Cerebrospinal Fluid in Clinical Practice

Author: David N. Irani MD

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 CEREBROSPINAL FLUID IN CLINICAL PRACTICE Copyright © 2009 by Saunders, an imprint of Elsevier Inc.

ISBN: 978-1-4160-2908-3

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 their 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 Authors 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 Cerebrospinal fluid in clinical practice / [edited by] David N. Irani. p. ; cm. Includes bibliographical references. ISBN 978-1-4160-2908-3 1. Cerebrospinal fluid. 2. Nervous system—Diseases. I. Irani, David N. [DNLM: 1. Central Nervous System Diseases—cerebrospinal fluid. 2. Cerebrospinal Fluid—physiology. WL 203 C4139 2009] QP375.C43 2009 612.8′042—dc22 2007051348

Acquisitions Editor: Adrianne Brigido Developmental Editor: Joan Ryan Project Manager: Bryan Hayward Design Director: Karen O’Keefe Owens

Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

Contributors Eric M. Aldrich, MD, PhD Associate Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

John W. Griffin, MD Professor, Departments of Neurology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Jennifer L. Berkeley, MD, PhD Instructor, Neurosciences Critical Care and Stroke, Departments of Neurology and Anesthesia and Critical Care Medicine, The Johns Hopkins School of Medicine; Instructor, Department of Anesthesia and Critical Care Medicine, The Johns Hopkins Hospital, Baltimore, Maryland

Dima A. Hammoud, MD Staff Neuroradiologist, Department of Diagnostic Radiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Anish Bhardwaj, MD, FAHA, FCCM Professor, Departments of Neurology, Neurosurgery, Anesthesiology/Peri-Operative Medicine, Oregon Health & Science University, Portland, Oregon Jaishri Blakeley, MD Assistant Professor, Departments of Neurology, Neurosurgery, and Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Peter A. Calabresi, MD Associate Professor, Department of Neurology, The Johns Hopkins University School of Medicine; Director, Johns Hopkins Multiple Sclerosis Center, The Johns Hopkins Hospital, Baltimore, Maryland Irene Cortese, MD Staff Clinician, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland Joao A. Gomes, MD Attending Neurologist, Department of Neurology, Hartford Hospital, Hartford, Connecticut Benjamin M. Greenberg, MD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Diane E. Griffin, MD, PhD Professor and Chair, Department of Molecular Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

Adam L. Hartman, MD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Jennifer Huffman, MD Fellow, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland David N. Irani, MD Associate Professor, Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan Richard T. Johnson, MD Professor, Departments of Neurology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland Douglas A. Kerr, MD, PhD Associate Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Matthew Koenig, MD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland John J. Laterra, MD, PhD Professor, Departments of Neurology, Neurosurgery, and Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Justin C. McArthur, MBBS, MPH Professor and Chair, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

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Contributors

Brett M. Morrison, MD, PhD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Avindra Nath, MD Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Richard J. O’Brien, MD, PhD Associate Professor, Department of Neurology, The Johns Hopkins University School of Medicine; Chairman, Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Katherine B. Peters, MD, PhD Fellow, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Gerald V. Raymond, MD Associate Professor, Department of Neurology, The Johns Hopkins School of Medicine; Director of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland Daniel S. Reich, MD, PhD Fellow, Division of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland Daniele Rigamonti, MD Professor and Vice Chairman, Department of Neurosurgery, The Johns Hopkins University School of Medicine; Professor, Co-Director of Hydrocephalus Program, Director of Center for Inherited Neurovascular Diseases, and Director of Stereotactic Radiosurgery, The Johns Hopkins Hospital, Baltimore, Maryland Jason D. Rosenberg, MD, PhD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Jeffrey A. Rumbaugh, MD, PhD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Ai Sakonju, MD Pediatric Neuromuscular Fellow/Neurophysiology Fellow, Department of Neurology, Clinical Neurosciences Center, University of Utah; Neurophysiology Fellow, Department of Neurology, University of Utah Hospital; Pediatric Neuromuscular Fellow, Department of Pediatric Neurology, Primary Children’s Medical Center, Salt Lake City, Utah Constance Smith-Hicks, MD, PhD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Katherine P. Thomas, MD Fellow, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland L. Christine Turtzo, MD, PhD Fellow, Department of Neurology, University of Connecticut Health Center, Farmington, Connecticut Anita Venkataramana, MB, BS Staff Neurologist, Multiple Sclerosis Comprehensive Center of Central Florida, Orlando Regional Health System, Orlando, Florida Arun Venkatesan, MD, PhD Assistant Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Eileen P. G. Vining, MD Professor, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Michael A. Williams, MD Attending Neurologist and Director, LifeBridge Health Brain & Spine Institute; Sinai Neurology Associates, Baltimore, Maryland Robin K. Wilson, MD, PhD Attending Neurologist, LifeBridge Health Brain & Spine Institute; Sinai Neurology Associates, Baltimore, Maryland Wendy Wright, MD Assistant Professor, Departments of Neurology and Neurosurgery, Emory University Hospital, Atlanta, Georgia

Preface I suspect I speak for many colleagues who completed their clinical training in neurology over the past few decades, when I say that one of the most beloved and highly consulted textbooks of my career has been Dr. Robert Fishman’s Cerebrospinal Fluid in Diseases of the Nervous System, Second Edition (1992). Indeed, my own copy is so worn and highlighted to be in dire need of replacement. While throughout his text Dr. Fishman acknowledges the classic monographs on the subject that came before his (Merritt and Fremont-Smith (1938), Davson (1967), Wood (1980, 1983), and Davson, Welch, and Segal (1987) to mention a few), his book has been so scholarly and yet accessible to me that it was daunting to even consider the prospect of taking on the subject myself. Still, advances in many fields such as neuroimaging, molecular diagnostics, genomics, and proteomics have shed much new light on the pathogenesis of neurological disease in recent years, and the time seemed right to organize a new text on the subject of human cerebrospinal fluid. Thus, when a group of very talented and energetic house officers at Johns Hopkins where we were all working at the time (Drs. Blakeley, Cortese, Greenberg, Hartman, Koenig, Morrison, and Smith-Hicks) collectively threw down the gauntlet regarding such a project, my reservations dissipated and the challenge was accepted. In conceiving of what has now become Cerebrospinal Fluid in Clinical Practice, my main goal has been to focus as directly as possible on issues that are most relevant to practicing clinicians. As can be observed from our list of chapters, Section 1 of our text encompasses a review of normal anatomy and physiology related to cerebrospinal fluid that now includes separate coverage of important issues such as the various examination, monitoring, and diversion techniques available to practitioners (Chapter 7), as well as modern methods for imaging of the cerebrospinal

fluid compartment (Chapter 9). I personally undertook the task of covering normal human cerebrospinal fluid findings (Chapter 10), in part because I felt that many of these reference values could not be found in a single place. Section 2 of our book addresses the cerebrospinal fluid findings in many different categories of neurological disease, and chapters on cerebrospinal fluid pressure and recirculation dynamics (Chapter 12), individual viral infections including those associated with human immunodeficiency virus (Chapter 21), and neoplastic and paraneoplastic disorders (Chapter 26), in particular, provide information not easily found together elsewhere. I am particularly grateful to the authors of the chapters in Section 3, who provide helpful guidance in the approach to the patient with particular common cerebrospinal fluid abnormalities. Finally, Section 4 is my personal nod to colleagues who are experimentalists and whose studies in animal models have taught us important lessons to keep in mind as we confront challenging patients, as well as some thoughts about the future of cerebrospinal fluid analysis. I am enormously grateful for the vision, talent, and dedication of the staff at Elsevier Publishing, particularly Susan Pioli who helped me get this project off the ground and more recently Adrianne Brigido and Joan Ryan without whom I would not have reached the finish line. I wish to thank my own teachers of neurology, particularly Dick Johnson as well as Jack and Diane Griffin, all of whom have instilled in me a love of the field and a thirst to serve the patients we confront every day. Finally, I would be totally lost without the love and support of my wife, Laurel, and my kids, Kate and Dan, who have encouraged me at every step of the process in bringing this project from concept to completion. David N. Irani, MD

CHAPTER

1

Historical Perspective Benjamin M. Greenberg

INTRODUCTION The purposeful accession of the cerebrum has occurred for many centuries, as evidenced by skulls recovered in Europe, Asia, America, and Africa that show evidence of trephination. Several skulls dated as far back as 10,000 BC reveal evidence of callus formation indicating that the individuals who underwent the procedure actually survived.1 There is no clear evidence, however, that these early intracranial interventions were intended to treat specific disorders of the cerebrospinal fluid (CSF) or for diagnostic purposes.

used to refer to excess water within the head, the location of the fluid was thought be in the subdural or the subarachnoid spaces and it was probably not used to define ventricular hydrocephalus. A more accurate description of hydrocephalus in a human was provided by Vesalius in 1555.2 He described enlarged ventricles, filled with fluid, in a 2-year-old child who died with a profoundly enlarged head. This report corrected the earlier misconceptions that hydrocephalus was caused by surface collections of fluid.

DIAGNOSTIC AND THERAPEUTIC SAMPLING OF CEREBROSPINAL FLUID NORMAL ANATOMY AND PHYSIOLOGY Ventricular drainage and catheters The first description of the meninges, ventricles, and CSF appeared in the Edwin Smith Surgical Papyrus (author unknown) believed to be written in the 17th century BC. The famous Greek physician, Galen (130–200 AD), described the anatomy of the ventricles, relying mostly on animal dissections, and referred to CSF as a clear liquid.2 Once human dissection became routine during the Renaissance, Leonardo da Vinci generated an accurate representation of human ventricular anatomy in 1510.3 While many further insights about the anatomy and physiology of the CSF system followed, it was not until 1875 that the first definitive work on the subject was published. Here, Ernst Key and Magnus Retzius of Sweden proved that CSF was produced by the choroid plexus, flowed through the ventricular system in a prescribed manner, and ultimately was reabsorbed back into the venous system at the arachnoid granulations.1

HYDROCEPHALUS The first scientific description of hydrocephalus is ascribed to Hippocrates (466–377 BC).4 While the term was accurately

In October 1744, Le Cat performed the first ventricular puncture, leaving behind a wick to allow for continued fluid drainage.5 These first attempts at ventricular drainage proved to be uniformly fatal. Various subsequent approaches, including drainage of ventricular CSF into the subcutaneous tissue, subdural and subarachnoid spaces, temporal sinus, sagittal sinus, and perintoneal cavity, were attempted with varying success. Wernicke used a lateral approach to access the trigone of the lateral ventricle in 1881.1 In 1905, Kausch was the first to use a tube to connect this space to the peritoneal cavity. Although the patient died of overdrainage, this technique would be further refined and now forms the basis of a ventriculoperitoneal shunt.5

Lumbar puncture The first lumbar puncture (LP) was attempted by Corning in 1885 for the purpose of instilling a medication into the CSF.6 There since has been much debate about whether Corning’s needle ever broke into the subarachnoid space, because he reported that no fluid was removed as he tried to study the anesthetic properties of intrathecal cocaine.

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Historical Perspective

Thus, the first successful LP recorded in history is attributed to Quincke in April 1891.7,8 He wrote: “… I punctured the subarachnoid space in the lumbar area, passing a very fine cannula two centimeter deep between the third and fourth lumbar spinal arches and drop by drop I drained a few cubic centimeters of watery clear fluid.” Still, at approximately the same time as Quincke’s procedure, Wynter described an alternative technique for draining CSF from the lumbar region. In his May 1891 paper in Lancet, he described making a small incision in the midlumbar region of a patient with tuberculous meningitis, dissecting down to the intervertebral space, and subsequently introducing a drainage tube into the subarachnoid space.7

Diagnostic analysis of cerebrospinal fluid After reporting his first successful LP, Quincke went on to describe his analyses of the various characteristics of CSF, including its cellularity and protein and glucose concentrations.8 As such, he probably deserves credit for introducing the LP into routine clinical practice.8 Queckenstedt published on the use of LP for measuring CSF pressure in various pathological conditions as well as on the analysis of CSF protein levels in various diseases.7 Mestrezat was one of the first to collect data and to report on the CSF findings in a large number of neurological disorders, and his monograph on the subject was considered a standard reference for many years.9 In the United States, texts generated by Levinson and by Merritt and Fremont-Smith both provided reference data on CSF abnormalities in human disease that remain valid today.10,11 The modern experimental literature on the physiology and pathophysiology of CSF has been elegantly recorded in the monographs of Davson and of Wood.12–14 Most recently, the field is indebted to Fishman for his scholarly works on the subject.15,16

PRESENT AND FUTURE In 1990, polymerase chain reaction (PCR) technology was first used to amplify herpes simplex virus DNA from the CSF of patients with herpes encephalitis.17 In many ways,

this study opened the modern era of molecular diagnostics for human neurological diseases in its practical application of a cutting edge scientific technique to human CSF samples. From here, it can easily be envisioned that the next century may bring the use of proteomics, lipomics, largescale nucleic acid microarray methods, and improved nucleic acid detection techniques to the hospital diagnostic laboratory. This, in turn, may expand the indications for and the usefulness of CSF analysis. A more complete vision of what the future of CSF-based diagnostic assays might hold is outlined in Chapter 34. REFERENCES 1. Aschoff A, Kremer P, Hashemi B, Kunze S. The scientific history of hydrocephalus and its treatment. Neurosurg Rev 1999;22:67–95. 2. Torack RM. Historical aspects of normal and abnormal brain fluids. I. Cerebrospinal fluid. Arch Neurol 1982;39:197–201. 3. Gjerris F, Snorrason E. The history of hydrocephalus. J Hist Neurosci 1992;1:285–312. 4. Aronyk KE. The history and classification of hydrocephalus. Neurosurg Clin N Am 1993;4:599–609. 5. Haynes I. Congenital internal hydrocephalus. Ann Surg 1913;57:449–484. 6. Gorelick PB, Zych D. James Leonard Corning and the early history of spinal puncture. Neurology 1987;37:672–674. 7. Sakula A. A hundred years of lumbar puncture: 1891–1991. J R Coll Physicians Lond 1991;25:171–175. 8. Frederiks JA, Koehler PJ. The first lumbar puncture. J Hist Neurosci 1997;6:147–153. 9. Mestrezat W. Le Liquide Céphalo-rachidien Normal et Pathologique. Paris: A. Maloine; 1912. 10. Levinson A. Cerebrospinal Fluid in Health and Disease. 3rd ed. St. Louis: C.V. Mosby; 1929. 11. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: W.B. Saunders; 1938. 12. Davson H. Physiology of the Cerebrospinal Fluid. London: Churchill; 1967. 13. Davson H, Welch K, Segal MB. The Physiology and Pathophysiology of the Cerebrospinal Fluid. New York: Churchill Livingstone; 1987. 14. Wood JH. Neurobiology of Cerebrospinal Fluid. Vols. 1 and 2. New York: Plenum Press; 1980, 1983. 15. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. Philadelphia: W.B. Saunders; 1980. 16. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: W.B. Saunders; 1992. 17. Powell KF, Anderson NE, Frith RW, Croxson MC. Non-invasive diagnosis of herpes simplex encephalitis. Lancet 1990;335:357–358.

CHAPTER

2

Normal Anatomy of the Cerebrospinal Fluid Compartment Adam L. Hartman

INTRODUCTION Anatomy of the cerebrospinal fluid (CSF)-containing spaces has occupied the attention of clinicians and scientists since even before the various functions of CSF were surmised. This chapter will cover topics related to CSF production, circulation, and absorption, with particular emphasis on the macroscopic anatomical features that have functional relevance to human disease states. Knowledge of this anatomy will aid in the understanding of many developmental and acquired disorders of the nervous system. Issues pertaining to CSF production, circulation, and absorption at a cellular and molecular level will be reviewed in Chapter 3. The cellular and molecular features of the blood–brain barrier (BBB) and blood–CSF barriers (BCB) will be covered in Chapter 6.

ANATOMY AND DEVELOPMENT OF THE CSF-CONTAINING SPACES AND THEIR SURROUNDING STRUCTURES The ventricular system The cerebral ventricles are the major intracranial CSFcontaining spaces (Fig. 2-1). Experimental evidence in lower vertebrates has shown that ventricular formation begins at an early stage of neural tube development. The central cavity of the neural tube, the neurocele, and the rostral neuropore, both close at this time, thereby preventing any physical communication with the amniotic fluid and allowing for the development of a pressure gradient in the ventricular system.1 Enlargement of the cerebral hemispheres occurs in part from this increase in CSF pressure and volume, as the process can be reversed in animals by cannulating the ventricles in utero at this stage.2 Ventricular zone cells adjacent to the cerebral ventricles also require

growth factors present in the CSF for neuronal development to proceed normally.2 In adults, normal circulation of CSF proceeds in a consistent and uniform manner through the ventricular system (Fig. 2-1). After production at the intraventricular choroid plexus (CP), CSF flows throughout the lateral ventricles, through the foramina of Monro, and into the third ventricle that lies amidst the diencephalon. Fluid then passes through the aqueduct of Sylvius into the fourth ventricle. Most CSF then flows into the subarachnoid space via the foramen of Magendie (midline) and the bilateral foramina of Luschka (lateral); only a minute amount enters the central canal of the spinal cord. Outside the brain, CSF collects in subarachnoid cisterns surrounding the brainstem. These spaces include the cisterna magna (posterior to the medulla and inferior to the cerebellar vermis), the medullary cistern (anterior to the medulla), the pontine cistern (anterior to the pons), the interpeduncular cistern (between the cerebral peduncles), the ambient cistern (around the midbrain), and the suprasellar cistern. Two other structures in infants that may contain CSF (and occasionally cause confusion on radiographic studies) include the cavum septum vergae, located between leaflets of the septum pellucidum, and a cavum velum interpositum, a posterior extension of the septum vergae, located above the third ventricle and below the corpus callosum. The cerebral ventricles are lined by a single layer of ciliated squamous or columnar ependymal cells.3 This ependymal lining is not a major permeability barrier that separates CSF from the underlying parenchyma.4 Found primarily in development but also at specific sites in the mature human brain, a specific type of transitional cell known as the tanycyte has radially oriented processes that extend into the neuropil, where they contact blood vessels, neurons, and glia.3 Tanycytes give rise to common ependymal cells as they mature.3 The ependyma does not regenerate well in response to pathological insults.3

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Normal Anatomy of the Cerebrospinal Fluid Compartment

Inf sagittal Choroid sinus plexus III v. Sup sagittal sinus

Arachnoid granulations Subarachnoid space

Dura

Dura Corpus callosum

Fornix

Straight sinus Foramen of Munro

Pons

Foramen of Luschka Choroid plexus IV v. Foramen of Magendie Figure 2-1 Patterns of CSF recirculation and flow. CSF is produced in the choroid plexus within the ventricles. It circulates in the lateral ventricles, then flows through the foramen of Monro into the third ventricle. Flow progresses through the aqueduct of Sylvius into the fourth ventricle and leaves the brain via the foramina of Luschka and Magendie. CSF bathes the spinal cord, then is resorbed at various levels, including the arachnoid granulations and along the subarachnoid spaces of certain cranial nerves and in spinal nerve roots.

Meninges The meninges constitute sequentially layered membranes that serve to encase and protect the central nervous system (CNS). The outermost layer is the thick, inelastic dura mater, which contains a rich vascular network, an extensive nerve supply, and its own lymphatic drainage channels. The two layers of dura mater are ordinarily adherent to each other, but they become separated in places to form the walls of the intracranial venous sinuses where CSF is eventually absorbed.5 The inner dural layer also forms a short sleeve around each cranial and spinal nerve as it leaves the CNS, and it extends caudally through the foramen magnum and into the spinal canal where it ensheaths the entire spinal cord and forms the lumbar thecal sac.4,5 The arachnoid mater is a layer of connective tissue with fine trabeculae that connect to the underlying pia mater and form a meshwork through which CSF recirculates.5 It lacks its own innervation and blood supply, likely deriving all of its metabolic support from the CSF itself. The arachnoid extrudes macroscopic pouches (arachnoid granulations) through the dura that form the intracranial venous sinuses as well as microscopic protuberances (arachnoid villi) into both cranial and spinal veins that are important routes of

CSF absorption back into the bloodstream.4 The pia mater is the innermost layer of the meninges and is directly adherent to the surface of the brain and spinal cord itself. Blood vessels entering or leaving the CNS that travel in the subarachnoid space have a sleeve of pia mater that penetrates into the parenchyma and forms the outer border of the perivascular space. The pia mater and the arachnoid mater together constitute the leptomeninges, while the layers of dura mater by themselves are often referred to as the pachymeninges. The microscopic and ultrastructural features of the meninges are covered in Chapters 3 and 6.

Choroid plexus The CP is found within the lateral, third, and fourth ventricles, and is the main site of CSF production. Developmentally, the CP forms shortly after the neural tube closes out of pseudorosettes created from the contact of ependymal epithelium and mesodermally derived tissues that protrude into the neural tube at sites where the cerebral ventricles are forming.2,6,7 Differentiation of these cells is largely complete by 22 weeks of gestation.3

Anatomy of CSF Production and Macroscopic Features of the CSF

These pseudorosettes enclose a core of loose mesenchyme and developing capillaries. CP cells in the lateral ventricles progress through various stages of differentiation, starting as pseudostratified tall epithelium, progressing through stages with low columnar and cuboidal morphology, and completing the process as cuboidal or squamous epithelium.2 Glycogen content, as well as villous, stromal, and vascular anatomy, vary between these stages as well.2 The pattern of protein expression in fetal CP epithelium is different from that seen in the ependyma and CP of adults.7 The arterial supply of the CP of the lateral ventricle arises from the anterior choroidal artery (a branch of the internal carotid artery), and the medial and lateral posterior choroidal arteries (branches of the posterior cerebral artery). There are extensive anastomoses between these two vascular sources. The third ventricle CP is supplied by the posterior cerebral artery, while the inferior cerebellar arteries usually supply the CP of the fourth ventricle.4 Venous drainage of these tissues is via the thalamostriate, internal cerebral, and basal veins. The extensive anastomotic network likely explains the rarity of infarcts involving the CP.8

Subcommissural organ The subcommissural organ (SCO), an important component of lower vertebrate CSF physiology, is present during human fetal life but regresses throughout early childhood. This tissue actively secretes glycoproteins into the CSF, although the exact roles played by these substances in normal and pathological states are poorly understood.9 One case report noted a hypoplastic SCO in two fetuses with obstructive hydrocephalus, raising the possibility that the SCO secretes factors that help maintain the patency of the aqueduct of Sylvius during normal development.10 However, since the hydrocephalus may have been the cause of the structurally abnormal SCO in these patients, confirmation of this hypothesis is necessary to establish a causal relationship between these two events.

Circumventricular organs Permeability of the BBB is altered in certain specialized areas of the brain, collectively referred to as the circumventricular organs (CVO). The ependymal lining at these sites has discontinuous gap junctions and few tight junctions, and the nearby endothelial cells have actual fenestrations.4 Structures of the CVO include the median eminence, the neurohypophysis, the pineal gland, the organum vasculosum of the lamina terminalis, the subfornical organ, the area posterma, and the CP.5 Cells in these areas have unique functions and are not composed of typical neural tissue – some are involved in secretory functions (e.g., the neurohypophysis), while others provide surveillance functions for the CNS (e.g., area postrema).

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Perivascular spaces It has long been recognized that CSF-containing perivascular channels, also known as Virchow-Robin spaces, surround major vessels as they course through the CNS parenchyma and maintain continuity with the subarachnoid space. Anatomical evidence suggests that as an artery enters the brain parenchyma, an extension of the pia mater surrounds it to form a definable sleeve. As they penetrate more deeply from the parenchymal surface, however, these pial layers approximate themselves with adjacent glia to the point where no definable perivascular space exists at the capillary level.5 These pial–glial cell interfaces form the adventitia of vessels and communicate with the subarachnoid space via gaps between leptomeningeal cells.5 Intracerebral veins have similar structures, but the meningeal layer around them is not as complete.5

ANATOMY OF CSF PRODUCTION AND MACROSCOPIC FEATURES OF THE CSF The CP that produces CSF within the lateral, third, and fourth ventricles is found where the pia mater and the ependyma join to form a seam. CSF is also produced to a lesser degree by the brain parenchyma itself via bulk flow along perivascular spaces and axon tracts.11 Although it is secreted continuously, there is a circadian variation to CSF production, with less made in the evening hours and larger volumes formed in the early morning hours.12 Details regarding the cellular and molecular aspects of CSF production are reviewed in Chapter 3. The average volume of the CSF-containing spaces in adults is reported to be about 150 ml, although these estimates are based primarily on older post mortem drainage studies.4 Given the potential for fixation artifact and post mortem changes in the brain, however, more recent studies in humans have used magnetic resonance imaging (MRI) technology for CSF volumetric and flow studies. Here, the entire intracranial CSF volume has been estimated at approximately 155 ml, while the average intraventricular CSF volume is about 25 ml.13 These volumes increase progressively with age and account for approximately 11% of the total intracranial volume in middle-aged adults.13 In the spine, most of the CSF is contained within the lumbar thecal sac. Recent MRI studies estimate that the volume of this compartment ranges between 30 and 45 ml in most healthy adults, but it can be as high as 60 ml in some individuals and as low as 10 ml in patients with documented spinal stenosis.14,15 Interestingly, the physiologic changes associated with hyperventilation and abdominal compression can reduce this volume by 10% and 28%, respectively, and this is directly attributable to engorgement of the epidural venous plexus that compresses the thecal sac.14 An average of 650 ml of CSF is produced in a 24-h period in adults, although there are significant individual variations in this amount.12

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Normal Anatomy of the Cerebrospinal Fluid Compartment

ANATOMICAL ROUTES OF CSF FLOW After exiting the brain, CSF circulates in the subarachnoid space, around the cerebral convexities, spinal cord, and nerve roots, and then gets reabsorbed through a variety of pathways to be discussed below. The physical movement of CSF is facilitated by hydrostatic pressure during its production, by arterial pulsations, and by directional beating of ependymal cilia.6 The contribution each parameter makes to net CSF flow is believed to vary based on the size of the lumen through which the fluid is passing; bulk flow likely predominates in the larger ventricles, while cilia are a more important variable in the more narrow regions such as the aqueduct of Sylvius. The major vessels of the circle of Willis course through the subarachnoid space and give rise to prominent vascular pulsations at the base of the brain, although arterial pulsations driving CSF flow have also been demonstrated within the ventricles. CSF pulsations over the convexities may be asynchronous, causing mixed directional flow of CSF at the level of the cervical spine.5 Abnormal ciliary function may rarely cause hydrocephalus in children with the immotile cilia syndrome.16 Other than the sites of its resorption, CSF may flow in a few other unique locations. In the inner ear, the cochlear aqueduct connects the subarachnoid space of the posterior fossa with the scala tympani, and the perilymph of the scala tympani in large part derives from CSF.4 Still, the actual rate of flow between these two structures via this channel is unclear. A study of 101 temporal bones showed that the patency of this duct varies between individuals, without any consideration of age or gender.17 In some individuals,

a simple low cuboidal epithelium may separate the perilymphatic space from the lumen of the duct.18 The physiological role of this flow is uncertain, but the channel may contribute to the spread of infection from the inner ear to the meninges.

BLOOD–CSF BARRIERS There are three major barriers that separate blood from the various CNS compartments, including two that directly involve the CSF. While the BBB separates blood from the brain interstitium, two BCB exist: one that is formed by cells of the CP, and another that exists at the level of the arachnoid granulations (Fig. 2-2).11,19 Brain capillaries differ from their systemic counterparts by the presence of tight junctions (limiting the movement of molecules), fewer pinocytotic vesicles, a greater number of mitochondria (reflecting high metabolic activity), a thicker basement membrane (to maintain structural rigidity in the face of hydrostatic stresses), and the presence of adjacent astrocytic end-feet.5,20 Capillaries of the CP, in contrast, have more notable fenestrations.19,20 The microscopic nature and functions of these structures are discussed in detail in Chapter 6.

ANATOMY OF CSF RESORPTION After circulating over the convexities of the brain, CSF gets resorbed through the small arachnoid villi and the larger arachnoid granulations. Most fluid passes through these

Choroid plexus endothelium

Brain capillary

Interstitium Tight junctions

Tight junctions Neuron Astrocyte

Figure 2-2 Location of tight junctions at the blood–brain barrier (left) and blood–CSF barrier (right). In the BBB, tight junctions are located in the wall of the brain capillaries, whereas in the BCB tight junctions are located at the level of the arachnoid epithelium.

Conclusions

structures into the intracranial venous sinuses and the bloodstream, but a small amount gets resorbed through villi present along the sheaths surrounding blood vessels and various cranial nerves. These sheaths, in turn, drain into extracranial lymphatic channels, and effluent eventually passes into deep cervical lymph nodes.11 Thus, in experimental animals, tracers injected into deep graymatter structures are sequentially detected in perivascular spaces, then in the subarachnoid space around the olfactory lobes and nerves. These substances are then found in the nasal submucosa, which contains a dense lymphatic plexus, and finally in the deep cervical chain.5 CSF also circulates around the spinal cord and the spinal nerve roots that project from it (Fig. 2-3). As these structures leave the spinal canal, arachnoid villi and arachnoid granulations form along the dura of the root sleeves and project into draining spinal veins.4 The arachnoid membrane reflects back on the proximal portion of emerging nerve root and does not accompany it for any great length; this is known as the subarachnoid angle, where proliferations of arachnoid cells invade the dura and mark the limit of the subarachnoid space.5 The base of these proliferations is continuous with the subarachnoid space and can penetrate the dura to varying degrees, allowing various amounts of CSF drainage among individuals.5 It is fair to say that the relative contribution of these structures to net CSF reabsorption is poorly understood. From a developmental standpoint, arachnoid villi and arachnoid granulations are largely imperceptible at birth, but they start to develop around this time and slowly increase in number with age.5 This finding, however, implies that there are other routes of CSF resorption during fetal and early post-natal life. In neonatal lambs, tracer studies have shown that global CSF transport rates and CSF outflow resistance are both nearly identical to measurements made in adult animals, despite the absence

Radicular vein

Dura mater Arachnoid Pia mater

CSF

9

of any defined arachnoid villi.21,22 Furthermore, although radiolabeled proteins could be detected in the superior sagittal sinus of neonatal animals in the setting of elevated intracranial pressure,22 the preferred site of CSF tracer efflux under normal pressures was actually via extracranial lymphatic pathways, especially through the cribiform plate.21 A direct connection between the subarachnoid space and nasal lymphatic channels has since been confirmed in humans,23 implying that this route of CSF drainage from the CNS may be active until the time that the arachnoid villi and arachnoid granulations are fully developed.

STRUCTURAL CORRELATES THAT PERTAIN TO NORMAL CSF FUNCTION Physiological functions of the CSF are many: mechanical protection of delicate neural structures, provision of metabolic support to the CNS, removal of metabolic waste products, and relative immunological protection to mention a few. It goes without saying that optimal service of these functions depends on the maintenance of many homeostatic balances involving the CSF (production, composition, flow, and resorption), or conversely, that disruption of these balances can directly underlie many CNS disorders. Practically speaking, however, most perturbations that cause overt disease occur at the level of CSF flow or CSF resorption; there are many fewer disorders that primarily disrupt CSF production or CSF composition. In terms of impaired CSF flow, areas of relative anatomical narrowing such as the foramen of Munro, the third ventricle, the aqueduct of Sylvius, the fourth ventricle, and the outflow foramina of Magendie and Luschka are particularly susceptible to both congenital and acquired disorders that cause obstructive hydrocephalus. In contrast, communicating hydrocephalus commonly develops in the setting of an event that allows cellular debris to collect within the arachnoid villi (such as in the wake of a subarachnoid hemorrhage or bacterial meningitis) or less commonly as a result of defects that impair venous drainage from the brain causing venous hypertension and impaired bulk CSF flow into the venous plexuses. On the other hand, only rarely does CSF overproduction cause hydrocephalus (such as in the setting of a choroid plexus papilloma). Successful treatment of these conditions often requires a surgically implanted shunt to provide an alternate conduit for CSF drainage. Chapter 12 will review these disorders in greater detail.

Spinal root

CONCLUSIONS Figure 2-3 CSF drainage at the level of spinal nerve roots. As spinal roots exit the spinal canal, arachnoid villi and arachnoid granulations penetrate the dura of the root sleeves projecting into the spinal veins, providing a path for drainage of CSF into radicular veins.

CSF is produced at the CP and to a lesser degree in the brain parenchyma. It flows through defined anatomical structures in a fairly predictable manner as it serves its various functions. Structural barriers isolate and protect the

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Normal Anatomy of the Cerebrospinal Fluid Compartment

CSF from the blood. Resorption occurs at the arachnoid granulations and arachnoid villi in adults, although passage into the cervical lymphatics may be an important alternative route in infants and young children. Understanding the anatomy and structure of the CSF-containing spaces is critical in the successful approach to many pathological states involving these spaces and the CSF itself. REFERENCES 1. Catala M. Embryonic and fetal development of structures associated with the cerebrospinal fluid in man and other species. Arch Anat Cytol Path 1998;46:153–169. 2. Dziegielewska KM, Ek J, Habgood MD, Saunders NR. Development of the choroid plexus. Microsc Res Tech 2001;52:5–20. 3. Bruni JE. Ependymal development, proliferation, and functions: a review. Microsc Res Tech 1998;41:2–13. 4. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadephia: W.B. Saunders; 1992. 5. Davson H, Segal MB. Physiology of the CSF and Blood-Brain Barriers. Boca Raton: CRC Press; 1996. 6. Perez-Figares JM, Jimenez AJ, Rodriguez EM. Subcommissural organ, cerebrospinal fluid circulation, and hydrocephalus. Microsc Res Tech 2001;52:591–607. 7. Sarnat HB. Histochemistry and immunocytochemistry of the developing ependyma and choroid plexus. Microsc Res Tech 1998;41:14–28. 8. Liebeskind DS, Hurst RW. Infarction of the choroid plexus. AJNR Am J Neuroradiol 2004;25:289–290. 9. Rodriguez EM, Oksche A, Montecinos H. Human subcommissural organ, with particular emphasis on its secretory activity during the fetal life. Microsc Res Tech 2001;52:573–590. 10. Castaneyra-Perdomo A, Meyer G, Carmona-Calero E, et al. Alterations of the subcommissural organ in the hydrocephalic human fetal brain. Dev Brain Res 1994;79:316–320. 11. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 2004;45:545–552.

