, et al: The importance of the cortico-motoneuronal system for control of grasp. Novartis Found Symp 1998; 218:202-218. Kurtzer I, Herter TM, Scott SH: Random change in cortical load representation suggests distinct control of posture and movement. Nat Neurosci 2005; 8:498-504. Strens LH, Fogelson N, Shanahan P, et al: The ipsilateral human motor cortex can functionally compensate for acute contralateral motor cortex dysfunction. Curr Biol 2003; 13:1201-1205. Pierrot-Deseilligny E: Propriospinal transmission of part of the corticospinal excitation in humans. Muscle Nerve 2002; 26:155-172. Fetz EE, Perlmutter SI, Prut Y, et al: Roles of primate spinal interneurons in preparation and execution of voluntary hand movement. Brain Res Brain Res Rev 2002; 40:53-65.
CHAPTER
32
APRAXIA ●
●
●
●
Ramón C. Leiguarda
Apraxia is one of the more frequent consequences of brain damage and can lead to severe disabilities in daily life. The term apraxia covers a wide spectrum of higher order motor disorders caused by acquired brain disease that affects the performance of skilled, learned movements with or without preservation of the ability to perform the same movement outside the clinical setting in the appropriate situation or environment. The disturbance of purposive movements cannot be termed apraxia, however, if it results from a language comprehension disorder or from dementia or if the patient suffers from any elementary motor or sensory deficit (i.e., paresis, dystonia, ataxia) that could fully explain the abnormal motor behavior.1-3 Apraxia is found mostly in patients with stroke, but the disorder can result from a wide variety of other focal lesions (i.e., trauma, tumors) or from diffuse brain damage as observed in Alzheimer’s disease or corticobasal degeneration.2 Praxic disorders may affect various body parts, such as the eyes, face, trunk, or limbs, and may involve both sides of the body (i.e., ideational and ideomotor apraxias), one side preferentially (i.e., limb-kinetic apraxia [LKA]), or, alternatively, interlimb coordination, as in the case of apraxia of gait.
LIMB APRAXIAS Hugo Liepmann originally posited that the idea of the action, or movement formula, containing the space-time picture of the movement, was stored in the left parietal lobe and that in order to carry out a skilled movement, the space-time plan must first be retrieved and associated via cortical connections with the innervatory pattern stored in the left sensorimotorium— mainly the premotor cortex—which in turn conveys the information on formula to the left primary motor areas. When the left limb performs the movement, the information must be transmitted from the left to the right sensorimotorium through the corpus callosum to activate, thereafter, the right motor cortex. Liepmann conceived of ideational apraxia as a disruption of the space-time plan or its proper activation, so that it was impossible to construct the idea of the movement; the patient would not know what to do. In contrast, in ideomotor apraxia, the space-time plan was intact but it could no longer guide the innervatory engrams that implemented the movement because it was disconnected from them; the patient knew
402
what to do but not how to do it. Finally, LKA appeared when the disruption of the innervatory engrams interfered with the selection of the muscle synergies necessary to perform the skilled movement.4,5 Liepmann’s initial description and classification of these three types of apraxia have such clarity and influence that they still underlie the most widely used existing schemes of apraxic disturbances. In 1985, Roy and Square6 advanced a model for the organization of action that was based on the operation of a two-part system involving both conceptual and production components. The conceptual system involves knowledge of objects and tools in terms of the actions and functions they serve and knowledge of actions independent of tools or objects but in which the use of tools and objects may be incorporated. On the other hand, the production system incorporates a sensorimotor component of knowledge, as well as encompassing the perceptual motor processes for organizing and executing action. According to this model, dysfunction of the praxis conceptual system would give rise to conceptual or ideational apraxia, whereas impairment of the praxis production system would induce ideomotor apraxia.6 Thereafter, an influential cognitive neuropsychological model, also mapped onto the model of language processing, was introduced by Rothi and colleagues.7 They proposed to separate input pathways for verbal and visual stimuli to explain the dissociation between the ability to perform an action on command versus on imitation; to separate semantic and nonsemantic pathways to account for dissociations in the ability to represent meaningful versus meaningless actions; and to separate input and output lexicons to allow for differences in the ability to conceptualize actions and to perform them.7 More recently, Buxbaum and associates8 proposed an interplay between a dynamic body-centered representation of actions and stored representation of learned actions in order to explain the different forms of ideomotor apraxia, and Leiguarda and Marsden9 suggested that the most common form of ideomotor apraxia as well as of LKA can be interpreted as caused by disruption of multiple parallel parietofrontal circuits involved in sensorimotor transformations.
Evaluation of Limb Praxis A systematic evaluation of limb praxis is crucial in order to (1) identify the presence of apraxia, (2) classify correctly the nature
chapter 32 apraxia T A B L E 3 2 – 1.
403
Assessment of Limb Praxis
Intransitive movements Transitive movements Tool* selection tasks Alternative tool selection tasks Mechanical problem-solving task Multiple-step tasks Gesture recognition and discrimination tasks
Nonrepresentational (e.g., touch your nose, wiggle your fingers). Representational (e.g., wave goodbye, hitchhike) (e.g., use a hammer or use a screwdriver) under verbal, visual, and tactile modalities Imitation of meaningful and meaningless movements, postures, and sequences To select the appropriate tool to complete a task, such as a hammer for a partially driven nail To select an alternative tool such as pliers to complete a task such as pounding a nail, when the appropriate tool (i.e., hammer) is not available (e.g., to select the appropriate one of three novel tools for lifting a wooden cylinder out of a socket). (e.g., to prepare requiring actions such as prepare a letter for mailing) To assess the capacity to comprehend gestures, either verbally (to name gestures performed by the examiner) or nonverbally (to match a gesture performed by the examiner with cards depicting the tool/object† corresponding to the pantomime); and to assess the ability to discriminate a well from a wrongly performed gesture
From Leiguarda R: Apraxias as traditionally defined. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 303-338. *Tool: implement with which an action is performed (e.g., hammer, screwdriver). † Object: the recipient of the action (e.g., nail, screw).
of limb praxis deficit according to the errors committed by the patient and the modality through which these errors are elicited, and (3) gain an insight into the underlying mechanism of the patient’s abnormal motor behavior (Table 32–1). A patient’s performance should be assessed in both forelimbs if an elementary sensorimotor deficit does not preclude testing the limb contralateral to the damaged hemisphere. Several types of intransitive and transitive movements must be evaluated because apraxic patients commonly perform some but not all movements in a particularly abnormal manner and/or because individual differences appear in some but not all components of a given movement. Therefore, the dissimilar complexity and particular features of each skill movement should be considered in order to analyze and interpret praxic errors accurately. For instance, (1) movements may or may not be repetitive in nature (e.g., hammering versus using a bottle opener to remove a cap); (2) an action may be composed of sequential movements (e.g., reaching for a glass and raising it to one’s lips to drink); (3) a movement may primarily reflect proximal limb control (transport) (e.g., transporting the wrist when carving a turkey), proximal and distal limb control (e.g., reaching for and grasping a glass of water), or primarily distal control (e.g., manipulating a pair of scissors); and (4) movements may be performed in the peripersonal space (e.g., carving a turkey) or in a body-centered space (e.g., brushing teeth) or require the integration of both (e.g., drinking). Transitive movements should be assessed under different modalities, including verbal, visual (seeing the tool or the object on which the tool works), and tactile (using actual tools and/or objects), as well as on imitation, because impairment can be seen under some performance conditions but not others. Nevertheless, the most sensitive test for apraxia is to ask patients to pantomime to verbal commands, because actions must be performed without guidance through visual or tactile feedback from the object and thus are almost entirely dependent on stored movement representations. In addition to the specific praxis assessment tasks listed in Table 32–1, it is important to carry out a complete cognitive evaluation, because findings may contribute to an understanding of the neural mechanisms of some praxic deficits. Analysis of a patient’s performance is based on both accuracy and error patterns (Table 32–2). Detailed error analysis is
crucial both for unveiling and for properly classifying an apraxic disorder; patients with ideational apraxia have difficult mainly with sequencing actions (e.g., making coffee) and exhibit content errors or semantic parapraxias (e.g., mimicking use of a hammer when requested to use a knife). Patients with ideomotor apraxia show primarily temporal and spatial errors, which are more evident when they perform transitive rather than intransitive movements. Errors in LKA represent slowness, coarseness, and fragmentation of finger and hand movements.2,3 Three-dimensional motion analysis of different types of movements has provided a better and more accurate method of objectively capturing the nature of the praxis errors observed in clinical examination. Patients with ideomotor apraxia caused by focal left hemisphere lesions, by different asymmetrical cortical degenerative syndromes, and by basal ganglion disease have shown several kinematic abnormalities of dissimilar complexity, such as slow and hesitant build up of hand velocity, irregular and nonsinusoidal velocity profiles, abnormal amplitudes, alterations in the plane of motion and in the directions and shapes of wrist trajectories, decoupling of hand speed and trajectory curvature, and loss of interjoint coordination (Fig. 32–1).10,11 The study of manipulating finger movements in patients with LKA also disclosed severe abnormalities that unveiled the nature of the motor deficit. The workspace is highly irregular and of varying amplitude, there is breakdown of the temporal profiles of the scanning movements, and, overall, severe lack of coordination between fingers has been found (Fig. 32–2).12
Lateralization of Praxic Functions Apraxia, as tested by the imitation of gestures and object use pantomime, has been found in about 50% of patients with left hemisphere damage and in fewer than 10% of those with right hemisphere damage,1 which means that some praxic functions or some specific components of learned skilled movement are bilaterally represented or are preferentially processed in the right hemisphere. Nevertheless, most of the errors exhibited by patients with ideomotor apraxia are seen equally in patients with left or right hemisphere damage when they pantomime
404
Section
VII
Motor System and Motor Diseases
T A B L E 3 2 – 2. Types of Praxis Errors Temporal S = sequencing: Some pantomimes require multiple positionings that are performed in a characteristic sequence. Sequencing errors involve any perturbation of this sequence, including addition, deletion, or transposition of movement elements as long as the overall movement structure remains recognizable. T = timing: This error reflects any alterations from the typical timing or speed of a pantomime and may include abnormally increased, decreased, or irregular rate of production or searching or groping behavior. O = occurrence: Pantomimes may involve either single (i.e., unlocking a door with a key) or repetitive (i.e., screwing in a screw with a screwdriver) movement cycles. This error type reflects any multiplication of single cycles or reduction of a repetitive cycle to a single event. Spatial A = amplitude: Any amplification, reduction, or irregularity of the characteristic amplitude of a target pantomime. IC = internal configuration: When pantomiming, the fingers and hand must be in specific spatial relation to one another to reflect recognition and respect for the imagined tool. This error type reflects any abnormality of the required finger/hand posture and its relationship to the target tool. For example, when asked to pretend to brush teeth, the subject’s hand may close tightly into a fist with no space allowed for the imagined toothbrush handle. BPO = body-part-as-object: The subject uses his/her finger, hand, or arm as the imagined tool of the pantomime. For example, when asked to smoke a cigarette, the subject might puff on his or her index finger. ECO = external configuration orientation: When pantomiming, the fingers/hand/arm and the imagined tool must be in a specific relationship to the “object” receiving the action. Errors of this type involve difficulties orienting to the “object” or in placing the “object” in space. For example, the subject might pantomime brushing teeth by holding his/her hand next to his/her mouth without reflecting the distance necessary to accommodate an imagined toothbrush. Another example would be when asked to hammer a nail, the subject might hammer in differing locations in space, reflecting difficulty in placing the imagined nail in a stable orientation or in a proper plane of motion (abnormal planar orientation of the movement). M = movement: When acting on an object with a tool, a movement characteristic of the action and necessary to accomplish the goal is required. Any disturbance of the characteristic movement reflects a movement error. For example, a subject, when asked to pantomime using a screwdriver, may orient the imagined screwdriver correctly to the imagined screw but instead of stabilizing the shoulder and wrist and twisting at the elbow, the subject stabilizes the elbow and twists at the wrist or shoulder. Content P = perseverative: The subject produces a response that includes all or part of a previously produced pantomime. R = related: The pantomime is an accurately produced pantomime associated in content with the target. For example, the subject might pantomime playing a trombone for a target of a bugle. N = nonrelated: The pantomime is an accurately produced pantomime not associated in content with the target. For example, the subject might pantomime playing a trombone for a target of shaving. H = the patient performs the action without benefit of a real or imagined tool: For example, when asked to cut a piece of paper with scissors, he or she pretends to rip the paper. Other NR = no response. UR = unrecognizable response: The response shares no temporal or spatial features of the target. From Rothi LJG, Heilman KM, eds: Apraxia: The Neuropsychology of Action. East Sussex, UK: Psychology Press, 1997.
nonrepresentative and representative/intransitive gestures, but they are observed predominantly in patients with left hemisphere damage when they pantomime transitive movements, because this action is performed outside the natural context. Moreover, it has been suggested that, whereas either hemisphere would be able to process both intransitive movements and transitive movements with tools/objects, the left hemisphere would be dominant not only for the “abstract” performance (pantomiming to verbal command) of transitive movements but also for learning and reproducing novel movements such as meaningless movements and sequences.3 The left hemisphere also seems to be specialized for the selection of limb movements that are appropriate for the use of an object and for the retrieval of action knowledge in general, including knowledge related to tools.3 Most functional neuroimaging studies in which researchers have evaluated pantomiming tool-use gestures have revealed activation of parietofrontal areas predominantly in the left hemisphere, regardless of which hand was used.13-15 Frydman and colleagues16 specifically studied the lateralization of praxis assessed through pantomiming transitive gestures. They found that transitive gestures involving mainly distal muscles when pantomimed with the right hand activated frontoparietal asso-
ciation areas in the left hemisphere. When the same movement was performed with the left hand, activation also predominated on the left hemisphere, with the exception of the premotor cortex, which showed bilateral activation in most subjects. In turn, transitive gestures involving proximal limb movements performed with either the right or the left hand caused bilateral parietofrontal activation. Thus, transitive gestures, when pantomimed in response to verbal command, are differentially represented interhemispherically and intrahemispherically, depending on whether the movement involves predominantly proximal or distal musculature and whether it is performed with the right or the left hand.16
Types of Limb Apraxia Ideational or Conceptual Apraxia Liepmann defined ideational apraxia as an impairment in performing tasks that required a sequence of several acts with tools and objects (e.g., prepare a letter for mailing).5 However, other authors use the term to denote a failure to use single tools appropriately.2 To overcome this confusion, Ochipa and associ-
chapter 32 apraxia 200
405
350
150 100
250
50 0 150 ⫺50 ⫺100 ⫺200 ⫺150 ⫺100 ⫺50 0 50 100 Position X (mm)
150
200
250
50
Lateral view
⫺340
⫺250
⫺220
⫺180
Frontal view
Z (mm)
350
Shoulder 200 250 100 Hand 150
0 Elbow
Wrist
00 500
A ■
400
300
200
100
Lateral view
50 ⫺400
⫺300
⫺200
Frontal view
Figure 32–1. Kinematic correlates of ideomotor praxis errors. A, Lateral and frontal views of reconstructed trajectories of limb segments during a slicing gesture performed by a control subject and by a patient with ideomotor apraxia (IMA). In the control, wrist trajectories (top left and right) follow a path perpendicular to the target/object and are aligned along the sagittal plane with slight vertical and horizontal displacement, whereas the patient (bottom left and right) exhibits abnormal lateral wrist displacement and incorrect movement axis orientation. B, Superior, lateral, and frontal views of wrist paths in a control subject (left) and in patients with ideomotor apraxia (right). C, Interjoint coordination in a control subject (top left and right) and in a patient with ideomotor apraxia (bottom left and right). The control subject shows a smooth and linear relationship between elbow flexion/extension and upper arm yaw; as the elbow extends, the upper arm moves laterally across the body in a well-coordinated pattern. The patient, in contrast, shows distorted angle/angle relationships as a result of poor coordination between elbow flexion/extension and upper arm yaw, as well as asynchronous intersegmental joint velocities. Continued
ates17 suggested restricting the term ideational apraxia to a failure to conceive a series of acts leading to an action goal, and they introduced the term conceptual apraxia to denote a loss of knowledge of how objects are used. However, a strict difference between ideational and conceptual apraxia is not always feasible, inasmuch as patients with ideational apraxia not only fail on tests of multiple object use but may also perform abnormally when using a single object. Thus, ideational apraxia or conceptual apraxia could be defined as a deficit in the conception of a single movement or of a sequence of them, so that the patient does not know what to do.3
Patients with ideational or conceptual apraxia exhibit primarily content errors or semantic parapraxias (e.g., using a comb as a toothbrush) in the performance of transitive movements (see Table 32–2). They are unable to associate tools with the objects that receive their action; thus, when a partially driven nail is shown, the patient may select a pair of scissors rather than a hammer from an array of tools to complete the action and may also fail to describe the function of a tool or be unable to point out a tool when its function is described by the examiner. In addition, a patient may have difficulties in matching objects for shared purposes: for example, when asked to
406
Section
VII
Motor System and Motor Diseases
B 109
86
126
Wrist velocity (m/s)
Elbow flexor extension (degrees)
140
112 98
64
43
84
21
70
0 0
0
22
Upper arm yaw (degrees)
44
66
88
111
37
47
Elbow velocity (m/s)
54
Wrist velocity (m/s)
Elbow flexor extension (degrees)
09 52
50
48
46
07 05 03 01
44 0 80
0
Upper arm yaw (degrees)
09
18
28
Elbow velocity (m/s)
C ■
Figure 32–1, cont’d.
chapter 32 apraxia
407
Amplitude (cm)
2 Thumb 1
0
Index
5
0
10
15
Time (sec)
C A
Amplitude (cm)
6 Thumb 4
2 Index 0 0
5
10
15
Time (sec)
D
B ■
Figure 32–2. Kinematic analysis of manipulative finger movements. Spatial and temporal characteristics of manipulative finger movements in a control subject (top left and right) and in a patient with LKA (bottom left and right). In A and C, three-dimensional views of fingertips are displayed. In B and D, the temporal variation of movement trajectories is shown. The movements of the patient with limb-kinetic apraxia (LKA) showed highly disrupted spatial organization and deranged temporal characteristics, distinctly different from those of the control subject.
complete an action and the appropriate tool is not available (e.g., a hammer to drive a nail), the patient may select not the most adequate tool for that action (e.g., a wrench) but rather one that is inadequate (e.g., a screwdriver).18 Patients with ideational apraxia are impaired in the sequencing of tool/object use, exhibiting many types of errors including deletion, addition, omission, misuse, substitution, and perseveration and are disabled in everyday life, because they use tools/objects improperly, select the wrong tools/objects for an intended activity, perform a complex sequential activity (e.g., making espresso) in a wrong order, or cannot complete the task at all.19 Ideational
apraxia has been traditionally allocated to the left parietooccipital and parietotemporal regions, although left frontal and frontotemporal lesions may also cause ideational apraxia or conceptual apraxia.5,18,19 Nevertheless, semantic or conceptual errors are observed particularly in patients with temporal lobe pathology (e.g., semantic dementia).20
Ideomotor Apraxia Ideomotor apraxia has been defined as “an impairment in the timing, sequencing, and spatial organization of gestural
408
Section
VII
Motor System and Motor Diseases
movements.”7 Patients with ideomotor apraxia exhibit mainly temporal and spatial errors. The movements are incorrectly produced, but the goal of the action can usually be recognized. Transitive movements are more affected than intransitive ones when patients pantomime in response to commands, and patients usually do better on imitation than when responses are elicited through verbal commands. Acting with tools/objects is performed better than pantomiming their use, but even so, movements may not be entirely normal. Ideomotor apraxia is commonly associated with damage to the parietal association areas surrounding the intraparietal sulcus, less frequently with lesions of the premotor and prefrontal cortices and supplementary motor area, and usually with disruption of the intrahemispheric white matter bundles that interconnect parietal and frontal areas. Small lesions of the basal ganglia and thalamus may cause ideomotor apraxia, but in the majority of patients, the pathology extends to the internal capsule, as well as to the periventricular and peristriatal white matter.2,9
Callosal Apraxia
Limb-Kinetic Apraxia
Modality-specific or dissociation apraxias are praxic deficits exhibited by patients who commit errors only, or predominantly, when the movement is evoked by one but not all modalities.7,29 Thus, some patients may perform abnormally only under verbal commands; this deficit has been attributed to a left hemispheric lesion probably located in the parietal lobe, which disrupts the lexicomotor transformation process, or in the corpus callosum.28,30,31 Investigators have also described patients who performed poorly in response to seeing an object but performed considerably better when given the object tactile input or when asked to gesture to the name of the object.32 As an exception, some patients may be unable to use tool/objects but can correctly pantomime their use on commands.33 Furthermore, investigators have described patients who, unlike those with ideomotor apraxia who improved on imitation, were more impaired when imitating than when pantomiming in response to command (conduction apraxia)34 or could not imitate but performed flawlessly under other modalities; this situation is termed visuoimitative apraxia.35 Deficits may be restricted solely to the imitation of meaningless gestures with preserved imitation of meaningful gestures36,37 (see later discussion).
Many clinicions do not consider LKA a true apraxia but merely the expression of a basic motor (corticospinal) deficit. However, studies performed since 2000 clearly demonstrated— as Kleist and Liepmann originally suggested5,21,22—that LKA is a higher order motor disorder over and above a corticospinal or basal ganglia deficit.9,12 The deficit in LKA is confined mainly to finger and hand movements contralateral to the lesion, regardless of the affected hemisphere, with preservation of power and sensation. Manipulative finger movements are predominantly affected. However, in most cases, all movements, either complex or routine and independently of the modality needed to evoke them, are involved. There is a delay in the initiation of movements, as well as slowing in their execution, but what is especially striking is the temporal disordering of cooperative muscle action and loss of selective muscle activation; the fingers no longer act in concert, and there is lack of interfinger coordination. Simultaneous and sequential actions of individual fingers are distorted, and the resulting movement becomes coarse, fragmented, and mutilated. Fruitless attempts usually precede wrong movements, which in turn are frequently contaminated by extraneous movements. Imitation of finger postures is also abnormal, and some patients use the less affected or normal hand to reproduce the requested posture. The severity of the deficit is consistent, exhibited to the same degree in everyday activities as in the clinical setting; not presenting therefore voluntary-automatic dissociation.5,3,12,23 Performance with the limb-kinetic apraxic hand may superficially resemble tactile apraxia caused by posterior parietal lesions, inasmuch as both are unilateral finger and hand apraxias, with gross disturbances of object exploration and manipulation. However, intransitive and expressive movements are preserved, and imitation of hand and finger movements is normal in tactile apraxia. Tactile apraxia is a unimodal somatosensorimotor transformation disorder characterized by a specific inability to engender adequate finger movements required for the exploration of an object held in the hand. No apraxia is present when the patient sees the object; it appears only when he or she is blindfolded and starts actively touching it. Somatosensory functions, particularly tactile recognition, may be normal or moderately disturbed.3
Damage to the body of the corpus callosum (with or without associated genu involvement) may induce a unilateral apraxia deficit of the nondominant limb, the characteristics of which may vary according to the type of test given and the lateralization pattern of praxic skills present in each patient, although the most enduring defect is demonstrated when verbal-motor tasks, such as pantomiming in response to command, are used.24-27 Some patients cannot correctly pantomime in response to verbal commands with their left hands but perform normally on imitation and object use,28 whereas others cannot use their left hands on command, by imitation or while holding the object.25,27 Moreover, a few patients cannot pantomime in response to verbal commands or while holding the object, but they perform fairly well on imitation or improve over time on imitation and object use.26
Modality-Specific or Dissociation Apraxias
Neural Processes Underlying Limb Praxis Neural Representation of Gestures and the Selection of Actions Skillful and competent conventional use of objects and tools requires a normal prehension system, intact representations of functional actions for an adequate utilization behavior, and an intact semantic knowledge.3 Visually guided reaching, grasping, and object manipulation are paramount components in any task-related movement. Such object-oriented action implies a cerebral interface set up to align sensory information concerning position and shape of both object and limb, with specific motor commands encoding distance, velocity, direction, and grip.38 Research on primates has identified a series of segregated parietofrontal circuits that work in parallel, each one involved in a specific sensorimotor transformation process. The proposed functions of the main
chapter 32 apraxia parietofrontal circuits are as follows: (1) visual and somatosensory transformation for reaching; (2) somatosensory transformation for posture, as well as transformation of body part location data into information necessary to control body part movements; (3) visuomotor transformation for grasping and manipulation; (4) coding peripersonal space for limb and neck movements; (5) internal representation of actions; and (6) visual transformation for eye movements.39 Several functional brain imaging studies on reaching, grasping, and object manipulation in humans have demonstrated activation of the parietal (Brodmann areas 7, 39, and 40) and frontal areas (dorsal premotor, ventral premotor, and supplementary motor areas), as well as of the primary sensorimotor cortex, corresponding to those involved in the circuits described in monkeys. In addition, activation has been documented in the caudate and putamen, globus pallidus, thalamus, and cerebellum.40-43 Grasping specifically activates the lateral bank of the anterior intraparietal sulcus, whereas during grasping and manipulation, the ventral premotor cortex is involved.43 Most studies investigating tool and action knowledge have shown activation in posterior left superior and middle temporal gyri. The left posterior temporal areas are usually activated together with neural systems associated with semantic retrieval (left inferior and middle temporal gyri/Brodmann areas 20 and 21); left inferior frontal cortex (Brodmann areas 44, 45, and 47), and left premotor and left frontomarginal gyri (Brodmann areas 10 and 12).44-47 The generation of action verbs related to tool/object use also activates the left angular gyrus, which indicates that the system mediating access to verbs is anatomically close to those the system that supports concepts of movements and space-time relationships.48 Functional brain imaging studies on tool use skills have demonstrated activation, predominantly in the left hemisphere, of an extensively distributed control network made up of the inferior and superior parietal lobules, the posterior superior and middle temporal areas, the premotor (dorsal and ventral) and dorsolateral prefrontal cortices, and the supplementary motor area. The dorsolateral prefrontal cortex and posterior temporal areas are preferentially involved during action planning, whereas parietal, premotor, and supplementary motor areas are engaged during action execution in addition to action planning.15 The only brain region activated during manipulation with the tool, in comparison with the fingers, is the lateral edge of the intraparietal sulcus.49 In conclusion, skillful and competent use of tool/object depends on tool-/object-specific conceptual knowledge, as well as on several sensorimotor transformation processes involved in reaching, grasping, and manipulation; it is therefore subserved by an extensive temporoparietofrontal system that integrates tool/object knowledge with the ideation and generation of actions. A putative temporoparietal route may constitute an intermediate and necessary step for integrating objects’ functional properties into adequate movement patterns such as those required for utilization behavior.3 To date, there have been no studies designed to evaluate the representation of intransitive gestures. Intransitive gestures are usually much less complex than transitive movements, are geared to sociocultural contexts, and are stimulated by environmental cues (e.g., salute) rather than constrained by the shape and function of tools/objects, as in the case of transitive movements. It has therefore been suggested that intransitive
409
movements and postures are subserved by a more widely and differently distributed intrahemispheric network and/or that they are bilaterally represented.3 Neurophysiological, neuroimaging, and clinical studies have delineated at least two well-distributed neural systems essential for the selection of limb movement responses and for the selection of object-oriented responses. The first system consists of the lateral premotor (Brodmann area 6) and parietal cortices, basal ganglia, thalamus, and white matter fascicles participating in the selection of limb movement responses. The other is an adjacent system made up of lateral area 8 and interconnected parietal regions, thalamus, striatum, and white matter fascicles and is concerned with the selection of object-oriented responses.50
Pathophysiology of Limb Apraxia Ideational or conceptual types of praxic deficits Competent conventional use of objects and tools depends primarily on an intact semantic knowledge. Two possible models of semantic system functioning have been postulated. According to the model based on a multimodal distributed semantic architecture, objects of all types are represented by visual, tactile, and motor/proprioceptive nodes in proportion to the degree to which these various sensory and motor systems are involved as the representation is acquired and elaborated. In the case of tools and body parts, the dominant “channel” of experience involves sensorimotor (i.e., how the tool is held and used/manipulated) and functional information (i.e., knowing the usage context).51 According to the second model, a verbal, propositional semantic system operates by “reading” the sensorimotor representations or gestural engrams20; thus, skill and appropriate object use require the combination of dorsal stream processing (“how” system) with the product of ventral pathway processing (“what” system), which provides access to semantics.52 Therefore, ideational apraxia or conceptual apraxia may result from disruption of normal integration processes between the system subserving the functional knowledge of action and those involved in object knowledge, or it may result from damage to the putative conceptual system involving in toolaction knowledge.6,9 On the basis of studies of patients with semantic dementia syndrome, however, it has been alternatively proposed that patients with conceptual apraxia are impaired in the use of objects for which they have lost conceptual knowledge (e.g., naming and object descriptions). Their ability to select and use novel tools normally (mechanical problem solving), which unveils the capacity to infer function from structure, is usually preserved.20 The finding that some patients with ideational apraxia or conceptual apraxia may use some objects normally may be ascribed to degraded but partially retained conceptual knowledge about such objects, enhanced by sensorimotor information53 or, more precisely, to reliance on visual/tactile affordance, together with good problem-solving skills, because patients may be able to efficiently manipulate novel tools.20 Finally, the impairment in carrying out sequences of actions requiring the use of various objects (i.e., the original definition of ideational apraxia) may be the consequence of disruption of the subsystem involved in short-term script ordering31 (see later discussion).
410
Section
VII
Motor System and Motor Diseases
Ideomotor types of praxic deficits There are two major subtypes of ideomotor apraxia. The largest subtype results from disruption at the movement execution stage of gesture performance (anterior or dynamic ideomotor apraxia) and has been attributed to dysfunction of parietofrontal circuits involved in sensorimotor transformation. The second subtype, posterior or representational ideomotor apraxia, has been suggested to be caused by the inability to store or access representational memories of complex body posture and movements or by a deficit in the selection of actions.2
Dysfunction of frontoparietal circuits involved in sensorimotor transformation A subgroup of patients with ideomotor apraxia usually commit spatial and temporal errors when performing both transitive and intransitive symbolic or communicative movements under all modalities of elicitation (i.e., verbal command, imitation, seeing and handling the object), although performance usually improves on imitation and with object use. These patients also exhibit errors when imitating meaningless postures and novel motor sequences. It was originally suggested that the crucial underlying neural mechanism in this group of patients with ideomotor apraxia was a disruption of multiple parietofrontal circuits and their subcortical connections, which subserve the computations necessary to translate an action goal into movements by integrating sensory input with central representation of actions that is based on prior experience.9,54 Whereas damage to specific circuits causes unimodal deficit, such as tactile apraxia, involvement of several circuits by a larger lesion or disruption of their integration in supramodal reference frames causes ideomotor apraxia. Thus, damage to circuits devoted to sensorimotor transformation for grasping, reaching, and posture; for transformation of body part location into information required to control body part movements; and for coding extrapersonal space would produce incorrect finger and hand postures and abnormal orientation of the tool/object, inappropriate arm configuration and faulty movement orientation (with regard to both the body and the target of the movement in extrapersonal space), and movement trajectory abnormalities. Patients select the correct movements but have difficulties in translating the selected response into action because of an “execution” disturbance; the online guidance of movements may be defective, and patients may complain of disability in everyday activities.3
Disruption of action selection Another subgroup of patients with ideomotor apraxia exhibits spatial and temporal errors predominantly when pantomiming in response to verbal command with either hand (i.e., outside the appropriate context). They improve on imitation and when handling the object. These patients do not complain of difficulties in everyday activities; there is an automatic voluntary dissociation. Their online guidance of movements is normal, and they have no pointing and/or grasping deficits; thus, pragmatic representations for object-oriented actions are not directly affected, inasmuch as this is a higher level deficit involving a premovement neural process. The deficits arise when the subject has to shift from a strategy in which objectoriented actions are processed automatically to a more cogni-
tive mode, because of inability to select the appropriate motor schemas from stored motor representations and organize them into purposive action. They may also have deficits in mentally evoking (imaging) the action and may be unable to discriminate correct from incorrect gestures.3 In the study conducted by Rushworth and associates,50 all patients with deficits in the selection of learned actions and apraxia had lesions in the left hemisphere, predominantly in the parietal lobe, but in many, lesions also involved the lateral premotor cortex, as well as interconnecting white matter fascicles and basal ganglia and the thalamus. Therefore, patients in whom performance is impaired predominantly when pantomiming in response to verbal commands may be those with lesions involving systems subserving movement selection; circuits devoted to sensorimotor transformation are preserved. As a matter of fact, it has been possible to distinguish in monkeys an impairment in movement selection from an impairment in kinematics.3 The improvement in performance that patients may show when seeing and handling the object may be explained by the affordance provided by the visual/tactile cues from the tool/ object, which in addition provides a more natural context and facilitates the correct hand/limb position for the gesture. Finally, some patients with the ideomotor type of apraxia have deficits in forming correct hand configuration appropriate for object use only; this means they show inadequate hand grasp when the object has to be manipulated with the intention to use it, but neither during visually guided (“on-line”) reaching and grasping movements nor when grasping novel objects. These patients can correctly name and recognize fingers and objects and can also define their functions verbally, but they are unable to discriminate between normal and abnormal hand postures, and they exhibit deficits in the perception of self-generated movements and in mentally simulating hand gestures. These types of deficits have been associated with left inferior parietal cortex lesions; damage to these regions may degrade the storing of or interrupt the access to representations of learned complex body postures and/or movements associated with familiar objects.55
Limb-kinetic type of praxic deficit Proper grasping and manipulation require the integrity of the corresponding sensorimotor transformation circuit, the capacity to generate independent finger movements, and the capacity to perform and to exert a delicate somatosensory control process.38 On the basis of the anatomical connections and functional properties of F5 and anterior intraparietal areas, a sensorimotor circuit for grasping has been proposed in which parietal neurons represent the entire hand action and frontal neurons encode particular segments of the action. In turn, direct corticomotoneural projection systems underpin the ability to perform relatively independent finger movements. However, movements of individual digits require activation of a complex set of muscles; this muscular activity must not only generate the digit movement required but also stabilize the bony chain and prevent unwanted digit movements. Both cortical inhibition and corticospinal inhibition seem to be essential for the selection and control of hand muscle activity. When the object is finally grasped, a delicate somatosensory control of finger movement is necessary for precise manipulation to be performed.
chapter 32 apraxia Leiguarda and Marsden9 proposed that the most typical examples of LKA, such as those seen in corticobasal degeneration, are caused by disruption of the frontoparietal circuits devoted to grasping and manipulation, combined with impaired generation and control of independent finger movements caused by disruption of intracortical inhibitory circuits, as well as dysfunction of somatosensory control of manipulation. However, because patients with corticobasal degeneration and LKA have neither clinical signs of corticospinal deficit nor involvement of fast-conducting corticomotoneural projections, as evaluated with transcranial magnetic stimulation, and a defect in somaesthesis may not be present, this distinctive apraxic disorder may basically result from dysfunction of the nonprimary cortical motor areas, as previously suggested.9 In support, transcranial magnetic stimulation of Brodmann area 44 produces slowing and clumsiness of fine finger movements without paresis.56 All pathologically confirmed cases of LKA suffered a degenerative process such as corticobasal degeneration and Pick’s disease, involving frontal and parietal cortices or, predominantly, the premotor cortex.9
Imitation of Actions Imitation is an important component of nonverbal communication. Testing the ability to imitate is an essential aspect of apraxia assessment, particularly in patients with aphasia. Defective performance in gesture imitation has been found in patients with lesions in several cortical regions but essentially with parietofrontal damage. These patients tend to exhibit more errors when imitating transitive than intransitive and meaningless movements.54 Moreover, patients with left parietal lobe damage seem to have more difficulties when imitating meaningful transitive gestures on their own bodies than when imitating movements with reference to external objects.57 Imitation of meaningless hand and finger postures discloses differential susceptibility to right- and left-brain damage. Patients with leftbrain damage have more difficulties imitating hand than finger postures, whereas patients with right-brain damage commit more errors with finger postures.58,59 Thus, imitation seems to be body part specific; the gesture’s visual appearance is mentally transformed into categories of body part relationships. Difference in action imitation between meaningful and meaningless action/postures can be predicted on the basis of a cognitive imitation model, which postulates disparate processing routes to the motor system. Imitation of meaningless actions/postures would be processed through a nonsemantic route from visual analysis, including mental transformation of another person’s body part and temporary holding in working/short-term memory of the observed movement/ posture, to the motor system for actual execution. Imitation of meaningful actions/postures, in turn, can be achieved by either a nonsemantic or a semantic route through a longterm/semantic memory station. This model has received support from functional neuroimaging studies that showed involvement of the dorsal pathway when a meaningless action/posture is imitated and of the dorsal together with the ventral pathway when a meaningful action/posture is perceived with the aim to be imitated.45,46
Representation of sequential movements and actions Functional brain imaging has shown that different neural systems are actively engaged in planning and executing sequen-
411
tial movements, depending on whether the sequence has been relearned or is a new one and contingent on the complexity of the movement sequence. The supplementary motor area, the primary sensorimotor cortex, the midposterior putamen, and the cerebellum are involved primarily in the execution of automatic, overlearned sequential movements, whereas the prefrontal, premotor, and parietal association cortices and the anterior part of the caudate/putamen are specifically recruited—in addition to such areas engaged in the execution of simple movement sequences—when a complex or newly learned sequence, which requires attention, integration of multimodal information, and working memory processing for its appropriate selection and monitoring, has to be performed.3 Patients with ideomotor apraxia may exhibit several types of errors such as omissions, deletions, additions, transpositions, and perseverations when performing sequencing limb movements and have been found to be particularly impaired in planning and implementing sequences of various hand movements. Abnormalities in movement sequencing have been reported most commonly in patients with left parietal lobe lesions but also with left frontal and basal ganglion involvement.60-63 Thus, different neural systems would be engaged, depending on the characteristics of movement sequences needed to be executed during praxis evaluation. Most of the sequences used to test praxis are new (e.g., sequencing of movements in the movement imitation test) or part of an otherwise well-learned sequence that has to be represented explicitly. In any case, the system comprising the prefrontal, premotor, and parietal cortices and the caudate would be specifically engaged. When the sequence is well known, automated, or overlearned, the supplementary motor area–putamen would be preferentially recruited. Interestingly, activation shifts back to caudateanterior putamen when attention was paid to the overlearned action. In addition, it might be possible that within this system, there are many different subsystems subserving functionally separate cognitive computations involved in motor sequencing (i.e., working memory, attention, selection of limb movements), which, in turn, may be selectively damaged by the pathological process and so produce different types of sequencing impairment in apraxic patients.9 The sequential organization of actions, rather than movements, has been studied with the use of script event ordering to address the cognitive activity that occurs during action planning at a covert level.31 A script consists of a goal-oriented sequence of events that typically occur in a specific and systematic order. Functional imaging studies have shown that short-term scripts as those used in testing ideational apraxia (e.g., peeling, opening, and eating an orange) cause activation in the left hemisphere of the dorsolateral prefrontal cortex, supramarginal gyrus, inferior temporal gyrus, and middle occipital gyrus. Patients with ideational apraxia caused by damage of the left parietotemporal region or damage of the frontal lobe fail on naturalistic, multiple object tests requiring a sequential structuring of common everyday actions (shortterm script ordering, such as making coffee).5,18-20
Recognition of actions and perception of self-generated movements A subset of neurons in area F5 have been found to discharge during the time a monkey observes meaningful hand movements made by the experimenter, particularly when interacting
412
Section
VII
Motor System and Motor Diseases
with objects; these were called mirror neurons and were considered to belong to an observation/execution matching system involved in understanding the meaning of motor events, as well as in action imitation.39 Neurons with properties similar to those of mirror neurons in area F5 are also found in the superior temporal sulcus in monkeys. Two other types of neurons that may contribute to the recognition and imitation of postures and actions have also been found in the superior temporal sulcus. One type encodes the visual appearance of particular parts of the body (i.e., fingers, hands, arms), which combine in such a way that the collection of components can specify a particular meaningful posture or action. The second type encodes specific body movements, such as walking and turning. Cells responding to hand-object interaction are also present in the rostral part of the inferior parietal lobe, which sends its cortical output to the F5 area; in turn, the inferior parietal lobe receives projection from the superior temporal sulcus region, and the latter is interconnected with the frontal lobe, thus completing a cortical circuit involved in the perception of handobject interaction. The crucial cognitive role of the superior temporal sulcus—inferior parietal lobe—F5 network would be the internal representation of actions that, when evoked by an action made by other people, would be involved in two related functions: namely, action recognition and action imitation. Findings of functional neuroimaging studies in humans parallel neurophysiological findings in monkeys.64 Action recognition deficits have been observed in patients with parietal, temporal, frontal, and basal ganglion lesions predominantly in the left hemisphere.65,66 However, Halsband and colleagues57 compared gesture comprehension and imitation in patients with parietal and frontal lesions and found that when lesions affected the left parietal cortex, sparing temporal lobe structures, gesture comprehension was slightly disturbed, although action imitation was severely impaired. The lack of consistent gesture comprehension deficits in these patients could result from preservation of the left temporal cortex, which seems to be crucial for the knowledge of actions.57 Apraxic patients with left parietal damage may also have difficulties when they are required to discriminate from their own hand an external hand that performs the same movement. The impairment in correctly attributing the ownership of the movement may result from the inability to evaluate and compare internal and external feedback about movements.67
Treatment of Limb Apraxia Apraxic impairments are ecologically significant because communicative gestures can compensate for inadequate verbal expression in patients with aphasia and because the improper use and selection of tools/objects and the inability to perform a routine, naturalistic action, directly interfere with activities of daily living. Studies of spontaneous recovery from apraxia have concentrated on imitation of gestures and performance of meaningful gestures, such as pantomiming of object use on command. On these tests, only about one half of the patients who were apraxic in the first week after a stroke were still apraxic 3 months later, and only 20% continued to be apraxic after 1 year. Two different approaches can be used to rehabilitate apraxia. A top-down approach would be characterized by teaching the
patients general principles of tool and object use, which they can then deliberately apply to novel and difficult activities. A bottom-up approach, by contrast, could be established through gradual shaping and subsequent rehearsal of one particular activity until a routine is established, which will occur automatically when the trained activity is to be performed. In one study, investigators used a cross-over design to compare the efficacy of top-down and bottom-up training for the same activities in the same patients. Their top-down approach, “exploration training,” was aimed at teaching patients to infer possible functions of tools and objects from their structural properties. Patients were told to compare tools with similar or different function with regard to their structural properties (e.g., contrasting the teeth of a cutting knife and of a saw with the plain edge of a knife used for spreading) or to make drawings of them that emphasized these structural details. In contrast, “direct training” was intended to establish a routine through performing the task and may hence be classified as being bottom-up. Direct training led to a significant reduction of errors and of the need for assistance, whereas exploration training had no significant practical effects.68
DISTRIBUTION OF THE APRAXIAS IN OTHER BODY PARTS Although face apraxia has been generally equated with oral nonverbal apraxia—that is, the inability to perform skilled movements of the lips, checks, and tongue1—early reports of patients with facial apraxia described eye and/or eyebrow movement deficits.69 Therefore, face apraxia should refer to a disturbance of upper and lower face movements not explained by elementary motor or sensory deficits. Patients exhibit spatial and temporal errors of similar quality to those observed in limb apraxia when performing representational and nonrepresentational movements such as sticking out the tongue, blowing out a match, smiling, blowing a kiss, showing the teeth, blinking the left or right eye, looking down, or sucking on a straw. Face apraxia often co-exists with Broca’s aphasia and thus is more frequently observed with left hemisphere lesions, particularly those involving the frontal and central operculum, insula, centrum semiovale, and basal ganglia; however, it can also be seen with lesions confined to left posterior cortical regions, as well as with right hemisphere damage.3,69 Trunk movement impairments, labeled trunk apraxia, were originally reported as part of a syndrome associated with bilateral frontal lobe lesions encompassing stance and gait apraxia. However, in some patients, trunk apraxia is overwhelming; they experience difficulties in dancing or turning around and may even be unable to adapt their body in order to use furniture; they have difficulty sitting down in a chair, showing hesitation, sitting in the wrong position (e.g., on the edge of the chair) and in incorrect directions (e.g., facing the back of the chair). When lying in bed, their bodies are not aligned parallel along the major axis of the bed, or they place the pillow in an unusual position. Patients may have minimal or no difficulty in standing or getting up, in contrast to features of some basal ganglion disorders such as parkinsonism.3 It is still controversial whether trunk apraxia results from only left hemisphere damage or whether bilateral hemispheric lesions are necessary. It is often observed in cortical degenera-
chapter 32 apraxia tive syndromes such as progressive apraxia and corticobasal degeneration, in which parietofrontal involvement is prominent, but it has also been found in patients with left hemisphere damage, particularly in those with cortical and subcortical vascular lesions confined to the territory of the middle cerebral artery. Trunk apraxia in these patients can be found without association with limb apraxia.70 The precise nature and localization of gait apraxia still defy exact identification. Gerstmann and Schilder71 described apraxia of gait as a genuine disturbance of walking caused by frontal lesions; more recently, however, it has been considered not as a disorder but a spectrum of higher order walking syndromes.72 Nevertheless, apraxia of gait may be defined as the loss of ability to use the lower limbs properly in the act of walking, a loss that cannot be accounted for by demonstrable sensory impairment or motor weakness.73 Such patients’ gait is characterized by slowness of initiation; loss of balance; “magnetic attraction of the foot to the ground”; counterproductive parasitic movements; difficulty in stopping and turning; and inability to pedal, to kick, or to trace a circle with the foot, as well as increased tone and brisk reflexes in the lower limbs with grasping foot responses. The disorder is caused by bilateral damage mainly to the medial frontal lobes or by white matter lesions that interrupt the connections between premotor cortex, supplementary motor area, and cerebellum and basal ganglia.74
K E Y
P O I N T S
●
Apraxias are common but poorly recognized disorders that can result from a wide variety of focal (e.g., stroke) or diffuse (i.e., corticobasal degeneration, Alzheimer’s disease) brain damage.
●
Limb apraxias all bear ecological significance because communicative gestures can compensate for inadequate verbal expression in patients with aphasia, and because improper use and selection of tools/objects, as well as inability to perform routine movements in a natural manner, significantly affect activities of daily living.
●
Limb apraxias are attributable to disruption of a large neural network, which is distributed both intrahemispherically and interhemispherically, although mainly lateralized to the left, and is made up of many interrelated systems pertaining to dissimilar levels of action representation.
●
Damage to one or more of these systems, depending on the location and extension of the pathological process involved, would cause different types of apraxic disorders and would explain the clinical dissociations commonly observed.
●
Therefore, a battery of tests is necessary to identify and categorize apraxic deficits appropriately.
●
Precise identification of abnormal motor behaviors and a better understanding of their underlying neural mechanisms will help clinicians design rehabilitation strategies targeting specific apraxic deficits.
413
Suggested Reading Jeannerod M, Leiguarda R, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press 2005, pp 303-338. Johnson-Frey S, Newman-Norlund R, Grafton S: A distributed left hemisphere networks active during planning of everyday tooluse skills. Cereb Cortex 2005; 15:681-695. Leiguarda R: Apraxias as traditionally defined. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 303-338. Leiguarda R, Merello M, Nouzeilles MI, et al: Limb-kinetic apraxia in corticobasal degeneration: clinical and kinematic findings. Mov Disord 2003; 18:49-59. Nutt J: Higher-order disorders of gait. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 237-248. Rossetti I, Rode G, Goldenberg G: Perspectives on higher-order motor deficit rehabilitation. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 475-498.
References 1. De Renzi E: Apraxia. In Boller F, Grafman J, eds: Handbook of Neuropsychology, vol 2. Amsterdam: Elsevier Science, 1989, pp 245-263. 2. Rothi LJG, Heilman KM, eds: Apraxia: the Neuropsychology of Action. East Sussex, UK: Psychology Press, 1997. 3. Leiguarda R: Apraxias as traditionally defined. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 303-338. 4. Liepmann H: Die linke hemisphare und das handeln [The left hemisphere and action]. Munch Med Wochenschr 1907; 49:2322-2326, 2375-2378. [Translations from Liepmann’s essays on apraxia. In Research Bulletin 506, Department of Psychology, University of Western Ontario, 1980.] 5. Liepmann H: Apraxie. Ergenbnisse der Gesamten Medizin 1920; 1:516-543. 6. Roy EA, Square PA: Common considerations in the study of limb, verbal, and oral apraxia. In Roy EA, ed: Neuropsychological Studies of Apraxia and Related Disorders. Amsterdam: North-Holland, 1985, pp 111-161. 7. Rothi LJG, Ochipa C, Heilman KM: A cognitive neuropsychological model of limb praxis. Cogn Neuropsychol 1991; 8:443458. 8. Buxbaum LJ, Giovannetti, Libon D: The role of the dynamic body schema in praxis: evidence from primary progressive apraxia. Brain Cogn 2000; 44:166-191. 9. Leiguarda R, Marsden CD: Limb apraxias: higher-order disorders of sensorimotor integration. Brain 2000; 123:860879. 10. Poizner H, Mack L, Verfaellie M, et al: Three-dimensional computer graphic analysis of apraxia. Brain 1990; 113:85101. 11. Leiguarda R, Merello M, Balej J, et al: Disruption of spatial organization and interjoint coordination in Parkinson’s disease, progressive supranuclear palsy, and multiple system atrophy. Mov Disord 2000; 15:627-640. 12. Leiguarda R, Merello M, Nouzeilles MI, et al: Limb-kinetic apraxia in corticobasal degeneration: clinical and kinematic findings. Mov Disorder 2003; 18:49-59. 13. Moll J, de Oliveira-Souza R, Passman LJ, et al: Functional MRI correlates of real and imagined tool-use pantomimes. Neurology 2000; 54:1331-1336. 14. Choi SH, Na DL, Kang E, et al: Functional magnetic resonance imaging during pantomiming tool-use gestures. Exp Brain Res 2001; 139:311-317.
414
Section
VII
Motor System and Motor Diseases
15. Johnson-Frey S, Newman-Norlund R, Grafton S: A distributed left hemisphere networks active during planning of everyday tool-use skills. Cerebral Cortex 2005; 15:681-695. 16. Fridman E, Carpintiero S, Amengual A, et al: Hemispheric lateralization of pantomiming tool-use gestures: a fMRI study. Manuscript in preparation. 17. Ochipa C, Rothi LJG, Heilman KM: Conceptual apraxia in Alzheimer’s disease. Brain 1992; 115:1061-1071. 18. Heilman KM, Maher LH, Greenwald L, et al: Conceptual apraxia from lateralized lesions. Neurology 1997; 49:457464. 19. De Renzi E, Lucchelli F: Ideational apraxia. Brain 1988; 113:1173-1188. 20. Hodges J, Bozeat S, Lambon Ralph M, et al: The role of conceptual knowledge in object use evidence from semantic dementia. Brain 2000; 123:1913-1925. 21. Kleist K: Kortikale (innervatorische) Apraxie. Jahrb Psychiat Neurol 1907; 28:46-112. 22. Kleist K: Gehirnpathologische und lokalisatorische Ergebnisse: das Stirnhirn im engeren Sinne und seine Störungen. Z ges Neurol Psychiatry 1931; 131:442-448. 23. Faglioni P, Basso A: Historical perspectives on neuroanatomical correlates of limb apraxia. In Roy EA, ed: Neuropsychological Studies of Apraxia and Related Disorders. Amsterdam: North-Holland, 1985, pp 3-44. 24. Liepmann H, Maas O: Eie Fall von linksseitiger Agraphie und Apraxie bei rechtsseitiger Lähmung. Monatsschrift fur Psychiatrie und Neurologie 1907; 10:214-227. 25. Watson RT, Heilman KM: Callosal apraxia. Brain 1983; 106:391-403. 26. Graff-Radford NR, Welsh K, Godersky J: Callosal apraxia. Neurology 1987; 37:100-105. 27. Leiguarda R, Starkstein S, Berthier M: Anterior callosal haemorrhage: a partial interhemispheric disconnection syndrome. Brain 1989; 112:1019-1037. 28. Geschwind N, Kaplan E: A human cerebral disconnection syndrome. Neurology 1962; 12:675-685. 29. De Renzi E, Faglioni P, Sorgato P: Modality-specific and supramodal mechanisms of apraxia. Brain 1982; 105:301-312. 30. Heilman KM: Ideational apraxia: a re-definition. Brain 1973; 96:861-864. 31. Ruby P, Sirigu A, Decety J: Distinct areas in the parietal cortex involved in long-term and short-term action planning: a PET investigation. Cortex 2002; 38:321-339. 32. Pilgrim E, Humphreys GW: Impairment of action to visual objects in a case of ideomotor apraxia. Cogn Neuropsychol 1991; 8:459-473. 33. Motomura N, Yamadori A: A case of ideational apraxia with impairment of object use and preservation of object pantomime. Cortex 1994; 30:167-170. 34. Ochipa C, Rothi LJ, Heilman KM: Conduction apraxia. J Neurol Neurosurg Psychiatry 1994; 57:1241-1244. 35. Merians AS, Clark M, Poizner H, et al: Visual-imitative dissociation apraxia. Neuropsychologia 1997; 35:1483-1490. 36. Mehler MF: Visuo-imitative apraxia [Abstract]. Neurology 1987; 34(Suppl 1):129. 37. Goldenberg G, Hagmann S: The meaning of meaningless gestures: a study of visuo-imitative apraxia. Neuropsychologia 1997; 35:333-341. 38. Jeannerod M, Arbid MA, Rizzolatti G, et al: Grasping objects: the cortical mechanisms of visuomotor transformation. Trends Neurosci 1995; 18:314-320. 39. Rizzolatti G, Luppino G, Matelli M: The organization of the cortical motor system: new concepts. Electroencephalogr Clin Neurophysiol 1998; 106:283-296. 40. Grafton ST, Arbid MA, Fadiga L, et al: Localization of grasp representation in humans by PET: 2. Observation compared with imagination. Exp Brain Res 1996; 112:103-111.
41. Rizzolatti G, Fadiga L, Matelli M, et al: Localization of grasp representations in humans by positron emission tomography. 1. Observation versus execution. Exp Brain Res 1996; 111:246252. 42. Faillenot I, Toni I, Decety J, et al: Visual pathways for objectoriented action and object recognition: functional anatomy with PET. Cereb Cortex 1997; 7:77-85. 43. Binkofski F, Phil M, Posse S, et al: Human anterior intraparietal area subserves prehension: a combined lesion and functional MRI activation study. Neurology 1998; 50:1253-1259. 44. Martin A, Haxby JV, Lalonde FM, et al: Discrete cortical regions associated with knowledge of color and knowledge of action. Science 1995; 270:102-105. 45. Decety J, Grezes J, Costes N, et al: Brain activity during observation of action: influence of action content and subject’s strategy. Brain 1997; 120:1763-1777. 46. Grèzes J, Costes N, Decety J: The effects of learning and intention on the neural network involved in the perception of meaningless actions. Brain 1999; 122:1875-1887. 47. Phillips JA, Noppeney U, Humphreys GW, et al: Can segregation within the semantic system account for category-specific deficits? Brain 2002; 125:2067-2080. 48. Grèzes J, Decety J: Functional anatomy of execution, mental simulation, observation, and verb generation of actions: a meta-analysis. Hum Brain Mapp 2001; 12:1-19. 49. Inoue K, Kawashima R, Sugiura M, et al: Activation in the ipsilateral posterior parietal cortex during tool use: a PET study. Neuroimage 2001; 14:1469-1475. 50. Rushworth MFS, Nixon PD, Wade DT, et al: The left hemisphere and the selection of learned actions. Neuropsychologia 1998; 36:11-24. 51. McCarthey RA, Warrington EK: Evidence for modality specific meaning systems in the brain. Nature 1988; 334:428-430. 52. Milner AD, Goodale MA: The Visual Brain in Action. Oxford, UK: Oxford University Press, 1995. 53. Buxbaum LJ, Schwartz MF, Carew TG: The role of semantic memory in object use. Cogn Neuropsychol 1997; 14:219-254. 54. Haaland KY, Harrington DL, Knight RT: Neural representations of skilled movement. Brain 2000; 123:2306-2313. 55. Sirigu A, Cohen L, Duhamel JR, et al: A selective impairment of hand posture for objects utilization in apraxia. Cortex 1995; 31:41-55. 56. Vozumi T, Tamagawa A, Hashimoto T, et al: Motor hand representation in cortical area 44. Neurology 2004; 62:757761. 57. Halsband U, Schmitt J, Weyers M, et al: Recognition and imitation of pantomimed motor acts after unilateral parietal and premotor lesions: a perspective on apraxia. Neuropsychologia 2001; 39:200-216. 58. Goldenberg G: Matching and imitation of hand and finger postures in patients with damage in the left or right hemispheres. Neuropsychologia 1999; 37:559-566. 59. Goldenberg G, Straus S: Hemisphere asymmetries for imitation of novel gestures. Neurology 2002; 59:893-897. 60. De Renzi E, Faglioni P, Lodesani M, et al: Performance of left brain-damaged patients on imitation of single movements and motor sequences: frontal and parietal-injured patients compared. Cortex 1983; 19:333-343. 61. Harrington DL, Haaland KY: Motor sequencing with left hemisphere damage: are some cognitive deficits specific to limb apraxia? Brain 1992; 115:857-874. 62. Benecke R, Rothwell JC, Dick JPR, et al: Disturbance of sequential movements in patients with Parkinson is disease. Brain 1987; 110:361-379. 63. Luria AR: Higher Cortical Function in Man, 2nd ed. New York: Basic Books, 1980. 64. Rizzolatti G, Craighero L: The mirror-neuron system. Annu Rev Neurosci 2004; 27:169-192.
chapter 32 apraxia 65. Ferro J, Martins I, Mariano G, et al: CT scan correlates of gesture recognition. J Neurol Neurosurg Psychiatry 1983; 46:943-952. 66. Varney N, Damasio H: Locus of lesion in impaired pantomime recognition. Cortex 1987; 23:699-703. 67. Sirigu A, Daprati E, Pradat-Diehl P, et al: Perception of selfgenerated movement following left parietal lesion. Brain 1999; 122:1867-1874. 68. Rossetti I, Rode G, Goldenberg G: Perspectives on higher-order motor deficit rehabilitation. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 475-498. 69. Bizzozero I, Costato D, Della Sala S, et al: Upper and lower face apraxia: role of the right hemisphere. Brain 2000; 123:22132230.
415
70. Spinazzola L, Cubelli R, Della Sala S: Impairment of trunk movements following left or right hemisphere lesions: dissociation between apraxic errors and postural instability. Brain 2003; 126:2656-2666. 71. Gerstmann J, Schilder P: Über eine besondere Gangstörung bei Stirnhirner krankung. Wien Med Wochenschr 1926; 76:97102. 72. Nutt J: Higher-order disorders of gait. In Freund H, Hallett M, Jeannerod M, et al, eds: Higher-Order Motor Disorders. Oxford, UK: Oxford University Press, 2005, pp 237-248. 73. Meyer JS, Barron DW: Apraxia of gait: a clinico-physiological study. Brain 1960; 83:261-284. 74. Della Sala S, Francescani A, Spinnler H: Gait apraxia after supplementary motor area lesions. J Neurol Neurosurg Psychiatry 2002; 72:77-85.
CHAPTER
33
TREMOR ●
●
●
●
Günther Deuschl and Jan Raethjen
Tremor is the most common movement disorder encountered in clinical neurology. It denotes a rhythmic involuntary movement of one or several regions of the body.1 Although most tremors are pathological, a low-amplitude physiological action tremor can also be detected in healthy subjects and may even be of functional relevance for normal motor control.2 Pathological tremor is visible to the naked eye and mostly interferes with normal motor function. The disabilities caused by these tremors are as diverse as their clinical appearance, pathophysiology, and etiologies. Although there are numerous medical treatment options, their efficacy is limited, and therefore refined stereotactic surgical approaches have become increasingly important. Here, we provide some general clinical definitions and then describe all these aspects for each of the most important pathological tremor syndromes separately.
CLINICAL DEFINITIONS The clinical examination of tremor patients should focus on certain aspects of the tremor that form the basis for the differential diagnosis (Tables 33−1 and 33−2) and should always be documented: Topography: Tremors can occur in any joint or muscle that is free to oscillate. The patient should be examined carefully under different conditions (see later) to be able to detect all the affected body parts. By far the most common locations are the arms and hands, but they can be spared and are typically combined with tremor in other regions. The degree of symmetry between the two sides of the body can be an important hint (see Tables 33−1 and 33−2). Activation: Different states of muscle innervation can lead to an activation that is the appearance or marked increase of tremor. Resting tremor occurs when the muscles of the affected body part are not voluntarily activated (ideally completely relaxed, e.g., resting on a couch); its amplitude typically increases during mental stress (e.g., counting backward, Stroop test, etc.) and markedly decreases during voluntary activation, especially when moving the affected limb. Action tremor is any tremor that is produced by voluntary contraction of muscles. Its subgroups are clinically meaningful and always need to be defined: Postural tremor is present while voluntarily maintaining a position against gravity or additional weight. Kinetic tremor occurs during
any voluntary movement and can again be subdivided into a simple kinetic tremor that is present during simple voluntary movements that are not goal directed (e.g., slow up and down movements of the hands) and a tremor during goal-directed movements (intention tremor) that only occurs during movements directed at a certain target (e.g., target reaching movements). Classic intention tremor typically increases as the target is approached and the amplitude and velocity may fluctuate from beat to beat. These tremors must be separated from rarer forms of action tremor that occur only during certain positions or certain tasks (e.g., task-specific or position-specific tremor or isometric tremor). Frequency: For exact frequency measurement, a signal analysis of accelerometric or electromyographic recordings of the affected body part is necessary. However, with some experience the three main frequency ranges can be separated on inspection: high (>7 Hz), medium (4 to 7 Hz), and low (<4 Hz). Additional symptoms: Although not strictly related to the tremor syndrome itself, additional signs and symptoms are almost equally important. For example, a parkinsonian syndrome, cerebellar ataxia, and dystonia in the region of the tremor are important diagnostic and etiological hints (see later).
ENHANCED PHYSIOLOGICAL TREMOR Normal physiological tremor is an action tremor and usually not visible. It can only be measured with sensitive accelerometers. An increase of the amplitude leads to enhanced physiological tremor (EPT). The pathological tremor amplitudes are typically short lived and reversible once the cause (see Etiology) is removed. Other neurological symptoms or diseases that could cause tremor must be excluded.1
Epidemiology There are no studies available on the epidemiology of EPT as a whole. The short-lived transient form is very likely the most common form of tremor; most people have experienced this on stressful or frightening occasions. Some of the causes (side effect of drugs, endogenous intoxication, etc.) of EPT are
417
418
Section
VII
Motor System and Motor Diseases
T A B L E 33-1. Clinical Presentation of Tremors Diagnosis
Topography
Activation
Enhanced physiological tremor Essential tremor syndromes: Classic essential tremor
Arms (head); bilateral symmetrical
Posture/movement
6 to 13 Hz
None
Arms/head/tongue/voice bilateral, often asymmetrical Legs (trunk, arms, facial muscles); bilateral Task specific
Posture/movement/intention
4 to 11 Hz
Mild ataxia (when advanced)
Primary orthostatic tremor Task- and position-specific tremor Dystonic tremor
Standing
Frequency
13 to 18 Hz
Additional Symptoms
Main symptom: postural instability None
Task/position specific
5 to 10 Hz
Head/arm or other limbs; unilateral, often monomelic
Posture/movement
5 to 10 Hz
Dystonic posturing of affected region
Parkinsonian tremor Rest/re-emergent (types I and II) Action (types II and III)
Arm/leg/face; unilateral begin, asymmetrical Arms; often more symmetrical
Rest/posture
4 to 7 Hz
Posture/movement
6 to 13 Hz
Holmes tremor
Arm (leg); unilateral
3 to 6 Hz
Neuropathic tremor
Arms (legs); bilateral, usually symmetrical Arms/head/leg + other limbs, bilateral, usually symmetrical Arm/leg/head /trunk; often unilateral or asymmetrical
Rest/posture/movement/ intention Posture/movement
Akinesia, rigidity, postural instability Akinesia, rigity, postural instability Akinesia, rigidity, postural instability/ataxia Symmetrical distal sensory loss, paresis Very diverse depending on etiology Other somatizations
Toxic and drug-induced tremor Psychogenic tremor Palatal tremor Essential Symptomatic
Soft palate Soft palate/facial muscles/(arm)
common, so it is likely one of the most common forms of tremor.
Pathophysiology EPT relies on the same physiological mechanism as normal physiological tremor, and the physiology of normal tremor is meanwhile well defined. Two different physiological tremor mechanisms have been established. The first is based on simple mechanical properties. Any movable limb can be regarded as a pendulum with the capability to swing rhythmically, that is to oscillate. These oscillations automatically assume the resonant frequency of this limb, which is dependent on its mechanical properties⎯the greater its weight, the lower is its resonant frequency, and the greater the joint stiffness, the higher is this frequency. Any mechanical perturbation can activate such an oscillation. In the case of the hands, which are most often affected by tremors, the main and most direct mechanical influence comes from the forearm muscles. Indeed, it has been shown that the tremor measured in normal subjects during muscle activation mainly emerges from an amplification of the muscles’ effect on the hand at its resonant frequency.3-5 Thus, although the muscles show normal nonrhythmic isometric activity, they contribute to these resonant oscillations, which account for most of the tremor seen in the physiological situation.6 Such a pure resonant phenomenon does not produce pathological tremors as its amplitude is typically quite low. However, as this low-amplitude oscillation leads to rhythmic activation of muscle receptors, it activates segmental (spinal) or long (e.g., transcortical) reflex loops that can greatly
5 to 10 Hz
Posture/movement/ (rest/intention) Rest/posture/(movement)
3 to 10 Hz 4 to 9 Hz
Rest Rest/(posture/movement)
2 to 5 Hz 2 to 7 Hz
Rhythmic ear click Brainstem/cerebellar symptoms
enhance this oscillation. Such a reflex enhancement of the physiological mechanical oscillation is one well-established pathophysiological basis for the emergence of pathological tremor amplitudes in the case of EPT.7 The second less frequent mechanism in physiological tremor is a transmission of oscillatory activity within the central nervous system to the peripheral muscles. The rhythmic activity of the muscles then leads to tremor. In contrast to the mechanical-reflex oscillations, central oscillations occur at the centrally determined frequency and are independent of the limbs’ mechanics.8,9 It has been shown that such a central tremor component is present in a small proportion of normal subjects in parallel to the more common mechanical reflex oscillations.6,10-12 An enhancement of this component is another basis for EPT.13 Such central oscillations generally are the most common pathophysiological mechanism in pathological tremors4,9,14 (see later). Accelerometric tremor recordings with different weight loads in combination with the electromyogram recorded from the driving muscles can distinguish between such central and peripheral resonant (possibly reflex enhanced) tremors.
Etiology The causes of an enhancement of one or both of the physiological tremor components are diverse. The well-known trembling with excitement, fear, or anxiety is the most common form of EPT. It is believed to be mediated through an increased sympathetic tone that results in a β-adrenergically driven sensitization of the muscle spindles increasing the gain in the
chapter 33 tremor
419
T A B L E 33-2. Differential Diagnosis of Tremors Diagnosis
Clinical Clues
Neurophysiology
Brain Imaging
Essential tremor (ET) versus enhanced physiological tremor (EPT) ET versus asterixis (AS) ET versus orthostatic tremor (OT) ET versus parkinsonian tremor (type I)
Family history (ET), duration of tremor (ET > EPT), medical history (ET), concomitant medication (EPT) Jerky tremor (AS) Tremor only during stance (OT)
Frequency under loading conditions, frequency below 8 Hz in early ET
Not useful
Polygraphic EMG (pathognomic) Polygraphic EMG (pathognomic)
Not useful Not useful
Subclinical low-frequency rest tremor (PD) on accelerometric or EMG spectrum Inhibition (PD) versus activation (ET) of tremor amplitude during movement
DAT-scan (PD), MIBG-scintigraphy (PD)
Frequency (DT ≤ ET), Quantified effect of a geste maneuver (DT)
Rarely lesions on MRI (DT)
Frequency (CT < ET)
CT/MRI: cerebellar lesions or degeneration (CT)
Frequency (HT < CT)
MRI: lesions/degeneration (CT) DAT-Scan: positive (HT),
Entrainment (PsT) Quant. distract. (PsT) Coherence l.-r. (PsT) Variable frequency (PsT)
Maybe useful depending on the cause of OrT
Burst duration (Mcl < Tr), Spectral peak width (Tr < Mcl), Synchronous bursts in different muscles (Mcl > Tr)
MRI depending on the cause of Mcl
ET versus dystonic tremor (DT)
ET versus cerebellar tremor (CT) CT versus Holmes tremor (HT)
Organic tremor (OrT) versus psychogenic tremor (PsT)
Tremor (Tr) versus myoclonus (Mcl)
Rest tremor (PD), unilateral beginning (PD), other PD symptoms (PD), alcohol responsivity (ET), kinetic tremor (ET), family history (ET), leg tremor (PD > ET), face tremor (PD > ET), head tremor (ET > PD), voice tremor (ET > PD), Family history (ET), Alcohol response (ET), Geste antagonistique (DT), Focal (DT), Further dystonic symptoms (DT), Alcohol response (ET), Intention tremor (CT > ET), Ataxia (CT > ET), Eye movements (CT) Rest tremor (HT), Low frequency (HT), Irregularity (HT), Parkinsonian symptoms (HT), Ataxia (CT > HT), Distractibility (PsT), Variable presentation (PsT > OrT), Selective disabilities (PsT), Entrainment (PsT), Coactivation (PsT > OrT), Somatizations (PsT > OrT), Rhythmic (Tr), More irregular (Mcl),
reflex loops.7 A similar origin via the sympathetic nervous system has been proposed for the tremor in reflex sympathetic dystrophy.15 The majority of other causes for EPT are related to drugs or toxins that can enhance the peripheral and the central component of physiological tremor (see Toxic Tremors).
Differential Diagnosis As both EPT and early essential tremor are not accompanied by any other neurological symptoms, they can be difficult to distinguish. The positive family history in essential tremor, its chronic course, and the lack of an overt cause for the tremor are important hints. Sometimes the diagnosis can only be made after having observed the tremor for some time. EPT is usually bilateral and thus any tremor manifesting unilaterally, even with a high frequency and a pure postural component, must be suspected of being a symptomatic tremor (see Table 33−2). Electrophysiology (spectral analysis of accelerometry and electromyography) can be helpful in cases where EPT emerges from a reflex enhancement of physiological tremor, as essential tremor is a centrally driven tremor.14,16 Electromyographic bursts below 8 Hz seem to be in favor of essential tremor rather than EPT.17
Treatment The short-lived emotional trembling in certain situations usually does not require any treatment. A single dose of a βblocking agent (e.g., propranolol 30 to 100 mg) just before a stressful situation can usually help to suppress this transient tremor that may interfere with important (e.g., professional) functions. Treatment of thyreotoxic tremor is recommended with propranolol (<160 mg daily) but other β blockers (atenolol [<200 mg daily], metoprolol [<200 mg daily]; acebutolol [<400 mg daily], oxprenolol [<160 mg daily], nadolol [<80 mg daily], and molol [<20 mg daily]) have a similar effect. This finding is at variance with the effects of β blockers other than propranolol in essential tremor.
ESSENTIAL TREMOR Essential tremor is a slowly progressive tremor disorder that causes severe disability but is not life limiting. It is defined by the following core criteria:1,18 ■ Bilateral tremor of the hands or forearms with predominant
kinetic tremor and resting tremor only in advanced stages of the disease
420
Section
VII
Motor System and Motor Diseases
■ Or isolated head tremor without evidence of abnormal
posture (e.g., dystonic signs) ■ And absence of other neurological signs with the exception of cogwheel phenomenon and slight gait disturbances Experts believe that the following criteria are supporting the diagnosis, although prospective studies on their diagnostic value are not yet available: ■ Duration longer than 3 years ■ Alcohol responsiveness ■ Family history
Some criteria involve the severity of the tremor,19 which are falling short when applied to a slowly developing condition. But the criteria mentioned here also have difficulties as the differential diagnosis to enhanced physiological tremor is not yet clear enough. Essential tremor usually starts with a postural tremor but can still be suppressed during goal-directed movements. In advanced stages an intention tremor can develop. This has been found in roughly 50% of an outpatient population and is accompanied by signs of cerebellar dysfunction of hand movements like movement overshoot and slowness of movements.20 In more advanced stages a tremor at rest can develop. Also, a mild gait disorder prominent during tandem gait is frequently found.21 Oculomotor disturbances are found with subtle electrophysiological techniques but cannot be detected by means of clinical assessment. The condition may begin very early in life and the incidence is increasing above 40 years with a mean onset of 35 to 45 years in different studies and an almost complete penetrance at the age of 60.22,23 The topographic distribution shows hand tremor in 94%, head tremor in 33%, voice tremor in 16%, jaw tremor in 8%, facial tremor in 3%, leg tremor in 12%, and tremor of the trunk in 3% of the patients.22-24 In some of the topographic regions (e.g., head, voice, and chin), tremor may occur in isolation.25 About 50% to 90% of the patients improve with ingestion of alcohol, which can be used as an important feature of medical history. So far only few data are available on the progression of the condition and have shown a decrease of tremor frequency and a tendency to develop larger amplitudes.26 Intention tremor develops at various intervals between 3 and 30 years after the onset of postural tremor.20 The disease-related disability varies significantly and is dependent on the severity of intention tremor.27 For a generic quality of life questionnaire (SF-36), essential tremor patients scored worse in all eight SF-36 domains. Tremor severity correlated with some of the physical domains as well as with social function of the mental domains.28 An essential tremor-specific quality of life questionnaire has been validated.29 Up to 25% of the patients seeking medical attention must change jobs or retire from work.30 Nontremor symptoms have been described as a mild frontal dysexecutive syndrome31 and slight personality changes,28,32 which have both been interpreted to reflect a cerebellar dysfunction. Furthermore, a deficit of hearing33 and olfaction was found independent from disease duration and severity.34
Epidemiology The prevalence of essential tremor has been assessed in many studies to be between 1.3% and 5.1% when only studies with
convincing methodological approaches are taken into account.35 Such methodological problems are the lack of a test for the validation of the diagnosis as many other conditions may manifest with a slowly progressive action tremor. Convincing studies on the incidence are not available. Patients with essential tremor were found in retrospective studies to live longer than those without essential tremor,36 but other studies failed to find this. There is at least no evidence for a shortening of life span due to essential tremor.
Etiology The majority of cases are hereditary. The families that have been described hitherto have shown an autosomal dominant inheritance with an almost complete penetrance at the age of 60 years. Twin studies allow to estimate the heritability, which was estimated to be low in a relatively small study37 but almost 100% in a larger study of twins of old age (>70 years).38 Thus, in families with familial essential tremor, the heritability seems to be extremely high and the role of environmental factors is probably limited. However, there is a proportion of approximately 20% to 40% of the patients who have no family history of essential tremor and therefore may not be genetic. Linkage has been found for two chromosomes, 3q1339 and 2p22.40 For the latter locus, a rare variant of the HS1-BP3 protein has been described,41 which binds to motor neurons and Purkinje cells and regulates the Ca2+/calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase. Further confirmation is needed. On chromosome 3, a gain of function-mutation of the DRD3-gen is considered to be responsible. The environmental factors that may cause tremor are also understudied. β-Carboline alkaloids are known to cause tremor in animals and humans42 and were found to be elevated in the blood of patients with essential tremor.43 Also, the lead concentration was found to be elevated in essential tremor.44 Controlled epidemiological studies are necessary.
Pathophysiology The pathophysiology of essential tremor was reviewed45,46 and is covered only briefly here. Essential tremor is likely enhanced by peripheral reflex mechanisms, but its main origin must be within the central nervous system for various reasons: either a preformed mechanism in the brain that is producing rhythmic movements is overactive or pathology has created a system to oscillate, which is usually stable. The oscillator is most likely located within the olivocerebellorubral triangle. The cerebellum shows some mild to moderate signs of malfunction demonstrated in a number of motor tests. The rhythmic movement is obviously mediated through different channels of both hemispheres for the different extremities as the trembling is independent in the four extremities.47 It is assumed that the rhythmic discharges are mediated through the thalamus to the premotor and motor cortex projecting down to the motor neurons. At both locations, tremor-related activity can be detected with electrophysiological techniques. Alternative pathways, mainly from the cerebellar nuclei through reticulospinal pathways to the spinal cord, have been proposed.
chapter 33 tremor Differential Diagnosis The following criteria are considered red flags for the diagnosis (see also Table 33−2): ■ Isolated tremor in the voice, tongue, chin, or legs ■ Unilateral tremor or leg tremor ■ Presence of known causes of enhanced physiological tremor ■ ■ ■ ■ ■ ■ ■ ■
(e.g., drugs, anxiety, depression, hyperthyroidism) History of recent trauma preceding the onset of tremor History or presence of psychogenic tremor Sudden onset or stepwise progression Isolated head tremor with abnormal postures (e.g., dystonia) Drugs Other systemic disorders (e.g., endocrine, renal) Primary orthostatic tremor Isolated position-specific or task-specific tremors, including occupational tremors and primary writing tremor
Treatment Tremor of the Hands Propranolol and primidone are the drugs of first choice for this indication, and both have been carefully studied (for review, see Findley48). Propranolol was introduced in 197149 as a treatment for essential tremor. Drugs with predominant β1 effects have been shown to be less effective than those acting on the β2 receptor, and none has proved superior to propranolol. Only 25% maintain their initial good response for 2 years. Contraindications are cardiac insufficiency or arrhythmia and diabetes. As propranolol acts on the peripheral (reflex) enhancement of tremors, it is helpful for many other tremors like parkinsonian or cerebellar tremor.50,51 Primidone is efficient for essential tremor52 but tachyphylaxia may occur. The major problems are early adverse effects with nausea, dizziness, sedation, and headache. The combination of propranolol and prinidone is recommended whenever one of the drugs is insufficient. Arotinolol has been tested in a crossover study with a similar effect as propranolol.53 Gabapentin is also effective
421
following two double-blind studies,54 but another double-blind study showed no convincing effect.55 Topiramate was shown to be effective in a small double-blind study.56 Levetiracetam is just beginning to be explored for the treatment of essential tremor and single-dose studies are promising.57,58 Acetazolamide (and methazolamide) are not significantly better than placebo.59 Alprazolam is helpful in essential tremor.60 Clonazepam is recommended for patients with predominant action and intention tremor in essential tremor61 but not effective in uncomplicated essential tremor.62 Botulinum toxin at a dosage of 50 units or 100 U of Botox has a significant but clinically limited effect and carries a high risk of a clinically meaningful but completely reversible paresis63 (Table 33−3 and, for drug dosages, Table 33−4). Surgery is the accepted treatment for patients resistant to medical treatment and severe disability. Multicenter studies have shown that thalamic deep-brain stimulation is effective,64-67 and one study has shown that deep-brain stimulation of the Vim has a better effect than Vim-thermocoagulation and even fewer side effects.68 The selection of patients for surgery is a crucial point for a good therapeutic effect. Each patient should test the treatments of first choice before surgery and each patient proposed for surgery must have a significant handicap. Gamma knife surgery for the treatment of tremors is proposed in some centers, but prospective studies are lacking and the risks are not yet fully clear.69-71
Head and Voice Pharmacological treatment of essential head and voice tremor is less efficient than the one of hand tremor. Propranolol and primidone, each alone or both combined, have been recommended72,73 for essential head tremor. Clonazepam is often recommended for this indication, but careful studies are not available. One of the promising therapies for head tremor is the local injection of botulinum toxin.74 Deep brain stimulation is also effective for head and voice tremor. As bilateral thalamotomies carry a high risk of dysarthria and bilateral interventions show better effects on these “midline” tremors,75,76 mostly Vim stimulation is applied.66,77 An evidence-based medicine-
T A B L E 33-3. Drugs and Dosages for Essential Tremor Choice
Drug
Dosage
Remarks
First choice
Propranolol
First choice
Primidone
First choice
Contraindications: cardiac, pulmonary, diabetes, etc. Hand and head tremors Hand and head tremors Preferentially for patients with age >60 years Try always before using second- and third-choice drugs
Second choice Second choice
Combination: propranolol/ primidone Arotinolol Gabapentine
30 to 320 mg, 3 doses (standard or long-acting) 62.5 to 500 mg, single dose in the evening Maximum dosage for each 10 to 30 mg 1800 to 2400 mg daily
Second choice Second choice Third choice
Topiramate Clonazepam Botulinum toxin
<400 mg 0.75 to 6 mg
Third choice
Clozapine
Test: 12.5 mg, 30 to 50 mg daily
If drug therapy fails
Surgery
Crossover study with propranolol Conflicting results of three double-blind studies: one without, two with benefit! So far, small double-blind study only For predominant kinetic tremor Double-blind study with a significant result, but weakness as a significant side effect Less well documented effect than for Parkinson’s disease. Often ineffective Vim stimulation or thalamotomy
422
Section
VII
Motor System and Motor Diseases
T A B L E 33-4. Dosages of Various Substances Applied for the Treatment of Tremor Initial Dose
Increase in Steps of
High Dose
62.5 mg 50 mg
62.5 mg/d 50 mg/d
750 mg 600 mg
Dopamine agonists Bromocriptine Lisuride α-Dihydroergocryptin Pergolide Pramipexole Ropinirole Cabergoline
5 mg 0.1 mg 10 mg 0.15 mg 1.5 mg 3 mg 2 mg
5 mg/wk 0.1 mg/wk 10 mg/wk 0.10 mg/d 0.5 mg/wk 1.5 mg/d 1 mg/wk
20 mg 1.2 mg 90 mg 3.0 mg 4.5 mg 15 mg 6 mg
Anticholinergics Bornaprine Biperiden Metixen Trihexyphenidyl
3 mg 1 mg 7.5 mg 1 mg
3 mg/wk 2 mg/wk 7.5 mg/wk 2 mg/wk
12 mg 12 mg 60 mg 10 mg
b Blockers Propranolol Nadolol
30 mg 10 mg
30mg/wk 30 mg/wk
240 mg 120 mg
Miscellaneous Clozapine Amantadine Primidone Clonazepam Alprazolam
12.5 mg 100 mg 62.5 mg 0.5 mg 0.75 mg
12.5 mg/d 100 mg/d 125 mg/d 0.5 mg/d 0.75 mg/d
75 mg 300 mg 500 mg 6 mg 4 mg
L-Dopa L-Dopa L-Dopa
+ benserazid + carbidopa
For some substances (e.g., anticholinergics), a slow titration is strictly recommended. Treatment for parkinsonian tremor must be customized to the individual patient, and we have indicated which dosages we consider to be high for the indication tremor.
Etiology and Pathophysiology Orthostatic tremor is considered an idiopathic condition. However, other movement disorders often occur simultaneously: Parkinson’s disease, vascular parkinsonism, and Restless legs syndromes (RLS) have all been described in orthostatic tremor, but there is no convincing evidence that any of these conditions are pathophysiologically related. It is of special interest that dopaminergic terminals are significantly reduced in this condition82 but clinical trials with L-dopa and dopamine agonists are usually unsuccessful. Surface electromyography (e.g., from the quadriceps femoris muscle) while standing shows a typical (pathognomic) 13- to 18-Hz burst pattern. All of the leg, trunk, and arm muscles show this pattern, which is in many cases absent during tonic innervation when sitting and lying.83-85 Besides asterixis, orthostatic tremor is the only tremulous condition for which electromyography is mandatory for the diagnosis. Arm tremor may occur in roughly one half of the patients and is usually more evident during stance.86,87 The high-frequency electromyographic pattern is coherent in all the muscles of the body,88 leading to the hypothesis that a bilaterally descending system must underlie orthostatic tremor. Such projections originate only from the brainstem and not from the hemispheres. Therefore, the generator for this tremor is assumed to be located within the brainstem or cerebellum.89
Differential Diagnosis Other idiopathic tremors like essential tremor and also cerebellar tremors can manifest with similar complaints. The most important test to separate them is electromyography.
Treatment based review on treatments for essential tremor was published.78
ORTHOSTATIC TREMOR Primary orthostatic tremor is a unique tremor syndrome79,80 characterized by a subjective feeling of unsteadiness during stance but only in severe cases during gait. Some patients show sudden falls. None of the patients has problems when sitting and lying. The only clinical finding is sometimes visible but mostly only palpable fine-amplitude rippling of leg muscles. This tremor is suspected mainly based on the complaints of the patients rather than on clinical findings.
Epidemiology Orthostatic tremor is a relatively rare condition (only small case series have been published adding up to fewer than 200 cases), but epidemiological data are lacking. Other movement disorders are common in orthostatic tremor. The condition occurs only in patients older than 40 years, and in the series of Gerschlager and colleagues,81 the mean age at onset was lower for women (50 years) compared with men (60 years). So far, it is not considered a hereditary disease.
Orthostatic tremor has been documented to be responsive to clonazepam and primidone.90 Valproate and propranolol were applied in single cases with varying success. Abnormalities of dopaminergic innervation of the striatum have been described, although L-dopa has not consistently shown efficiency.82,91 According to small double-blind studies92,93 and our experience, gabapentin seems to have an excellent and most consistent beneficial effect.94 We use it as the drug of first choice for orthostatic tremor (1800 to 2400 mg daily). The drug of second choice, in our hands, is clonazepam.
PARKINSONIAN TREMORS Parkinsonian tremor has been defined as tremor that occurs in Parkinson’s disease.1 The most common forms are the following: Classic parkinsonian tremor (type I) is defined as tremor at rest (ideally resting on a couch) that increases in amplitude under mental stress and is suppressed during initiation of a movement and often during the course of a movement. Tremor frequency is 4 to 6 Hz but can be as high as 6 Hz, especially in early Parkinson’s disease. It may also be seen in the hands during walking or when sitting as a typical pill-rolling tremor of the hand. The postural/kinetic tremor (with similar frequencies for rest and postural/kinetic tremors) seems to be a
chapter 33 tremor continuation of the resting tremor under postural and action conditions. The frequencies for resting and postural/action tremor can be considered to be equal if they do not differ by more than 1.5 Hz. Unilateral tremor or leg tremor are often seen and are typical for type I tremor. A clinically important specific variant of Parkinson’s disease is the monosymptomatic tremor at rest or benign tremulous parkinsonism. This is defined as a classic Parkinson’s disease type I tremor without other symptoms sufficient to diagnose Parkinson’s disease.1 In some patients, a second form of postural and action tremor with a different frequency from resting tremor (>1.5 Hz) may occur, which is labeled type II tremor. This postural/action tremor can be extremely disabling. Some patients have a predominant postural tremor in addition to their resting tremor. The postural/action tremor has a higher and non−harmonically related frequency to the resting tremor. This form is rare (<15% of patients with Parkinson’s disease) and has often been described as a combination of an essential tremor with Parkinson’s disease.95 Some of these patients had their postural tremor long before the onset of other symptoms of Parkinson’s disease. A high-frequency action tremor also described as “rippling” is often found in Parkinson’s disease and has been described as type III tremor in Parkinson’s disease.1
423
but that there are no clear-cut differences in the positron emission tomography imaging of the presynaptic or postsynaptic dopaminergic terminals in patients with monosymptomatic tremor at rest compared with classic Parkinson’s disease patients.104,105 Interestingly, reduction in 5-hydroxytryptamine1A binding in the midbrain raphe region is correlating with tremor severity but not with rigidity or bradykinesia.106 Thus, degeneration of transmitter systems other than dopamine may be responsible for the erratic behavior of tremor as a symptom in Parkinson’s disease. Nevertheless, L-dopa and dopamine agonists are potent drugs to treat Parkinson’s disease tremor. Beyond all of these unsolved problems, animal experiments and human data converge to suggest that parkinsonian tremor is generated within the basal ganglia.107 In the 1-methyl 4phenyl 1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease it has been shown that the cells within the basal ganglia loop are topographically organized through the whole loop and well segregated for the different muscle groups and functional regions. In MPTP animals, these cells become abnormally synchronized, and this may be the reason for synchronized activity leading to peripheral tremor.108 Recordings in humans are compatible with this view.109
Treatment Epidemiology Tremor at rest is common in Parkinson’s disease. It is estimated that 90% of all patients with Parkinson’s disease have a classic rest tremor at any time of their disease and that 75% of all parkinsonian syndromes are idiopathic. Thus, the occurrence of the classic tremor at rest in a patient with parkinsonism has a likelihood of more than 95% to reflect idiopathic Parkinson’s disease.
Etiology and Pathophysiology It is one of the mysteries of Parkinson’s disease that the typical type I tremor is a symptom with such a high specificity for Parkinson’s disease but that the symptom of tremor does not correlate with disease progression96,97 nor does tremor severity correlate with the amount of dopaminergic degeneration measured with positron emission tomography or single-photon emission computed tomography imaging.98-100 Pathology suggests that in patients with predominant tremor the retrorubral Aδ part of the substantia nigra is specifically degenerating101-103
T A B L E 33–5.
Drug treatments differ for the different forms of tremor in Parkinson’s disease (for drug dosages, see Table 33−4). Our personal approach to the treatment of patients is included in Table 33−5. L-Dopa is the most effective treatment for the majority of symptoms in Parkinson’s disease. Among the tremors in Parkinson’s disease, mainly the resting tremor is improved, but other forms may also respond. Generally, the effect on tremor is highly variable in patients with Parkinson’s disease, and the tremor may even worsen, especially for the action tremor with frequencies different from the resting tremor frequency. All of the available double-blind studies of different dopamine agonists failed to demonstrate a superior effect of one or the other agonist on tremor, although all of them obviously have a significant effect. For pramipexol, a double-blind-study has shown a favorable effect on tremor.110 Although the treatment of tremors with anticholinergics is often recommended, there are only a few double-blind studies. The anticholinergic bornaprine has been found to be effective in two double-blind studies.111,112 Trihexyphenidyl has been tested alone and compared with amantadine and L-dopa.113 Possible side effects are dry mouth,
Suggestions for the Treatment of Tremors in Parkinson’s Disease
Tremor type
step 1.
step 2.
step 3.
Classic parkinsonian tremor or monosymptomatic rest tremor
L-Dopa Dopamine agonists Anticholinergics Propranolol Primidone
Amantadine Propranolol Clozapine Dopamine Dopamine agonists Anticholinergics Clozapine Amantadine
STN-stimulation
Rest and postural tremor with different frequencies Isolated action tremor
Propranolol Anticholinergics
STN-stimulation
424
Section
VII
Motor System and Motor Diseases
visual disturbances, constipation, glaucoma, disturbance of micturition, and memory deficits. Especially in elderly subjects, confusional states can occur, which are reversible after cessation of the drug. Discontinuation may induce a severe rebound effect. A study has provided ample evidence that patients treated with anticholinergics have a higher incidence of Alzheimer pathology.114 The favorable effect of clozapine on rest tremor has been confirmed in several studies,115,116 which have shown a good effect on resting tremor—even when other drugs failed.117 No tolerance has been observed over 6 months. The dosage was 18 to 75 mg. Major side effects are sedation and leukopenia as a serious, even lethal complication in some patients. Functional neurosurgery is a useful treatment for some patients who cannot be treated otherwise. Thalamic thermocoagulation or deep brain stimulation (DBS) of the Vim improves tremor but does not improve akinesia. Lesional surgery cannot be applied bilaterally due to speech disturbances (but DBS can) and therefore is no longer the surgical treatment of first choice.68 Pallidotomy, as well as stimulation of the pallidum, also improves tremor. Subthalamic nucleus (STN) stimulation improves tremor118,119 as well as akinesia and rigidity and is the preferred surgery. Further controlled studies are necessary.
DYSTONIC TREMOR SYNDROMES Different forms of tremor can be associated with dystonia. Typical dystonic tremor occurs in the body region affected by dystonia. It is defined120 as a postural/kinetic tremor usually not seen during complete rest. Usually, these are focal tremors with irregular amplitudes and varying frequencies (mostly below 7 Hz). Some patients exhibit focal tremors even without overt signs of dystonia. These tremors have been included with dystonic tremors121 because in some of them, dystonia develops later. Tremor associated with dystonia is a more generalized form of tremor in extremities that are not affected by the dystonia. This is a relatively symmetrical, postural, and kinetic tremor usually showing higher frequencies than actual dystonic tremor, often seen in the upper limbs in patients with spasmodic torticollis.122
Epidemiology The prevalence of dystonic tremor is not known. In one Brazilian cross-sectional study, it was estimated that around 20% of patients with dystonia present with postural tremor.123 This proportion does not differ between primary and secondary dystonia but seems to be more common in cervical dystonia than in other locations.124 In a large survey among patients from a large Indian movement disorder center, dystonic tremor constituted about 20% of all patients presenting with non-parkinsonian and noncerebellar tremors (essential tremor, 60%).125
Pathophysiology and Etiology Dystonic tremor is still an entity that is under debate, and different definitions have been proposed by clinicians.126-128 Its pathophysiology is largely unknown but is likely related to the central nervous system (basal ganglia) abnormality postulated
for dystonia itself.120 Tremor associated with dystonia may be a “forme fruste” of essential tremor.127 However, it is not yet clear if they share common genes (the DYT1 locus is already excluded), and the pathophysiological mechanisms seem to be different in some of the patients.122
Differential Diagnosis In many patients with dystonic tremors, antagonistic gestures lead to a reduction of the tremor amplitude. This is well known for dystonic head tremor in the setting of spasmodic torticollis. A reduction in tremor is seen when the patient touches the head or only lifts the arm.129 As this sign is absent in essential head tremor, it can be an important differential diagnostic hint in unclear head tremors in which the dystonic posture is not obvious. The effect of these maneuvers can be difficult to observe clinically, and it can be helpful to record surface electromyography from the affected muscles and look for electromyographic suppression.129 Other important but less specific differential diagnostic clues are the focal nature and relatively low frequency of dystonic tremor (see Table 33−2). The tremor associated with dystonia is more difficult to separate from essential tremor, especially when the accompanying dystonia has not evolved completely.
Treatment A positive effect of propranolol has been described earlier in studies of dystonic head tremor. The effectivity of botulinum toxin for dystonic head130 tremor and in tremulous spasmodic dysphonia is well documented. A double-blind study has also documented the efficacy of botulinum toxin for hand tremor,63 but the use of this drug for this indication is limited because of the paresis associated with this treatment. Severe cases in the setting of a generalized dystonia have been successfully treated with deep brain stimulation of the pallidum.131 Stimulation of the ventrolateral thalamus can also alleviate the tremor drastically but can occasionally lead to worsening of the dystonia itself. Tremor associated with dystonia often responds to the medication for classic essential tremor (for drug dosages, see Table 33−4).
CEREBELLAR TREMOR SYNDROMES The classic cerebellar tremor is an intention tremor that may occur unilaterally or bilaterally depending on the underlying cerebellar abnormality. The tremor frequency is almost always below 5 Hz. Simple kinetic and postural tremor may also be present. Some patients with a mild cerebellar ataxia present with an isolated postural and simple kinetic tremor above 5 Hz resembling essential tremor. Titubation is another tremor manifestation of cerebellar disease and is a low-frequency oscillation (around 3 Hz) of the head and trunk depending on postural innervation. If the low-frequency action tremor is severe, it may sometimes be seen in a seemingly resting position because the patient is unable to completely relax.
Epidemiology and Etiology This type of tremor can be caused by insults of various etiologies and degenerations, so no epidemiological data are avail-
chapter 33 tremor able. One of the most common causes of cerebellar tremor certainly is demyelinating lesions in multiple sclerosis.132 Cerebellar strokes can also manifest with tremor, especially when the brainstem is involved.133 Degenerations of cerebellar neurons of various etiologies often produce tremor. Whereas the hereditary ataxias are rare syndromes, toxic cerebellar degeneration due to alcohol abuse predominantly of the anterior lobe is common and often manifest with low-frequency (2 to 3 Hz) stance tremor in the anteroposterior direction.134
425
symptomatic improvement can be obtained with stereotactic high-frequency stimulation or thalamotomy in select patients.68,144,145 Functional outcome after surgery, however, greatly varies and depends on the presence of other motor symptoms of the disease; patients with tremor in Multiple Sclerosis (MS) with a frequency above 3 Hz and significant tremorrelated disabilities were found to respond favorably.144 Accelerometric tremor recordings and frequency analysis may help to distinguish patients with predominant MS tremor from those with tremor and ataxia. The long-term follow-up in a larger cohort has not yet been assessed.
Pathophysiology The pathophysiology of the classic cerebellar intention tremor seems to be distinct from the mechanisms underlying most of the other central tremors in that it most likely does not emerge from oscillating groups or loops of neurons but is due to altered characteristics of feedforward or feedback loops. It is meanwhile well established in animals and humans135-137 that one of the striking abnormalities in cerebellar dysfunction is a delay of the second and third phases of the triphasic electromyographic pattern in ballistic movements138 or a delay of the reflexes regulating stance control.139 During goal-directed movements or sway during stance, this causes the breaking movement to occur late and thereby produce an overshoot, in turn producing a quasi-rhythmic movement that is compatible with intention tremor during goal-directed movements or the low-frequency body tremor during stance. However, the higher-frequency postural and action tremors in some patients with cerebellar disease most likely reflect the existence of a separate central oscillator.
Differential Diagnosis Intention tremor is a unique form of tremor that can usually be separated from other tremor forms clinically. However, the fact that intention tremor can also occur in advanced essential tremor45 can make the differentiation difficult. The most important clinical clue in this situation is the degree to which ataxia is present and the absence of clinically detectable oculomotor abnormalities in essential tremor. whereas in essential tremor only a mild dysmetria45 and tandem gait disturbance21 have been described, these dominate the cerebellar syndrome, in which lesions or atrophy can often be seen in brain imaging studies (see Table 33−2).
HOLMES’ TREMOR This is a rare symptomatic tremor due to a lesion in the region of the midbrain. It has been labeled under different names in the past (rubral tremor, midbrain tremor, myorhythmia, Benedikt’s syndrome). It is the only tremor with resting, postural, and intentional components. It typically shows low frequencies (<4.5 Hz) and often manifests as irregular, not as rhythmic as are other tremors. If the date of the lesion is known (e.g., in case of a cerebrovascular accident), a variable delay between the lesion and the first occurrence of the tremor is typical (usually 2 weeks to 2 years). This is among the most disabling forms of tremor because it disturbs rest and all kinds of voluntary and involuntary movements. It mainly affects the hands and proximal arm and is mostly unilateral.
Pathophysiology and Etiology It is generally accepted that this unique tremor form is caused by lesions that seem to be centered in the brainstem/cerebellum and the thalamus. The pathophysiological basis of Holmes tremor is a combined lesion of the cerebellothalamic and nigrostriatal systems as suggested by autopsy data,146 positron emission tomography data,147 and clinical observations.148,149 Any lesion involving fiber tracts from both systems can produce this tremor. The exact location of the lesions seen in these patients may vary. Because of these lesions the tremors can be accompanied by a cerebellar as well as parkinsonian syndrome. Central oscillators are causing this tremor. It seems likely that the rhythm of resting tremor is usually blocked during voluntary movements by the cerebellum. If this cerebellar compensation is absent, the rhythm of rest tremor spills into movements,148 thereby producing the low-frequency intention (action) tremor.
Treatment Cerebellar tremors are difficult to treat and good results are rare. Double-blind studies are lacking. Studies with cholinergic substances (physostigmine, lecitine [a precursor of choline]) have shown improvement in some patients but failed in the majority. Isoniazid failed to show significant results.140 5-HTP has been found to be effective in some patients.141,142 Another proposal has been to administer amantadine. Open studies or single-case observations have shown favorable results with propranolol, clonazepam, carbamazepine, tetrahydrocannabiol, and trihexyphenidyl. Limited improvements have been observed after loading of the shaking extremity, but most clinicians do not use it because the patients adapt rapidly to the new weight. Cannabis is not effective.143 Probably the best
Differential Diagnosis A specific tremor syndrome associated with thalamic lesions can be difficult to differentiate from Holmes tremor. It has been presented often in the past but was further analyzed with modern imaging techniques. The label thalamic tremor150 has been used for this entity. A more detailed study has shown that this tremor is part of a specific dystonia-athetosis-chorea-action tremor following lateral-posterior thalamic strokes.151,152 The combination of tremor, dystonia, and a severe sensory loss following this stroke seems to be the important clue for the diagnosis. The “thalamic” tremor itself is a mixture of action tremor with an intentional component and dystonia in the setting of a
426
Section
VII
Motor System and Motor Diseases
well-recovered severe hemiparesis. Proximal segments are often involved. This tremor syndrome is also developing with a certain delay after the initial insult. Cerebellar tremor that continues under seemingly resting conditions due to a lack of relaxation can be mistaken for Holmes tremor. The irregularity, the lower frequency, and an accompanying parkinsonian syndrome can help to recognize Holmes tremor in this situation (see Table 33−2).
Treatment No generally accepted therapy is available. Nevertheless, treatment is successful in a higher percentage than for patients with cerebellar tremor. Some patients respond to L-dopa, anticholinergics, or clonazepam (for drug dosages, see Table 33−4). The effect of functional neurosurgery for this tremor syndrome is poorly documented. Such patients have been operated on but they are diagnosed as having post-traumatic tremors or poststroke tremors and the clinical features are not described in detail. Several patients received thalamic surgery (lesion or DBS153-155) with some improvement.
PALATAL TREMOR SYNDROMES Palatal tremors are rare tremor syndromes that were earlier classified among the myoclonias (palatal myoclonus).156 Because they are rhythmic, they have been reclassified among the tremors. Palatal tremor can be separated into two forms.157,158 Symptomatic palatal tremor (SPT) is characterized by rhythmic movements of the soft palate (levator veli palatini). This is clinically visible as a rhythmic movement of the edge of the palate. Other brainstem-innervated (leading to oscillopsia in case of eye muscle involvement) or extremity muscles can also be involved.146 It typically follows a brainstem/cerebellar lesion with a variable delay159,160 and is often associated with a cerebellar syndrome.161 Essential palatal tremor occurs without any overt central nervous pathology and is characterized by rhythmic movements of the soft palate (tensor veli palatini), usually with an ear click. The tensor contraction is visible as a movement of the roof of the palate. Extremity or eye muscles are not involved.158,161,162
Pathophysiology and Etiology Although the pathophysiological basis of essential palatal tremor is unknown, the emergence of SPT has been studied in detail and carries important implications for central mechanisms of tremors in general. After the cerebellar/brainstem lesion, an inferior olivary pseudohypertrophy (which can be demonstrated on MRI) develops most likely as a consequence of an interruption of inhibitory GABAergic fibers terminating in the inferior olive.158 It is well established that inferior olivary neurons are prone to oscillate spontaneously and can be easily synchronized through gap junctions.163 The disinhibition and hypertrophy lead to enhanced synchronized oscillations and build the basis for the rhythmic movement disorder. Interestingly, this rhythm is also reflected in rhythmic electromyographic inhibition in extremity muscles, sometimes leading to a mild postural tremor.158,164 Therefore, it has been postulated that the inferior olive (and the olivocerebellar system) may be
a key structure in producing postural tremors8 and that these tremors are characterized by a rhythmic inhibition of ongoing contractions rather than rhythmic activation, which may be the basis of the etiologically different resting tremors.158
Treatment The disability of patients with SPT is mostly due to other clinical symptoms of the underlying cerebellar lesion. The rhythmic palatal movement in SPT does not cause discomfort or disability for the patient except when the eyes are involved or when there is an extremity tremor. Oscillopsia is difficult to treat. Single cases have been described with a favorable response to clonazepam. Other oral drugs that have been proposed are trihexyphenidyl and valproate. Botulinum toxin has been used for the treatment of oscillopsia. The toxin can be injected into the retrobulbar fat tissue, or specific muscles can be targeted selectively.165,166 So far no controlled studies are available. In our hands, this treatment is helpful for some patients but is not always accepted for long-term use. For the treatment of extremity tremors, only single case reports have described a response to clonazepam167 or trihexiphenidyl.168 The only complaint of patients with essential palatal tremor is the ear click. A number of medications have been reported to be successful: valproate,169 trihexyphenidyl,168 and flunarizine.170 Sumatriptane has been found to be effective in a few patients171,172 but was unsuccessful in others.173 The antagonism of 5-hydroxytryptamine receptors may thus play a role at least for some of the patients. As a long-term therapy, this drug is not applicable for various reasons. The most established therapy is the treatment of the click by injection of botulinum toxin into the tensor veli palatini.174 Low dosages of botulinum toxin (e.g., 4 to 10 units of Botox) are injected under electromyographic guidance. The critical point is to ascertain by endoscopy and electromyography with an electromyography injection needle (isolated up to the tip) that the toxin is definitely injected in the tensor muscle. Spread of botulinum toxin in the soft palate or too large dosages can otherwise cause severe side effects. Although we have never seen any such complications in our patients, it must be mentioned that the injection of botulinum toxin into the palatal muscles in rabbits has been introduced as an animal model for middle ear infections (for drug dosages, see Table 33−4).
TREMOR SYNDROMES IN PERIPHERAL NEUROPATHY Several peripheral neuropathies regularly manifest with tremors (Table 33-1). The tremors are mostly postural and action tremors. The frequency in hand muscles can be lower than in proximal arm muscles. Abnormal position sense need not be present.
Epidemiology Dysgammaglobulinemia and chronic Guillain-Barré syndrome are the acquired neuropathies manifesting most frequently with tremor. In a series of 62 patients with dysgammaglobu-
chapter 33 tremor linemic polyneuropathy, postural and action tremor of the hands was present in 70% to 80% of the cases.175 However, it only rarely represents the dominant source of disability in these patients.176 A similar type of tremor can be observed in around 40% of patients with hereditary polyneuropathy. Many of these patients have a family history of tremor.177
Pathophysiology and Etiology The tremor in dysimmune neuropathies seems to be somewhat related to the severity of the peripheral neuronal damage,178 and it has been postulated that an abnormal peripheral feedback to central tremor generating structures could be the basis for the tremor enhancement in this situation.179 The tremor in hereditary polyneuropathy seems to be largely unrelated to the severity of neuropathic syndromes, and it may also occur in family members without a neuropathy. Thus, it has been suggested that it is pathogenetically related to essential tremor.177 There is an ongoing debate as to whether the combination of a hereditary neuropathy with postural tremor (Roussy-Lévy syndrome) actually constitutes a distinct disease entity.180
Treatment No convincing therapies are reported for this type of tremor. Successful treatment of the underlying neuropathy can improve the tremor in some of the patients.178 In our hands, propranolol and primidone have been helpful for some patients at similar dosages as for essential tremor. One patient was successfully implanted with DBS electrodes.181
PSYCHOGENIC TREMOR Psychogenic tremors have very diverse clinical manifestations. Most of them are action tremors but many also remain during rest and often show very unusual combinations of rest/postural and intention tremors.182 Typical clinical features are a sudden onset and sometimes spontaneous remissions, decrease of tremor amplitude or variable frequency during distraction, selective disability, and a positive “coactivation sign.” (This is tested as with rigidity testing, at the wrist. Variable, voluntarylike force exertion can be felt in both movement directions.183) Some of the patients have a history of somatizations in the past or additional, unrelated (psychogenic) neurological symptoms and signs.183
Epidemiology In a large series of 842 patients presenting with a movement disorder, only 3.3 % were diagnosed with a psychogenic movement disorder. Among those, psychogenic tremor was the most common diagnosis (50%).184
Pathophysiology and Etiology Two pathogenetic mechanisms seem to play a role in psychogenic tremor. Voluntary-like rhythmic movements can be
427
detected by a coupled (coherent) tremor oscillations in different limbs. This resembles the situation in voluntarily sustained rhythmic movements in normal subjects, as it is extremely difficult to keep up two completely independent rhythms in different limbs.185,186 In pathological, organic tremor (clearly involuntary rhythmic movements), the oscillations are typically independent between different limbs.47,187 Such independent rhythms can also be found in psychogenic tremor patients.188 They most likely represent physiological but involuntary oscillations, such as clonus-like mechanisms, which are enhanced by the ongoing co-contraction of antagonistic muscles detected as the coactivation sign.183 These findings may easily explain the motor control mechanisms underlying these tremors. They do not allow conclusions to be drawn on the underlying psychological mechanisms.
Differential Diagnosis Psychogenic tremors manifest very variably and can mimic virtually all organic tremors. The tremor phenomenology does not help to differentiate them. The typical conditions of tremor appearance or disappearance, enhancement or attenuation described earlier are important clinical clues. The coupling between the oscillations in both arms, which is present only in psychogenic tremor and is absent in organic tremors, can be used as an electrophysiological diagnostic tool. The surface electromyography from both arm muscles can be analyzed using “coherence,” which is a reliable mathematical measure of the oscillatory coupling. If the patients show only unilateral tremor, a voluntarily sustained rhythmic hand movement on the unaffected side is related to the tremor on the affected side (“coherence entrainment test”).189 This test is very specific, and the entrainment of psychogenic tremor by a contralateral rhythmic movement can sometimes be visible even clinically. However, it is not very sensitive; some psychogenic tremor patients show unrelated rhythms in different limbs resembling organic tremors.188 An accelerometric quantification of the distractibility can also be helpful.190
Treatment No studies on the treatment effects in psychogenic tremor are available.191 Psychotherapy is helpful only in the minority of patients. We recommend physiotherapy aiming at a decontraction of the muscles during voluntary movements. Additionally, we administer propranolol at medium or high dosages to desensitize the muscle spindles, which are necessary to maintain the clonus mechanism in these patients. Conclusive data on the prognosis and long-term outcome in these patients are lacking, but the prognosis is generally believed to be poor.192
DRUG-INDUCED AND TOXIC TREMORS Drug-induced tremors can manifest with the whole range of clinical features of tremors depending on the drug and probably on individual predisposition of the patients. The most common form is enhanced physiological tremor following, for example, sympathomimetics or antidepressants. Another frequent form is parkinsonian tremor following neuroleptic or, more generally, antidopaminergic drugs (dopamine receptor
428
Section
VII
Motor System and Motor Diseases
blockers, dopamine-depleting drugs such as reserpine, flunarizin, etc). Intention tremor may occur following lithium intoxication and ingestion of some other substances. The withdrawal tremor from alcohol or other drugs has been characterized as enhanced physiological tremor with tremor frequencies mostly above 6 Hz. However, this has to be separated from the intention tremor of chronic alcoholism, which is most likely related to cerebellar damage following alcohol ingestion. A specific variant is tardive tremor associated with longterm neuroleptic treatment.193,194 The risk factors to develop this tremor are not well known, but many clinicians believe that patients with essential tremor, older age, and females represent a higher risk to develop this tremor. Its frequency range is 3 to 5 Hz, it is most prominent during posture but is also present at rest and during goal-directed movements. The tremor in Wilson’s disease can also be regarded a toxic tremor as it results from copper toxicity. All kinds of movement disorders, including cerebellar syndromes, can be observed.195 Tremor is one of the most common neurological manifestations and occurs in around 30% to 50% of the patients. Resting, postural, and kinetic tremors have all been described. The treatment of these tremors is usually to stop the medication or toxin ingestion. If this is not possible, propranolol may be tried in action tremors if it does not have negative interactions with the causative drug. It has been shown to be effective in a small open series of valproate-induced tremors.196 Treatment attempts for tardive tremor have been with trihexyphenidyl or clozapine. The treatment of Wilson’s disease with copper chelators (D-penicillamine) also improves the tremor and other neurological manifestations.197,198 In patients with very severely disabling neurological symptoms (tremor), a liver transplantation may be considered even with normal liver function.199
MYOCLONUS Myoclonus is defined as a sudden, brief, shocklike involuntary movement caused by muscle contractions or inhibitions. It can be of cortical, subcortical, or spinal origin and occurs in different neurodegenerative diseases, in focal structural lesions of the respective region of the central nervous system, and as idiopathic diseases.200 It can be difficult to differentiate from tremor when the myoclonic jerks occur repetitively with only short intervals sometimes looking rhythmically. This type of rhythmic myoclonus is not well defined but has been described as low frequency (usually below 5 Hz) muscle jerks topographically limited to segmental levels. A similar picture can be seen in asterixis in which an ongoing contraction is repetitively interrupted by inhibitions of different duration (‘negative myoclonus’). It can manifest as “flapping tremor” and typically results from focal lesions of the contralateral hemisphere (unilateral form) or endocrine dysfunction, intoxication, and liver disease (bilateral form). Both myoclonus and asterixis should be diagnosed on the basis of polymyographic recordings revealing irregular short bursts or inhibitions occurring synchronously in different muscles. Cortical tremor is considered a specific form of rhythmic myoclonus201,202 manifesting with high-frequency, irregular tremor-like postural and action myoclonus. On electrophysiological analysis, they show the typical features of cortical myoclonus with a related electroencephalographic spike pre-
ceding the electromyographic jerks and often enhanced longloop-reflexes and/or giant SEP. This form is mostly hereditary but has also been described in corticobasal degeneration203,204 and even after focal lesions205 or celiac disease.206 There is an overlap between these cortical myoclonias and epileptic phenomena, being most obvious in epilepsia partialis continua (EPC), a focal epilepsy producing (mostly lowfrequency) rhythmic jerks of an extremity. Resting and rarely postural/intention tremors (e.g., Holmes tremor) can be mimicked by EPC. A medical history for epilepsy and presence of electroencephalographic spikes, short electromyographic bursts, and jerk-locked averaging are diagnostically helpful. Clonus also is a rhythmic movement mostly around one joint elicited through the stretch reflex loop and increasing in strength (or amplitude) by maneuvers affecting the stretch reflex.207 Passive stretching of the muscles increases the force of clonus and serves as a diagnostic criterion. According to the clinical definition (see earlier), all of those myoclonic syndromes can manifest as tremors when they are rhythmic; however, they often show more irregular or even arrhythmic bursts, and most of them show pathophysiological features that are distinct from all the other pathological tremors described earlier. Thus, it seems justified and diagnostically useful to separate them from the tremor syndromes.
CONCLUSIONS Tremor or tremulous phenomena are so common in neurology that this chapter could not give a full account of all the diseases manifesting with tremor and instead concentrated on the clinical characteristics and distinctive features of the most important tremor syndromes. An exact diagnostic classification of tremors can be an important hint in the differential diagnosis of the neurological syndrome as a whole and is indispensable to the correct treatment decisions. Based on our current knowledge of the pathophysiology of tremors, good hypotheses exist as to which brain structures are involved in the generation of the tremor oscillation. This has stimulated the development or refinement of a number of new therapies, the most prominent of which is the extremely effective stereotactic deep brain stimulation. However, the underlying causes that trigger the enhanced oscillatory activity are far from being understood in the majority of tremors, and most of our treatment options are purely symptomatic. Future progress in this field will undoubtedly lead to an improvement and increasingly causal approaches in the rational therapy of tremor.
K E Y
P O I N T S
●
Tremor is commonly encountered in clinical neurology. It can manifest as an isolated symptom or as a sign of another neurological disease.
●
Each tremor form is characterized clinically by the conditions of activation (rest, posture, and goal-directed movements), its topographic distribution, the frequency, and additional neurological symptoms.
●
The most common tremors are enhanced physiological, essential, and parkinsonian tremor.
chapter 33 tremor ●
The following tremors are less frequent but important: orthostatic tremor, cerebellar tremor, Holmes tremor, tremor in neuropathies, drug-induced tremor, and psychogenic tremor.
●
The differential diagnosis mainly relies on clinical characteristics, but additional tests, including recordings of the limb oscillations or the underlying electromyographic activity or special brain imaging techniques, can help to differentiate the various forms of tremor.
●
The pathophysiological background seems to be different for the different forms of tremor, and thus different tremors respond to different medical treatments.
●
For some tremors, well-established therapies are available. For uncommon tremors, only small studies exist.
●
Developments in the field of stereotactic deep brain operations have added an important new and very effective second-line option to the treatment of severe tremors.
Suggested Reading Deuschl G, Bain P, Brin M, Ad Hoc Scientific Committee: Consensus statement of the Movement Disorder Society on Tremor. Mov Disord 1998; 13:2-23. Findley LJ, Koller WC, eds: Handbook of Tremor Disorders. New York: Marcel Dekker, 1995. Pahwa R, Lyons KE, eds: Handbook of Essential Tremor and Other Tremor Disorders. Philadelphia: Taylor & Francis, 2005.
References 1. Deuschl G, Bain P, Brin M, Ad Hoc Scientific Committee: Consensus statement of the Movement Disorder Society on Tremor. Mov Disord 1998; 13:2-23. 2. Vallbo AB, Wessberg J: Organization of motor output in slow finger movements in man. J Physiol Lond 1993; 469:673-691. 3. Elble RJ, Randall JE: Mechanistic components of normal hand tremor. Electroencephalogr Clin Neurophysiol 1978; 44:72-82. 4. Hömberg V, Hefter H, Reiners K, et al: Differential effects of changes in mechanical limb properties on physiological and pathological tremor. J Neurol Neurosurg Psychiatr 1987; 50:568-579. 5. Timmer J, Lauk M, Pfleger W, et al: Cross-spectral analysis of physiological tremor and muscle activity. I. Theory and application to unsynchronized electromyogram. Biol Cybern 1998; 78:349-357. 6. Raethjen J, Pawlas F, Lindemann M, et al: Determinants of physiologic tremor in a large normal population. Clin Neurophysiol 2000; 111:1825-1837. 7. Marsden CD, Gimlette TM, McAllister RG, et al: Effect of betaadrenergic blockade on finger tremor and Achilles reflex time in anxious and thyrotoxic patients. Acta Endocrinol (Copenh) 1968; 57:353-362. 8. Deuschl G, Raethjen J, Lindemann M, et al: The pathophysiology of tremor. Muscle Nerve 2001; 24:716-735. 9. Elble RJ: Central mechanisms of tremor. J Clin Neurophysiol 1996; 13:133-144. 10. Elble RJ: Characteristics of physiologic tremor in young and elderly adults. Clin Neurophysiol 2003; 114:624-635.
429
11. Elble RJ, Randall JE: Motor-unit activity responsible for 8- to 12-Hz component of human physiological finger tremor. J Neurophysiol 1976; 39:370-383. 12. Lyons KE, Pahwa R, Comella CL, et al: Benefits and risks of pharmacological treatments for essential tremor. Drug Saf 2003; 26:461-481. 13. Raethjen J, Lemke MR, Lindemann M, et al: Amitriptyline enhances the central component of physiological tremor. J Neurol Neurosurg Psychiatry 2001; 70:78-82. 14. Deuschl G, Krack P, Lauk M, et al: Clinical neurophysiology of tremor. J Clin Neurophysiol 1996; 13:110-121. 15. Deuschl G, Blumberg H, Lücking CH: Tremor in reflex sympathetic dystrophy. Arch Neurol 1991; 48:1247-52. 16. Raethjen J, Lauk M, Koster B, et al: Tremor analysis in two normal cohorts. Clin Neurophysiol 2004; 115:2151-2156. 17. Elble RJ, Higgins C, Elble S: Electrophysiologic transition from physiologic tremor to essential tremor. Mov Disord 2005; 20:1038-1042. 18. Bain P, Brin M, Deuschl G, et al: Criteria for the diagnosis of essential tremor. Neurology 2000; 54:S7. 19. Louis ED, Ford B, Lee H, et al: Diagnostic criteria for essential tremor: a population perspective. Arch Neurol 1998; 55:823-828. 20. Deuschl G, Wenzelburger R, Loffler K, et al: Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain 2000; 123(Pt 8):1568-1580. 21. Stolze H, Petersen G, Raethjen J, et al: The gait disorder of advanced essential tremor. Brain 2001; 124:2278-2286. 22. Bain PG, Findley LJ, Thompson PD, et al: A study of hereditary essential tremor. Brain 1994; 117(Pt 4):805-824. 23. Lou JS, Jankovic J: Essential tremor: clinical correlates in 350 patients. Neurology 1991; 41:234-238. 24. Koller WC, Busenbark K, Miner K: The relationship of essential tremor to other movement disorders: report on 678 patients. Essential Tremor Study Group. Ann Neurol 1994; 35:717-723. 25. Jankovic J: Essential tremor: clinical characteristics. Neurology 2000; 54: S21-S25. 26. Elble RJ: Essential tremor frequency decreases with time. Neurology 2000; 55:1547-1551. 27. Louis ED, Ford B, Wendt KJ, et al: Clinical characteristics of essential tremor: data from a community-based study. Mov Disord 1998; 13:803-808. 28. Lorenz D, Schwieger D, Moises H, et al: Quality of life and personality in essential tremor. Mov Disord 2006. 29. Troster AI, Pahwa R, Fields JA, et al: Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord 2005; 11:367-373. 30. Louis ED, Barnes L, Albert SM, et al: Correlates of functional disability in essential tremor. Mov Disord 2001; 16:914920. 31. Troster AI, Woods SP, Fields JA, et al: Neuropsychological deficits in essential tremor: an expression of cerebellothalamo-cortical pathophysiology? Eur J Neurol 2002; 9:143151. 32. Chatterjee A, Jurewicz EC, Applegate LM, et al: Personality in essential tremor: further evidence of non-motor manifestations of the disease. J Neurol Neurosurg Psychiatry 2004; 75:958-961. 33. Ondo WG, Sutton L, Dat Vuong K, et al: Hearing impairment in essential tremor. Neurology 2003; 61:1093-1097. 34. Louis ED, Bromley SM, Jurewicz EC, et al: Olfactory dysfunction in essential tremor: a deficit unrelated to disease duration or severity. Neurology 2002; 59:1631-1633. 35. Louis ED, Ottman R, Hauser WA: How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998; 13:5-10.
430
Section
VII
Motor System and Motor Diseases
36. Jankovic J, Beach J, Schwartz K, et al: Tremor and longevity in relatives of patients with Parkinson’s disease, essential tremor, and control subjects. Neurology 1995; 45:645-648. 37. Tanner CM, Goldman SM, Lyons KE, et al: Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology 2001; 57:1389-1391. 38. Lorenz D, Frederiksen H, Moises H, et al: High concordance for essential tremor in monozygotic twins of old age. Neurology 2004; 62:208-211. 39. Gulcher JR, Jonsson P, Kong A, et al: Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet 1997; 17:84-87. 40. Higgins JJ, Loveless JM, Jankovic J, et al: Evidence that a gene for essential tremor maps to chromosome 2p in four families. Mov Disord 1998; 13:972-977. 41. Higgins JJ, Lombardi RQ, Pucilowska J, et al: A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005; 64:417-421. 42. Lucotte G, Lagorde JP, Funalot B, Sokoloff P: Linkage with the SergGly DRD3 polymorphism in essential tremor families. Clin Genet 2006; 69:437-440. 43. Louis ED, Zheng W, Jurewicz EC, et al: Elevation of blood beta-carboline alkaloids in essential tremor. Neurology 2002; 59:1940-1944. 44. Louis ED, Applegate L, Graziano JH, et al: Interaction between blood lead concentration and delta-amino-levulinic acid dehydratase gene polymorphisms increases the odds of essential tremor. Mov Disord 2005; 20:1170-1177. 45. Deuschl G, Elble RJ: The pathophysiology of essential tremor. Neurology 2000; 54: S14-S20. 46. Raethjen J, Deuschl G: Pathophysiology of essential tremor. In Lyons KE, Pahwa R, eds: Handbook of Essential Tremor and Other Tremor Disorders. Boca Raton, FL: Taylor & Francis, 2005, pp 27-50. 47. Raethjen J, Lindemann M, Schmaljohann H, et al: Multiple oscillators are causing parkinsonian and essential tremor. Mov Disord 2000; 15:84-94. 48. Findley LJ: The pharmacological management of essential tremor. Clin Neuropharmacol 1986; 9(Suppl 2): S61-S75. 49. Winkler GF, Young RR: The control of essential tremor by propranolol. Trans Am Neurol Assoc 1971; 96:66-68. 50. Koller WC: Long-acting propranolol in essential tremor. Neurology 1985; 35:108-110. 51. Meert TF: Pharmacological evaluation of alcohol withdrawalinduced inhibition of exploratory behaviour and supersensitivity to harmine-induced tremor. Alcohol Alcohol 1994; 29:91-102. 52. Findley LJ, Cleeves L, Calzetti S: Primidone in essential tremor of the hands and head: a double blind controlled clinical study. J Neurol Neurosurg Psychiatry 1985; 48:911915. 53. Lee KS, Kim JS, Kim JW, et al: A multicenter randomized crossover multiple-dose comparison study of arotinolol and propranolol in essential tremor. Parkinsonism Relat Disord 2003; 9:341-347. 54. Gironell A, Kulisevsky J, Barbanoj M, et al: A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor. Arch Neurol 1999; 56:475-480. 55. Pahwa R, Lyons K, Hubble JP, et al: Double-blind controlled trial of gabapentin in essential tremor. Mov Disord 1998; 13:465-467. 56. Connor GS: A double-blind placebo-controlled trial of topiramate treatment for essential tremor. Neurology 2002; 59:132134. 57. Bushara KO, Malik T, Exconde RE: The effect of levetiracetam on essential tremor. Neurology 2005; 64:1078-1080. 58. Sullivan KL, Hauser RA, Zesiewicz TA: Levetiracetam for the treatment of essential tremor. Mov Disord 2005.
59. Busenbark K, Pahwa R, Hubble J, et al: Double-blind controlled study of methazolamide in the treatment of essential tremor. Neurology 1993; 43:1045-1047. 60. Huber SJ, Paulson GW: Efficacy of alprazolam for essential tremor. Neurology 1988; 38:241-243. 61. Biary N, Koller W: Kinetic predominant essential tremor: successful treatment with clonazepam. Neurology 1987; 37:471474. 62. Thompson C, Lang A, Parkes JD, et al: A double-blind trial of clonazepam in benign essential tremor. Clin Neuropharmacol 1984; 7:83-88. 63. Brin MF, Lyons KE, Doucette J, et al: A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology 2001; 56:1523-1528. 64. Kolek M, Mrozek V, Schenk P: [Cardiac manifestations of Friedreich’s ataxia]. Cas Lek Cesk 2004; 143:48-51. 65. Koller W, Pahwa R, Busenbark K, et al: High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997; 42:292-299. 66. Limousin P, Speelman JD, Gielen F, et al: Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. J Neurol Neurosurg Psychiatry 1999; 66: 289-296. 67. Pahwa R, Lyons KL, Wilkinson SB, et al: Bilateral thalamic stimulation for the treatment of essential tremor. Neurology 1999; 53:1447-1450. 68. Schuurman PR, Bosch DA, Bossuyt PM, et al: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000; 342:461468. 69. Ohye C, Shibazaki T, Sato S: Gamma knife thalamotomy for movement disorders: evaluation of the thalamic lesion and clinical results. J Neurosurg 2005; 102(Suppl):234-240. 70. Siderowf A, Gollump SM, Stern MB, et al: Emergence of complex, involuntary movements after gamma knife radiosurgery for essential tremor. Mov Disord 2001; 16:965-967. 71. Young RF, Jacques S, Mark R, et al: Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg 2000; 93(Suppl 3):128-135. 72. Calzetti S, Sasso E, Negrotti A, et al: Effect of propranolol in head tremor: quantitative study following single-dose and sustained drug administration. Clin Neuropharmacol 1992; 15:470-476. 73. Massey EW, Paulson GW: Essential vocal tremor: clinical characteristics and response to therapy. South Med J 1985; 78:316-317. 74. Pahwa R, Busenbark K, Swanson-Hyland EF, et al: Botulinum toxin treatment of essential head tremor. Neurology 1995; 45:822-824. 75. Koller WC, Lyons KE, Wilkinson SB, et al: Efficacy of unilateral deep brain stimulation of the VIM nucleus of the thalamus for essential head tremor. Mov Disord 1999; 14:847-850. 76. Ondo W, Almaguer M, Jankovic J, et al: Thalamic deep brain stimulation: comparison between unilateral and bilateral placement. Arch Neurol 2001; 58:218-222. 77. Pollak P, Benabid AL, Gervason CL, et al: Long-term effects of chronic stimulation of the ventral intermediate thalamic nucleus in different types of tremor. Adv Neurol 1993; 60:408413. 78. Zesiewicz TA, Elble R, Louis ED, et al: Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005; 64:2008-2020. 79. Heilman KM: Orthostatic tremor. Arch Neurol 1984; 41:880881. 80. Pazzaglia P, Sabattini L, Lugaresi E: [On an unusual disorder of erect standing position (observation of 3 cases)]. Riv Sper Freniatr Med Leg Alien Ment 1970; 94:450-457.
chapter 33 tremor 81. Gerschlager W, Munchau A, Katzenschlager R, et al: Natural history and syndromic associations of orthostatic tremor: a review of 41 patients. Mov Disord 2004; 19:788-795. 82. Katzenschlager R, Costa D, Gerschlager W, et al: [123I]-FPCIT-SPECT demonstrates dopaminergic deficit in orthostatic tremor. Ann Neurol 2003; 53:489-496. 83. Deuschl G, Lucking CH, Quintern J: [Orthostatic tremor: clinical aspects, pathophysiology and therapy]. EEG EMG Z Elektroenzephalogr Elektromyogr Verwandte Geb 1987; 18:13-19. 84. McManis PG, Sharbrough FW: Orthostatic tremor: clinical and electrophysiologic characteristics. Muscle Nerve 1993; 16:1254-1260. 85. Thompson PD, Rothwell JC, Day BL, et al: The physiology of orthostatic tremor. Arch Neurol 1986; 43:584-587. 86. Boroojerdi B, Ferbert A, Foltys H, et al: Evidence for a nonorthostatic origin of orthostatic tremor. J Neurol Neurosurg Psychiatry 1999; 66:284-288. 87. McAuley JH, Britton TC, Rothwell JC, et al: The timing of primary orthostatic tremor bursts has a task-specific plasticity. Brain 2000; 123(Pt 2):254-266. 88. Britton TC, Thompson PD: Primary orthostatic tremor. BMJ 1995; 310:143-144. 89. Wu YR, Ashby P, Lang AE: Orthostatic tremor arises from an oscillator in the posterior fossa. Mov Disord 2001; 16:272279. 90. Poersch M: Orthostatic tremor: combined treatment with primidone and clonazepam. Mov Disord 1994; 9:467. 91. Wills AJ, Brusa L, Wang HC, et al: Levodopa may improve orthostatic tremor: case report and trial of treatment. J Neurol Neurosurg Psychiatry 1999; 66:681-684. 92. Evidente VG, Adler CH, Caviness JN, et al: Effective treatment of orthostatic tremor with gabapentin. Mov Disord 1998; 13:829-831. 93. Onofrj M, Thomas A, Paci C, et al: Gabapentin in orthostatic tremor: results of a double-blind crossover with placebo in four patients. Neurology 1998; 51:880-882. 94. Rodrigues JP, Edwards DJ, Walters SE, et al: Gabapentin can improve postural stability and quality of life in primary orthostatic tremor. Mov Disord 2005. 95. Koller WC, Vetere-Overfield B, Barter R: Tremors in early Parkinson’s disease. Clin Neuropharmacol 1989; 12:293297. 96. Jankovic J, McDermott M, Carter J, et al: Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 1990; 40:1529-1534. 97. Louis ED, Tang MX, Cote L, et al: Progression of parkinsonian signs in Parkinson disease. Arch Neurol 1999; 56:334-337. 98. Brooks DJ: PET and SPECT studies in Parkinson’s disease. Baillieres Clin Neurol 1997; 6:69-87. 99. Leenders KL, Oertel WH: Parkinson’s disease: clinical signs and symptoms, neural mechanisms, positron emission tomography, and therapeutic interventions. Neural Plast 2001; 8:99-110. 100. Tissingh G, Bergmans P, Booij J, et al: Drug-naive patients with Parkinson’s disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]beta-CIT SPECT. J Neurol 1998; 245:1420. 101. Hirsch EC, Mouatt A, Faucheux B, et al: Dopamine, tremor, and Parkinson’s disease. Lancet 1992; 340:125-126. 102. Jellinger KA: Post mortem studies in Parkinson’s disease—is it possible to detect brain areas for specific symptoms? J Neural Transm Suppl 1999; 56:1-29. 103. Paulus W, Jellinger K: The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol 1991; 50:743-755.
431
104. Brooks DJ, Playford ED, Ibanez V, et al: Isolated tremor and disruption of the nigrostriatal dopaminergic system: an 18Fdopa PET study. Neurology 1992; 42:1554-1560. 105. Ghaemi M, Raethjen J, Hilker R, et al: Monosymptomatic resting tremor and Parkinson’s disease: a multitracer positron emission tomographic study. Mov Disord 2002; 17:782788. 106. Doder M, Rabiner EA, Turjanski N, et al: Tremor in Parkinson’s disease and serotonergic dysfunction: an 11C-WAY 100635 PET study. Neurology 2003; 60:601-605. 107. Bergman H, Deuschl G: Pathophysiology of Parkinson’s disease: from clinical neurology to basic neuroscience and back. Mov Disord 2002; 17(Suppl 3): S28-S40. 108. Bergman H, Raz A, Feingold A, et al: Physiology of MPTP tremor. Mov Disord 1998; 13 Suppl 3:29-34. 109. Hurtado JM, Rubchinsky LL, Sigvardt KA, et al: Temporal evolution of oscillations and synchrony in GPi/muscle pairs in Parkinson’s disease. J Neurophysiol 2005; 93:15691584. 110. Pogarell O, Gasser T, van Hilten JJ, et al: Pramipexole in patients with Parkinson’s disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study. J Neurol Neurosurg Psychiatry 2002; 72:713-720. 111. Cantello R, Riccio A, Gilli M, et al: Bornaprine vs placebo in Parkinson disease: double-blind controlled cross-over trial in 30 patients. Ital J Neurol Sci 1986; 7:139-143. 112. Piccirilli M, D’Alessandro P, Testa A, et al: [Bornaprine in the treatment of parkinsonian tremor]. Rev Neurol 1985; 55:3845. 113. Koller WC: Pharmacologic treatment of parkinsonian tremor. Arch Neurol 1986; 43:126-7. 114. Perry EK, Kilford L, Lees AJ, et al: Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs. Ann Neurol 2003; 54:235-238. 115. Fischer PA, Baas H, Hefner R: Treatment of parkinsonian tremor with clozapine. J Neural Transm Park Dis Dement Sect 1990; 2:233-238. 116. Pakkenberg H, Pakkenberg B: Clozapine in the treatment of tremor. Acta Neurol Scand 1986; 73:295-297. 117. Jansen EN: Clozapine in the treatment of tremor in Parkinson’s disease. Acta Neurol Scand 1994; 89:262-265. 118. Krack P, Benazzouz A, Pollak P, et al: Treatment of tremor in Parkinson’s disease by subthalamic nucleus stimulation. Mov Disord 1998; 13:907-914. 119. Sturman MM, Vaillancourt DE, Metman LV, et al: Effects of subthalamic nucleus stimulation and medication on resting and postural tremor in Parkinson’s disease. Brain 2004; 127:2131-2143. 120. Deuschl G: Dystonic tremor. Rev Neurol (Paris) 2003; 159:900-905. 121. Rivest J, Marsden CD: Trunk and head tremor as isolated manifestations of dystonia. Mov Disord 1990; 5:60-65. 122. Munchau A, Schrag A, Chuang C, et al: Arm tremor in cervical dystonia differs from essential tremor and can be classified by onset age and spread of symptoms. Brain 2001; 124:1765-1776. 123. Ferraz HB, De Andrade LA, Silva SM, et al: [Postural tremor and dystonia. Clinical aspects and physiopathological considerations]. Arq Neuropsiquiatr 1994; 52:466-470. 124. Bartolome FM, Fanjul S, Cantarero S, et al: [Primary focal dystonia: descriptive study of 205 patients]. Neurologia 2003; 18:59-65. 125. Shukla G, Behari M: A clinical study of non-parkinsonian and non-cerebellar tremor at a specialty movement disorders clinic. Neurol India 2004; 52:200-202. 126. Jedynak CP, Bonnet AM, Agid Y: Tremor and idiopathic dystonia. Mov Disord 1991; 6:230-236.
432
Section
VII
Motor System and Motor Diseases
127. Marsden CD: Dystonia: the spectrum of the disease. Res Publ Assoc Res Nerv Ment Dis 1976; 55:351-367. 128. Vidailhet M, Jedynak CP, Pollak P, et al: Pathology of symptomatic tremors. Mov Disord 1998; 13 Suppl 3:49-54. 129. Masuhr F, Wissel J, Muller J, et al: Quantification of sensory trick impact on tremor amplitude and frequency in 60 patients with head tremor. Mov Disord 2000; 15:960964. 130. Jankovic J, Schwartz K: Botulinum toxin treatment of tremors. Neurology 1991; 41:1185-1188. 131. Coubes P, Roubertie A, Vayssiere N, et al: Treatment of DYT1generalised dystonia by stimulation of the internal globus pallidus. Lancet 2000; 355:2220-2221. 132. Alusi SH, Worthington J, Glickman S, et al: A study of tremor in multiple sclerosis. Brain 2001; 124:720-730. 133. Louis ED, Lynch T, Ford B, et al: Delayed-onset cerebellar syndrome. Arch Neurol 1996; 53:450-454. 134. Neiman J, Lang AE, Fornazzari L, et al: Movement disorders in alcoholism: a review. Neurology 1990; 40:741-746. 135. Flament D, Hore J: Movement and electromyographic disorders associated with cerebellar dysmetria. J Neurophysiol 1986; 55:1221-1233. 136. Flament D, Hore J: Comparison of cerebellar intention tremor under isotonic and isometric conditions. Brain Res 1988; 439:179-186. 137. Hore J, Flament D: Evidence that a disordered servo-like mechanism contributes to tremor in movements during cerebellar dysfunction. J Neurophysiol 1986; 56:123-136. 138. Hallett M, Shahani BT, Young RR: EMG analysis of patients with cerebellar deficits. J Neurol Neurosurg Psychiatry 1975; 38:1163-1169. 139. Mauritz KH, Schmitt C, Dichgans J: Delayed and enhanced long latency reflexes as the possible cause of postural tremor in late cerebellar atrophy. Brain 1981; 104:97-116. 140. Hallett M, Ravits J, Dubinsky RM, et al: A double-blind trial of isoniazid for essential tremor and other action tremors. Mov Disord 1991; 6:253-256. 141. Rascol A, Clanet M, Montastruc JL, et al: L5H tryptophan in the cerebellar syndrome treatment. Biomedicine 1981; 35:112-113. 142. Trouillas P, Xie J, Getenet JC, et al: [Effect of buspirone, a serotonergic 5-HT-1A agonist in cerebellar ataxia: a pilot study. Preliminary communication]. Rev Neurol (Paris) 1995; 151:708-713. 143. Fox P, Bain PG, Glickman S, et al: The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 2004; 62:1105-1109. 144. Alusi SH, Aziz TZ, Glickman S, et al: Stereotactic lesional surgery for the treatment of tremor in multiple sclerosis: a prospective case-controlled study. Brain 2001; 124:15761589. 145. Lozano AM: VIM thalamic stimulation for tremor. Arch Med Res 2000; 31:266-269. 146. Masucci EF, Kurtzke JF, Saini N: Myorhythmia: a widespread movement disorder. Clinicopathological correlations. Brain 1984; 107:53-79. 147. Remy P, de Recondo A, Defer G, et al: Peduncular ‘rubral’ tremor and dopaminergic denervation: a PET study [see comments]. Neurology 1995; 45:472-477. 148. Deuschl G, Wilms H, Krack P, et al: Function of the cerebellum in Parkinsonian rest tremor and Holmes’ tremor. Ann Neurol 1999; 46:126-128. 149. Krack P, Deuschl G, Kaps M, et al: Delayed onset of “rubral tremor” 23 years after brainstem trauma. Mov Disord 1994; 9:240-242. 150. Miwa H, Hatori K, Kondo T, et al: Thalamic tremor: case reports and implications of the tremor-generating mechanism. Neurology 1996; 46:75-79.
151. Kim JS: Delayed onset mixed involuntary movements after thalamic stroke: clinical, radiological and pathophysiological findings. Brain 2001; 124:299-309. 152. Lehericy S, Grand S, Pollak P, et al: Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions. Neurology 2001; 57:1055-1066. 153. Kim MC, Son BC, Miyagi Y, et al: Vim thalamotomy for Holmes’ tremor secondary to midbrain tumour. J Neurol Neurosurg Psychiatry 2002; 73:453-455. 154. Kudo M, Goto S, Nishikawa S, et al: Bilateral thalamic stimulation for Holmes’ tremor caused by unilateral brainstem lesion. Mov Disord 2001; 16:170-174. 155. Nikkhah G, Prokop T, Hellwig B, et al: Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions. Report of two cases. J Neurosurg 2004; 100:10791083. 156. Lapresle J: Palatal myoclonus. Adv Neurol 1986; 43:265273. 157. Deuschl G, Mischke G, Schenck E, et al: Symptomatic and essential rhythmic palatal myoclonus. Brain 1990; 113:16451672. 158. Deuschl G, Toro C, Valls SJ, et al: Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain 1994:775-788. 159. Deuschl G, Wilms H: Clinical spectrum and physiology of palatal tremor. Mov Disord 2002; 17(Suppl 2):S63-S66. 160. Samuel M, Torun N, Tuite PJ, et al: Progressive ataxia and palatal tremor (PAPT): clinical and MRI assessment with review of palatal tremors. Brain 2004; 127:12521268. 161. Deuschl G, Jost S, Schumacher M: Symptomatic palatal tremor is associated with signs of cerebellar dysfunction. J Neurol 1996; 243:553-556. 162. Deuschl G, Toro C, Hallett M: Symptomatic and essential palatal tremor. 2. Differences of palatal movements. Mov Disord 1994; 9:676-678. 163. Llinas R, Volkind RA: The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp Brain Res 1973; 18:69-87. 164. Elble RJ: Inhibition of forearm EMG by palatal myoclonus. Mov Disord 1991; 6:324-329. 165. Leigh RJ, Averbuch HL, Tomsak RL, et al: Treatment of abnormal eye movements that impair vision: strategies based on current concepts of physiology and pharmacology. Ann Neurol 1994; 36:129-141. 166. Repka MX, Savino PJ, Reinecke RD: Treatment of acquired nystagmus with botulinum neurotoxin A. Arch Ophthalmol 1994; 112:1320-1324. 167. Bakheit AM, Behan PO: Palatal myoclonus successfully treated with clonazepam [letter] [see comments]. J Neurol Neurosurg Psychiatry 1990; 53. 168. Jabbari B, Scherokman B, Gunderson CH, et al: Treatment of movement disorders with trihexyphenidyl. Mov Disord 1989; 4:202-212. 169. Borggreve F, Hageman G: A case of idiopathic palatal myoclonus: treatment with sodium valproate. Eur Neurol 1991; 31:403-404. 170. Cakmur R, Idiman E, Idiman F, et al: Essential palatal tremor successfully treated with flunarizine. Eur Neurol 1997; 38:133-134. 171. Gambardella A, Quattrone A: Treatment of palatal myoclonus with sumatriptan [letter]. Mov Disord 1998; 13:195. 172. Scott BL, Evans RW, Jankovic J: Treatment of palatal myoclonus with sumatriptan. Mov Disord 1996; 11:748-751. 173. Pakiam AS, Lang AE: Essential palatal tremor: evidence of heterogeneity based on clinical features and response to Sumatriptan. Mov Disord 1999; 14:179-180.
chapter 33 tremor 174. Deuschl G, Lohle E, Heinen F, et al: Ear click in palatal tremor: its origin and treatment with botulinum toxin. Neurology 1991; 41:1677-1679. 175. Yeung KB, Thomas PK, King RH, et al: The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol 1991; 238:383-391. 176. Busby M, Donaghy M: Chronic dysimmune neuropathy. A subclassification based upon the clinical features of 102 patients. J Neurol 2003; 250:714-724. 177. Cardoso F, Jankovic J: Movement disorders. Neurol Clin 1993; 11:625-638. 178. Dalakas MC, Teravainen H, Engel WK: Tremor as a feature of chronic relapsing and dysgammaglobulinemic polyneuropathies. Incidence and management. Arch Neurol 1984; 41:711-714. 179. Bain PG, Britton TC, Jenkins IH, et al: Tremor associated with benign IgM paraproteinaemic neuropathy. Brain 1996; 119:789-799. 180. Plante-Bordeneuve V, Guiochon-Mantel A, Lacroix C, et al: The Roussy-Lévy family: from the original description to the gene. Ann Neurol 1999; 46:770-773. 181. Ruzicka E, Jech R, Zarubova K, et al: VIM thalamic stimulation for tremor in a patient with IgM paraproteinaemic demyelinating neuropathy. Mov Disord 2003; 18:1192-1195. 182. Kim YJ, Pakiam AS, Lang AE: Historical and clinical features of psychogenic tremor: a review of 70 cases. Can J Neurol Sci 1999; 26:190-195. 183. Deuschl G, Koster B, Lucking CH, et al: Diagnostic and pathophysiological aspects of psychogenic tremors. Mov Disord 1998; 13:294-302. 184. Factor SA, Podskalny GD, Molho ES: Psychogenic movement disorders: frequency, clinical profile, and characteristics. J Neurol Neurosurg Psychiatry 1995; 59:406-412. 185. Brown P, Thompson PD: Electrophysiological aids to the diagnosis of psychogenic jerks, spasms, and tremor. Mov Disord 2001; 16:595-599. 186. McAuley JH, Rothwell JC, Marsden CD, et al: Electrophysiological aids in distinguishing organic from psychogenic tremor. Neurology 1998; 50:1882-1884. 187. Lauk M, Koster B, Timmer J, et al: Side-to-side correlation of muscle activity in physiological and pathological human tremors. Clin Neurophysiol 1999; 110:1774-1783. 188. Raethjen J, Kopper F, Govindan RB, et al: Two different pathogenetic mechanisms in psychogenic tremor. Neurology 2004; 63:812-815. 189. McAuley J, Rothwell J: Identification of psychogenic, dystonic, and other organic tremors by a coherence entrainment test. Mov Disord 2004; 19:253-267.
433
190. Zeuner KE, Shoge RO, Goldstein SR, et al: Accelerometry to distinguish psychogenic from essential or parkinsonian tremor. Neurology 2003; 61:548-550. 191. Koller W, Lang A, Vetere OB, et al: Psychogenic tremors. Neurology 1989; 39:1094-1099. 192. Feinstein A, Stergiopoulos V, Fine J, et al: Psychiatric outcome in patients with a psychogenic movement disorder: a prospective study. Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:169-176. 193. Ebersbach G, Tracik F, Wissel J, et al: Tardive jaw tremor. Mov Disord 1997; 12:460-462. 194. Stacy M, Jankovic J. Tardive tremor. Mov Disord 1992; 7:5357. 195. Oder W, Grimm G, Kollegger H, et al: Neurological and neuropsychiatric spectrum of Wilson’s disease: a prospective study of 45 cases. J Neurol 1991; 238:281-287. 196. Karas BJ, Wilder BJ, Hammond EJ, et al: Treatment of valproate tremors. Neurology 1983; 33:1380-1382. 197. Starosta-Rubinstein S, Young AB, Kluin K, et al: Clinical assessment of 31 patients with Wilson’s disease. Correlations with structural changes on magnetic resonance imaging. Arch Neurol 1987; 44:365-370. 198. Takahashi W, Yoshii F, Shinohara Y: Reversible magnetic resonance imaging lesions in Wilson’s disease: clinicalanatomical correlation. J Neuroimaging 1996; 6:246-248. 199. Schumacher G, Platz KP, Mueller AR, et al: Liver transplantation: treatment of choice for hepatic and neurological manifestation of Wilson’s disease. Clin Transplant 1997; 11:217-224. 200. Caviness JN: Myoclonus and neurodegenerative disease— what’s in a name? Parkinsonism Relat Disord 2003; 9:185192. 201. Ikeda A, Kakigi R, Funai N, et al: Cortical tremor: a variant of cortical reflex myoclonus. Neurology 1990; 40:1561-1565. 202. Toro C, Pascual LA, Deuschl G, et al: Cortical tremor. A common manifestation of cortical myoclonus. Neurology 1993; 43:2346-2353. 203. Chen R, Ashby P, Lang AE: Stimulus-sensitive myoclonus in akinetic-rigid syndromes. Brain 1992; 115:1875-1888. 204. Thompson PD, Day BL, Rothwell JC, et al: The myoclonus in corticobasal degeneration. Evidence for two forms of cortical reflex myoclonus. Brain 1994; 44:578-591. 205. Wang HC, Hsu WC, Brown P: Cortical tremor secondary to a frontal cortical lesion. Mov Disord 1999; 14:370-374. 206. Fung VS, Duggins A, Morris JG, et al: Progressive myoclonic ataxia associated with celiac disease presenting as unilateral cortical tremor and dystonia. Mov Disord 2000; 15:732-734. 207. Jung R: Physiologische Untersuchungen über den Parkinsontremor und andere Zitterformen beim Menschen. Zsch Neurol Psychiat 1941; 173:263-332.
CHAPTER
34
MYOCLONUS ●
●
●
●
Hiroshi Shibasaki
The term myoclonus originates from report of a case by Friedreich in 1881 with the title of “paramyoclonus multiplex.” The patient was a 50-year-old man manifesting involuntary small muscle jerks mostly in the resting state. Myoclonus is defined as involuntary shocklike movements associated with sudden contraction of skeletal muscles ( positive myoclonus), sudden interruption of the ongoing muscle contraction (negative myoclonus), or a combination of the two.
CLASSIFICATION Myoclonus can originate from either the central nervous system or the peripheral nervous system, but most of myoclonic jerks occur in association with disorders of the central nervous system.1 It can originate from the motor cortex, brainstem, and spinal cord, and there are some other forms of myoclonus whose source has not been clarified completely (Table 34–1). Cortical myoclonus occurs either spontaneously or through a reflex mechanism in response to external stimulus (cortical reflex myoclonus). Epilepsia partialis continua is a focal, continuous form of cortical myoclonus, usually involving the distal part of the upper or lower limb. Cortical myoclonus is often epileptic in nature and thus is also called epileptic myoclonus. Palatal tremor, reticular reflex myoclonus, and startle syndrome are known to originate from brainstem structures. There are two forms in spinal myoclonus: segmental and propriospinal. Periodic myoclonus and dystonic myoclonus are easily recognized from their unique clinical features, but their underlying mechanisms have not been elucidated precisely.
CLINICAL FEATURES Myoclonic jerks are usually detectable by visual observation without much difficulty. However, when the jerks are small, palpation of the corresponding muscles helps in identifying the myoclonus. Because most myoclonic jerks are associated with co-contraction of agonist and antagonist muscles, it is useful to palpate, in the case of hand myoclonus, the wrist flexors and extensors simultaneously. Cortical myoclonus appears as brisk, shocklike movements involving fingers, hands, arms, facial muscles, and/or legs, and sometimes trunk muscles, independently (Fig. 34–1). When
hand intrinsic muscles are involved, it appears as small twitches of each individual finger or a group of fingers. When, in contrast, proximal muscles of an extremity are involved, it appears as big jerks. When the jerks rapidly spread from proximal to distal muscles of an extremity, it appears as if the whole extremity is involved almost simultaneously. Moreover, a jerk of one hand can be followed by another jerk in the other hand by a very short time interval: in fact, as short as 10 milliseconds, corresponding to the transcallosal conduction time. In this case, it appears as if both upper extremities are almost simultaneously involved. Cortical myoclonus appears rhythmic when it repeats in the same muscle groups at a fast rate (7 to 8 Hz), and thus it often resembles tremor (cortical tremor) (Fig. 34–2). Rhythmic cortical myoclonus is commonly seen in corticobasal ganglionic degeneration, familial adult myoclonic epilepsy, postanoxic myoclonus, and Angelman’s syndrome. Cortical myoclonus is induced or enhanced when the patient attempts to move or actually moves the corresponding part of the body or other parts of the body (action myoclonus). Furthermore, it is often stimulus-sensitive; for example, jerks are elicited by tendon tap during neurological examination. In this case, it appears as if the deep tendon reflex is exaggerated, but the cortical reflexmyoclonus occurs slightly later than the expected time for the monosynaptic spinal reflex. In addition, it can be differentiated from the enhanced deep tendon reflex in that cortical reflex myoclonus spreads to other parts of the corresponding extremity (e.g., from distal to proximal muscles) and even to the contralateral extremity. In patients with spastic paraparesis, the deep tendon reflex in response to the patellar tendon tap may be recognized also in the contralateral leg; a typical example is the crossed adductor reflex. This phenomenon, however, is the result of simultaneous mechanical activation of the proprioceptive input to the contralateral spinal segment by the knee tap, which causes a visible reflex in the contralateral leg as a result of the hyperactive state of the contralateral anterior horn cells. Furthermore, cortical myoclonus is elicited or enhanced when the corresponding limb is passively moved or when its posture is changed. These maneuvers are thought to induce a kind of proprioceptive reflex myoclonus. Cortical reflex myoclonus is sometimes elicited by flash stimulus and is noticed when the pupillary light reflex is tested (photic cortical reflex myoclonus). Typical examples have been reported in the advanced stage of Creutzfeldt-Jakob disease (CJD).
435
436
Section
VII
Motor System and Motor Diseases ■
F3’
Figure 34–1. Electroencephalographic (EEG)– electromyographic (EMG) polygraph recorded from a patient with progressive myoclonus epilepsy. EMG discharges associated with cortical myoclonus are abrupt and very brief in duration, involving one or more muscles of the right (Rt) upper extremity almost synchronously. There are frequent sharp spikes or multiple spikes on EEG, some of which are associated with the myoclonus. EEG electrode placement is in approximate accordance with the International 10-20 System as indicated by a prime symbol (′). ECR, extensor carpi radialis muscle; 1stDI, first dorsal interosseous muscle.
Fz’ F4’ C3’ C1’ Cz’ C2’ C4’ P3’ Pz’ 100 V
P4’ Rt thenar Rt 1stDI Rt ECR Rt biceps 1s
■
Lt biceps br.
Figure 34–2. Electromyographic (EMG) polygraph obtained from a patient with clinical diagnosis of corticobasal ganglionic degeneration. Repetitive discharges are seen in the right (RT) biceps and triceps muscles almost synchronously at an approximate rate of 7 to 8 Hz. br., brachii; Lt, left.
Triceps br.
Rhomboid
Rt biceps br. Triceps br.
Rhomboid 500 V 1 sec
Cortical myoclonus sometimes manifests as negative myoclonus, which is caused by sudden interruption of the ongoing muscle contraction (silent period of the electromyogram [EMG]). Most of the negative myoclonus are either immediately preceded or immediately followed by abrupt muscle contraction (positive myoclonus), but on occasion, the isolated form of negative myoclonus is seen. Thus, the pure negative myoclonus can be easily overlooked unless the extremity is examined during sustained muscle contraction: for example, while the wrists are kept in an extended posture. When the trunk muscles are suddenly involved by negative myoclonus, the patient may fall down abruptly (drop attack). On occasion, negative myoclonus is induced by somatosensory or photic
stimulus through a transcortical reflex mechanism (cortical reflex negative myoclonus). Epilepsia partialis continua manifests as continuous, repetitive focal muscle jerks at the rate of 1 to 6 Hz, localized unilaterally to one finger, several fingers, or a foot. Palatal tremor used to be called palatal myoclonus, but the name was changed after the first International Congress of Movement Disorders, held in Washington, D.C., in 1990, because of the lack of shocklike features and its resemblance to tremor, especially when other skeletal muscles are also involved. Essential palatal tremor is characterized by repetitive elevation of the soft palate at a rate of 2 to 3 Hz, often associated with ear click. Familial cases of essential palatal tremor
chapter 34 myoclonus T A B L E 34–1. Classification of Myoclonus Cortical Myoclonus Spontaneous cortical myoclonus Cortical reflex myoclonus Epilepsia partialis continua Brainstem Myoclonus Palatal tremor (“palatal myoclonus”) Reticular reflex myoclonus Startle syndrome Spinal Myoclonus Segmental spinal myoclonus Propriospinal myoclonus Unclassified Periodic myoclonus Dystonic myoclonus
have been reported. The movement may be associated with repetitive, brisk muscle contractions of other cranial muscles, which are approximately synchronous with the palatal movement. Symptomatic palatal tremor consists of rhythmic vertical oscillation of the soft palate and is frequently associated with rhythmic vertical oscillation of eyes (ocular myoclonus). This condition is commonly associated with organic lesions of brainstem or cerebellum and often involves other cranial and extremity muscles. In this condition, the movement of extremities is not very shocklike and may resemble real tremor. This form of palatal tremor may be persistent even during sleep. Reticular reflex myoclonus is a rare form of reflex myoclonus, characterized by shocklike jerks first appearing in the sternocleidomastoid and/or trapezius muscles and then spreading rostrally to the masseter, orbicularis oris, and orbicularis oculi muscles in this order, as well as caudally from proximal to distal muscles of extremities. Diagnosis of this condition requires demonstration of the characteristic spread of jerks by polygraphic recording of surface EMG from different muscles. Startle syndrome is a group of diseases characterized by exaggerated startle responses to sudden unexpected acoustic or tactile stimuli. Physiologically, this condition is considered to be an exaggerated form of physiological startle reaction. Familial startle disease, or hyperexplexia, is mostly an autosomal dominant disorder characterized by muscular rigidity in the neonatal period and the exaggerated startle responses. This condition has drawn special attention in relation to the discovery of heterogeneous mutation of genes encoding inhibitory glycine receptors. Segmental spinal myoclonus is seen as brisk contraction of muscles innervated by a certain spinal segment. It is often quasi-rhythmic or periodic and may be stimulus-sensitive. Propriospinal myoclonus involves mainly trunk muscles. Each jerk starts at a certain segmental level, most commonly at the thoracic segments, and spreads rostrally as well caudally at a slow speed of approximately 5-10 m/second. Within each individual patient, the jerk starts always from the same segment, although it may shift one or two segments during the course of illness. The term propriospinal is derived from the propriospinal tract, which connects successive spinal segments. The causative lesion in spinal myoclonus, either segmental or propriospinal,
437
is often difficult to be identified even by extensive laboratory investigation. Underlying mechanisms have not been disclosed for other kinds of myoclonus, including periodic myoclonus and dystonic myoclonus. There are two representative forms of periodic myoclonus; one seen in CJD and the other seen in subacute sclerosing panencephalitis. Periodic myoclonus seen in CJD is quasi-periodic repetition of shocklike, quasi-synchronous jerks involving extremities and facial muscles at a rate of about 1 Hz. It might shift from one extremity to others and continue during sleep, although the rate and the periodicity might change from time to time. It is often associated with periodic synchronous discharge (PSD) on electroencephalographic (EEG) recording, but there is no fixed time relationship between PSD and periodic myoclonus in this condition (Fig. 34–3). In contrast, periodic myoclonus seen in subacute sclerosing panencephalitis is really periodic, with almost constant interval of 6 to 8 seconds, and associated with PSD with a fixed time relationship. The muscle contraction in this condition is rather slow and is characterized by twisting nature of the movement, resembling dystonia rather than myoclonus. Therefore, the involuntary movement in this condition might be called periodic dystonic myoclonus. Myoclonus can be seen in association with other involuntary movements, such as tremor and/or dystonia, either concurrently or independently. For example, patients with writer’s cramp, as a typical example of focal hand dystonia, might exhibit a combination of muscle cramp, tremor, and myoclonic jerks. The term dystonic myoclonus is used when myoclonus has a twisting feature. In this regard, periodic dystonic myoclonus seen in patients with subacute sclerosing panencephalitis is a representative form of dystonic myoclonus. The term myoclonic dystonia is used to indicate almost the same condition as dystonic myoclonus. However, inherited myoclonus-dystonia syndrome is characterized by independent occurrence of myoclonus and dystonia in the same patient. In this case, myoclonic jerks commonly involve the proximal limb muscles and trunk, and they respond to ethanol in just the same way as essential tremor. Autosomal dominant trait with mutation of the gene encoding ε-sarcoglycan is one of the diseases that causes this condition.
UNDERLYING DISEASES Myoclonus can be caused by a number of different diseases. Representative diseases causing cortical myoclonus are listed in Table 34–2. Progressive myoclonus epilepsy is a group of diseases manifesting postural/action myoclonus and generalized convulsive seizures. Most of them are hereditary, and gene abnormalities have been identified for many of these diseases (Table 34–3).2 Among other diseases, postanoxic myoclonus (Lance-Adams syndrome) is most commonly encountered. In this condition, myoclonus develops in patients who survived the acute phase of anoxic encephalopathy, and it is often refractory to various drug treatments. Most jerks are of cortical origin, although reticular reflex myoclonus has been described in this condition. In contrast with progressive myoclonus epilepsy, generalized convulsive seizures are rather rare in this condition. It is noteworthy that cortical myoclonus can be present in metabolic encephalopathy, such as the disease caused by
438
Section
VII
Motor System and Motor Diseases
F3 C3 CP3 P3 F4 C4 CP4 P4 Fz A1 EOG1 EOG2 Lt FDI Lt FCR Lt FCU
128 V
100 V
500 ms ■
Figure 34–3. Electroencephalographic (EEG)–electromyographic (EMG) polygraph recorded from a patient with Creutzfeldt-Jakob disease. The rectified EMG discharge associated with jerks involving the left upper limb is relatively long in duration and varies from one to the other jerk in its waveform. The myoclonus is associated with periodic synchronous discharge on the EEG, but their time relationship is not fixed.
T A B L E 34–2. Diseases Causing Cortical Myoclonus Progressive myoclonus epilepsy (PME) Unverricht-Lundborg disease Lafora’s disease Neuronal ceroid lipofuscinosis Myoclonus epilepsy associated with ragged-red fibers (MERRF) Lipidosis Dentatorubral-pallidoluysian atrophy (DRPLA) Familial adult myoclonic epilepsy Angelman’s syndrome Celiac disease Progressive myoclonus epilepsies of unknown cause Progressive myoclonic ataxias Juvenile myoclonic epilepsy Postanoxic myoclonus (Lance-Adams syndrome) Alzheimer’s disease Creutzfeldt-Jakob disease (advanced stage) Metabolic encephalopathy Corticobasal ganglionic degeneration Olivopontocerebellar atrophy Rett’s syndrome
uremia. Thus, this condition is not necessarily associated with organic brain lesions and is reversible when the underlying cause is successfully treated. In relation to this, hepatic encephalopathy characteristically shows rhythmic negative myoclonus (asterixis), although the mechanism of this condition is not known. The diagnosis of essential myoclonus is made when myoclonus is not found to be associated with generalized convulsive seizures or other neurological deficits in spite of clinical observation over a long period of time. It is often familial and may be related to the inherited dystonia-myoclonus syndrome (see previous discussion). The physiological mechanism
of essential myoclonus has not been elucidated, but at least some of them might be of cortical origin. Many drugs can cause myoclonus as a side effect (druginduced myoclonus). Myoclonus of this category is often of negative form, associated with the EMG silent period (Fig. 34–4). Thus, whenever negative myoclonus develops in a patient who takes anticonvulsants, this possibility has to be considered. In other words, some cases of negative myoclonus in patients with cortical myoclonus may be, in fact, a side effect of anticonvulsants that they are taking. The physiological mechanisms underlying drug-induced myoclonus may not be homogeneous. It is most likely that some of them may be of cortical origin and the others subcortical.
PHYSIOLOGICAL MECHANISMS As far as cortical myoclonus is concerned, its physiological mechanisms have been elucidated to some extent. This is because most activities of the sensorimotor cortex are remarkably exaggerated in this condition, which makes it easier to assess those activities physiologically by EEG or magnetoencephalographic recording from the head surface. Cortical myoclonus is characterized by increased excitability of the primary motor cortex, extreme enhancement of cortical response to somatosensory stimulus, and enhanced long-loop, transcortical reflex (Fig. 34–5). When a part of the primary motor cortex is suddenly involved by epileptic activity, the muscles innervated by that particular cortical area show sudden contraction at a latency of about 20 milliseconds for a hand and 40 milliseconds for a foot. The cortical activity related to myoclonus may be actually recognized as a spike on EEG recording. In this condition, the somatosensory cortex reacts to tactile or proprioceptive input with magnitude of 10 times
chapter 34 myoclonus
439
T A B L E 34–3. Major Forms of Progressive Myoclonus Epilepsy and Their Gene Abnormality Disorder
Locus/Chromosome
Gene Product
Unverricht-Lundborg disease Lafora’s disease
EPM1/21q22.3 EPM2A/6q24 EPM2B/6p22.3 MTTK/mtDNA NEU1/6p21 DRPLA/12p13
Cystatin B Laforin (dual-specificity phosphatase) Malin tRNALys Neuraminidase 1 Atrophin 1
CLN1/1p32 CLN2/11p15 CLN3/16p12
Palmitoyl-protein thioesterase 1 Tripeptidyl peptidase 1 CLN3 (membrane protein of unknown function)
MERRF Sialidosis DRPLA Neuronal ceroid lipofuscinosis Infantile Late infantile Juvenile
Modified from Lehesjoki A-E: Molecular background of progressive myoclonus epilepsy. EMBO J 2003; 22:34733478, with help from Dr. Lehesjoki. DRPLA, dentatorubral-pallidoluysian atrophy; MERFF, myoclonic epilepsy associated with ragged-red fibers.
■
Figure 34–4. Polygraphic record consisting of accelerometer (Acceler.), electromyographic (EMG), and electroencephalographic (EEG) recordings from a patient with anticonvulsant-induced negative myoclonus. There are frequent interruptions of EMG discharges of the right extensor carpi radialis (RECR) muscle, associated with the wrist drop as shown in the accelerometer record. The longer the EMG silent period, the more conspicuous is the asterixis. There is no special EEG activity associated with the negative myoclonus. R-FCR, right flexor carpi radialis.
Acceler. R–ECR EMG R–FCR F3 F4 C3 EEG C4 P3 100 V
P4 1 sec
or more in comparison with the physiological reaction. This activity can be recorded as an enormously enhanced (giant) somatosensory evoked potential (SEP). Furthermore, tapping of a hand, for example, elicits reflex muscle contraction in that hand at a latency of about 45 milliseconds. This response can be recorded as an EMG response (long-loop reflex or C reflex) through the use of the surface electrodes.
LABORATORY TESTS The main laboratory test is aimed at confirming and classifying the myoclonus and understanding its pathophysiology, by using a battery of electrophysiological tests (Table 34–4).3,4 The most essential test for any kind of myoclonus is the EMG recording of myoclonic jerks with the surface electrodes. In order to find the distribution and spread of myoclonus, it is
more effective to record simultaneously from as many muscles as possible. This is also useful for finding the most appropriate muscle for carrying out other physiological studies as described later. For recording EMG from a large muscle, a pair of disk electrodes are placed on the skin overlying the muscle belly about 3 cm apart from each other; for recording from a small muscle such as hand intrinsic muscles, one electrode is placed over the muscle, and the other electrode on the skin covering the adjacent bone. A band-pass filter of 30 to 1000 Hz is adequate. Application of low-frequency filter (high-pass filter) is mainly for eliminating movement artifacts. Cortical myoclonus is associated with an EMG discharge of abrupt onset and of short duration, lasting less than 50 milliseconds (see Fig. 34–1). Usually, agonist and antagonist muscles contract simultaneously. The contraction may spread from proximal to distal muscles at the speed of about 50
440
Section
VII
Motor System and Motor Diseases
Cortical Reflex Myoclonus
Cortical Myoclonus Spike
Giant SEP
Stim.
T A B L E 34–4. Essential Physiological Tests of Myoclonus Technique
Purpose
Surface electromyography
Confirmation of myoclonus and its classification To know the relationship with cortical activity Detection of myoclonus-related cortical activity, and to know its temporal and spatial relationship to myoclonus To confirm giant SEPs
Jerk-locked back averaging of electroencephalogram Somatosensory evoked potential (SEP) Long-loop reflex
Figure 34–5. Schematic diagrams illustrating the hypothesized impulse flow for cortical reflex myoclonus and spontaneous cortical myoclonus. In the latter case (right), excessive discharge arising from the hand area of the motor cortex, seen as a spike on electroencephalographic (EEG) recording, causes abrupt muscle contraction in the corresponding hand in 20 milliseconds via the fast conducting corticospinal tract. In cortical reflex myoclonus (left), the somatosensory input (Stim.) generates giant somatosensory evoked potential (SEP) at a latency of 20 to 25 milliseconds in the sensorimotor cortex, which then gives rise to a reflex muscle contraction (C reflex) at a latency of 45 milliseconds.
Myoclonus
C reflex
EEG-EMG polygraphy
■
To confirm the reflex nature of myoclonus
EEG, electroencephalogram; EMG, electromyogram.
m/second, which corresponds approximately to the conduction velocity of α motor fibers. In case of hand myoclonus, it may be seen in the homologous muscles of the contralateral upper extremity 10 to 15 milliseconds later. Simultaneous EEG recording with the surface EMG is especially useful for the confirmation of cortical myoclonus. EEG recording is accomplished by placing electrodes in accordance with the International 10-20 System recommendations. Referential derivation with ipsilateral earlobe reference or bipolar derivation is used. Usually a band-pass filter of 1 to 500 Hz is used. When the number of EEG channels, the recording time, or both are limited, EEG may be recorded from a limited number of electrodes: for example, from C3, Cz, and C4 of the International 10-20 System in reference to the ipsilateral earlobe. Demonstration of spikes or multiple spikes on EEG is highly suggestive of the cortical origin of myoclonus. The spikes may or may not be associated with myoclonic jerks (see Fig. 34–1). Absence of EEG spikes, however, does not rule out the cortical myoclonus, because small spikes may not be
detected by the scalp recording as a result of attenuation of the electric potential by the skull. Demonstration of PSD is almost pathognomonic of either CJD or subacute sclerosing panencephalitis, depending on the waveform. EEG findings similar to the CJD type of PSD are sometimes encountered in anoxic encephalopathy, but PSD in this condition is not persistent. The technique of jerk-locked back averaging can be used for detecting spikes associated with myoclonus that are not detectable on the conventional EEG-EMG polygraph and for investigating the time and spatial relationship between the EEG spikes and myoclonus. EEG and EMG are recorded simultaneously, just as for the conventional polygraph, and the onset of EMG discharges associated with myoclonus is used as a fiducial point for back averaging the EEG (Fig. 34–6). The EMG may be rectified to avoid the canceling effect of averaging, and integrated. The onset of the rectified, integrated EMG waveform is used as a fiducial point for back averaging, as well as for obtaining the averaged EMG waveforms. Averaging of 100 sweeps is usually sufficient, but it is important to confirm the reproducibility of the results. In order to obtain a record of high quality, it is important to choose the most appropriate muscle for obtaining the fiducial point, to distinguish the myoclonic discharges from the background EMG activities, and to avoid artifacts such as head movements. When the myoclonic jerks occur infrequently in the resting condition, passive or active movement of the corresponding limb might help increase the number of jerks. In case of hand myoclonus, the positive peak or the onset of the negative peak of the EEG spike precedes the myoclonus by 20 milliseconds, on average, and it is localized to the central region of the contralateral head. SEPs are recorded by stimulating the median nerve at wrist by electric shock of 0.2 to 0.3 milliseconds duration with the stimulus intensity 10% above the motor threshold delivered at a frequency of 1 Hz. Averaging of 100 sweeps is usually sufficient, but it is important to confirm the reproducibility of the results. The initial peak of the cortical SEP, N20/P20, is not significantly enlarged, but the subsequent peaks (P25, N30/P30,
chapter 34 myoclonus
441
EEG Correlates of Myoclonus (Jerk–locked back averaging)
Back Averaging
Myoclonus
Fiducial point ■
Figure 34–6. Diagram showing the method of jerk-locked back averaging for demonstrating an electroencephalographic (EEG) correlate of myoclonus. The electromyogram (EMG) associated with myoclonus is recorded simultaneously with EEG, and the onset of the rectified EMG is used as a fiducial point for back averaging the EEG as well as the rectified EMG.
N35) are extremely enlarged in the majority of patients with cortical reflex myoclonus. It is convenient to record the long-loop reflex at the time of SEP recording. When the median nerve is electrically stimulated for recording SEP, the surface EMG can be recorded from the thenar muscle of that hand by a pair of surface electrodes. The transcortical reflex (C reflex) is seen at the latency of about 45 milliseconds. In case of severe cortical reflex myoclonus, the reflex EMG response is seen not only in the thenar muscle but also in other muscles of the same limb and also in the thenar muscle of the contralateral hand. In this case, the C reflex of the contralateral hand occurs 10 to 15 milliseconds later than that of the stimulated hand. When the patient is likely to have reflex myoclonus that is sensitive to visual stimulus, it is worthwhile to record photic evoked responses and photically evoked long-loop reflex, just as in the case of SEP and somatosensory evoked long-loop reflex. In addition to these electrophysiological tests, other tests such as magnetic resonance imaging and chemical tests of blood should be performed, depending on the underlying diseases that are possible according to the history and physical findings in each case.
EXPERIMENTAL MODEL The rat model of posthypoxic myoclonus has been extensively studied by Truong’s group.5 They observed auditory stimulusinduced myoclonus in the rats that survived the acute stage of coma and seizures caused by mechanically induced cardiac arrest. The myoclonus was thought to be of brainstem origin, but in contrast to startle response, the acoustic reflex
myoclonus did not show habituation. It was maximal about 4 days after the anoxic insult, and it subsided in 3 to 4 weeks. Histologically, neuronal degeneration was seen extensively in the motor cortex, somatosensory cortices, thalamic reticular nucleus, hippocampus, and cerebellum. Hypofunction of serotonergic system in the frontal cortex was found in this experimental condition, and clonazepam, sodium valproate, and piracetam were found to reduce the myoclonus. Most human cases of posthypoxic myoclonus are of cortical origin, although reticular reflex myoclonus is occasionally encountered. Dichlorodiphenyltrichloroethane (p,p′-DDT) causes spontaneous myoclonus in rats, but in this condition, hyperfunction of 5-hydroxyindole acetic acid (5-HIAA) was demonstrated. Injection of picrotoxin, a γ-amino butyric acid type A (GABAA) antagonist, into the reticular nucleus of the thalamus in rats induces rhythmic, spontaneous myoclonus, which is also evoked by acoustic stimulus. Complex neuropharmacological abnormalities seem to be involved in these experimental conditions, mainly involving serotonergic and GABAergic systems.
TREATMENT Symptomatic treatment of cortical myoclonus is achieved by anticonvulsants such as clonazepam, sodium valproate, and, on occasion, primidone to a variable degree, depending on the patient (Table 34–5). In addition, piracetam or levetiracetam may be effective for cortical myoclonus. This can be given either in combination with those anticonvulsants or alone. L-5-hydroxytryptophan (5-HTP) has been reported to be effective, especially for posthypoxic myoclonus. Other forms of myoclonus also respond to clonazepam.
442
Section
VII
Motor System and Motor Diseases
T A B L E 34–5. Treatment of Cortical Myoclonus Drug Clonazepam Sodium valproate Piracetam Levetiracetam Primidone L-5-Hydroxytryptophan (5-HTP)
Initial Dosage
Maintenance Dosage
0.5-1.0 mg/day 200 mg/day 12 g/day 1000 mg/day 125 mg/day 100 mg/day
2-6 mg/day 600-1200 mg/day 12-21 g/day 3000 mg/day 375-750 mg/day 500-1500 mg/day
Prepared with help from Dr. Akio Ikeda.
K E Y ●
Suggested Reading Caviness JN, Brown P: Myoclonus: current concepts and recent advances. Lancet Neurol 2004; 3:598-607. Lehesjoki A-E: Molecular background of progressive myoclonus epilepsy. EMBO J 2003; 22:3473-3478. Shibasaki H, Hallett M: Electrophysiological studies of myoclonus. Muscle Nerve, 2005; 31:157-174. Shibasaki H: Myoclonus and startle syndromes. In Jankovic J, Tolosa E, eds: Parkinson’s Disease and Movement Disorders, 5th ed. Philadelphia: Lippincott Williams & Wilkins. In press. Truong DD, Kirby M, Kanthasamy A, et al: Posthypoxic myoclonus animal models. In Fahn S, Frucht SJ, Truong DD, et al, eds: Advances in Neurology, vol 89: Myoclonus and Paroxysmal Dyskinesias. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 295-306.
P O I N T S
Myoclonus is a group of involuntary movements characterized by a shocklike appearance.
●
Myoclonus is associated with brisk muscle contraction (positive myoclonus), brisk interruption of ongoing muscle contraction (negative myoclonus), or a combination of the two.
●
It is important to distinguish myoclonus from other involuntary movements, especially for finding its most appropriate treatment.
●
It is important to recognize cortical myoclonus because it is often epileptic in nature.
●
Electrophysiological studies are useful for the confirmation and classification of myoclonus and for the understanding of its pathophysiology.
References 1. Caviness JN, Brown P: Myoclonus: current concepts and recent advances. Lancet Neurol 2004; 3:598-607. 2. Lehesjoki A-E: Molecular background of progressive myoclonus epilepsy. EMBO J 2003; 22:3473-3478. 3. Shibasaki H, Hallett M: Electrophysiological studies of myoclonus. Muscle Nerve, 2005; 31:157-174. 4. Shibasaki H: Myoclonus and startle syndromes. In Jankovic J, Tolosa E, eds: Parkinson’s Disease and Movement Disorders, 5th ed. Philadelphia: Lippincott Williams & Wilkins. In press. 5. Truong DD, Kirby M, Kanthasamy A, et al: Posthypoxic myoclonus animal models. In Fahn S, Frucht SJ, Truong DD, et al, eds: Advances in Neurology, vol 89: Myoclonus and Paroxysmal Dyskinesias. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 295-306.
CHAPTER
35
DYSTONIA ●
●
●
●
T. T. Warner
The dystonias are an unusual group of movement disorders whose main feature is involuntary muscle contraction or spasm. The term dystonia was originally introduced by Hermann Oppenheim in 1911 to describe alterations in muscle tone and postural abnormalities that are seen in this condition. The concept of dystonia can be confusing because the term has been used to describe a symptom (e.g., a dystonic arm posture), a disease (primary torsion dystonia), or a syndrome. The dystonias constitute a relatively common group of movement disorders that encompass a wide range of conditions from those in which the only manifestation is dystonic muscle spasms to those in which dystonia is one part of a more severe neurological condition.
DEFINITION AND CLASSIFICATION Dystonia is characterized by involuntary sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures.1 The movements range from slower twisting athetosis to rapid, shocklike jerky movements. They are repetitive and sometimes rhythmic and can be accompanied by tremor. Dystonic movements can be aggravated by movement (action dystonia) that can be nonspecific or task-specific (e.g., writing). Over time the dystonia can occur with less specific movements and eventually can be present at rest, leading to sustained abnormal postures. Three basic approaches are used to classify dystonia: age at onset, distribution of affected body parts, and etiology. The categories of age at onset and affected body distribution (Table 35–1) are important in describing clinical signs and have clinical implications for prognosis and treatment.
Age at Onset Dystonia can develop at any age, although those with earlier age at onset are more likely to have a more severe course affecting more of the body. The ages at onset were initially divided into childhood (0 to 13 years), adolescence (13 to 21 years) and adulthood (>21 years), but a more pragmatic division into early (<26 years) and late (>26 years) onset is now used.
Distribution The distribution distinguishes patients on the basis of whether dystonia is localized to a single body region (focal), whether it has spread to contiguous (segmental) or noncontiguous (multifocal) regions, or whether the legs are affected along with other body regions (generalized). The age at onset and the body distribution are related: The earlier the age at onset, the more likely dystonia is to be severe, spreading to a generalized distribution. In addition, the body region first affected is also important: Onset in the legs is most frequent during childhood, and with increasing age, the site of onset ascends to the arms/hands, neck, and then cranial muscles. Thus, childhood limb onset dystonia usually generalizes; writer’s cramp occurs with a mean onset in the 30s and can spread to become segmental dystonia; cervical dystonia has a mean onset in the 40s, and blepharospasm usually starts in the sixth decade, and both usually remain focal.
Etiology The third approach to classification is by etiology. Dystonia can be divided into primary and secondary or symptomatic dystonia. Primary torsion dystonia (PTD) comprises a group of dystonias with predominantly genetic causes. Phenotypically, in PTD, dystonia must be the only clinical feature (except for tremor of the arms or head and neck), and there must be no evidence of neuronal degeneration or acquired cause. Secondary dystonias make up all other causes and are divided into inherited, complex, and acquired causes. Among the inherited causes are the dystonia-plus syndromes, which are characterized by the presence of dystonia plus other neurological features and have a genetic basis without evidence of neurodegeneration. Dystonia can also be part of a more widespread neurological disorder in which there is underlying neurodegeneration (such as Wilson’s disease), and these are referred to as heredodegenerative causes.
EPIDEMIOLOGY The true population incidence and prevalence of dystonia are unknown. The prevalence data available are usually based on studies of diagnosed cases only and therefore are under-
443
444
Section
VII
Motor System and Motor Diseases
T A B L E 35–1. Classification of Dystonia Age at Onset Early: <26 years Late: >26 years Distribution: Focal: Single body part affected Neck: cervical dystonia (spasmodic torticollis) Eyelids: blepharospasm Mouth: oromandibular dystonia Larynx: laryngeal dystonia Hand or arm: writer’s cramp and other limb dystonias Segmental: two or more contiguous body parts Cranial: head and/or neck Axial: neck and trunk Brachial: one arm and axial; both arms ± neck ± trunk Crural: one leg and trunk, both legs ± trunk Generalized: segmental crural and any other segment Multifocal: two or more noncontiguous parts Hemidystonia: ipsilateral arm and leg Etiology Primary Dystonia is only sign, plus tremor; no acquired or degenerative cause Secondary Inherited Dystonia-plus syndromes Heredodegenerative disorders Acquired Structural lesions, drugs, toxins, etc. Complex/unknown Dystonia associated with parkinsonism ±, with or without.
estimates of the real numbers. This is particularly the case with dystonia, which can manifest in a variety of ways, and a significant number of cases of focal dystonia are undiagnosed or even misdiagnosed. In an early study in the United States that was based on case note review, the prevalence for PTD was estimated to be 329 per million population. In more recent studies of diagnosed cases in Japan and Europe, the prevalence was estimated to be between 101 and 150 per million. The most reliable estimate is from an ongoing study in the northeast of England, where ascertainment was more complete, and some previously undiagnosed cases were identified. This finding has implied a prevalence rate of 485 per million. The prevalence of secondary dystonia is unknown, although it is estimated from case series that it may be less than 20% to 25% the rate for PTD. The most prevalent form of PTD is focal dystonia, of which cervical dystonia is the commonest, with prevalence rates reported between 57 and 290 per million population. Rates for blepharospasm are 17 to 80 per million, and for writer’s cramp, 14 to 61 per million. In a study in South Tyrol in Austria, a random sample of the population older than 50 years was examined.2 Primary dystonia was diagnosed in 6 of the 707 individuals studied, implying a prevalence of 7320 per million in this age-selected population, although 95% confidence intervals were very wide, at 3190 to 15,640, because of the small sample. However, this indicates that in the aging population, dystonia is a relatively common neurological disorder.
T A B L E 35–2. Clinical Features Suggestive of Secondary Dystonia Abnormal birth/perinatal history Developmental delay Seizures Exposure to drugs (e.g., dopamine blockers) Continuous progression of symptoms Prominent bulbar involvement Unusual distribution (e.g., hemidystonia) Additional neurological symptoms Pyramidal, cerebellar, cognitive decline Signs of other system involvement (e.g., organomegaly)
CLINICAL FEATURES The diagnosis of dystonia is based on clinical findings. Primary dystonia has no other neurological features apart from dystonia and tremor.3 Features suggestive of a secondary cause of dystonia are listed in Table 35–2. Investigations are usually performed to help rule out a secondary cause of dystonia.
Primary Dystonia Early-Onset Primary Torsion Dystonia (Dystonia Musculorum Deformans, Oppenheim’s Dystonia) The commonest cause of early onset PTD is mutation in the DYT1 gene on chromosome 9q34, which is inherited as an autosomal dominant trait with reduced penetrance (30% to 40%). The disorder typically manifests in childhood or adolescence (mean age at onset, 12 years) with dystonia causing posturing of a foot, leg, or arm. Dystonia is usually first apparent with specific actions (e.g., writing or walking) but becomes evident with less specific actions over time and spreads to other body regions. No other neurological abnormalities are present apart from postural arm tremor. Disease severity varies considerably even within the same family, and isolated writer’s cramp may be the only sign. However, approximately 60% to 70% of individuals have progression to generalized or multifocal dystonia involving at least a leg and an arm, and often axial muscles. In 10% of cases, segmental dystonia develops, and only 25% remain focal. The cranial muscles are involved in about 10% of affected patients. Key investigations are to exclude treatable differential diagnoses, such as Wilson’s disease and dopa-responsive dystonia (DRD). DYT1 dystonia is diagnosed through molecular genetic testing of the TOR1A gene, which reveals a three–base pair deletion in all affected individuals. There is a higher prevalence of DYT1 PTD in the Ashkenazi Jewish population, which is the result of a founder mutation that appeared about 250 years ago. Most forms of early-onset PTD are genetic in origin, and Table 35–3 lists the genetic forms that have been identified to date. Most are autosomal dominant, some reported only in single families. The existence of autosomal recessive forms (DYT2) is controversial.
Focal Primary Torsion Dystonia These are by far the commonest forms of dystonia. Usually sporadic, they have onset in adult life and remain focal in distri-
chapter 35 dystonia
445
T A B L E 35–3. Genetic Forms of Primary Dystonia Type
Clinical Features
Frequency
Age at Onset
Genetics
DYT1
Limb onset, generalizes, can manifest as focal
50% cases early onset in nonJews, 90% in Ashkenazi Jews
Childhood; most present by 26 years
DYT2
Focal and generalized
Childhood to adult
DYT4
Laryngeal and cervical, some generalize Focal or generalized; cranial, cervical, or limb
Spanish Gypsy families and a single Iranian Single Australian family Two families: one Mennonite, one Amish
Mean age at onset: 19 years
AD TOR1A on chromosome 9q34 Protein torsin A AR Locus and gene unknown AD Locus and gene unknown AD DYT6 Chromosome 8p21-q22 AD DYT7 Chromosome 18p AD DYT13 Chromosome 1p36
DYT6
13-37 years
DYT7
Focal dystonia, cervical and laryngeal
Single German family
28-70 years
DYT13
Cranial or cervical; some generalize
Single Italian family
Childhood to adult
AD, autosomal dominant; AR, autosomal recessive.
bution. Families with autosomal dominant forms have been described, and it is believed that a proportion of the apparently sporadic cases may represent manifestation of a dominant gene with very low penetrance (estimated at 12% to 15%). The individual types are discussed as follows.
Cervical dystonia (spasmodic torticollis) Cervical dystonia is a focal dystonia that affects cervical muscles, leading to abnormal postures and movements of the head, neck, and shoulders. It is the most common form of dystonia, usually with onset in the fifth decade (mean age at onset, 42 years) and affects women more than men (ratio, 1.4 : 1 to 1.6 : 1). The dystonic muscle activity can be tonic, phasic, or tremulous and leads to symptoms of neck pain, head posturing, or repetitive jerking, producing tremor of the head. Cervical dystonia symptoms tend to worsen over the first 5 years and then stabilize. Twisting of the head around the horizontal axis (torticollis) is the most common movement, present in 80% of patients and caused by overactive contralateral sternomastoid and ipsilateral splenius capitis muscles. Laterocollis (head sideways) is seen in 10% to 20% and caused by overactivity in the ipsilateral splenius, sternomastoid, and levator scapulae muscles. Retrocollis (head back) and antecollis (head forward) are less frequent. Many patients, however, present with combinations of torticollis and laterocollis. Pain is present in 75% of patients and can cause significant disability. Many patients with cervical dystonia have sensory tricks (geste antagoniste) that can alleviate symptoms. These can involve touching the back of the head, cheek, or temple and lead to reduction in abnormal dystonic muscle spasm. Spontaneous remission of symptoms occurs in less than 20% of patients; unfortunately for most of these patients, there will be a subsequent relapse. Focal cervical dystonia can spread to other body parts, including the face and arms, but rarely generalizes. The long-term complications of cervical dystonia include cervical spine degeneration, which leads to radicular or myelopathic symptoms. Cervical dystonia also has a significant effect on quality of life and is associated with a higher incidence of anxiety and depression.
Blepharospasm and other cranial dystonias Blepharospasm is the second commonest form of dystonia and is caused by dystonic muscle spasms of the orbicularis oculi muscles. Like cervical dystonia, it is more common in women, with female-to-male ratios of between 1.8 : 1 and 2.5 : 1. Onset usually occurs in the sixth or seventh decade and is insidious, often with soreness or dryness of the eyes, followed by excessive blinking, especially with bright light or reading. This can worsen over months to years, leading to sustained muscle spasms and eye closure, and, when severe, can render a patient functionally blind for significant periods of time. The spasms are sometimes accompanied by perioral muscle involvement. Oromandibular dystonia can manifest with predominant jaw opening (lateral pterygoid muscles, muscles of the floor of the mouth, and infrahyoid muscles), jaw closing (masseter and medial pterygoid muscles), or a mixed type. There can also be involvement of the tongue, facial, and pharyngeal muscles. Oromandibular dystonia can be present at rest but often worsens on eating or talking, with dysarthria and dysphagia. It is an extremely visible form of dystonia and can be very distressing and stigmatizing for patients. Complications include temporomandibular joint impairment and muscular pain.
Writer’s cramp and task-specific limb dystonias Writer’s cramp is the most common form of task-specific dystonia and, in contrast to craniocervical dystonia, is more common in men than in women. Onset usually occurs between the ages of 30 and 50 years and often starts with a feeling of tension in fingers and forearms that interferes with writing fluency. The pen is held abnormally forcefully as a result of dystonic contraction of hand and/or forearm muscles. This commonly involves excessive flexion of the thumb and index finger with pronation of the hand and ulnar deviation of the wrist. Affected individuals may also experience lifting of the thumb or index finger off the pen or isolated extension of fingers. Up to 50% of patients also experience upper limb tremor, either on writing or a postural tremor. Strain and aching, particularly in
446
Section
VII
Motor System and Motor Diseases
affected forearm muscles, is common on writing, but pain is an uncommon feature. Writing difficulty is often intermittent at onset but usually progresses so that cramping starts soon after starting writing. In a minority of patients, dystonia occurs on performing other manual tasks, and this can be a feature that develops with time. Spontaneous remission is rare. Many patients whose writing has become illegible therefore learn to write with their nondominant hands. Unfortunately, in up to 10% of cases, writer’s cramp can develop in that hand as well. Dystonic patterns of involuntary muscle contractions are also seen in the context of other highly learned motor skills. These are most commonly seen in professional musicians, craftsmen, and sportsmen whose work involves frequent, repetitive movements of particular muscle groups. They have been reported in fewer than 1% of professional musicians, more frequently men. In pianists, for instance, the fourth and fifth fingers of the right hand are most commonly involved, whereas for guitarists, the third finger of the right hand is affected. For wind instrument players, the hand supporting the instrument and doing fingering at the same time is most involved. Less commonly, lip or orofacial dystonia can develop. Tremor can accompany task-specific dystonias in less than 40% of cases. Other manual tasks associated with task-specific dystonia include typing, painting, and sports such as golf, tennis, and snooker.
Laryngeal dystonia Laryngeal dystonia is relatively rare and can be divided into cases in which the predominant problem is spasm of the adductor muscles and spasms involving abductor muscles. It can occur in isolation or sometimes as part of a segmental craniocervical dystonia. In one family with autosomal dominant inheritance (DYT3 locus), it is the presenting feature in individuals who developed generalized dystonia. Adductor spasmodic dysphonia is the commonest form and is characterized by intermittent voice stoppages, particularly with vowels. This is caused by hyperadduction of the vocal cords caused by involuntary spasm of thyroarytenoid and/or lateral cricoarytenoid muscles. Abductor spasmodic dysphonia occurs in about 15% of patients and manifests with breathy breaks in speech, especially with consonants. In some cases, this is caused by involvement of vocal fold opening muscles, such as the posterior cricoarytenoid and cricothyroid muscles. Spasmodic dysphonia is task specific and occurs only during speech. Laughter, crying, and breathing are unaffected. Voice tremor often occurs with both types of spasmodic dysphonia and is also speech specific. Other laryngeal disorders that can be confused with laryngeal dystonia can occur in other neurological conditions, but the presence of additional neurological signs should alert the clinician to alternative diagnoses. Examples are vocal fold paralysis in motor neuron disease, airway obstruction in multiple-system atrophy, hypophonia in Parkinson’s disease, and abductor vocal fold paralysis in hereditary motor neuronopathy.
Secondary/Symptomatic Dystonias Dystonia-Plus Syndromes Dystonia-plus syndromes describe a group of conditions that can be distinguished from PTD on the basis of clinical charac-
teristics found in addition to dystonia, or specific pharmacological responses. They usually have a genetic etiology but do not have underlying neurodegeneration. The group comprises three distinct conditions: DRD, myoclonus dystonia syndrome, and rapid-onset dystonia parkinsonism (RDP).
Dopa-responsive dystonia DRD was first described in Japan in 1977 by Masaya Segawa. Patients typically present in childhood with gait disturbance caused by foot dystonia. The dystonia frequently worsens as the day goes on (diurnal variation) and is relieved by rest or sleep. Progression is variable; some patients develop severe generalized dystonia, whereas others develop features suggestive of lower limb spasticity. Parkinsonian features such as bradykinesia and rigidity can develop in later life in some affected individuals but can also be the presenting features in adult life in a minority of cases. On occasion, DRD can manifest with adultonset limb dystonia (e.g., writer’s cramp), with cranial or cervical dystonia, or with signs resembling spastic paraplegia. In most cases, DRD is inherited as an autosomal dominant trait with reduced penetrance. The key feature in DRD is a dramatic and sustained response to small doses of levodopa (L-dopa), often as low as 50 to 200 mg. Benefit is usually apparent within days to weeks, and the motor complications of L-dopa treatment seen with Parkinson’s disease rarely develop, even with long-term treatment. Anticholinergic drugs also can be beneficial. The principal considerations in the differential diagnosis for childhood DRD are early-onset PTD, spastic paraplegia and cerebral palsy, and early-onset parkinsonism, especially when it is caused by mutations in the parkin gene. The patients thought to have early-onset parkinsonism often present with dystonia and show good initial response to L-dopa. However, clues to the diagnosis come from the inheritance pattern (usually autosomal recessive for the parkin gene) and the occurrence of motor fluctuations and dyskinesias with L-dopa treatment. Positron emission tomography (PET) with markers for presynaptic dopaminergic terminals (18F–dopa) or single photon emission computed tomography can also differentiate between the two conditions. The gene for dominant DRD has been mapped to chromosome 14 (DYT5) and mutations within the gene for guanosine triphosphate (GTP) cyclohydrolase 1 have been identified. Numerous mutations have been identified in all five exons, which makes genetic testing laborious. Other extremely rare forms of DRD have been reported, including a recessive form with genetic deficiency of tyrosine hydroxylase and defects in other enzymes involved in pterin synthesis. The diagnosis can usually be confirmed by an excellent response to L-dopa treatment in dosages slowly increasing up to 400 mg a day. Alternatively detecting reduced levels of pterins in the cerebrospinal fluid or an abnormal oral phenylalanine loading test can substantiate the diagnosis.
Myoclonus-dystonia syndrome Myoclonus-dystonia syndrome (MDS) is characterized by the presence of dystonia in combination with brief lightning-like myoclonic jerks. It is frequently inherited as an autosomal dominant trait, caused by mutations in the gene for εsarcoglycan (DYT11), although sporadic cases also occur. A further autosomal dominant locus (DYT14) has been mapped to chromosome 18.
chapter 35 dystonia MDS usually has onset in childhood or early adolescence, with myoclonic jerks affecting the upper limbs and axial muscles (trunk and neck). The myoclonus can occur on rest and also be precipitated by action. Dystonia occurs in approximately two thirds of patients; cervical dystonia and writer’s cramp are the most common forms. On occasion, dystonia affects the legs. Several reports have identified psychiatric features associated with MDS, including obsessive-compulsive disorder, panic attacks, and anxiety. Most affected patients note significant relief of symptoms with alcohol or benzodiazepines and can have marked rebound of symptoms after administration of these drugs. This can often lead to abuse of these substances.
Rapid-onset dystonia parkinsonism Rapid-onset dystonia parkinsonism (RDP) is a rare autosomal dominant movement disorder with reduced penetrance. It is characterized by abrupt or subacute onset of both dystonia and parkinsonism with prominent bulbar involvement. Symptoms, including dystonic posturing of the limbs, bradykinesia, dysarthria, and dysphagia, and postural instability, develop over hours to days, followed by little or no progression. Onset is usually in adolescence or young adulthood, and the subacute extrapyramidal storm can be preceded by stable mild limb dystonia for a number of years. Potential triggers in some families include emotional trauma, extreme heat, or physical exertion. Investigation with magnetic resonance imaging (MRI), computed tomography, and PET of the presynaptic dopamine uptake sites has yielded normal results. In some patients, reduced levels of cerebrospinal fluid dopamine metabolites have been detected. The current assumption is that RDP is caused by neuronal dysfunction rather than neurodegeneration. The condition is rare, and only a small number of families with evidence of autosomal dominant inheritance with reduced penetrance have been described. The gene was mapped to chromosome 19q13.2 (DYT12), and mutations in the gene for the Na+/K+–adenosine triphosphatase α3 subunit (ATP1A3) have been identified in seven unrelated kindreds with RDP. This finding implicates the Na+/K+ pump, which is crucial for maintaining the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.
447
T A B L E 35–4. Secondary Causes of Dystonia Cause
Examples
CNS lesion
Brain tumor, stroke, hypoxia, intracranial hemorrhage, CNS trauma, congenital malformations, cervical cord lesions Cerebral palsy, delayed-onset dystonia, perinatal hypoxia, kernicterus Subacute sclerosing panencephalopathy, Reye’s syndrome, viral encephalitis, Creutzfeld-Jakob disease, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren’s syndrome
Perinatal cerebral injury Infectious, postinfectious, and inflammatory
Peripheral nerve injury Drug-induced Dopaminergic agents (L-dopa, dopamine agonists), dopamine receptor–blocking drugs (neuroleptics, prochlorperazine, metoclopramide), selective serotonin reuptake inhibitors, MAO inhibitors, antiepileptic drugs, ergots, flecainide, cocaine, ranitidine, calcium antagonists, anesthetic agents Toxin-induced Manganese, carbon monoxide, carbon disulfide, cyanide, methanol, disulfiram, wasp sting venom Metabolic Hypoparathyroidism CNS, central nervous system; L-dopa, levodopa; MAO, monoamine oxidase.
been described for a number of drugs, including dopamine receptor–blocking (DRB) agents, antidepressants (selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), calcium antagonists, general anesthetic agents, anticonvulsants (carbamazepine, phenytoin), L-dopa, ranitidine, 3,4methylenedioxymethamphetamine (“ecstasy”), and cocaine. Tardive dystonia is usually seen with use of dopamine receptor–blocking drugs and is defined as dystonia present for at least 1 month and occurring either during or within 3 months of discontinuation of a dopamine receptor–blocking drug. It most commonly affects the face and neck but can spread and even generalize in some cases. Toxins such as manganese and carbon monoxide that can directly affect the basal ganglia also result in secondary dystonia.
Secondary Dystonia The term secondary implies that an identifiable cause for the dystonia can be found. Many of these directly involve the basal ganglia and lead to contralateral hemidystonia. Table 35–4 summarizes the most common causes of secondary dystonia. Strokes, tumors, vascular malformations, and traumatic injuries to the basal ganglia are well-described causes of dystonia, but dystonia also, more rarely, occurs after injury to cortical or brainstem structures, the spinal cord, and even peripheral nerves. Perinatal injury may cause dystonia at the time of brain injury (dystonic or choreoathetoid cerebral palsy) or can lead to delayed-onset dystonia, which can begin years after the injury and progress. Infectious, postinfectious, and inflammatory syndromes associated with dystonia usually manifest in combination with other movement disorders, such as parkinsonism, chorea, athetosis, and tics. Drugs may also cause transient or chronic (tardive) dystonia. Acute dystonic reactions occur shortly after the introduction of a drug and have
Heredodegenerative Disorders Dystonia also occurs in a wide range of heredodegenerative disorders in which there is progressive neuronal loss with a mixture of neurological symptoms and signs, sometimes with systemic involvement. Table 35–5 lists the various heredodegenerative disorders that can be divided into those with disorders of metabolism, mitochondrial disease, trinucleotide repeat diseases, parkinsonian disorders, and other degenerative processes without defined causes.
Psychogenic Dystonia The concept of psychogenic dystonia is difficult because in the first half of the 20th century many cases of organic dystonia were thought to be psychiatric in origin as a result of the unusual and variable nature of the symptoms. Psychogenic dystonia does exist, often resulting in profound disability, but is a
448
Section
VII
Motor System and Motor Diseases
T A B L E 35–5. Heredodegenerative Disorders That Can Cause Dystonia Metabolic Disorders Metal and mineral metabolism Lysosomal storage disorders Inborn errors of metabolism Amino and organic acidurias
Wilson’s disease, neurodegeneration with brain iron accumulation type I, neuroferritinopathy, idiopathic basal ganglia calcification (Fahr’s disease) Niemann-Pick disease type C, GM1 and GM2 gangliosidoses, metachromatic leukodystrophy, Krabbe’s disease, Pelizaeus-Merzbacher disease, fucosidosis Lesch-Nyhan syndrome, triosephosphate isomerase deficiency, glucose transport defects Glutaric aciduria type I, homocystinuria, propionic acidemia, methylmalonic aciduria, 4-hydroxybutyric aciduria, 3-methylglutaconic aciduria, 2-oxoglutaric aciduria, Hartnup’s disease
Mitochondrial Disorders Leigh’s disease Leber’s hereditary optic neuropathy Mohr-Tranebjaerg syndrome (dystonia/deafness) Trinucleotide Repeat Disorders Huntington’s disease Spinocerebellar ataxias Parkinsonian Disorders Parkinson’s disease (especially familial young-onset forms) Progressive supranuclear palsy Multiple-system atrophy Corticobasal ganglionic degeneration X-linked dystonia–parkinsonism (“Lubag”) Others Ataxia-telangiectasia Chorea-acanthocytosis Rett’s syndrome Infantile bilateral striatal necrosis Ataxia with vitamin E deficiency Progressive pallidal degeneration Sjögren-Larsson syndrome Ataxia–amyotrophy–mental retardation–dystonia syndrome
rare form of dystonia. As with organic dystonias, it is difficult to diagnose with certainty, and the assessment should be undertaken only by a neurologist with considerable experience with organic dystonias. One reason for this is the absence of a specific diagnostic test for dystonia. The diagnosis is based on the presence of clinical inconsistencies and incongruities with organic dystonia. The pathophysiology is poorly understood. Prompt diagnosis and treatment are necessary, in view of the poor prognosis of conversion disorders when there has been considerable delay between symptom onset and diagnosis, and treatment often involves a combination of psychotherapy, physical therapy, and psychopharmacologic therapy.
accumulation type 1 (Fig. 35–1), typical changes in the midbrain of a patient with Wilson’s disease, or basal ganglia calcification in Fahr’s disease. If MRI appearance is normal, further tests should be performed to exclude Wilson’s disease as it is potentially treatable. Slit-lamp examination for Kayser-Fleischer rings (Fig. 35–2), serum ceruloplasmin measurement, and 24-hour urinary copper excretion measurement are required. For cases of possible secondary dystonics, futher investigations for metabolic and heredodegenerative disorders are required, with testing for serum amino and organic acids and investigation for specific enzymatic disorders in white blood cell or fibroblast cultures.
INVESTIGATIONS
PATHOPHYSIOLOGY OF DYSTONIA
Table 35–6 list potential investigations. However, the clinical presentation determines which of these are appropriate. For instance, a woman aged 60 presenting with blepharospasm alone may need no investigation, whereas a child with dystonia and other neurological features would need extensive tests to identify a potential secondary cause. A history of birth injury, a family history of other neurological disorders, and exposure to dystonia-inducing drugs are important. Hemidystonia is highly suggestive of a contralateral lesion of the basal ganglia, and cranial imaging with MRI is mandatory. For young-onset generalized dystonia, imaging may also aid in diagnosis, such as revealing the “eye of the tiger” sign in brain iron
Neurophysiological Studies The hallmark of dystonia is involuntary sustained muscle contractions, which are characterized by an abnormal pattern of EMG activity: excessive co-contraction of antagonist muscles during an action and overflow into extraneous muscles. Other findings include prolongation of EMG bursts. These findings have been described in patients with primary focal hand dystonia, and it was also noted that there was loss of selectivity to perform independent finger movements, occasional failure of willed activity, and tremor. These features emphasize that in
chapter 35 dystonia
449
T A B L E 35–6. Investigation of Dystonia Dystonia Phenotype Primary torsion dystonia Early onset (<28 years)
Late onset (>28 years)
Secondary dystonia
Investigation Copper studies, slit-lamp examination Brain MRI DYT1 gene analysis Trial of L-dopa Copper studies, slit-lamp examination if younger than 50 years Brain MRI Spine MRI if dystonia fixed or painful EMG if painful axial muscle spasm Brain/spine MRI Nerve conduction studies Copper studies, slit-lamp examination, liver biopsy Genetic test for neurodegenerative disorders (e.g., Huntington’s disease) White blood cell enzymes α-Fetoprotein, immunoglobulins Lactate, pyruvate, mtDNA analysis; muscle biopsy Blood film for acanthocytes Urine amino acid, organic acid, oligosaccharide measurements Bone marrow biopsy Phenylalanine loading test, CSF pterin measurement ERG, retinal examination
CSF, cerebrospinal fluid; EMG, electromyography; ERG, electroretinogram; MRI, magnetic resonance imaging; mtDNA, mitochondrial deoxyribonucleic acid.
■
Figure 35–2. Typical Kayser-Fleischer ring (arrow) in a patient with Wilson’s disease.
■
Figure 35–1. Cranial magnetic resonance image from a patient with brain iron accumulation type 1, showing the “eye of the tiger” sign.
dystonia, there is excessiveness of movements and lack of fine control. The problem of excessive co-contraction of agonist and antagonist muscles appears to be caused in part by loss of reciprocal inhibition, a mechanism present at many levels in the central nervous system that has been shown to be impaired in generalized dystonia, writer’s cramp, cervical dystonia, and blepharospasm. Studies of other spinal and brainstem inhibitory reflexes have also confirmed that a common theme in various forms of primary dystonia is the reduction in inhibitory processes within the motor system. However, it has become clear that dystonia is not a pure motor disorder and that individuals with dystonia have sensory abnormalities that play an important role in causing motor dysfunction. Studies have demonstrated evidence of abnormalities in both somatosensory spatial discrimination and temporal
450
Section
VII
Motor System and Motor Diseases
discrimination (the shortest time two successive stimuli are perceived as separate). The importance of the sensory system in dystonia is also evident from study of the sensory tricks (geste antagoniste), which are various maneuvers used by patients with focal dystonia to temporarily relieve the dystonic spasms; for example, a finger placed on the face of an individual with cervical dystonia can eliminate neck muscle spasm. There is also evidence to suggest that abnormal sensory input can trigger dystonia, such as trauma to a body part before the dystonia. Another line of evidence comes from study of processing of muscle spindle input. In patients with hand cramps, vibration can induce the patient’s dystonia, and cutaneous input similar to that which produces the sensory trick can reverse this vibration-induced dystonia. Studies of intracortical inhibition with transcranial magnetic stimulation paradigms have shown that there is motor cortex hyperexcitability in dystonia. This has been shown to result from deficient intracortical inhibition in the cortical hand muscle representation, not only in focal hand dystonia but also in blepharospasm, in which hand muscles are clinically normal. This defect in inhibition appears to occur specifically during dystonic muscle contraction and not during more normal movements, which implies that the contraction is dystonic because of the deficient inhibition. These findings of reduced intracortical inhibition, shorter silent period, and abnormal spinal reciprocal inhibition have also been demonstrated in patients with DYT1 generalized dystonia. It is therefore believed that the excessive muscle contractions that occur in dystonia are generated by loss of inhibition, particularly loss of “surround inhibition”: the suppression of unwanted movements when a specific motor task is performed. Surround inhibition is believed to be essential for the production of precise, functional movement, just as surround inhibition in the visual system leads to more precise perceptions. Studies with transcranial magnetic stimulation and PET/ functional MRI have supported the view that deficient intracortical inhibition leads to hyperexcitability of the motor cortex, which in turn could lead to the excessive movement seen in dystonia. Most of the clinical evidence points to the basal ganglia as the site of the pathology in dystonia. There is experimental evidence that the basal ganglia output can influence cortical inhibition and also that the basal ganglia are anatomically organized to work in a center-surround mechanism, which would allow surround inhibition.
Molecular Genetic Studies Dopa-responsive dystonia is the best characterized genetic form of dystonia. Mutations within the GTP cyclohydrolase 1 gene lead to marked reduction in the activity of the enzyme it encodes. GTP cyclohydrolase 1 is the rate-determining enzyme in the synthesis of tetrahydrobiopterin, a key cofactor in the monoamine synthesis pathway. Reduced levels of tetrahydrobiopterin lead to reduced dopamine synthesis, which appears to play a key role in the production of dystonia in this condition. The central role of abnormal dopaminergic neurotransmission in dystonia is supported by the finding that dopamine-blocking drugs can produce both acute and tardive dystonia. In DYT1 dystonia, the protein product torsin A, which normally resides
in the endoplasmic reticulum, becomes mislocated to the nuclear envelope and abnormal inclusions that also contain proteins involved in dopaminergic transport. Whether mutant torsin A affects neurotransmission, however, is unclear.
Summary Evidence therefore suggests that dystonia is characterized pathophysiologically by abnormal sensory processing and deficient cortical inhibition.4 The current model implicates abnormal surround inhibition as the substrate that leads to generation of uncontrolled dystonic movements. Dystonia could result from lesions in the basal ganglia, which disrupt intricate pathways and push normal movements to abnormal. Genetic defects (such as those found in DYT1 dystonia) may also affect these pathways, possibly through abnormal dopaminergic neurotransmission. Repetitive movements or use of a body part may also lead to dystonia. Thus, a combination of factors may lead to the cortical abnormality that results in the production of dystonic movements.
TREATMENT OF DYSTONIA Treatment options for dystonia have increased dramatically since the mid-1980s. This has been the result of the use of botulinum toxin and a renewed interest in functional neurosurgery for dystonia. Drug treatment has some use, particularly for DRD and MDS and the more severe childhoodonset primary dystonias. Table 35–7 lists the treatment options for various forms of dystonia.
Drug Therapy Drug treatment of dystonia has changed little since the mid1980s. Although many forms of dystonia are relatively unresponsive to drugs, there is still an important role for drug therapy for primary generalized dystonia, dystonia-plus conditions, and some forms of secondary dystonia.
Dopaminergic Agents Patients with DRD show dramatic response to low doses of Ldopa (with decarboxylase inhibitor) and all patients with youngonset dystonia should undergo an L-dopa trial. The mean daily dose effective in DRD is 250 mg, although higher doses are sometimes required. Symptoms of DRD may also respond to dopamine agonists and anticholinergic drugs. The role of dopaminergic agents in the treatment of primary dystonia is less clear. Reviews of small treatment trials suggest that improvement with these drugs was rarely dramatic. Twenty percent of patients believed that they actually deteriorated, but on occasion there was benefit.
Anticholinergic Drugs Trihexyphenidyl can be useful for childhood-onset primary dystonia. One prospective placebo-controlled trial revealed that 67% of treated patients showed improvement and 68% continued to benefit after 2.4 years at a mean daily dose of 40 mg. It appears to be less useful for adult-onset primary focal dystonia. In both children and adults, the dose of anticholinergic must
chapter 35 dystonia
451
T A B L E 35–7. Treatment Options for Dystonia Therapy
Agent/Procedure
Uses
Drugs
Dopaminergic agents
DRD, sometimes primary and secondary dystonia Primary and secondary dystonia and DRD Childhood primary dystonia
Anticholinergics Baclofen (oral or intrathecal) Benzodiazepines Antidopaminergic agents Botulinum toxin
Type A and B
Destructive neurosurgery
Selective peripheral denervation Myectomy/myotomy Intradural rhizotomy/ nerve sectioning Pallidotomy, thalamotomy
Functional stereotactic neurosurgery
Deep brain stimulation
Primary and secondary dystonia, MDS Occasional primary/secondary dystonia Main treatment of focal and segmental dystonia Cervical dystonia Cervical dystonia/blepharospasm Cervical dystonia (rarely used) Primary and secondary generalized or hemidystonia Primary generalized and segmental dystonia
DRD, dopa-responsive dystonia; MDS, myoclonus-dystonia syndrome.
be titrated up gradually to minimize side effects, particularly of dry mouth, gastrointestinal upset, and confusion.
Baclofen Baclofen is a derivative of γ-amino butyric acid that reduces spinal cord interneuron and motor neuron excitability. A retrospective study showed it to have useful benefit, especially in childhood-onset primary dystonia, but only in a minority of adult cases. It appeared to be better tolerated by the younger patients, but significant side effects of lethargy, dizziness, and confusion have been reported. Intrathecal baclofen has also been used with benefit, particularly for secondary generalized dystonia and in patients with dystonia and spasticity. Intrathecal baclofen is administered through an implanted infusion pump connected to an intrathecal catheter, which is inserted at approximately the L2-L3 level and advanced to C7-T1.
Benzodiazepines Benzodiazepines have been frequently used, although there are no data from controlled trials. They appear to be effective, although use is limited by sedation, ataxia, and habituation. Diazepam and clonazepam are the benzodiazepines most frequently used.
Other Drugs Numerous other drugs have been used to treat various forms of dystonia. Paradoxically, some patients with dystonia appear to improve with use of antidopaminergic drugs, such as tetrabenazine and haloperidol. The concern with dopamineblocking drugs is the development of tardive dystonia and dyskinesia. Other drugs that have been used to treat dystonia in single cases include carbamazepine, propranolol, phenytoin, clonidine, tizanidine, lithium, and cannabidiol.
Botulinum Toxin Botulinum toxin injections are the first line of treatment for focal and segmental dystonias.5 Botulinum toxin consists of a number of serotypes of a potent neurotoxin that acts by inhibiting neurotransmitter release at the neuromuscular junction, which leads to temporary weakness of the muscle. Botulinum toxin types A and B are most commonly used in clinical practice. Its principal mode of action in dystonia is to cause denervation of motor end plates, although there is evidence that its effect on sensory symptoms may also be important, possibly by modulating muscle spindle input to the central nervous system. Local injection of botulinum toxin type A into overactive dystonic muscles can provide very effective relief of symptoms. Double-blind placebo-controlled trials have shown botulinum toxin type A to be efficacious in treating cervical dystonia and blepharospasm (60% to 70% patients showed improvement), and retrospective and open-label studies have also demonstrated its efficacy for laryngeal dystonia, writer’s cramp, and limb dystonias and for selected cases of oromandibular dystonia. Botulinum toxin has a temporary effect; patients require repeat injections at intervals, usually every 12 to 16 weeks. For uncomplicated cases of blepharospasm and cervical dystonia, muscles to receive injection are usually selected clinically. For more complex cases and other types of dystonia, EMG guidance is often required. The most common side effects are of unwanted weakness, which is related to the dose used and local spread of toxin. Thus, for cervical dystonia, transient dysphagia can occur, especially when the sternocleidomastoid muscles have received injections. Ptosis is a common complication of injections for blepharospasm. Another problem is the development of resistance to botulinum toxin as a result of the formation of neutralizing antibodies, which occurs in up to 10% of patients. The development of neutralizing antibodies is a serious problem because it essentially prevents further response to that type of toxin, although the patient may respond to a different serotype of botulinum toxin.
452
Section
VII
Motor System and Motor Diseases
Surgery Surgical treatment options for patients with medically refractory dystonia have gained increasing acceptance.
Peripheral Surgery Peripheral surgery for cervical dystonia and blepharospasm has been used for patients who do not respond to botulinum toxin injections and involves either destruction of nerves supplying the dystonic muscles, myotomy/myectomy, or sometimes a combination of procedures. One of the commonest procedures, selective peripheral denervation, involves sectioning of the peripheral branch of the spinal accessory nerve to the sternocleidomastoid muscle in combination with posterior ramisectomy from C1 to C6. Beneficial results have been reported in 70% to 90% of patients, although there is risk of recurrence, and in a retrospective long-term study at a mean of 5 years after surgery, there was a reduction in dystonia by 30% in about one third of patients. For blepharospasm the most frequently used operations are limited or full myectomies of the orbicularis muscles and sometimes corrugator superficialis.
Functional Stereotactic Surgery Current functional stereotactic options include lesion induction and deep-brain stimulation (DBS) of the globus pallidus internus and the thalamus. Because of the relatively small numbers of patient series, variations in surgical technique, and inconsistent use of outcome measures, no definite recommendations about ideal surgical targets or optimal methods can be made. In general, however, the globus pallidus internus appears to be the preferred target in primary dystonias. The pallidal target is located in the posteroventral lateral globus pallidus internus, which is the same site as that used in Parkinson’s disease. Pallidotomy has been reported to be effective in various forms of dystonia, including primary generalized and segmental dystonia and hemidystonia, with a number of studies reporting 50 to 80% improvement in symptoms. In general, patients with primary dystonia (especially DYT1) had a better response than did those with secondary dystonia.6 The focus of stereotactic surgery for dystonia is now on DBS because there is a lower risk in bilateral surgery than in lesion induction. Pallidal DBS is the most frequent stereotactic procedure for dystonia and involves implanting quadripolar electrodes within the globus pallidus internus and applying continuous stimulation. In contrast to DBS in Parkinson’s disease, it may take months before full benefit of pallidal DBS is seen with dystonia. However, the dystonia may recur within hours of switching off the implantable pulse generators. DBS has advantages over lesion-induction surgery in that it is reversible and adaptable, avoids the concerns over the effects of lesions in the developing brain in childhood, and has lower morbidity in bilateral surgery. However, problems with DBS include hardware and battery failure, high costs and timeconsuming follow-up, and perioperative risks of infection and possible hemorrhage. The most striking results for DBS are found for children with primary (notably DYT1) dystonia. One case series demonstrated a mean improvement in the Burke-Fahn-Marsden Dystonia Rating Scale motor score of 71% in 15 patients with DYT1
generalized dystonia 1 year after pallidal DBS. Other case series have demonstrated lesser or no effect, and it has become clear that case selection is critical; secondary cases usually show much less response. There is also some evidence for improvement in primary segmental and focal dystonias, particularly for medically refractory cervical dystonia.
Dystonic Crisis (Status Dystonicus) A rare but potentially fatal development is the dystonic storm or crisis. This usually occurs in patients with more severe generalized forms of dystonia, often secondary, in which they develop increasingly frequent and relentless episodes of devastating generalized dystonia that can lead to respiratory compromise that necessitates ventilation. It can be precipitated by infection or drugs changes or even failure of DBS (e.g., battery failure). Treatment is difficult but involves a combination of drugs, including benzodiazepines, anticholinergic drugs, and sometimes antidopaminergic drugs. Pallidotomy has been reported as a potential treatment option for this condition.
PAROXYSMAL DYSKINESIAS These are a rare group of conditions that manifest with abnormal involuntary movements that occur episodically and are of brief duration. The abnormal movements are mixed but include dystonia, chorea, and ballism. They can be acquired or genetic in origin, and between attacks, the patient is normal.
Paroxysmal Kinesigenic Dyskinesia (PKD) In this condition, the dyskinetic movements are precipitated by sudden movement. Onset is usually in childhood, the disease is more common in boys, and it is often familial, exhibiting autosomal dominant inheritance. Attacks frequently are of dystonia or chorea-dystonia induced by sudden change in position or running. Often they affect one side of the body, which can alternate, and are brief, lasting seconds or, on occasion, minutes. Numerous attacks can occur in a day. For idiopathic or genetic forms, the prognosis is good, and frequency of attacks decreases with age and often abates in adulthood. A genetic locus for PKD has been mapped to chromosome 16, which may be allelic with a locus found for families with infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome), although there is also evidence for genetic heterogeneity. PKD responds well to antiepileptic drugs, particularly carbamazepine in low doses. Reports also suggest benefit with gabapentin, lamotrigine, topiramate, and levetiracetam.
Paroxysmal Nonkinesigenic Dyskinesia (PKND) PKND is characterized by attacks of dyskinesia that are frequently precipitated by alcohol ingestion, caffeine ingestion, stress, or fatigue. The episodes are often dystonic or choreic and have longer duration (minutes to hours) and are less frequent (on to three per day) than those in PKD. There may be longer attack-free intervals, and, again, boys are more often affected than girls. It is often familial, showing autosomal dominant inheritance, with onset in childhood and attacks diminishing
chapter 35 dystonia in adulthood. A locus on chromosome 2q31-36 has been mapped in a number of families. Most patients with PKND do not benefit from antiepileptic drugs, but some response to clonazepam or clobazam has been reported. In general, it is more difficult to treat than PKD, and patient often learn to avoid precipitants.
453
Treatment can be difficult, but the use of botulinum toxin can be very successful for focal dystonias, and there is increasing evidence of the efficacy of DBS for medically refractory cases of dystonia. The underlying pathogenesis of dystonic movements is not fully understood but appears to involve basal ganglia defects that lead to abnormal sensory processing and reduced inhibition within the motor system at many levels.
Paroxysmal Exercise-Induced Dyskinesia In this condition, episodes of involuntary movements occur after exercise such as walking or swimming. These usually take the form of dystonia, which resolves 10 to 15 minutes after the patient ceases exercising. The dystonic movements take longer to begin and last longer than those in PKD. Cold exposure may also bring on an attack. Sporadic cases have been described, but it is frequently familial with autosomal dominant inheritance. As with PKND, the control in paroxysmal exercise-induced dyskinesia are often difficult to treat, although some response to antiepileptic drugs has been reported. If the dystonia is unilateral and severe, stereotactic surgery may be an option.
K E Y ●
The dystonias are a relatively common group of movement disorders, with primary focal dystonia being the most prevalent.
●
Diagnosis is clinical, and investigations are used to rule out secondary causes.
●
The underlying pathogenesis of the abnormal movements is thought to be abnormal sensory processing and deficient motor cortex inhibition.
●
Genetic factors are important to the development of primary dystonia.
●
Treatment is tailored to the individual type of dystonia, with the use of botulinum toxin injections for focal and segmental dystonia and of medication or surgery for more severe forms.
Paroxysmal Hypnogenic Dyskinesias Paroxysmal hypnogenic dyskinesia is a term used to describe brief episodes of involuntary dystonic or ballistic limb movements that waken the patient from sleep and can occur frequently during the night. The majority of these cases, particularly familial forms, have been found to be due to mesial frontal lobe seizures, now described as autosomal dominant nocturnal frontal lobe epilepsy. To date, mutations in two genes, the α4 subunit of neuronal acetylcholine receptor (CHRNA4) and the β subunit of the nicotinic acetylcholine receptor subunit genes, have been described in some families.
Secondary Paroxysmal Dyskinesias Secondary or symptomatic paroxysmal dyskinesias are notable for variability of age at onset, the presence of both kinesigenic and nonkinesigenic symptoms in some patients, the prevalence of sensory precipitants, and the reversal of symptoms if the underlying condition can be treated. The presence of other neurological symptoms and signs also points to a secondary cause. The association of PKD and PKND with multiple sclerosis is well described. Other causes include stroke, antiphospholipid syndrome, central and peripheral nervous system trauma, human immunodeficiency virus infection, hypoglycemia and hyperglycemia, hypoparathyroidism, pseudohypoparathyroidism, basal ganglia calcification, and kernicterus.
CONCLUSIONS The dystonias represent a relatively common group of movement disorders whose diagnosis is predominantly clinical. They have diverse causes with both primary (genetic) and secondary causes. The most common forms in clinical practice are the primary focal dystonias.
P O I N T S
Suggested Reading Albanese A: The clinical expression of primary dystonia. J Neurol 2003; 250:1145-1151. Comella CL, Pullman SL: Botulinum toxin in neurological disease. Muscle Nerve 2004; 29:628-644. Fahn S, Bressman S, Marsden CD: Classification of dystonia. Adv Neurol 1998; 78:1-10. Hallett M: Abnormal movements result from loss of inhibition. Adv Neurol 2004; 94:1-11. Vidailhet M, Vercueil L, Houeto JL, et al: Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005; 352:459-500.
References 1. Fahn S, Bressman S, Marsden CD: Classification of dystonia. Adv Neurol 1998; 78:1-10. 2. Muller J, Kiechl S, Wenning GK, et al: The prevalence of primary dystonia in the general community. Neurology 2002; 59:941943. 3. Albanese A: The clinical expression of primary dystonia. J Neurol 2003; 250:1145-1151. 4. Hallett M: Abnormal movements result from loss of inhibition. Adv Neurol 2004; 94:1-11. 5. Comella CL, Pullman SL: Botulinum toxin in neurological disease. Muscle Nerve 2004; 29:628-644. 6. Vidailhet M, Vercueil L, Houeto JL, et al: Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005; 352:459-500.
CHAPTER
36
GAIT DISTURBANCES ●
●
●
AND FALLS
●
Nir Giladi, Bastiaan R. Bloem, and Jeffrey M. Hausdorff
Gait, the action of walking from one place to another on two legs, is one of the most fundamental human motor tasks. Unlike all other mammals, it takes about 1 year for a human baby to start walking independently on two legs and 2 to 3 additional years until gait is fully coordinated and the response to external restrictions is well developed. Many congenital or perinatal psychomotor disturbances first manifest as a delayed initiation of walking, and this underscores how much normal gait depends on mature and intact central and peripheral nervous systems. Furthermore, gait also requires intact musculoskeletal and cardiovascular systems, from the very first year of life. For the next six or seven decades of their lives, humans generally walk independently and largely automatically, without any apparent need for paying special attention to this essential daily task. Remarkably, healthy adults fall only rarely, despite multiple and often unexpected challenges in the everyday environment, such as slippery floors or doorsteps. At around the seventh to ninth decade of life, walking again becomes an issue of concern that is often related to fear and anxiety about falls. Falls are the most serious and dangerous complications of gait disturbances. The fear from this terrifying experience alone can keep an elderly person at home in selfimposed house arrest. Furthermore, loss of independent locomotion and abnormal balance are two major causes for institutionalization. This chapter describes the basic requirements for locomotion and the ways of characterizing normal gait and classifying, assessing, and quantifying gait disturbances. We also highlight the close relationship of gait to abnormalities in balance and to falls. The last part of the chapter discusses interventional modalities for improving gait, reducing the incidence of falls, and preventing deterioration in mobility.
LOCOMOTION, EQUILIBRIUM, AND THE SUPPORT SYSTEMS Multiple support systems are required to rise up on both legs, maintain balance, initiate the first step, and maintain rhythmic and effective stepping while interacting with the environment and internal restrictions. The first essential ones are the musculoskeletal and cardiovascular systems that provide the ability to safely stand erect and move without collapsing because of weakness or hemodynamic deprivation. The visual, vestibular,
and proprioceptive senses play a major role as support systems that provide the central nervous system (CNS) with essential feedback about ongoing movements and environmental constraints. Similarly, the ability to learn, memorize, retrieve, plan, and execute walking as a sensorimotor integrated task is critical to gait and requires cognitive abilities. Locomotion starts with the first shift of the center of mass over the support foot and tilting of the pelvis in order to lift and swing the first leg. This first step—which is based on preplanning and execution of a complex motor task—is especially challenging because all the supporting and executive systems are activated. The next step is the beginning of synchronized, rhythmic, and largely automatic motor planning that leads to continuous stepping. Stepping is done while responding to internal (personal) factors, such as the purpose and goal of the walk, as well as the chosen motor plan for each specific walk, such as walking fast to catch a bus or marching in the army. In addition, one has to take into account the external (environmental) factors, such as the route, the surface, and the possible obstacles on the way, as well as the walker’s physical state. All these factors act together, and so the responses or modifications of the walking motor plan have to take place in a coordinated manner. Disharmony in the integration of the multiple systems involved in locomotion obviously has a devastating effect on gait and may also increase the likelihood of falls. Balance is the other major player in locomotion. The ability not only to stand erect on two feet but also to stand on one leg for about one third of the gait cycle is a precondition to locomotion. Again, the support systems are critical enablers of safe, forward movement. Afferent sense of limb and trunk position, vestibular and visual information, and judgment of fall risk during specific circumstances will influence the choice of a strategic plan at any given time. Both locomotion and postural responses must be fully integrated to plan and to instantly respond to any unexpected event in real time. The fact that healthy people fall so rarely while functioning in a constantly changing internal and external environment reflects the extraordinarily harmonic integration of all the systems involved in normal walking. Not surprisingly, any defect in this orchestration can lead to gait disturbances, insecurity, and falls. Clinical syndromes, however, depend on the corrective mechanisms that are called into action in response to a mismatch or defect in the normal physiology. An efficient corrective system can mask major pathology and maintain normal function.
455
456
Section
VII
Motor System and Motor Diseases
Central Locomotion Generators Locomotion is controlled by several centers at different levels of the CNS. There is strong evidence that the most basic rhythmic, bipedal, synchronized stepping of mammalian quadrupeds originates in centers in the spinal cord referred to as the central pattern generators. Indeed, decerebrate cats can produce a rhythmic stepping pattern if they are put on a treadmill. Although anatomical demonstration of the existence of such centers is lacking in humans, central pattern generator–like centers probably exist in humans as well. The human central pattern generator also controls the timed coupling between arm and leg movements during normal walking.1 In primates, including humans, the central pattern generator is probably located within the spinal cord, as is suggested by the production of gaitlike movements in paraplegic patients who, when placed with support on a moving treadmill, can also produce rhythmic stepping. Such spinal central pattern generators are under the influence of brainstem control mechanisms, which are most probably situated at the level of the mesencephalon in the brain. In humans, the caudal cholinergic mesencephalic nucleus, also referred to as the pedunculopontine nucleus (PPN), is considered as the human mesencephalic locomotion center. It is believed to control spinal pattern generators or to play a similar role as the spinal central pattern generator in animals and is considered the human mesencephalic locomotion center.2 The PPN receives afferent GABAergic projections (secreting the neurotransmitter gamma-amino-butyric acid [GABA]) from the internal globus pallidus, subthalamic nucleus, and the substantia nigra pars reticulata. It sends efferent cholinergic and glutamatergic projections (secreting the neurotransmitters acetylcholine and glutamic acid) to the substantia nigra pars compacta and downward to the brainstem and spinal cord. The PPN is the only nucleus associated with the basal ganglia that has a direct connection with the spinal cord and, as such, it is believed to play a major role in motor control of gait and posture. PPN stimulation can induce stepping in primates while a lesion at the PPN causes severe akinesia and parkinsonism in primates that is reversed by blocking GABAergic stimulation of the PPN. Furthermore, a focal stroke within the dorsal mesencephalon (presumably involving the PPN) has been shown to cause severe gait initiation problems in a human patient. Higher centers at the level of the basal ganglia, thalamus, and cortex are parts of the locomotion network that controls walking as a motor behavior, and they constantly interact with the internal and external environments. The frontal lobe and its premotor area are of special importance for planning, initiating, and continuous adjustment of the walking motor plan. The visual cortex produces information about the space where walking takes place, and this information is interpreted in other cortical areas in terms of visuospatial orientation, danger, and significance. The basal ganglia pass on information needed for the generation of a rhythmic gait pattern (i.e., internal cueing of gait) and play an especially critical role when there is a need for constant alertness and focused attention to the motor task or to a changing environment. Cortical and subcortical white matter and basal ganglionic lesions can lead to complete inability to initiate locomotion (akinesia), severe unsteady gait (disequilibrium), unorganized and dysfluent locomotion, and pathological interaction with the environment. Altogether, these types of lesions often lead to loss of mobility and a high risk for falls.
Walking is dependent heavily on the musculoskeletal system for its execution. Strong bones with flexible joints and elastic feet and spine are essential for effective gait. Similarly, strong muscles are responsible for maintaining the correct posture and moving the bones in harmonic fashion to create motion in space. The peripheral nervous system executes the motor plan of walking at the level of the spinal cord through the motor neurons and provides online information from the sensory receptors about the internal (e.g., sense of position) and the external environments. The centrally generated gait motor plan is tested by the degree of scaling and synchronized activation of multiple muscle groups at multiple levels of the spinal cord. Walking is not possible if muscle weakness or activation dyssynchronization exceeds a certain threshold. Similarly, an abnormal sensory input from the periphery leads to instability and frequent falls because balance is heavily dependent on data from the environment.
The Gait Cycle Walking can be regarded as a composite of numerous small and similar gait cycles, each based on an alternating single step accomplished by both legs. A full cycle can be calculated from any given point because of the rhythmic and stereotypic manner of locomotion. Classically, spatial description of the gait cycle starts when the right heel touches the ground while the right knee is stretched (locked) and the right foot is dorsiflexed. The foot rolls on the ground and carries most or all of the body mass as part of the stance phase. As the body mass moves forward, the heel leaves the ground. After a forced plantar flexion that pushes the body center of mass forward, the toes also leave the ground. When the toes of the right foot leave the ground, the swing phase of the right leg starts. In the swing phase, the right leg swings forward after the right hip is pulled up (flexed) while the knee initially will be flexed and later extended to reach the ground in a locked position. During the swing phase, the foot is dorsiflexed to avoid any contact of the toes with the ground. The cycle ends when the right heel again comes in contact with the ground (Fig. 36–1). The gait cycle can also be characterized temporally. The right foot normally touches the ground for about 60% to 65% of the gait cycle. Only one leg is in contact with the ground (single support time) during 30% to 40% of the cycle, and both legs touch the ground in the double support phase during one third of that time or 20% to 25% of the whole cycle. Based on this time frame, the swing phase of the right leg and the stance phase of the left leg (single support time of the left leg), which, by definition are equal in time, take place during 35% to 40% of the gait cycle. The proportion of each phase of the gait cycle is changed in relation to the speed of walking, as well as in relation to the individual’s physical state, security, and equilibrium. Accelerated walking is associated with shortening of all phases, but proportionally more of the double-limb support time shrinks. Aging, physical weakness, and disequilibrium lead to slower gait speed and increased double-limb support time. Three additional spatiotemporal features of locomotion are stride length, cadence, and step width. Stride length is the distance between the places where the right heel first touches the ground at the initiation of one gait cycle to the place where it touches the ground again at the beginning of the next gait cycle. Stride length is also the summation of the distances of two steps (left plus right). Cadence is the step rate or the
chapter 36 gait disturbances and falls
Right initial contact
Left terminal contact
Left initial contact
Right terminal contact
Right initial contact
Right stance
Right swing
Left swing
Left stance
Right double support
457
Left terminal contact
Left double support
Left step
Right step ■
Figure 36–1. The gait cycle.
number of steps in a given time (e.g., steps per minute), and step width describes the distance between the two feet along the perpendicular axis to the walking direction for a given step.
ASSESSMENT OF GAIT The quantitative assessment of gait and balance can be stratified into three levels: no tech, low tech, and high tech.3 Each has an appropriate time and place. The decision to use one or the other of these approaches partly depends on the purpose of the evaluation, the degree of sensitivity and specificity required, and trade-offs of cost, time, and convenience. Many volumes have been written on each of these approaches.4 Here, we briefly describe some of the more salient features of each of them and common approaches.
Clinical Assessment The “bedside examination” of gait and balance involves taking a careful history and a detailed physical examination.
History Taking Interviewing patients about their problems with gait or balance can be a challenge. When asking about gait problems, the clinician has to understand the amount of walking a person does in daily life. In addition, the nature of the questions themselves should try to help the patient describe his difficulties in terms of walking speed, amount of effort required, confidence or degree of fear from falling, and whether any assistance or walking aids are used. It is informative to look at the patient’s step length as a good general marker and to note if one can hear the soles dragging on the floor during each step as a practical marker for the height and duration of the swing phase. For patients presenting with gait disorders, try to distinguish between consistently present walking difficulties versus an episodic gait disorder, such as freezing of gait, festination, or sensory ataxia in the dark. When asking about possible freezing of gait, one must specifically inquire about the characteristic subjective feeling of the feet “being glued to the ground.”
A specific Freezing of Gait Questionnaire has been developed that may assist in screening for and rating the severity of freezing of gait.5 To make sure that the patient understands what is meant by freezing of gait, it may be useful to demonstrate an imitation of a typical freezing of gait episode. Falls are one of the most serious complications of gait disturbances and should receive special attention. Many elderly persons tend to forget their falls, particularly when there is concurrent cognitive impairment, as is often the case. Some persons may even purposely deny the occurrence of falls because they fear being admitted to a nursing home or another form of sheltered care. Many elderly persons find it extremely difficult to indicate under which circumstances their falls occur. Nevertheless, obtaining a careful fall history is important, because the presence of a prior fall in the preceding 6 to 12 months consistently emerges as an excellent, simple predictor for repeated falls in the future.6 Patients should be asked not only about falls but also about the presence of “near-falls.” These are at least as common and can be debilitating in their own right. In light of the characteristic amnesia for falls, eyewitness reports are often indispensable, and every effort must be made to retrieve the accounts of bystanders who witness falls. Table 36–1 can serve as a guideline for the interview. Several important elements of this clinical approach are discussed in more detail next. For any patient presenting with falls, the first thing to do is to clarify the circumstances surrounding the fall and, in particular, to identify any specific pattern, because this may reveal the underlying pathophysiology and offer opportunities for prevention. The second step involves a distinction between single versus recurrent (two or more) falls and between “internal” and “external” falls, features that are important for secondary prevention. One should therefore evaluate whether any environmental factors were obviously responsible for the falls. When the role of environmental factors is unclear or frankly denied, the fall can then be classified as “intrinsic” (usually defined as a fall that was caused by gait or balance disorders or misperception of the environment). The third step is to inquire whether any transient loss of consciousness preceded the fall. The absence of a preceding transient loss of consciousness indicates a probable involvement of an underlying gait disorder
458
Section
VII
Motor System and Motor Diseases
T A B L E 36–1. Elements of History Taking in Persons With Gait Disorders or Falls Continuous or episodic gait disorder? Walking worse in the dark? Relationship between walking and falls? Frequency of prior (near-) falls Specific fall pattern distinguishable? Apparent cause of the falls: None (“spontaneous”) Environment (e.g., slippery floor)* (Sudden) change of posture Performing several activities simultaneously Hazardous behavior Inappropriate footwear Symptoms preceding the fall: Loss of consciousness “Funny turn” (vertigo; presyncope) Palpitations/chest pain/breathlessness Sudden weakness of the legs Symptoms after the fall: Inability to stand up Loss of consciousness Physical injury Fear of falling Use of walking aids: Difficulties in use If none: why not? Medical history: Prior/current diseases (Psychoactive) medication and drug combinations Intoxications (alcohol) Protective factors: Exercise level Adaptation of behavior/activities
Physical Examination Table 36–2 lists several important elements of the physical examination. The examination should include a battery of functional tests to capture the full repertoire of gait and balance abnormalities. Ideally, physicians should examine the patients in the environment where they walk and function in daily life (i.e., home and surroundings), but this is not practical. A homemade video can sometimes be extremely informative, especially for episodic gait disturbances. Similarly, examining the patient immediately after a fall can help with the identification of its cause(s) and consequences, but this is rarely possible. A problem with the inevitably “interictal” examinations is that the observed abnormalities may not be causally related to the gait disturbance or the fall. Physical examinations can appear to be entirely normal in between freezing of gait or fall episodes.
General Physical Examination This should include measurements of height and weight, because a low body mass index increases the risk of major injury and indicates frailty. Examination of the musculoskeletal system should mainly include “functional” tests. Rating the strength of individual muscles is less informative than asking a patient to stand up from a chair (a measure of, among others, proximal leg strength). Measurements of blood pressure in both the recumbent and standing positions can detect orthostatic hypotension.
Gait *If needed, evaluate domestic situation by community nurse, physiotherapist, or occupational therapist.
and/or balance deficit. This will become evident during physical examinations between falling episodes. If the gait or balance disorder is severe enough, even small movements can be destabilizing and the patient may start to fall almost spontaneously. In patients with apparently unprovoked falls, care must be taken not to miss a possible preceding transient loss of consciousness. Explicit inquiry into the use of medication is vitally important, because this is one of the most common risk factors for gait disorders, falls, and hip fractures in elderly persons. In particular, benzodiazepines and antidepressants are associated with falls in the elderly, but other psychotropic medications (e.g., neuroleptics) and drugs causing orthostatic hypotension or arrhythmia also increase the risk of falls. Dopaminergic medication may paradoxically increase the fall frequency of patients with Parkinson’s disease by causing excessive dyskinesias, orthostatic hypotension, or confusion. The risk of falls increases dramatically if different drugs are used at the same time (Fig. 36–2). The psychological consequences of falls can be severe. Thus, it is important to assess whether a patient has a fear of falls and whether this fear is reasonable (in persons with extremely poor balance) or if it is inappropriate (a pathological fear induced by a single but otherwise innocent fall). “Self-confidence” (confidence in not falling) should also be evaluated as this provides valuable complementary information about the impact of falls on activities of daily living and independence. Some patients feel overly confident despite marked balance deficits, and they have a high risk of falling.
Most examination rooms are too small to assess gait properly. It is therefore helpful to monitor the patient while walking to and from the examination room or even follow him down the corridor. The reduced step height observed in mildly affected patients such as those with mild spasticity or parkinsonism may be better heard than seen. Inspecting their shoes may reveal excessive wear on the medial and anterior side of the sole on the side of a spastic leg. A reduced support phase on one leg suggests an antalgic gait (e.g., that of someone with a twisted ankle). Dystonic gait disorders can be task specific (e.g., evident during regular walking but disappearing during walking backward or running). Freezing of gait is particularly difficult to elicit in the physician’s examination room and is best examined as patients walk along a specifically developed trajectory, periodically passing through narrow paths and performing turns of 180 or 540 degrees. Abnormalities to be noted during turning movements include the “pivoting” strategy, where the trunk rotates stiffly (“en bloc”) with the legs, shuffling of the feet with multiple small steps or even overt freezing of gait. Providing patients with one or more secondary “distracting” tasks while walking can be informative because impaired multiple task performance may detect balance problems that might otherwise remain unnoticed. Furthermore, multiple task performance provides insight into actual falling risks because falls in daily life commonly occur when subjects attempt to do more than one thing at the same time. Cognitively impaired patients may try to perform all tasks equally well, but pay a price in terms of poor gait or balance. The simplest test is to start a routine conversation while walking beside the patient. An inability to walk and talk at the same time (usually manifested by a stop in the conversation) has a good predictive value for falls in cognitively
chapter 36 gait disturbances and falls
459
Falls Single
Obvious extrinsic cause
Recurrent
Insufficient extrinsic cause
Treating injuries suffices
Stereotypical pattern? → If multiple: analyze each pattern separately!
Review medical notes
Search for risk factors “Spontaneous” (*)
Identified risk factors Interaction? “Intrinsic” (patient-related)
“Extrinsic” (environmental) No preceding TLC
Preceding TLC
Preceding “funny turn”
No preceding “funny turn”
Presyncope? (**)
Gait or balance disorder?
Yes
No
Yes
• Syncope
• Vertigo
• Neurological • Orthopedic • Others
■
No
• Drop attacks • Cataplexy • Hyperexplexia
• Syncope • Epilepsy • Others
Figure 36–2. The clinical work-up of falls. An “obvious extrinsic cause” refers to an overwhelming external hazard, which would make almost every person fall (e.g., a pedestrian being knocked down by an automobile). Medical notes provide a wealth of easily accessible information about relevant risk factors (age, sex, medical history, and medication) that could serve to guide the selection of patients at risk for falls. TLC, transient loss of consciousness. *In patients with seemingly spontaneous falls, consider one of the following three possibilities: TLC that was apparently forgotten or misperceived by the patient; a mimic of TLC (drop attacks, cataplexy, or hyperexplexia); or a seemingly spontaneous fall that was in fact caused by a severe underlying gait or balance disorder. (Modified from Bloem BR, Boers I, Cramer M, et al: Falls in the elderly. I. Identification of risk factors. Wien Klin Wochenschr 2001; 113:352-362, with permission.)
impaired elderly persons, but probably not in patients without cognitive impairment. Other examples of secondary tasks include avoiding obstacles or carrying objects such as a tray while walking. Various different tasks can be combined to challenge balance and gait even further.
Balance This must be reviewed not only during slowly performed tasks, but also during more abrupt movements (e.g., turning around quickly on command), because they more closely resemble everyday fall circumstances. The Functional Reach test is a commonly used measure of dynamic balance control that evaluates the individual’s limits of postural stability in standing. With outstretched arms, subjects are instructed to reach forward as far as possible, while keeping their feet in place. This test may identify fallers in the general elderly population, but
not in a high-risk population such as patients with Parkinson’s disease. The retropulsion test (pull test) measures protective responses by delivering an external disturbance in motion— usually a sudden shoulder pull from behind and sometimes a push to the chest. Drawbacks include the difficulty in standardizing test execution and the lack of a generally accepted scoring system. Assessment of the patient’s tandem stance and/or single leg standing abilities may also be useful.
Timed Tests Some clinicians advocate the use of timed tests because they produce a quantifiable result. One example is the Timed Up and Go test (TUaG), which is a reliable measure of functional performance that captures transfers, gait, and turning movements.7 In this test, the subject is asked to rise from a chair, walk 3 m, turn around, return to the chair, and sit down. In its
460
Section
VII
Motor System and Motor Diseases
T A B L E 36–2. Elements of Physical Examination in Patients With Gait Disorders or Falls General Body mass index Cardiovascular examination Joints (ankles, knees, hips) Orthostatic hypotension Depression Neurological examination, including: Cognition Vision (with/without correction) Strength of the legs Proprioception of the legs Vestibular tests Walking* Gait ignition Gait speed† Arm swing Festination Step height and length Stance width Instability while turning‡ Freezing§ Circumstances (e.g., turning or narrow passages) Effect of cues Dual tasking “Stops walking when talking” Avoiding obstacles Carrying object in hands Combinations of the above Posture¶¶ Seated and standing Frontal and lateral views Balance Transfers Righting reactions (rising from chair or bed) Sitting or lying down Supporting reactions (quiet stance, eyes open/closed) Anticipatory reactions (lifting object from floor; arm raising) Reactive/protective postural responses (retropulsion test)¶ Tandem gait Romberg test Climbing stairs Quantifiable Tests Functional reach test Timed Up and Go test Walking distance (e.g., in 6 minutes)** Standardized Rating Scales Generic Tinetti Mobility Index Berg Balance Scale Disease specific†† *Use sufficient space! †Speed of performance less important than safety. ‡Instruct to execute slowly and abruptly; note occurrence of freezing. §Often difficult to assess during routine clinical examination; preferentially use standardized trajectory (from Schaafsma JD, Balash Y, Gurevich T, et al: Characterization of freezing of gait subtypes and the response of each to levodopa in Parkinson’s disease. Eur J Neurol 2003; 10:391-398.) ¶Elements to be noted include the trunk (stooped; marked lateroflexion, or Pisa syndrome) and neck (retrocollis, anterocollis, or laterocollis). ¶¶Difficult to standardize and score. **As a measure of cardiopulmonary condition. ††Specific rating scales are available for some disorders, but there is a general lack of validated measures for posture, balance, and gait. Modified from Bloem and Bhatia 2004, with permission.
original form, this was a subjective test in which the performance of this task was assessed qualitatively. It has since become timed, however, to lessen its subjective nature. The TUaG test predicts falls and may be used to screen for fall risk. Part of the reason that the TUaG test is used so widely is that it evaluates different important mobility functions (e.g., transfers, gait, and turning), it takes only a very short time to complete, and it requires minimal expertise or training. Subjects who perform the TUaG test in more than 13.5 seconds are believed to have an increased risk of falls.8 The TUaG test could be classified as a low-tech measure of gait. Another measurement is stance duration on one leg, which may predict falls. Judging the safety of gait and balance maneuvers, however, may be more important than measuring timing: indeed, emphasizing the aspect of timing deleteriously influences the quality of the movements.
Rating Scales Standardized rating scales are comprised of combinations of different tests and this helps to systematically rate most aspects of gait and balance. A widely used example is the standardized version of Tinetti’s test9 (also known as the Performance Oriented Mobility Assessment [POMA]). It includes an evaluation of balance under challenging conditions (e.g., while rising from a chair, after a nudge to the sternum, standing with eyes closed, and while turning) and an evaluation of gait characteristics (including gait initiation, step height, length, continuity and symmetry, trunk sway, and path deviation). Scoring is based on clinical judgement and takes only about 15 minutes. Poor performance on this scale is associated with an increased risk of falls in the elderly population. One disadvantage is that very unstable patients cannot (or refuse to) perform all the elements of these rating scales. Another disadvantage is that the rating scales lack validity in general and have never been validated for specific disorders of balance or gait.
Quantitative Assessment of Gait Gait mats provide another increasingly popular method for quantifying gait. Subjects walk across an instrumented carpet or walkway that is sensitive to the pressure changes caused by walking. A major advantage of this type of system is that the subject is not required to wear any special shoes, markers, or inserts. The instrumented walkway quantifies stride length, stride width, stride time, and the timing of the gait cycle, typically as averaged over 5 to 10 strides (depending on the size of the walkway). A number of studies have demonstrated the validity, reliability, and clinical usefulness of these types of systems in various clinical populations. Ambulatory monitoring systems enable the quantitative measurement of the timing of gait. The subject might be equipped with accelerometers, foot switches, or other wearable sensors. A key advantage of such systems is that they are not tethered to any computer or stationary system and therefore allow the measurement of multiple strides in almost any environment. This, in turn, enables evaluation of gait rhythmicity and the stride-to-stride fluctuations of gait timing (Fig. 36–3). Several studies have shown that such measures of gait variability or dynamics are sensitive to subtle changes that occur with aging and neurodegenerative diseases, such as Parkinson’s
chapter 36 gait disturbances and falls ■
RECORD DKTESTO Signal O 0:00 Signal I
Signal O 1:00 Signal I
Signal O 1:00 Signal I
Signal O 2:00 Signal I
Signal O 2:00 Signal I
Signal O 3:00 Signal I
Signal O 3:00 Signal I
Signal O 4:00 Signal I
Signal O 4:00 Signal I
Signal O 5:00 Signal I
Signal O 5:00 Signal I
Signal O 6:00 Signal I
Signal O 6:00 Signal I
Signal O 7:00 Signal I
Signal O 7:00 Signal I
Signal O 8:00 Signal I
Figure 36–3. Continuous recording of the vertical ground reaction force by an ambulatory gait analysis system. Such a long-term (several minutes) recording is the basis for assessment of gait dynamics and stride-to-stride variation (fluctuation). Signals 0 and 1 represent data from left and right feet.
Parkinson’s disease (PD)
1400 1200 1000
Huntington’s disease (HD)
1400 1200 Stride time (msec)
disease, Huntington’s disease, and Alzheimer’s disease10-13 (see, for example, Fig. 36–4). Stride-to-stride fluctuations reflect the consistency or steadiness of gait and the ability of the locomotor system to regulate gait from one stride to the next. Thus, it is easy to understand how such measures have clinical efficacy in the identification and prospective prediction of elderly fallers14 (see, for example, Fig. 36–5). Gait laboratories offer the most comprehensive means of quantifying gait. Typically, a modern gait laboratory includes a camera or marker-based system to measure the movement of various body segments (termed “kinematics”), force-platforms to measure the ground reaction forces, (i.e., the forces exerted by the foot on the ground [termed “kinetics”]), and electromyographic equipment to measure muscle activity. Such systems provide a highly detailed assessment of walking, including the position, velocity, and acceleration of different joint segments and angles and muscle forces and timing. This combination can provide insightful information into changes in gait mechanics. Studies of children with cerebral palsy, especially when they are candidates for surgery, probably represent the most popular applications of a full-scale gait laboratory. For many clinical purposes, however, some of the simpler approaches described earlier may be sufficient.
461
1000
Amyotrophic lateral sclerosis (ALS)
1400 1200 1000
Healthy control (CO)
1400 1200 1000
Gait Disturbances
0
2
3
4
5
Time (min)
Etiology and Pathophysiology Gait disturbances can be the result of a lesion or functional derangement at any level, from the toes to all areas of the cortex. In many instances, it is easy and straightforward to identify the etiology of a gait disturbance just by observing the patient walking and by performing physical and neurological
1
■
Figure 36–4. Example of time series of patients with three neurodegenerative diseases and a healthy control subject. The stride-to-stride fluctuations of the stride time are much larger in the patients; this reflects an irregular and unsteady gait. (Adapted from www.physionet.org. For more information, see Hausdorff et al.10,13)
462
Section
VII
Motor System and Motor Diseases
84-year-old Non-faller
T A B L E 36–3. System-Oriented Classification of Gait Syndromes
1.5
Peripherally Originating Gait Syndromes Musculoskeletal Joints, bones, ligaments, tendons, muscles, peripheral nerves Sensory Proprioceptive, vestibular, visual
Stride time (sec)
1.4
1.3
1.2
1.1 1.0 0
1
2
3
4
5
6
Time (min) 78-year-old Faller 1.5
Stride time (sec)
1.4
1.3 *The etiology of many gait syndromes is not always readily attributable to a single cause. For example, fear of falling may be due to changes in frontal and/or extrapyramidal function.
1.2
1.1 1.0 0
1
2
3
4
5
6
Time (min) ■
Centrally Originating Gait Syndromes Spinal Spastic paraparesis Sensory ataxia Pyramidal Spastic Paretic Cerebellar Ataxic Extrapyramidal Bradykinetic/hypokinetic Rigid Dyskinetic Episodic High Level Disequilibrium “Apratic” Unclassified Cautious/fear of falling*
Figure 36–5. Stride-to-stride fluctuations in the stride time, were much larger in this subject who subsequently experienced a fall during the 12-month follow-up period than in the non-faller. Group results were similar. Measures of the stride-to-stride variability prospectively predicted falls; older adults with increased variability were more likely to fall during the 12-month follow-up period compared with those with a lower variability. (See Hausdorff et al.14 for further details.)
examinations. The origin of gait disturbances in a person with orthopedic problems as seen in feet, joint, or spinal diseases can be easily diagnosed similar to the way that visual, vestibular, cardiovascular, respiratory, or muscular disturbances can often be readily identified. The effect of those and other peripheral neuropathies on gait is secondary. As a result, any therapeutic intervention should be focused on the primary etiology. Due to the critical role of gait in normal daily function, however, a compensatory approach frequently has to be taken, even before solving the primary problem, simply in order to promote mobility and independence. Due to the complex nature of the central gait network, different lesions at multiple levels of the CNS can cause gait disturbances. In some instances, such as stroke and hemiparesis or cerebellar disease and ataxia, the association between focal brain dysfunction and a distinct gait disturbance is clear-cut and easily diagnosed. When it comes to disturbances in the extrapyramidal-limbic-prefrontal locomotion network, the clinical-pathological relationships may be less clear. The gait
disturbance also becomes more difficult to describe, even from a phenomenological perspective. The pathophysiology of those disturbances, which were first described by Nutt and colleagues as “high level gait disturbances,”15 is not completely defined. Nonetheless, there is justification for associating those gait disturbances with the frontal lobe in general and, more specifically, with the prefrontal-limbic-anterior basal ganglia network. (See Table 36–3 for gait classification.) Frequently, the patient complains about a gait disturbance or fear of falling but the formal examination may not detect any specific cause. As a result, frontal gait disturbances are often mistakenly associated with the normal aging process or with parkinsonism just because the patient walks slowly and with a stooped posture. In addition, the frontal gait disorders may look bizarre and be suggestive of “apraxia” of gait. A major symptomatic aspect of the frontal gait disorders is a feeling of insecurity and of disequilibrium associated with anxiety, fear, and depression that might not be associated with a history of falls or proportional to the degree of imbalance or postural disturbances.16 This group of gait disturbances poses a real challenge from the diagnostic and therapeutic points of view. General atrophy with enlarged lateral ventricles may be seen on brain imaging. Many such patients undergo surgery in which a ventriculoperitoneal shunt is inserted, occasionally with partial and transient improvement. Based on clinical and neuroimaging techniques, it is very difficult to differentiate between normal pressure hydrocephalus and frontal gait disorders: only those cases with a very long-term and clear-cut response to ventriculoperitoneal shunting can be diagnosed—retrospectively—as having typical normal pressure hydrocephalus. From the functional point of view, one of the most important features of gait disturbances is that it has a characteristic time course. Abnormal gait that develops slowly over a period
chapter 36 gait disturbances and falls T A B L E 36–4. Examples of Episodic Gait Disturbances Freezing of gait Start/turning hesitation Tight quarters hesitation Hesitation while reaching destination Hesitation during mental overload or stressful situations Festinating gait Paroxysmal disequilibrium—vestibular Psychogenic gait (Pre-)syncope Drop attacks Sensory ataxia It is helpful to distinguish between those gait disturbances that occur continuously, whenever walking occurs (e.g., bradykinetic gait) and those that are transient and episodic in nature. Examples of the latter are listed in this table.
of weeks or months can be incorporated into the daily routine with a relatively low risk of falls. For example, a person who develops continuous locomotion disturbances, such as slow gait, unsecured gait, hemiparetic gait, or even spastic gait, can use a walking aid, compensate for the difficulty by slowing the walking speed, and, very often, broaden the walking base. In contrast, the episodic gait disturbances (Table 36–4) are characterized by their unexpected and transient appearance. As a result, episodic gait disturbances often lead to falls or fear of falling and are associated with self-imposed restrictions of daily activities. As mentioned earlier, freezing of gait refers to the phenomenon where patients experience brief and sudden moments where the feet subjectively become “glued to the floor.” Freezing of gait most commonly appears when patients make turns (thereby explaining why patients with Parkinson’s disease frequently fall while turning), but it may also occur spontaneously during straight walking, while crossing narrow spaces, when trying to initiate gait (“start hesitation”), or when reaching a target. Freezing of gait is a particularly common source of falls, because the legs fail to follow through with the forward motion of the trunk. An objective demonstration of freezing of gait episode is demonstrated in Figure 36–5 using the ambulatory gait assessment technique. It may be difficult to distinguish freezing of gait from festination, another episodic gait disorder that commonly leads to falls. Festination is characterized by a sudden change in locomotion rhythm because of an inability to maintain the base of support (the feet) beneath the forward moving trunk during gait, forcing the patient to rapidly take increasingly small steps (hastening) to avoid a fall. Festination leads to propulsion when patients walk forward or to retropulsion when patients lose their balance and take corrective steps backward. Festination or freezing of gait can also be embarrassing due to their unusual and bizarre nature, leading to the avoidance of situations in which they might occur. For example, patients may try to avoid crowds, walking in the street, crossing through doorways, or entering elevators. These episodic gait disturbances may be especially responsive to external cues like rhythmic auditory stimulation, lines on the floor, or changing the normal gait pattern to marching or walking sideway.17
Classification There are many ways to classify gait disturbances. It is, however, important to have a common understanding of terms when
463
describing changes in walking patterns, to facilitate communication between clinicians and investigators. Classification of gait should give phenomenological information to form a faithful picture of the nature of the individual’s gait, as well as temporal data about its course and linkage to possible etiologies. Table 36–5 was developed to provide a practical stepwise classification of gait disturbances. The classification moves from phenomenology to examination to etiological options. Gait disturbances are divided into six general categories that are based on observation of a patient walking and should help describe gait at a given moment. It is important to note that a patient might have one or more types of general gait disturbances. For example, a parkinsonian patient can have bradykinetic, dyskinetic, and episodic (freezing) gait disturbances, with each type probably reflecting a different pathophysiology; each type should therefore be discussed (and treated) separately. The second column of Table 36–5 presents a more detailed but again observational characterization of gait. The observational description is followed by the physical and neurological examination. Based on the results of detailed and focused observation and examination (with or without the help of more advanced methods, such as motion analysis imaging, etc.), one can move to etiological categorization. The last column of Table 36–5 provides examples of the different types of gait disturbances in the different categories. The main reason for classifying a patient’s gait is the need to understand the pathophysiology behind the gait disturbance to plan appropriate therapeutic strategies.
GAIT AND MENTAL FUNCTION Traditionally, the first lessons of controlling gait comprise a hierarchical system with control taking place on many levels in the CNS. For example, central pattern generators (putatively) exist at multiple levels of the spinal cord, and their output is regulated at several levels, including feedback by the brainstem that contains the mesencephalic locomotor region and the premotor and dorsolateral-prefrontal cortex. The basal ganglia may also be included in this picture as a regulator of motor control, but gait is typically viewed first and foremost as an automatic process with little or no input from higher-level cognitive function. The result is that we tend to blame deficits in muscle function, balance, and motor control when we think about gait disturbances and falls. Although these factors are, indeed, essential for successful and safe walking, it is also important to keep in mind that cognitive functions may play a strong role. In other words, gait is much more than automated muscles and reflexes. Epidemiological evidence indicates that among older adults, fall risk increases in those with impaired cognitive function.8 This highlights the importance of cognitive function in gait and walking steadiness. In addition, the stability of gait and balance declines in certain populations when subjects are asked to walk and perform a second task (dual tasking).18 If gait were really automatic, one would anticipate that the performance of an additional task would have no influence on gait. An exacerbated dual-task decrement in walking ability has, however, been observed in idiopathic elderly fallers, in patients with Parkinson’s disease (primarily a motor disorder) (Fig. 36–6), and in patients with Alzheimer’s disease (primarily a cognitive disorder).19-23 Moreover, patients with dementia have an
464
Section
VII
Motor System and Motor Diseases
T A B L E 36–5. Gait Disorders Classified by Phenomenology and Examination, 2005 General Category
Gait Characteristics
On Examination
Etiology Categories
Examples
I
Paretic/Hypotonic Gait (Weakness of one or two legs or the pelvis girdle)
Symmetrical/asymmetrical Dropped foot with or without high pull-up of the knee while swinging Dragging one or two feet on the ground Exaggerated pelvic tilt or swing (waddling gait) Hyperextension or locking of the knee Short strides Weak “push off” (from the ground)
True leg(s) weakness, proximal or distal Reduced or absent tendon reflexes Decreased or normal muscle tone
1. Neurogenic a. Peripheral nervous system b. Central nervous system 2. Myopathic 3. Neuromuscular junction 4. Mixed
Lower motor neuron lesion Acute upper motor neuron lesion Motor neuropathy Radicular lesion Myopathy Myasthenic syndromes
II
Stiff Gait (Increased muscle tone in legs or trunk)
Symmetrical or asymmetrical Hyperadduction of thighs with or without scissoring
Increased tone: rigidity, dystonia, spasticity
Upper motor neuron lesion Parkinsonism Fear of falling
Circumduction while swinging Plantar flexion on swinging Decreased knee flexion Stiffed spine Dragging feet on the ground Low swing of legs
Inability to fully relax the muscles Decreased joint range of motion Flexors and feet extensors Joint disease
1. Neurogenic a. Upper motor neuron disturbance b. Extrapyramidal disorder c. Frontal paratonia 2. Nonneurogenic a. Musculoskeletal b. Secondary to pain c. (Lump this with musculoskeletal) 3. Psychogenic (see above)
Symmetrical/asymmetrical Slow speed Short or normal stride
Parkinsonism Turning “en bloc” Compensatory
Parkinson’s disease Parkinson plus syndromes Secondary parkinsonism
Dragging feet on the ground Pain while walking
Exercise intolerance Fatigue
Poor physical state (in particular cardiopulmonary function!)