12. Nilsson C, Stahlberg F, Thomsen C, Henriksen O, Herning M, Owman C. Circadian variation in human cerebrospinal fluid production measured by magnetic resonance imaging. Am J Physiol 1992;262:20–24. 13. Matsumae M, Kikinis R, Morocz IA, et al. Age-related changes in intracranial compartment volumes in normal adults assessed by magnetic resonance imaging. J Neurosurg 1996;84:982–991. 14. Lee RR, Abraham RA, Quinn CB. Dynamic physiologic changes in lumbar CSF volume quantitatively measured by three-dimensional fast spin-echo MRI. Spine 2001;26:1172–1178. 15. Sullivan JT, Grouper S, Walker MT, Parrish TB, McCarthy RJ, Wong CA. Lumbosacral cerebrospinal fluid volume in humans using three-dimensional magnetic resonance imaging. Anesth Analg 2006;103:1306–1310. 16. Greenstone MA, Jones RWA, Dewar A, Neville BG, Cole PJ. Hydrocephalus and primary ciliary diskinesia. Arch Dis Child 1984;59:481–482. 17. Gopen Q, Rosowski JJ, Merchant SN. Anatomy of the normal human cochlear aqueduct with functional implications. Hearing Res 1997;107:9–22. 18. Toriya R, Arima T, Kuraoka A, Uemura T. Fine structure of the human cochlear aqueduct: a light and transmission electron microscopic study of decalcified temporal bones. Eur Arch Otorhinolaryngol 1994;251(Suppl 1):S38–S42. 19. Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 1969;40: 648–677. 20. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006;7:41–53. 21. Papaiconomou C, Bozanovic-Sosic R, Zakharov A, Johnston M. Does neonatal cerebrospinal fluid absorption occur via arachnoid projections or extracranial lymphatics? Am J Physiol 2002;283: 869–876. 22. Papaiconomou C, Zakharov A, Azizi N, Djenic J, Johsnston M. Reassessment of the pathways responsible for cerebrospinal fluid absorption in the neonate. Childs Nerv Syst 2004;20:29–36. 23. Johnston M, Zakharov A, Papaiconomou C, Salmasi G, Armstrong D. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res 2004;1:2.

CHAPTER

3

Physiology of Cerebrospinal Fluid Secretion, Recirculation, and Resorption Brett M. Morrison

INTRODUCTION The brain actually has two discrete fluid compartments: the interstitial fluid (ISF) space that surrounds the neurons and glia, and the cerebrospinal fluid (CSF) that fills the ventricles and the external surfaces of the brain. The classic studies of Cserr et al. have shown that there is a slow turnover of brain ISF into the CSF,1,2 thus reinforcing Davson’s earlier concept of the CSF as a “sink for the brain.”3 Indeed, despite comprising a relatively small proportion of total intracranial and intraspinal volume, normal function of the central nervous system (CNS) depends on the CSF in many ways. This chapter will review the physiological roles of CSF, focusing particularly on the state of knowledge regarding the cellular and molecular mechanisms involved in its production, recirculation, and resorption.

NORMAL FUNCTIONS OF CSF The presence of a fluid compartment within and around the brain and spinal cord is advantageous to humans for several reasons. First, CSF has supported the expansion of brain size during human evolution. The average adult human brain now weighs approximately 1500 g, but when suspended in CSF, its effective weight is only 50 g.4 Thus, the brain literally floats in CSF; without it, gravity would render dependent portions of the brain more susceptible to trauma against the base of the skull. The presence of CSF has minimized the effects of this trauma and has made conditions more advantageous for brain growth over time. In a similar manner, CSF encases the brain and spinal cord and provides a cushion against external trauma. Still another of its protective capacities occurs in response to sudden fluctuations in intracranial pressure (ICP), where an extrusion of CSF from the cranial vault through the foramen magnum helps to normalize the pressure created

by obstructed venous outflow or an expanding mass lesion. This function is reflected in the Munro-Kellie doctrine, which holds that total intracranial volume equals the sum of brain, intracranial blood, and intracranial CSF volumes.5 Since intracranial volume remains constant in adults due to the fixed dimensions of the skull, any alteration in intracranial blood or brain volume must be matched by a compensatory decrease in CSF volume to maintain normal ICP. The physiology of CSF pressure dynamics is reviewed in detail in Chapter 4. A second critical function of CSF is the removal of metabolic by-products generated by the activity of neuronal and glial cells. Since there is no defined lymphatic system in the brain, all extracellular waste products must be removed by either passing directly from the ISF back into venous blood or by collecting in the CSF. Based on studies where the composition of venous blood in the jugular veins has been measured, it is clear that the cerebral vasculature clears a substantial amount of carbon dioxide (CO2), lactate, and hydrogen ions from the brain.6 Still, CSF resorbed at the arachnoid membrane (reviewed later) has already been added to this blood, and it has been difficult to estimate what proportion of these by-products come via the CSF rather than directly across the blood–brain barrier (BBB). It is clear from experimental intraventricular infusion studies, however, that polar molecules such as sucrose can be cleared via the extracranial CSF into the venous circulation.7 A third essential function of CSF is the distribution of biologically active substances throughout the brain. A well-characterized example of this process involves the hypothalamic–pituitary axis. From the hypothalamus, thyrotropin-releasing hormone and luteinizing-releasing hormone leave the neurosecretory cells and pass into the CSF of the third ventricle. Fluctuating levels of these hormones in CSF exert physiological changes in animals,8 and axon terminals of these neurosecretory cells abut the ventricular margins, suggesting that such CSF fluctuations and physiological changes directly result from activity of

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CSF Secretion, Recirculation, and Resorption

these specialized neurons.9 In terms of CSF serving as an afferent conduit of signals that alters regional brain activity, it is clear that CSF-contacting neurons in the circumventricular organs respond to changes in CSF composition. Thus, changes in CSF sodium (Na+) concentrations are known to alter water and sodium intake behaviors in mice through the actions of specialized Na+ channels expressed on neurons in the subfornical organ.10 Similarly, neurons in the medulla and spinal cord can respond to changes in CSF pressure and flow, while neurons in the septal and preoptic nuclei alter their firing in response to the presence of melatonin in the CSF.9

CSF SECRETION Overview of CSF production Production of CSF is a highly specialized process accomplished mainly by the choroid plexus (CP). Thus, less than 10% of CSF is produced by extrachoroidal sources, mostly arising from the ISF of the brain. The total volume of CSF in humans ranges from 140 to 270 ml, with about 25% filling the ventricles and the rest circulating in the basal cisterns, the subarachnoid space over the convexities of the brain, and around the spinal cord.11 The actual secretive capacity of the CNS is much greater, however, as the entire CSF volume is replaced about four times a day, with 24 h production levels exceeding 600 ml (~0.4 ml/min).11,12 Originally thought to be an ultrafiltrate of blood, CSF is now known to be actively secreted by the CP. The total mass of the human CP is approximately 2 g, meaning that CSF production occurs at a rate of about 0.21 ml/min/g tissue, many-fold higher than other epithelial surfaces.11,12

with numerous cytoplasmic mitochondria and an apical border with abundant microvilli and cilia that faces the ventricles.11 The CP is structurally unrelated to specialized regions of the arachnoid membrane that forms the other main blood–CSF barrier (BCB).

Composition of CSF Although the ionic composition of human CSF is quite similar to that of plasma, careful studies have revealed differences confirming that CSF cannot be formed by passive ultrafiltration as previously believed but must be made by active secretion. First, the osmolality of CSF is identical to that of blood, a finding that would not be expected with an ultrafiltrate. Second, the CSF concentration of most ions remains constant even in the setting of wide plasma fluctuations.13,14 Finally, CP cells isolated and cultured in vitro have the capacity to produce all the components of CSF without any associated blood supply.11,12 In comparing the two fluids, the main differences in CSF are that Na+ and potassium (K+) are a little lower, chloride (Cl−) is higher, and calcium (Ca2+) and magnesium (Mg2+) both have differences too large to be accounted for on the basis of simple equilibration (Table 3-1). The pH of CSF is slightly acidic, reflecting its higher pCO2 content and diminished buffering capacity compared to plasma (Table 3-1). Levels of glucose and amino acids are measurably lower in CSF versus plasma, and total protein content of the fluid is markedly reduced compared to what is present in circulation (Table 3-1). The protein concentration of CSF depends on many variables besides BCB permeability (i.e., developmental stage, site of sampling, recent or remote CNS disease, rate of CSF production, and CSF drainage resistance among others), and indeed, plasma may be the source of only a minor fraction of CSF proteins. Recent studies using highly

Cellular anatomy of the choroid plexus The CP are highly vascularized structures that consist of a single layer of epithelial cells surrounding a core of fenestrated capillaries and venules. They are located in the lateral, third, and fourth ventricles of the brain, and they are continuous with and branch out of the ependymal lining of these cavities. Small molecules, ions, and water readily diffuse through the CP vessels but are prevented from reaching the CSF by junctional complexes that connect the apical portions of the epithelial cells as they abut one another. These junctions are different from ones between the endothelial cells of the BBB, although some of the molecular components of these tight junctions are shared between the two sites.11 Transepithelial resistance offered by the CP is still the matter of some debate, as in vivo recordings have proven difficult. Most in vitro data suggest that the barrier is relatively low resistance (i.e., rather “leaky”), consistent with its large secretory capacity and the absence of steep concentration gradients for most solutes between plasma and CSF. At a microscopic level, the CP epithelium is highly adapted to its secretory role,

Table 3-1 Average Concentrations of Various Solutes (mEq/kg, unless otherwise specified) in Plasma and Lumbar CSF of Normal Human Subjects Solute Na+ K+ Mg2+ Ca2+ Cl− HCO3− Amino acids Total protein (mg/dl) Glucose (mg/dl) Osmolality (mOsm/kg) pH pCO2 (mmHg)

Plasma

CSF

150.0 4.63 1.61 4.70 99.0 26.8 2.62 6987.2 96.2 289.0 7.397 41.1

147.0 2.86 2.23 2.28 113.0 23.3 0.72 39.2 59.7 289.0 7.300 50.5

RCSF* 0.98 0.62 1.39 0.49 1.14 0.87 0.27 0.0056 0.62 1.00 – –

*RCSF = concentration in CSF/concentration in plasma. (Adapted from Davson H, Segal MB. Physiology of the CSF and Blood-Brain Barriers. Boca Raton, FL: CRC Press, 1996.)

CSF Secretion

the secretion of the CSF at the apical CP membrane. The importance of carbonic anhydrase was first demonstrated experimentally in rats and rabbits where administration of the carbonic anhydrase inhibitor, acetazolamide, reduced CSF production by as much as 50%.16,17 As a result, this drug is now used in humans with pseudotumor cerebri, presumably to lower ICP by slowing the rate of CSF production.18 The apical membrane of the CP, i.e., the side facing the ventricle, is the site of actual CSF secretion. The critical molecular components of this membrane include a Na+/potassium (K+) ATPase that transports three Na+ ions out of the cell in exchange for two K+ ions via energy provided by ATP hydrolysis, a Na+/K+/2Cl− co-transporter that moves all three of these ions out of the cell and is driven by the intracellular Cl− gradient, and channels for the selective secretion of K+ and HCO3− (Fig. 3-1). The important role of the Na+/K+ ATPase in CSF production was first demonstrated in studies using ouabain to inhibit the pump, resulting in the reduced movement of Na+ into the CSF and decreased overall CSF production.17 This ATPase is critical for creating a Na+ gradient that is used by many other transporters and exchangers in the CP cells, as well as for removing excess K+ from the CSF. Apical K+ channels utilize the electrochemical gradient generated by the Na+/K+ ATPase to drive its function, while the HCO3− channels depend directly on carbonic anhydrase for their function.11 The net effect of all these processes is the unidirectional secretion of NaCl and NaHCO3 into the ventricle, which is accompanied by the simultaneous movement of water from the bloodstream, across the apical membrane of the CP epithelium, and into the ventricle to form CSF. Aquaporins are regulated channels present on the apical (and probably also the basolateral) membrane that allow this movement of water down the osmotic gradient created by the ionic fluxes described above. Unlike other epithelial membranes, the paracellular movement of water across the CP is negligible.

sensitive detection and identification methodologies have identified more than 2,500 unique proteins in wellcharacterized pooled human CSF samples, with only about 400 of these species also being found in a database of human plasma proteins.15 The protein composition of normal human CSF will be reviewed in greater detail in Chapter 10.

Mechanisms of CSF secretion at the choroid plexus The driving force for fluid secretion across the CP is the active, unidirectional flux of ions from one side of the epithelial layer to the other, creating an osmotic gradient that is accompanied by the movement of water. This movement of ions across these cellular membranes is mediated by specific transporters and ion channels that are distributed unequally on the basolateral and apical sides of the CP epithelial layer (Fig. 3-1). Beginning at the basolateral surface adjacent to where ISF has leaked from the fenestrated capillaries, two molecules directly involved in CSF production are the Na+/ hydrogen (H+) and the Cl−/ bicarbonate (HCO3−) ion exchangers that bring Na+ and Cl− into the cell in exchange for H+ and HCO3−, respectively. These exchangers control both intracellular pH and ionic composition. Six isoforms of the Na+/H+ exchanger and three isoforms of the Cl−/HCO3− exchanger have been identified. Specific roles for each of these individual molecules have not yet been elucidated.11 An important intracellular enzyme involved in CSF production is carbonic anhydrase, a molecule that catalyzes the conversion of water and CO2 into HCO3− and H+. The HCO3− and H+ ions produced by its actions are then exchanged via the Na+/H+ and Cl−/HCO3− exchangers in the basolateral membrane, although a small amount of HCO3− exits the cell into the CSF via an apical channel. Intracellular Na+ and Cl− are then directly involved in

Basolateral

13

Apical 3 Na+ Na+ 2 K+

H+

Cl–

Na+ K+ 2 Cl– K+

HCO3– Carbonic anhydrase CO2 + H2O H+ + HCO3– BLOOD

HCO–3

VENTRICLE H2O

Figure 3-1 Distribution of ion transporters, co-transporters, and ion channels at the choroid plexus involved in CSF secretion. The epithelial cells that cover the fenestrated capillaries and venules have microvilli and cilia on their apical (CSF) side and are bound together by occluding bands of tight junctions (black square). On the blood (basolateral) side, the Na+/H+ and Cl−/HCO3− ion exchangers bring Na+ and Cl− into the cell (dark ovals). Inside the cell, carbonic anhydrase converts water and CO2 into H+ and HCO3−. On the CSF (apical) side, a Na+/K+ ATPase and a Na+/K+/2Cl− co-transporter (dark ovals) facilitate the unidirectional movement of Na+, Cl−, and HCO3− into the ventricle that drives the transcellular movement of water into the CSF via aquaporin channels (open rectangle).

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CSF Secretion, Recirculation, and Resorption

The importance of the aquaporins in this process has recently been demonstrated in studies showing reduced CSF production in transgenic animals lacking aquaporin-1.19 Because CSF production was not completely blocked in these animals, however, redundant mechanisms that move water into the CSF likely exist. Finally, although the exact degree of extrachoroidal CSF production is not known (it is estimated to be 10% of total CSF production), evidence supporting these alternative sites of CSF formation is convincing. First, CSF can be produced in vitro by extrachoroidal tissues such as an isolated sylvian aqueduct preparation from rabbits and in vivo within the lumbar thecal sac of patients with a complete cervical cord block.20 Second, CSF production is reduced but not totally eliminated by surgical choroid plexotomy.21 Finally, transependymal CSF formation was directly shown to contribute to ventricular CSF in rabbits.22 This latter process was presumed to result from cellular metabolism and/or the ultrafiltration of the blood through cerebral vessels. Further investigation into the mechanisms of extrachoroidal CSF production, as well as its role in the normal and the diseased brain, is needed to enhance our understanding of the overall processes involved in CSF production.

aqueduct and around the foramen magnum and cervical cord, and these studies can now be used to confirm structural patency at these sites.27 At a molecular level, recent studies in transgenic mice have identified some of the genes that regulate the formation and motility of ependymal cilia necessary to generate CSF flow.28,29 These data confirm reports in humans that defects in ciliary function predispose to abnormal CSF flow and the development of hydrocephalus.30 Another newly recognized role of ependymal cilia and CSF flow relates to the directional migration of neuronal precursors from the subventricular zone where they originate to distant regions such as the olfactory system in the process normal neurogenesis.31 Finally, since CSF absorption can occur at many locations over the cerebral convexities and along cranial and spinal nerves, it is logical to conclude that effective CSF recirculation does not ultimately have to be directed to one final common location. Together, these data suggest that the dynamics of CSF flow are poorly understood and that further study is necessary to better define these important processes.

CSF RESORPTION Overview of CSF resorption

Control of CSF secretion CSF is secreted in a slow, continuous manner, and at first pass there seems little reason to believe that this process should be actively controlled. There is, however, a complex autonomic innervation of the CP, and both noradrenergic and peptidergic signaling have been implicated in altering CSF production.23 Thus, CSF secretion appears tonically inhibited by local sympathetic innervation independent of any effect on choroidal blood flow.24 This control is exerted by β2 adrenergic receptors, and it may serve to dampen CSF secretion should resistance to resorption increase for whatever reason.25 Other studies have implicated an effect of vasoactive intestinal peptide (VIP) and neuropeptide Y in this process.23

CSF RECIRCULATION AND FLOW According to the classical paradigm of CSF circulation, fluid produced by the CP flows in a uniform manner from within the ventricles into the subarachnoid space that surrounds the brain and spinal cord and is finally resorbed by the arachnoid granulations. Based in part on current knowledge of CSF production and absorption, however, it is likely that CSF recirculation patterns are far more complex. Thus, while CSF does generally move through the ventricular system into the subarachnoid space, flow may be pulsatile and bidirectional rather than laminar in nature.26 Modern magnetic resonance imaging (MRI) sequences demonstrate this pulsatile CSF flow, especially through areas of anatomical narrowing such as the cerebral

In contrast to CSF secretion, which is a highly orchestrated event, CSF absorption occurs via bulk flow physiology and not by any regulated transport process. In normal individuals, the rate of CSF absorption is matched to the rate of CSF production. Although it was initially thought that CSF was resorbed exclusively into the sagittal sinus through the arachnoid granulations and villi, evidence now exists for bulk flow of CSF into venous blood throughout the cranial and spinal compartment. Furthermore, some CSF can also be resorbed by the CP itself, and thus pass into cervical and thoracic lymphatic channels as it leaves the CNS. In general, disrupted CSF resorption, much more so than any defect on the production side, is believed to underlie the pathogenesis of such disorders as adult hydrocephalus and pseudotumor cerebri. These conditions that result in pathologically increased CSF volume and pressure, respectively, are reviewed in Chapter 12.

Physiology of the arachnoid villi Arachnoid villi are microscopic herniations of the arachnoid membrane that penetrate the overlying dura and invaginate through the walls of the superior sagittal sinus and other venous structures. Arachnoid granulations are macroscopic structures composed of multiple villi and are primarily found within the superior sagittal sinus. There are many more villi than granulations, and the relative volume of CSF transported by each type of structure is not known. Arachnoid villi act as one-way valves for the flow of CSF into venous blood, and hydrostatic pressure is the main stimulus that causes these valves to open. In an early

CSF Resorption

experimental model where isolated sections of primate cerebral venous sinuses were studied ex vivo, CSF flow across these structures proved to be unidirectional and required a minimum pressure of 20 mmH20 to occur.32 Furthermore, the flow rate depended on the pressure gradient, with increasing pressure resulting in increased flow. Conversely, CSF composition did not measurably affect absorption, as particles ranging from 0.2 μm to 7.5 μm passed through these isolated villi at the same rate.33 These data provide strong experimental evidence that CSF absorption across the arachnoid villi occurs via bulk flow. Subsequent reports by Tripathi et al. and Levine et al. clarified actual flow mechanisms.34,35 These studies demonstrated the presence of giant vacuoles in the arachnoid granulations that readily took up contrast material that had been injected into the cisterna magna. This vacuolar material was then released into the vasculature through pores in the endothelial cells (Fig. 3-2). The dependence on CSF pressure was explained by a variable number of these vacuoles and pores found in primates that had been sacrificed at times of normal, low, or high CSF pressures.35 Thus, under normal or high pressure conditions, large vacuoles and pores were seen by electron microscopy, while they were absent (and replaced by an entirely smooth endothelium) in animals with low CSF pressure.35 In vivo measurement of CSF absorption in humans has proven somewhat more difficult to accomplish, but Cutler et al. used the technique of ventriculolumbar perfusion to

Venous sinus

Pressure

Pressure

Subarachnoid CSF

Figure 3-2 Structure of an arachnoid villus. Each villus is formed by an outpouching of the arachnoid membrane that penetrates the dura and allows the subarachnoid space to come into close contact with venous blood (circular image, left). At a higher magnification, hydrostatic pressure creates giant vacuoles (some of which elongate to become actual pores) that transport CSF unidirectionally from the subarachnoid space into the bloodstream exiting the CNS (square image, right). Transport is transcellular; the arachnoid cells have tight intercellular junctions. (Adapted with permission from Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System, second edition. Philadelphia: W.B. Saunders Company, 1992.)

15

monitor the rates of both CSF formation and CSF absorption at different levels of CSF pressure. They found that while CSF formation remained relatively constant at about 0.35 ml/min over a CSF pressure range of 0 to 220 mmH2O, measurable CSF absorption began at around 68 mmH2O and increased in a linear fashion up to pressures of 250 mmH2O and to a maximum rate of 1.5 ml/min.36 Formation and absorption rates were equal at pressures of about 112 mmH2O.36 These data are important because they show the low resistance to CSF absorption in humans, and they indicate that a very large increase in the rate of CSF formation would be required to raise CSF pressure into a pathological range. The fact that absorption falls below production at a measurable pressure level suggests the presence of a homeostatic response to stabilize ICP and CSF volume. Likewise, increased absorption rates with high ICP would serve to mitigate the sequelae of high pressures. Since the early experimental work on the function of arachnoid villi in primate cerebral venous sinuses, electron microscopic studies of human tissues have confirmed the presence of arachnoid villi along some cranial nerves as well as along nerve roots in the spinal cord that appear to drain CSF into the surrounding spinal venous plexus.37,38

Alternative routes of CSF resorption While the arachnoid villi provide a simple mechanism for resorbing CSF, several pieces of evidence suggest that alternative mechanisms may operate as well. Thus, while the CP develops early in gestation and CSF production begins late in the first trimester,39 anatomically defined arachnoid villi do not appear until some time well after birth.40,41 Similarly, the pressure gradient necessary for CSF absorption across the arachnoid villi is not reached until several weeks after birth.42 Finally, abnormalities of the arachnoid villi have not been convincingly linked to the occurrence of congenital hydrocephalus. If this were the sole mechanism of CSF resorption at this stage of life, examples of hydrocephalus due to disruption of the villi would surely be evident. Together, these data suggest the existence of alternate CSF absorption routes, some of which appear to involve the lymphatic system and the CP itself. In addition to its function in CSF secretion, the CP can also absorb specific compounds from the CSF. This has been convincingly demonstrated in vivo with the clearance of organic acids or penicillin injected into the subarachnoid space.43,44 In vitro studies have confirmed these findings, and specific membrane carriers responsible for this function have been identified.4 While the contribution of the CP to overall CSF clearance is likely quite small, this pathway may be important for resorption of specific molecules from the CSF. The brain traditionally has been considered to be devoid of a lymphatic drainage system. Nevertheless, it has long been known that contrast material injected into the subarachnoid space can later be found in lymph nodes.

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CSF Secretion, Recirculation, and Resorption

Further studies using specific tracers have demonstrated that CSF is able to pass into the connective tissue surrounding the cranial nerves and spinal nerve roots. Early studies showed that ink injected into the lateral ventricle of rabbits traveled to the subarachnoid regions surrounding lumbosacral and cervical nerve roots, and then into paraspinal lymph nodes over only a few hours.45 Thereafter, specific proteins injected into the brain could be found in the cervical lymphatic system.46 Such an efflux pathway has been proposed to be one mechanism by which antigens may leave the CNS for eventual recognition by the immune system.47 The subarachnoid space is continuous with dural sleeves that ensheath the acoustic, optic, and olfactory nerves. For this reason, contrast material injected into the cisterna magna rapidly accumulates around these structures.48,49 Although any of these pathways could conceivably allow CSF to pass into the lymphatic system, the olfactory nerves and the pathways that traverse the cribiform plate to reach the nasal mucosa have been a specific area of focus. After reaching the nasal mucosa, CSF is absorbed by local lymphatic channels and ultimately is filtered by the cervical lymph nodes.50 Some investigators have suggested that up to 50% of CSF absorption in rats occurs through the extracranial lymphatics.51 This fraction appears to be closer to 30% in cats and rabbits, but its magnitude in humans is not known.52,53 In another experimental approach, blocking outflow at the cribiform plate using bone wax dramatically reduced CSF absorption.54 This presumably reduced CSF drainage into the nasal lymphatics. Taken together, these studies suggest a significant role for lymphatic drainage in CSF absorption. Further studies in humans will be necessary to determine the relative importance of lymphatic efflux compared to other absorptive mechanisms.

CONCLUSIONS Despite the importance of CSF in maintaining normal function of the nervous system, surprisingly little is known about the physiology of CSF production, recirculation, and resorption. CSF production by the CP has been studied at a molecular level, which has led to the identification of drugs that can regulate this process to the benefit of many patients. On the other hand, relatively little is known about disruptions to CSF dynamics that lead to the development of disorders such as hydrocephalus and pseudotumor cerebri. Similarly, while it seems intuitive that CSF is an important interface between the nervous system and the immune system, we have only a limited understanding of how antigens are carried out of the brain and spinal cord for the process of immune recognition. Further study of the cellular and molecular physiology of the CSF dynamics will likely shed important light on the pathogenesis of a number of human neurological diseases.

REFERENCES 1. Cserr HF, Cooper DN, Milhorat TH. Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res 1977;25(Suppl.):461–473. 2. Cserr HF, Cooper DN, Suri PK, Patlak CS. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol 1981;240:F319–F328. 3. Bito LZ, Bradbury MWB, Davson H. Factors affecting the distribution of iodide and bromide in the central nervous system. J Physiol 1966;185:323–354. 4. Cserr HF. Physiology of the choroid plexus. Physiol Rev 1971;51:273–311. 5. Ropper AH, Gress DR, Diringer MN, Green DM, Mayer SA, Bleck TP. Neurological and Neurosurgical Intensive Care. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004. 6. Nilsson B, Siesjo BK. A venous outflow method for measurement of rapid changes of the cerebral blood flow and oxygen consumption in the rat. Stroke 1983;14:797–802. 7. Ghersi-Egea JF, Finnegan W, Chen JL, Fenstermacher JD. Rapid distribution of intraventricularly administered sucrose into cerebrospinal fluid cisterns via subarachnoid velae in rat. Neuroscience 1996;75:1271–1288. 8. Knigge KM, Schock SA, Silverman AJ, et al. Role of the ventricular system in neuroendocrine processes: synthesis and distribution of thyrotropin releasing factor (TRF) in the hypothalamus and third ventricle. Can J Neurol Sci 1974;1:74–84. 9. Vigh B, Manzano e Silva MJ, Frank CL, et al. The system of cerebrospinal fluid-contacting neurons. Its supposed role in the nonsynaptic signal transmission of the brain. Histol Histopathol 2004;19:607–628. 10. Hiyama TY, Watanabe E, Okado H, Noda M. The subfornical organ is the primary locus of sodium-level sensing by Na(x) sodium channels for the control of salt-intake behavior. J Neurosci 2004;24:9276–9281. 11. Redzic ZB, Segal MB. The structure of the choroid plexus and the physiology of the choroid plexus epithelium. Adv Drug Deliv Rev 2004;56:1695–1716. 12. Speake T, Whitwell C, Kajita H, Majid A, Brown PD. Mechanisms of CSF secretion by the choroid plexus. Microsc Res Tech 2001;52:49–59. 13. Pollay M, Hisey B, Reynolds E, Tomkins P, Stevens FA, Smith R. Choroid plexus Na+/K+-activated adenosine triphosphatase and cerebrospinal fluid secretion. Neurosurgery 1985;17:768–772. 14. Murphy VA, Smith QR, Rapoport SI. Homeostasis of brain and cerebrospinal fluid calcium concentrations during chronic hypo- and hypercalcemia. J Neurochem 1986;47:1735–1741. 15. Pan S, Zhu D, Quinn JF, et al. A combined dataset of human cerebrospinal fluid proteins identified by multi-dimensional chromatography and tandem mass spectrometry. Proteomics 2007;7:469–473. 16. Maren TH, Broder LE. The role of carbonic anhydrase in anion secretion into cerebrospinal fluid. J Pharmacol Exp Ther 1976;172:197–202. 17. Davson H, Segal MB. The effects of some inhibitors and accelerators of sodium transport on the turnover of 22Na+ in the cerebrospinal fluid and the brain. J Physiol 1970;209:139–153. 18. Friedman DI. Pseudotumor cerebri. Neurol Clin N Am 2004;22:99–131. 19. Oshio K, Watanabe H, Song Y, Verkman AS, Manley GT. Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 2005;19:76–78. 20. Pollay M, Curl FD. Secretion of cerebrospinal fluid by the ventricular ependyma of the rabbit. Am J Physiol 1967;213:1031–1038. 21. Bering EA, Sato O. Hydrocephalus: changes in formation and absorption of cerebrospinal fluid within the cerebral ventricles. J Neurosurg 1963;20:1050–1063. 22. Curl FD, Pollay M. Transport of water and electrolytes between brain and ventricular fluid in the rabbit. Exp Neurol 1968;20:558–574.

References

23. Nilsson C, Lindvall-Axelsson M, Owman C. Neuroendocrine regulatory mechanisms in the choroid plexus-cerebrospinal fluid system. Brain Res Rev 1992;17:109–138. 24. Alm A, Bill A. The effect of stimulation of the cervical sympathetic chain on retinal oxygen tension and on uveal, retinal, and cerebral blood flow in rats. Acta Physiol Scand 1973;88:84–94. 25. Nathanson JA. Beta-adrenergic-sensitive adenylate cyclase in choroid plexus: properties and cellular localization. Mol Pharmacol 1980;18:199–209. 26. Du Boulay G, O’Connell J, Currie J, Bostick T, Verity P. Further investigations on pulsatile movements in the cerebrospinal fluid pathways. Acta Radiol Diagn 1972;13:496–523. 27. McCormack EJ, Egnor MR, Wagshul ME. Improved cerebrospinal fluid flow measurements using phase contrast steady-state free precession. Magn Reson Imaging 2007;25:172–182. 28. Ibanez-Tallon I, Pagenstecher A, Fliegauf M, et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet 2004;13:2133–2141. 29. Banizs B, Pike MM, Millican CL, et al. Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development 2005;132:5329–5339. 30 Greenstone MA, Jones RWA, Dewar A, Neville BG, Cole PJ. Hydrocephalus and primary ciliary diskinesia. Arch Dis Child 1984;59:481–482. 31. Sawamoto K, Wichterle H, Gonzalez-Perez O, et al. New neurons follow the flow of cerebrospinal fluid in the adult brain. Science 2006;311:629–632. 32. Welch K, Friedman V. The cerebrospinal fluid valves. Brain 1960;83:454–469. 33. Welch K, Pollay M. Perfusion of particles through arachnoid villi of the monkey. Am J Physiol 1961;201:651–654. 34. Tripathi BJ, Tripathi RC. Vacuolar transcellular channels as a drainage pathway for cerebrospinal fluid. J Physiol 1974;239:195–206. 35. Levine JE, Povlishok JT, Becker DD. The morphological correlates of primate cerebrospinal fluid absorption. Brain Res 1982;241:31–41. 36. Cutler RWP, Page L, Galicich J, Walters GV. Formation and absorption of cerebrospinal fluid in man. Brain 1968;91:707–720. 37. Kido DK, Gomez DG, Pavese AM, Potts DG. Human spinal arachnoid granulations. Neuroradiology 1976;11:221–228. 38. Edsbagge M, Tisell M, Jacobsson L, Wikkelso C. Spinal CSF absorption in healthy individuals. Am J Physiol 2004;287:R1450–R1455. 39. Johanson CE. Ventricles and cerebrospinal fluid. In: Conn P, ed. Neuroscience in Medicine. Philadelphia: J.B. Lippincott; 1995: 171–196.