Lack of internal drive to walk
1. Neurogenic a. Parkinsonism b. Mental lack of drive c. Visual insecurity d. Balance difficulties 2. Non-neurogenic a. Exercise intolerance b. Peripheral vascular disease c. Pain syndromes associated with walking d. Psychogenic 3. Mixed
III Bradykinetic/ Hypokinetic Gait (Mainly slow)
Musculoskeletal pain
II
Stiff Gait (Increased muscle tone in legs or trunk)
III Bradykinetic/ Hypokinetic Gait (Mainly slow)
Disequilibrium Dystonia Pain while walking Joint disease (e.g., arthritis) Stiff muscles
Poor cardiovascular/respiratory condition General weakness Depression Cognitive changes
Decreased arm swing Lack of motivation Increased cadence with shorter strides Slow initiation or response
Poor leg blood supply Visual disturbances Physiological Disequilibrium
Symmetrical/asymmetrical Hyperadduction of thighs with or without scissoring Circumduction while swinging Plantar flexion on swinging Decreased knee flexion Stiff spine Springy steps Dragging feet on the ground Feet are plantar flexed while swinging Low swing of legs
Increased tone: rigidity, dystonia, spasticity Inability to fully relax the muscles Decreased joint range of motion Weakness of hip flexors and feet extensors Joint disease
1. Neurogenic a. Upper motor neuron disturbance b. Extrapyramidal disorder c. Frontal paratonia 2. Non-neurogenic a. Skeletal b. Secondary to pain c. Fibromuscular 3. Psychogenic
Upper motor neuron lesion Parkinsonism Fear of falling Disequilibrium Dystonia Arthropathy Pain while walking Arteritis. joint disease Stiff muscles
Slow speed Short or normal stride Dragging feet on the ground Pain while walking Poor physical state Decreased arm swing Lack of motivation Increased cadence with shorter strides Slow initiation or response
Parkinsonism Compensatory Exercise intolerance Fatigue Lack of internal drive to walk Musculoskeletal pain Poor leg blood supply Visual disturbances Physiological Disequilibrium
1. Neurogenic a. Parkinsonism b. Mental lack of drive c. Visual insecurity d. Balance difficulties 2. Non-neurogenic a. Exercise intolerance b. Peripheral vascular disease c. Pain syndromes associated with walking d. Psychogenic
Parkinson’s disease Parkinson plus syndromes Secondary parkinsonism Poor cardiovascular/ respiratory condition
Intermittent claudications Pain related to walking Blindness Normal aging Insecurity/disequilibrium
General weakness Depression Cognitive changes Intermittent caudications Pain related to walking Blindness Normal aging
chapter 36 gait disturbances and falls
465
T A B L E 36–5 Gait Disorders Classified by Phenomenology and Examination, 2005—cont’d General Category
Gait Characteristics
On Examination
IV
Ataxic Gait (Unsteadiness)
Wide base Short stride, slow speed Dragging feet on the ground Hesitancy, looking for support Increased double support Constant deviation to one side (particularly with eyes closed) Aggravation of unsteadiness with eye closure (in case of sensory ataxia or vestibular problems) Often a tendency to lock the knees
1. Objective balance 1. Peripheral problem a. Peripheral sensory Abnormal sense of neuropathy position b. Musculoskeletal Abnormal disturbances cerebellar function c. Vestibular Disturbed postural disturbance responses d. Visual disturbances Severe visual 2. Central disturbances Cerebellar Vestibular Vestibular disturbances Frontalsubcortical Fear of falling Psychogenic 2. Only subjective 3. Mixed balance problems
V
Dyskinetic Gait (Extra movements that affect gait)
Extra movement of legs, trunk, or head while walking Can be task specific Dystonic gait Choreic gait Dysrhythmic locomotion
Continuous dyskinesia Only during 1. Involuntary walking a. Extrapyramidal Legs or general syndrome dystonia b. Psychogenic Chorea Compensatory movements to improve security or confidence or to decrease pain
Episodic Gait Disturbances (freezing, festination, intermittent disequilibrium)
Normal locomotion between episodes Abnormal locomotion between episodes “FREEZING” Feet get “glued” to the ground with transient akinesia or legs shaking in place or forward motion with very small and fast steps: Start hesitation, turning hesitation, hesitation at tight quarters, stressful situations or in open runway FESTINATION Uncontrolled tendency to increase walking speed with small steps and a tendency to fall forward Episodic disequilibrium Episodic weakness
Parkinsonism Orthostatic hypotension Vestibulopathy Psychogenic syndrome
VI
impaired gait and an extremely high, not fully explained, risk of falls,24 despite only minimal involvement of their disease in the classic motor control systems. Walking and the maintenance of upright balance during gait clearly require more than “auto-pilot” control. Instead, walking and the proper integration of the many steps that are involved in walking should be viewed as a complex motor task that needs higher-level cognitive input. With this in mind, one can better appreciate the groundbreaking study by Lundin-Olson and associates.25 They investigated “stops walking when talking” in a mixed group of community-dwelling older adults, some of whom had dementia or depression or were poststroke or a combination. About 80% of the subjects who were unable to walk and talk fell at least once during a 6-month follow-up period, whereas about 80% of the subjects who were able to walk and talk did not fall. In other words, subjects who were unable to coordinate walking
Etiology Categories
Examples
3. Mixed
Insecurity/disequilibrium
1. With parkinsonism 2. No other significant neurological abnormality 3. Frontal gait disorders 4. Psychogenic
Peripheral sensory neuropathy Stiff and distorted feet Spinocerebellar ataxia Parkinsonism Hydrocephalus Multiple cerebral lesions mainly in white matter Basal ganglia, thalamus, (lacunar state, demyelination, etc.) Blindness Vestibulopathy Previous falls Anxiety Huntington’s disease Primary or secondary dystonia/chorea Tourette’s syndrome Pain syndromes Weakness Drug induced
Parkinsonism primary/ secondary Normal pressure hydrocephalus Primary freezing of gait Vestibular disorder Frontal gait disorders Dysautonomia
and talking such that they had to completely stop one task in order to perform the second task were at increased risk of falls, a further demonstration of the reliance of safe walking and falls on cognitive function. This idea that higher-level cognitive function is critical to walking also partially accounts for the intriguing results of prospective studies that reported impaired mobility that was not attributable to a specific disease predicts future dementia as much as 6 years into the future.26,27 If walking is a complex task that requires harmonic function of multiple brain networks, one can understand why even minor changes in locomotion reflect brain dysfunction, which may predict the future development of dementia. Furthermore, this concept suggests the possibility that interventions designed to improve cognitive function28 might enhance gait and reduce the fall risk of certain patient populations. To ensure that gait disturbances are truly minimized and that walking and safety are optimized, it is
466
Section
VII
Motor System and Motor Diseases
Healthy control—normal walking
Healthy control—Cognitively challenged
40
40
35
35
30
30
25 20
25 0
10
20
30
40
50
20
0
Parkinson’s patient—Normal walking
40
10
20
30
40
50
Parkinson’s patient—Cognitively challanged 40
35
35
30
30
25
25 20
20 0 ■
10
20
30
40
50
0
10
20
30
40
50
Figure 36–6. Effects of “dual tasking,” performance of a cognitively challenging task, on stride variability in a subject with Parkinson’s disease. Note the large stride-to-stride fluctuation and instability during dual tasking. (Adapted from Yogev G, Giladi N, Peretz C, et al: Dual tasking, gait rhythmicity, and Parkinson’s disease: which aspects of gait are attention demanding? Eur J Neurosci 2005; 22:1248-1256.)
essential to keep in mind that there is much more to gait than automated musculoskeletal movements.
Therapeutic Interventions Gait disturbances can be treated by physical therapy, exercise, and medical or surgical approaches. Many gait disorders can lead to a significant decrease in mobility in daily activities. As a result, muscle weakness stemming from the atrophy of disused muscles can further exacerbate the functional disturbance and decrease daily mobilization. The first step in any intervention designed to improve gait is to get the patients back on their feet and start walking again. This can be achieved by instructions for an individual exercise routine or by a physical therapy program. One important aspect of the intervention program should be the assessment for a need of a walking aid. A walking stick, a walker or, if nothing can keep a patient on his/her feet, a wheelchair should always be considered and used according to clinical judgment. The ultimate goal is always to give a patient the tools to mobilize himself or herself independently, but maintenance of mobilization by a wheelchair is frequently the only or preferred solution.
Rehabilitation Strategies Physical Therapy and Exercise Exercises, strength training, and gait or balance rehabilitation can help to improve the subject’s fitness and reduce the number of falls (Table 36–6). There is good evidence to suggest that a home exercise program can prevent injuries in older people.29 Because leg weakness is associated with falls in the elderly, fall prevention programs often include strength training. Balance training using Tai Chi Quan techniques may also help to reduce fall risk in this population. Gait or balance training will not cure
the underlying neurological deficits, but patients can be taught to cope better with existing mobility problems. For example, patients can learn to make safer transfers by using alternative motor strategies. Physiotherapists could also play a role in restoring balance confidence and reduce the fear of falls. Furthermore, physiotherapists can train patients to avoid hazardous activities, such as sudden changes of posture or the performance of simultaneous tasks. By training and promoting regular exercise, physical therapy can lead to improvement of general fitness and reduce cardiovascular comorbidity and mortality.30 Regular exercises also help to arrest the development or progression of osteoporosis and increase bone mass, density, and strength. When exercise, such as daily walking, is combined with oral bisphosphonates, the risk of bone fracture as the result of a fall can be decreased. Although the effects of exercise on bone strength are most prominent when initiated at a young age, beneficial effects can also be seen in elderly persons.
CUEING One of the most powerful modes of intervention to improve gait initiation and walking is the cueing technique. Despite even severe locomotion disturbances, patients (classically those with Parkinson’s disease) can walk almost normally by adopting special behavioral techniques, by being exposed to special sensory stimulations, or by using learned cognitive tricks.17 The challenge lies in enabling patients to access this ability at will and to apply it in their normal, daily function. Different cueing techniques have been used, and the population that most dramatically benefits from them are patients with Parkinson’s disease. All cueing techniques, in essence, intervene with the automatic walking brain network through behavioral sensory or cognitive techniques. The rationale behind these powerful behavioral modification techniques is that the normal locomotion network is dysfunctional and the
chapter 36 gait disturbances and falls T A B L E 36–6. Gait and Balance Rehabilitation A. Physiotherapy Exercise therapy (e.g., daily walks; home trainer) Improve cardiopulmonary fitness Prevention/arrest of: Osteoporosis Constipation Venous thrombosis Airway infections (pneumonia!) Pressure sores Contractures Improve sleep quality Increase self-respect Better feeling of control Interaction with others Split complex movements into simple components (“chaining”) Practice everyday routines Climbing stairs Transfer training Rising from chair, sitting down Getting out of bed, lying down Gait training Increase step height Practice safe turns Maneuvers to rise from floor after a fall Strength training (particularly legs) Anti-orthostatic maneuvers B. Home Visits Remove domestic hazards Training in own environment C. Treatment of Secondary Complications Reduce fear of falls Fall training* Prevention of injuries Hip or wrist protectors Protective helmets Shock-absorbing floors Restriction of unsupervised activities D. Assistive Devices Choose optimal walking aid Train proper use Replace unsafe footwear Heightened heels (to reduce backward falls) Optimize vision *For example, learning to direct the fall toward bed or chair.
cues “force” the brain to use other alternative locomotion programs by partly bypassing the primary network. Two common examples of behavioral cues are marching and climbing stairs. Lifting the knees and thinking about each step can enable a patient to walk almost normally when a regular walking pattern is impossible due to severe freezing of gait. Although stairs may pose a challenge to many older adults, patients (mainly those with Parkinson’s disease) who struggle to put together continuous steps on level ground can easily manage stair climbing. This is because the stairs act as an external cue. Another powerful external cue is rhythmic auditory stimulation, which intervenes with a deficient internal gait rhythm system. Rhythmic auditory stimulation has been shown to be very effective, not only for improving general walking but also for enhancing internal gait rhythmicity and stride-to-stride fluctuations (gait dynamics).17 When walking with rhythmic auditory stimulation, patients with Parkinson’s disease are able to match their cadence to a beat set at 10% faster than their baseline values,
467
thereby significantly improving their velocity, cadence, and stride length.31-33 These improvements remained evident in the immediate short term even after the cues were removed. The fact that the improvements persisted suggests that rhythmic auditory stimulation may also provide some sort of rhythmic training mechanism. Walking on a treadmill can also be considered an external pacemaker for providing an external cue and enhancing gait.34 Another commonly used and very effective group of external cues is that of working through the visual system to set the proper stride length, thus providing external information to help augment the defective scaling motor set, which is commonly downregulated in extrapyramidal disorders.35 Placement of floor markers is one technique that can be very effective in regulating stride length and demonstrating to the patient the potential value of cues. Floor markers were reported to be effective for improving gaits of patients with Parkinson’s disease as early as 1967.36 Some studies found that these patients retained a positive “carryover” effect even after the visual cues were removed.37,38 This suggests that a certain degree of training had taken place, even with only a short exposure to the visual cues. Visual cues have also been found to be helpful in alleviating freezing of gait episodes. The cognitive tricks are all attentional cues that have been used to focus attention on walking and thus remove it from the automatic mode of action. As a clinical tool, patients with deficient internal pacing mechanisms should be taught about the different cueing options. Repeated demonstration accompanied by the appropriate integration of cueing into the daily routine may go a long way toward enhancing mobility and quality of life.
Walking Aids Promoting the use of walking aids is important. Too few elderly persons use walking aids, partly because physicians fail to recommend them and partly because many elderly persons are ashamed to revert to them. Others who do try to use a walker or wheeled rollator fail to do so properly and so give up. On the other hand, many persons who are properly instructed are very pleased with their renewed mobility and independence. A wheeled rollator is usually more effective than a frame, which is often merely carried rather than used for support. The use of well-fitting and sturdy footwear with leather soles can help to reduce accidental trips or slips. Narrow high heels must be discouraged. Persons who are prone to sustain backward falls can be prescribed adaptive footwear with slightly heightened heels to reduce retropulsion. Ankle braces can be recommended for patients who trip by “catching their toe.”
Medical Treatment Drugs can sometimes improve gait dramatically to the extent of freeing a person from the use of a wheelchair. Drugs can be given orally, parenterally (subcutaneous, intramuscular, or intravenous), or intrathecally (directly into the spinal subarachnoid space). In general, drugs that can improve gait can be subdivided into the following six categories: Antispastic drugs—to decrease spasticity. One drawback is the reduction in muscle tone, which may aggravate the supportive abilities of the legs and thereby aggravate the gait
468
Section
VII
Motor System and Motor Diseases
disorder. Another problem is that adequate relief of spasticity often calls for high dosages, which may cause some sedation: one possible solution is focal treatment with botulinum toxin. Dopaminomimetic drugs—to improve parkinsonian and hypokinetic gait disorders. In patients with Parkinson’s disease, the hypokinetic elements of gait often improve with dopaminergic medication. Freezing of gait usually occurs during OFF periods (i.e., when the antiparkinson medication has lost its efficacy), and this OFF-period freezing usually responds well to dopaminergic medication. However, less often freezing of gait is actually caused by dopaminergic medication, and this ON-period freezing improves when the dosage of antiparkinson medication is reduced. Balance impairment and falls in Parkinson’s disease are usually resistant to (and sometimes aggravated by) dopaminergic medication. Antidyskinetic drugs—to improve dystonic or choreatic gait. The same concerns mentioned for the antispastic drugs apply here as well. Neuroleptics prescribed for choreatic gait may reduce excessive involuntary movements, but this often comes at the price of increased bradykinesia (which often accompanies the chorea in patients with Huntington’s disease). Vestibular stabilization drugs—to improve vestibular disturbances associated with disequilibrium. Although these are frequently prescribed, no drug has shown convincing efficacy in properly designed studies. Psychostimulants—to improve fatigue, somnolence, and general weakness. An example of such an approach is the recent use of methylphenidate (Ritalin) in patients with Parkinson’s disease.39 Pain-relieving drugs—to improve antalgic gait. Drugs should always be prescribed with caution because of possible side effects and may paradoxically exacerbate the gait disturbance. In general, however, medical treatment should always be considered because of its significant potential therapeutic benefit.
Surgical Interventions Surgery can have a dramatic therapeutic effect in keeping patients on their feet and maintaining mobility and independence. Surgical interventions can be divided into musculoskeletal orthopedic interventions, peripheral nerve surgery, and functional surgeries at the level of the CNS.
by treating compressive neuropathies, such as by releasing entrapments or adhesions, disc herniations, and other compressive causes. As a result, muscles can become reinnervated and regain strength. Similarly, treating a cause for compression can alleviate pain, which is frequently the cause of abnormal gait. Causing loss of function is mainly used for the treatment of spasticity. Dorsal rhizotomy has been used for many years as a potential antispasticity intervention with some benefit in very resistant cases.
Functional Intervention Functional interventions at the level of the CNS can be divided into manipulation of cerebrospinal fluid flow or drainage and electrical stimulations at the level of the spinal cord or the basal ganglia. Ventriculoperitoneal or lumboperitoneal drainage (shunt) have varying and usually temporary efficacy for the treatment of gait disturbances associated with hydrocephalus. A ventriculoperitoneal shunt is commonly used for the treatment of normal pressure hydrocephalus. which classically present with the triad of gait disturbance, urinary incontinence, and cognitive decline. It is not easy to predict who will benefit from a ventriculoperitoneal shunt, but a subgroup of patients with normal pressure hydrocephalus often experience dramatic improvement that can last for years. The other functional surgical intervention is high-frequency deep-brain stimulation. This approached has recently gained much interest when it was discovered that high-frequency (60 to 185 Hz) and low-voltage (0 to 10 μA) continuous electrical stimulation of the internal globus pallidum or the subthalamic nucleus via deeply implanted electrodes can significantly improve parkinsonian and dystonic gait. This approach is now under investigation and, in the future, electrodes might be implanted at the human locomotion network/center for further intervention in the locomotion network.
SUMMARY Gait disturbances and falls are commonplace and debilitating. Identification of the underlying causes and the recommendation of appropriate interventions may help patients regain mobility abilities, a key to independence.
K E Y ●
Gait disturbances and falls are commonplace and debilitating. Identification of the underlying causes and the recommendation of appropriate interventions may help patients regain mobility abilities, a key to independence.
●
Musculoskeletal and cardiovascular support systems, along with visual, vestibular, and proprioceptive senses, are required to stand, maintain balance, and walk while interacting with the environment.
●
For any patient presenting with falls, the first thing to do is to clarify the circumstances surrounding the fall and, in particular, to identify any specific pattern, because this may reveal the underlying pathophysiology and offer opportunities for prevention.
Peripheral Surgical Interventions Orthopedic interventions are made at the levels of the feet, ankle, knee, hip, and spine for improvement of joint or spine position and to improve function while walking. The classic surgeries are those for children with cerebral palsy or chronic joint diseases. Tendon transfer or elongations, replacement of joints, and discectomies with spine stabilization have been used for many years and can preserve a person’s ability to walk. Similarly, stabilization of unstable joints can improve stabilization and balance to the degree of regaining secure mobility. Peripheral nerves can be manipulated surgically for gain of function or loss of function. Gain of function can be achieved
P O I N T S
chapter 36 gait disturbances and falls Suggested Reading Bloem BR, Visser JE, Allum JH: Posturography. In Hallett M, ed: Handbook of Clinical Neurophysiology. Amsterdam: Elsevier Science BV, 2003, pp 295-336. Emere M, Aarsland D, Albanese A, et al: Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509-2518. Herman T, Giladi N, Gurevich T, et al: Gait instability and fractal dynamics of older adults with a “cautious” gait: why do certain older adults walk fearfully? Gait Posture 2005; 21:178185. Nutt JG, Carter JH, Sexton GJ: The dopamine transporter: importance in Parkinson’s disease. Ann Neurol 2004 ;55:766773.
References 1. Wannier T, Bastiaanse C, Colombo G, et al: Arm to leg coordination in humans during walking, creeping and swimming activities. Exp Brain Res 2001; 141:375-379. 2. Pahapill PA, Lozano AM: The pedunculopontine nucleus and Parkinson’s disease. Brain 2000; 123:1767-1783. 3. Alexander NB: Clinical evaluation of gait disorders: no-tech and low-tech. In Hausdorff JM, Alexander NB, eds: Evaluation and Management of Gait Disorders. New York: Marcel Dekker Inc, 2005. 4. Bloem BR, Visser JE, Allum JH: Posturography. In Hallett M, ed: Handbook of clinical neurophysiology. Amsterdam: Elsevier Science BV, 2003, pp 295-336. 5. Giladi N, Shabtai H, Simon ES, et al: Construction of Freezing of Gait Questionnaire for patients with parkinsonism. Parkinson Relat D 2000; 6:165-170. 6. Tinetti ME: Clinical practice. Preventing falls in elderly persons. N Engl J Med 2003; 348:42-49. 7. Podsiadlo D, Richardson S: The timed “Up & Go:” a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991; 39:142-148. 8. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopedic Surgeons Panel on Falls Prevention: Guideline for the prevention of falls in older persons. J Am Geriatr Soc 2001; 49:664-672. 9. Tinetti ME: Performance-oriented assessment of mobility problems in elderly persons. J Am Geriatr Soc 1986; 34:119126. 10. Hausdorff JM, Cudkowicz M, Firtion R, et al: Gait variability and basal ganglia disorders: stride-to-stride variations of gait cycle timing in Parkinson’s disease and Huntington’s disease. Mov Disord 1997; 13:428-437. 11. Herman T, Giladi N, Gurevich T, et al: Gait instability and fractal dynamics of older adults with a “cautious” gait: why do certain older adults walk fearfully? Gait Posture 2005; 21:178185. 12. Nakamura T, Meguro K, Sasaki H: Relationship between falls and stride length variability in senile dementia of the Alzheimer type. Gerontology 1996; 42:108-113. 13. Hausdorff JM, Schaafsma JD, Balash Y, et al: Impaired regulation of stride variability in Parkinson’s disease subjects with freezing of gait. Exp Brain Res 2003;149:187194. 14. Hausdorff JM, Rios D, Edelberg HK: Gait variability and fall risk in community-living older adults: a 1-year prospective study. Arch Phys Med Rehabil 2001; 82:1050-1056. 15. Nutt JG, Marsden CD, Thompson PD: Human walking and higher-level gait disorders, particularly in the elderly. Neurology 1993; 43:268-279.
469
16. Giladi N, Herman T, Rieder I, et al: Clinical characteristics of the idiopathic gait disorders of the elderly: evidence suggestive of a distinct neurodegenerative syndrome. J Neurol 2005; 252:300-306. 17. Rubenstein TC, Giladi N, Hausdorff JM: The power of cueing to circumvent dopamine deficits: a review of physical therapy treatment of gait disturbances in Parkinson’s disease. Mov Disord 2002; 17:1148-1160. 18. Woollacott M, Shumway-Cook A: Attention and the control of posture and view of an emerging area of research. Gait Posture 2002; 16:1-14. 19. Shumway-Cook A, Brauer S, et al: Predicting the probability for falls in community-dwelling older adults using the timed Get Up and Go test. Phys Ther 2000; 80:896-903. 20. Bloem BR, Valkenburg VV, Slabbekoorn M, et al: The multiple tasks test. Strategies in Parkinson’s disease. Exp. Brain Res 2001; 137:478-486. 21. Sheridan PL, Solomont J, Kowall N, et al: Influence of executive function on locomotor function: divided attention increases gait variability in Alzheimer’s disease. J Am Geriatr Soc 2003; 51:1633-1637. 22. Yogev G, Giladi N, Peretz C, et al: Dual tasking, gait rhythmicity, and Parkinson’s disease: which aspects of gait are attention demanding? Eur J Neurosci 2005; 22:1248-1256. 23. Hausdorff J M, Balash J, Giladi N: Effects of cognitive challenge on gait variability in patients with Parkinson’s disease. J Geriatr Psychol Neurol 2003; 16:53-58. 24. Shaw FE, Bond J, Richardson DA, et al: Multifactorial intervention after a fall in older people with cognitive impairment and dementia presenting to the accident and emergency department: randomised controlled trial. BMJ 2003; 326: 73. 25. Lundin-Olsson L, Nyberg L, et al: “Stops walking when talking” as a predictor of falls in elderly people. Lancet 1997; 349:617. 26. Verghese J, Lipton RB, Hall CB, et al: Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med 2002; 347:1761-1768. 27. Marquis S, Moore MM, Howieson DB, et al: Independent predictors of cognitive decline in healthy elderly persons. Arch Neurol 2002; 59:601-606. 28. Emere M, Aarsland D, Albanese A, et al: Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509-2518. 29. Robertson MC, Campbell AJ, Gardner MM, et al: Preventing injuries in older people by preventing falls: a metaanalysis of individual-level data. J Am Geriatr Soc 2002; 50:905-911. 30. Hakim AA, Petrovitch H, Burchfiel CM, et al: Effects of walking on mortality among nonsmoking retired men. N Engl J Med 1998; 338:94-99. 31. Cunnington R, Iansek R, Bradshaw J, et al: Movementrelated potentials in Parkinson’s disease: presence and predictability of temporal and spatial cues. Brain 1995; 118: 935-950. 32. McIntosh GC, Brown SH, Rice RR, et al: Rhythmic auditorymotor facilitation of gait patterns in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 62:22-26. 33. McIntosh G, Thaut M, Rice R, et al: Stride frequency modulation in Parkinsonian gait using rhythmic auditory stimulation. Ann Neurol 1994; 36:316. 34. Frenkel-Toledo S, Giladi N, Peretz C, et al: Treadmill walking as an external cue to improve gait rhythm and stability in Parkinson’s disease. Mov Disord 2005; 20:1109-1114. 35. Morris ME, Iansek R, Matyas TA, et al: Ability to modulate walking cadence remains intact in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1994; 57:1532-1534.
470
Section
VII
Motor System and Motor Diseases
36. Stern GM, Lander CM, Lees AJ. Akinetic freezing and trick movements in Parkinson’s disease. J Neural Transm Suppl 1980; 16:137-141. 37. Morris ME, Iansek R, Matyas TA, et al: Stride length regulation in Parkinson’s disease. Normalization strategies and underlying mechanisms. Brain 1996; 119:551-568.
38. Bagley S, Kelly B, Tunnicliffe N, et al: The effect of visual cues on the gait of independently mobile Parkinson’s disease patients. Physiotherapy 1991; 77:415-420. 39. Nutt JG, Carter JH, Sexton GJ: The dopamine transporter: importance in Parkinson’s disease. Ann Neurol 2004; 55:766773.
CHAPTER
37
RESTLESS LEGS SYNDROME ●
●
●
●
Wolfgang H. Oertel and Karin Stiasny-Kolster
Restless legs syndrome (RLS) is the most common neurological sleep disorder. It was first described in 1672 and was rediscovered in 1945 by K. A. Ekbom,1 who extensively studied this disorder and contributed important findings that are still relevant today. Major advances in the clinical definition of RLS, in understanding the basic mechanisms, the discovery of genetic factors, and the successful treatments of RLS have increased medical attention in the field of neurology. However, awareness of the disorder among general physicians is still low, despite its high prevalence and significant morbidity. RLS is often misdiagnosed, underdiagnosed, or undiagnosed. One survey showed that the rate of correct diagnosis of RLS by general physicians is less than 7% of that of correct diagnosis by specialists. Even when diagnosed, RLS is often not appropriately treated.2 However, the prevalence of individuals whose symptoms of RLS are sufficiently severe for them to seek medical advice is estimated at approximately 3% of general practice populations.2 Increased awareness will improve the rate of recognition and treatment of RLS, which most often dramatically improves patients’ lives.
CLINICAL FEATURES AND DEFINITION OF RESTLESS LEGS SYNDROME RLS is a distressing neurological sensorimotor disorder characterized by an almost irresistible urge to move the limbs that is most often but not necessarily accompanied by uncomfortable sensations in the legs. RLS symptoms are evoked by rest, such as lying down or sitting, and are worse in the evening or night. Patients describe the sensations, most commonly deep in the legs, as “creepy-crawly,” “like an electric current,” “pulling,” “tearing,” “itching bones,” “aching,” or “throbbing.” Because the symptoms are unfamiliar, patients often find them extremely difficult to describe. The regions between the knees and the ankles are especially affected, whereas the feet are frequently spared. In response to the discomfort, patients often rub or stretch and flex their legs, turn in bed, or pace the floor, because passive or active movement characteristically provides temporary relief. The arms may also be involved, particularly in patients with severe RLS. Because the symptoms of RLS occur predominantly in the evening or during the night, RLS has a significant effect on sleep, and patients often present with a sleep problem. In addition to difficulty initiating sleep, many
patients with RLS have problems maintaining sleep, with frequent awakenings or short arousals that result in poor sleep efficiency. Patients with moderate to severe RLS may sleep on average less than 5 hours per night and may chronically have less sleep time than do patients with almost any other persistent disorder of sleep.3 In many patients with RLS, quality of life is poor, and these patients are at increased risk for depressive and anxiety disorders.4,5 Approximately 80% to 90% of the patients with RLS have associated nocturnal, involuntary periodic limb movements (PLMs)—during sleep (PLMSs) or during wakefulness (PLMWs)—which are usually present in the legs.6 PLMs are mostly rhythmic extensions of the big toe and dorsiflexion of the ankle that resemble the Babinski reflex, with occasional flexion of the knee and hip.7 Movements are often bilateral, involving both legs, but may be predominant in one leg or alternate between legs. The quantification of PLMs is routinely performed in the sleep laboratory by recording both anterior tibialis muscles with surface electrodes. Polysomnographic recordings show that they tend to occur every 20 to 40 seconds and are frequently associated with arousals or complete awakenings. Thus, PLMs further contribute to sleep fragmentation, especially in advanced cases in which the PLMS arousal index (number of PLMS-associated arousals per hour total sleep time) may be very high. PLMs may be assumed if bed partners of patients with RLS report nocturnal kicking of the leg or sometimes if patients themselves experience involuntary jerks of the legs while lying in bed.
EPIDEMIOLOGY Well-performed epidemiological studies have concordantly shown that the prevalence of RLS in the general population is between 5% and 10%8-13 and that RLS prevalence is higher in women with more births.2,9,12-15 In addition, one study showed that the frequency of RLS in women increases by the number of births.13 The time of onset varies between early childhood and 80 years of age or even older. In retrospective surveys, 23%16 and 13%6 of adult patients with RLS reported the onset of RLS before the age of 10 and 25% between 10 and 20 years.6,16 Although valid data about the prevalence of RLS in adults exist, respective data for the adolescent population or children are lacking. However, existing data suggest that RLS and sleep disturbances caused by RLS are a frequent but undiagnosed
471
472
Section
VII
Motor System and Motor Diseases
problem in this younger age group. RLS varies in severity, and the prevalence of adults in a general practice population whose RLS is severe enough to seek medical advice has been shown to be about 3.4%.2 Despite the prevalence, there is a lack of awareness of RLS among health care providers. One epidemiological study showed that only 12.9% of cases were accurately diagnosed by the general practitioner, although patients explicitly reported their symptoms. The rate of correct diagnosis of RLS by general practitioners is less than 7% that by specialists. Even when diagnosed, RLS is often not appropriately treated.2
Primary Restless Legs Syndrome Most affected individuals suffer from primary RLS, which shows a familial association in more than 50% of cases.17-19 Patients with familial RLS have an earlier onset of symptoms than do those suffering from the sporadic type, and the progression is slower. The relevant age at onset of the disease at which to subdivide patients with RLS into early- and late-onset groups remains to be investigated. One study revealed that patients who were younger than 45 years at onset have a greater probability of having an affected first-degree relative than do those who were older than 45 years at onset.20 In another study, earlyonset RLS (with onset at younger than 30 years) has been found to be genetically different from late-onset RLS: In early-onset RLS, it was suggested that a major gene is segregating in an autosomal dominant mode of inheritance with an additional multifactorial component.19 Genome-wide studies have been conducted to map genes that play a role in the vulnerability to RLS. So far, linkage was found to a chromosomal locus on 12q,21 which was not confirmed in four other families; on 14q,22 which was replicated in one family23; and on 9p.24 Inspection of huge pedigrees indicates anticipation and variable penetrance.25,26 Investigations of candidate gene coding for receptors and enzymes related to dopaminergic transmission27,28 revealed no differences in the genotypic or allelic distributions between RLS and control subjects.
with attention deficit/hyperactivity disorder may have PLMS or in fact suffer from RLS.43-45
PATHOPHYSIOLOGY Although RLS pathophysiology is still unknown, knowledge about it has developed significantly, which has led to diverse hypotheses.46 The medication responses indicate that RLS results from abnormal functioning in the nervous system.47 Overall, the central nervous system areas involved in RLS pathophysiology are unknown, and the role of the peripheral nervous system, if any, is uncertain.48 Several studies have provided evidence that RLS is associated with peripheral neuropathy; therefore, it is possible that peripheral nerve lesions are a trigger for RLS.
Dopaminergic Function in Restless Legs Syndrome Dopaminergic mechanisms are supposed to play an important role, particularly inasmuch as dopaminergic drugs have shown to be especially beneficial in RLS. In addition, the circadian manifestation of RLS symptoms coincides with lower levels of central dopamine activity.49 However, several investigations, including positron emission tomography and single photon emission computed tomography studies of the dopaminergic nigrostriatal system,50 cerebrospinal fluid analysis of dopaminergic metabolites,51,52 and even histopathological studies, have not provided evidence of a primary dopaminergic deficit or neurodegeneration in the basal ganglia53 that favors a functional impairment or a modulating effect of the dopaminergic system. The fact that melatonin secretion, which is increased at night, is correlated with the severity of RLS symptoms54 supports the dopamine hypothesis, inasmuch as melatonin exerts an inhibitory effect on central dopamine secretion. Daytime and nighttime melatonin excretion per se is normal in patients with RLS.55
Iron Metabolism in Restless Legs Syndrome Secondary Restless Legs Syndrome Although most RLS cases may be idiopathic, RLS is often linked to other medical or neurological disorders. The most important associations of RLS are with end-stage renal disease29,30 and with iron deficiency.31,32 RLS may also develop during pregnancy33,34 or may intensify after treatment with various drugs. In many reports, RLS has been linked to dopamine antagonists, such as typical and atypical neuroleptics and metoclopramide, or to antidepressants, such as tricyclic and tetracyclic antidepressants, serotonin reuptake inhibitors, and lithium. Although supporting data are limited, peripheral neuropathies, such as axonal neuropathy,35 cryoglobulinemic neuropathy,36 familial amyloid polyneuropathy,37 Charcot-Marie-Tooth disease type 2,38 and small-fiber neuropathies39 may be associated with RLS. Because the prevalence of RLS among patients with peripheral polyneuropathies has been shown to be only 5.2%40 and thus does not exceed that in the general population, this association is of unclear significance. Other neurological diseases that have been reported to be linked with RLS are radiculopathies41 and myelopathies, such as multiple sclerosis or syringomyelia.42 It has also been shown that some children who were diagnosed
A strong negative correlation between serum ferritin levels and RLS severity,31,32 the therapeutic effect of iron in RLS,56 the reduction of iron in the substantia nigra as shown by magnetic resonance imaging,57 and reduced cerebrospinal fluid ferritin levels and increased cerebrospinal fluid transferrin levels58 in patients with RLS indicate that an impaired iron metabolism may be another important factor in the pathophysiology of RLS. Neuropathological investigations have shown that iron and heavy-ferritin staining was markedly decreased (and lightferritin staining was strong) in the substantia nigra. In addition, transferrin receptor staining on neuromelanin-containing cells was decreased in brains of patients with RLS, whereas transferrin staining in these cells was increased.59 These data suggest that iron acquisition is compromised in neuromelanin cells, which may interfere with dopaminergic mechanisms.
Role of the Nociceptive System Stiasny-Kolster and colleagues (2004)60 showed that the nociceptive system is involved in RLS pathophysiology. Patients with RLS exhibited a profound static mechanical hyperalgesia
chapter 37 restless legs syndrome in response to punctate stimuli. This type of hyperalgesia improved significantly after long-term treatment with dopaminergic drugs. These findings suggests that RLS may be associated with central sensitization of spinal neurons, such as that in chronic neuropathic pain resulting from abnormal peripheral input and/or from altered descending inhibition (i.e., involving the supraspinal dopaminergic system). Thus, in addition to being a motor and sleep disorder, RLS may also be a pain disorder. These findings may also explain why substances that are well accepted for the treatment of neuropathic pain, such as opioids or anticonvulsants, alleviate RLS symptoms.
Localization of the Dysfunction Regardless of the neurotransmitter systems and neurophysiological mechanisms involved in RLS pathophysiology, the site of the underlying neurological alteration is still unclear. Cortical involvement was previously considered unlikely because of the absence of cortical activity in functional magnetic resonance imaging (fMRI) studies and the absence of a Bereitschaftspotential61 associated with the involuntary movements in RLS. Spectral power analysis of electroencephalographic studies, however, provides evidence that characteristic involuntary leg movements in RLS are preceded by a preparatory cortical activation. In addition, several neurophysiological studies with single or paired pulse stimulation showed a reduced intracortical inhibition62 and a shortened cortical silent period in patients with RLS.63,64 This cortical disinhibition may result from a shift in the balance of excitatory and inhibitory mechanisms toward either more excitability or less inhibition (e.g., as a result of increased sensory input or impaired subcortical mechanisms). Interestingly, levodopa (Ldopa) leads to a prolongation of the silent period and thus to an improvement of impaired inhibitory mechanisms.64 Some studies have suggested the involvement of subcortical areas in RLS pathophysiology. Lesions in the dopaminergic diencephalospinal tract (A11 neurons) have been proposed as an animal model for RLS65 and are discussed as potential underlying cause of RLS in humans.66 The effects of acute dopaminergic treatment on RLS symptoms and long-term dopaminergic treatment on static mechanical hyperalgesia support this suggestion. Thus, the dopaminergic system is either directly or indirectly involved in the central sensitization in RLS.60 The only fMRI investigations in patients with RLS conducted so far67 revealed a bilateral activation of the cerebellum and a contralateral activation of the thalamus during sensory symptoms. During the occurrence of PLMs and sensory symptoms, the patients showed additional activation in the red nuclei and brainstem close to the reticular formation. These results support aforementioned neurophysiological studies that suggested that subcortical cerebral generators are involved in the pathogenesis of RLS. During the combined condition (PLMs and sensory symptoms), the activation was still larger in the cerebellum than during each condition alone, which points to a neuronal participation of the cerebellum in the motor and sensory process as well. This finding is in agreement that in healthy subjects, the cerebellum is involved in sensory processing. When the distribution of the fMRI-activated cerebellar areas (subcortical in both hemispheres) were compared with histological autoradiographical studies of the human cerebellum, a similar distribution of opioid μ receptors could be detected. Thus, the cerebellum could be another possible site
473
of interaction of opioidergic agents. The spinal cord may also play a major role in the pathophysiology of RLS. Patients with spinal cord lesions, particularly those with transsection of the spinal cord, often have PLMs, which suggests that PLMs are generated in the spinal cord.68-71 In these cases, however, the number of PLMs is lower and the circadian rhythmicity and the response to dopaminergic agents are less pronounced than in patients with RLS.69,72,73 Flexor reflex studies showed an increased spinal cord excitability during sleep in patients with RLS, which indicates that signal processing in the spinal cord is altered. In addition, the presence of mechanical hyperalgesia in RLS indicates central sensitization of spinal neurons. However, the central sensitization in RLS may also be based on afferent input–induced plasticity of spinal nociceptive transmission,74 and long-standing abnormal peripheral input may explain various kinds of secondary RLS: for example, RLS triggered by polyneuropathies. Thus, it is conceivable that at least in a subgroup of patients with RLS, peripheral lesions may represent a pathophysiological factor for the development or aggravation of RLS.
DIAGNOSTIC CRITERIA FOR RESTLESS LEGS SYNDROME RLS is a clinical diagnosis that relies entirely on the patient’s symptoms. According to international diagnostic criteria75 (Walters, 1995) and a consensus established by the International Restless Legs Syndrome Study Group76 (Allen et al, 2003) RLS is characterized by four essential criteria (Table 37–1). To make a definite diagnosis of RLS, all four diagnostic criteria must be established. In some cases, these criteria may be inadequate for ruling out conditions mimicking RLS, such as peripheral neuropathy, leg cramps, positional discomfort, or parkinsonian symptoms, inasmuch as these conditions may sometimes lead to positive answers referring to different problems. If these features are comorbid with RLS, it can, in turn, also be difficult to recognize RLS. The following supportive features that are not necessary to make the diagnosis RLS but may, especially in doubtful cases, help to diagnose or exclude RLS have been established.76
T A B L E 37–1. Essential Diagnostic Criteria of the International Restless Legs Syndrome Study Group An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (sometimes the urge to move is present without the uncomfortable sensations, and sometimes the arms or other body parts are involved in addition to the legs) The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues The urge to move or unpleasant sensations are worse in the evening or night than during the day or occur only in the evening or at night (when symptoms are very severe, the worsening at night may not be noticeable but must have been previously present) From Allen R, Picchietti D, Hening WA, et al: Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from The Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health. Sleep Med 2003; 4:101-119.
474
Section
VII
Motor System and Motor Diseases
Positive Family History A positive family history is present in more than 50% of patients with RLS. The prevalence of RLS among first-degree relatives of people with RLS is three to five times greater than in people without RLS.
Positive Response to Dopaminergic Treatment Several controlled studies have shown that most patients with RLS have a positive therapeutic response to dopaminergic drugs. According to clinical experience, more than 90% of patients report some relief of their symptoms when treated with these agents.
Periodic Limb Movements in Sleep PLMSs are reported to occur in 80% to 90% of patients with RLS. However, PLMS also commonly occur in other disorders and in the elderly. A PLMS index (number of PLMSs per hour of sleep) of greater than 5 is considered pathological, although data supporting this feature are very limited. The occurrence of PLMs during nocturnal periods of wakefulness (PLMW) is considered to be more specific for RLS.77 Thus, the presence of a high number of PLMs is supportive for RLS, but the absence of PLMs does not exclude RLS. In addition to the essential and supportive criteria, the natural clinical course, the presence and character of sleep disturbances, and the physical examination findings are other features that may be helpful for diagnosis of RLS.76
Natural Clinical Course RLS is usually a chronic disease, and symptoms typically increase over time. As mentioned, the age at onset of RLS varies widely, from childhood to 80 years of age and even older. Patients with early-onset RLS are more likely to have affected family members than are those with late-onset RLS.19 When RLS symptoms appear at a young age, the onset is more often insidious. RLS symptoms may be present intermittently for many years with fluctuating severity. Initially, mild RLS may occur in single nights, sometimes with or without sleep disturbances, or in aggravating situations during the day, such as during a long overseas flight. There may be long periods of remission, but the severity and frequency typically increase over time. Many patients with RLS experience their RLS as nightly events with difficulty falling asleep and several awakenings with walking around or other actions that may lead to temporary relief, such as taking a cold foot bath. Other patients progress to daily symptoms within several years. Many of these patients have disease onset in late adult life and have secondary RLS. The natural clinical course may be influenced by the development of augmentation as a result of medication side effects (see following discussion).
Sleep Disturbances Because of the nocturnal appearance of the disease, sleep disturbances caused by RLS are very frequent. In some patients, sleep is already affected in the very beginning, during single
nights when RLS symptoms show up occasionally. In others, sleep disturbances develop when RLS severity increases to a certain degree. In RLS, the underlying alerting motor activity and, even more, the methods to relieve sensory and motor symptoms of RLS interfere with the conditions needed to initiate sleep. This applies not only for the start of sleep but also for the time after an awakening that is caused mostly by PLMS. Prolonged sleep onset and several awakenings with brief or agonizing periods of wakefulness caused by RLS symptoms often result in reduced total sleep time and poor sleep efficiency. In addition, numerous PLMS associated with short-lasting arousals frequently contribute to a fragmented and unrestorative sleep. The number of PLMS arousals or PLMWs rather than the PLMSs, which does not necessarily indicate an interference with sleep, may be considered as an indicator for the severity of RLS. For patients with mild RLS, sleep disturbances may be less of a problem.
Medical Examination The physical examination and medical evaluation findings are generally normal and do not contribute to the diagnosis except for conditions that may be comorbid or secondary forms, such as end-stage renal disease, pregnancy, and iron deficiency. The presence of peripheral neuropathy, radiculopathy, or myelopathy should be determined because these conditions have a possible, although uncertain, association and may necessitate different treatment.
EVALUATION OF RESTLESS LEGS SYNDROME Medical History When a patient meets the four essential diagnostic criteria and when mimicking conditions can be ruled out, the evaluation of RLS (Table 37–2) is minimal. In any case, however, a thorough medical history should be obtained with special attention to the time course, the appearance of symptoms during the 24-hour day, type and severity of sleep disturbances, and daytime vigilance. An atypical course of the disease with an abrupt onset and daily symptoms from the beginning may be suggestive of secondary forms of RLS. The time of RLS symptom onset during the day is important to know because medication intake should be individually tailored. Patients in whom severe RLS symptoms are already present in the late afternoon must take medication earlier than do patients with late-evening symp-
T A B L E 37–2.
Evaluation of Restless Legs Syndrome
Basic Evaluation Medical history, including sleep history, family history, drug history General medical and neurological examination Measurement of serum iron and ferritin Other Studies Sometimes Necessary Electrophysiological studies Cardiorespiratory polysomnography (with electromyography of both tibialis anterior muscles) Levodopa test
chapter 37 restless legs syndrome toms. Patients with problems initiating sleep may require other medication or another time of medication intake, in comparison with those who have problems maintaining sleep. It is also important to figure out why a patient’s sleep is disturbed. Even if RLS symptoms are adequately treated, sleep disturbances may remain if back pain or depression additionally interferes with sleep. A careful drug history should detect substances that may aggravate RLS or sleep disturbances. Thus, it is worthwhile to invest some time in a detailed history, particularly in the initial contact with an RLS patient.
Blood Tests When evaluating patients with RLS, the clinician must look for factors that may exacerbate symptoms of RLS, because these may alter the treatment plan or make effective treatment more difficult to establish. With regard to laboratory findings, not only low iron but also low-normal serum ferritin levels (<50 μg/L) have been related to increased severity of RLS and may be associated with an increased risk of RLS even in patients with normal hemoglobin levels.31,32 Therefore, evaluation of serum iron and ferritin levels is strongly recommended as part of the medical evaluation for RLS, because these patients may benefit from iron supplements. When iron therapy is initiated, patients need to be routinely monitored to check the response to iron and to avoid iron overload. The iron storage disease hemochromatosis, which can coexist with RLS, requires special attention because it would be aggravated by iron supplementation.51,78 Other blood tests should be conducted, depending on the clinician’s reasonable suspicion, although it should be clear that patients are not in renal failure.
Electrophysiological Studies Nerve conduction studies or electromyography (EMG) may be necessary if peripheral neuropathy is suspected. If peripheral neuropathy exists, it has to be determined by an even more detailed history and possibly by further tests (e.g., L-dopa test, polysomnography) if it is comorbid with RLS or if the complaints are completely explained by the peripheral neuropathy and RLS does not even exist. Although symptoms of peripheral neuropathy are usually present throughout the day, they may increase or are experienced as more intense at night. However, complete and persistent relief while walking is rarely obtained in peripheral neuropathy. The report of frequent involuntary movements in resting positions during the day (indicative of PLMW) may be a hint for a marginal affection of the spinal cord even if neurological examination findings are unremarkable. In these cases, transcranial magnetic stimulation studies with assessment of the central motor conduction time is recommended.
Polysomnographic Recordings Sleep studies may be helpful in uncertain or complicated cases and if another sleep disorder such as sleep apnea is suspected. The presence of PLMs and, even more, of PLMSs associated with arousals supports the diagnosis of RLS.77 However, for the interpretation of polysomnographic recordings, it is important to consider that not all patients with RLS have PLM, that the
475
presence and frequency of PLMs varies between nights, and that even patients with advanced RLS may have nights with nearly undisturbed sleep. Thus, the absence of PLMs does not preclude RLS. In addition, PLMSs can occur in a variety of disorders or even in normal individuals and are not specific for RLS. In the majority of these cases, however, PLMs are less frequent and less often associated with arousals. Although a higher number of PLMs are sometimes detected in sleep apnea, the arousals are caused mostly by the respiratory event. A sensitive technique must be used to monitor breathing during polysomnography, such as pressure transducer airflow monitoring or esophageal manometry, to reasonably rule out sleep-disordered breathing as the direct cause of the PLMSs.79 When PLMSs are independently present in a patient with sleep-disordered breathing and without a history of RLS, then a separate diagnosis of periodic limb movement disorder (PLMD) may be considered if the PLMSs are still seen with adequate continuous positive airway pressure and if clinical sleep-wake disturbance that is not otherwise explained remains. In RLS, the number of PLMS arousals may be considered as a marker for the severity of the disease, which can be used for monitoring treatment effects. In general, polysomnographic recordings should be performed without drugs known to either suppress PLMs (e.g., dopaminergic drugs, opioids, anticonvulsants, benzodiazepines) or enhance PLMs (e.g., neuroleptics, antidepressants). Withdrawal of such medication, however, is often not possible and may also lead to a PLM rebound. In these cases, the significance of polysomnography is limited. Polysomnography during treatment may be helpful for optimizing therapy, for determining the reason for nonresponse, or if other sleep disturbances are suspected. PLMs can also be detected with actigraphic monitoring. Accelerometers that record movements and not electrical potentials, as in EMG, are generally placed on the ankle or foot. In comparison of technologies, it remains uncertain whether the more important phenomenon is the electrical potential or the actual movement. It has been suggested that EMG can overcount PLMs by counting potentials that do not result in any appreciable movement. The disadvantage of actigraphy is that it provides less or no information about the context of movements to sleep and sleep-related respiratory disturbances. For differential diagnosis, PLMs can be examined not only during polysomnography but also in a provocative test called the suggested immobilization test.77,80 In this test, the subject is asked to sit quietly, typically for an hour, while leg movements, usually determined by EMG and subjective complaints, are monitored. Most patients with RLS experience greater sensory discomfort than do normal persons and have a fair number of movements, which fulfill criteria for PLMWs.80 A combination of increased discomfort during the suggested immobilization test and PLMWs during polysomnography (using optimal thresholds) has been reported to provide a better discrimination from control subjects than does any single measure, with a sensitivity of 82% and a specificity of 100%.80
Levodopa Test The response to a single oral dose of L-dopa can be used in clinical practice to support the diagnosis RLS. This is of particular value in untreated patients, in patients in whom the initial
476
Section
VII
Motor System and Motor Diseases
therapeutic effect of dopaminergic substances is not reliably assessable (e.g., dosage unknown, inappropriate time of drug intake, no accurate statement from the patient), and particularly in patients with mild RLS in whom polysomnography frequently fails to detect PLMs. A combined dose of 100 mg of L-dopa with 25 mg of dopa decarboxylase inhibitor is taken after onset of the leg symptoms, independently of the time of day. The severity of the symptoms in the legs is rated by the patient before medication intake and afterwards for a period of about 1 to 2 hours on a visual analog scale (0 = no symptoms to 100 = very severe symptoms). A positive test result is defined as a 50% improvement at any time within 2 hours after administration. The L-dopa test has a sensitivity of 88% and a specificity of 100%; this means that 88% of patients with RLS have a positive test result (>50% improvement) and that all patients with leg symptoms that are not caused by RLS, such as peripheral neuropathy, have a negative test result (<50% improvement) with L-dopa. On the basis of this 50% cutoff criterion, 90% of cases can be correctly diagnosed with the L-dopa test. However, a negative test result, defined as less than 50% improvement, does not preclude RLS, inasmuch as some patients report only mild improvement with 100 mg of L-dopa. Complete nonresponse, particularly in hitherto untreated patients, strongly argues against RLS (Stiasny-Kolster et al).81
Severity Assessment The severity of RLS may be quantified by the validated 10-item International Restless Legs Syndrome Study Group Rating Scale (IRLS) (Fig. 37–1)82 (International Restless Legs Syndrome Study Group, 2003) or the RLS-6 rating scales (Fig. 37–2).83 These scales are used in treatment trials to assess the therapeutic efficacy of drugs referring to the severity of RLS symptoms and sleep disturbances. The IRLS additionally addresses the frequency of RLS symptoms and the effect of RLS on quality of life. Both scales are easy to use in clinical practice.
DIFFERENTIAL DIAGNOSIS OF RESTLESS LEGS SYNDROME Various conditions that may be similar to RLS need to be considered in the differential diagnosis (Table 37–3). However, most of them do not fulfill all four essential criteria for RLS or
T A B L E 37–3. Legs Syndrome
Differential Diagnosis of Restless
Nocturnal cramps Peripheral neuropathy, especially small-fiber neuropathy Painful legs and moving toes Myelopathy (spinal cord compression, spinal vascular malformation) Chronic pain disorders Positional discomfort or ischemia Habitual limb shaking Arthritic, muscular, or vascular disorders Nonspecific restlessness Neuroleptic-induced akathisia Depression with somatic symptoms Periodic limb movement disorder Sensorimotor symptoms of Parkinson’s disease
do not have a circadian variation with nocturnal accentuation. Restriction to rest may also be absent, and relief with movement may be either not present or only temporary with continued movement. Nocturnal leg cramps and polyneuropathy may meet all four diagnostic criteria of RLS. Nocturnal leg cramps are often unifocal; are associated with a contracted, indurated muscle; often occur in single attacks with subsequent relief; and are usually extremely painful. In peripheral neuropathy, particularly in small-fiber neuropathy, symptoms may be noticed more intensely in resting positions in the evening or during the night and may be experienced less with movement. However, these symptoms usually include the feet and are persistently present from the beginning, being mild initially and gradually increase in severity over time. Complete relief of pronounced symptoms is almost never reported. Peripheral neuropathy and sometimes somatic features of depression may be most difficult to delimit. Of course, it is possible that RLS could coexist with any mimicking conditions. Therefore, the presence of a mimicking disorder does not necessarily rule out RLS. Patients with PLMD have sleep fragmentation caused by PLM and consecutively have complaints of daytime sleepiness. To diagnose PLMD other causes of PLMS or associated disorders such as sleep apnea syndrome or RLS have to be ruled out. Sensory complaints and akathisia are fairly common in Parkinson’s disease,84 and lower limb restlessness may accompany wearing-off episodes in patients with motor fluctuations, thus mimicking RLS.85
TREATMENT Nonpharmacological treatment consists of good sleep hygiene. Patients should be advised to avoid caffeine, alcohol, and heavy meals before going to bed. Bedtime hours should be regular and activity gradually reduced in the evening. Patients should sleep in a bedroom that should be used only for sleep or intimacy and not for watching television. In a next step, secondary causes of RLS should be excluded and/or associated disorders be primarily treated. The clinician should consider whether antidepressants, neuroleptic agents, or dopamine-blocking antiemetics such as metoclopramide may be contributing and whether discontinuation is possible without causing the patient harm. Successful kidney transplantation may lead to a complete remission in patients with RLS with renal insufficiency.17,86 Complete loss of all RLS symptoms in affected pregnant women after delivery is also frequently observed.33,87,88 The most important underlying cause may be iron deficiency. Iron supplementation has been shown to improve RLS in patients with iron deficiency31 but not in patients with normal iron levels.89 A common regimen is 325 mg of ferrous sulfate three times a day in combination with 100 to 200 mg of vitamin C with each dose to enhance absorption. Oral iron therapy can cause obstipation and abdominal discomfort, and the dosage may need to be reduced in some patients. Iron tablets are ideally taken on an empty stomach to enhance absorption, but if gastrointestinal symptoms develop, they should be taken with food. Iron should not be prescribed empirically because it may result in iron overload. Magnesium supplements may be beneficial in patients with mild RLS.90 Taking 12.4 mmol of magnesium in the evening has been shown to be beneficial in patients with a postulated magnesium deficiency in an open trial.91 There are no Text continued on p. 48.
chapter 37 restless legs syndrome
International Restless Legs Syndrome (IRLS) Study Group Rating Scale (Investigator Version 2.2)
Have the patient rate his/her symptoms for the following ten questions. The patient and not the examiner should make the ratings, but the examiner should be available to clarify any misunderstandings the patient may have about the questions. The examiner should mark the patient’s answers on the form.
In the past week. . . (1) Overall, how would you rate the RLS discomfort in your legs or arms? 4
Very severe
3
Severe
2
Moderate
1
Mild
0
None
In the past week. . . (2) Overall, how would you rate the need to move around because of your RLS symptoms? 4
Very severe
3
Severe
2
Moderate
1
Mild
0
None
In the past week. . . (3) Overall, how much relief of your RLS arm or leg discomfort did you get from moving around?
■
4
No relief
3
Mild relief
2
Moderate relief
1
Either complete or almost complete relief
0
No RLS symptoms to be relieved
Figure 37–1. International Restless Legs Syndrome Study Group Rating Scale (IRLS). Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, Trenkwalder C; International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003 Mar; 4(2):121-32. Copyright IRLS Study Group 2001. How to obtain the IRLS: Please contact the Information Resources Centre of Mapi Research Trust, 27 rue de la Villette, 69003 Lyon, FRANCE – Tel: +33(0)472 13 65 75 – Fax: +33(0)472 13 66 82 – Email:
[email protected] – Internet: www.mapi-trust.org (conditions of use and (User)-agreement are provided). Useful information about the IRLS (such as references, translations available, scoring and others) is available on the Quality of Life Instrument Database (QOLID), available on the Internet at www.Qolid.org. Continued
477
478
Section
VII
Motor System and Motor Diseases
In the past week. . . (4) How severe was your sleep disturbance due to your RLS symptoms? 4
Very severe
3
Severe
2
Moderate
1
Mild
0
None
In the past week. . . (5) How severe was your tiredness or sleepiness during the day due to your RLS symptoms? 4
Very severe
3
Severe
2
Moderate
1
Mild
0
None
In the past week. . . (6) How severe was your RLS as a whole? 4
Very severe
3
Severe
2
Moderate
1
Mild
0
None
In the past week. . . (7) How often did you get RLS symptoms? 4
Very often (This means 6 to 7 days a week)
3
Often (This means 4 to 5 days a week)
2
Sometimes (This means 2 to 3 days a week)
1
Occasionally (This means 1 day a week)
0
Never ■
Figure 37–1, cont’d.
chapter 37 restless legs syndrome In the past week. . . (8) When you had RLS symptoms, how severe were they on average? 4
Very severe (This means 8 hours or more per 24-hour day)
3
Severe (This means 3 to 8 hours per 24-hour day)
2
Moderate (This means 1 to 3 hours per 24-hour day)
1 0
Mild (This means less than 1 hour per 24-hour day) None
In the past week. . . (9) Overall, how severe was the impact of your RLS symptoms on your ability to carry out your daily affairs, for example, carrying out a satisfactory family, home, social, school, or work life? 4
Very severe
3
Severe
2
Moderate
1
Mild
0
None
In the past week. . . (10) How severe was your mood disturbance due to your RLS symptoms—for example, angry, depressed, sad, anxious, or irritable? 4
Very severe
3
Severe
2
Moderate
1
Mild
0
None
The sum of the item scores serves as the global score for the scale. Higher scores indicate more impairment/higher severity.
1 – 10 = mild RLS 11 – 20 = moderate RLS 21 – 30 = severe RLS 31 – 40 = very severe RLS ■
Figure 37–1, cont’d.
479
480
Section
VII
Motor System and Motor Diseases
RLS-6 Rating Scales
■
Figure 37–2. RLS-6 Rating Scales. (Copyright R. Kohnen, W. H. Oertel, K. Stiasny-Kolster, H. Benes, and C. Trenkwalder [Version 06, May 2003]. The RLS-6 may not be used without written confirmation of the authors [e-mail
[email protected]].)
chapter 37 restless legs syndrome controlled studies that have shown a beneficial effect of other supplements such as zinc, vitamin B1, vitamin B12, vitamin E, or vitamin C. Pharmacological therapy should be restricted to patients who meet the specific diagnostic criteria and suffer from clinically relevant RLS symptoms. Several factors—such as the frequency and severity of symptoms, the temporal appearance of symptoms, the kind of sleep disturbances, and the degree to which RLS interferes with the quality of life—influence treatment strategies.
Levodopa According to Hening and colleagues (2004), if pharmacological therapy is initiated, dopaminergic agents are considered the first-line agents for treatment of RLS.92 In September 2000, L-Dopa/benserazide (Restex and Restex retard) became the first drug licensed for RLS, in two European countries, Germany and Switzerland.93-95 Doses of 50/12.5 to 100/25 mg of standard L-dopa/dopadecarboxylase inhibitor improve RLS symptoms about 1 hour after drug intake, resulting in an improved quality of sleep. In correlation to the plasma half-life of L-dopa (1 to 2 hours), the beneficial effect decreases, and RLS may persist into the second half of the night. If so, an additional dose of slowrelease L-dopa/dopadecarboxylase inhibitor (100/25 mg given in combination with standard L-dopa/benserazide 1 hour before or at bedtime) is recommended.94 In general, L-dopa is best used by patients with mild RLS. The immediate response to L-dopa without a long titration period is appreciated by the patient and indicates to the treating physician that the diagnosis is correct. In patients with sporadic RLS, L-dopa can be given on demand. Pills are generally taken at bedtime, perhaps supplemented by a dose earlier in the day to control evening or daytime symptoms. For maximal absorption, L-dopa should not be taken with high-protein foods. In more severely affected patients, RLS symptoms may not be adequately controlled for the whole night even with the combination of standard and slow-release preparations. These patients benefit from a dopamine agonist. In others, RLS symptoms may shift to the early evening or daytime, become more intense, or involve other body parts after L-dopa therapy has been started. This phenomenon has been called augmentation.96 Consequently, these patients are frequently treated with multiple and higher dosages of L-dopa throughout the 24 hours to control RLS symptoms. If L-dopa therapy is complicated by augmentation, L-dopa should be completely substituted by a dopamine agonist. Because augmentation seems to be more frequent in patients with higher L-dopa dosages, maximum dosages of 300 to 400 mg should not be exceeded. It is also possible that augmentation may be triggered if patients are treated with higher L-dopa dosages than are needed or if daily L-dopa therapy is recommended although symptoms appear only intermittently. Therefore, in some patients with mild symptoms, 50 mg L-dopa, perhaps on demand, may be sufficient.
Dopamine Agonists Because of their longer half-lives and fewer problems (at least according to current clinical observations) with augmentation, dopamine agonists are preferred especially in patients with advanced daily RLS. Given once in the early evening—in
481
dosages that are usually lower than those for Parkinson’s disease—dopamine agonists cover sensory and motor symptoms of RLS throughout the night. As a consequence, sleep and quality of life markedly improve in most patients. To date, several large-scale placebo-controlled trials with dopamine agonists with the goal of approval by the European Medicines Agency or the U.S. Food and Drug Administration have been performed. Convincing data are available for the dopamine agonists cabergoline,97-99 pergolide,100-102 ropinirole,102,103 and pramipexole104,105 and the dopamine agonist patch rotigotine.106 Apart from general considerations, several factors determine the physician’s decision about a certain substance and its dosage, such as the half-life, the duration of upward titration, the structure (nonergot or ergot), individual efficacy and tolerability, and, the physician’s experience with regard to a single dopamine agonist. Shorter-acting dopamine agonists may necessitate twice-daily doses, with an earlier dose in the late afternoon and a second dose in the evening. With longer acting dopamine agonists, a single evening dose (2 to 3 hours before bedtime) is sufficient. If insomnia remains to a considerable degree even though sensorimotor symptoms are well controlled by the dopaminergic drug, other factors and possibly other treatment options must be considered. Characteristics of various dopamine agonists are given in Table 37–4.
Other Substances Opioids have shown to be effective in RLS, and their analgesic or sedative effect may be advantageous in individual patients, but data from placebo-controlled trials are very limited and available for only oxycodone.107 Opioids may be highly effective particularly in advanced RLS and should not be withheld from appropriate patients because of fear of potential development of tolerance or dependence. Escalation of dosage is rare, as is dependence in the absence of a history of substance abuse. If opioids are used, treatment regimens like those for in chronic pain syndromes should be applied. Severely affected patients in particular may profit from opioid patch applications. To avoid constipation, lactulose should be added to the regimen from the beginning. Gabapentin may be an alternative choice, particularly for less intense RLS, for RLS perceived as painful, for RLS in combination with a painful peripheral neuropathy, or for an unrelated chronic pain syndrome. Gabapentin should be used in once- or twice-daily doses in the late afternoon or evening (one third of the dose) or before sleep (two thirds of the dose). Treatment should commence with 300 mg per dose or even less because of the possible tendency to cause somnolence and gait unsteadiness, especially in elderly patients. A controlled trial has shown that a mean dosage of 1800 mg/day is needed for efficacy.108 The anticonvulsants carbamazepine and valproic acid seem to be less effective against RLS than gabapentin. Other anticonvulsants with antinociceptive effect are currently under investigation in patients with RLS. Benzodiazepines are sometimes employed for residual insomnia but should be used with caution, particularly in older patients. Better alternatives are zaleplon (5 to 10 mg), zolpidem (5 to 10 mg), and zopiclone (3.75 to 7.5 mg). In some patients, combination therapies with dopaminergic agents, opioids, anticonvulsants, and benzodiazepines may be a necessary option, but this has not been formally studied.
482
Section
VII
Motor System and Motor Diseases
T A B L E 37–4. Characteristics of Dopamine Agonists in the Treatment of Restless Legs Syndrome Half-Life (Hours) α-Dihydroergocryptine Bromocriptine Cabergoline Lisuride Pergolide Pramipexole HCl*† (nonergot) Ropinirole (nonergot) Rotigotine (nonergot)
Initial Dosage
Titration
Dosage in Restless Legs Syndrome
Maximal Dosage
10-15 3-8 >65 2-3 7-16
5 mg 1.25 mg 0.5 mg 0.1 mg 0.05 mg
5 mg/3 days 1.25 mg/week 0.5 mg/week 0.1 mg/week 0.05 mg/3 days
10-40 mg 2.5-5 mg 0.5-2 mg 0.1-2 mg 0.1-0.75 mg
80 mg 7.5 mg 4 mg 4 mg 1.5 mg
8-12 3-10 5 (constant plasma levels because of patch application)
0.125 mg 0.25 mg 1.25 mg (2.5 cm2) or 2.5 mg (5 cm2)
0.125 mg/3 days 0.25 mg/3 days 1.25 mg/day More than 4.5 mg: 2.25 mg/day
0.125-0.75 mg 0.5-6 mg 1.25-6.75 mg (2.5-15 cm2)
1.5 mg 8 mg 9 mg
*In some European countries, it is declared that free base 0.088 mg pramipexole = 0.125 mg pramipexole HCl. † At least two randomized, placebo-controlled clinical trials with a sufficient number of patients have been conducted.
K E Y
P O I N T S
●
With a prevalence of 5% to 10%, RLS is one of the most common neurological disorders with a significant impact on the patient’s sleep.
●
The key feature is an irresistible urge to move the legs which appears during periods of rest predominantly in the evening hours and is relieved by movement at least as long as the activity continues. Sleep complaints due to RLS are often the main reason for the patient to seek medical advice.
●
Diagnosis can usually be based exclusively on the patient history, and the positive response to dopaminergic therapy strongly supports the diagnosis. In unclear cases polysomnography may be helpful but can be negative especially in early diagnosis.
●
The dopaminergic system and iron metabolism–related components have been extensively investigated and contribute to the pathophysiology of RLS. New findings point toward an underlying role of the nociceptive system.
●
Not all patients require treatment, but for those that do there is a range of therapies available for effective management. Dopaminergic agents in dosages usually much lower than those prescribed in Parkinson’s disease are considered the first-line treatment in RLS.
Selected Reading Allen R, Picchietti D, Hening WA, et al: Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4:101-119. Hening WA, Allen RP, Earley CJ, et al: An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine interim review. Sleep 2004; 27:560-583. The International Restless Legs Syndrome Study Group: Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs. Sleep Med 2003; 4:121132.
Stiasny-Kolster K, Kohnen R, Möller JC, Trenkwalder C, et al: Validation of the “L-dopa test” for diagnosis of restless legs syndrome. MOV Disord in press. Stiasny-Kolster K, Magerl W, Oertel WH, et al: Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain 2004; 127:773-782. Walters AS: Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995 10:634-642.
References 1. Ekbom KA: Restless legs syndrome. Acta Med Scand 1945; 158(Suppl):4-122. 2. Hening W, Walters AS, Allen RP, et al: Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med 2004; 5:237-246. 3. Allen RP, Earley CJ: Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurol 2001; 18:128-147. 4. Winkelmann J, Prager M, Lieb R, et al: “Anxietas tibiarum.” Depression and anxiety disorders in patients with restless legs syndrome. J Neurol 2005; 252:67-71. 5. Sevim S, Dogu O, Kaleagasi H, et al: Correlation of anxiety and depression symptoms in patients with restless legs syndrome: a population based survey. J Neurol Neurosurg Psychiatry 2004; 75:226-230. 6. Montplaisir J, Boucher S, Poirier G, et al: Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997; 12:61-65. 7. Smith RC: Relationship of periodic movements in sleep (nocturnal myoclonus) and the Babinski sign. Sleep 1985; 8:239243. 8. Ulfberg J, Nystrom B, Carter N, et al: Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001; 16:1159-1163. 9. Rothdach AJ, Trenkwalder C, Haberstock J, et al: Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and Morbidity in Augsburg Elderly. Neurology 2000; 54:1064-1068. 10. Phillips B, Young T, Finn L, et al: Epidemiology of restless legs syndrome in adults. Arch Intern Med 2000; 160:21372141.
chapter 37 restless legs syndrome 11. Ulfberg J, Nystrom B, Carter N, et al: Restless legs syndrome among working-aged women. Eur Neurol 2001; 46:17-19. 12. Högl B, et al: Prevalence of restless legs syndrome in the central European alpine region of South Tyrol. Sleep 2003; 26:A344. 13. Berger K, Luedemann J, Trenkwalder C, et al: Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004; 164:196-202. 14. Kageyama T, Kabuto M, Nitta H, et al: Prevalences of periodic limb movement–like and restless legs–like symptoms among Japanese adults. Psychiatry Clin Neurosci 2000; 54:296-298. 15. Ohayon MM, Roth T: Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002; 53:547-554. 16. Walters AS, Hickey K, Maltzman J, et al: A questionnaire study of 138 patients with restless legs syndrome: the “NightWalkers” survey. Neurology 1996; 46:92-95. 17. Stautner A, Stiasny K, Collado-Seidel V, et al: Comparison of idiopathic and uremic restless legs syndrome: results of a database of 134 patients [Abstract]. Mov Disord 1996; 11(Suppl):98. 18. Ondo W, Jankovic J: Restless legs syndrome: clinicoetiologic correlates. Neurology 1996; 47:1435-1441. 19. Winkelmann J, Muller-Myhsok B, Wittchen HU, et al: Complex segregation analysis of restless legs syndrome provides evidence for an autosomal-dominant mode of inheritance in early age at onset families. Ann Neurol 2002; 52:279-302. 20. Allen, RP, Earley CJ: Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset. Sleep Med 2000; 1:11-19. 21. Desautels A, Turecki G, Montplaisir J, et al: Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet 2001; 69:1266-1270. 22. Bonati MT, Ferini-Strambi L, Aridon P, et al: Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 2003; 126(Pt 6):1485-1492. 23. Levchenko A, Montplaisir JY, Dube MP, et al: The 14q restless legs syndrome locus in the French Canadian population. Ann Neurol 2004; 55:887-891. 24. Chen S, Ondo WG, Rao S, et al: Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 2004; 74:876885. 25. Trenkwalder C, Seidel VC, Gasser T, et al: Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996; 11:389-394. 26. Lazzarini A, Walters AS, Hickey K, et al: Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord 1999; 14:111-116. 27. Desautels A, Turecki G, Montplaisir J, et al: Dopaminergic neurotransmission and restless legs syndrome: a genetic association analysis. Neurology 2001; 57:1304-1306. 28. Dichgans M, Walther E, Collado-Seidel V, et al: Autosomaldominant restless legs syndrome: genetics model and evaluation of 22 candidate genes. Mov Disord 1996; 11:87. 29. Collado-Seidel V, Kohnen R, Samtleben W, et al: Clinical and biochemical findings in uremic patients with and without restless legs syndrome. Am J Kidney Dis 1998; 31:324328. 30. Gigli GL, Adorati M, Dolso P, et al: Restless legs syndrome in end-stage renal disease. Sleep Med 2004; 5:309-315. 31. O’Keeffe ST, Gavin K, Lavan JN: Iron status and restless legs syndrome in the elderly. Age Ageing 1994; 23:200-203. 32. Sun ER, Chen CA, Ho G, et al: Iron and the restless legs syndrome. Sleep 1998; 21:371-377. 33. McParland P, Pearce JM: Restless legs syndrome in pregnancy. Case reports. Clin Exp Obstet Gynecol 1990; 17:5-6.
483
34. Manconi M, Govoni V, De Vito A, et al: Restless legs syndrome and pregnancy. Neurology 2004; 63:1065-1069. 35. Iannaccone S, Zucconi M, Marchettini P, et al: Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995; 10:2-9. 36. Gemignani F, Marbini A, Di Giovanni G, et al: Cryoglobulinaemic neuropathy manifesting with restless legs syndrome. J Neurol Sci 1997; 152:218-223. 37. Salvi F, Montagna P, Plasmati R, et al: Restless legs syndrome and nocturnal myoclonus: initial clinical manifestation of familial amyloid polyneuropathy. J Neurol Neurosurg Psychiatry 1990; 53:522-525. 38. Gemignani F, Marbini A, Di Giovanni G, et al: Charcot-MarieTooth disease type 2 with restless legs syndrome. Neurology 1999; 52:1064-1066. 39. Polydefkis M, Allen RP, Hauer P, et al: Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 2000; 55:1115-1121. 40. Rutkove SB, Matheson JK, Logigian EL: Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996; 19:670-672. 41. Walters AS, Wagner M, Hening WA: Periodic limb movements as the initial manifestation of restless legs syndrome triggered by lumbosacral radiculopathy [Letter]. Sleep 1996; 19:825-826. 42. Winkelmann J, Wetter TC, Trenkwalder C, et al: Periodic limb movements in syringomyelia and syringobulbia. Mov Disord 2000; 15:752-755. 43. Chervin RD, Archbold KH, Dillon JE, et al: Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep 2002; 25:213218. 44. Walters AS, Mandelbaum DE, Lewin DS, et al: Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group. Pediatr Neurol 2000; 22:182-186. 45. Picchietti DL, Underwood DJ, Farris WA, et al: Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord 1999; 14:1000-1007. 46. Trenkwalder C, Paulus W: Why do restless legs occur at rest?—Pathophysiology of central and peripheral structures in RLS. Neurophysiology of RLS (part 2). Clin Neurophysiol 2004; 115:1975-1988. 47. Winkelmann J, Schadrack J, Wetter TC, et al: Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients. Sleep Med 2001; 2:57-61. 48. Happe S, Zeitlhofer J: Abnormal cutaneous thermal thresholds in patients with restless legs syndrome. J Neurol 2003; 250:362-365. 49. Sowers JR, Vlachakis N: Circadian variation in plasma dopamine levels in man. J Endocrinol Invest 1984; 7:341-345. 50. Garcia-Borreguero D, Odin P, Schwarz C: Restless legs syndrome: an overview of the current understanding and management. Acta Neurol Scand 2004; 109:303-317. 51. Earley CJ, Hyland K, Allen RP: CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome. Mov Disord 2001; 16:144-149. 52. Stiasny-Kolster K, Moller JC, Zschocke J, et al: Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients. Mov Disord 2004; 19:192-196. 53. Pittock SJ, et al: Neuropathology of primary restless legs syndrome: Absence of specific tau- and alpha-synuclein pathology. Mov Disord 2004; 19(6):695-699. 54. Michaud M, et al: Circadian rhythm of restless legs syndrome: relationship with biological markers. Ann Neurol 2004; 55:372-380.
484
Section
VII
Motor System and Motor Diseases
55. Tribl SJ, Waldhauser F, Sycha T, et al: Urinary 6-hydroxymelatonin-sulfate excretion and circadian rhythm in patients with restless legs syndrome. J Pineal Res 2003; 35:295-296. 56. Earley CJ, Heckler D, Allen RP: The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 2004; 5:231-235. 57. Allen RP, Barker PB, Wehrl F, et al: MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001; 56:263-265. 58. Earley CJ, Connors JR, Allen RP: RLS patients have abnormal reduced CSF ferritin compared to normal controls. Neurology 1999; 52(Suppl 2):A111-A112. 59. Connor JR, Wang XS, Patton SM, et al: Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 2004; 62:1563-1567. 60. Stiasny-Kolster K, Magerl W, Oertel WH, et al: Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain 2004; 127:773782. 61. Trenkwalder C, Bucher SF, Oertel WH, et al: Bereitschaftspotential in idiopathic and symptomatic restless legs syndrome. Electroencephalogr Clin Neurophysiol 1993; 89:95-103. 62. Tergau F, Wischer S, Paulus W: Impaired motor cortex excitability in patients with restless legs syndrome. Neurology 1998; 50:A223. 63. Entezari-Taher M, Singleton JR, Jones CR, et al: Changes in excitability of motor cortical circuitry in primary restless legs syndrome. Neurology 1999; 53:1201-1205. 64. Stiasny-Kolster K, Haeske H, Tergau F, et al: Cortical silent period is shortened in restless legs syndrome independently from circadian rhythm. Suppl Clin Neurophysiol. 2003; 56:381-389. 65. Ondo W: Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 2000; 15:154-158. 66. Akpinar S: The primary restless legs syndrome pathogenesis depends on the dysfunction of EEG alpha activity. Med Hypotheses 2003; 60:190-198. 67. Bucher SF, Seelos KC, Oertel WH, et al: Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol 1997; 41:639-645. 68. de Mello MT, et al: Incidence of periodic leg movements and of the restless legs syndrome during sleep following acute physical activity in spinal cord injury subjects. Spinal Cord 1996; 34(5):294-296. 69. de Mello MT, Poyares DL, Tufik S: Treatment of periodic leg movements with a dopaminergic agonist in subjects with total spinal cord lesions. Spinal Cord 1999; 37:634-637. 70. Dickel MJ, Renfrow SD, Moore PT, et al: Rapid eye movement sleep periodic leg movements in patients with spinal cord injury. Sleep 1994; 17:733-738. 71. Yokota T, Hirose K, Tanabe H, et al: Sleep related periodic leg movements (nocturnal myoclonus) due to spinal cord lesion. J Neurol Sci 1991; 104:13-18. 72. Culpepper WJ, Badia P, Shaffer JI: Time-of-night patterns in PLMS activity. Sleep 1992; 15:306-311. 73. Pollmächer T, Schulz H: Periodic leg movements (PLM): their relationship to sleep stages. Sleep 1993; 16:572-577. 74. Sandkühler J: Learning and memory in pain pathways. Pain 2000; 88:113-118. 75. Walters AS: Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995; 10:634-642. 76. Allen R, Picchietti D, Hening WA, et al: Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4:101-119.
77. Montplaisir J, Boucher S, Nicolas A, et al: Immobilization tests and periodic leg movements in sleep for the diagnosis of restless leg syndrome. Mov Disord 1998; 13:324-329. 78. Barton JC, Wooten VD, Acton RT: Hemochromatosis and iron therapy of restless legs syndrome. Sleep Med 2001; 2:249-251. 79. Exar EN, Collop NA: The association of upper airway resistance syndrome. Sleep 2001; 24:188-192. 80. Michaud M, Lavigne G, Desautels A, et al: Effects of immobility on sensory and motor symptoms of restless legs syndrome. Mov Disord 2002; 17:112-115. 81. Stiasny-Kolster K, Kohnen R, Möller JC, Treukwalder C, et al: Validation of the “L-dopa test” for diagnosis of restless legs syndrome. MOV Disord in press. 82. The International Restless Legs Syndrome Study Group: Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs. Sleep Med 2003; 4:121132. 83. Kohnen R, Oertel WH, Stiasny-Kolster K, et al: Severity rating of restless legs syndrome: review of ten years experience with the RLS-6 scales in clinical trials. Sleep 2003; 26:A342. 84. Lang AE, Johnson K: Akathisia in idiopathic Parkinson’s disease. Neurology 1987; 37:477-481. 85. Poewe W, Högl B: Akathisia, restless legs and periodic limb movements in sleep in Parkinson’s disease. Neurology 2004; 63(Suppl 3):S12-S16. 86. Yasuda T, Nishimura A, Katsuki Y, et al: Restless legs syndrome treated successfully by kidney transplantation—a case report. Clin Transpl 1986; 12:138. 87. Goodman JD, Brodie C, Ayida GA: Restless leg syndrome in pregnancy. BMJ 1988; 297:1101-1102. 88. Lee KA, Zaffke ME, Baratte-Beebe K: Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J Womens Health Gend Based Med 2001; 10:335-341. 89. Davis BJ, Rajput A, Rajput ML, et al: A randomized, doubleblind, placebo-controlled trial of iron in restless legs syndrome. Eur Neurol 2000; 43:70-75. 90. Silber MH, Ehrenberg BL, Allen RP, et al: An algorithm for the management of restless legs syndrome. Mayo Clin Proc 2004; 79:916-922. 91. Hornyak M, Voderholzer U, Hohagen F, et al: Magnesium therapy for periodic leg movements–related insomnia and restless legs syndrome: an open pilot study. Sleep 1998; 21:501-505. 92. Hening WA, Allen RP, Earley CJ, et al: An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine interim review. Sleep 2004; 27:560-583. 93. Trenkwalder C, Stiasny K, Pollmacher T, et al: L-Dopa therapy of uremic and idiopathic restless legs syndrome: a doubleblind, crossover trial. Sleep 1995; 18:681-688. 94. Collado-Seidel V, Kazenwadel J, Wetter TC, et al: A controlled study of additional SR-L-dopa in L-dopa responsive RLS with late night symptoms. Neurology 1999; 52:285-290. 95. Benes H, Kurella B, Kummer J, et al: Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. Sleep 1999; 22:10731081. 96. Allen RP, Earley CJ: Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996; 19:205-213. 97. Stiasny K, Robbecke J, Schuler P, et al: Treatment of idiopathic restless legs syndrome (RLS) with the D2-agonist cabergoline—an open clinical trial. Sleep 2000; 23:349-354. 98. Stiasny-Kolster K, Benes H, Peglau I, et al: Effective cabergoline treatment in idiopathic restless legs syndrome (RLS). Neurology 2004; 63:2272-2279. 99. Oertel WH, Benes H, Happe S, et al: Efficacy of cabergoline for the treatment of sensori-motor symptoms and sleep
chapter 37 restless legs syndrome
100. 101. 102.
103.
disturbances in restless legs syndrome: A placebo-controlled, 5-week, double-blind, randomized, multicenter, polysomnographic study. Mov Disord 2004; 19(Suppl. 9):S425. Wetter TC, Stiasny K, Winkelmann J, et al: A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999; 52:944-950. Stiasny K, Wetter TC, Winkelmann J, et al: Long-term effects of pergolide in the treatment of restless legs syndrome. Neurology 2001; 56:1399-1402. Trenkwalder C, Garcia-Borreguero D, Montagna P, et al: Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004; 75:92-97. Walters AS, Ondo WG, Dreykluft T, et al: Ropinirole is effective in the treatment of restless legs syndrome: TREAT RLS 2: a 12-week double-blind, randomized, parallelgroup, placebo-controlled study. Mov Disord 2004; 19:14141423.
485
104. Montplaisir J, Nicolas A, Denesle R, et al: Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999; 52:938-943. 105. Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al: Efficacy of Pramipexole in restless legs syndrome: a 6-week, multicenter, randomize, double-blind study. Submitted for publication. 106. Stiasny-Kolster K, Kohnen R, Schollmayer E, et al: Patchapplication of the dopamine agonist rotigotine to patients with moderate to advanced stages of restless legs syndrome— a double-blind placebo-controlled pilot study. Mov Disord 2004; 19:1432-1438. 107. Walters AS, Wagner ML, Hening WA, et al: Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993; 16:327-332. 108. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al: Treatment of restless legs syndrome with gabapentin: a doubleblind, cross-over study. Neurology 2002; 59:1573-1579.
CHAPTER
38
SPINE
AND SPINAL CORD: DEVELOPMENTAL DISORDERS ●
●
●
●
Valerie S. Tay, Andrew Kornberg, and Mark Cook
Developmental disorders of the spine and spinal cord occur because of defects in the development and maturation of the nervous system. A basic understanding of embryology is therefore important in appreciating the nature and scope of these disorders. There are various ways of approaching and thinking about the developmental disorders: 1. Clinicoanatomical: This is a logical viewpoint because the anatomical defect is correlated with the neurological impairment, disabilities experienced, and overall functional outcome. Disorders can be classified anatomically on the basis of the structures (e.g., bony elements, supporting soft tissues, or neural elements) or the level of the neuraxis involved. Clinically, the developmental disorders of the spine and spinal cord can manifest in various domains, and clinical features can generally be thought of as neurological or myelopathic, as orthopedic and biomechanical, or as multisystem features of a widespread developmental disorder. 2. Molecular genetics: In the area of developmental disorders, research into the molecular genetics is increasingly important in advancing knowledge of the mechanisms underlying these disorders, in reclassifying the syndromes, and in providing a common link between some of the disorders. As knowledge and understanding of these disorders continue to expand, the most reasonable approach is to integrate advances in genetic and etiological models within the traditional phenotypic clinicoanatomical framework. Developmental disorders can be classified anatomically, depending on whether they affect primarily the spinal cord and neural tissues or the spine and supporting structures (Table 38–1). There is a wide spectrum of developmental disorders affecting the spine and spinal cord, ranging in age at presentation, in clinical manifestations, and in severity. Although more likely to manifest in the pediatric population, some milder forms may manifest later in life as well. Neurologists for both pediatric and adult populations should have an awareness and appreciation of the range and manifestations of these disorders. The aim of this chapter is to provide a broad overview and appreciation of the developmental disorders affecting the spine and spinal cord, with a few select disorders covered in greater depth. A host of vascular malformations and metabolic conditions may affect the spine and spinal cord; they remain, however, beyond the scope of this chapter and are not discussed.
488
NORMAL DEVELOPMENT OF THE NERVOUS SYSTEM The human embryonic period spans the first 8 postfertilization weeks and is classified on the basis of a morphological system. There are 23 distinct Carnegie stages, each stage covering a period of 2 to 3 days. This staging system facilitates an understanding of the timing and sequence of embryonic development. The fetal period spans the 9th week after fertilization to birth. Fetal age is thought of mainly as measurements, inasmuch as a similar morphological staging system is not available. The great majority of congenital malformations begin during the embryonic period.1-3 The neural tube is the embryonic structure that develops into the brain and spinal cord. Primary neurulation refers to the development of the neural tube from the neural plate. Complete development and closure of the neural tube occurs from days 17 to 30 after conception and spans Carnegie stages 8 to 12 in the embryonic period (Table 38–2). The caudal eminence is the continuation of the primitive streak and develops into the terminal portions of the notochord, somites, vertebrae, and hindgut. The neural cord arises from the caudal eminence and forms the caudal portion of the spinal cord. This process is secondary neurulation. The level of the junction between primary and secondary neurulation is at the level of the future second sacral vertebra. There is elongation of the previous neural tube together with formation of the lower sacral and coccygeal segments. This part of the development of the nervous system commences in stage 12 at 4 weeks and ends approximately at stage 20.2-6 The vertebral bodies of the spine are generated from the mesenchymal cells. The process of gastrulation occurs at day 14 in embryonic life to generate the mesenchymal cells that will in turn develop into the head, cardiac, and the paraxial and lateral mesoderm. At 20 to 30 days in embryonic life, the paraxial mesoderm, in a process of somatogenesis, subdivides into spherical somite segments on each side of the spinal cord in a rostral-tocaudal direction. The somites first appear in stage 9; differentiation commences at stage 10. The somites mature and further subdivide into the sclerotome to form the vertebral bodies, the myotome to form the musculature, and the dermatome to form the dermis. The sclerotome undergoes a resegmentation process in which the caudal end of one somite links with the rostral end of the next somite to form a vertebral body.7-9
chapter 38 spine and spinal cord: developmental disorders
489
T A B L E 38–1. Developmental Disorders That Can Affect Vertebrospinal Structures Disorders Affecting the Spine
Disorders Affecting the Spinal Cord and Neural Tissues
Disorders of the craniovertebral junction, including: Klippel-Feil anomaly Basilar invagination and platybasia Occipitalization of the atlas Congenital atlantoaxial dislocation
Chiari malformation Syrinx Neural tube defects Split cord malformations Sacral agenesis Tethered cord syndrome Lipomas Tight filum terminale Dural bands Congenital sinus tracts and intraspinal dermoid, epidermoid Developmental cysts
Scoliosis
Vascular Malformations A variety of vascular malformations can affect the spine and spinal cord
T A B L E 38–2. Important Stages in Primary Neurulation and the Formation and Closure of the Neural Tube Development Stage No.
Days in Embryonic Life
8 9 10
17-19 19-21 22-23
11 12
23-26 26-30
Nervous System Development Development of the neural plate Development of the neural folds First steps in the fusion of the neural folds: There are two initial sites of fusion: fusion proceeds bidirectionally from the lower medullary rhombencephalic site and in a caudal direction from the higher prosencephalic site. The fusions terminate in two neuropores: the rostral and caudal neuropores. Closure of the rostral neuropore Closure of the caudal neuropore
Based on a table from Lemire RJ: Neural tube defects. JAMA 1988; 259:558-562 Copyright © 1988 American Medical Association. All rights reserved; and on information from O’Rahilly R, Muller F: The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology 2002; 65:162-170.
DEVELOPMENTAL DISORDERS AFFECTING THE SPINE The developmental disorders affecting the spine that are covered in this chapter include scoliosis and a cluster of disorders originating primarily at the craniocervical junction. Some of the other generalized spinal disorders, including metabolic disorders, are covered in other chapters.
Klippel-Feil Anomaly Definition The Klippel-Feil anomaly comprises a heterogeneous spectrum of conditions with the unifying feature of congenital synostosis of some or all of the cervical vertebrae. There have been many classification systems put forth for Klippel-Feil, including those based on anatomy and the extent of cervical fusion and on genetic transmission.
Epidemiology The Klippel-Feil anomaly occurs in 1 per 40,000 to 1 per 42,000 births, with a female-to-male ratio of 3:2.8
Clinical Features Individuals with Klippel-Feil anomaly may be asymptomatic. Clinical manifestations can range from pain, through orthopedic or neurological manifestations, to a more widespread malformation disorder. The initial description was of a classical triad of shortening of the neck, limited range of neck movement, and a low posterior hairline. Affected individuals may complain of cervical pain and present with cosmetic deformities. The Klippel-Feil anomaly may be associated with spinal instability. This occurs if there are unstable fusion patterns or if stenosis and arthritis develop at the interspaces between the fused joints. The associated axial and spine anomalies include cervical or fused ribs, cleft vertebrae or hemivertebrae, and kyphoscoliosis.8 Neurological impairment depends on the presence and degree of neurocompression. For instance, a cervical rib can cause neurocompression with upper limb numbness and pain. Cervical cord compression can lead to a myelopathic picture. A traditional observation is the presence of mirror movements. This can be demonstrated by asking the patient to supernate/pronate a single arm. Mirror movements are those in which the other limb supernates/pronates at the same time. The Klippel-Feil anomaly may be associated with other spinal developmental disorders, including syrinx, tethered cord, and split cord malformations (SCMs). Alternatively, the Klippel-
490
Section
VIII
Spine and Spinal Diseases
Feil anomaly could be part of a widespread multisystem developmental disorder as well, in which other features include hearing deficits, congenital heart disease, and genitourinary manifestations.8
lize the spine is indicated if there is neurological impairment or symptomatic cervical instability. Surgical options include occipitocervical arthrodesis and combined atlantoaxial and subaxial arthrodesis.8
Etiology and Pathophysiology
Basilar Impression
The Klippel-Feil anomaly results from failure of normal segmentation of the vertebral column in early embryonic life. The exact cause and mechanism behind this syndrome are unclear; the Klippel-Feil anomaly may result from disruptions in isolated genes that govern segmentation, or it may result from complex gene-gene or gene-environment interactions.8
Definition
Management Diagnostic investigations center on imaging studies. Goodquality radiographs and computed tomographic (CT) scans of the cervical spine are necessary to show the extent of cervical fusion and to evaluate potential instability (Fig. 38–1). Magnetic resonance imaging (MRI) studies, including flexion and extension views, are useful for evaluating instability or stenosis in the cervical spine and for assessing neurocompression of the spinal cord. MRI should be performed on the whole neuraxis in order to look for the associated developmental anomalies. Further evaluation is targeted at the associated conditions, including audiology assessments and cardiac and renal investigations.8 Management depends on the symptoms and the presence of other malformations. Treatment modalities may include simple measures of modifying activities and the use of traction and bracing to alleviate deformities. Surgical intervention to stabi-
Basilar impression (or basilar invagination) occurs when there is an abnormal upward displacement of the basilar and condylar portions of the occipital bone. This leads to invagination of the foramen magnum into the posterior cranial fossa with associated translocation of the upper cervical vertebrae into this depression. We believe the terms basilar impression and basilar invagination are interchangeable, but some authors differentiate basilar impression from basilar invagination on the basis of differences in anatomical definitions and causation (e.g., acquired or primary).10,11 Some texts include platybasia in the spectrum of basilar impression. Platybasia is an abnormal flattening of the base of the skull with an abnormally obtuse angle between the plane of the clivus and the plane of the anterior fossa. This may occur together with basilar impression but is of no real clinical significance. Basilar impression has traditionally been defined on the basis of a deviation from set anatomical and radiological parameters: 1. Chamberlain’s line is drawn from the dorsal edge of the hard palate to the dorsal lip of the foramen magnum. 2. McGregor’s line is from the upper surface of the posterior edge of the hard palate to the lowest level of the occipital bone.
■
Figure 38–1. Computed tomographic image of a Klippel-Feil anomaly. The coronal image (A) shows fusion of C2 and C3 and a large block fusion from C5 to T2. B, A three-dimensional reconstruction in the same patient.
A
B
chapter 38 spine and spinal cord: developmental disorders 3. McRae’s line is a line from the anterior to the posterior border of the foramen magnum. 4. Bull’s angle is an angle at the intersection of the plane of the hard palate and the plane of the atlas (line formed by joining the midpoints of the anterior and posterior arches of the atlas). The normal upper limit for this angle is 13 degrees. For instance, if Chamberlain’s line is the defining parameter, basilar impression is present when more than one third of the odontoid process lies above this line.10,12
Epidemiology Basilar impression is the most common of the craniocervical malformations; clinical manifestations usually occur from the second decade onward.11 The true incidence is unclear.
491
modalities for symptomatic basilar impression include cervical traction and surgical intervention. Cervical traction has been reported to cause vertebral artery dissection, as well as potentially causing infection, cranial fractures, and hemorrhage. Anterior compression is managed with an anterior surgical approach; posterior or circumferential compression is managed with a posterior approach. The role of prophylactic surgery or prolonged immobilization with asymptomatic lesions is unclear.10,12
Occipitalization of the Atlas Definition This is a congenital disorder in which the atlas either is completely or incompletely fused to or is incorporated into the occiput.
Clinical Features Basilar impression may be asymptomatic or may manifest with deformities, including a shortened neck. Movement or exerciseinduced occipital headache is a common feature. Oculomotor features include horizontal and upward-beat or downward-beat nystagmus. Other cranial nerve symptoms include facial nerve spasm, trigeminal sensory symptoms, and trigeminal neuralgia. Pontomedullary compression can lead to pyramidal tract signs, with the lower limbs typically more affected than the upper limbs. Sleep apnea and respiratory depression have been described.11,12 Primary basilar impression is often associated with other developmental anomalies, including occipitalization of the atlas, the Klippel-Feil anomaly, the Arnold-Chiari malformation, and syringomyelia or syringobulbia.12
Epidemiology Occipitalization of the atlas occurs in 1% of the population.13
Clinical Features This condition may be asymptomatic. However, atlantoaxial dislocation can occur in up to 60% of affected patients. In this condition, there is excessive compensatory stress on the atlantoaxial joint as a result of the decreased movement of the atlantooccipital joint. This situation increases the possibility of developing traumatic dislocation or cervical degenerative joint disease. Occipitalization of the atlas is associated with other developmental disorders as well, including basilar impression, Klippel-Feil anomaly, and Chiari malformations.13
Etiology and Pathophysiology Neurological manifestations occur in basilar impression as a result of direct compression on the brainstem and of vascular abnormalities. Basilar impression can be classified on the basis of etiology into two categories: 1. Primary basilar impression, a primary developmental defect with a familial tendency in which there is no underlying bone abnormalities. 2. Secondary basilar impression, in which an underlying generalized bone disorder leads to bone softening. Secondary basilar impression has been described with achondroplasia, osteogenesis imperfecta, osteomalacia, hyperparathyroidism, Paget’s disease, Hurler’s syndrome, and HajduCheney syndrome.11,12
Management Imaging studies are necessary to fully evaluate basilar impression and associated anomalies. CT scans are useful in reviewing the bony anatomy, whereas MRI is particularly useful in evaluating neural structures for neurocompression, cerebellar tonsillar herniation, and syrinx. Other investigations for an underlying systemic disorder include measurements of calcium, phosphate, and alkaline phosphatase. The treatment goal is to relieve current compression, and to prevent future compression, of the neuraxis. The treatment
Atlantoaxial Dislocation Definition A variety of congenital anomalies can affect the atlantoaxial junction and cause atlantoaxial dislocation. These anomalies include the following: 1. Congenital C1 anomalies, which may include partial or complete agenesis or dysgenesis of the posterior arch and hypoplasia of the atlas with an intact arch.14 2. Abnormalities of the dens, including hypoplasia, bifid dens, and tripartite dens. 3. Os odontoideum, in which the odontoid process fails to fuse to the body of the axis.
Epidemiology The various degrees of C1 malformations have a quoted prevalence rate of 4%, which is based on autopsy studies.14
Clinical Features Abnormalities in this region may be asymptomatic and found incidentally, or they may manifest with pain. The vertebral anomalies may lead to atlantoaxial instability and dislocation.
492
Section
VIII
Spine and Spinal Diseases
This may result in cervicomedullary compression, which may manifest either spontaneously or after trauma. Affected individuals are especially prone to cord compression during extension injuries: for instance, with intubation or after neck injuries. These anomalies should be considered when a child presents with a neurological deficit or neck pain after minor trauma.14,15 Congenital atlantoaxial instability may be seen in association with Down’s syndrome. Other congenital craniovertebral junction and spinal disorders may occur in tandem as well, including Chiari type I and SCMs. It is important to be aware that atlantoaxial instability may not be congenital in nature but may be caused by an underlying condition, such as rheumatoid arthritis.14,15
Etiology and Pathophysiology The craniovertebral junction malformations arise from defects during the ossification process. The malformations lead to instability in the atlantoaxial joint with subsequent dislocation. Subluxation usually occurs in the horizontal plane, with C1 moving anteriorly to C2. In other settings, progressive cervical myelopathy rarely occurs above C2; the usual scenario of a myelopathy is in the context of acquired degenerative change and usually occurs below C3. The risk of neurocompression depends on the underlying malformation and the joint stability. The actual degree of neurocompression depends on the extent of the subluxation and the width of the spinal canal. The normal sagittal diameter of the spinal canal is 16 to 25 mm at the level of the atlas; the spinal cord is at risk when the canal diameter is less than 14 mm.14
Management The use of high-quality imaging with plain radiographs, CT scans (including fine cuts), and MRI is necessary in the evaluation of atlantoaxial dislocation and craniocervical anomalies. Flexion and extension views are especially useful for assessing joint stability. MRI is crucial in the assessment of the neural structures, especially with regard to cord compression. Surgery is indicated in order to decrease the possibility that significant neurological deficits may develop and should be considered when there is neurocompression or when the individual is symptomatic. Surgery for atlantoaxial and craniocervical instability is a challenging field, especially because surgeons have to work with abnormal anatomy while taking into account the ongoing growth potential for the child. Depending on the underlying malformation, surgical management consists of decompression procedures and joint fusion and stabilization.14-17
Scoliosis
Epidemiology Idiopathic scoliosis affects 2% to 4% of children aged 10 to 16 years. The incidence is equal in boys and girls for curves of less than 20 degrees. Girls, however, significantly outnumber boys, at 5:1, for curves of more than 20 degrees. Secondary neurogenic scoliosis is more common in the younger population. For instance, of patients with the Chiari malformation and syringomyelia, 82% younger than 20 years have scoliosis, as opposed to only 16% of those older than 20 years.18,19
Clinical Features Individuals with scoliosis may present with back pain or, more obviously, with the spinal curvature deformity. In evaluating scoliosis, it is imperative to be aware that the spinal deformity may be the presenting feature of an underlying spinal cord or brainstem anomaly in 4% to 58% of affected patients. Individuals with scoliosis may present with the neurological or orthopedic features of the underlying developmental disorder.18,19
Etiology and Pathophysiology Secondary scoliosis is thought to arise from a generalized paresis of truncal musculature or congenital changes in the vertebrae. In addition, scoliosis in the Chiari-syringomyelia complex may be caused by the abnormal intramedullary pressures within the spinal cord that interfere with the postural tonic reflexes.18,19
Management It is important to treat or rule out an underlying spinal cord or brainstem disorder in a young patient with scoliosis. Evaluation includes the use of radiographs (Fig. 38–2) to chart the pattern of scoliosis and MRI to look for associated anomalies in the neural elements. Posterior fossa decompression for the Chiari-syringomyelia malformation can lead to an improvement in the scoliosis, especially if done early in the patient’s life. Initial treatment may involve use of a spinal orthotic brace as well. Spinal fusion surgery may ultimately be required for surgical correction of the scoliosis.18,19
DEVELOPMENTAL DISORDERS AFFECTING THE SPINAL CORD AND NEURAL TISSUES The developmental disorders affecting the spinal cord and neural tissues broadly includes the craniospinal anomalies, including the Chiari malformation and syringomyelia, and a diverse range of spinal cord abnormalities, including NTDs and the various causes of spinal dysraphism.
Definition Scoliosis is diagnosed on the basis of a 10-degree lateral curve with associated vertebral rotation. Scoliosis may be either primary (idiopathic scoliosis) or secondary. Neurogenic scoliosis is usually secondary to a developmental disorder, including the Chiari malformation, hydrosyringomyelia, and neural tube defects (NTDs).
Chiari Malformation Definition In 1891, Hans Chiari first described the disorder that now bears his name as cerebellar tonsillar herniation below the plane of the foramen magnum into the spinal canal. Further contribu-
chapter 38 spine and spinal cord: developmental disorders
■
Figure 38–2. Plain radiograph of scoliosis in a patient with spina bifida. The radiograph is best done in a standing position. The radiograph shows a C-shaped scoliosis of the spine centered at L1 with the convexity toward the patient’s left. There is a windswept appearance to the pelvis, with the right iliac crest sitting higher than the left as a result of the underlying scoliosis.
tions and observations were made by Julius Arnold and John Cleland. Chiari malformations are also known as cerebellar ectopy and are classified into four types: 1. Type I: Herniation of the cerebellar tonsils. This may be associated with elongation of the medulla. Tonsillar herniation is deemed to be pathological if it extends more than 5 mm below the foramen magnum. 2. Type II: Herniation of the caudal part of the cerebellum, the fourth ventricle, the pons, and the medulla. Chiari type II malformation is often associated with a lumbar myelomeningocele. 3. Type III: Rare condition with cerebellar herniation associated with a cervical or occipital encephalocele. 4. Type IV: Severe cerebellar and brainstem hypoplasia.20-22
Epidemiology Chiari type I malformations have a prevalence of 0.6% to 0.9% in studies based on MRI. Symptomatic Chiari type I malformations are slightly more common in girls and women, with a female-to-male ratio of 1.3:1 to 1.7:1.22,23
Clinical Features As with the other developmental disorders, the Chiari malformation may be asymptomatic or, alternatively, may be symptomatic with a wide spectrum of clinical manifestations. A very common manifestation is headaches with or without
493
cervical pain. The headache is typically a protracted occipitalsuboccipital headache and is exacerbated by the Valsalva maneuver, postural changes, and coughing or straining. Another common complaint is of weakness and altered sensation, including paresthesia and dysesthesias. A myelopathy may manifest with the sensorimotor or sphincter disturbances. Individuals with Chiari malformations may present with ataxia and other cerebellar signs. Downward-beating nystagmus and other oculomotor disturbances may occur. Other features of brainstem dysfunction may result, including cranial neuropathies, neuro-otological symptoms, sleep apnea, and dysphagia.21-24 Syringomyelia occurs in 32% to 74% of individuals with Chiari type I malformations. A cervical syrinx may manifest with upper limb neurological deficits, whereas a thoracic syrinx may lead to scoliosis. In addition, osseous anomalies of the base of skull, including basilar impression, may be seen with Chiari type I malformations. Chiari type II malformations are often associated with an NTD, other brainstem deformities, and hydrocephalus. Features of raised intracranial pressure are commonly the clinical manifestations of the associated hydrocephalus. The Chiari type I malformation is usually asymptomatic in childhood and tends to manifest in the second to third decade of adulthood. The Chiari type II malformation, however, is usually evident in childhood.21,23,24
Etiology and Pathophysiology The Chiari malformation probably arises from underdevelopment of the occipital enchondrium, which leads to an undeveloped occipital bone with a small and shallow posterior fossa. This in turn leads to overcrowding of the posterior fossa and a downward herniation of the brain. The occipital enchondrium originates from the occipital somite, which in turn is derived from paraxial mesoderm. If the occipital enchondrium is more severely affected, basilar impression may result as well. The degree of tonsillar herniation is thought to be correlated to some extent with the severity of symptoms.21,24
Management The main investigation for a suspected Chiari malformation is MRI of the neuraxis. Sagittal views are particularly important in confirming the diagnosis and demonstrating the degree of cerebellar and brainstem herniation and compression (Fig. 38–3). MRI is also useful for identifying the associated hydrocephalus or syrinx and identifying other developmental disorders, including NTDs, although these are usually obvious clinically. If there are neurological symptoms or signs, surgical intervention is usually indicated, to stabilize or ameliorate symptoms. The goal of surgery is to relieve brainstem and cerebellar compression. Ventral compression can be surgically treated with a transoral clivus odontoid resection. If there is no ventral compression, posterior fossa decompression is usually undertaken. A ventriculoperitoneal shunt may be inserted for associated hydrocephalus. The syrinx usually improves after recovery of cerebrospinal fluid (CSF) flow dynamics. If indicated, especially if the syrinx persists despite decompression, a shunt procedure for the syrinx can be undertaken as well.18,19
494
Section
VIII
Spine and Spinal Diseases
Etiology and Pathophysiology
■
Figure 38–3. Magnetic resonance image of a Chiari type I malformation. This sagittal T2 image shows tonsillar herniation and narrowing of the space around the foramen magnum.
Syrinx
The source of fluid in syringomyelia has been postulated to be CSF itself. The exact mechanism for the formation of syringomyelia in a Chiari malformation is unclear. There are two initial principal theories that rely on a patent communication between the fourth ventricle and the syrinx: According to the “water-hammer” theory, the pulsatile transmission of CSF from the choroid plexus is transmitted via an abnormal fourth ventricle to hammer out a dilatation within the spinal cord. The abnormal communication is considered to result from a delayed and incomplete embryonic opening of the outlet of the fourth ventricle. According to the “one-way-valve” theory, there are intermittent high pressures generated in the spinal cord, as a result of an uneven pressure gradient during the Valsalva maneuver. During the Valsalva maneuver, high intrathoracic pressures are transmitted to the epidural spinal veins, leading to an ascending pressure wave pushing CSF from the spinal column to the cranial subarachnoid space. Because there is a downward obstruction to the flow of CSF, this pressure is then translated into CSF movement from the fourth ventricle through the patent central canal into the syrinx. Investigators have reexamined the mechanism of syringomyelia formation, in which magnetic resonance images did not demonstrate a patent communication between the fourth ventricle and syrinx. Instead, it was postulated that during systole, the brain expands with blood. This imparts a systolic pressure wave that moves the cerebellar tonsils downward and acts on the spinal CSF along the surface of the cord to compress the cord and propel fluid in the syrinx longitudinally with each pulse.18,19,25,28
Definition
Management
Hydromyelia is an abnormal dilatation of the central spinal canal, which usually communicates with the fourth ventricle. A syrinx is a fluid-filled cavity either within the spinal cord (syringomyelia) or within the brainstem (syringobulbia). A syrinx is described as either communicating or noncommunicating, depending on whether there is a connection to the CSF pathways.
MRI is crucial in the evaluation of a syrinx because it shows the syrinx itself and the associated neurological disorders, including malformations at the craniocervical junction (Fig. 38–4).27 Surgical management consists mainly of either drainage or posterior fossa decompression. Traditionally, surgical intervention involved drainage with syringostomy and aspiration of the intramedullary fluid. There was later a paradigm shift with foramen magnum decompression, with or without plugging of the obex. More recently, there has been increasing interest in drainage procedures again, mainly because of the advent of microsurgical techniques and better shunt materials. Currently, surgery is indicated for a symptomatic syrinx and can be done either with posterior fossa decompression or as a shunt procedure. Shunts inserted in a syringosubarachnoid, syringopleural, or syringoperitoneal position are potentially associated with many complications, including shunt obstruction, dislocation or infection, spinal cord tethering, and septation within the syrinx cavity.27,29
Clinical Features A syrinx may occur in isolation or may be associated with an abnormality in the craniocervical junction. A common association is with the Chiari type I malformation. The level of the syrinx is variable and may in fact be several levels below the foramen magnum. Syringes may also be secondary to either trauma or focal spinal cord pathology, including tumors.25 The clinical picture in syringomyelia can be variable. The typical description is of a dissociated suspended sensory loss of compromised pain and temperature sensation with intact vibration and joint position sense, in a capelike distribution over the arms and trunk. Associated motor features include myelopathy, leading to spasticity and weakness with lower motor neurone signs at the level of the lesion and upper motor neuron signs below the level of the syrinx. A syrinx can manifest with pain, including radicular pain, neck pain, and headaches. Involuntary movements were characterized in 22% of patients with syringomyelia and syringobulbia, including torticollis, myoclonus, tremors, dystonia, myokymia, respiratory synkinesis, and inverse masticatory muscle activity.26,27
Neural Tube Defects Definition NTDs result either from a failure of fusion of the neural tube in early postconceptional life or from a reopening of a previously closed neural tube.3,6 NTDs can be classified according to the following:
chapter 38 spine and spinal cord: developmental disorders
495
■ Encephalocele or cranial meningocele is an unfused
midline defect in the skull that results in a closed lesion with eventration of the brain tissue and its coverings (encephalocele) or filled with only cerebrospinal fluid (cranial meningocele). These defects are classified by location into occipital, parietal, and anterior lesions.3,6 3. Level of the spinal neural tube: Terminology in this area can be confusing. Some authors refer to this defect in the spinal neural tube as spina bifida. There is incomplete fusion of the caudal neural tube, which leads to lesions affecting the spinal cord, vertebrae, and skin. Other authors, however, consider spina bifida to encompass a more wide-ranging spectrum involving the whole central nervous system. In this chapter, we refer to the former definition of spina bifida. In addition, the terms rachischisis and myelodysplasia are occasionally used as well to define a spinal NTD.3,6,30 Within the spine and spinal cord itself, spina bifida can span a wide range of anomalies, from mild defects with absent spinous processes to the huge defects seen with a myelomeningocele. There are two major working classification systems for spina bifida. Spina bifida can be classified depending on the pattern of the defect (Fig. 38–5):
A ■
B
Figure 38–4. Magnetic resonance images of a thoracic syrinx. There is a syrinx of the cord, largest at the midthoracic level, where it occupies 60% of the cord width. A syrinx is usually central within the cord and has a fusiform appearance. The signal characteristic of a syrinx is isointensity of cerebrospinal fluid on both T1 and T2. For instance, the syrinx appears hypointense on the T1 sequence (A) and hyperintense on the T2 sequence (B).
1. The level at which they occur within the nervous system. 2. The timing of the defect: Neurulation defects occur during the neurulation process, whereas postneurulation defects occur later. 3. Whether they are open or closed: In an open lesion, the neural tissues are exposed, whereas in a closed lesion, the defect is covered by skin. Open lesions occur as neurulation defects and closed lesions as postneurulation defects. The postneurulation defects are closed lesions because the embryonic ectoderm covers the surface of the embryo, this coverage having occurred with earlier closure of the neural tube. Clinically, it is best to consider NTDs according to the level at which they occur within the neuraxis: 1. Level of both the cranial and spinal portions of the neural tube ■ Craniorachischisis is an open lesion in which there is total dysraphism, with the brain and spinal cord exposed to the surface. Craniorachischisis occurs from failures in the very initial stages of neurulation. ■ Iniencephaly is a closed lesion with significant abnormalities of the brain, spinal cord, skull, and vertebrae. Dysraphia in the occipital region is accompanied by severe retroflexion of the neck and trunk.3,6 2. Level of the cranial neural tube ■ Anencephaly consists of partial or total absence of the brain, with the undeveloped brain exposed to the surface through a defect in the skull and scalp.
1. Closed spina bifida is a defect is covered by normal skin. There can be a visible herniation covered by normal skin, or there may be no external sac or other visible stigmata, such as subcutaneous lipomata and cutaneous manifestations. 2. Open spina bifida is a failure of fusion of the posterior vertebral arches with secondary herniation of exposed neural tissue and meninges that is not covered by skin or that is covered only by a membrane in a visible cystic mass. The other classification system categorizes spina bifida as follows: 1. Spina bifida occulta refers to a concealed form of spina bifida with few cutaneous clues to the underlying spinal disorder. 2. Spina bifida aperta refers to lesions that communicate with the environment. 3. Spina bifida cystica refers to either a meningocele or a myelomeningocele: ■ Meningocele is a protrusion of the dura and arachnoid through the defect in the vertebral laminae, leading to a cystic swelling. The spinal cord remains within the spinal canal. This normally occurs in the lumbosacral region. ■ Myelomeningocele is a defect in which the spinal cord and/or the cauda equina, together with the meninges, are extruded within an externalized lumbosacral sac. This is the most common form of spina bifida and occurs mainly in the lumbar region (Figs. 38–6 and 38–7).3,6,30
Epidemiology In the United States, NTDs occur in 1 per 1000 pregnancies. Rates of NTDs are higher in Mexico and northern China. NTDs are more common in girls than in boys.5,6
Clinical Features It is important to recognize the cutaneous manifestations of a closed NTD in the caudal regions. These can include lipomas,
496
Section
VIII
Spine and Spinal Diseases
Spina Bifida Occulta and Spina Bifida Cystica Conus Lumbar vertebral body
Filum terminale Spinous processes Absent spinous process
Sacrum
A. Spina Bifida Occulta. This is a closed defect and can be relatively minor. Conus
Filum terminale
Meningocele pouch
B. Meningocele. This is an outpouching of the meninges without the neural elements.
■
Figure 38–6. A large myelomeningocele. The neural elements are visible within this membrane-covered protrusion.
Thin membrane
C. Myelomeningocele. This is an outpouching of the meninges with the neural elements within and may be covered by only a thin membrane. ■
Figure 38–5. Diagrammatic representation of spina bifida occulta (A) and spina bifida cystica with a meningocele (B) and with a myelomeningocele (C).
epidermoid sinus, dermoid cysts, hemangiomas, cutaneous nevi, and a deep sacral dimple. Clinicians must maintain a high index of suspicion when they see these cutaneous lesions and not dismiss them merely as isolated benign lesions.3 The actual clinical manifestations and functional outcomes in spina bifida depend mainly on the level of the defect and the severity of the lesion. Neurological dysfunction results from sensory abnormalities and manifests through leg weakness and paralysis to bladder and bowel dysfunction. Spina bifida most commonly occurs in the lumbosacral region: 1. Spina bifida in the sacral region commonly affects bladder and bowel function and results in sexual dysfunction. The lower limbs may not be affected. 2. A lesion affecting the lower lumbar and sacral regions affects the lower limbs, with the lower legs and the feet more affected than the more proximal hip flexors or quadriceps. The buttocks tend to be involved as well. 3. Spina bifida in the upper lumbar region affects the hip flexors and knee extensors and occasionally spares the feet and lower legs. Urological abnormalities are common; most affected individuals lack sphincter control, and 80% have a neurogenic
chapter 38 spine and spinal cord: developmental disorders
497
including sleep apnea, swallowing difficulties, stridor, headache, quadriparesis, scoliosis, and balance and coordination difficulties. Hydromyelia occurs in approximately 40% of individuals with myelomeningocele and manifests as progressive scoliosis, weakness of the upper limbs, spasticity, and an ascending motor loss in the lower limbs. Meningitis and serious nervous system infections cause significant morbidity as well.3,5,32 Individuals with spina bifida have a normal overall IQ score. Despite this, they have selective cognitive disabilities, including distractibility, a short attention span, and difficulties with perceptual organization and visual-motor integration. Practitioners involved in the care of individuals with spina bifida must monitor for the psychosocial complications of having a chronic disorder that is potentially disabling and deforming. All these factors have a significant effect on an individual’s ability to participate in education and employment opportunities and to engage in independent living.31
Prognosis
■
Figure 38–7. Magnetic resonance image of a myelomeningocele. This sagittal T2 image shows a well-defined myelomeningocele sac with the filum terminale extending into the sac.
bladder. Although mainly in the lumbosacral region, spina bifida can also affect the thoracic region and, in rare cases, the cervical region. A lesion affecting the thoracic level significantly compromises lower limb strength.5,31 Orthopedic abnormalities, including clubfoot, contractures, and dislocated hips, can occur as well. Of all children with spina bifida, 90% have spinal curvature problems as well, including kyphosis, scoliosis, and kyphoscoliosis. Community ambulation is defined as the ability to move about the community without using a wheelchair. This can be achieved by 100% of patients with sacral and lower lumbar lesions and by 63% of patients with higher-level lesions. Other than the neurological level of the lesion and musculoskeletal deformities, other important factors influencing mobility and ambulation include balance disturbances, spasticity in the knees and hips, and the number of shunt revisions made.32,33 A host of late complications can occur in spina bifida, either as a consequence of the disorder and the deficits or as a consequence of the surgical intervention. The extent and severity of the neurological deficit itself can lead to severe medical complications as well. For instance, a neurogenic bladder can lead to recurrent urinary tract infections and chronic renal dysfunction. Severe sensorimotor deficits can lead to decubitus pressure sores and ulcers and other consequences of reduced mobility. Other late neurological complications include progressive hydrocephalus and the Chiari type II malformation, spinal cord tethering, and hydromyelia. Of individuals with myelomeningocele, 75% have an associated Chiari type II malformation that can be identified radiologically. Up to a third have clinically symptomatic lesions with manifestations,
Spina bifida is a complex developmental disorder that is associated with relatively longer survival. Approximately 78% of all individuals with spina bifida survive to 17 years, and approximately 52% to 68% with spina bifida survive to the third decade. Survival depends significantly on the availability and delivery of optimal medical and surgical care. For instance, the early infant mortality rate in spina bifida is 10% in the United States and nearly 100% in northern China. The prognosis in spina bifida is relatively good, in contrast to anencephaly (affected children either are stillborn or die shortly after birth) and craniorachischisis (most affected fetuses are lost in early spontaneous abortion, or infants die after birth).3,5,6 The overall long-term prognosis in spina bifida, however, is not good in that there is significant morbidity associated with the condition. Survivors of spina bifida can have a multitude of problems ranging from the neurological deficits to the medical complications to the emotional and psychological scars. There is a significant burden of care on the community as well. The average monetary cost of medical care over a lifetime for an infant born in 1988 with spina bifida was $294,000 (in 1992 monetary terms).6
Etiology and Pathophysiology The causes of spina bifida are heterogenous and consist of genetic and environmental factors. Spina bifida is likely to be the culmination of an interplay of genetic susceptibility and environmental factors. The combination of environmental and genetic triggers for spina bifida is supported by the geographical variation in the incidence rates.5,6 A genetic basis for NTDs is suggested by the racial differences in incidence and by the familial recurrence patterns. For instance, NTDs are more common in Hispanic and nonHispanic white persons than in black persons in the United States. In addition, there is a degree of disease aggregation in families. The siblings of affected individuals have a 3% to 8% chance of having spina bifida, anencephaly, or both. There is also an increased risk of spina bifida in second- and third-degree relatives of affected individuals.5,6 The exact etiological factors remain unknown for the majority of cases of spina bifida. In a minority, there are recognized
498
Section
VIII
Spine and Spinal Diseases
syndromes causing the spina bifida. Of all children with NTDs, 20% have additional congenital malformations. Genetic abnormalities, including chromosomal abnormalities and single gene mutations, and teratogenic causes are identified in 10% of affected children.5,6 Of all the environmental factors studied, inadequate maternal intake of either natural folate or synthetic folic acid before conception and during the early stages of pregnancy has the most robust association with the development of NTDs. The exact mechanism of protection from folic acid is unclear but is likely to be mediated by genes that regulate folate transport and metabolism. Various genetic defects in the folate-homocysteine metabolism and folate transport have been identified as being associated with NTDs.5 Only a few specific environmental factors, including maternal diabetes and maternal use of anticonvulsants, have been identified in the causation of NTDs. A history of pregestational diabetes in women is associated with a twofold to tenfold increase in the risk of malformations of the central nervous system, including spina bifida, in their children. The risk is related to the level of maternal metabolic control. Use of valproic acid or carbamazepine by women is associated with a 1% to 2% risk of spina bifida in their children. Other factors shown to lead to an increased risk of NTDs include maternal obesity and maternal hyperthermia.5,6
Prevention Maternal folic acid supplementation before conception and during early pregnancy has been shown to prevent at least half the cases of NTDs and up to 70% of the cases of spina bifida. In 1991, a British study demonstrated that recurrent NTDs could be reduced by taking 4000 μg/day of folic acid. This was followed in 1992 by a Hungarian study that demonstrated that 800 μg/day of folic acid reduced the first occurrence of a neural tube defect. In a later (1999) study, a daily dose of 400 μg/day of folic acid was sufficient to prevent NTDs in an area of China with a high incidence of NTDs.5,6 The recommended dose is 400 μg/day of folic acid in women of childbearing age, especially if they are contemplating or planning a pregnancy. This is most consistently achieved through nutritional supplements. Other sources of folic acid include foods fortified with folic acid, including cereals and grains, and foods naturally rich in folate, including fruits and vegetables. There has been some concern that universal fortification of common foods may mask vitamin B12 deficiency.5,6
Management There are four phases in the management of spina bifida, described as follows.
Prenatal diagnosis and management considerations Prenatal management centers on diagnosis of the NTD and discussions about subsequent management. NTDs can be screened with maternal serum α-fetoprotein measurements and ultrasonography. The maternal serum α-fetoprotein level can be tested at the 16th week of pregnancy. False-positive results can arise from other malformations, the presence of multiple fetuses, and incorrect calculation of gestation dates. Ultrasonography is useful in diagnosing the NTD and in providing
■
Figure 38–8. Magnetic resonance image of a Chiari malformation and a neural tube defect in a 35-week-old fetus. This scan demonstrates hydrocephalus and a Chiari malformation with tonsillar herniation. In addition, there is a neural tube defect in the lumbar region.
useful information about the overall growth of the fetus. It may, however, miss small myelomeningoceles. Once an NTD is diagnosed, ultrasonography is used to assess for other associated malformations and general limb movement, deformity, and paralysis. The use of fetal MRI is increasingly studied in this area as well (Fig. 38–8). Such prenatal imaging may have a bearing in predicting neurological deficit and functional outcome.3,5 Amniocentesis is a more invasive investigation that can be used to follow up positive screening test results. The αfetoprotein levels in the amniotic fluid at the 15th or 16th week of gestation are elevated in cases of an open NTD. Similarly, acetylcholinesterase levels are also elevated in cases of an open NTD. Fetal karyotype studies can be undertaken as well to investigate for chromosomal anomalies.3,5 Elective abortion for NTDs is an area of medicine fraught with ethical dilemmas and questions. Each situation must be dealt with on an individual basis within the foundations of a sound therapeutic relationship, with all the intertwined psychosocial factors and religious, moral, and ethical considerations taken into account. Damage to the neural tissue can occur either in utero, as a result of exposure to toxic substances in the amniotic fluid or mechanical damage from contact with the uterine wall, or during delivery, as a result of contact with the birth canal. Despite this, there is currently insufficient medical evidence to
chapter 38 spine and spinal cord: developmental disorders support any particular mode of delivery in minimizing the neurological impairments from spina bifida. The elective use of cesarean section, however, may be warranted to minimize trauma if there is a large lesion and to reduce the risk of dehiscence after in utero surgical treatment.5,6
Perinatal surgical considerations The next stage in management involves exploring the various surgical and therapeutic treatment options available. There is the choice of either in utero fetal surgery or the more traditional postnatal surgery. Postnatal surgical closure of a spinal lesion is usually undertaken within the first 48 hours after birth. If there is associated hydrocephalus, a ventricular shunt is usually inserted as well.5 There have been various studies exploring the role of in utero surgical repair of NTDs in fetuses as young as 22 weeks of gestational age. Studies have shown complete reversal of hindbrain herniation and a lower proportion of cases of hydrocephalus necessitating shunting (43% versus 85%). Initial reports have shown resolution of the associated Chiari type II malformations and a lower incidence of moderate to severe hindbrain herniation and hydrocephalus necessitating shunting. The urodynamic and leg function, however, remain similar in comparison with that in infants who are treated postnatally. The exact role of in utero surgery is unclear, especially with regard to the overall fetal and maternal risk-benefit ratio.5,6
Early childhood management
499
monitoring and judicious management of complications that can arise. This is best achieved through a multidisciplinary approach and within a primary prevention framework. Throughout the life of such a patient, it is important to monitor for psychological manifestations as well and to consider neuropsychological assessments as appropriate. Approximately 47% of hospital admissions for spina bifida result from potentially preventable secondary complications, including recurrent urinary tract infections and skin ulceration.6 Careful urological monitoring and advice are important. This is especially so in providing techniques for complete bladder emptying and in ensuring adequate catheter management, balanced with judicious use of pharmacological agents and surgical intervention. Skin care is of prime importance, with strategies to minimize skin friction and to ensure early attention to skin irritation and ulcers. Approximately 43% of people with spina bifida have a latex allergy. Latex-containing products should be avoided in the care of patients with spina bifida.6
Tethered Cord Syndrome Definition The tethered spinal cord is a syndrome complex in which there is progressive neurological deterioration as a result of pathological tethering of the spinal cord to an abnormal caudal position. The syndrome can be caused by a group of congenital vertebrospinal conditions, including the following:
A multidisciplinary setting is of critical importance in the ongoing early childhood assessment and management of spina bifida. The core participants in medical care include the primary care physician, the pediatrician, the pediatric neurosurgeon, the urologist, the orthopedic surgeon, a nurse clinician, the physiotherapist, and the social worker. Assessing and optimizing ambulation and mobility are of prime importance in the management of spina bifida. The orthopedic deformities can be treated with early surgical intervention. If left untreated, orthopedic deformities, including scoliosis, kyphosis, and hip dysplasias, can compromise mobility and functional outcomes. Supportive aids, including braces, canes, and walkers, can be used to maintain erect posture to achieve effective community ambulation. Wheelchair assessment is also important, especially if the combination of deficits weigh against successful independent ambulation.5,6 The potential complications must be considered and sought. For instance, the medical team should watch for progressive hydrocephalus with baseline imaging studies and serial head circumference measurements. Children who have had shunt surgery need to be evaluated on a regular basis for potential markers of shunt malfunction, including the development of seizures. Urodynamic studies and renal tract ultrasonography are important in assessing urological function.5 Growth is affected in spina bifida. Growth hormone has been successfully used in improving the growth of children with spina bifida. The overall long-term outcomes, however, are unknown at this stage.6
1. Thickened, tight filum terminale, which is one of the commonest causes of a tethered cord and occurs as the cord is pinned down to the sacrum by the thickened filum. 2. Intradural fibrous adhesions. 3. Intradural lipomas (Figs. 38–9 and 38–10): There are various classification systems for spinal lipomas according to either location in relation to the neural elements (e.g., caudal, dorsal, or transitional lipoma) or degree of herniation (e.g., lipomyelomeningocele). 4. Myelomeningocele, including occult lesions. 5. SCMs. 6. Dermal sinus tracts, which may be connected with an intraspinal dermoid cyst. 7. Developmental cysts.
Lifelong management and considerations
There are four modes of presentation of TCS:
The ongoing lifelong phase in the management of spina bifida essentially involves regularly scheduled evaluation for
1. Cutaneous stigmata: Affected individuals may be asymptomatic and present with only a cutaneous marker, including
All these causative conditions are sometimes grouped under the umbrella term spinal dysraphism, despite the clear structural and anatomical differences. The term refers broadly to this assorted group of congenital anomalies affecting the spine and spinal cord that have similarities in clinical manifestation and the consequent neurological deficits and deformities.34-36 Tethered cord syndrome (TCS) may also occur as a secondary condition as a result of surgical treatment for these disorders. For instance, the syndrome has been reported in 15% of patients with a previously repaired myelomeningocele, in whom surgical closure has led to posterior attachment of the neural placode at the site of repair.34,36
Clinical Features
500
Section
VIII
Spine and Spinal Diseases
A ■
■
Figure 38–9. Magnetic resonance image of an intradural lipoma and tethered cord. This sagittal T2 image shows a low-lying spinal cord tethered to the intradural lipoma (in black, as opposed to the surrounding white cerebrospinal fluid). The spinous processes are not visualized in the sacral region.
a subcutaneous lipoma, hypertrichosis, or a nevus. Cutaneous features are more likely to occur in patients who present in childhood (Fig. 38–11). 2. Pain in the back, lower limbs, or anorectal region. This is less common in affected children but is a common feature in affected adults, occurring in 78%. The lower limb pain can be either unilateral or bilateral and may be diffuse, in a nondermatomal distribution. The pain tends to occur after prolonged sitting or bending forward. A radicular pattern of pain is rare in TCS. There have been reports of a Lhermittetype effect as well, with shocklike sensations traveling up and down the spine upon forward bending. 3. Progressive neurological deficits: Sensorimotor deficits localize to the lumbosacral region, may be mild, and manifest with minimal sensory disturbance and slight walking difficulties, or they may be severe with diffuse sensory disturbance and progressive weakness. Multiple cord segments or nerve root lesions may be affected bilaterally, in a combination of upper and lower motor neuron signs. Although the distal muscles are usually the most severely affected, the whole lower limb may be involved. Affected individuals may also present with rapidly progressive calf atrophy. Sensory disturbance is likely to occur in a saddle distribution. Neurogenic bladder and bowel dysfunction may occur. The bladder dysfunction may occur in either an upper or a lower motor neuron pattern, with either overactive or underactive detrusor function. Affected individuals may have an upper motor neuron pattern with a spastic, small-capacity bladder
B
Figure 38–10. Magnetic resonance images of an intradural lipoma associated with a lumbar syrinx. The lipoma lies dorsal to the tethered cord, with the conus at the level of L5/S1. The lipoma follows the subcutaneous fat signal; it is brighter and hyperintense on the sagittal T1 image (A) and relatively hypointense and less visible on the T2 image (B). In contrast, the syrinx has signal characteristics similar to those of the cerebrospinal fluid, appearing hypointense on the T1 image and hyperintense on the T2 image. The syrinx extends from T11-T12 to L4-L5 and occupies 75% of the cord diameter.
and voiding frequency and urgency. Alternatively, there may be a hypotonic large-capacity bladder with dribbling incontinence and a patulous anus with fecal incontinence. Infants may present with fewer dry diapers, whereas young children may also present with enuresis and problems with toilet training. Individuals may present with complications may arise from these neurological deficits, including trophic ulceration and urinary tract infections. 4. Progressive orthopedic deformities of the lower limb and spine, including equinovarus deformities and worsening scoliosis. This is more common as a presenting feature in children (Fig. 38–12).34,37 TCS tends to present in childhood. The age at symptom onset depends on the actual [VT1][VT2] degree of cord traction. The causative pathology itself does not appear to be correlated with either time of symptom onset or particular clinical manifestations. The milder lesions may manifest later in adulthood either as a result of the accumulated effects over time of tension on the conus during normal head and neck flexion or in the setting of an aggravating factor. Circumstances that have precipitated or worsened symptoms have included the following: 1. Activities that stretch the conus: lithotomy position for childbirth, prolonged sitting, straight-leg raising exercises. 2. Conditions that narrow the spinal canal: lumbar spondylosis, heavy lifting.
chapter 38 spine and spinal cord: developmental disorders
A
C
■
B
3. Direct trauma to the back, further compromising the neural tissues. Spinal cord tethering may occur after surgery for spinal dysraphism; hence, neurological deterioration or progression must be carefully evaluated after surgery. A history of myelomeningocele repair in childhood is an important clue to underlying TCS if an adult presents with clinical features suggestive of the syndrome.34,36
Etiology and Pathophysiology The spinal cord reaches the sacral-coccygeal region in early embryonic life. After 16 weeks of gestation, there is then a growth differential in which the bony vertebral column lengthens and grows beyond the spinal cord itself. This leads to ascension of the spinal cord to the level of L3 at 30 weeks of
501
Figure 38–11. Patients with obvious midline cutaneous manifestations of underlying spinal dysraphism. The images show patients with a subcutaneous lipoma (A), a nevus (B), and a midline area of hypertrichosis overlying a patch of hyperpigmentation (C).
gestation and to the adult level of L1 or L2 by 2 months after birth.34,37 In embryonic life, the normal pattern of ascent is compromised if the conus is hinged to an abnormally low level by any of the underlying causative pathological entities responsible for TCS. In addition to the low-lying position, the neural tissues are abnormally stretched vertically. Studies have shown that, when placed under traction, the lumbosacral cord is vulnerable to hypoxic stress, with neuronal dysfunction resulting from mitochondrial oxidative derangement. Over time, neuronal dysfunction leads to neuronal damage. Other contributory factors include impairment of blood supply and problems with glucose metabolism. In essence, the TCS results from abnormal longitudinal traction that causes cord injury. There may be an additional factor with a compressive element from the underlying pathology: for instance, with a lipoma.34-36,38
502
Section
VIII
Spine and Spinal Diseases
Management
■
Figure 38–12. Patient with spinal dysraphism showing scoliosis, a visible lumbar region lipoma, and a left foot equinovarus deformity.
With normal growth and development—for instance, during the growth spurts—there is further stretching of the spinal cord, causing increasing neuronal damage. This leads to the onset of neurological features in early childhood in individuals with more severe cord tethering. Alternatively, symptoms may emerge later in milder cases, either in the setting of aggravating features as discussed previously or over time after repeated normal day-to-day stretching of the spinal cord from head and neck flexion. The sudden tension may lead to irreversible neuronal damage in an already chronically tethered cord. The tension from the tethered spinal cord can be transmitted up the cord, with neural elements stretched at levels away from the site of the tethering. This is one of the factors explaining the combination of upper and lower motor neuron signs that may be seen.34,35,38
MRI is of critical importance in the evaluation of TCS. MRI is useful for assessing conus position and thickness of the filum terminale and in looking for associated vertebrospinal anomalies. The conus is low-lying when the tip is abnormally located below the lower border of the L2 vertebral body, and the filum is thickened if it appears wider than 1.5 to 2.0 mm on MRI. The other clues of TCS include posterior placement of the spinal cord, thickened filum terminale, and the sacral roots’ running in a lateral or cephalic course, as opposed to the usual cephalocaudal orientation. Plain radiographs and CT scans are useful in delineating the associated bony vertebral abnormalities. Although the advent of MRI has rendered most of the older procedures obsolete, including the use of hyperbaric and gas myelography, there is occasionally a role for myelography in further defining the nerve root anatomy and pathways.34,36 Evaluation of TCS is incomplete without urodynamic studies, because neurogenic bladder dysfunction may occur even in the absence of symptoms. It is therefore important to refer individuals with TCS for urodynamic assessment. It is especially useful to perform assessments both preoperatively and postoperatively.37 Surgical management is aimed at untethering the spinal cord and neural elements and leads to good neurological outcomes and improvement in symptoms. Compressive lesions, if present, should be removed as well. Improvement after untethering surgery is especially convincing if the deficits are mild or treated early. In an analysis of TCS in adults, 83% experienced relief of significant pain and 67% experienced an improvement in sensorimotor deficits. Improvement in sphincter disturbance, however, is more variable. In one study, for instance, only 39% of patients with sphincter disturbance experienced an improvement. There have been occasional reports as well of bladder dysfunction occurring after surgery. Although there are no differences in the clinical presentation for the different pathologies, there are differences in ease of surgical management, depending on causative etiology. Complex lipomas and adhesions from previous operations prove to be the most challenging. Despite this, the overall rate of complications from surgery is low, with reported immediate postoperative neurological morbidity rates of 0% to 5%. Postoperative CSF fistula is a possible complication that should be treated early with further surgery and dural repair.34,36,37 Together, all these factors positively support the role of surgical intervention. Early surgery is particularly crucial for preventing further neuronal damage. Surgery is recommended in infants upon diagnosis of a tethered cord, to prevent neurological deficits. Surgery is also advocated in later presentations with progressive neurological deterioration. Retethering may occur after surgery and must be differentiated from incomplete untethering during the initial operation. There is a range of operative options for retethered cords.34,36-38
Split Cord Malformations Definition The traditional terms used for double spinal cord malformations were diplomyelia, for a twinning and doubling of the cord within a single dural sac, and diastematomyelia, for two hemicords in separate dural sacs separated by a midline spur. These
chapter 38 spine and spinal cord: developmental disorders terms were derived from Greek words: myelos, meaning marrow or cord; diplous, meaning double; and diastema, meaning cleft. These malformations have been categorized as SCMs. They are rare disorders with complete or incomplete division of the spinal cord by an osseocartilaginous or fibrous septum, leading to double spinal cords. In type I SCM, there are two hemicords separated by a rigid dura-sheathed osseocartilaginous septum, each hemicord housed within its own dural tube. In type II SCM, the spinal cord sits within a single dural tube and is split into two independent segments for a variable vertical extent by a nonrigid fibrous median septum.39,40
Clinical Features SCMs can be either asymptomatic or symptomatic. Affected children are more likely than affected adults to be asymptomatic. Both affected adults and children may present with cutaneous manifestations, the most common being hypertrichosis. Other cutaneous signs include capillary hemangiomas, a lipoma, and dermal sinus openings. SCMs may manifest with pain. This is a common feature in adulthood, and the pain may be localized to the spine at the site of the split cord, or it may be diffuse with a dysesthetic component. Neurological deficits, including progressive gait disturbance, worsening sensorimotor disturbance, and bladder or bowel dysfunction, may occur. SCMs most commonly affect the lumbar region; they also can occur in the cervical and thoracic regions. A cervical region SCM involves the upper limbs as well. Neurological decline is independent of SCM pattern and location type; neurological features occur equally in type I and type II SCMs, and progression rates are similar for cervical and thoracolumbar lesions. Trophic changes and nonhealing ulcers may eventuate in SCM. Urinary tract manifestations may include features of a neurogenic bladder, renal impairment, recurrent urinary tract infections, or incontinence. Urinary tract dysfunction, however, may be asymptomatic and must be carefully evaluated with urodynamic studies. Children can also present with orthopedic deformities, including scoliosis and foot deformities.30,40 SCMs may occur in conjunction with other vertebrospinal anomalies. The incidence of an coexisting myelomeningocele is 26% to 39% in individuals with SCM and is more common with type I SCM. The neural placode may involve both hemicords or only one of the hemicords as a hemimyelocele. Alternatively, involvement may be more limited with strands of neural tissue flowing from the hemicords to enter the myelomeningocele sac. SCMs may be associated with a low-lying conus and other tethering lesions, including tight filum terminale and lipomas. Abnormalities in the vertebral bodies adjacent to the SCM, including a bifid body, a widened body, and vertebral fusion, may be seen. Individuals with a cervical SCM may have an associated Klippel-Feil anomaly, with torticollis, a short neck, and webbed trapezii.30,40 Overall, the clinical manifestations are similar to those of TCS. There is one notable difference: Individuals with SCM may have a significant left-right differential with regard to lower limb neurology. This occurs either in the setting of a hemimyelocele, in which the side with the hemicord involved with the myelocele has much reduced function, or in the setting of an asymmetrical split within the spinal cord. In the latter situation, there is a large, major hemicord and a smaller, minor hemicord, with reduced function on the minor side.40
503
Epidemiology There may be a slight female preponderance for SCM. The average age at diagnosis ranges from 3.9 to 5.7 years.30
Etiology and Pathophysiology The exact cause of SCMs is unknown. Initially, diastematomyelia was thought to be a developmental disorder resulting from abnormal tissue protrusions splitting the spinal cord. Diplomyelia, on the other hand, was postulated to result from an abnormal twinning response in early embryonic development. Later work, however, has shown the two entities to be the same and suggests that SCMs arise from a common embryogenetic mechanism. In the early embryonic period, adhesions are formed between the ectoderm and endoderm. These adhesions develop into an accessory neurenteric canal, which subsequently condenses into the endomesenchymal tract. This abnormal tract splits the notochord and neural plate into two hemineural plates.39
Management Investigations in SCMs are twofold. The first is to characterize the malformation, especially as part of an extensive presurgical workup. Plain radiographs are often unhelpful, although they occasionally show the bone abnormalities involved. CT scans and MRI have complementary roles. MRI is particularly valuable in demonstrating spinal cord anatomy and in defining the level and extent of the hemicord (Fig. 38–13). The number of vertebral bodies crossed is used to define the length of the split segment. In addition, it is important to perform MRI of the whole neuraxis to look for associated anomalies, including NTDs and lipomas. The high-resolution CT scan with finecut slices is especially useful in defining the spur characteristics and the bony vertebral body and posterior arches. The second role of investigations is to map out complications that may arise. Urodynamic studies are particularly important in this regard, especially if there are no overt renal tract features.40 Most surgeons advocate prompt identification and early surgical intervention for SCMs to either improve outcomes or prevent further functional deterioration. The pain component responds the best to surgical management; improvement occurs within a month. With neurological deficits, surgery may improve symptoms or may prevent further progression. Neurological recovery is inversely proportional to the duration of symptoms before surgical intervention. Results with sphincter dysfunction, however, are generally less encouraging, with an overall 40% improvement rate. Surgery involves excision of the midline spur, together with the dural sheath encasing the spur and any associated soft tissue bands that may be attached to the hemicord. The surgical morbidity rate is slightly higher in type I SCM. Complications may include wound complications and CSF leakage. Coexisting anomalies can be surgically treated as well. Orthopedic deformities can occasionally be managed with appropriate operations, including tendon transfer and joint arthrodesis. Management of bladder dysfunction with monitoring of renal function and judicious use of catheterization is also important. There have been reports in the literature of SCMs’ being diagnosed prenatally with ultrasonography.40
504
Section
VIII
Spine and Spinal Diseases 4. Type IV: total sacral agenesis with the lumbar vertebrae lying superior to the fused ilia. Some authors make a further distinction, with sacral agenesis referring to a symmetrical absence and sacral dysgenesis referring to an asymmetrical deformity. The syndrome of caudal regression encompasses a constellation of malformations in which multiple embryological defects of the caudal region occur in addition to sacral agenesis. The term caudal dysplasia refers to the anomalies of the spine and lower extremities that may be seen in infants of diabetic mothers.41-43
Epidemiology Sacral agenesis is a rare congenital malformation. A maternal history of diabetes mellitus is strongly associated with sacral agenesis; 16% to 64% of individuals with caudal vertebral deformity or sacral agenesis have a diabetic mother.42,43
A
Clinical Features
B ■
Figure 38–13. Magnetic resonance images of a split cord malformation. A, Two hemicords are shown enclosed in a single dural sac. B, The septum separating the two hemicords is visible. (Courtesy of Dr. Rachel Evans.)
Sacral Agenesis Definition In sacral agenesis, there is partial or complete absence of the sacral and coccygeal bones. Lumbosacral agenesis is a more severe point of the spectrum: complete sacral agenesis, together with variable lumbar agenesis. Sacral agenesis and lumbosacral agenesis are occasionally referred to together as distal spinal agenesis. This spectrum of anomalies was classified by Renshaw as follows: 1. Type I: unilateral sacral agenesis, partial or total. 2. Type II: partial and symmetrical bilateral defects. 3. Type III: total sacral agenesis with the lumbar vertebrae articulating with the ilia.
The features of sacral agenesis depend on the severity and extent of the lesion. Minor defects in the sacrum and coccyx may be asymptomatic, or typical cutaneous stigmata (e.g., lipoma, nevus) may be exhibited. Affected individuals may complain of back pain or may present with orthopedic and musculoskeletal features, including lower limb deformities and contractures, scoliosis, spine instability, and hip dislocations. Complete sacral agenesis, especially if affecting the lumbar region as well, leads to completely thin and flaccid lower limbs. The neurological deficit tends to correlate with the level of the vertebral abnormality and is often associated with bladder or bowel dysfunction. Ambulatory capacity is correlated with the type of sacral agenesis.41-43 Two distinct subgroups have been identified. Individuals with high agenesis have high blunt conus termination and tend to present with the typical features of flat buttock cheeks and prominent iliac crests. Such morphological changes are less pronounced with low agenesis and a low-lying conus. The recurring theme of multiple developmental defects applies to sacral agenesis as well; other congenital vertebrospinal deformities, including syrinx, myelomeningocele, and lumbosacral lipoma, may be present.41-43 The features of the syndrome of caudal regression may be more variable and span a wider range of potential problems, including cleft lip or palate and gastrointestinal and genitourinary malformations. Gastrointestinal tract abnormalities include imperforate anus and malrotation of the bowel. Genitourinary malformations include a pelvic or solitary kidney, a urogenital sinus, a perineal urethra, labial abnormalities, and penile atrophy. A combination of orthopedic and neurological problems may lead to a “Buddha” position, with marked flexion and overlapping of the lower limbs and equinovarus. The most severe end of the spectrum includes the dramatic sirenomelia malformation, in which the “mermaid” fusion of the lower limbs is accompanied by extreme malformations of lower gastrointestinal and genitourinary tracts, including total agenesis of the kidneys, renal tract, anus, and rectum.41,43
Etiology and Pathophysiology The exact cause of sacral agenesis is unclear but appears to be a defect either late in or after the neurulation stage of embryo-
chapter 38 spine and spinal cord: developmental disorders
505
tomatic; typical clinical features involve cutaneous lesions, pain, neurological deficits, and orthopedic deformities. Most of the disorders do not occur in isolation and tend to be associated with the other vertebrospinal anomalies. Imaging techniques, including CT scans and MRI, are useful in the delineation and characterization of these disorders. Clinicians need to be aware of the whole spectrum of disorders and the manifestations that may occur, in order to facilitate early diagnosis and appropriate management within a multidisciplinary health care team to improve neurological and functional outcomes.
K E Y
■
●
An understanding of the basic aspects of the embryology and development of the nervous system is necessary to appreciate the spectrum and severity of developmental disorders affecting the spine and spinal cord.
●
There are many developmental disorders that can affect the spine and spinal cord. In approaching the treatment of these disorders, it is important to clarify definitions in order to avoid confusion, and it is useful to have a working classification system within which to approach treatment.
●
Many developmental disorders and malformations coexist rather than being isolated. In addition, the clinical manifestations of the developmental disorders are varied and can manifest during both childhood and adulthood. For clinicians, it is important to recognize the whole range of developmental disorders and the myriad of clinical features in order to optimize investigation and treatment of the primary disorder and coexisting malformations.
●
The neural tube defects are particularly important because they are among the more common serious malformations affecting the spine and spinal cord for which there is relative success in prevention and treatment.
●
Imaging modalities, including computed tomographic and magnetic resonance imaging techniques, are essential for the diagnosis of many developmental disorders. It is vital for clinicians to understand the role and interpretation of these techniques.
Figure 38–14. Sagittal T2 magnetic resonance image of sacral agenesis. Only the first two sacral segments are identified. In addition, there is an abrupt termination of the conus at T12 with a blunt end, rather than the usual tapering structure.
genesis. This view is derived from the observation that sacral agenesis is a closed defect. An insult to the caudal eminence may be the cause of high agenesis, whereas a milder or later insult affecting differentiation may be the cause of the low agenesis.43
Management As with the other vertebrospinal conditions, evaluation with MRI is necessary to delineate the neural structures and associated anomalies (Fig. 38–14). Bony definition may be improved on CT scanning. The primary aim of orthopedic intervention is to improve mobility or sitting and standing balance. This may be achieved through the use of orthotics and a range of surgical measures, including soft tissue releases, osteotomies, and open reduction of hip dislocations. Limb amputation has been undertaken for severe deformities that cannot be corrected or ameliorated with simpler operations. The role of neurosurgery is not as well defined, inasmuch as there are conflicting accounts of benefit in sacral agenesis. There have been reports favoring early preemptive neurosurgery for the low-lying variant.41,43
P O I N T S
Suggested Reading Botto LD, Moore CA, Khoury MJ, et al: Neural-tube defects. N Engl J Med 1999; 341:1509-1519. Lemire RJ: Neural tube defects. JAMA 1988; 259:558-562. Mitchell LE, Adzick NS, Melchionne J, et al: Spina bifida. Lancet 2004; 364:1885-1895. Pang D, Dias MS, Ahab-Barmada M: Split cord malformation: Part I: a unified theory of embryogenesis for double spinal cord malformations. Neurosurgery 1992; 31:451-480. Pang D, Wilberger JE Jr: Tethered cord syndrome in adults. J Neurosurg 1982; 57:32-47.
CONCLUSION The developmental disorders of the spine and spinal cord encompass a wide spectrum of anomalies with variable clinical manifestations. The disorders may be asymptomatic or symp-
References 1. O’Rahilly R, Muller F: Prenatal ages and stages—measures and errors. Teratology 2000; 61:382-384.
506
Section
VIII
Spine and Spinal Diseases
2. O’Rahilly R, Muller F: Minireview: summary of the initial development of the human nervous system. Teratology 1999; 60:39-41. 3. Lemire RJ: Neural tube defects. JAMA 1988; 259:558-562. 4. O’Rahilly R, Muller F: The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology 2002; 65:162-170. 5. Mitchell LE, Adzick NS, Melchionne J, et al: Spina bifida. Lancet 2004; 364:1885-1895. 6. Botto LD, Moore CA, Khoury MJ, et al: Neural-tube defects. N Engl J Med 1999; 341:1509-1519. 7. O’Rahilly R, Muller F: Somites, spinal ganglia, and centra. Enumeration and interrelationships in staged human embryos, and implications for neural tube defects. Cells Tissues Organs 2003; 173:75-92. 8. Tracy MR, Dormans JP, Kusumi K: Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin Orthop Relat Res 2004; (424):183-190. 9. Muller F, O’Rahilly R: Segmentation in staged human embryos: the occipitocervical region revisited. J Anat 2003; 203:297-315. 10. Dickinson LD, Tuite GF, Colon GP, et al: Vertebral artery dissection related to basilar impression: case report. Neurosurgery 1995; 36:835-838. 11. Hayes M, Parker G, Ell J, et al: Basilar impression complicating osteogenesis imperfecta type IV: the clinical and neuroradiological findings in four cases. J Neurol Neurosurg Psychiatry 1999; 66:357-364. 12. Bhangoo RS, Crockard HA: Transmaxillary anterior decompressions in patients with severe basilar impression. Clin Orthop Relat Res 1999; (359):115-125. 13. Jain VK, Takayasu M, Singh S, et al: Occipital-axis posterior wiring and fusion for atlantoaxial dislocation associated with occipitalization of the atlas. Technical note. J Neurosurg 1993; 79:142-144. 14. May D, Jenny B, Faundez A: Cervical cord compression due to a hypoplastic atlas. Case report. J Neurosurg Spine 2001; 94:133-136. 15. Lowry DW, Pollack IF, Clyde B, et al: Upper cervical spine fusion in the pediatric population. J Neurosurg 1997; 87:671676. 16. Dickman CA, Sonntag VK: Surgical management of atlantoaxial nonunions. J Neurosurg 1995; 83:248-253. 17. Gluf WM, Brockmeyer DL: Atlantoaxial transarticular screw fixation: a review of surgical indications, fusion rate, complications, and lessons learned in 67 pediatric patients. J Neurosurg Spine 2005; 2:164-169. 18. Eule JM, Erickson MA, O’Brien MF, et al: Chiari I malformation associated with syringomyelia and scoliosis: a twenty-year review of surgical and nonsurgical treatment in a pediatric population. Spine 2002; 27:1451-1455. 19. Muhonen MG, Menezes AH, Sawin PD, et al: Scoliosis in pediatric Chiari malformations without myelodysplasia. J Neurosurg 1992; 77:69-77. 20. Koehler PJ: Chiari’s description of cerebellar ectopy (1891). With a summary of Cleland’s and Arnold’s contributions and some early observations on neural-tube defects. J Neurosurg 1991; 75:823-826. 21. Nishikawa M, Sakamoto H, Hakuba A, et al: Pathogenesis of Chiari malformation: a morphometric study of the posterior cranial fossa. J Neurosurg 1997; 86:40-47.
22. Meadows J, Kraut M, Guarnieri M, et al: Asymptomatic Chiari Type I malformations identified on magnetic resonance imaging. J Neurosurg 2000; 92:920-926. 23. Wu YW, Chin CT, Chan KM, et al: Pediatric Chiari I malformations: do clinical and radiologic features correlate? Neurology 1999; 53:1271-1276. 24. Pascual J, Oterino A, Berciano J: Headache in type I Chiari malformation. Neurology 1992; 42:1519-1521. 25. Oldfield EH: Syringomyelia. J Neurosurg Spine 2001; 95:153155. 26. Nogues MA, Leiguarda RC, Rivero AD, et al: Involuntary movements and abnormal spontaneous EMG activity in syringomyelia and syringobulbia. Neurology 1999; 52:823-834. 27. Vaquero J, Martinez R, Arias A: Syringomyelia-Chiari complex: magnetic resonance imaging and clinical evaluation of surgical treatment. J Neurosurg 1990; 73:64-68. 28. Oldfield EH, Muraszko K, Shawker TH, et al: Pathophysiology of syringomyelia associated with Chiari I malformation of the cerebellar tonsils. Implications for diagnosis and treatment. J Neurosurg 1994; 80:3-15. 29. Batzdorf U, Klekamp J, Johnson JP: A critical appraisal of syrinx cavity shunting procedures. J Neurosurg 1998; 89:382388. 30. Kumar R, Bansal KK, Chhabra DK: Occurrence of split cord malformation in meningomyelocele: complex spina bifida. Pediatr Neurosurg 2002; 36:119-127. 31. Simeonsson RJ, McMillen JS, Huntington GS: Secondary conditions in children with disabilities: spina bifida as a case example. Ment Retard Dev Disabil Res Rev 2002; 8:198-205. 32. Bartonek A, Saraste H: Factors influencing ambulation in myelomeningocele: a cross-sectional study. Dev Med Child Neurol 2001; 43:253-260. 33. McLone DG: Spina bifida today: problems adults face. Semin Neurol 1989; 9:169-175. 34. Pang D, Wilberger JE Jr: Tethered cord syndrome in adults. J Neurosurg 1982; 57:32-47. 35. Yamada S, Zinke DE, Sanders D: Pathophysiology of “tethered cord syndrome.” J Neurosurg 1981; 54:494-503. 36. Kirollos RW, Van Hille PT: Evaluation of surgery for the tethered cord syndrome using a new grading system. Br J Neurosurg 1996; 10:253-260. 37. Zoller G, Schoner W, Ringert RH: Pre- and postoperative urodynamic findings in children with tethered spinal cord syndrome. Eur Urol 1991; 19:139-141. 38. Yamada S, Iacono RP, Andrade T, et al: Pathophysiology of tethered cord syndrome. Neurosurg Clin North Am 1995; 6:311323. 39. Pang D, Dias MS, Ahab-Barmada M: Split cord malformation: part I: a unified theory of embryogenesis for double spinal cord malformations. Neurosurgery 1992; 31:451-480. 40. Pang D: Split cord malformation: part II: clinical syndrome. Neurosurgery 1992; 31:481-500. 41. Guidera KJ, Raney E, Ogden JA, et al: Caudal regression: a review of seven cases, including the mermaid syndrome. J Pediatr Orthop 1991; 11:743-747. 42. Van Buskirk CS, Ritterbusch JF: Natural history of distal spinal agenesis. J Pediatr Orthop B 1997; 6:146-152. 43. O’Neill OR, Piatt JH Jr, Mitchell P, et al: Agenesis and dysgenesis of the sacrum: neurosurgical implications. Pediatr Neurosurg 1995; 22:20-28.
CHAPTER
39
PRIMARY MYELOPATHIES (DEGENERATIVE, INFECTIVE, METABOLIC) ●
●
●
●
Mark Paine
A number of conditions may selectively involve the spinal cord; some of these conditions also involve other neural tissues, to a lesser extent. The spinal cord neurons are relatively extensive, and as a result, they may be particularly susceptible to defects, which impair intraneuronal transport mechanisms. This chapter covers primary disorders of the spinal cord, excluding spinal cord trauma, spinal cord compression, and developmental spinal disorders; those topics are covered in Chapters 38, 40, and 99. For discussion, it is convenient to divide the primary myelopathies into acute (including subacute) and chronic clinical manifestations.
ACUTE MYELOPATHIES Acute myelopathy, or acute transverse myelopathy, is a disorder of acute or subacute spinal cord dysfunction resulting from a variety of causes, as listed in Table 39–1. In a clinical study, de Seze and colleagues (2001) found the commonest cause to be multiple sclerosis (43%); other causes included systemic disease (16.5%), spinal cord infarction (14%), infectious or parainfectious conditions (6%), and radiation myelopathy (4%). No underlying cause was found in the remaining 16.5%, despite an average of 29 months’ follow-up. The criteria for the clinical diagnosis of acute transverse myelopathy include (1) acute/subacute onset of sensory and motor symptoms, including symptoms of sphincter dysfunction; (2) spinal segmental level of sensory disturbance with a well-defined upper limit; (3) occurrence of symptoms over no more than 3 weeks and sustained for a period of at least 48 hours; (4) no clinical or radiological evidence of spinal cord compression; and (5) no known history of neurological disease or neurological symptoms. New cases of acute transverse myelopathy occur at a rate of 1 to 4 per million people per year. There is no gender predisposition, in contrast to the predominant female predisposition in multiple sclerosis. Fifty percent of patients develop almost complete paraparesis, most have bladder dysfunction, and 80% to 94% have sensory disturbance. The recovery of the neurological deficit is somewhat variable: One third of patients recover with little or no deficit, one third have moderate disability, and one third have severe disability. Acute transverse myelopathy may be an initial presenting feature of multiple sclerosis. Typically, such patients who ultimately go on to develop multiple sclerosis have an asymmetri-
cal partial transverse myelitis: that is, predominant sensory disturbance with relative motor sparing. Magnetic resonance imaging (MRI) of the spine characteristically shows lesions extending over less than two spinal segments. MRI of the brain may show characteristic demyelinating lesions (in up to 50% of cases manifesting as a clinically isolated syndrome). The cerebrospinal fluid may reveal unmatched oligoclonal bands (in up to 50% of cases manifesting as a clinically isolated syndrome). The diagnostic evaluation of a patient with suspected acute transverse myelopathy initially involves neuroimaging of the spine (usually MRI with gadolinium) to rule out a compressive myelopathy. After a compressive spinal lesion is ruled out, a lumbar puncture helps distinguish an inflammatory myelopathy from a noninflammatory myelopathy. The cerebrospinal fluid analysis includes a cell count determination and differential, protein and glucose level measurements, oligoclonal band analysis, and cytologic studies. If an inflammatory myelopathy is suspected, brain MRI and evoked potentials may indicate whether there is a multifocal inflammatory process, suggestive of multiple sclerosis, acute disseminated encephalomyelitis or neuromyelitis optica (also known as Devic’s syndrome). In the case of neuromyelitis optica, patients may be tested for a specific neuromyelitis optica–immunoglobulin G autoantibody, as recently described by Lennon and associates. A possible infectious/parainfectious cause may manifest with certain clinical features: fever, rash, meningismus, concurrent systemic infection, immunocompromised state, recurrent genital infection, radicular burning pain with vesicles (suggestive of herpes zoster), and lymphadenopathy. In such cases, further investigation includes serum and cerebrospinal fluid viral and bacterial cultures, cerebrospinal fluid viral and bacterial polymerase chain reaction studies, and acute and convalescent serum antibody studies for the infectious agents listed in Table 39–1. Alternatively, certain clinical features such as arthritis, erythema nodosum, xerostomia, Raynaud’s phenomenon, rash, and ulcers may be suggestive of an underlying systemic disease, such as systemic lupus erythematosus, Sjögren’s syndrome, sarcoidosis, mixed connective tissue disease, Behçet’s disease, or antiphospholipid antibody syndrome. If a systemic autoimmune disease is suspected, serum should be analyzed for antinuclear antibodies, double-stranded DNA antibodies, Ro and La antibodies, cardiolipin antibodies, lupus anticoagulant,
507
508
Section
VIII
Spine and Spinal Diseases
T A B L E 3 9 – 1.
Causes of Acute Transverse Myelopathy
T A B L E 3 9 – 2.
Demyelination
Multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica Systemic lupus erythematosus, sarcoid, Sjögren’s syndrome, Behçet’s syndrome, antiphospholipid syndrome, mixed connective tissue disease Herpes simplex viruses 1 and 2, herpes zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, enterovirus, human immunodeficiency virus, human T cell lymphotrophic virus type 1, mycoplasma, Lyme disease, syphilis Arterial, venous, watershed, arteriovenous malformation, fibrocartilaginous embolism Radiation myelopathy, epidural lipomatosis
Spinal multiple sclerosis Primary lateral sclerosis Hereditary spastic paraplegia Spinal muscular atrophy Subacute combined degeneration Radiation myelopathy Paraneoplastic myelopathy Hepatic myelopathy Adrenomyeloneuropathy Infections (human T cell lymphotrophic virus type 1, parasites, toxoplasmosis) Systemic disease (e.g., systemic lupus erythematosus, Sjögren’s syndrome)
Systemic disorders
Infectious/ parainfectious
Vascular Miscellaneous Idiopathic
angiotensin-converting enzyme level, β2-glycoprotein level, and complement levels. Schirmer’s test, lip/salivary gland biopsy, and chest computed tomographic scan should also be considered.
CHRONIC MYELOPATHIES The commonest causes of chronic myelopathy seen in neurological practice include spinal multiple sclerosis, cervical spondylitic radiculomyelopathy, and sporadic motor neuron disease. These topics are covered in more detail elsewhere in the book. Patients with chronic myelopathy typically present with gradually progressive spastic paraparesis and varying spastic paresis of the upper limbs. The extent of sensory loss varies according to the nature of the underlying neuropathology. Sphincter dysfunction is also commonly seen. Causes of chronic myelopathy are listed in Table 39–2.
Causes of Chronic Myelopathy
logical features such as amyotrophy, dementia, epilepsy, optic atrophy, retinopathy, extrapyramidal disease, ataxia, mental retardation, deafness, ichthyosis, and peripheral neuropathy. Patients present at any age, typically with gait disturbance. A patient may present with toe walking, with a tendency to trip because the feet catch on uneven ground, or with premature wear on footwear. In childhood cases, walking may be delayed. Spasticity predominates over weakness, particularly in the lower limbs. The upper limbs are rarely affected. Brisk tendon reflexes with extensor plantar responses are found. Sensory loss, if present, involves mild impairment of vibration sense. Similarly, sphincter involvement is usually mild and results in urinary urgency, frequency, and hesitancy. Some affected patients may be so severely disabled by spasticity that they require a walking aid or wheelchair, despite having normal performance on muscle testing. Some affected family members may be minimally affected or even asymptomatic. The prognosis is highly variable; however, early-onset cases (manifesting before age 35 years) may have a very slowly progressive course with ambulation remaining, whereas later onset cases (after age 35 years) may progress rapidly, rendering patients nonambulatory. The diagnosis is usually made by exclusion of alternative causes, although gene testing is available for some cases.
Hereditary Spastic Paraplegia Hereditary spastic paraplegia is a rare, genetically determined degenerative disorder affecting predominantly corticospinal neurons. The condition is outlined in more detail in Chapter 69. Hereditary spastic paraplegia was first described by Adolf von Strümpell and M. Lorrain during the late 19th century. Although the phenotypic variants are well described elsewhere, knowledge of the genetic basis of this condition has undergone vast changes since the mid-1990s. At the time of this writing, more than 20 genetic loci (labeled SPG1 to SPG23) and nine defined gene products have been discovered. These gene products include spastin (which accounts for 40% of dominantly inherited hereditary spastic paraplegia cases), atlastin, NIPA1, kinesin heavy chain, heat shock protein 60, seipin, paraplegin, spartin, L1 cell adhesion molecule, and proteolipid protein. The precise functions of these gene proteins are not well understood; however, knowledge in this area is rapidly expanding. Hereditary spastic paraplegia displays marked phenotypic and genotypic variabilities. The inheritance may be autosomal dominant, autosomal recessive, or X-linked. The disorder has traditionally been divided clinically into pure and complicated forms; the latter has been associated with additional neuro-
Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a hereditary degenerative disorder involving the anterior horn cells, spinal interneurons, and, in some cases, the bulbar nuclei. The childhood-onset, autosomal recessive, proximal form is the commonest variation of the disorder. The incidence ranges from 1 per 6000 to 1 per 10,000. It is a common genetic cause of death and disability in childhood. The disorder has traditionally been classified into types I, II, and III by age at onset and by severity. Type I, also known as Werdnig-Hoffman disease, is characterized by early age at onset (before 6 months of age) and severe muscle weakness, muscle wasting, and hypotonia. Death from respiratory failure often occurs before the age of 2 years. Type III, also known as Kugelberg-Welander disease, begins after the age of 18 months and is of milder severity. Affected patients usually survive into adulthood, and many can walk or stand without assistance. Type II is an intermediate form. Additional clinical features of SMA include hyporeflexia, tongue fasciculations, and hand tremor. Sensory loss and sphincter disturbance are absent. The electrophysiological investigations reveal changes in denervation on electromyography and normal sensory/motor
chapter 39 primary myelopathies (degenerative, infective, metabolic) conduction velocities. Muscle biopsy also reveals denervative changes with hypertrophic fibers. Genetic linkage analysis has linked SMA types I, II, and III to defects on chromosome 5q11.2-13.3. A mutation in the survival motor neurone gene (SMN1) was discovered as the causative factor. A copy gene, SMN2, acts as a modifier gene, possibly rescuing the phenotype. The SMN1 gene codes for a 38-kD protein, which plays a multifunctional role in ribonucleoprotein metabolism and premessenger RNA splicing. There appears to be a dose effect of the SMN protein, which determines the clinical subtype and therefore the severity of the condition. A number of less common variants of SMAs also occur. A rare subtype of SMA type I, SMARD1, constitutes 1% of cases of infantile SMA. This variant is characterized by severe diaphragmatic weakness with eventration of abdominal contents, which results in respiratory distress. The muscle weakness is usually predominantly distal rather than proximal, as opposed to the more commonly occurring SMA type I. Another subtype is dominant distal SMA, also known as “spinal CMT 2D.” In this variant, there is a predominance for upper limb weakness; the condition is linked to chromosome 7p and has been found to be caused by a mutation in the glycyl transfer RNA synthetase gene. A further variant is X-linked severe SMA with arthrogryposis and bone fractures.
509
gerated deep tendon reflexes (11%). Brisk deep tendon reflexes with extensor plantar responses and lower limb spasticity were found in just 6%. The evaluation of a patient with suspected cobalamin deficiency should begin with a serum cobalamin level measurement, and if the level is in the low normal range and the clinical index of suspicion is high, then serum methylmalonic acid and homocystine levels should be measured. If the serum cobalamin level is reduced, measurement of intrinsic factor antibodies and parietal cell antibodies may be useful in diagnosing autoimmune pernicious anemia. Schilling’s test may then be helpful in determining the cause of cobalamin deficiency. Spinal MRI may show characteristic T2 signal changes in the posterior and lateral columns, and somatosensory evoked potentials may demonstrate impairment of central conduction defects. Treatment of cobalamin deficiency requires 1000 μg of intramuscular cobalamin daily for 5 days, followed by monthly doses of similar amount. Exposure to nitrous oxide, either through its use as an anesthetic or through recreational use, may trigger an acute or subacute myelopathy by interfering with cobalamin metabolism. The treatment is the same as for subacute combined degeneration as described previously.
Copper Deficiency Myelopathy Cobalamin Deficiency Myelopathy or Subacute Combined Degeneration Neurological disorders associated with pernicious anemia were first identified in the late 19th century. Although the myelopathy associated with cobalamin deficiency is the predominant neurological manifestation, other recognized features include dementia, neuropathy, and, in rare cases, optic neuropathy. A more comprehensive discussion of the cobalamin deficiency is presented in Chapter 109; however, the myelopathy is briefly described here. Classically, a patient presenting with numbness and weakness in the legs is found to have macrocytic anemia. The examination reveals a smooth tongue, prematurely graying hair, and yellow skin. The diagnosis is then confirmed by demonstration of a low serum cobalamin level. Frequently, however, affected patients present with atypical clinical or laboratory features, such as neurological manifestations without anemia, macrocytosis, or depressed serum cobalamin level. In the last situation, elevated levels of cobalamin metabolites (methylmalonic acid and homocystine) may provide a clue to the diagnosis. Healton and colleagues reported the first large series of patients with neurological manifestations from cobalamin deficiency since the introduction of modern diagnostic techniques and therapeutic measures. Of 369 patients with cobalamin deficiency, 189 (51%) had neurological symptoms and 114 (31%) had neurological symptoms as their presenting symptom. Of those with neurological manifestations, paresthesias occurred in 70% and were disabling in 10%. Twenty-one percent had neurological symptoms but with normal findings on neurological examination. On examination, impaired lower limb vibration sense (88%) and diminished proprioception in the toes and ankles (59%) were the predominant findings. Other findings included impaired touch/pain sensation (30%), gait ataxia (23%), limb weakness (13%), positive Romberg test results (11%), absent or reduced deep tendon reflexes (33%), and exag-
A progressive myelopathy/myeloneuropathy associated with copper deficiency has been recognized. The condition may have been hitherto underrecognized. Kumar and associates (2004) reported a series of such cases with a clinical syndrome resembling subacute combined degeneration. The patients typically presented with a spastic ataxic gait and marked posterior column sensory deficits. MRI may demonstrate posterior column signal changes, and somatosensory evoked potentials may show evidence of central proprioceptive pathway conduction defects. Reduced ceruloplasmin levels were the initial clue to the diagnosis. The cause of reduced levels of serum copper was not known in most cases. Copper supplementation restores the serum copper levels and may prevent further neurological deterioration. Some cases of copper deficiency were associated with elevated zinc levels. As with subacute combined degeneration from cobalamin deficiency, copper deficiency–related myelopathy occurred in the absence of hematological manifestations.
Paraneoplastic Myelopathy Progressive myelopathy has rarely been reported in the context of systemic cancer. Mancall and Rosales reported cases of subacute necrotizing myelopathy associated with visceral carcinoma. Subacute ascending flaccid areflexic paraplegia with sphincter paresis and sensory involvement was the characteristic presentation. The cerebrospinal fluid analysis shows pleocytosis and elevated protein. MRI of the spine shows spinal cord enlargement and T2 signal abnormalities. There is no specific cancer described with the syndrome, and there are no recognized testable autoantibodies that can serve as a marker for a paraneoplastic process.
Hepatic Myelopathy A rare progressive myelopathy may occur in the setting of chronic liver disease and may be part of the clinical spectrum,
510
Section
VIII
Spine and Spinal Diseases
which includes acquired hepatocerebral degeneration. Patients typically have spastic paraparesis with minimal sensory involvement. Pathologically, there is symmetrical demyelination of the lateral pyramidal tracts with a degree of axonal loss. Differential effects of the exposure to toxic metabolic substances that bypass the liver may explain the resultant neurological manifestations (i.e., hepatic myelopathy versus acquired hepatocerebral degeneration).
Adrenomyeloneuropathy Adrenomyeloneuropathy is regarded as a milder variant of adrenoleukodystrophy. Adrenoleukodystrophy is discussed in greater detail in Chapter 80. It is an X-linked disorder caused by a mutation in the Xq28 gene, which codes for a peroxisomal membrane transporter protein (ALDP). The precise role of ALDP is unknown; however, the ALDP mutation leads to the accumulation of very-long-chain fatty acids, particularly tetracosanoic acid (C24:0) and hexacosanoic acid (C26:0) in neural tissue, adrenal glands, and testes. A typical patient with adrenomyeloneuropathy presents with a slowly progressive spastic paraparesis during the third to fourth decades of life. Early sphincter involvement and defects in posterior column sensory function are characteristic. Signs of adrenal and testicular insufficiency may precede, occur synchronously with, or follow the onset of the neurological manifestations. Nevertheless, 15% of affected male patients and 99% of affected female patients (symptomatic carriers) do not develop adrenal insufficiency. Of all patients with adrenomyeloneuropathy, 40% to 50% have cerebral white matter lesions on MRI (“cerebral” adrenomyeloneuropathy). Those without such cerebral white matter lesions (i.e., “pure” adrenomyeloneuropathy) have a better prognosis, whereas 25% of patients with “cerebral” adrenomyeloneuropathy develop a catastrophic course like that of childhood cerebral adrenoleukodystrophy. Pathological studies of adrenomyeloneuropathy suggest a noninflammatory distal axonopathy involving the spinal cord tracts and, to a lesser extent, peripheral nerves. The diagnosis is based on the demonstration of increased levels of serum very-long-chain fatty acids and mutation analysis. In other inborn errors of metabolism (e.g., globoid leukodystrophy and metachromatic leukodystrophy), myelopathy may be part of the clinical manifestation; however, such conditions produce not isolated myelopathy but rather a multisystem neurological disorder.
K E Y ●
P O I N T S
Acute transverse myelopathy can result from a variety of inflammatory processes, including idiopathic transverse myelitis, multiple sclerosis, and neuromyelitis optica; a variety of infectious/parainfectious disorders; and systemic autoimmune disorders such as systemic lupus erythematosus.
●
The syndrome of acute transverse myelopathy may also result from noninflammatory processes such as spinal cord infarction and radiation myelopathy.
●
Myelopathy resembling subacute combined degeneration can be caused by cobalamin deficiency and also copper deficiency.
●
Advances in molecular genetics are rapidly expanding knowledge of the hereditary degenerative myelopathies such as hereditary spastic paraplegia and spinal muscular atrophy.
Suggested Reading De Seze J, Stojkovic T, Breteau G, et al: Acute myelopathies: clinical, laboratory and outcome profiles in 79 cases. Brain 2001; 124:1509-1521. Green R, Kinsella L: Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995; 45:1435-1440. Kumar N, Gross JB, Ahlskog JE: Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004; 63:33-39. Miller AE (ed): Spinal cord disorders [June issue]. Continuum: Lifelong Learning in Neurology 2005; 11(3). Transverse Myelitis Consortium Working Group: Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59:499-505.
References Anderson K, Talbot K: Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling. Curr Opin Neurol 2003; 16:595-599. Elliott JL: Beginning to understand hereditary spastic paraplegia atlastin. Arch Neurol 2004; 61:1842-1843. Fink JK: The hereditary spastic paraplegias: nine genes and counting. Arch Neurol 2003; 60:1045-1049. Fink JK, Rainier S: Hereditary spastic paraplegia: spastin phenotype and function. Arch Neurol 2004; 61:830-833. Healton EB, Savage DG, Brust JCM, et al: Neurologic aspects of cobalamin deficiency. Medicine 1991; 70:229-244. Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364:2106-2112. Lewis M, Howdle PD: The neurology of liver failure. Q J Med 2003; 96:623-633. McDermott CJ, White K, Bushby K, et al: Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry 2000; 69:150-160. Mancall EL, Rosales RK: Necrotizing myelopathy associated with visceral carcinoma. Brain 1964; 87:639-656. Moser H, Dubey P, Fatemi A: Progress in X-linked adrenoleukodystrophy. Curr Opin Neurol 2004; 17:263-269. Nicole S, Diaz CC, Frugier T, et al: Spinal muscular atrophy: recent advances and future prospects. Muscle Nerve 2002; 26:4-13. Powers JM, DeCierco DP, Ito M, et al: Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol 2000; 59:89-102. Rudnicki SA, Dalmau J: Paraneoplastic syndromes of the spinal cord, nerve and muscle. Muscle Nerve 2000; 23:1800-1818.
CHAPTER
40
SPINAL DISEASE: NEOPLASTIC, DEGENERATIVE, AND INFECTIVE SPINAL CORD DISEASES AND SPINAL CORD COMPRESSION ●
●
●
●
Shalini A. Amukotuwa and Mark J. Cook
The long, cylindrically shaped spinal cord sits within the bony vertebral canal, tightly enveloped by the meninges. It extends from the foramen magnum to the first lumbar vertebra, where it terminates in the conus medullaris. Below this, the lumbosacral nerve roots form the cauda equina. Anatomically, the spinal cord has a distinctive structural arrangement, illustrated in Figure 40–1A. Functionally, the spinal cord plays a key role in sensorimotor conduction. Because of its special features and relatively primitive reflexes, diseases of the spinal cord give rise to a number of distinctive, sometimes overlapping clinical syndromes (Tables 40–1 and 40–2; see Fig. 40–1B). Segmental (myotomal) lower motor neuron weakness, with depressed or absent deep tendon reflexes, muscle atrophy, and flaccidity/decreased tone, may be present at the level of the lesion, as a result of involvement of anterior horn motor neurons or anterior (motor) nerve roots; this helps clinicians localize the lesion (Table 40–3). Segmental (dermatomal) sensory loss may also be present (Fig. 40–2). Radicular symptoms and signs (see Table 40–2) result from irritation and compression of spinal nerve roots by extramedullary spinal cord lesions, usually before the involvement of long tracts (radiculomyelopathy). Radicular features are unusual with intramedullary lesions; when they do occur, they are most often present in the context of demyelinating disease. Sensorimotor long tract signs usually arise as a result of compression, rather than invasion or destruction, of spinal white matter fasciculi and occur early with intramedullary lesions. Either sensory or motor function may be affected first; the distribution and extent of long tract symptoms and signs are dependent on the site and size of the lesion. A sensory level, below which perception of pain and temperature is altered or lost, is pathognomonic of a spinal cord lesion and should prompt imaging of the spinal cord. Often the signs are subtle in the early stages, and the description of a sensory level should alert the clinician. The highest level of sensory deficit indicates the lower possible level of the lesion, and the pathology may be present anywhere above this level; the sensory level may in fact be well below the actual lesion, and this must be kept in mind
when imaging is ordered. Lamination of sensory fibers (see Fig. 40–1A) can give rise to suspended sensory deficits (i.e., isolated sensory deficit) at the level of the lesion or several segments caudally. Sacral sensation may be spared with deeper intramedullary lesions caused by spinothalamic tract lamination. Progressive spinal cord lesions, such as intramedullary neoplasms, may engender sequential deficits. Back or neck pain is a common complaint with spinal cord disease and may help the clinician localize the level of a structural lesion, such as an epidural abscess or compressive metastatic epidural deposit. Intrinsic spinal lesions tend to produce poorly localized pain. Exacerbation of pain with increased intraspinal pressure (coughing or straining), movement, or recumbency is suggestive of an extramedullary extradural lesion. Focal tenderness on palpation of the spinous process, as well as restriction of movement, may be associated with such lesions. The time course of symptoms is of value in determining the cause of spinal cord dysfunction. An acute onset suggests a mechanical or vascular lesion, whereas inflammatory and infective processes typically follow a subacute course, sometimes with fluctuation over days or weeks. Compressive lesions may follow an acute, subacute, or more protracted course, depending on the underlying process. Degenerative myelopathies classically are insidiously progressive.
IMAGING Magnetic resonance imaging (MRI) has enabled characterization of spinal cord diseases, including their location and internal structure, with the use of different magnetic resonance scanning sequences. The basic spinal MRI study includes T1and T2-weighted sequences in the sagittal plane and contrast material (gadolinium)–enhanced T1-weighted images in the sagittal and axial planes. Myelography involves the introduction of radiopaque dye to the spinal fluid, through lumbar or sometimes cervical roots, but is limited in resolution and the length of cord that can be imaged in one episode. Obstruction to the
511
512
VIII
Section
Dorsal nerve root
Spine and Spinal Diseases
Spinous process
Central canal Dorsal columns C T
Neural exit foramen
Dorsal root ganglion
L S Corticospinal tract
Le Tr A Ventral nerve root
Vertebral body Temperature
LT C
Pain
Lateral spinothalamic tract
Touch
A
i
ii
iii
B ■
Figure 40–1. Anatomy of the spinal cord. A, Schematic diagram of the cross-section of the spinal cord, demonstrating sensory and motor long tracts, and gray matter. Myelinated fibers, forming the long tracts, are located peripherally, subjacent to the pia mater, and are laminated (C, cervical; T, thoracic; L, lumbar; S, sacral; A, arm; Le, leg; Tr, trunk). The gray matter is composed of cell bodies of motor neurons innervating skeletal muscles (anterior horns) and sensory neurons involved in conduction of pain and thermal sensation (dorsal horns). The central canal is surrounded by fibers conveying pain and thermal sensation, which cross the midline before joining fibers from more caudal levels to form the anterolateral (spinothalamic) tract. The primary sensory neurons, which innervate peripheral sensory receptors, have their cell bodies within the dorsal root ganglia, which lie within the neural exit foramina. B, Some patterns of spinal cord disease, with accompanying spinal cord syndrome: i, Complete transverse cord syndrome; ii, Brown-Séquard syndrome; iii, syringomyelic/central cord syndrome. (Adapted from Thompson PD, Blumbergs PC: Myelopathies. In Asbury AK, McKhann GM, McDonald WI, et al, eds: Diseases of the Nervous System: Clinical Neuroscience and Therapeutic Principles, 3rd ed, vol 1. Cambridge, UK: Cambridge University Press, 2002, p 717.)
cerebrospinal column and distortion and enlargement of the cord may all be directly visualized. Combining myelography with computed tomographic scanning of the spine is useful, allowing a greater extent of the cord to be accurately imaged in the one sitting. Plane films of the spine may reveal bony lesions and other local pathological processes, but their utility is quite limited.
SPINAL CORD INFECTIONS Potentially any structure of the spinal cord and its surrounding meninges and vertebral column may be involved in infectious processes. The causative agents include bacteria, viruses, parasites, and fungi (Table 40–4).
chapter 40 spinal disease T A B L E 4 0 – 1. Red Flag Features Indicative of Cord Disease Gait disturbance Lhermitte’s phenomenon: “electric” paresthesias radiating down the back and arms, induced by neck movement (characteristically flexion), indicative of a dorsal column spinal cord lesion Localized back pain (tumor, abscess) and spinal tenderness Segmental/radicular symptoms or sensory/motor deficit Sensory or motor level Paraplegia or quadriplegia: often a late event, by which time neurological damage is usually irreversible Sphincter dysfunction (urinary retention and constipation), usually late in extramedullary lesions and early in intramedullary lesions; may be an early feature, preceding paralysis, in conus medullaris and cauda equina lesions Sexual dysfunction: Erectile dysfunction (male) Impaired perineal and vaginal sensation (female), especially if unilateral
T A B L E 4 0 – 2.
513
Infectious and Parainfectious Myelopathies Myelitis is a process intrinsic to the spinal cord; this definition excludes expansive lesions.1 Transverse myelitis is characterized by a focal inflammatory process within the spinal cord, leading to varying degrees of neural injury and dysfunction of neural pathways passing through the inflamed segment.2 This in turn leads to the abrupt onset of varying degrees of weakness, sensory alteration, and autonomic dysfunction. The diagnostic criteria for transverse myelitis include the following:1,3 1. A disturbance of motor capacity and continence; in acute transverse myelitis, the deficit reaches a maximum no later than 4 weeks after initial onset. 2. Bilateral segmental sensory loss. 3. No medullary compression. 4. Consistent MRI and neurophysiological findings.
Spinal Cord Syndromes
Syndrome
Features
Complete transverse spinal cord syndrome (see Fig. 40–1Bi)
Paralysis and anesthesia below level of lesion Often a rim of hyperesthesia at upper level of sensory deficit Paraparesis or paraplegia: lesion at or rostral to lower cervical cord Quadriparesis or quadriplegia: lesion of the upper cervical cord Caused by unilateral spinal cord lesion; may be partial or complete Ipsilateral upper motor neuron (pyramidal) weakness and dorsal column sensory deficit Contralateral spinothalamic (pain and temperature) sensory deficit (vertical stripes in Fig. 40–1Bii) Light touch is usually preserved Caused by involvement of white matter fasciculi Corticospinal tract involvement: upper motor neuron limb weakness (arm and leg weakness caused by cervical cord lesion; leg weakness caused by a lesion rostral to the upper lumbar spine): Hypertonia and clonus (spasticity) Hyperreflexia Extensor planar responses (lesion above the L5 segment, which innervates extensor digitorum longus) Long sensory tracts: paresthesias and sensory loss Dorsal column: paresthesias, numbness, impaired vibration sense, and loss of proprioceptive function (resulting in sensory ataxia); decreased fine motor control of hands Spinothalamic tract: cutaneous dysesthesias, abnormal thermal sensations, loss of pain and temperature sensation, hyperesthesias and hyperpathia; deficits occur contralaterally (i.e., a dissociated loss), as pain and temperature fibers decussate shortly after entering the spinal cord Dorsal (sensory) nerve root involvement: Radicular pain (lancinating pain, radiating distally along the affected dermatome Dermatomal burning dysesthesias or hyperesthesias Sensation loss or diminution in dermatome(s) supplied by compressed root Diminished or absent segmental tendon and cutaneous reflexes (see Fig. 40–2) Ventral (motor) nerve root involvement: Segmental myotomal weakness Wasting Flaccidity/hypotonia Diminished or absent reflexes (see Table 40–3) Seen in syringomyelia and certain other intramedullary lesions Brachial amyotrophy (upper limb weakness, with wasting, and depressed or absent deep tendon reflexes) Segmental suspended dissociated sensory loss, caused by interruption of decussating pain and temperature fibers around central spinal canal Caused by selective involvement of the motor neurons; segmental weakness, atrophy, fasciculations, and absent or diminished reflexes Usually associated with vascular lesions of the anterior spinal artery, resulting in ischemia and neurological deficits within its area of supply (see Fig. 40–2); bilateral upper motor neuron weakness and spinothalamic sensory deficit below the lesion; dorsal column function is spared Pain usually an early feature; asymmetrical lower motor neuron (areflexic, flaccid, atrophic) paralysis of lower limbs; sphincter dysfunction (urinary or fecal incontinence, diminished anal tone) and radicular sensory loss; may difficult to differentiate clinically from lesions of the lumbosacral plexus Early and prominent sphincter dysfunction; back pain; sensory disturbance in sacral dermatomes (perineal: S3-S5; leg: L5-S2); loss of anal tone and reflex; impotence; leg weakness inconsistent, usually mild
Brown-Séquard (hemicord) syndrome (see Fig. 40–1Bii) Sensorimotor spinal tract syndrome
Radicular syndrome
Syringomyelic or central cord syndrome (see Fig. 40–1Biii) Anterior horn syndrome Anterior spinal cord syndrome Cauda equina syndrome Conus medullaris lesions
514
Section
VIII
Spine and Spinal Diseases
T A B L E 4 0 – 3. Segmental Innervation of Muscles and Tendon and Cutaneous Reflexes Segment/ Nerve Root C3, C4 C4, C5 C5 C5, C6 C6 C7 C8 T1 T7-10 T10-12 L1 L2 L3, L4 L4 L5 L5, S1 S1 S1, S2 S4, S5
Muscle
Tendon or Cutaneous Reflex
Trapezius Rhomboids Deltoid Supraspinatus, infraspinatus, biceps Brachioradialis Triceps, extensor digitorum Flexor digitorum superficialis and profundus Intrinsic muscles of hand Upper rectus abdominis Lower rectus abdominis Iliopsoas Adductor magnus Quadriceps femoris Tibialis anterior Extensor hallucis longus Hamstrings Extensor digitorum brevis Soleus, gastrocnemius
— — — Biceps reflex Brachioradialis reflex Triceps reflex Finger-jerk reflex — Upper abdominal reflex Lower abdominal reflex Cremasteric reflex Adductor and cremasteric reflexes Knee-jerk (patellar) reflex — Plantar reflex Ankle-jerk reflex — — Anal reflex
■
C2 C2 C3 C4
C3 C4 T1 T2 T3 T4 T5 T6 T7 T8
C5
C6
C7
C8
L1 L2
C6
T9 T10
T11 T12
C7
T1 T2 T3 T4 T5 T10 T11 T12 L4
C8 T6 T7 T8 T9 L1 L2 L3
L5 S1
S2
L3 S2 L4
L5
S1
C5
L5 L4
Figure 40–2. Distribution of dermatomes on the anterior surface of the body. (From Merck and Company: Merck Manual of Diagnosis and Therapy, Section 14: Neurologic Disorders; redrawn from Keegan JJ, Garrett FD: The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 102:409-437, 1948.)
chapter 40 spinal disease T A B L E 4 0 – 4. Infections of the Spinal Cord Anterior (Anterior Horn Cell) Myelitis Viral Enteroviruses (e.g., poliovirus, enterovirus 71, Coxsackie A7 virus, echovirus) Tickborne encephalitides Flaviviruses (e.g., Japanese encephalitis virus, Murray Valley encephalitis virus, West Nile virus) Herpes viruses (e.g., CMV, EBV, VZV) Transverse Myelitis Viral Herpes viruses (e.g., HSV, VZV, EBV, CMV) HTLV-1 Rabies B virus Enteroviruses (Coxsackie A and B viruses, echoviruses) Other Mycoplasma pneumoniae Dorsolateral Column Myelitis Vacuolar myelopathy of AIDS Tabes dorsalis (syphilitic myelopathy, caused by tertiary Treponema pallidum infection) Necrotizing Ascending Myelopathy VZV myelitis in immunocompromised state AIDS-related opportunistic infections Pyogenic Infections Subacute bacterial meningomyelitis Intraspinal abscess Spinal epidural abscess Vertebral osteomyelitis Tuberculous disease: vertebral osteomyelitis (Pott’s disease), tuberculous meningomyelitis, tuberculoma (caseating granuloma) of spinal cord or epidural space Fungal and Parasitic Infections Epidural abscess, granuloma (noncaseating) Meningomyelitis AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; EBV, EpsteinBarr virus; HSV, herpes simplex virus; HTLV-1, human T cell leukemia/lymphoma virus type 1; VZV, varicella-zoster virus.
Transverse myelitis forms a part of a spectrum of neuroinflammatory conditions and may occur as part of a multifocal central nervous system (CNS) disease, such as multiple sclerosis; as part of a multisystem disease, such as systemic lupus erythematosus; or as an idiopathic, isolated entity.2 Of all cases of idiopathic transverse myelitis, 30% to 60% were preceded by a respiratory, gastrointestinal, or systemic infectious illness.2-5 The underlying pathogenesis of transverse myelitis is varied, depending on the specific underlying disease process. For instance, connective tissue disease–associated transverse myelitis may be secondary to a CNS vasculitis or thrombotic infarction of the cord.6 Most patients have cerebrospinal fluid (CSF) pleocytosis and foci of blood-brain barrier breakdown within the spinal cord.2 Two large etiological groups of inflammatory transverse myelitis are identifiable: the inflammatory demyelinating autoimmune myelopathies, such as multiple sclerosis, and the usually monophasic infectious encephalomyelitides.1 More than 40 such infectious encephalomyelitides have been identified, of which approximately 10 have been established as “pure infectious” myelitides by CSF virus isolation or polymerase chain reaction (PCR) techniques, which indicate that neuro-
515
logical injury resulted directly from microbial infection.1,2,8 The remainder are believed to be parainfectious, caused namely by a microbial infection, which in turn incites an immune response against neural tissue. In the latter, the infection may be remote from the immunological response.2 The latency between myelitis and preceding infection does not significantly differ between infectious and postinfectious myelitis. An interval of 9 ± 6 days has been reported for parainfectious cases, 5 days in mumps-related myelitis, 12 days in zoster-related myelitis, and 10 days in Mycoplasma-related myelitis.3,9-11 Although diagnosis of infectious and parainfectious transverse myelitis requires identification of the infectious agent within the CNS, some autoimmune mechanisms, such as molecular mimicry and superantigen-mediated disease, require only peripheral immune activation.2 In molecular mimicry, the putative mechanism of neural injury is antibody-mediated damage, secondary to cross-reaction of antibodies against an infectious agent with molecularly similar antigens in host neural tissue.2 Transverse myelitis is associated pathologically on tissue sampling (biopsy or autopsy) with inflammation.2 Both gray and white matter compartments are affected, although in postinfectious myelitis, white matter changes, demyelination, and axonal injury are prominent. Focal infiltration by lymphocytes and monocytes into segments of the spinal cord and perivascular spaces and activation of astroglial and microglial cells are observed.2 In some biopsies performed during the acute phase of myelitis, infiltration of CD4+ and CD8+ lymphocytes is prominent. Subsequently, during the subacute phase, monocyte and macrophage infiltration may become more prominent. In cases in which transverse myelitis is associated with autoimmune disease such as systemic lupus erythematosus, focal areas of ischemia or infarction secondary to vasculitis may be present, without prominent inflammation, a finding not usually seen in most cases of infectious transverse myelitis.12 PCR techniques, performed on serum and CSF, have facilitated the rapid, sensitive, and noninvasive diagnosis of many infectious forms, particularly viral, of myelitis.1,13,14 Diagnosis is often based on the detection of viral DNA in CSF by PCR.13 Further supportive evidence for a particular viral agent as the cause of myelitis, of value when viral PCR results are negative, is the presence of specific immunoglobulins M (IgM) and G (IgG) antibodies in the CSF, suggestive of intrathecal synthesis.1,13 This is especially the case when the serum:CSF ratio of these antibodies is depressed in relation to total IgG and albumin levels. Infectious and parainfectious transverse myelitis are the focus of discussion in this chapter. The list of antecedent infections includes herpesviruses and Listeria monocytogenes, although in most of these cases, causality has not been established. Infectious and parainfectious transverse myelitis can be further subdivided, on the basis of the components of the neural axis involved, into meningomyelitis, transverse myelitis without meningitis, encephalomyelitis, and anterior horn syndrome with meningitis, among other entities.1 Meningitis is defined here as the clinical syndrome of fever and neck stiffness.1,2
Clinical Features The clinical picture of acute transverse myelitis is one of rapid evolution of neurological deficit; however, the distribution of
516
Section
VIII
Spine and Spinal Diseases
dysfunction, including the modalities affected, depends on the extent and distribution of inflammation within the spinal cord.2 On examination, there is often a clearly defined level of sensory dysfunction.2 When the maximum level of neurological deficit is reached, approximately 50% of affected patients are paraplegic, and 80% to 94% of patients experience sensory disturbances, including numbness, paresthesias, and bandlike dysesthesias.2-5,15,16 Manifestations of autonomic dysfunction include urinary urgency, urinary or fecal incontinence, difficulty or inability opening bladder or bowels, and sexual dysfunction.1
Imaging Acute inflammation is evident on spinal MRI.1,2 This includes swelling of the spinal cord, in inflamed segments, as well as increased signal intensity on T2-weighted imaging. In cases in which nerve roots are involved in the inflammatory process (radiculomyelitis), enhancement of the affected nerve roots with administration of intravenous gadolinium contrast material may be seen.2,13 However, there are several reports in the literature of clinical cases of myelitis in which there is no demonstrable abnormality of the spinal cord on imaging.1,2,13
Differentiating between Infectious/Parainfectious Transverse Myelitis and Multiple Sclerosis In multiple sclerosis, it is unusual to have complete transverse myelitis; there was only one such case of 308 in the Göteborg series.18 The weakness and numbness tend to be less severe in multiple sclerosis.19 Pathologically, CSF oligoclonal bands present in multiple sclerosis are absent in infectious transverse myelitis.1,19 Differences in MRI of the spine are also reported.1,18-20 In multiple sclerosis, the areas of T2 hyperintensity tend to be multifocal, smaller, and limited to one segment of the cord in transverse segments; in infectious and parainfectious transverse myelitis, in contrast, T2 hyperintensities are confluent and elongated, often extending over several spinal segments. Furthermore, plaques of demyelination are usually seen on cerebral MRI in multiple sclerosis but not in infectious transverse myelitis.
Specific Entities Echovirus meningomyelitis There have been case reports of echovirus (types 11 and 18) isolated from either pharyngeal exudate or CSF of children with clinical meningomyelitis, with transient T2 hyperintensity of the spinal cord.21,22
Coxsackie virus–related myelitis and meningomyelitis There exist several case reports of patients with clinical and MRI evidence of transverse myelitis with or without meningitis, from whom Coxsackie virus (B4, B3, B5, A5, and A9) had been isolated or in whom a high titer of specific antibody to this virus had been demonstrated in the CSF or serum.1,23,24 For instance, in one case report of a 6-year-old with rapidly progressive paraplegia, with associated bladder and bowel dysfunction, a rising titer of serum anti-Coxsackie virus B5 antibody was demonstrated.25 The virus was also isolated from the stool. MRI in this
case demonstrated diffuse swelling of the spinal cord on T1weighted imaging.
Mumps-related meningomyelitis The commonest neurological manifestation of mumps virus infection is meningitis; encephalitis occurs in fewer than 0.1% of cases.9 However, there are case reports of myelitis associated with mumps viremia. For instance, a 10-year-old boy developed flaccid paraparesis and neck stiffness in the setting of parotitis and orchitis that are clinically indicative of mumps infection.26 MRI demonstrated T2 hyperintensity from C2 to T12 spinal cord segments, in keeping with myelitis. Mumps infection was confirmed by the presence of IgM class antibodies against mumps in the serum. In another report, a young woman was diagnosed with mumps-associated transverse myelitis on the basis of clinical findings, MRI demonstration of a swollen spinal cord with uniform high-signal change on T2 weighting, and acute mumps viremia.27 No reports of mumps virus isolation from the CSF, in the setting of transverse myelitis, have been found.
Herpes simplex virus–related myelitis Although a well-known cause of viral encephalitis, herpes simplex virus (HSV) is a rare cause of myelitis.13,28-30 This entity was first described by Klatersky and associates and has since been reported in both immunocompromised and immunocompetent patients.13,30 Subtle spinal cord involvement by HSV infection may be underrecognized. HSV type 2 infection and, less frequently, HSV type 1 infection cause genital infection, with vesicles and ulceration.9,32 After primary genital infection, the virus persists latently within the sensory neurons of the dorsal root ganglia and produces recurrent cutaneous disease with intermittent reactivation and retrograde spread along the sensory nerve.9,13,32 On occasion, HSV reactivation may be followed by radiculomyelitis, variably affecting the cauda equina, conus medullaris, and thoracic cord.32 The pathogenesis of HSVassociated myelitis is not well understood, although intraaxonal spread of virus from the sensory ganglion into the spinal cord through the dorsal roots is thought to be the likely mechanism.28 Most cases of HSV-related myelitis described in the literature have been associated with type 2 infection, probably reflective of the recurrence of latent infection mainly with the more commonly HSV type 2 venereal infections.13 In six of a series of nine patients with HSV-related myelitis reported by Nakajima and colleagues, disease onset was marked by bilateral lower limb sensorimotor disturbance and urinary symptoms, with ascending progression of the myelopathy to thoracic or cervical level within the course of a few weeks.13 Most cases of HSV-related myelitis described in the literature followed a similar clinical pattern of an acute, monophasic, usually fatal ascending necrotizing myelitis, with death resulting from respiratory paralysis or meningoencephalitis.13 However, other clinical patterns, including a self-limited, resolving transverse myelitis, a relapsing-remitting form, and chronic myelitis, have been described since the development of improved diagnostic techniques such as PCR which have enabled noninvasive diagnosis.13,28-30,33 In three of the nine patients studied by Nakajima and colleagues, transverse myelitis started in the cervicothoracic cord, with a nonascending pattern and milder sequelae than in the cases of ascending
chapter 40 spinal disease myelitis. There have also been other case reports of transverse myelitis of the cervical and thoracic cord, caused by HSV, that resolved.34 In these cases, demyelination without necrosis was postulated to be the underlying pathological process responsible for myelitis.13 In early reports, HSV-related myelitis was described as being frequently associated, in close temporal relation, with cutaneous herpetic eruptions, which provided a clue as to the diagnosis.13,30 However, it has since then been suggested that this association is seen in very few cases of HSV-related myelitis, and therefore this feature is not useful for early diagnosis. HSV per se is rarely isolated from the CSF.13 Subtle clinical involvement of the spinal cord in patients with genital HSV infections are probably much more common than appreciated, however, and symptoms related to cord involvement are often a prominent feature of the prodromal phase of the illness. The diagnosis of HSV meningoencephalitis is usually based on the detection of HSV DNA in CSF by PCR, with reported sensitivity and specificity of 98% and 94%, respectively.35 In most cases reported since 2000, PCR has been used in the diagnosis of HSV-related myelitis, although numbers have been too small to obtain data on specificity and sensitivity.28 Further evidence of herpetic infection as the cause of myelitis is the presence of anti-HSV IgM and IgG antibodies in the CSF, suggestive of intrathecal synthesis.28 Although demonstration of seroconversion against HSV concurrent with the episode of myelitis enables diagnosis, it should be kept in mind that anti-HSV antibody titers are not always elevated during the early stage of disease.13 CSF pleocytosis, although usually present, is also not a constant feature.29 MRI findings include enlargement of the conus medullaris; intramedullary T2 hyperintensity, particularly of the posterior funiculi; and gadolinium enhancement of the affected dorsal nerve roots, with no enhancement of the ventral roots.13,28 This is in keeping with the expected pattern of involvement of spinal cord structures, if infection is indeed caused by retrograde spread of virus into the cord from dorsal root ganglia. In one case, both T1 and T2 hyperintensities were observed, suggestive of hemorrhagic necrosis of the affected parts of the cord.13 Follow-up imaging may demonstrate atrophy of the cord in the previously inflamed regions.33 Treatment of HSV-related encephalitis with acyclovir is established; however, there are case reports of the value of this antiviral agent only in the treatment of HSV-related myelitis.28 Corticosteroids, in conjunction with antiviral therapy, may prevent ascending necrotizing myelopathy and improve survival.28 With regard to long-term prognosis, in the series by Nakajima and colleagues, three patients recovered, whereas the remaining six had severe persistent neurological deficits, such as paraplegia, despite antiviral therapy.13
Zoster-related transverse myelitis Varicella-zoster virus (VZV) infection may be associated with a wide spectrum of neurological complications, myelitis being the most poorly characterized of these.36 Several reports describe a postinfectious VZV-related myelitis, which is usually an acute, relatively benign transverse myelopathy, associated with a self-limiting paraparesis and sometimes sensory symptoms and sphincter disturbance.37 Chronic and remittingrelapsing temporal profiles of myelopathy have been described in association with VZV.36
517
Less commonly, a progressive ascending myelopathy, usually fatal in outcome, is seen in immunocompromised individuals and is thought to be caused by direct VZV invasion of the spinal cord.10,38 Ten cases of necrotizing vasculitis associated with VZV meningoencephalomyelitis have been reported in the literature, all with underlying immunodeficiency, secondary to either malignancy or human immunodeficiency virus (HIV) infection, and all cases fatal within 4 to 32 days.38 The patients typically developed radicular or central back pain within 2 weeks of zoster infection, in association with bilateral motor and sensory signs. The diagnosis of VZV-related myelitis is historically based on the onset of myelopathy within days to weeks of a typical rash.37 The symptoms may be most pronounced ipsilateral to and at the level of the rash. However, there are reports of VZVrelated myelitis, confirmed by positive VZV PCR or culture from the CSF, with no history of cutaneous rash.37,39 VZV per se is rarely isolated from blood or CSF, although the latter usually shows an often profound pleocytosis.37 PCR techniques have enabled the detection of VZV DNA in the CSF of patients suspected of having VZV-related myelopathy, even months later, which enables confirmation of the diagnosis and suggests a role of virus persistence in the pathogenesis of disease.37,38 VZV as the etiological agent in myelopathy is also supported by the presence of antibody (IgG and IgM) to VZV in the CSF, indicative of presence of viral antigen in the nervous system and intrathecal antibody synthesis.37,40 The underlying pathological process in VZV-related myelitis is thought to be a small- or large-vessel vasculopathy, depending on the immune status of the patient.38 Small-vessel disease is seen almost exclusively in immunocompromised patients and includes a necrotizing vasculitis of leptomeningeal vessels, especially around the spinal cord and brainstem.38 VZV has been detected in large and small vessels of the nervous system by PCR, in situ hybridization for VZV antigen, and immunohistochemistry in these cases.38,41,42 Pathological examination may demonstrate intranuclear viral inclusions.38 VZV-related vasculopathy may occur as late as 5 to 6 months after the zoster rash.39 In these patients, the detection of antibody to VZV in CSF, even in the absence of amplifiable VZV DNA, is diagnostic.39,40 There are other reports of zoster-related myelitis in which PCR results for VZV were negative in the presence of anti-VZV antibodies in the CSF or became positive only after several days of clinical symptoms.38,40 It is presumed that the reason why patients with VZV-related vasculopathy may not contain VZV DNA is that active viral replication is confined to CNS arteries.39 Hence CSF PCR for VZV DNA is not as sensitive a test as CSF PCR for HSV.40 MRI demonstrates hyperintensity and swelling, consistent with edema, on T2-weighted sequences.36,38 On T1-weighted images, with gadolinium contrast material, leptomeningeal enhancement over the cerebellum and brainstem is seen in cases of ascending myelitis.38 The treatment of VZV-related myelitis is aggressive antiviral therapy, usually with intravenous acyclovir; however, response is variable.36 VZV strains that are resistant to acyclovir, as well as to related newer compounds such as famciclovir and valacyclovir, have been reported, in both immunodeficient and immunocompetent patients.38,43,44 Resistance results from deficiency or absence of viral thymidine kinase, the enzyme on which these drugs are dependent for intracellular activation via phosphorylation.38,44 These thymidine kinase–deficient VZV
518
Section
VIII
Spine and Spinal Diseases
mutant strains are, however, susceptible to foscarnet and acyclic nucleoside phosphonates, which are active independently of thymidine kinase.44 Because diagnostic tests for VZVmediated myelitis are potentially insensitive, management of patients suspected of having this condition should include broadening of antiviral therapy to overcome possible resistance if there is clinical progression or inadequate response to therapy.38
Cytomegalovirus-related myelitis In the setting of cellular immunodeficiency, such as the acquired immunodeficiency syndrome (AIDS), cytomegalovirus infection of the cord can produce a necrotizing transverse myelitis, typically when CD4 counts are less than 50.45 It is exceedingly rare in immunocompetent persons, although five such cases of cytomegalovirus-associated transverse myelitis were reported by Giobbia and coworkers.46 In all these cases, CSF PCR for cytomegalovirus yielded negative results. The diagnosis was instead obtained on the basis of serological data: namely, cytomegalovirus antigenemia (positivity for cytomegalovirus pp65 antigen) and high serum titers of specific cytomegalovirus IgM and IgG antibodies, positive blood PCR results for cytomegalovirus, and blood or urine cultures. Of note, however, PCR performed on CSF of patients with AIDS demonstrated this test to predict histopathologically confirmed cytomegalovirus-associated CNS disease, including myelitis.47 It is unclear as to whether neuronal injury is immune mediated or caused by a cytotoxic effect of viral infection.
Epstein-Barr virus–related myelitis Epstein-Barr virus, like VZV, can infect multiples sites of the neuraxis and can therefore produce protean clinical manifestations.48 Both CNS and peripheral nervous system disease can occur, with reports of meningitis, encephalitis, transverse myelitis, neuritis, and overlapping syndromes.48-50 The incidence of Epstein-Barr virus–related neurological disease is not known; however, it has been estimated to occur in 1% to 5% of individuals with infectious mononucleosis.48 The mechanism by which Epstein-Barr virus produces neurological disease is unknown; however, the development of neurological disease over weeks is suggestive of either a subacute to chronic viral infection or a postinfectious, immune-mediated process.48 CSF typically shows pleocytosis, with elevated protein levels.48 The diagnosis is made by the isolation of Epstein-Barr virus DNA from CSF, as well as from peripheral blood monocytes, and the exclusion of other herpesvirus infections through PCR techniques.48,51 Serological evidence is supportive.48 Findings on MRI are variable and may demonstrate increased T2 signal intensity; however, normal findings are also reported in the presence of neurological deficits.48 Unfortunately, no definitive treatment for Epstein-Barr virus nervous system infections exists. Although corticosteroids and immunoglobulins have been used, their effect on disease progression is unknown.48 Antiviral agents have not been shown to be clinically useful. Significant neurological deficits may persist after resolution of the acute phase of myelitis.48,51
Mycoplasma-related myelitis It is estimated that CNS manifestations, most commonly encephalitis, occur in 1 per 1000 patients with Mycoplasma pneumoniae infections.52 Myelitis, albeit atypical, and radiculi-
tis have been reported in association with meningitis. In 19 cases of Mycoplasma-associated transverse myelitis, patients often developed a flaccid paraparesis, with bladder paresis.11 A definite sensory level was described in only a few cases. There is usually slight CSF pleocytosis, and M. pneumoniae was isolated in at least seven reported cases. In one case, in a patient who had no antecedent respiratory infection, M. pneumoniae was cultivated from a nasopharyngeal aspirate and detected in the CSF by PCR.11,53 Treatment is with doxycycline for 14 days, although the effects of therapy are debated.1 The overall prognosis is generally good, with complete recovery in most cases, although there is one case report of persistent paraplegia after Mycoplasma-associated transverse myelitis.54
Other Rare Infectious Causes of Myelitis Cases of transverse myelitis associated with Burkholderia pseudomallei (melioidosis) have been described.55 Borrelia recurrentis may also produce myelitis, usually radiculomyelitis rather than isolated myelitis.56 Even so, only 5% of 330 cases of neuroborreliosis were classified as acute meningomyelitis or meningomyeloradiculitis. Transverse myelitis may occur in tuberculous meningitis, usually with severe leptomeningitis.1
Other Myelopathies Subacute combined degeneration of the cord, classically described in association with vitamin B12 deficiency, affects the posterior and lateral columns of the spinal cord.57 A similar syndrome of posterior column degeneration is also seen in tertiary syphilis (Treponema pallidum infection), and is referred to as tabes dorsalis.57 This manifests clinically with a spastic weakness and ataxia of the lower limbs. Chronic meningeal inflammation may be present and may involve the ventral nerve roots. Other clinical spinal syndromes described in association with syphilitic infection are syphilitic meningomyelitis (a chronic meningitis resulting in subpial myelinated fiber loss, with predominantly bilateral corticospinal tract involvement) and spinal meningovascular syphilis, which may result in an anterior spinal artery syndrome.57 The myelopathy associated with the late stages of AIDS also affects the posterior and lateral columns, as demonstrated in histological studies.1,57 Clinical features of spinal cord disease are often obscured by other neurological complications of AIDS, such as neuropathy and encephalopathy, which result from HIV per se or from opportunistic infections. Vacuolation of myelin and relative sparing of the axons occur, and lipidladen macrophages are typically abundant.57,58 This vacuolar myopathy was seen in 48% of autopsy examinations of the cord of 90 patients with AIDS, although the frequency of encephalitis was higher in this population.58 There was no correlation between the proviral HIV type I load and the degree of myelopathy.58 Likewise, there was no correlation between opportunistic infections, particularly cytomegalovirus, and the presence and severity of myelopathy. In a separate series of 21 patients with AIDS-associated myelopathy, MRI demonstrated spinal cord atrophy in 15 cases and diffuse intrinsic signal abnormality in six cases.59 Tropical spastic paraparesis is a syndrome of slowly progressive central paraparesis of proximal lower limb dominance, caused by infection with the human T cell leukemia/lymphoma
chapter 40 spinal disease virus type 1 (HTLV-1). Sensory signs are characteristically minimal and usually only in the lower limbs; paresthesias and ataxia, with diminished proprioceptive function and vibration sense, have been described.57,60 Sphincter dysfunction usually occurs early. An associated polyneuropathy has been reported. Levels of CSF antibodies to HTLV-1 are elevated.57 On pathological examination, the corticospinal tracts and posterior columns are affected by an inflammatory myelitis, with focal spongiform demyelination and necrosis.57,60 Foci of gray matter destruction are also seen.
Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis occurs typically after childhood viral exanthemata, upper respiratory tract infection, or vaccination, with a short latency.1 Although the majority of postinfectious cases follow viral infections, such as measles, mumps, and Epstein-Barr virus infection, acute disseminated encephalomyelitis can occur after bacterial or parasitic infections.1,2 Most cases are disseminated, as the name implies, with alteration of sensorium; however, in some cases, spinal disease dominates the clinical picture.1
Anterior Horn Cell Syndromes The hallmark of damage to lower motor neurons is flaccid paralysis. Viral infection and the resultant inflammation cause direct damage to the motor neurons residing in the anterior horns of the spinal cord, producing an anterior myelitis.61 Viral invasion of anterior horn cells usually occurs as part of an acute viral meningitic illness, with fevers, headache, and meningism.61 This is followed by the rapid onset of asymmetrical weakness without any sensory deficits.61 Bulbar and respiratory musculature may be affected, and ventilatory support may be needed. Examination of CSF demonstrates moderate pleocytosis.61 Neurophysiological testing demonstrates low compound muscle action potential, normal sensory nerve action potentials, and sharp waves and fibrillations on electromyography.61 Flaccid weakness also occurs with damage to peripheral nerves, such as acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy, and should be considered in the differential diagnosis. In contrast to anterior myelitis, the weakness is typically symmetrical and ascends gradually in the neuropathies, and CSF studies demonstrate elevated protein levels but no pleocytosis. Electrophysiological studies enable distinction of polyneuropathy from anterior myelitis, with delayed distal latencies and reduced conduction velocities in both sensory and motor fibers in the former.
Poliomyelitis Acute poliomyelitis is now rarely encountered in the industrialized world, because of the World Health Organization’s global eradication program. Nonetheless, pockets of endemic disease persist in sub-Saharan Africa and the Indian subcontinent, and it continues to occur sporadically elsewhere.62 There is also a small incidence of live vaccine–related poliomyelitis.62 Poliomyelitis is caused by an enterovirus whose main route of infection is via the gastrointestinal tract.62 In approximately 5% of infections, after nonspecific flulike symptoms, nervous system infection occurs and is initially manifested as meningi-
519
tis, with high fevers, neck stiffness, and headache.62 The onset of spinal poliomyelitis is heralded by myalgias, with the subsequent development of asymmetrical, lower limb–predominant flaccid weakness or paralysis, reaching a maximum within 48 hours of onset.62 Diagnosis is based on virus isolation of nasopharyngeal secretions and/or the stool. CSF examination demonstrates elevated protein levels and pleocytosis. Serological diagnosis, with demonstration of antipoliovirus IgG and IgM antibodies, can establish the diagnosis in the absence of viral isolate. PCR techniques now enable rapid diagnosis, identification of serotype, and differentiation of wild-type from vaccine-related disease.63 MRI may demonstrate high signal intensity on T2-weighted imaging in the region of the anterior horn cells.64 There is, unfortunately, no curative treatment.62 Management is supportive, aimed at symptom control with analgesia and prevention of complications. The aim of strict bed rest is to prevent progression of paralysis. Passive exercise during the acute phase, followed by more intensive physiotherapy, can prevent or minimize contractures.65
Poliomyelitis-like Syndromes Acute flaccid paralysis secondary to anterior horn cell disease may be associated with other enteroviruses (e.g., enterovirus 71, Coxsackie virus A7, echoviruses), tickborne encephalitides, flaviviruses (e.g., Japanese encephalitis, Murray Valley encephalitis virus, and West Nile virus), herpesviruses (cytomegalovirus, Epstein-Barr virus, VZV), and HIV-related opportunistic infections.57,61-68 West Nile virus, a flavivirus, usually causes a mild febrile illness.61 Neurological disease is reported in 1 per 150 infected persons and usually consists of meningitis and encephalitis; however, there are numerous reports of patients with poliomyelitis-like acute flaccid paralysis, occurring during the acute febrile illness.61,68 Diagnosis is based on identification of anti–West Nile virus antibodies in serum or CSF.61 Confirming an anterior horn cell process, high signal intensity in the anterior horns on T2-weighted MRI has been demonstrated.69 Histopathological examination of autopsy specimens has demonstrated anterior myelitis, with perivascular lymphocytic infiltrate, monocytic infiltration, and gliosis.70 Enterovirus 71, which causes outbreaks of hand-foot-andmouth disease, a common exanthema of childhood characterized by fevers, palmar and plantar rash, and oromucosal ulceration, may be associated with neurological complications, including an acute flaccid paralysis.66
Spinal Epidural Abscess Spinal epidural abscess is an uncommon condition, occurring with an estimated incidence of 0.2 to 2.8 cases per 10,000 per year.71-74 The incidence peaks in the sixth and seventh decades of life.71 Although this condition is potentially fatal, with devastating neurological sequelae if left untreated, early recognition and prompt institution of appropriate therapy can avert complications. Risk factors for spinal epidural abscess include immunocompromised states and are identified in Table 40–5.72 In 20% of cases, there is no identifiable risk factor.71,76 The most common causative agent is Staphylococcus aureus, accounting for 57% to 75% of reported cases.72,73
520
Section
T A B L E 4 0 – 5.
VIII
Spine and Spinal Diseases
Risk Factors for Spinal Epidural Abscess
Hematogenous Seeding Intravenous drug abuse Blunt spinal trauma Immunocompromised states Diabetes mellitus Alcohol abuse Chronic renal failure Malignancy AIDS Direct Inoculation Spinal surgery Open spinal trauma Epidural catheterization AIDS, acquired immunodeficiency syndrome.
Mycobacterium tuberculosis is the next most frequent cause, accounting for 25% of spinal epidural abscess in one series.77 Tuberculous osteomyelitis of the vertebra (Pott’s disease) can give rise to epidural extension, with abscess formation.57 Tuberculous meningitis may also occur. Gram-positive cocci other than S. aureus were cultured in 10% of patients, gramnegative organisms in 18%, and anaerobes in 2% in one series.75 Fungal infections of the spinal cord are rare, and usually occur in immunocompromised persons.57,76 Blastomyces, Coccidioides, and Aspergillus organisms may invade the epidural space via the intervertebral foramina or as a result of direct extension from a focus of vertebral osteomyelitis.57 Both Coccidioides and Blastomyces organisms may hematogenously seed the spinal cord or surrounding meninges. Cryptococcus infection, which can cause meningoencephalitis, is a rare cause of spinal infection.57 In the majority of cases, spinal epidural abscess is thought to arise from hematogenous spread of organisms from remote mucocutaneous sources, such as the site of pharyngitis or dental sepsis.72 These abscesses are usually located posteriorly in the epidural space, the thoracic spine, or the lumbar spine. Contiguous spread of infection into the epidural space from a source adjacent to the spine, such as that of diskitis or vertebral osteomyelitis, is also well described and usually results in an anterior epidural abscess.72,76 Direct extension from retropharyngeal or retroperitoneal abscesses via the vertebral foramina may occur.72 Blunt trauma precedes spinal epidural abscess in 15% to 35% of cases.78 The postulated mechanism in such cases is hematogenous seeding of the nutrient-rich environment of a vertebral hematoma. The mechanism leading to neurological dysfunction in spinal epidural abscess is incompletely understood. Neurological deficits are disproportionate to the degree of direct compression of neural structures by the extradural mass within the rigid bony spinal canal.71 Epidural edema and inflammation with involvement of the epidural venous plexus, resulting in venous ischemia and infarction of the spinal cord, are postulated to potentiate the effects of compression.74,75
Clinical Features Clinical manifestation is usually nonspecific, and symptoms can evolve over a few hours to several months.71 The most common presenting symptoms are fever, malaise, and back
pain.71 The presence of overt neurological symptoms, including radicular pain, weakness, and sphincter dysfunction, is suggestive of disease progression. Systemic sepsis may occur. In patients with chronic infection, constitutional symptoms of fever, anorexia, and weight loss may dominate the clinical picture. There may be focal tenderness of the spine, and neurological deficits may be evident.71 Laboratory investigation usually reveals leukocytosis, with elevated levels of inflammatory markers (C-reactive protein and, if the process is more chronic, erythrocyte sedimentation rate). Blood cultures are positive in more than 60% of cases.75 The imaging modality of choice for diagnosis is MRI with gadolinium contrast material, because it enables the abscess to be distinguished from adjacent compressed thecal sac and differential diagnoses such as herniated intervertebral disk (Fig. 40–3).71 During the early phlegmonous stage of infection, homogenous enhancement is seen. Once the necrotic center liquefies, with surrounding inflammatory tissue, peripheral enhancement is seen with gadolinium. Open biopsy or computed tomography–guided aspiration provides tissue for culture, to isolate the causative organism and facilitate directed therapy.71,72
Treatment The treatment of choice in most patients is surgical evacuation and decompression, followed by intravenous broad-spectrum bactericidal antibiotic therapy for at least 4 to 6 weeks.72 Less invasive endoscopic and percutaneous drainage procedures have been described.79 In patients who present with minimal neurological dysfunction or who are poor surgical candidates, conservative treatment in the form of long-term antibiotic therapy may be undertaken.72 Serial MRI and close neurological monitoring are imperative in these cases; indications for surgical intervention are neurological progression and increasing size of the abscess. Neither conservative management nor surgical treatment has been shown to be superior; evidence indicates that both modalities have good outcomes if treatment is initiated promptly.81,82 Prognosis is dependent on the clinical, particularly neurological, condition of the patient at presentation. Poorer outcomes have been reported when treatment has been delayed.72 Good outcomes are reported when the duration of neurological deficit is less than 72 hours, when the degree of thecal sac compression is less than 50%, and in patients younger than 60 years.82 The rate of mortality from epidural abscess is approximately 14%.72
Intramedullary Spinal Cord Abscess This rare entity, first described by Hans Chiari in 1900, is indistinguishable on the basis of symptoms from epidural abscess, producing fever, pain, and motor and sensory deficits with progression.57 It may occur in the setting of systemic sepsis, either septicemia or infective endocarditis, with hematogenous seeding of the spinal cord. Contiguous spread from a local source of sepsis, via the intervertebral foramina, is also possible. CSF examination demonstrates pleocytosis, with elevated protein levels. MRI is the imaging modality of choice.57 Causative agents reported in the literature include Listeria monocytogenes and M. pneumoniae. Solitary tuberculoma of the spinal cord is extremely rare.57
chapter 40 spinal disease
521
Vertebral Osteomyelitis
A
Accounting for approximately 2% to 7% of all cases of osteomyelitis, spinal osteomyelitis occurs more often in elderly persons.83 As in epidural abscess, the most common causative agent, reported to account for more than 50% of cases, is S. aureus.83,84 Hematogenous seeding in association with conditions producing bacteremia, such as infective endocarditis, and, less frequently, with direct inoculation of bacteria result in pyogenic infection.83 Infection is characteristically confined to the vertebral body and intervertebral disk; however, in as many as 20% of cases, the posterior osseous elements are involved.83,84 Clinical features are usually insidious. Back and neck pain is the commonest manifestation, occurring in 90% of affected patients, and neurological deficits secondary to nerve root or spinal cord impingement are reported in 20%.83,84 Complications include spinal deformity secondary to vertebral destruction and epidural abscess formation, both of which may lead to compression of spinal cord and nerve roots.83 Paraspinal or retrospinal abscess formation may occur in association with spinal osteomyelitis. Laboratory investigations are of limited value. MRI is the preferred diagnostic imaging modality, with an accuracy of approximately 90%, enabling visualization of spinal cord, nerve roots, extradural space, and bony elements.83 Single photon emission computed tomography with gallium 67, a functional imaging modality, has also been shown to be of value in diagnosis and may be a valuable adjunct in patients in whom the diagnosis remains uncertain.83 Early surgical decompression, with internal fixation to provide spinal stability, is the contemporary approach to vertebral osteomyelitis with neurological deficit and focal spinal deformity.85 Nonsurgical management—namely, broad-spectrum intravenous bactericidal antibiotic therapy—is indicated in patients with minimal or no neurological deficits and localized kyphotic deformities, although it may fail, necessitating surgical intervention.85
Spinal Meningitis and Meningomyelitis
B ■
Figure 40–3. Spinal epidural abscess. An epidural mass is seen on sagittal (A) and axial (B) views, with peripheral enhancement on gadolinium T1-weighted spin-echo imaging (B, sagittal view).
Parasitic Spinal Cord Disease Parasitic infections of the spinal cord are rare; however, schistosomiasis (Schistosoma haematobium, Schistosoma japonicum and Schistosoma mansoni) is a cause of myelitis encountered in eastern Asia, Africa, and South America.57 The ova of the schistosomes evoke a granulomatous myelomeningoradiculitis, with destruction of both gray and white matter. Less commonly, an acute transverse myelitis and spinal cord compression caused by a localized granuloma may be present.57
Infections of the spinal meninges may involve primarily the pia mater and arachnoid mater, to produce a leptomeningitis, or the dura mater, causing a pachymeningitis.57 These processes may be either acute or chronic. When the spinal cord is also involved, the process is referred to as meningomyelitis. Viral agents reported to cause myelomeningitis and meningitis include Coxsackie viruses, enteroviruses, and herpesviruses.57 Bacteria, including M. tuberculosis and T. pallidum (syphilis), may cause meningomyelitis, as may some fungal and parasitic infections. Involvement of pial blood vessels can lead to thrombosis, with infarction of the spinal cord (myelomalacia).57 Progressive pial constrictive fibrosis (spinal arachnoiditis) can result from chronic meningeal inflammation, resulting in compression of neural structures and their vascular supply.57 Damage to spinal nerve roots, particularly in the dorsal roots in the lumbosacral region, may occur with protracted meningitis, as seen in syphilitic myelomeningitis (tabes dorsalis).57 Clinical features include those of meningeal irritation (fever, neck or back pain) and symptoms and signs attributable to the particular pattern of involvement of spinal structures. Examination of CSF demonstrates pleocytosis, with elevated
522
Section
T A B L E 4 0 – 6.
VIII
Spine and Spinal Diseases
Classification of Syringomyelia
Type I: Syringomyelia with obstruction of the foramen magnum and dilatation of the central canal A: With Chiari type I malformation B: With other obstructive lesions of the foramen magnum Type II: Syringomyelia without foramen magnum obstruction Type III: Secondary syringomyelia A: Spinal cord tumors B: Traumatic myelopathy C: Spinal arachnoiditis and pachymeningitis Type IV: Pure hydromyelia with or without hydrocephalus
protein levels.57 Gram and other specialized stains may reveal causative agents in cases of pyogenic meningitis, and microbial culture is an imperative diagnostic investigation. MRI with gadolinium contrast material demonstrates leptomeningeal enhancement.57
DEGENERATIVE DISEASES OF THE SPINAL CORD
tracts. Indeed, the frequent association of syrinx with craniocervical junction malformations, which could potentially block the flow of CSF, supports this theory. In a more recent report, it was postulated that the primary event in the formation of syrinx in many cases is reduced volume of the posterior cranial fossa, such as that caused by basilar invagination, with resultant Chiari malformation caused by caudal displacement of structures. Long-standing pulsatile pressure of the herniated structures on the spinal cord leads to syrinx formation as a tertiary event. It was suggested that this was a mechanism serving to protect vital neural structures at the level of the craniovertebral junction at the cost of spinal cord. One report questioned prevailing hydrodynamic theories, on the basis of the facts that syrinx pressure exceeds CSF pressure and the composition of syrinx fluid is not identical to that of CSF.89 An alternative theory is abnormal spinal cord structure, with a tendency to cavitate.57,87 The syrinx initially occupies the central gray matter of the cervical spinal cord, interrupting the crossing spinothalamic tract fibers in the anterior commissure over several cord segments. Progressive symmetrical or asymmetrical enlargement leads to interruption of the posterior and anterior horns of the spinal cord and, finally, the white matter funiculi (lateral and posterior).57
Syringomyelia Primary syringomyelia is a chronic, progressive degenerative disease of the spinal cord, characterized by brachial amyotrophy and dissociated segmental sensory deficit. Cavitation of the central spinal cord is seen, usually in the cervical region, although extension of the process rostrally into the medulla and pons of the brainstem (syringobulbia) or caudally into the thoracic and even the lumbar spine may be seen.57 Syringomyelia may also occur in association with intramedullary spinal cord tumors, mostly gliomas, in 25% to 57% of cases in some series.86 Traumatic myelopathy, radiation myelopathy, myelomalacia (spinal cord infarction), hematomyelia, and spinal arachnoiditis are other associated conditions.57 Bony abnormalities of the vertebral column (e.g., thoracic scoliosis and fusion of vertebrae [Klippel-Feil anomaly]) and the base of the skull (e.g., platybasia or basilar invagination) are frequently associated conditions.57,87 Caudal displacement of the posterior fossa structures—namely, the brainstem and cerebellum—producing a Chiari type I malformation is seen in approximately 90% of cases of syringomyelia.57 A suggested scheme of classification is found in Table 40–6.88
Pathogenesis A number of hypotheses regarding the mechanism of formation of syrinx have been put forward. Many of these suggest that disturbances in CSF hydrodynamics result in interruption of CSF flow between the spinal and intracranial subarachnoid compartments.57,87,89 An early theory was that syringomyelia arose from the prevention of normal flow of CSF by congenital failure of opening of the outlets of the fourth ventricle (foramina of Luschka and Magendie).90 A pulse wave of CSF pressure, generated by systolic pulsation of the choroid plexuses, is transmitted into the spinal cord via the central canal, resulting in dilatation of the central canal, with a diverticulum that ramifies from the central canal and dissects along gray matter and white matter
Clinical Features Types I and II syringomyelia are sporadic and usually begin in middle age; in some cases, an abnormality may be evident at birth. Symptoms develop insidiously, although there are reports of sudden and dramatic worsening after violent strain or a paroxysm of coughing.57 Intermittent progression is the usual course, with patients being bedridden within 5 to 10 years; however, the course is extremely variable, and some patients remain stable for many years.57 The clinical picture varies according to subtype of syringomyelia, particularly the presence or absence of a Chiari malformation. The cross-sectional and longitudinal extent of syrinx determines the clinical profile at any given time in the evolution of the disease. Pain, which is usually unilateral or asymmetrical, is experienced by approximately 50% of patients with types I and II syringomyelia.57 The key clinical feature is dissociated segmental sensory loss—namely, loss of pain and temperature sensation as a result of interruption of spinothalamic pathways—with preservation of dorsal column sensory functions. Tactile sense may, however, be impaired in the region of most dense anesthesia. The distribution of sensory loss is over the neck, shoulders, and arms (cape), often extending to the face, back of the head, and trunk. It is usually bilateral; however, asymmetry, even unilateral sensory loss, may occur. Segmental weakness and atrophy of the upper limbs, which may be asymmetrical, with loss of deep tendon reflexes, are also characteristic. However, there are exceptions in which motor function is preserved. Eventually, spastic lower limb weakness and ataxia develop, with impairment of lower limb proprioception and vibration sense, as a result of corticospinal and posterior column involvement in the inferior medulla and cervical spinal cord, respectively. In some instances, especially when there is a coexistent Chiari malformation, an upper motor neuron pattern of weakness may also be seen in the upper limbs. The presence of a Chiari malformation or a foramen
chapter 40 spinal disease
523
T A B L E 4 0 – 7. Static Factors Contributing to Cervical Spondylotic Myelopathy Congenital stenosis of the spinal canal (anteroposterior diameter <13 mm) Intervertebral disk herniation Vertebral body osteophyte formation Degenerative osteophytic lipping of the uncovertebral and facet joints Hypertrophy of the ligaments: ligamentum flavum and posterior longitudinal ligament
Cervical Spondylotic Myelopathy Cervical spondylotic myelopathy (CSM) results from narrowing of the spinal canal, secondary to degenerative or congenital vertebral and disk disease. It is the commonest spinal cord disease in patients older than 55 years.93-95 Clinical manifestations are diverse, and it is often asymptomatic.
Pathophysiology
■
Figure 40–4. Syringomyelia. Enlargement of the central canal of the cervical spinal cord is demonstrated.
magnum lesion is also indicated by nystagmus, cerebellar ataxia, and occipitonuchal pain with maneuvers that increase intracranial pressure.57 Ipsilateral Horner’s syndrome results with involvement of the intermediolateral cell column at C8, T1, and T2 levels.57 MRI is the investigation of choice, demonstrating syrinx and associated abnormalities, including Chiari malformation and foramen magnum lesions (Fig. 40–4).57
Treatment Several surgical procedures have been reported for the treatment of syringomyelia, with the approach tailored to the individual clinical and imaging characteristics.91 There have been no controlled, prospective, or multi-institutional studies on which to base management decisions, reflective of the complexity of treatment selection. The two major approaches to types I and II are syringosubarachnoid shunting and decompression of the foramen magnum and upper cervical spinal canal.91 Decompression has been reported to ameliorate lower limb signs and symptoms; however, upper limb sensorimotor deficits persist.92 Conversely, shunting has produced unpredictable results, although there is some evidence that it may be superior to decompression as a first-line treatment for syringomyelia with Chiari I malformation.57
The primary pathophysiological abnormality is reduced sagittal diameter of the spinal canal, and a dimension of less than 13 mm is thought to be critical in the later development in relation to superimposed degenerative change.93 The mechanical factors involved in the process of CSM fall into two groups: static factors (Table 40–7) and dynamic changes in the spinal column and spinal cord during flexion and extension of the cervical spine under normal physiological loads.93,96 Direct compression of neural structures, as a result of these mechanical factors, is compounded by ischemia of the spinal cord, secondary to compression of the arterial supply (either larger vessels, such as the anterior spinal artery, or the pial plexuses and small penetrating arteries) or draining veins of the spinal cord and nerve roots by degenerative elements.93 Indeed, the highest frequency of myelopathy occurs at the C5-C7 level, which has the most tenuous vascular supply.93
Clinical Features Symptoms and signs are varied, and there are no pathognomonic clinical features. Onset tends to be insidious. Neck, subscapular, or shoulder pain may occur. Loss of hand dexterity may be a marked early feature. Gait disturbance, the commonest presenting symptom of CSM, is a manifestation of long tract dysfunction, with upper motor neuron weakness resulting from corticospinal tract involvement and compounded by proprioceptive (dorsal column) dysfunction.93 Bowel and bladder dysfunction is also common, reported to occur in 15% to 50% of affected patients.93-98 Segmental lower motor neuron deficits are seen at the compressed level of the spinal cord, most commonly at the C5-C6 level. The differential diagnosis includes such important entities as multiple sclerosis, motor neuron disease, spinal cord tumors, and syringomyelia. Like CSM, multiple sclerosis tends to cause both sensory and motor deficits, and the former may be dissociated; however, cranial nerve signs may also occur, in contrast to CSM. In both CSM and motor neuron disease, a combination of upper and lower motor neuron signs may be present; however, no sensory abnormalities occur in the latter.
524
Section
VIII
Spine and Spinal Diseases However, there are a number of arguments in favor of surgery over medical management. Up to 70% of patients treated medically show no improvement or deteriorate neurologically, as measured by the degree of motor disability and the ability to perform activities of daily living.93 Furthermore, patients with CSM are at increased risk of spinal cord injury from relatively mild traumatic events, because the spinal cord has limited room to move.93 Finally, it has been shown that early surgical intervention can improve prognosis, particularly if symptoms are of less than 1 year’s duration.95,100,101 The two traditional surgical approaches to CSM are a dorsal approach—namely, cervical laminectomy—and a ventral approach, either diskectomy or corpectomy at one or more levels, with interbody fusion.93 After corpectomy, cervical plating is typically necessary to provide stability until fusion occurs.93 No significant difference in outcome of one approach over the other has been demonstrated.93,98,101,102 The choice is therefore guided by the surgeon’s preference, the relative location of the stenosis (dorsal versus ventral), and the alignment of the spinal cord (kyphosis versus lordosis), as well as by individual patient factors.93 Cervical total disk replacement is an evolving modality for the treatment of disk degeneration and herniation in the cervical spine.103
Spondylotic Lumbar Stenosis
■
Figure 40–5. Cervical spondylotic myelopathy. T2-weighted spinecho image, demonstrating grossly narrowed cervical spinal canal, with mild hyperintensity of the spinal cord at the level of compression, caused by myelomalacia.
Diagnosis MRI is the imaging modality of choice for evaluating cervical degenerative disease, enabling evaluation of the spinal cord, vertebral bodies, disks, osteophytes, and ligaments.93 In addition to indentation, T2 hyperintensity of the spinal cord may be seen at the level of compression, caused by edema, inflammatory changes, ischemia, myelomalacia, or gliosis (Fig. 40–5).93 The responsible lesion may be difficult to distinguish from clinically silent cord compression on MRI, particularly in elderly patients. In order to avert the high rate of morbidity associated with extensive spinal surgery, the use of electrophysiological measurement of spinal cord evoked potentials may be a valuable adjunctive tool for localizing the spinal level at which clinically significant compression occurs in cervical myelopathy.99 Most often, however, careful clinical judgment is necessary to distinguish clinically relevant CSM from the sometimes striking incidental changes seen in older patients. Some clinicians believe that flexion-extension views of the spine are a useful discriminatory test.
Treatment Traditionally, first-line management is conservative, because of the significant morbidity associated with spinal surgery.93
Osteoarthritic or spondylitic changes in the lumbar region, compounded by an unusually small spinal canal, may lead to compression of the cauda equina, with the nerve roots compressed between the posterior surface of the vertebral body and the ligamentum flavum posterolaterally.57 Symptoms of gradually ascending numbness and leg pain, associated with weakness, occur in the upright position or with ambulation (especially downhill) and are relieved by sitting down or lying down with hips and knees flexed.57 The intermittent nature of these symptoms and their relation to ambulation (hence the term neurogenic claudication) may lead to misdiagnosis of lower limb vascular insufficiency. Back pain occurs in varying severity, and sphincter disturbance is rare. Diagnosis is based on MRI demonstration of narrowing of the lumbar spinal canal, and treatment is decompressive surgery.57
Degenerative Lumbar Intervertebral Disk Disease Herniation of lumbar intervertebral disks is a major cause of morbidity, resulting in severe, chronic, or recurrent low back pain. The incidence peaks in the third to fourth decades of life.57 The disk between the L5 and S1 vertebrae is most commonly involved, with the more cranial intervertebral disks affected with diminishing frequency.57,104 Thoracic disks are rarely affected, accounting for only 0.5% of all surgically confirmed disk prolapses.57 Protrusion of the nucleus pulposus posteriorly (through the annulus) occurs with a flexion injury, with a maneuver that increases intraspinal pressure (e.g., sneezing), or even with a trivial movement, in the setting of degenerative changes within the nucleus pulposus, annulus fibrosus, and posterior longitudinal ligaments. In severe cases, the nucleus pulposus may protrude entirely through the annulus. More often, a fragment extrudes or protrudes through tears in the annulus, usually to a side, to impinge on a nerve root. A large fragment may compress the root or roots against the articular process or lamina,
chapter 40 spinal disease T A B L E 4 0 – 8. Features of Herniated Lumbar Intervertebral Disk Pain, exacerbated by sitting and standing up from a seated position: Mechanical: back and deep to the buttock (inferolateral to the sacroiliac joint) Radicular: lancinating pain, radiating into the thigh, calf and foot (sciatica); may be elicited by palpation along the course of the sciatic nerve Paresthesias Stiff, deformed spine Back tenderness, particularly on palpation over the L5 and S1 spinous processes Radicular neurological deficit: Motor: hyporeflexia or areflexia; myotomal weakness; hypotonia Sensory: dermatomal hyperesthesia or hypoesthesia Position of greatest comfort: dorsal decubitus position (supine, with legs flexed at knees and hips; shoulders elevated on pillows in order to obliterate the lumbar lordosis Posture: antalgic Affected leg slightly flexed at knee and hip (VA); sciatic scoliosis and tilted trunk, caused by reflex contraction of the paraspinal muscles to minimize irritation of nerve root(s) by protruded disk material Gait: antalgic: brief, cautious weight-bearing on the painful leg Positive Lasègue’s maneuver (hip flexion with extended knee): stretch of nerve roots elicits sciatica Restricted straight-leg raising Fajersztajn’s sign: raising of the contralateral leg elicits ipsilateral pain, of lesser severity
giving rise to radicular symptoms. Because this extruded material is often not resorbed, chronic irritation of neural structures may result. Herniation of the disk into the adjacent vertebral body gives rise to a Schmorl nodule, which may be associated with back pain but no signs or symptoms of nerve root compression.
Clinical Features The full complement of features of the syndrome of prolapsed lumbar intervertebral disk is detailed in Table 40–8.57,104 Disk
T A B L E 4 0 – 9.
525
degeneration without herniation may lead to low back pain. The pain of disk herniation can be severe, necessitating bed rest and avoidance of any movement. Signs of nerve root involvement may be elicited on the affected side. The clinical features associated with compression of particular nerve roots are detailed in Table 40–9. Frequently, more than one nerve root is compressed by a single herniated disk, giving rise to multilevel signs and symptoms.57 Large central protrusions can produce bilateral features, as well as cauda equina syndrome; however, this is rare.
Diagnosis MRI of the lumbosacral spine is the “gold standard” investigation for diagnosis, demonstrating the protruded disk and annular tears and excluding differential diagnoses such as extradural tumor (Fig. 40–6).104,105 Oblique views, in addition to the traditional protocol of axial and sagittal views, enable visualization of the neural exit foramina, facilitating detection of foraminal nerve root impingement.106 MRI also allows other sites of degenerative disease, including clinically silent lesions, to be identified. Electromyography and nerve conduction studies are valuable adjuncts, particularly when the clinical significance of a lesion is unclear and other differential diagnoses such as a peripheral neuropathy are being entertained. Prolonged F wave latencies and denervation potentials in the paraspinal muscles and in other muscles in a myotomal distribution indicate a radicular rather than a peripheral nerve lesion.57
Treatment Most patients with herniated lumbar intervertebral disk may be treated conservatively, with analgesia and bed rest for the first 48 hours, followed by gradual mobilization and physiotherapy.107 Indications for surgical management include the presence of cauda equina compression, progressive or profound neurological deficit, and disabling pain after 4 to 6 weeks of conservative management.107 Spinal fusion is the traditional surgical approach.107
Clinical Features Associated with Compression of Particular Nerve Roots Disk Protruded
Feature
L5-S1
L4-L5
L2-L3, L3-L4
Nerve root affected Distribution of pain (see Fig. 40–1)
S1 Midgluteal region, posterior thigh, posterior calf (to the heel), lateral plantar surface of foot, and fourth and fifth toes Distal part of leg and outer toes
L5 Hip, posterolateral thigh, lateral calf (to external malleolus), dorsal surface of the foot, and first to third toes In distribution of pain, usually distally Great toe extension (extensor hallucis longus) and foot dorsiflexion; hip abduction (positive Trendelenburg’s test)
L3; L4 Anterolateral thigh and knee Anterolateral thigh and anteromedial leg (L4)
Distribution of paresthesias and sensory deficit Motor deficit
Ankle jerk Knee jerk Location of tenderness
Flexion of foot and toes, toe abduction and knee flexion (hamstrings)
Usually absent or diminished; often the only objective sign Unaffected Midgluteal region (over sacroiliac joint), posterior thigh, and calf
Usually normal; may be diminished or absent Unaffected Lateral gluteal region and near femoral head
Anterolateral thigh and knee and anteromedial leg Knee extension (quadriceps: L2, L3, L4) and hip flexion (iliopsoas: L1, L2, L3); foot dorsiflexion (tibialis anterior: L4) Unaffected Diminished/absent —
526
Section
VIII
Spine and Spinal Diseases
B
■
Figure 40–6. Intervertebral disk prolapse. A, Sagittal view of a large central L4-S5 intervertebral disk prolapse, obliterating the spinal canal, and compressing the cauda equina. B, Axial view of a central L5-S1 disk prolapse.
A
TUMORS OF THE SPINAL CORD Most of these tumors are potentially surgically resectable; therefore, early detection, before the occurrence of irreversible neurological damage, is imperative. Tumors of the spinal cord can be divided into primary neoplasms, arising from the cord itself or the surrounding meninges, and secondary neoplasms, which have metastasized to the spine from elsewhere in the body. Further subdivision, into intramedullary and extramedullary lesions, is based on the anatomical distribution within the spinal canal (Table 40–10). Primary spinal tumors are usually intradural, in contrast to the majority of secondary tumors, which are extradurally based.
Epidemiology Spinal cord tumors are rarer than brain tumors, and in contrast to the latter, the majority are benign.57 A Mayo Clinic series of 8784 primary tumors of the CNS revealed that 15% arose from the spinal cord.57 Most seen in the general hospital population are extramedullary; approximately 40% are intradural-extramedullary, 55% are extradural-extramedullary, and only 5% are intramedullary.57
Clinical Features The clinical sequelae of most spinal cord tumors result from local compressive effects rather than direct invasion. The onset of
T A B L E 4 0 – 10. Spinal Cord Tumors Intramedullary Spinal Cord Tumors (20%) Arising within the substance of the spinal cord itself Primary Gliomatous: ependymoma; astrocytoma; subependymoma; ganglioglioma Nongliomatous: hemangioblastoma, paraganglioma, lymphoma and primitive neuroectodermal tumors (PNET), lipomas, dermoids, epidermoids, hemangiomas, and germ cell tumors Secondary (metastatic) (See Table 40–2) Extramedullary Spinal Cord Tumors (80%) Arising outside the spinal cord; extradural: arising within the epidural tissues or the vertebral bodies; intradural: arising within the spinal roots or the leptomeninges Primary Meningioma, neurofibroma, schwannoma, sarcomas, teratomas, vascular tumors, chordomas, and epidermoid tumors Secondary Metastatic carcinoma, lymphoma, and multiple myeloma/plasmocytoma
symptoms is usually gradual, progressing over weeks to months, and asymmetrical.57 Patients often complain of pain in the spine; about one half experience tenderness of spinous processes over the tumor. The pain is characteristically central or dermatomal and is exacerbated by maneuvers increasing intraspinal pressure, such as sneezing, coughing, and recumbency.
chapter 40 spinal disease There are three major, sometimes overlapping clinical neurological syndromes that spinal cord tumors can engender, addressed in the overview:57 (1) a sensorimotor spinal tract syndrome, (2) a painful radicular-spinal cord syndrome, and (3) a syringomyelic syndrome. Spinal cord compression, manifested by clinical features of segmental and long tract involvement, is covered in greater detail later in this chapter. It is often preceded by radicular symptoms, which are common. Tumors in the region of the foramen magnum may produce quadriparesis, with pain in the occipitonuchal region, neck stiffness, weakness, and atrophy of hand and dorsal neck muscles, as well as varying sensory signs.57 In rare cases, extramedullary tumors of the thoracolumbar spine may be associated with dementia and communicating hydrocephalus, ameliorated by shunting and tumor excision.57 When features of spinal disease are present, imaging is imperative, to achieve a diagnosis. Important differential diagnoses to consider include spondylitic degenerative disease, epidural abscess, tuberculous infection, meningomyelitic processes, and adhesive arachnoiditis. In the case of intramedullary lesions, vascular malformations must be considered.
Imaging MRI has enabled characterization of spinal cord tumors, including their location within the spinal canal and internal structure, through the use of different magnetic resonance scanning sequences.108 The basic spinal magnetic resonance study includes T1- and T2-weighted sequences in the sagittal plane, and contrast material (gadolinium)–enhanced T1-weighted images in the sagittal and axial planes.108,109 In comparison with intracranial neoplasms, most spinal cord tumors, even lowgrade forms, are enhanced after the administration of intravenous contrast material, which enables differentiation of solid from cystic components of the tumor. Identification of the extent of the solid enhancing component of tumors is vital, because current neurosurgical practice dictates that laminotomy and laminectomy be limited to this area, in order to minimize the surgical morbidity associated with spinal surgery.
527
momas or astrocytomas, although rarer types such subependymomas do occur in the spinal cord.108 Metastases are far less common in the intramedullary than the extramedullary compartment.57,108 There is usually a long antecedent history before the diagnosis.108 Pain is the most common symptom, with mixed sensorimotor tract symptoms and signs.108 Involvement of the central gray matter leads to a syringomyelic central cord syndrome.57 Sacral sparing has been reported to help distinguish between intramedullary and extramedullary tumors; however, no clinical feature is unique to intramedullary tumors.108 Therefore, distinction between the clinical profiles of intramedullary and extramedullary lesions is seldom dependable, and imaging is vital for diagnosis. The key findings in intramedullary spinal cord tumors on MRI are as follows:108,110,111 1. Expansion of the spinal cord. 2. At least some enhancement with gadolinium contrast material in most cases. 3. Cysts, either tumoral or nontumoral, in many cases. Polar cysts, located at the rostral or caudal extent of solid lesions, represent reactive dilatation of the central canal (syringomyelia). They are seen in approximately 60% of intramedullary spinal tumors and are not enhanced with contrast material.108 Conversely, tumoral cysts occur within the tumor itself and usually demonstrate peripheral enhancement. They occur more commonly in astrocytomas than in ependymomas.108 There is an increased incidence of intramedullary spinal cord tumors in patients with neurofibromatosis.112 Ependymomas are associated with type 2 disease, whereas astrocytomas are seen more frequently in type 1 disease. Interestingly, cytogenetic analysis has revealed the mutations of type 2 neurofibromatosis in some cases of sporadic spinal cord ependymoma.
Glial Neoplasms Ependymoma
Management Treatment is dictated by type of lesion and clinical picture. Intradural extramedullary lesions and benign extradural tumors necessitate surgical intervention, because of the risk of progression to spinal cord compression. Extradural tumors are managed according to their histological type, with radiotherapy, hormonal therapy, surgery, and chemotherapy, as well as corticosteroids, in various combinations.
Intramedullary Spinal Cord Neoplasms Intramedullary spinal cord neoplasms are rare, accounting for 4% to 10% of all CNS tumors and 20% of all intraspinal tumors in the adult population.108 They arise within the substance of the spinal cord itself, distorting, invading and destroying white matter tracts and the central gray matter structures. Primary intramedullary tumors have the same cellular origins as primary tumors of the brain.108 Ninety percent to 95% are gliomas, the majority of these being either ependy-
Ependymoma is the most common intramedullary spinal neoplasm in adults, reported to account for 60% of all glial cord tumors.113 The mean age at presentation is 38.8 years, and there is a male preponderance.108,113-115 They are believed to arise from the ependymal cells that line the central canal and are usually slow-growing tumors, which displace rather than infiltrate adjacent neural tissue; the mean duration of symptoms before diagnosis is 36.5 months.108,113-114 They tend to produce symmetrical expansion of the cord, as a result of their central location. Syringomyelia occurs in 9% to 50% of cases.108 Polar cysts are common. The cervical region is most often affected (44% of cases), with 23.5% of cases occurring at the cervicothoracic junction, and 26% occur in the thoracic cord alone.108 Metastasis to the retroperitoneum, lungs, and lymph nodes, may occur.115 Six histological subtypes are recognized: cellular (the most common type), papillary, clear cell, tanycytic, myxopapillary, and melanotic (the rarest).116 Almost all ependymomas are, however, low grade (World Health Organization classification grade I or grade II).108 Myxopapillary ependymomas,
528
Section
VIII
Spine and Spinal Diseases
constituting 13% of all spinal ependymomas, tend to occur in the conus medullaris and filum terminale, in contrast to other subtypes, and consequently are the most common neoplasm in this region of the cord.108 Most affected patients have relatively mild symptoms and are ambulatory at presentation.108 Back or neck pain is reported in 67%.114,117,118 There are often no objective neurological signs. Sensory deficits predominate and are reported in 52%, probably caused by compression or interruption of spinothalamic tracts.108 Motor weakness is reported in 46% but may predominate in very large ependymomas, and sphincter dysfunction occurs in 15%.113,114,117,118 In rare cases, ependymomas may cause subarachnoid hemorrhage.119 On computed tomographic imaging, ependymomas appear either isoattenuated or slightly hyperattenuated in relation to the adjacent normal spinal cord tissue, but they are enhanced intensely after the administration of iodinated intravenous contrast material.113 On T1-weighted MRI (Fig. 40–7), most are isointense or hypointense in relation to normal spinal cord, but they are hyperintense on T2-weighted sequences.120,121 Approximately 20% to 33% of these tumors demonstrated a rim of hypointensity at the poles, the “cap sign,” on T2-weighted images, corresponding to hemosiderin deposition as a result of hemorrhage.117,120,121 Edema surrounding the tumor mass is seen in 60% of cases.117 At least some enhancement is seen with gadolinium in 84% of cases, with 89% of those displaying welldefined margins on contrast material–enhanced images.120,121 The treatment of choice is laminectomy and microsurgical resection.113,117,118 Adjuvant radiotherapy is reserved for cases of recurrent disease.113,117 In the immediate postoperative period, patients often deteriorate neurologically; this is secondary to edema and possibly transient interference with spinal cord blood flow. Preoperative neurological status is the key predictor of ultimate outcome.114 Milder neurological deficits at presentation, smaller lesions, and shorter symptom duration are factors associated with better postoperative outcome. The 5year survival rate is 82%, regardless of neurological status at presentation.108,113
Astrocytoma Astrocytomas constitute approximately one third of all spinal cord gliomas and are the most common intramedullary tumor in children. As with ependymoma, there is a male preponderance (58% of cases); however, the mean age at presentation is younger (29 years) (Table 40–11).117 The thoracic cord is most
commonly involved (67% of cases), followed by the cervical cord (49%).122 Holocord (involvement of the entire spinal cord) occurs in up to 60% of children with this condition.117 Astrocytomas are characteristically ill-defined, fusiform intramedullary enlargements.117 Small, eccentric tumor cysts are common, and syringes may be present. Histologically, astrocytomas are highly cellular and have no surrounding capsule, as a result of which malignant cells infiltrate along the network of normal astrocytes, oligodendrocytes, and axons.115 The degree of pleomorphism correlates with the biological behavior of these tumors. The World Health Organization’s system of classification subdivides astrocytomas into four grades.107,115 Grade I tumors are the most benign, accounting for 75% of spinal cord astrocytomas. Grade II lesions are the classic low-grade astrocytomas, whereas grade III lesions, known as anaplastic astrocytomas, are less differentiated. Grade IV astrocytomas, known as glioblastoma multiforme and displaying the most aggressive biological behavior, are rare in the spinal cord, constituting only 0.2% to 1.5% of spinal cord astrocytomas. The most common manifestations are pain and sensory deficit, occurring in approximately 53% of cases.117 In contrast to ependymomas, in which dysesthesias dominate the sensory symptoms as a result of spinothalamic tract involvement, astrocytomas tend to manifest with paresthesias.118 Motor dysfunction is less common (41.4%), and sphincter dysfunction is infrequent.117 On examination, objective neurological deficits are often absent in lower grade (grades I and II) astrocytomas, which results in diagnostic delay.117 In young children, symptoms occur sooner, with a median duration of 5 months before diagnosis; however, the lesions tend to be low grade, with slow growth and low recurrence rates.123 MRI features of astrocytomas include poor margination and isointensity or hypointensity in relation to normal spinal cord on T1-weighted sequences, with contrast material enhancement.108,123 On T2-weighted imaging, these lesions are hyperintense. In contrast to ependymomas, astrocytomas tend to occur eccentrically (57%) in the cord, reflective of their parenchymal origin, and the “cap sign” is not seen.124 Leptomeningeal spread is reported for 60% of intramedullary glioblastoma multiforme tumors.125 The prognosis for adult patients with astrocytoma is worse than that for ependymoma; mortality rates are much higher than in patients with comparable ependymomas, even in cases of gross total resection.126 This is probably reflective of the infiltrative nature of astrocytomas, with extension of the
T A B L E 4 0 – 11. Features of Ependymoma and Astrocytoma Feature
Ependymoma
Astrocytoma
Characteristic population (mean age at presentation) Location within spinal cord Gross morphology Presence of hemorrhage Contrast enhancement Conus medullaris/filum terminale involvement
Adult (38.8 years)
Pediatric (29 years)
Central Circumscribed Common Intense, focal, homogenous Yes
Eccentric Poorly defined Uncommon Patchy, irregular No
Adapted from Koeller KK, Rosenblum S, Morrison AL: Neoplasms of the spinal cord and filum terminale: radiologic-pathologic correlation. Radiographics 2000; 20:1721-1749.
chapter 40 spinal disease
A
529
B
■
Figure 40–7. Magnetic resonance images of ependymoma. A, On T1-weighted spin-echo image, an intrinsic, expansile lesion of the thoracic spinal cord, isointense in relation to normal spinal cord, is seen. B, The lesion is hyperintense on T2-weighted spin-echo imaging, with a rim of hypointensity at the poles (“cap sign”). C, Enhancement is seen after gadolinium administration on T1weighted spin-echo imaging.
C
530
Section
VIII
Spine and Spinal Diseases
neoplastic cells well beyond the gross margin of the tumor, which therefore necessitates more extensive resection of spinal cord, with increased risk of postsurgical neurological deficits.126 The treatment of these tumors is therefore somewhat controversial.108 Some neurosurgeons advocate gross total resection, whereas others prefer initial intraoperative biopsy and frozen section examination, proceeding to debulking in highgrade lesions.117,126 As malignant cells invariably remain despite apparent total macroscopic debulking, gross total resection may not be carried out, with the aim of averting significant neurological morbidity.126 Radiotherapy may be administered, with the aim of eradicating residual disease. Annual surveillance MRI is recommended after treatment.126
Nonglial Neoplasms Hemangioblastoma Constituting 1.0% to 7.2% of all spinal cord neoplasms, these tumors usually occur in patients younger than 40 years and may be extramedullary in 25%.108,117,127 They grow slowly and usually involve either the thoracic (50%) or cervical (40%) cord.108 Most cord hemangioblastomas are solitary; however, multiple lesions are seen in the von Hippel–Lindau syndrome, which is reported to occur in one third of patients with hemangioblastoma.128,129 Spinal hemangioblastomas are highly vascular, circumscribed lesions, which characteristically display prominent dilated, tortuous surface vessels.117,127 Histopathologically, the tumors are composed of sheets of large, pale stromal cells with hyperchromatic nuclei, interspersed with blood vessels of varying sizes.108 Foci of hemorrhage are usually prominent.108 Clinical manifestations, usually slowly progressive, include sensory symptoms (39%), usually impaired proprioception; motor dysfunction (31%); and pain (31%).108 Subarachnoid hemorrhage and hematomyelia are rare complications.128 Spinal angiography demonstrates a highly vascular mass, with a dense, prolonged blush and prominent draining veins.108 On T1-weighted MRI, hemangioblastomas display varying signal intensity, usually isointensity (50%) or hyperintensity (25%) in relation to normal cord, with intense and homogenous contrast material enhancement.117,124 High signal intensity, with flow voids, is seen on T2-weighted images; however, there are reports of hemangioblastomas that are not visible on this sequence.108,117 Three-dimensional magnetic resonance angiography can provide valuable noninvasive preoperative information regarding the architecture of feeding vessels.130
T A B L E 4 0 – 12. Intramedullary Spinal Cord Metastases Primary Tumor Lung carcinoma Breast Melanoma Renal cell carcinoma Colorectal carcinoma Unknown primary tumor
40%-85% 11% 5% 4% 3% 5%
cases), sphincter dysfunction (60%), and paresthesias (50%) are other common manifestations.108,132 MRI typically reveals mild cord expansion over several segments, with a central area of low signal intensity on T1weighted imaging and high signal intensity, reflecting edema and tumor infiltration, on T2-weighted sequences.133 Intense, homogenous enhancement is seen with administration of contrast material.108 Peritumoral edema is often florid, and cysts are rare, in contrast to primary intramedullary neoplasms.108 Radiotherapy and corticosteroids are the mainstays of therapy in the setting of widely metastatic disease, although microsurgical resection of discrete lesions has been advocated, to improve the quality of remaining life.131,132 Prognosis is almost universally poor, with two thirds of these patients dying within 6 months of diagnosis.131
Lymphoma CNS lymphoma is a rare condition, accounting for only 1% of all lymphomas.134-136 Most cases of spinal cord lymphoma involve the vertebra and the epidural compartment, although isolated intramedullary lymphoma occurs in 3.3% of cases of CNS lymphoma, and is usually a solitary lesion. The mean age at presentation is 47. The cervical cord is most often affected.108,134-136 Clinical features include weakness, progressive gait dysfunction, and sensory disturbance.135 Spinal cord lymphoma is usually of B cell phenotype, as demonstrated on immunohistochemistry study, although primary spinal cord T cell lymphomas have been reported, and this may be related to previous human T cell lymphoma virus–related myelopathy.134,135 On MRI, spinal cord lymphomas demonstrate high T2-weighted signal intensity, with intense enhancement after administration of contrast material. Management consists of radiotherapy to the lymphomatous mass, with systemic and intrathecal chemotherapy.134,135
Metastases
Extramedullary Spinal Cord Neoplasms
Intramedullary spinal metastases are rare, reported to be found in 0.9% to 2.1% of patients with cancer at autopsy.131 The most common primary cancer to metastasize to the spinal cord is lung carcinoma, followed by breast carcinoma (11%) (Table 40–12).132 The cervical cord is most commonly affected (45%) and then the thoracic cord (35%); the lumbar spinal cord is infrequently involved (8%).132 Most metastases are solitary.132 Symptoms progress rapidly, in contrast to the gradual onset of symptoms characterizing primary intramedullary neoplasms.108 Weakness is almost universal, and pain (70% of
Extramedullary tumors arise outside the spinal cord and are subdivided on the basis of their relationship to the dura mater: extradural if they arise within the epidural tissues or the vertebral bodies and intradural if they arise within the spinal roots or the leptomeninges. Intradural tumor growth, accounting for approximately 10% of CNS tumors, usually takes the form of a leptomeningeal carcinomatosis or lymphomatosis.57,137,138 The commonest extramedullary tumors are meningiomas and neurilemmomas (neurofibroma and schwannoma), together constituting 55% of all spinal neoplasms, and these
chapter 40 spinal disease
A ■
531
B Figure 40–8. Magnetic resonance images of meningioma. An intradural extramedullary mass lesion is seen at the T4 level, lying anterior to the cord, an appearance characteristic of meningioma. It is isointense in relation to the spinal cord on T1-weighted spin-echo imaging (A), with intense enhancement after administration of gadolinium (B).
are more often intradural than extradural.57 Metastatic tumors and lymphoma usually occur in the extramedullary extradural compartment and are far commoner than intramedullary disease.57 In fact, extradural myeloma, lymphoma, and carcinoma together form the largest group of spinal tumors. They either seed the extradural space hematogenously or extend directly from vertebral deposits or extraspinal sites via the intervertebral foramina.137
Meningioma Meningiomas represent 16% to 25% of all spinal tumors and 25% to 46% of primary spinal cord tumors.139-141 They are usually encapsulated and extradural and tend to develop on the lateral or posterolateral surface of the spinal cord, which renders them readily surgically resectable.142 However, an “en plaque” form, which usually occurs intradurally, characterized by growth in a sheetlike or collar-like manner around the spinal cord with infiltration of the pia mater, was reported to occur in 3.1% of cases.143 These rare variants also have a tendency to infiltrate the arachnoid plane and the spinal cord parenchyma and are difficult to resect.142 Meningiomas tend to be slow growing, although the clinical history is shorter with the en plaque variant, and produce symptoms through compression of neural structures.139-141
MRI is the imaging modality of choice for the demonstration of meningiomas, with either isointensity or hypointensity on T1-weighted imaging and hyperintensity on T2-weighted sequences, and intense enhancement with intravenous administration of gadolinium (Fig. 40–8).143 The extent of extradural extension and compression of neural structures can be delineated on MRI. Computed tomography is useful for detecting the presence of calcification, an adverse factor in surgical outcome.141 Surgical resection is the mainstay of therapy, with radiotherapy used as an adjuvant treatment or as alternative therapy in patients who are poor surgical candidates.141
Schwannoma Schwannomas are benign, solitary, slow-growing neoplasms, composed of differentiated neoplastic Schwann cells derived from nerve sheaths.138,144,145 They account for approximately 20% of all primary spinal neoplasms.138,144 They usually occur in the intradural extramedullary compartment, and approximately 40% of intradural extramedullary tumors are either schwannomas or neurofibromas.57,138 Spinal cord schwannomas arise predominantly in association with dorsal sensory nerve roots.144 Treatment is surgical excision, usually via a posterior or posterolateral approach, with good outcomes reported.145
532
Section
VIII
Spine and Spinal Diseases
SPINAL CORD COMPRESSION Any of the tumors just mentioned, particularly the extramedullary, may produce spinal cord compression; however, the most common neoplastic cause is metastatic extradural disease, which is the focus of this discussion. Metastatic epidural spinal cord compression (MESCC) is defined as compression of the dural sac and its contents (spinal cord and/or cauda equina) by an extradural tumor mass, with lower motor neuron features at this level and upper motor neuron features below this level of the spinal cord.57,146 Radiological evidence for this is indentation of the theca at the level of clinical features.146 Subclinical MESCC is defined as the presence of radiographic features in the absence of clinical features. It is imperative that symptoms and signs of MESCC be detected early to prevent profound neurological deficits by instituting therapy early. Delay in recognition and inappropriate referral for treatment can result in deterioration and irreversible motor deficit. Education of patients (and clinicians) about the symptoms of MESCC is therefore important, especially for patients known to have vertebral disease or asymptomatic MESCC.146
Epidemiology A population-based study of 3400 patients from 1990 to 1995 demonstrated that MESCC is relatively common; 2.5% who died from their disease had had at least one admission with this complication in the 5 years preceding death.147 The incidence of MESCC varies widely with the type of primary tumor; 7% of patients with myeloma experienced MESCC, in contrast to 0.2% of patients with pancreatic cancer.147 In one retrospective analysis, breast, lung, and prostate cancers, which have a particular predilection for bony metastasis, accounted for 21%, 24%, and 20%, respectively, of episodes of MESCC; 15% of patients experienced multiple episodes.148 A multivariate analysis of patient, imaging, and neurological factors in 258 patients revealed six major predictive risk factors for MESCC (Table 40–13).146,149 Patients with none of these six risk factors had a 4% risk of developing MESCC, in contrast to a 87% risk of MESCC in those with all six risk factors. The estimated lifetime risk of MESCC was 19.3% for asymptomatic patients with all risk factors identified in Table 40–13, whose primary malignancies were prostate cancer, breast cancer, and renal carcinoma and myeloma. Conversely,
T A B L E 4 0 – 13. Factors Predictive of Risk of Metastatic Epidural Spinal Cord Compression
From Talcott JA, Stomper PC, Drislane FW, et al: Assessing suspected spinal cord compression: a multidisciplinary outcomes analysis of 342 episodes. Support Care Cancer 1999; 7:31-38.
the estimated lifetime incidence of MESCC for neurologically asymptomatic patients with leukemia, ovarian, gastric, and pancreatic primary cancers was 0.048%. The natural history of untreated MESCC is usually of progressive and relentless pain, paralysis, sensory deficit, and sphincter dysfunction.146 Approximately 70% of patients are reported to suffer loss of neurological function between the onset of symptoms and the start of treatment.150 The majority of delays were attributable to lack of symptom recognition by the patient and diagnostic delay at the primary care level. In a study of 98 patients, Rades and colleagues found that those with slower development of motor deficits before treatment (>14 days) had the best functional outcome, in comparison with patients with more rapid development (<14 days) of motor deficits.151
Clinical Features Again, a high degree of suspicion for cord compression in patients who present with vague sensorimotor or sphincteric dysfunction is crucial in this clinical emergency. Any suggestion of a sensory or motor level in a neurological syndrome, with or without signs, particularly in patients known to be at risk for cord compression cannot be ignored, and the most significant delays in treatment occur at the primary care level through failure to recognize the syndrome and its importance. Minimizing disability through early therapy is the key to successful treatment. Approximately 90% of patients with MESCC have pain (local back pain or radicular pain), and up to 50% are paretic (nonambulatory and paraparetic) or paraplegic.152-154 Other frequent symptoms of MESCC are weakness, sensory alteration, and bladder dysfunction154 (see Table 40–2 for features of spinal cord compression).