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40. Osaka K, Handa H, Matsumoto S, Yasuda M. Development of the cerebrospinal fluid pathway in the normal and abnormal human embryos. Child’s Brain 1980;6:26–38. 41. Fox RJ, Walji AH, Mielke B, Petruk KC, Aronyk KE. Anatomic details of intradural channels in the parasagittal dura: a possible pathway for flow of cerebrospinal fluid. Neurosurgery 1996;39:84–91. 42. Johnston M, Papaiconomou C. Cerebrospinal fluid transport: a lymphatic perspective. News Physiol Sci 2002;17:227–230. 43. Pappenheimer JR, Heisey SR, Jordan EF. Active transport of diodrast and phenylsulfonphthalein from cerebrospinal fluid to blood. Am J Physiol 1961;200:1–10. 44. Fishman RA. Blood-brain and CSF barriers to penicillin and related organic acids. Arch Neurol 1966;15:113–124. 45. Brierley JB. The penetration of particulate matter from the cerebrospinal fluid into the spinal ganglia, peripheral nerves and perivascular spaces of the central nervous system. J Neurchem 1950;13:203–215. 46. Yamada S, DePasquale M, Patlak SC, Cserr HF. Albumin outflow into deep cervical lymph nodes from different regions of rabbit brain. Am J Physiol 1991;261:H1197–H1204. 47. Cserr HF, Knopf PM. Cervical lymphatics, the blood-brain barrier, and the immunoreactivity of the brain: a new view. Immunology Today 1992;13:507–512. 48. Faber W. The nasal mucosa and the subarachnoid space. Am J Anat 1937;62:121–148. 49. Davson H, Welch K, Segal M. Physiology and Pathophysiology of the Cerebrospinal Fluid. New York: Churchill Livingstone; 1987. 50. Kida S, Pantazis A, Weller RO. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology, and immunological significance. Neuropathol Appl Neurobiol 1993;19:480–488. 51. Boulton M, Flessner M, Armstrong D, Mohamed R, Hay J, Johnston M. Relative contribution of arachnoid villi and extracranial lymphatics to the clearance of a CSF tracer in the rat. Am J Physiol 1999;276: R818–R823. 52. Courtice FC, Simmonds WJ. The removal of protein from the subarachnoid space. Aust J Exp Biol Med Sci 1951;29: 255–263. 53. Bradbury MW, Cole DC. The role of the lymphatic system in drainage of cerebrospinal fluid and aqueous humour. J Physiol 1980;299: 353–365. 54. Bradbury MW, Westrop RJ. Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J Physiol 1983;339:519–534.

CHAPTER

4

Normal Intracranial Pressure Physiology Joao A. Gomes and Anish Bhardwaj

INTRODUCTION AND HISTORICAL PERSPECTIVES Intracranial pressure (ICP) is defined as the pressure within the craniospinal compartment, a closed system that comprises a fixed volume of neural tissue, blood, and cerebrospinal fluid (CSF). At any given moment, ICP is derived from the relationship between changes in intracranial volume and the ability of the craniospinal compartment to compensate for such volume changes. ICP can also be expressed in terms of the difference between CSF pressure and atmospheric pressure. Quincke is generally credited with developing the modern technique of lumbar puncture (LP) in the late 1870s.1 He was also a strong proponent of routine pressure measurement at the beginning and end of the procedure, and he was the first to perform these measurements using a glass pipette.1 Subsequently, Queckenstedt then Tobey and Ayer proposed jugular compression during CSF pressure recording to evaluate for the presence of spinal subarachnoid block and lateral dural venous sinus thrombosis, respectively.2,3 Ayala generated a formula to estimate the volume of the ventriculo-subarachnoid space utilizing pressure measurements derived from a large clinical series in which ICP was systematically measured in normal subjects and diseased individuals.4 These results have remained a standard reference since their original publication in 1925. Merritt and Fremont-Smith measured lumbar CSF pressures in over 1000 patients and concluded that values of up to 180 mm CSF were normal, while those between 180 and 200 mm CSF should be considered “doubtful.”5 Similarly, pressures measured at the level of the cisterna magna in 1500 patients by Spina-França ranged between 41 and 197 mm CSF in normal individuals.6 Based on these seminal observations, it is currently accepted that normal physiologic ICP ranges between 5 and 15 mmHg (65 to 195 mm CSF) in routine clinical practice. Table 4-1 lists the upper limit of what should be considered normal ICP based on age.

Adson and Lillie introduced ventricular puncture with catheter insertion in 1927, allowing for a more direct assessment of ICP.7 Langfit et al. demonstrated in 1964 that during transtentorial herniation, lumbar and infratentorial pressures lag far behind supratentorial measurements, rendering lumbar CSF pressure assessment less useful and potentially dangerous in this setting.8,9 These results prompted the measurement of ICP using fluid-filled catheters placed directly into the ventricular system,10 which has since led to the development of the technologies still widely used today. International symposia on ICP are held regularly in a continual attempt to advance knowledge on ICP physiology, pathology, and treatment.

ANATOMY AND PHYSIOLOGY OF THE INTRACRANIAL COMPARTMENT WITH NORMAL AND ELEVATED ICP In adults, the intracranial space is defined by the inner surface of the skull. It therefore has a finite, non-distensible volume. The foramen magnum communicates directly with the spinal subarachnoid space and represents the main exit from the calvarium. Within the skull, reflections of the dura mater further compartmentalize the intracranial contents. Thus, a small incisura of the cerebellar tentorium serves as the thruway between the middle and the posterior fossae.11 The intracranial compartment is filled with three main components, none of which is particularly compressible. Brain parenchyma takes up an estimated volume of 1300–1500 ml, intracranial CSF comprises approximately 75 ml (about 33% of which is contained within the ventricles), and cerebral blood volume (CBV) accounts for another 75 ml (some 70% of which is in the low-pressure, high-capacity venous system). In various pathological conditions causing increased intracranial volume (i.e., tumor, hemorrhage, or brain edema),

20

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Table 4-1

●

Normal Intracranial Pressure Physiology

rewrote the Monro-Kellie hypothesis, stating that while the volume of the intracranial compartment remains constant, CBV and CSF volume vary inversely with each other.14

Upper Limit of Normal ICP by Age

Age group

ICP (mmHg)

Term infants Children Adults

<7.5 <10 <15

NORMAL CSF PULSATIONS AND ABNORMAL ICP WAVEFORMS compensatory mechanisms play a major role in preventing or minimizing changes in ICP. Initially, CSF is displaced from the intracranial compartment through the foramen magnum and into the spinal subarachnoid space. Thereafter, CBV falls, primarily at the expense of the venous contents, but also through changes in the diameter of the basal arteries. Ultimately, if the pathological insult in question continues to progress, or if these compensatory mechanisms fail to control ICP, brain tissue is forced from one compartment to another or through the foramen magnum causing various cerebral herniation syndromes. This complementary relationship between the volumes of brain parenchyma, blood, and CSF has been termed the Monro-Kellie doctrine. In 1783, Monro postulated that “because, being enclosed in a case of bone, the blood must be continually flowing by the veins, that room may be given to the blood which is entering the arteries. For, as the substance of the brain, like that of other solids in our body, is nearly incompressible, the quantity of blood within the head must be the same, or very nearly the same at all times.”12 Several years later, Kellie made further observations on autopsy specimens that corroborated Monro’s original assumptions.13 Still, both Monro and Kellie failed to consider the contribution of CSF dynamics to these compensatory mechanisms. Burrows amended this oversight and

Since the introduction of the LP into routine clinical practice, small pulsations of the CSF column related both to respiration and to the cardiac cycle have been observed. During normal breathing, CSF pressure drops during inspiration and rises during expiration by 2–5 mm CSF. These fluctuations in CSF pressure are accentuated with deep breathing (5–10 mm CSF), and they have been attributed to the negative intrathoracic pressure and improved venous return that occur during the inspiratory phase. Simultaneous lumbar, cisternal, and intraventricular pressure measurements have shown that the carotid artery pulse wave is immediately followed by a ventricular wave of similar configuration that can be recorded along the craniospinal axis (Fig. 4-1).15 While pulsations of the basal arteries comprising the circle of Willis could contribute to this ventricular waveform, the choroid plexus is traditionally credited as being the site where the arterial pulse is transferred to the CSF. Indeed, experiments in dogs having undergone choroid plexectomy showed that the characteristic ventricular pulsation disappeared after this procedure.15 The waveforms recorded from the cisternal space are similar in configuration to the ventricular CSF pulse, while the lumbar pulse wave has a significantly lower peak, occurs much later, and has a rather different

CSF pulse

Cerebral ventricle

(Pr. G, V)

10 mmH2O V 62 mmH2O

Carotid artery 20 mmHg C 49 mmH2O

30 mmH2O

Right atrium Figure 4-1 Waveform morphologies of CSF pressures (right) measured within the ventricle (V), cisterna magna (C), and lumbar thecal sac (L) in relation to carotid and right atrial pressures (left) and ECG (below). (Reproduced with permission from Bering EA. Choroid plexus and arterial pulsation of cerebrospinal fluid. Arch Neurol Psychiat 1955;73:165–172.)

20 mm H2O

ECG

0.1 sec

L 29 mm

ECG

0.1 sec

Intracranial Compliance and Pressure–Volume Relationships

morphology (Fig. 4-1). These transmitted pressures form a gradient along the craniospinal axis in a rostrocaudal fashion (they are some 60% lower in the lumbar space), and this gradient is thought to facilitate the movement of CSF from the ventricles into the subarachnoid space.15 Du Boulay estimated that with each cardiac pulse, 0.75 ml of CSF exits the intracranial space into the spinal thecal sac during systole, with return of a similar volume during diastole.16 This to-and-fro movement facilitates the mixing and circulation of CSF.16 The waveform recorded during routine intraventricular pressure monitoring has three distinct components.17 In the normal situation (Fig. 4-2, top), the first peak (P1) results from the transmission of arterial pressure from the choroid plexus to the CSF and is therefore known as the “percussive wave.” The second peak (P2), or “tidal wave,” is thought to reflect intracranial compliance as its amplitude is inversely related to this variable. In a non-compliant system (Fig. 4-2, bottom), P2 typically exceeds the height of the P1 waveform and this finding can be an ominous clinical sign. The “dicrotic wave” (P3) is believed to correspond with closure of the aortic valve.17 In a landmark series of experiments reported in 1960 that were conducted in both animals and human subjects, Lundberg described different pathological CSF pressure waveforms, each with its own particular clinical significance. Direct continuous recordings of ventricular CSF pressure

P1

P2 P3

21

using fluid-filled catheters coupled to pressure transducer systems were undertaken in a variety of intracranial disease states. This monitoring lasted from hours to several days, and recordings were made with an ink-writing potentiometer. In this way, ICP trends over time, rather than isolated waveform analysis, could be assessed.10 Based on these investigations, Lundberg described three distinct types of pathological waveforms.10 Plateau waves (also called A waves) are characterized by a sharp rise in ICP (typically between 50 and 100 mmHg) lasting anywhere from 5 to 30 min, followed by a steep decline back to baseline or near baseline levels (Fig. 4-3, left). These waves are commonly associated with intracranial pathology and can occur in conjunction with paroxysmal signs of brainstem dysfunction (i.e., transtentorial herniation). Plateau waves are thought to occur due to increases in CBV from arterial vasodilatation that is triggered by inadequate cerebral perfusion pressure (CPP).10,18,19 Waves occurring with a frequency of 1 to 6 per min and having amplitudes of up to 20–30 mmHg above baseline ICP are termed B waves (Fig. 4-3, right). They are typically repetitive in nature, persist for more than 10 min in duration, and have been associated with a Cheyne-Stokes pattern of respiration. Although B waves are not considered deleterious per se, they may represent instability of the medullary vasomotor center in the setting of borderline CPP and reduced intracranial compliance. Many clinicians consider these waves to be an indication for ICP-lowering measures (i.e., the shunting of patients with suspected hydrocephalus).10,18 Lundberg C waves are thought to represent the transmission of arterial blood pressure to the ICP. They are of limited pathological significance, although some consider them to be a sign of terminal vasoparalysis. Their frequency fluctuates between 4 and 8 per min, while their amplitude rarely exceeds 20 mmHg.10

INTRACRANIAL COMPLIANCE AND PRESSURE–VOLUME RELATIONSHIPS P2 P1 P3

Figure 4-2 Ventricular CSF pressure waveform morphologies recorded from a patient with normal intracranial compliance (top) and impaired compliance (bottom). (Reproduced with permission from Citerio G, Andrews PJD. Intracranial pressure, part two: clinical applications and technology. Intensive Care Med 2004;30:1882–1885.)

Intracranial compliance is defined as the change in volume (DV) per unit change in ICP (DP). In essence, it is a reflection of the craniospinal space reserve and the ability to compensate for ICP changes. Elastance is the inverse of compliance.20 Masserman first described the effects of rapid and repeated removal of CSF in humans and noted that ICP decrement followed a constant ratio, given by the quotient DV/DP.21 Based on these findings, the concept of a “coefficient of volume elasticity of the ventriculo-subarachnoid system” was introduced.21 Subsequent experiments showed that changes in ICP following the addition of CSF to the craniospinal space produced a pressure–volume curve with a hyperbolic shape (Fig. 4-4).22 This technique of raising CSF volume and measuring the corresponding change in ICP is known as the volume–pressure response

Chapter 4

22

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Normal Intracranial Pressure Physiology

25 20 ICP mmHg

mmHg

100 80 60 40

15 10 5

20 0

0 1

2

3

4

5

6

7

8

Time (minutes) Figure 4-3 Plateau waves (A waves) are characterized by sudden rapid elevations from 10–20 mmHg to 80–100 mmHg that are sustained for 5–20 min and terminated rapidly (left). B waves are characterized by intracranial pressure elevations of 5–10 mmHg above baseline, occurring every 0.5–2 min (right). (Reproduced with permission from Geocadin RG, Williams MA. Intracranial pressure monitoring. In Parrillo JE and Dellinger RP (eds), Critical Care Medicine. Principles and Management in the Adult. 2nd ed. pp. 249–259.)

(VPR), a reflection of the elastance of the craniospinal system.23,24 Ryder et al. considered the CSF space to be under a dynamic control or equilibrium, such that four parameters (rate of CSF production, intracranial compliance, resistance to CSF outflow, and intradural sinus pressure) interact with each other at any given moment to achieve this steady state.24 Therefore, if intracranial volume increases, a concomitant rise in ICP will cause CSF absorption rates to be enhanced thereby allowing ICP to normalize over time.24 In an effort to further clarify the kinetics of intracranial VPR, Marmarou et al. developed a mathematical model of the CSF system and derived a general equation that predicted the time course of ICP changes that follows

volume changes.25 This model was subsequently verified in experimental animals, where a non-linear relationship between pressure and volume was confirmed.25 Furthermore, the volume–pressure curve was found to be exponential, and therefore, when plotted using a semi-logarithmic axis, to approximate a straight line (Fig. 4-5). Two important facts derive from these observations: (1) the slope of the volume–pressure curve demonstrates that as ICP increases, compliance decreases, and (2) the slope of the line using the semi-logarithmic axis is equal to the pressure volume index (PVI).25 PVI is best defined as the amount of volume required to raise ICP by a factor of 10, and can be calculated as follows:

ICP (mmHg)

PVI = DV / (log10 Po / Pm)

ΔP´

where DV represents volume of CSF, Po is the initial ICP, and Pm is the final ICP. In the clinical setting, PVI is usually determined by removing 2 ml of CSF from an intraventricular catheter and noting the change in ICP. A value of 25 ml is considered normal, whereas a PVI below 15 ml is reflective of a “tight brain.” This index has the advantage of representing the craniospinal VPR over the entire physiological range of ICP and can be used to calculate intracranial compliance, as follows:26 C = 0.4343(PVI / ICP)

ΔP Peq Veq

ΔV

ΔV Volume (ml) craniospinal compartment

Figure 4-4 Pressure–volume relationship (elastance curve) within the intracranial compartment. (Reproduced with permission from Avezaat CJJ, van Eijndhoven JHM, Wyper DJ. Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships. J Neurol Neurosurg Psychiat 1979;42:687–700.)

In situations where increased ICP is not a clinical concern, PVI can be determined by injecting a bolus of saline into the ventricular CSF space. Limitations of PVI determination include: (1) an increased risk of infection related to manipulation of the ventricular drainage system, (2) the need for an experienced operator at the bedside, (3) compliance, as calculated using the above formula, only reflects the median part of the pressure–volume curve, and (4) significant variability in the recordings that often necessitates the averaging of serial measurements.20 These limitations led Avezaat et al. to analyze the pulse pressure of the CSF waveform (CSFPP) as an indirect

Systemic Influences on ICP

23

1.0

V

Figure 4-5 Volume–pressure curve of intracranial vault is exponential (left), but becomes linear when plotted using a semi-logarithmic axis (right). (Reproduced with permission from Marmarou A, Shulman K, Rosende RM. A nonlinear analysis of the cerebrospinal fluid system and intracranial pressure dynamics. J Neurosurg 1978;48:332–344.)

Volume (ml)

0.8 0.6 Slope (PVI)=0.9ml

0.4 0.2 0 -0.2

Po

10 Po

Po

-0.4 10

method of evaluating intracranial compliance, mostly because this value can be measured by less invasive means (Fig. 4-4).27 Although it had long been known that CSFPP increased concomitantly with ICP, recent studies have shown a linear relationship between these two variables up to an ICP level of 60 mmHg.27–29 Above this level, a breakpoint occurs where CSFPP shows a steeper increase, likely due to a loss of vascular autoregulation. Furthermore, an increase in CSFPP might occur before any detectable changes in ICP take place, and therefore might represent an early sign of decreased intracranial compliance. The slope of the CSFPP–ICP graph can be used to calculate the elastance coefficient (E1).22,25,27–29

20

30

40

50

20

10

30 40

60

100

CSF pressure (mmHg)

response to its metabolic demand for oxygen and glucose (neuronal activity). While the mechanisms that couple neuronal activity to changes in CBF remain incompletely elucidated, it has been proposed that “vasoactive factors” released from nearby neurons mediate local arterial control. Among these, adenosine, nitric oxide, vasoactive intestinal polypeptide, potassium, hydrogen, and products of the cyclooxygenase-2 pathway have been shown to influence vascular smooth muscle relaxation.34 Direct innervation of cerebral vessels and the physical proximity of astrocyte foot processes are also thought to play a major role in autoregulation.34

Systemic venous pressure Arterial blood pressure and cerebral blood flow (CBF) Early CSF pressure measurements in cadavers produced values equal to or lower than atmospheric pressure, but never higher.30,31 Although early reports suggested that this finding was related to absent CSF production,31 subsequent studies postulated that arterial blood pressure had a positive effect on ICP that was no longer present after death.30 Using infusions of amyl nitrite (which increases ICP and lowers blood pressure) and arterenol (which decreases ICP and increases blood pressure), Ryder et al. were able to demonstrate that changes in ICP are related to CBF rather than to blood pressure, and they firmly established CBF as a primary determinant behind acute changes in ICP.32,33 Indeed, Merritt and Fremont-Smith had already found that within physiological ranges, blood pressure had no direct effect on ICP levels.5 Interactions between ICP and mean arterial pressure (MAP) affect CBF and determine CPP (CPP = MAP − ICP). Under normal circumstances, CBF remains constant over a wide range of CPP as a function of cerebrovascular autoregulation (Fig. 4-6). Thus, the cerebral vasculature maintains a complex regulatory system that allows the brain to finely regulate its own blood supply in direct

The relationship between ICP and intracranial venous pressure has been well-known since Queckenstedt first performed his jugular compression test.2 Within a certain pressure range, however, this relationship tends to be

Maximum dilatation Cerebral blood flow (ml/100g/min)

SYSTEMIC INFLUENCES ON ICP

Maximum constriction

Zone of normal autoregulation

100 50 mmHg 80 mmHg Range of hypoperfusion

75

C

50

A B

25

Normal autoregulation Disrupted autoregulation

0 0

25

50

75

100

125

150

Cerebral perfusion pressure (mmHg)

Figure 4-6 Relationship between CPP and CBF with normal and disrupted cerebrovascular autoregulation. Changes in vascular diameter (top) help to control CBF over a wide range of CPP. (Reproduced with permission from Dunn LT. Raised intracranial pressure. J Neurol Neurosurg Psychiat 2002;73 (suppl I): i23–i27.)

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Normal Intracranial Pressure Physiology

one-sided; increased intracranial venous pressure (i.e., with dural sinus thrombosis) can be readily transmitted to the CSF space, but experimental increases in ICP often fail to alter torcular pressure.32 Still, sudden and extreme ICP increases are not only transmitted to the venous system, but they also eventually lead to partial obliteration of the dural sinuses.32 The interaction between systemic venous pressure and ICP is more complex. During the Valsalva maneuver, high intrathoracic pressures are transmitted to the venous system, causing a concomitant rise in ICP. After cessation of this maneuver ICP normalizes, although a second surge in CSF pressure may follow due to a sudden increase in cardiac output.35 Due to the lack of valves within the venous system, acute congestive heart failure and superior vena cava obstruction of any etiology can increase central venous pressure and lead to increases in ICP. In more chronic conditions, however, collateral drainage through Batson’s veins can attenuate or completely prevent any ICP rise.36–40

CBF by 6% per degree celsius below normal values.43,44 Despite this known relationship, however, the clinical use of hypothermia has been limited due to systemic complications and rebound ICP increases that occur during the re-warming period. Kety and Schmidt first observed changes in the diameter of pial arteries in relation to changes in arterial blood gas measurements.45 With hyperventilation and decreases in blood CO2 content, they showed an 8% decrease in the caliber of the arteries causing an associated decrease in ICP.45 Small increases in CO2 levels, however, caused a rapid dilatation of pial vessels; CBF increased by 2–6% for every mmHg rise in blood CO2 content driving up ICP.45 Since then, hypoxemia has also been shown to cause arteriolar dilatation and increased CBF and ICP, although these effects are less pronounced than changes induced by hypercarbia. Increasing blood O2 content does not significantly affect CBF, making hypocarbia a much stronger stimulus for lowering CBF. These responses are likely mediated by the local effects of hydrogen ions on cerebral blood vessels (Fig. 4-7).

Body position SUMMARY AND CONCLUSIONS Contents of the intracranial vault (brain, blood, and CSF) tightly regulate ICP under physiological conditions according to the Monroe-Kellie doctrine. Extracranial stimuli that have an effect on ICP include head position, PaO2, PaCO2, body temperature, and regional CBF controlled via autoregulation. Derangements in any of these stimuli can lead to increased ICP with attendant brain injury due to compromised regional CBF. Conversely, these same physiological parameters can be readily manipulated to lower ICP for cerebral resuscitation purposes.

140 PaO2 PaCO2

120 CBF (mL/100g/min)

Orthostatic changes have complex interactions with ICP. In the sitting position, the difference in ICP and lumbar CSF pressure is equal to the height of the hydrostatic column,41 while simultaneous recordings of cisternal and lumbar pressures show inverse changes when the body is tilted from the recumbent to the sitting position.41 Interestingly, the increment in the lumbar CSF pressure is only approximately 40% of that predicted based on the height of the fluid column.42 Similarly, subjects tilted vertically head-down show a rise in ICP that is 3-fold higher compared to the magnitude of decrement when they are tilted head-up.42 Factors other than hydrostatic pressure, including the elasticity of the lumbar thecal sac and venous collapse along the neuraxis, clearly influence orthostatic changes in ICP. The hydrostatic indifference point (HIP), a point along the neuraxis at which pressures recorded in the sitting and in the recumbent position are exactly the same, has been localized to the lower cervical/upper thoracic spinal region and corresponds with the level at which venous pressure is atmospheric.42 On the other hand, the level of zero CSF pressure in the sitting position (ZPS) is typically found somewhere between the occipital protuberance and the spinous process of the seventh cervical vertebrae. Above this level, CSF pressure tends to be negative, while below it CSF pressure is positive.42

100 80 60 40 20 0 25

Temperature, PaO2, and PaCO2 The close relationship between temperature and CBF (and ICP) is well known. Thus, CBF increases linearly with core temperatures up to 42°C, while hypothermia reduces

75

125

175

Pressure (mmHg) Figure 4-7 Effect of PaO2 and PaCO2 on CBF, and thus on CBV and ICP. Altering PaCO2 through the manipulation of a patient’s respiratory rate remains the most effective means to lower CBF, thereby reducing ICP.

References

REFERENCES 1. Quinke H. Über den druck in transsudaten. Dtsch Arch Klin Med 1878;21:454–458. 2. Queckenstedt, H. Zur diagnose der Ruckenmarkskopression. Dtsch Z Nervenheilk 1916;15:325. 3. Tobey GJ, Ayer JB. Dynamic studies of the cerebrospinal fluid in the differential diagnosis of lateral sinus thrombosis. Arch Otolaryngol 1925;2:50–57. 4. Ayala G. Die Physiopathologie der mechanic des liquor cerebrospinalis und der rachidealquotient. Msch Psychiatr Neurol 1925;58:65–101. 5. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: W.B. Saunders; 1938. 6. Spina-França A. Physiological variations in cerebrospinal fluid pressure in the cisterna magna. Arq Neuropsiquiatr 1963;21:19–24. 7. Adson AW, Lillie WL. The relationship of intracerebral pressure, choked disc, and intraocular tension. Trans Am Acad Ophthalmol Otolaryng 1927;30:138–154. 8. Langfit TW, Weinstein JD, Kassell NF, et al. Transmission of increased intracranial pressure: I. Within the craniospinal axis. J Neurosurg 1964;21:989–997. 9. Langfit TW, Weinstein JD, Kassell NF, et al. Transmission of increased intracranial pressure: II. Within the supratentorial space. J Neurosurg 1964;21:998–1005. 10. Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Acta Psychiatr Scand 1960;36 (Suppl 149):1–193. 11. Adler DE, Milhorat TH. The tentorial notch: anatomical variation, morphometric analysis, and classification in 100 human autopsy cases. J Neurosurg 2002;96:1103–1112. 12. Monro A. Observations on the Structure and Functions of the Nervous System. Edinburgh: Creech and Johnson; 1783. 13. Kellie G. An account of the appearances observed in the dissection of two or three individuals presumed to have perished in the storm of the 3rd, and whose bodies were discovered in the vicinity of Leith on the morning of the 4th, November 1821 with some reflections on the pathology of the brain. Trans Edinb Med Chir Soc 1824;1:84–169. 14. Burrows G. On disorders of the cerebral circulation. London: Longman; 1846. 15. Bering EA. Choroid plexus and arterial pulsation of cerebrospinal fluid. Arch Neurol Psychiat 1955;73:165–172. 16. Du Boulay G. Pulsatile movements in the CSF pathways. Br J Radiol 1966;39:255–262. 17. Citerio G, Andrews PJ. Intracranial pressure, part two: clinical applications and technology. Intensive Care Med 2004;30:1882–1885. 18. Geocadin RG, Williams MA. Intracranial pressure monitoring. In: Parrillo JE, Dellinger RP, eds. Critical Care Medicine. Principles of Diagnosis and Management in the Adult. 2nd ed. St. Louis: Mosby; 2002:249–259. 19. Risberg J, Lundberg N, Ingvar DH. Regional cerebral blood volume during acute transient rises of the intracranial pressure. J Neurosurg 1969;31:303–310. 20. Andrews PJD, Citerio G. Intracranial pressure, part one: historical overview and basic concepts. Intensive Care Med 2004;30:1730–1733. 21. Masserman JH. Cerebrospinal hemodynamics: V. Studies of the volume elasticity of the human ventriculo-subarachnoid system. J Comp Neurol 1935;61:543–552. 22. Avezaat CJJ, van Eijndhoven JHM, Wyper DJ. Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships. J Neurol Neurosurg Psychiat 1979;42:687–700. 23. Masserman JH. Cerebrospinal hydrodynamics: IV. Clinical experimental studies. Arch Neurol Psychiat 1934;32:523–553.

25

24. Ryder HW, Espey FF, Kimball PD, et al. Mechanism of the change in cerebrospinal fluid pressure following an induced change in the volume of the fluid space. J Lab Clin Med 1953;41: 428–435. 25. Marmarou A, Shulman K, Rosende RM. A nonlinear analysis of the cerebrospinal fluid system and intracranial pressure dynamics. J Neurosurg 1978;48:332–344. 26. Müller JU, Piek J, Oertel J, et al. Intracranial pressure (ICP) and cerebrospinal fluid (CSF) dynamics. Pan Arab J Neurosurg 2000;4:74–87. 27. Avezaat CJJ, van Eijndhoven JHM, Wyper DJ. Effects of hypercapnia and arterial hypotension and hypertension on cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships. J Neurol Neurosurg Psychiat 1980;43:222–234. 28. van Eijndhoven JHM, Avezaat CJJ. Cerebrospinal fluid pulse pressure and the pulsatile variation in cerebral blood volume: an experimental study in dogs. Neurosurgery 1986;19:507–522. 29. Avezaat CJJ, van Eijndhoven JHM. Clinical observations on the relationship between cerebrospinal fluid pulse pressure and intracranial pressure. Acta Neurochirurgica 1986;79:13–29. 30. O’Connell JEA. The vascular factor in intracranial pressure and the maintenance of the cerebrospinal fluid circulation. Brain 1943;66:204–228. 31. Masserman JH, Schaller WF. Intracranial hydrodynamics: I. Experiments on human cadavers. Arch Neurol Psychiat 1933;29: 1222–1231. 32. Dunn LT. Raised intracranial pressure. J Neurol Neurosurg Psychiat 2002;73(Suppl I): i23–i27. 33. Ryder HW, Espey FF, Kimbell FD, et al. Influence of changes in cerebral blood flow on the cerebrospinal fluid pressure. Arch Neurol Psychiat 1952;68:165–169. 34. Iadecola C, Niwa K. Neural regulation of the cerebral circulation. In: Pinsky MR, ed. Update in Intensive Care and Emergency Medicine: Cerebral Blood Flow. Berlin: Springer-Verlag; 2002:7–16. 35. Weed LH, Flexner LB. The relations of the intracranial pressures. Am J Physiol 1933;105:266–272. 36. Davson H, Welch K, Segal MB. Physiology and Pathophysiology of the Cerebrospinal Fluid. New York: Churchill Livingstone; 1987. 37. Ryder HW, Espey FF, Kimbell FD, et al. Effect of changes in systemic venous pressure on cerebrospinal fluid pressure. Arch Neurol Psychiat 1952;68:175–179. 38. Fitz-Hugh GS, Robins RB, Craddock WD. Increased intracranial pressure complicating unilateral neck dissection. Laryngoscope 1966;76:893–906. 39. Loman J. Components of cerebrospinal fluid pressure as affected by changes in posture. Acta Neurol Psychiat 1934;31:679–681. 40. von Storch TJC, Carmichael EA, Banks TE. Factors producing lumbar cerebrospinal fluid pressure in man in the erect posture. Arch Neurol Psychiat 1937;38:1158–1175. 41. Magnaes B. Body position and cerebrospinal fluid pressure, part 1: clinical studies on the effect of rapid postural changes. J Neurosurg 1976;44:687–697. 42. Magnaes B. Body position and cerebrospinal fluid pressure, part 2: clinical studies on orthostatic pressure and the hydrostatic indifferent point. J Neurosurg 1976;44:698–705. 43. Albert FN, Fazekas JF. Cerebral haemodynamics and metabolism during induced hypothermia. Curr Res Anesth Analg 1956;35:381–388. 44. Carlsson C, Hagerdal M, Seisjo BK. The effect of hypothermia upon oxygen consumption and upon organic phosphates, glycolytic metabolites, citric acid cycle intermediates and associated amino acids in rat cerebral cortex. J Neurochem 1976;26:1001–1036. 45. Kety SS, Schmidt CF. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure and normal values. J Clin Invest 1948;27:476–483.

CHAPTER

5

Developmental and Pregnancy-Related Changes in Cerebrospinal Fluid Dynamics and Composition Constance Smith-Hicks

INTRODUCTION The presence of fluid in and around the brain has been recognized for centuries, but it was not until the early 1800s that systematic studies regarding its dynamics and composition were first performed.1 Since that time, many advances have been made in understanding human cerebrospinal fluid (CSF) in both normal individuals and in various disease states. Evaluation of CSF is often undertaken in infants and young children in cases of suspected infection, to assess for elevated intracranial pressure (ICP), and on rare occasions to evaluate for underlying inborn errors of metabolism presenting with seizures. During pregnancy, the CSF space may be accessed in evaluating for infection, inflammation, or to measure pressure dynamics. The proper identification of pathological processes in both these clinical situations depends on well-established normative data. In pediatric cases in particular, however, it is difficult to justify performing lumbar punctures (LP) in totally healthy children, and normal CSF data must be gathered in other ways. In most cases, this information has been obtained from subjects who are sick enough to warrant an LP on clinical grounds, but who are ultimately found to have unrelated central nervous system (CNS) or systemic processes. The use of reference values derived from these “near normal” subjects, although suboptimal from a conceptual basis, still accomplishes the main clinical goal of distinguishing life-threatening conditions from more benign processes. This chapter will review what is known about the physiological changes in CSF dynamics and composition that occur in early childhood development and during pregnancy.