Investigations Studies evaluating the utility of MRI in identifying MESCC support the use of whole-spine MRI for patients with known malignancy and suspected MESCC.146,155 Findings on MRI are of an epidural mass with indentation of the thecal sac (Fig. 40–9).
Role of Systemic Corticosteroids The role of corticosteroids in the management of MESCC is somewhat controversial, and there is a paucity of evidence supporting clinical practice.146 High-dose maintenance dexamethasone has been shown to significantly improve ambulation in comparison with no corticosteroids—however, with an increased incidence of adverse effects, including psychosis and gastric ulcers that necessitate surgery.156 In a small randomized controlled trial (n = 37), high-dose (100-mg) bolus dexamethasone was compared with moderate-dose (10-mg) bolus dexamethasone, before maintenance dexamethasone (16 mg daily for the duration of radiotherapy). Eight percent of patients administered the moderate dose and 20% of those administered high-dose dexamethasone demonstrated improved neurological status, although this difference was not statistically significant.157
chapter 40 spinal disease
A ■
533
B Figure 40–9. Metastatic epidural spinal cord compression: T1-weighted spin-echo magnetic resonance images. A, Severe pathological compression fracture of T5, in association with a large extradural mass with significant cord compression. B, Multiple metastatic deposits seen through the cervical, thoracic, and lumbar vertebrae. Complete collapse of the C4 vertebra, with an associated epidural mass, causes moderate cord compression at this level. A metastatic deposit at T6 also has an epidural component, which contacts the anterior thoracic cord.
Treatment Radiotherapy Radiotherapy is the mainstay of treatment of MESCC for both radiosensitive and radioresistant tumors, and many studies have addressed its role. The evidence suggests that patients who have no bony compression stand to benefit most, whereas those with bony compression may require surgical decompression in addition.146 Patients with bony compression, particularly those with mild to moderate motor deficit, were less likely to recover or retain the ability to ambulate after radiotherapy than were patients without bony compression.146 Results of an analysis of ambulatory outcomes in patients with MESCC with and without bony compression or spinal instability suggested that the presence of bony compression is a negative predictive factor for the ability to ambulate after radiotherapy.146 For instance, in one retrospective review of 46 patients treated with radiotherapy for MESCC, 66% (23 of 35) of patients with no bony compression were ambulant after radiotherapy, whereas only 27% (3 of 11) of those with bony compression were able to walk.158
In one of the most publicized trials in the area of management of MESCC, Patchell and colleagues compared maximum decompressive surgical resection in addition to radiotherapy (30 Gy in 10 fractions) with radiotherapy alone, in a randomized, nonblinded multicenter trial.159 The primary endpoints were the ability to walk and ambulatory time after treatment. Patients who underwent combined-modality treatment had better outcomes than did those treated with radiotherapy alone, in terms of more time ambulatory (median ambulation 126 versus 35 days, respectively, P = 0.006) and better analgesic control, in addition to a trend toward improved survival (P = 0.08). Only 3 (19%) of patients undergoing radiotherapy alone regained ambulation, in contrast to 9 (58%) of 16 patients treated with the combined-modality approach (P < 0.03). Criticisms of Patchell and colleagues’ study include its relatively small size and its restrictive inclusion criteria, particularly a single focus of MESCC, which may be unrealistic in the cancer population affected by MESCC and may limit the applicability of this study. The prescription of radiotherapy used to treat MESCC varies both within and between centers, as reflected in the various study protocols published. Dosages studied include 30 Gy in 10
534
Section
VIII
Spine and Spinal Diseases
fractions, 37.5 Gy in 15 fractions, 40 Gy in 20 fractions, 28 Gy in 7 fractions and split doses of 15 Gy in 3 fractions followed by 15 Gy in 5 fractions.146 No one regimen has been demonstrated to be superior to the others for any cohort of patients.146 Patients who develop recompression in-field may be candidates for repeated irradiation, particularly if the latency between the completion of the last course of radiotherapy and recurrence of MESCC is more than 6 weeks. Repeated irradiation may lead to radiation myelopathy in a relatively short interval; however, one retrospective review reported no occurrence of radiation myelopathy when the cumulative dose to the cord was less than 100 Gy.160
Surgery Before the availability of radiotherapy for MESCC, surgical decompression, via laminectomy, was the mainstay of therapy.146 However, since the introduction of radiotherapy, and in the context of several large trials demonstrating no benefit from surgery alone or in combination with radiotherapy, there is little consensus regarding the operative indications in patients with MESCC. It is generally accepted by those who manage MESCC that spinal instability is an indication for surgical intervention.146,159 Patchell and colleagues found that MESCC patients undergoing surgery in addition to radiotherapy were more likely to retain or regain their ambulatory status than were patients receiving radiotherapy alone (P = 0.006).159 Surgery is, however, associated with significant morbidity in this population of cancer patients, even in the preradiotherapy setting, and may be an essentially palliative procedure.146 Postoperative complication rates of up to 54% have been reported in the literature, as have mortality rates of 0% to 13%, which must be taken into consideration in the decision between surgery and radiotherapy.146 A posterior surgical approach, with laminectomy, is traditionally adopted. However, the compressive mass in most cases of MESCC originates anteriorly, from the vertebral body.161,162 Laminectomy per se does not remove this compressive mass, which may be difficult to access posteriorly.146,162 Furthermore, this approach may contribute to mechanical instability of the spinal column, by removing the intact posterior osseous elements, thereby potentiating spinal cord compression.162 With anterior and lateral surgical approaches, several uncontrolled studies have demonstrated good outcomes, with improved neurological status and analgesia, even in patients with severe motor deficits.163 However, there is an absence of randomized trials supporting these alternative approaches.
Nonneoplastic Spinal Cord Compression Various nonneoplastic causes of spinal cord compression have been described. Causes addressed elsewhere in this chapter include benign spinal tumors, spinal epidural abscess, degenerative disk disease, and spondylotic disease. The last is easily the most common cause of cord compression but is often asymptomatic. Paget’s disease causes enlargement of the vertebral bodies, laminae, and pedicles, producing narrowing of the spinal canal, which may lead to a clinical picture of spinal cord compression.57 Other causes include traumatic or osteopenic vertebral fracture, tuberculous granulomata and hemangiomas, and intraspinal (either extradural or intradural) lipoma.57 Rare causes of spinal cord compression include solitary osteochondromas of vertebral bodies, vertebral extramedullary hematopoiesis, and arachnoid diverticula.57 Spinal cord sarcoidosis is another rare cause of spinal cord compression.165 Neurological manifestations occur in 5% of patients with sarcoidosis, but spinal cord lesions occur in fewer than 10% of these. Intramedullary, intradural extramedullary, and extradural disease can occur, with the midcervical and thoracic cord being most often affected. MRI demonstrates isointensity on T1-weighted imaging and typically hyperintensity on T2-weighted imaging.165
K E Y ●
Diseases of the spinal cord are numerous, with widely varying causes, and for many, there is no curative or disease-modifying treatment.
●
They are often catastrophic, resulting in progressive and disabling neurological dysfunction, and may be fatal, as a result of respiratory paralysis or complications of neurological disability.
●
Effective therapy, to delay progression or even reverse neurological deficits, is available for some spinal cord diseases, including certain infections and neoplasms, prolapsed intervertebral disk, and cervical spondylopathy.
●
The likelihood of reversal of damage to spinal cord structures diminishes with the duration of the insult and increasing severity of deficit; paralysis usually occurs late, by which stage the damage is often irreversible.
●
Recognition of potentially treatable conditions enables timely intervention and preservation of neurological function.
●
Despite the importance of early recognition, diagnostic delay is common, often because of late presentation or a low index of suspicion by clinicians, who fail to attribute signs and symptoms to a spinal cord disease process.
●
Knowledge of signs and symptoms suggestive of spinal cord disease is therefore vital (see Table 40–1).
●
Often there is a disparity between the extent of spinal cord pathology and clinical features.
●
Magnetic resonance imaging is the “gold standard” imaging investigation for diagnosis of spinal cord diseases.
Prognosis The strongest prognostic factor for overall survival and ability to ambulate after treatment is pretreatment neurological status, particularly motor function.146 In one series of patients with MESCC without bony compression, 100% of ambulatory patients retained ambulation after radiotherapy, whereas patients who were ambulatory with assistance, were paraparetic, or were paraplegic had ambulatory rates of 94%, 60%, and 11%, respectively.164 Patients with paralysis either at presentation or after treatment have a much shorter life expectancy than do ambulatory patients.146,153,164
P O I N T S
chapter 40 spinal disease Suggested Reading Andersen O: Myelitis. Current Opin Neurol 2000; 13:311-316. Kaplin AI, Krishnan C, Deshpande DM, et al: Diagnosis and management of acute myelopathies. Neurologist 2005; 11:2-18. McCormick WE, Steinmetz MP, Benzel EC: Cervical spondylotic myelopathy: make the difficult diagnosis, then refer for surgery. Cleve Clinic J Med 2003; 70;899-904. Nakajima H, Furutama D, Fimura F, et al: Herpes simplex myelitis: clinical manifestations and diagnosis by the polymerase chain reaction. Eur Neurol 1998; 38:163-168. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005; 366:643-648.
References 1. Andersen O: Myelitis. Current Opin Neurol 2000; 13:311-316. 2. Kaplin AI, Krishnan C, Deshpande DM, et al: Diagnosis and management of acute myelopathies. Neurologist 2005; 11:218. 3. Jeffery D, Mandler R, Dacis L: Transverse myelitis: retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Arch Neurol 1993; 50:532-535. 4. Berman M, Feldman S, Alter M, et al: Acute transverse myelitis: incidence and aetiologic considerations. Neurology 1981; 31:966-971. 5. Christensen PB, Wermuth L, Hinge HH, et al: Clinical course and long-term prognosis of acute transverse myelopathy. Acta Neurol Scand 1990; 81:431-435. 6. Adrianakos AA, Duffy J, Suzuki, et al: Transverse myelitis in systemic lupus erythematosus: report of three cases and review of the literature. Ann Intern Med 1975; 83:616-624. 7. Nakano I, Mannen T, Mizutani T, et al: Peripheral white matter lesions of the spinal cord with changes in small arachnoid arteries in systemic lupus erythematosus. Clin Neuropathol 1989; 8:102-108. 8. Griffin D: Encephalitis, myelitis and neuritis. In Mandell G, Bennett J, Dolin R, eds: Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone, 2000, pp 1009-1016. 9. Gnann J: Mumps virus diseases. In McKendall R, Stroop W, eds: Handbook of Neurology. New York: Dekker, 1994, pp 563573. 10. Devinsky O, Cho E, Petito C, et al: Herpes zoster myelitis. Brain 1991; 114:1181-1196. 11. Albucher J, Lauque D, Geyer I, et al: Transverse myelitis caused by Mycoplasma pneumoniae infection. Rev Neurol (Paris) 1995; 151:350-353. 12. de Macedo DD, de Mattos JP, Borges TM: [Transverse myelopathy and systemic lupus erythematosus: report of a case and review of the literature]. Arq Neuropsiquiatr 1979; 37:76-84. 13. Nakajima H, Furutama D, Fimura F, et al: Herpes simplex myelitis: clinical manifestations and diagnosis by the polymerase chain reaction. Eur Neurol 1998; 38:163-168. 14. Aurelius E, Johansson B, Skoldenberg B, et al: Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991; 337:189192. 15. Misra UK, Kalita J, Kumar S: A clinical, MRI and neurophysiological study of acute transverse myelitis. J Neurol Sci 1996; 138:150-156. 16. Lipton HL, Teasdall RD: Acute transverse myelopathy in adults: a follow up study. Arch Neurol 1973; 28:252-257.
535
17. Sakakibara R, Hattori T, Yasuda K, et al: Micturition disturbance in acute transverse myelitis. Spinal Cord 1996; 34:481485. 18. Runmarker B, Andersen O: Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow up. Brain 1993; 116:117-134. 19. Scott T, Bhagavatula K, Snyder R, et al: Transverse myelitis: comparison with spinal cord presentations of multiple sclerosis. Neurology 1998; 50:429-433. 20. Bakshi R, Kinkel RR, Mechtler LL, et al: Magnetic resonance imaging findings in 22 cases of myelitis: comparison between patients with and without multiple sclerosis. Eur J Neurol 1998; 5:35-48. 21. Kibe T, Fujimoto S, Ishikawa T, et al: Serial MRI findings of benign poliomyelitis. Brain Dev 1996; 18:147-149. 22. Takahashi S, Miyamoto A, Oki J, et al: Acute transverse myelitis caused by ECHO virus type 18 infection. Eur J Paediatr 1995; 154:378-380. 23. Ku B, Lee K: Acute transverse myelitis caused by Coxsackie virus B4 infection: a case report. J Korean Med Sci 1998; 13:449-453. 24. Graber D, Fossoud C, Grouteau E, et al: Acute transverse myelitis and Coxsackie A9 virus infection. Paediatr Infect Dis J 1994; 13:77. 25. Minami K, Tsuda Y, Maeda H, et al: Acute transverse myelitis caused by Coxsackie virus B5 infection. J Paediatr Child Health 2004; 40:66-68. 26. Bansal R, Kalita J, Misra U, et al: Myelitis: a rare presentation of mumps. Paediatr Neurosurg 1998; 28:204-206. 27. Bajaj NP, Rose P, Clifford-Jones R, et al: Acute transverse myelitis and Guillain-Barré syndrome overlap with serological evidence for mumps viraemia. Acta Neurol Scand 2001; 104:239-242. 28. Gobbi C, Tosi C, Stadler C, et al: Recurrent myelitis associated with herpes simplex virus type 2. Eur Neurol 2001; 46:215-219. 29. Petereit HF, Bamborschke S, Lanfermann H: Acute transverse myelitis caused by herpes simplex virus. Eur Neurol 1996; 36:52-53. 30. Klatersky J, Cappel R, Snoeck JM, et al: Ascending myelitis in association with herpes simplex virus. N Engl J Med 1972; 287:182-184. 32. Kueker W, Schaade L, Ritter K, et al: MRI follow up of herpes simplex virus (type 1) radiculomyelitis. Neurology 1995; 52:1102-1103. 33. Shyu WC, Lin JC, Chang BC, et al: Recurrent ascending myelitis: an unusual presentation of herpes simplex virus type 1 infection. Ann Neurol 1993; 34:625-627. 34. Hirai T, Korogi Y, Hamatake S, et al: Case report: varicellazoster virus myelitis—serial MR findings. Br J Radiol 1996; 69:1187-1190. 35. Lakeman FD, Whitley RJ: Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1995; 171:857-863. 36. Gilden DH, Beinlich B, Rubinstein EM, et al: Varicella-zoster virus: an expanding spectrum. Neurology 1994; 44:18181823. 37. Gilden DH, Mahalingam R, Dueland AN, et al: Herpes zoster: pathogenesis and latency. In Melinck J, ed: Progress in Medical Virology, vol 39. Basel, Switzerland: S. Karger, 1992, pp 19-75. 38. McKelvie PA, Collins S, Thyagarajan D, et al: Meningoencephalomyelitis with vasculitis due to varicella zoster virus: a case report and review of the literature. Pathology 2002; 34:88-93.
536
Section
VIII
Spine and Spinal Diseases
39. Morita Y, Osaki Y, Doi Y, et al: Chronic active VZV infection manifesting as zoster sine herpete, zoster paresis and myelopathy. J Neurol Sci 2003; 212:7-9. 40. Gilden DH, Bennett JL, Kleinschmidt-deMasters BK, et al: The value of cerebrospinal fluid antiviral antibody in the diagnosis of neurological disease produced by varicella zoster virus. J Neurol Sci 1998; 159:140-144. 41. Chretien F, Gray F, Lescs MC, et al: Acute varicella-zoster virus ventriculitis and meningomyeloradiculitis in acquired immunodeficiency syndrome. Acta Neuropathol (Berlin) 1993; 86:659-665. 42. Gray F, Belec L, Lescs MC, et al: Varicella-zoster virus infection of the central nervous system in the acquired immune deficiency syndrome. Brain 1994; 117:987-999. 43. Fillet AM, Dumont B, Caumes E, et al: Acyclovir-resistant varicella-zoster virus: phenotypic and genetic characteristics. J Med Virol 1998; 55:250-254. 44. Snoek R, Andrei G, De Clercq E: Current pharmacological approaches to the therapy of varicella zoster infections: a guide to treatment. Drugs 1999; 57:187-206. 45. Corti M, Soto I, Villafane NF, et al: [Acute necrotising myelitis in an AIDS patient]. Medicina 2003; 63:143-146. 46. Giobbia M, Carniato A, Scotton PG, et al: Cytomegalovirusassociated transverse myelitis in a non-immunocompromised patient. Infection 1999; 27:228-230. 47. Burke D, Leonard D, Imperiale T, et al: The utility of clinical and radiographic features in the diagnosis of cytomegalovirus central nervous system disease in AIDS patients. Mol Diag 1999; 4:37-43. 48. Majid A, Galetta SL, Sweeney CJ, et al: Epstein-Barr virus myeloradiculitis and encephalomyeloradiculitis. Brain 2002; 125:159-165. 49. Rubin DI, Daube JR: Subacute sensory neuropathy associated with Epstein-Barr virus. Muscle Nerve 1999; 22:1607-1610. 50. Feinberg WM, Zonis J, Minnich LL: Epstein-Barr virus–associated myelopathy in an adult. Arch Neurol 1984; 41:454-455. 51. Merelli E, Bedin R, Sola P, et al: Encephalomyeloradiculopathy associated with Epstein-Barr virus: primary infection or reactivation? Acta Neurol Scand 1997; 96:416-420. 52. Koskiniemi M: CNS manifestations associated with Mycoplasma pneumoniae infections: summary of cases at the University of Helsinki and review. Clin Infect Dis 1993; 17:S52-S57. 53. Abele-Horn M, Franck W, Busch U, et al: Transverse myelitis associated with Mycoplasma pneumoniae infection. Clin Infect Dis 1997; 26:909-912. 54. Heller L, Keren O, Mendelson L, et al: Transverse myelitis associated with Mycoplasma pneumoniae: case report. Paraplegia 1990; 28:522-525. 55. Haran MJ, Jenney AW, Keenan RJ, et al: Paraplegia secondary to Burkholderia pseudomallei myelitis: a case report. Arch Phys Med Rehab 2001; 82:1630-1632. 56. Oschmann P, Dordorf W, Hornig C, et al: Stages and syndromes of neuroborreliosis. J Neurol 1998; 245:262272. 57. Adams RD, Victor M: Diseases of the spinal cord. In Adams RD, Victor M, eds: Principles of Neurology, 5th ed. New York: McGraw-Hill, 1993, pp 1078-1116. 58. Shepherd E, Brettle R, Liberski P, et al: Spinal cord pathology and viral burden in homosexuals and drug users with AIDS. Neuropathol Appl Neurobiol 1999; 25:2-10. 59. Chong J, Di Rocco A, Tagliati M, et al: MR findings in AIDSassociated myelopathy. Am J Neuroradiol 1999; 20:14121416. 60. Manns A, Hisada M, La Grenado L: Human T-lymphotropic virus type 1 infection. Lancet 1999; 353:1951-1958. 61. Solomon T, Willison H: Infectious causes of acute flaccid paralysis. Curr Opin Infect Dis 2003; 16:375-381.
62. Howard RS: Poliomyelitis and the postpolio syndrome. BMJ 2005; 330:1314-1318. 63. Kilpatrick DR, Nottay B, Yang CF, et al: Group specific identification of poliovirus by PCR using primers containing mixed-base or deoxyinosine residues at positions of codon degeneracy. J Clin Microbiol 1996; 34:2990-2996. 64. Rao DG, Bateman DE: Hyperintensities of the anterior horn cells on MRI due to poliomyelitis. J Neurol Neurosurg Psychiatry 1997; 63:720. 65. Jubelt B, Agre JC: Characteristics and management of postpolio syndrome. JAMA 2000; 284:412-414. 66. Chen CY, Chang YC, Huang C, et al: Acute flaccid paralysis in infants and young children with enterovirus 71 infection: MR imaging findings and clinical correlates. Am J Neuroradiol 2001; 22:200-205. 67. Leis AA, Stokic DS, Polk JL, et al: A poliomyelitis-like syndrome from West Nile virus infection. N Engl J Med 2002; 347:1279-1280. 68. Mostashari F, Bunning ML, Kitsutani PT, et al: Epidemic West Nile encephalitis, New York 1999: results of a householdbased seroepidemiological survey. Lancet 2001; 358:261-264. 69. Li J, Loeb JA, Shy ME, et al: Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection. Ann Neurol 2003; 53:703-710. 70. Leis AA, Fratkin J, Stokic DS, et al: West Nile poliomyelitis. Lancet Infect Dis 2003; 3:9-10. 71. Chao D, Nanda A: Spinal epidural abscess: a diagnostic challenge. Am Fam Physician 2002; 65:1341-1346. 72. Mackenzie AR, Laing RBS, Smith CC, et al: Spinal epidural abscess: the importance of early diagnosis and treatment. J Neurol Neurosurg Psychiatry 1998; 65:209-212. 73. Baker AS, Ojemann RG, Swartz MN, et al: Spinal epidural abscess. N Engl J Med 1975; 293:463-468. 74. Hlavin ML, Kaminski KJ, Ross JS, et al: Spinal epidural abscess: a 10 year perspective. Neurosurgery 1990; 27:177184. 75. Danner RL, Hartman BJ: Update of spinal epidural abscess: 35 cases and review of the literature. Rev Infect Dis 1987; 9:265-274. 76. Vilke GM, Honingford EA: Cervical spine epidural abscess in a patient with no predisposing risk factors. Ann Emerg Med 1996; 27:777-780. 77. Kaufman DM, Kaplan JG, Litman N: Infectious agents in spinal epidural abscess. Neurology 1980; 30:844-850. 78. Verner EF, Musher DM: Spinal epidural abscess. Med Clin North Am 1985; 69:375-384. 79. Hori K, Kano T, Fukushige T, et al: Successful treatment of epidural abscess with percutaneously introduced 4French catheter for drainage. Anesth Analg 1997; 84:13841386. 80. Wang JS, Fellows DG, Vakharia S, et al: Epidural abscess: early magnetic resonance imaging detection and conservative therapy. Anesth Analg 1996; 82:1069-1071. 81. Manfredi PL, Herskovitz S, Folli F, et al: Spinal epidural abscess: treatment options. Eur Neurol 1998; 40:58-60. 82. Khanna RK, Malik GM, Rock JP, et al: Spinal epidural abscess: evaluation of factors influencing outcome. Neurosurgery 1996; 39:958-964. 83. Love C, Patel M, Lonner BS, et al: Diagnosing spinal osteomyelitis: a comparison of bone and Ga-67 scintigraphy and magnetic resonance imaging. Clin Nucl Med 2000; 25:963-977. 84. Sapico FL, Montgomerie JZ: Pyogenic vertebral osteomyelitis: report of nine cases and review of the literature. Rev Infect Dis 1979; 1:754. 85. Rezai AR, Woo HH, Errico TJ, et al: Contemporary management of spinal osteomyelitis. Neurosurgery 1999; 44:10181025.
chapter 40 spinal disease 86. Keung YK, Cobos E, Whitehead RP, et al: Secondary syringomyelia due to intramedullary spinal cord metastasis: case report and review of the literature. Am J Clin Oncol 1997; 20:577-579. 87. Goel A: Is syringomyelia pathology or a natural protective mechanism? J Postgrad Med 2001; 47:87-88. 88. Barnett HJM, Foster JB, Hodgson P: Syringomyelia. Philadelphia: WB Saunders, 1973. 89. Levine DN: The pathogenesis of syringomyelia associated with lesions at the foramen magnum: a critical review of existing theories and proposal of a new hypothesis. J Neurol Sci 2004; 220:3-21. 90. Gardner WJ: Hydrodynamic mechanism of syringomyelia: its relationship to myelocele. J Neurol Neurosurg Psychiatry 1965; 28:247. 91. Hida K, Iwasaki Y, Koyanagi I, et al: Surgical indication and results of foramen magnum decompression versus syringosubarachnoid shunting for syringomyelia associated with Chiari I malformation. Neurosurgery 1995; 37:673-678. 92. Logue V, Edwards MR: Syringomyelia and its surgical treatment: an analysis of 75 cases. J Neurol Neurosurg Psychiatry 1981; 44:273. 93. McCormick WE, Steinmetz MP, Benzel EC: Cervical spondylotic myelopathy: make the difficult diagnosis, then refer for surgery. Cleve Clin J Med 2003; 70:899-904. 94. Small JM, Dillin WH, Watkins RG: Clinical syndromes in cervical myelopathy. In Herkowitz H, Garfin SR, Balderston RA, et al, eds: The Spine, 4th ed. Philadelphia: WB Saunders, 1999, pp 465-474. 95. Montgomery DM, Brower RS: Cervical spondylotic myelopathy: clinical syndrome and natural history. Orthop Clin North Am 1992; 23:487-493. 96. White AA, Panjabi MM: Biomechanical considerations in the surgical management of cervical spondylitic myelopathy. Spine 1988; 13:856-860. 97. Lundsford LD, Bissonette D, Dorub D: Anterior surgery for cervical disc disease, part 2. J Neurosurg 1980; 53:12-19. 98. Hukuda S, Mochizuki T, Ogata M, et al: Operations for cervical spondylotic myelopathy: a comparison of the results of anterior and posterior procedures. J Bone Joint Surg Br 1985; 67:609-615. 99. Tanaka N, Fujimoto Y, Yasunaga Y, et al: Functional diagnosis using multimodal spinal cord evoked potentials in cervical myelopathy. J Orthopaed Sci 2005; 10:3-7. 100. Phillips DG: Surgical treatment of myelopathy with cervical spondylosis. J Neurol Neurosurg Psychiatry 1973; 36:879884. 101. Ebersold MJ, Pare MC, Quast LM: Surgical treatment for cervical spondylotic myelopathy. J Neurosurg 1995; 82:745-751. 102. Iwasaki M, Ebara S, Miyamoto S, et al: Expansive laminoplasty for cervical radiculomyelopathy due to soft disc herniation. Spine 1996; 21:32-38. 103. Durbukhula MM, Ghiselli G: Cervical total disc replacement part I: rationale, biomechanics and implant types. Orthop Clin North Am 2005; 36:349-354. 104. Boden SD, Wiesel SW: Lumbar spine imaging: role in clinical decision making. J Am Acad Orthop Surg 1996; 4:238-248. 105. Haughton VM: MR imaging of the spine. Radiology 1988; 166:297-301. 106. Humphreys SC, An HS, Eck JC, et al: Oblique MRI as a useful adjunct in evaluation of cervical foraminal impingement. Loyola Univ Orthop J 1997; 6:4-7. 107. Humphreys SC, Eck JC: Clinical evaluation and treatment options for herniated lumbar disc. Am Fam Physician 1999; 59:575-582, 587-588. 108. Koeller KK, Rosenblum S, Morrison AL: Neoplasms of the spinal cord and filum terminale: radiologic-pathologic correlation. Radiographics 2000; 20:1721-1749.
537
109. Sze G, Stimac GK, Bartlett C, et al: Multicenter study of gadopentetate dimeglumine as an MR contrast agent: evaluation in patients with spinal tumors. Am J Neuroradiol 1990; 11:967-974. 110. Takemoto K, Matsumura Y, Hashimoto H, et al: MR imaging of intraspinal tumors: capability in histological differentiation and compartmentalisation of extramedullary tumors. Neuroradiology 1988; 30:303-309. 111. Lee M, Epstein FJ, Rezai AR, et al: Non-neoplastic intramedullary spinal cord lesions mimicking tumors. Neurosurgery 1998; 43:788-795. 112. Lee M, Rezai AR, Freed D, et al: Intramedullary spinal cord tumors in neurofibromatosis. Neurosurgery 196; 38:32-37. 113. Ferrante L, Mastronardi L, Celli P, et al: Intramedullary spinal cord ependymomas: a study of 45 cases with long term follow up. Acta Neurochir 1992; 119:74-79. 114. Hoshimaru M, Koyama T, Hashimoto N, et al: Results of microsurgical treatment for intramedullary spinal cord ependymomas: analysis of 36 cases. Neurosurgery 1999; 44:264-269. 115. Wolff M, Santiago H, Duby MM: Delayed distant metastasis from a subcutaneous sacrococcygeal ependymoma: case report with tissue culture, ultrasound observation and review of the literature. Cancer 1972; 30:1046-1067. 116. Burger PC, Scheithauer BW: Tumors of neuroglia and choroid plexus epithelium. In Burger PC, Scheithauer BW, eds: Tumors of the Central Nervous System. Washington, DC: Armed Forces Institute of Pathology, 1994, pp 25-161. 117. Brotchi J, Fischer G: Treatment. In Fisher G, Brotchi J, eds: Intramedullary Spinal Cord Tumors. Stuttgart, Germany: Thieme, 1996, pp 60-84. 118. Epstein FJ, Fermer JP, Freed D: Adult intramedullary spinal cord ependymomas: the result of surgery in 38 patients. J Neurosurg 1993; 79:204-209. 119. Djindjian M, Djindjian R, Houdart R, et al: Subarachnoid haemorrhage due to intraspinal tumors. Surg Neurol 1978; 9:223-229. 120. Fine MJ, Kricheff II, Freed D, et al: Spinal cord ependymomas: MR imaging features. Radiology 1995; 197:655-658. 121. Kahan H, Sklar EML, Post MJD, et al: MR characteristics of histopathologic subtypes of spinal ependymoma. Am J Neuroradiol 1996; 17:143-150. 122. Epstein F, Epstein N: Surgical treatment of spinal cord astrocytomas of childhood. J Neurosurg 1982; 57:685-689. 123. Constatini S, Houten J, Miller D, et al: Intramedullary spinal cord tumors in children under the age of 3 years. J Neurosurg 1996; 85:1036-1043. 124. Froment JC, Baleriaux D, Turjman F, et al. In Fisher G, Brotchi J, eds: Intramedullary Spinal Cord Tumors. Stuttgart, Germany: Thieme, 1996. 125. Ciapetta P, Salvati M, Capoccia G, et al: Spinal glioblastomas: report of seven cases and review of the literature. Neurosurgery 1991; 28:302-306. 126. Cooper P: Outcome after operative treatment of intramedullary spinal cord tumors in adults: intermediate and long term results in 51 patients. Neurosurgery 1989; 25:855859. 127. Murota T, Symon L: Surgical management of hemangioblastoma of the spinal cord: report of 18 cases. Neurosurgery 1989; 25:699-708. 128. Neumann HPH, Eggert HR, Weigel K, et al: Hemangioblastomas of the central nervous system: a 10 year study with special reference to von Hippel–Lindau syndrome. J Neurosurg 1989; 70:24-30. 129. Browne TR, Adams RD, Robertson GH: Hemangioblastoma of the spinal cord. Arch Neurol 1976; 33:435-441. 130. Mascalchi M, Quilici N, Ferrito G, et al: Identification of the feeding arteries of spinal vascular lesions via phase-contrast
538
131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141.
142. 143. 144.
145.
146.
147. 148. 149.
Section
VIII
Spine and Spinal Diseases
MR angiography with three-dimensional acquisition and phase display. Am J Neuroradiol 1997; 18:351-358. Costigan DA, Winkelman MD: Intramedullary spinal cord metastasis: a clinicopathological study of 13 cases. J Neurosurg 1985; 62:227-233. Findlay JM, Bernstein M, Vanderlinden RG, et al: Microsurgical resection of solitary intramedullary spinal cord metastases. Neurosurgery 1987; 21:911-915. Post MJD, Quencer RM, Green BA, et al: Intramedullary spinal cord metastasis, mainly of nonneurogenic origin. Am J Neuroradiol 1987; 8:339-346. Koeller KK, Smirniotopoulos JG, Jones RV: Primary central nervous system lymphoma: radiologic-pathologic correlation. Radiographics 1997; 17:1497-1526. Schild SE, Wharen RE Jr, Menke DM, et al: Primary lymphoma of the spinal cord. Mayo Clin Proc 1995; 70:256-260. Bluemke DA, Wang H: Primary spinal cord lymphoma: MR appearance. J Comput Assist Tomogr 1990; 14:812-814. McCormick PC, Stein BM: Spinal cord tumors in adults. In Youmans JR, ed: Neurological Surgery. Philadelphia: WB Saunders, 1996, pp 3102-3122. McCormick PC, Post KD, Stein BM: Intradural extramedullary tumors in adults. Neurosurg Clin North Am 1990; 1:591-608. Gezen F, Kahraman S, Çanakci Z, et al: Review of 36 cases of spinal cord meningioma. Spine 2000; 25:727-731. Levy WJ, Bay J, Dohn D: Spinal cord meningioma. J Neurosurg 1982; 57:804-812. Roux FX, Nataf F, Pinaudeau M, et al: Intraspinal meningiomas: review of 54 cases with discussion of poor prognosis factors and modern therapeutic management. Surg Neurol 1996; 46:458-464. Nicholas DS, Weller RO: The fine anatomy of the human spinal meninges: light and scanning electron microscopy study. J Neurosurg 1988; 69:276-282. Caroli E, Acqui M, Roperto R, et al: Spinal en plaque meningiomas: a contemporary experience. Neurosurgery 2004; 55:1275-1279. O’Toole JE, McCormick PC: Midline ventral intradural schwannoma of the cervical spinal cord resected via anterior corpectomy and reconstruction: technical case report and review of the literature. Neurosurgery 2003; 52:1482-1486. Conti P, Pansini G, Mouchaty H, et al: Spinal neurinomas: retrospective analysis and long-term outcome of 179 consecutive operated cases and review of the literature. Surg Neurol 2004; 61:34-43. Loblaw DA, Perry J, Chambers A, et al: Systematic review of the diagnosis and management of malignant extradural spinal cord compression: The Cancer Care Ontario Practice Guidelines Initiative’s Neuro-Oncology Disease Site Group. J Clin Oncol 2005; 23:2028-2037. Loblaw DA, Laperriere NJ, Mackillop WJ: A population-based study of malignant spinal cord compression in Ontario cancer patients. Clin Oncol (R Coll Radiol) 2003; 15:211-217. Loblaw DA, Smith K, Lockwood G, et al: The Princess Margaret Hospital experience of malignant spinal cord compression. Proc Am Soc Clin Oncol 2003; 22:19. Talcott JA, Stomper PC, Drislane FW, et al: Assessing suspected spinal cord compression: a multidisciplinary out-
150. 151.
152. 153. 154.
155.
156.
157.
158. 159.
160. 161.
162. 163. 164.
165.
comes analysis of 342 episodes. Support Care Cancer 1999; 7:31-38. Husband DJ: Malignant spinal cord compression: prospective study of delays in referral and treatment. BMJ 1998; 317:1821. Rades D, Heidenreich F, Karstens JH: Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2002; 53:975979. Perrin RG: Metastatic tumors of the axial spine. Curr Opin Oncol 1992; 4:525-532. Sundaresan N, Galicich JH: Treatment of spinal metastases by vertebral body resection. Cancer Invest 1984; 2:383397. Helweg-Larsen S, Sorensen PS: Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients. Eur J Cancer 1994; 30A:396-398. Cook AM, Lau TN, Tomlinson MJ, et al: Magnetic resonance imaging of the whole spine in suspected malignant spinal cord compression: impact on management. Clin Oncol (R Coll Radiol) 1998; 10:39-43. Sorensen S, Helweg-Larsen S, Mouridsen H, et al: Effect of high dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. Eur J Cancer 194; 30A:22-27. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al: Initial bolus of conventional versus high dose dexamethasone in metastatic spinal cord compression. Neurology 1989; 39:1255-1257. Pigott KH, Baddeley H, Maher EJ: Pattern of disease in spinal cord compression on MRI scan and implications for treatment. Clin Oncol (R Coll Radiol) 1994; 6:7-10. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005; 366:643-648. Wong CS, van Dyk J, Milosevic M, et al: Radiation myelopathy following single courses of radiotherapy and retreatment. Int J Radiat Oncol Biol Phys 1994; 30:575-581. Young RF, Post EM, King GA: Treatment of spinal epidural metastases: randomised prospective comparison of laminectomy and radiotherapy. J Neurosurg 1980; 53:741748. van den Bent MJ: Surgical resection improves outcome in metastatic epidural spinal cord compression [Comment]. Lancet 2005; 366:609-610. Sundaresan N, Rothman A, Manhart K, et al: Surgery for solitary metastases of the spine: rationale and results of treatment. Spine 2002; 27:1802-1806. Maranzano E, Latini P, Beneventi S, et al: Radiotherapy without steroids in selected metastatic spinal cord compression patients: a phase II trial. Am J Clin Oncol 1996; 19:179183. Hamasaki T, Noda M, Kamei N, et al: Intradural extramedullary mass formation in spinal cord sarcoidosis: case report and literature review. Spine 2003; 28:E420E423.
CHAPTER
41
ANATOMY
AND PHYSIOLOGY OF CEREBRAL AND SPINAL CORD CIRCULATION ●
●
●
●
Omar Touzani and Eric T. MacKenzie
Of all the mammalian organs, the central nervous system is the most privileged and protected. Claude Bernard developed the now near-axiomatic concept of the maintenance of the “milieu interieur.” It is essential to recognize that the stability of the internal environment of the brain is primordial and that the homeostasis of other organs is subordinated to the vital stability of the neuronal environment in the central nervous system. Before entering into the anatomical and the physiological details that are specific to the brain, it is worth reflecting on the major general systems that protect the body—above all, the central nervous system. Baroreceptors, strategically placed at the origin of each internal carotid artery, are the sensors to maintain mean arterial pressure—the driving force necessary for a constant perfusion pressure of the central nervous system. Chemoreceptors are essentially located in the carotid bodies but also in the brainstem. Accordingly, PaO2, PaCO2, and pH are controlled and crucially, as is the tissue pH of the brain, as protons do not cross the blood-brain barrier. Hypothalamic regulatory systems include the osmoreceptors, the thermoreceptors, and the general mechanisms controlling metabolic pathways. Integrated control of the cardiovascular system is localized in the brainstem. Finally, the central nervous system processes signals from the external senses that allow the body to react appropriately to the surrounding environment: olfaction, vision, taste, hearing, and touch. However, all these systems are insufficient to optimally ensure functionality of the brain. As further lines of defense, the brain possesses several secondary, even tertiary, systems to optimize the survival of this organ. Simplistically, these defenses can be divided into two major categories: anatomical and physiological. Each is dealt with in subsequent sections.
ANATOMY OF THE CEREBRAL CIRCULATION The brain’s function and survival are highly dependent on the constant and finely regulated provision and regional distribution of oxygen and energy-producing substrates. In order to fulfill its needs, this complex neuronal system uses a high proportion of total body blood flow. Indeed, this organ, that represents only about 2% of total body weight, receives approximately 15% of total resting cardiac output, and consumes about 20% of the body’s resting metabolism. The brain’s
540
energy requirements render it highly susceptible to damage following ischemia. The cerebral vascular supply is constructed to protect the cerebral hemispheres and brainstem from the consequences of a major decrease in blood flow.
Arterial Supply The arterial supply to the human brain consists of four major afferent arterial trunks: two internal carotid and two vertebral arteries. The internal together with the external carotid arteries derive from the common carotid artery. In humans, the carotid arteries are quantitatively more important; each contributes approximately 40% to the total perfusion of the brain. The internal carotid arteries enter the cranial cavity through the os petrosum. The vertebral arteries enter the cranial cavity through the foramen magnum, where, after traversing the anterolateral aspect of the medulla oblongata, they fuse to form the basilar artery at the level of the pontomedullary junction (Fig. 41–1). This artery unites with the two internal carotids to form, at the base of the brain, an equalizing distributor named the circle of Willis (see Fig. 41–1). Having fused with the basilar artery, each internal carotid artery divides into four major branches: the anterior cerebral, the middle cerebral, the anterior choroidal, and the posterior communicating arteries. The latter anastomose with the posterior cerebral arteries, which originate from the basilar artery to complete the circle of Willis (see Fig. 41–1). These major cerebral arteries divide into progressively smaller arteries, which, in turn, enter the brain parenchyma at a right angle to the surface of the brain to supply blood to specific regions. The anterior cerebral arteries irrigate the frontal pole and the medial aspects of both frontal and parietal lobes, the corpus callosum, the anterior limb of the internal capsule, and the most rostral part of the caudate nucleus and the putamen. The middle cerebral arteries supply most of the lateral aspects of the cerebral hemispheres, as well as portions of the caudate nucleus and the putamen. The anterior choroidal arteries supply several structures such as the choroid plexus of the lateral ventricle, the optic tract, the hippocampus, the tail of the caudate nucleus, and the amygdala. The posterior communicating arteries supply the genu of the corpus callosum, part of the posterior limb of the internal capsule, the rostral thalamus, and the wall of the third ventricle. The posterior cerebral arteries supply the inferior and medial aspects
chapter 41 anatomy and physiology of cerebral and spinal cord circulation
541
Anterior communicating artery
Anterior cerebral artery
Internal carotid artery Anterior choroidal artery
Middle cerebral artery Lenticulostriate artery Posterior communicating artery
Posterior cerebral artery Superior cerebellar artery Pontine arteries Basilar artery Internal auditory artery Anterior inferior cerebellar artery
Posterior inferior cerebellar artery Vertebral artery
Anterior spinal artery
■
Figure 41–1. Basal view of major cerebral arteries and the circle of Willis. (From Sokoloff L: Anatomy of the Cerebral Circulation. In Welch KMA, Caplan LR, Reis DJ, et al, eds: Primer on Cerebrovascular Diseases. Academic Press, 1997.)
of the temporal and the occipital lobes, parts of the hippocampus, and the thalamus (Fig. 41–2). Before giving rise to the posterior cerebral arteries, the basilar artery sends several branches to supply the cerebellum and the brainstem (see Fig. 41–1).
Collateral Blood Supply of the Brain Several types of anastomoses are found in the cerebral circulation.1 The following are the most important.
Circle of Willis As mentioned, the circle of Willis is an anastomosis between the anterior and the posterior circulation via the anterior and the posterior communicating arteries (see Fig. 41–1). Considerable intraspecies and interspecies variability exists in the anatomy of the circle of Willis. In humans, a symmetrical circle is found in only 50% of brains.2 In addition, in most species other than primates, the anterior cerebral communicating artery is absent and the anterior cerebral arteries fuse earlier to form the pericallosal artery.3 This anastomotic ring protects from the disastrous consequences of occlusion of a single supply vessel to the brain. However, under physiological con-
ditions, the blood from the internal carotid and the basilar arteries does not mix because the blood pressure in each arterial trunk is almost identical.
External Carotid-Internal Carotid Anastomoses In humans, this anastomotic pathway is relatively negligible. The ophthalmic artery is the most significant conduit that is capable of bridging the external and internal circulations. However, in many species such as the dog, cat, and sheep, rich and complex connections exist between the internal and external carotid arteries via a structure termed the rete mirabile.3
Leptomeningeal Anastomoses The leptomeningeal anastomoses, organized in the subarachnoid space between the arterial boundary zones, represent connections between distal branches of major cerebral arteries (i.e., between the anterior cerebral and middle cerebral arteries and between the middle cerebral and the posterior cerebral arteries) (Fig. 41–3). These arterial boundary zones, also termed “watershed zones,” are especially susceptible to damage following any generalized decrease in blood flow as in the case of severe systemic hypotension.
542
■
Section
IX
C e r e b r o va s c u l a r D i s e a s e
Figure 41–2. Cerebral areas irrigated by the anterior cerebral arteries (orange), the middle cerebral artery (yellow) and the posterior cerebral arteries (green). Left: a left lateral view, middle: a right medial view, and right: a basal view with dissection of the left temporal lobe and cerebellar hemisphere. (From Edvinsson L, McCulloch J, MacKenzie ET: General and comparative anatomy of the cerebral circulation. In Edvinsson L, MacKenzie ET, McCulloch J, et al, eds: Cerebral Blood Flow and Metabolism. New York: Raven Press, 1993.)
Venous Drainage
Blood Supply to the Spinal Cord
The venous circulation of the central nervous system is particular in that (1) the veins do not run parallel to arteries as in many other organs and (2) the major fraction of blood that drains the brain is collected in the dural sinuses, which represent the final intracranial collecting blood vessels.4 Briefly, there are three groups of valveless vessels that allow for drainage. These are the superficial cortical veins located on the surface of the cortex, the deep or central veins, and the venous sinuses within the dura (Fig. 41–4). The superficial veins convey blood from the cortex and the adjacent white matter and empty into the dural venous sinuses. The deep cerebral veins drain blood in a centripetal direction from the deep white matter, the basal ganglia, and the diencephalon toward the lateral ventricles. Large subependymal veins empty into the internal cerebral and basal veins, which unite and contribute to the formation of the great cerebral vein also known as the “vein of Galen.” The cerebral venous system is also exceptional in that these vessels are endowed with arachnoid villae, which allow cerebrospinal fluid and various metabolites to drain into the systemic circulation.
The basic pattern of blood supply to the spinal cord consists of three longitudinal trunks, as follows: 1. The ventral spinal artery that lies in the ventral fissure of the spinal cord, and gives rise to the vertical arteries that pass through the center of the cord and supply most of the gray matter 2. Two dorsolateral spinal arteries that run along the dorsolateral aspect of the cord A network of irregular anastomosing arteries connects the ventral spinal and dorsolateral arteries. The dorsolateral arteries and their anastomosing branches give rise to radial arteries that supply both gray and white matter in the spinal cord. Each body segment has paired spinal arteries that give rise to a dorsal root artery and a ventral root artery, which follow the nerve connections on each side of the cord. These arteries feed into a spinal arterial ring that surrounds the cord at the level of each intervertebral foramen. The venous architecture of the spinal cord is considerably more variable than the corresponding arterial distribution, and the blood vessels are more tortuous. There
ACA MCA PCA Watershed zone
■
Figure 41–3. The cerebral arterial boundary zones in man. (From Edvinsson L, McCulloch J, MacKenzie ET: General and comparative anatomy of the cerebral circulation. In Edvinsson L, MacKenzie ET, McCulloch J, et al, eds: Cerebral Blood Flow and Metabolism. New York: Raven Press, 1993.)
chapter 41 anatomy and physiology of cerebral and spinal cord circulation
543
Superior sagittal sinus Inferior sagittal sinus
Great anastomotic vein of Trolard
Great vein of Galen
Internal cerebral vein Basal vein
Straight sinus Intercavernous sinus Torcular Herophili Right sinus
Cavernous sinus Basilar plexus Pterygoid plexus
Occipital sinus Anastomotic vein of Labbé External jugular vein
Inferior petrosal sinus Superior petrosal sinus
Internal jugular vein Common facial vein ■
Figure 41–4. The brain venous system. (From Sokoloff L: Anatomy of the cerebral circulation. In Welch KMA, Caplan LR, Reis DJ, et al, eds: Primer on Cerebrovascular Diseases. New York: Academic Press, 1997.)
tends to be a prominent midline vein that in general follows the course of the posterior median sulcus. Otherwise, the veins follow the same pattern as the intrinsic, radial, and segmental arteries (for details, see Shamji et al5).
Microcirculation The main arteries enter the subarachnoid space and divide many times before penetrating the substance of the brain to form smaller arterioles and capillaries. The smallest pial arteries enter the brain parenchyma at a right angle to the surface of the brain. These pial arteries are formed by endothelial and smooth muscle cell layers as well as an outer layer of cells, termed the adventitia, which contains collagen, fibroblasts, and perivascular nerves. The penetrating arterioles are surrounded by an invagination of the pia matter, creating a perivascular space (Virchow-Robin space) that is contiguous with the subarachnoid space. As the arterioles penetrate deeper into the brain, this space disappears and the vascular basement membrane comes into direct contact with the astrocytic end-feet (intracerebral arterioles and capillaries). Capillaries are formed by one layer of endothelial cells and show a marked heterogeneous distribution that is correlated with synaptic density and local energy metabolism.6,7 In most regions of the brain, endothelial cells are unique in that they lack fenestrations and are interconnected by specific intercellular junctions, known as tight junctions. These morphological features, in conjunction with metabolic activity that is essentially limited to cerebral endothelial cells, constitute the blood-brain barrier that excludes large molecules, neurotransmitters, and toxins by both forming a physical barrier and lacking the typical transport mechanisms that operate in blood vessels most in other regions of the body. It should be emphasized, however, that the endothelial cell is more than the anatomical interface between
cerebrovascular muscle and the blood; it plays an important functional role in the regulation of cerebral blood flow.8 Indeed, the cerebrovascular endothelium is able to produce a variety of vasodilatatory and constrictory agents. Intraparenchymal blood vessels are almost completely ensheathed by astrocyte processes. Recent reports indicate that astrocytes are involved in local regulation of blood supply in response to neuronal activation.9,10 In the central nervous system, pericytes are found and are closely apposed to the abluminal surface of the capillaries of which they cover, on average, 25%. The function of pericytes is not well known, but some studies suggest that they may influence the diameter of capillaries because they display contractile properties.11 One distinguishing feature of the cerebrovascular bed is the presence of a rich and complex innervation.12 Large intracranial and pial vessels are densely innervated by perivascular nerves that originate from autonomic and sensory ganglia (extrinsic innervation) and contain many agents that can potentially modify vascular tone. Intracerebral arterioles and capillaries are contacted by neural processes that originate from local interneurons or from central pathways (intrinsic innervation). These processes also contain many vasoactive substances. These neurally produced transmitters and modulators are likely to participate in the control of the microvascular tone and, thereby, local cerebral blood flow.
Physiology of the Cerebral Circulation Pressure-Flow Relationships If the cerebral vascular bed was a system of nondistensible pipes, cerebral blood flow (F) would be, according to Ohm’s law, a simple function derived from the perfusion pressure (the difference between arterial inflow and downstream pressure ΔP)
IX
C e r e b r o va s c u l a r D i s e a s e
divided by the resistance to flow along these pipes (F = ΔP/R). Resistance to flow is determined by the caliber of the vascular segment, its length, and the nature of the fluid that flows along it. By analogy to Poiseuille’s equation that applies to a rigid system of tubing perfused by a newtonian fluid: F=
p r 4 ⋅ ΔP 8hL
where F is flow, r is vascular radius, ΔP is the pressure gradient between inflow and outflow, η is viscosity, and L is length. Although this equation cannot be totally applicable to the cerebrovascular bed, because it is not a rigid system, its effective length is not known, and blood is a non-newtonian fluid, Poiseuille’s law can reasonably describe the fundamental relationships between cerebral blood flow, perfusion pressure, and resistance. Of great interest, this equation emphasizes that cerebral blood flow is related to the fourth power of vessel radius; thus even minor changes in arterial diameter have a significant impact on cerebral blood flow. Cerebral perfusion pressure is the difference between intraarterial pressure where the vessels enter the subarachnoid space and pressure in the thin-walled veins in the subarachnoid space. Venous pressure changes in parallel to intracranial pressure and is normally 2 to 5 mm Hg higher than intracranial pressure. Under physiological conditions, the intracranial pressure is determined by the volume of three compartments: brain parenchyma, quantity of cerebrospinal fluid, and intravascular blood pool. Because of the rigidity of the cranium, increases in the size of one component of the intracranial contents must be accompanied by removal of an equivalent amount of another otherwise intracranial pressure will increase.13
Cerebral Autoregulation Autoregulation of blood flow is a regulatory mechanism that allows blood flow in a vascular bed to remain relatively constant during variations of arterial pressure. This is particularly well developed in the brain and plays an important protective role against the danger of hypoxia at low perfusion pressure and the risk of brain edema at higher arterial pressure. Indeed, in normotensive humans, cerebral blood flow remains relatively but not absolutely constant over a range of perfusion pressures (approximately 60 to 160 mm Hg) (Fig. 41–5). These two values determine the lower and the upper limits of autoregulation, respectively. The relative constancy of cerebral blood flow during autoregulation is due to the variations of cerebrovascular resistance (Fig. 41–6). Once the limits of autoregulation are reached, cerebral blood flow increases or decreases passively with concomitant increases or decreases in perfusion pressure (see Fig. 41–5). Nonetheless, it should be emphasized that the lower limit of autoregulation does not correspond to maximal vasodilatation because cerebral resistance arteries continue to dilate to some degree below that limit.14 When perfusion pressure decreases below the lower limit of autoregulation, cerebral blood flow decreases in parallel. However, the brain oxygen metabolism remains essentially unaffected because of an increase in oxygen extraction fraction from blood. In this stage, qualified as oligemia, no clinical symptoms of functional disruption are observed. However, further decreases in cerebral perfusion pressure further compromise cerebral blood flow, and so when the oxygen extraction fraction reaches the limit of 100% it becomes insufficient to satisfy the metabolic demands
200
200
100
Diameter
100
100 Flow
50
Autoregulatory plateau
0 0 ■
100
50 100 150 Arterial pessure (mm Hg)
50 0 200
Cerebral blood flow (% control)
Section
Arterial diameter (% control)
544
Figure 41–5. Schematic representation of the autoregulation of cerebral blood flow. (From Chillon JM, Baumbach GL: Autoregulation of cerebral blood flow. In Welch KMA, Caplan LR, Reis DJ, et al, eds: Primer on Cerebrovascular Diseases. New York: Academic Press, 1997.)
of the cerebral tissues. This stage, defined as ischemia, results in functional disturbance and, depending on its duration, neuronal death may occur.15,16 When mean arterial pressure increases above the upper limit of autoregulation, resistance arteries in the brain cannot sustain vasoconstriction. An early sign is the appearance of the ‘‘sausage string’’ phenomenon characterized by an alternating pattern of dilated arterial segments with focal regions of constriction. The dilated segments represent regions of passive dilatation, and the constricted segments, regions of sustained autoregulation. Further increases in cerebral perfusion pressure result in general arteriolar dilatation and cerebral blood flow increases passively. This is accompanied by damage to the cerebrovascular endothelium and disruption of the blood-brain barrier, which leads to extravasation of plasma proteins through the vessel wall and subsequent edema.14 The limits of autoregulation are not fixed but vary with physiological stimuli and in disease states. Activation of the sympathetic nerves results in upward shift of both the lower and upper limits of autoregulation—a potentially protective response because acute elevations in arterial pressure are usually accompanied by sympathetic activation. The autoregulatory plateau is shifted to higher values in patients with chronic hypertension. This protective response can have deleterious effects if there is significant hypotension, when symptoms of ischemia may occur at a relatively higher arterial pressure.14 The mechanisms underlying cerebral blood flow autoregulation are not definitively understood. Three classic hypotheses involve neurogenic, myogenic, and metabolic factors. According to the myogenic hypothesis, smooth muscle in the resistance arteries directly contracts or relaxes in response to increases or decreases in perfusion pressure respectively. The rapidity of the autoregulatory response supports a myogenic hypothesis.17 Autoregulation is preserved in animals that have undergone sympathetic and parasympathetic denervation, suggesting that this factor is not of primary importance. Autonomic nerves, however, may play a role by modulating autoregulation. Indeed, it has been shown that sympathetic stimulation or parasympathetic denervation results in a shift of the lower autoregulatory limit toward higher levels of blood pressure.14,18 The metabolic hypothesis states that reductions in cerebral blood flow stimulate the release of vasoactive sub-
chapter 41 anatomy and physiology of cerebral and spinal cord circulation ■
Astrocyte Presynaptic neuron
Glutamate
Glu
Ca2+
545
Figure 41–6. Schematic representation of potential mechanisms of neuronal activitymediated cerebrovascular dilatation. AA, arachidonic acid; COX, cyclooxygenase; EETs, epoxyeicosatrienoic acids; Glu, glutamate; mGluR, metabotropic glutamate receptor; NOS, nitric oxide synthase; PGs, prostaglandins; P450, cytochrome P450 epoxygenase. (Modified from Anderson CM, Nedergaard M: Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 2003; 26:340-344.)
AA Glu
Glu
mGluR
P450 COX
K+
EETs PGs Ca2+ K+
Postsynaptic neuron
NOS COX
NO PGs K+,H+ Lactate Adenosine
stances from the brain, which in turn stimulates the dilatation of cerebral resistance arteries. Several candidates for this role have been proposed—including carbon dioxide, hydrogen ions, oxygen, adenosine, potassium, and calcium—but no definitive role has been demonstrated for any of these.19
Neurogenic Regulation of the Cerebral Circulation As mentioned, cerebral vessels are endowed with a dense and complex innervation that originates from the autonomic nerves (sympathetic, parasympathetic, and sensory nerves) as well as from intracerebral neurons. This innervation involves a variety of transmitters of different chemical natures, which have potent vascular actions (Table 41–1). The role and influence of the perivascular nerves on cerebral blood flow regulation have been the subject of considerable controversy. The description of their actions is beyond the scope of this chapter; the reader can refer to published reviews.20 Here, we briefly illustrate the concepts by taking the cholinergic system as an example. Morphological and functional evidence exists to support a role of cholinergic neurons in the regulation of local cerebral blood flow. Major cerebral arteries and small pial vessels are innervated by parasympathetic cholinergic nerves that originate mainly from the sphenopalatine and the otic ganglia. However, vessels located within the cerebral cortex mainly receive projections from cholinergic neurons located in the basal forebrain.21 Electrical or chemical stimulation of these
Arteriole
intrinsic cholinergic neurons has been shown to induce a marked vasodilatation and subsequently a cerebral blood flow increase in the cerebral cortex. These vascular effects are reduced by the administration of atropine, an antagonist of muscarinic receptors, and potentiated by the administration of physostigmine, an inhibitor of acetylcholine esterase—findings that support the involvement of acetylcholine in neurovascular regulation.22 Moreover, Vaucher and colleagues23 demonstrated T A B L E 41–1. Vasoactive Transmitters Implicated in Neurovascular Regulation Transmitters Norepinephrine Acetylcholine Serotonin Dopamine Nitric oxide Vasoactive intestinal peptide Neuropeptide Y Pituitary adenylate cyclase–activating polypeptide Substance P Calcitonin gene–related peptide Neurokinin A
Effect of Stimulation on Cerebral Blood Flow − + +/− + + + − + + + +
+, −, and +/− indicate increase, decrease, and both increase and decrease in cerebral blood flow, respectively.
546
Section
IX
C e r e b r o va s c u l a r D i s e a s e
that the vasodilatation induced by stimulation of cholinergic neurons of the basal forebrain was not accompanied by any change in brain metabolism. Overall, these studies indicate that the changes in perfusion cannot be attributed to increased metabolic activity but rather to a direct action of cholinergic neurons on cerebral blood vessels. Another argument to support the involvement of the cholinergic system in the regulation of intraparenchymal vessels is that lesions of the basal forebrain result in considerable reduction of cerebral blood flow in the cerebral cortex.24 Nonetheless, the significance of the cholinergic system in the regulation of local blood flow in response to cerebral activation is not fully investigated.22 Apart from the direct innervation of cerebral vessels, a neurogenic control of blood flow can also be produced by stimulation of neurotransmitter receptors. As an example, activation of glutamate receptors induces vasodilatation and increase of cerebral blood flow. These effects are mediated by vasoactive factors whose synthesis is triggered by the changes in intracellular Ca2+ associated with the activation of glutamatergic receptors. The increase in Ca2+ activates Ca2+-dependent enzymes that produce potent vasodilators such as nitric oxide and certain arachidonic acid products (see Fig. 41–6).25 A glutamate-induced Ca2+ increase activates the neuronal isoform of nitric oxide synthase (nNOS), which produces nitric oxide. The vasodilatation produced by the topical application of N-methyl-D-aspartate or glutamate is reduced by nNOS inhibitors. Moreover, the cortical cerebral blood flow increase induced by sensory stimulation is generally associated with nitric oxide release and is attenuated by nNOS inhibitors.25 These findings indicate an important role for nitric oxide in the mechanisms of vasodilatation seen during functional activation. An increase in intracellular Ca2+ evoked by glutamate also activates phospholipase A2, leading to production of arachidonic acid. Arachidonic acid is then metabolized by the cyclooxygenase (COX) pathway, producing vasodilatatory prostaglandins. Functionally, the cerebral blood flow increase evoked by somatosensory stimulation is attenuated by COX-2 inhibitors or in COX-2–null mice, whereas COX-1 does not participate in this response.26 The COX-2 metabolites responsible for vasodilatation are likely to involve vasodilatatory prostaglandins. Other arachidonic acid products involved in functional hyperemia include metabolites of the P450 pathway, such as epoxyeicosatrienoic acids.10,27 There is a growing body of evidence to show that neurovascular regulation of cerebral vessels implicates not only neurons but also glial cells.10,25 Zonta and associates28 showed, through the use of brain slices, that neuronal activation induces glutamate release, which activates metabotropic glutamate receptors located on cortical astrocytes, leading to increases in Ca2+ concentrations in perivascular end-feet, which in turn cause arteriolar dilatation by release of vasoactive cyclooxygenase products (see Fig. 41–6). Similar results were obtained in studies performed in mice using in vivo imaging, further supporting the pivotal role of astrocytes in cerebral blood flow regulation in response to neuronal synaptic activity.29
Metabolic Regulation of the Cerebral Circulation According to the metabolic hypothesis of regulation of blood flow, neurons release products of neuronal activity that diffuse
to the vasculature and result in vasodilatation. This concept of coupling was introduced in a seminal paper by Roy and Sherrington in 1890,30 in which they proposed that “the chemical products of cerebral metabolism . . . can cause variations of the caliber of the cerebral vessels.” Several factors have been implicated in this type of regulation, including vasoactive ions (K+ and H+), CO2, lactate, and adenosine (see Fig. 41–6). It could well be that the co-release of two or several factors is necessary to meaningfully effect changes in cerebrovascular tone.
Potassium Potassium ions are released by the extracellular ionic currents induced by action potentials and synaptic transmission. It is well known that increases in extracellular K+ up to 10 mM cause dilatation of arterioles both in vitro and in vivo.31,32 This effect is mediated by the opening of K+ channels on the membrane of arterial smooth muscle cells, leading to their hyperpolarization and subsequent relaxation.8
Carbon Dioxide The effect of carbon dioxide on the cerebral vasculature is one of the most pronounced and reproduced phenomena observed in the cerebral circulation. Hypercapnia causes cerebral vasodilatation with a cerebral blood flow increase and hypocapnia causes cerebral vasoconstriction with a cerebral blood flow decrease. In humans, 5% CO2 inhalation raises cerebral blood flow by approximately 50%, and 7% CO2, by 100%.33 It is not the CO2 tension per se that is responsible for the flow changes but the accompanying shift in perivascular pH. Increases of arteriolar CO2 tension in the cerebrospinal fluid do not affect pial arteriolar caliber unless acidification of the milieu occurs.34 Other mediators, such as prostaglandins and nitric oxide, have been shown to modify cerebral blood flow responses to increased CO2 tension.35,36
Adenosine Several published studies indicate that adenosine, a purinergic nucleoside, is one of the major regulators of the cerebral circulation.37 In general, administration of exogenous adenosine potently relaxes cerebral arterioles and arteries with a subsequent increase in cerebral blood flow.37 Adenosine concentrations are rapidly elevated in response to a number of stimuli known to increase cerebral blood flow, such as hypoxia, hypotension, seizures, and neuronal activation. Theophylline, an antagonist of adenosine receptors, blocks the hyperemia observed during cerebral activation, findings that implicate adenosine, which can be produced during adenosine triphosphate catabolism, in the coupling between brain metabolism and blood flow.38
Endothelial Regulation One of the major mechanisms involved in the regulation of cerebrovascular tone implicates endothelial factors. Indeed, more than simply a physical barrier, endothelial cells play a critical role in the regulation of brain perfusion through the production and release of potent relaxing and contracting factors that regulate the tone of underlying vascular muscle in
chapter 41 anatomy and physiology of cerebral and spinal cord circulation Endothelial cells
PGI2 NO PGE2 EDHF
Relaxation
PGF2α ET-1 TXA2
Constriction
Vascular smooth muscle cells ■
Figure 41–7. Endothelium-derived factors that affect vascular smooth muscle tone. NO, nitric oxide, EDHF, endothelium-derived hyperpolarizing factor, PGI2, prostaglandin I2, PGE2, prostaglandin E2, ET-1, endothelin-1, TXA2, thromboxane A2, PGF2α, prostaglandin F2α.
response to chemical and mechanical stimuli. These factors include nitric oxide, endothelium-derived hyperpolarizing factors, certain eicosanoids, and endothelin-18,39 (see Fig. 41–7). In this section, we discuss briefly the involvement of nitric oxide and eicosanoids.
Nitric Oxide Nitric oxide, a molecular messenger synthesized by NOS, is involved in a wide variety of biological processes. There are three isoforms of NOS: nNOS, inducible (iNOS), and endothelial (eNOS). In endothelial cells, eNOS is constitutively expressed and requires an elevation of intracellular calcium concentration for activation. The multitude of nitric oxide sources and the lack of specific inhibitors of eNOS have rendered difficult the definition of the relative involvement of neuronal and endothelial nitric oxide in the regulation of vascular tone. Under basal conditions, tonic release of nitric oxide is a significant regulator of resting cerebral blood flow. Accordingly, NOS inhibition constricts cerebral arteries both in vitro and in vivo and decreases cerebral blood flow.8,39 Nitric oxide generated by eNOS diffuses from the endothelium to the smooth muscle where it binds to and stimulates soluble guanylate cyclase resulting in relaxation of smooth muscle. Reductions of cerebral blood flow in response to N-nitro-L-arginine, a nonselective NOS inhibitor, are absent in mice that are deficient in expression of the gene for eNOS, suggesting that endothelium is the primary source of nitric oxide that influences basal tone.40 Nitric oxide has also been shown to play an essential role in cerebral vasodilatation induced by shear stress, acetylcholine, bradykinin, and other humoral agents.8
Eicosanoids Eicosanoids are a diverse group of substances derived from arachidonic acid, which is metabolized via three general path-
547
ways that involve cyclooxygenases (COX), lipooxygenases, and cytochrome P450 monooxygenases.41 These various eicosanoids can either promote vasodilatation or vasoconstriction. The eicosanoids are synthesized in a variety of cellular types, including neurons, astrocytes, and endothelial cells. As discussed, certain eicosanoids, released by astrocytes, have been implicated in the hyperemia associated with neuronal activation. Among the various eicosanoids, those produced by the COX pathway, namely prostaglandins and thromboxanes, are the most extensively studied. Prostaglandin I2, prostaglandin E2, and prostaglandin D2 are vasodilators, whereas prostaglandin F2α and thromboxane A2 mediate vasoconstriction.41 In contrast to the complex effects of the prostaglandins on the cerebral circulation, the cyclooxygenase inhibitor, indomethacin, consistently decreases cerebral blood flow in basal conditions and in response to certain stimuli such as hypercapnia.35,42 Prostaglandin I2 and stable prostaglandin I2 analogs produce relaxation of cerebral arteries in vitro and cerebral arterioles in vivo8 (see Fig. 41–7). After synthesis, PGI2 diffuses to the smooth muscle, where it activates adenylate cyclase through G protein–coupled receptors, increasing cyclic adenosine monophosphate and protein kinase A activity. The activation of protein kinase A causes K+ channels to open and produces smooth muscle hyperpolarization.43,44 Under normal conditions, prostaglandin I2 is the primary prostaglandin produced by the endothelium and is thought to play an important role in regulation of blood flow in response to intraluminal pressure, shear stress, and humoral agents.41 However, the relative contributions of prostaglandin I2 and the other prostaglandins to cerebrovascular tone are not well known and may vary as a function of age, species, vessel size, and external stimulation. These prostaglandins also show complex interactions with other endothelium-derived factors such as nitric oxide. Overall, it is clear that the cerebral circulation is subject to complex and fine regulation. This regulation should and cannot be conveniently subdivided according to the effects of independent factors such as metabolic and neurogenic regulation. Regulation is rather multifactorial and results from several factors of different nature produced by various cellular types in the brain.
K E Y
P O I N T S
●
The brain is a complex and heterogeneous organ that is critically dependent on its blood supply. Compared with the peripheral circulations, the cerebral circulation has unique anatomical and functional features.
●
Autoregulation in the cerebral circulation is a crucial mechanism that protects the brain against the dangers of hypoxia at low arterial pressure and against the risks of brain edema at high perfusion pressure.
●
The regulation of the cerebral circulation in response to functional activation or to other stimuli is likely to be mediated by a myriad of vasoactive factors that derive from neurons, glia, and cerebral blood vessels, acting as an integrated unit.
548
Section
IX
C e r e b r o va s c u l a r D i s e a s e
Suggested Reading Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002. Faraci FM, Heistad DD: Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 1998; 78:53-97. Iadecola C: Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 2004; 5:347-360.
References 1. Liebeskind DS: Collateral circulation. Stroke 2003; 34:22792284. 2. Alpers BG, Berry RG, Paddison RM: Anatomical studies in the circle of Willis in normal brains. Arch Neurol Psychiatry 1959; 81:409-418. 3. Edvinsson L, MacKenzie ET: General and comparative anatomy of the cerebral circulation. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002, pp 3-29. 4. Capra NF, Kapp JP: Anatomic and physiologic aspects of the venous system. In Wood JH, ed: Cerebral Blood Flow: Physiologic and Clinical Aspects. New York: McGraw-Hill Book Company, 1987, pp 37-58. 5. Shamji MF, Maziak DE, Shamji FM, et al: Circulation of the spinal cord: an important consideration for thoracic surgeons. Ann Thorac Surg. 2003; 176:315-321. 6. Dunning HS, Wolff HG: The relative vascularity of various parts of the central and peripheral nervous system of the cat and its relation to function. J Comp Neurol 1937; 67:433-450. 7. Sokoloff L, Reivich M, Kennedy C, et al: The (14C)-deoxyglucose method for measurement of local cerebral glucose utilisation: theory, procedure, and normal values in the conscious and anesthetised albino rat. J Neurochem 1977; 28:897-916. 8. Faraci FM, Heistad DD: Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 1998; 78:53-97. 9. Anderson CM, Nedergaard M: Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 2003; 26:340-344. 10. Koehler RC, Gebremedhin D, Harder DR: Role of astrocytes in cerebrovascular regulation. J Appl Physiol. 2006; 100:307-317. 11. Shepro D, Morel NM: Pericyte physiology. FASEB J. 1993; 7:1031-1038. 12. Edvinsson L, Hamel E: Perivascular nerves in brain vessels. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002, pp 43-70. 13. Miller JD, Bell BA: Cerebral blood flow variations with perfusion pressure and metabolism. In Wood JH, ed: Cerebral Blood Flow: Physiologic and Clinical Aspects. New York: McGraw-Hill Book Company, 1987, pp 119-130. 14. Paulson OB, Strandgaard S, Edvinsson L: Cerebral autoregulation. Cerebrovasc Brain Metab Rev. 1990; 2:161-192. 15. Powers WJ: Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol 1991; 29:231-240. 16. Baron JC: Positron tomography in cerebral ischemia. A review. Neuroradiology 1985; 27:509-516. 17. Kontos HA, Wei EP, Navari RM, et al: Responses of cerebral arteries and arterioles to acute hypotension and Hypertension. Am J Physiol 1978; 234:H371-H383. 18. Morita Y, Hardebo JE, Bouskela E: Influence of cerebrovascular parasympathetic nerves on resting cerebral blood flow, spontaneous vasomotion, autoregulation, hypercapnic vasodilation and sympathetic vasoconstriction. J Auton Nerv Syst 1994; 49:S9-S14.
19. Chillon JM, Baumbach GL: Autoregulation: arterial and intracranial pressure. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia, Lippincott, Williams and Wilkins, 2002, pp 395-412. 20. Goadsby PJ, Edvinsson L: Neurovascular control of the cerebral circulation. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia, Lippincott, Williams and Wilkins, 2002, pp 172-190. 21. Dauphin F, MacKenzie ET: Cholinergic and vasoactive intestinal polypeptidergic innervation of the cerebral arteries. Pharmacol Ther 1995; 67:385-417. 22. Hamel E, Lacombe P: Acetylcholine. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia, Lippincott, Williams and Wilkins, 2002, pp 222-247. 23. Vaucher E, Borredon J, Bonvento G, et al: Autoradiographic evidence for flow-metabolism uncoupling during stimulation of the nucleus basalis of Meynert in the conscious rat. J Cereb Blood Flow Metab 1997; 17:686-694. 24. Waite JJ, Holschneider DP, Scremin OU: Selective immunotoxin-induced cholinergic deafferentation alters blood flow distribution in the cerebral cortex. Brain Res 1999; 818:1-11. 25. Iadecola C: Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 2004; 5:347-360. 26. Niwa K, Araki E, Morham SG, et al: Cyclooxygenase 2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci 2000; 20:763-770. 27. Peng X, Carhuapoma JR, Bhardwaj A, et al: Suppression of cortical functional hyperemia to vibrissal stimulation in the rat by epoxygenase inhibitors. Am J Physiol 2002; 283:H2029H2037. 28. Zonta M, Angulo MC, Gobbo S, et al: Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 2003; 6:43-50. 29. Takano T, Tian GF, Peng W, et al: Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 2006; 9:260-267. 30. Roy CS, Sherrington C: On the regulation of the blood supply of the brain. J Physiol 1890; 11:85-108. 31. Kuschinsky W, Wahl M, Bosse O, et al: Perivascular potassium and pH as determinants of local pial arterial diameter in cats. A microapplication study. Circ Res 1972; 31:240-247. 32. Nguyen TS, Winn HR, Janigro D: ATP-sensitive potassium channels may participate in the coupling of neuronal activity and cerebrovascular tone. Am J Physiol 2000; 278:H878H885. 33. Kety SS, Schmidt CF: The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 1948; 27:484-492. 34. Kontos HA, Raper AJ, Patterson JL: Analysis of vasoactivity of local pH, PCO2 and bicarbonate on pial vessels. Stroke 1977; 8:358-360. 35. Pickard JD, Mackenzie ET: Inhibition of prostaglandin synthesis and the response of baboon cerebral circulation to carbon dioxide. Nat New Biol 1973; 245:187-188. 36. Iadecola C: Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci U S A 1992; 89:3913-3916. 37. O’Regan M: Adenosine and the regulation of cerebral blood flow. Neurol Res 2005; 27:175-181. 38. Ko KR, Ngai AC, Winn HR: Role of adenosine in regulation of regional cerebral blood flow in sensory cortex. Am J Physiol 1990; 259:H1703-H1708. 39. Andresen J, Shafi NI, Bryan RM: Endothelial influences on cerebrovascular tone. J Appl Physiol 2006; 100:318-327. 40. Ma J, Meng W, Ayata C, et al: L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice. Am J Physiol 1996; 71:H1717-H1719.
chapter 41 anatomy and physiology of cerebral and spinal cord circulation 41. Busija DW: Prostaglandins and other eicosanoids. In Edvinsson L, Krause DN, eds: Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott, Williams and Wilkins, 2002, pp 325-338. 42. Schumann P, Touzani O, Young AR, et al: Effects of indomethacin on cerebral blood flow and oxygen metabolism: a positron emission tomographic investigation in the anaesthetized baboon. Neurosci Lett 1996; 220:137-141.
549
43. Parkington HC, Coleman HA, Tare M: Prostacyclin and endothelium-dependent hyperpolarization. Pharmacol Res 2004; 49:509-514. 44. Corriu C, Feletou M, Canet E, et al: Endothelium-derived factors and hyperpolarization of the carotid artery of the guinea-pig. Br J Pharmacol 1996; 119:959-964.
CHAPTER
42
ISCHEMIC STROKE: MECHANISMS, EVALUATION, AND TREATMENT ●
●
●
●
Bernardo Liberato and John W. Krakauer
Stroke is a major public health problem. An estimated 500,000 new and 200,000 recurrent strokes occur in the United States annually, and the number of stroke survivors is estimated to be about 4.8 million. Stroke is the leading cause of disability and the third leading cause of death in the United States (after coronary heart disease and cancer) and accounts for a health care cost burden estimated at $53 billion spent in the year 2004.1 Of all cases of stroke, 80% are ischemic and 20% are hemorrhagic (parenchymal and subarachnoid hemorrhages). This chapter focuses exclusively on ischemic stroke, discussing underlying causes, syndromes, acute treatment, and strategies for secondary prevention.
DEFINITION Ischemic stroke is defined as an acute neurological deficit caused by damage to an area in the central nervous system (CNS) as a result of decreased blood flow. The majority of ischemic strokes are arterial in origin, caused by occlusion of a feeding artery by a thromboembolic process. Reduction in tissue perfusion below a certain threshold renders neurons ischemic and dysfunctional, and then, if flow is not restored, the tissue becomes irreversibly damaged (infarction).
TRANSIENT ISCHEMIC ATTACK Transient ischemic attacks (TIAs) have traditionally been distinguished from ischemic stroke on the basis of symptom duration, with the assumption, largely justified, that otherwise the two entities share risk factors and causes and that evaluation findings and secondary prophylaxis are similar for the two. TIA has traditionally been defined as a focal neurological deficit of abrupt onset, referable to a vascular territory, that lasts less than 24 hours. However, the 24-hour definition is arbitrary and is not based on any plausible biological mechanism. In fact, most TIAs resolve in less than an hour. In addition, studies have demonstrated that a significant proportion of clinically defined TIAs are not necessarily transient at the tissue level; there is evidence of tissue infarction on magnetic resonance imaging (MRI) performed early in the course of the syndrome.2,3 Indeed, in view of the advances in neuroimaging and epidemiological studies, a panel of experts has proposed that TIA be defined as a brief episode of neurological dysfunction caused by retinal
or brain ischemia with symptoms lasting less than 1 hour and without evidence of acute infarction on neuroimaging (diffusion-weighted imaging [DWI] or computed tomography [CT] scan).4 When the symptoms and signs do not fit criteria for a TIA—that is, they persist for more than 1 hour and/or there is evidence on neuroimaging of tissue infarction—the syndrome is classified as an ischemic stroke. The modified duration for TIA is of practical benefit, in view of the new time window–dependent strategies for acute stroke management, when a decision for acute intervention should not be contingent on resolution of a patient’s signs and symptoms within 24 hours. However, the neuroimaging component of the proposed new definition is problematic because it sidesteps what is arguably most important about clinically defined TIAs: their reversibility. If symptoms resolve in under an hour but a lesion is identified with DWI, then what is the difference between this entity and ischemic stroke whose symptoms do not resolve? In addition, a definition of TIA based on the absence of a DWI lesion has the odd consequence of eliminating duration as an important distinguishing feature, inasmuch as studies have shown that a substantial proportion of patients with symptoms lasting less than an hour have DWI lesions. Indeed, one DWI study revealed that symptom duration could not distinguish TIA from ischemic stroke.5 Study findings support the contention that it is symptom duration or, more specifically, the rate of symptom reversal from time of onset, that is the essential characteristic of TIA; data indicate that risk of recurrent stroke is substantially higher in patients with rapid recovery than in those with fixed deficits and subsequent slow recovery.6-8 The largest study of risk of recurrent stroke after TIA showed that 50% of all ischemic strokes after TIA occur within 48 hours of the TIA.9 Thus, the presence or absence of lesions on DWI should not be required for a definition of TIA, only that the deficit substantially reverses, not necessarily fully, in less than an hour. This is not to say that DWI does not provide useful information about TIA mechanisms. For example, it has been shown that patients with deficits that reverse in less than 24 hours but who have DWI lesions have the highest risk of in-hospital recurrent stroke. This subgroup may have made up a substantial proportion of the patients in the large study mentioned previously. The critical implication of the spate of studies on TIA is that TIA reflects a more unstable condition than does stroke and merits immediate attention. A TIA is to the brain what
551
552
Section
IX
C e r e b r o va s c u l a r D i s e a s e
unstable angina or non–Q-wave myocardial infarction is to the heart, a condition of fluctuating tissue perfusion that is unstable and threatens tissue viability. TIA should be viewed as a medical emergency that necessitates immediate diagnostic workup and treatment. The clinical seriousness of TIA makes accurate diagnosis very important, but because the symptoms have nearly always resolved by the time the patient is seen by a physician, careful history taking is essential. This can be a challenge because a large number of nonischemic conditions, such as migraine, seizures, and multiple sclerosis, cause transient neurological symptoms. TIAs themselves vary in their mode of presentation, variation attributable primarily to the underlying cause. Different TIA presentations are therefore discussed as follows as they relate to each stroke subtype.
ISCHEMIC STROKE Ischemic strokes usually cause sudden loss of one or more functions as a result of acute damage to specific CNS structures supplied by a particular vessel. However, symptoms can also give patients the sense that something unpleasant, such as vertigo or hiccoughing, has been acquired rather than lost. The presentation can be more or less fulminant and depends on the specific structures involved and the amount of tissue damage. All strokes are ultimately caused by tissue perfusion failure. The brain goes through a series of autoregulatory protective responses as cerebral perfusion pressure (CPP) drops, as a result of either systemic hypotension or a local arterial stenosis, or both. As CPP falls, arterioles dilate to maintain cerebral blood flow (CBF), which results in an increase in cerebral blood volume. When no further vasodilation is possible, CBF becomes passively dependent on CPP, but over a certain range of low CPP, neuronal metabolism (the cerebral metabolic rate of oxygen) can be maintained by increasing the blood oxygen extraction fraction (OEF). OEF is usually about 30% to 40% but can increase to near 100%. Experimental studies in nonhuman animals and observations in patients indicate that there are two critical CBF thresholds. Below the first, 16 to 18 mL/100 g/minute, there is loss of neuronal electrical function (electrical failure). Below the second, 10 to 12 mL/100 g/minute, there is loss of cellular ion homeostasis (membrane failure). The concept of the ischemic penumbra is of central importance to therapeutic approaches to stroke and follows directly from the observation that there are separate CBF thresholds for electrical and membrane failure. The ischemic penumbra is a shell of electrically unexcitable but still viable neuronal tissue surrounding a core of ischemic irreversibly damaged tissue. The ischemic penumbra is in a state of misery perfusion where CBF is reduced, OEF is increased, and cerebral metabolic rate of oxygen is relatively preserved. The therapeutic importance is that a state of misery perfusion cannot be sustained indefinitely, and if CBF is not restored, the tissue proceeds to infarction. In order to salvage penumbral tissue, CBF must be restored in the critical time window between electrical and membrane failure. There is good evidence, obtained mainly with positron emission tomographic (PET) studies,10 that ischemic penumbra exists in human and nonhuman primates and that it remains viable for longer and more variable periods of time than was suggested by initial small mammal experiments. Advances in MRI have made significant inroads in identifying
the ischemic penumbra in patients after stroke and making it a target for therapeutic intervention (see “Stroke Evaluation” section). TIA might represent a form of penumbral phenomenon without an infarct core, and new data on the instability of TIA reflect the high risk of proceeding to infarction in this penumbral tissue.
STROKE CLASSIFICATION BY MECHANISM (STROKE SUBTYPES) Despite the final common pathway for tissue ischemia and infarction, it is important to classify ischemic strokes according to their etiological subtype. This is achieved on the basis of clinical features and results of ancillary tests. Accurate subclassification ensures consistency in terminology for larger registries and clinical trials, and conversely, correct translation to the practice setting of knowledge obtained from clinical trials. Assigning a stroke a subtype designation implies an inference about mechanism and natural history, both crucial for treatment and prognosis. Causes of ischemic strokes are generally subdivided into large-artery atherosclerosis (LAA), penetrating small-artery disease, cardiac embolism, cryptogenic stroke, and strokes of other determined cause such as hypercoagulability, migraine, and cervical artery dissection. These subdivisions are not mutually exclusive in terms of stroke mechanism. For example, atherosclerosis with superimposed thrombus in a large vessel may lead to occlusion of an exiting perforator. Thus, although the underlying cause is LAA, the mechanism of stroke is small-vessel occlusion. Similarly, the mechanisms of stroke in the category of strokes of other determined cause overlap substantially with those of the other four categories, but they nevertheless have unique etiological features that merit individual consideration.
Large-Artery Atherosclerosis This subtype is characterized by evidence for atherosclerosis (anterior or posterior circulation) in the large-vessel vascular distribution of a brain infarction, in the absence of a cardiac source of embolism. The most common location for atherosclerotic changes is at the bifurcation or proximal takeoff of the large vessels, where the shear stress on the wall, from turbulent flow usually related to long-standing hypertension, is maximal. The arterial narrowing can be either extracranial (in the carotid or vertebral arterial system) or intracranial (in the many tributaries of the circle of Willis and their branches). The pattern of parenchymal involvement can be small or large, cortical or subcortical, and is determined largely by the status of pial-pial collaterals and the circle of Willis. There are two other infarction patterns associated with proximal large vessel disease: border zone and watershed. Border zone infarction corresponds to involvement of areas at the junction of the distal fields of two nonanastomosing arterial systems. Watershed infarctions occur at a zone of pial-pial artery anastomoses between two large vessels: for example, the middle cerebral artery (MCA)–posterior cerebral artery (PCA) watershed. There are internal border zones (misleadingly also referred to as internal watersheds) in the centrum semiovale and paraventricular corona radiata, regions at the junction of subcortical and
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment medullary penetrators off the MCA, and in the subinsular zone, a region between small insular penetrating arteries and the lateral lenticulostriate vessels.11 Thus, for example, critical internal carotid artery (ICA) stenosis or occlusion can cause watershed infarction at (1) the boundary of the anterior cerebral artery (ACA) and MCA, manifesting as a thin wedge extending from the anterior horn of the lateral ventricle to the frontal cortex or a string of infarction at the medial convexity surface; (2) the MCA/ACA/PCA boundary, often more difficult to distinguish from MCA branch occlusion, but again appearing as a cortical wedge extending from the occipital horn of the lateral ventricle to parieto-occipital cortex; and (3) a confluent or discontinuous long lesion in the centrum semiovale running parallel to the lateral ventricle. Interpretation of patterns of infarction from large vessel disease is based on assumptions about underlying mechanisms: (1) large-vessel stenosis or occlusion by in situ disease or artery-to-artery embolism and (2) flow-failure distally from a more proximal occlusion or hypotension. However, these mechanisms are likely to coexist. A high-grade ICA or MCA stenosis may be both emboligenic and cause a low-flow state. The low-flow state reduces the chances of clearing small embolic particles from distal arterial beds, leading to a border zone or watershed pattern of infarction.12 In addition to producing cortical , subcortical, and watershed patterns of infarction, LAA can occlude the os of a single penetrating small vessel, causing a lacunar infarct (see later discussion). Thus, the variety of infarct patterns possible with LAA makes diagnosis based on clinical examination or infarct pattern alone difficult. A bruit on examination and the presence of other atherosclerotic risk factors or markers such as hypertension, elevated cholesterol, diabetes, smoking history, peripheral arterial disease, and coronary artery disease, are marginally helpful at best. Indeed, it is debatable whether there is any significant difference in modifiable risk factor profile and predisposition to LAA versus small-vessel disease.13 Information regarding race/ethnicity can be helpful, inasmuch as white persons have a higher incidence of extracranial atherosclerosis, whereas Asian, black, and Hispanic persons have a higher incidence of intracranial atherosclerosis. Interestingly, unlike completed infarction, LAA-associated TIAs do have distinctive features that help make the diagnosis. Intermittent flow-failure through a critical stenosis, often brought on when the patient stands up suddenly or by overly aggressive antihypertensive therapy, can cause focal neurological deficits that reverse when the patient lies down. More rarely, patients manifest a “limb-shaking” TIA, consisting of brief periods of shaking of an extremity brought on by standing or sitting up, easily confused with a focal motor seizure. Another strong clue to LAA is an unstable course in the first 24 hours after stroke onset, manifested by deterioration after improvement.14 Determination of LAA as the underlying cause of a stroke through ancillary testing (see “Stroke Evaluation” section) is important because there is a high rate of early stroke recurrence in this subgroup of patients,15 both for extracranial and intracranial atherosclerosis. This is also true for the long term because patients with symptomatic ICA stenosis with greater than 70% diameter reduction have a stroke recurrence risk of 26% in 2 years.16 The recurrence rate for patients with symptomatic MCA stenosis is about 10% a year.17,18 Because of this relatively high risk of early recurrence and the established benefit of early
553
endarterectomy in long-term stroke prevention for ICA stenosis, identification of this subtype of stroke is critical.19
Small-Vessel Atherosclerosis (Lacunar Strokes) The definition of lacunar infarction has become quite confused. We believe that it should be a combined clinical and radiological diagnosis that is based on a presentation with one of a handful of typical syndromes (see “Lacunar Syndromes” section) and imaging evidence for a small infarct (2 to 20 mm in diameter) in the deep cerebral white matter, basal ganglia, thalamus, or pons. Evidence suggests that in situ single perforator disease is the cause in the majority of cases. Exclusion of LAA and a cardiac source of embolism is important, because lacunar infarction is estimated to originate from emboli or LAA in about 10% to 15% of cases.20 This may be true particularly for patients who have a lacunar syndrome with evidence of multiple subacute lesions on neuroimaging.21 The lacunar hypothesis remains controversial, and some commentators have gone as far as to recommend abolishing the category and substituting it with “small stroke,” assuming the same risk factors and causes as large strokes. This understandable exasperation stems from the tendency to use the term lacune for any small subcortical stroke, with the associated erroneous assumption that all subcortical strokes are caused by in situ small vessel disease. Thus, it should be emphasized that the term should be reserved for the clinicoradiological definition given at the beginning of this section. Subcortical strokes can also arise from occlusion of medullary penetrators that supply the centrum semiovale, from internal border zone infarctions, and from multiple perforator involvement resulting from embolic or intrinsic large-vessel disease (e.g., striatocapsular infarction from MCA stem disease). However, despite these concerns, evidence favors preserving the lacunar infarction stroke category from a pathophysiological standpoint. First, the presence of lacunar infarcts is correlated with leukoaraiosis and with subcortical microhemorrhages.22 These correlations suggest that lacunar infarcts are manifestations of a more diffuse abnormality of small cerebral arterioles.23 Second, the proportion of embolic sources identified in patients with lacunar infarction is lower than that of hemispherical ischemic strokes. Third, after a lacunar infarction, a recurrent stroke is more likely to be lacunar than nonlacunar.23a This would not be expected if lacunar infarcts shared the same mechanism with larger cortical strokes. In addition, the early stroke recurrence rate is lower than those for LAA and cardioembolic stroke. Fourth, in a primate model, only 6% of even the smallest particles injected in the carotid artery ended up in the lenticulostriate vessels.23b The pathology underlying lacunar infarction is still debated, mainly because lacunar infarcts are seldom fatal and cases are thus rarely subjected to autopsy. Nevertheless, it is assumed that lacunar infarction results from occlusion of a small penetrator by atheroma blocking its origin, by embolus, or by an intrinsic process, lipohyalinosis (narrowing the lumen at points along its length). Lenticulostriate pathology after lacunar infarction has been visualized with MRI.24 These images show a linear structure with signal features consistent with perforator occlusion by thrombus or leakage of vessel contents into the surrounding parenchyma. These findings support the idea of a pathological process unique to deep perforating
554
Section
IX
C e r e b r o va s c u l a r D i s e a s e
arteries, which can cause lacunar infarction. Occlusion of the vessel itself might cause infarction, or blood vessel contents might be toxic to surrounding parenchyma. A spectrum of perforator disease with luminal thrombus and leakage of contents into the blood vessel wall and then into the perivascular tissue might explain the previously mentioned correlation among lacunar infarcts, leukoaraiosis, and deep microhemorrhages. In addition, a leakage mechanism might also explain an interesting feature of TIAs associated with lacunar infarction: the “capsular warning syndrome.” This consists of a stuttering cluster of stereotypical events over a period of about 72 hours. These events are brief bursts of typical lacunar phenomena that can come and go over minutes. Many of these patients progress to a fixed deficit; it is possible that the capsular warning syndrome evolves because a single penetrator undergoes occlusion or leakage damages surrounding tissue directly.23
Cardioembolic Strokes Embolism of cardiac origin accounts for about 20% to 40% of ischemic strokes. Atrial fibrillation is the best established cause of cardioembolic stroke, and its identification is extremely important, in view of the relatively high recurrence rates (about 10% a year) and the effective prophylaxis (approximately 60% absolute risk reduction) achieved with chronic oral anticoagulation. Other known emboligenic sources, treated with anticoagulation, are valvular disease (especially prosthetic valves), documented intraventricular thrombus present in severe cardiomyopathies, and recent myocardial infarction. In one study, transesophageal echocardiography (TEE) was used to assess 151 consecutive patients, 1 week after ischemic stroke or TIA.24a Intracardiac thrombus was identified in 26% of the patients (70% in the left atrial appendage). Multivariate analysis showed an association with large stroke, symptomatic coronary artery disease, and evidence for ischemia on electrocardiogram. Interatrial septal abnormalities, such as patent foramen ovale (PFO) and atrial septal aneurysm (ASA), result from failure of the septum to close at birth and occur in about 25% of the general population.24b Interatrial septal abnormalities are thought to be an important cause of embolic stroke in patients younger than 55. A PFO is an intact interatrial connection through the two overlapping septa that form the interatrial septum. An ASA is a hypermobile piece of the atrial septum that can protrude through the PFO into the left atrium during the cardiac cycle. PFOs can serve as a conduit for embolism originating from the venous circulation (lower extremity or pelvic venous thromboses) to the arterial circulation through rightto-left shunting of blood during the cardiac cycle and especially during Valsalva maneuvers. ASAs seem to enhance the stroke risk of a PFO, possibly by directing flow through the PFO or acting as a nidus for thrombus formation itself. A metaanalysis revealed a 24-fold increased risk of stroke in patients younger than 55 who had both a PFO and an ASA, in comparison with a fivefold risk in patients with only a PFO.25 The high frequency of interatrial septal abnormalities in the general population in comparison with the relatively low incidence of stroke in persons younger than 55 suggests that a second factor needs to combine with PFO in order for stroke to occur. Studies have shown increased frequency of two inherited hypercoagulable disorders, the factor V Leiden and the prothrombin 20210 mutations, in young patients with stroke and PFO.25a,25b Thus, perhaps a combination of PFO and an underlying hypercoagu-
lable state, either acquired or inherited, is required in order for a PFO-related stroke to occur. In contrast to patients younger than 55, it does not seem that interatrial septal abnormalities are a substantial stroke risk in older patients, possibly because left-sided atrial pressures increase with aging. In all patients with stroke and PFO, it is important to emphasize the need for a thorough search for the other potential causes of stroke before attributing it to the PFO. Prospective studies have shown that aortic arch atheroma is found more often in patients with stroke and that the presence of aortic arch atheroma, detected by TEE, is associated with increased risk of future stroke. A meta-analysis of these prospective studies gave an odds ratio for recurrent stroke of 3.76, similar in magnitude to those for atrial fibrillation and high-grade carotid stenosis.26 Aortic arch atheroma, occurring with increasing age and in people with vascular risk factors,27 may be just a marker for atherosclerosis. However, a number of observations suggest that aortic arch atheroma causes embolic stroke. First, aortic arch atheroma is often present in patients with stroke but without concomitant carotid disease. Second, stroke risk is highest for atheroma with mobile components. Third, stroke is more common in the presence of aortic arch atheroma than with atheroma in the thoracic aorta.28 Fourth, left hemisphere events are more common than right hemisphere events, and most atheroma is found in the middle to distal arch, after takeoff of the innominate artery.29 Less common sources of embolism from the heart are infectious and noninfectious (marantic) endocarditis, fibroelastoma, air, and atrial myxoma. In addition, there are a number of cardiac abnormalities whose embolic potential remains uncertain but is likely to be low. These include mitral valve prolapse, valvular strands, and mitral annulus calcification. A number of clinical features and radiographic features suggest cardioembolic stroke: (1) sudden onset with rapid progression to maximal focal neurological deficit (<5 minutes); (2) simultaneous or sequential strokes in multiple arterial territories, such as a left homonymous hemianopia and a right hemiparesis; (3) Wernicke’s aphasia (inferior division of the left MCA) and visual field cuts (distal PCA); (4) a large deficit that then rapidly regresses, probably as a result of recanalization of a large proximal vessel; (5) appearance on imaging, especially DWI, of bihemispherical, both anterior and posterior territory, or bilateral or multilevel posterior circulation infarcts (the typical pattern of stroke on MRI is a wedge-shaped lesion with its base at the cortex and the apex located subcortically); (6) hemorrhagic transformation of an ischemic infarct as a result of recanalization and irrigation of infarcted tissue or, less likely, dissection at the site of thrombus impact; and (7) the presence of single or multiple small subcortical infarcts in the absence of cortical infarcts, which makes the diagnosis of embolic stroke less likely.30
Cryptogenic Strokes Despite extensive diagnostic workup, about 40% of all ischemic strokes are secondary to other unknown processes other than atherosclerosis or cardiac embolism. This frequency may be even higher in young patients without the common atherosclerotic risk factors. The patient with cryptogenic stroke lacks a documented cardioembolic source despite investigation with transthoracic echocardiography (TTE) or TEE; does not show evidence of
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment extracranial or intracranial large-artery pathology on ultrasonographic or angiographic studies; and does not have the expected risk factor profile, clinical syndrome, and imaging characteristics for a diagnosis of a lacunar stroke. The neuroimaging features can be variable and may include cortical or subcortical pattern or even the presence of infarcts in multiple arterial territories not explained by a readily identifiable embolic source. It is likely that in the near future, as diagnostic accuracy improves, the overall frequency of diagnosis of cryptogenic strokes will decrease.
Stroke of Other Determined Cause Other determined causes can be found in about 5% of patients with stroke after extensive diagnostic investigation. Causes include arterial dissection (spontaneous or traumatic), migraine, moyamoya disease, inherited or acquired hypercoagulable states, inflammatory vasculopathy (primary or secondary CNS angiitis), hyperviscosity, and vasospasm (secondary to aneurysmal subarachnoid hemorrhage, vasoconstrictive drugs, or pregnancy). Some of these are discussed in more detail as follows. Dissection is a tear in the intima or the media that allows luminal blood to be redirected into a false lumen within the blood vessel wall, with formation of an intramural hematoma, which may limit flow (Fig. 42–1) or cause aneurysmal dilatation. Arterial dissection of the extracranial portions of the carotid and vertebral arteries accounts for only about 2% of all ischemic strokes but for up to 25% of ischemic strokes in patients younger than 55. Cervical artery dissection can occur after clear-cut neck trauma (motor vehicle accidents, attempted
■
Figure 42–1. Lateral angiographic view after right common carotid artery injection, showing occlusion of the right internal carotid artery above its origin in a young woman with fibromuscular dysphasia. This appearance is consistent with an internal carotid artery dissection.
555
strangulation, fall with neck injury), after relatively trivial mobilization of the neck (hair washing, chiropractic manipulation),31 or spontaneously, without any obvious precipitant. The latter two scenarios probably reflect an underlying structural weakness of the arterial wall, inasmuch as dermal connective tissue abnormalities have been detected in up to a third of these cases. Approximately 5% of spontaneous dissections can be attributed to inherited disorders of collagen structure, the most common of which is Ehlers-Danlos syndrome type IV. Others include Marfan’s syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I. In addition, about 5% of patients have a family history of dissection. Approximately 15% of patients have angiographic evidence of fibromuscular dysplasia. Infection, migraine, and elevated homocysteine have also been associated with dissection, but these risk factors have mainly been assessed with casecontrol studies, which are subject to information and selection bias, as well as confounding.32 The extracranial carotid and vertebral arteries are particularly prone to dissection because they are mobile and thus susceptible to injury from bony structures such as the cervical vertebrae or the styloid process. In addition, exposure of the media to blood leads to thrombus formation, which can embolize distally. Carotid dissection usually occurs 1 to 2 cm above the bifurcation and classically manifests with a subset or with all of the following: unilateral facial, retroorbital, or neck pain; partial Horner’s syndrome (facial anhidrosis is not present because facial sweat glands are innervated by sympathetic nerves traveling on the external carotid artery); and cerebral or retinal ischemia at a delay of hours to days. The lower cranial nerves, most often the hypoglossal, can also be affected. Vertebral dissection usually occurs either at the level of the first and second cervical vertebrae or proximally, just before entry into the intervertebral foramen, and classically manifests with posterior neck pain radiating to the occiput and delayed ischemia in the posterior circulation; with posterior inferior cerebellar artery (PICA) territory infarction being most common. There is fairly good evidence of a relationship between migraine and stroke, but proving causality is much more difficult: Does a stroke precipitate a migraine attack in predisposed patients, or does migraine lead to infarction? The truth, as always, is likely to be that both can occur. The best evidence for migraine as a direct cause of stroke is migrainous infarction, defined as a stroke that occurs during a migraine attack, and the deficit is a persistent version of the patient’s typical aura. For example, homonymous hemianopia is a frequent aura in patients with migraine, and the occipital cortex is the most frequent site pf migrainous infarction. Even in this scenario, which is rare, the diagnosis of migrainous infarction should be made only if no other cause of the stroke can be determined. Migrainous infarction tends to occur after prolonged migraine attacks, which suggest that efforts should be made to abort such attacks. In addition to migrainous infarction, migraine with aura is a risk factor in women younger than 45 for stroke occurring outside a period of migraine attack, a risk that is substantially increased by smoking and/or oral contraceptive use. Moyamoya disease occurs in younger patients and is characterized by a progressive intracranial occlusive noninflammatory vasculopathy of the distal ICA and its bifurcation into the middle and anterior cerebral arteries. Its hallmark is the development of deep intracranial collateral vessels, usually in the
556
Section
IX
C e r e b r o va s c u l a r D i s e a s e T A B L E 42–1. Classic Lacunar Syndromes with Vascular Territories and Anatomical Structures Most Commonly Affected Lacunar Syndromes (Structures Affected)
Vessel Distribution
Pure Sensory Syndrome Thalamus
Thalamic perforators
Pure Motor Hemiparesis Basis pontis Posterior limb of internal capsule Cerebral peduncle
Pontine penetrators (basilar branch) Lenticulostriate vessels (MCA branches) Basilar or PCA penetrators
Dysarthria–Clumsy Hand Syndrome Anterior limb or genu of Lenticulostriate vessels (MCA internal capsule branches) Basis pontis Pontine penetrators (basilar branch)
■
Figure 42–2. Lateral angiographic view after internal carotid artery injection, demonstrating occlusion of the proximal middle cerebral artery with dilated lenticulostriate collateral vessels. This appearance is consistent with the moyamoya pattern.
lenticulostriate vessels, giving its peculiar characteristic defined by Japanese investigators as “puff-of-smoke” (Fig. 42–2). Its cause is unclear but does not seem to be an inflammatory process, as in the primary CNS vasculitides. A similar pattern can occur with other conditions such as prior pituitary tumor irradiation, Down syndrome, neurofibromatosis, and sickle cell disease. In these situations, the pattern appears secondary to the underlying condition and is described as moyamoya syndrome rather than moyamoya disease. It should be suspected in young patients with deep hemispherical hemorrhage but without the associated risk factors for intracerebral hemorrhage (ICH) and in young patients with cryptogenic ischemic stroke, especially if one of the commonly associated conditions listed previously is present.
CLINICAL SYNDROMES Lacunar Syndromes There are five classical lacunar syndromes (Table 42–1): pure motor hemiparesis, pure sensory syndrome, sensorimotor syndrome, dysarthria–clumsy hand syndrome, and ataxic hemiparesis. It should be emphasized however, that many additional, albeit rarer, lacunar syndromes almost certainly exist and that nonlacunar subcortical and cortical strokes can cause the classical syndromes.32a For example, an embolus to the rolandic branch of the MCA could affect the primary sensorimotor cortex and cause sensorimotor syndrome. Another example is occlusion of a paramedian pontine penetrator by basilar artery atheroma, causing pure motor hemiparesis. However, studies have shown an excellent positive predictive value of the lacunar syndromes for the presence of lacunar infarction on brain imaging.
Ataxic Hemiparesis Contralateral basis pontis Contralateral thalamus Posterior limb of internal capsule
Pontine penetrators Thalamic penetrators Lenticulostriate branches
Sensorimotor Syndrome Posterior limb of internal capsule and thalamus
Lenticulostriate branches
MCA, middle cerebral artery; PCA, posterior cerebral artery.
The typical clinical presentations of a lacunar stroke reflect the most commonly involved structures: putamen, caudate, thalamus, basis pontis, internal capsule, and corona radiata.
Pure Motor Hemiparesis This is the most common manifestation of a lacunar stroke. In this syndrome, there is motor involvement of the face, arm, and leg, sometimes with more involvement of one than the other, but with absence of sensory, visual, language, or other cortical symptoms. There are often varying degrees of dysarthria and dysphagia, as a result of involvement of corticobulbar tracts. Structures commonly involved in this syndrome reflect the descending course of the corticospinal tract: the corona radiata, the posterior limb of the internal capsule (Fig. 42–3), and the basis pontis. Less often, a midbrain peduncular or medullary pyramidal infarct (with sparing of the face) can also cause this syndrome. The diagnosis of brainstem pure motor hemiparesis requires the absence of all the following: vertigo, deafness, tinnitus, diplopia, nystagmus, and ataxia. Traditionally, it has been taught that isolated monoparesis, usually brachial, is rarely caused by lacunar infarct but instead indicates a cortical or centrum semiovale lesion, regions where the motor homunculus is more spatially separated. However, with the advent of MRI, this has been shown not to be the case. Isolated monoparesis is compatible with small-vessel disease: for example, in the corona radiata and pons.33
Pure Sensory Syndrome Although this is considered the sensory analogue of pure motor hemiparesis, it occurs far less frequently than pure motor hemiparesis. It is usually caused by infarction of the ventro-
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment
557
hand, and leg weakness. The usual stroke locations are the anterior limb or genu of the internal capsule and the basis pontis.
Ataxic Hemiparesis The classic syndrome, caused by basis pontis infarction, was described as limb ataxia ipsilateral to distal leg paresis with minimal or no facial or arm weakness. This diagnosis can be difficult to establish, because limb dysmetria must be out of proportion to the hemiparesis. Other typical locations of infarction are the corona radiata, the anterior or posterior limb of the internal capsule, and the thalamus. The cerebellum has been implicated in some cases. Larger cortical strokes involving the ACA territory may manifest in a similar way, but the more pronounced leg involvement and the many behavioral abnormalities occurring with ACA-distribution strokes may help differentiate the two (see Table 42–1).
Cortical Syndromes ■
Figure 42–3. Diffusion-weighted MR image revealing a lacunar infarction in the posterior limb of the internal capsule on the right.
posteromedial and ventroposterolateral nuclei of the thalamus as a result of involvement of the inferolateral artery off the P2 segment of the PCA, but it can also result from corona radiata infarction through interruption of thalamocortical projections. Both spinothalamic and lemniscal modalities are usually affected, but selective sensory impairment can also occur. Perfect splitting of the midline on sensory testing can be observed, and involvement of midline structures such as tongue and genitalia may also be present. The hemisensory deficits may be complete or incomplete with a cheiro-oral predominance. Some patients may develop a chronic pain syndrome, especially with right thalamic lesions, with pronounced dysesthesias and paresthesias on the side contralateral to the thalamic involvement (Dejerine-Roussy syndrome). This syndrome usually appears in the subacute or chronic period and can be difficult to manage.
Sensorimotor Syndrome This condition is a combination of sensory and motor deficits. Although single penetrator disease can probably cause this syndrome, there have been only a few autopsy studies, and the specificity of this syndrome for a lacunar mechanism is probably lower than for the other four syndromes. Nevertheless, most authors postulate predominant involvement of the thalamus with impingement on the adjacent posterior limb of the internal capsule. An alternative explanation, however, is that both the sensory loss and hemiparesis result from thalamic involvement alone, inasmuch as the inferolateral artery also supplies the ventrolateral nucleus, which projects to motor cortex.34 It is likely that MRI will help to better define the anatomical basis of this syndrome.
Dysarthria–Clumsy Hand Syndrome In this uncommon syndrome, there is a predominance of dysarthria and upper limb ataxia over the other clinical features. Less pronounced findings are mild to moderate facial,
The most commonly encountered clinical syndromes (Table 42–2) are briefly reviewed according to vessel distribution and associated stroke causes.
Anterior Circulation Middle Cerebral Arteries The MCAs account for about 80% of the blood flow to the cerebral hemispheres and are the arteries most commonly involved in hemispherical strokes. Also, because of the key structures supplied by them, they give rise to some of the most florid and dramatic ischemic stroke syndromes found in clinical practice. The mechanisms by which the MCAs can be affected are multiple but most commonly involve either an embolism from a more proximal source such as the heart, aorta, or the large cervical vessels (i.e., cardioembolic and large-artery strokes, progressive intracranial disease from atherosclerosis) or other less common conditions such as sickle cell disease, postirradiation changes, moyamoya syndrome, primary CNS angiitis, and focal intracranial dissection. The location in which embolic material can lodge is variable and includes the proximal MCA stem (usually associated with a more severe syndrome due to involvement of lenticulostriate arteries), its bifurcation (in which case the deep lenticulostriate branches are spared), or at one of the more distal branches beyond the bifurcation (the superior or inferior division and their smaller distal branches). The site of vessel occlusion and the extent of the collateral supply in a given individual determine the amount of tissue damage and therefore the clinical presentation. Individuals with limited collateral supply (from distal branches of the large vessels in the circle of Willis or from extracranial to intracranial anastomoses) are the more severely affected and have the worst prognosis. These patients usually have very large hemispherical strokes affecting the cortical and subcortical territories and are prone to massive hemispherical swelling and subsequent herniation (the “malignant MCA syndrome”).
Middle Cerebral Artery Stem Occlusion The proximal syndrome is usually dramatic and reflects damage to the basal ganglia and internal capsule, supplied by the medial
558
Section
IX
C e r e b r o va s c u l a r D i s e a s e
T A B L E 42–2. Clinical Stroke Syndromes with Corresponding CNS Structures and Arterial Territory Affected Artery Involved Carotid Artery Territory Anterior choroidal artery
Anterior cerebral artery
Middle cerebral artery Stem: lenticulostriate vessels (M1)
CNS Structures Involved
Clinical Syndromes
Etiologies
Posterior limb of internal capsule, medial pallidum, head of caudate, lateral geniculate body, optic radiation, medial temporal lobe Medial upper frontal and parietal lobes, paramedian hemispheres, anterior corpus callosum, anterior limb of internal capsule, anterior putamen, caudate nucleus
Contralateral hemiparesis/hemisensory deficits (face/arm/leg), homonymous hemianopia with sparing of horizontal segment Contralateral weakness (distal leg and shoulder), abulia, mutism, left-hand apraxia (anterior disconnection syndrome), transcortical motor aphasia Frontal release signs, urinary incontinence
Focal atherosclerosis Emboli (cardiac, arterial) Aneurysm surgery (ICA)
Cortical and subcortical frontoparietal hemisphere Corona radiata, striatum, external and internal capsule (posterior limb), lateral temporal lobe
Contralateral hemisensory/motor syndrome (face/arm/leg), global aphasia with dominant hemisphere involvement, visuospatial neglect when non-dominant hemisphere involvement Contralateral gaze paresis, contralateral homonymous hemianopia Obtundation or agitated delirium Contralateral hemisensory/motor syndrome (face and arm more than leg), motor (Broca’s) aphasia with dominant hemisphere involvement, variable visuospatial neglect with nondominant hemisphere involvement Contralateral gaze paresis Hemispatial neglect, hemianopia/ quadrantanopia, sensory (Wernicke’s) aphasia, agitated delirium
Artery-to-artery emboli Cardiac emboli In-situ thrombosis Focal stenosis Intracranial dissection Vasospasm (SAH, drugs)) Moyamoya syndrome
Superior division (M2)
Lateral frontal hemisphere, corona radiata Sparing of structures supplied by lenticulostriate branches (internal capsule, basal ganglia)
Inferior division (M2)
Lateral temporal lobe, lower parietal lobe, angular gyrus
Vertebral Artery Territory Posterior inferior cerebellar artery
Basilar Artery Territory Anterior inferior cerebellar artery
Artery-to-artery embolism Cardiac embolism In situ thrombosis (rare) Vasospasm (SAH, drugs) CNS angiitis
Artery-to-artery emboli Cardiac emboli CNS angiitis Vasospasm (SAH, drugs)
Artery-to-artery emboli Cardiac emboli CNS angiitis Vasospasm (SAH, drugs)
Inferior and posterior aspects of the cerebellar hemispheres, inferior vermis inferior cerebellar peduncle, inferior/ lateral medulla (descending sympathetic tract and spinothalamic tract) Lateral medulla involved more commonly as a result of involvement of intracranial vertebral artery
Ipsilateral Horner’s syndrome when lateral medulla involved Vertigo, nystagmus, ataxia, dysphagia, dysarthria, gaze paresis, lethargy, and coma
Cardiac/arterial emboli Vertebral artery dissection
Anterior and inferior surfaces of cerebellum (flocculus, superior cerebellar lobule), middle cerebellar peduncle, lower lateral pontine tegmentum (trigeminal nuclei and spinothalamic tract)
Vertigo, vomiting, nystagmus Ipsilateral facial anesthesia and weakness Ipsilateral Horner’s syndrome Ipsilateral deafness Contralateral decrease in temperature and pain sensation in limbs Ipsilateral ataxia Lacunar syndromes such as pure motor hemiparesis, ataxia-hemiparesis, dysarthria–clumsy hand syndrome Variable syndrome depending on level involved and cranial nerve affected Vertigo, nystagmus, ipsilateral Horner’s syndrome, contralateral cranial nerve IV palsy, ipsilateral ataxia, ipsilateral tremor/dyskinesia, contralateral decreased sensation to pain/temperature in the trunk
Atherosclerosis Arterial emboli Cardiac emboli
Paramedian and circumferential basilar penetrators
Paramedian/lateral pons and midbrain, including the nuclei of cranial nerves III to VIII
Superior cerebellar artery
Vermis, superior half of cerebellar hemisphere, dentate nucleus, superior cerebellar peduncle, upper pontine tegmentum (descending sympathetic tract and spinothalamic tract)
Lipohyalinosis/ microatheroma
Cardiac emboli Artery-to-artery emboli Atherosclerosis
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment
559
T A B L E 42–2. Clinical Stroke Syndromes with Corresponding CNS Structures and Arterial Territory Affected—cont’d Artery Involved
CNS Structures Involved
Clinical Syndromes
Etiologies
Posterior Cerebral Artery
Mediobasal temporal lobes, occipital lobes Midbrain, thalamus, medial and lateral geniculate bodies (through deep perforating branches)
Contralateral homonymous hemianopsia (macular sparing if purely cortical stroke) If bilateral, Balint’s or cortical blindness with/without Anton’s syndrome (denial of blindness) Dysnomic aphasia with alexia without agraphia (when dominant side involved) Memory disturbance, color dysnomia Agitated delirium Hemisensory deficits with thalamic stroke
Cardiac emboli Artery-to-artery emboli Intracranial atherosclerosis Vasospasm (SAH, drugs) Transtentorial herniation CNS angiitis
CNS, central nervous system; ICA, internal carotid artery; SAH, subarachnoid hemorrhage.
■
Figure 42–4. Diffusion-weighted MR image showing a large right hemispherical infarction from a right middle cerebral artery stem occlusion.
■
Figure 42–5. Angiogram after left internal carotid artery injection. Left middle cerebral artery shows a blockage distal to the origin of the lenticulostriate vessels, predominantly affecting the middle cerebral artery superior division.
and lateral lenticulostriate branches that arise from the dorsal surface of the MCA stem, as well as large areas of cortical infarction in the territories of the superior and inferior divisions of the MCA (Fig. 42–4). The typical patient presents with contralateral hemiplegia with equal involvement of the arm and leg, variable degrees of primary sensory abnormality, dysphagia, and hemianopia. There is forced eye deviation toward the side of the affected hemisphere, sometimes with accompanying ipsilateral head deviation. With dominant hemispherical involvement, there is usually global aphasia, buccofacial apraxia, and ideomotor apraxia. In the first few days there may be frank mutism. With nondominant hemispherical involvement, there is usually contralateral hemineglect, contralateral anosognosia, and delirium. Less frequently, syndromes more often associated with bilateral hemispherical damage, such as prosopagnosia and the reduplicative paramnesias, can be present with unilateral nondominant hemisphere damage.
Individuals with an MCA stem occlusion are the most likely to develop massive hemispherical swelling with midline shift, and subfalcine and transtentorial herniation. The prognosis for these patients is guarded, and in complete MCA-distribution strokes, the mortality rate can be as high as 80% despite neurointensive care efforts.
Middle Cerebral Artery Upper Division Occlusion Isolated involvement is uncommon because the superior trunk is short, but when it occurs, it is usually caused by ICA or MCA atherosclerosis (Fig. 42–5). This division supplies most of the frontal convexity and anterior parietal lobe, and the syndrome resembles stem occlusion with a contralateral hemiparesis, forced eye and head deviation toward the side of the lesion, and
560
Section
IX
C e r e b r o va s c u l a r D i s e a s e
variable degrees of aphasia and hemineglect. In contrast to stem occlusion, motor deficits are characterized by a gradient of weakness with the contralateral side of the face and arm (brachiofacial pattern) more severely affected than the leg, reflecting the involvement of the corresponding cortical structures rather than the internal capsule. A visual field defect is usually absent. With dominant hemispherical involvement, there is language disturbance characterized in the acute phase by global aphasia, which tends to reduce to predominantly Broca’s aphasia and speech apraxia. This highlights the fact that in the acute stroke setting, vascular aphasias are often global and nonclassic in their presentation.35 With nondominant involvement, there may be some degree of visuospatial neglect but usually not as pronounced as with a larger territorial infarct. Acute agitated delirium is usually not present, because this requires infarction of the right middle temporal gyrus and inferior parietal lobule, supplied by the inferior division of the MCA (see later discussion). Because of the smaller volume of tissue infarction, upper-division MCA-distribution strokes do not cause the same high rate of mortality observed with holo-MCA strokes but carry a significant degree of long-term disability that necessitates intensive rehabilitation.
■
Figure 42–6. Diffusion-weighted MR image showing a right parasagittal infarction in the distribution of the right anterior cerebral artery.
Middle Cerebral Artery Lower Division Occlusion This condition is usually caused by cardiac embolism. In this syndrome, hemiparesis and forced eye-head deviation are usually absent, because there is sparing of perirolandic structures. Hemianopia can be present from involvement of the optic radiations, but the most obvious abnormalities are in the domains of language and behavior. With involvement of the dominant hemisphere, a predominantly fluent (sensory or Wernicke’s) or a conduction-type aphasia (inability to repeat spoken language) can be present in isolation, although an initial global aphasia can also be present. When the nondominant hemisphere is affected, behavioral abnormalities predominate with confusion/delirium and mild degrees of visuospatial inattention. Sensory aprosody may also occur in the acute state. The prognosis after such a stroke is relatively good, and the potential for rehabilitation can be greater than for other types of MCA-distribution strokes, because of the smaller territory involved and the absence of significant motor or sensory deficits. There are syndromes associated with occlusion of each of the 12 vessels that branch off the two main MCA trunks. Space precludes description of MCA branch syndromes, but suffice to say that subcomponents of the trunk syndromes are observed and more subtle behavioral abnormalities may be apparent, because they are not obscured by more global abnormalities present with stem and trunk occlusions.
Anterior Cerebral Arteries In comparison with strokes in the MCA distribution, ACAdistribution strokes are uncommon and are most often secondary to embolism from a proximal source such as the carotid artery or the heart. Less frequent causes of an ACA-distribution stroke include vasospasm from a ruptured saccular aneurysm (anterior communicating artery), in which case the strokes may be bilateral, and inflammatory vasculopathy involving the intracranial vessels. The most common manifestations of an
infarct in the distal territory of the ACA are a function of the territories supplied: anterior and medial frontal lobes, including the motor-sensory cortex for the contralateral foot and leg; the supplementary motor area; and the central bladder representation, and also of lesion side36 (Fig. 42–6). Left-sided infarction causes transient akinetic mutism (abulia), transcortical motor aphasia, contralateral leg and shoulder weakness with sparing of the distal upper extremity and face, and contralateral deficits in higher order sensory functions such as stereognosis (ability to discriminate two simultaneous stimuli) and joint-position sense discrimination. Right-sided infarction causes acute confusional state, motor hemineglect, transient akinetic mutism, contralateral hemiparesis, and sensory deficits in the pattern described for leftsided infarction. Predominant leg weakness is not unique to ACA infarction; it is also present with MCA-territory cortical infarction. It can also be present with capsular and pontine infarcts. In general, lesions that affect the medial premotor cortex, the supplementary motor area, and the rear portion of the medial part of the precentral gyrus, or their projections, can cause leg-predominant hemiparesis.37 Bilateral ACA infarction causes persistent akinetic mutism, sphincter dysfunction (urinary more than defecatory incontinence) and paraplegia or tetraplegia. Bilateral ACA strokes can occur when both ACAs originate from the same carotid system, when only one ACA supplies both medial hemispheres (azygous ACA), in vasospasm from subarachnoid hemorrhage, or in the setting of an extrinsic lesion compressing both the ACAs (intraparenchymal hemorrhage, head trauma, subfalcine herniation). In addition to abulia and predominant leg weakness, callosal disconnection syndromes can help distinguish ACA from MCA infarcts. The three main syndromes are left unilateral ideomotor apraxia, agraphia, and tactile anomia. All three syndromes affect the left hand in right-handed patients. Left unilateral
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment ideomotor apraxia, also called the anterior disconnection syndrome, is the inability to perform overlearned skilled movements in response to verbal command. Patients with left-hand agraphia have severely impaired handwriting with their left hands but not their right. Patients with unilateral tactile anomia are unable to name objects placed in their left hands. All three syndromes are probably caused by interruption of transcallosal information to or from the language areas in the left hemisphere. They usually result from infarcts in different regions of the corpus callosum caused by interruption of pericallosal branches of the ACA. However, these syndromes, although of phenomenological interest, are overemphasized, in view of their low frequency of occurrence. They are relatively rare probably because the anterior corpus callosum is supplied by both ACAs. The two to four recurrent arteries of Heubner arise near the junction of the anterior communicating artery and the ACA and supply the inferior part of the head of the caudate nucleus, the adjacent anterior limb of the internal capsule, and the subfrontal white matter. Caudate infarcts cause prominent behavioral abnormalities, including abulia, agitation, aphasia, and hemineglect. Extension of the infarct into the anterior limb of the internal capsule and anterior putamen can lead to dysarthria, movement disorders, and mild hemiparesis. However, the only study to associate symptomatic caudate infarcts with their culprit vascular territory showed that only one infarct was in the territory of Heubner’s arteries; the rest were in the territory of lenticulostriate vessels off the MCA.
Anterior Choroidal Artery The anterior choroidal artery (AChA) is the most distal branch of the ICA, originates just after the origin of the posterior communicating artery, and courses posterolaterally to supply the anterior medial temporal lobe, the optic tract, the geniculate body, the medial globus pallidus, the medial third of the cerebral peduncle, portions of the ventral and pulvinar thalamus, and the posterior limb of the internal capsule. There is controversy over whether the AChA or the lateral lenticulostriate vessels supply the posterior paraventricular region of the corona radiata. The regions most often infarcted are the posterior limb of the internal capsule, the medial globus pallidus, and the lateral geniculate body. As a result, the most common clinical syndrome includes a contralateral hemiparesis and contralateral visual field defect. The visual field defect can consist of a complete homonymous hemianopsia or may manifest with a distinctive feature—sparing of the meridian, called sectoranopsia—a fact explained by the arrangement of the afferent visual fibers as they course through the geniculate ganglia. There can also be variable degrees of hemisensory loss (proprioception is usually spared) from capsular and ventrolateral thalamic involvement. Traditionally, the absence of a higher cognitive deficit in a patient with a hemiparesis and homolateral visual field deficit has been considered suggestive of involvement of the AChA, as opposed to the MCA. However, apraxia, hemineglect, and aphasia have been described with AChA territory infarction. The likely cause of AChA infarction is small-artery focal atherosclerosis secondary to long-standing hypertension and diabetes when the infarct is restricted to the posterior limb of the internal capsule and medial globus pallidus, but
561
more extensive infarcts are probably caused by cardiac or ICA disease.
Internal Carotid Artery When a stroke involves a combination of the syndromes described previously, it can be devastating and probably represents the involvement of the ICA before it branches off into the above divisions. The occlusive process can be extracranial or intracranial and has varied causes. The most common process leading to focal occlusive disease of the ICA is advanced atherosclerosis with progressive narrowing and significant reduction in distal blood flow. As described earlier in this chapter, a focus of atherosclerosis also represents a source of thrombus with potential for distal embolization. Less common processes include extracranial spontaneous or traumatic ICA dissection and postirradiation ICA stenosis. An acute cardiac embolism that lodges at the top of the ICA intracranially, blocking the origins of the ipsilateral MCA and ACA, can also be present and is usually associated with a more sudden dramatic manifestation. The clinical syndrome observed with an acute ICA-distribution stroke is usually a combination of the syndromes described previously with involvement of both MCA and ACA territories. Sometimes, however, the ACA territory is spared in patients with adequate collateral circulation through an intact circle of Willis, where blood is diverted from the other hemisphere through a functional anterior communicating artery. The manifestation is often stepwise, reflecting slow failure of distal collateral vessels as the ICA occlusive process progresses. When the occlusion is total and hemodynamic reserve is no longer sufficient, the patient has a sudden decline and is prone to rapid deterioration from extensive ongoing ischemia and hemispherical swelling. Many times, it is difficult to differentiate an ICA-territory infarction, especially when the onset is abrupt, from embolic MCA strokes. The hallmark of a proximal ICA disease is a history of a preceding TIA, either retinal (transient monocular blindness or amaurosis fugax) or hemispherical. Its presence is strongly suggestive of ICA disease proximal to the origin of the ophthalmic artery and should prompt rapid investigation of the extracranial carotid system. ICA dissection is another possible cause (see Table 42–2).
Posterior Circulation Twenty percent of ischemic events involve areas supplied by the posterior circulation, but they are often incorrectly diagnosed. For example, isolated lightheadedness, syncope, and vertigo are frequently blamed on a posterior circulation process even though it is almost never the cause of these symptoms. Conversely, a patient with multiple stroke risk factors may present with vertigo and gait ataxia resulting from brainstem ischemia, but vestibular neuronitis may be diagnosed. The term vertebrobasilar insufficiency, although popular, is vague with regard to mechanism and should be avoided. Overall, in patients with posterior circulation TIA and minor stroke, the risk of subsequent stroke or death is similar to that in patients presenting with carotid disease, although their risk is probably slightly higher than that of carotid patients in the acute phase. Posterior circulation TIAs carry a higher risk of recurrence than do anterior circulation TIAs.
562
Section
IX
C e r e b r o va s c u l a r D i s e a s e
Vertebrobasilar Territory Strokes Extracranial Vertebral Arteries The extracranial vertebral arteries (ECVAs) are frequently affected by atherosclerosis and this condition is a relatively common cause of posterior circulation strokes. The most common sites for atherosclerosis are at or near their origin from the subclavian arteries, analogous to atherosclerosis at the ICA origin, and at their entry point into the skull. The ECVAs are also susceptible to traumatic or spontaneous dissection (see “Stroke of Other Determined Causes” section). Progressive narrowing at the vertebral artery origin can eventually lead to total occlusion or serve as a nidus for thrombosis and distal embolization. Occlusion of one vertebral artery is usually well tolerated when the contralateral artery is patent and of sufficient caliber. In addition, the ECVA, unlike the ICA, gives off muscular branches and therefore can be reconstituted distally in the setting of origin stenosis. Thus, TIAs and strokes caused by ECVA stenosis result from embolism rather than from flow failure. The most common recipient sites for emboli from the ECVAs are the ipsilateral intracranial vertebral artery (ICVAs) and the top of the basilar artery.
Intracranial Vertebral Arteries The most common site for ICVA atherosclerosis is the distal segment of the artery near the vertebrobasilar junction, after takeoff of the PICA and lateral medullary penetrators. The most common stroke syndrome associated with focal ICVA disease is the lateral medullary syndrome (Wallenberg’s syndrome), and it usually represents involvement of vertebral artery branches directly supplying the lateral medulla. In contrast, involvement of PICA itself usually causes cerebellar rather than medullary infarction and results from cardiac or ECVA embolism. Lateral medullary syndrome manifests with a subset of the following symptoms and signs: vertigo, dysphagia, hoarseness, ipsilateral facial and contralateral trunk and limb thermoanalgesia, ipsilateral oculosympathetic dysfunction, ipsilateral limb ataxia, gait ataxia, nausea, and vomiting. The specific constellation of symptoms depends on the rostrocaudal and horizontal extent of the medullary lesion. Occlusion of the medial PICA branch causes infarction of the dorsal medulla and the inferior cerebellar vermis. Involvement of the lateral PICA branch causes infarction of the posteroinferior cerebellar hemisphere, with truncal ataxia and ipsilateral limb ataxia. Brainstem signs such as vertigo and dysarthria are usually not present. Full PICA territory infarction causes vomiting, gait and ipsilateral limb ataxia, and truncal lateral pulsion. Multidirectional nystagmus may also be present. A full PICA infarction can lead to considerable edema, usually within 24 to 48 hours, with “pseudotumoral” mass effect. This can be rapidly fatal as a result of progressive pontine and medullary compression. Surgical decompression is necessary. Clues to brainstem compression include headache, vomiting, drowsiness, ipsilateral gaze preference, and ipsilateral hemiparesis.
Basilar Artery Branches The basilar artery originates from the confluence of the two vertebral arteries at the pontomedullary junction and represents the main vascular supply to the brainstem and rostral cerebellum. Atherosclerosis is by far the most important pathology of the basilar artery, strokes are usually preceded by TIAs, and
the paramedian pontine base is the most common site of infarction. The main branches off the basilar artery arise in pairs: the anterior inferior cerebellar artery, the superior cerebellar artery, and the PCA. Throughout its course, the basilar artery gives rise to multiple penetrating and circumferential branches that supply the brainstem; it is responsible for the whole blood supply of the pons and much of the distal brainstem. Anterior Inferior Cerebellar Arteries. Infarction in this territory, usually resulting from in situ atherosclerosis unless there is bilateral involvement, is dominated by brainstem (the caudolateral pontine syndrome) rather than cerebellar symptoms. The mid-pons and middle cerebellar peduncle are the areas most often involved. The typical manifestation is ipsilateral peripheral facial weakness, Horner’s syndrome, deafness, limb ataxia, and contralateral hemiparesis with limb and trunk hypesthesia. In very rare cases, and only in patients with diabetes, isolated involvement of the internal auditory artery can manifest with isolated vertigo and/or hearing loss. This is mentioned to emphasize the fact that, apart from this exception, isolated vertigo is almost never caused by ischemic vertebrobasilar disease. Superior Cerebellar Arteries. Traditionally, it was thought that isolated superior cerebellar artery territory infarcts were rare but instead occurred in combination with midbrain, thalamic, and PCA territory infarcts, as a result of embolism to the top of the basilar artery. However, modern MRI suggests that the occurrence of isolated superior cerebellar artery infarcts has been underestimated.38 These infarcts can be small or territorial, both most commonly caused by embolism. The superior cerebellar artery supplies most of the cerebellar cortex, the cerebellar nuclei, and the superior cerebellar peduncle. Superior cerebellar artery infarcts result in a combination of the following signs and symptoms: vertigo and dizziness, nystagmus, limb ataxia, gait ataxia, and mild hemiparesis. Clinical brainstem signs are usually absent. Basilar Artery and Its Penetrators. The posterior wall of the basilar artery gives rise to small paramedian and short circumferential arteries that supply the paramedian and lateral pontine regions. These arteries can be affected by either microatheroma at their origins or lipohyalinosis along their length. These are believed to be distinct pathological processes. Stroke from basilar artery disease is very variable and can range from a mild lacunar stroke, resulting from a small penetrator disease, to a large, devastating syndrome with extensive destruction of the brainstem from complete or almost complete basilar occlusion (Fig. 42–7). Pontine syndromes reflect the particular structures affected, with a basic division between strokes that predominantly affect the anterior pons and those that affect predominantly the pontine tegmentum. Anterior pontine infarctions can manifest as classic lacunar syndromes with pure motor hemiparesis or ataxic hemiparesis/dysarthria– clumsy hand syndrome, as a result of damage to the corticospinal tract and crossing corticopontocerebellar fibers. Strokes that predominantly affect the pontine tegmentum manifest with a constellation of brainstem signs as a result of involvement of the medial lemniscus, the medial longitudinal fasciculus, the cerebellar peduncles, the abducens nucleus, and the vestibular nuclei.
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment
563
A
■
B
Locked-in Syndrome. One of the most devastating conditions in clinical neurology is observed after basilar artery occlusion with extensive infarction of the ventral pons (basis pontis) and is commonly referred to as locked-in syndrome. Because of infarction of key motor structures in the basis pontis (pontine nuclei, corticospinal tract, and corticobulbar tract), the patients present with tetraparesis evolving to tetraplegia, pronounced dysphagia, and anarthria. Extraocular movements are affected, most notably with bilateral gaze paresis, often with preserved vertical gaze. Vertical gaze, as well as normal alert-
Figure 42–7 A, Extensive infarction of brainstem, occipital lobes, temporal lobes, and bilateral thalamus, resulting from acute basilar occlusion. B, Angiographic lateral view in the same patient, demonstrating midbasilar and distal basilar occlusion with distal reconstitution through superficial cerebellar collateral vessels.
ness, is intact because of preservation of the rostral structures in the midbrain and pontine tegmentum, respectively. Blinking may be spared, and in these cases patients can communicate only with vertical eye movements or blinking of the eyes. With a more extensive damage and rostral midbrain involvement, blinking can also be affected, and patients may have bilateral ptosis, a situation difficult to differentiate from a comatose state. The locked-in syndrome usually results from extensive in situ thrombosis of the basilar artery and carries a poor prognosis.
564
Section
IX
C e r e b r o va s c u l a r D i s e a s e
Top-of-the-Basilar Syndrome. When an embolic particle arises either from the heart or from the proximal vertebral arteries, it travels all the way downstream until it lodges in a vessel with a diameter equal to or less than that of the particle size. Because of the relatively large diameter of the basilar artery, this usually occurs at the distal segment, where it gives rise to both superior cerebellar arteries and PCAs and leads to a constellation of signs and symptoms commonly referred to as the “top-of-thebasilar” syndrome. Infarction of the rostral midbrain (tectum, posterior commissure, red nucleus) leads to oculomotor abnormalities such as vertical gaze palsies, convergence retractive nystagmus, bilateral hyperconvergence (“pseudo-sixth” nerve palsy), and eyelid retraction. The involvement of the more caudal midbrain results in damage to the cranial nerve III nucleus and fascicle and is responsible for cranial nerve III palsy with bilateral ptosis, midposition and poorly reactive pupils, and internuclear ophthalmoparesis. Midbrain involvement also includes damage to the ascending reticular activating system with consequent somnolence or stupor. In rare cases, patients may present with vivid, well-formed visual hallucinations after strokes in the distal basilar territory, a phenomenon called peduncular hallucinosis. There exist few pathological studies of the usual location and nature of the lesions causing such a syndrome, but it is thought to occur from rostral midbrain or thalamic involvement. Other structures that can be affected by an embolus to the distal basilar artery include the occipital lobes, medial temporal lobes, and thalami (Fig. 42–8). Their involvement can be either unilateral or bilateral and gives rise to multiple signs or symptoms referable to the involvement of the PCA territory (see next section).39 Posterior Cerebral Arteries. The PCAs are the terminal branches arising from the basilar artery. In about 30% of patients, one PCA arises from the ipsilateral ICA; this is a socalled fetal PCA. Infarcts in the PCA territory are mainly caused by emboli, which is perhaps not surprising because the PCAs are the end territory of the posterior circulation. The first, P1, segment of the PCA courses posteriorly around the midbrain and gives off small branches to the midbrain and medial thalamus before it becomes the P2 segment, which supplies the ventral and lateral thalamus, the occipital lobe, and the medial temporal lobe. The three most prominent symptoms and signs after PCA territory infarction are headache, positive and negative visual field defects, and hemisensory disturbances. The most common visual field abnormality is a hemianopia from infarction of the optic radiations or calcarine cortex. If the field cut is transient, release hallucinations can occur at its edges as it clears. Involvement of the lateral thalamus and surrounding afferent white matter tracts is responsible for hemisensory disturbances, which can range from hemibody tingling to frank hemianesthesia in all sensory modalities. Sometimes the sensory complaints are accompanied by clumsiness and ataxia, also probably attributable to thalamic involvement, whereas dense hemiparesis results from infarction of the cerebral peduncle. In addition to the common symptoms and signs described previously, there are unique neuropsychological deficits in up to 60% of patients with visual field defects. These neuropsychological deficits are hemisphere specific or hemisphere predominant. Some of the neuropsychological deficits are more florid when there is bilateral PCA infarction. Infarction in the
■
Figure 42–8. Computed tomographic scan demonstrating bilateral thalamic strokes secondary to embolization to the top of the basilar artery (“top-of-basilar” syndrome) from a cardiac source.
territory of the left PCA that extends to the splenium of the corpus callosum or to its neighboring parieto-occipital white matter leads to alexia without agraphia. Visual perception is normal in the preserved left hemifield, but the information cannot reach language areas of the left hemisphere. In addition, there is color anomia because color percepts are purely visual and therefore no other sensory modality can be evoked to provide a clue to the left language region. In addition to alexia without agraphia and color anomia, some patients have visual object agnosia. Alexia with agraphia, along with some anomia, occurs with infarcts in the left temporo-occipital junction. Infarction of the left medial temporal lobe can lead to anterograde and retrograde amnesia, which can last months. Presumably, the contralateral hippocampus can take over with time. It follows that permanent anterograde amnesia can result from bilateral PCA infarcts. Prosopagnosia can occur with right inferior occipitotemporal lesions. Other behavioral syndromes associated with right PCA infarction are less specific and probably reflect right parietal syndromes, inasmuch as the PCA sometimes supplies parts of the right posterior parietal lobe. Balint’s syndrome can arise after unilateral or bilateral infarction of the superior parietal lobule at the parietooccipital junction, supplied by the MCA-PCA watershed. The syndrome, also known as optic ataxia, is characterized by defective directional control of visually guided reaching movements, but motor execution is normal when other sensory modalities are used. On-line control is more impaired than feedforward planning, and errors in reaching are variable with no appreciable constant errors. Anton’s syndrome is denial of blindness
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment despite clear physiological evidence for it after bilateral occipital infarction. This syndrome can be accompanied by agitation/delirium, possibly from the decreased visual input or concomitant involvement of the temporal lobes.
STROKE EVALUATION Parenchymal Imaging Critical in the evaluation of a presumed ischemic stroke, especially in the hyperacute period, is assessment of the extent and location of affected brain parenchyma, as well as ruling out stroke mimics such as ICH, subdural hematoma, subarachnoid hemorrhage, and brain tumor. CT scanning of the head should be the first step in such an evaluation, because of its widespread availability and short scanning time. CT scan is still considered the “gold standard” for detecting hyperacute hemorrhage, although one prospective study showed 100% sensitivity for hyperacute ICH with T2* MRI. Besides obvious intraparenchymal hemorrhage, abnormalities on CT scan related to hyperacute stroke, include blurring of the gray-white matter interface, effacement of the sulcal margins, loss of the normal sharp definition between the basal ganglia and surrounding white matter, and effacement of the insular cortex. These abnormalities confirm ischemia as the most likely cause of the acute syndrome and help predict not only the area at risk and ultimate infarct size but also which patients are likely to develop significant brain edema and require more aggressive monitoring in the intensive care unit. The extent of these early changes also has a direct relationship with the risk of symptomatic intracranial hemorrhage from systemic thrombolysis and is predictive of a poor outcome.40,41 In the subacute period, infarcted tissue becomes more evident as one or more clear-cut areas of hypodensity. In the early subacute period, the focus of the evaluation of the CT scan then shifts from the initial diagnostic purpose to the prediction and monitoring of changes compatible with hemorrhagic conversion and cerebral edema with consequent brain herniation. In the late subacute to chronic periods, the CT scan demonstrates progressive gliosis with loss of tissue volume (i.e., encephalomalacia). MRI, increasingly available for the evaluation of ischemic stroke in the acute setting, is more sensitive than CT scanning for detecting acute ischemia and is the only reliable method for detecting ultra-early ischemic changes (<1 hour after stroke onset). Different magnetic resonance sequences are available, each emphasizing different tissue components and different degrees of tissue definition and contrast. The sequences of most utility in the evaluation of patients with stroke are T1-weighted imaging, T2-weighted imaging, fluid-attenuated inversion recovery, DWI, proton density imaging, and gradient-echo imaging, the last being the most sensitive for detection of hemorrhage in all stages of evolution. In the hyperacute evaluation, DWI identifies early ischemic lesions and distinguishes them from old infarcts. Ischemia is characterized by a hyperintense signal, which represents the restricted intracellular diffusion of hydrogen ions, which normally diffuse freely in interstitial fluid but are shifted intracellularly because of cytotoxic edema in the affected area. In humans, DWI is able to detect ischemia as early as 40 minutes after stroke onset and in one study, based on con-
565
firmation at autopsy, had a sensitivity of 88% and a specificity of 96.6%. Abnormalities observed on DWI can be short lived, resolving within 2 weeks of the ischemic insult; this feature is not seen with the other magnetic resonance sequences.42,43 However, hyperintense lesions on DWI do not distinguish reversible from irreversible ischemia, can be observed with other conditions (brain abscess, seizure, acute multiple sclerosis plaque, hypoglycemia, and brain tumors), and may result from T2 decay (T2 shine-through) rather than a diffusion abnormality. T2 shine-through can be ruled out with computation of a directionally averaged diffusion coefficient (ADC). On an ADC map, only ischemia appears dark, indicative of a low ADC. The utility of ADC values to reliably distinguish differing degrees of ischemia—a critical issue, inasmuch as the entire rationale for acute treatment of stroke is to rescue areas of reversible ischemia—is under active investigation but seems questionable. Currently, rather than reliance on differential ADC values, the favored approach with MRI is to identify areas of reduced perfusion beyond the boundaries of the DWI abnormality (see next section).
Vascular Imaging In addition to identification of areas of reversible and irreversible parenchymal injury, it is also necessary to establish whether there is a persistent stenosis or occlusion in an intracranial or extracranial artery that continues to put viable brain tissue at risk and to ascertain the extent of compensation by collateral arteries. Noninvasive tests should be performed first and include duplex Doppler imaging of the extracranial and intracranial circulation, magnetic resonance angiography (MRA), and computed tomographic angiography (CTA). These tests have been extensively studied and have proved valuable and reliable when used by experienced operators. However, these noninvasive methods do not have perfect sensitivity and specificity, and often a combination of two or more of them is necessary to obtain optimal anatomical information.
Duplex Doppler and Transcranial Doppler Imaging The Doppler effect is noted through detection of flow velocity of a moving object, determined by the time between insonation and reflection of ultrasound waves through a given medium. In the case of duplex Doppler study, anatomical imaging is determined through the B-mode gray scale whereas Doppler shift values are determined through the reflection of the ultrasound waves by the moving red blood cells in the extracranial and intracranial vessels. When the intracranial vasculature is studied, both technologies can be used, but the use of Doppler studies, without the anatomical definition provided by the Bmode gray scale, is the most widely available. Duplex study of the extracranial circulation is most useful in the determination of the degree of stenosis of the ICA (Fig. 42–9). This determination is crucial because of the difference in the approach to patients with a recent ischemic stroke related to an ipsilateral ICA stenosis (see later discussion). Analysis of the ECVAs also provides valuable information in patients with posterior circulation strokes. When duplex Doppler imaging is compared with the “gold standard” for anatomical definition (digital subtraction angiog-
566
Section
IX
C e r e b r o va s c u l a r D i s e a s e
raphy), the sensitivity and specificity for hemodynamically significant (>70% diameter narrowing) extracranial ICA stenosis varies between 85% to 90% and 75% to 80%, respectively.44 On the basis of these numbers, the best approach is to combine duplex Doppler study with another noninvasive imaging modality, such as MRA, because both tests, when concordant, have been shown to accurately predict significant extracranial ICA stenosis in more than 90% of the cases.45,46 Nonconcordance most often occurs because ultrasonography and MRA can differ in the degree of stenosis they reveal, with a tendency for MRA to overcall degree of stenosis. Another concern is whether noninvasive techniques can reliably differentiate high-grade stenosis from occlusion, a critical factor in surgical decision making. For example, Doppler imaging might demonstrate total ICA occlusion, whereas, in fact, a string sign is present; conversely, an ascending pharyngeal artery or muscular branch may be mistaken for residual flow through an occluded ICA. In such a situation, conventional angiography, CTA, or gadoliniumenhanced MRA should be considered. Transcranial Doppler (TCD) imaging is used to determine the blood flow velocities of the large and medium-sized intracranial arteries, and indirectly, estimate flow. The approaches used when TCD imaging is performed can be the
transtemporal approach (ACA, MCA, and PCA), the transforaminal approach (vertebrobasilar system), and the transorbital approach (ophthalmic vessels and carotid siphons). Flow velocities can help identify a focal stenosis, proximal occlusion with decreased distal flow, or complete occlusion of one of the three cerebral arteries. TCD imaging is particularly helpful in cases of stenosis of the intracranial arteries, such as those in atherosclerotic or inflammatory vasculopathies, and is a test of proven utility in helping determine the need for exchange transfusion in patients with sickle cell disease. TCD imaging is a valuable tool in the assessment of the intracranial consequences of cervical carotid or vertebral stenosis. Specifically, TCD imaging can detect blunted waveforms and recruitment of collateral pathways (e.g., cross-filling from the anterior communicating artery) (Fig. 42–10). TCD imaging can also provide information on adequacy of collateral flow through the use of vasodilatory challenges such as carbon dioxide inhalation (see later discussion). Also, TCD imaging can be used to monitor the MCAs for evidence of intermittent embolization from a proximal arterial or cardiac (PFO, atrial fibrillation) source (Fig. 42–11).
Computed Tomographic Angiography This technique combines injection of intravenous contrast as a bolus, with high-speed continuous CT scanning of a volume of interest, followed by three-dimensional reconstruction of the extracranial and intracranial vasculature from the original cross-sectional images. CTA is of great potential benefit for evaluation of patients for acute thrombolytic treatment, because these patients must obtain a CT scan anyway to rule out hemorrhage, and CT scanning is still much more available than MRI in the emergency setting. If occlusion and high-grade stenosis of intracranial vessels off the circle of Willis are not identified, perhaps because of spontaneous recanalization, then mobilization of an interventional radiology team may not be justified. CTA has some important limitations, however. First, CTA cannot always reliably distinguish between moderate and highgrade stenosis. This is especially true when mural calcification is present. Second, patients undergoing CTA must ingest an intravenous contrast agent, which can be toxic to the kidneys in patients with preexisting renal insufficiency, dehydration, and poorly controlled diabetes.
■
Figure 42–9. Duplex Doppler image of the extracranial carotid system, demonstrating high-degree stenosis at the origin of the internal carotid artery (ICA). CCA, common carotid artery.
cm/s
24
100 50 0 –50 –100 ■
0
Magnetic Resonance Angiography Like CTA, this is a noninvasive modality to study the intracranial and extracranial circulation. The objective of any MRA
84 cm/s 56 DEPTH MEAN 100 1.17 83 50 PI POWER 0 15 SAMPLE
139 –50 SYS –100
24
0
46 56 DEPTH MEAN 83 POWER
0.76 PI
15 SAMPLE
68 SYS
Figure 42–10. Transcranial Doppler image after bilateral middle cerebral artery insonation, demonstrating blunted waveform on the right in comparison with the left. This appearance is compatible with a proximal internal carotid artery high-grade stenosis.
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment cm/s 120
24
■
50 DEPTH
100 80
59 POWER
60 40
567
Figure 42–11. Transcranial Doppler image after agitated saline injection, demonstrating multiple microembolic signals (MES) compatible with a right-toleft cardiac shunting from a patent foramen ovale (PFO). PI, pulsatility index.
15 SAMPLE
20 0
65 MEAN
–20 –40 –60
1.10 PI
–80 –100 –120 0
technique is to maximize signal coming from the vessel while minimizing background signal. The most popular sequences are two- and three-dimensional time-of-flight (TOF) MRA. TOF MRA is based on flow-related enhancement of blood signal, which allows blood to be differentiated from stationary tissues. The data may be acquired as single slices (two-dimensional) or as a thick slab that is subsequently reconstructed into thin sections (three-dimensional). In the case of three-dimensional imaging, blood flow must be more rapid in order to traverse the whole slab before saturation occurs with attendant loss of signal. Thus, three-dimensional TOF is usually better for vessels in which flow velocity is high (i.e., cervical arteries and the circle of Willis), whereas two-dimensional TOF is better for assessing cerebral veins and sinuses. Phase-contrast MRA is another technique that is time-consuming and has not had much application in the workup of ischemic stroke so far. One scenario in which phase-contrast MRA can be helpful is when an arterial lumen is stenosed by subacute thrombus, which is bright on T1 images. Thus, a TOF MRA might misread a bright vessel as patent when it is in fact occupied by subacute thrombus. This high signal is subtracted out in phase-contrast imaging. TOF MRA is helpful as a screening test for significant (>70% diameter reduction) ICA stenosis because it has comparable sensitivity to digital subtraction angiography. However, TOF images can be contaminated by artifacts in the presence of slow flow or turbulence. This is a problem mainly when slow flow caused by ICA stenosis leads to signal dropout, which is mistaken for very high-grade stenosis or complete ICA occlusion. Therefore, when no ICA stenosis is identified on MRA, no further testing is necessary, but when significant stenosis is detected, imaging with another noninvasive modality should be obtained (duplex Doppler imaging or CTA).46 In the case when MRA suggests complete occlusion, CTA, gadolinium-enhanced three-dimensional MRA, or conventional angiography should be used as confirmatory tests, despite the high sensitivity and specificity of MRA in complete ICA occlusion reported in some studies.47 MRA also has utility in detecting intracranial athero-
117 SYS
stenotic disease but, again, tends to overestimate the degree of stenosis and should be followed by digital subtraction angiography for better spatial definition and determination of whether the lesion is amenable to interventional radiological approaches. Other pathologies detectable by MRA are extracranial dissection, Takayasu’s arteritis, and moyamoya syndrome. MRA is usually followed by digital subtraction angiography when intervention is planned.
Assessing Cerebral Tissue Perfusion As outlined in “Ischemic Stroke”, stroke ultimately results when the metabolic demands of brain tissue outstrip perfusion. Both chronic and acute arterial occlusive disease can lead to a state of reduced tissue perfusion, which can lie along a spectrum from autoregulated to oligemia to ischemic penumbra (misery perfusion). There are a number of scenarios in which determination of a patient’s condition along the perfusion spectrum guides clinical management. Two examples are as follows: (1) A patient with an acute stroke is found to have an M1 occlusion. Identification of penumbral areas beyond the infarct core can help make the decision whether to instigate intra-arterial thrombolytic therapy or mechanical extraction to open the occlusion. (2) A patient is discovered to have a chronic asymptomatic high-grade ICA stenosis or a symptomatic ICA occlusion. In either case, the decision to intervene surgically can be informed by identifying tissue in a state of misery perfusion. A variety of imaging methods are available to address questions about perfusion. PET scans can quantitate CBF, cerebral blood volume, cerebral metabolic rate of oxygen and OEF, but are expensive, not widely available, and require injection of a radioactive tracer. Single photon emission computed tomography (SPECT) can only estimate relative CBF and also requires injection of a radionuclide agent. Neither PET scanning nor SPECT is practical for making decisions in the acute stroke setting, but they nonetheless have a role in decisions about revascularization procedures in patients with chronic occlusive
568
Section
IX
C e r e b r o va s c u l a r D i s e a s e
disease. For example, PET scanning is being used in an ongoing study of extracranial-intracranial bypass surgery in patients with stroke and carotid occlusion (Carotid Occlusion Surgery Study, described later). Xenon CT scanning is another reliable test for quantifying CBF and can be performed at the time of the initial head CT scanning, but the technique has lost ground despite its reliability because of the need for xenon, its intolerance to head motion, and the development of perfusion MRI and CT scanning. Magnetic resonance perfusion-weighted imaging (PWI) involves acquisition of sequential images during intravascular transit of an endogenous contrast agent (arterial spin-labeled protons) or an exogenous contrast agent (gadolinium) in order to analyze areas of hypoperfusion. At the current time, because of several technical considerations, only gadolinium PWI has application in the setting of acute stroke. The raw images obtained during intravascular transit of gadolinium are used to generate images that depict regional variation in several perfusion-related parameters; these include relative cerebral blood volume, relative CBF, and mean transit time. The utility of these measures for guiding therapeutic decisions in the management of acute stroke is under active investigation, but because the goal of acute stroke treatment is to identify viable tissue at risk of imminent infarction, the use of techniques that measure physiological variables rather than minutes and hours, can be expected only to grow (see “Intravenous Thrombolysis Beyond the 3-hour Period”). Identification of misery perfusion resulting from chronic arterial occlusive disease can be accomplished by vasodilatory challenge. The main concept behind these techniques is that the first autoregulatory response to occur in reaction to reduced CPP is arteriolar vasodilation. This means that any additional vasodilatory challenge will elicit a reduced response because the vessels are already partially or completely dilated. The most often used techniques are TCD imaging after CO2 inhalation and SPECT before and after acetazolamide injection. The first test relies on the potent vasodilatory capacity of CO2 and the changes in blood flow velocity observed in normal subjects after the inhalation of 5% CO2. Shortly after the inhalation of this gas, flow velocity increases in normal subjects (about 4% for every 1-mm Hg increase in arterial CO2 tension), defining the normal autoregulatory curve. In patients with an exhausted capacity for vasodilation (present with proximal stenosis or occlusion of the ICA or MCA), such response does not occur, and they are said to have an exhausted compensatory state. Similar information is obtained with SPECT after acetazolamide injection. Because of its potent vasodilatory effects (probably secondary to reduction of the pH in the cerebrospinal fluid), acetazolamide helps determine which areas have a limited ability to vasodilate because they are hypoperfused and already maximally dilated.
Other Laboratory Tests The initial laboratory evaluation of an ischemic stroke patient serves three main purposes: 1. Detection of antecedent pathology that might have directly contributed to the acute stroke: for example, diabetes, hyperlipidemia, hypercoagulability, and hemoglobinopathy. 2. Detection of antecedent pathology with a less well understood but possibly significant role in ischemic stroke, such
as anemia and elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, interleukins). 3. Determination of the minimal laboratory inclusion/ exclusion criteria for acute use of thrombolytics, if otherwise eligible. Tests that should be routinely obtained in patients with ischemic stroke include complete blood cell count; basic metabolic profile with evaluation of renal and hepatic function; and measurement of glucose levels, including glycosylated hemoglobin; lipid profile; coagulation profile (prothrombin time and partial thromboplastin time); and platelet count. In an individual with clear risk factors, it might not be necessary to obtain further studies, unless dictated by other medical conditions. In patients without a clear-cut risk factor profile, and especially in young patients with a cryptogenic stroke, a more comprehensive diagnostic workup should be obtained. This should include evaluation for prothrombotic states with determination of factor V Leiden, prothrombin gene mutation, anticardiolipin antibodies, lupus anticoagulant, hemoglobin electrophoresis (depending on the ethnic background), C-reactive protein as a marker of proinflammatory state, and autoimmune serological profiles, if immune-mediated diseases are a consideration. A search for genetic markers predisposing to early accelerated atherosclerosis such as lipoprotein (a) can also be considered, especially for patients with a positive family history. Other tests addressing hypercoagulable states, such as determinations of proteins C and S and antithrombin III levels produce results less likely to be associated with arterial thrombosis and have a low yield.
Workup for a Cardioembolic Source Ischemic stroke is a vascular disease and is frequently caused by cardiac embolism. Thus, investigation of the cardiovascular system is an integral part of the diagnostic workup. Electrocardiography is helpful in determining the baseline rhythm, as well as identifying markers of cardiovascular risk factors such as ventricular or atrial enlargement and evidence of a prior myocardial infarction. When the initial electrocardiogram yields little information, 24-hour Holter monitoring should be considered, especially when the presentation, neurological examination findings, and pattern of infarction are suggestive of embolus. TTE should also be performed in patients after stroke to rule out mechanical abnormalities of the cardiac chambers or valves predisposing to thrombus formation. TTE is especially important in patients with prior large myocardial infarction, to rule out ventricular aneurysm with superimposed thrombus. When TTE does not reveal a potential embolic source, TEE should be considered. With the exception of the patient with an otherwise obvious source of distal embolism such as tight ipsilateral ICA stenosis or known atrial fibrillation, all other patients should undergo evaluation with TEE to definitely rule out a cardiac embolic source. TEE has considerably higher sensitivity and specificity than TTE for valvular abnormalities, including vegetations; left atrial and atrial appendage thrombus; atrial myxoma and other cardiac tumors; presence of spontaneous echo contrast in the atrium; and PFO with associated ASA. TTE, because of the close proximity of the left ventricle to the thoracic wall, has a higher yield than does TEE for left ventricular thrombus.
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment ACUTE TREATMENT Pre–Emergency Room Management The earlier that therapeutic intervention is initiated after stroke onset, the better the outcome is likely to be (“time is brain”). Thus, initial recognition and prompt presentation to the hospital are crucial. Management of an acute stroke starts with recognition by the patient or by family members that certain signs and symptoms might represent a stroke and, more important, that help should be sought immediately. Multiple prospective and retrospective studies have demonstrated a consistent delay before patients seek medical attention after stroke onset; thus, they miss the optimal time for intravenous thrombolytic therapy. One reason for the delay, failure to recognize the signs and symptoms of a stroke, has been implicated in many studies.
Emergency Room Evaluation Although symptom recognition and stroke awareness are important limiting factors for timely stroke evaluation, studies have also shown that triage is often inadequate and have identified significant in-hospital delays for physician evaluation and for obtaining and interpreting initial CT scans.48,49 Dedicated acute stroke teams and an algorithm for emergency evaluation of acute stroke in the emergency department are necessary to overcome these obstacles. Evaluation by emergency room physicians has been validated by multiple studies and should improve as more community hospitals assume an active role in treating acute stroke.50,51 In many smaller hospitals, where a consulting neurologist might not be immediately available, the emergency room physician ultimately evaluates and treats those patients in the crucial first few hours after ictus. The initial management of a patient with acute stroke is no different from that in other medical emergencies, with assessment of the status of the airway, of ventilation/oxygenation, and of the circulation. Specific areas that require particular attention in the first few hours of stroke are addressed in the following sections.
Adequate Oxygenation Despite promising results with animal models52,53 and anecdotal reports of clinical efficacy, there is currently no definitive evidence to support the use of supplemental oxygen therapy, despite its widespread use in victims of acute stroke.54 When hypoxemia is present, it should be treated aggressively because it is extremely detrimental to penumbral brain tissue. All efforts in the emergency room should be geared toward avoiding further neuronal loss through transformation of the ischemic penumbra into infarct.
Blood Pressure Management Many patients with acute stroke have an elevated blood pressure in the first few hours to days after the ictus. The levels may be above 200 mm Hg for systolic blood pressure but usually normalize without treatment within a few days. In view of the current notion of a viable ischemic penumbra and loss of local vessel tone in the area surrounding an acute infarction (where
569
cerebral vascular resistance is less responsive to changes in CPP), it is imperative that no attempt is made to reduce the blood pressure in the acute peristroke period. Moreover, in chronically hypertensive individuals, the upper and lower limits of the autoregulatory curve are shifted upward, and therefore blood pressure reduction to within the normal range may extend infarction into penumbral regions. Two important exceptions are made: (1) for patients eligible for intravenous tissue-type plasminogen (tPA), because current guidelines require that systolic blood pressure be less than 185 mm Hg and diastolic pressure less than 110 mm Hg, and (2) patients with evidence of ongoing or imminent end-organ damage, such as pulmonary edema, acute myocardial infarction, acute aortic dissection, or acute renal insufficiency.55 In such patients, careful gradual blood pressure lowering can be attempted with parenteral medications such as β blockers (labetalol) or calcium channel blockers (nicardipine). When possible, these agents are preferred over direct venodilators such as nitroprusside or nitroglycerin. Research has focused on the dependence of peri-infarct brain perfusion on systemic blood pressure and its relevance for short- and long-term recovery. Investigators using SPECT found a negative relationship between blood pressure reduction and improvement in CBF,56 but the sample size was too small to extrapolate the results to the general stroke population. In two prospective studies, investigators found deleterious effects of acute blood pressure lowering on outcomes at 21 days57 and at 3 months, respectively.58 In the debate on how to better manage blood pressure in the peristroke period, a new concept has arisen: pharmacologically induced hypertension in patients in whom acute, reversible flow failure is suspected on clinical grounds or from perfusion MRI/CT scan. The approach seems most plausible for patients with acute large-vessel stenosis or occlusion, in whom penumbral tissue would benefit from increased perfusion and further recruitment of collateral channels. However, except for small pilot studies,59 no universally accepted protocol is in place, and this strategy cannot be recommended outside of a clinical trial.
Glycemic Control The notion that hyperglycemia is detrimental to ischemic brain tissue is not new.60 Only since 2000, however, have the concepts of neuronal damage and infarct expansion been demonstrated for hyperglyamia in humans by neuroimaging61 and functional outcomes studies.62 In the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) trial, hyperglycemia was identified as an independent predictor of worse outcomes as well as a risk factor for ICH complicating treatment with thrombolytics.63 Hyperglycemia also seems to reduce the effect of thrombolysis, probably by making the ischemic penumbra less amenable to the benefits of reperfusion.64 The effects of hyperglycemia are likely to predispose to acute clinical worsening65 and possibly play a significant role in long-term recovery and mortality.66 Although there is nearly consensus on the detrimental effects of hyperglycemia in the acute stroke period, more studies are needed to determine its optimal management. The only large multicenter trial to date to address the safety of aggressive glycemic control was the United Kingdom Glucose Insulin Trial (GISTUK). The investigators concluded that continuous infusion of glucose/potassium/insulin solutions is feasible and safe in the peristroke period.67 A smaller group of patients has been
570
Section
IX
C e r e b r o va s c u l a r D i s e a s e
reported in whom tight glycemic control was maintained with a continuous insulin infusion, but symptomatic, readily reversible hypoglycemia occurred in 20% of the patients.68 It is currently not known whether aggressive control of blood glucose translates into short- or long-term benefits or whether there is increased risk of hypoglycemic episodes. Despite the lack of current guidelines and formal recommendations, it seems reasonable that the patients with acute stroke, particularly those eligible for thrombolytic treatment, should undergo aggressive correction of hyperglycemia.
T A B L E 42–3. Modified Rankin Scale Grade
Description
0 1
No symptoms No significant disability despite symptoms: able to carry out all usual duties and activities Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance Moderate disability: requiring some help but able to walk without assistance Moderate-severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability: bedridden, incontinent, requiring constant nursing care Dead
2 3 4
Temperature Control
5
Although hypothermia seems plausible as a neuroprotective strategy, studies are still scarce, and no clear recommendations can be made at this point. Animal studies have reliably demonstrated adverse outcomes associated with hyperthermia in the peristroke period, but only as recently as 2000 have objective data in humans shown an effect of elevated temperature on clinical outcomes.69 Two large studies demonstrated the benefit of induced hypothermia in hypoxic-ischemic brain damage after cardiac arrest, but there are no comparable studies on the effects of hypothermia on focal ischemic lesions.70,71 It is reasonable to recommend control of peristroke pyrexia with the usual measures available in current clinical practice, acetaminophen and cooling blankets, until more data become available.
6
Recanalization Strategies Intravenous Thrombolysis With the demonstration of efficacy of intravenous thrombolytics in acute myocardial infarction, it was only a matter of time until a similar approach was investigated in the setting of acute ischemic stroke. On the basis of successful animal studies, the first large trials to employ intravenous thrombolytics were conducted with streptokinase administered within 6 hours of stroke onset.72,73 Both studies revealed excess mortality in the groups treated with streptokinase, especially when streptokinase was combined with aspirin in the acute setting. In 1996, the Australian Streptokinase Study (ASK) investigated the efficacy of streptokinase within 3 hours and between 3 and 6 hours of stroke onset. The results showed worse outcomes for those receiving streptokinase within 3 and 6 hours of stroke onset and a significant decrease in mortality in patients treated within 3 hours in comparison with those treated between 3 and 6 hours. This, however, was not translated into a significant clinical benefit for thrombolysis at 3 months in comparison with placebo.74 In view of these results, streptokinase was abandoned, and attention shifted to rt-PA, a more selective, fibrindependent plasmin generator. Results from multiple animal studies, which showed efficacy of rt-PA for recanalization and with lower rates of ICH than streptokinase, paved the way for clinical trials in humans. The first large, randomized, multicenter clinical trial to evaluate the use of rt-PA in acute ischemic stroke was the European Cooperative Acute Stroke Study (ECASS). Patients were enrolled within 6 hours of their ischemic stroke and were randomly assigned to received rt-PA (alteplase) at 1.1 mg/kg or placebo. The primary outcomes analyzed were the Barthel index (a measure of functional impairment in the activities of daily
living) and the modified Rankin scale (a measure of neurological disability) at 3 months (Table 42–3). Even though the overall rate of ICH was not different between the two groups, the rate of large ICH was significantly higher in the treated group. No definite benefit was observed for the tPA group, but a post hoc analysis revealed a statistically insignificant treatment effect in patients treated within 3 hours, which suggested that this time window should be further explored.75 In 1995, the NINDS rt-PA Stroke Study group published the results of their trial.76 It was a randomized, placebo-controlled, multicenter trial that enrolled patients within 3 hours of the onset of an acute ischemic stroke who were then randomly assigned to receive either intravenous rt-PA (0.9 mg/kg) or placebo. There were strict exclusion criteria to ensure adequate patient selection and to improve the odds of a favorable result (Table 42–4). The dose of rt-PA chosen was lower than that for ECASS, and the blood pressure exclusion criteria were stricter (systolic blood pressure <185 mm Hg and diastolic blood pressure <110 mm Hg) (Table 42–5). Endpoints were defined in two parts: Part 1 required an improvement in the first 24 hours of more than 4 points in the National Institutes of Health Stroke Score (NIHSS) scale. Part 2 required improvement at 3 months on the Barthel Index (score = 95 to 100), the modified Rankin Scale (score = 1), and the Glasgow Outcome Scale (score = 1). The results of part 1 did not show a significant difference between the two groups. In part 2, benefit from tPA was observed in all outcome measures: Patients treated with tPA were 30% to 50% more likely to have no or minimal disability at 3 months than were those treated with placebo.76 The benefit was maintained regardless of stroke subtype and was still present 6 months and 1 year after stroke.77 The rate of symptomatic ICH was 6.4% in the tPA-treated individuals, in comparison with 0.6% in the placebo arm, but the mortality rates at 3 months and 1 year were not different between the two groups. Predictors of better outcome were treatment within 90 minutes78 (Fig. 42–12) and decrease in NIHSS score at 24 hours.79 Independent risk factors for symptomatic ICH were the severity of the stroke (measured by the NIHSS score), brain edema, or mass effect at baseline CT scan.80 Later studies showed that elevated blood glucose level at the time of treatment was also independently associated with higher risk of ICH.63 In 1996, on the basis of these favorable results, the U.S. Food and Drug Administration (FDA) approved the use of intra-
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment T A B L E 42–4. Inclusion and Exclusion Criteria for rt-PA Administration According to the National Institute of Neurological Disorders and Stroke Study
571
T A B L E 42–5. National Institute of Neurological Disorders and Stroke rt-PA Study Protocol for Intravenous Thrombolysis in Acute Ischemic Stroke
Inclusion Criteria for rt-PA Administration Measurable neurological deficit of <3 hours of onset Brain CT without evidence of hemorrhage Exclusion Criteria for rt-PA Administration Rapidly improving or mild symptoms Symptoms suggestive of subarachnoid hemorrhage Head trauma or prior stroke in previous 3 months Myocardial infarction in the previous 3 months Gastrointestinal or urinary tract hemorrhage in previous 21 days Major surgery in the previous 14 days Arterial puncture at a noncompressible site in the previous 7 days History of previous intracranial hemorrhage Persistently elevated blood pressure (systolic >185 mm Hg and/or diastolic >110 mm Hg) Evidence of active bleeding or acute trauma (fracture) on examination If oral anticoagulant being taken and INR > 1.5 Heparin in previous 48 hours and prolonged aPTT Platelet count <100,000 mm3 Blood glucose concentration <50 mg/dL or > 400 mg/dL Seizure at the onset with postictal residual neurological impairments Adapted from Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587. aPTT, activated partial thromboplastin time; CT, computed tomography; INR, international normalized ratio; rt-PA, recombinant tissue plasmin activator.
venous tPA for acute ischemic stroke within 3 hours of onset in patients who met inclusion/exclusion criteria. After a post hoc analysis of ECASS demonstrated benefit in patients treated within 3 hours of stroke onset, a second trial (ECASS II) was conducted. The changes in the original protocol included a lower dose of tPA (0.9 mg/kg) and the exclusion of patients with CT evidence of large infarction (more than one third of the MCA territory involved, diffuse swelling). Other exclusion criteria were similar to those in the NINDS trial. The final analysis showed no significant difference between the treatment and the placebo recipients when the favorable outcome of a modified Rankin Scale score of 0 or 1 was considered (minimal or no disability). However, a post hoc analysis dichotomizing patients as either functionally dependent (modified Rankin Scale score > 2) or independent (modified Rankin Scale score = 2) found a significant 8.3% absolute difference in favor of the treatment recipients.41 As observed in the NINDS trial, the rate of symptomatic ICH was higher in the treatment recipients (8.8%) than in the placebo recipients (3.4%), but the 3-month mortality rates were similar. The FDA approval of intravenous tPA for acute stroke, along with subsequent favorable reanalyses and meta-analyses of existing intravenous tPA trials, has led to a broad consensus that it is an effective treatment for acute stroke. However, there have been many criticisms of the NINDS trial, and there remain many questions that will be answered only by further trials, not by reanalyzing old data. It is notable that the American Heart Association/American Stroke Association guidelines for intravenous tPA did not change from 2003 to 2005; which reflects the absence of new information. Some of the major concerns with the extant tPA trials and meta-analyses, along with questions that remain, are as follows:
From Adams, HP, Adams RJ, Brott T, et al: Guidelines for the early management of patients with ischemic stroke. Stroke 2003; 34:1056-1083. CT, computed tomography; rt-PA, recombinant tissue plasmin activator.
(1) The efficacy of intravenous tPA is small and available to only a very limited group of patients. (2) The NINDS trial is the only one to show benefit based on prespecified outcome measures. The other trials required post hoc analysis to show a benefit. (3) There was a statistically significant difference between the treatment groups in the NINDS study. Of note, in the 91- to 180-minute time window within which most patients receive intravenous tPA, there were over four times more patients in the mildest stroke severity category who received intravenous tPA than patients who received placebo. (4) Information on stroke etiology was inadequate, and therefore it is still not known which stroke subtypes are best treated with intravenous tPA. For example, it is unclear whether lacunar infarcts in the absence of large vessel disease are really ameliorated with intravenous tPA. (5) The effects of age, prior aspirin use, white matter disease, and stroke subtype on hemorrhage risk are unknown. (6) It is not known whether there are systematic differences in recanalization rates for ICA, MCA stem, basilar, and branch occlusions. (7) Recent data suggest that patients with rapidly improving or mild symptoms should still receive tPA. (8) Patients with very high NIHSS scores show only minimal benefit from tPA.
572
■
Section
IX
C e r e b r o va s c u l a r D i s e a s e
Figure 42–12. Graph of model estimating odds ratio for favorable outcome at 3 months in patients treated with recombinant tissue plasminogen activator (rt-PA) in comparison with those treated with placebo by time from stroke onset to treatment. Odds ratio > 1 indicates greater odds that rt-PA treated patients will have a favorable outcome at 3 months in comparison with the placebo-treated patients. (From Marler JR, Tilley BC, Lu M, et al: Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000; 55:1649-1655).
Intravenous Thrombolysis Beyond the 3-Hour Period The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study was designed in an attempt to expand the narrow window for intravenous tPA use.81 The study tested the safety and effectiveness of intravenous tPA (0.9 mg/kg) within 5 hours of stroke onset. The primary endpoint was excellent neurological recovery (NIHSS score = 1) at day 90. The tPA dose and the other inclusion and exclusion criteria were similar to those of the NINDS trial. The result was negative; tPA treated patients had higher rates of symptomatic ICH and mortality at 90 days. The delayed time window drove the negative result, as only 15% of patients were treated within 3 hours of onset. A meta-analysis of pooled data from the NINDS, ATLANTIS, and ECASS trials has been performed. A total of 2775 patients treated with either placebo or intravenous thrombolysis within 360 minutes of stroke onset were analyzed. The odds ratios of a favorable outcome at 3 months were 2.81 for the patients treated within 90 minutes and 1.55 for those treated within 91 to180 minutes. There was no significant difference in mortality between patients treated within 270 minutes, but the mortality rate among patients given thrombolytics more than 270 minutes after stroke onset was in excess of 45%. Hemorrhage rate did not appear to be related to the time for thrombolysis but was related to age and the use of thrombolytics as opposed to placebo.82 Of note, this meta-analysis, like a Cochrane review,82a also suggested some benefit in patients treated between 180 and 270 minutes after stroke onset (odds ratio, 1.4). Nevertheless, intravenous thrombolysis is currently not recommended more than 3 hours after stroke onset. It is clear that 3 hours is not a magic number, and more physiological measures are sorely needed to optimally select patients for recanalization therapy. There are almost certainly patients in whom recanalization and completion of infarction have occurred within 3 hours and who would therefore not benefit from intravenous tPA and only be placed at unnecessary risk
for hemorrhage. Conversely, there may be other patients, with persistent occlusion and large areas of misery perfusion, who could still benefit from recanalization more than 3 hours after stroke onset. The critical measures are likely to be the demonstration of both large-artery occlusion and the presence of a substantial volume of penumbral tissue beyond the infarct core. A way forward is to use the combination of DWI, PWI, and MRA to provide a rapid assessment of the ischemic infarct core (DWI), the presence of arterial occlusion (MRA), and tissue at risk, defined as an area of reduced perfusion that extends beyond the boundaries of the diffusion abnormality. This is known as PWI-DWI mismatch. The concept of PWI-DWI mismatch has recently been modified for two reasons. First, as noted in the “Ischemic stroke” section, there is a spectrum of reversible ischemia from benign oligemia to impending necrosis. Second, DWI abnormalities are not always indicative of irreversible ischemia. Thus, the new definition of the penumbra (tissue at risk) excludes a rim of benign oligemia and includes some of the DWI core with high ADC values.83 A recent magnetic resonance study of the evolution of DWIand PWI-observed lesion volumes, from acute to subacute time points, showed a contraction of the PWI-observed lesion by 85% and an expansion of the DWI-observed lesion by 136%.84 The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) pilot study showed improved recanalization, reduced DWI expansion, and penumbral salvage in patients who received intravenous tPA within 6 hours.61 The magnetic resonance surrogate measures were correlated with clinical outcome measures. These theoretical considerations, observational studies, and pilot studies have led to five ongoing studies (EPITHET; Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution [DEFUSE]; Desmoteplase in Acute Ischemic Stroke Trial [DIAS]; MR and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE]; and ReoPro Retavase Reperfusion of Stroke Safety Study [ROSIE]) evaluating tPA or mechanical thrombolysis on the basis of penumbral dynamics. Preliminary data are favorable,85 but it is necessary to wait until the trials are completed because many intuitively appealing ideas for stroke treatment have been shown to be untenable after completion of properly randomized trials.
Thrombolysis in the Community With the approval of intravenous tPA for acute stroke treatment, multiple groups tried to ascertain whether the benefits observed in the NINDS trial were reproducible at the community care level. In 2000, Katzan and colleagues published the experience at 29 hospitals in the Cleveland area and determined the rate of use of thrombolytics, related complications, and protocol violations.86 Their results showed that only 1.8% of all patients admitted with a diagnosis of ischemic stroke received intravenous tPA. Moreover, of the treated patients, 15.7% had symptomatic ICH, and the NINDS protocol was violated in 50% of the cases. The analysis also showed higher in-hospital mortality rates in the tPA-treated patients than in the placebotreated patients.86 Protocol violations were also high in another community-based study87; not surprisingly, there was a higher rate of symptomatic ICH than in the original NINDS trial. With increased awareness of its indications and the importance to adhere strictly to the published protocol, tPA use was reanalyzed in the Cleveland area 2 years after the first study. A higher percentage (2.7%) of patients received treatment; they
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment represented 18.8% of all eligible patients. Protocol violations occurred for 19% of patients, and symptomatic ICH occurred in 6.4%,88 a significant improvement from the original study. Familiarity with the use of thrombolytics and better adherence to published guidelines were likely reasons for the observed improvement. However, the overall tPA usage rates were not impressive, and this raises the possibility that specialized centers, analogous to designated trauma centers, might be a better option. In 2001 Grotta and associates published the Houston experience with tPA for acute stroke. In a period of 4 years, 15% of all patients presenting with an acute ischemic stroke were treated with intravenous tPA; almost a third of those were treated within 2 hours after onset. The rate of symptomatic ICH was 4.5%, and protocol violations occurred for 13% of all treated patients. This study proved that a well-organized team approach and adherence to currently accepted protocols are key to successful implementation of intravenous thrombolysis.89 In 2002, a group from Canada evaluated their experience with over 1000 patients treated with intravenous tPA over a period of 30 months. Their results were similar to the NINDS trial, in which 30% of the treated patients had no or minimal deficits at 90 days. The ICH rate was 4.6%, and protocol violations were observed in 15% of cases.90 Other studies have yielded similar results.
Intra-Arterial Thrombolysis For more than a decade, small case series were published on the feasibility and angiographic efficacy of intra-arterial delivery of thrombolytics. There has since been great improvement in angiographic catheter technology, as well as an increase in the experience of interventionalists. In many academic settings, intra-arterial thrombolysis is commonly employed in patients for whom the 3-hour window for intravenous thrombolysis is past or in those with an absolute contraindication to systemic thrombolysis. The potential advantages are the higher rates of recanalization achieved by delivering the drug locally at the site of the occlusive thrombus/embolus and fewer systemic side effects. It is unclear whether any particular agent is more effective, but those that are more fibrin selective might have a theoretical advantage (tPA, recombinant tPA, recombinant prourokinase) over less selective agents, such as urokinase. Despite the inherent plausibility of an intra-arterial approach, only one placebo-controlled, double-blind multicenter trial has been completed. The Prolyse in Acute Cerebral Thromboembolism Trial (PROACT) was published in two parts. In PROACT I, recombinant prourokinase, a highly fibrin-selective agent, was administered intra-arterially, and its effects were compared with those of placebo in patients with an angiographically documented MCA (M1 or M2) occlusion within 6 hours of stroke onset. Inclusion criteria included a NIHSS score of at least 4, as well as the other NINDS tPA trial inclusion/exclusion criteria, including those for blood pressure. Heparin was administered concomitantly for 4 hours in both groups, and mechanical clot disruption was not allowed in either group. Forty patients were enrolled, and the rate of angiographically proven recanalization was 57.7% for the treatment recipients and 14.3% for the placebo recipients. Among patients who received higher doses of intravenous heparin together with the intra-arterial recombinant prourokinase, recanalization and symptomatic ICH rates were higher
573
(81.8% and 27%, respectively). The recanalization rate was lower in the patients given lower dose heparin (40%), but the rate of symptomatic ICH was also significantly lower (6%). Overall, the rate of ICH was 15.4% among patients receiving thrombolytics and 14.3% among those receiving placebo. The trend toward effectiveness in this phase 2 trial prompted the second part of the trial (PROACT II), which tested clinical efficacy. The inclusion criteria in PROACT II were similar to those of PROACT I except, as in to ECASS, patients with CT hypodensity representing involvement of more than a third of the MCA territory were excluded. The baseline severity of strokes was higher than in the NINDS tPA trial (mean NIHSS scores = 17 versus 14) and the median time from onset to treatment was 5.3 hours. The primary outcome was the proportion of patients with a modified Rankin Scale score of 2 or less (independent) at 90 days. The study found a 15% absolute benefit in the patients who received treatment (intra-arterial recombinant prourokinase followed by intravenous heparin for 4 hours) in comparison with those who received placebo (only intravenous heparin for 4 hours). This translates into a number-needed-totreat of seven. Symptomatic ICH occurred in 10% of recombinant prourokinase recipients and 2% of the control group, and recanalization rates at 2 hours were 66% for the treatment recipients and 18% for the control group. No difference in mortality rates was observed between the two groups.91,92 Data from the PROACT suggest that patients outside the currently accepted treatment window for intravenous tPA could benefit from an aggressive interventional approach. However, the results of PROACT II did not suffice for FDA approval. Nevertheless, this approach is likely to be particularly useful for those patients with either ICA or MCA occlusion (Fig. 42–13A and B), in whom the rate of recanalization with systemic thrombolysis appears to be much lower than that with locally delivered thrombolytics. The existence of a sizable subgroup of patients who cannot receive systemic thrombolysis (because of recent surgery, recent nonhead trauma, previous stroke) is a strong incentive for development of intra-arterial therapies. Areas under active investigation include the use of mechanical extraction devices that remove an obstructing clot without many of the attendant risks of a thrombolytic agent. Several such devices are currently under investigation. The use of PWI-DWI mismatch, as previously discussed, is certain to be used in the future to select patients most likely to benefit from intraarterial therapy. Vertebrobasilar thrombosis has extremely high overall morbidity and mortality rates (approximately 70% to 80%), whereas successful recanalization is associated with a survival rate of 55% to 75%. Thus, basilar thrombosis is another situation in which intra-arterial thrombolysis may prove more efficacious than systemic thrombolysis. Despite the absence of a large randomized study to prove its safety and efficacy, the potential longer window (up to 24 or even 72 hours in selected cases) for therapy, based on multiple case series, makes acute basilar thrombosis a compelling scenario for use of intra-arterial thrombolysis or mechanical clot extraction.
Combined Intravenous and Intra-Arterial Thrombolysis The rate of complete recanalization of ICA or MCA occlusion after intravenous tPA appears to be low, ranging from 10% to 30%. Moreover, in many instances, recanalization is followed
574
Section
IX
C e r e b r o va s c u l a r D i s e a s e
A ■
B
Figure 42–13. A, Complete occlusion of the left middle cerebral artery stem. B, Recanalization of the middle cerebral artery stem and its branches after intra-arterial tissue plasminogen activator was administered to a patient with onset of a stroke 2 hours earlier, who was not a candidate for intravenous thrombolysis.
by reocclusion and neurological worsening. The Emergency Management of Stroke (EMS) pilot study aimed at establishing the safety and feasibility of lower dose intravenous thrombolysis (0.6 mg/kg) within 3 hours, followed by intra-arterial tPA for presumed MCA or ICA occlusion (NIHSS score > 5). The rationale behind this approach is to combine speed of delivery of intravenous tPA with the higher recanalization rate and extended time window of intra-arterial tPA. The study results showed that the combination of intravenous and intra-arterial thrombolysis led to higher recanalization rates and more bleeding complications, without appreciable effect on overall outcome.93 A follow-up study, the Interventional Management of Stroke (IMS) trial, enrolled 44 patients to the intravenous/ intra-arterial tPA treatment group. The rate of symptomatic ICH was 6.3%. In comparison with the historical data from the NINDS intravenous tPA trial, in which 36% of patients with a NIHSS score higher than 10 achieved a good outcome, 56% of such patients in the IMS study had a good outcome, which is suggestive of added benefit from intra-arterial therapy in patients with probable large-vessel occlusion.94 Currently, however, such an approach is experimental and is not recommended outside a clinical trial setting.
SECONDARY PREVENTION Antiplatelet Therapy Aspirin Aspirin use is a time-honored strategy for secondary prevention of ischemic stroke in both the acute and chronic settings. Mul-
tiple clinical trials have been conducted, the most important being the French, British, European, and Canadian trials. They revealed a benefit ranging from 20% to 30% relative risk reduction for stroke and vascular death. The Antithrombotic Trialists Collaboration addressed the role of aspirin among patients at high risk for vascular events, including those with a prior ischemic stroke. The benefit of aspirin was modest, with a 22% relative risk reduction for vascular events (stroke, myocardial infarction, vascular death) in patients with a prior TIA/stroke. The absolute benefit of aspirin, across all doses, was a modest 2.5% (Fig. 42–14).95 Whereas most studies agree on the benefit of aspirin, its optimal dose has been a matter of some controversy. The Dutch trial showed equal benefit for very low and moderate doses of salicylates (30 mg/day versus 283 mg/day),95a a finding similar to that in the British trial,95b in which very different dosing schedules were used (300 mg/day versus 1200 mg/day). In view of the potential side effects, mainly from gastrointestinal bleeding and ulceration, it is reasonable to prescribe low-dose aspirin (81 mg/day) for long-term secondary stroke prevention, although efficacy at this low dose of aspirin for long-term stroke prevention has not been determined. The International Stroke Trial (IST) evaluated patients within 48 hours of an acute stroke and established the benefit of 300 mg/day of aspirin in reducing recurrent strokes at 14 days and death or dependency at 6 months.96 The Chinese Acute Stroke Trial (CAST) evaluated the use of 160 mg/day of aspirin within 48 hours of suspected ischemic stroke (13% of patients had no confirmatory CT scan before randomization).97 Analysis of the results showed a 12% relative risk reduction of death or recurrent stroke within 4 weeks for the aspirin recipients. Together, the IST and CAST trials showed an improved outcome for patients receiving
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment Benefit per 1000 patients (SE): Adjusted % of patients (+1 SE)
P value:
6(2)
25(5)
7(4)
15(5)
0.0009
<0.0001
0.04
0.002
Antiplatelet therapy Control 1248/ 11527 (10.8%)
10 957/ 11493 (8.3%)
5
0 Outcome:
1475/ 11527 1303/ (12.8%) 11493 (11.3%) 1003/ 915/ 11527 11493 (8.7%) (8.0%)
251/ 191/ 11338 11310 (23%) (1.7%)
Non-fatal myocardial infarction
Non-fatal stroke recurrence
Vascular death
aspirin within 48 hours of a stroke, with 13 fewer dead or dependent patients in the months after the event.96,97 Aspirin is often discontinued for elective surgery or bleeding complications. There have been concerns for some time that discontinuation of aspirin, and other antiplatelet agents, might lead to a transient prothrombotic “rebound” effect that increases the risk of ischemic stroke. This concern is supported by a case-control study whose results suggest that aspirin discontinuation can increaset the risk of ischemic stroke, especially in patients with multiple cardiovascular risk factors.97a
Clopidogrel Clopidogrel inhibits adenosine diphosphate–induced platelet aggregation. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study investigated its use for the prevention of ischemic strokes. Patients with nondisabling ischemic strokes, patients with recent myocardial infarction, and patients with symptomatic peripheral arterial disease were randomly assigned to receive aspirin (325 mg/day) or clopidogrel (75 mg/day). The primary outcome was an aggregate of myocardial infarction, ischemic stroke, and vascular death. Overall, events occurred in 5.3% of patients receiving clopidogrel and 5.8% in those receiving aspirin; this represented a relative risk reduction of 8.7% in favor of clopidogrel. This benefit was achieved mainly from a relative risk reduction of 23.8% in the patients with peripheral arterial disease and was not observed in the patients with a prior ischemic stroke, in whom a nonsignificant relative risk reduction of 7.3% in favor of clopidogrel was observed. The rate of gastrointestinal hemorrhage was lower in the clopidogrel recipients (1.99%) than in those taking aspirin (2.66%), but the rates of ICH were similar. These results suggest that in patients with a prior ischemic stroke, clopidogrel is no more effective than aspirin. Its use is justified in patients with aspirin intolerance and in patients with symptomatic peripheral arterial disease. The history of a prior gastrointestinal bleeding episode during aspirin therapy would, in theory, also justify using clopidogrel. Thrombotic thrombocytopenic purpura is a concern with clopidogrel, but CAPRIE did not show a higher risk of fatal thrombocytopenia than with the use of aspirin.
■
575
Figure 42–14. Absolute effects of antiplatelet therapy on various outcomes in patients with previous stroke or transient ischemic attack (21 trials). In the “any death” columns, nonvascular deaths are represented by lower horizontal lines (and may be calculated by subtracting vascular deaths from any deaths). (From Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomized trials of antiplatelet therapy for the prevention of death, MI, and stroke in high risk patients. BMJ 2002; 324:71-86.)
Any death
Combination Antiplatelet Therapy Clopidogrel and Aspirin The rationale behind combination antiplatelet therapy is that the agents have different mechanisms of antiplatelet activity. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study evaluated the role of the combination of clopidogrel and aspirin in comparison with aspirin alone in patients with non–ST-elevation acute coronary syndrome. The combination therapy led to a 20% relative risk reduction in the composite outcome of myocardial infarction, ischemic stroke, and vascular death in comparison with aspirin alone. Even though the rates of ICH were small and not different between the two groups, the CURE trial results could not be extrapolated to secondary stroke prevention because most of the patients were stroke free at the time of enrollment. To specifically answer the question whether the clopidogrelaspirin combination is more effective in reducing the risk of stroke recurrence than aspirin alone, the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic or Ischemic Stroke (MATCH) trial was conducted. The 7599 patients already taking clopidogrel (75 mg/day) who had had a recent TIA or stroke (and at least one other risk factor) were randomly assigned to receive aspirin or placebo. The duration of treatment and follow-up was 18 months. The primary endpoint was a composite of ischemic stroke, myocardial infarction, vascular death, or hospitalization for acute ischemic event (including TIA, angina, or peripheral arterial disease). The primary endpoint was reached by 15.7% of patients receiving clopidogrel/aspirin and by 16.7% of those receiving aspirin alone. This relative risk reduction of 6.4% was offset by the significantly higher rates of life-threatening bleeding episodes in the patients receiving combination therapy (2.6% versus 1.3%). The degree to which the MATCH results apply to secondary stroke prevention in general is questionable for a number of reasons. First, 70% of the patients enrolled had diabetes. The study was designed to enroll patients with multiple stroke risk factors to increase the background stroke recurrence rate, which was high in both groups. It is possible that this population has such severe small-vessel disease that
576
Section
IX
C e r e b r o va s c u l a r D i s e a s e
inhibiting platelets was not sufficient to prevent lacunar infarction. Indeed, 54% of the recurrent strokes were lacunar. The question, extrapolated from CURE, of whether patients with TIA or stroke from LAA might benefit from aspirin and clopidogrel, was not really addressed by MATCH. For example, in the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial, dual antiplatelet therapy with clopidogrel and aspirin was superior to aspirin alone for reduction of embolic signals in the MCA in patients with symptomatic carotid stenosis. This was admittedly a small study with a surrogate marker, but the results do tend to support the idea that LAA might be more amenable to combination therapy than is small-vessel disease. Nevertheless, in view of the elevated risk of hemorrhage and the nonsignificant increase in protection, combination therapy of clopidogrel and aspirin cannot currently be recommended for secondary stroke prevention, with the possible exception of patients with extracranial or intracranial stents.
Dipyridamole and Aspirin The European Stroke Prevention Study II (ESPS-II) was a double-blind, randomized investigation of the different efficacy of placebo in comparison with aspirin (25 mg twice daily), extended-release dipyridamole (200 mg twice daily), and the combination of aspirin and extended-release dipyridamole. The outcomes of stroke and/or death were measured over a followup period of 2 years. The results showed a stroke rate of 15.8% in the placebo recipients, 13.2% in the extended-release dipyridamole recipients, 12.9% in the aspirin recipients, and 9.9% in the combination recipients. The combination therapy yielded a 23% relative risk reduction in comparison with either aspirin or dipyridamole alone and a 37% relative risk reduction in comparison with placebo.98 Moderate to severe bleeding events were almost twice as common in the aspirin recipients; mortality rates were not statistically different among the four groups. The combination is therefore a valid first-line option for secondary prevention after a noncardioembolic stroke and is being increasingly used in clinical practice. The main limitation of this therapy is the frequent headaches observed at the initiation of therapy (present in as many as 40% of patients). However, a slow dose-escalation schedule and use of over-thecounter pain medications usually lead to resolution of headaches within 2 weeks. Overall, the aspirin trials—CAPRIE, ESPS-2, Warfarin Aspirin Recurrent Stroke Study (WARSS), and MATCH—have not shown a relative risk reduction beyond 25%, and the number needed to treat to prevent one recurrent stroke is approximately 25 for all agents studied thus far. In contrast, trials that focused on a single underlying stroke mechanism, such as atrial fibrillation or high-grade carotid stenosis, have demonstrated more dramatic relative risk reductions, of about 60% to 70%. This discrepancy raises doubts about the utility of large secondary prevention trials, which lump together all stroke etiological subtypes. Instead, there should be more detailed characterization of each enrolled patient’s stroke subtype and trials powered to differentiate between these stroke subtypes. Alternatively, trials should be conducted on a single stroke subtype only. Until this is done, it can be envisaged that antiplatelet trials will continue to yield unimpressive results because some stroke causes will respond favorably to the agent in question but the mean effect will be diluted by other causes
that respond poorly or not at all. A final point is that a shift in focus from inhibition of platelet aggregation to inhibition of platelet adhesion might provide greater benefit and reduced hemorrhagic risk.
Anticoagulants Heparin and Heparinoids The debate over the use of anticoagulants in the acute stroke setting continues relentlessly. Proponents of anticoagulation favor its use on the basis of biologically plausible arguments: 1. Anticoagulation in the acute setting stops clot propagation and embolization and optimizes the action of the intrinsic fibrinolytic system to maintain collateral flow to penumbral tissue. 2. Anticoagulation in the acute setting stabilizes a ruptured atherosclerotic plaque by decreasing in situ thrombosis, thereby reducing the chances of fluctuating or “crescendo” TIAs or “stroke in evolution.” 3. The anti-inflammatory effects of intravenous heparin, suggested by animal studies, decrease the amount of local cytokine production, leukocyte migration, and tissue destruction. 4. Anticoagulation in the acute stage prevents deep venous thrombosis and pulmonary embolism, especially after a hemiplegic stroke. However, despite these arguments, the use of unfractionated or low-molecular-weight heparin (LMWH) in the acute stroke setting is not supported by current evidence. In 1997, the IST evaluated the use of subcutaneous unfractionated heparin in the acute stroke setting. Chosen outcomes measures were death at 14 days and death and dependency at 6 months. The investigators used a factorial design in which patients were given subcutaneous unfractionated heparin (5000 IU or 12,500 IU twice a day), placebo in addition to aspirin (300 mg/day), or placebo. Treatment was started within 48 hours of an acute stroke and continued for 14 days. Among heparin-treated patients, there were nonsignificantly fewer deaths within 14 days than among patients who received no heparin (9.0% versus 9.3%, respectively), corresponding to 3 fewer deaths for every 1000 patients treated. Also, there was no difference between the groups in dead or dependent patients at 6 months. Patients receiving heparin had significantly fewer recurrent ischemic strokes within 14 days (2.9% versus 3.8%), a finding offset by a similar increase in hemorrhagic strokes (1.2% versus 0.4%). Heparin use was also associated with a greater risk of any extracranial hemorrhage and hemorrhages necessitating transfusion; the higher risks were present with higher heparin doses. The nonsignificant decrease in deaths at 14 days was similar to that observed with the use of aspirin alone. Indeed, the reduction at 6 months in death or nonfatal recurrent stroke was greater in the aspirin group than in the heparin group, predominantly because of lower rates of ICH in the aspirin-treated group. The conclusion drawn from this study was that heparin is of no obvious benefit in the prevention of either stroke recurrence, death, or disability, and therefore there is no support for the use of high-dose subcutaneous heparin (exceeding 5000 IU twice daily) in the acute stroke setting.96 The major limitations of the IST study were the open-label nature of the study,
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment absence of initial CT scan in up to one third of all patients, lack of anticoagulation parameter control in the heparin-treated patients, and lack of weight adjustment of the heparin dose. In the late 1980s, Duke and colleagues investigated the role of intravenous unfractionated heparin or placebo up to 24 hours after an acute, stable, noncardioembolic ischemic stroke. Rates of stroke progression, death, and recovery were similar in the two groups.99 Many smaller studies and case series have been published since, with most results suggesting no benefit from acute use of intravenous unfractionated heparin. The use of LMWH in acute ischemic stroke has also been investigated in small studies, the majority of which revealed no significant benefit of subcutaneous LMWH in the prevention of recurrence or death after an acute ischemic stroke. Most notable, the Tinzaparin in Acute Ischemic Stroke Trial (TAIST) evaluated the efficacy of two different doses of subcutaneous LMWH (tinzaparin), in comparison with aspirin, for 10 days after an acute ischemic stroke. The results revealed no differences in outcome of clinical deterioration and stroke recurrence in 15 days or in modified Rankin Scale score at 6 months between the two groups, in all subtypes of ischemic stroke, including cardioembolic stroke. There was a higher rate of symptomatic intracranial hemorrhage in the tinzaparin-treated patients and a higher rate of venous thromboembolism in the aspirin-treated patients.100 The Trial of ORG 10172 in Acute Stroke Treatment (TOAST) enrolled approximately 1300 patients to receive either placebo or intravenous danaparoid (LMWH) for 7 days after an acute ischemic stroke.101 The primary endpoint was a favorable outcome (based on scores on the Glasgow Outcome Scale and the Barthel index) at 3 months. The level of anticoagulation was corrected according to anti–factor Xa levels. The outcomes of neurological worsening and recurrent ischemic stroke at 7 days and the 3-month outcomes were similar in the two groups. When the subgroups were evaluated according to stroke subtype, the early recurrence rates for patients with cardioembolic stroke were similar in the two treatment groups. However, in contrast to the TAIST trial, the only patients who showed a trend toward benefit from intravenous danaparoid were those with LAA. When embolic stroke subtypes are considered, the results of the Heparin in Acute Embolic Stroke (HAEST) trial provide some insight.102 It was a double-blind, randomized investigation of the effectiveness of LMWH (dalteparin) given subcutaneously in comparison with aspirin (160 mg/day) in patients with an acute stroke presumably secondary to atrial fibrillation. The patients were assigned to receive either dalteparin or aspirin within 30 hours of the ischemic stroke and were treated for 10 days. The primary outcome of recurrent stroke within 14 days occurred in 7.5% of the aspirin-treated patients and 8.5% of the dalteparin-treated patients, with a trend toward more ICH in the dalteparin-treated group. This study emphasizes that the recurrence after a cardioembolic stroke is lower than previously thought and that emergency anticoagulation may be more harmful than helpful. In summary, the role for acute heparin use after an ischemic stroke, including those with a cardioembolic mechanism, is not supported by current evidence.103 In some cases, however, scenarios may arise that were not systematically investigated by existing trials. In such scenarios, the underlying pathophysiology (arterial dissection, “stuttering” TIAs, acutely symptomatic critical arterial stenosis, large left ventricular thrombus) might
577
nonetheless justify anticoagulation. In these circumstances, a careful weighing of the (at best theoretical) benefit of acute anticoagulation against its risks should be the rule.
Oral Anticoagulation Cardioembolic Strokes Atrial fibrillation, valvular heart disease, prosthetic valves, and reduced cardiac contractility predispose to ischemic stroke by blood stasis, thrombus formation, and distal embolization. Stroke registries have shown cardioembolic strokes to represent about 25% of all ischemic stroke subtypes. The annual risk of stroke in chronic atrial fibrillation ranges from 5% to 12% a year, with the highest statistics in patients with other risk factors, concomitant valvular disease, and a prior stroke. The importance of atrial fibrillation is evident when its prevalence in the population is considered: 5% of persons at the age of 65 and 10% of persons aged 80 or older have chronic atrial fibrillation. Atrial fibrillation does not put all patients at the same risk level. The presence of other risk factors such as age older than 65, prior stroke or TIA, hypertension, and impaired left ventricular function increase the risk considerably in comparison with absence of those risk factors (“lone” atrial fibrillation). Women older than 75 and diabetic patients also have an increased risk of stroke. In view of the modest benefit of aspirin in both primary and secondary stroke prevention in patients with atrial fibrillation, various studies investigated warfarin as a more effective prophylactic agent. Multiple randomized clinical trials established the effectiveness of warfarin for both primary and secondary stroke prevention in patients with chronic atrial fibrillation.104 When all results are considered, warfarin has shown relative risk reductions of 59% in primary prevention and 68% in secondary prevention, with overall acceptable bleeding risk ranging from 0.3% to 2.0% per year. These results are put into perspective when the absolute risk reductions for warfarin (3% per year for primary prevention and 8% per year for secondary prevention) are compared with those of aspirin (1.5% and 2.5%, respectively). The recommended intensity of anticoagulation in nonvalvular atrial fibrillation is an international normalized ratio (INR) between 2.0 and 3.0, given the increased risk of bleeding with higher levels.105 On the basis of the trial results, the choice to administer anticoagulants to patients with atrial fibrillation (either chronic or paroxysmal) should be based on stratification of their stroke risk. All patients with a prior cardioembolic stroke or TIA should undergo long-term anticoagulation unless a strong contraindication is present. For primary prevention, the patients who would benefit the most from long-term anticoagulation are the ones with the risk factors mentioned previously. For patients without risk factors (lone atrial fibrillation) and/or younger than 65, aspirin is justifiable, in view of the low incidence of ischemic stroke (1% per year). Alternative oral anticoagulants are under investigation for stroke prevention in patients with atrial fibrillation. The Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF III) trial was a study of ximelagatran, a non–vitamin K-dependent direct thrombin inhibitor.106 It was an open-label study that randomly assigned patients with atrial fibrillation and one or more other stroke risk factors to receive
578
Section
IX
C e r e b r o va s c u l a r D i s e a s e
either dose-adjusted warfarin (target INR of 2.0 to 3.0) or fixed-dose ximelagatran (36 mg twice daily). Results showed that patients receiving ximelagatran had fewer ischemic strokes or systemic emboli than did those receiving warfarin (1.6% versus 2.3% per year, respectively), with a relative risk reduction of 29%. Rates of disabling or fatal stroke, mortality, and major bleeding were similar in both groups, but combined minor and major hemorrhage rates were lower with ximelagatran than with warfarin (29.8% versus 25.8% per year). The major side effect from ximelagatran in this study was elevation in serum alanine aminotransferase level. The major advantages of this direct thrombin inhibitor over warfarin are the fixed dose with more predictive effects without the need for constant monitoring and the lack of significant food or drug interactions. Liver toxicity is the main limitation, and the use of ximelagatran is not currently approved in the United States. There is less evidence for the use of chronic anticoagulation in other cardiac conditions such as valvular heart disease and severely reduced left ventricular function. Dilated cardiomyopathy predisposes to thrombus formation in as many as 50% of affected patients and is therefore a significant risk factor for cardioembolic stroke (3% to 4% per year). Currently, two large trials (Warfarin vs. Aspirin in Reduced Ejection Fraction [WARCEF] and Warfarin and Antiplatelet Trial in Chronic Heart Failure [WATCH]) are evaluating the benefits of chronic anticoagulation over the use of aspirin in the rates of stroke and death in patients with severely reduced ejection fraction (<35%).107 Previous myocardial infarction confers a risk of stroke of 1% to 2% per year, with higher rates in the first 3 months after the event and particularly with anterior wall myocardial infarction. The modest risk reduction offered by conventional dosages of warfarin balanced against the increased risk of hemorrhagic complications does not allow the recommendation of long-term anticoagulation in unselected patients after a myocardial infarction. In patients with an anterior wall myocardial infarction, in whom the risk of mural thrombus formation can be as high as 40%, and in patients with documented ventricular thrombus, in whom the annual risk of systemic embolization may be as high as 20%, anticoagulation with warfarin is indicated. Despite the lack of randomized studies, current practice is for patients to receive anticoagulants for 6 months after an anterior wall myocardial infarction with documented intraventricular thrombus. Resolution of the thrombus should be assessed by serial echocardiographic studies and the length of therapy adjusted accordingly. In cases of an anterior wall myocardial infarction but no documented thrombus, a shorter period of anticoagulation is reasonable. Prosthetic valves also carry a high risk of systemic embolization and therefore are a significant risk factor for cardioembolic stroke. Mechanical valves carry a greater risk and warrant lifelong anticoagulation with warfarin with a target INR of 2.5 to 3.5. The combination of aspirin and warfarin provides more protection than does warfarin alone but at the expense of more bleeding complications. Bioprosthetic valves carry a smaller risk and do not necessitate long-term anticoagulation. In those instances, warfarin is often used in the first 3 months when the risk of embolization is greatest. Long-term anticoagulation is recommended for patients with bioprosthetic valves and other risk factors for atrial stasis such as mitral valve prosthesis, atrial fibrillation, and documented left atrial thrombus.
Noncardioembolic Stroke Traditionally, neurologists used long-term anticoagulation in patients with noncardioembolic stroke in whom secondary prevention with aspirin was deemed ineffective (“aspirin failure”). The poor prognosis associated with strokes secondary to intracranial atherosclerosis despite the use of antiplatelet agents has also been a common justification for long-term anticoagulation. Two studies have shed light onto these two issues. The WARSS was the first large trial to investigate whether warfarin was superior to aspirin for the secondary prevention of noncardioembolic ischemic stroke. It was a multicenter, double-blind, randomized trial that enrolled more than 2200 patients to receive either aspirin (325 mg/day) or warfarin for a target INR of 1.4 to 2.8. At the 2-year follow up, the primary endpoint of recurrent stroke or death was observed in 16% of patients receiving aspirin and 17.8% of those receiving warfarin; these percentages represented a statistically insignificant difference. The beneficial effects of warfarin seemed to be mostly in the INR range of 1.5 without significant additive benefits above that range. The endpoint was achieved in a similar proportion of patients in both groups regardless of the underlying stroke etiology, with a comparable rate of bleeding complications in the two groups (2.22%/year for warfarin and 1.49%/year for aspirin). The WARSS investigators concluded that aspirin and warfarin are equivalent in efficacy in the secondary prevention of noncardioembolic strokes, with a comparable relatively low risk of bleeding complications.108 The risk of recurrent stroke in large-vessel intracranial atherosclerosis can be as high as 10% per year. The retrospective portion of the Warfarin Aspirin for Symptomatic Intracranial Disease (WASID) trial evaluated the efficacy of anticoagulation in comparison with antiplatelet therapy for the secondary prevention of strokes attributable to posterior circulation intracranial atherosclerosis.109 The results of the retrospective analysis, showing recurrence rates of 10.4% per year in the aspirin recipients and 3.6%/year in the warfarin recipients, led to a prospective trial. The prospective part of the WASID study was a double-blind randomized trial that enrolled patients with symptomatic, angiographically proven, high-degree (>50% diameter reduction) intracranial stenosis. Patients were assigned to receive either warfarin (INR goal of 2.0 to 3.0) or aspirin (1300 mg/day). Determination of recurrent stroke or vascular death at 3-year follow-up was planned, but the study was prematurely interrupted after a mean follow-up of only 1.8 years because interim analysis showed higher rates of major hemorrhagic complications in the warfarin-treated group (8.3% for warfarin versus 3.2% for aspirin). The rates for all strokes or vascular death were similar in both groups (21.8% for warfarin versus 22.1% for aspirin). These results argue against the widespread practice of chronic anticoagulation for patients with symptomatic intracranial atherosclerosis.18 However, they also attest to the inadequacy of either medication. Further evidence for the nonsuperiority of warfarin over aspirin was provided by a Cochrane review.110 A meta-analysis of five trials (>4000 patients) that compared anticoagulation with antiplatelet therapy for the secondary prevention of noncardioembolic strokes showed similar rates of recurrent stroke at all levels of anticoagulation (INR ranges 1.4 to 2.8, 2.1 to 3.6, and 3.0 to 4.5) in comparison with antiplatelet therapy. Major bleeding rates were significantly higher in patients receiving high-intensity anticoagulation but similar in the patients
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment receiving low- and medium-intensity anticoagulation in comparison with antiplatelet therapy.
Strokes Associated with Antiphospholipid Antibodies The best therapy, antiplatelet or anticoagulation, for patients with stroke who also have positive results on tests for antiphospholipid antibody is still a matter of debate. A WARSS substudy, the Antiphospholipid Antibodies and Stroke Study (APASS), sought to answer this question. Of the 1770 patients from WARSS who had blood tests for antiphospholipid antibodies, 41% were found to have positive results. These patients showed no differences in the rates of death or thrombotic events in comparison with those who had negative results for antibodies. Of more importance, there was no difference in outcome of recurrent stroke or death when the treatment with either aspirin or warfarin was considered.111 However, the WARSS population had an average age of more than 50, and the study was not powered to answer questions of antibody titer or subtype. It remains possible that patients younger than 45 with high titers of immunoglobulin G antiphospholipid antibody, who evidence suggests are at risk for arterial stroke as well as venous thrombosis, might benefit from anticoagulation.
Stroke Associated with a Patent Foramen Ovale In patients with a cryptogenic stroke and a documented PFO, the best strategy for secondary prevention has been a matter of intense debate. The results of a prospective study evaluating young patients (<55 years old) with cryptogenic stroke and a PFO found the risk of recurrent stroke to be 15% over 4 years, with aspirin, when the PFO was associated with an ASA. This recurrence rate was dramatically higher than for isolated PFO112 and suggested that aspirin is inadequate. The Patent foramen ovale In Cryptogenic Stroke Study (PICSS), another substudy of WARSS, is the only randomized, double-blind study to investigate the best medical management of PFO.113 Six hundred and thirty patients from WARSS underwent a transesophageal examination; a PFO was found in 39% of patients with cryptogenic strokes and in 29.9% of patients with other known causes. Besides reinforcement of the notion of a PFO being a risk factor for a first-ever stroke, other aspects of the PICSS results are worth noting: 1. For the entire study population, there was no significant difference in the primary outcome between the groups with and without a PFO and in the groups with a cryptogenic or other known stroke mechanism. 2. The size of the PFO and the presence of an associated ASA were not determinants of recurrent stroke. 3. After 2 years of follow-up, the rates of recurrent stroke or death were similar in the patients treated with warfarin and those treated with aspirin (16.5% and 13.2%). These results do not support long-term anticoagulation for unselected patients with a cryptogenic stroke and a PFO, without a known underlying venous thrombosis or a hypercoagulable state. Unfortunately, the average age of the patients in WARSS was 59, and so the applicability of these results to the population younger than 45 without conventional risk factors is highly questionable. The role for endovascular or surgical
579
closure of such a defect is currently being investigated by a clinical trial and cannot be routinely recommended at this point; however, closure might be appropriate in a young patient with stroke who is found to have a large PFO and associated ASA.
Blood Pressure Control for Secondary Stroke Prevention Many studies have shown the benefit of blood pressure control in primary stroke prevention, but only a few studies have assessed the effect of blood pressure control on secondary stroke prevention. The Heart Outcomes Prevention Evaluation (HOPE) study was a double-blind, randomized trial that investigated the role of angiotensin-converting enzyme (ACE) inhibitor (ramipril) as a protective strategy for patients with evidence of coronary artery disease, peripheral vascular disease, or prior stroke. Diabetes and at least one vascular risk factor were required for inclusion in the study. The study had a 2 × 2 factorial design in which 9297 patients were randomly assigned to receive ramipril (10 mg/day), vitamin E (400 IU/day), or placebo. Patients were monitored for over 5 years. Primary endpoints were myocardial infarction, stroke, and vascular death. Approximately 11% of patients in both ramipril and placebo groups had a history of prior stroke, and approximately 80% had a history of coronary artery disease. There was a statistically significant reduction in all primary outcomes in the ramipril recipients, in comparison with the placebo recipients (14% versus 17.8%). Stroke was the primary outcome in 3.4% of patients receiving ramipril and 4.9% of those receiving placebo. Fatal strokes occurred in 0.4% and 1.0%, and ischemic strokes in 2.2% and 3.4%, of patients receiving ramipril and the placebo groups, respectively.114 Only a small part of the benefit was attributable to reduction in blood pressure, inasmuch as only a minority of patients were hypertensive at baseline. A benefit for ramipril was observed regardless of the degree of blood pressure reduction.115 These results, although more applicable to primary stroke prevention in patients at high risk, make a strong case for long-term ACE inhibitor therapy as part of secondary stroke prevention, perhaps independent of baseline blood pressure. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was conducted to investigate the effects of a blood-pressure regimen with the ACE inhibitor perindopril on hypertensive and nonhypertensive patients with prior stroke or TIA. The study enrolled 6105 patients with a history of a prior stroke or TIA in the preceding 5 years, and they were randomly assigned to receive placebo or active treatment consisting of perindopril (4 mg/day) with or without the addition of the thiazide diuretic indapamide (2 to 2.5 mg/day), at the discretion of the treating physician (58% received combination therapy and 42% received perindopril alone). More individuals with baseline hypertension were identified in PROGRESS than in the HOPE trial. The primary outcome was fatal or nonfatal stroke. After 4 years of follow-up, 10% of patients receiving perindopril and 14% of patients receiving placebo had had a stroke, with an annual rate of stroke of 2.7% and 3.8%, respectively. This reduction occurred with both ischemic and hemorrhagic strokes, and fewer patients receiving perindopril had had fatal or disabling strokes. The association of perindopril with indapamide conferred a 43% relative risk reduction in comparison
580
Section
IX
C e r e b r o va s c u l a r D i s e a s e
with placebo, whereas the use of perindopril alone had no discernible effect in stroke risk reduction. This medication combination was also associated with a more significant blood pressure reduction than the one produced with perindopril alone (12/5 mm Hg versus 5/3 mm Hg), and the benefit was observed in patients with or without hypertension at baseline.116 Whether the results observed were secondary to blood pressure control or to a direct effect of both the ACE agent and the diuretic remains unknown. The PROGRESS and HOPE studies suggest that ACE inhibitors, together with antithrombotics, should be considered first-line agents for secondary stroke prevention.
Cholesterol-Reducing Strategies Most prospective studies of cholesterol-lowering strategies have focused on ischemic heart disease. Only a few trials have focused on statin agents and secondary stroke prevention. The Heart Protection Study (HPS) was a randomized trial in which simvastatin (40 mg/day) was compared with placebo for prevention of vascular events (myocardial infarction, stroke, vascular death) in patients at high risk between 40 and 80 years old. High risk was defined as having prior occlusive arterial disease, diabetes, and elevated cholesterol. More than 3000 of the total 20,000 patients had a history of ischemic stroke or TIA. Over 5 years, the mean total cholesterol was reduced by 20%, and the odds for all ischemic strokes were reduced by 25% and for fatal strokes by 19%. All major vascular events were decreased by 30% in the simvastatin recipients. Of importance, ICH was observed with equal frequency in the two groups.117 In other smaller trials (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm [ASCOT-LLA]; Cholesterol and Recurrent Events [CARE]; Long-term Intervention with Pravastatin in Ischaemic Disease [LIPID]; and Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE IT]), researchers also examined the effect of various statins on prevention of vascular events, including strokes. Most showed a 15% to 25% reduction in the incidence in TIA or stroke. However, although these results show that statins are effective as a primary prevention strategy for TIA/stroke in patients at high risk, their effects on secondary prevention cannot be fully appreciated, because most patients enrolled in such studies were stroke free. Another unexpected result from these studies is the possibility that statins might be as effective in patients with normal cholesterol levels as they are in patients at high risk with elevated total cholesterol, elevated low-density lipoprotein, and low high-density lipoprotein levels. Current recommendations are that all patients with prior stroke and elevated cholesterol levels should take a statin. For patients with a prior TIA/stroke and other vascular risk factors, the use of statins also seems indicated. More data are necessary to determine whether a statin is indicated for patients with TIA/stroke but without elevated cholesterol or other vascular risk factors. In addition to antiplatelet, blood pressure, and cholesterollowering medications, lifestyle modification, through smoking cessation, dietary changes, increased physical activity, and moderate alcohol consumption, should also be encouraged. Tight control of glucose levels in diabetic patients
is also an important component of secondary stroke prevention.
Control of Other Potential Risk Factors Elevated Homocysteine Level Elevated blood homocysteine levels have been observed in patients with coronary artery disease, as well as in patients with a prior TIA/stroke. Whether these represent a marker of advanced atherosclerosis or have a causal role in the pathogenesis of vascular disease remains to be determined. Blood homocysteine levels are inversely related to the dietary intake of folic acid, vitamin B6, and vitamin B12. However, whether dietary supplementation with these vitamins to lower homocysteine levels decreases cardiovascular risk is uncertain. In the Vitamin Intervention for Stroke Prevention (VISP) trial, in which more than 10,000 patients with a prior TIA/stroke were given vitamin supplementation (folate, vitamin B6, and vitamin B12) or placebo, results showed that vitamin supplementation did not reduce the risk of recurrent stroke over 2 years.118 The Vitamins To Prevent Stroke (VITATOPS) study was also an evaluation of the effect of vitamin supplementation on a large population of patients with prior TIA/stroke. Preliminary results revealed no significant reduction in markers of vascular inflammation (C-reactive protein) or hypercoagulability (prothrombin fragments, D-dimer), despite reduction in total homocysteine levels.119,120 The benefits, if any, on stroke recurrence will be known only after completion of the study. Routine use of folic acid, cobalamin, and pyridoxine supplementation is not currently recommended for secondary stroke prevention.
Hormone Replacement Therapy The use of hormone replacement therapy, with either estrogen or a combination of estrogen and progesterone, has increased dramatically since the mid-1990s. The main indication is prevention of postmenopausal osteoporosis. Accumulating evidence, however, points to an increased risk of cardiovascular disease. In the Women’s Estrogen for Stroke Trial (WEST), estrogen replacement was compared with placebo in more than 600 menopausal women with a history of a prior TIA/stroke. After a mean follow-up period of 2.8 years, estrogen was not shown to provide any protection against minor strokes (odds ratio = 1.0) but was shown to be associated with increased risk of fatal strokes in comparison with placebo (odds ratio = 2.8). Even though the numbers of minor strokes were comparable in both groups, strokes in the estrogen recipients were associated with slightly worse neurological and functional deficits.121 Those results were reinforced by the Women’s Health Initiative (WHI) study. The main goal of the WHI study was to investigate primary prevention of cardiovascular disease in postmenopausal women and hormone replacement therapy. Nevertheless, it demonstrated an odds ratio for ischemic stroke of 1.5, independent of all other stroke risk factors.122 On the basis of these results, hormone replacement therapy is not recommended as primary prevention for stroke and certainly should not be used in women with a history of prior TIA/stroke. In postmenopausal women without cardiovascular risk factors, its use may be considered if truly indicated.
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment Surgical and Interventional Strategies for Secondary Stroke Prevention Carotid Endarterectomy In the early 1980s, resection of the stenotic portion of the ICA, or carotid endarterectomy (CEA), was a common surgical procedure. The conviction that CEA was an optimal form of secondary stroke prevention arose from recognition of the fact that large-artery atherosclerotic strokes are associated with a high rate of early recurrence. However, in the middle to late 1980s, the uncertainty about the efficacy of CEA in comparison with optimal medical therapy and the failure of the extracranialintracranial bypass trial led to a decrease in enthusiasm for the CEA. However, in 1991, the North American Symptomatic Carotid Endarterectomy (NASCET) trial published its results.123 There was an absolute risk reduction in the incidence of recurrent stroke of 17% for CEA in comparison with medical treatment in symptomatic patients with ICA stenosis of more than 70% diameter reduction. In absolute numbers, strokes recurred within 2 years in 26% of the medically treated patients and 9% of the surgically treated patients; this was a 66% relative risk reduction for CEA. The risks of major or fatal ipsilateral stroke in the surgically and medically treated patients were 2.5% and 13.1%, respectively.16 When all centers were considered, the overall surgical morbidity and mortality rate was 5.8%. In their latest results, the NASCET investigators found that in patients with a moderate degree of ICA stenosis (50% to 69% diameter reduction), the benefit was more modest, with a 5-year rate of stroke in the surgically and medically treated patients of 15.7% and 22.2%, respectively.124 The Veterans Affairs Cooperative Study yielded similar results, with an absolute risk reduction of 11.7% for surgery versus medical therapy at 1 year of follow-up. Patients had ICA stenosis that ranged from 50% to 99% diameter reduction, and, as in the NASCET trial, the results showed greater benefit for patients with higher degrees of stenosis. The perioperative morbidity and mortality rate was approximately 5%.125 The European Carotid Surgery Trial (ECST) was conducted around the same time as the two other CEA trials. There were some important differences between ECST and NASCET, which led to slightly different results. The main methodological differences were in the angiographic measurement of the degree of stenosis (the ECST method overestimated degree of stenosis in comparison with the NASCET method) and in the definition of the stroke outcome (ECST defined stroke as a deficit persistent for >7 days, and NASCET defined stroke as a neurological deficit persisting for >24 hours). The final ECST results for 3-year risk of stroke or death showed a 26.5% risk in medically treated patients with a symptomatic ICA stenosis of more than 80% diameter reduction, and a 14.9% risk for patients undergoing CEA; the absolute benefit for surgery was 11.6%. The risk of major stroke or death complicating surgery was 7%.126-128 Reanalysis of the ECST results, with degree of stenosis recalculated with the NASCET method, revealed an absolute risk reduction of 21.2% for 5-year risk of stroke or death after CEA in comparison with medical treatment in patients with ICA stenosis of 70% to 99% diameter reduction.128 Various post hoc analyses have been performed to further stratify recurrent stroke and surgical risk in patients with symptomatic high-degree ICA stenosis in order to better select
581
patients who will maximally benefit from CEA. In medically treated patients, certain features other than the degree of stenosis are associated with a higher risk of stroke. These include absence of adequate collateral circulation on angiogram, ulcerated plaque or intraluminal thrombus, contralateral occlusion, male gender, hemispherical as opposed to retinal symptoms, and stroke as opposed to TIA as the presenting syndrome. Similarly, for patients treated with CEA, certain features are predictive of higher risk of perioperative stroke. These include female gender, age older than 75, contralateral occlusion, intraluminal thrombus, ulcerated plaque, peripheral vascular disease, and neurological instability. Traditionally, CEA was delayed for 4 to 6 weeks after an acute stroke to reduce the risk of ICH, perhaps caused by reperfusion at higher pressure than the hemisphere was used to. However, an analysis of pooled NASCET and ECST data showed maximal benefit from CEA if it was performed within 2 weeks of nondisabling stroke. Similar information on timing of CEA after TIA is not available, but in view of data that show a greater risk of stroke after TIA than after stroke, it is likely that these patients should also undergo CEA within a week or two, as long as they are stable. The smallest benefit of CEA was observed in patients undergoing operation after 12 weeks. To qualify for these trials, patients had to have had an ipsilateral event within 6 months of random assignment. At 2 years, the annual stroke risk never exceeded 3%. Another reanalysis showed a small benefit for CEA with stenosis of 50% to 69% diameter reduction and no benefit for 30% to 49% diameter reduction. Symptomatic complete ICA occlusion is a special case that is not amenable to CEA. No benefit was observed for extracranial-intracranial bypass surgery in unselected patients in a trial in 1985,129 which failed to show a benefit from the surgical procedure as a result of high complication rates. However, the elevated risks of recurrent stroke in this patient population (as high as 14% per year in some studies), justifies another trial with better selection of candidates based on preoperative evaluation of hemodynamic reserve, because it is thought that recurrent stroke in these patients is caused by flow failure rather than embolus. The Carotid Occlusion Surgery Study is currently under way and aims to determine whether extracranial-intracranial bypass is superior to medical therapy in patients with recently symptomatic unilateral ICA occlusion and with evidence on PET scan for misery perfusion with increased OEF. Although these results are not available, risk factor modification, antiplatelet medications, and aggressive cholesterol control are the recommended treatment modalities for these patients.
Angioplasty and Stenting Angioplasty and stenting are currently considered preferable to surgery in cases of ICA stenosis secondary to prior radiation therapy in the neck, previous CEA with recurrent stenosis, contralateral ICA occlusion, and surgically inaccessible high bifurcation of the common carotid artery.130 In addition, angioplasty and stenting might be preferable in patients with multiple comorbid conditions who might not be ideal surgical candidates. The efficacy of angioplasty and stenting in comparison with CEA remains to be determined by ongoing trials (Carotid Revascularization Endarterectomy versus Stent Trial [CREST]; Stent-protected Percutaneous Angioplasty of the Carotid vs. Endarterectomy [SPACE]; International Carotid Stenting Study
582
Section
IX
C e r e b r o va s c u l a r D i s e a s e
of the Carotid and Vertebral Artery Transluminal Angioplasty Study [CAVATAS-2]). The first large study to compare the safety and efficacy of CEA and angioplasty was the Carotid and Vertebral artery Transluminal and Angioplasty Study (CAVATAS). About 500 patients were randomly assigned to undergo either CEA or angioplasty (with or without stent implantation) and were monitored for 1 year. Major perioperative morbidity, mortality, and stroke rates were similar in the two groups at 30 days, and stroke rates were similar at 1 year, although the rate of restenosis was greater for the patients who underwent angioplasty. Of importance, angioplasty was followed by stent implantation, a procedure thought necessary to maintain vessel patency, in only 26% of the patients undergoing endovascular treatment. In addition, no distal protection device to minimize embolization was used in this trial.131 CAVATAS-2 is currently under way and should answer some questions with regard to equivalency to CEA, when both stent deployment and distal protection devices are used during the endovascular procedure. The recent Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial was designed to determine the noninferiority of angioplasty with stent implantation with ICA stenosis in comparison with CEA. The SAPPHIRE study showed a 7.9% absolute benefit in the outcome of stroke/myocardial infarction/death at 30 days and ipsilateral stroke or death at 1 year in favor of angioplasty with stent implantation over CEA in patients considered to be at high risk (with associated medical comorbid conditions). For the patients undergoing angioplasty and stent implantation, the perioperative morbidity and mortality rate was about half of that observed after CEA. However, a major problem with this study is that almost 70% of the patients were asymptomatic. It is already known from the CEA trials for high-grade asymptomatic carotid stenosis (see Chapter 46) that patients with medical comorbid conditions should not undergo operation because they need to be alive at 5 years to show the modest benefit. Thus, it is not clear why asymptomatic patients with associated medical comorbid conditions should undergo angioplasty and stent implantation at all. What are needed are studies of angioplasty with stent implantation versus CEA as a secondary prevention strategy in patients without comorbid conditions and those at high risk. The ongoing CREST should answer the former question. Angioplasty and stent implantation for symptomatic intracranial stenoses remain investigational and controversial. The seriousness of intracranial atherosclerosis was made plain by the WASID study (discussed previously), which showed, over a 1.8-year follow-up period, that ischemic stroke recurrence rate for intracranial stenoses of more than 50% diameter reduction ranged from 17% to 20%, almost half being fatal or disabling strokes. In view of this poor prognosis and the lack of better secondary prevention strategies, small studies have been performed to investigate safety, feasibility, and efficacy of interventional procedures in patients with symptomatic intracranial atherosclerosis. A review of a single center’s experience with intracranial stent implantation over a 6-year period revealed a very high overall periprocedural complication rate of 28% for patients in whom the procedure was deemed a last resort.132 Unfortunately, the idea of last resort assumes good natural history data for medically treated symptomatic intracranial stenoses; however, such data are not available. There have been two studies of elective stent implantation with symptomatic M1 stenosis. The rationale for pursuing this treatment is that
symptomatic M1 stenosis carries an annual stroke recurrence rate of about 8%. One study enrolled 14 patients, and the other enrolled 40. The former had morbidity and mortality rates of 33.3% and 8.3%, respectively; the latter, 10% and 2.5%. In the larger study, M1 lesions were classified on the basis of their location, morphology, and access. All three factors were relevant to periprocedural complication rates and efficacy at 10month median follow-up. The Stenting for Symptomatic Atherosclerotic Lesions in the Vertebral and Intracranial Arteries (SSYLVIA) trial, the only prospective multicenter trial of intracranial angioplasty and stent implantation to date, investigated the feasibility of intracranial stent implantation for patients with symptomatic intracranial LAA. In 95% of the patients, a stent was successfully deployed with a 30-day stroke rate of 6.6%. All strokes were observed in the posterior circulation, but no deaths occurred. At 6 months, one third of the patients after intracranial stent implantation experienced restenosis involving more than 50% diameter reduction, about 40% of these stenoses being symptomatic. SSYLVIA had important limitations. First, patients who entered this trial were not “medication failures”; that is, they had not necessarily received currently accepted maximal medical therapy (antiplatelets, statins, and aggressive risk factor modification). Second, it was not a randomized study; therefore, it could not answer the questions of whether intracranial angioplasty is superior to currently accepted medical therapy. These few studies indicate that angioplasty and stent implantation for symptomatic intracranial stenoses carry relatively high morbidity and mortality rates. However, the disease itself seems to have a poor natural history, according to existing data. Prospective randomized trials with a maximal medical therapy condition are needed.
K E Y
P O I N T S
●
Stroke is the third leading cause of death and the leading cause of long-term disability in the United States. Annually, about 700,000 strokes occur in the United States and 150,000 in the United Kingdom.
●
Eighty percent of strokes are ischemic, and 20% are hemorrhagic.
●
The majority of ischemic strokes can be classified, with regard to etiology, into one of the following groups: large artery, lacunar, embolic, cryptogenic, or stroke of other determined cause.
●
Identification of a patient’s stroke syndrome provides insight into underlying mechanism, prognosis, and plan for rehabilitation.
●
Large clinical trials often “lump” many stroke types together, but advances in diagnostic technology provides the capability to distinguish strokes into mechanistic subtypes. It can be predicted that future therapeutic trials will be directed at specific stroke subtypes in order to target specific pathophysiological mechanisms.
●
Stroke mortality has declined in the last few years, probably as a result of better medical care and dedicated stroke and neurointensive care units.
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment ●
Intravenous recombinant tissue plasminogen activator is approved for all ischemic stroke subtypes within 3 hours of onset if the inclusion and exclusion criteria are met. Advances in imaging of the ischemic penumbra may enable identification of patients who would benefit from intravenous tissue-type plasminogen activator outside the 3-hour window. Intra-arterial thrombolysis or mechanical extraction is an alternative treatment after the 3-hour window period.
●
Multiple clinical trials have established the efficacy of antiplatelet agents for secondary stroke prevention. Oral anticoagulation is the treatment of choice for primary and secondary stroke prevention in patients with atrial fibrillation.
●
Evidence does not support the use of heparin (either low-molecular-weight or unfractionated) in acute stroke treatment.
●
Carotid endarterectomy is well established as the treatment of choice for symptomatic patients with high-degree internal carotid artery stenosis. A lesser benefit is observed for asymptomatic patients, but more strict selection criteria should be used. Angioplasty and stent implantation in the carotid artery are available as alternative treatments for patients with high operative risk because of comorbid medical conditions or for surgically inaccessible lesions.
Suggested Reading Algra A, De Schryver ELLM, van Gijn J, et al: Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischemic attack or minor stroke of presumed arterial origin. Cochrane Database Syst Rev 2006; 3:CD001342. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325:445-453. Hacke W, Donnan G, Fieschi C, et al: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363:768-774. Hart RG, Palacio S, Pearce LA: Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke 2002; 33:2722-2727. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587.
References 1. American Heart Association: Heart Diseases and Stroke Statistics—2005 Update. Dallas: American Heart Association, 2005, pp 16-20. 2. Saver JL, Kidwell C: Neuroimaging in TIAs. Neurology 2004; 62(8, Suppl 6):S22-S25. 3. Rovira A, Rovira-Gols A, Pedraza S, et al: Diffusion-weighted MR imaging in the acute phase of transient ischemic attacks. AJNR Am J Neuroradiol 2002; 23:77-83. 4. Albers GW, Caplan LR, Easton JD, et al: TIA working group (2002). Transient ischemic attack—proposal for a new definition. N Engl J Med 2002; 347:1713-1716.
583
5. Ay H, Koroshetz W, Benner T, et al: Transient ischemic attack with infarction: a unique syndrome? Ann Neurol 2005; 57:679-686. 6. Hill MD, Yiannakoulias N, Jeerakathil T, et al: The high risk of stroke immediately after transient ischemic attack. Neurology 2004; 62:2015-2020. 7. Lovett JK, Dennis MS, Sandercock PAG, et al: Very early risk of stroke after a first transient ischemic attack. Stroke 2003; 34:e138-e142. 8. Lisabeth LD, Ireland JK, Risser JMH, et al: Stroke risk after transient ischemic attack in a population-based setting. Stroke 2004; 35:1842-1846. 9. Johnston SC, Gress DR, Browner WS, et al: Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000; 284:2901-2906. 10. Baron JC: Mapping the ischaemic penumbra with PET: implications for acute stroke treatment. Cerebrovasc Dis 1999; 9:193-201. 11. Wong EW, Pullicino PM, Benedict R: Deep cerebral infarcts extending to the subinsular region. Stroke 2001; 32:22722277. 12. Wong KS, Gao S, Chan YL, et al: Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study. Ann Neurol 2002; 52:74-81. 13. Jackson C, Sudlow C: Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke 2005; 36:891-901. 14. Alexandrov AV, Felberg RA, Demchuck AM, et al: Deterioration following spontaneous improvement: sonographic findings in patients with acutely resolving symptoms of cerebral ischemia. Stroke. 2000; 31:915-919. 15. Eliasziw M, Kennedy J, Hill MD, et al: Early stroke risk after a transient ischemic attack in patients with internal carotid artery disease. CMAJ 2004; 170:1105-1109. 16. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445-453. 17. Arenillas JF, Molina CA, Montaner J, et al: Progression and clinical recurrence of symptomatic middle cerebral artery stenosis: a long-term follow-up transcranial Doppler ultrasound study. Stroke 2001; 32:2898-2904. 18. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al: Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352:1305-1316. 19. Gasecki AP, Ferguson GG, Eliasziw M, et al: Endarterectomy for severe carotid artery stenosis after a nondisabling stroke: results from the North American Symptomatic Carotid Endarterectomy Trial. J Vasc Surg 1994; 20:288-295. 20. Gan R, Sacco RL, Kargman DE, et al: Testing the validity of the lacunar hypothesis: the Northern Manhattan Stroke Study experience. Neurology 1997; 48:1204-1211. 21. Ay H, Oliveira-Filho J, Buonanno FS, et al: Diffusion weighted imaging identifies a subset of lacunar infarction associated with embolic source. Stroke 1999; 30:2644-2650. 22. Kato H, Izumiyama M, Izumiyama K, et al: Silent cerebral microbleeds on T2*-weighted MRI: correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke 2002; 33:1536-1540. 23. Wardlaw JM: What causes lacunar stroke? J Neurol Neurosurg Psychiatry 2005; 76:617-619. 23a. Cerebrovasc Dis 2004; 17(Suppl 5):52. 23b. Macdonald RL, Kowalczuk A, Johns L: Emboli enter penetrating arteries of monkey brain in relation to their size. Stroke 1995; 26:1247-1250. 24. Wardlaw JM, Dennis MS, Warlaw CP: Imaging appearance of the symptomatic perforating artery in patients with lacunar
584
Section
IX
C e r e b r o va s c u l a r D i s e a s e
infarction: occlusion or other vascular pathology? Ann Neurol 2001; 50:208-215. 24a. Sen S, Laowatana S, Lima J, Oppenheimer SM: Risk factors for intracardiac thrombus in patients with recent ischemic cerebrovascular events. J Neurol Neurosurg Psychiatry 2004; 75:1421-1425. 24b. Hagen PT, Scholz DG, Edwards WD: Incidence and size of patient foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59:17-20. 25. Overell JR, Bone I, Lees KR: Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55:1172-1179. 25a. Karttunen V, Hiltunen L, Rasi V, et al: Factor V Leiden and prothrombin gene mutation may predispose to paradoxical embolism in subjects with patient foramen ovale. Blood Coagul Fibrinolysis 2003; 14:261-268. 25b. Pezzini A, Del Zotto E, Magoni M: Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke 2003; 34:28-33. 26. Mcleod MR, Amarenco P, Davis SM, et al: Atheroma of the aortic arch: an important and poorly recognised factor in the aetiology of stroke. Lancet Neurol 2004; 3:408-414. 27. Agmon Y, Khanderia BK, Meissner I, et al: Relation of coronary artery disease and cerebrovascular disease with atherosclerosis of the thoracic aorta in the general population. Am J Cardiol 2002; 89:262-267. 28. Amarenco P, Cohen A, Tzourio C, et al: Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474-1479. 29. Tunick PA, Perez JL, Kronzon I: Protruding atheromas in the thoracic aorta and systemic embolization. Ann Intern Med 1991; 115:423-427. 30. Chowdhury D, Wardlaw JM, Dennis MS: Are multiple acute small subcortical infarctions caused by embolic mechanisms? J Neurol Neurosurg Psychiatry 2004; 75:1416-1420. 31. Dziewas R, Konrad C, Drager B, et al: Cervical artery dissection—clinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003; 250:1179-1184. 32. Rubinstein SM, Peerdeman SM, van Tulder MW, et al: A systematic review of the risk factors for cervical artery dissection. Stroke 2005; 36:1575-1580. 32a. Arboix A, Lopez-Grau M, Casasnovas C, et al: Clinical study of 39 patients with atypical lacunar syndrome. J Neurol Neurosurg Psychiatry 2006; 77:381-384. 33. Paciaroni M, Caso V, Milia P: Isolated monoparesis following stroke. J Neurol Neurosurg Psychiatry 2005; 76:805-807. 34. Schmahmann JD: Vascular syndromes of the thalamus. Stroke 2003; 34:2264-2278. 35. Godefroy O, Dubois C, Debachy B, et al: Vascular aphasias: main characteristics of patients hospitalized in acute stroke units. Stroke 2002; 33:702-705. 36. Kumral E, Bayulkem G, Evyapan D, et al: Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings. Eur J Neurol 2002; 9:615-624. 37. Schneider R, Gautier JC: Leg weakness due to stroke. Site of lesions, weakness patterns and causes. Brain 1994; 117(Pt 2):347-354. 38. Kumral E, Kisabay A, Atac C: Lesion patterns and etiology of ischemia in superior cerebellar artery territory infarcts. Cerebrovasc Dis 2005; 19:283-290. 39. Caplan LR: “Top of the basilar” syndrome. Neurology 1980; 30:72-79. 40. Barber PA, Demchuk AM, Zhang J, et al: Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670-1674.
41. Hacke W, Kaste M, Fieschi C, et al: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 352:1245-1251. 42. Davis S, Fisher M, Warach S (eds): Magnetic Resonance Imaging in Stroke. Cambridge, UK: Cambridge University Press, 2003. 43. Li F, Silva MD, Sotak CH, et al: Temporal evolution of ischemic injury evaluated with diffusion-, perfusion-, and T2weighted MRI. Neurology 2000; 54:689. 44. Buskens E, Nederkoorn P, Tineke BW, et al: Imaging of carotid arteries in symptomatic patients: cost-effectiveness of diagnostic strategies. Radiology 2004; 233:101-112. 45. Long A, Lepoutre A, Corbillon E, et al: Critical review of nonor minimally invasive methods (duplex ultrasonography, MRand CT-angiography) for evaluating stenosis of the proximal internal carotid artery. Eur J Vasc Endovasc Surg 2002; 24:4352. 46. Johnston DCC, Goldstein LB: Clinical carotid endarterectomy decision making: noninvasive vascular imaging versus angiography. Neurology 2001; 56:1009-1015. 47. El-Saden SM, Grant EG, Hathout GM, et al: Imaging of the internal carotid artery: the dilemma of total versus near total occlusion. Radiology 2001; 221:301-308. 48. Wester P, Radberg J, Lundgren B, et al: Factors associated with delayed admission to hospital and in-hospital delays in acute stroke and TIA: a prospective, multicenter study. Stroke 1999; 30: 40-48. 49. Morris DL, Rosamond W, Madden K, et al: Prehospital and emergency department delays after acute stroke. The Genentech Stroke Presentation Survey. Stroke 2000; 31:2585-2590. 50. Kothari RU, Brott T, Broderick JP, et al: Emergency physicians: accuracy in the diagnosis of stroke. Stroke 1995; 26:2238-2241. 51. Ferro JM, Pinto AN, Falcao I, et al: Diagnosis of stroke by the nonneurologist. A validation study. Stroke 1998; 29:11061109. 52. Flynn EP, Auer RN: Eubaric hyperoxemia and experimental cerebral infarction. Ann Neurol 2002; 52:566-572. 53. Singhal AB, Dijkhuizen RM, Rosen B, et al: Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke. Neurology 2002; 58:945-952. 54. Pancioli AM, Bullard MJ, Grulee ME, et al: Supplemental oxygen use in ischemic stroke patients: does utilization correspond to need for oxygen therapy? Arch Intern Med 2002; 162:49-52. 55. Goldstein L: Blood pressure management in patients with acute ischemic stroke. Hypertension 2004; 43:137-141. 56. Lisk DR, Grotta JC, Lamki LM, et al: Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography. Arch Neurol 1993; 50:855-862. 57. Wahlgren NG, MacMahon DG, DeKeyser J, et al: Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischemic stroke. Cerebrovasc Dis 1994; 4:204-210. 58. Oliveira-Filho J, Silva SCS, Trabuco CC, et al: Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset. Neurology 2003; 61:1047-1051. 59. Rordorf G, Koroshetz WJ, Ezzeddine MA, et al: A pilot study of drug-induced hypertension for treatment of acute stroke. Neurology 2001; 56:1210-1213. 60. Pulsinelli WA, Waldman S, Rawlinson D, et al: Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology 1982:1239-1246. 61. Parsons MW, Barber A, Desmond PM, et al: Acute hyperglycemia adversely affects stroke outcome: a magnetic reso-
chapter 42 ischemic stroke: mechanisms, evaluation, and treatment
62. 63. 64.
65. 66. 67. 68. 69. 70. 71. 72.
73. 74.
75.
76. 77.
78. 79.
80. 81.
nance imaging and spectroscopy study. Ann Neurol 2002; 52:20-28. Baird TA, Parsons MW, Phanh T, et al: Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke 2003; 34:2208-2214. Bruno A, Levine SR, Frankel MR, at al: Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002; 59:669-674. Alvarez-Sabin J, Molina C, Ribo M, et al: Impact of admission hyperglycemia on stroke outcome after thrombolysis: risk stratification in relation to time to reperfusion. Stroke 2004; 35:2493-2499. Leigh R, Zaidat OO, Suri MF, et al: Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy. Stroke 2004; 35:1903-1907. Williams LS, Rotich J, Qi R, et al: Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology 2002; 59:67-71. Gray CS, Hildreth AJ, Alberti GKMM, et al: Poststroke hyperglycemia. Natural history and immediate management. Stroke 2004; 35:122-126. Bruno A, Saha C, Williams LS, et al: IV Insulin during acute cerebral infarction in diabetic patients. Neurology 2004; 62:1441-1442. Hajat CH, Hajat S, Sharma P: Effects of poststroke pyrexia on stroke outcome: a meta-analysis of studies in patients. Stroke 2000; 31:410-414. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557-563. The Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-556. Multicentre Acute Stroke Trial—Italy (MAST-I) Group: Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346:1509-1514. The Multicenter Acute Stroke Trial—Europe Study Group (MAST-E): Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335:145-150. Donnan GA, Davis SM, Chambers BR, et al: Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996; 276:961-966. Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274:1017-1025. The NINDS rt-PA Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581-1587. Kwiatkowski TG, Libman RB, Frankel M, et al: Effects of tissue plasminogen activator for acute ischemic stroke at one year. NINDS Recombinant Tissue Plasminogen Activator Stroke Study. N Engl J Med 1999; 10:1781-1787. Marler JR, Tilley BC, Lu M, et al: Early stroke treatment associated with better outcome. The NINDS rt-PA Stroke Study. Neurology 2000; 55:1649-1655. Broderick JP, Lu M, Kothari R, et al: Finding the most powerful measures of effectiveness of tissue plasminogen activator in the NINDS t-PA Stroke Trial. Stroke 2000; 31:2335-2341. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. NINDS rt-PA Stroke Study Group. Stroke 1997; 28:2109-2118. Clark WM, Wissman S, Albers GW, et al: Recombinant tissuetype plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS study: a randomized controlled trial. JAMA 1999; 282:2019-2026.
585
82. The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363:768-774. 82a. Wardlaw JM, Zoppo G, Yamaguchi T, Berge E: Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003; (3):CD000213. 83. Kidwell CS, Alger JR, Saver JL: Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke 2003; 34:27292735. 84. Barber PA, Parsons MW, Desmond PM, et al: The use of PWI and DWI measures in the design of “proof-of-concept” stroke trials. J Neuroimaging 2004; 14:123-132. 85. Kidwell C, Starkman S, Jahan R, et al: Pretreatment MRI penumbral pattern predicts good clinical outcome following mechanical embolectomy [Abstract]. Stroke 2004; 35:294. 86. Katzan IL, Furlan AJ, Lloyd LE, et al: Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000; 283:1151-1158. 87. Lopez-Yunez AM, Bruno A, Williams L, et al: Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke 2001; 32:12-16. 88. Katzan IL, Hammer MD, Furlan AJ, et al: Quality improvement and tissue-type plasminogen activator for acute ischemic stroke. A Cleveland update. Stroke 2003; 34:799-800. 89. Grotta J, Burgin WS, El-Mitwalli A, et al: Intravenous tissuetype plasminogen activator therapy for ischemic stroke. Arch Neurol 2001; 58:2009-2013. 90. Hill MD, Buchan AM: Canadian Activase for Stroke Effectiveness Study (CASES). Can J Neurol Sci 2001; 28:232-238. 91. Del Zoppo GJ, Higashida RT, Furlan AJ, et al: PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke 1998; 29:4-11. 92. Furlan AJ, Higashida RT Wechsler L, et al: Intra-arterial prourokinase for acute ischemic stroke—The PROACT II study: a randomized controlled trial. JAMA 1999; 282:2003-2011. 93. Lewandowski CA, Frankel M, Tomsick TA, et al: Combined intravenous and intra-arterial t-PA versus intra-arterial therapy for acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 1999; 30:2598-2605. 94. Tomsick T, Broderick JP, Pancioli AP, at al: Combined IV-IA tPA treatment in major acute ischemic stroke [Abstract]. Stroke 2002; 33:359. 95. Antithrombotic Trialists’ Collaboration: Collaborative metaanalysis of randomized trials of antiplatelet therapy for the prevention of death, MI, and stroke in high risk patients. BMJ 2002; 324:71-86. 95a. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. N Engl J Med 1991; 325:1261-1266. 95b. Farrell B, Godwin J, Richards S, Warlow C: The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54:1044-1054. 96. International Stroke Trial Collaborative Group: The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997; 349:1569-1581. 97. Chinese Acute Stroke Trial collaborative group: CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349:16411649. 97a. Maulaz AB, Bezerra DC, Michel P, Bogousslavsky J: Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 2006; 62:1217-1220.
586
Section
IX
C e r e b r o va s c u l a r D i s e a s e
98. Diener HC, Cunha L, Forbes C, et al: European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143:1-13. 99. Duke RJ, Bloch RF, Fong HC, et al: Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Ann Intern Med 1986; 105:825-828. 100. Bath PM, Lindenstrom E, Boysen G, et al: Tinzaparin in Acute Ischemic Stroke (TAIST): a randomised aspirin-controlled trial. Lancet 2001; 358:702-710. 101. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) investigators. JAMA 1998; 279:1265-1272. 102. Berge E, Abdelnoor M, Nakstad PH, et al: Low molecularweight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355:1205-1210. 103. Hart RG, Palacio S, Pearce LA: Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke 2002; 33:2722-2727. 104. Hart RG, Benavente O, McBride R, et al: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131:492-501. 105. SPIRIT study: a randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. Ann Neurol 1997; 42:857-865. 106. Olsson SB, Executive Steering Committee on behalf of the SPORTIF III Investigators: Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362:1691-1698. 107. Pullicino PM, Halperin JL, Thompson JL: Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology 2000; 54:288-294. 108. Mohr JP, Thompson JL, Lazar RM, et al: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345:1444-1451. 109. Chimowitz MI, Kokkinos J, Strong J, et al: The WarfarinAspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45:1488-1493. 110. Algra A, De Schryver ELLM, van Gijn J, et al: Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischemic attack or minor stroke of presumed arterial origin. Cochrane Database Syst Rev 2006; 3:CD001342. 111. Levine SR, Tilley BC, Thompson JL, et al: Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 2004; 291:576-584. 112. Mas JL, Arquizan C, Lamy C, et al: Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysms or both. N Engl J Med 2001; 345:1740-1746. 113. Homma S, Sacco RL, Di Tullio MR, et al: Effect of medical treatment in stroke patients with patent foramen ovale. Circulation 2002; 105:2625-2631. 114. Bosch J, Yusuf S, Pogue J, et al: Use of ramipril in preventing stroke: double blind randomized trial. BMJ 2002; 324:699-704. 115. Yusuf S, Sleight P, Pogue J, et al: Effects of angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:145153. 116. PROGRESS Collaborative group: Randomised trial of a perindopril-based blood pressure-lowering regimen among
117.
118.
119.
120.
121. 122.
123.
124.
125.
126.
127. 128.
129. 130.
131. 132.
6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033-1041. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002; 360:7-22. Toole JF, Malinow MR, Chambless LE, et al: Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004; 291:565-575. Dusitanond P, Eikelboom JW, Hankey GJ, et al: Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial. Stroke 2005; 36:144-146. VITATOPS Trial Study Group: The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteinelowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis 2002; 13:120-126. Viscoli CM, Brass LM, Kernan WN, et al: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345:1243-1249. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al: Effect of estrogen plus progestin on stroke in postmenopausal women. The Women’s Health Initiative: a randomized trial. JAMA 2003; 289:2673-2684. North American Symptomatic Carotid Endarterectomy Trialist’s Collaborative Group: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339:1415-1425. Mayberg MR, Wilson SE, Yatsu F, et al: Veterans Affairs Cooperative Studies Program 309 Trialist Group. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA 1991; 266:3289-3294 European Carotid Surgery Triallists Collaborative Group: MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or mild (0-29%) carotid stenosis. Lancet 1991; 337:1235-1243. European Carotid Surgery Trialists’ Collaborative Group: Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Surgery Trial (ECST). Lancet 1998; 351:1379-1387. Rothwell PM, Gutnikov SA, Warlow CP: Reanalysis of the final results of the European Carotid Surgery Trial. Stroke 2003; 34:514-523. Rothwell PM, Eliasziw M, Gutnikov SA, et al: Sex difference in the effect of time from symptoms to surgery on benefit from carotid endarterectomy for transient ischemic attack and nondisabling stroke. Stroke 2004; 35:2855-2861. Brott TG, Brown RD, Meyer FB, et al: Carotid revascularization for prevention of stroke: carotid endarterectomy and carotid artery stenting. Mayo Clin Proc 2004; 79:1197-1208. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001; 357:1729-1737. Yadav JS, Wholey MH, Kuntz RE, et al: Protected carotidartery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004; 351:1493-1501. SSYLVIA Study Investigators: Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke 2004; 35:1388-1392.
CHAPTER
43
INTRACRANIAL HEMORRHAGE: ANEURYSMAL, IDIOPATHIC, AND HYPERTENSIVE ●
●
●
●
Jon Sen, Rasheed Afinowi, Neil Kitchen, and Antonio Belli
Bleeding in the cranial space, or intracranial hemorrhage (ICH), often results in disastrous consequences for patients. ICH can be classified in terms of location, being either intraparenchymal or within spaces such as the subarachnoid, ventricular, subdural, or extradural space. Bleeding may be spontaneous or traumatic; sometimes no cause is found. It should be remembered that intracranial vascular abnormalities can also manifest without bleeding; early signs may be caused by compression of surrounding anatomical structures. The effect of ICH on the general population can be fully grasped when viewed within the broader category of stroke, currently the leading cause of neurological deficit in the world and the third leading cause of death in the United States, accounting for 15% of all U.S. deaths annually.1 ICH accounts for 10% to 17% of all strokes, and the rate of mortality from ICH is considerably higher than that from nonhemorrhagic or ischemic stroke; some studies quote a mortality rate as high as 90%.2 This chapter focuses on ICH with particular regard to cerebral aneurysm and hypertensive and idiopathic hemorrhage.
ANEURYSMAL INTRACRANIAL HEMORRHAGE More than 50% of cases of nontraumatic ICH are secondary to rupture of an intracranial aneurysm. Approximately 20% of patients with subarachnoid hemorrhage (SAH) present with an associated intracerebral hematoma. Outcome is related to extent of neuronal loss at the time of the hemorrhage (primary brain injury) and in the subsequent days (secondary brain injury). Further neuronal death secondary to cerebral ischemia is the final common pathway of secondary brain damage; this is preventable, and prevention forms the basis of management. Occlusion of the aneurysm is an integral part of this management strategy, because of the high risk of catastrophic rebleeding.
Epidemiology Cerebral aneurysm has been recognized as a cause of human illness since the end of the 19th century, but the actual incidence is difficult to estimate. In autopsy studies, the prevalence ranges from 0.2% to 7.9%. Other studies indicate a prevalence
of 5%.3 The ratio of ruptured aneurysm to unruptured (incidental) aneurysm is 5:3 to 5:6 (rough estimate is 1:1; i.e., 50% of these aneurysms rupture).4 Only 2% of aneurysms manifest during childhood.5
Etiology The exact pathophysiology of the development of aneurysms is controversial, but abnormal vascular anatomy and flow dynamics are important factors. In contrast to extracranial blood vessels, there is less elastic in the tunica media and adventitia of cerebral blood vessels, the media has less muscle, the adventitia is thinner, and the internal elastic lamina is more prominent.6,7 Outpouching is more likely to occur because of this, but it is also noteworthy that aneurysms are usually found at vessel bifurcations at sites of greatest flow. This, together with the fact that large cerebral blood vessels lie within the subarachnoid space with little supporting connective tissue,8,8a may predispose these vessels to the development of saccular aneurysms. Aneurysm formation is more common in women and in smokers. Beyond the third decade in particular, SAH is usually caused by rupture of a cerebral aneurysm. Other than size of aneurysm alone, the “aspect ratio” (aneurysm depth to aneurysm neck) has also been shown to be a potentially useful predictor of rupture (Figs. 43–1 and 43–2).9 The etiology of aneurysms may be any of the following: ■ Congenital predisposition (e.g., defect in the muscular layer
of the arterial wall) ■ “Atherosclerotic” or hypertensive, the presumed etiology of
■ ■ ■ ■ ■
most saccular aneurysms; probably interacts with congenital predisposition Embolic: as in atrial myxoma Infectious (“mycotic aneurysms”) Traumatic Associated with other conditions Location related
Saccular, or berry, aneurysms are usually located at bifurcations of the major cerebral arteries. Aneurysms located more peripherally do occur, but these tend to be associated with infection (mycotic aneurysms) or trauma. Fusiform aneurysms are more common in the vertebrobasilar system.
587
588
Section
IX
C e r e b r o va s c u l a r D i s e a s e
(Lactate, Pyruvate)
50
26.3
4.5 h
Hypertensive, pupils fixed
500
135
0
12:00
00:00 16/11/2002
12:00 17/11/2002
00:00
Of all saccular aneurysms, 85% to 95% are located in the carotid system, with the following three most common locations: (1) the anterior communicating artery (ACom) for 30% (aneurysms in the ACom and anterior cerebral artery are more common in male patients); (2) the posterior communicating artery for 25%; and (3) the middle cerebral artery for 20%. Of the remaining saccular aneurysms, 5% to 15% are located in posterior circulation (vertebrobasilar); 10%, at the basilar tip (most common), followed by the basilar artery–superior cerebellar artery junction, basilar artery–vertebral artery junction, and anterior inferior cerebellar artery; and 5%, on the vertebral artery (vertebral artery–posterior inferior cerebellar artery
12:00 18/11/2002
junction most common). Twenty percent to 30% of patients with aneurysm have multiple aneurysms.10
Manifestation of Aneurysms Major rupture is the most frequent manifestation leading to SAH. Clinical features may vary from sudden headache to a moribund comatose state. Neurological deficits, if present, depend on location and size of the hematoma. Signs of meningism with photophobia, neck stiffness, and vomiting are often seen. Progressive neurological deficit or decreasing con-
■
40 20 0 500
L/P ratio Glycerol Glutamate TCD
0 50
0 200
0 00:00 09/11/2002
00:00 12/11/2002
00:00 00:00 15/11/2002
Figure 43–1. Plot 1 with markers. Microdialysis markers of 64-year-old woman who presented with a World Federation of Neurosurgical Societies grade 5 subarachnoid hemorrhage. The patient recovered to the point of full consciousness, but she had to be sedated and paralyzed for the management of a chest infection. Time is on the x axis (one tick = 24 hours). The vertical red line on the left marks the beginning of a gradual deterioration of the brain metabolic state, illustrated by a surge in lactate/ pyruvate (L/P) ratio and glycerol level above normal values, in the absence of any other clinical signs. A few hours later, the patient became hypertensive, and her pupils became fixed and dilated (vertical red line on the right). A computed tomographic scan confirmed the development of a large infarct in the right middle cerebral territory, ipsilateral to the microdialysis probe.
L/P ratio Glycerol
0
Glycerol, M
■
3:30 am
19:00
00:00 18/11/2002
00:00 21/11/2002
Figure 43–2. Plot 2 with markers. Microdialysis markers of 53-year-old woman who presented with a World Federation of Neurosurgical Societies grade 5 subarachnoid hemorrhage. The patient died several days later without regaining consciousness. Values of lactate/pyruvate (L/P) ratio, glycerol (μmol/L), glutamate (μmol/L) and transcranial Doppler (TCD) imaging velocities (cm/second) of the ipsilateral middle cerebral artery are plotted against time (one tick = 24 hours). Values above the dotted horizontal lines are considered abnormal. The plot shows persistent high levels of microdialysis markers, indicating a prolonged metabolic crisis of the brain. Many TCD imaging values are above the dotted line, which suggests the presence of cerebral vasospasm, and appear to parallel glutamate levels closely.
chapter 43 intracranial hemorrhage scious level may occur as a result of mass effect from a growing hematoma or the development of hydrocephalus. Ruptured cerebral aneurysm may be accompanied by the following: ■ Intracerebral hemorrhage, which occurs in 20% to 40% of
affected patients (more common with aneurysms distal to the circle of Willis; e.g., middle cerebral artery aneurysms). ■ Intraventricular hemorrhage, which occurs in 13% to 28%.11 ■ Subdural hemorrhage, which occurs in 2% to 5%. Intraventricular hemorrhage occurs with 13% to 28% of ruptured aneurysms in clinical series (higher in autopsy series)11 and may lead to obstructive hydrocephalus. The presence of intraventricular hemorrhage is an indicator of poor prognosis11 (64% rate of mortality); ventricular size on admission is the most important prognostic factor (large ventricles being worse). Patterns that may occur include the following: ■ ACom aneurysm, which tends to produce intraventricular
hemorrhage by rupture through the lamina terminalis into the lateral or anterior third ventricles. ■ Distal basilar or carotid terminus aneurysms, which may rupture through the floor of the third ventricle. ■ Distal posterior inferior cerebellar artery aneurysms, which may rupture directly into the fourth ventricle through the foramen of Luschka.12
Other Possible Presentations Mass effect can give rise to possible “warning signs”: for example, giant aneurysms can include brainstem compression, which produces hemiparesis and cranial neuropathies; cranial neuropathy (average latency from symptom to SAH was 110 days) can include non–pupil-sparing third nerve palsy produced by expanding posterior communicating artery aneurysm; rarer cranial neuropathies produce visual loss as a result of compressive optic neuropathy12 (ophthalmic artery aneurysms) and chiasmal syndromes (ophthalmic, ACom, or basilar apex aneurysms). Facial pain syndromes in the ophthalmic or maxillary nerve distribution that may mimic trigeminal neuralgia can occur with intracavernous or supraclinoid aneurysms.13,14 Also, intrasellar aneurysm may produce disturbances in the endocrine system.15 Warning or sentinel hemorrhage (minor bleeding) may occur; this condition has the shortest latency (10 days) between symptom onset and SAH.16 Headache without hemorrhage may occur; this may be acute, severe, and “thunderclap” in nature, sometimes described as the “worst headache of my life.” It may be caused by aneurysmal expansion, thrombosis, or intramural bleeding17 (all without rupture). Alternatively, it can be chronic, having usually been present for more than 2 weeks, is unilateral (often retro-orbital or periorbital) in about one half of cases, and is possibly caused by dural irritation. In the other one half of cases, it is diffuse or bilateral, possibly caused by mass effect that produces raised intracranial pressure. Asymptomatic aneurysm may be discovered incidentally on angiography, computed tomographic (CT) scan, or magnetic resonance imaging obtained for other reasons. Conditions associated with aneurysms include the following: ■ Autosomal dominant polycystic kidney disease ■ Fibromuscular dysplasia
589
■ Arteriovenous malformations ■ Connective tissue disorders: Ehlers-Danlos syndrome type ■ ■ ■ ■
IV, Marfan’s syndrome Osler-Weber-Rendu syndrome Family history of intracranial aneurysms Bacterial endocarditis Coarctation of the aorta
Diagnosis and Investigations Diagnosis of aneurysmal SAH is crucial, and there are two main components to this: identification of blood on CT scan and demonstration of blood breakdown products on spectroscopy. Computed tomography is 98% sensitive for detection of SAH in the first 12 hours after the ictus, but this rate declines to approximately 70% by day 3. Thus, without other diagnostic facilities, CT scanning alone may miss SAH. Lumbar puncture performed 12 hours after the onset of symptoms is therefore vital for diagnosis if CT scan results are negative or equivocal. The presence of bilirubin in the cerebrospinal fluid confirms SAH. Cerebral angiography is the “gold standard” for demonstrating the cerebral vasculature and is mandatory in SAH. An adequate study should reveal the causative aneurysm. Computed tomographic angiography is being increasingly used to diagnose and provide information for treatment of intracranial aneurysms. Conventional angiography is usually carried out by a neuroradiologist through a femoral artery puncture with local anesthetic, whereas computed tomographic angiography can be performed with injection of contrast medium into a forearm vein. This can be done in the computed tomography suite immediately after the diagnostic CT scan.