CSF DYNAMICS AND COMPOSITION IN INFANCY AND EARLY CHILDHOOD CSF is secreted by the choroid plexus (CP), a highly vascular epithelium that lines the lateral, third, and fourth ventricles, and that is supplied by branches of the internal carotid, posterior cerebral, and posterior inferior cerebellar arteries (reviewed in Chapter 3). Although capillaries of the CP have large fenestrations that offer little resistance to the passage of ions and small macromolecules, the ionic composition of CSF remains very different from that of plasma. Indeed, CSF secretion has been shown to depend on a series of active transport processes across the adjacent epithelial barrier.2 Tight junctions at the apical contacts between epithelial cells of the CP limit the passive diffusion of ionic molecules and give rise to the blood–CSF barrier.2 Studies examining CSF levels of serum components show that some increased permeability of this barrier is normal in both premature and full-term neonates, likely accounting for much of the early, age-dependent differences in CSF composition.3

CSF production rates The rate of CSF production in children depends to a significant degree on their height and weight, and may ultimately correlate with the total amount of CP they have. Evaluation of hourly CSF output in 100 children with hydrocephalus undergoing external ventricular drainage showed that the rate of CSF production rapidly increases during the first year of life and reaches two-thirds of the hourly rate of an adult (calculated to be ~0.35 ml/min) by

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Developmental and Pregnancy-Related Changes in CSF

2 years of age.2,4 In newborns, total CSF production may be as little as 25 ml per day, while this amount may exceed 500 ml per day in a healthy adult. Other than the rare case of CP papilloma, there is no convincing evidence that CSF production rates are altered in pathological states that result in increased CSF volumes or elevated ICP in infancy (i.e., hydrocephalus).2

Access to the CSF compartment As in adults, CSF is usually obtained from infants via the lumbar thecal sac. However, the classic positioning strategies used in an adult must often be modified when performing an LP in an infant. For one thing, an upright position is often preferred to facilitate identification of the midline. Head position is also important, as lumbar CSF may not flow if the head is flexed too far forward. In most cases, a 22 gauge, 1.5 inch spinal needle is inserted at the L3–L4 interspace. If CSF flow is not obtained after the infant’s head position is adjusted, a tuberculin syringe may be used to apply gentle suction to exclude the possibility that flow is compromised due to low pressure. It goes without saying that this maneuver should be undertaken with extreme caution. Regarding complications, Bonadio et al. examined the depth of needle insertion with successful LP in infants and children in order to establish guidelines aimed to minimize the incidence of a traumatic procedure.5 In 158 infants and children ranging in age from 1 day to 18 years (mean 22 months), these authors showed that the proper insertion depth correlated closely with the body surface area, and, most importantly, that it should be no greater than 2.5 cm in small infants.5 If this depth is reached without obtaining CSF, the needle should be withdrawn and reinserted.5 Unique complications of LP in infants include hypoxemia due to improper patient positioning and even the subsequent development of an intraspinal epidermoid tumor that may occur with seeding of ectopic tissue when the spinal needle is used without a stylet.2

CSF pressure dynamics The measurement of CSF opening pressure is often an important part of the diagnostic LP in infants and young children. In infants and children below the age of 6 years, normal lumbar CSF pressures range from 10 to 100 mmH2O (Table 5-1). This compares with adults where an upper limit of normal pressure can be as high as 200 mmH2O.6

Table 5-1 Normal Range of CSF Pressures in Infants and Children Age (Months)

Pressure (mmH2O)

Ref.

0–1 1–24 25–72

10–14 20–70 40–100

29 30 29, 31

Merritt and Fremont-Smith showed that the age at which children reach the adult range of lumbar CSF pressure is between 6 and 8 years.7 The ability to non-invasively measure ICP in infants and children has been pursued with great interest over the years. This would avoid the potential complications of LP and would allow for serial measurements. In the past, some clinicians have estimated ICP in infants by palpation of the anterior fontanelle, an unreliable approach that is subject to error and should not be used. More recently, investigators have monitored ICP through the anterior fontanelle using a device known as a Rotterdam transducer.8 It would appear that the device is reliable, although direct comparative studies with lumbar opening pressures still need to be performed.

CSF composition CSF composition varies with age and is measurably different between premature infants, normal neonates, older infants, children, and adults. In terms of its gross appearance, CSF is often slightly xanthochromic in normal neonates during the first 24–48 h of life.9 Both free and conjugated forms of bilirubin are found in the CSF at this time, although levels decrease as the serum concentration declines over the first days to weeks of life. A study conducted by Nasralla et al. showed that CSF bilirubin is higher in premature neonates when compared to full-term and older infants. In this report, premature infants had a mean CSF bilirubin concentration of 0.61 mg/dl, while full term infants averaged 0.24 mg/dl, and older subjects had a mean value of 0.10 mg/dl.3 As discussed earlier, this finding is likely explained by relative immaturity of the blood–CSF barrier. In a report by Ahmed et al., 108 non-infected term neonates (0–30 days old) were selected from a larger group of subjects who had been enrolled in a study of suspected aseptic meningitis.10 This subgroup met stringent criteria including an atraumatic LP (<1000 red blood cells (RBC)/mm3), no antibiotic therapy before the procedure, sterile blood, CSF, and urine bacterial cultures, negative CSF viral cultures, and negative CSF enteroviral polymerase chain reaction (PCR) assays. The authors showed that the mean CSF white blood cell (WBC) count in this cohort was 7.3 ± 14.0 cells/mm3, with a 95% confidence interval of 6.6–8.0 cells/mm3 and a range of 0–130 WBC/mm3.10 They also showed that there was no significant difference in WBC counts between subgroups in this age range (Table 5-2).10 These results support earlier studies showing an average of 6–7 WBC/mm3 in the CSF of normal neonates, with a range of up to 32 WBC/mm3.9,11 In most studies, 50–60% of these leukocytes were polymorphonuclear, reflecting the WBC differential in blood. Taken together, these data indicate that only a CSF WBC count of greater that 30 cells/mm3 (i.e., more that 2.5 standard deviations above the mean) should be considered abnormal in preterm and full-term neonates.

29

CSF Dynamics and Composition During Pregnancy

Table 5-2

Normal CSF Composition in Preterm and Full-Term Neonates WBC Count (cells/mm3)

Age (days)

Number in Group

Protein (mg/dl)

Glucose (mg/dl)

Mean ± SD

Range

Mean ± SD or Mean (range)

Mean ± SD or Mean (range)

Ref.

0–7 8–14 15–21 22–30

17 33 25 33

18.0 ± 33.4 10.8 ± 4.7 12.5 ± 26.4 8.7 ± 9.3

1–130 0–15 0–62 0–18

80.8 ± 30.8 69.0 ± 22.6 59.8 ± 23.4 54.1 ± 16.2

45.9 ± 7.5 54.3 ± 17.0 46.8 ± 8.8 54.1 ± 16.2

10 10 10 10

Preterm Full-term

30 87

9.0 ± 8.2 8.2 ± 7.1

0–29 0–32

115 (65–150) 90 (20–170)

50 (24–63) 52 (34–119)

13 13

Full-term 0–30

44 62

7 7

0–32 0–34

77 (51–99) 73 (40–148)

59 (29–93) 63 (39–82)

11 9

Preterm Full-term

39 64

14 ± 18 10 ± 9

4–44 1–62

107 (67–169) 84 (48–149)

57 (34–99) 49 (29–82)

12 12

Normal glucose levels in CSF are much closer to those of plasma in both premature and full-term neonates.12 This is presumed to be due not only to immaturity of the blood–CSF barrier, but also to much higher rates of cerebral blood flow.2 Thus, a CSF:serum glucose ratio of 0.75–0.80 is considered normal in this age group, compared to the normal range of 0.50–0.67 in adults.2 Furthermore, unlike in adults, there is often significant overlap in the CSF:serum glucose ratio in normal infants compared to infants with confirmed bacterial meningitis.13 Thus, great care must be taken when interpreting this CSF parameter in the setting of suspected CNS infection among infants. In the series reported by Ahmed et al., CSF protein concentrations were significantly higher in younger subgroups of neonates (0–7 days and 8–14 days of age) compared to older cohorts (15–22 and 23–30 days).10 Levels reached a maximum concentration of 130 mg/dl in the youngest patients.10 These findings are again consistent with other studies showing that in a select group of pediatric subjects, CSF protein levels were highest (and most variable) in neonates, reaching a maximum of 100 mg/dl.14 In this study, CSF protein concentrations decreased rapidly to less than 20 mg/dl by 6 months of age and remained low throughout childhood, seldom rising above 30 mg/dl.14 Similarly, a study by Abramowicz showed that 30 normal children aged 6 months to 11 years had CSF protein levels ranging from 7 to 28 mg/dl, with a mean value of 17.5 ± 6.25 mg/dl.15 The normal ranges of total CSF protein concentration in infants and children based on age as summarized from seven studies are listed in Table 5-3.

CSF DYNAMICS AND COMPOSITION DURING PREGNANCY The three trimesters of normal pregnancy It is now generally agreed that there are no demonstrable differences in CSF cell counts or protein levels between pregnant and non-pregnant women.16,17 In one study of

44 pregnant women undergoing spinal anesthesia for delivery, opening pressure and routine CSF chemistries and cellularity were all found to be in the normal range.16 It is assumed that CSF pressure and composition are normal at earlier stages of gestation as well.

Labor and delivery Arachnoid villi are found throughout the spine, and, as in the brain, these structures drain CSF from the subarachnoid space into adjacent venous plexuses and contribute to the process of CSF resorption.18,19 The interface of blood and CSF in the lumbar region has generated questions regarding the impact of abdominal distention by a full-term fetus on venous pressure and consequently on lumbar CSF dynamics. Furthermore, the effects of uterine contractions on CSF pressure dynamics during labor remain incompletely understood, and there are conflicting reports regarding the effects of labor on CSF pressure. While some authors have suggested that bearing down causes an increase in CSF pressure by as much as 20–51 mmHg,20 others have suggested that uterine contractions cause CSF pressure elevations only when the patient experiences pain.21 Hopkins and colleagues sought to address this question in a study of CSF pressure in 20 women during induced or spontaneous labor where the effects of pain were eliminated by providing continuous anesthesia for all subjects. They determined that the average basal CSF pressure in

Table 5-3 Normal Range of CSF Protein Concentrations in Infants and Children Age range Preterm 0–30 days 1–3 months 3–6 months 6 months – 10 years

Protein (mg/dl)

Ref.

60–170 20–150 20–100 15–50 15–30

12,13 9–13 14,15 14,15 14,15

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Developmental and Pregnancy-Related Changes in CSF

these patients was 13 mmHg, with a mean rise of 2.5 mmHg during a typical, effective uterine contraction.22 This rise occurred with contractions during sleep and with total sensory block, thus seemingly independent of perceived labor pain. They also found that external fundal pressure and bearing down by the patient increased CSF pressure on average by 8 mmHg.22 These data show that at the time of delivery, CSF pressures can increase by 20–25%. They do not really clarify the purported association between pseudotumor cerebri and pregnancy, a link that remains somewhat controversial.2

Post-partum changes Pregnancy and the post-partum period are associated with an increased risk of affective disorders, particularly depression. Furthermore, various hormones and neurotransmitters are known to play a role in mood disorders. To examine the effects of pregnancy on levels of these mediators, CSF samples were obtained from 21 healthy pregnant women undergoing elective cesarean section and 22 healthy age-matched non-pregnant controls. Levels of gamma-aminobutyric acid (GABA) and 3-methoxy4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine, were reduced in the CSF of pregnant women, while glutamate, 5-hydroxyindolacetic acid (5-HIAA, a metabolite of serotonin) and homovanillic acid (HVA, a metabolite of dopamine) showed no difference between both groups (Table 5-4).23 There was also a greater than 7-fold increase in CSF prolactin levels in pregnant as compared to the non-pregnant subjects.23 Although the duration of these changes is unclear, these data reveal neurochemical changes in CSF that may relate to psychiatric disturbances that can occur with greater frequency at the time of delivery.

Eclampsia Eclampsia is a condition unique to pregnancy, and the CSF is abnormal in most patients with this disorder. Early studies showed that CSF pressure was elevated in one-half of Table 5-4 CSF Levels of Hormones and Neurotransmitters in Non-Gravid and Pregnant Women

eclamptic women, while the fluid was grossly bloody in 25% of these patients.24 More recently, studies on a defined cohort of 21 women showed that routine CSF composition was abnormal in most patients with eclampsia. Here, total protein concentrations were increased in 18 of 21 patients (mean 78 mg/dl, range 42–200 mg/dl), while glucose levels were uniformly normal.25,26 A CSF leukocytosis was not seen in these patients, but RBC counts were increased in 20 of 21 individuals.25,26 Interestingly, another consistent abnormality in this cohort was elevated CSF uric acid levels; these were increased in all 21 cases (mean 1.9 mg/dl, range 1.0–2.8 mg/dl) compared to a normal upper limit of 0.3 mg/dl.25,26 This increase reflected the high plasma uric acid levels that were also found in all of these women.25,26 Modern proteomic analysis methodologies applied to the CSF of eclamptic women have now revealed a biomarker that reliably distinguishes severe disease from those with mild preeclampsia or non-disease controls.27 Samples from patients with severe preeclampsia in this study uniformly had nanomolar amounts of free hemoglobin in them, presumably reflecting a more extreme underlying pathology in these cases. Finally, although magnesium sulfate is commonly used in the treatment of this disorder, one study suggested that neither serum nor CSF magnesium levels were different in preeclamptic patients compared to women with normal pregnancies.28

CONCLUSIONS The physiological states of early childhood development and pregnancy can both result in measurable changes in CSF dynamics and composition. In infants, CSF tends to have relatively higher protein content, modestly increased cellularity, and low pressure compared to samples from older children and adults. During pregnancy, although CSF composition appears measurably unchanged compared to non-gravid women, pressure dynamics can be altered during labor and delivery. Furthermore, the state of eclampsia that is unique to pregnancy commonly manifests CSF abnormalities. The proper identification of pathological states involving the nervous system in infancy and with pregnancy requires that normal CSF characteristics in these settings be clearly defined.

Substance (pmol/ml)

Pregnant (n=21)

Non-Pregnant (n=22)

REFERENCES

Glutamate GABA MHPG HVA Prolactin 5-HIAA

8.2 ± 1.2 42.6 ± 3.0 37.0 ± 7.0 256 ± 58 12.6 ± 1.3 153 ± 23

6.6 ± 1.2 55.0 ± 4.8 64.0 ± 8.0 259 ± 48 1.6 ± 0.1 131 ± 18

1. Bowsher D. Cerebrospinal fluid dynamics in health and disease. American lectures in living chemistry. Springfield, IL: C.C. Thomas; 1960. 2. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: W.B. Saunders; 1992. 3. Nasralla M, Gawronska E, Hsia DY. Studies on the relation between serum and spinal fluid bilirubin during early infancy. J Clin Invest 1958;37:1403–1412. 4. Yasuda T, Tomita T, McLone DG, Donovan M. Measurement of cerebrospinal fluid output through external ventricular drainage in one

(Data adapted from Altemus, M., Fong, J., Yang, R., Damast, S., Luine, V., Ferguson, D. Changes in cerebrospinal fluid neurochemistry during pregnancy. Biol Psychiatry 2004;56:386–392.)

References

5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

15. 16. 17.

hundred infants and children: correlation with cerebrospinal fluid production. Pediatr Neurosurg 2002;36:22–28. Bonadio WA, Smith DS, Metrou M, Dewitz B. Estimating lumbar puncture depth in children. N Engl J Med 1988;319:952–953. Minns RA, Engleman HM, Stirling H. Cerebrospinal fluid pressure in pyogenic meningitis. Arch Dis Child 1989;64:814–820. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: W.B. Saunders; 1938. Massager N, Wayenberg JL, Vermeylen D, Brotchi J. Anterior fontanelle pressure recording with the Rotterdam transducer: variation of normal parameters with age. Acta Neurochir Suppl 1998;71:53–55. Naidoo BT. The cerebrospinal fluid in the healthy newborn infant. S Afr Med J 1968;42:933–945. Ahmed A, Hickey SM, Ehrett S, et al. Cerebrospinal fluid values in the term neonate. Pediatr Infect Dis J 1996;15:298–303. Widell S. On the cerebrospinal fluid in normal children and in patients with acute bacterial meningoencephalitis. Acta Paediatr Suppl 1958;47(Suppl 115):1–102. Otila E. Studies on the cerebrospinal fluid in premature infants. Acta Paediatr Suppl 1948;35(Suppl 8):3–100. Sarff LD, Platt LH, McCracken GH. Cerebrospinal fluid evaluation in neonates: comparison of high-risk infants with and without meningitis. J Pediatr 1976;88:473–477. Wong M, Schlaggar BL, Buller RS, Storch GA, Landt M. Cerebrospinal fluid protein concentration in pediatric patients: defining clinically relevant reference values. Arch Pediatr Adolesc Med 2000;154: 827–831. Abramowicz M. Normal values for cerebrospinal fluid protein concentration in children. What is the upper limit of normal? Clin Pediatr 1969;8:300–304. Davis LE. Normal laboratory values of CSF during pregnancy. Arch Neurol 1979;36:443–445. Meeks GR, Morrison JC, Fish SA. Cerebrospinal fluid alterations in pregnancy and eclampsia. In: Wood JH, ed. Neurobiology of Cerebrospinal Fluid. Vol. 2. New York: Plenum Press; 1983: 603–613.

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18. Welch K, Pollay M. The spinal arachnoid villi of the monkeys Cercopithecus aethiops sabaeus and Macaca irus. Anat Rec 1963;145:43–48. 19. Chiro GD, Hammock MK, Bleyer WA. Spinal descent of cerebrospinal fluid in man. Neurology 1976;26:1–8. 20. McCausland AM, Holmes F. Spinal fluid pressures during labor: preliminary report. West J Surg Obstet Gynecol 1957;65:220–231. 21. Marx GF, Oka Y, Orkin LR. Cerebrospinal fluid pressures during labor. Am J Obstet Gynecol 1962;84:213–219. 22. Hopkins EL, Hendricks CH, Cibils LA. Cerebrospinal fluid pressure during labor. Am J Obstet Gynecol 1965;93:907–916. 23. Altemus M, Fong J, Yang R, Damast S, Luine V, Ferguson D. Changes in cerebrospinal fluid neurochemistry during pregnancy. Biol Psychiatry 2004;56:386–392. 24. Spillman R. Lumbar puncture in the treatment of eclampsia. Surg Gynecol Obstet 1922;4:568–571. 25. Morrison JC, Whybrew DW, Wiser DW, Bucovaz ET, Fish SA. Laboratory characteristics in toxemia. Obstet Gynecol 1972;39: 866–872. 26. Fish SA, Morrison JC, Bucovaz ET, Wiser DW, Whybrew DW. Cerebral spinal fluid studies in eclampsia. Am J Obstet Gynecol 1972; 112:502–512. 27. Norwitz ER, Tsen LC, Park JS, et al. Discriminatory proteomic biomarker analysis identifies free hemoglobin in the cerebrospinal fluid of women with severe preeclampsia. Am J Obstet Gynecol 2005;193:957–964. 28. Fong J, Gurevitsch ED, Volpe L, Wagner WE, Gomillion MC, August P. Baseline serum and cerebrospinal magnesium levels in normal pregnancy and preeclampsia. Obstet Gynecol 1995;85:444–448. 29. Gerlach J. Paediatrische Neurochirurgie mit Klinischer Diagnostik und Differentialdiagnostik. In: Jensen HP, Koos W, eds. Paediatrie und Neurologie. Stuttgart: Georg Thieme Verlag; 1969: 139–151. 30. Welch K. The intracranial pressure in infants. J Neurosurg 1980; 52:693–699. 31. Levinson A. Cerebral Spinal fluid in infants and children. Am J Dis Child 1928;36:799–814.

CHAPTER

6

The Blood–Brain and Blood–Cerebrospinal Fluid Barriers Irene Cortese

INTRODUCTION In order to maintain normal homeostasis and optimal function, the central nervous system (CNS) must be protected from fluctuations in substrate availability and from cellular stressors or toxins. The blood–brain barrier (BBB) and blood–cerebrospinal fluid (CSF) barrier (BCB) are the anatomical structures that provide these specialized functions. Considering the high metabolic demands of the CNS, accounting for some 20% of total body oxygen and glucose consumption, the BBB must guarantee the CNS the proper supply of nutrients. These tasks are accomplished primarily by means of specific molecular transport systems. Thus, the functions of the BBB can be considered to be 3-fold: a dynamic regulator of ionic balance, a facilitator of nutrient transport into the CNS, and a barrier against the entry of potentially harmful molecules.1 Recent studies have also focused attention on the important immunological functions of the BBB and BCB. To integrate these various concepts, the normal cellular anatomy and physiology of the BBB and BCB will be reviewed here.

HISTORICAL BACKGROUND The concept of the BBB first arose in the late 19th century when Paul Ehrlich observed that certain dyes administered intravenously to animals stained all organs except the brain. Ehrlich’s interpretation was that the brain had a lower affinity for dye than other tissues. In 1913, Edwin Goldmann injected trypan blue directly into the CSF of rabbits and dogs, observing that the dye readily stained the entire CNS but did not enter the bloodstream or other organs. These observations showed that the CNS is separated from the blood by some sort of a physical barrier,2 leading to our current view which holds there are two principal barriers in the CNS: the BBB situated along almost all

of the brain’s capillary endothelium, and the BCB located at the level of the choroid plexus epithelium.3

GROSS ANATOMY OF THE BBB AND BCB The BBB is present in all brain and spinal cord regions, with the notable exceptions of the circumventricular organs (area postrema, median eminence, neurohypophysis, pineal gland, subfornical and subcommisural organs, and lamina terminalis). Blood vessels in these regions have fenestrations that permit the diffusion of blood-borne molecules across the vessel wall into the CNS. These relatively unprotected areas of the brain regulate autonomic and neuroendocrine function and must therefore have free access to the bloodstream for efficient operation. Most brain areas without a BBB are isolated from other regions by specialized ependymal cells called tanycytes present along the ventricular surface. Tight junctions maintained between tanycytes prevent free exchange between the circumventricular organs and the CSF.4 While there is no barrier separating CSF from brain, diffusion between blood and CSF is restricted. The BCB is situated at the choroid plexus and in the meninges. Unlike the cerebral capillaries that form the BBB, endothelial cells of the choroid plexus capillaries are fenestrated. Instead, the barrier function of the BCB is subserved by the adjacent choroid plexus epithelial cells and the tight junctions that link them. Like the BBB, the BCB is thought to have three general barrier functions. First, it forms a physical barrier to the diffusion of molecules between blood and CSF. Second, it expresses a variety of molecules that degrade proteins, including carboxy-, amino-, and endopeptidases, to form a metabolic barrier. Third, it maintains a wide variety of transporter proteins that allow for the entry of nutrients from blood and the removal of waste products from the CSF.5

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CELLULAR ANATOMY OF THE BBB Our understanding of the cellular and subcellular structures comprising the BBB exploded following development of electron microscopy in the 1950s. It is now clear that the BBB results from specialized properties of the brain capillary endothelial cells, surrounded by pericytes, a dense basement membrane, and astrocytic processes. All of these components working together are essential for normal BBB function (Fig. 6-1). Cerebral capillary endothelial cells are unique in their absence of fenestrations, extensive intercellular tight junctions, and sparse intracellular vesicular transport. A single cell typically spans the entire circumference of a cerebral capillary lumen (~7–8 μm). Attached at irregular intervals to their abluminal membranes are pericytes. Pericytes and endothelial cells are then ensheathed by a dense basal lamina, a membrane 30–40 nm thick composed of collagen type IV, heparin sulfate proteoglycans, laminin, fibronectin, and other extracellular matrix proteins. This structure is contiguous with the plasma membranes of astrocytic processes referred to as end-feet, which fully ensheath the cerebral capillary structure. The BBB is enormous; the endothelial lining of all brain microvessels has been estimated to span a 20 m2 area for the average adult.6

Intra- and intercellular junctions The main structures that account for the physical barrier function of the BBB and BCB are molecular complexes between endothelial cells, including tight junctions and adherens junctions (Fig. 6-2). Tight junctions in brain endothelium significantly restrict the movement of even small ions. Indeed, the measurement of transendothelial electrical resistance (TEER), typically at the level of 2–20 ohm/cm2 in peripheral capillaries, is often well over 1000 ohm/cm2 in the brain.7 These structures form a continuous seal that prevents solutes from diffusing between cells (gate function), and they segregate the apical and basal domains of each cell

Pericyte Tight junction

Lumen

membrane (fence function). Thus, the cerebral capillary endothelia take on some of the polarized (apical-basal) properties that are more common at epithelial barriers.6,7 At a molecular level, tight junctions and adherens junctions are composed of a network of intracellular and transmembrane proteins specific to each complex. Tight junctions consist of at least three types of transmembrane proteins: occludin, claudins, and junctional adhesion molecules (JAMs). Occludin is a 60–65 kDa protein with four transmembrane domains and both its amino- and carboxy-terminus located inside the cell. It is distributed in a continuous pattern along the cell margins of cerebral endothelial cells. Occludin increases TEER, and decreased expression of occludin is associated with disrupted BBB function in a number of disease states.8 The claudins are a superfamily of small transmembrane proteins (20–24 kDa) composed of at least 24 members. Structurally, each contains two extracellular loops and four transmembrane domains. Experimental data suggest that the claudins form the primary seal of the tight junction, with occludin acting as an additional support structure. Claudin-1, -3, and -5 are abundant on brain endothelium.3 JAMs are transmembrane molecules that also co-localize with tight junctions. JAM-1 is a 40 kDa member of the immunoglobulin superfamily and is found at the apical portion of these structures.3 Some data would suggest that JAMs help to regulate the transendothelial migration of leukocytes, but their function in the mature BBB is still largely unknown.8 The carboxy-terminus of occludin and the claudins located inside the endothelial cell interact with a number of cytoplasmic zonula occludens (ZO) proteins, including ZO-1, ZO-2, and ZO-3. These molecules belong to the membrane-associated guanylate kinase protein family and can interact with both signaling molecules and cytoskeletal proteins.3 Adherens junctions form a continuous belt that holds neighboring cells together, hence their importance in the maintenance of tight junctions and the entire junctional complex. Adherens junctions are made up of transmembrane glycoproteins primarily of the cadherin superfamily. These glycoproteins are linked to the cytoskeleton via cytoplasmic anchor proteins, the catenins. Catenins also play a crucial role in intracellular signaling.6 Although disruption of adherens junctions can lead to increased BBB permeability, it is primarily the tight junctions that confer low transcellular permeability and high TEER at the endothelial cell level.

Endothelium Basement membrane

Astrocytes at the BBB

Gap junction

The perivascular end-feet of astrocytes, which are closely opposed to the abluminal walls of brain microvessels, show several specialized features unique to this location. These include a high density of orthogonal arrays of particles (OAP) that contain the aquaporin-4 (AQP4) water channel and the Kir4.1 potassium channel; both are critical for the astrocytic control over ion and volume regulation

Astrocyte

Figure 6-1 Schematic components of the BBB in transverse section. All of these structures work together in combination to form an intact BBB.

Cellular Anatomy of the BBB

ZO-1

ZO-2

35

Claudins Tight junction

Actin Occludin

JAMs Cadherin

Adherens junction

Figure 6-2 Schematic of the junctional complex between two cerebral capillary endothelial cells. Tight junctions contain occludin, claudins, and junctional adhesion molecules (JAMs). This structure is primarily responsible for the high transendothelial electrical resistance (TEER) of the BBB compared to microvessels in other organs. Adherens junctions keep neighboring cells opposed to each other and support the entire junctional complex via members of the cadherin superfamily.

in the brain.7 Astrocytes also secrete a range of chemical mediators including transforming growth factor-β (TGF-β), glial-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), and angiopoietin 1 (ANG1), all of which can induce endothelial cells to acquire features of the BBB in vitro. Emerging evidence suggests that continuing astrocyte induction during adult life is necessary for the maintenance of BBB function.7

Pericytes Pericytes are cells that wrap around the endothelial cells of capillaries, venules, and arterioles in the brain. Their lineage and identity are still not fully characterized, and they may be a morphologically, biochemically, and physiologically heterogeneous population. These cells express non-muscle actins and α-smooth muscle actin (α-SMA) that is characteristic of vascular smooth muscle cells. However, they appear to be pluripotent and can differentiate into fibroblasts, osteoblasts, chondrocytes, and adipocytes in vitro. Furthermore, pericytes have some macrophage-like activities, including phagocytosis. Pericytes are thought to provide structural support and vasodynamic capacity to the cerebral microvasculature.4,9 Pericyte-derived angiopoietin can induce endothelial cells to express occludin, indicating that these cells also help induce and/or maintain the barrier properties between cerebral endothelial cells in a manner similar to astroglia.8

Basal lamina The extracellular matrix proteins of the basal lamina also play an important role in the structure and function of the BBB. These proteins serve as an anchor for the endothelium via interactions between laminin and other matrix proteins and endothelial integrin receptors. Such cell–matrix interactions can stimulate a number of intracellular signaling pathways. Matrix proteins can also influence the expression of endothelial tight junction proteins, indicating that they are likely involved in their maintenance.

Circulating leukocytes that cross the BBB must traverse this dense basal lamina, and recent data suggest that production of degradative enzymes such as matrix metalloproteinases (MMPs) is one important means to accomplish this task.10

Dynamic regulation of structure and function at the BBB The term barrier suggests a relatively fixed structure, but many features of the BBB can be modulated in response to physiological and pathological stimuli. Tight junctions are dynamic structures that respond to local chemical signals to cause cytoskeletal reorganization and alter transcellular permeability.6 For example, opening of BBB tight junctions can occur with brain inflammation, and upregulation of glucose transporter expression at the BBB is seen in response to starvation and hypoxia. In addition, there is anatomical evidence of direct innervation of microvascular endothelium and associated astrocytic processes by noradrenergic, serotonergic, cholinergic, and GABAergic neurons.8 This suggests the potential for complex signaling between the BBB and the brain itself. Interestingly, a small proportion of vessels in normal brain (2–5%) show signs that tight junctions are partially open.11 As a result, it is now held that in normal BBB physiology, the barrier may open focally and transiently, in a way such that overall brain homeostasis is not compromised. Thus, histamine released from local nerve terminals might allow for the passage of circulating growth factors into the brain or transient “sampling” of plasma composition. Conversely, neurally mediated BBB tightening could be important in conditions of stress or hypoxia since it is known that conditions where intracellular cyclic AMP concentrations rise can lead to increased TEER and induction of efflux transporter systems.11

Epithelial features at the BCB Choroid plexus epithelial cells are morphologically similar to secretory epithelia found in other tissues. These cells

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have a rich apical brush border as well as many basolateral interdigitations. The choroid plexus epithelium is also richly endowed with mitochondria. As with brain capillary endothelium, a major feature of the choroid plexus epithelium is the tight junctions that link the cells together. Although they share a similar overall structure, quantitative differences in the tightness of these barriers exist. Thus, the best estimates of electrical resistance suggest that recordings across the BBB are generally 5–10-fold higher than across the BCB.5 Likewise, it has been estimated that the permeability of inert substances such as mannitol or inulin across the BCB is some 10–100-fold higher than across the BBB.5

TRANSPORT ACROSS THE BBB AND BCB Four general properties influence the passage of molecules across the BBB: size, lipid solubility, electrical charge, and whether a specific transporter is available or not (Fig. 6-3). Most small molecules pass through the BBB quite readily. Thus, the entry rate and steady state CSF:plasma concentration ratios of sucrose (360 Da), inulin (5000 Da) and albumin (69,000 Da) are inversely proportional to their molecular weights. The relative exclusion of large molecules from the CSF is illustrated by the 0.005 CSF:plasma ratio of albumin in otherwise healthy humans. In general, rapid entry and equilibration of a solute between the blood and brain or CSF also depend upon its high lipid solubility, low ionization at physiological pH, and absence of binding to albumin or other plasma proteins. Thus, calcium and magnesium ions, metabolites such as bilirubin, and many drugs that bind serum proteins are restricted in their entry into CSF and brain. Carbon dioxide, oxygen, and drugs that are highly lipid-soluble (e.g., nicotine, ethanol, heroin, and chloramphenicol) all cross the barrier easily.2 This permits the efficient exchange of lipid-soluble gases such as O2 and CO2, an exchange limited only by the surface area of the blood vessel and by cerebral blood flow. The permeability coefficient for many other substances is directly proportional to their lipid solubility as measured by the oil–water partition coefficient. Still, the passage of molecules such as glucose and vinca alkaloids is not accurately predicted by their respective lipid solubilities. This is due to the presence of a selective endothelial transporter for one (glucose) and an enzyme system that

a

b

c

d

e

increases substrate efflux out of the CNS for the other (vinca alkaloids).2

Specific transport mechanisms In addition to the physicochemical properties of solutes that influence their passage across endothelial and choroidal cell barriers in the CNS, highly specific transport systems are also found on brain endothelial cells. Facilitated diffusion is a form of carrier-mediated transport where a solute binds to a specific transporter and is shuttled across the membrane. This process is passive (i.e., energy-independent), and can only move solutes down a concentration gradient. This mechanism contributes to transport of substances such as hexoses and some amino acids across the BBB. Active transport, on the other hand, depends on energy or is linked to the co-transport of another substance such as sodium ions. This mechanism permits the passage of a solute from regions of low concentration to ones of higher concentration. Another transport process is endocytosis, with can be further segregated into bulk-phase, fluid-phase, receptormediated, and absorptive-mediated. Bulk-phase endocytosis involves the nonspecific uptake of extracellular fluids and occurs to a very limited degree in the endothelial cells of the cerebral microvasculature. Receptor-mediated endocytosis (RME) provides a means for the selective uptake of macromolecules. Cells have receptors to allow for the uptake of many different types of ligands, including hormones, growth factors, enzymes, and plasma proteins. RME occurs at the brain for substances such as transferrin and insulin, and is a highly specific type of energy-dependent transport. Absorptive-mediated transport (AME) is triggered by an electrostatic interaction between a positively charged substance, usually a charged residue on a peptide, and the negatively charged plasma membrane surface. AME has a lower affinity and a higher capacity than receptormediated endocytosis. Another significant transport mechanism found at the BBB is carrier-mediated efflux. This mechanism can actually extrude substances from the brain, and, while beneficial in some circumstances, it is also a major obstacle in applying many pharmacological agents for use in the CNS.12 The ATP binding cassette (ABC) transporter, P-glycoprotein (Pgp), is one of the best-known efflux transport mechanisms and will be reviewed in detail later in this chapter.

f

Figure 6-3 Schematic of the various transport mechanisms at the BBB. Transcellular pathway used by lipophilic agents (a); carrier-mediated transport, such as used by the large neutral amino acids and glucose (b); paracellular pathway used by water-soluble agents (c); specific receptor-mediated endocytosis, such as those used by insulin and transferrin (d); adsorptive endocytosis used by cationic proteins, such as albumin (e); efflux pumps for moving xenobiotics and drugs back out of the CNS (f).

Transport Across the BBB and BCB

Glucose transport The brain consumes 18% of total body energy, yet it only represents 2% of total body weight. It also cannot store glucose for energy synthesis, and thus the BBB plays a crucial role in supplying glucose to the brain by means of specific glucose transporters.13 Two types of brain glucose transporters are known at present: sodium-dependent (secondary active) transporters, and sodium-independent (facilitative) transporters. These are classified as the SGLT and GLUT families, respectively.14 The predominant transporter at the BBB, glucose transporter isotype-1 (GLUT-1), has been well characterized. It consists of 492 amino acids, and has 12 putative transmembrane domains. It is a facilitative, saturable, and stereospecific transporter that functions at both the luminal and the abluminal endothelial cell membranes. Because it is not energy-dependent, it cannot move glucose against a concentration gradient. The net flux is entirely driven by the relatively higher concentration of glucose in plasma compared to brain or CSF.

Amino acid transport Currently, nine amino acid transport systems have been identified at the BBB. These systems differ in substrate specificity, inhibition by model ligands, and dependence on sodium co-transport. They have since been classified in terms of these functional characteristics. Early experimental studies of amino acid transport at the BBB identified facilitative transporters on the luminal membrane that were both saturable and stereoselective. Three broad classes of these facilitative carriers exist, mediating the transport of large neutral amino acids, cationic amino acids, and acidic amino acids. Four specific facilitative carriers have now been identified: L1, y+, xG-, and n (Table 6-1). L1 and y+ are present at both the luminal and abluminal cell membranes, whereas xG- and n are restricted to the luminal side. The L system was identified when it was discovered that essential neutral amino acids moved from blood to brain more readily than nonessential neutral amino acids. This transport was subsequently shown to be facilitative and sodium-independent. The high-affinity form of this transport system is now referred to as L1. Substrates include leucine, valine, methionine, histidine, isoleucine, tyrosine, tryptophan, phenylalanine, and threonine. This system is also thought to be important for drug delivery to the CNS due to its broad substrate specificity for relatively large molecules. It is presumed to transport agents such as L-DOPA, baclofen, and gabapentin across the BBB. The in vivo significance of this system in L-DOPA transport across the BBB is indirectly revealed by the decreased effectiveness of the drug after a protein-rich meal in humans. System y+ is the primary cationic amino acid transporter of the BBB. It has an affinity for amino acids with cationic side chains including lysine, arginine, ornithine, and homoarginine. This system exists in both cell membranes,

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Table 6-1 Facilitative Amino Acid Transport Systems at the BBB System Nonessential

Essential in Brain

Location

L1

Asparagine, glutamine

Luminal and abluminal

y+

Arginine, ornithine

Histidine, threonine, methionine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan Lysine

n

Asparagine, glutamine Aspartate, glutamate

xG-

Histidine

Luminal and abluminal Luminal Luminal

(Adapted from Hawkins RA, O’Kane RL, Simpson IA, Vina JR. Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr 2006;136 (1 Suppl):218S–226S.)

but it predominates on the abluminal surface. Additional facilitative transport systems for glutamine (System n) and glutamate (System xG−) have been described on the luminal membrane of the BBB. The concentrations of all naturally occurring amino acids in the CSF, with the exception of glutamine, are some 10% or less than in plasma. This concentration gradient is maintained by active (sodium-dependent) transport systems on the abluminal endothelial membrane (Table 6-2). To date, the known sodium-dependent transport systems include System A (mediating the transport of small, neutral amino acids such as alanine, proline, glycine, methionine, and glutamine); System ASC (mediating the transport of alanine, serine, and cysteine); System N (mediating the transport of nitrogen-rich amino acids including glutamine, asparagine, and histidine); the excitatory acidic acid amino acid transporter (EAAT) family (mediating transport of aspartate and glutamate); and a recently described system that transports primarily essential large neutral amino acids (LNAA), which has not yet been named and is currently Table 6-2 Sodium-Dependent Amino Acid Transport Systems at the BBB System

Nonessential

Essential in Brain

A

Alanine, serine, proline, asparagine, glutamine Serine, asparagine, glutamine Glycine, alanine, serine

Histidine

N ASC

Na+-LNAA

Glycine, alanine

EAAT

Aspartate, glutamate

Histidine Threonine, cysteine, methionine, valine, leucine, isoleucine Histidine, threonine, methionine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan

(Adapted from Hawkins RA, O’Kane RL, Simpson IA, Vina JR. Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr 2006;136 (1 Suppl):218S–226S.)

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referred to as Na+-LNAA. It has a high affinity for leucine. The spectrum of amino acids transported by Na+-LNAA is similar to that of the facilitative system L1, allowing entry of essential LNAA down their concentration gradients. This abluminal, energy-dependent carrier provides a mechanism for the control of the LNAA content in the brain. Overall, the brain gains access to all essential amino acids through the facilitative systems L1 and y+, while the sodium-dependent transport systems provide a parallel mechanism for the elimination of nonessential amino acids and toxic amino acids as well as for maintaining the optimal concentrations of all other amino acids.15,16

Macromolecule transport Because most peptides are large hydrophilic molecules, it is often difficult for them to penetrate the BBB. Overall, peptides can be delivered to the brain by carrier-mediated transport, RME, or AME mechanisms. The opioid peptides, enkephalin and its structural analogues, appear to use such specific, saturable transport processes. Likewise, peptides including epidermal growth factor, thyrotropin-releasing hormone, arginine vasopressin, α-melanocyte stimulating hormone, and interleukin-1, to name a few, have all been shown to cross the BBB by saturable transport mechanisms. AME may be used to deliver large peptides into the brain. Various cationic peptides, including cationized albumin, have been shown to cross the BBB via this mode. RME is used by several other peptide molecules to enter the CNS. Transferrin, by means of the transferrin receptor that is highly abundant at the BBB, is an example of this process.14,17

through ABCG). Pgp, the encoded protein product of the human MDR-1 (ABCB1) gene was the first efflux transporter to be described. In addition to Pgp, ABC transporters of the multi-drug resistance proteins (MRPs, also known as the ABCC family) and the breast cancer resistance protein (BCRP or ABCG2 group) are also expressed at the BBB. Pgp is the most studied efflux pump. It has a broad tissue distribution; even within the CNS it is expressed on different cell types, including capillary endothelial cells, perivascular astrocytes, parenchymal astrocytes, and neurons. It is a 170 kDa transmembrane protein with two ATP-binding sites. Pgp is present at the luminal surface of the brain capillary endothelial cells, and substrates entering these cells are immediately pumped back into the blood.18–20 Table 6-3 summarizes many of the known pharmacological substrates of this transporter. In contrast, data on the expression and function of other ABC transporters at the BBB are more limited. The ABCC transporter family currently has 12 members that act as organic anion transporters, but can also transport neutral organic drugs. MRP and Pgp are transport proteins with distinct substrate spectrum; Pgp generally moves unconjugated cationic substances, whereas MRP transports conjugated anionic substances. There are, however, exceptions to this general rule, such that several drugs are substrates for both transporter families. In humans, MRP1, MRP2, MRP3, MRP4 and MRP5 are expressed at the BBB.18–20 BCRP was first discovered in a chemotherapy-resistant breast cancer cell line, but, like Pgp, it also has broad tissue distribution including the BBB. There, it is located on the luminal surface of capillary endothelial cells.19,20

Efflux transport systems The octanol/buffer partition coefficient is an established method to predict the probability that molecules with molecular weights below 400–600 Da can be passively transported across a lipophilic membrane. Still, many lipophilic compounds, including vincristine, cisplatin, and cyclosporine A, show much lower brain penetration than would be predicted based on this calculation. Transmembrane efflux pump mechanisms have now been identified to explain these differences.18 Apart from effluxing therapeutic compounds out of the CNS, the main role of these transporters is to protect neural cells against the damaging effects of naturally occurring toxins and xenobiotics by restricting their penetration into and facilitating their extrusion from the brain. Efflux is now known to be mediated by a large superfamily of proteins referred to as multi-drug resistance (MDR) proteins, most of which belong to the ABC family of transporters. These molecules are multi-domain integral membrane proteins that use the energy of ATP hydrolysis to move solutes across cellular membranes. The ABC genes can be divided into families based on the organization of functional domains and by amino acid homology (ABCA

Table 6-3 Drug Class

Known P-glycoprotein Substrates Examples

Antineoplastics

Doxorubicin, daunorubicin, vinblastine, vincristine, etoposide, teniposide, paclitaxel, methotrexate Immunosuppressants Cyclosporin a Corticosteroids Dexamethasone, hydrocortisone, corticosterone, cortisol, aldosterone Analgesics Morphine Antiretrovirals Amprenavir, indinavir, saquinavir Antidiarrheals Loperamide Histamine-2 receptor antagonists Cimetidine Calcium channel blockers Verapamil Antiepileptics Phenytoin, carbamazepine, lamotrigine, phenobarbital, felbamate, gabapentin, topiramate Antiemetics Domperidone, ondansetron Cardiac gllycosides Digoxin Antidepressants Amitriptyline, nortriptyline, doxepin, venlafaxine, paroxetine Antibiotics Erythromycin, malinomycin, tetracyclines, fluoroquinolones (Adapted from Loscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2005;2:86–98.)

Ion and Volume Regulation at the BBB

Newly discovered categories of efflux transporters include the organic anion transporter (OAT) and the organic anion transporting-polypeptide (OATP) families. In contrast to the ABC transporters, OATs and OATPs are not primary hydrolyzers of ATP and generally function by exchanging a drug for another molecule or ion. The precise localization of most OATs and OATPs in the brain is not clear.18,19 Members of the organic cation transporter (OCT) family have also been identified in the brain. They transport a variety of cationic compounds, including monoamine neurotransmitters, out of the CNS.14,21 Lactic acid, ketone bodies, and other monocarboxylic acid compounds are abundant in the CNS, and their brain concentrations are regulated by specific uptake and efflux transporters found at the BBB. Monocarboxylic acid transporter (MCT)-1, present on both the luminal and abluminal membranes of the BBB, is driven by a proton gradient. It transports relatively small acidic compounds with molecular weights up to 200 Da. Drugs transported by this system include valproic acid, HMG-CoA reductase inhibitors (statins), acetic acid, salicylic acid, and benzoic acid.14–17 Neurotransmitter inactivation is critical for proper neural function. Reuptake and metabolism of neurotransmitters by neurons and astrocytes have been well characterized. While the main role of the BBB in this process had previously been believed to be the retention of neurotransmitters in the brain, recent studies have identified neurotransmitter transporters at the BBB. These include the GABA transporter (GAT2/BGT-1), the norepinephrine transporter (NET), and the serotonin transporter (SERT). These findings imply an additional physiological role of the BBB as a regulatory interface for neurochemicals that mediate synaptic transmission.13,22

THE BBB AND BCB AS METABOLICALLY ACTIVE STRUCTURES Beyond their various functions to control the bidirectional movement of solutes in and out of the CNS, the BBB and BCB are both sites where other important metabolic reactions occur. For example, specific enzyme systems at the BBB detoxify circulating substances before they enter the brain, while others found on the abluminal side can break down unwanted waste products. The first and best characterized of these systems is the barrier to L-DOPA. Plasma L-DOPA enters brain endothelial cells by means of the L-system amino acid transporter. The relatively high levels of DOPA decarboxylase and monoamine oxidase in cerebral capillary endothelial cells rapidly convert L-DOPA into 3,4-dihydroxyphenylacetic acid, thereby inhibiting the actual entry of L-DOPA to the brain. Other blood-borne amines, including catecholamines, are likewise inactivated by the monoamine oxidases of brain endothelium. The BBB also contains many other detoxifying and drugmetabolizing enzymes such as cytochrome P-450-linked

39

monooxygenases, epoxide hydrolase, NADPH:cytochrome P-450 reductase, 1-naphthol UDP-glucuronosyl transferase, and a multi-drug transport protein, P170. In this way, many smaller lipophilic molecules that enter cerebral capillary endothelial cells are rapidly metabolized before they pass into the brain. This process not only helps to prevent the uptake of potentially harmful chemicals present in blood, but it also assists the brain in the elimination of unwanted waste products.1

ION AND VOLUME REGULATION AT THE BBB Like other organs, brain volume is determined primarily by mechanisms that control water exchange across its capillaries. Yet the brain differs from other organs in its highly sophisticated capillary membrane structure – the BBB. In addition to its other physiological functions, the BBB is the most important regulator of cerebral volume.23 Fluid in the CNS is distributed between the intracellular and extracellular spaces of the brain parenchyma, the cerebrospinal fluid, and the vascular compartment. Regulated exchange of fluid between these CNS compartments occurs at the BBB, the ventricular ependyma and choroid plexus, and the pia mater on the surface of the brain. The brain is normally very permeable to water, but considerably less so to ions, including the principal osmotic electrolytes. Evidence for specific transport systems at the cerebral capillary endothelium, for example high Na+/K+ ATPase activity and the presence of a Na+/H+ transporter at the abluminal surface, suggests that cerebral microvessels play a much more active part in regulating brain volume and ion homeostasis than do capillaries in other vascular beds.24 The concentration gradients of Na+, K+, and Ca2+ between intracellular and extracellular spaces underlie the role these cations play in nerve excitation and conduction as well as in signal transduction. During normal brain activity, neurons release neurotransmitters and K+ and take up Na+, while glucose metabolism generates water. The neurotransmitters and ions are generally recycled, whereas water must be removed from the brain and excreted. The astrocytes forming the perivascular end-feet at the BBB occupy a strategic position between capillaries and neurons and play an important role in these processes. Gap junctions between astrocyte processes allow them to communicate with each other, thereby efficiently coordinating this function. Any increase in the extracellular concentration of K+ around astroglial processes leads to K+ entry and membrane depolarization, and the electrochemical gradient that results can lead to K+ efflux at distant cell processes that may not be experiencing locally elevated K+ levels. This is termed the K+ spatial buffer. The high density of K+ channels on perivascular end-feet, particularly the inwardly rectifying Kir4.1 channel, makes them well suited for spatial buffering and for depositing excess K+ in the adjacent perivascular space. As brain endothelium has a low K+ permeability, this

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The Blood–Brain and Blood–CSF Barriers

K+ is not lost from the brain, but is recycled by reversal of the spatial buffer when neural activity declines. Astrocytes can also take up K+ through specific transporters, most notably the Na+/K+ ATPase and the Na+/K+/2Cl− cotransporter. For both channel- and transporter-mediated K+ uptake, the net ion gain results in osmotic water uptake and slight cell swelling; the high density of AQP4 water channels in perivascular astrocytic end-feet facilitates the redistribution of this water.7 The actual movement of ions and polar molecules across the BBB is variably restricted; it takes many hours for Na+ and K+ to reach equilibrium in the brain. The rate of K+ movement from blood to brain is extremely low, although flux from brain to blood is not as limited. This outward movement of K+ is mediated by a Na+/K+ ATPase found on the abluminal membrane of brain capillary endothelial cell.25 Studies suggest the presence of two saturable Na+ entry mechanisms at the BBB, including a luminal Na+ pore and a Na+/Cl− co-transporter. In addition, there is evidence of a Na+/H+ exchanger on the abluminal membrane, and the Na+-LNAA transporter has a similar distribution.15,16,26 Water, on the other hand, can pass through the BBB almost without restriction. Deuterium or tritiated labeled water reaches equilibrium in the brain following intravenous administration very rapidly, almost as a function of cerebral blood flow. Ninety-three percent of an injected bolus of labeled water freely exchanges with the brain, as compared to 97% of a bolus of ethanol.2

is far below that occurring in other tissues.27 Rather than being viewed as a site of immune privilege, the CNS is now more properly considered to be a site of selective immune reactivity. In addition to the presence of the BBB, CNS immune privilege was also attributed to the absence of classic lymphatic vessels. Studies in rodents, however, have shown that antigenic material injected into CSF can drain into cervical lymph nodes.28 Since defined lymphatic vessels are not found in CNS tissue, the CSF itself might be viewed as the functional equivalent of lymph for the CNS. The ependymal lining of the ventricles lacks tight junctions, placing relatively little impediment against the passage of material from the extracellular fluid of CNS white matter into ventricular CSF. Likewise, interstitial fluid of CNS grey matter also equilibrates with the CSF at the surface of the brain where specialized perivascular spaces around penetrating arteries, so-called Virchow-Robin spaces, are continuous with the subarachnoid space. Either way, antigens from the brain can enter the CSF and drain directly to deep cervical lymph nodes along perineural and periarterial spaces. Thus, CNS antigens can readily access lymphoid tissues through the CSF via cervical lymphatics, and, after appropriate processing and presentation, can stimulate antigen-specific responses by T cells that express cognate receptors.27

Specific routes of leukocyte entry into the CNS THE BBB AND THE IMMUNE SYSTEM Immune surveillance of the CNS Traditional dogma held that the normal CNS was completely isolated from circulating elements of the immune system. As a site harboring complex cellular structures with limited regeneration potential, evolutionary pressure was felt to have established a state of complete immune privilege within the brain. Specifically, the BBB was thought to be a strict barrier against the passage of leukocytes into the CNS. This concept, however, has been revised with the recent recognition that activated T cells can enter the CNS through an intact BBB under physiological conditions, a process referred to as immune surveillance. Immune surveillance of the CNS occurs via mechanisms similar to those found in other organs, with differences that are quantitative rather than qualitative in nature. T cells, in particular, possess the ability to pass into CNS parenchyma in search of their specific antigen, although their numbers are very low in the absence of disease. However, when a strong immunological reaction occurs in the host, even if the nervous system is not directly involved, increased numbers of T cells can be detected within the CNS. Thus, if the immune system is stimulated by some specific challenge, the entire body, including the brain, is surveyed. Still, on a direct weight-to-weight basis, the overall level of CNS surveillance

Three distinct routes of leukocyte entry into the nervous system have been described.10 The first pathway follows the formation of CSF. Here, leukocytes extravasate across the fenestrated endothelium of the choroid plexus vasculature, migrate through the stromal core to the villi, and interact with epithelial cells of the choroid plexus to enter the CSF at the site of its formation. At present, this pathway seems most likely to be a route by which T cells enter the CNS under physiological conditions. Leukocytes found in the CSF of healthy individuals have a distinctive phenotype, indicating their presence is the result of a regulated process. Indeed, neutrophils, the main population of circulating leukocytes, are almost never detected in the CSF under non-diseased conditions. Instead, normal CSF leukocytes are about 80% T cells, even though they constitute no more than 45% of white cells in blood.29 Furthermore, the ratio of CD4+ to CD8+ T cells is higher in CSF than in the periphery, suggesting that CD4+ T cells are the main effectors of CNS immune surveillance. Monocytes constitute only about 5% of normal CSF cells, and fewer than 1% are B cells. The CD4+ T cells in CSF mainly express cell-surface markers of central memory phenotype.10 In the second pathway, circulating leukocytes extravasate across post-capillary venules found at the pial surface of the brain and pass into the Virchow-Robin perivascular spaces. In the third pathway, leukocytes enter

The BBB and Maintenance of CSF Homeostasis

the CNS parenchyma directly, passing through the branching vascular tree of arterioles and capillaries deep within the brain, and extravasating through post-capillary venules even when there is not a clearly defined perivascular space. In this case, leukocytes must cross the BBB as well as the endothelial basal lamina in order to come into direct contact with neural cells.10

Molecular determinants of leukocyte extravasation across the BBB The passage of leukocytes across the BBB and into the parenchyma of the CNS is a tightly regulated event. Much of this control occurs within the lumen of cerebral microvessels in the form of specific molecular interactions between adhesion receptors found on the surface of leukocytes and cognate adhesion ligands expressed by endothelial cells. In the absence of disease, BBB endothelial cells express very low levels of the adhesion molecules used for leukocyte emigration, although these proteins can be rapidly induced in response to a variety of stimuli. The generally accepted theory is that activated T cells, independent of their antigen specificity, can still cross the BBB, even when the adjacent endothelial cells are not highly activated. Transendothelial migration of leukocytes across the BBB is a sequential process involving multiple steps: (1) tethering of leukocytes to endothelial cells via interactions between members of the selectin family and carbohydrate adhesion molecules known as addressins, (2) activation of leukocytes by chemokine stimulation of G-protein linked receptors, (3) arrest and firm adhesion of leukocytes to endothelial cells mediated by interactions between integrins and immunoglobulin superfamily adhesion molecules, and (4) extravasation. Migration of T cells across non-activated brain microvascular endothelial cells is mediated by LFA1/ICAM-1 interactions, while VLA-4/ VCAM-1 interactions have additionally been implicated in T cell migration across activated endothelial barriers. Once they have adhered, there is no uniform agreement as to the precise transendothelial route(s) taken by various subsets of leukocytes as they traverse the BBB during inflammatory conditions. Evidence from ultrastructural studies of cerebrovascular endothelial cells in culture suggests that there may be unique pore-like regions on the EC surface adjacent to the junctional complexes. These might serve as a parajunctional route for the passage of some leukocytes.30 Following transendothelial migration, T cells shift their protein expression in a way that causes a downregulation of α4β1 integrins (VLA-4) and an induction of MMPs. This MMP upregulation enables the degradation of extracellular matrix components so that T cells can traverse the basal lamina and migrate into the CNS parenchyma. T cell activation and migration across the BBB is often then followed by the nonspecific recruitment of other inflammatory cells such as B cells and monocytes. Monocyte infiltration, in particular, amplifies

41

Table 6-4 Steps in Leukocyte Transendothelial Migration across the BBB Step

Molecules Involved

Tethering/rolling Firm adhesion Integrin activation Extracellular matrix degradation

PSGL-1/P-selectin LFA-1/ICAM-1, VLA-4/VCAM-1 CCR2/CCL2, CXCR3/CXCL10, CCR5/CCL5 MMP-9

CNS inflammatory reactions and these cells can be major effectors of tissue damage. Table 6-4 summarizes the main steps and molecules involved in lymphocyte transendothelial migration at the BBB. The mechanisms governing monocyte transmigration across the BBB are not as well understood as those regulating T cell recruitment, although a similar set of steps is presumed. Monocytes moving from the blood into the CNS can differentiate into macrophages and contribute to neuroinflammatory processes via the production of a wide range of mediators that further stimulate inflammatory cascades. Monocyte-derived inflammatory products such as pro-inflammatory cytokines, reactive oxygen species, and nitric oxide can further recruit leukocytes into the CNS or themselves be effectors of either beneficial or injurious immune function within the CNS.3 In sum, the concept that the normal brain is simply ignored by the immune system has shifted to a more dynamic scenario where immune tolerance is actively maintained by a variety of mechanisms. This tight control, however, comes at a price; the CNS microenvironment is much less efficient and permissive in mounting immune responses against invading infectious pathogens. Still, from a teleological point of view, it may be less detrimental for the host to tolerate the presence of a few latent neurotropic viruses rather than have the immune system working to eliminate every infected neuron. Take away this normal immune surveillance, however, and problems are bound to arise; recent experience has shown that restricting the passage of all T cells into the CNS by means of a treating antibody against VLA-4 that blocks adhesion to CNS microvessels (natalizumab) can occasionally lead to the expansion of latent pathogens such as the normally wellcontrolled JC virus to cause progressive multifocal leukoencephalopathy.31

THE BBB AND MAINTENANCE OF CSF HOMEOSTASIS For the most part, the CSF maintains a relatively constant ionic composition in the face of major changes in serum ion concentrations, and the BBB plays an active role in maintaining this homeostasis. Admittedly, while CSF sodium (the main osmotically active cation in CSF) closely parallels changes in serum, CSF potassium, calcium, and

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magnesium levels are all maintained in narrow concentration ranges despite wide fluctuations in the serum. The normal physiology of ionic secretion into CSF is reviewed in detail in Chapter 3, while the CSF response to systemic metabolic derangements involving common anions and cations is covered later in Chapter 18. These issues are raised here simply to highlight that one of the many functions of the BBB and BCB is to control CSF composition.

DYSFUNCTION OF THE BBB IN NEUROLOGICAL DISEASE AND CONCLUSIONS Normal function of the BBB can be altered in many CNS disease states. Likewise, primary pathology at the BBB can result in severe neurological sequelae. Breakdown of the barrier can occur with loss of tight junction proteins, proteolysis of basement membranes, disrupted endothelial cell–glial cell interactions, and altered expression or function of the various transporter systems. Many of these changes are reflected in altered CSF composition and will be discussed elsewhere throughout this text. In general, however, infection, inflammation, ischemia, and neoplasms of the CNS are all prominent contributors to BBB dysfunction. In multiple sclerosis, for example, a loss of occludin, claudins, and/or ZO-1 can be observed in the microvasculature, while laminin can disappear from the basement membrane.7,8 Hypoxia leads to increased BBB permeability due to tight junction disruption from altered expression of occludin and increased passage via the transcellular route. This problem is accentuated by endothelial membrane failure, free radical formation, and activation of cytokines such as tumor necrosis factor and interleukin-1 that cause upregulation of vascular adhesion molecules. As a result, leukocytes can penetrate the BBB, releasing proteases that result in both cytotoxic and vasogenic edema.8 With brain tumors, the BBB is frequently more permeable at the center of the lesion, whereas the well vascularized, actively proliferating, and infiltrating edge may exhibit a more variable degree of BBB integrity. These differences often result in altered concentrations of chemotherapeutic agents at the rapidly growing periphery due to limited diffusion from the central region. This is termed the sink effect, and it can contribute to chemotherapy failure.12 Finally, as one might predict, situations arising at the BBB such as the congenital loss of the GLUT1 glucose transporter have severe implications for the health and wellbeing of the host. These various pathological states serve to highlight the broad range of normal functions of the BBB. REFERENCES 1. Betz AL. An overview of the multiple functions of the blood-brain barrier. NIDA Res Monogr 1992;120:54–72.

2. Moody DM. The blood-brain barrier and blood-cerebral spinal fluid barrier. Semin Cardiothorac Vasc Anesth 2006;10:128–131. 3. Pachter JS, de Vries HE, Fabry Z. The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 2003;62:593–604. 4. Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 2004;16:1–13. 5. Segal MB. The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cell Mol Neurobiol 2000;20:183–196. 6. Petty MA, Lo EH. Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol 2002;68:311–323. 7. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006;7:41–53. 8. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005;57:173–185. 9. Lai CH, Kuo KH. The critical component to establish in vitro BBB model: Pericyte. Brain Res Brain Res Rev 2005;50:258–265. 10. Ransahoff RM, Kivisakk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003;3:569–581. 11. Abbott NJ. Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell Mol Neurobiol 2005;25:5–23. 12. Neuwelt EA. Mechanisms of disease: the blood-brain barrier. Neurosurgery 2004;54:131–142. 13. Ohtsuki S. New aspects of the blood-brain barrier transporters; its physiological roles in the central nervous system. Biol Pharm Bull 2004;27:1489–1496. 14. Tsuji A. Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems. NeuroRx 2005;2:54–62. 15. Hawkins RA, O’Kane RL, Simpson IA, Vina JR. Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr 2006;136(1 Suppl):218S–226S. 16. Smith QR. Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr 2000;130(4S Suppl):1016S–1022S. 17. Tamai I, Tsuji A. Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 2000;89:1371–1388. 18. Bart J, Groen HJ, Hendrikse NH, van der Graaf WT, Vaalberg W, de Vries EG. The blood-brain barrier and oncology: new insights into function and modulation. Cancer Treat Rev 2000;26:449–462. 19. Loscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2005;2:86–98. 20. Loscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 2005;76:22–76. 21. Kusuhara H, Sugiyama Y. Efflux transport systems for organic anions and cations at the blood-CSF barrier. Adv Drug Deliv Rev 2004;56:1741–1763. 22. Hosoya K, Ohtsuki S, Terasaki T. Recent advances in the brain-to-blood efflux transport across the blood-brain barrier. Int J Pharmaceut 2002;248:15–29. 23. Nordstrom CH. The Lund concept: is this logical? Acta Neurochir Suppl 2005;95:475–480. 24. Go KG. The normal and pathological physiology of brain water. Adv Tech Stand Neurosurg 1997;23:47–142. 25. Keep RF, Xiang J, Betz AL. Potassium transport at the blood-brain and blood-CSF barriers. Adv Exp Med Biol 1993;331:43–54. 26. Betz AL. Transport of ions across the blood-brain barrier. Fed Proc 1986;45:2050–2054. 27. Hickey WF. Basic principles of immunological surveillance of the normal central nervous system. Glia 2001;36:118–124. 28. Cserr HF, Knopf PM. Cervical lymphatics, the blood-brain barrier, and the immunoreactivity of the brain: a new view. Immunol Today 1992;13:507–512.

References

29. Provencio JJ, Kivisakk P, Tucky BH, Luciano MG, Ransohoff RM. Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients. J Neuroimmunol 2005;163:179–184. 30. Lossinsky AS, Shivers RR. Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. Histol Histopathol 2004;19:535–564.

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31. Pedemonte E, Mancardi G, Giunti D, Corcione A, Benvenuto F, Pistoia V, Uccelli A. Mechanisms of the adaptive immune response inside the central nervous system during inflammatory and autoimmune diseases. Pharmacol Ther 2006;11:555–566.

CHAPTER

7

Cerebrospinal Fluid Examination, Monitoring, and Diversion Techniques Matthew Koenig and L. Christine Turtzo

INTRODUCTION This chapter will review the main techniques used to access cerebrospinal fluid (CSF) spaces within and around the brain and spinal cord for the purposes of diagnostic examination, therapeutic drainage, and measurement of intracranial pressure (ICP). More detailed discussions of the anatomy and physiology of the CSF pathways are covered in Chapter 2 and Chapter 3, respectively. The first part of this chapter is devoted to a discussion of the lumbar puncture (LP), as the most common means of accessing the subarachnoid space. The use of cisternal and lateral cervical puncture, external ventricular drainage, ventricular and lumbar shunting techniques, third ventriculostomy, and the application of ICP monitoring devices will also be reviewed.

LUMBAR PUNCTURE Background The first documented LP was performed by Corning in 1885 for the purpose of introducing medications into the CSF.1 Wynter then removed CSF by LP in 1889 in the treatment of a patient with meningitis.1 Quincke perfected the LP technique in 1891 with the use of a specialized needle having a straight bevel and a fitted stylet.1 Since then, the Quincke needle has become a standard tool for performing an LP. The Touhy needle, having a curved bevel, is often preferred by anesthesiologists for the placement of epidural catheters in order to lower the risk of actual dural puncture.