Treatment Exclusion of the Aneurysm Aneurysmal rebleeding carries high rates of morbidity and mortality. Risk is highest in the first 24 to 48 hours after hemorrhage, but there is a continuing risk of about 50% over the first month. Removal of the aneurysm from the circulation is therefore crucial, although this forms only a part of the whole management plan. Traditionally, aneurysmal occlusion was achievable only with craniotomy and dissection of the aneurysm in the basal cisterns and surgical clipping of the aneurysm neck. However, endovascular occlusion with platinum coils is being increasingly used as an alternative to craniotomy. This trend has been influenced by the results of the International Subarachnoid Aneurysm Trial (ISAT), which concluded that coiling is a safer treatment option than surgery (Molyneux et al, 2002).18 This remains a controversial area, however, and long-term studies investigating the risk of rebleeding (i.e., efficacy) after coiling are particularly required.
Cerebral Vasospasm Cerebral vasospasm is constriction of the cerebral arterial vasculature that leads to delayed cerebral ischemia. The
590
Section
IX
C e r e b r o va s c u l a r D i s e a s e
pathophysiology is poorly understood. Traditionally, rebleeding was the major concern after rupture of a cerebral aneurysm. However, the general shift to early occlusive therapy has minimized the effect of rebleeding. Indeed, except for the initial hemorrhage, cerebral vasospasm is now recognized as the most significant cause of death and disability, killing 7% of patients and leading to severe disability in another 7%.19 It is present in 20% to 30% of cases of aneurysmal SAH and is seen in 30% to 70% of angiograms at day 7 after SAH with and without clinical deficit. Vasospasm typically occurs at days 3 to 5 but has been reported up until day 21. Common manifestations include reduced Glasgow Coma Scale (GCS) score, confusion, and focal deficit. Risk is related to amount of blood seen on CT scan (Fisher grade), location (more risk in ACom than in middle cerebral artery), and the World Federation of Neurological Surgeons grade (a useful scale that combines GCS score with the presence or absence of neurological deficit). Management of vasospasm combines triple-H therapy (hypervolemia, hypertension, and hemodilution) with the calcium channel antagonist nimodipine20 and transcranial Doppler ultrasonography. Hypertension is achieved with inotropes and is facilitated by early occlusion of the aneurysm. Several studies have shown the benefit of volume expansion in reversing deficits,21 but triple-H therapy has yet to be tested in a randomized controlled trial. In total, 11 trials of calcium channel antagonists have been reported, and the evidence suggests that they reduce the risk of vasospasm, although the results depended mainly on one trial with nimodipine.22 The exact mechanism of action of nimodipine remains unknown, but it is now standard therapy for vasospasm prophylaxis. Detection and monitoring of vasospasm are also possible with measurement of transcranial Doppler velocities, but this technique is unreliable: It is not “on-line,” and interoperator variability is large. Developments such as the application of microdialysis to the injured human brain may improve monitoring and detection of cerebral vasospasm.23 There is good evidence that an increase in ratio of lactate to pyruvate precedes onset of vasospasm by several hours.24 Other studies point to the possibility that outcome after SAH is genetically predetermined.25
Outcome The outcome depends on the severity of the primary brain injury and the extent to which secondary injury has been offset. Removal of an aneurysm from the cerebral circulation by surgical clipping or coiling is crucial but is only part of the overall medical management, which includes hydration, judicious control of blood pressure with inotropes if necessary, and administration of nimodipine to reduce the risk of delayed cerebral ischemia and further neurological deterioration as a consequence. More research is needed to elucidate the natural history of aneurysms and to clarify many issues regarding their treatment.
HYPERTENSIVE INTRACRANIAL HEMORRHAGE Hypertension is a major cause of spontaneous (i.e., nontraumatic) ICH. Hypertensive hemorrhage most often occurs into the brain parenchyma (cerebral hemispheres, cerebellum, and
brainstem) and may also involve, by extension, the ventricular system, subarachnoid spaces, or subdural spaces.
Epidemiology Stroke is the third most common cause of mortality and the leading cause of chronic neurological morbidity worldwide.26–30 Spontaneous intracerebral hemorrhage accounts for approximately 10% to 15% of all cases of stroke, with an estimated annual incidence of 37,000 cases in the United States; hypertension causes 40% to 60% of spontaneous intracerebral hemorrhages.28,36 ICH is associated with a much higher rate of mortality than are ischemic forms of stroke.27,28,56,57
Etiology Hypertensive hemorrhages may result from both chronically and acutely raised blood pressures, causes of which are listed as follows: ■ ■ ■ ■
Chronic hypertension (most common cause)29,40,48,49 Primary (essential) hypertension Secondary systemic hypertension Acute rise in blood pressure32 after (sympathomimetic) rise in blood pressure induced by drugs (amphetamines, cocaine, pseudoephedrine, and heroin); cold exposure; trigeminal stimulation; and acute increase in cerebral blood flow with resulting intracranial arterial hypertension after carotid endarterectomy or cardiac surgery
Pathology Chronic hypertension is believed to alter vascular wall structure, resulting in degenerative weakening and consequent rupture, but the exact pathological process involved remains controversial.31a,33 Jean-Martin Charcot and Charles-Joseph Bouchard first described miliary aneurysms, which were thought to be responsible for hypertensive hemorrhages, inasmuch as they are commonly found on the perforating arteries of the basal ganglia and pons (common sites of hypertensive hemorrhages) and were believed to be more common in hypertensive patients. Fischer demonstrated these to be false aneurysms representing small (0.2- to 1.0-mm) healed foci of arteriolar bleeds. He attributed hypertensive hemorrhages to lipohyalinosis (found closer to sites of rupture than Charcot-Bouchard miliary aneurysms), as well as to plasmatic destruction and atherosclerosis of the vessel wall.38,39 It has also been hypothesized that the walls of arteries supplying regions that commonly bleed are thinner than vessels of similar size and are, in addition, subject to higher pressures as they originate from larger vessels.42
Distribution of Hypertensive Hemorrhage In most hypertensive hemorrhages, bleeding is primarily into the brain parenchyma. This may be associated with extensions into the ventricular system, the subarachnoid space, and, in rare cases, the subdural space. Subarachnoid and intraventricular hemorrhages, occurring in the absence of parenchymal bleeding, usually result from other pathology, such as
chapter 43 intracranial hemorrhage T A B L E 4 3 – 1. Distribution (Frequency) of Hypertensive Parenchymal Hemorrhage Location Supratentorial Infratentorial Putamen Thalamus Subcortical white matter Cerebellum Pons
Frequency 80% 20% 55% 10% 15% 10% 10%
591
and subarachnoid or intraventricular extension. Magnetic resonance imaging and angiography are less useful in the acute phase but may be useful in the differential diagnosis.36,37 It is necessary to rule out other causes of hemorrhage before a diagnosis of hypertensive hemorrhage can be made.
Treatment Medical treatment is the mainstay in the initial management of hypertensive ICH.26 Treatment is aimed at several objectives: ■ Intensive monitoring and care in specialist units, including
serial neuroimaging in the early stages. ■ Control of raised intracranial pressure: hyperventilation,
aneurysms.52 Table 43–1 shows the distribution (frequency) of hypertensive parenchymal hemorrhage.59
Pathophysiology After a parenchymal hemorrhage, a circular hematoma forms and directly destroys and may compress and displace adjacent brain tissue, which results in neurological deficit. Surrounding the hematoma is a salvageable ischemic area of brain, the penumbra, loss of which results in secondary damage.31 Bleeding is usually brief but may continue for some hours, resulting in large or irregular-shaped hematomas and may occur in patients with a bleeding diathesis.41,51,53,58 A hematoma may track along white matter tracts or dissect brain parenchyma with extension into the ventricular system or subarachnoid space. Parenchyma immediately surrounding a hematoma undergoes necrosis and is invaded by inflammatory cells with resolution of liquefied clot, leaving a smaller hemosiderinstained cavity surrounded by an area of gliosis.43
Clinical Features Clinical features depend on the location and size of hemorrhage, and manifestation may be asymptomatic. The more common features are summarized as follows:44 ■ Putaminal hemorrhage: hemiplegia, dysphasia, and con-
■ ■ ■ ■ ■
■
jugate gaze paresis with deviation toward the side with hematoma. Thalamic hemorrhage: hemiplegia, hemisensory loss, dysphasia, abnormalities of vertical gaze, and pupillary changes. Cerebellar hemorrhage: severe headache (occipital), nausea and vomiting, and ataxia; motor deficit is not usual. Pontine hemorrhage: coma, pinpoint pupils, decerebrate posture, and locked-in state. Cortical hemorrhage: headache, seizures, and focal neurological deficits. Intraventricular extension: decreased consciousness, autonomic dysfunction, obstructive hydrocephalus, and high mortality rate. Subarachnoid extension: headache, nausea, meningism, photophobia, and decreased consciousness.
Diagnosis Definitive diagnosis of ICH requires neuroimaging. CT scan shows the location, size, and mass effect (parenchymal and ventricular shift or compression) of hemorrhages, hydrocephalus,
head elevation, diuretics (mannitol, frusemide), ventricular drainage. ■ Treatment of hypertension.35,55 ■ Treatment of systemic disorders and complications: coagulation; fever; hypoxia; seizures; gastrointestinal, endocrine, pulmonary, and cardiovascular disease; infections; and electrolyte abnormalities. Surgical treatment is generally reserved for cases in which medical treatment fails to control intracranial pressure or to relieve compression and herniation, and it is more often performed for infratentorial hemorrhages, because of the high risk of herniation. Ventriculostomy involves placement of catheters in the cerebral ventricles and enables monitoring of intracranial pressure and drainage of cerebrospinal fluid when decompression is needed. Hematomas may necessitate evacuation through stereotactic aspiration or open surgery.34
Prognosis Prognosis after hemorrhage depends on several factors, of which size and location of the hemorrhage and GCS score play primary roles:28,45,50,54 ■ Size (poor prognosis if supratentorial hematoma >50 mL). ■ Location (worse prognosis if brainstem or diencephalon is
affected). ■ GCS score <8 (60% rate of mortality). ■ Intraventricular extension (poor prognosis if volume >20
mL). ■ Age. ■ Presence of complications: neurological (cerebral edema,
obstructive hydrocephalus, herniation) and systemic (pulmonary, cardiovascular, gastrointestinal, and endocrine disorders; electrolyte abnormalities; and infections).
IDIOPATHIC INTRACRANIAL HEMORRHAGE The cause of ICH is not always apparent on initial investigation and is often multifactorial in nature (e.g., hypertension may coexist with other disorders and may be a reflex response to raised intracranial pressure). It is important, however, to establish the cause of all hemorrhages in order to target management strategies appropriately. The various causes of ICH are listed as follows:46,47,49 ■ Hypertension: chronic and acute ■ Vascular: aneurysms, arteriovenous malformations and
fistulas, amyloid angiopathy, cavernous and venous
592
■ ■ ■ ■
■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■
Section
IX
C e r e b r o va s c u l a r D i s e a s e
angiomas, telangiectasias, arterial dissection, caroticocavernous fistula Coagulation: clotting factor deficiency, leukemia, thrombocytopenia Tumors Alcohol Drugs: sympathomimetic drugs (cocaine, amphetamine, pseudoephedrine), anticoagulants, antiplatelet drugs, thrombolysis Vasculitis Postoperative: intracranial, carotid, and cardiac operations Delayed post-traumatic hemorrhage (spät-apoplexie) Infectious: mycotic aneurysms, septic arteritis Hemorrhagic transformation of arterial infarct Intracranial venous thrombosis Migraine Moyamoya syndrome Pregnancy Neonatal Pituitary apoplexy Sickle cell disease Unknown cause
Difficulty in establishing a definite cause of hemorrhage should prompt extensive and thorough reassessment of the history, which may contribute to clarification of the diagnosis. Initial CT scan does not always reveal the underlying pathology, and it may be useful to consider reviewing or repeating the scan and other investigations or to investigate the patient with magnetic resonance imaging or angiography. Despite intensive investigation, some vascular lesions remain occult.26
Spontaneous Intracranial Hemorrhage: Early Surgery or Initial Conservative Management? The role of surgery in spontaneous supratentorial ICH has been a point of controversy for many years. However, a prospective randomized trial was performed to compare early surgery with initial conservative treatment for such patients59 and appears to have shed some light on the appropriate course of management. The authors used a parallel-group trial design. Early surgery combined hematoma evacuation (within 24 hours of random assignment) with medical treatment. Initial conservative treatment entailed medical treatment, although later evacuation was allowed if necessary. In this study, 1033 patients from 83 centers in 27 countries were randomly assigned to undergo early surgery (503) or receive initial conservative treatment (530). At 6 months, 51 patients could not be monitored for follow-up, and 17 were alive with unknown status. Of 468 patients who underwent early surgery, 122 (26%) had a favorable outcome, in comparison with 118 (24%) of 496 who received initial conservative treatment (odds ratio = 0.89 [95% confidence interval = 0.66 to 1.19], P = 0.414); the absolute benefit was 2.3% (−3.2 to 7.7), and the relative benefit was 10% (−13 to 33). The authors concluded that patients with spontaneous supratentorial intracerebral hemorrhage in neurosurgical units show no overall benefit from early surgery in comparison with initial conservative treatment.
K E Y
P O I N T S
●
Intracranial hemorrhage (ICH) is bleeding in the cranial space and may be classified as spontaneous (nontraumatic) or traumatic or, alternatively, in terms of hemorrhage location. It accounts for 10% to 17% of all types of stroke and has a very high mortality rate.
●
More than 50% of cases of ICH are secondary to rupture of an intracranial aneurysm. Surgical or neuroradiological occlusion of the aneurysm is central to management. Apart from the initial hemorrhage, further neuronal death secondary to cerebral vasospasm is the main cause of death and disability in affected patients, and medical management of this is crucial in outcome.
●
Hypertension is a major cause of spontaneous (nontraumatic) ICH. Hypertensive hemorrhages may result from both chronically and acutely raised blood pressures. Computed tomographic scan is the primary method of demonstrating the hemorrhage, but it is necessary to exclude all other causes of hemorrhage before a diagnosis of hypertensive ICH is made.
●
The cause of idiopathic ICH may not be apparent on initial assessment and investigation and is often multifactorial in nature. The potential underlying cause may remain occult despite extensive attempts at diagnosis.
Suggested Reading Edlow JA, Caplan LR: Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000; 342:29-36. Kase CS, Mohr JP, Caplan LR: Intracerebral hemorrhage. In Barnett HJM, Mohr JP, Stein BM, et al, eds: Stroke: Pathophysiology, Diagnosis, and Management, 2nd ed. New York: Churchill Livingstone, 1992. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002; 360:1267-1274. van Gijn J, Rinkel GJ: Subarachnoid hemorrhage: diagnosis, causes, and management. Brain 2001; 124:249-278. Woo D, Haverbusch M, Sekar P, et al: Effect of untreated hypertension on hemorrhagic stroke. Stroke 2004; 35:1703-1708.
References 1. Kuller LH: Incidence, rates of stroke in the 80s. Stroke 1989; 20:841-843. 2. Wolf PA, Kannel WB, McGee DL, et al: Epidemiology of strokes in North America. In Barnett HJM, Mohr JP, Stein BM, et al, eds: Stroke: Pathophysiology, Diagnosis, and Management. New York: Churchill Livingstone, 1986, pp 19-29. 3. Wiebers DO, Whisnant JP, Sundt TM, et al: The significance of unruptured intracranial saccular aneurysms. J Neurosurg 1987; 66:23-29. 4. Fox JL: Intracranial Aneurysms. New York: Springer-Verlag, 1983. 5. Almeida GM, Pindaro J, Plese P, et al: Intracranial arterial aneurysms in infancy and childhood. Childs Brain 1977; 3:193199.
chapter 43 intracranial hemorrhage 6. Fang H: A comparison of blood vessels of the brain and peripheral blood vessels. In Wright IS, Millikan CH, eds: Cerebral Vascular Diseases. New York: Grune & Stratton, 1958, pp 1722. 7. Wilkinson IMS: The vertebral artery: extracranial and intracranial structure. Arch Neurol 1972; 27:392-396. 8. Youmans JR, ed: Neurological Surgery, 3rd ed. Philadelphia: WB Saunders, 1990. 8a. Nader-Sepahi A, Casimiro M, Sen J, et al: Is aspect ratio a reliable predictor of aneurysmal rupture? Neurosurgery 2004; 54:1343-1348. 9. Nehls DG, Flom RA, Carter LP, et al: Multiple intracranial aneurysms: determining the site of rupture. J Neurosurg 1985; 63:342-348. 10. Mohr G, Ferguson G, Khan M, et al: Intraventricular hemorrhage from ruptured aneurysm: retrospective analysis of 91 cases. J Neurosurg 1983; 58:482-487. 11. Yeh HS, Tomsick TA, Tew JM: Intraventricular hemorrhage due to aneurysms of the distal posterior inferior cerebellar artery. J Neurosurg 1985; 62:772-775. 12. Raps EC, Galetta SL, Solomon RA, et al: The clinical spectrum of unruptured intracranial aneurysms. Arch Neurol 1993; 50:265-268. 13. Sano H, Jain VK, Kato Y, et al: Bilateral giant intracavernous aneurysms: technique of unilateral operation. Surg Neurol 1988; 29:35-38. 14. White JC, Ballantine HT: Intrasellar aneurysms simulating hypophyseal tumors. J Neurosurg 1961; 18:34-50. 15. Okawara S H: Warning signs prior to rupture of an intracranial aneurysm. J Neurosurg 1973; 38:575-580. 16. Verweij RD, Wijdicks EFM, van Gijn J: Warning headache in aneurysmal subarachnoid hemorrhage: a case-control study. Arch Neurol 1988; 45:1019-1020. 17. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002; 360:1267-1274. 18. Kassel NF, Torner JC, Haley EC Jr: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1. Overall management results. J Neurosurg 1990; 73:18. 19. Sen J, Belli A, Albon H, et al: Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. Lancet Neurol 2003; 2:614-21. 20. Kassel NF, Peerless SJ, Durward QJ: Treatment of ischemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension. Neurosurgery 1982; 11:337-343. 21. Rinkel GJE, Feigin VL, Algra A, et al: Calcium antagonists for aneurysmal subarachnoid haemorrhage (Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software. 22. Sen J, Belli A, Petzold A, et al: Extracellular fluid S100B in the CNS: a future surrogate marker of acute brain injury. Acta Neurochir, in press. 23. Unterberg AW, Sakowitz OW, Sarrafzadeh AS, et al: Role of bedside microdialysis in the diagnosis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 2001; 94:740-749. 24. Morgan L, Montgomery H, Grieve J, et al: Association of interleukin 6–174G/C and –572G/C promoter polymorphisms with cerebral aneurysms. Interv Neuroradiol 2003; 9:168. 25. Batjer HH, Kopitnik TA Jr, Friberg L: Spontaneous intracerebral and intracerebellar haemorrhage: differential diagnosis. In Youmans JR, ed: Neurological Surgery, 4th ed, vol 2. Philadelphia: WB Saunders, 1996, pp 1449-1464. 26. Bozzola FG, Gorelick PB, Jensen JM: Epidemiology of intracranial hemorrhage. Neuroimaging Clin North Am 1992; 2:1.
593
27. Broderick JP, Brott TG, Duldner JE, et al: Volume of intracerebral hemorrhage: a powerful and easy to use predictor of 30-day mortality. Stroke 1993; 24:987-993. 28. Broderick JP, Brott T, Tomsick T, et al: Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993; 78:188-191. 29. Brown RD, Whisnant JP, Sicks JD, et al: Stroke incidence, prevalence and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996; 27:373-380. 30. Camarata PJ, Heros RC, Latchaw RD: “Brain attack:” the rationale for treating stroke as a medical emergency. Neurosurgery 1994; 34:144-158. 31. Caplan L: Intracerebral hemorrhage revisited. Neurology 1988; 38:624-627. 31a.Challa VR, Moody DM, Bell MA: The Charcot-Bouchard aneurysm controversy: impact of a new histologic technique. J Neuropathol Exp Neurol 1992; 51:264-271. 32. Crowell RM, Ojemann RG, Ogilvy CS: Brain hemorrhage. In Ojemann RG, Ogilvy CS, Crowell RM, et al, eds. Surgical Management of Neurovascular Disease, 3rd ed. Baltimore: Williams & Wilkins, 1995, pp 561-580. 33. Dandapani BK, Suzuki S, Kelley RE, et al: Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke 1995; 26:21-24. 34. Drury ID, Whisnant JP, Garraway WM: Primary intracerebral hemorrhage: impact of CT on incidence. Neurology 1984; 34:653. 35. Findlay JM: Current management of aneurysmal subarachnoid haemorrhage. Guidelines from the Canadian Neurological Society. Can J Neurol Sci 1997; 24:161-170. 36. Fischer CM: Pathological observations in hypertensive cerebral hemorrhage. J Neuropathol Exp Neurol 1971; 30:536-550. 37. Fischer CM: Cerebral miliary aneurysms in hypertension. Am J Pathol 1972; 66:313-330. 38. Frankowski RF: Epidemiology of stroke and intracerebral hemorrhage. In Kaufman HH, ed: Intracerebral Hematomas. New York: Raven Press, 1992. 39. Fujii Y, Tanaka R, Takeuchi S, et al: Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg 1994; 80:51-57. 40. Garcia JH, Ho K-L: Pathology of hypotensive arteriopathy. Neurosurg Clin North Am 1992; 3:497. 41. Garcia JH, Ho K-L, Caccamo DV: Intracerebral hemorrhage: pathology of selected topics. In Kase CS, Caplan LR, eds: Intracerebral Hemorrhage. Boston: Butterworth-Heineman, 1994. 42. Hamilton MG, Zabramski JM: Intracerebral hematomas. In Carter LP, Spetzler RF, Hamilton MG, eds: Neurovascular Surgery. New York: McGraw-Hill, 1995, pp 477-496. 43. Juvela S: Risk factors for impaired outcome after spontaneous intracerebral hemorrhage. Arch Neurol 1995; 52: 1193-1200. 44. Juvela S, Hillbom M, Palomaki H: Risk factors for spontaneous intracerebral hemorrhage. Stroke 1995; 26:1558-1564. 45. Kase C: Intracerebral hemorrhage: non-hypertensive causes. Stroke 1986; 17:4590-4595. 46. Kase CS, Mohr JP, Caplan LR: Intracerebral hemorrhage. In Barnett HJM, Mohr JP, Stein BM, et al, eds: Stroke: Pathophysiology, Diagnosis, and Management, 2nd ed. New York: Churchill Livingstone, 1992. 47. Kaufman HH: Spontaneous intracerebral hematomas. In Grossman RG, Hamilton WJ, eds: Principles of Neurosurgery. New York: Raven Press, 1991, pp 65-78. 48. Lampl Y, Gilad R, Eshel Y, et al: Neurological and functional outcomes in patients with supratentorial hemorrhages: a prospective study. Stroke 1995; 26:2249-2253. 49. Lee K, Bae H, Yun I: Recurrent intracerebral hemorrhage due to hypertension. Neurosurgery 1990; 26:586-590.
594
Section
IX
C e r e b r o va s c u l a r D i s e a s e
50. Mayberg MR, Batjer HH, Dacey R, et al: Guidelines for the management of aneurysmal subarachnoid haemorrhage. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1994; 25:2315-2328. 51. Mayer SA, Sacco RL, Shi T, et al: Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology 1994; 44:1379-1384. 52. Mori S, Sadoshima S, Ibayashi S, et al: Impact of thalamic hematoma on 6-month mortality and motor and cognitive functional outcome. Stroke 1995; 26:620-626. 53. Powers WJ: Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology 1993; 43:461-467. 54. Sacco RL, Wolf PA, Bharucha NE, et al: Subarachnoid and intracerebral hemorrhage: Natural history, prognosis, and precursive factors in the Framingham study. Neurology 1984; 34:847.
55. Schuetz H, Dommer T, Boedeker R-H, et al: Changing pattern of brain hemorrhage during 12 years of computed axial tomography. Stroke 1992; 23:653. 56. Wijdicks EFM, Fulgham JR: Acute fatal deterioration in putaminal hemorrhage. Stroke 1995; 26:1953-1955. 57. Wiener H, Cooper P: The management of spontaneous intracerebral hemorrhage. Contemp Neurosurg 1992; 14(21):1-8. 58. Wityk RJ, Caplan LR: Hypertensive intracerebral hemorrhage: epidemiology and clinical pathology. Neurosurg Clin North Am 1992; 3:521. 59. Mendelow AD, Gregson BA, Fernandes HM, et al: Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365:387397.
CHAPTER
44
ARTERIOVENOUS MALFORMATIONS THE BRAIN AND SPINAL CORD ●
●
●
OF
●
Soke Miang Chng, Hortensia Alvarez, Georges Rodesch, and Pierre Lasjaunias
An arteriovenous malformation (AVM) consists of one or more arteriovenous shunts, which corresponds to an abnormal capillary bed with a shortened arteriovenous transit time. Two broad categories of arteriovenous shunts can be recognized: AVMs and arteriovenous fistulae (AVFs). AVMs are characterized by a network of abnormal channels (nidi) between the arterial feeders and the draining veins. AVFs, in contrast, consist of a direct communication or opening between a feeding artery and a draining vein. AVMs and AVFs are the two basic forms of arteriovenous shunts that can be found throughout the central nervous system. AVMs of both the brain and the spinal cord are not common diseases. Spinal cord AVMs (SCAVMs) in particular are still underdiagnosed entities that can give rise to acute-subacute spinal cord symptoms or progressive myelopathy. Clinical signs and symptoms vary, depending on the location and angioarchitecture of the lesion. A complete clinical evaluation combined with imaging information are necessary for making the correct therapeutic decision. The primary diagnostic modality is currently magnetic resonance imaging (MRI), which is excellent in topographically localizing lesions. Digital subtraction angiography (DSA) gives important complementary information regarding the angioarchitecture and hemodynamics of lesions, which is crucial in treatment planning. The aim of treatment should be a significant improvement over the natural history of the disease, in comparison with the risks of therapy. In the past, most AVMs were diagnosed during clinically recognized episodes. The access to imaging facilities has allowed their preclinical diagnosis. Follow-up of this incidentally discovered population of patients with AVMs suggests that the clinical course is more benign than previously believed. The classic postulate that AVMs are congenital malformations, hence implying their presence at birth, has not been supported by antenatal or pediatric imaging. On the contrary, it is likely that lesions found in young adults, although probably resulting from an early in utero “event,” are not present at birth. Pediatric cases or even neonatal series represent only a small portion of the cases and pertain to specific disease groups (hereditary hemorrhagic telangiectasia [HHT], vein of Galen malformations, pial AVFs).1 The purpose of this chapter is to give an overview of the classifications, angioarchitectures, clinical manifestations, and
natural history of these diseases, with a brief review of the diagnostic and therapeutic approaches.
BRAIN ARTERIOVENOUS MALFORMATION Incidence The prevalence of brain AVMs (BAVMs) in a given population is difficult to estimate. It is believed that between 0.14% and 0.8% of the population may present with a BAVM in a given year.2,3 The variation in statistics results from studies of disparate populations, ranging from the residents in a small community4 to subjects of autopsy series.3 As previously alluded to, these numbers represent data collected before the era of noninvasive high-quality imaging modalities.
Classification and Angioarchitecture There are two broad categories of arteriovenous shunts: malformations (AVMs) and fistulae (AVFs). AVMs may be small (micro-AVMs) with one or more “normal”-sized arteries, one or more draining veins, and a nidus smaller than 1 cm in diameter. Macro-AVMs, in contrast, have arteries and veins that are larger than normal; the size of the nidus is larger than 1 cm in diameter. Compartments can be observed within lesions either during angiography or at surgery. Each compartment may have a single or multiple arterial feeders. There may be single or multiple draining veins (Fig. 44–1). Similarly, AVFs may be of the micro or macro type. AVFs are more frequent in children and are rare in adults (Fig. 44–2). The architecture of an AVM is specific to the lesion. However, the chronicity of the shunt and the shear stresses on the remaining vasculature create nonmalformative secondary changes called high-flow angiopathy. These may by themselves create additional symptoms; under certain circumstances, they may also regress if the AVM is treated even partially.
Topography The topography of a BAVM is best assessed by combining both MRI and angiographic information. Lesions in most locations
595
596
A
Section
IX
C e r e b r o va s c u l a r D i s e a s e
B
■
C
recruit predictable arterial feeders and specific draining veins (Table 44–1). The primary defect is at the capillary level. In contrast to aneurysms (arterial defective) or cavernomas (venous defective), in which associated arterial and venous anomalies are seen, respectively, the arterial tree from where the AVM feeders originate and the venous system that drains the AVM have a classic anatomical disposition. Several general types of lesions can be differentiated on the basis of location. Of note, however, is that both macro- and micro-AVFs are encountered mostly on the surface of the brain. All so-called BAVMs are subpial in location with regard to the meningeal spaces. Vein of Galen aneurysmal malformation and
Figure 44–1. Arteriovenous malformation (AVM) in the brain. The patient, a 57-year-old woman, presented with chronic headache for several years. There was no associated seizure or neurological deficit. A and B, Magnetic resonance imaging (axial T2-weighted images) showed a nidus-type AVM located in the left precentral sulcus, displacing the precentral gyrus anteriorly. This AVM drained via a superficial cortical vein. C, Angiography (left carotid injection, arterial phase) showed the corresponding precentral cortical vein draining into the superior sagittal sinus.
adult choroidal AVMs are separate groups located outside the subpial space.
Lesions at the cortex Arteriovenous lesions exclusively involving the cortex are exclusively fed by cortical arteries and drain into superficial veins. These lesions represent sulcal AVMs, as described by Valavanis and Yasargil.5 Cortical-subcortical lesions recruit cortical arteries and drain into superficial veins but may also drain into the deep venous system if the transcerebral venous system is patent.
chapter 44 arteriovenous malformations of the brain and spinal cord
A B
C ■
D Figure 44–2. Brain arteriovenous fistula (AVF). The patient, a 4-year-old girl, presented at the age of 3 years with language delay. There was no family history to suggest hereditary hemorrhagic telangiectasia. A and B, Magnetic resonance imaging (coronal T2weighted and axial fluid-attenuated inversion recovery images) revealed a single-hole AVF located in the left sylvian fissure, associated with a large venous pouch. C and D, Angiography (left carotid injection in the frontal and lateral projections) showed a single, ectatic arterial feeder arising from the left middle cerebral artery, opening directly into the venous pouch. Venous drainage was via an embryonic tentorial sinus into the left sigmoid sinus, with reflux into the opposite transverse and sigmoid sinuses. Embolization of this fistula was subsequently performed.
597
598
Section
IX
C e r e b r o va s c u l a r D i s e a s e
T A B L E 4 4 – 1. Topography of Intracranial Arteriovenous Lesions and Vascular Territories
From Berenstein A, Lasjaunias P, Ter Brugge KG: Surgical Neurorangiography, vol 2.2: Clinical and Endovascular Treatment Aspects in Adults, 2nd ed., Berlin: SpringerVerlag, 2004. +, involved; −, not involved. *Can be recruited via transcerebral veins. † Insular and cerebellar.
These represent the gyral type of AVMs described by Valavanis and Yasargil.5 In both cortical and cortical-subcortical lesions, some regions of the cortex drain to deeply located veins that should not be considered as truly part of the “deep venous system.” Such vessels include the medial veins of the temporal lobe and the basal vein of Rosenthal, the veins of the cerebellar vermis, and the precentral cerebellar veins. Corticoventricular arteriovenous lesions correspond to the classic pyramid-shaped malformation, reaching the ventricular wall at their apex. Feeding arteries are both perforating and cortical. Draining veins are also deeply and superficially located. Corticocallosal lesions belong to the corticoventricular group, inasmuch as they have the same venous characteristics, but they do not recruit “basal perforating” arteries. They drain into the subependymal veins and, later, into the deep venous system. The arterial supply to the corpus callosum is linked to the cortical arterial network (even though it may simulate perforating arterial channels in the supraoptic region) and to choroidal arteries at the splenium.
bral veins. These extra-axial lesions, too, can be distinguished from intra-axial ones with angiographic criteria.
Deep-seated lesions
Calcifications
Deep-seated lesions can be located supratentorially or infratentorially in the depth of the telencephalon, diencephalon, brainstem, or cerebellum. The nidus involves the deep nuclei and the long fiber tracts with their arterial and venous connections. They recruit exclusively perforating arteries and drain into the deep venous system. They may use transcerebral veins if patent, either as a direct venous outlet or as a collateral pathway. Transcortical arteries from the insular branches of the middle cerebral artery and the hemispherical collateral vessels of the cerebellar arteries can be involved in lenticulostriate and in dentate nuclear lesions, respectively. MRI and DSA are able to distinguish these deep-seated lesions from corticosubcortical lesions, particularly because the dominant supply of the intracerebrally located deep lesions arises from the perforators.
Calcifications in BAVMs are usually related to venous ischemia. In children, calcifications may occur at a distance from the shunt, in watershed venous zones, in the white matter, or in the deep nuclei.
Angioarchitecture Analysis of the angioarchitecture of BAVMs should include the study of the various components of the lesion (arteries, nidus, and veins) and how these components affect the rest of the circulation. The clinician should be able to distinguish the primary abnormality (the BAVM) from the secondary changes (high flow angiopathy) that occur in response to an increased diastolic fraction resulting from arteriovenous shunting. These include arterial stenosis, aneurysms, angiectasia, venous stenosis and ectasia, and angiogenesis. The high-flow hemodynamics and/or decreased tissue perfusion associated with chronic arteriovenous shunting stimulate these angiogenetic developments. Thrombosis of a draining vein, development of transdural supply, or intranidal ectasias may also be observed after previous hemorrhage within the AVM. These changes may be temporary or permanent.
Multiple Brain Arteriovenous Malformations Multiple BAVMs are rare. In this heterogeneous group of multifocal BAVMs, three types of patients can be distinguished: (1) those with HHT, also known as Rendu-Osler-Weber disease; (2) those with cerebrofacial arteriovenous metameric syndrome (CAMSs); and (3) those with unclassified multiple lesions. This distinction refers to the timing of the insult that created the malformations, later to be revealed morphologically or clinically (e.g., germinal, somatic-segmental).
Choroid plexus lesions Choroid plexus AVMs are important to recognize because of their extra-axial location. These lesions are fed by choroidal and subependymal arteries arising from the circle of Willis. There is no cortical arterial supply in this type of lesion. Drainage is via ventricular veins, with occasional recruitment of transcere-
Hereditary hemorrhagic telangiectasia HHT is an autosomal dominant disorder characterized by a multisystemic vascular dysplasia and recurrent hemorrhage.6 Two gene mutations have been identified: on chromosome 9 (affecting production of endoglin; this form is known as type
chapter 44 arteriovenous malformations of the brain and spinal cord 1)7 and on chromosome 12 (affecting production of activin receptor–like kinase; this form is known as type 2). An uncharacterized third mutation is also suspected. These mutations lead to the formation of abnormal vessels and abnormal connections between vessels. It has to be emphasized that the target of dysfunction in HHT is not in arteries but in venules. In the general population of patients with BAVMs, up to 2.2% of cases may be associated with HHT.8 With multiple BAVMs, however, up to 25% of cases are associated with HHT.9 Ten percent to 20% of HHT patients have cerebral involvement.10 In these patients, the cerebral vascular malformations manifest in three main phenotypes: large AVFs, small AVMs with a nidal diameter between 1 and 3 cm, and micro-AVMs with a nidal diameter smaller than 1 cm. These AVMs are often multiple and are almost exclusively located near the cortex.8,11 Although characteristic telangiectasia occur in the skin, oral mucosa, and the lips of patients with HHT, telangiectasia is not known to develop in the brain. High-flow type AVFs with venous ectasias are seen in children younger than 5 to 6 years of age; nidus-type lesions both large and small are seen in older children and in adults.1,12-14 Twenty-five percent of single AVFs in children and 50% of multifocal AVFs occur in patients with HHT. Cerebral DSA may demonstrate multiple areas of arteriovenous shunting, always cortical in location, either supratentorial or infratentorial. In addition, high-quality cerebral DSA can demonstrate tiny lesions, particularly micro-AVMs, which may appear occult on MRI, because these lesions usually have normal-sized feeding arteries and draining veins.10 However, patients with HHT who present with systemic complaints are more likely to develop acute neurological symptoms from embolic phenomena related to underlying pulmonary AVFs (recurrent brain abscesses, embolic stroke) than to the presence of a BAVM per se.
Cerebrofacial arteriovenous metameric syndromes CAMSs,15 also called Wyburn-Mason or Bonnet-DechaumeBlanc syndrome, are associated with ipsilateral AVMs of the brain, retina, and facial regions. Their segmental expression reflects their common origin from tissues involved in cerebrofacial vasculogenesis and angiogenesis. The metameric pattern of involvement is suggestive of a disorder of the neural crest or adjacent cephalic mesoderm15 at early segmental stages of differentiation.
Unclassified multiple brain arteriovenous malformations Several case reports have described so-called multifocal BAVMs. They seem to be twice more frequent in children than in adults. They can be randomly spread on the cortex; mirror-image deepseated nidi have been reported. One half of multifocal AVFs in children belong to this group.1,14
False Arteriovenous Malformations
599
normal brain parenchyma, and the veins are either normal sized or only slightly enlarged. The “nidus” is typically diffuse, involving a hemisphere. There are no dominant arterial feeders. The early venous filling that is observed results from a faster capillary transit time rather than true arteriovenous shunting. Late proximal cerebral arterial occlusion may occur, resulting in ischemic phenomena and diffuse transdural angiogenesis. The most common clinical manifestation is seizures. Headaches and progressive neurological deficit are less common, and hemorrhage is exceptional. Treatment is directed at the management of seizures with medical therapy. Embolization is employed in exceptional cases: when there is evidence of focal angioarchitectural weakness within the lesion, for which partial targeted embolization to reduce any constraints to functional parts of the brain may be beneficial. The effects of medication on headaches and seizure are often beneficial. The role of surgery is limited to the correction of hemispherical ischemia by bur holes, as in moyamoya disease, when spontaneous transdural angiogenesis is absent or insufficient. Hemorrhagic angiopathy is another entity that typically manifests with an episode of hemorrhage. Encountered in some rare cases of intracerebral hematomas in children most often after the age of 5 years, it corresponds to a network of intracerebral subcortical arterioles with normal structure and sequential venous drainage. Recurrent hemorrhage is frequent and therefore therapy is indicated. These lesions are extremely sensitive to radiation. Partial embolization of focal areas of weakness in the angioarchitecture can also be performed to reduce future hemorrhagic risk.
Developmental venous anomalies with ectasias Developmental venous anomalies (DVAs) are anatomical variations that can involve one or both hemispheres and can also be located infratentorially. They involve extremes in variations in the venous drainage of white matter. Superficial DVAs represent the superficial medullary veins that drain the deeper medullary regions into the cortical veins. The deep group of DVAs drains the subcortical territories of the superficial medullary veins into the deep venous collectors. The venous channels are morphologically normal and drain normal functioning brain, although transit time through their venules is sometimes rapid and almost as rapid as that in slow-flow BAVMs. The frequent incidental appearance of DVAs on crosssectional imaging and angiography attest to their benign nature. Any associated clinical symptom is caused primarily by associated malformations (cavernomas or arteriovenous shunts). Their lack of flexibility as a result of being an anatomical variant of the venous drainage to the brain in the region may also produce ischemic episodes of varying severity. However, because DVAs drain normal areas of the brain, they should never be eradicated. Rarely does a true AVM drain into a DVA. In this instance, a true arteriovenous shunt is demonstrated within an otherwise normal network of vessels. Treatment of such patients requires extreme care to preserve normal venous channels.
Proliferative and hemorrhagic angiopathies Proliferative and hemorrhagic angiopathies are entities often confused with BAVMs. They are rare, proliferative, vascular lesions seen usually in children and young women. The appearance of proliferative angiopathy is typically that of a nidus-like cortical network of vessels intermingled with
Pathophysiology, Clinical Manifestation, and Natural History The clinical manifestation of BAVM may be related to the shunt itself or to secondary changes (visible on high-flow angiopathy)
600
Section
IX
C e r e b r o va s c u l a r D i s e a s e
that occur in response to chronic shunting. It also depends on the age of the patient. Manifesting clinical features include chronic headaches, seizures, cerebral hemorrhage, and neurological deficits.
Neonates, Infants, and Children Neonates with BAVMs may present with high-output cardiac failure related to the presence of high-flow shunts in the AVM. In young children, alterations in cerebrospinal fluid circulation and absorption in the immature brain caused by increased venous pressure may lead to water retention, macrocrania, and hydrocephalus, and venous congestion may rapidly lead to focal ischemia, convulsions, and hemorrhage. Meltingbrain syndrome can occur in neonates and young infants. This involves a rapid destruction of the brain, usually the white matter, with ventricular enlargement. This phenomenon, which is never encountered in adults, corresponds to a regional decrease in the cerebral blood flow caused by retrograde venous hypertension and subsequent venous congestion leading to hydrovenous dysfunction. It is usually bilateral and symmetrical, associated with severe neurological manifestations and no signs of increased intracranial pressure, although they are usually present before the syndrome manifests.
Hemorrhage Hemorrhage in a patient with a BAVM represents a significant change in the compliance of the vascular system. Bleeding can result from rupture of the AVM nidus, arterial aneurysm rupture, or venous rupture, which may occur close to or remote from the AVM. It has been shown that arterial aneurysms are not significantly associated with hemorrhagic manifestation,5 of BAVMs. The presence of aneurysms within an AVM nidus is, however, noted to significantly worsen the natural history of future hemorrhages.16 Deep venous drainage and deep location of a BAVM are associated with a higher risk of hemorrhagic manifestation.17
Seizure and Neurological Deficit Seizure is the second most frequent manifesting symptom in all BAVM patients and occurs in up to 53% of cases. The AVM locations most frequently associated with seizure production are the motor-sensory strip and the temporal areas, representing close to 70% of cases of BAVM with seizures. For most of the less functional brain areas, seizure manifestations may be overlooked unless secondarily generalized. Neurological deficit not associated with hemorrhage, in contrast, is an infrequent symptom, occurring in only 8% of patients over a 10-year period.18 Neurological deficits and seizures may be caused by an AVM by several possible mechanisms: (1) ischemia, (2) hemorrhage, (3) direct or indirect mechanical compression, and (4) postseizure neurological deficit. Arterial ischemia may theoretically result from two types of mechanism: a “steal” phenomenon or occlusive changes. The concept of “steal” is based on the angiographic nonvisualization of vessels in a normal area of the brain that should have been visualized at the time of injection. However, careful angiographic evaluation always demonstrates the “missing” branches through leptomeningeal anastomoses from adjacent territories,
thus expressing the adaptability of the brain’s circulation. Arterial stenosis and occlusion proximal to an AVM may range in appearance from a single vessel narrowing to a moyamoya pattern. Such changes are usually slowly progressive, allowing for stepwise compensation, including leptomeningeal angiectasia, which accounts for their clinically silent development. These changes may eventually lead to progressive symptoms such as headaches, neurological deficits, and seizures. Multivariate analysis has shown that patients with such occlusive changes and angiogenesis may have lesser hemorrhagic risk than do patients without such changes.19 The concept of venous ischemia is accepted by most authors involved in the management of cerebral arteriovenous lesions but is rarely acknowledged for its significance. It is important to remember that 60% to 80% of the cerebral blood volume is located in the venules of the cerebral venous system. They have all the necessary characteristics for active exchange with the surrounding tissue, a testament to their role in nutrient exchange. Flow in venules in the white matter is bidirectional, allowing them to fulfill their nutrient role even in a retrograde manner. This function is disrupted with increasing pressure in the veins. The progressive nature of deficits in relation to some BAVMs and their fluctuation reflect the attempts of the collateral circulation to overcome increased pressure in the venous outlet of a shunt. Decreased tissue perfusion secondary to venous ischemia may produce virtually any type of neurological symptom (e.g., motor or sensory deficits, neuropsychological alteration, seizures). Most of the symptoms result in effects remote from the nidus. Posterior fossa AVMs may thus manifest with supratentorial manifestations. The greater the distance between the shunt site and its venous drainage into a dural sinus, the higher are its chances of interfering with the normal brain circulation. The onset of seizures in a previously healthy individual may also reflect an acute change in hemodynamics, which may be caused by rerouting of drainage from the malformation through a vein that previously drained normal areas of the brain. The increase in pressure produces secondary neurological dysfunction of the affected areas of the brain, and seizures may result. New-onset seizures and headaches can also occur when venous thrombosis develops in association with a BAVM.
Headache Headache is the first symptom in approximately 60% of patients with BAVM. These headaches can be divided into (1) those that accompany an episode of intracranial hemorrhage or venous thrombosis and (2) those that are more subacute or chronic in nature. The acute headaches associated with hemorrhage or acute venous thrombosis typically manifest abruptly and are usually severe in nature, associated with photophobia, nausea, vomiting, convulsion, and loss of consciousness. Constant headaches or episodes of throbbing (“migrainelike”) headaches can occur in the same patient. The headaches are often localized to the same side as the AVM. In most cases, the exact cause of the headache remains unclear, although in some patients, there may be a relationship between the angioarchitectural features and the headaches. Dural and posterior cerebral artery supplies to a BAVM are known to be potentially responsible for headaches that tend to disappear after emboliza-
chapter 44 arteriovenous malformations of the brain and spinal cord tion therapy, in our experience. Conversely, embolization of middle and anterior cerebral artery supply to a parietal lobe BAVM may worsen headaches if the posterior cerebral artery supply is increased after such embolization. It does not seem that transdural supply to an AVM causes headache; such a feature is suggestive of ischemia of the underlying cortex.
Diagnosis, Management, and Treatment The current modes of therapy for BAVMs include endovascular embolization with glue (N-butyl cyanoacrylate), surgery, stereotactic radiation therapy, and or combined therapy. The type of treatment may vary from center to center and is dependent on physicians’ strengths and capabilities. The discovery of a BAVM in a patient does not represent an automatic indication for treatment. There is growing evidence in both the surgical and endovascular literature that every BAVM is unique and that different BAVMs do not carry a similar risk for future symptoms.20 The risk associated with treatment should be lesser than that of the natural history of a particular lesion. The age of the patient is also important, and the therapeutic strategy should be based on the post-therapeutic clinical benefit expected over time and the therapeutic risks associated with therapy. The treatment of BAVMs requires complete information with regard to the clinical circumstances and the imaging characteristics, including the angioarchitecture of the AVM and the brain. The angioarchitecture of the AVM influences both the approach to a lesion and the expected chances of reaching the therapeutic goal.
Imaging Modalities The topographic location of a malformation is best assessed by MRI or computed tomography. MRI delineates accurately the location of the lesion and is more sensitive than computed tomography in demonstrating secondary effects on the brain parenchyma, particularly the changes in white matter edema secondary to chronic venous congestion and hemosiderin from previous hemorrhage. DSA, however, enables the anatomical identification of the arterial feeders, the angioarchitecture of the nidus, the draining veins, and the hemodynamic aspects of the shunt. The presence of other associated vascular lesions and significant arterial and venous variations, as well as the vascular anatomy and physiology of the normal cerebral vasculature, may also be visualized. This complete information is necessary in deciding and planning a treatment strategy. New data from advanced MRI techniques such as diffusionweighted imaging, perfusion imaging, and functional MRI with neuronal activation have also been useful in studying abnormal brain areas near or remote from the AVM nidus. These techniques are able to show hemodynamic and neuronal adaptive phenomena in the areas involved by the AVM and in the surrounding areas of the brain. For example, reduced cerebral perfusion in the areas around the AVM related to venous congestion may be demonstrated. Functional MRI with mapping of cortical function in relation to the AVM can also be performed. This information may help the clinician correlate clinical symptoms with their anatomical and functional substrate and influence any decisions about invasive therapy.21
601
Indications for Intervention The information obtained by the angiographic investigation plays a key role in the decision about the need for treatment. This is based on the demonstration of evidence of weakness in the angioarchitecture, which may point to a potential instability. The presence of a pseudoaneurysm or an associated arterial aneurysm (on the feeding pedicle or in the nidus), venous thrombosis, outflow restriction, venous hyperpressure, venous pouches, or venous dilatations is a factor favoring active intervention. But when the risk of total elimination of the malformation (by either embolization or microsurgery or by a combination of therapies) is prohibitive, then a different management strategy, such as partial targeted embolization to eliminate the points of weakness to reduce further risk of hemorrhage, must be considered, rather than an attempt to achieve a complete cure of the lesion. An important part of the management of incidentally discovered BAVMs is to provide the patient with information regarding the natural history as it may apply to the particular situation, as well as the treatment options and associated risks that are available in the local treatment environment. If no angioarchitectural weaknesses are demonstrated, a medical follow-up treatment strategy can be proposed with the patient reassured that he or she is expected to lead a normal, productive life without restrictions. However, the evolution of BAVMs is not linear, and biological events may produce unexpected changes, which may remain subclinical for a long time. Followup is therefore crucial in all patients, including those for whom a decision not to treat was chosen. Follow-up is usually clinical with imaging (MRI), but if clinical or imaging changes are noted, then repeat angiography may be indicated.
Specific Factors Affecting Therapeutic Decisions Hemorrhage The treatment strategy after presentation with hemorrhage is dependent on how well the hemorrhage is tolerated. When surgical intervention is necessary to remove an intracerebral hematoma, excision of the malformation at the same time is sometimes possible. Most hemorrhages are well tolerated,22 and no immediate AVM treatment is usually necessary. There is seldom a need for urgent treatment after BAVM hemorrhage, and a treatment strategy can be planned accordingly. Careful analysis of the angioarchitecture is important in order to look for suspicious angiographic features that are probably responsible for the hemorrhage (prenidal or intranidal aneurysm, pseudoaneurysm). These represent an indication for early treatment targeted toward obliteration of such weak points (partial targeted embolization). Large size of a BAVM is associated with increased risk of future hemorrhage.23 Partial targeted embolization with reduction of nidal size and specific angioarchitectural features has been shown to reduce future risk of hemorrhage.24
Seizures Seizures occur at presentation in 10% to 53% of patients with BAVMs, the majority being partial or partial complex seizures. Subsequent seizure control with antiepileptic medication is achieved in most patients; therefore, seizure control by itself
602
Section
IX
C e r e b r o va s c u l a r D i s e a s e
rarely becomes an indication for intervention. Refractory status epilepticus is an exception that may represent an indication for endovascular treatment, and such management has been successful in bringing seizure management under control. Worsening or new onset of seizures after treatment is rare.
Age The younger the patient is at the time of presentation, the more likely it is that active treatment should be considered. Presentation at an early age represents an early imbalance between the lesion and host. Newborns with congestive heart failure are the most dramatic examples of such an imbalance. Hydrocephalus in infants may also be secondary to cerebrospinal fluid absorption abnormalities and may result in irreversible developmental delay if endovascular treatment is not undertaken. The melting brain syndrome may also develop rapidly in some young infants if treatment is delayed.25 Patients older than 60 years at presentation are at a higher risk of bleeding,18 up to 89% by 9 years, in comparison with a 15% risk in the same period for patients aged 20 to 29. In addition, in older patients, bleeding carries very high rates of morbidity and mortality, because the older brain has less plasticity to recover. This may influence the management strategy for partial targeted therapy to restore once again the equilibrium between host and AVM.
Modes of Therapy The role of surgery, endovascular glue embolization, stereotactic radiosurgery, and/or combined therapy in the treatment of BAVMs varies from center to center, depending on the expertise available. The location of a malformation, the size, and deep venous drainage are the most important factors in determining the risks of surgical resection of an AVM,26 whereas these features are of only minor concern in the endovascular approach. Technically, morbidity associated with embolization is related to the capacity to reach the lesion endovascularly and to remain strictly within the nidus during glue embolization. Therefore, deep lesions such as brainstem, thalamic, or basal ganglia lesions, although obviously more risky to treat, can be obliterated by careful embolization, whereas surgery in such locations would carry much higher risks. Stereotactic radiosurgery with the gamma beam, linear accelerator, or proton beam is another accepted mode of BAVM therapy. Radiosurgery leads to progressive occlusion of BAVMs by inducing vessel wall thickening, thrombosis, and, finally, occlusion of the vessel lumen. This occurs over a period of typically 2 years. During this period of 2 years, however, it does not provide immediate protection from future hemorrhage. The efficacy of radiosurgery also depends on lesion size and volume,27-29 the success rate being lower for large lesions, which require a much higher radiation dose. Radiosurgery is therefore generally an option for nidus-type lesions that are smaller than 3 cm and are not easily accessible via endovascular or surgical means. Combination treatments may facilitate the complete cure of an AVM that might not have been possible with a single modality alone. Presurgical embolization has a well-accepted role in facilitating surgical removal of AVMs. Often, the role of endovascular embolization in such cases is to eliminate a deep arterial feeder, to occlude an intranidal fistula, or to reduce overall size and flow through the nidus before surgery.
Embolization before radiosurgery may also be performed with the aim of achieving reductions in lesion size and volume, and embolization may be targeted toward specific angioarchitectural features such as intranidal aneurysms, false sacs, or intranidal fistulae. When using combination therapy, the clinician must always bear in mind the increased therapeutic risk to the patient (combined risk of the different treatment modalities), and weigh this against the overall benefits of the combined therapy.
SPINAL CORD ARTERIOVENOUS MALFORMATIONS Incidence Vascular malformations of the spine and spinal cord are considered uncommon lesions. Their incidence, expressed as a percentage of the total number of the various types of spinal space-occupying lesions, ranges from 3%30 to 16%.31 The discrepancy is explained by the introduction of better diagnostic modalities. Nevertheless, the true incidence of spine and spinal cord vascular malformations may be underestimated. Although cerebral vascular malformations are more common than spinal ones, the comparative incidence in relation to brain versus spinal tumors is very similar, ranging from 2% to 4%.32,33 This suggests that the frequency of SCAVMs in comparison with BAVMs is correlated with the mass or volume ratio between spinal cord and brain tissue. The prevalence of incidental or asymptomatic spinal vascular malformations is difficult to ascertain, inasmuch as the spinal cord is usually not inspected on routine autopsy.
Classification and Angioarchitecture SCAVMs are arteriovenous shunts located intradurally and supplied by radicular arteries (radiculomedullary and radiculopial), the anterior spinal artery, the pial network, their perforators, or any combination of these. The lesion may be located along the surface of the cord (extramedullary), within the cord substance (intramedullary), or both. This group also includes AVMs that are located along the intradural portion of the spinal nerves and on the filum terminale. They are likely to be both subarachnoid and subpial because the pial veins of the cord are subarachnoid. These lesions are distinct from AVMs that are extradural or paraspinal in location and from spinal dural AVFs, which are located within or on the outer surface of dura along the spinal canal. As in the brain, SCAVMs may be divided into nidal (AVMs) or fistulous types (AVFs). Nidus-type lesions are characterized by a network of abnormal channels (nidi) between the arterial feeders and the draining veins (Fig. 44–3). Fistula-type lesions, in contrast, consist of a direct communication or opening between a feeding artery and a draining vein (Fig. 44–4). Large nidus-type lesions are usually embedded within the spinal cord, whereas small lesions are often more superficial, near the surface of the cord. Fistula-type lesions, which may also be distinguished as large (macro-AVFs) and small (micro-AVFs), are always found on the surface of the spinal cord (extramedullary). SCAVMs may be classified into three main groups (Table 44–2), described as follows.34
chapter 44 arteriovenous malformations of the brain and spinal cord ■
603
Figure 44–3. Arteriovenous malformation (AVM) in the spinal cord. The patient, an 18-yearold man, presented with sudden onset of paraplegia associated with urinary symptoms. A and B, Magnetic resonance imaging (MRI) (sagittal T2- and T1-weighted images) showed a hematoma within the spinal cord at the second thoracic level, associated with cord edema extending from the upper thoracic to the cervical level. Dilated vessels were noted along the dorsal surface of the spinal cord. continued
A
B
Genetic Hereditary Lesions This first group of SCAVMs is caused by a genetic hereditary disorder, in which vascular germinal cells are affected by disease. The main syndrome in which genetic links can be recognized is HHT (see section on BAVMs). SCAVMs associated with HHT are almost always single macro-AVFs, particularly in the pediatric population. Indeed, macro-AVFs may be the first expression of the disease in children; the discovery of a spinal cord macro-AVF
T A B L E 4 4 – 2.
should therefore raise the possibility of this underlying genetic hereditary disease.13,35 These lesions are usually single at the cord but can be associated to intracranial ones.36
Genetic Nonhereditary Lesions This second group of SCAVMs is not related to a hereditary disorder; it includes multifocal lesions potentially sharing metameric links (see also section on BAVMs).37
Classification of Spinal Cord Arteriovenous Malformations
Rodesch G, Hurth M, Alvarez H, et al: Classification of spinal cord arteriovenous shunts: proposal for a reappraisal—the Bicêtre experience with 155 consecutive patients treated between 1981 and 1999. Neurosurgery 2002; 51:374-380. *Multifocal lesions sharing metameric links. AVF, arteriovenous fistula; AVM, arteriovenous malformation.
604
Section
IX
C e r e b r o va s c u l a r D i s e a s e ■
Figure 44–3, cont’d. C and D, Angiography (left third thoracic intercostal artery injection) showed an AVM nidus associated with a false aneurysm sac, which corresponded to the hematoma seen on MRI. Dilated veins could be seen draining superiorly, with smaller veins draining inferiorly, contributing to venous congestion and cord edema. Embolization of this AVM was performed with glue (N-butyl cyanoacrylate), which succeeded in removing the false aneurysm during the first session.
C
D
Each segment in the spine involves the spinal cord (corresponding myelomere); nerve root; bone; and paraspinal, subcutaneous, and skin tissues. A patient may therefore present with multiple shunts, which involve several different myelomeres (segments) of the spinal cord (multimyelomeric SCAVMs) both on the cord and on intradural nerve roots. The association of a SCAVM with a nerve root AVM in the same patient is metameric if the spinal cord segment (myelomere) involved corresponds to that of the nerve involved. This spinal arteriovenous metameric syndrome, also known as Cobb’s syndrome, can be numbered from 1 to 31, depending on its location at the vertebral and metameric levels. Klippel-Trénaunay and Parkes-Weber syndromes are characterized by cutaneous capillary hemangiomas or port wine stains, varicosities and lymphedema, and bone and soft tissue hypertrophy of the affected extremity, usually the lower limb. Parkes-Weber syndrome is also associated with the presence of AVMs in the involved extremity. Associated SCAVMs are known to occur in these syndromes.34,38 In such cases, the SCAVMs are usually multiple, and a metameric disposition is suspected but cannot be definitely demonstrated. Other multifocal spinal cord lesions have been described without metameric linkage.
Single Lesions This third group of SCAVMs consists of all classic single lesions, either nidal or fistulous. This group may reflect an incomplete expression of one of the previously described situations and includes lesions of the spinal cord, nerve root, and filum terminale.
Clinical Presentation In SCAVM series that include adults and children, the mean age of presentation is in the mid-20s.39-41 However, in close to 20% of cases, the lesion is diagnosed in children younger than 16 years of age.42 In a more recent series,43 30% were children. Common clinical manifestations include acute neurological symptoms usually caused by hemorrhagic events, chronic progressive neurological deficit associated with venous congestion, and acute nonhemorrhagic symptoms.
Spinal Hemorrhage The most striking symptom in the clinical presentation of SCAVMs is the high incidence of hemorrhage, which may be
chapter 44 arteriovenous malformations of the brain and spinal cord ■
605
Figure 44–4. Spinal cord arteriovenous fistula (AVF). The patient, an 11-month-old boy, had presented at the age of 3 months with progressive paraparesis, associated with increasing spasticity of the lower limbs and sphincteric problems. A, Magnetic resonance imaging (MRI) showed a large vascular pouch within the spinal canal. B, Angiography showed a macroAVF. The vascular pouch seen on MRI was due to an ectatic venous pouch. The presence of a macro-AVF was suggestive of hereditary hemorrhagic telangiectasia, but no family history could be found. This fistula was successfully embolized with glue (Nbutyl cyanoacrylate) in two sessions.
A
B
either subarachnoid or within the spinal cord itself (hematomyelia) and occurs in 50% of all SCAVM patients. Hemorrhage, particularly hematomyelia, is associated with the onset of new, significant, and often devastating neurological deficits or with aggravating preexisting deficits. Hemorrhage is seen more frequently in cervical lesions than in thoracic and lumbar lesions.39-41 Hemorrhage is also more common in children.43 Hemorrhage may be caused by rupture of associated aneurysms, rerupture of a false aneurysm, rupture of spinal cord veins, or rupture of the AVM nidus. Hemorrhagic transformation of venous infarction is not observed in the cord. The typical syndrome of spinal hemorrhage is severe pain, which frequently starts in the interscapular region and/or at the site of the rupture and then rapidly spreads to the rest of the back, to the nuchal area, and to the legs. When hemorrhage is profuse or, in cervical lesions, when blood extends into the intracranial cavity, there may be headaches and disturbance of consciousness. In severe cases, papilledema, cranial nerve palsies, and convulsions may be observed. The signs and symptoms can be so severe and rapid in their onset that they may be mistaken for intracranial subarachnoid hemorrhage. In other cases, limb weakness, sensory loss, and disorders of micturition or defecation may follow bleeding within the cord itself (hematomyelia) or may result from compression of the cord by
a blood clot. In rare instances, in cases of severe upper cord dysfunction, respiratory paralysis can occur.
Nonhemorrhagic Symptoms Acute, nonhemorrhagic neurological deficit may result from acute intralesional venous thrombosis. This may occur as a venous response to chronic hemodynamic changes in the SCAVM. More often, patients present with chronic progressive neurological symptoms caused by venous congestion within the spinal cord. Of note is that the venous proportion of the vascular system is of greater hemodynamic significance in the spinal cord than in the cerebral circulation. This can be explained by the contragravity venous drainage of the spinal cord (which is mostly below the level of the heart), in comparison with that of the brain. Chronic progressive symptoms may manifest in a continuous or stepwise manner. Early symptoms include nerve root or back pain. Weakness eventually develops in over 90% of affected patients. Other common symptoms include sensory changes and impotence. Bowel and bladder dysfunction is present in almost all patients. The presence of a bruit is a relatively uncommon finding. If present, however, a bruit is strongly suggestive of a high-flow lesion.
606
Section
IX
C e r e b r o va s c u l a r D i s e a s e
Muscle atrophy and sensory disturbances that may result in multiple injuries can be observed in patients with SCAVMs. Spinal deformities such as kyphosis and scoliosis are also seen. In addition, complications common to other types of spinal cord dysfunction, such as urinary tract infections, respiratory infections, and decubitus ulcerations, may also be present and must be taken into consideration in determining the morbidity and final outcome of these patients.
Diagnosis and Clinical Assessment The first step in the assessment of patients with suspected vascular disorders of the spinal cord is a complete clinical history and physical examination. The neurological status needs to be accurately determined and often must be repeated in time to objectively establish stability or worsening of neurological status. This is followed by a complete pretherapeutic evaluation, including noninvasive imaging techniques and spinal angiography.
Noninvasive Imaging Techniques MRI has become the modality of choice in the preliminary assessment of patients referred for investigation of vascular pathology of the spinal cord. Computed tomography and myelography no longer have a significant role in the initial screening of suspected SCAVM, except for cases in which MRI is contraindicated. MRI is both sensitive in lesion detection and able to demonstrate the extent of an AVM, including the demonstration of any extraspinal extension in cases of metameric syndromes. MRI is also useful in delineating intramedullary pathologic processes such as spinal cord hematoma, intravascular thrombosis, and subarachnoid hemorrhage and the secondary changes of cord edema, intramedullary cavities, or cord atrophy secondary to chronic venous hypertension. Changes at a distance from the malformation may be present and may explain otherwise confusing neurological symptoms. MRI remains limited in its ability to accurately locate the site of arteriovenous communication and the evaluation of the angioarchitecture of an AVM. Pitfalls of this technique in the assessment of patients with vascular lesions of the spinal cord are related primarily to cerebrospinal fluid pulsation artifacts that may produce images highly suggestive of spinal cord vascular lesions.44 This is of particular importance in pediatric patients, in whom such artifacts may lead to unnecessary angiographic exploration. If, however, the study findings are negative or inconclusive and if the diagnosis is compatible with venous congestion from a small arteriovenous shunt draining into the ventral spinal cord vein, spinal DSA should be performed.45 For treatment planning, spinal DSA still remains the study of choice.
Spinal Angiography DSA remains a “gold standard” in the diagnosis and treatment planning of vascular lesions of the spine and spinal cord. Spinal DSA is usually performed with the patient under general anesthesia and with controlled respiration.
Spinal DSA is performed according to different protocols at different institutions and may be guided by MRI. However, as in any other vascular study, a territorial approach must be undertaken. As in all other anatomical areas, the angiographic examination must outline the normal vasculature around the vascular pathology to ensure that the full extent of the lesion is visualized and that the effect of the lesion on the remainder of the spinal cord is understood and in order to properly plan and monitor treatment. Specific attention should be paid to the angioarchitecture of the lesion and remaining vascular supply to the cord. Features such as radicular aneurysms, intranidal aneurysms, and venous congestion should be noted.
Treatment and Management The final outcomes of patients with vascular lesions of the spinal cord are directly related to the prompt diagnosis and treatment of the abnormality.
Endovascular Embolization and Surgery The main modes of therapy are surgery and endovascular embolization. In current practice, the first line of treatment for SCAVMs is usually endovascular embolization with glue (Nbutyl cyanoacrylate). In rare instances in which endovascular embolization is not possible or may carry high risk, surgery may be considered. Radiosurgery currently has no role in the treatment of SCAVMs. The indications for treatment include all symptomatic lesions that can be cured. Factors that modify the objectives in a particular patient include (1) the age of the patient; (2) the clinical manifestation (e.g., hemorrhage, more than one hemorrhage); (3) the angioarchitecture of the lesion (the presence of, e.g., an aneurysm, venous ectasia); and (4) impaired arterial flow or venous drainage of the spinal cord (stagnation in the anterior spinal artery circulation; nonvisualization of the medullary veins, indicating impaired venous drainage). In the young symptomatic patient, treatment should be pursued aggressively. As in BAVMs, even when complete cure may not be possible at an acceptable level of risk, partial targeted treatment can be proposed with the aim of arresting or improving the clinical situation or favorably modifying the natural history of disease. The purpose of a partial targeted approach is to obliterate weak points in the angioarchitecture (e.g., arterial aneurysm and nidus aneurysm) and to reduce nidal size and flow to decongest the venous drainage. These procedures relieve the venous drainage of the normal spinal cord, often with beneficial effect. In the acute stage after a spinal hemorrhage, the neurological deficit may be severe, including total loss of function. Although rebleeding is a risk, most patients improve significantly over the next several weeks or months. Emergency and aggressive intervention is generally unnecessary and may interfere with the process of natural recovery. Spinal angiography may be performed early to rule out a pseudoaneurysm or another potentially risky angioarchitectural feature that may justify early targeted embolization, usually if more than one hemorrhage has occurred. In patients with a fixed deficit or severe clinical signs of cord transection, treatment is of unlikely functional benefit. Nonetheless, treatment is indicated, especially in cases of
chapter 44 arteriovenous malformations of the brain and spinal cord repeated hemorrhage and in high cord lesions, to reduce the risk of repeated life-threatening spinal hemorrhage. In some patients with severe pain related to compressive symptoms, palliative embolization may also be beneficial.
neonatal series represent only a small proportion of AVMs and pertain to specific disease groups. ●
Magnetic resonance imaging and digital subtraction angiography are currently the modalities of choice in the diagnosis and evaluation of these lesions.
●
The aim of treatment is an improvement over the expected natural history of the disease rather than a morphological endpoint. The treatment strategy is specific to each patient and based on the clinical circumstances, the age of the patient, and the angioarchitecture of the lesion.
Medical Therapy Medical treatment for the various complications of spinal vascular lesions is an important part of patient management and should be provided. Physical therapy, nursing, pain control management, and psychotherapy all play important roles in the management of patients with SCAVMs. A properly trained team is essential for obtaining the best overall results.
607
CONCLUSION
Suggested Reading
Both BAVMs and SCAVMs are relatively uncommon diseases. The exact incidence of these diseases is, however, difficult to estimate. Differences in the disease prevalence reported in the literature are probably related to differing referral patterns and population differences, as well as the diagnostic modalities available. Patients may present with a wide range of clinical symptoms, which vary according to lesion location, the angioarchitecture of the malformation, and the age of the patient. When either a BAVM or SCAVM is suspected in a patient, a complete clinical and neurological assessment is crucial. This is essential both in the pretreatment evaluation and for subsequent follow-up of the patient’s progress after therapy. Current imaging modalities in the evaluation of these vascular lesions involve mainly MRI and DSA, the latter being necessary for the accurate delineation of lesion angioarchitecture and hence in treatment planning. Of the therapeutic modalities discussed, endovascular embolization is becoming an increasingly important tool in the treatment of both BAVMs and SCAVMs. Whereas a complete cure is often obtained in single-hole fistulae or small AVMs, it may not be possible in many complex lesions without risk of increased morbidity. In such cases, a partial targeted approach may be taken instead, to treat high-risk areas within such lesions. The aim of treatment is, above all, to improve the natural history of the disease, in comparison with the risk of therapy, and to achieve amelioration of clinical symptoms when possible.
Berenstein A, Lasjaunias P, Ter Brugge KG: Surgical Neurorangiography, vol 2.2: Clinical and Endovascular Treatment Aspects in Adults, 2nd ed. Berlin: Springer-Verlag, 2004, pp 609-735, 760-847. Hofmeister C, Stapf C, Hartmann A, et al: Epidemiological, clinical and morphological characteristics of 1289 patients with cerebral arteriovenous malformation. Stroke 2000; 31:13071310. Lasjaunias P: Vascular Diseases in Neonates, Infants and Children: Interventional Neuroradiology Management. Berlin: SpringerVerlag, 1997, pp 203-319. Mansmann U, Meisel J, Brock M, et al: Factors associated with intracranial hemorrhage in cases of cerebral arteriovenous malformation. Neurosurgery 2000; 46:272-281. Meisel HJ, Mansmann U, Alvarez H, et al: Cerebral arteriovenous malformation and associated aneurysms: analysis of 305 cases from a series of 662 patients. Neurosurgery 2000; 46:793802. Rodesch G, Hurth M, Alvarez H, et al: Angioarchitecture of spinal cord arteriovenous shunts at presentation. Clinical correlations in adults and children: the Bicêtre experience on 155 consecutive patients seen between 1981-1999. Acta Neurochir 2004; 146:217-227. Stefani MA, Porter PJ, Ter Brugge KG, et al: Angioarchitectural factors present in brain arteriovenous malformations associated with hemorrhagic presentation. Stroke 2002; 33:920-924. Valavanis A, Yasargil MG: The endovascular treatment of brain arteriovenous malformations. Adv Tech Stand Neurosurg 1998; 24:131-214.
References
K E Y ●
P O I N T S
Arteriovenous malformations (AVMs) in the brain and spinal cord are uncommon. The concept that AVMs are congenital (morphologically detectable at birth) is not supported by antenatal or pediatric imaging and clinical experience. On the contrary, it is likely that lesions found in young adults, although likely to result from an early in utero “event,” are not present at birth but appear later as a result of various (unknown) exogenous or endogenous “revealing” triggers. This empirical observation contributes to the evolution of the malformation concept from a morphological (detectable) to a biological (quiescent) one. Pediatric cases or even
1. Weon YC, Yoshida Y, Sachet M, et al: Supratentorial cerebral arteriovenous fistulas (AVFs) in children: review of 41 cases with 63 non choroidal single-hole AVFs. Acta Neurochir 2005; 147:17-31. 2. Garretson HD: Intraranial arteriovenous malformations. In Wilkins RH, Rengachary SS, eds: Neurosurgery. New York: McGraw-Hill, 1985, pp 1448-1457. 3. Jellinger K: Vascular malformations of the central nervous system: a morphological overview. Neurosurg Rev 1986; 9:177216. 4. Mohr JP: Neurological manifestations and factors related to therapeutic decisions. In Wilson CB, Stein BM, eds: Intracranial Arteriovenous Malformations. Baltimore: Williams & Wilkins, 1984, pp 12-23. 5. Valavanis A, Yasargil MG: The endovascular treatment of brain arteriovenous malformations. Adv Tech Stand Neurosurg 1998; 24:131-214.
608
Section
IX
C e r e b r o va s c u l a r D i s e a s e
6. Guttmacher AE, Marchuk DA, White RIJ: Hereditary hemorrhagic telangiectasia. N Engl J Med 1995; 333:918-924. 7. McAllister KA, Grogg KM, Johnson DW: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary hemorrhagic telangiectasia type 1. Nat Genet 1994; 8:345-351. 8. Mahadevan J, Ozanne A, Yoshida Y, et al: Hereditary haemorrhagic telangiectasia cerebrospinal localization in adults and children: review of 39 cases. Interv Neuroradiol 2004; 10:2735. 9. Willinsky RA, Lasjaunias P, Ter Brugge KG, et al: Multiple cerebral arteriovenous malformations: review of our experience from 203 patients with cerebral vascular lesions. Neuroradiology 1990; 32:207-210. 10. Fullbright RK, Chaloupka JC, Putman CM, et al: MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 1998; 19:477-484. 11. Matsubara S, Mandzia JL, Ter Brugge KG, et al: Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. AJNR Am J Neuroradiol 2000; 21:1016-1020. 12. Krings T, Ozanne A, Chng SM, et al: Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age: review of 50 consecutive patients aged 1 day–60 years. Neuroradiology 2005; 47:711-720. 13. Garcia-Monaco R, Taylor W, Rodesch G, et al: Pial arteriovenous fistula in children as presenting manifestation of RenduOsler-Weber disease. Neuroradiology 1995; 37:60-64. 14. Yoshida Y, Weon YC, Sachet M, et al: Posterior cranial fossa single-hole arteriovenous fistulae in children: 14 consecutive cases. Neuroradiology 2004; 46:474-481. 15. Bhattacharya J, Luo CB, Suh DC, et al: Wyburn-Mason or Bonnet-Dechaume-Blanc as cerebrofacial arteriovenous metameric syndromes (CAMS): a new concept and a new classification. Interv Neuroradiol 2001; 7:5-17. 16. Meisel HJ, Mansmann U, Alvarez H, et al: Cerebral arteriovenous malformation and associated aneurysms: analysis of 305 cases from a series of 662 patients. Neurosurgery 2000; 46:793802. 17. Stefani MA, Porter PJ, Ter Brugge KG, et al: Angioarchitectural factors present in brain arteriovenous malformations associated with hemorrhagic presentation. Stroke 2002; 33:920-924. 18. Crawford PM, West CR, Chadwick DW, et al: Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry 1986; 49:1-10. 19. Mansmann U, Meisel J, Brock M, et al: Factors associated with intracranial hemorrhage in cases of cerebral arteriovenous malformation. Neurosurgery 2000; 46:272-281. 20. Hofmeister C, Stapf C, Hartmann A, et al: Epidemiological, clinical and morphological characteristics of 1289 patients with cerebral arteriovenous malformation. Stroke 2000; 31:1307-1310. 21. Ducreux D, Desal H, Bittoun J, et al: Diffusion, perfusion and activation functional MRI studies of brain arteriovenous malformations. J Neuroradiol 2004; 31:25-34. 22. Berenstein A, Lasjaunias P, Ter Brugge KG: Goals and objectives in the management of brain arteriovenous malformations. In Surgical Neurorangiography, vol 2.2: Clinical and Endovascular Treatment Aspects in Adults, 2nd ed. Berlin: Springer-Verlag, 2004, p 703. 23. Stefani MA, Porter PJ, Ter Brugge KG, et al: Large and deep brain arteriovenous malformations are associated with risk of future hemorrhage. Stroke 2002; 33:1220-1224. 24. Meisel HJ, Mansmann U, Alvarez H, et al: Effect of partial targeted NBCA embolization in brain AVM. Acta Neurochir 2002; 144:879-888.
25. Lasjaunias P: Vascular Diseases in Neonates, Infants and Children: Interventional Neuroradiology Management. Berlin: Springer-Verlag, 1997, p 41. 26. Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 1986; 65:476-483. 27. Karlsson B, Lindquist C, Steiner L: Prediction of obliteration after gamma knife surgery for cerebral arteriovenous malformations. Neurosurgery 1997; 40:425-431. 28. Pollock B, Flickinger J, Lunsford D, et al: Factors associated with successful arteriovenous malformation radiosurgery. Neurosurgery 1998; 42:1239-1247. 29. Schlienger M, Atlan D, Lefkopoulos D, et al: Linac radiosurgery for cerebral arteriovenous malformations: results in 169 patients. Int J Radiation Oncol Biol Phys 2000; 46:1135-1142. 30. Wyburn-Mason R: The Vascular Abnormalities and Tumours of the Spinal Cord and Its Membranes. London: H. Kimpton, 1943. 31. Pia HW, Vogelsang H: Diagnose und Therapie spinaler Angiome [Diagnosis and therapy of spinal angioma]. Dtsch Z Nervenheilkd 1965; 187:74-96. 32. Olivecrona H: The cerebellar angioreticulomas. J Neurosurg 1957; 9:317-330. 33. Krenchel NJ: Intracranial Racemose Angiomas: a Clinical Study. Copenhagen: Universitetsforlaget i Aarhus, 1961. 34. Rodesch G, Hurth M, Alvarez H, et al: Classification of spinal cord arteriovenous shunts: proposal for a reappraisal—the Bicêtre experience with 155 consecutive patients treated between 1981 and 1999. Neurosurgery 2002; 51:374-380. 35. Mandzia JL, Ter Brugge K, Faughnan ME, et al: Spinal cord arteriovenous malformations in two patients with hereditary hemorrhagic telangiectasia. Childs Nerv Syst 1999; 15:80-83. 36. Mazighi M, Porter P, Alvarez H, et al: Associated cerebral and spinal AVM in infant and adult: report of two cases treated by endovascular approach. Intervent Neuroradiol 2000; 6:321326. 37. Matsumaru Y, Pongpech S, Laothamas J, et al: Multifocal and metameric spinal cord arteriovenous malformations: review of 19 cases. Interv Neuroradiol 1999; 5:27-34. 38. Nimii Y, Ito U, Tone O, et al: Multiple spinal perimedullary arteriovenous fistulae associated with the Parkes-Weber syndrome. Interv Neuroradiol 1998; 4:151-157. 39. Djindjian M, Djindjian R, Hurth M, et al: Spinal cord arteriovenous malformations and the Klippel-Trénaunay-Weber syndrome. Surg Neurol 1977; 8:229-237. 40. Rosenblum B, Oldfield EH, Doppman JL, et al: Spinal arteriovenous malformations: a comparison of dural arteriovenous fistulae and intradural AVM’s in 81 patients. J Neurosurg 1987; 67:795-802. 41. Berenstein A, Lasjaunias P: Surgical Neuroangiography, vol 4. Berlin: Springer-Verlag, 1992, pp 197-251. 42. Yasargil MG, Symon L, Teddy PG: Arteriovenous malformations of the spinal cord. In Symon L, ed: Advances and Technical Standards in Neurosurgery, vol 11. Vienna: SpringerVerlag, 1984, pp 61-102. 43. Rodesch G, Hurth M, Alvarez H, et al: Angio-architecture of spinal cord arteriovenous shunts at presentation: clinical correlations in adults and children. The Bicêtre experience on 155 consecutive patients seen between 1981-1999. Acta Neurochir 2004; 146:217-227. 44. Levy LM, di Chiro G, Brooks RA, et al: Spinal cord artifacts from truncation errors during MR imaging. Radiology 1988; 166:479-483. 45. Lasjaunias P, Berenstein A, Terbrugge KG: Spine and spinal cord arteries and veins. In Surgical Neuroangiography, vol 1: Clinical Vascular Anatomy and Variations, 2nd ed. Berlin: Springer-Verlag, 2001, pp 73-164.
CHAPTER
45
PROTHROMBOTIC STATES AND RELATED CONDITIONS ●
●
●
●
Paul Bentley and Pankaj Sharma
THE HEMOSTATIC SYSTEM
PATHOLOGY OF EXCESSIVE HEMOSTASIS
The human circulatory system does not act simply as an array of inert, lifeless pipes that convey blood between organs; it is an organ itself with functions beyond those of the various compounds and cells that pass through its conduits. One of these functions is the maintenance of its own structural integrity, essential for transmitting blood pressure, ensuring continuity of flow, and minimizing spread of infection. There has evolved a complex hemostatic system that enables on-line monitoring of a large area of endothelial space (approximately 600 m2, or the equivalent of three tennis courts), with rapid, local restoration of breaches as they occur. This system is composed of multifarious actions and interactions among solid-phase vessel wall, cellular platelets, and humoral coagulation factors; Figure 45–1 is a basic schema of the events that follow vessel injury. It is preferable to talk about this system as a whole rather than as a separate “coagulation system” because of the strong interdependence among these three components. An important attribute of hemostasis is the requirement of both “on knobs” and “off knobs,” delicately adjusted, to prevent a response to vessel wall injury from overshooting and resulting in a sealing of both the defect (which is desired) and the vessel lumen itself (which would cause local hypoperfusion). Endogenous anticoagulant systems are shown in Figure 45–2. As with most metabolic systems, the physiological state is optimized by both prohemostatic and antihemostatic reactions occurring simultaneously (i.e., a dynamic system); the net outcome depends on local vessel integrity. This chapter is concerned with states that predispose to excessive hemostasis (vessel closure) and their neurological effects. By far the commonest mechanism by which vessels close off pathologically is the formation of thrombus, and so such states are commonly referred to as prothrombotic states. A thrombus is a concretion of activated platelets and fibrin, the latter product being the insoluble end product of the coagulation cascade. However, vessel closure may also occur through embolism, progressive thickening of the arterial wall, vasospasm, or cell sludging. Within the neurological system, the most likely outcome of vessel closure is ischemic stroke, but other diseases, such as peripheral nerve ischemia, optic neuropathy, spinal cord infarction, dementia, and parkinsonism, may also be the consequence of ischemic injury to nervous tissue.
In the same way that the physiology of hemostasis is shared among the trio of vessel wall, platelets, and clotting factors, the pathophysiology of excessive hemostasis can be summarized by its own triad. This so-called Virchow’s triad represents three sets of factors, each of which may give rise to vessel closure, thrombosis being a final common pathway in most cases (Fig. 45–3). A modern-day listing of Virchow’s triad has changed little since its original formulation in 1860: 1. Vessel wall defect (especially with endothelial disruption). 2. Stasis of blood (including turbulence). 3. Hypercoagulability (or excessive platelet activation). Figure 45–4 lists the various causes within each of these categories, including states predisposing to thrombosis or vessel closure by other means (e.g., vasospasm). These causes can be remembered by the mnemonic “ADVISE OR HEPARINISE.” In reality, it is likely that a synergistic interaction of two or three factors contribute to thrombosis. In the arterial circulation, although normal cerebral vessels can withstand a pressure of approximately 1500 mm Hg, the commonest scenario is as follows: An atherosclerotic plaque ruptures or hemorrhages (through a vessel wall defect), thereby inducing local activation of coagulation factors and platelets (hypercoagulability), as well as turbulence with pockets of slow or reversed flow (stasis). In the venous circulation, the initiating event is usually a combination of stasis (e.g., immobility), and a hypercoagulable state (e.g., stress response secondary to recent surgery). In general, vessel wall defects are far more predominant and likely to result in thrombosis in arteries or arterioles, whereas stasis is found in the parts of the circulation in which rate of blood transit is at its lowest: namely, veins. Hypercoagulable states are associated with both arterial and venous thromboses but more commonly result in the latter, possibly because of the prior requirement of local stasis in order for an activated coagulation cascade to result in a significant accumulation of fibrin. A thrombosis consists of a solid aggregation of platelets and erythrocytes within a fibrin mesh adherent to the vessel wall. Microscopic observation reveals that thrombi within arteries have a higher platelet composition (in relation to fibrin) than do those in veins. Because fibrin tends to adhere to red blood
609
C e r e b r o va s c u l a r D i s e a s e
Endothelial disruption
Stenosis vasospasm
Intrinsic pathway XIIa XI
Platelet release reaction ␣-granules: release vWF, fibrinogen, V ␦-granules: release ADP, serotonin, calcium Tubular system: thromboxane A2
vWF, VIIIa
VII XIa
IX
VIIa
+ Tissue factor IXa
X
Xa
II
←
XII
Extrinsic pathway
←
Platelet adhesion Via glycoprotein-Ib—von Willebrand factor adherence to subendothelial microfibrils
Exposure of: i) Collagen ii) Tissue factor
Removal of inhibitors: i) Prostaglandin I2 ii) Heparin, AT-III, tPA
←
Turbulence – pockets of stasis
Release of: i) von Willebrand factor ii) Fibronectin
←
IX
←
Section
←
610
Va
Fibrinogen ←
XIII Common pathway
IIa (Thrombin) ←
Platelet metamorphosis i) Exposes GP IIb-IIIa to fibrinogen ii) Exposes other glycoproteins for platelet– monocyte interactions
Fibrin
XIIIa Cross-linked fibrin
Platelet-fibrin thrombus ■
Figure 45–1. Hemostatic system showing interdependence among vessel wall, platelets, and coagulation cascade. ADP, adenosine diphosphate; AT-III, antithrombin III; GP, glycoprotein; t-PA, tissue-type plasminogen activator; vWF, von Willebrand factor.
cells, arterial thrombi appear relatively white, whereas venous thromboses, with a higher fibrin content, appear red.
NEUROLOGICAL CONSEQUENCES OF EXCESSIVE HEMOSTASIS Stroke represents the neurological consequence of a disordered hemostatic system; causes may be logically divided into excessive hemostasis, which results in ischemia, or inadequate hemostasis, which results in hemorrhage. Ischemic strokes, accounting for about 80% of all strokes, result predominantly from arterial occlusion but occasionally result from venous blockage. Most arterial strokes, whether ischemic or hemorrhagic, occur because of lesions affecting the vessel wall component of the hemostatic system. Atherosclerosis results in stenosis of large-vessel arteries, which itself predisposes to development of superimposed thrombosis and resultant vessel occlusion. Diseases of the myocardium result in impaired contractility, which may secondarily cause blood stasis, cardiac thrombus, and eventually embolism into arteries of the brain,
spinal cord, or eye (as well as into arteries of other organs). Arterial aneurysms are predisposed to rupture, which overwhelms the hemostatic system’s ability for self repair. Not all strokes are caused by dysfunctional hemostasis: one such example is severe hypotension, such as that caused by cardiac arrhythmia, which results in temporary arrest of blood flow in watershed areas of the brain. Venous occlusion typically occurs in the venous sinuses located posteriorly within the cranium or in the superior cerebral, ophthalmic, or spinal veins and causes focal ischemia and infarction in the tissue drained by the occluded vein. Because arterial blood continues to enter the infarcted region, capillaries enlarge and eventually rupture, which accounts for the frequent presentation of venous thrombosis as multiple intracerebral hemorrhages. An alternative manifestation is raised intracranial pressure (causing coma or papilledema, for instance) that may be explained by the fact that the cerebral venous sinuses act as the outflow for cerebrospinal fluid drainage. Thromboembolism represents the commonest cause of ischemic stroke; other pathological processes may also result
chapter 45 prothrombotic states and related conditions
Anticoagulants derived from endothelium (local) or liver (circulating)
Prostaglandin I2 (prostacyclin)
Heparin Anti-thrombin-III
Tissue factor pathway inhibitor
XIa
IX
VIIa
IXa
X
Plasminogen
Xa
Plasmin
Va IIa
Fibrinogen
←
Protein S
←
Platelet metamorphosis
Tissue plasminogen activator (tPA)
+ Tissue factor
←
XI
←
vWF, VIIIa
VII
XIIa ←
Activated protein C
←
XII
Platelet release reaction
tPA Inhibitor
Extrinsic pathway
Intrinsic pathway
Platelet adhesion
←
Nitric oxide
Vasodilatation
611
II
Protein C
Common pathway
Fibrin
Fibrin degradation products Activation
Platelet–fibrin thrombus ■
Inhibition
Figure 45–2. Hemostatic system showing endogenous anticoagulation, fibrinolytic, and antiplatelet systems. vWF, von Willebrand factor.
in vessel closure to produce regional ischemia within the nervous system. Examples of such pathological processes are vasospasm (that in the brain results in migrainous auras), arteriosclerotic lipohyalinosis (commonly caused by hypertension and resulting in isolated “lacunar” strokes or, when diffuse, a subcortical dementia), and vasculitis. Figure 45–5 depicts the varied neurological effects of ischemia secondary to thromboembolism or other processes resulting in vessel closure.
VESSEL WALL DEFECTS Atherosclerosis Atherosclerosis describes the pathological appearance of the vessel wall in most cases of strokes and myocardial infarctions. Microscopically, it is characterized by the accumulation of lipid and inflammatory cells within the arterial intima. However, these lesions build up over decades and have relatively inconsequential hemodynamic effects until they encroach on a significant proportion of the vessel lumen. Even when significant stenosis has developed, it is usually insufficient to result in endorgan damage unless a fall in blood pressure across the diseased
blood vessel occurs. Hence, the additional factor that appears necessary in the pathogenesis of most clinical syndromes of infarction is the formation of thrombus on a preexisting atherosclerotic plaque. This development probably occurs rapidly, over hours, and is triggered by conformational or biochemical changes within the atherosclerotic lesion and/or by the appearance of prothrombotic substances within the blood. Because any atherosclerotic lesion has the potential of suddenly transforming itself into a substrate for thrombosis, conditions that predispose to atherosclerosis should be regarded as contributing (albeit indirectly) to a prothrombotic state. Postmortem appearances of arteries from people who died from nonischemic causes have shown that atherosclerotic lesions are virtually universal after middle age, especially in residents of industrialized nations. In fact, the strong geographical dependence of atherosclerosis risk corresponds to recognized environmental factors that may initiate atherogenesis (Fig. 45–6). The most important predisposing state is a high circulating triglyceride (lipid) load, especially during the postprandial period—which for many residents of the industrialized world represents most of the waking day. Because triglyceride-rich particles (very-low-density lipoprotein) continuously exchange their triglycerides with cholesterol found within high-density lipoprotein particles, the
612
Section
IX
C e r e b r o va s c u l a r D i s e a s e
ARTERIAL THROMBOSIS
Stenosis
Endothelial disruption
VENOUS THROMBOSIS
VENOUS ± ARTERIAL THROMBOSIS
Stasis
Hypercoagulability tPAI Heparin Anti-thrombin-III
tPA
Platelet adhesion
Platelet metamorphosis
IX
XIa
VIIa
+ Tissue factor IXa
X
←
Activated protein C
XI
←
vWF, VIIIa
VII
XIIa ←
XII
Platelet release reaction
←
tPA Inhibitor
←
tPA
Plasminogen
Plasmin
Xa
Va
Protein C
■
Fibrinogen
IIa ←
II
←
CARDIAC (mural) THROMBOSIS
Protein S
Fibrin
FDPs
Figure 45–3. Virchow’s triad superimposed on the hemostatic system: Each main factor may cause vessel closure (principally thrombosis), although the relative contribution each factor provides depends on the part of the circulatory system at which the occluding lesion occurs. FDP, fibrin degradation products; t-PA, tissue-type plasminogen activator; t-PAI, t-PA inhibitor; vWF, von Willebrand factor.
level of high-density lipoprotein–cholesterol is inversely correlated with, and an accurate predictor of, atherosclerosis risk. The level of low-density lipoprotein (LDL)–cholesterol is less predictive of atherosclerosis, although a subset of LDLcholesterol particles formed under high triglyceride conditions, called small, dense LDL-cholesterol, are highly atherogenic (after oxidation or glycation). Although diet is the leading global factor in accounting for the distribution of atherosclerosis-related diseases, there are multiple other associations. Some of these factors act through secondary effects on lipid metabolism. Diabetes mellitus results in both a high circulating triglyceride level and glycation of small, dense LDL-cholesterol, both predisposing to premature atherosclerosis. Of interest, most genetic types of hypertriacylglyceridemia are not associated with atherosclerosis, whereas familial hypercholesterolemia (usually caused by a LDLcholesterol receptor mutation) is strongly associated with premature atherosclerosis; homozygous patients suffer
ischemic heart disease or strokes in their 20s. There are other genetic factors for atherosclerosis that may or may not result from interactions with lipid metabolism (Table 45–1). Both lipoprotein(a) and homocysteine levels are risk factors for atherosclerosis that also have strong genetic influences; these factors also have prothrombotic effects as a result of interactions with the coagulation cascade (see later discussion). Certain factors, such as hypertension, smoking, and epinephrine (present with, e.g., “easily stressed” personalities) act as synergistic factors with lipid metabolism for atherogenesis. Exercise and fish oils rich in omega-3 fatty acids (e.g., eicosapentaenoic acid) engender a more favorable lipid profile and correspondingly reduce atherosclerosis. Although the influences of lipid and glucose metabolism on atheroma formation are well established, the contributions played by the immune system on both atherogenesis and plaque destabilization are becoming increasingly appreciated. Inflammation is triggered at the first sign of vessel wall injury and
chapter 45 prothrombotic states and related conditions ARTERIAL THROMBOSIS or CLOSURE
CAUSES Atherosclerosis Arteriosclerosis—hypertension Dissection Dysplasia, fibromuscular Vasculitis - Autoimmune, sarcoid, infection Injury - Iatrogenic: radiation, catheter Spasm: migraine Extra: embolism, compression
Vessel wall defect
VENOUS ± ARTERIAL THROMBOSIS or CLOSURE
VENOUS THROMBOSIS or CLOSURE Stasis
CAUSES Operation, especially: Orthopedic or Obstetric (i.e., peripartum) Obesity Overland flights (i.e., long-haul) Reduced circulating volume (i.e., hypovolemia) Right-sided heart failure CARDIAC (mural) THROMBOSIS CAUSES Atrial fibrillation Aneurysm - Congenital - Myocardial infarction Cardiomyopathy
■
613
Hypercoagulability Platelets
Coagulation cascade —fibrinolysis
CAUSES Hereditary: factor V Leiden, prothrombin mutations Endocrine: estrogen (OCP, HRT), testosterone, diabetes hyperosmolar nonketotic coma Polycythemia and other hematological, including platelets: Paraproteinemia, paroxysmal nocturnal hemoglobinuria, sickle cell anemia Platelets: sticky platelet syndrome; thrombocythemia Autoimmune: antiphospholipid syndrome, Behçet’s syndrome Renal: nephrotic syndrome, volume depletion Infection: systemic: TB, chlamydia, any cause of raised CRP local: otitis media or mastoiditis Neoplasia: adenocarcinoma, acute myeloid leukemia, head-neck carcinoma Injury: fracture, sympathetic stress response Smoking (also causes atherosclerosis) Exogenous: chemotherapy, COX-2 inhibitors
Figure 45–4. Pathological causes of Virchow’s triad. COX-2, cyclooxygenase 2; CRP, C-reactive protein; HRT, hormone replacement therapy; OCP, oral contraceptive pill; TB, tuberculosis.
results in upregulation of cell-adhesion molecules, release of chemotaxins and reactive oxygen species, and facilitation of lipid influx and storage. Eventually, the fibrinous cap and endothelial lining of an atherosclerotic plaque becomes degraded by proteolytic enzymes derived from the inflammatory infiltrate, and at this point, rapid thrombus development is triggered. The effects of local inflammation within the vessel wall can often be observed through levels of circulating inflammatory markers. Hence, levels of C-reactive protein, an acute-phase reactant, and of CD3 provide indexes of the risk of ischemic heart disease or stroke. In addition to mirroring the inflammatory turnover within atherosclerotic lesions, these proteins act together to accelerate atheroma formation. Of interest, statins have been found to have anti-inflammatory effects, including reduction of C-reactive protein levels, and these effects have been associated with reduction of stroke or myocardial infarction risk, independent of the effect that these drugs have through lowering cholesterol.
Arteriosclerosis Arteriosclerosis is the progressive replacement of smooth muscle cells with proteinaceous material (predominantly collagen) within the media of small arteries and arterioles (40 to 400 μm in diameter). The microscopic appearance is of concentric layers of a hyaline substance in the same location where smooth muscle normally occurs. The most strongly associated risk factors are hypertension and diabetes. As the process continues, the lumen constricts, which results in progressive tissue hypoperfusion. The latter is exacerbated during periods of hypotension, because the loss of smooth muscle prevents vasodilation. In certain cases, especially with accelerated hypertension, the same vessels develop a more disorganized process, which results in patchy fibrinoid accumulation, necrosis, and foam cell formation. When this accumulation is rapid, the end result may be acute small-vessel or lacunar infarction. From a therapeutic point of view, this knowledge is important, because
A
C ■
B
D Figure 45–5. Diverse neurological consequences of vessel closure, usually caused by thromboembolism. A, Middle cerebral artery infarction with secondary edema. B, Superior sagittal sinus venous thrombosis with bilateral cerebral infarctions and secondary hemorrhage. C, Bilateral subcortical ischemia (Binswanger’s leukoencephalopathy), resulting from chronic hypertension and causing dementia and gait apraxia. D, Thoracic spinal cord infarction, resulting from embolism from a cardiac source and causing paraparesis, anesthesia of lower limbs, and double incontinence. Continued
614
chapter 45 prothrombotic states and related conditions
615
T A B L E 4 5 – 1. Genetic Causes of Thrombophilia Genetic Causes of Hypercoagulability Prothrombin G20210A mutation Factor V Leiden mutation (activated protein C resistance) Protein C deficiency Protein S deficiency Tissue plasminogen activator inhibitor–1 overactivity Plasminogen deficiency Hyperhomocysteinemia: MTHFR: C667T mutation Lipoprotein(a) elevation Hyperfibrinogenemia Dysfibrinogenemia (β-chain variants) Genetic Causes of Atherosclerosis Familial hyperlipidemias Familial hypercholesterolemia: LDL receptor mutation Familial combined hyperlipidemia Familial dysbetalipoproteinemia (hypertriacylglyceridemia) Hyperhomocysteinemia: MTHFR: C667T mutation Lipoprotein(a) elevation Hyperfibrinogenemia Dysfibrinogenemia (β-chain variants)
E LDL, low-density lipoprotein; MTHFR, methylene tetrahydrofolate reductase.
Vasculitis
F ■
Figure 45–5, cont’d. E, Inferior branch retinal artery occlusion secondary to embolism, causing monocular altitudinal (superior) loss of visual acuity. F, Left abducens nerve palsy resulting from small-vessel infarction of the sixth cranial nerve in a diabetic patient. (B, From http://www.aic.cuhk.edu.hk/web8/ 0294_Cerebral_venous_haemorrhagic_infarction.jpg. Copyright © Chanles Gomersall. C, From http://www.kup.at/kup/ images/thumbs/336.jpg. E, From The Robert Bendheim Digital Atlas of Ophthalmology, The New York Eye and Ear Infirmary, http://www.nyee.edu/page_deliv.html?page_no=50. F, From http://medicine.ucsd.edu/clinicalmed/eyes-cn6-palsy3.jpg.)
it explains why anticoagulation and thrombolysis have no effect on stroke from this cause.
Dissection Large arteries may be injured by an externally applied stretch or twist to cause, first, an endothelial breach and, subsequently, an elongating, longitudinal split between intima and media that is driven by the shearing forces within the arterial lumen. As blood enters the wall defect, the intimal aspect is forced into the lumen to create stenosis, with resultant turbulence and stasis. Together with the original endothelial breach, these conditions are ripe for thrombus formation within the true lumen. The initiating event for such dissections may be an apparently trivial movement, such as lifting or looking up, but the history is one classically of the patient’s suffering at the hands of overenthusiastic hairdressers or osteopaths.
Inflammation centered on the vessel wall results in progressive luminal narrowing as a result of cellular infiltration and deposition of proteins, including fibrin. At the same time, inflammatory cell and cytokine interactions with platelets and coagulation factors favor a prothrombotic state. There are multiple causes of this lesion type, ranging from primary endogenous “vasculitides” to exogenous factors such as infections (e.g., herpes zoster or tuberculosis), toxins, and radiotherapy. An important example with neurological consequences is giant cell arteritis, a large-artery vasculitis in elderly people that results in headache, ischemic optic neuropathy, and stroke. In younger patients, the large or medium-sized vessel vasculitides Takayasu’s arteritis, polyarteritis nodosa, or ChurgStrauss syndrome should be considered, especially in patients with recurrent ischemic events, renal dysfunction, rash, or constitutional symptoms such as fever, myalgia, and testicular pain.
Spasm The commonest neurological result of vasospasm—indeed one of the commonest neurological conditions—is migraine. More specifically, intracranial arterial spasm results in focal cerebral or brainstem ischemia that correlates with the migrainous “aura” phase in which affected patients complain of a focal sensory disturbance, typically a visual scotoma or flickering jagged lines. A rare but well-recognized complication of the migrainous aura is progression of the ischemia to infarction, typically in a small-vessel territory.
STASIS Wherever the circulation becomes sluggish, activated clotting factors may accumulate to reach a concentration that surpasses
616
Section
IX
C e r e b r o va s c u l a r D i s e a s e INFLAMMATION—TISSUE-BOUND 1. Differentiation of monocytes into macrophages 2. Absorption of remnant particles and oxidized-LDL cholesterol into macrophages via “scavenger receptor” CD36 to form “foam cells”
Pressure effect, hemorrhage into plaque
Sub-endothelial space ENDOTHELIAL ACTIVATION 1. Expression of cell-adhesion molecules (CAMs) and selectins 2. Formation of reactive oxygen species (ROS) 3. Downregulation of nitric oxide synthase (NOS) Lumen
PLAQUE DESTABILIZATION Lipid influx
INITIATION 1. Dyslipidemia: LDL-cholesterol, especially small, dense (becomes oxidized or glycated) VLDL—cholesterol Free fatty acids—obesity Remnant particles Lipoprotein(a), homocysteine 2. Shear stress—hypertension 3. Glucose—diabetes mellitus 4. Smoking 5. Sympathetic tone—type A personality ■
Adhesion + Transmigration of monocytes + T lymphocytes
INFLAMMATION—CIRCULATING
THROMBUS FORMATION Degradation of fibrin cap by • Neutrophil-derived elastase or gelatinase • Matrix metalloproteinases • TNF-␣ • ROS
Recruitment of monocytes, neutrophils, and lymphocytes via chemokines IL-6 (induces CRP in liver), IL-8, MCP-1 LDL: low-density lipoprotein VLDL: very-low-density lipoprotein ROS: reactive oxygen species IL: interleukin MCP: monocyte chemoattractant protein TNF: tumor necrosis factor CRP: C-reactive protein
Figure 45–6. Pathogenesis of atherosclerosis and subsequent plaque destabilization with thrombus formation.
a critical threshold, potentiating formation of an expanding fibrin core and, ultimately, thrombus. The most common predisposing circumstance is prolonged immobility, when thrombosis tends to form in the deep leg veins and usually when an additional hypercoagulability risk factor, such as infection or genetic status, prevails. The usual clinical consequences of this are local pressure effects in the leg and, more devastatingly, pulmonary embolism. However, in patients with a right-to-left cardiopulmonary shunt, a dislodged venous thrombus may course into the arterial circulation to cause, among other outcomes, cerebral embolism. This “paradoxical embolism” occurs most commonly in patients with either congenital cyanotic heart disease or a pulmonary arteriovenous malformation (e.g., as part of hereditary hemorrhagic telangiectasia), but in rare cases, it occurs in patients with a patent foramen ovale (present in up to 25% of the population) during, for example, inadvertent performance of the Valsalva maneuver. Stasis of venous circulation may also cause neurological disease through the formation of intracranial venous
thrombosis, most often within the superior sagittal or transverse sinuses. Factors that tend to encourage intracranial venous stasis are hypovolemia (e.g., from prolonged vomiting), raised central venous pressure (e.g., from heart failure), obesity, and pregnancy. Intracranial venous thrombosis may also be triggered by vessel wall defects that secondarily result in turbulence and stasis effects, such as tumor compression or indwelling catheter within the jugular vein or superior vena cava, causing back-propagation of thrombosis; bacterial or fungal infection of a bony sinus or orbit; or traction of sinuses after lumbar puncture (rarely associated with thrombosis). Neoplastic and infective processes are also associated with hypercoagulability (see later discussion). Stasis may also be caused by hyperviscosity as a result of increase in circulating cell numbers, reduced cell deformability, or increased plasma proteins. Because some of these conditions also encourage coagulation, they are discussed as follows.
chapter 45 prothrombotic states and related conditions HYPERCOAGULABILITY Hereditary Many of the recognized genetic causes of hypercoagulability (and ischemic stroke) can be appreciated by reference to the endogenous coagulation and anticoagulation pathways (see Fig. 45–3 and Table 45–1). Hence, one of the most common abnormalities, factor V Leiden mutation, can be explained as an insensitivity of factor V to deactivation by protein C, which leads to deregulation of the production of thrombin. Mutations of endogenous anticoagulant/coagulant proteins are associated most strongly with venous thrombosis, although certain mutations (mainly factor V Leiden and prothrombin mutations and protein S deficiency) are also associated with arterial thrombosis, including stroke. The odds ratio associated with these conditions is approximately 10 for development of venous thrombosis and less than 3 for development of an arterial thrombosis. Whether a particular mutation results in an ischemic event depends on whether other prothrombotic or vascular risk factors coexist. Factor V Leiden and prothrombin mutations occur in approximately 10% and 5% of the population, respectively. Most affected people are heterozygous for the mutations although the relative risk for thrombosis is much greater in people with homozygous mutations. Deficiencies of protein C, protein S, and antithrombin III occur in fewer than 1% of the population for each. Most of these mutations are autosomal dominant, except for plasminogen deficiency, which is autosomal recessive. Screening of children or young adults who present with arterial stroke has revealed that fewer than 25% have a recognized inherited prothrombotic state. Measurements of
baseline coagulation and anticoagulation factor activity are often depressed for several weeks after an ischemic event (because of peripheral factor consumption), which necessitates delay in measurements of functional components of the thrombophilia screen. Genetic mutation analyses are, however, time independent. Also, measurements from functional assays of certain coagulation components (e.g., protein C) increase with age, which necessitates use of appropriate normal ranges. Protein S deficiency may also be acquired (e.g., because of infection or antiphospholipid syndrome). When a known prothrombotic mutation is identified, genetic counseling can be offered and family members tested. Although anticoagulation or antiplatelet drugs are not recommended for asymptomatic carriers or homozygotes, such information may influence future care in the event of illness. Both hyperhomocysteinemia and elevated lipoprotein(a) levels are strong risk factors for ischemic stroke in either arterial or venous circulations, which indicates that these conditions incur risks of both atherosclerosis and hypercoagulability. The main determinant of the population’s distribution of homocysteine levels lies with the methylene-tetrahydrofolate reductase (MTHFR) genotype: high levels are predicted by the TT genotype and low levels by the CC wild-type (abbreviations refer to a single nucleic acid polymorphism within the gene). A high homocysteine level may be exacerbated by deficiencies of folate or vitamin B12, both of which are required for the metabolism of homocysteine (Fig. 45–7). Homocysteine interacts with all three components of the hemostatic system: increasing platelet adhesiveness, activating coagulation factors, and resulting in endothelial disruption; it is also involved in the conversion of LDL-cholesterol into proatherogenic forms. Hyperhomocysteinemia may be treated with supplemental folic acid and vitamins B12 and B6, although there is insufficient
Dietary folate
dUMP (deoxy-Uridine MonoPhosphate)
S-Adenosyl Homocysteine
MTHF (5,10-MethyleneTetraHydra Folate)
Demyelination
Thrombosis
Homocysteine
Atherogenesis MTHF reductase Vitamin B12
Vitamin B6 dTMP (deoxy-Thymidine MonoPhosphate)
Nucleotide synthesis ■
Tetrahydrafolate
617
Methionine
S-Adenosyl Methionine
Cysteine
Deficiency causes demyelination
Figure 45–7. Relationships of homocysteine, folate, vitamin B12, and vitamin B6 metabolism, showing pathological effects of impaired homocysteine breakdown. Vitamin B12 and vitamin B6 act as co-factors, rather than being intermediary products.
618
Section
IX
C e r e b r o va s c u l a r D i s e a s e
evidence at present to support this form of treatment routinely for prophylaxis against arterial events. Lipoprotein(a) is a cholesterol-rich lipoprotein that also has close homology with plasminogen, the latter fact helping explain its influence on coagulation.
Endocrine Estrogen exerts a prothrombotic influence and is associated with deep venous thrombosis. A diagnosis of cerebral venous sinuses thrombosis should therefore be considered in all women who present with headache, epilepsy, or confusion who are taking oral contraceptive pills, are taking hormone replacement therapy (HRT), or are peripartum. The risk of venous thrombosis with the oral contraceptive pill, approximately threefold greater than in control subjects, is increased by concomitant thrombophilic factors, including a family history of deep vein thrombosis, obesity, or when taken as a combined preparation containing a third-generation progestagen (e.g., desogestrel or gestodene). The oral contraceptive pill is also associated with arterial stroke, especially in migraine sufferers who have experienced aura (i.e., focal cerebral ischemia), smokers, or hypertensive patients. Estrogens also have a modulatory effect on atherogenesis, although the manner of this relationship differs between physiological and pharmacologically induced states. The risk of atherosclerosis, myocardial infarction, and ischemic stroke is decreased in women in relation to men of the same age, but only up to menopause (even when this occurs prematurely). However, the supplementation of estrogen in women after menopause in the form of HRT has been found either to confer no protection or even to increase the risk of atherosclerosisrelated disease, including stroke. The reason for this may relate to the rise in C-reactive protein found with conjugated equine estrogen (the commonly administered form of HRT). Another endocrinological association with thrombosis is excessive levels of either testosterone or erythropoietin, both of which can result in excessive circulating cell counts (polycythemia) and predispose to thrombosis. Both of these hormones may be taken illicitly by athletes, testosterone in the form of anabolic steroids. The antiandrogen cyproterone acetate, often used in women to counter virilization, is also associated with venous thrombosis, even more strongly than oral contraceptive pills. Further examples of endocrinological association with thrombosis are diabetes mellitus (which accelerates atherogenesis and may be associated with a hypovolemic and prothrombotic state, especially during hyperosmolar nonketotic acidosis) and acromegaly (which accelerates atherosclerosis).
Polycythemia and Other Hematological Disorders An increase in the number of any circulating cell lineage predisposes to thrombosis both because of hyperviscosity (which encourages stasis) and because of the facilitation that cell surfaces provide to an activated coagulation cascade (via interactions with phospholipids and glycoproteins). Increases in platelet counts, most notably with essential thrombocythemia or splenectomy, are especially likely to predispose to arterial and venous thromboses. Hyperviscosity, particularly in the form of paraproteinemia (especially immunoglobulin M type)
and cryoglobulinemia, may also be caused by increased plasma proteins, and each should be tested for separately. These substances also serve to interfere with coagulation proteins and so such patients are at risk for both cerebral hemorrhages and infarcts. Sickle cell anemia is strongly associated with arterial and venous thromboses as a result of hyperviscosity, despite a reduced circulating erythrocyte count. The fundamental defect arises when hemoglobin S polymerizes within the erythrocyte into long rods under hypoxic or acidotic conditions. Such polymerization constrains the erythrocyte membrane, which adopts its rigid shape that fails to deform as the red blood cell travels through the microcirculation. In consequence, ischemic strokes tend to occur in deep small arteries, especially in the watershed regions of the cerebral convexities, the brainstem, spinal cord, and retina. Large-artery occlusive disease (e.g., in the distal carotid artery or circle of Willis) also occurs, possibly because of initial occlusion of the vasa vasorum, their own blood supply, which leads to intimal and smooth muscle proliferation within the large vessel walls with consequent luminal stenosis.
Autoimmune Disorders Arterial and venous thromboses, as well as thrombotic endocarditis, are complications of multisystemic autoimmune conditions such as systemic lupus erythematosus and Behçet’s disease. One cause of vessel closure, including arterial stroke, in these conditions is vasculitis (see “Vessel Wall Defects” section). However, thrombosis itself may be triggered by an activated immune system or by autoantibodies directed against platelets or components of the coagulation cascade. One of the most well-recognized thrombophilic autoimmune conditions is the antiphospholipid syndrome, which may occur on its own or in association with systemic lupus erythematosus. Patients with this condition have an approximately 10-fold greater risk of arterial or venous thromboses, including recurrent strokes, than do healthy individuals. Recurrent miscarriages and certain rashes (e.g., livedo reticularis) also characterize this syndrome. Autoantibodies found in such patients undoubtedly play a pathogenic role in that their targets include β2-glycoprotein I, a component of the platelet-coagulation interaction, and prothrombin. These antibodies have in common the property of targeting plasma proteins bound to anionic surfaces, the latter of which are most commonly phospholipids (e.g., cardiolipin) on outer cell surfaces. Paradoxically, these antibodies are also termed lupus anticoagulants because the original method of detecting their presence was through their in vitro effect of prolonging phospholipiddependent clotting times, such as the activated partial thromboplastin time. A further paradox, in view of the thrombophilic nature of the disease, is that patients often exhibit an immunemediated thrombocytopenia.
Renal Disorders Nephrotic syndrome predisposes to venous thrombosis because of preferential renal loss of anticoagulants, such as antithrombin III, and by encouraging hypovolemia. In the long term, it is associated with hypercholesterolemia and
chapter 45 prothrombotic states and related conditions accelerated atherosclerosis as a result of filtering of apolipoproteins.
Inflammation Generalized inflammation, such as that secondary to infection or neoplasia, can result in a prothrombotic state and predispose to ischemic stroke. One mechanism for this is through activation of the complement system that leads to increased binding of protein S to C4b, resulting in apparent protein S deficiency. Certain causes of intracranial venous thrombosis are an inflammatory state; for example, bacterial mastoiditis or paranasal sinusitis results in thrombosis within contiguous transverse or cavernous venous sinuses, respectively. The association of diffuse head injury with cerebral venous thrombosis may also arise from inflammatory factors. Systemic infection may also result in widespread thromboses; for example, virus-associated purpura fulminans is caused by acquired protein C, protein S, and antithrombin III deficiencies, and enterohemorrhagic Escherichia coli food poisoning results in thrombotic thrombocytopenic purpura. Treatment entails infusion of both fresh-frozen plasma and anticoagulant factor concentrates in the former condition, and plasma exchange in the latter condition.
619
depending on the circumstance: heavy acute or chronic consumption increases, whereas mild chronic consumption decreases stroke risk. Both cocaine and amphetamines predispose to arterial ischemic stroke through sympathomimeticdriven vasoconstriction and hypertension, vasculitis, and, in the case of cocaine, depletion of protein C and antithrombin III. It has been found that the newest class of nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors such as rofecoxib, is linked to an increase in arterial ischemic events including strokes. This has been attributed to the cyclooxygenase-2 enzyme’s being essential for formation of the prostaglandin prostacyclin (which inhibits thrombogenesis), whereas the platelet-derived prostanoid thromboxane (which activates platelets) is dependent on the cyclooxygenase-1 form of the enzyme. The main pharmacological association of cerebral venous thrombosis is estrogen-containing contraceptive pills (see previous discussion), but another recognized thrombophilic drug is asparaginase, used in treating childhood leukemias.
K E Y
P O I N T S
●
Impaired blood flow underlies some of the commonest neurological conditions, such as ischemic stroke, migraine with aura, and multi-infarct dementia.
●
Causes of impaired blood flow can be categorized into insufficient cardiac output, which causes global hypoperfusion, or vessel stenosis and occlusion, which cause regional ischemia or infarction.
●
The pathogenesis of vessel stenosis and occlusion involves the three components of hemostasis: vessel wall, platelets, and coagulation cascade.
●
The commonest mechanism of vascular occlusion is the formation of thrombus, a solid-phase composite of activated platelets and fibrin, in which fibrin represents the end product of the coagulation cascade.
●
Causes of thrombus formation can be divided according to “Virchow’s triad”—endothelial injury, blood stasis or turbulence, and hypercoagulability—although most instances of thrombus are caused by two or three of these categories, acting synergistically.
●
The commonest cause of endothelial injury is atherosclerosis—irregular, focal deposits of lipid and inflammation—which predisposes to acute syndromes of arterial occlusion, such as ischemic stroke and myocardial infarction.
Exogenous
●
Many drugs of abuse are associated with stroke, although the pathogenesis of each is often multifactorial. Tobacco smoke promotes atherosclerosis, damages endothelium (both directly through nicotine and indirectly through its hypertensive effect), increases platelet reactivity and fibrinogen levels, inhibits prostacyclin formation, and eventually predisposes to a hypoxic and polycythemic state. Both arterial and venous thromboses are linked to smoking. Ethanol has both prothrombotic and antithrombotic consequences, the net outcome
Blood stasis typically occurs in the large-capacitance venous system. Venous thrombi most commonly occur in deep leg veins but may occur in the cerebral venous sinuses to cause cerebral infarction, hemorrhage, or raised intracranial pressure alone.
●
A large range of hypercoagulability states exists. Common causes include prothrombin and factor V Leiden mutations, oral contraceptive pills, smoking, infection (either locally within the brain or septicemia), and adenocarcinoma.
Neoplasia The classic association of a generalized thrombophilic state with neoplasia is that seen with mucinous adenocarcinoma of the lung, stomach, or pancreas. Although both arterial and venous thromboses are encouraged, the commonest cause of symptomatic cerebral infarcts in such patients is nonbacterial thrombotic endocarditis (caused by valvular accumulations of fibrin and platelets). The cause of this phenomenon lies in the release of procoagulant substances from the tumor, including sialic acid residues, phospholipid, and tissue factor, as well as interleukin-6, which acts as a stimulant for thrombocytosis. A related paraneoplastic syndrome is disseminated intravascular coagulation, in which excessive consumption of clotting factors and platelets results in widespread small-vessel cerebral, venous sinus, and endocarditic thrombi, as well as predisposing to intracranial hemorrhage. This occurs with adenocarcinomas, as well as myeloid leukemia. Strokes may also occur with tumors (lung and rectum carcinoma) as a result of thrombotic thrombocytopenic purpura, vasculitis (lung and lymphoproliferative disease), or development of antiphospholipid antibodies.
620
Section
IX
C e r e b r o va s c u l a r D i s e a s e
Suggested Reading Bogousslavsky J, Caplan LR: Uncommon Causes of Stroke. Cambridge, UK: Cambridge University Press, 2001. International Congress on Thrombosis. 18th Congress, Ljubljana, June 2004: Reports [special issue]. Pathophysiol Haemost Thromb 2003/2004; 33:233-506.
Kullo IJ, Ballantyne CM: Conditional risk factors for atherosclerosis. Mayo Clin Proc 2005; 80:219-230. Meschia JF, Brott TG, Brown RD Jr: Genetics of cerebrovascular disorders. Mayo Clin Proc 2005; 80:122-132. Stam J: Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005; 352:1791-1798.
CHAPTER
46
CEREBRAL VENOUS THROMBOSIS ●
●
●
●
Gian Luigi Lenzi, Alessio Mercurio, and Marta Altieri
Cerebral vein and sinus thrombosis (CVST) is a rare event in comparison with arterial stroke, accounting for less than 1% of all strokes. CVST occurs in all age groups, peaking in incidence among neonates and young adults. Clinical diagnosis is difficult, because of the wide spectrum of clinical symptoms of CVST. The achievements of neuroimaging since the 1970s have been fundamental for diagnosing and treating CVST and for a better understanding of its pathogenesis. Early diagnosis of CVST is crucial, because therapy, based mainly on anticoagulation, reduces the risk of fatal outcome and severe disability.1,2
ANATOMY OF THE INTRACRANIAL VENOUS SYSTEM Cortical Cerebral Veins These veins drain blood from the superficial part of the brain (cortex and the adjacent white matter) and are composed of three systems: 1. The dorsomedial system drains into the superior sagittal sinus (SSS) and the inferior sagittal sinus (ISS), receiving blood from the convexity and the midline of the brain. 2. The posteroinferior system drains into the lateral sinus, receiving blood from the temporo-occipital areas. 3. The anterior system drains into the cavernous or the pterygoid venous plexus through sylvian veins, receiving blood from the frontal pole, the inferior part of the frontal lobe, and the anterior part of the temporal lobe. These systems show variations among the population: Any of the three major components may be missing or hypoplastic. In these cases, the other components are hypertrophic. Cortical veins are connected to the dural sinuses by the so-called bridging veins.
Deep Cerebral Veins These veins drain the deepest parts of the white matter, the basal ganglia, and the diencephalon. The septal and thalamostriate veins, called the subependymal veins, are the most important and drain into the internal cerebral vein.
1. The septal veins receive blood from the genu of the corpus callosum, from the septum pellucidum, and from the anterior part of the caudate nucleus, and they drain into the thalamostriate veins. 2. The thalamostriate veins receive blood from the basal ganglia and from the internal and external capsules; they pass through the roof of the third ventricle, cross in the interventricular foramen of Monro, and end in the internal cerebral veins. 3. The posterior choroidal veins drain blood from the pineal gland and from the choroid plexus of the lateral ventricles and end in the thalamostriate veins. 4. The internal cerebral veins run parallel beneath the choroidal vein of the third ventricle to join their counterpart and form the vein of Galen. 5. The vein of Galen, unique and median, runs from the posterior part of the diencephalon up to the straight sinus, between the cerebellum and the splenium of the corpus callosum; early in its course, it receives the paired basal veins of Rosenthal. 6. The basal veins of Rosenthal drain the bottom parts of the basal ganglia; the bottom parts of the temporal, frontal, and occipital lobes; and the medial parts of the insula and the temporal lobe. These veins originate in correspondence to the anterior perforated substance near the confluence of two vessels—the anterior limbic vein and the deep middle cerebral vein (or insular vein)—and then they “tie” into a bow around the mesencephalon before ending in the vein of Galen. Sometimes they receive the posterior limbic veins, the hippocampal veins, and the middle superior cerebellar veins. 7. The anterior limbic veins drain the cingulate circumvolution. In correspondence with the genu and the rostrum of the corpus callosum, they bend to reach the basis of the brain, in order to join the deep middle cerebral vein on the same side and to form the homolateral basal vein of Rosenthal.
Posterior Fossa Veins The venous drainage of the posterior fossa is highly variable. Four main systems can be outlined: 1. The posterosuperior system drains the dorsal cerebellum, vermis, and the upper portion of the brainstem into the vein
621
622
Section
IX
C e r e b r o va s c u l a r D i s e a s e
of Galen. The most important vessels of this group are the superior cerebellar hemispheric veins and the superior vermian veins. 2. The anteromedial system is formed by the anterior pontomesencephalic vein, which drains into the basal vein of Rosenthal on both sides. 3. The anterolateral system is formed by the petrosal veins, which drain the ventral cerebellum and the upper part of the brainstem, and by the choroidal vein of the fourth ventricle, which drains the lower part of the brainstem. 4. The posteroinferior system is formed by the inferior cerebellar hemispheric veins, which are tributaries of the transverse sinus, and by the bilateral posterior spinal vein, which ends in the inferior retrotonsillar vein; this vein and the superior retrotonsillar vein form the inferior vermian vein. This vessel is finally a tributary of the ISS.
2.
3.
4.
Dural Sinuses The dural sinuses are situated between the leaves of the falx and the tentorium and are triangular in section. They drain blood from the cortex, the meninges, and the scalp (through the calvarian veins) and deliver it to the internal jugular veins. They are connected with the extracranial veins in the scalp by the emissary veins. This may explain dural involvement after cutaneous contusions or infections (Fig. 46–1). 1. The SSS begins at the foramen cecum, before the crista galli, and runs along the curve of the inner table of the skull to reach the torcular Herophili, where it converges with the straight sinus. Their combined flows drain into the transverse sinus. The SSS receives blood from frontal, parietal, and occipital superior regions of the cortex. The SSS, and other sinuses, contains the arachnoid villi and granulations in which the absorption of cerebrospinal fluid takes place. There is a direct dependency of cerebrospinal fluid pressure on the intracranial venous pressure, which explains the frequent increase in intracranial pressure in CVST. The dura mater adjacent to the sinus contains important venous plexuses, which represent a potential alternative drainage route when a sinus is occluded; this explains the “empty-
Caudate Dural nucleus vein Foramen of Monro Choroid vein
Ant. pillars of fornix Median plexus
Optic nerve Internal carotid artery Oculomotor nerve Diaphragma sellae Attached margin Free margin of tentorium of tentorium Superior sagittal sinus Venous lacuna
Verous lacuna
Great cerebral vein ■
6.
Velum Choroid plexus
Velar veins
A
5.
delta” sign, which is visible on computed tomographic (CT) scan in occlusion of the SSS. The straight sinus is formed by the junction of the tentorium, falx cerebri, and falx cerebelli and receives blood from the vein of Galen and from the ISS. It ends in the torcular Herophili or in the left transverse sinus. The ISS runs parallel to the SSS in correspondence to the free margin of the cerebral falx, receiving blood from the middle regions of the brain that drains into the SSS through the venous vessels of the cerebral falx. The lateral sinus connects the torcular Herophili with the internal jugular veins on both sides and is formed by two components: the transverse sinus, which lies in the peripheral margin of the tentorium cerebelli, and the sigmoid sinus. The transverse sinuses are frequently of unequal size; the left one, which receives blood from the SSS, is usually larger. Atresia or agenesis of the transverse sinus is related to alternative filling of the sigmoid sinus by the vein of Labbé. The sigmoid sinus starts at the end of the transverse sinus and reaches the jugular vein; agenesis and atresia of this sinus are very uncommon. The cavernous sinuses are situated on the sphenoid bone, laterally to the sella turcica. Their walls contain the cranial nerves III, IV, V2, and V3 of both sides, whereas the cranial nerve V1, the intracavernous tract of the internal carotid artery, and the pericarotid sympathetic plexus are contained in their lumen. They drain the ophthalmic veins, the anterior and middle cranial fossa, and the sphenoparietal sinus (the medial extension of the superficial sylvian vein). Blood drains posterolaterally along petrosal sinuses to the lateral sinus and the jugular vein through the inferior petrosal sinus. The two cavernous sinuses are connected by the intracavernous sinus, which lies on the clivus behind the sella turcica: this strict anatomical connection explains their frequent simultaneous involvement (Fig. 46–2). The petrosal sinuses are four in number, two for each side (superior and inferior). The first one is the anterior continuation of the transverse sinus and corresponds to the oblique insertion of the tentorium on the rocca petrosa, ending in the cavernous sinuses. The second begins at the
B
C
Figure 46–1. A, Anatomy of the deep venous circulation of the brain. B, Anatomy of the superior sagittal sinus. C, Anatomy of the lateral sinus (divided into its components: transverse sinus and sigmoid sinus) and the straight sinus.
chapter 46 cerebral venous thrombosis Internal carotid artery Cavernous sinus Oculomotor nerve Trochlear nerve Ophthalmic nerve Abducent nerve
Maxillary nerve
■
Figure 46–2. Anatomy of the cavernous sinus.
inferior part of the intercavernous sinus to end, together with the sigmoid sinus, in the jugular vein. 7. The occipital sinus is located at the insertion of the falx cerebelli on the occipital bone, and it drains blood from the dorsal regions of the cerebellum vermis.
Venous Anastomoses The intracranial venous system has no valves and therefore allows reversals of the blood flow direction, following pressure gradients. The most important vessels of this system are (1) the great anastomotic vein of Trolard that runs from the sylvian fissure to the SSS, thus forming an anastomosis between the SSS and the petrosal sinuses, and (2) the little anastomotic vein of Labbé, which connects the superficial sylvian vein with the transverse sinus or connects the SSS with the transverse sinus (depending on interindividual variability). There are also other, less important links, such as those between the little cortical veins and the adjacent sinuses or those between the basal vein of Rosenthal and the cortical veins. Transcerebral veins are virtual vessels that, when necessary, connect superficial and deep veins, crossing the cerebral parenchyma. The dural sinuses also communicate with the meningeal, diploic, and calvarian veins through the emissary veins.1-5
EPIDEMIOLOGY CVST may manifest with such a wide spectrum of clinical signs and symptoms that it goes unrecognized in quite a few patients. It follows that epidemiological studies are difficult to perform. On the basis of retrospective trials, CVST accounts for about 0.1% to 9% (mean, about 1%) of all deaths for stroke, with great geographic and ethnic variabilities.1,2,6-8 In industrialized countries, the incidence of CVST is estimated between 1.5 and 2.5 cases per 100,000 per year.6 Although these numbers, based on CT scan or magnetic resonance imaging (MRI) findings, are remarkably higher than those observed before the neuroimaging era, they still account for only patients who present with the more severe consequences of CVST: namely, hemorrhagic or ischemic venous strokes. As the frequency of venous stroke ranges from 30% to 80% of all cases, the prevalence of patients
623
who develop symptoms related to intracranial hypertension might be considerably higher.6,9-12 In a multicenter prospective observational study, 624 patients with CVST were enrolled. Female gender was prevalent (74.5%); the mean age was 39 years. Patients were predominantly white (79.2% versus 9.3% Hispanic, 5% black, 3.4% Asian, and 3.1% other races). Ischemic venous infarction was present in 46.5% patients, and hemorrhagic lesions were detected in 39.3% patients. Ischemic and hemorrhagic infarcts coexisted in some patients; the cumulative rate of parenchymal lesions at neuroimaging was 62.9%. The SSS was the most frequently involved (62%), followed by the left lateral sinus (44.7%), the right transverse sinus (41.2%), the straight sinus (18%), the choroidal vein (17.1%), and the jugular veins (11.9%). The deep venous system was involved in 10.9% of patients, and the cavernous sinuses in 1.3%. A posterior fossa vein thrombosis was reported in only 0.3%.13 In one study, researchers have investigated the distribution of risk factors and clinical features of CVST among white and African-Brazilian patients. The female/male ratio was higher among the African-Brazilian patients than among the white patients (4.75 versus 1.36), whereas the mean ages were similar. African-Brazilian patients had higher rates of focal deficits (60.8% versus 46.1%) and decreased consciousness (47.8% versus 27%); however, these differences were not significant.7 A high incidence of CVST in young women, especially during pregnancy and the puerperium, has been reported in several studies.6,11,12 As a matter of fact, estimates of CVST associated with pregnancy and the puerperium range from 2 to 60 per 100,000 deliveries in western Europe and North America and from 200 to 500 per 100,000 in India.1,2 The use of oral contraceptives appears to be a risk factor for CVST.1,2,6,10-13
PATHOPHYSIOLOGY The causal factors leading to CVST are essentially four: (1) prothrombotic state; (2) venous stasis; (3) direct involvement of the venous wall; and (4) abnormal blood viscosity.14 Symptoms of sinovenous occlusion may arise directly from the primary or underlying process, venous obstruction, vascular inflammation, or secondary complications. Venous obstruction causes a rise of venous and parenchymal pressure in its competence territory, which leads to venous distension and edema. Many of the clinical consequences of CVST arise from brain swelling and increased intracranial pressure caused both by venous engorgement and by decreased cerebrospinal fluid absorption secondary to venous hypertension. Furthermore, in the majority of cases, thrombosis involves multiple dural sinuses or both sinuses and veins.1,2,13,15 Experimental studies have contributed to a better definition of the pathological features of CVST. A subacute occlusion of SSS provokes clinical manifestations only when the occlusion spreads to cortical or bridging veins.16-20 SSS occlusion is usually associated with brain swelling, an increase in intracranial pressure, and diffuse cellular damage.16-21 On the other hand, occlusion of bridging and cortical veins produces a localized well-shaped venous infarction, with both ischemic and hemorrhagic features, surrounded by brain swelling and edema.19-23 In cats, the ligature of SSS provokes a stroke only when located after the confluence between this sinus and the rolandic vein, because the anterior third of the sinus is well
624
Section
IX
C e r e b r o va s c u l a r D i s e a s e
compensated by collateral vessels. What is remarkable is that ischemic/hemorrhagic lesions are absent at 2 hours but present at 24 hours; this demonstrates that the acute occlusion of a dural sinus, at least in experimental conditions, is related not to an acute infarction but only to a subacute one.19 This observation could also apply to humans, inasmuch as the majority of patients with dural sinus involvement exhibit a subacute onset of the CVST signs and symptoms. Also remarkable is that neither the site nor the extent of a sinus occlusion is indicative of the final site and size of the corresponding ischemic lesion. On the contrary: The thrombosis of a cortical vein produces a definite area of infarction in the gray and superficial white matter. As a consequence, patients with cortical and deep vein thrombosis show the worst clinical outcome,22 because the deep vein thrombosis produces a widespread lesion that involves the thalamus, the deep white matter, and the upper parts of the brainstem.1,2,24
DIAGNOSIS AND CLINICAL FEATURES CVSTs manifest with a wide spectrum of signs and symptoms; therefore, the differential diagnosis should account for a number of possible conditions. The variability of clinical features of CVST is high in relation to the site and extent of thrombosis, the rate of propagation of the occlusion, the age of the patient, and the underlying pathology. Spinal cord venous involvement in these thrombotic processes is also possible, but it is very rare and related mostly to the propagation of an infectious thrombophlebitis of the pelvic veins. Headache is the most frequent presenting symptom and the most common complaint (75% of cases).1,2,12,25 The headache is usually diffuse and progressive, with no typical clinical characteristics or temporal profile. In the 2004 International Classification of Headache Syndromes, headache associated with CVST is classified as follows: (1) any new headache, with or without neurological signs, that fulfills the second and third criteria; (2) headache with neuroimaging evidence of CVST; (3) headache (and neurological signs, if present) that develops in close temporal relation to CVST.26 Despite its polymorphism, the most frequent clinical features of CVST can be grouped into three syndromes, according to their physiopathology: (1) intracranial hypertension syndrome (IHS); (2) stroke-related syndrome; and (3) encephalopathic syndrome.