Techniques Proper understanding of the underlying anatomy and careful positioning of the patient are the two main keys to performing a successful LP.1–3 Regarding positioning strategies, patients may be placed in either the lateral recumbent

position with the neck and knees bent, or sitting upright with the neck and back flexed forward such as when leaning over a table. If accurate measurement of an opening pressure is required, the patient should be maneuvered into the lateral recumbent position.3,4 Several authors have attempted to formulate corrections by which the opening pressure can be accurately measured from the sitting position. One method subtracts the distance from the needle insertion site to the level of the cisterna magna from the measured value.1 However, this method remains poorly validated, and in our opinion, is still best avoided. In the lateral recumbent position, the patient’s neck, hips, and knees should be flexed. The entire spine should be parallel to the table, and the coronal plane of the trunk should form a right angle to the floor. Care must be taken to ensure that the patient’s shoulders are perpendicular to the table, since inward rotation of the shoulders will make it more difficult to enter the selected interspace. Flexing the back will compensate for the normal lumbar lordosis by widening the space between adjacent spinous processes.3 Although many practitioners find LP to be easier in patients who are seated, individuals may inadvertently flex at the hips without truly flexing their spine, leaving the lumbar interspaces less accessible. In one technique to overcome hip flexion, patients are asked to place their hands on their hips and arch their spine rather than focusing on bending forward. Once the patient is properly positioned in either the lateral recumbent or the seated position, the insertion site is located. The examiner places an index finger on the superior portion of the iliac crests, with the thumbs meeting in the midline. Bisection of the line joining the top of both iliac crests identifies the L3–L4 interspace or the tip of the L4 spinous process.5 The examiner can usually then identify other spinous processes and interspaces by palpation, although this can admittedly be more difficult in patients with obesity or edema.6 The conus medullaris ends at the level of the L1–L2 interspace in 94% of adults, and

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CSF Examination, Monitoring, and Diversion Techniques

it extends one interspace lower in the remaining 6% of individuals.1,7 The L1–L2 and L2–L3 interspaces should therefore be avoided during LP in order to minimize the risk of damage to the conus medullaris.8 Conversely, the L3–L4, L4–L5, and L5–S1 interspaces are more appropriate because they safely avoid this structure. Because the conus medullaris extends below L1–L2 in infants and children, the lowest possible interspace should always be used in young patients,1,7 with needle insertion preferably no higher than at L4–L5.3 Once the appropriate interspace has been identified and marked, the overlying skin should be sterilized and draped using standard aseptic technique. The tissue should be locally anesthetized using 1% lidocaine, first injected subcutaneously and then infiltrated into deeper layers. Once the anesthetic has taken effect, LP is performed by slowly inserting an 18- to 26-gauge spinal needle with a wellfitting stylet. Most neurologists use either a 20- or a 22-gauge needle since those sizes are better for determination of CSF pressure, while anesthesiologists often prefer 25- or 26-gauge needles for injection of anesthetic agents because there is little risk of CSF leak and subsequent headache.1 One professional society recently issued guidelines related to needle gauge and the risk of post-LP headache,9 although practical considerations may supersede these recommendations as adequate sample collection is distinctly slower when using a smaller needle. The bevel of the needle is inserted in the midline, parallel to the longitudinal fibers of the dura, and directed toward the umbilicus. Positioning the bevel in this manner (with its flat portion and the notch in the stylet hub facing one of the patient’s sides) allows dural fibers to be separated instead of cut.2,3 Insertion of the needle in the midline reduces the chance of injury to laterally exiting nerve roots.1 Still, a lateral approach can sometimes be used, where the needle is inserted 2–3 cm off the midline in order to access CSF spaces more directly surrounding the nerve roots. This technique may decrease the chance of causing a “traumatic” puncture, but it may also increase the chance of nerve root injury. The needle will pass through the supraspinous ligament and the ligamentum flavum, often yielding a “pop” when the dura is pierced and the subarachnoid space is entered.1–3 The stylet should always remain tightly locked within the bevel when the needle is advanced in order to minimize the chance of introducing tissue into the spinal canal.10 When the stylet is removed, CSF should readily appear. If it does not, the stylet should be replaced and the needle rotated 90 degrees. If CSF still does not flow, the stylet should be replaced and the needle advanced incrementally – with frequent removal of the stylet – until CSF is obtained or bone is encountered. If the first pass is unsuccessful, the needle must be withdrawn all the way to the surface of the skin and redirected. Once fluid appears at the needle hub, a manometer with a three-way stopcock should be gently connected. If CSF

rises very slowly in the manometer, there may be partial obstruction of the needle tip by a nerve root or meningeal membrane or the CSF pressure may be low.1 Slight rotation of the needle should reposition it away from any partial obstruction. If this adjustment does not improve CSF flow, then an assistant can apply firm abdominal pressure (Quincke’s maneuver). If there is no obstruction and the CSF pressure is low, abdominal pressure will cause a rapid and reversible rise in the pressure recording.1 The patient can also be asked to bear down in order to increase intraabdominal pressure if CSF pressure is low. It should go without saying that CSF should be passively collected, never aspirated.2,3 Finally, some controversy exists as to whether the stylet should be replaced prior to withdrawing the needle. Most neurologists believe that reintroduction of the stylet will minimize the risk of nerve root or dural flap herniation, which may lead to radiculopathy or a persistent CSF leak.10 Still, the incidence of these events is rare, and neither has been convincingly linked to stylet placement. Other practitioners maintain that replacement of the stylet has the potential to transect a nerve root that has become trapped within the needle bevel or to introduce infection into the CSF space.2

Contraindications LP is an extremely safe procedure when performed by an experienced or properly supervised practitioner using standard methods and techniques. Contraindications include infection – such as cellulitis, sacral decubitis ulcers, or known epidural abscess – overlying the lumbar spine that places the patient at risk for iatrogenic meningitis. LP should also be avoided in patients with a known coagulopathy related to anticoagulant medications, liver failure, or thrombocytopenia. Still, there is no well-studied threshold for international normalized ratio (INR), partial thromboplastin time (PTT), or platelet count below or above which the procedure is proven to be safe. As a matter of practice, most physicians will not perform an LP in patients with an INR greater than 1.4 or a platelet count of less than 50,000/mm3.1 If necessary, the procedure can be done in thrombocytopenic patients undergoing simultaneous platelet transfusion. In borderline patients, care should be taken to minimize the number of needle passes and to select the smallest-gauge needle that is practical. LP is also contraindicated in patients with intracranial space-occupying brain lesions that result in midline shift or pressure on the contents of the posterior fossa.1 Again, there is no clear threshold for distance of midline shift below which LP is uniformly safe. If LP must be performed in patients with space-occupying lesions, care should be taken to minimize the possibility of persistent CSF leakage as well as the amount of CSF removed. The many reported complications of LP are discussed in detail in Chapter 8.

Temporary Lumbar Catheters and Lumboperitoneal Shunts

CISTERNAL PUNCTURE AND LATERAL CERVICAL PUNCTURE Background An alternative means of accessing the spinal CSF space is via puncture of the dura surrounding the cisterna magna at the cervicomedullary junction. Cervical punctures can be performed using either a posterior midline approach directly into the cisterna magna or via a lateral approach into the C1–C2 interspace. Puncture of the cisterna magna was first introduced by Ayer in 1920.1 Prior to the development of contrast myelography, cisternal puncture was widely used in conjunction with LP for the diagnosis of spinal block by looking for a pressure gradient between the two sites.1 Currently, cervical punctures are only performed when LP fails to yield CSF or if the procedure is contraindicated due to local infection overlying the lumbar spine, arachnoiditis, or the presence of a known spinal tumor.11,12

Techniques, indications, and complications Cisternal puncture can be performed with patients in either the seated or lateral recumbent position, and is best done using fluoroscopic guidance. The lateral position is often preferred due to low CSF pressures when the patient is in the seated position.1 With a laterally placed patient, the shoulders should be kept perpendicular to the table, and a pillow placed under the head to straighten the cervical spine. The skin overlying the occiput is shaved, cleaned with antiseptic solution, and draped. The uppermost spinous process (C2) is then palpated, and after local anesthesia is administered, a 20- or 22-gauge spinal needle is inserted in the midline, just above this spinous process.11,12 The needle is advanced upward toward the plane between the external auditory meatus and the glabella until it strikes the occiput. It is then withdrawn slightly, and redirected caudally to penetrate the dura. The cisterna magna is typically encountered 4–6 cm from the surface of the skin.11,12 There is usually another 2.5 cm between the dura and the medulla, although tenting of the dura may reduce this distance.12 The needle should never be inserted more than 7.5 cm without fluoroscopic guidance.1 Up to 25 ml of CSF can safely be removed from the cisterna magna.1,11 Complications are similar to LP, with the added potential risk of direct injury to the medulla and stroke resulting from injury to a vertebral artery.13 Traumatic puncture and post-procedural headache are reported to occur less commonly with cisternal puncture than with LP.1 Cisternal puncture is contraindicated in patients with a known Chiari malformation or a posterior fossa tumor.11,12 The lateral cervical puncture was introduced after cisternal puncture in order to minimize the possibility of direct brainstem injury. The C1–C2 interspace is favored because there is no overlap of the cervical vertebrae laterally at the atlantoaxial joint, and because the intervertebral space is

47

particularly wide at this level.11 The patient is placed supine, with the neck maintained as straight as possible. The side of the neck is sterilized and draped. A 20-gauge needle is inserted 1 cm caudal and 1 cm posterior to the tip of the mastoid process, in a plane that is parallel to the table and perpendicular to the neck.12 Several “pops” are often felt during passage of the needle through individual tissue planes. The stylet should be removed after each of these to look for CSF flow and to ensure that the needle has not been advanced too deeply. If bone is encountered, the needle should be withdrawn to the surface and advanced again with a small directional adjustment in the rostrocaudal plane.1,12 Complications of lateral cervical puncture are similar to those with cisternal puncture, with a somewhat greater theoretical possibility of injuring the vertebral artery but less chance of direct injury to the medulla.1

TEMPORARY LUMBAR CATHETERS AND LUMBOPERITONEAL SHUNTS Background Temporary externalized lumbar catheters and more permanent internalized lumboperitoneal shunts are used for the treatment of drainage-dependent patients with communicating hydrocephalus or idiopathic intracranial hypertension. Patients with reversible causes of communicating hydrocephalus, such as with cryptococcal meningitis, may also be treated with repeated large-volume LP. Lumboperitoneal shunts are most commonly used for treatment of idiopathic intracranial hypertension, usually because of a perceived difficulty in cannulating the small lateral ventricles that are common in these patients. In addition, lumbar drainage is believed to selectively drain CSF from the subarachnoid rather than the ventricular space, making it theoretically more useful for the treatment of slit-like ventricles.13 Temporary lumbar spinal catheters are usually used for pressure monitoring and drainage trials in the evaluation of patients with suspected normal pressure hydrocephalus. These catheters can provide this sequential monitoring and drainage function to evaluate for a therapeutic response that was missed by LP.

Techniques Lumbar drains are inserted using techniques similar to LP. A 14-gauge introducer needle with a curved bevel is first inserted, through which a flexible plastic catheter is passed into the subarachnoid space below the L2–3 level. The catheter is advanced 6–10 cm rostrally with or without the use of a flexible guidewire.14 The external end of the catheter is then temporarily anchored to the skin and connected to a drainage chamber or a pressure transducer, both of which need to be leveled relative to the patient’s

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position in order to validate recordings and control CSF flow. Lumboperitoneal shunts, on the other hand, feature several different types of valves, including the commonly used differential pressure valve. When the lumbar CSF pressure exceeds the pre-set “pop off ” pressure of the valve, the drainage cannula opens passively and fluid drains until the pressure gradient has dissipated. CSF flows into the peritoneal cavity through a subcutaneously tunneled catheter where it is promptly reabsorbed. Lumboperitoneal shunts differ from ventricular shunts (discussed below) by being subject to variable pressure according to the patient’s body position.15 As discussed for LP, CSF pressure in the sitting or standing position is greatly increased due to the influence of gravity on the contiguous fluid column.15 In patients with a lumboperitoneal shunt, this phenomenon could over-drain CSF while in the upright position without a position sensor. Valves on these shunts, therefore, typically require two separate differential pressure mechanisms, with a gravity-operated ball-valve mechanism directing flow to the appropriate portion of the shunt based on upright or supine posture.15 There are several advantages of lumbar drainage when compared to a ventricular catheter, making this technique well suited for patients who require temporary CSF drainage over an intermediate time frame. Lumbar drains and shunts of course do not need to be inserted through brain tissue, and therefore do not suffer from the attendant risks of hemorrhage, cerebritis, and seizures.16 In addition, lumboperitoneal shunts may have a lower infection rate compared to ventricular catheters. The lifetime infection rate of lumboperitoneal shunts has been reported as between 1 and 5% in various case series.17–19 This compares favorably to the reported lifetime infection rate of 11% with ventricular shunts.20 Lumboperitoneal shunts also provide the theoretical advantage of draining both the subarachnoid space and the ventricles, thereby allowing for a more physiological drainage pattern.13,16 In addition, because of the large pool of CSF present in the lumbar cistern, there is a relatively low probability of collapsing the ventricles from over-drainage.16

Complications Complications related to temporary external lumbar drains have been reported in up to 44% of patients,21 although events such as infection, over-drainage, and nerve root injury likely occur much less than 10% of the time. In this particular series, controlled CSF drainage was performed for 5–10 days using a closed, continuous system. Unusual complications included the occurrence of tension pneumocephalus in 5% of individuals.21 The authors speculated that head elevation combined with spinal drainage resulted in a heightened negative gradient between atmospheric pressure and ICP. Such a gradient could potentially siphon air into the CSF space through an existing defect such as a

sinus fistula or a skull fracture. Entrapment of air may then exert a mass effect on the underlying brain.21 Tension pneumocephalus has been associated with seizures, declining level of consciousness, and clinical signs of cerebral herniation.14

Meningitis The incidence of meningitis with continuous external lumbar CSF drainage has been reported as between 4 and 10%.21–23 Most authors have not found a clear association between the development of meningitis and duration of drainage. In one series, many cases developed within the first 24 h of drainage, with rates leveling off after several days.23 The use of prophylactic antibiotics to reduce the risk of meningitis is also controversial, with most studies reporting a shift in the causative organisms rather than an actual reduction in the frequency of infections.23 The most common organisms resulting in lumbar drain-associated meningitis remain coagulase-negative Staphylococci followed by Gram-negative bacilli.23 Factors associated with an increased risk of these infections include presence of bloody CSF that may stimulate bacterial growth, drain manipulation or flushing, CSF leakage around the drain, and diabetes mellitus.23 A diagnosis of meningitis in these situations can sometimes be difficult due to baseline CSF abnormalities. Many of these patients already have inflammatory CSF from bacterial or fungal meningitis or as a reaction to blood products such as following subarachnoid hemorrhage. In these circumstances, fever, peripheral leukocytosis, hypoglycorrhachia, elevated CSF protein, and CSF leukocytosis can be unreliable markers of infection.23 A rising CSF leukocyte count on serial examinations and the presence of bacteria on direct CSF smear or culture are the most specific markers of catheter-associated meningitis.23 The risk of meningitis with a lumboperitoneal shunt is much lower than with an external lumbar drain (1–5% lifetime frequency).17–19

Catheter obstruction Obstruction is the most common complication of indwelling lumboperitoneal shunts, occurring in up to 50% of patients in the first year, and ultimately responsible for 65% of all shunt revisions.24 Indeed, up to 85% of these patients require at least one shunt revision within the first 2 years.25 Some patients appear particularly prone to developing recurrent shunt obstructions and require multiple revisions, but specific risk factors have not been elucidated.25 Some series suggest that younger and more obese patients are more likely to experience shunt obstruction.24,25 Obstruction occurs more commonly with lumboperitoneal shunts than with ventricular shunts, which is a major factor why many neurosurgeons are reluctant to implant these devices. Obstruction also occurs more frequently in patients with hemorrhagic CSF and most often within the proximal cannula rather than in the valve or at the distal end.24

External Ventricular Drains and Ventricular Shunts

CSF over-drainage Secondary intracranial hypotension is the next most common indication for shunt revision after obstruction, accounting for 15% of repeat procedures.24 As occurs with LP, this syndrome results in postural headache, nausea, meningeal signs, radiographically apparent thickening and/or enhancement of the pachymeninges, and occasional lower cranial neuropathies. CSF over-drainage has also rarely been associated with transient blindness, hearing loss, and even vocal cord paralysis.14,21 Prolonged intracranial hypotension may predispose to the development of acquired Chiari malformations, as the cerebellar tonsils are pulled caudally through the foramen of Monro by gravity. The resulting compression of the upper spinal cord may also lead to syringomyelia.24,26 The radiographic appearance of a Chiari malformation was reported to occur in 70% of patients undergoing long-term follow-up of their lumboperitoneal shunts in one series, although the frequency of symptomatic tonsillar compression was much lower.26 The mean interval between lumboperitoneal shunt placement and development of symptomatic Chiari malformation was 7 years in another series.24 Such acquired Chiari malformations often necessitate lower shunt removal and placement of a ventricular shunt if the patient remains drainage-dependent.

EXTERNAL VENTRICULAR DRAINS AND VENTRICULAR SHUNTS Background Although trephination was practiced for centuries, the earliest documented ventricular puncture was performed by LeCat in 1744.27 Continuous external ventricular drainage has been undertaken since the beginning of the twentieth century. Surgical placement of an externalized ventricular drain or a ventricular shunt is undertaken when patients require short- or long-term CSF drainage, respectively. Common indications include hydrocephalus and idiopathic intracranial hypertension. Ventricular drainage is generally preferred in processes that result in ventriculomegaly, although it can also be undertaken in conditions with small or even slit-like ventricles.

Techniques Both external ventricular drains and ventricular shunts require a small craniotomy and passage of a specialized cannula through both the dura and the brain parenchyma into the lateral ventricle. The highly vascular choroid plexus within the lateral ventricle must be avoided to minimize the risk of intraventricular hemorrhage that can lead to drain obstruction.28 The catheter may be placed via a frontal, an occipital, or – more rarely – a temporal approach. The neurosurgical literature remains divided on

49

the ideal technique, with one study suggesting longer shunt survival through a frontal compared to a posterior approach.29 Still, most neurosurgeons continue to prefer a posterior placement.28 The intraventricular portion of the cannula has multiple fenestrations to minimize the risk of occlusion. When a frontal approach is used, the length of drain to be inserted can be approximated by measuring the distance from the coronal suture two-thirds of the way to the external auditory canal.28 The required burr hole is placed just anterior to the coronal suture in the plane of the medial canthus. The trajectory of the catheter in the sagittal plane is found by aiming toward a point 1.5 cm anterior to the tragus.28 After the burr hole is drilled, a spinal needle is used to fenestrate the dura several times. When it enters the lateral ventricle, CSF refluxes through the catheter and the introducer is removed. In external ventricular drains, a second skin incision is then made 6–10 cm lateral to the burr hole and the catheter is tunneled subcutaneously to exit through this second site. Tunneling of these catheters has been shown to decrease the risk of meningitis.28 The distal portion of a ventricular shunt is tunneled subcutaneously to a variety of extracerebral sites, including large central veins or the right atrium of the heart, the gallbladder, the pleural space, the peritoneal cavity, and – historically – the ureter and bladder. Modern ventricular shunts are made up of three components: a proximal catheter, an extracranial one-way valve, and a distal catheter. Several different valve designs are currently in use, including flow-dependent valves, pressure-dependent valves, and programmable valves that can be adjusted externally using a hand-held magnetic device. One challenge for ventricular shunts is the effect of gravity on the CSF pressure in the upright versus the recumbent position. Positional over-drainage can be counteracted by inclusion of an anti-siphon device near the valve, which references the intracranial pressure to atmospheric pressure transmitted across the overlying scalp.30 The valve is tunneled underneath the scalp and can easily be palpated by the examining physician. Shunt patency can be grossly evaluated by manual pumping of the shunt valve. This is achieved by compressing the distal portion of the shunt, then firmly pressing the valve pump. The pump mechanism should compress easily, then rapidly refill with CSF from the ventricle. This verifies the patency of the proximal catheter. The distal catheter is tested by compressing the proximal portion of the shunt, then pressing the valve pump again. Rapid and smooth compression of the valve pump suggests that the distal catheter is patent.31 Shunt patency can also be formally tested via the use of radionuclide tracers injected directly into the shunt bulb.

Complications The major complications of ventricular shunting can be divided into problems intrinsic to the ventricular placement

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Chapter 7

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CSF Examination, Monitoring, and Diversion Techniques

of the shunt and those related to the location of the distal catheter. Intrinsic shunt complications include shunt tract hemorrhage, shunt misplacement, seizures, subdural hematoma or effusion, secondary intracranial hypotension, intraventricular hemorrhage, meningitis or ventriculitis, and shunt occlusion or disconnection. The distal catheter can generate compartment-specific complications. Ventriculoperitoneal shunts – like lumboperitoneal shunts – can cause visceral perforation and fistula formation with bowel, bladder, and other pelvic organs. Reports of shunts eroding into abdominal and pelvic organs and migrating out the anus or vagina are not rare.28 Infection or inflammation around the distal catheter may also result in bowel obstruction, volvulus, intussusception, and pseudocyst formation. The presence of a pseudocystic collection of unabsorbed CSF surrounded by a wall of inflammatory tissue is nearly always an indication of distal catheter infection and usually necessitates shunt revision.28 Distal catheters placed into the great veins or the right atrium of the heart can result in venous thrombosis, chronic bacteremia, pulmonary embolism, arrhythmia, cor pulmonale, and cardiac tanponade. Thrombosis around the catheter tip occurs in up to 40% of ventriculoatrial shunts.32 In one autopsy series, the incidence of pulmonary embolism among patients with ventriculoatrial shunts was 59.7% with concomitant pulmonary hypertension in 6.3%.33 Chronic infection of the distal catheter in these sites may also result in serum sickness and renal failure from diffuse glomerulonephritis related to immune complex deposition.

Catheter obstruction Obstruction of the proximal catheter, although less frequent with ventricular shunts than with lumbar shunts, remains the most common shunt-related complication regardless of the distal catheter location. This complication results in 50% of all shunt revision surgeries.34 Indeed, the median survival of ventricular shunts prior to occlusion was only 73 months in one series.35 Proximal occlusion is caused either by the displacement of the catheter into the brain parenchyma during growth, or by blockage of multiple shunt ports with debris, inflammatory tissue, blood products, or choroid plexus.34 The risk of proximal occlusion is increased by placement of the catheter close to the choroid plexus and in patients with small ventricles.34 Contrary to surgical lore, elevated CSF protein alone does not increase the risk of shunt occlusion.36 Distal or valvular shunt occlusions occur more rarely, and often relate to shunt infection or disconnection of tubing. The patency of the distal shunt components can be assessed by fluoroscopic monitoring of radiotracer injected into the shunt bulb. More grossly, physical continuity of the shunt can be assessed by CT or via a plain radiographic “shunt series” to visualize areas of disconnection.

Ventriculitis Proximal shunt infection may result in meningitis or ventriculitis. In a large series of almost 6,000 patients

undergoing ventricular shunt placement, the overall infection rate was 8.6%.37 A review of shunt-related meningitis reported the incidence to vary between 0 and 38%.38 Several factors appear to increase the risk of shunt infection, including internalization of a previous external shunt, extremes of age, and the presence of intraventricular blood, which may act to facilitate bacterial growth.39 The most frequent organisms resulting in meningitis are Staphylococcus species, including S. aureus and coagulasenegative Staphylococcus species.34,39 Iatrogenic meningitis is a much greater concern with external ventricular drain placement, which become infected in 0–22% of cases.40 Risk factors for external drain-related meningitis include depressed skull fracture, CSF leak, catheter irrigation, concurrent systemic infections such as bacteremia or urinary tract infection, and concurrent corticosteroid use.40 The duration of external drainage appears to correlate with the risk of catheter-related infection, but this relationship remains controversial.40,41 Also controversial are the use of prophylactic antibiotics or empiric catheter replacement or exchange after an arbitrary duration.40 As there is no evidence to support routine catheter exchange, this practice is currently not recommended.40 Although evidence supporting the use of prophylactic antibiotics is poorly controlled and conflicting, the practice widely persists.42 As with lumbar drains, the diagnosis of catheter-related meningitis is not straightforward because of prophylactic antibiotic use and baseline CSF abnormalities associated with the underlying disease. In one series, the only specific early marker for CSF infection was an increase in leukocyte count on serial CSF examinations.41 Other serum, CSF, and clinical markers of infection – including hypoglycorrhachia, Gram stain, fever, and peripheral leukocytosis – proved unreliable.41

CSF over-drainage The other major category of complications associated with ventricular shunts relate to over-drainage of CSF. As discussed earlier, ventricular shunts preferentially drain the ventricles rather than the subarachnoid space. This pattern of CSF drainage is probably advantageous in diseases such as normal pressure hydrocephalus where there is disproportionate ventriculomegaly. Overly rapid or aggressive ventricular drainage, however, may result in subdural hematomas due to tearing of fragile bridging veins as the brain parenchyma collapses away from the rigid dura. The incidence of subdural hematoma in this situation varies between 4.5 and 21%, and typically occurs within 12 to 24 months of shunt placement.34 CSF over-drainage may also result in symptomatic intracranial hypotension with postural headaches and associated lower cranial neuropathies.43 Slit ventricle syndrome is another poorly understood late complication of ventricular over-drainage. In this condition, chronic gliosis surrounding the collapsed ventricles results in decreased ventricular compliance.34 This collapse, in turn, reduces the natural capacity of

Intracranial Pressure Monitoring Devices

ventricular CSF to buffer the arterial pulse pressure that is conducted across the choroid plexus. The net result of these changes is that increased intracranial pressure may develop in the presence of slit-like ventricles and the absence of significant subdural effusions. Patients may be asymptomatic, or they may present with all of the classic features of elevated intracranial pressure – including papilledema – in the setting of a falsely reassuring radiographic appearance.34

THIRD VENTRICULOSTOMY Internal diversion of CSF from the third ventricle was the earliest surgical treatment of non-communicating hydrocephalus, even prior to the development of ventriculoperitoneal shunting. This procedure involves cannulation of the third ventricle via the cerebral aqueduct and diversion of CSF into the fourth ventricle, intrapeduncular cistern, or cisterna magna.44 Traditionally, the third ventricle was surgically accessed frontally with division of the optic nerve or via a subtemporal approach with diversion of the third ventricle directly into the intrapeduncular cistern.44 Because of high surgical morbidity, third ventriculostomy was abandoned for many years until the development of intraventricular endoscopy. Currently, endoscopic third ventriculostomy is performed by cannulation of the right frontal horn of the lateral ventricle via a burr hole. The endoscope is then directed through the foramen of Monro into the third ventricle. The cerebral aqueduct is then bluntly dissected under direct endoscopic guidance with or without subsequent stenting. Third ventriculostomy has been best studied in patients with acquired aqueduct stenosis. In this population, success rates up to 88% have been reported, where success was defined as the avoidance of subsequent ventriculoperitoneal shunting.45 Complications of third ventriculostomy include intraventricular hemorrhage, cranial neuropathies, hypothalamic dysfunction, and injury to the basilar artery.44

CSF CHANGES AFTER VENTRICULAR SHUNT PLACEMENT There are very few published reports detailing changes in CSF composition after placement of a ventricular shunt, either in samples extracted directly from the shunt bulb or by LP. One series, however, examined CSF from 17 patients with normal pressure hydrocephalus before ventriculoperitoneal shunt placement and at 3 and 12 months postoperatively.46 The pre-operative CSF protein concentration was normal in the majority of patients. Three months postoperatively, however, protein levels increased in 88% of patients to a mean of 150 mg/dl.46 Protein concentrations greater than 100 mg/dl were found in nearly half of patients, with a maximum of 400 mg/dl. They remained

51

elevated in 50% of patients at 1 year.46 There also was a transient CSF leukocytosis at 3 months, with 38% of patients having more than 5 leukocytes/mm3, with a maximum of 15 leukocytes/mm3. Cell counts normalized at 1 year in all patients.46 There are also several reports of CSF eosinophilia occurring after shunt placement.47,48 Eosinophils are not normally present within the CSF, and in these cases the eosinophilia was believed to occur as an inflammatory reaction to the shunt material. In another review of 106 patients undergoing various shunt-related procedures, 34% of patients had greater than 8% eosinophils in the CSF at some point after the shunt was placed.47 Patients with CSF eosinophilia were more likely to require multiple shunt revisions for occlusion, and shunt infections occurred more commonly in this group.47 Patients with CSF eosinophilia were also more likely to have an elevated CSF protein level.46

INTRACRANIAL PRESSURE MONITORING DEVICES CSF pressure monitoring can be accomplished using either fluid-coupled or solid-state devices inserted into the ventricles, the lumbar thecal sac, the brain parenchyma, or the epidural space. The physiology of CSF monitoring is discussed in detail in Chapter 4, but the most common pressure transduction devices are reviewed here. The simplest devices are fluid-coupled cannulae that directly communicate with the CSF space, either in the ventricles or in the lumbar thecal sac. Using a three-way stopcock, one end can be used to drain CSF, while the other can be attached to a pressure transducer via saline-filled tubing for continuous monitoring of ICP. The transducer position must be changed and the system “re-zeroed” each time the position of the head or lumbar spine is changed. While ventriculostomy catheters remain the gold standard for ICP monitoring, they carry all of the risks discussed in the section on external ventricular drains, including cerebral hemorrhage and infection.49 The major advantage of CSF catheters is that they allow treatment of elevated ICP in addition to pressure monitoring, via drainage of CSF. Epidural transducers (“bolts”) are commonly placed when the ventricles are difficult to cannulate or global cerebral edema is present, such as in patients with head trauma or severe hepatic encephalopathy. Epidural bolts provide the advantage of not penetrating the dura, thereby minimizing the risk of brain injury, CSF leakage, and infection.49 These devices, however, cannot be recalibrated and are prone to baseline pressure drift after a few days.49 Several publications comparing ICP measured simultaneously by a ventricular fluid-coupled cannula and an epidural bolt have shown marked differences, casting doubt on the accuracy of the epidural bolt.50,51 These devices also do not allow CSF sampling or drainage. More recently, intraparenchymal solid-state pressure transducers have been popularized.

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CSF Examination, Monitoring, and Diversion Techniques

These devices can be inserted into any intracranial compartment and are composed of either fiber-optic or microwire transducers. Intraparenchymal transducers have a low rate of infection, cause minimal trauma, and do not need to be recalibrated with change of head position.49 The accuracy of ICP measurement with solid-state tranducers compares favorably with intraventricular fluid-coupled cannulae when measured simultaneously.52 Disadvantages include the inability to recalibrate the device after implantation, high cost compared to ventriculostomy catheters, and the inability to drain CSF.49 REFERENCES 1. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. New York: W.B. Saunders; 1992:157–182. 2. Roos KL. Lumbar puncture. Semin Neurol 2003;23:105–114. 3. Boon JM, Abrahams PH, Meiring JH, et al. Lumbar puncture: anatomical review of a clinical skill. Clin Anat 2004;17:544–553. 4. Van Dellen JR, Bill PL. Lumbar puncture – an innocuous diagnostic procedure? S Afr Med J 1978;53:666–668. 5. Ievins FA. Accuracy of placement of extradural needles in the L3–4 interspace: comparison of two methods of identifying L4. Br J Anaesth 1991;66:381–382. 6. Broadbent CR, Maxwell WB, Ferrie R, et al. Ability of anaesthetists to identify a marked lumbar interspace. Anaesthesia 2000;55: 1122–1126. 7. Reimann AF, Anson BJ. Vertebral level of termination of the spinal cord with report of a case of sacral cord. Anat Rec 1944;88:127–138. 8. Reynolds F. Damage to the conus medullaris following spinal anaesthesia. Anaesthesia 2001;56:238–247. 9. Armon C, Evans RW: Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Addendum to assessment: Prevention of post-lumbar puncture headaches: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005;65:510–512. 10. Strupp M, Brandt T, Muller A. Incidence of post-lumbar puncture syndrome reduced by reinserting the stylet: a randomized prospective study of 600 patients. J Neurol 1998;245:589–592. 11. Kendell B. How to do a cisternal puncture. Br J Hosp Med 1980;24:571. 12. Ward E, Orrison WW, Watridge CB. Anatomic evaluation of cisternal puncture. Neurosurgery 1989;25:412–415. 13. Khorasani L, Sikorski CW, Frim DM. Lumbar CSF shunting preferentially drains the cerebral subarachnoid over the ventricular spaces: implications for the treatment of slit ventricle syndrome. Pediatr Neurosurg 2004;40:270–276. 14. Roland PS. Marple BF, Meyerhoff WL, et al. Complications of lumbar spinal fluid drainage. Otolaryngol Head Neck Surg 1992;107:564–569. 15. Garton HJL. Cerebrospinal fluid diversion procedures. J Neuro-Ophthalmol 2004;24:146–155. 16. Rekate HL, Wallace D. Lumboperitoneal shunts in children. Pediatr Neurosurg 2003;38:41–46. 17. Aoki N. Lumboperitoneal shunt; clinical applications, complications and comparisons with ventriculoperitoneal shunt. Neurosurgery 1990;26:998–1004. 18. Yadav YR, Pande S, Raina VK, et al. Lumboperitoneal shunts: review of 409 cases. Neurol India 2004;52:188–190. 19. Duthell R, Christophe N, Fotso MJ, et al. Lumboperitoneal shunting. In: Schmidek HH, Sweet WH, eds. Operative Neurosurgical Techniques, Indications, Methods, and Results. Philadelphia: WB Saunders; 2000:604–607. 20. Epstein MH, Duncan JA. Surgical management of hydrocephalus in adults. In: Schmidek HH, Sweet WH, eds. Operative Neurosurgical Techniques, Indications, Methods, and Results. Philadelphia: WB Saunders; 2000:595–603.

21. Açikbas SC, Akyüz M, Kazan S, et al. Complications of closed continuous lumbar drainage of cerebrospinal fluid. Acta Neurochir 2002;144:475–480. 22. Schade RP, Schinkel J, Visser LG, et al. Bacterial meningitis caused by the use of ventricular or lumbar cerebrospinal fluid catheters. J Neurosurg 2005;102:229–234. 23. Coplin WM, Avellino AM, Kim DK, et al. Bacterial meningitis associated with lumbar drains: a retrospective cohort study. J Neurol Neurosurg Psychiatry 1999;67:468–473. 24. Eggenberger ER, Miller NR, Vitale S. Lumboperitoneal shunt for the treatment of pseudotumor cerebri. Neurology 1996;46:1524–1530. 25. Karabatsou K, Quigley G, Buxton N, et al. Lumboperitoneal shunts: are the complications acceptable? Acta Neurochir 2004;146:1193–1197. 26. Chumas PD, Kulkarni AV, Drake JM, et al. Lumboperitoneal shunting: a retrospective study in the pediatric population. Neurosurgery 1993; 32:376–383. 27. Aschoff A, Kremer P, Hashemi B, et al. The scientific history of hydrocephalus and its treatment. Neurosurg Rev 1999;22:67–93. 28. Li V. Methods and complications in surgical cerebrospinal fluid shunting. Neurosurg Clin N Am 2001;36:685–693. 29. Albright AL, Haines SJ, Taylor FH. Function of parietal and frontal shunts in childhood hydrocephalus. J Neurosurg 1988;69:883–886. 30. Bergsneider M. Management of hydrocephalus with programmable valves after traumatic brain injury and subarachnoid hemorrhage. Current Op Neurol 2000;13:661–664. 31. Naradzay JFX, Browne BJ, Rolnick MA, et al. Cerebral ventricular shunts. J Emergency Med 1999;17:311–322. 32. Forrest D, Cooper D. Complications of ventriculoatrial shunts – a review of 455 cases. J Neurosurg 1968;29:506–512. 33. Pascual JMS, Prakash UBS. Development of pulmonary hypertension after placement of a ventriculoatrial shunt. Mayo Clin Proc 1993; 68:1177–1182. 34. Blount JP, Campbell JA, Haines SJ. Complications in ventricular cerebrospinal fluid shunting. Neurosurg Clin N Am 1993;4:633–656. 35. Piatt JH, Carlson CV. A search for determinants of cerebrospinal fluid shunt survival: retrospective analysis of a 14-year institutional experience. Pediatr Neurosurg 1993;19:233–242. 36. Brydon HL, Hayward R, Harkness W, et al. Does the cerebrospinal fluid protein concentration increase the risk of shunt complications? Br J Neurosurg 1996;10:267–273. 37. Cochrane DD, Kestle J. Ventricular shunting for hydrocephalus in children: patients, procedures, surgeons, and institutions in English Canada, 1989–2001. Eur J Pediatr Surg 2002;12:S6–S11. 38. Quigley MR, Reigel DH, Kortyna R. Cerebrospinal fluid shunt infections. Pediatr Neurosurg 1989;15:111–120. 39. Wang KW, Chang WN, Shih TY, et al. Infection of cerebrospinal fluid shunts: causitive pathogens, clinical features, and outcomes. Jpn J Infect Dis 2004;57:44–48. 40. Lozier AP, Sciacca RR, Romagnoli MF, et al. Ventriculostomy-related infections: a critical review of the literature. Neurosurgery 2002; 51:170–182. 41. Pfisterer W, Mühlbauer M, Czech T, et al. Early diagnosis of external ventricular drainage infection: results of a prospective study. J Neurol Neurosurg Psychiatry 2003;74:929–932. 42. Zingale A, Ippolito S, Pappalardo P, et al. Infections and re-infections in long-term external ventricular drainage. J Neurosurg Sci 1999;43:125–133. 43. Mokri B. Low cerebrospinal fluid pressure syndromes. Neurol Clin 2004;22:55–74. 44. Drake JM. Ventriculostomy for treatment of hydrocephalus. Hydrocephalus 1993;4:657–666. 45. Kelly PJ. Stereotactic third ventriculostomy in patients with nontumoral adolescent/adult onset acqueduct stenosis and symptomatic hydrocephalus. J Neurosurg 1991;75:865–873. 46. Wikkelsø C, Blomstrand C. Cerebrospinal fluid proteins and cells in normal-pressure hydrocephalus. J Neurol 1982;228:171–180. 47. Tung H, Raffel C, McComb JG. Ventricular cerebrospinal fluid eosinophilia in children with ventriculoperitoneal shunts. J Neurosurg 1991;75:541–544.

References

48. Tzvetanova EM, Tzekov CT. Eosinophilia in the cerebrospinal fluid of children with shunts implanted for the treatment of internal hydrocephalus. Acta Cytol 1986;30:277–280. 49. Zhong J, Dujovny M, Park HK, et al. Advances in ICP monitoring techniques. Neurol Res 2003;25:339–350. 50. Powell MP, Crockard HA. Behavior of an extradural pressure monitor in clinical use. Comparison of extradural with intraventricular pressure in

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patients with acute and chronically raised intracranial pressure. J Neurosurg 1985;63:745–749. 51. Czech T, Korn A, Reinprecht A, et al. Clinical evaluation of a new epidural pressure monitor. Acta Neurochir 1993;125:169–172. 52. Gambardella G, Zaccone C, Cardia E, Tomasello F. Intracranial pressure monitoring in children: comparison of external ventricular device with the fiberoptic system. Childs Nerv Syst 1993;9:470–473.

CHAPTER

8

Cerebrospinal Fluid Acquisition and Analysis in Modern Clinical Practice L. Christine Turtzo

INTRODUCTION Many neurological disorders are associated with changes in the dynamics and/or composition of the cerebrospinal fluid (CSF), and clinicians commonly depend on CSF analysis to diagnose and manage their patients. Lumbar puncture (LP), the most widely used method to collect CSF samples, has been performed for over a century in routine clinical practice. The first reported LP was undertaken by Walter Essex Wynter in 1889 via an open incision and insertion of a drainage catheter into the lumbar subarachnoid space.1 Percutaneous LP was first performed by Heinrich Quincke in 1890 on a child, and the next year on an adult.2,3 Today, a decision about whether or not to perform an LP requires a careful consideration of the indications for the procedure as well as a reasonable search for any contraindications that may exist for doing so. This chapter will discuss the various indications, contraindications, and potential complications of LP, then it will address issues and controversies related to the choice of diagnostic tests to be performed on the acquired CSF samples. The techniques and approaches used to perform an LP are reviewed in Chapter 7.

INDICATIONS FOR LUMBAR PUNCTURE The first step in performing an LP entails determining whether the procedure is truly indicated or not. Patients should be carefully informed of both the reasons for its need as well as the potential risks and complications involved. For the clinician, the procedure is primarily a diagnostic undertaking; only in a few circumstances does it provide therapeutic benefit itself or allow access to the subarachnoid space for the application of intrathecal therapies. Nevertheless, a complete CSF analysis can assist in the diagnosis and management of many central nervous system (CNS) and peripheral nervous system (PNS) disorders. The results of assays performed on these samples, regardless of

what they actually show, commonly guide clinical decisionmaking efforts. The precise indications to perform an LP vary widely, and all-encompassing guidelines cannot be provided. In the most extreme situations, the procedure is considered urgent or even emergent and must be carried out before a search for all contraindications has been completed. Some of the strongest indications for an urgent LP include cases of suspected CNS infection (meningitis, meningoencephalitis, or encephalitis), the occurrence of unexplained fever in an infant or an immunocompromised host, or in the increasingly uncommon situation of possible subarachnoid hemorrhage (SAH) in the setting of a negative cranial computed tomography (CT) scan. Even when time is not so clearly of the essence, an LP can be useful in the evaluation of possible neuroimmunological disorders such as multiple sclerosis, transverse myelitis, neurosarcoidosis, or Guillian-Barré syndrome; to evaluate for suspected idiopathic intracranial hypertension (pseudotumor cerebri); and to search for possible carcinomatous meningitis or CNS lymphoma. These indications, among many others, are discussed elsewhere throughout this book. An LP is less commonly indicated in routine cases of dementia (unless it is rapidly progressive, occurs in a younger patient, or is considered in the setting of positive serological tests for syphilis), ischemic stroke, or recurrent seizures. The appropriate use of a lumbar CSF drainage trial for the identification of those patients with suspected adult hydrocephalus is reviewed in Chapter 12.

CONTRAINDICATIONS TO LUMBAR PUNCTURE After confirming that CSF analysis will serve an important diagnostic purpose, each patient must be carefully screened for contraindications that would unduly raise the risk of a complication from the LP (Table 8-1). Every patient should be carefully examined for the presence of focal neurological

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Table 8-1

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CSF Acquisition and Analysis in Modern Clinical Practice

Contraindications to Lumbar Puncture

Known posterior fossa mass lesion Evidence of intracranial lesion with mass effect by cranial CT or MRI scan Evidence of midline shift on cranial CT or MRI scan Poor visualization of the fourth ventricle and/or quadrigeminal cistern on cranial CT or MRI scan INR greater than 1.5 Platelet count less than 50,000/mm3 Known suppurative infection in the lumbar region overlying the spinal canal (cellulitis, furunculosis, epidural abscess)

deficits or evidence of increased intracranial pressure (ICP). This must include a fundoscopic exam to search for any evidence of papilledema. There is general agreement that a cranial CT or magnetic resonance imaging (MRI) scan is obligatory for any patient who presents with focal neurological deficits, new-onset seizures, altered level of consciousness, and/or papilledema before an LP can safely be performed.4,5 A cranial MRI scan is recommended for all immunocompromised patients to evaluate for occult mass lesions. If the clinical presentation or neurological examination is consistent with a posterior fossa mass lesion, a cranial MRI scan is warranted over a CT scan to provide better visualization of the involved structures. When the fourth ventricle or quadrigeminal cistern cannot be adequately visualized, if an overt lesion with mass effect is found, or if there is evidence of midline shift of intracranial structures, the LP is contraindicated.6 There remains some debate as to whether it is necessary to obtain a brain imaging study prior to LP in circumstances that suggest acute meningitis but in the absence of certain clinical features.5,7 In general, if acute bacterial meningitis is suspected and an emergent head CT scan cannot be quickly obtained, the LP should either be deferred or performed based solely on the examination findings.7 Broad-spectrum antibiotics must be initiated immediately, given the high morbidity and mortality associated with this disorder in the absence of treatment. If there is no evidence of a mass lesion or elevated ICP by examination or imaging, the next consideration is whether or not the patient is at any increased risk of bleeding from the procedure. LP is relatively contraindicated in patients whose platelet count is less than 50,000/mm3 or whose international normalized ratio (INR) is greater than 1.5.4 In patients with thrombocytopenia where there is a strong clinical indication for an LP, particular those whose platelet count is below 20,000/mm3, platelets should be transfused just prior to the procedure to reduce the risk of a procedure-related hemorrhage.8 Anticoagulation therapy should be stopped or reversed prior to performance of an LP whenever possible. Protamine can be administered to patients on heparin therapy, and vitamin K and/or fresh-frozen plasma may be given to reverse the effects of warfarin.9 Resumption of heparin therapy should be held for at least 1–2 h after an LP, given the risk of symptomatic

subarachnoid or subdural hemorrhage if therapy is reinitiated too early.10 Finally, every patient should be carefully examined for evidence of suppurative infection at the site where the LP is to be performed. The presence of cellulitis, furunculosis, or an epidural abscess overlying the lumbar spinal canal is an absolute contraindication to LP, given the risk of iatrogenic bacterial meningitis resulting from introduction of bacteria into the CSF as the spinal needle traverses the infected area and enters the lumbar cistern.9

OTHER PRE-PROCEDURE CONSIDERATIONS After a patient has been evaluated for any contraindication to LP, the next step is to obtain informed written consent from the patient or the patient’s surrogate. The consent form should list all the potential complications of the procedure including (but not necessarily limited to) pain, headache, bleeding, infection, nerve damage, herniation, and death. If the patient’s illness is acute, or if there is any possibility that the patient might be at some risk of brain herniation, the LP should be performed in a hospital setting where careful post-procedural monitoring is available. If the patient’s disease is more chronic and the patient is clinically stable, the LP may be safely done in the outpatient setting after all contraindications have been excluded. For the safety of both the patient and the physician, all LPs should be performed under sterile conditions. At a minimum, the physician should wear sterile gloves, eye protection, and a mask. A gown should also be considered to better preserve the sterile field, and this protective item is considered mandatory in all suspected cases of meningitis, meningoencephalitis, or encephalitis. Finally, careful thought should always be given to the sample volume that will be needed to perform all the desired assays (see Table 8-2), and whether any specimens will require special handling or immediate processing. For example, proper cytopathological analysis of the cellular

Table 8-2 Assays

Volumes of CSF Needed for Individual

CSF Assay

Sample Volume Needed

Cell count and differential Glucose and protein concentration Bacterial Gram stain and culture Viral PCRs AFB smear and culture Flow cytometry and cytopathology Oligoclonal bands, myelin basic protein, IgG index*, ACE

1 ml each in tube #1 and tube #4 1 ml Minimum of 1 ml 1 ml per viral PCR 5 ml Minimum of 5 ml, preferably 10–15 ml 0.5 ml per test

* Measurement of an IgG index requires that a paired serum sample accompany the CSF specimen.

Complications of Lumbar Puncture

constituents of CSF requires that the sample be processed immediately to avoid degradation and morphological changes to the cells, a process that can begin within 1–2 h after it has been collected. It makes little sense to perform the LP at times when the lab is not available to process the sample right away (overnight refrigeration in this situation is not an acceptable option). Likewise, flow cytometry requires that the sample be analyzed within a few hours of acquisition to avoid artifactual staining results.

CHOICE OF DIAGNOSTIC TESTS It can be reasonably argued that every CSF sample should undergo some minimum level of analysis once obtained. A “standard” profile might include documentation of the opening pressure, measurement of the cell count and differential in the first and the fourth tube collected, determination of the glucose and protein concentrations, and a check of the bacterial Gram stain and culture status. It is important to obtain a serum glucose measurement within an hour of the LP so that the CSF:serum glucose ratio can be calculated. Beyond the standard analysis profile, the patient’s suspected diagnosis will dictate the choice of additional tests to be performed. In cases of possible acute CNS infection (meningitis, meningoencephalitis, or encephalitis), CSF should be sent for the appropriate smears, cultures, and rapid diagnostic assays (reviewed in Chapters 20, 21, and 23). Virus-specific polymerase chain reaction (PCR) assays now include screens for herpes simplex viruses, varicella zoster virus, Epstein-Barr virus, and enteroviruses. In the appropriate clinical situation, PCR testing for West Nile virus is also indicated. If a patient is known or suspected to be immunocompromised, CSF should also be screened for Cryptococcus, and viral PCR assays for cytomegalovirus and JC virus should be considered. Additional details regarding the use of viral PCR assays on CSF are presented elsewhere (Chapter 21). If CNS tuberculosis is suspected, CSF can be screened for the presence of acid-fast bacilli (AFB) using a smear of the CSF sediment, a PCR assay, and a culture (Chapter 23). For possible spirochetal infections, serological tests should be conducted on both serum and CSF samples (Chapter 23). Other possible CSF tests to be considered in the infectious workup of a patient with otherwise unexplained neurological symptoms include the PCR for Whipple’s disease and testing for the presence of 14-3-3 protein in cases of possible Creutzfeldt-Jakob disease. These and other infectious disease screens are discussed in greater detail in later chapters (Chapters 22 and 23). In the diagnostic workup of suspected neuroimmunological disorders such as multiple sclerosis, transverse myelitis, or neurosarcoidosis, testing the CSF for the presence of unique oligoclonal bands, elevated immunoglobulin (Ig) G levels compared to serum by determining the IgG index,

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myelin basic protein, and angiotensin converting enzyme (ACE) can be useful. The utility and interpretation of these studies are discussed in the chapter on inflammatory and demyelinating disorders (Chapter 24). A careful CSF analysis can also facilitate the diagnosis of malignancy affecting the CNS or proximal components of the PNS. Flow cytometric and cytopathologic analyses can be used to search for abnormal cells suspended in the CSF (Chapters 26 and 31). As discussed earlier, if these assays are indicated, the clinician is advised to coordinate the LP at a time when the lab can begin processing the samples in a timely fashion. Paraneoplastic antibodies can also be checked in CSF, although most assays are first run on serum samples (see Chapter 27). Finally, anyone performing an LP on a hospitalized patient with an uncertain diagnosis is advised to set aside a few extra milliliters of CSF in a clinical refrigerator whenever possible. This extra sample can sometimes save a patient a second LP when an additional test is deemed appropriate after the first round of testing. Such stored samples are usually adequate for PCR and antibody assays, even though cellular constituents have degraded.

ALTERNATIVES TO LUMBAR PUNCTURE Alternatives to LP include puncture of the cisterna magna or undertaking a lateral cervical puncture, both of which were originally developed as bedside procedures.11,12 These approaches should only be pursued if lumbar fluid is not obtainable (even under fluoroscopic guidance) or if there is a localized infection in the lumbar region and CSF analysis is deemed essential for the patient’s diagnosis and management.9 Given the higher risk of neurological injury with these alternative procedures, they should only be pursued with the assistance of an interventional radiologist using fluoroscopic guidance. A full discussion of these alternate procedures is covered in Chapter 7. One must also always consider the possibility of treating the patient empirically, without obtaining a CSF sample, if the risk of any procedure is judged to be unacceptably high. Careful documentation of the rationale behind such an approach is essential.

COMPLICATIONS OF LUMBAR PUNCTURE While LP is almost always well tolerated by patients when an experienced physician performs the procedure, it is not without its potential hazards and complications. These can include brain herniation, infection, bleeding, backache, radicular symptoms, headache, and even the rare occurrence of diplopia, hearing loss, and other cranial neuropathies (Table 8-3). The most important of these complications will be discussed in detail below.

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Chapter 8

Table 8-3 Puncture

●

CSF Acquisition and Analysis in Modern Clinical Practice

Potential Complications of Lumbar

Brain herniation Bleeding Spinal (subarachnoid, subdural, epidural) Intracranial (subarachnoid, subdural) Traumatic puncture (“bloody tap”) Infection Headache Backache/radicular symptoms Other Cranial neuropathies (diplopia, hearing loss) Implantation of an epidermoid tumor Spurious laboratory data

Brain herniation In patients with intracranial mass lesions or elevated ICP, there can be a large pressure differential between the cranial and spinal compartments when there is a preexisting obstruction in the CSF pathways connecting the cranial compartment and the spinal subarachnoid space. Under these circumstances, if pressure in the lumbar compartment is further lowered by the removal of CSF via LP, transtentorial and foramen magnum herniation can occur. When this complication develops, neurological signs are usually seen within a few hours of the procedure.4 In a patient already obtunded or comatose due to an intracranial mass lesion, it can be difficult to ascertain whether the change happened secondary to the procedure or whether it reflected worsening of the underlying disease process itself if deterioration is not immediate.13 In a study of 401 patients with a variety of primary and metastatic brain neoplasms, 128 (32%) of whom had documented papilledema, Lubic and Marotta noted only a single case of herniation out of a total of 447 LPs performed.14 In another series of 129 patients, all of whom had papilledema or elevated ICP in the absence of papilledema, the incidence of herniation-related complications following LP was less than 1.6%.15 Yet another paper reported a series of 30 patients with high ICP, all of whom were severely ill with altered mental status, headache, and focal neurological signs, whose conditions worsened after LP.16 Half of these individuals lost consciousness shortly after the procedure and five worsened within 12 h.16 Cerebral or cerebellar herniation has been reported after LP in patients with meningitis. Three cases of fatal cerebral herniation were documented in a series of 175 children with purulent meningitis following LP.17 Nineteen episodes of post-LP herniation occurred in another series of 445 children with bacterial meningitis, 2/3 of which occurred within 12 h of the procedure.18 In yet another review of 493 cases of bacterial meningitis in adults, five patients developed clinical signs of herniation within minutes to hours after their LP.19 In a series of 55 patients with SAH who underwent LP within 2 h of symptom onset, seven patients experienced a

dramatic deterioration during the course of their procedure.20 Another series of four SAH patients who deteriorated neurologically after LP was also reported.21 In both of these reports, worsening invariably occurred in patients who either had evidence of an actual clot on head CT or a dilated pupil, clinically indicating mass effect from either the aneurysm or from early uncal herniation.20,21 In sum, although rare, herniation can occur in at-risk patients following LP. A brain imaging study (CT or MRI) is indicated in every patient who has evidence of papilledema, focal neurological deficits, new-onset seizures, or an altered consciousness in order to evaluate whether or not the procedure can be safely performed.4,6,19 If bacterial meningitis is strongly suspected and the patient has signs of high ICP, focal neurological findings, and/or abnormal neuroimaging, antibiotics should be given right away and the LP deferred.18,19

Infection If there is any evidence of localized infection such as furunculosis, cellulitis, or epidural abscess near to the LP site, the procedure is contraindicated because of the risk that bacteria will be introduced into the CSF via local passage of the needle.9 Otherwise, infection following an LP is extremely rare if proper sterile technique is used. Still, infectious complications ranging from vertebral osteomyelitis, discitis, epidural abscess, and bacterial meningitis have all been reported in the literature to follow LP.9, 22–26 A retrospective study of consecutive neuroradiological procedures requiring LP reported that bacterial meningitis occurred with an incidence of 0.2% soon after the procedure.26 Infection can spread outward as well; one case report described a retroperitoneal abscess that occurred secondary to dural laceration and leakage of infected CSF into the retroperitoneal space in a patient with confirmed meningitis.27

Bleeding Subarachnoid, subdural, or epidural bleeding in the spine are all rare complications of LP that present with similar clinical findings. Spinal subarachnoid hematomas complicating an LP occur either due to an unusual anatomical location of the radiomedullary artery of Adamkiewicz and its vein along the lumbar nerve roots or from injury to one of the small radicular vessels of the cauda equina.8,28,29 Not surprisingly, patients with coagulopathies or who are on therapeutic anticoagulation are at particularly high risk for this form of subarachnoid or subdural bleeding.8,29 Patients who experience this complication typically present with severe low back or radicular pain soon after their procedure. Symptoms of paresis, sensory loss in a radicular or saddle distribution, and impaired sphincter function progress over hours to days.28,30–32 Emergent spinal MRI that includes several levels above and below the LP site is

Complications of Lumbar Puncture

indicated in all patients with these signs and symptoms.4 Treatment requires emergent decompressive laminectomy and evacuation of the hematoma.28 While patients with coagulopathies are at higher risk of local spinal bleeding secondary to an LP, intracranial subdural hematoma or SAH are both rare complications of the procedure in otherwise healthy individuals.33,34 The mechanism by which subdural hematoma develops post-LP is believed to be due to traction on the meninges and tearing of bridging dural blood vessels secondary to low CSF pressure.34 These clots can be either unilateral or bilateral, develop anywhere from a few days to several months after the procedure, and occur in patients ranging from 22 to 79 years of age.33–36 When SAH has been reported following an LP, it typically occurs in the context of an existing aneurysm, with bleeding thought to result from low CSF pressure that causes increased traction on an already fragile region of a blood vessel.33 Up to 72% of all diagnostic LPs are complicated by some form of local trauma with blood in the CSF.37 A traumatic tap usually occurs following puncture of blood vessels attached to each nerve root, and much less commonly from injury to epidural veins when the needle is advanced too far anteriorly or placed too far laterally.13,37–39 The vexing clinical conundrum of the “bloody tap” is reviewed in Chapter 29.

Spinal nerve root irritation and injury Contact between the spinal needle and nerve roots of the cauda equina leading to transient electric shocks or dysesthesias occured with an incidence of 13% during LP in one study.13,40 In practice, these symptoms are usually selflimited and decrease or disappear with repositioning of the spinal needle.4 Permanent sensory and/or motor loss is extremely rare.41 Another extremely rare complication involving lumbar nerve roots relates to their potential trapping within the spinal needle if it is withdrawn without replacing the stylet. In a few cases, this has resulted in externalization of the root outside the dura.42

Cranial nerve dysfunction A number of case reports describe dysfunction of cranial nerves III, IV, V, VI, VII, and/or VIII after LP, with the associated signs being transient in most cases.13,43–47 Symptoms of diplopia, facial numbness or weakness, and hearing loss are usually described. Such cranial neuropathies are thought to occur secondary to direct traction on the involved structures as a result of intracranial hypotension.13 In one large study, the incidence of either visual or auditory symptoms was 0.4% after dural puncture.48

Headache Headache is the most common complication of LP, occurring in up to one-third of patients after a routine

59

diagnostic procedure.13,49,50 The head pain is typically bilateral, can be frontal, occipital, or generalized, often is described as a pressure or throbbing sensation, and is exacerbated by head motion, coughing, or sneezing. Its most characteristic clinical feature, however, is that it is made worse by maintaining an upright position and that it decreases or resolves entirely when the patient is supine.13,51 In some cases the headache may begin within minutes of the procedure, although 80% start within 48 h and 90% within 72 h after the LP.49,51,52 In the majority of patients the headache lasts for less than 5 days,52 but some individuals report that pain persists up to 12 months.53 The exact pathophysiology of post-LP headache is unclear, but the disorder is thought to result from traction on pain-sensitive intracranial structures (i.e., meninges and blood vessels) due to persistent intracranial hypotension rather than a low CSF pressure per se. Thus, a CSF leak into the epidural and paraverterbral spaces at the dural puncture site can exceed the rate of new CSF production.54 In support of this leakage hypothesis, the incidence of post-LP headache is known to be inversely related to the size of the needle used for the procedure (i.e., fewer post-procedural headaches occur when smallergauge needles are used).55,56 The risk of post-LP headache also declines when the bevel of the needle is inserted parallel rather than perpendicular to the longitudinal axis in which the dural fibers run.57–61 Contrary to popular belief, the occurrence of a post-LP headache is not influenced by the volume of CSF removed, by maintaining a recumbent position after the procedure, or by any pre-medication regimen.9 When a post-LP headache occurs, the patient should be encouraged to lie flat as much as possible and to drink caffeinated beverages every 4–6 h.4,62 Oral caffeine in doses of 300 mg once or twice per day has been shown to be effective in reducing headache intensity,63 while intravenous caffeine sodium benzoate can treat those individuals who are refractory to or unable to tolerate oral therapy.64,65 Patients with moderate to severe post-LP headache that has persisted for greater than 24 h are candidates for a blood patch placed into the epidural space close to the original lumbar puncture site.13,60 An epidural blood patch consists of the slow injection of 10–20 ml of the patient’s own blood into the lumbar epidural space at the same interspace of the original procedure or at the interspace immediately below it.13,66,67 The goal is to tamponade the ongoing leak of CSF into the epidural space with a small hematoma. Patients must lie flat for 1–2 h after the procedure.68 Cumulative data would suggest that 85% of post-LP headaches are successfully treated with a single epidural blood patch, and this percentage rises to nearly 98% following a second injection.60,69 The procedure is optimally performed by a clinician such as an anesthesiologist who is experienced in identifying the epidural space.

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Chapter 8

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CSF Acquisition and Analysis in Modern Clinical Practice

CONCLUSIONS Although collecting and analyzing CSF samples is an important part of the diagnostic process for many patients, LP should only be undertaken for clear reasons, after a careful search for any contraindications is complete, and with the patient having been advised of the wide spectrum of possible complications that may occur. The experienced clinician will also consider how much sample must be obtained, as well as whether any portion of it will require special handling or processing before the procedure is started. During LP, strict adherence to sterile technique will militate against iatrogenic complications. Afterwards, the prompt delivery of samples to the various diagnostic laboratories will reduce the risk of spurious results. One is always advised to be familiar with the normative values of the clinical facility when data returning from the lab are analyzed. REFERENCES 1. Wynter WE. Four cases of tubercular meningitis in which paracentesis of the theca vertebralis was performed for the relief of fluid pressure. Lancet 1891;1:981–982. 2. Quincke HI. Uber hydrocephalus. Verhandlung des Congress Innere Medizin 1891;10:321–339. 3. Quincke HI. Die lumbarpunktion des hydrocephalus. Klin Wochenschr 1891;28:929–933, 965–968. 4. Roos KL. Lumbar puncture. Semin Neurol 2003;23:105–114. 5. van Crevel H, Hijdra A, de Gans J. Lumbar puncture and the risk of herniation: when should we first perform CT? J Neurol 2002;249:129–137. 6. Gower DJ, Baker AL, Bell WO, Ball MR. Contraindications to lumbar puncture as defined by computed cranial tomography. J Neurol Neurosurg Psychiatry 1987;50:1071–1074. 7. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001;345:1727–1733. 8. Edelson RN, Chernik NL, Posner JB. Spinal subdural hematomas complicating lumbar puncture. Arch Neurol 1974;31:134–137. 9. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: W.B. Saunders; 1992.. 10. Ruff RL, Dougherty JH Jr. Complications of lumbar puncture followed by anticoagulation. Stroke 1981;12:879–881. 11. Heinz ER. Development of the C1-C2 puncture in neuroradiology: a historical note. Am J Neuroradiol 2005;26:5–6. 12. Zivin JA. Lateral cervical puncture: an alternative to lumbar puncture. Neurology 1978;28:616–618. 13. Evans RW. Complications of lumbar puncture. Neurol Clin 1998;16:83–105. 14. Lubic LG, Marotta JT. Brain tumor and lumbar puncture. Arch Neurol Psychiat 1954;72:568–572. 15. Korein J, Cravioto H, Leicach M. Reevaluation of lumbar puncture; a study of 129 patients with papilledema or intracranial hypertension. Neurology 1959;9:290–297. 16. Duffy GP. Lumbar puncture in the presence of raised intracranial pressure. Br Med J 1969;1:407–409. 17. Swartz MN, Dodge PR. Bacterial meningitis – a review of selected aspects. 1. General clinical features, special problems and unusual meningeal reactions mimicking bacterial meningitis. N Engl J Med 1965;272:842–848. 18. Rennick G, Shann F, de Campo J. Cerebral herniation during bacterial meningitis in children. Br Med J 1993;306:953–955.

19. Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993;328:21–28. 20. Duffy GP. Lumbar puncture in spontaneous subarachnoid haemorrhage. Br Med J 1982;285:1163–1164. 21. Hillman J. Should computed tomography scanning replace lumbar puncture in the diagnostic process in suspected subarachnoid hemorrhage? Surg Neurol 1986;26:547–550. 22. Schelkun SR, Wagner KF, Blanks JA, Reinert CM. Bacterial meningitis following Pantopaque myelography. A case report and literature review. Orthopedics 1985;8:73–76. 23. Lanska DJ, Lanska MJ, Selman WR. Meningitis following spinal puncture in a patient with a CSF leak. Neurology 1989;39:306–307. 24. Torres E, Alba D, Frank A, Diez-Tejedor E. Iatrogenic meningitis due to Streptococcus salivarius following a spinal tap. Clin Infect Dis 1993;17:525–526. 25. Bhatoe HS, Gill HS, Kumar N, Biswas S. Post lumbar puncture discitis and vertebral collapse. Postgrad Med J 1994;70:882–884. 26. Domingo P, Mancebo J, Blanch L, Coll P, Martinez E. Iatrogenic streptococcal meningitis. Clin Infect Dis 1994;19:356–357. 27. Levine JF, Hiesiger EM, Whelan MA, Pollock AA, Simbekoff MS, Rahal JJ. Pneumococcal meningitis associated with retroperitoneal abscess. A rare complication of lumbar puncture. JAMA 1982;248:2308–2309. 28. Scott EW, Cazenave CR, Virapongse C. Spinal subarachnoid hematoma complicating lumbar puncture: diagnosis and management. Neurosurgery 1989;25:287–292; discussion 292–293. 29. Masdeu JC, Breuer AC, Schoene WC. Spinal subarachnoid hematomas: clue to a source of bleeding in traumatic lumbar puncture. Neurology 1979;29:872–876. 30. Dana CL. Puncture headache. JAMA 1917;68:1017. 31. Bills DC, Blumbergs P, North JB. Iatrogenic spinal subdural haematoma. Aust NZ J Surg 1991;61:703–706. 32. Adler MD, Comi AE, Walker AR. Acute hemorrhagic complication of diagnostic lumbar puncture. Pediatr Emerg Care 2001;17:184–188. 33. Hart IK, Bone I, Hadley DM. Development of neurological problems after lumbar puncture. Br Med J 1988;296:51–52. 34. Vos PE, de Boer WA, Wurzer JA, van Gijn J. Subdural hematoma after lumbar puncture: two case reports and review of the literature. Clin Neurol Neurosurg 1991;93:127–132. 35. Newrick P, Read D. Subdural haematoma as a complication of spinal anaesthetic. Br Med J 1982;285:341–342. 36. Whiteley SM, Murphy PG, Kirollos RW, Swindells SR. Headache after dural puncture. Br Med J 1993;306:917–918. 37. Breuer AC, Tyler HR, Marzewski DJ, Rosenthal DS. Radicular vessels are the most probable source of needle-induced blood in lumbar puncture: significance for the thrombocytopenic cancer patient. Cancer 1982;49:2168–2172. 38. Mehl AL. Interpretation of traumatic lumbar puncture. A prospective experimental model. Clin Pediatr (Phila) 1986;25:523–526. 39. Boon JM, Abrahams PH, Meiring JH, Welch T. Lumbar puncture: anatomical review of a clinical skill. Clin Anat 2004;17:544–553. 40. Dripps RD, Vandam LD. Hazards of lumbar puncture. JAMA 1951;147:1118–1121. 41. Dahlgren N, Tornebrandt K. Neurological complications after anaesthesia. A follow-up of 18,000 spinal and epidural anaesthetics performed over three years. Acta Anaesthesiol Scand 1995;39:872–880. 42. Trupp M. Stylet injury syndrome. JAMA 1977;237:2524. 43. Thorsen G. Neurological complications after spinal anaesthesia. Acta Chir Scand 1947;121(suppl):1–272. 44. King RA, Calhoun JH. Fourth cranial nerve palsy following spinal anesthesia. A case report. J Clin Neuroophthalmol 1987;7:20–22. 45. Broome IJ. Hearing loss and dural puncture. Lancet 1993; 341:667–668. 46. Lybecker H, Andersen T. Repetitive hearing loss following dural puncture treated with autologous epidural blood patch. Acta Anaesthesiol Scand 1995;39:987–989.