Intracranial Hypertension Syndrome Headache is the most common clinical symptom of IHS, reported in 75% to 95% of patients.6 It represents the inaugural symptom in 70% to 75% of cases and is often the unique clinical manifestation of IHS.6-27 The headache may be any grade of severity, diffuse or localized, and persistent or intermittent. The onset is usually subacute (2 to 30 days) but can also be acute (>2 days) or chronic (>30 days).1,2 Attacks may mimic migraine or may be interpreted as a subarachnoid hemorrhage manifesting as a thunderclap-type headache, with instantaneous onset and coming on very quickly.27 Papilledema is observed in about 50% of affected patients.11 Only 20% to 40% of patients have the complete syndrome of isolated IHS with headache, nausea, vomiting, papilledema, transient visual obscurations, and eventually cranial nerve VI
palsy. The involvement of other cranial nerves is very rare.6 IHS resulting from CVST should be differentiated by the idiopathic intracranial hypertension or pseudotumor cerebri, with a complete neuroradiological workup. IHS is more frequently caused by the occlusion of the dural sinuses, particularly the SSS.1,2,27
Stroke-Related Syndrome This syndrome is typically related to the occurrence of a venous infarction that can be both ischemic and hemorrhagic. In the majority of cases, the pattern is represented by multiple small intraparenchymal hemorrhages, surrounded either by normal parenchyma or by ischemic areas. Its clinical features are illdefined and differ from those of an arterial stroke, which is more sharply outlined and wedge-shaped. The abundance of collateral vessels and anastomosis of the venous circulation, in comparison with the arterial circulation, is responsible for the lack of topographic localization of the lesions. Focal neurological signs (sensory and motor deficits, speech disturbances, hemianopia) are present in 40% to 60% of all cases.6 Headache, vomiting, and ataxia with acute onset are the most frequent symptoms in patients with cerebellar vein thrombosis, which is always associated with a concomitant effect on the lateral sagittal sinus and SSS.6
Encephalopathic Syndrome This condition is the least frequent manifestation of CVST but also the most severe. It is typically related to the involvement of the deep venous system, with diffuse damage of the white matter, basal ganglia, thalamus, and mesencephalon. Parenchymal damage may be related to necrosis, hemorrhages, and brain swelling.1,2,28 The clinical syndrome is characterized by generalized seizures, psychiatric disturbances, confusion, and variable levels of consciousness, disorders of which range from stupor to coma.1,2,6,10,11,25 Major cognitive impairments are reported in only 15% to 19% of cases.6 Focal or generalized seizures are present in more than 40% of patients with CVST2 and may occur in every related clinical syndrome. During the puerperium, the incidence is even higher (76%).6,12 Among the focal forms, the jacksonian type is the most common and is characteristically associated with Todd’s postconvulsive paresis, which is rare in idiopathic epilepsy.6,12,29 Nonetheless, only a few cases progress to epilepsy.29 Cavernous sinus thrombosis provokes a peculiar neurological syndrome characterized by any combination of unilateral chemosis, proptosis, and eyelid edema (caused by inadequate ocular venous drainage from the ophthalmic vein), with diplopia resulting from the involvement of the oculomotor nerves. Myosis and ptosis may also be present as a result of involvement of the third cranial nerve, as may mydriasis, caused by the involvement of the pericarotic sympathetic plexus. Retro-orbital and/or frontotemporal pain and anesthesia in the territories of the first and second branches of the trigeminus may also be present, constituting the so-called painful ophthalmoplegia. In the case of slow occlusion of the sinus, the only clinical manifestation may be limited to the sixth nerve palsy accompanied with pain. The thrombosis may extend to the contralateral sinuses. The differential diagnosis should take into consideration other causes of painful oph-
chapter 46 cerebral venous thrombosis thalmoplegia such as the Tolosa-Hunt syndrome, which is an idiopathic granulomatous inflammation of the dural wall of the cavernous sinuses; giant cells arteritis; sarcoidosis; local or general neoplasm; pseudotumor orbitae; and infectious thrombophlebitis caused by the propagation of a septic process from the face or neck into the cavernous sinuses.30
DIAGNOSTIC METHODS Venous angiography was the first instrumental technique used to diagnose CVST. Today, its clinical use is limited to dubious cases because of its excellent sensitivity. Angiography shows venous thrombosis as an interruption of flow that may be differentiated by sinus aplasia by the presence of a tortuous collateral circulation, consisting of “corkscrew vessels.”1,2 These vessels cannot be visualized by any other technique, and thus angiography remains the most important diagnostic tool in these cases.31 CT scan is usually the first investigation performed in the emergency department6; thus, it plays an important role in differential diagnosis, allowing the clinician to rule out disorders that may mimic CVST, such as tumors, encephalitis, brain abscesses, and subarachnoid hemorrhage.32 However, CT scans may be normal in 25% to 30% of patients.6 On CT scan, CVST may show direct and indirect signs. Direct signs are as follows: 1. The empty delta sign is the most frequent direct sign of CVST, being detected in 25% to 30% of patients with CSVT.6 Visible only after injection of contrast material, it appears as a hypodense area, because of the presence of a clot in the torcular Herophili, surrounded by a hyperdense triangular (delta-shaped) image, because of the enhancement of collateral vessels developed in the context of the dural wall.1,2,6,10,11,33 False-positive findings may result from early division, septa, or duplications of SSS.6,10 2. The cord sign is a focus of increased density, resulting from the presence of fresh thrombus, on the vessel parallel to the scanning plane. Its specificity is low. 3. The triangle sign is a fresh thrombus localized in the posterior part of SSS and may be visualized as a hyperdense triangle in the coronal slices without contrast. A hyperdensity may also be visible in other sinuses when they are involved in the thrombotic process. Indirect signs, more frequent than the direct ones, are not specific but may be suggestive of a CVST: 1. Local or generalized brain swelling, as indicated by the presence of small ventricle and sulci and diffuse relative low density of the white matter. 2. Intense contrast enhancement of the falx cerebri or the tentorium cerebelli, as a result of dural venous collaterals or stasis. 3. Hypodense parenchymal lesions corresponding to venous infarction or hyperdense lesions related to hemorrhagic areas. Hemorrhagic infarcts range from a large hematoma (very rare) to petechial areas within a hypodensity.1,2,6,11 Unlike the arterial hemorrhage, a venous one is frequently caused by diapedesis and not the breaking of a vessel. A bilateral altered density of thalami is highly suggestive of cerebral deep venous system thrombosis, and it is associated with a poor prognosis.
625
4. Subarachnoid hemorrhage is a rare event, but it is possible in CVST, particularly when it achieves a gyral extension. In a subarachnoid hemorrhage secondary to CVST, vascular alterations are absent.34 Subdural hemorrhage related to CVST is possible, but it is a rare event. Since 2000, new CT techniques have improved the diagnostic sensitivity in detecting CVST. In particular, helical CT venography has improved the sensitivity of computed tomography to 95%,35 demonstrating an even higher sensitivity than digital subtraction angiography of the venous phase used to visualize thrombosis in cavernous sinuses and ISS. Multislice CT angiography is frequently available in the emergency department, and it is useful to differentiate arterial from venous infarction.36 Nowadays, MRI is the “gold standard” for diagnosing CVST. The signal characteristics of venous thrombi evolve in several stages. In the first days, the thrombus is isointense on T1-weighted sequences and hypointense on T2-weighted sequences. If the posterior part of the SSS is involved, a dural wall hyperintensity, similar to the CT delta sign, is visible after gadolinium injection. Afterward, the clot becomes hyperintense, first in T1-weighted sequences and later also in T2weighted sequences, with a characteristic progression of the hyperintensity from the periphery to the center. This phenomenon results from the transformation of hemoglobin into methemoglobin.6,11,24 After the first month, the hyperintensity disappears, first in T1- and then in T2-weighted sequences; therefore, the persistent occlusion can be visible, as an isointense signal, only in flow-sensitive gadolinium-enhanced sequences.1,2,6,11,24 Venous infarction on MRI appears as multiple areas of hyperintensity mixed with isointense or hypointense areas.6,24 Magnetic resonance venous angiography is an excellent tool for diagnosing the sharp interruption of a dural sinus; however, its capability to diagnose thrombosis of specific cortical veins is still weak, because of the individual variability and complexity of the cerebral venous system. Resolution and sensitivity are increased with the phase-contrast technique in regard to the time-of-flight technique.6 Magnetic resonance venous angiography is also useful for studying the hypoplasia of intracranial sinuses, an important source of pitfalls in the diagnosis of CVST.37 A promising technique is the gadolinium-enhanced auto-triggered elliptical centric-ordered magnetic resonance venography, which produces three-dimensional and digitally amplified images and is more sensitive than the classic gadolinium-enhanced magnetic resonance venography.38 Diffusion-weighted imaging (DWI) has demonstrated high sensitivity in detecting ischemic strokes in their initial phase. In CVST, DWI may be used to diagnose a venous infarction in the earlier hours, when it is more likely to be ameliorated with adequate medical intervention.6,24 It demonstrates the coexistence in the venous infarction of cytotoxic and vasogenic edema24,39,40 (Fig. 46–3). Another possible application of DWI may be to detect early recanalization, as demonstrated by Bousser and coworkers. Twenty-eight patients with recent CVST were studied with DWI in the acute phase, in order to identify hyperintense signals in the sinuses that corresponded to the thrombus. DWI hyperintense signals in the sinuses were detected in 12 of the 28 patients (43%) corresponding to 20 occluded veins or sinus. Two or three months after the beginning of anticoagulant administration, this phenomenon
626
A ■
Section
IX
C e r e b r o va s c u l a r D i s e a s e
B
C
Figure 46–3. Fluid-attenuated inversion recovery (A), T2-weighted (B), and diffusion-weighted (C) magnetic resonance imaging sequences of a thalamocapsular venous infarction in a patient with transverse sinus thrombosis.
significantly decreased (35% versus 88%; P = 0.05) probably because of the different molecular structure of the clot.41 Since 2000, some advances have been made in testing possible applications of transcranial Doppler (TCD) imaging in CVST. In patients with CVST, higher values of peak systolic, end-diastolic, and mean blood flow velocities have been reported in the deep venous system than in controls.42,43 However, although blood flow alterations in patients with CVST are more frequent than in controls, the sensitivity of TCD imaging is lower than that of MRI.43,44 Interestingly, patients with CVST showed a decrease in velocity values after starting heparin therapy, with a rebound of velocity values immediately after heparin suspension. Higher velocities in the acute phase were significantly associated with disturbances of consciousness. No relation was found between increased flow velocities and disease onset, severity of motor deficits, and presence of bleeding. In addition, the initial blood flow velocity was not predictive of stroke outcome.44 In another study, 26 patients with CVST, all treated with intravenous heparin and then with warfarin for 12 months, were monitored for a mean of 316 days, in order to evaluate whether hemodynamic factors, related to alternative flow patterns, could predict stroke outcome. All patients underwent TCD sonography at admission. The majority of patients (69%) showed pathological blood flow velocities at admission. Four alternative drainage patterns were found: 1. In the cavernous sinus drainage type, there was increased flow into this sinus and its major contributors (sphenoparietal sinus and the superior petrosal sinus). Headache was the only symptom affected patients complained of, and the outcome was good. It was related to sigmoid sinus thrombosis. 2. In the deep cerebral venous drainage type, there was increased flow in the galenic system. It was related to SSS occlusion, and affected patients had a good prognosis. 3. In the reverse flow in the basal vein of Rosenthal drainage type, inversion of flow in this vein resulted from the occlu-
sion of the straight sinus. Headache was the only symptom, and the outcome was good. 4. In the transverse sinus drainage type, inversion of flow in the proximal part of the sinus occurred when the distal was occluded; an increased flow in the contralateral transverse sinus was found in proximal occlusions. This TCD pattern was related to the encephalopathic syndrome, and affected patients had the worst outcome.45 The Doppler technique is also useful in patients with CVST in detecting microembolic signals in the internal jugular vein, which are higher than in controls.46 Echocontrast techniques have been applied in order to increase TCD resolution.47
RISK FACTORS Several conditions have been found to be associated with CVST, but only few of them produce an effective increase of the relative risk. The most common risk factors for CVST are listed in Table 46–1. Idiopathic cases account for 25% to 30% of cases of CVST.1,2,10,11,25 Etiological factors may be divided into two main categories: septic CVST, which accounts for 5% to 15% of the cases, and aseptic CVST, which is predominant in industrialized countries. There are local and general causes for CVST. Local causes are related to head and neck infections (10.3%), tumors (2.2%), head injuries (1.1%), and neurosurgery (0.6%)13,48 (Fig. 46–4). Lumbar puncture, particularly with an intrarachidian injection of drugs (1.9%), may also produce CVST.49,50 In women, the most frequent general causes are pregnancy, puerperium, use of oral anticoagulants, and hormone replacement therapy. All these conditions are associated with high estrogen levels13,51-53 (Fig. 46–5). In the absence of thrombophilias, recurrence of CVST during another pregnancy is very rare.54 On the other hand, recurrences are very frequent in cases of puerperal CVST, which carry the greatest day-by-day risk of development of a vein thrombosis.6 Thus, anticoagulation is recommended in all
chapter 46 cerebral venous thrombosis ■
627
Figure 46–4. A, Magnetic resonance image of a brain abscess of the right temporal lobe, caused by a septic otomastoiditis in a young adult without human immunodeficiency virus. B, Magnetic resonance venous angiogram in the same patient, showing septic thrombosis in the right superior sagittal sinus, straight sinus, and petrosal sinus.
A T A B L E 4 6 – 1. Septic thrombosis Head injuries Hematological disorders Thrombophilic disorders Metabolic disorders Neoplasia Inflammatory states Phakomatoses Hormonal Vascular disorders Medications Others
B Risk Factors for Cerebral Vein and Sinus Thrombosis Bacterial (including syphilis), fungal (Mucor, Aspergillus, Rhizopus), viral (HIV, herpes zoster) and parasitic (Trichinella) infections Penetrating and nonpenetrating head injuries, surgery, intravascular foreign bodies, iopamidol myelography Polycythemia vera, altitude-induced polycythemia, sickle cell anemia, cryofibrinogenemia, paroxysmal nocturnal hemoglobinuria, thrombocytosis, multiple myeloma, severe anemia Antithrombin III deficiency, protein C and/or protein S deficiency, activated protein C resistance, G20210A prothrombin mutation, antiphospholipid antibody syndrome, disseminated intravascular coagulation, MTHFR mutation, hyperhomocysteinemia, factor V Leiden, transfusion reaction, nephrotic syndrome Homocystinuria, carbon monoxide, diabetes, thyroid disorders, hypertriglyceridemia Metastatic (usually hematogenous malignancies), nonmetastatic complications, meningioma Behçet’s syndrome, inflammatory bowel disease (ulcerative colitis, Crohn’s disease), Wegener’s granulomatosis, Cogan’s syndrome, Köhlmeier-Degos disease, polyarteritis nodosa, systemic lupus erythematosus, sarcoidosis, thromboangiitis obliterans, rheumatoid arthritis Sturge-Weber syndrome Pregnancy and puerperium, thyrotoxicosis Arteriovenous malformations, arterial occlusions, jugular catheter occlusion, dural fistula Androgens, oral contraceptives, progestogens, L-asparaginase, pentosan, hormone replacement therapy, cocaine Dehydration, fever, cardiac decompensation, skull abnormalities (achondroplasia, craniometaphyseal dysplasia), lumbar puncture, epidural anesthesia, CSF hypotension
CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; MTHFR, methylene-tetrahydrofolate reductase.
patients with previous puerperal thrombosis.55 Thrombophilias, both hereditary and acquired, are reported in 20% to 50% of patients with CVST.13 In a series of 121 patients with CVST, prothrombin G20210A was present in 21.5% of patients, factor V Leyden in 12.4%, protein C deficiency in 5.2%, protein S deficiency in 3.1%, and antithrombin III deficiency in 2.5%.56 The presence of prothrombin G20210A and factor V Leyden increased the odds of developing CVST even in the heterozygous form by acting as cofactors with other conditions.56 Less common genetic thrombophilias such as hyperfibrinogenemia, alteration in the plasmin cascade,57 and hyperhomocysteinemia are associated with an increased risk of developing CVST.56,58 Hyperhomocysteinemia may provoke CVST, inducing endothelial toxicity, which is higher for the cerebral vascular system,59,60 and interferes with the clotting cascade.60,61 In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT),
the rate of with hyperhomocysteinemia in the whole population was 4.5%, reaching 27% in the series specifically dedicated to estimate the incidence and the risk of CVST associated with thrombophilic disorders.13 Acquired thrombophilic disorders accounted for 6.5% of patients: 5.9% were referable to antiphospholipid antibody syndrome and 0.6% to nephrotic syndrome.13 Another important category of risk factors for CVST is represented by systemic inflammatory disorders, especially if associated with vasculitis. In the ISCVT, systemic lupus erythematosus was found in 1% of patients, Behçet’s disease in 1%, rheumatoid arthritis in 0.2%, thromboangiitis obliterans in 0.2%, inflammatory bowel disease (ulcerative colitis and Crohn’s disease) in 1.6%, and sarcoidosis in 0.2%13 (Fig. 46–6). Systemic infections are reported in 4.3% of patients; cultures and sensitivities are necessary to determine treatment.
628
Section
IX
C e r e b r o va s c u l a r D i s e a s e ■
Figure 46–5. A, Magnetic resonance image of frontal hematoma related to complete thrombosis of the left transverse sinus and superior sagittal sinus and partial thrombosis of the right transverse sinus occurred during the puerperal period. B, Magnetic resonance venogram of the same patient.
A
B tant cause of thrombosis in neonates and young children. These patients are also very frequently at risk for anemia with CVST.62,63 Aseptic cerebral venous thrombosis is also reported in association with tuberculosis.64
TREATMENT Treatment of CVST should address the thrombotic process (causal treatment), the consequences of CVST (symptomatic treatment), and the underlying causes.
Treatment of the Thrombotic Process
■
Figure 46–6. Complete left transverse sinus and partial right transverse sinus thrombosis in a female patient affected by Sjögren’s syndrome.
More diffuse in the past and related to very poor hygienic conditions and the absence of antibiotics, they remain an important cause of CVST and deep vein thrombosis in less industrialized countries. Systemic infections may be an impor-
Among the causal treatments, anticoagulants are the more widely used. They are expected not to eliminate an already formed thrombus but to prevent extension of thrombosis to other venous channels. Nonetheless, the use of anticoagulants in patients with CVST is still debated.65-69 The main argument against anticoagulation is the risk of a major hemorrhage in the venous infarct, which is often already a hemorrhagic infarct. Several retrospective trials have shown a potential benefit of anticoagulation in patients with CVST.65,68 To date, however, findings from only two randomized placebocontrolled trials of anticoagulation in CVST are available. The first case-control study involved dose-adjusted intravenous heparin and was prematurely discontinued because of a statistically significant difference in favor of treated patients over controls.67 This was the first study demonstrating that the benefits of intravenous heparin also apply to patients with intracranial hypertension. Furthermore, no additional intracranial hypertension was detected during heparin treatment. In the European double-blind, controlled multicenter trial, weightadjusted subcutaneous nadroparin for 3 weeks, followed by oral anticoagulation for 3 months, was compared with placebo in 60 patients with CVST. After 3 weeks, a poor outcome (defined as a Barthel Index <15) was observed in 20% of patients receiving nadroparin, in comparison with 24% of the controls. At 12
chapter 46 cerebral venous thrombosis weeks, a poor outcome was observed in 10% of patients receiving nadroparin, in contrast to 21% of the controls. A complete recovery was observed in 12% of patients receiving nadroparin and 28% of the controls. None of these differences was statistically significant.70 A meta-analysis of the two reported trials showed an absolute risk reduction of 14% in mortality and 15% in mortality and dependency combined in patients undergoing anticoagulation.69 These results, although not statistically significant, are encouraging and strongly endorse, in our opinion, the use of anticoagulants in CVST irrespective of the presence of intracranial hypertension.69,71,72 Anticoagulant treatment should be continued orally for a period of at least 3 to 6 months. In case of puerperium, it should be prolonged for 12 months.73 If prothrombotic risk factors are present, long-term treatment is mandatory.6,73 Of importance is that during pregnancy, particularly in the first 3 months, vitamin K antagonists such as warfarin should be avoided, because they are linked with an increased rate of malformations.73 The first therapeutic choice in this case is therefore lowmolecular-weight heparin.6 The use of thrombolytic agents in CVST has been evaluated.65,74-88 Thrombolytic therapy aims at rapid recanalization of the occluded vessel, including, in our case, the cortical veins.71,72 The efficacy and safety of this treatment are debated.74-88 Two different thrombolytic agents have been used in CVST. Urokinase was compared with intravenous heparin in SSS thrombosis. It was fairly well tolerated and more effective than heparin.74-77,83,85,88 The intrathrombus combination of recombinant tissue-type plasminogen activator (rtPA) and intravenous heparin was compared with intravenous heparin alone in patients with sinuses thrombosis. Both treatments were effective and safe, although the outcome was worse in patients with major hemorrhages treated with rtPA.79,82 A retrospective meta-analysis (72 studies, 169 patients enrolled) demonstrated that thrombolytic treatment is associated with a better outcome and is sufficiently safe.83 Nevertheless, to date there is no proof that thrombolytic therapy is better than anticoagulation in patients with CVST. Therefore, it should be used as second choice of therapy in patients whose condition worsens in spite of correct anticoagulation.76,84,89 The use of antiaggregates in patients with acute CVST has been poorly investigated. Experimental studies revealed a better neurological outcome and a higher rate of recanalization with rtPA in combination with the glycoprotein IIb/IIIa direct inhibitor abciximab, in comparison with the association of rtPA with enoxaparine.90 So far, clinical studies investigating the use of glycoprotein IIb/IIIa direct inhibitors in CVST have never been performed. There is little information concerning the use of mechanical treatments, such as rheolytic catheter thrombectomy or angioplasty in CVST, and further evidence of their efficacy is needed.91-99 A great limitation of these techniques is represented by the inaccessibility to some intracranial vessels, particularly cortical, bridging, and deep veins, because of their size in comparison with the caliber of the catheter.91-93 Open surgical thrombectomy, combined with local infusion of rtPA, showed a good outcome when used in patients with severe dural sinus thrombosis and deterioration despite anticoagulation. All patients returned to normal activities after surgical treatment.100,101
629
Symptomatic Treatment The prophylactic use of anticonvulsants in patients with CVST is still controversial because of their negative effects on brain metabolism and on the level of consciousness. The general attitude, and our advice, is to use these drugs only in patients with seizures.1,2,6,25,29 Focal neurological deficits, cerebral edema, and infarction (especially hemorrhagic) observed on neuroimaging seem to be significant predictors of seizure in patients with CVST.29 A prophylactic treatment with anticonvulsants might be justified in these patients. Treatment of increased intracranial pressure caused by brain swelling is based on the use of mannitol, seldom in association with other diuretics such as acetazolamide or furosemide. Steroids are not indicated, because of their antifibrinolytic activity (although there are no clinical trials demonstrating a worse outcome in CVST patients treated with steroids).1,2,6,11,25 Tris(hydroxymethyl)aminomethane, which decreases intracranial pressure by alkalotic vasoconstriction, could be used in ventilated patients.6 Treatment of septic CVST must be based on the antibiogram, but while the clinician waits for these findings, an empirical treatment may be started with a third-generation cephalosporin (such as ceftriaxone or cefotaxime) or with a penicillinaseresistant penicillin. Metronidazole is the first choice when an anaerobic infection is suspected; in the nosocomial infections, meropenem, ceftazidime, and vancomycin may be used.
PROGNOSIS CVST was long thought to be a rare disease with a poor prognosis.1,2,9-11 Since the mid-1970s, neuroimaging has produced a better understanding of this disease, and the use of anticoagulant therapy has increased the number of good outcomes. In the ISCVT study, after a 16-month median follow-up period, 13.4% of the patients had a modified Rankin scale score of more than 2, and 8.3% had died. Multivariate predictors of death or dependence were central nervous system infections (HR = 3.3%), cancer (HR = 2.9), deep venous system involvement (HR = 2.9), coma (HR = 2.7), age older than 37 years (HR = 2), mental status disorders (HR = 2), hemorrhage visible on CT scan (HR = 1.9), and male gender (HR = 1.6). Only 2.2% of the patients had a recurrent sinus thrombosis, and 4.3% had other thrombotic events.13 The rate of recurrences in patients with CVST ranges from 0% to 11.7%,102 and it is most common in the first year after the previous thrombosis.6,102 The mortality rate ranges between 6% and 33%, and it is higher in septic CVST.11 In one study, researchers investigated the variables influencing the delay between the onset of symptoms and hospital admission for patients with CVST. Twenty-two percent of patients were admitted within 24 hours and 75% within 13 days. In multiple logistic regression analysis, admission within 24 hours was associated positively with mental status disorders (delirium/ abulia) and negatively with headache. Intracranial hypertension was associated with an admission delay of more than 4 days, and papilledema, with a delay of more than 13 days. Mean delay between onset and hospital admission was 4 days. Not surprisingly, anticoagulation was started earlier in patients with a more precocious diagnosis, but the proportion of patients treated was not influenced by the delay of admission. Headache was the most common presenting symptom; therefore, CVST
630
Section
IX
C e r e b r o va s c u l a r D i s e a s e
should be considered in patients with a new-onset headache or an important change in the clinical features of a preexisting one.11,27 A number of researchers investigated the relationship between delay of anticoagulant treatments and CVST prognosis.103-105 So far, there is no evidence that delay in admission (and diagnosis) might influence CVST prognosis. Female gender, pregnancy, and puerperium, all related to high estrogens levels, seem to be predictive of a good outcome.6,106 Early recanalization, which is a common phenomenon on neuroimaging, has no influence on outcome.107
CONCLUSION The thrombotic process in CVST leads to a wide spectrum of clinical symptoms varying from isolated headache to focal neurological signs or even coma. Neuroimaging techniques allow a quick diagnosis, limiting the number of cases that remain uncertain to few. Anticoagulation is the first-line therapy for CVST, but some patients may require no therapy at all, whereas others may benefit from more aggressive treatment, such as thrombolysis.
K E Y
P O I N T S
●
CVST accounts for fewer than 1% of all strokes and for about 0.1% to 9% (mean, about 1%) of all deaths from cerebrovascular diseases. There is great geography- and ethnicity-associated variability.
●
The causal factors leading to CVST have been classically grouped into (1) prothrombotic state, (2) venous stasis, (3) direct involvement of the venous wall, and (4) abnormal blood viscosity.
●
The clinical features of CVST can be grouped into three syndromes: (1) intracranial hypertension syndrome; (2) strokerelated syndrome; and (3) encephalopathic syndrome.
●
Early diagnosis of CVST is crucial, because anticoagulation reduces the risk of fatal outcome and severe disability.
Suggested Reading Canhao P, Batista P, Falcao F: Lumbar puncture and dural sinus thrombosis: a causal or casual association? Cerebrovasc Dis 2005; 19:53-56. Camargo EC, Massaro AR, Bacheschi LA, et al: Ethnic differences in cerebral venous thrombosis. Cerebrovasc Dis 2005; 19:147151. Ferro JM, Lopes MG, Rosas MJ, et al: Delay in hospital admission of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2005;19:152-156. Rottger C, Madlener K, Heil M, et al: Is heparin treatment the optimal management for cerebral venous thrombosis? Effect of abciximab, recombinant tissue plasminogen activator, and enoxaparin in experimentally induced superior sagittal sinus thrombosis. Stroke 2005; 36:841-846. Stolz E, Rahimi A, Gerriets T, et al: Cerebral venous thrombosis: an all or nothing disease? Prognostic factors and long-term outcome. Clin Neurol Neurosurg 2005; 107:99-107.
References 1. Ginsberg MD, Bogousslavsky J: Cerebrovascular Diseases, vol 2. Malden, MA: Blackwell Science, 1998. 2. Bogousslavsky J, Caplan L: Stroke Syndromes. Cambridge, UK: Cambridge University Press, 2001. 3. Williams PL, Warwick R: Gray’s Anatomy, 37th ed, vol 2. Essex, UK: Longman Group, 1989. 4. Mazzocchi G, Nussdorfer G: Anatomia Funzionale del Sistema Nervoso. Padua, Italy: Libreria Cortina, 1993. 5. Netter FH: Atlante di Anatomia Umana [Italian ed]. Origgio, Italy: Ciba-Geigy, 1990. 6. Masuhr F, Mehraein S, Einhaupl K: Cerebral venous and sinus thrombosis. J Neurol 2004; 251:11-23. 7. Camargo EC, Massaro AR, Bacheschi LA, et al: Ethnic differences in cerebral venous thrombosis. Cerebrovasc Dis 2005; 19:147-151. 8. Liu HS, Kho BC, Chan JC, et al: Venous thromboembolism in the Chinese population: experience in a regional hospital in Hong Kong. Hong Kong Med J 2002; 8:400-405. 9. Stolz E, Rahimi A, Gerriets T, et al: Cerebral venous thrombosis: an all or nothing disease? Prognostic factors and longterm outcome. Clin Neurol Neurosurg 2005; 107:99-107. 10. Bousser MG, Ross Russel R: Cerebral Venous Thrombosis, vol 1. London: WB Saunders, 1997. 11. Crassard I, Bousser MG: Cerebral venous thrombosis. J Neuroophthalmol 2004; 24:156-163. 12. Ameri A, Bousser MG: Cerebral venous thrombosis. Neurol Clin 1992; 10:87-111. 13. Ferro JM, Canhao P, Stam J, et al: Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004; 35:664-670. 14. Lowe GD: Virchow’s triad revisited: abnormal flow. Pathophysiol Haemost Thromb 2003/2004; 33(5-6):455-457. 15. Gettelfinger DM, Kokmen E: Superior sagittal sinus thrombosis. Arch Neurol 1977; 34:2-6. 16. Gotoh M, Ohmoto T, Kuyama H: Experimental study of venous circulatory disturbance by dural sinus occlusion. Acta Neurochir 1993; 124:120-126. 17. Tychmanowicz K, Czernicki Z, Czosnyka M, et al: Early pathomorphological changes and intracranial volume-pressure: relations following the experimental sagittal sinus occlusion. Acta Neurochir Suppl 1990; 51:233-235. 18. Tuzgen S, Canbaz B, Kaya AH, et al: Experimental study of rapid versus slow sagittal sinus occlusion in dogs. Neurol India 2003; 51:482-486. 19. Schaller B, Graf R, Wienhard K, et al: A new animal model of cerebral venous infarction: ligation of the posterior part of the superior sagittal sinus in the cat. Swiss Med Wkly 2003; 133(29-30):412-418. 20. Cervos-Navarro J, Kannuki S, Matsumoto K: Neuropathological changes following occlusion of the superior sagittal sinus and cerebral veins in the cat. Neuropathol Appl Neurobiol 1994; 20:122-129. 21. Vosko MR, Rother J, Friedl B, et al: Microvascular damage following experimental sinus-vein thrombosis in rats. Acta Neuropathol 2003; 106:501-505. 22. Fries G, Wallenfang T, Hennen J, et al: Occlusion of the pig superior sagittal sinus, bridging and cortical veins: multistep evolution of sinus-vein thrombosis. J Neurosurg 1992; 77:127-133. 23. Bergui M, Bradac GB, Daniele D: Brain lesions due to cerebral venous thrombosis do not correlate with sinus involvement. Neuroradiology 1999; 41:419-424. 24. Haage P, Krings T, Schmitz-Rode T: Nontraumatic vascular emergencies: imaging and intervention in acute venous occlusion. Eur Radiol 2002; 12:2627-2643.
chapter 46 cerebral venous thrombosis 25. Loeb C, Favale E: Neurologia di Fazio-Loeb, 3rd ed. Rome: Casa Editrice Universo, 2003. 26. Headache Classification Subcommittee of the International Headache Society: The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004; 24(Suppl 1):1160. 27. Iurlaro S, Beghi E, Massetto N, et al: Does headache represent a clinical marker in early diagnosis of cerebral venous thrombosis? A prospective multicentric study. Neurol Sci 2004; 25(Suppl 3):S298-S299. 28. Madan A, Sluzewski M, van Rooij WJ, et al: Thrombosis of the deep cerebral veins: CT and MRI findings with pathologic correlation. Neuroradiology 1997; 39:777-780. 29. Ferro JM, Correia M, Rosas MJ, et al: Seizures in cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2003; 15:78-83. 30. Lenzi GL, Fieschi C: Superior orbital fissure syndrome: review of 130 cases. Eur Neurol 1977; 16:23-30. 31. Wetzel SG, Kirsch E, Stock KW, et al: Cerebral veins: comparative study of CT venography with intraarterial digital subtraction angiography. Am J Neuroradiol 1999; 20:249255. 32. Giraud P, Thobois S, Hermier M, et al: Intravenous hypertrophic Pacchioni granulations: differentiation from venous dural thrombosis. J Neurol Neurosurg Psychiatry 2001; 70:700-701. 33. Deus-Silva L, Voetsch B, Nucci A, et al: An unusual “empty delta sign.” J Neurol Neurosurg Psychiatry 2004; 75:1287. 34. Chang R, Friedman DP: Isolated cortical venous thrombosis presenting as subarachnoid hemorrhage: a report of three cases. Am J Neuroradiol 2004; 25:1676-1679. 35. Casey SO, Alberico RA, Patel M, et al: Cerebral CT venography. Radiology 1996; 198:163-170. 36. Klingebiel R, Busch M, Bohner G, et al: Multi-slice CT angiography in the evaluation of patients with acute cerebrovascular disease: a promising new diagnostic tool. J Neurol 2002; 249:43-49. 37. Alper F, Kantarci M, Dane S, et al: Importance of anatomical asymmetries of transverse sinuses: an MR venographic study. Cerebrovasc Dis 2004; 18:236-239. 38. Farb RI, Scott JN, Willinsky RA, et al: Intracranial venous system: gadolinium-enhanced three-dimensional MR venography with auto-triggered elliptic centric-ordered sequence—initial experience. Radiology 2003; 226:203209. 39. Lovblad KO, Bassetti C, Schneider J, et al: Diffusion-weighted MRI suggests the coexistence of cytotoxic and vasogenic oedema in a case of deep cerebral venous thrombosis. Neuroradiology 2000; 42:728-731. 40. Keller E, Flacke S, Urbach H, et al: Diffusion- and perfusionweighted magnetic resonance imaging in deep cerebral venous thrombosis. Stroke 1999; 30:1144-1146. 41. Favrole P, Guichard JP, Crassard I, et al: Diffusion-weighted imaging of intravascular clots in cerebral venous thrombosis. Stroke 2004; 35:99-103. 42. Schreiber SJ, Stolz E, Valdueza JM: Transcranial ultrasonography of cerebral veins and sinuses. Eur J Ultrasound 2002; 16:59-72. 43. Canhao P, Batista P, Ferro JM: Venous transcranial Doppler in acute dural sinus thrombosis. J Neurol 1998; 245:276279. 44. Valdueza JM, Hoffmann O, Weih M, et al: Monitoring of venous hemodynamics in patients with cerebral venous thrombosis by transcranial Doppler ultrasound. Arch Neurol 1999; 56:229-234. 45. Stolz E, Gerriets T, Bodeker RH, et al: Intracranial venous hemodynamics is a factor related to a favorable outcome in cerebral venous thrombosis. Stroke 2002; 33:1645-1650.
631
46. Valdueza JM, Harms L, Doepp F, et al: Venous microembolic signals detected in patients with cerebral sinus thrombosis. Stroke 1997; 28:1607-1609. 47. Ries S, Steinke W, Neff KW, et al: Echocontrast-enhanced transcranial color-coded sonography for the diagnosis of transverse sinus venous thrombosis. Stroke 1997; 28:696700. 48. Knudson MM, Ikossi DG: Venous thromboembolism after trauma. Curr Opin Crit Care 2004; 10:539-548. 49. Canhao P, Batista P, Falcao F: Lumbar puncture and dural sinus thrombosis—a causal or casual association? Cerebrovasc Dis 2005; 19:53-56. 50. Aidi S, Chaunu MP, Biousse V, et al: Changing pattern of headache pointing to cerebral venous thrombosis after lumbar puncture and intravenous high-dose corticosteroids. Headache 1999; 39:559-564. 51. de Bruijn SF, Stam J, Koopman MM, et al: Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in (correction of who are) carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group. BMJ 1998; 316:589592. 52. Buccino G, Scoditti U, Pini M, et al: Low-oestrogen oral contraceptives as a major risk factor for cerebral venous and sinus thrombosis: evidence from a clinical series. Ital J Neurol Sci 1999; 20:231-235. 53. Vander T, Medvedovsky M, Shelef I, et al: Postmenopausal HRT is not independent risk factor for dural sinus thrombosis. Eur J Neurol 2004; 11:569-571. 54. Derex L, Philippeau F, Nighoghossian N, et al: Postpartum cerebral venous thrombosis, congenital protein C deficiency, and activated protein C resistance due to heterozygous factor V Leiden mutation. J Neurol Neurosurg Psychiatry 1998; 65:801-802. 55. Cantu C, Barinagarrementeria F: Cerebral venous thrombosis associated with pregnancy and puerperium: review of 67 cases. Stroke 1993; 24:1880-1884. 56. Martinelli I, Battaglioli T, Pedotti P, et al: Hyperhomocysteinemia in cerebral vein thrombosis. Blood 2003; 102:13631366. 57. Baumeister FA, Auberger K, Schneider K: Thrombosis of the deep cerebral veins with excessive bilateral infarction in a premature infant with the thrombogenic 4G/4G genotype of the plasminogen activator inhibitor-1. Eur J Pediatr 2000; 159:239-242. 58. Cattaneo M: Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81:165-176. 59. Gupta M, Gupta S, Saxena R, et al: Familial hyperhomocysteinemia: multiple venous thrombosis in four generations of a family. Ann Hematol 2003; 82:178-180. 60. Harpel PC, Zhang X, Borth W: Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr 1996; 126(4, Suppl):S1285-S1289. 61. Ventura P, Cobelli M, Marietta M, et al: Hyperhomocysteinemia and other newly recognized inherited coagulation disorders (factor V Leiden and prothrombin gene mutation) in patients with idiopathic cerebral vein thrombosis. Cerebrovasc Dis 2004; 17:153-159. 62. Farstad H, Gaustad P, Kristiansen P, et al: Cerebral venous thrombosis and Escherichia coli infection in neonates. Acta Paediatr 2003; 92:254-257. 63. Benedict SL, Bonkowsky JL, Thompson JA, et al: Cerebral sinovenous thrombosis in children: another reason to treat iron deficiency anemia. J Child Neurol 2004; 19:526531. 64. Kakkar N, Banerjee AK, Vasishta RK, et al: Aseptic cerebral venous thrombosis associated with abdominal tuberculosis. Neurol India 2003; 51:128-129.
632
Section
IX
C e r e b r o va s c u l a r D i s e a s e
65. Brucker AB, Vollert-Rogenhofer H, Wagner M, et al: Heparin treatment in acute cerebral sinus venous thrombosis: a retrospective clinical and MR analysis of 42 cases. Cerebrovasc Dis 1998; 8:331-337. 66. Benamer HT, Bone I: Cerebral venous thrombosis: anticoagulants or thrombolytic therapy? J Neurol Neurosurg Psychiatry 2000; 69:427-430. 67. Einhaupl KM, Villringer A, Meister W, et al: Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597-600. 68. Stam J, de Bruijn S, deVeber G: Anticoagulation for cerebral sinus thrombosis. Stroke 2003; 34:1054-1055. 69. Stam J, de Bruijn SF, DeVeber G: Anticoagulation for cerebral sinus thrombosis. Cochrane Database Syst Rev 2002; (4):CD002005. 70. de Bruijn SF, Stam J: Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484-488. 71. Lewis MB, Bousser MG: Cerebral venous thrombosis: nothing, heparin, or local thrombolysis? Stroke 1999; 30:1729. 72. Bousser MG: Cerebral venous thrombosis: nothing, heparin, or local thrombolysis? Stroke 1999; 30:481-483. 73. Bates SM, Greer IA, Hirsh J, et al: Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3, Suppl):627S-644S. 74. Aoki N, Uchinuno H, Tanikawa T, et al: Superior sagittal sinus thrombosis treated with combined local thrombolytic and systemic anticoagulation therapy. Acta Neurochir 1997; 139:332-335. 75. D’Alise MD, Fichtel F, Horowitz M: Sagittal sinus thrombosis following minor head injury treated with continuous urokinase infusion. Surg Neurol 1998; 49:430-435. 76. Ciccone A, Canhao P, Falcao F, et al: Thrombolysis for cerebral vein and dural sinus thrombosis. Stroke 2004; 35:2428. 77. Di Rocco C, Iannelli A, Leone G, et al: Heparin-urokinase treatment in aseptic dural sinus thrombosis. Arch Neurol 1981; 38:431-435. 78. Eskridge JM, Wessbecher FW: Thrombolysis for superior sagittal sinus thrombosis. J Vasc Interv Radiol 1991; 2:89-93. 79. Frey JL, Muro GJ, McDougall CG, et al: Cerebral venous thrombosis: combined intrathrombus rtPA and intravenous heparin. Stroke 1999; 30:489-494. 80. Gebara BM, Goetting MG, Wang AM: Dural sinus thrombosis complicating subclavian vein catheterization: treatment with local thrombolysis. Pediatrics 1995; 95:138-140. 81. Horowitz M, Purdy P, Unwin H, et al: Treatment of dural sinus thrombosis using selective catheterization and urokinase. Ann Neurol 1995; 38:58-67. 82. Kim SY, Suh JH: Direct endovascular thrombolytic therapy for dural sinus thrombosis: infusion of alteplase. Am J Neuroradiol 1997; 18:639-645. 83. Canhao P, Falcao F, Ferro JM: Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis 2003; 15:159-166. 84. Ciccone A, Canhao P, Falcao F, et al: Thrombolysis for cerebral vein and dural sinus thrombosis. Cochrane Database Syst Rev 2004; (1):CD003693. 85. Gerszten PC, Welch WC, Spearman MP, et al: Isolated deep cerebral venous thrombosis treated by direct endovascular thrombolysis. Surg Neurol 1997; 48:261-266. 86. Spearman MP, Jungreis CA, Wehner JJ, et al: Endovascular thrombolysis in deep cerebral venous thrombosis. Am J Neuroradiol 1997; 18:502-506. 87. Ferro JM, Lopes GC, Rosas MJ, et al: Do randomised clinical trials influence practice? The example of cerebral vein and dural sinus thrombosis. J Neurol 2002; 249:1595-1596.
88. Wasay M, Bakshi R, Kojan S, et al: Nonrandomized comparison of local urokinase thrombolysis versus systemic heparin anticoagulation for superior sagittal sinus thrombosis. Stroke 2001; 32:2310-2317. 89. Barnwell SL, Nesbit GM, Clark WM: Local thrombolytic therapy for cerebrovascular disease: current Oregon Health Sciences University experience (July 1991 through April 1995). J Vasc Interv Radiol 1995; 6(6, Pt 2 Su):78S-82S. 90. Rottger C, Madlener K, Heil M, et al: Is heparin treatment the optimal management for cerebral venous thrombosis? Effect of abciximab, recombinant tissue plasminogen activator, and enoxaparin in experimentally induced superior sagittal sinus thrombosis. Stroke 2005; 36:841-846. 91. Curtin KR, Shaibani A, Resnick SA, et al: Rheolytic catheter thrombectomy, balloon angioplasty, and direct recombinant tissue plasminogen activator thrombolysis of dural sinus thrombosis with preexisting hemorrhagic infarctions. AJNR Am J Neuroradiol 2004; 25:1807-1811. 92. Opatowsky MJ, Morris PP, Regan JD, et al: Rapid thrombectomy of superior sagittal sinus and transverse sinus thrombosis with a rheolytic catheter device. Am J Neuroradiol 1999; 20:414-417. 93. Dowd CF, Malek AM, Phatouros CC, et al: Application of a rheolytic thrombectomy device in the treatment of dural sinus thrombosis: a new technique. Am J Neuroradiol 1999; 20:568570. 94. Baker MD, Opatowsky MJ, Wilson JA, et al: Rheolytic catheter and thrombolysis of dural venous sinus thrombosis: a case series. Neurosurgery 2001; 48:487-493. 95. Scarrow AM, Williams RL, Jungreis CA, et al: Removal of a thrombus from the sigmoid and transverse sinuses with a rheolytic thrombectomy catheter. Am J Neuroradiol 1999; 20:1467-1469. 96. Chaloupka JC, Mangla S, Huddle DC: Use of mechanical thrombolysis via microballoon percutaneous transluminal angioplasty for the treatment of acute dural sinus thrombosis: case presentation and technical report. Neurosurgery 1999; 45:650-656. 97. Chow K, Gobin YP, Saver J, et al: Endovascular treatment of dural sinus thrombosis with rheolytic thrombectomy and intra-arterial thrombolysis. Stroke 2000; 31:14201425. 98. Gomez CR, Misra VK, Terry JB, et al: Emergency endovascular treatment of cerebral sinus thrombosis with a rheolytic catheter device. J Neuroimaging 2000; 10:177-180. 99. Baker MD, Opatowsky MJ, Wilson JA, et al: Rheolytic catheter and thrombolysis of dural venous sinus thrombosis: a case series. Neurosurgery 2001; 48:487-493; discussion, 493494. 100. Ekseth K, Bostrom S, Vegfors M: Reversibility of severe sagittal sinus thrombosis with open surgical thrombectomy combined with local infusion of tissue plasminogen activator: technical case report. Neurosurgery 1998; 43:960965. 101. Chahlavi A, Steinmetz MP, Masaryk TJ, et al: A transcranial approach for direct mechanical thrombectomy of dural sinus thrombosis: report of two cases. J Neurosurg 2004; 101:347351. 102. Preter M, Tzourio C, Ameri A, et al: Long-term prognosis in cerebral venous thrombosis: follow-up of 77 patients. Stroke 1996; 27:243-246. 103. Ferro JM, Lopes MG, Rosas MJ, et al: Long-term prognosis of cerebral vein and dural sinus thrombosis: results of the VENOPORT study. Cerebrovasc Dis 2002; 13:272278. 104. Ferro JM, Lopes MG, Rosas MJ, et al: Delay in hospital admission of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2005; 19:152-156.
chapter 46 cerebral venous thrombosis 105. Breteau G, Mounier-Vehier F, Godefroy O, et al: Cerebral venous thrombosis 3-year clinical outcome in 55 consecutive patients. J Neurol 2003; 250:29-35. 106. Brill-Edwards P, Ginsberg JS, Gent M, et al: Safety of withholding heparin in pregnant women with a history of venous
633
thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med 2000; 343:1439-1444. 107. Stolz E, Trittmacher S, Rahimi A, et al: Influence of recanalization on outcome in dural sinus thrombosis: a prospective study. Stroke 2004; 35:544-547.
CHAPTER
47
VASCULAR DEMENTIA ●
●
●
●
Gustavo C. Román
Cerebrovascular disease constitutes a well-defined cause of dementia first recognized by Sir Thomas Willis in 1672 under the name postapoplectic dementia. Vascular dementia is considered the second major cause of dementia in elderly persons, after Alzheimer’s disease, representing 15% to 20% of all cases of dementia worldwide.1,2 Furthermore, it has been recognized that cerebrovascular disease may serve as a catalyst for converting low-grade Alzheimer’s disease to clinical dementia. The diagnosis of vascular dementia is relatively straightforward, particularly in cases with abrupt loss of cognitive functions after stroke or in individuals with a genetic history of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).3 The diagnosis may be less obvious in very old patients, in whom cerebrovascular disease and degenerative pathology (neurofibrillary tangles, amyloid deposits, Lewy bodies) may coexist. However, even in these cases of so-called mixed dementia, the contribution of the vascular pathology seems to outweigh the age-associated degenerative pathology. Moreover, vascular dementia is usually unrecognized in patients in whom cerebral hypoperfusion complicates cardiac failure and circulatory diseases. Judicious treatment of vascular risk factors at population level may lessen the predicted epidemic increase of dementia among elderly persons.
Diagnostic Criteria In most controlled trials in vascular dementia, investigators have used the clinical criteria proposed by Román and colleagues4 on behalf of the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN criteria). Most cases of acute poststroke vascular dementia fulfill criteria for probable vascular dementia, modified as follows:5 1. There is acute onset of dementia, demonstrated by executive dysfunction causing loss of functional independence. 2. Relevant cerebrovascular lesions are demonstrated by neuroimaging. 3. A temporal relation between stroke and cognitive loss is evident. This last criterion usually cannot be fulfilled in subacute forms of vascular dementia.
Vascular Cognitive Disorder Numerous diseases and syndromes can produce a vascular cognitive disorder.5 Table 47–1 provides a comprehensive list of potential causes of vascular cognitive disorder.
DEFINITIONS Vascular Cognitive Impairment Vascular Dementia Vascular dementia is an etiological category of dementia characterized by severe cognitive impairment resulting from ischemic or hemorrhagic stroke or from hypoperfusion affecting brain regions important for memory, cognition, and behavior. Vascular dementia is most frequently caused by the following lesions: 1. Hypoperfusive lesions such as global or selective ischemia, border-zone infarcts, and incomplete white matter ischemia. 2. Ischemic lesions involving large or small vessels: strategic single strokes, multi-infarct dementia (MID), small-vessel disease, lacunes, and venous occlusions.
This term designates a wide range of severity of cognitive alterations of vascular nature. However, the term is preferably restricted to cases of vascular cognitive impairment without dementia (vascular mild cognitive impairment).5
EPIDEMIOLOGY In some of the most heavily populated regions of the world— including China, Japan, India, and Mexico—a vascular etiology is the most frequent cause of dementia. As the population in most of the world ages, likely increases in stroke and heart disease associated with old age will render vascular dementia the most frequent cause of dementia worldwide.
635
636
Section
T A B L E 4 7 – 1. Primary vascular causes or hypoperfusion
Hemorrhage
Embolic causes
Hematologic disorders
Toxic causes
IX
C e r e b r o va s c u l a r D i s e a s e
Potential Etiologies of the Vascular Cognitive Disorder Amyloidosis angiopathy Arterial dissection Atherosclerosis of large or mid-sized arteries Cardiopulmonary arrest Diabetes mellitus Dural arteriovenous malformation Fibromuscular dysplasia Giant cerebral aneurysm with compression Hyperlipidemia Hypertensive arteriolosclerosis Moyamoya disease Recurrent hypotension with syncope Vasospasm/migraine Amyloid angiopathy Aneurysms Arteriovenous malformations Cavernous angioma Charcot-Bouchard aneurysm CNS hemosiderosis with recurrent bleeding Hematologic bleeding diathesis Hemorrhagic transformation of infarction Hypertension Neoplasm (glioblastoma or metastatic) Pharmacologic (e.g., anticoagulants) Posthemorrhagic normal-pressure hydrocephalus Telangiectasis Vasculitis Venous angioma Venous thrombosis Atherosclerotic stenosis with embolization Atrial fibrillation Atrial myxoma Cardiac surgery, including CAGB Cardiomyopathy Congenital heart disease Libman-Sacks endocarditis Marantic endocarditis Mitral valve prolapse syndrome Myocardial infarction with mural thrombus Nitrogen bubble emboli Prosthetic valves Rheumatic endocarditis and valvulopathies Septal defect with paradoxical emboli Septic, air, or fat emboli Subacute bacterial endocarditis Antiphospholipid/anticardiolipin antibodies Antithrombin III deficiency Arylsulfatase A pseudodeficiency Cryoglobulinemia Disseminated intravascular coagulation Dysfibrinogenemias Dysproteinemias Factor V Leyden mutation Factors V, VII, XII, and XIII deficiencies Hemoglobinopathies (e.g., sickle cell disease) Heparin cofactor II deficiency Hyperviscosity syndromes Idiopathic thrombocytosis Leukemias Nephrotic syndrome Polycythemia vera Pregnancy and oral contraceptives Protein C or S deficiency Thrombotic thrombocytopenic purpura Waldenström’s macroglobulinemia Amphetamines Arsenic Carbon monoxide Cocaine or crack Ergot alkaloids Oral contraceptives Radiation-induced vasculopathy
Noninfectious inflammatory or autoimmune causes
Infectious causes of stroke
Genetic causes
Allergic or hypersensitivity angiitis Anticardiolipin or antiphospholipid antibodies Behçet’s syndrome Burgher’s disease Cogan’s syndrome Dermatomyositis-polymyositis Disseminated neocortical and subcortical encephalopathies Drug-induced vasculitis Endocardial fibroelastosis Henoch-Schönlein purpura (radiation, tumor) Kawasaki syndrome Köhlmeier-Degos disease Lupus anticoagulant Polyarteritis nodosa Primary CNS vasculitis Relapsing polychondritis Rheumatoid arthritis with arteritis Sarcoidosis Scleroderma Sjögren’s syndrome Systemic lupus erythematosus Takayasu’s arteritis Temporal (giant cell) arteritis Thromboangiitis obliterans Thrombotic microangiopathy Ulcerative colitis Vogt-Koyanagi-Harada syndrome Wegener’s granulomatosis AIDS Bacterial meningitis with arteritis Cat-scratch disease Cysticercosis Herpes zoster ophthalmicus Lyme disease Meningovascular infectious arteritis Parasites and ova Rickettsial arteritis Syphilis Tuberculosis Viral arteritis Yeast and fungal arteritis 11β-hydroxylase deficiency 11β-ketoreductase deficiency 17α-hydroxylase deficiency Antithrombin III deficiency β-Thalassemia major Bannayan-Zonana syndrome Bloom’s syndrome CADASIL Chronic familial cerebral vasculopathy Cockayne’s syndrome Dysfibrinogenemia Ehlers-Danlos syndrome, especially type IV Fabry’s disease Factors VII to XIII deficiencies Familial atrial myxoma Familial cavernous angioma Familial hemiplegic migraine Familial hypercholesterolemia Familial hypoalphalipoproteinemia Familial intracranial aneurysm Familial oculoleptomeningeal amyloidosis Familial porencephaly Familial triglyceridemia Fibromuscular dysplasia Hemoglobin SC Heparin cofactor II deficiency Hereditary arteriovenous malformations Hereditary cardiac conduction disorder Hereditary cardiomyopathies Hereditary cerebral amyloidosis
chapter 47 vascular dementia T A B L E 4 7 – 1. Genetic causes (cont’d)
637
Potential Etiologies of the Vascular Cognitive Disorder—cont’d Hereditary platelet defect (Wiskott-Aldrich syndrome) Hereditary polycythemia Homocystinuria Hyperlipoproteinemia (types III and IV) Klippel-Trénaunay-Weber syndrome Leigh’s disease Marfan syndrome MELAS syndrome Menkes’ syndrome Methylmalonic, propionic, and isovaleric acidemia; glutamic aciduria type I Mitral valve prolapse Moyamoya disease Neurofibromatosis Plasminogen deficiency Progeria
Miscellaneous causes
Prekallikrein deficiency Protein C or protein S deficiency Pseudoxanthoma elasticum Rendu-Osler-Weber syndrome Rhabdomyomas Sickle-cell disease Sturge-Weber syndrome Sulfite oxidase deficiency Tangier disease Tuberous sclerosis Von Hippel–Lindau syndrome Metastatic deposits Neoplastic anagioendotheliosis Sneddon’s syndrome Spatz-Lindenberg disease Susac’s disease
Modified From Mendez MF, Cummings JL: Dementia: A Clinical Approach, 3rd ed. Philadelphia: Butterworth-Heinemann (Elsevier Science), 2003. AIDS, acquired immunodeficiency syndrome; CABG, coronary artery bypass graft; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS, central nervous system; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike symptoms (syndrome).
Prevalence Jorm and Jolley6 performed a meta-analysis of 47 international studies on the prevalence of vascular dementia and found the following consistent trends: 1. Age-specific rates: Vascular dementia increases exponentially with age. Prevalence rates double after age 70 with every 5.3year increase in age (in comparison with 4.5-year increases for Alzheimer’s disease), ranging from 1.5% at ages 70 to 75 years to 14% to 16.3% at ages 80 years and older. 2. Gender distribution: Vascular dementia is more common in men, especially before age 75. 3. Geographic (racial) variation: Vascular dementia is more prevalent in Asian, black, and Hispanic populations than in white populations. Hypertensive small-vessel disease is particularly common in the former groups.
Incidence Incidence data for vascular dementia are quite limited. Dubois and Herbert2 used age-standardized incidence ratios to analyze data from 10 incidence studies of vascular dementia. These ratios ranged from 0.42 to 2.68, confirming the geographic and racial variations of vascular dementia.
CLINICAL FEATURES Despite the apparent complexity of vascular dementia, the clinical diagnosis may be simplified into two major groups, acute and subacute, according to the temporal profile of presentation (Table 47–2).
Acute Forms of Vascular Dementia In acute forms, patients exhibit new-onset dementia after a vascular event (cerebral hemorrhage, ischemic “strategic” stroke). For instance, occlusion of the left posterior parietal branch of
the middle cerebral artery that damages the supramarginal gyrus usually produces cortical sensory loss, Wernicke’s aphasia, and Gerstmann’s syndrome with right-left disorientation, finger agnosia, acalculia, and agraphia.
Multi-infarct Dementia MID results from multiple cortical strokes; about one third (range, 25% to 41%) of all ischemic stroke survivors aged 65 years and older may develop vascular dementia.7,8 This represents about 125,000 new cases per year of poststroke vascular dementia in the United States. Table 47–3 lists the most important risk factors for poststroke vascular dementia.
Strategic Strokes Single ischemic strokes in three possible vascular territories— the posterior cerebral artery, anterior cerebral artery, and thalamus-basal ganglia—may produce vascular dementia.
Posterior cerebral artery infarctions involving the ventralmedial temporal lobe, occipital structures, and thalamus About 25% of affected patients develop amnesia from damage of the hippocampus-mammillothalamic-cingulum circuit. Leftsided lesions cause verbal amnesia, whereas right-sided lesions alter visuospatial (location) memory; bilateral damage causes global amnesia. Visual signs (homonymous hemianopsia, color agnosia, visual agnosia) occur in 80% or more of patients with posterior cerebral artery strokes. Left-sided lesions may produce transcortical sensory aphasia, or alexia without agraphia. Spatial disorientation occurs with right-sided lesions and Anton’s syndrome (cortical blindness with anosognosia) with bilateral occipital lesions. Bilateral parieto-occipital infarctions above the calcarine fissure may result in Balint’s syndrome (inability to direct the eyes to a certain point in the visual field) with simultagnosia, optic ataxia, and ocular apraxia.
638
Section
T A B L E 4 7 – 2.
IX
C e r e b r o va s c u l a r D i s e a s e
Clinical Forms of Vascular Dementia According to Temporal Pattern of Presentation
Acute Forms 1. Posterior forms caused by lesions in the territory of the PCA, inferomedial temporal lobes, hippocampus, thalamus Clinical features Amnesia, visual disturbances (homonymous hemianopsia, color agnosia, visual agnosia) Left-sided lesions: transcortical sensory aphasia, alexia without agraphia Right-sided lesions: spatial disorientation Bilateral occipital lesions: Anton’s syndrome Bilateral parieto-occipital lesions: Balint’s syndrome 2. Lesions in the ACA territory and medial frontal lobe Lesions Ruptured AComA aneurysm or proximal ACA Clinical features Severe anterograde amnesia for verbal or visuospatial material Severe apathy Lack of initiative and spontaneity Executive dysfunction 3. Thalamus and basal ganglia a. Thalamic dementia Lesions Anterior (polar) thalamic territories (polar thalamic artery, from PComA) DMn or mammillothalamic tract Clinical features Impairments of attention, motivation, initiative, executive functions, and memory Verbal and motor slowness and apathy Vertical gaze paresis, medial rectus paresis, and absent convergence; dysarthria and mild hemiparesis b. Inferior genu stroke Lesions Lacune in inferior genu of internal capsule Inferior capsular genu stroke, producing diaschisis of frontal lobes and cerebellum Clinical features Sudden change in cognition Fluctuating attention Confusion Abulia Striking psychomotor retardation Inattention Executive dysfunction Mild to absent focal findings such as hemiparesis or dysarthria 4. Multi-infarct dementia Lesions may involve posterior association areas such as the gyrus angularis, PCA territories, watershed or border-zone areas (superior frontal and parietal regions), bilateral ACA territories, anterior choroidal artery, basal forebrain, and frontal white matter lesions Subacute Forms 1. Subcortical ischemic vascular dementia (SIVD) Lesions Small-vessel disease with presence of white matter ischemic lesions and lacunae in basal ganglia and white matter Clinical features Subacute onset, chronic course, fluctuations, and progressive worsening Subcortical-type dementia, frontal lobe deficits, depressive mood, psychomotor slowing, parkinsonian features, pseudobulbar palsy, urinary urgency Main forms of SIVD: Binswanger’s disease, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and some types of cerebral amyloid angiopathy ACA, anterior cerebral artery; AComA, anterior communicating artery; DMn, dorsomedial nucleus of the thalamus; PCA, posterior cerebral artery; PComA, posterior communicating artery.
Anterior cerebral artery territory and medial frontal lobe lesions Ischemic injury of cholinergic nuclei in the basal forebrain may occur with subarachnoid hemorrhage from ruptured aneurysms of the anterior communicating artery or proximal anterior cerebral artery, usually after surgical repair. Such hemorrhage leads to severe anterograde amnesia, apathy, and executive dysfunction.
Lesions of the thalamus and basal ganglia Thalamic dementia occurs after paramedian thalamic ischemic strokes. The lesions involve the anterior thalamus, which is irrigated by the polar thalamic artery, a branch of the posterior communicating artery, or the medial and central thalamus, involving the dorsomedial nucleus and the mammillothalamic
tract. Damage of the mammillothalamic tract is critical in thalamic amnesia. Patients are initially unresponsive but improve over days to weeks, revealing impairments in attention, motivation, initiative, executive functions, and memory; verbal and motor slowness; and apathy. Gaze abnormalities include vertical gaze, medial rectus paresis, and absence of convergence. Dysarthria and mild hemiparesis occur with larger lesions. Left-sided thalamic lesions cause memory deficits more often than do right-sided ones. Global amnesia occurs with bilateral lesions or with simultaneous damage to the mammillothalamic tract and inferior thalamic peduncle. Severe attentional and motivational deficits play roles in the amnesia. Inferior genu stroke is a lacunar infarction of the inferior genu of the internal capsule, manifested by sudden change in cognitive function, often in association with fluctuating attention, confusion, abulia, striking psychomotor retardation, inat-
chapter 47 vascular dementia T A B L E 4 7 – 3. Vascular Dementia Age Education Personal factors Genetic factors Stroke type Stroke location Stroke volume
Stroke complications Stroke manifestations
Main Risk Factors for Poststroke Older age Lower educational level Lower income, current smokers Family history of dementia Recurrent strokes Left-sided lesions, “strategic strokes” Lesions larger than 50-100 mL of tissue destruction, large perilesional incomplete ischemic areas involving white matter, larger periventricular white matter ischemic lesions Hypoxic and ischemic complications of acute stroke (i.e., seizures, cardiac arrhythmias, aspiration pneumonia, hypotension) Dysphagia, gait limitations, urinary impairment
tention, executive dysfunction, and other features of frontal lobe dysfunction but with mild focal findings such as hemiparesis or dysarthria. These deficits are caused by ipsilateral blood flow reduction to the inferomedial frontal cortex, ipsilateral temporal lobe, and contralateral cerebellar hemisphere by a mechanism of diaschisis. Severed pathways that contain cholinergic fibers from the nucleus basalis of Meyner may have an effect in reducing blood flow.
Basal ganglia lacunes Neuropsychological deficits occur in up to 34% of patients with lacunes in the territory of deep middle cerebral artery perforators.
Caudate nucleus lesions Rare cases of vascular dementia have been reported after infarction of the caudate nucleus.
639
ponding thalamocortical connections. Many strokes in this common type of vascular dementia are clinically silent; that is, they do not appear with the usual sensorimotor manifestations associated with stroke but with changes in personality, mood, behavior, or cognition. Therefore, brain imaging (computed tomography/magnetic resonance imaging) is crucial for correct diagnosis. The main forms of SIVD are Binswanger’s disease, CADASIL, lacunar dementia (lacunar state, or état lacunaire) with multiple lacunes and extensive perifocal incomplete infarctions or with abundant microinfarctions, and some types of cerebral amyloid angiopathy.
Binswanger’s Disease The hallmark of this condition is an ischemic periventricular leukoencephalopathy that typically spares the arcuate subcortical U fibers. These periventricular, distal-territory, white matter lesions in the elderly brain are caused by chronic ischemia with incomplete infarction. Small-vessel disease and multiple lacunes often coexist in Binswanger’s disease. Clinical manifestations include a subcortical dementia with cognitive and motor executive dysfunction, loss of verbal fluency, perseveration, impersistence, inattention, difficulties with set shifting, and abnormal performance on Luria’s kinetic melody tests. Memory loss is characterized by poor retrieval and intact recognition. Apathy, depression, and behavioral problems are common. Mild residual hemiparesis, discrete focal findings, and short-stepped gait (marche à petits pas), dysarthria, and pseudobulbar palsy are common. Extrapyramidal features, such as inexpressive facies, slowness of movement, axial rigidity, loss of postural reflexes, frequent falls, increased urinary frequency, and nocturia are also common findings. Brain T2-weighted magnetic resonance imaging findings include extensive hyperintense lesions in the periventricular regions with frontal and parietal preponderance.
CADASIL Subacute Forms of Vascular Dementia Subcortical ischemic vascular dementia (SIVD) refers to forms of vascular dementia characterized by subacute onset, caused by small-vessel disease that produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter as a result of critical stenosis of medullary arterioles and hypoperfusion (Binswanger’s disease).7 The term subcortical refers both to the location of lesions that involve predominantly basal ganglia, cerebral white matter, and brainstem and to their manifestations with preponderant executive dysfunction (subcortical dementia as opposed to cortical dementia). The main mechanism of dementia causation in SIVD is ischemic brain injury; this label includes both complete infarction (mainly lacunar strokes and microinfarcts) as well as incomplete infarction of deep cerebral white matter. The temporal profile is typically subacute, with a chronic course marked by fluctuations and slowly progressive worsening. This subcortical type of dementia is manifested by motor and cognitive executive function slowing, forgetfulness, dysarthria, mood changes, pseudobulbar palsy, urinary symptoms, parkinsonian features, and short-stepped gait. Manifestations probably result from ischemic interruption of parallel circuits from prefrontal cortex to basal ganglia and corres-
This genetic form of vascular dementia was first identified in France in 1991.3 CADASIL is a systemic autosomal dominant arteriopathy caused by mutations of the Notch3 gene in chromosome 19.8 The vascular lesion shows fragmentation of the internal elastica and eosinophilic deposits in media. Electron microscopy reveals typical granular osmiophilic material in the basement membranes of vascular smooth muscle cells of arterioles (100 to 400 μm in diameter) and in capillaries, primarily in the brain but also in other organs. The diagnosis may be established by genetic studies and by skin biopsy with confirmation by immunostaining with a Notch3 monoclonal antibody. Neuropathology examination demonstrates lacunar strokes associated with extensive, confluent areas of frontal ischemic leukoencephalopathy. Clinically, CADASIL is a subcortical vascular dementia identical to Binswanger’s disease. Onset is early for stroke (mean age, 46 years) with recurrent transient ischemic attacks or lacunar strokes, in the absence of vascular risk factors, culminating in vascular dementia and death, usually about 20 years after onset. Migraine with aura and depression are common. The dementia is subcortical, frontal, and accompanied by gait disturbances, urinary incontinence, and pseudobulbar palsy. Magnetic resonance imaging shows
640
Section
IX
C e r e b r o va s c u l a r D i s e a s e
striking white matter changes with a typical predilection for the temporal lobes, along with lacunar strokes, in both symptomatic and asymptomatic members of families affected by CADASIL.
Hypertension
Risk factor
Arteriolosclerosis
Resultant cerebrovascular disease
PATHOLOGY AND PATHOPHYSIOLOGY The main mechanism of production of vascular dementia is ischemic brain injury, occurring as the result of either vascular occlusion or hypoperfusion. From the neuropathological viewpoint, ischemia includes both complete and incomplete infarctions.
Occlusion
Hypoperfusion
Cause of ischemia
Complete infarct
Incomplete infarct
Type of brain injury
Lacune
White matter signal hyperintensities
Lesion on MRI
Complete Infarctions These are typical embolic or atherothrombotic large-vessel ischemic infarcts involving well-defined arterial territories, cortical or cortical-subcortical in location, usually with perifocal incomplete white matter infarction. Small-vessel occlusion causes lacunes and microinfarcts.
Lacunar Infarcts Lacunes (Latin lacuna, plural lacunae: a minute cavity, hole, or pit) are small cavitating ischemic infarcts, less than 15 mm in diameter, typically located in the basal ganglia, internal capsule, thalamus, pons, corona radiata, and centrum semiovale. White matter lacunes may overlap with nonconfluent areas of ischemic white matter changes.
Microinfarcts These are minute areas of ischemic infarction, not visible to the naked eye and not visualized with current imaging techniques, ranging from a few microns to about one tenth the size of lacunes. They are usually noncavitated and found in cortical and subcortical structures.
Incomplete Infarctions These lesions are caused by hypoperfusion9 and typically affect watershed territories such as the CA1 sector of the hippocampus; the cortex posterior to the interparietal sulcus or the central white matter between deep territories at the boundaries between the anterior cerebral artery and middle cerebral artery in cases of extracranial internal carotid artery occlusion; and the periventricular white matter fed by long-penetrating endarterioles, as in Binswanger’s disease. White matter lesions include diffuse myelin pallor that spares the U fibers, astrocytic gliosis, loss of oligodendrocytes progressing to rarefaction, spongiosis (vacuolization), widening of perivascular spaces (état criblé), with myelin and axonal loss but without definite necrosis (incomplete white matter infarction) that culminates in necrosis and cavitations (lacunes). Pure incomplete white matter infarction, similar to that observed in the penumbra of large infarcts, is typically seen in hypoperfusive disease. Figures 47–1 and 47–2 illustrate the two main pathophysiological pathways leading to the aforementioned ischemic lesions:
Lacunar state ■
Binswanger’s disease
Clinical syndrome
Figure 47–1. Two pathophysiological pathways of ischemic brain injury. The pathway on the left is initiated by occlusion of an arterial lumen. This leads to discrete areas of complete infarction (i.e., lacunar infarcts) and functional disruption within a distributed network (e.g., dementia). The pathway on the right is defined by critical stenosis and hypoperfusion involving multiple small arterioles mainly in deep white matter. These two pathways often coexist in the same patient. MRI, magnetic resonance imaging. (From Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002; 1:426-436.)
1. Occlusion of the arteriolar lumen leads to lacunes and the lacunar state (état lacunaire). 2. Critical stenosis and hypoperfusion of multiple penetrating medullary arterioles causes widespread incomplete infarction of deep white matter in Binswanger’s disease. Table 47–4 summarizes important physical principles and pathophysiological mechanisms relevant to the microcirculation in SIVD; these include hemorheological factors, increased resistance to flow, decreased autoregulation, endothelial changes, blood-brain barrier dysfunction, and dilatation of perivascular spaces. Their combined effects result in hypoperfusion and incomplete infarction of deep white matter. Earlier concepts of MID required the loss of more than 50 to 100 mL of brain tissue from ischemia. Stroke location appears to be equally important. In fact, small lesions in strategic areas are capable of causing vascular dementia by interrupting memory and behavioral circuits, such as the prefrontal–basal ganglia–thalamocortical loops that are crucial for executive function and independent living.
DIAGNOSIS In practical terms, the diagnosis of vascular dementia should be suspected in patients with significant vascular risk factors, stroke, or heart disease who exhibit abrupt changes in cognition. Brain imaging demonstrating the presence of relevant lesions of cerebrovascular disease is crucial for the diagnosis of vascular dementia. Most of the diagnostic difficulties in vascular dementia occur with the subacute, slowly progressive forms of vascular dementia that, in the opinion of some clinicians,
chapter 47 vascular dementia
Ischemia
■
Hypoperfusion
Occlusion
Incomplete white matter infarction
Lacunar stroke
Figure 47–2. Factors leading to brain ischemia and hypoperfusion in elderly people. Striking age-dependent morphological changes in brain vessels include tortuosity with formation of skeins in cortical arterioles (A) and elongation, which results in loops and tangles (B), particularly of long penetrating arterioles supplying deep white matter. Increase in blood vessel length raises the blood pressure threshold for perfusion of periventricular white matter at the distal ends of the these vessels. Furthermore, the lumen is stenosed by senile concentric arteriolosclerosis (D), often with calcification of vessels (C, top right). Under normal conditions, autoregulatory mechanisms induce vasodilation in response to decreases in mean arterial perfusion pressure; these mechanisms become inoperative in patients with arteriolosclerosis and calcified vessels (C). The elderly brain is therefore more susceptible to hypotension and pump failure (cardiac arrhythmias and congestive heart failure). Delivery of oxygen to tissues and other metabolic exchanges are impeded by increased thickness of vessel walls (D) and widespread widening of perivascular spaces (état criblé) (C) with enlargement of perivascular spaces of Virchow-Robin, which results from tortuosity of elongated arterioles. (A from Duvernoy HM, Delon S, Vanson JL: Cortical blood vessels of the human brain. Brain Res Bull 1981; 7:519-579. B to D from GC Román: Vascular dementia. In Fisher M, ed: Clinical Atlas of Cerebrovascular Disorders. London: Wolfe/Mosby–Year Book Europe, 1994, pp 13.1-13.23.)
could be confused with Alzheimer’s disease. A closer look at these subcortical forms of vascular dementia reveals significant differences, as listed in Table 47–5.
641
chomotor performance in SIVD. Of the neuroprotective or nootropic agents, piracetam, oxiracetam, and nicergoline appear to be modestly effective for the MID form of vascular dementia. Citicoline showed positive short-term effects on memory and behavior in patients with vascular dementia. In the multicenter European Pentoxifylline Multi-Infarct Dementia Study,10 pentoxifylline, a xanthine derivative with hemorheological and immunomodulatory properties, produced significant cognitive improvement in MID, in comparison with placebo. Pentoxifylline is useful in Binswanger’s disease, improving hyperviscosity, sedimentation rate, hyperfibrinogenemia, and increased acute-phase reactants (tumor necrosis factor α). Currently, the most promising therapies for vascular dementia and vascular cognitive impairment include the cholinesterase inhibitors donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), as well as the N-methylD-aspartate (NMDA)–glutamate receptor antagonist memantine. Cholinesterase inhibitors, approved for the treatment of Alzheimer’s disease, appear to be an effective and safe alternative for patients with vascular dementia.11
PREVENTION Age, gender, ethnicity, and genetic makeup are nonmodifiable risk factors for stroke. However, a number of risk factors for vascular dementia (Table 47–6) can be prevented. Primary prevention is directed to the control of vascular risk factors in an effort to prevent stroke, ischemic heart disease, and vascular dementia. Secondary prevention addresses prevention of further ischemic episodes.
Primary Prevention Treatment of hypertension appears to decrease the incidence of dementia. Other treatable risk factors include diabetes mellitus, the metabolic syndrome, raised homocysteine level, and smoking. Homocysteine is lowered with oral folate and parenteral vitamin B12 supplementation. The beneficial cardiovascular effects of a Mediterranean diet rich in fruits and antioxidants have been well documented. Statins (3-hydroxy-3methylglutaryl–coenzyme A [HMG-CoA] reductase inhibitors) may reduce dementia risk, but its use in nondemented, nonhyperlipidemic patients cannot currently be recommended.
Secondary Prevention TREATMENT Recently, a number of treatment trials in patients with vascular dementia were successfully completed. Despite progress, there are no approved drugs for symptomatic treatment of vascular dementia. The antiplatelet agents aspirin, triflusal, and Ginkgo biloba have been used in patients with MID or with Alzheimer’s disease plus cerebrovascular disease, with modest results, mainly by decreasing vascular dementia progression by lowering the risk of recurrent stroke. Vasodilators have no proved effects on vascular dementia, except for niacin, which has lipid-lowering effects. The calcium-channel blockers nimodipine and nicardipine have moderate efficacy in tests of attention and psy-
Optimal management of acute stroke and swift implementation of secondary prevention are mandatory to prevent vascular dementia. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),12 blood pressure lowering in patients with previous stroke or transient ischemic attack reduced the incidence of secondary stroke by 28%, that of major vascular events by 26%, and that of major coronary events by 26%. These reductions were all magnified by approximately 50% in a subgroup of patients in whom the angiotensin-converting enzyme inhibitor perindopril was routinely combined with the diuretic indapamide. This combination alone could reduce the burden of stroke and could avert between 0.5 million and 1 million strokes each year worldwide.
642
Section
IX
C e r e b r o va s c u l a r D i s e a s e
T A B L E 4 7 – 4. Relevant Hemorheological and Autoregulatory Circulatory Factors in White Matter Hypoperfusion Hemorheological Factors O2 delivery to tissues depends on blood flow and red cell concentration. The rate of blood flow through a tubular vessel is determined by Poiseuille’s law: Blood flow = perfusion pressure · π · radius4/8 · η · length Blood flow declines as the length of the vessel increases and its radius decreases. A salient feature of the equation is the overriding influence of vessel radius (π · radius4). In vessels with small, fixed radius, such as in small-artery disease, the flow of blood is determined mainly by systolic blood pressure and by blood viscosity (η); i.e., by the force or “shear stress” required to overcome the resistance of the tube wall to the fluid at a given flow velocity. Blood is a nonhomogenous and nonnewtonian fluid; i.e., viscosity increases at low velocities in the arteriolar bed and microcirculation. Inside vessels affected by arteriolosclerosis; the resulting hyperviscosity may slow or halt blood flow. In arterioles, there is disproportionate increase of blood viscosity with increases in hematocrit, plasma viscosity, red blood cell deformability, hyperglycemia, and hyperlipidemia. Autoregulatory Changes Because of anatomical features, local cerebral blood flow is lowest in periventricular and deep white matter regions perfused by long, narrow, no-collateral end-arterioles. Perfusion threshold for ischemic injury increases if hypoperfusion persists over longer periods of time. With autoregulation, when cerebral perfusion pressure falls, blood vessels dilate increasing blood volume and initially maintaining regional cerebral blood flow (rCBF). When blood flow starts to decline, oxygen extraction fraction (OEF) increases to maintain cerebral oxygen metabolism (rCMRO2): rCMRO2 = OEF * arterial oxygen content * rCBF When failing perfusion pressure exceeds compensatory mechanisms, oxygen metabolism is compromised. Neuronal-glial function is lost, followed by irreversible necrosis. In infarcted tissue, both CMRO2 and OEF values are minimal. Thus, increased OEF is a transitional phenomenon, signaling a critical period of incipient ischemia. From Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002;1:426-436.
T A B L E 4 7 – 5. Important Feature Differences between Subcortical Vascular Dementia and Alzheimer’s Disease Clinical Feature
Alzheimer’s Disease
Vascular Dementia
Memory loss Language disorder Gait Falls Executive dysfunction Mood and personality Urinary problems Onset Progression
Early, severe amnesia Early aphasia Normal Rare Late Intact Late incontinence Slow Rapid
Forgetfulness, poor recall Loss of verbal fluency, dysarthria Abnormal, marche à petits pas Frequent Early and severe Changes: apathy, depression, crying spells Urgency, nocturia Abrupt Slow, stepwise, fluctuating
T A B L E 4 7 – 6.
Risk Factors for Vascular Dementia
Advanced age Long-term, untreated arterial hypertension Isolated systolic hypertension in elderly patients Diabetes mellitus Cigarette smoking Hyperlipidemia Hyperhomocysteinemia Hyperfibrinogenemia Congestive heart failure Atrial fibrillation Carotid disease Other cardiac arrhythmias Complicated stroke Recurrent stroke Orthostatic hypotension Obstructive sleep apnea Major surgery in elderly patients Coronary artery bypass graft (CABG) surgery
chapter 47 vascular dementia In brief, control of blood pressure in the general population could significantly decrease the social and economic burdens of dementia in years to come.
643
Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002; 1:426-436.
References
K E Y
P O I N T S
●
With aging of the world population, cardiovascular disease and stroke will increase steadily. For this reason, the incidence of dementia resulting from cerebrovascular disease will also rise. Vascular dementia is predicted to become the most common cause of cognitive decline in elderly persons.
●
Vascular dementia may result not only from large-vessel strokes (multi-infarct dementia) but also from ischemic lesions caused by small-vessel pathology, including lacunar strokes and incomplete white matter ischemia (subcortical ischemic vascular dementia), as well as from hypoperfusion caused by heart disease or circulatory disturbances.
●
Prevention of vascular dementia is achievable both by decreasing the risk of stroke (primary prevention) and by lowering the possibility of recurrent stroke (secondary prevention).
Suggested Reading Bowler JV, Hachinski V, eds: Vascular Cognitive Impairment: preventable Dementia. Oxford, UK: Oxford University Press, 2003. Erkinjuntti T, Román G, Gauthier S, et al: Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke 2004; 35:1010-1017. Paul RH, Cohen R, Ott BR, et al, eds: Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management. Totowa, NJ: Humana Press, 2005. Román GC, ed: Advances in vascular dementia [whole issue]. Semin Cerebrovasc Dis Stroke 2004; 4(2).
1. Lobo A, Launer LJ, Fratiglioni L, et al: Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology 2000; 54(Suppl 5):S4-S9. 2. Dubois MF, Herbert R: The incidence of vascular dementia in Canada: a comparison with Europe and East Asia. Neuroepidemiology 2001; 20:179-187. 3. Bousser MG, Tournier-Lasserve E: Summary of the Proceedings of the First International Workshop on CADASIL. Paris, May 19-21, 1993. Stroke 1994; 25:704-707. 4. Román GC, Tatemichi TK, Erkinjuntti T, et al: Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology 1993; 43: 250-260. 5. Román GC, Sachdev P, Royall DR, et al: Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004; 226:8187. 6. Jorm AF, Jolley D: The incidence of dementia: a meta-analysis. Neurology 1998; 51:728-733. 7. Román GC, Erkinjuntti T, Wallin A, et al: Subcortical ischaemic vascular dementia. Lancet Neurology 2002; 1:426436. 8. Tournier-Lasserve E, Joutel A, Melki J, et al: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 1993; 3:256-259. 9. Román GC: Brain hypoperfusion: a critical factor in vascular dementia. Neurol Res 2004; 26:454-458. 10. European Pentoxifylline Multi-Infarct Dementia Study. Eur Neurol 1996; 36:315-321. 11. Erkinjuntti T, Román G, Gauthier S, et al: Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke 2004; 35:1010-1017. 12. Tzourio C, Anderson C, Chapman N, et al: Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003; 163:1069-1075.
CHAPTER
REHABILITATION ●
●
48
AFTER ●
STROKE
●
Richard Greenwood and Nick Ward
Stroke, or vascular brain injury, has an incidence of between about 1.1 and 2.6 per 1000 adults1 and a prevalence of 5 to 8 per 1000.2 It is a leading cause of chronic disability worldwide; in the United Kingdom, it is the commonest single cause of severe disability in people living at home.3,4 About 75% of affected patients are older than 65 years, and 10% are younger than 55. Each year in England and Wales, stroke occurs in about 10,000 people younger than 55 and 1000 people younger than 30. Six to 12 months after stroke, only 60% of patients with hemiplegic stroke have achieved independence in personal care, and those with sensory or visual field loss are more disabled; 30% to 40% of survivors are depressed, 10% to 15% severely so; 50% need help with either housework, meal preparation, or shopping; and a similar percentage lack a meaningful social, recreational, or occupational activity during the day.5-8 In addition to the personal consequences, the economic consequences of stroke are also enormous; direct health care costs account for approximately 4% of total health care costs, or about £3 billion in the United Kingdom (about $5.3 billion in U.S. dollars) per annum at 2005 prices9; these costs will increase as the population ages. Neuroprotective interventions to reverse the immediate consequences of stroke are not widely applicable.10 In these circumstances, when reversal of pathology is incomplete, the majority of stroke survivors need the multidimensional process termed rehabilitation to enhance their functional activity and societal participation and to reduce the effect of limitations in these areas, so that life quality is improved and life is “worth living.”11 Rehabilitation goals are achieved through the prevention of secondary complications; through facilitation of neural protection, restoration, and substitution; and through functional compensation, which involves both behavioral adaptation and substitution, as well as modification of personal, environmental, and social contextual factors (Table 48–1). This process must also be accompanied by often difficult and less frequently admitted adjustment to loss and change, a need that is easily forgotten in the gym or during a functional imaging study. This chapter explores the delivery and effectiveness of these interventions during rehabilitation after stroke. The high incidence and prevalence of stroke have provided an opportunity to test the effectiveness of many components of the rehabilitation process. Trials have shown convincingly that organized care produces better outcomes than disorganized care; this result has far-reaching implications for health care
systems in general, let alone those focusing on stroke. Many of the areas addressed in this chapter are included in evidenceand expert opinion–based guidelines produced in the United Kingdom by the Royal College of Physicians12 and the Scottish Intercollegiate Guidelines Network,13 in Australia by the National Stroke Foundation,14 and in the United States by the Department of Veterans Affairs and the Department of Defense.15
COMPLEX ORGANIZATIONAL INTERVENTIONS Rehabilitation after single-incident brain injury, including stroke, should be delivered through polymodal inpatient and community-based service delivery systems that differ by structure and process. A classification of these different service options, as a “rehabilitation typology,” remains to be agreed upon, at least cross-culturally, and would facilitate comparisons of different studies.16 The use of each component is determined by a variety of clinical and social factors, including length of time since injury, level of dependency, characteristics of the residual impairment, age of the patient, and resources available.17 Recommendations that different types of care after stroke are incorporated into systems of clinical care (e.g., Schwamm et al18) also emphasize the use of acute and rehabilitation interventions in parallel rather than in series (Fig. 48–1), so that strategies optimizing neural protection acutely are combined with key factors identified in postacute care. The benefits of organized complex polymodal interventions so far reported are likely to reflect mainly the effects of preventing the complications described later in this chapter and shown in Table 48–2, functional interventions that focus on teaching new skills, and the use of aids and appliances and environmental modifications to help patients adapt to their impairments, rather than the effects of neural reorganization. Until about 1995, 20% to 50% of patients after stroke were managed acutely at home in some European countries,19 despite recommendations to the contrary.20 The benefits of stroke unit care and the gradual introduction of thrombolysis and neuroprotective agents are, alone, likely to reduce this percentage dramatically. Furthermore, patients randomly assigned to receive acute care at home after moderately severe stroke (sufficient to cause persistent neurological deficit affecting continence, mobility, and self-care, and necessitating multidisciplinary treatment), rather than to receive care in an acute and
645
646
Section
IX
C e r e b r o va s c u l a r D i s e a s e
rehabilitation stroke unit or a general ward with stroke team support, were significantly more likely at 1 year to be dead or institutionalized (24% versus 14%; P = 0.03) and less likely to be alive without severe disability (85% versus 71%; P = 0.002) than were patients admitted to the stroke unit.21 In their meta-analysis of 23 trials, the Stroke Unit Trialists’ Collaboration22 compared care in stroke units, nine of which were “comprehensive” and included both acute and rehabilitation components, with care given by alternative services, usually in a general medical or geriatric ward with or without a visiting stroke team. The meta-analysis showed that patients who receive unit-based inpatient care do not stay longer in hospital and are more likely to be alive, independent, and living
at home 1 year after the stroke, regardless of gender, age, and stroke severity (Fig. 48–2). Thus, in comparison with alternative services, stroke unit care produced reductions in the odds of death at 1 year (odds ratio, 0.86; 95% confidence interval,
Injury
Rehabilitation A Acute treatments NOT
T A B L E 48–1. Mechanisms of Recovery after Stroke Prevention of Complications Neural Protection, Restoration, and Substitution via Resolution of edema, mass effects, toxic-metabolic dysfunction, and diaschisis Neural regrowth and replacement Reorganization of use-dependent neuronal networks Functional Compensation via Behavioral adaptation and substitution Modification of personal, environmental, and social contextual factors
Acute treatments
B
Rehabilitation
Injury ■
Figure 48–1. Acute treatments focus on neural and systemic protection, whereas rehabilitation involves goal-directed restorative and compensatory training strategies. Both form the basis of practice in postacute stroke rehabilitation units. Optimal outcomes over time (→) are most likely to result from their use in parallel (A), not in series (B).
T A B L E 48–2. Complications after Stroke during Inpatient Rehabilitation and Their Management Cause and Effect
Stroke Unit Frequency % (95% Confidence Interval)
Management
Comorbid Conditions Hypertension/hypotension Cardiac events Fever GI bleed Drug side effects Musculoskeletal pain
15/8199 13199 20199 3196/4199 9198 14198/38197
Antihypertensive/treat cause Specific medical treatments Antipyretics ? Prophylaxis; avoid NSAIDs Drug withdrawal Physical therapies
Physical Dependency Pressure sores Sores and skin breaks Contractures PEs and DVTs Falls Shoulder pain
4198 21 (16-25)195/18196
Pressure care, 24-hr handling and positioning
3 (0-3)195/5198 25 (21-30)195/20256/11198 9 (6-12)195/24256
Thromboprophylaxis Risk assessment Handling and positioning
Neurological Damage Malnutrition and dehydration Chest infections Urinary tract infections Confusion and agitation Epilepsy Sleep-disordered breathing Fatigue
5198 and 10198/10199 22 (18-27)195/4199 23 (18-28)195/15256/31198 36 (30-41)195/4199 3 (1-5)195/2256/2198 62257 40-60223
NG/PEG feeding and dietetics Dysphagia management Toileting program Environmental management ± drugs AEDs if no other trigger CPAP ? Retraining
Vascular Brain Injury Mass effects Hydrocephalus Catastrophic illness Depression Anxiety Family breakdown
Neurosurgical decompression Shunting 16 (12-21)195/ 26256/13198 14 (10-18)195/8198
CBT ± drugs CBT ± drugs Information + training
AED, antiepileptic drug; CBT, cognitive-behavior therapy; CCF, congestive cardiac failure; CPAP, continuous positive airway pressure; DVT, deep vein thrombosis; GI, gastrointestinal; NG/PEG, nasogastric/percutaneous endoscopic gastrostomy; NSAID, nonsteroidal anti-inflammatory drug; PE, pulmonary embolism.
chapter 48 rehabilitation after stroke ■
ORGANIZATIONAL ASPECTS OF REHABILITATION Stroke Unit (SU) or Mixed Rehab (MR) vs General Medical Ward (GMW) ± Peripatetic Team (PT) Care Odds of death or institutional care SU vs GMW (13 trials; 3200 pts)
P = 0.008
SU vs Mixed Rehab (4 trials; 540 pts)
NS
Mixed Rehab vs GMW (5 trials; 580 pts)
P = 0.04
PT vs GMW (2 trials; 240 pts)
NS
SU vs GMW + PT (1 trial; 305 pts)
P = 0.0009
TOTAL
P = 0.0002 0.5 SU/MR better
1
647
Figure 48–2. Care in stroke units or mixed rehabilitation units can be organized and is thus more effective than in general medical wards where it remains disorganized, with or without input from a peripatetic team. NS, nonsignificant. (Adapted from Stroke Unit Trialists’ Collaboration: Organised inpatient [stroke unit] care for stroke. Cochrane Database Syst Rev 2001; [3]:CD000197.)
2 GMW better
0.71 to 0.94; P = 0.005), of death or institutionalized care (odds ratio, 0.80; 95% confidence interval, 0.71 to 0.90; P = 0.0002), and of death or dependency (odds ratio, 0.78; 95% confidence interval, 0.68 to 0.89; P = 0.0003). A subsequent systematic review of results from nine postacute units, which admitted patients more than 1 week after stroke, in comparison with an alternative service, revealed benefits similar to those resulting from combined acute and postacute units,23 and in the United States, compliance with postacute but not acute stroke unit guidelines (Table 48–3) has been shown to be correlated with outcome.16 Secondary analysis has indicated that the reduction in stroke unit deaths probably results from a reduction in the complications of immobility rather than in neurological or cardiovascular complications. The increased number of patients discharged home from stroke units and the reduced requirement for institutional care were attributable largely to an increase in the number of patients returning home physically independent (Rankin score, 0 to 2), rather than dependent (Rankin score, 3 to 5).24 Langhorne and Pollock25 identified aspects of care common to 11 stroke units, 8 of which included acute care, reporting beneficial effects between 1985 and 2000 in the Stroke Unit Trialists’ Collaboration’s systematic review.22 These included comprehensive medical, nursing, and therapy assessments; integration of nursing care within the multidisciplinary team; early mobilization and treatment of hypoxia, hyperglycemia, and suspected infection; avoidance of urinary catheterization; and formalized goal-oriented multidisciplinary team care, with early discharge planning and education and involvement of caretakers. Evans and associates26 found that many of these aspects of care were not delivered by a peripatetic specialist stroke team (PSST). They compared care delivered to 304 patients randomly assigned to an acute and rehabilitation stroke unit (n = 152) or to general wards supported by a PSST (n = 152). Patients in the stroke unit were monitored more frequently, and more of those patients received oxygen, antipyretics, measures to reduce aspiration, and early nutrition than those in general wards. Many aspects of multidisciplinary care occurred more fre-
T A B L E 48–3. Dimensions of Acute Rehabilitation after Stroke 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Multidisciplinary team coordination Baseline assessment Goal setting Treatment plan Monitoring of progress Management of impairments/disabilities Prevention of complications Prevention of recurrent stroke Family involvement Patient and family education Discharge planning
After Duncan PW, Horner RD, Reker DM, et al: Adherence to postacute guidelines is associated with functional recovery in stroke. Stroke 2002; 33:167-178. Compliance with these dimensions of process during postacute rehabilitation after stroke is correlated with outcome.
quently in the stroke unit, in which complications including stroke progression, chest infections, and dehydration were less frequent. Early feeding, stroke unit management, frequency of complications, and measures to prevent aspiration independently affected outcome. In 1984, a PSST’s input to general ward care was shown to nonsignificantly reduce mortality rates and significantly improve functional recovery in men.27 More recently, in a head-to-head comparison at 1 year of patients randomly assigned to receive care from the PSST with those receiving care in a combined acute and rehabilitation stroke unit, more patients in the PSST group were dead or institutionalized (30% versus 14%; P < 0.001) and fewer were alive without severe disability (66% versus 85%; P < 0.001).21 Retrospective data collected by van der Walt and colleagues28 before and 2 years after the introduction of a PSST to a general ward showed significant improvements in prophylaxis for deep vein thrombosis, incontinence management, premorbid function documentation, frequent neurological observations, and early occupational therapy, with fewer severe complications (9% after versus 24% before; P = 0.004), reduced median length
648
Section
IX
C e r e b r o va s c u l a r D i s e a s e
of stay (12.0 after versus 18.5 days before; P = 0.003), and more patients independent at discharge (32% after versus 9% before; P < 0.001). It is thus possible that practice developed in stroke units can now be delivered more effectively by a PSST, and further comparison of these two methods of service delivery remains legitimate. More recently, high-dependency care has been introduced immediately after stroke, providing continuous rather than manual monitoring for hypoxia, hyperglycemia, hypotension, cardiac arrhythmias, and elevated body temperature during the first 48 to 72 hours after admission.29,30 Currently, its effectiveness is relatively unexplored, but there is a suggestion that it may reduce mortality rates at 3 months and 1 year among patients with severe stroke, without increasing dependency.31,32 Remarkably, the differences between stroke unit and alternative care persist for many years. Indredavik and colleagues33 found that even 10 years after random assignment to an acute and rehabilitation stroke unit or a general ward, fewer patients in the stroke unit had died (75.5% versus 87.3%; P = 0.008), more were at home (19.1% versus 8.2%; P = 0.018), and more were at least partly independent with a Barthel Index score of 60 or higher (20.0% versus 8.2%; P = 0.012) or independent with a Barthel Index score of 95 or higher (12.7% versus 5.4%; P = 0.061). Increased survival times 5 years after random assignment to a stroke rehabilitation unit, versus a general medical or geriatric ward, were also reported by Lincoln and colleagues.34 Early discharge, supported by a multidisciplinary outreach team, of medically stable patients after mild and moderate stroke, with an admission Barthel Index score of more than 9, supplements initial stroke unit gains. A meta-analysis of individual patient data from 11 trials of early supported discharge versus conventional care showed that the patients with early supported discharge had a reduced risk of death or dependency (odds ratio, 0.79; 95% confidence interval, 0.64 to 0.97; P = 0.02), a hospital stay shortened by 8 days (P < 0.0001), and significant improvement in extended activities of daily living (P = 0.05), although not in subjective health status or mood in either patients or caretakers. Patients were moderately disabled at discharge with a median discharge Barthel Index score of 15.35 One study revealed that these gains can include better life quality, assessed by the Nottingham Health Profile, at 1 year,36 and another study revealed that gains in domestic and extended activities of daily living are still evident after 5 years.37 Once in the community, patients are known to be at risk of deteriorating as a result of multiple health problems, including falls, depression, and physical and social inactivity and isolation, in addition to age-related symptoms and comorbidity, and health-related quality of life has been shown to significantly decline in the 6 months after discharge.38 Nursing home care does not substitute for stroke unit care,39 but the place for and the optimal process in other service systems for patients later after stroke (e.g., nurse-led wards, nursing homes, or residential placements) remain to be examined. A meta-analysis of trials of therapy-based outpatient or domiciliary rehabilitation, delivered by either a multidisciplinary team or by a physiotherapist or occupational therapist, with the goal of improving task-oriented behaviors, has shown that deterioration is prevented (odds ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P = 0.009) and dependency in personal care reduced (95% confidence interval, 0.02 to 0.25; P = 0.02).40 The effective components and best location for this type
of service need further exploration, but benefit has been consistent in trials of community-based occupational therapy, which have provided sufficient data for a meta-analysis of eight trials that showed that intervention was associated with improved personal, extended, and leisure-based activities of daily living, depending on the intervention target.41 These findings were confirmed in a more wide-ranging systematic review of occupational therapy for stroke patients by Steultjens and associates,42 who also noted the need for further studies of the effectiveness of splinting. Most studies of physiotherapy in patients in the community after stroke investigate the effect of a particular physiotherapy treatment on upper or lower limb function at the level of impairment and mobility, which may improve, rather than on limitations in activity and independence, which, if examined, may not improve. Domiciliary physiotherapy within 6 months after stroke has been shown to reduce probability of readmission after an average of only 2.9 (range, 1 to 8) visits43 and to reduce dependency at less cost than for day hospital attendance.44,45 In patients more than 1 year after stroke, only four to five physiotherapy sessions produced a clinically small but significant improvement in mobility.46 Informal caretakers should be recognized as an important resource: They enable patients to remain in the community,47 their support is likely to facilitate patient outcomes,48 and depression is more severe in caretakers who feel poorly supported.49 Formal support for caretakers is difficult to obtain in the United Kingdom. Trials of psychosocial interventions to support caretakers of patients with stroke, involving information packages, specialist nurses, a mental health worker, or family support workers, have failed to show functional or psychological benefit in patients and only modest psychosocial benefit for caretakers.50-57 In contrast, there is evidence that caretaker adjustment is increased by education and counseling or by training in social problem-solving skills.58 Kalra and colleagues59,60 demonstrated that training informal caretakers in basic nursing skills and facilitation of personal care techniques reduced costs and caregiver burden and improved psychosocial outcomes for the caretaker and the patient, although there was still no change in patients’ rates of mortality, institutionalization, and disability.
MANAGEMENT OF NEUROLOGICAL IMPAIRMENTS Evidence of dysphagia, with consequent risk of dehydration, further malnutrition, and chest infections resulting from aspiration, has been reported to occur clinically in about 50% of all patients with stroke admitted to a hospital, with videofluoroscopic evidence of a swallowing abnormality in up to 65% of patients and of aspiration in about 20%.61,62 Videofluoroscopic and flexible endoscopic evaluation of swallowing increase the reliability with which aspiration can be identified63,64 when clinicians select which patients need tube feeding. However, whether other aspects of dysphagia management, including dietary modification and compensatory swallowing techniques, reduce the need for tube feeding or the risk of aspiration pneumonia remains unclear despite assertion to the contrary.65 The Feed or Ordinary Diet (FOOD) trials66 revealed that in 859 patients randomly assigned to receive nasogastric feeding within a week, in contrast to more than a week, after stroke,
chapter 48 rehabilitation after stroke absolute mortality rates were reduced by 5.8% (95% confidence interval, −0.8 to 12.5; P = 0.09) in the group fed early; in 321 patients randomly assigned to undergo percutaneous enteral gastrostomy (PEG) feeding or nasogastric tube feeding a median of 1 week after stroke, PEG feeding was associated with an absolute increase in risk of death of 1.0% (95% confidence interval, −10.0 to 11.9; P = 0.9) and an increased risk of death or other poor outcome of 7.8% (95% confidence interval, 0.0 to 15.5; P = 0.05). Thus, as is recommended current practice in hospitalized adult patients in general,67 nasogastric feeding should be used for dysphagic patients soon after stroke, whereas PEG feeding is reserved for patients who do not tolerate nasogastric feeding and as required in the longer-term care of dysphagic patients. After stroke, early incontinence is predictive of poor outcomes, including death, lengthy hospital stay, institutionalization, and severe disability.68 New urinary incontinence occurs in 40% to 50% of patients during the first week after admission and in 10% to 20% by 6-month follow-up68,69; it appears to remain at this level in the community over the long term.70 The proportions of stroke patients with new fecal incontinence on admission and at 6-month follow-up are lower, at 30% to 40% and 5% to 10%, respectively.68,69 Causes and predictors68,71,72 of fecal and urinary incontinence include age; stroke type and severity; “functional incontinence” resulting from strokerelated cognitive and communication difficulties and mobility problems; autonomic neuropathies, usually diabetic in origin; medications causing bladder and bowel hyporeflexia; preexisting bladder outflow obstruction in men or stress incontinence in women; and perhaps depression and lowered self-esteem that result from the incontinence itself.73,74 Current guidelines (e.g., Royal College of Physicians12) for the management of incontinence after stroke recommend initial definition of its cause and associations through a full clinical assessment. The neurogenic cause after stroke is usually disruption of suprapontine inhibition of bladder contractility resulting in detrusor hyperreflexia, but bladder hyporeflexia may occur after cerebellar stroke.75 Evidence for the effectiveness of methods promoting continence after stroke is currently derived largely from trials in other (nonstroke) patient groups. Management of urinary incontinence76 includes a combination of anticholinergic drug therapy, bladder training by prompted and/or timed voiding77,78 or biofeedback,79 and appropriate management of outflow obstruction and stress incontinence, for which one small study of 26 stroke patients randomly assigned to receive treatment or to control conditions showed no benefit from a 12-week pelvic floor muscle training program.80 Similar general principles apply to the management of fecal incontinence,81 which in inpatients or in discharged patients is associated with needing help to use the toilet82 and thus might be addressed by improving functional independence, whereas constipation but not fecal incontinence after stroke is improved by a single clinical/educational nurse intervention up to 6 months later.83 Impairment of trunk control and sitting balance after acute stroke is common, and recovery is a reliable predictor of functional outcome after stroke. Trunk control, measured by the trunk control test at rehabilitation admission a median of 5 weeks after stroke, accounted for 71% of the variance of the motor component of the Functional Independence Measure at discharge 10 weeks after stroke84; as measured by the Postural Assessment Scale for Stroke Patients within 2 weeks after
649
stroke, trunk control was strongly correlated with functional outcome, rated by a combined score of both personal (Barthel Index) and instrumental (Frenchay Activities Index) activities of daily living at 6 months after stroke.85 A positive correlation has also been found between sitting balance and the Barthel Index score86 and between sitting balance and gait at 6 months.87 Mudie and associates88 found that three specific treatment approaches implemented early after stroke improved sitting balance in the short term in comparison with a nonspecific control approach. Whether early targeting of sitting balance for treatment could improve mobility over the long term is an interesting question that remains to be explored. Disordered motor control of the limbs after stroke is usually caused by the positive and negative effects of the upper motor neuron syndrome, in which the central abnormality is usually muscle weakness and co-contraction resulting from a failure of coordinated high-frequency motor neuron firing during movement, rather than high tone resulting from spasticity and contracture found at rest,89 which is seen clinically in only 20% to 30% of hemiparetic patients 3 to 12 months after stroke.90,91 Spasticity at rest, when it is a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, is of diagnostic use but does not contribute significantly to impairment during active voluntary movement and function in either the leg or the arm92,93 and is only one factor contributing to increased muscle tone in the upper motor neuron syndrome, in which co-contraction and biomechanical changes contribute significantly to the resistance to passive movement.94 It has thus been easier to show that pharmacological treatments that reduce the hypertonus of spasticity and co-contraction benefit passive rather than active functional activities, including hand and perineal hygiene, dressing, pain, and limb position,95-100 and even correction of equinovarus at the ankle to improve weight bearing by the affected leg is unlikely to translate into functional improvements in gait101,102 unless it is followed by physical measures to reduce soft tissue shortening and a program of task-related training.103,104 Thus, although treatments for spasticity after stroke achieve passive functional goals by preventing contracture or reduce pain and are of particular value in dependent patients unable to participate in skill learning, the results of treatments for spasticity in general and after stroke have emphasized the fundamental truth of Landau’s statement in 1974105 that “If the major disability of the upper motor neuron syndrome is due to diminished neural input to segmental control of the final common path (negative symptoms), it follows that only some method of provoking [central nervous system] neuronal regeneration or of improving the potency of and control by surviving upper level neurons could provide a direct remedy.” Landau’s next sentence was “No such approach is on the horizon,” and at that time the focus in rehabilitation was on training in compensatory strategies and social and environmental modification. Since the mid-1990s, however, there have been investigations of neurobiological rehabilitation strategies designed to modify the neural processes and behaviors that occur during recovery (Fig. 48–3) (Dobkin, 2004).106 Meta-analyses of physiotherapy after stroke have revealed significant improvements in independence in activities of daily living and reduction in impairments with higher intensities of physiotherapy.107-109 Traditional physiotherapeutic strategies emphasize cutaneous and proprioceptive stimulation, reduction of tone, and therapist-induced central facilitation of
650
Section
IX
C e r e b r o va s c u l a r D i s e a s e
A
B ■
Figure 48–3. Both patient A and patient B suffered a stroke affecting the right hand. The T1-weighted magnetic resonance imaging scans on the left (“infarct”) demonstrate that patient A suffered a left pontine infarction and patient B suffered a left middle cerebral artery territory infarction. The five scans to the right of each structural scan show patterns of brain activation, measured with functional magnetic resonance imaging, during repetitive gripping with the affected right hand at different time points over the first 3 months after stroke. (The brain is seen from above, with the anterior aspect at the top of the image.) Recovery of function in patient A is associated with early widespread activation within recognized motor related areas, followed by a gradual focusing toward a normal lateralized pattern; the 3-month (far right) scan shows activity confined largely to the left sensorimotor cortex, as in normal subjects. Recovery of function in patient B is also associated with focusing of the early pattern of widespread activation, but in this instance activity focuses toward the right sensorimotor cortex, ipsilateral to the affected hand. Ipsilateral sensorimotor cortex activation is rarely seen in normal subjects. This focusing is due to increasingly efficient neural circuitry, very similar to that seen during learning of a new complex motor task in the undamaged human brain. However, it is possible to focus only onto regions of the brain that can still generate a motor output signal. In the case of patient B, many of the left hemisphere cortical motor regions have been disconnected by the infarct. Thus, there appears to be a reliance on right motor cortex to generate right hand movements. This “secondary” system is necessarily less efficient, and this is reflected in less complete recovery of patient B in comparison with patient A (hand grip of 64% of the unaffected side for patient B at 3 months, in comparison with 89% for patient A). This finding suggests two important consequences: (1) It ought to be possible to use therapies that are designed to drive this process toward the optimally configured motor system and (2) it helps clinicians appreciate that damage to brain structures is likely to be a major constraint to this process and that reorganization can take place only in surviving brain regions; this has implications about how much recovery can be expected.
normal movement, rather than voluntary activation of proximal or distal musculature to relearn functional tasks. This type of task-related motor relearning was first shown to be effective in improving the ability to balance during seated reaching activities late after stroke.110 Although this approach has not yet been consistently shown to improve functional outcomes and resource use early after stroke,111,112 its principles of repetition, task orientation, attention, and reward are similar to those that result in motor learning and cortical neural reorganization in nonhuman primates with and without ischemic cortical damage.113 It is thus a “neurobiological” approach to skill relearning in which repetition of graded and motivating taskrelated learning programs is envisaged to drive the acquisition of motor, linguistic, and cognitive skills and more complex behaviors through activity-dependent neural reorganization, regrowth, and replacement.114 Although these techniques can be shown to produce neuroplastic effects—in humans, usually by functional imaging techniques—these changes should not be confused with the potential clinical usefulness of these techniques, which requires a robust behavioral effect if measurable functional benefit is to occur. The effects of task-related training are seen most obvi-
ously in the function targeted for treatment; change has been demonstrated after stroke in upper and lower limb function and linguistic skills. Factors that optimize skill learning, including implicit rather than explicit feedback115 and a random rather than blocked learning schedule,116 are likely to affect the rate at which a task is learned and the extent of carryover into novel environments. In the arm, training is focused on practicing graded motivating functional tasks, including grasping, reaching, leaning, and manipulating clothing by the affected limb; in the trunk and leg, training is focused on the recovery of bed mobility, sitting and standing balance, transfers, gait stability and velocity, and stair climbing. Kwakkel and colleagues117 showed that leg training of this sort for an average of 30 minutes of therapy 5 days a week for 20 weeks after stroke onset, in contrast to immobilization of the limb in an inflatable cuff for a similar time, increased performance in activities of daily living (measured by the Barthel Index), walking ability, and also hand dexterity, whereas arm training increased arm dexterity alone. What determines when, in whom, and how task-oriented training should be carried out after stroke, in an individual as well as in a population, remains open to investigation. The duration in training can be increased: for example, to an
chapter 48 rehabilitation after stroke impractical 6 hours a day for 10 weekdays late after stroke. Training can be performed solely with a therapist or also automated with a robotic,118,119 most commonly as a treadmill with or without body weight support for gait training120 or in a virtual environment,121 or it can be encouraged, probably at both cortical122 and functional levels, and also in animals,123 by constraint of the unaffected upper limb.124-126 It can also be combined with a variety of impairment-based adjunctive therapies, including muscle-strengthening exercises,127 an orthotic,128 electrical stimulation of the arm or leg,129-131 sensory stimulation,132 mental imagery,133 and musical feedback.134 The available evidence for the effectiveness of these and other physical therapies was systematically reviewed in 2004 by van Peppen and colleagues.135 Which therapy modalities should be used, to what purpose, how they should be combined, at what stage after stroke, at what intensity and for how long, and in which patients are questions that are beginning to be answered clinically with an evidence base, rather than at best theory and at worst belief. The need to be able to do this is emphasized particularly by the evidence beginning to show long-term persistence of task-related training effects136,137 and the useful effects of interventions late after stroke (e.g., Werner and Kessler138 and van der Lee et al139). It is accompanied by a need to explore how the new technologies, which may not always yield benefit (e.g., Richards et al140), can best be put best to work. Similar principles are beginning to drive trials of rehabilitation therapies of the focal, rather than global,141 cognitive disorders observed after stroke. According to results of clinical measures, language impairments affect about 40% of the stroke population at stroke onset142 and about 10% at 6 months after stroke.143 Minimal spontaneous improvement in language functions occur more than 1 year after stroke. An early metaanalysis144 and review145 of trials of speech and language therapies concluded that there was evidence of effectiveness, but restriction of the evidence to randomized controlled trials, in comparison with no therapy, informal support, or another speech and language therapy, failed to yield clear evidence of effectiveness.146 However, Bhogal and colleagues147 found that increased intensity of therapy was associated with improvement, which occurred in four studies that provided an average of 9 hours of therapy per week for 11 weeks, in contrast to four studies with negative results that provided approximately 2 hours per week for 23 weeks. Although the type of therapy required remains unclear (e.g., Doesborgh et al148), Pulvermüller and colleagues149 suggested that the principles of (a) massed practice—for example, 30 to 35 hours of therapy over 10 days rather than the same therapy time over a longer period—and of (b) constraint (in this case of maladaptive methods of communication), and of (c) everyday behavioral relevance are important factors in generating neuroplastic and thus functional changes in language skills. The presence of other cognitive problems in the acute phase are important independent predictors of long-term outcome, in addition to neurological deficits rated by standard measures, particularly unilateral neglect150,151 and executive dysfunction.152 Neglect, as currently measured, is seen in more than 60% of patients assessed within 2 to 3 days of admission for stroke, more commonly after right than left hemisphere stroke.153 Of patients with neglect 2 to 4 weeks after stroke, 80% still exhibit aspects of neglect on testing at 6 months,154 and the poor functional outcome predicted by the presence of early neglect is still seen if neglect has resolved on testing,151 possibly as a result of residual problems with nonlateralized
651
attention.155 Neglect, like dysphasia, is heterogeneous; different combinations of lateralized and nonlateralized attentional and motor deficits are identifiable in each patient. A number of techniques have been shown to improve lateralized spatial representation, including caloric stimulation156,157; contralesional neck muscle vibration, in one trial with scanning training158; prism adaptation159; and contralesional limb activation,160 as well as alerting techniques to increase nonlateralized loss of attentional capacity.161 Some of these techniques have also been reported to improve activities of daily living, notably neck muscle vibration with scanning training158 and prism adaptation,162 and contralesional limb activation in one study reduced length of stay by 24 days.150 Whether a treatment battery tailored to the neglect subtypes present in each patient163,164 will prove sufficiently practical and robust to produce significant functional benefits, not yet evident in the literature on systematic review,165 remains to be explored. In the context of stroke, use-dependent neural reorganization after damage is facilitated by other extrinsic and intrinsic inputs that modulate neural excitability and augment long-term synaptic potentiation. Use-dependent network remodeling at cellular and systems levels is also likely to be needed for the successful application of techniques to promote neural regrowth and/or replacement.166,167 Adjunctive facilitators of this process include manipulation of attention168; increase or decrease of somatosensory input, shown to improve swallowing169 and leg170 and arm122 function; neuromodulatory drugs171; electrical172 and magnetic173 stimulation of the brain; and possibly exercise.174 Pharmacological facilitation and inhibition of neurological recovery after stroke are also likely to be of clinical relevance. The use-dependent plasticity that underpins motor training and perceptual learning is dependent on N-methyl-D-aspartate receptor activation and γ-amino butyric acid–mediated (GABAergic) inhibition,175,176 and these are in turn modulated by cholinergic, noradrenergic, serotonergic, and dopaminergic transmitter systems.171 Early experiments by Feeney and coworkers177 in rats showed that motor recovery after suction ablation of the sensorimotor cortex was improved by amphetamine before practice on a beam-walking task; neither practice nor amphetamine alone had any benefit. Subsequently, α2 antagonists, increasing noradrenergic effects, were found to facilitate motor recovery, and α1 antagonists and α2 agonists, which decrease norepinephrine release or block its postsynaptic effects, reinstate deficit in clinically recovered animals or slow their recovery.178,179 There is also evidence that modulation of other neurotransmitter systems has similar effects.180 The beneficial effect of these pharmacological interventions is dose dependent, and the timing of administration is likely to be important, the effect being dependent on close temporal linkage to behavioral experience. In animals, there is a strong correlation between the functional effects of altering levels of various neurotransmitters and their ability to facilitate increases in synaptic efficacy through long term potentiation.180 Attempts have been made to translate these findings into treatments for stroke patients. In the first clinical trial of noradrenergic enhancement coupled with physical therapy, patients who had suffered from hemiplegic stroke were randomly assigned to receive either 10 mg of dextroamphetamine or placebo 45 minutes before physiotherapy.181 Follow-up assessment 24 hours after treatment revealed a 40% improvement from baseline scores with dextroamphetamine in comparison with placebo. Small numbers of patients in this study made interpretation difficult. A subsequent failure to replicate
652
Section
IX
C e r e b r o va s c u l a r D i s e a s e
these findings by Borucki and associates182 was attributed to a different experimental design, particularly a failure to schedule physiotherapy immediately after amphetamine treatment. More recent studies with dextroamphetamine have had conflicting results,183,184 but positive results have been published for daily doses of levodopa (100 mg) used in conjunction with physiotherapy.185 Studies of the effects of drugs used in conjunction with speech therapy have yielded some success.186 Although larger scale studies are under way, the use of pharmacological agents to facilitate the effects of physical and speech therapy is currently only experimental. Conversely, there is some evidence to suggest that patients receiving drugs that reduce the effects of norepinephrine or dopamine, or increase the effects of GABA, at the time of stroke or shortly afterward have poorer outcomes than do patients who do not receive any of these drugs187; thus, care must be taken in their prescription. Maladaptive or ineffective neural reorganization after stroke may contribute to emotionalism, central poststroke pain (CPSP), and involuntary movement disorders, which include hemiballismus, hemichoreoathetosis, distal resting and/or action tremor, and proximal postural tremor. CPSP, originally described in 1906 as a phenomenon after thalamic stroke by Dejerine and Roussy,188 was found in 16 (8%) of 207 hospitalized stroke patients 6 months after stroke by Andersen and colleagues.48,49 Pain may result from stroke involving spinothalamocortical afferent pathways in the medulla, pons, midbrain, thalamus, subcortical white matter, and cortex. Leijon and colleagues189 found in 27 patients with CPSP that the thalamus was involved in only 9, lesions were in the lower brainstem in 8 and lateral and superior to the thalamus in 6, and onset of the pain was delayed by more than a month in 13 patients. The pain was described as “burning, aching, pricking, and lacerating”; the intensity was increased by external stimuli, either noxious (hyperalgesia) or not noxious (allodynia), the most common being joint movements, cold and light touch, and, in five patients, emotional stimuli. All patients had decreased temperature sensation. Hypersensitivity to cutaneous stimuli was found in 88% of the patients, and sensations of touch and vibration were abnormal in only 52% and 41%, respectively. There were also relatively low incidences of weakness and ataxia, which were present in 48% and 62%, respectively. Treatments in individual patients include all the drugs and physical methods used for neuropathic pain in general; descending modulation of pain pathways by electrical motor cortex stimulation,190 rather than deep brain stimulation,191 and more recently repetitive TMS over the hand area of the motor cortex192 have shown some promise in the treatment of CPSP. Both deep brain stimulation and electrical motor cortex stimulation have been used with some success to treat poststroke movement disorders,191 whereas antidepressants are effective in treating emotionalism.192–194
MANAGEMENT OF SYSTEMIC COMPLICATIONS In a prospective study of 311 consecutive patients recruited within 7 days of stroke onset, Langhorne and colleagues195 recorded complications in 85% of the patients during hospital admission (see Table 48–3); 6, 18, and 30 months after discharge, there was a high frequency of infections, falls, unexplained blackouts, pain, and symptoms of depression and anxiety. Seizures and chest infections tend to occur soon after admission; other common complications, including venous thromboem-
bolism, skin breakdown, urinary tract infections, falls, and depression, are still occurring at 30 days.196 More than 60% of patients have more than one complication during inpatient rehabilitation, and complications are more common with increasing age, stroke severity, premorbid disability, and low serum albumin level.195-197 The occurrence of a complication is more likely to be associated with death,196 and the causes of death most likely to be prevented by stroke unit care are those resulting from immobility, particularly as a result of infection and venous thromboembolism. More recently, emphasis on acute care after stroke has begun to define potentially avoidable complications that cause disordered physiological homeostasis acutely and may affect mortality rates, morbidity, length of stay, and longer-term outcome31,32,198; these include airway patency and disordered breathing (lowering blood oxygenation), cardiac problems, blood pressure control, temperature regulation, and glycemic control.30 The prevention and early treatment of the acute, early, and later systemic complications of stroke are thus an important aspect of organized multidisciplinary care and rehabilitation after stroke. They require at least easy access to acute care and diagnostic facilities,196,197 if not high-dependency care in the acute phase for some patients, with continuous monitoring of cardiac, respiratory, metabolic, and neurological functions during the first 72 hours after stroke. Venous thromboembolism was once common after stroke; symptomatic and asymptomatic deep vein thrombosis and pulmonary embolism were present in up to 70% of, respectively, all patients and those studied post mortem.200 In contrast, nearly 20 years later, Kelly and associates200,201 found that in 102 unselected patients receiving stroke unit care, aspirin, and compressive therapy with stockings, symptomatic deep vein thrombosis and pulmonary embolism occurred in only 3% and 5% of patients, respectively; however, noninvasive magnetic resonance direct thrombus imaging revealed the prevalence of venous thromboembolism, deep vein thrombosis, and pulmonary embolism to be high (40%, 18%, and 12%, respectively, and increasing to 63%, 30%, and 20%) in nonambulatory patients with a Barthel Index score of 9 two days after stroke. In the context of early mobilization and stroke unit care, either aspirin or low-dose unfractionated heparin has been shown to reduce the frequency of symptomatic pulmonary embolism to below 1%.203,204 Because there is no evidence that routine low-dose subcutaneous lowmolecular-weight heparin is superior to aspirin in preventing pulmonary embolism or deep vein thrombosis,205 current guidelines for routine venous thromboprophylaxis (e.g., Royal College of Physicians12) recommend aspirin, early mobilization, and, for patients with leg weakness, graduated compression stockings, which prevented deep vein thrombosis in all hospitalized patients in one study205 but for which there is insufficient evidence at present to show that this is the case after stroke.206 Factors thought to confer higher risk, such as previous deep vein thrombosis or pulmonary embolism, necessitate individualized treatment decisions, and management in other high-risk groups, such as those initially nonambulatory after stroke, probably requires further definition (e.g., Kelly et al201,202). The detraining effects of immobility and reduced activity208 compound the increased difficulty in completing activities of daily living that results from comorbid musculoskeletal and cardiorespiratory dysfunction and from the increased aerobic requirements of walking that are secondary to neurological impairments. Even in normal people, bed rest for 4 to 6 weeks results in a loss in exercise capacity of 0.9% per day209 and a
chapter 48 rehabilitation after stroke decrease in muscle strength of up to 40%.210 After stroke, exercise capacity is reduced to about 60% of normal at 1 month,211 making the performance of activities of daily living effortful and fatiguing. Although activities of daily living exert a training effect, so that exercise capacity improves, it remains reduced at 6 months212 and probably in the long term. Activity intolerance is thus common among stroke survivors, who may work close to their individual maximal exercise capacity while engaged only in domestic chores, in comparison with age- and weightmatched controls.213 Either aerobic training214 or muscle strengthening215,216 or both217 usually improve targeted physiological outcomes and sometimes balance, walking speed, and distance, but not consistently activities of daily living136,218; this finding is sufficient to contribute to recommendations for exercise after stroke from the American Heart Association.219 Detraining is likely to be one of the factors contributing to poststroke fatigue, which occurs in 40% to 70% of patients late after stroke in community studies,220-222 and patient-derived stroke-specific, health-related quality-of-life measures identify lack of energy as one of the four most consequential problems, together with those related to physical, psychosocial, and communication difficulties.223,224 Despite its relevance to quality of life, the natural history, causes, and management of poststroke fatigue remain underinvestigated. It often occurs independently of prestroke fatigue and depression and poststroke depression220,221,225 as “primary” poststroke fatigue, possibly resulting from stroke-disordered attention,226 or in association with physical impairment,221 psychological factors, sleep-disordered breathing and obstructive sleep apnea,227 or incidental systemic comorbid conditions. Management clearly starts with accurate differential diagnosis, but there are no guidelines to direct management of primary poststroke fatigue or evidence that modafinil, which may228 or may not229 be of benefit in multiple sclerosis, is of benefit after stroke. During hospital admission after stroke, patients suffering from undernutrition have a greater risk of pneumonia, other infections, and gastrointestinal bleeding than that in other patients.230 A higher risk of chest infection and poor nutritional status within the first month after stroke is predicted by abnormal swallowing, which is also associated with increased disability, length of hospital stay, and institutional care and is an independent predictor of mortality during the first 6 months after stroke61,62; rates of death from pneumonia over the longer term are also higher if dysphagia persists.231 Although the prevention of chest infections remains problematic, the prevention of undernutrition in hospital has been clarified. Routine oral supplementation versus no supplementation in admitted stroke patients could not be shown to reduce death or poor outcome when the rate of malnutrition on admission was only 8%232; whether it would with the higher rates of malnutrition on admission of about 40% reported before 1995233 has not been investigated. Nasogastric tube feeding within a week of stroke reduces the mortality rate,66 probably by preventing malnutrition, as it does in other groups of vulnerable hospitalized patients,234 rather than by reducing the incidence of chest infections, which nonetheless occurred, for example, in 44% of nasogastrically fed patients reported by Dziewas and colleagues.235 Pain after stroke is most often musculoskeletal in origin, rather than CPSP, and the result of an exacerbation of preexisting osteoarthritis and/or reduced movement and mobility caused by the stroke. Shoulder pain occurs in more than 60% of patients during the 6 months after stroke and its incidence
653
may increase after discharge.236 Its occurrence is correlated with prestroke shoulder pain, severe upper limb weakness, neglect, sensory loss, visual field defects, and glenohumeral subluxation, but their role in its pathogenesis remains uncertain, and shoulder subluxation is not clearly a cause. Vasomotor changes in the limb, shoulder-hand syndrome, and reflex sympathetic dystrophy may also be present but should not be confused with the painful shoulder, and other disorders of the shoulder including fractures should be ruled out. Shoulder pain causes considerable morbidity and, once established, is difficult to treat. Prevention, particularly in patients at high risk, should include support of the flaccid arm237 and appropriate handling techniques to avoid traction injury. Treatment is likely to be determined partly by the tone in shoulder muscles238: A flaccid shoulder requires support at all times and possibly benefits from functional electrical stimulation (e.g., Renzenbrink and IJzerman239), whereas a spastic shoulder requires maintenance of range of motion by physical techniques and possibly the addition of botulinum toxin. Local steroid injection should be avoided unless there is clear evidence of an inflammatory component to the pain. There is a high cumulative incidence of psychiatric disorder after stroke. It can be difficult to diagnose in the presence of speech disturbance, anosognosia, and abulia, and it includes major and minor depression, agoraphobia, social withdrawal, apathy and self-neglect, irritability, and pathological emotionalism. However, in 128 community-dwelling patients during the first year after stroke, House and colleagues240 found that little of it persisted, and only two cases of major depression manifested during the whole 12 months. This frequency is lower than that found in other studies: for example, about 25% in a rehabilitation unit within 3 months after stroke241 and 15% in community-dwelling patients 4 months after stroke in the study by Burvill and colleagues242 in Perth, Australia. There remains a suggestion that left-sided anterior strokes affecting frontal-subcortical circuits predispose to depression,243,244 but the majority of studies emphasize that the major risk factors for depression are nonspecific, of the sort seen in older people with other physical illness,245 and they include a history of previous depression, stroke severity, physical dependency, and social inactivity.48,49,246 Over the longer term, any association between stroke and depressive symptoms is attributable largely to physical limitations.247 Although depression soon after stroke probably reduces later functional outcome248 and its presence 1 year later is clearly related to a reduced quality of life,6 two systematic reviews revealed that the evidence of benefit from early prevention or diagnosis and treatment was minimal.249,250
FUTURE DEVELOPMENTS Further research and development in rehabilitation after stroke should continue to focus on maximizing effective service delivery and investigating new organizational systems and restorative techniques and their transfer into routine clinical use. Because of the evidence for the effectiveness of comprehensive acute and rehabilitation stroke unit care and subsequent supported discharge and intervention in the community, and the national recommendations and guidelines that this evidence makes possible, these service delivery systems of care and rehabilitation can be available to a greater proportion of patients admitted after stroke, particularly when linked to an
654
Section
IX
C e r e b r o va s c u l a r D i s e a s e
explicit multisite audit of the organization and process of stroke care of the sort undertaken at intervals by the Royal College of Physicians of London.251 Linkage of these stroke care systems into networks will be gradually developed to facilitate multicenter clinical research, hasten enlargement of the interventional evidence base,252 and promote the delivery of coordinated rather than fragmented systems of care.18 Parallel networks aiming to facilitate the transfer of proof-of-principle studies in the translational restorative neurosciences, while the pharmaceutical industry continues to focus on new methods of neural protection, are likely to follow. It is now established that the characteristic features of comprehensive stroke unit care include a standardized protocol for acute assessment, intermittent monitoring, medical treatments, and a strategy for the prevention of complications through the work of a multidisciplinary team integrating medical care, nursing, and rehabilitation. Clinical research networks will enable exploration of the effectiveness of further aspects of plant and process that contribute to outcome, including the usefulness of acute continuous physiological monitoring32; other strategies to detect and prevent complications, such as very early mobilization253; and further definition of the aspects of acute and early goal-focused interdisciplinary rehabilitation that optimize functional outcome.17 Since the mid-1990s, the neural reorganization that takes place longitudinally in response to damage and its relation to functional recovery have become better understood.254 This understanding has, for example, provided a biological rationale for the efficacy of task-related training and the need for intensive therapy, and it has led to investigations of how and whether other drivers of neural reorganization can increase function. Although these techniques may reduce impairme