References

47. Lybecker H, Andersen T, Helbo-Hansen HS. The effect of epidural blood patch on hearing loss in patients with severe postdural puncture headache. J Clin Anesth 1995;7:457–464. 48. Vandam LD, Dripps RD. Long-term follow-up of patients who received 10,098 spinal anesthetics; syndrome of decreased intracranial pressure (headache and ocular and auditory difficulties). JAMA 1956;161:586–591. 49. Kuntz KM, Kokmen E, Stevens JC, Miller P, Offord KP, Ho MM. Post-lumbar puncture headaches: experience in 501 consecutive procedures. Neurology 1992;42:1884–1887. 50. Dieterich M, Perkin GD. Postlumbar puncture headache syndrome. In: Brandt T, Caplan LR, Dichland J, eds. Neurological Disorders: Course and Treatment. San Diego: Academic Press; 1996:59–63. 51. Tourtellote WW, Haerer AF, Heller GL, Metz LN, Bryan ER, Allen RJ. Postlumbar puncture headaches. Springfield, IL: Charles C. Thomas; 1964. 52. Lybecker H, Djernes M, Schmidt JF. Postdural puncture headache (PDPH): onset, duration, severity, and associated symptoms. An analysis of 75 consecutive patients with PDPH. Acta Anaesthesiol Scand 1995;39:605–612. 53. Lance JW, Branch GB. Persistent headache after lumbar puncture. Lancet 1994;343:414. 54. Tourtellotte WW, Henderson WG, Tucker RP, Gilland O, Walker JE, Kokman E. A randomized, double-blind clinical trial comparing the 22 versus 26 gauge needle in the production of the post-lumbar puncture syndrome in normal individuals. Headache 1972;12:73–78. 55. Dieterich M, Brandt T. Is obligatory bed rest after lumbar puncture obsolete? Eur Arch Psychiatry Neurol Sci 1985;235:71–75. 56. Dittmann M, Schafer HG, Ulrich J, Bond-Taylor W. Anatomical re-evaluation of lumbar dura mater with regard to postspinal headache. Effect of dural puncture. Anaesthesia 1988;43:635–637. 57. Greene HM. Lumbar puncture and the prevention of postpuncture headache. JAMA 1926;86:391–392.

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58. Mihic DN. Postspinal headaches, needle surfaces and longitudinal orientation of the dural fibers. Results of a survey. Reg Anaesth 1986;9:54–56. 59. Norris MC, Leighton BL, DeSimone CA. Needle bevel direction and headache after inadvertent dural puncture. Anesthesiology 1989;70:729–731. 60. Tarkkila PJ, Miralles JA, Palomaki EA. The subjective complications and efficiency of the epidural blood patch in the treatment of postdural puncture headache. Reg Anesth 1989;14:247–250. 61. Lybecker H, Moller JT, May O, Nielsen HK. Incidence and prediction of postdural puncture headache. A prospective study of 1021 spinal anesthesias. Anesth Analg 1990;70:389–394. 62. Leibold RA, Yealy DM, Coppola M, Cantees KK. Post-dural-puncture headache: characteristics, management, and prevention. Ann Emerg Med 1993;22:1863–1870. 63. Camann WR, Murray RS, Mushlin PS, Lambert DH. Effects of oral caffeine on postdural puncture headache. A double-blind, placebo-controlled trial. Anesth Analg 1990;70:181–184. 64. Sechzer PH, Abel L. Post-spinal anesthesia headache treated with caffeine: evaluation with demand method. Part 1. Curr Ther Res 1978;24:307–312. 65. Jarvis AP, Greenawalt JW, Fagraeus L. Intravenous caffeine for postdural puncture headache. Anesth Analg 1986;65:316–317. 66. Carrie LE. Postdural puncture headache and extradural blood patch. Br J Anaesth 1993;71:179–181. 67. Turnbull DK, Shepherd DB. Post-dural puncture headache: pathogenesis, prevention and treatment. Br J Anaesth 2003;91:718–729. 68. Martin R, Jourdain S, Clairoux M, Tetrault JP. Duration of decubitus position after epidural blood patch. Can J Anaesth 1994;41:23–25. 69. Abouleish E, Vega S, Blendinger I, Tio TO. Long-term follow-up of epidural blood patch. Anesth Analg 1975;54:459–463.

CHAPTER

9

Neuroimaging of the Cerebrospinal Fluid Compartment Daniel S. Reich and Dima A. Hammoud

INTRODUCTION Imaging characteristics of the cerebrospinal fluid (CSF) compartment have long been used as both direct and indirect markers of brain disease. Early studies including contrast ventriculography and pneumoencephalography provided information about the size and shape of the CSF spaces – particularly the cerebral ventricles – that helped physicians to infer the presence of lesions within and around those spaces. In this chapter, we present an overview of contemporary techniques for imaging the CSF compartment. We focus on methods for imaging the gross anatomy of the CSF spaces, the dynamics of CSF flow, and the composition of CSF. In each section, we discuss ways in which common disease states can alter these normal imaging characteristics.

GROSS ANATOMY OF THE CSF SPACES Normal anatomy The normal anatomy of the CSF compartment is reviewed in Chapter 2. Because they are inseparably associated with the central nervous system (CNS) parenchyma, the CSF spaces are necessarily imaged as part of every crosssectional imaging study of the brain and spinal cord. The detail with which those spaces are evaluated depends on the type of study performed; when fine detail is required, contrast agents can be very helpful. The most commonly performed contrast study of the CSF spaces is myelography (Fig. 9-1), in which a contrast agent – usually an iodinated, radio-opaque dye – is instilled into the thecal sac, most often via lumbar puncture (LP). The procedure is performed under fluoroscopic guidance, and the column of injected contrast is followed as it fills the CSF spaces. Since the contrast material is instilled under pressure, the dynamics of the leading column cannot provide information regarding the normal dynamics of CSF flow. However, mass lesions

within or impinging on the CSF spaces will often be well visualized when they are first encountered by that column. Once the desired amount of contrast material is completely infused, axial computed tomography (CT) sections through the spine further delineate the relationship between normal and abnormal structures in the CSF spaces. Although performed far less often than myelography, ventriculography, in which a contrast agent is instilled directly into the ventricles via a ventriculostomy catheter, can sometimes provide useful information. Again, direct fluoroscopic visualization often reveals the location of obstructive processes within the ventricles. Follow-up cross-sectional CT imaging can be used to achieve higher anatomic detail and to better appreciate the relationships of the structures being imaged. Non-contrast cisternography and ventriculography have recently become more popular with the advent of magnetic resonance (MR) pulse sequences that provide highresolution, high-contrast images of the CSF spaces without the need for intrathecal or intraventricular injection of contrast material. Needless to say, this eliminates the risks associated with dural puncture, particularly meningitis. A non-contrast study that has gained widespread use in recent years uses a type of gradient echo pulse sequence generically called three-dimensional balanced steady-state free precession (3D-bSSFP; common manufacturer-specific acronyms include CISS [Siemens], FIESTA [General Electric], and balanced FFE [Philips]). These images are heavily T2-weighted and can be obtained in clinically reasonable scan times.1 The sequences sacrifice intraparenchymal (gray–white) contrast in return for providing very fine images of the CSF spaces, and they are generally used either to visualize the cranial nerves after they exit the brainstem and before they penetrate the skull base, or to evaluate the fluid spaces of the inner ear. Thus, lesions involving the cranial nerves or mass lesions in the CSF spaces that distort their anatomy are readily visualized with this technique. Three-dimensional reconstructions can be

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made from these images, providing virtual endoscopic views of the cisterns.2 Such reconstructions correlate with findings observed at the time of surgery, and can therefore be used for pre-operative planning. In the neonatal population, ultrasonography has been used for the same purpose.3

Imaging structural abnormalities within or impinging upon the CSF spaces In patients who cannot tolerate or have contraindications to MR imaging (MRI), myelography with post-myelographic CT can be used to visualize distortion of the spinal CSF spaces caused by herniated disc material or degenerative osteophytes (Fig. 9-1). In the cisterns surrounding the brainstem and cerebellopontine angle, masses involving the cranial nerves – most commonly acoustic neuromas – are clearly seen on non-contrast MR cisternograms obtained with 3D-bSSFP (Fig. 9-2). Although additional postcontrast MRI is usually required to confirm the diagnosis, high-resolution 3D-bSSFP images can provide fine anatomic detail to assess the patency of the CSF spaces and any mass effect on adjacent structures. Other intraventricular abnormalities, such as the lesions of neurocysticercosis, can also be demonstrated with either 3D-bSSFP or more standard fluidattenuated inversion recovery (FLAIR) MRI.4,5

IMAGING CSF FLOW DYNAMICS Evaluating normal CSF dynamics The dynamics of CSF flow are still most commonly studied using radionuclide tracers, although MR-based methods are receiving increasing attention and finding more clinical application. Indium-111-labeled diethylenetriaminepentaacetate (DTPA) is the most common radionuclide

Figure 9-1 Axial post-myelographic CT images in two patients with disc herniations. Contrast was instilled into the thecal sac under fluoroscopic guidance via LP prior to CT imaging. The left image demonstrates disc protrusion into the thecal sac at the C4–5 level, causing minimal effacement of the ventral CSF but no compromise of the spinal cord. The right image demonstrates a diffuse disc bulge causing effacement of the CSF ventral to the cauda equina at the L2–3 level. There was partial block of CSF flow at this level during the myelographic phase of the study (not shown).

used for this purpose because of its long half-life (2.8 days) and lack of transependymal resorption.6 At our institution, 500 μCi of this tracer are injected into the CSF via LP and images are obtained at 4 and 24 h post-injection, with additional imaging at 48 and 72 h if necessary. When CSF flow is normal, activity is seen within the basal cisterns at 4 h and over the cerebral convexities at 24 h following injection. Early visualization of the lateral ventricles was originally considered to be a sign of abnormal CSF flow. However, later studies revealed that up to 40% of healthy volunteers had filling of the lateral ventricles at 6 h following injection, with persistent intraventricular activity up to 24 h.7 Radionuclide ventriculography, again most commonly performed with Indium-111 DTPA, can be used to assess the patency of the interventricular foramina and cerebral aqueduct. This study is performed via ventriculostomy or through a pre-existing reservoir, often of the Ommaya type. In a similar fashion, the patency of ventricular shunts can be assessed using Technetium-99 DTPA. Here, the tracer is injected into the shunt reservoir and dynamic imaging is obtained to follow its course through the proximal and distal shunt catheters. Delayed images can be obtained as necessary. Normal functioning of ventriculoperitoneal shunts, for example, is demonstrated by the prompt spillage of tracer into the peritoneal cavity before the end of the initial imaging period.6 Pulsatile flow of CSF can be imaged with phase-contrast MR, which relies on the intrinsic link between the velocity of water molecules and the relative phases of their spins. Motion at different velocities causes different phase shifts, so the curve of CSF flow velocity versus time within the cardiac cycle can be plotted for any arbitrary location with the CSF spaces. Normal curves at different locations have been established.8

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Figure 9-2 A left-sided acoustic neuroma is seen on an axial post-contrast T1-weighted MR image (left image) and on a 3D balanced steady-state free precession (3D-bSSFP) image at the same level (right image). Note the fine detail with which neural structures in the CSF are seen, particularly in the normal (right) internal auditory canal.

Imaging abnormalities of CSF flow Because different disease states affect CSF flow in different ways, the suspected clinical situation dictates the preferred imaging method. Normal pressure hydrocephalus (NPH) is covered in detail in Chapter 12. As detailed there, no single imaging modality can definitively confirm a diagnosis of NPH, and direct measurement of CSF dynamics and the clinical response to temporary CSF drainage is required to predict a given patient’s response to shunting.9 Radionuclide cisternography is still performed in this situation, but with decreasing frequency.10 Patients with NPH may have early and prominent filling of the lateral ventricles, and in severe cases, the tracer never reaches the cerebral convexities.6 CSF flow in the cerebral aqueduct, as assessed with phase-contrast MRI, is sometimes increased in NPH, although this finding is variable and has not yet been shown to predict the clinical response to shunting.11 The hallmark of idiopathic intracranial hypertension – previously known as pseudotumor cerebri – is elevated pressure in the CSF compartment. As discussed in greater detail in Chapter 12, no single imaging finding has been found to reliably correlate with the increased CSF pressure found in this disorder, which is often associated with abnormalities in venous drainage from the brain. These abnormalities can range from total thrombosis of a major intracerebral venous sinus to hypoplasia of the lateral sinus; in one recent series, 27 of 29 patients with idiopathic intracranial hypertension, but only 4 of 59 controls, had abnormalities detected on contrast-enhanced MR venography.12 Because finding a sinovenous thrombosis may dramatically alter therapy, imaging of the cerebral veins is indicated in all patients suspected of having this disorder. Leakage of CSF must be diagnosed promptly because of the high incidence of subsequent meningitis, particularly after trauma.6 The most common site of post-traumatic CSF leak is through the cribiform plate into the nasal sinuses, causing CSF rhinorrhea. Radiotracer studies, CT,

and MR have all been used to confirm and localize such leaks.13,14 In the nuclear medicine approach, pledgets are placed into the nostrils and radiotracer is injected intrathecally. The pledgets are then removed and serum samples also obtained. The ratio of pledget-to-plasma radioactivity is calculated, and ratios of greater than 1.3:1 are considered suspicious for CSF leak.15 Interestingly, the closure of a CSF leak following myelography was recently reported.15 If this observation is borne out in larger clinical trials, the procedure would become attractive for both diagnosis and therapy in refractory cases that do not respond to more conservative treatments such as bed rest, hydration, and epidural blood patching. A related disorder – spontaneous intracranial hypotension – may result from a CSF leak. Often, the source of the leak is never found. The diagnosis is made on the basis of clinical features (usually postural headache), laboratory findings (low CSF opening pressure on LP), and imaging abnormalities. Typical imaging findings include diffuse pachymeningeal (dural) enhancement around the brain and spinal cord on post-contrast MRI, along with low-lying cerebellar tonsils often mimicking a Chiari I malformation (Fig. 9-3).16,17 A possible mechanism to explain the pachymeningeal enhancement seen in this condition is engorgement of the dural venous plexus.18 True Chiari I malformations are sometimes associated with occipital headaches, and MR phase-contrast flow studies have been used successfully to ascertain whether a patient’s symptoms might respond to suboccipital decompressive surgery.19 Finally, in patients with leptomeningeal metastases, the effective delivery of chemotherapy to the CSF compartment is crucial. Tumor cells can block the interventricular foramina and the cerebral aqueduct, however, resulting in poor drug circulation even when it is instilled directly into the ventricles through a reservoir.20 If this situation is of clinical concern, the patency of the CSF spaces can be determined by either intraventricular or intrathecal injection of radiotracer with delayed imaging.20,21 Some clinicians

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Figure 9-3 Intracranial hypotension. A sagittal non-contrast T1-weighted MR image (left image) shows low-lying cerebellar tonsils, a prominent feature of this disorder. After the administration of intravenous contrast material, pachymeningeal enhancement is prominent, as seen in both the axial (center image) and coronal (right image) planes.

have argued that these studies should be performed routinely in all these patients prior to the initiation of treatment.22

IMAGING CSF COMPOSITION Normal CSF characteristics On conventional CT images of the brain, CSF appears less dense than brain parenchyma and therefore is readily appreciated as a distinct CNS compartment. Similarly, the CSF spaces are well seen on most common MR sequences. Due to its high water content, CSF has low signal relative to brain parenchyma on T1-weighted images and high signal relative to brain parenchyma on T2-weighted sequences. Indeed, clinicians use the signal characteristics of CSF as their main tool to identify the type of MR sequence they are examining. Care must be taken in this regard, however, as features other than T1- and T2-weighting can affect the MR appearance of CSF. For example, CSF signal is suppressed (and therefore appears darker than brain parenchyma) on FLAIR sequences, which are otherwise T2-weighted. This characteristic of FLAIR sequences is, in fact, what makes them particularly useful in clinical neuroimaging.

In other instances, imaging findings may alert the clinician to the presence of disease within the CSF compartment, which might not otherwise have been suspected, thus leading to a more definitive diagnosis by other methods. Gadolinium-enhanced T1-weighted imaging of the brain and spine plays a crucial role in the diagnosis of leptomeningeal metastases, sometimes detecting disease even in the absence of positive CSF cytology.23–25 Nevertheless, cytologic examination of the CSF remains the gold standard for this diagnosis. On FLAIR images, hyperintense signal visualized in the sulci – so-called “non-suppression of the CSF” – can suggest the presence of subarachnoid hemorrhage,26 but can also be observed in other conditions where the protein content of CSF is elevated.27 These include meningitis (Fig. 9-4), and even stroke.28,29 Sensitivity for the presence of these conditions on FLAIR imaging may be increased by the intravenous injection of a gadolinium-based contrast agent with delayed imaging,30 although in the case of bacterial meningitis, post-contrast T1-weighted imaging still remains more useful.28

CONCLUSIONS CSF imaging characteristics in disease states Imaging has not yet become a useful tool for the assessment of the CSF content, and laboratory analysis of CSF will not likely be replaced by any imaging-based methodology in the foreseeable future. In some clinical situations, however, the imaging appearance of CSF may be specific enough that direct CSF examination is not necessary. The most obvious example is diffuse subarachnoid hemorrhage, which is almost always visible on a non-contrast CT examination of the head. The same holds true in other situations where blood is seen in the CSF, such as the rupture of an intraparenchymal hematoma into the ventricles.

Although imaging is not the primary investigative modality in the assessment of diseases involving the CSF, it plays an increasingly important ancillary role in many of these disorders. Thus, it is useful in detecting abnormalities of the anatomy of the CSF spaces, the dynamics of CSF flow, and increasingly, even the composition of CSF itself. As our imaging tools – particularly MRI – continue to develop, the role of non-invasive assessments of CSF is likely to grow. Clinicians should become familiar with the ways in which imaging can aid in neurological and neurosurgical diagnosis, so that the most appropriate tests are ordered to improve diagnostic certainty.

References

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Figure 9-4 The cerebral sulci show their normal dark appearance on an axial FLAIR MR image (left image), while non-suppression of the CSF signal in a case of bacterial meningitis shows a more hyperintense signal (right image).

REFERENCES 1. Casselman JW, Kuhweide R, Deimling M, Ampe W, Dehaene I, Meeus L. Constructive interference in steady state-3DFT MR imaging of the inner ear and cerebellopontine angle. AJNR Am J Neuroradiol 1993;14:47–57. 2. Rabinov JD, Barker FG, McKenna MJ, Curtin HD. Virtual cisternoscopy: 3D MRI models of the cerebellopontine angle for lesions related to the cranial nerves. Skull Base 2004;14:93–99. 3. Jodicke A, Accomazzi V, Reiss I, Boker DK. Virtual endoscopy of the cerebral ventricles based on 3-D ultrasonography. Ultrasound Med Biol 2003;29:339–345. 4. Govindappa SS, Narayanan JP, Krishnamoorthy VM, Shastry CH, Balasubramaniam A, Krishna SS. Improved detection of intraventricular cysticercal cysts with the use of three-dimensional constructive interference in steady state MR sequences. AJNR Am J Neuroradiol 2000;21:679–684. 5. Braga F, Rocha AJ, Gomes HR, Filho GH, Silva CJ, Fonseca RB. Noninvasive MR cisternography with fluid-attenuated inversion recovery and 100% supplemental O(2) in the evaluation of neurocysticercosis. AJNR Am J Neuroradiol 2004;25:295–297. 6. Ommaya AK, O’Tuama LA, Lorenzo AV. Hydrocephalus, shunts, and cerebrospinal fluid leaks. In: Wagner HN Jr, Szabo Z, Buchanan JW, eds. Principles of Nuclear Medicine. 2nd ed. Philadelphia: W.B. Saunders; 1995:576–647. 7. Bergstrand G, Oxenstierna G, Flyckt L, Larsson SA, Sedvall G. Radionuclide cisternography and computed tomography in 30 healthy volunteers. Neuroradiology 1986;28:154–160. 8. Bhadelia RA, Bogdan AR, Wolpert SM. Analysis of cerebrospinal fluid flow waveforms with gated phase-contrast MR velocity measurements. AJNR Am J Neuroradiol 1995;16:389–400. 9. Vanneste J, Augustijn P, Davies GA, Dirven C, Tan WF. Normal-pressure hydrocephalus. Is cisternography still useful in selecting patients for a shunt? Arch Neurol 1992;49:366–370. 10. Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PM. The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. Neurosurgery 2005; 57(3 Suppl):S17–S28.

11. Dixon GR, Friedman JA, Luetmer PH, et al. Use of cerebrospinal fluid flow rates measured by phase-contrast MR to predict outcome of ventriculoperitoneal shunting for idiopathic normal-pressure hydrocephalus. Mayo Clin Proc 2002;77:509–514. 12. Farb RI, Vanek I, Scott JN, et al. Idiopathic intracranial hypertension: the prevalence and morphology of sinovenous stenosis. Neurology 2003;60:1418–1424. 13. Stone JA, Castillo M, Neelon B, Mukherji SK. Evaluation of CSF leaks: high-resolution CT compared with contrast-enhanced CT and radionuclide cisternography. AJNR Am J Neuroradiol 1999;20:706–712. 14. El Gammal T, Sobol W, Wadlington VR, et al. Cerebrospinal fluid fistula: detection with MR cisternography. AJNR Am J Neuroradiol 1998;19:627–631. 15. Jeyrani R, Paul A, Doerfler A, Egelhof T. Intracranial hypotension due to leakage of cerebrospinal fluid: could myelography be a therapeutic option? Neuroradiology 2005;47:43–45. 16. Moayeri NN, Henson JW, Schaefer PW, Zervas NT. Spinal dural enhancement on magnetic resonance imaging associated with spontaneous intracranial hypotension. Report of three cases and review of the literature. J Neurosurg 1998;88:912–918. 17. Mokri B. Spontaneous intracranial hypotension and spontaneous CSF leaks. Headache Currents 2005;2:11–22. 18. Mokri B, Parisi JE, Scheithauer BW, Piepgras DG, Miller GM. Meningeal biopsy in intracranial hypotension: meningeal enhancement on MRI. Neurology 1995;45:1801–1807. 19. McGirt MJ, Nimjee SM, Floyd J, Bulsara KR, George TM. Correlation of cerebrospinal fluid flow dynamics and headache in Chiari I malformation. Neurosurgery 2005;56:716–721. 20. Grossman SA, Trump DL, Chen DC, Thompson G, Camargo EE. Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis. An evaluation using 111indium-DTPA ventriculography. Am J Med 1982;73:641–647. 21. Chamberlain MC. Spinal 111Indium-DTPA CSF flow studies in leptomeningeal metastasis. J Neurooncol 1995;25:135–141. 22. DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998;38:245–252. 23. Fouladi M, Gajjar A, Boyett JM, et al. Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal

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24. 25. 26. 27.

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disease in pediatric medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 1999;17:3234–3237. Freilich RJ, Krol G, DeAngelis LM. Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol 1995;38:51–57. Gomori JM, Heching N, Siegal T. Leptomeningeal metastases: evaluation by gadolinium enhanced spinal magnetic resonance imaging. J Neurooncol 1998;36:55–60. Noguchi K, Ogawa T, Inugami A, et al. Acute subarachnoid hemorrhage: MR imaging with fluid-attenuated inversion recovery pulse sequences. Radiology 1995;196:773–777. Melhem ER, Jara H, Eustace S. Fluid-attenuated inversion recovery MR imaging: identification of protein concentration thresholds for CSF hyperintensity. AJR Am J Roentgenol 1997;169:859–862.

28. Kamran S, Bener AB, Alper D, Bakshi R. Role of fluid-attenuated inversion recovery in the diagnosis of meningitis: comparison with contrast-enhanced magnetic resonance imaging. J Comput Assist Tomogr 2004;28:68–72. 29. Taoka T, Yuh WT, White ML, Quets JP, Maley JE, Ueda T. Sulcal hyperintensity on fluid-attenuated inversion recovery MR images in patients without apparent cerebrospinal fluid abnormality. AJR Am J Roentgenol 2001;176:519–524. 30. Bozzao A, Floris R, Fasoli F, Fantozzi LM, Colonnese C, Simonetti G. Cerebrospinal fluid changes after intravenous injection of gadolinium chelate: assessment by FLAIR MR imaging. Eur Radiol 2003;13:592–597.

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Properties and Composition of Normal Cerebrospinal Fluid David N. Irani

INTRODUCTION This chapter will review the physical characteristics and the cellular and biochemical composition of normal human cerebrospinal fluid (CSF). In advance of considering the data that address this broad issue, however, it should be kept in mind that most clinical decisions are still based on the measurement of only a small number of properties or constituents of CSF, even while hundreds of substances have been quantified in clinical samples for experimental purposes over the years. Indeed, compared to the large array of tests used to study blood or serum specimens, relatively few assays are routinely performed on CSF by clinical laboratories, and even fewer have proven to be useful in the diagnosis or management of patients with suspected neurological disease. Nevertheless, as the cellular and molecular underpinnings of more and more nervous system disorders are slowly unraveled, one might reasonably predict that measuring a broader array of CSF constituents could potentially come into more routine clinical use. In light of such a possibility, the considerable effort required to centralize data on the molecular content of normal human CSF has been undertaken here.

GENERAL APPEARANCE AND PHYSICAL PROPERTIES OF NORMAL CSF Turbidity and viscosity Under normal circumstances, CSF should appear clear and colorless. Its consistency should be similar to that of water, with no evidence of increased viscosity or a propensity to aggregate or clot over time. Any concern that the fluid appears cloudy, bloody, pigmented, or more viscous than anticipated should prompt further investigation. An aliquot of CSF should be visually inspected in direct comparison to an equal volume of water at the time of acquisition, preferably using clear glass tubes. Turbidity resulting from

increased cellularity can be seen under standard lighting conditions at counts starting around 400 cells/mm3, and CSF will appear pink at counts of 500–6,000 red blood cells (RBC) /mm3.1 The fluid becomes frankly bloody above 6,000 RBC/mm3.1 Leukocytes or erythrocytes present at concentrations as low as 50 cells/mm3 can also produce a sparkling effect when samples are gently agitated and held up to direct sunlight (Tyndall’s effect).1,2 Increased fluid viscosity, usually observed as the fluid drips from the spinal needle and runs into the collection tube, has been reported in cases of meningeal infiltration by a mucinous adenocarcinoma of the colon, with high CSF fungal load in cryptococcal meningitis, and even with the release of liquefied nucleus pulposus material into the CSF from a ruptured intervertebral disc.1

Pigmentation The term xanthochromia is used to describe the most common form of abnormal CSF pigmentation, that is, fluid with a slight pink or yellow coloration to it. This finding corresponds to the presence of pigmented compounds such as oxyhemoglobin, bilirubin, and methemoglobin that are usually derived from the breakdown of RBCs.1 Detection of xanthochromia has been facilitated since the 1950s by the spectrophotometric analysis of CSF,3 but is usually possible by simple visual inspection of a sample held in front of a white piece of paper. Heme pigments can be found in CSF within 12 h of subarachnoid bleeding, reach peak levels after 36–48 h, and typically disappear over the next 7–10 days.1 Bilirubin accumulation in CSF may occur via intrathecal conversion from hemoglobin-heme within macrophages and other leptomeningeal cells, or by passive diffusion from the circulation during periods of severe jaundice.1 In this latter setting, CSF is not usually stained until the total plasma bilirubin reaches 10–15 mg/dl.1 The presence of bilirubin in CSF is the main cause of xanthochromia associated with high spinal fluid protein content, usually found above levels of 150 mg/dl.1

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NORMAL CELLULAR CONSTITUENTS OF CSF Physiological turnover of cells in normal CSF It is generally agreed that CSF may contain a small number of leukocytes (principally T lymphocytes and monocytes) under normal circumstances, and that these cells derive largely from the circulation.4,5 Normal CSF may also rarely contain cells derived from the choroid plexus, the ependymal lining of the ventricles, or the arachnoid membrane.4 The white blood cells (WBCs) found in normal CSF are believed to provide immunological surveillance of the central nervous system (CNS), and most are felt to either cross the fenestrated endothelium of the choroid plexus or traverse post-capillary venules on the pial surface of the brain.6 Here, patrolling leukocytes enter the VirchowRobin perivascular spaces, invaginations of the cranial or spinal subarachnoid spaces around penetrating vessels, at which time they may interact with the occasional myeloid cell capable of antigen presentation.6 These physiological routes of leukocyte entry into the CNS are distinguished from pathological situations where immune cells traverse the blood–brain barrier (BBB) and collect in parenchymal perivascular spaces; not only are the sites of accumulation anatomically different, but the molecular interactions involved in these extravasation events are distinguishable.6,7 Few data are available in humans regarding the kinetics of cellular passage and turnover within the CSF, but studies in rodents using fluorescently labeled lymphocytes suggest that this process takes place over hours.7 The disappearance of WBCs from the CSF is poorly understood relative to the processes governing their entry, but reports suggest that this may occur either by local cytolysis or by emigration back into the bloodstream.1,4,5 Patrolling leukocytes leaving the CSF may also preferentially accumulate in cervical lymph nodes where important reactions relevant to normal immune surveillance of the CNS take place.8

Analysis methodologies The cellular content of CSF can be investigated by direct microscopic examination, via automated cell-counting methodologies, or by immunofluorescent staining of cells and analysis by flow cytometry. All samples destined for any such analysis should be collected into plastic tubes, as mononuclear phagocytes adhere strongly to glass and may lead to erroneously low cell counts. Analysis should be performed immediately after sample acquisition because leukocytes, particularly granulocytes, begin to lyse within an hour when kept at room temperature. Indeed, up to 40% of the WBCs present in CSF may degenerate after a 2h delay.1 While this spontaneous degradation can be slowed by refrigerating specimens, or by resuspending the cells in a balanced salt solution containing normal

serum proteins,9 all cytological analyses of CSF should begin immediately after the lumbar puncture (LP) has been performed. Manual hemocytometers, such as the classic Fuchs-Rosenthal chamber, can accurately determine the total number of cells present in a small volume of CSF by directly counting the cells present over a grid etched onto the counting surface. This method is standard in most hospital laboratories, although it is relatively time-consuming and requires an experienced laboratory technician. Automated cell counters are now becoming available, and recent studies suggest that results are highly accurate compared to manual counting methods.10 Multi-color flow cytometry can simultaneously quantify the expression of five or six surface markers on cells in suspension, and this method is standard for the phenotyping of CSF WBCs in research studies.11–14 In practice, however, its use is typically reserved for suspected cases of hematopoietic malignancy involving the CNS. Most WBC differential cell counts and cytological examinations of CSF are performed on samples where the cellular elements have been concentrated from larger volumes, spun onto glass slides, and then colorized using various histological stains. Although cellular morphology can be altered even with low-speed centrifugation, this approach allows for the examination of many more cells than is possible in routine (uncentrifuged) hemocytometer analysis. In most clinical laboratories, Wright’s stain is used to generate a leukocyte differential on CSF samples, while Papanicolaou’s stain is used to examine the cytomorphology of suspected tumor cells. The reader is also referred to Fishman’s landmark text on CSF for further review of this subject.1

Leukocyte counts in normal CSF There is general consensus that normal CSF should not contain more than 5 WBCs/mm3. As discussed earlier, these occasional leukocytes are typically mononuclear cells, mostly T lymphocytes and monocytes, that are thought to provide normal immune surveillance of the CNS.1,6,11,12 In contrast, any increase in total CSF cellularity above 5 WBCs/mm3 should prompt further investigation, as this can indicate either an immune response to a specific antigen sequestered within the CNS or a nonspecific host response to underlying tissue injury. When it comes to the more contentious issue of whether other leukocyte subtypes may be found in normal CSF, most of the controversy centers on interpreting the presence of polymorphonuclear (PMN) leukocytes in this compartment. This cell type, in the context of normal CSF, deserves separate consideration here. The blanket statement that PMNs (also known as granulocytes) are never found in normal CSF turns out to be based on older studies where CSF cell counts and leukocyte

Normal Protein Content of CSF

differentials were determined using non-concentrated samples analyzed with manual counting chambers.1 Yet in cytocentrifuged preparations of cells concentrated from larger volumes of CSF, one study by Simon and Koerper showed that 18 of 50 consecutive specimens taken from patients without known neurological disease contained up to 5 total PMNs.15 Although these cells were initially presumed to derive from blood introduced into the CSF sample at the time of its acquisition (i.e., a traumatic tap), their presence also supports the possibility that an isolated granulocyte in the CSF is not always a pathological finding. Thus, in patients with a total CSF cell count of 5 or fewer WBCs/mm3, the presence of 5 or fewer total PMNs on the associated differential may be interpreted as normal in the appropriate clinical setting. However, because a granulocytic pleocytosis can be an indicator of treatable infection of the CNS, such a conclusion should always be reached with extreme caution. The reader is referred to Chapter 30 for more advice regarding the approach to patients with abnormal CSF cellularity.

Other cells occasionally found in normal CSF As mentioned earlier, normal CSF may also rarely contain cells that derive from tissues in physical contact with the subarachnoid space, including the choroid plexus, the ependymal lining of the ventricles, and the arachnoid membrane itself.4 The diagnostic significance of finding such cells in otherwise normal CSF is largely unknown, but increased numbers of these cells have been reported in CSF samples from infants and children with hydrocephalus.16 Cartilage cells and cells derived from the bone marrow (presumably due to trauma from the spinal needle) have also been rarely identified in CSF samples,17,18 and these cells are commonly mistaken for malignant cells. Normal CSF should not contain erythrocytes; their presence reflects either local trauma at the time of CSF collection or bleeding into the subarachnoid space from some intracranial source. Approach to the patient with bloody CSF is reviewed in Chapter 29.

NORMAL PROTEIN CONTENT OF CSF Normal sources of CSF proteins Most proteins found in normal CSF are derived from the serum, although as much as 20% of total CSF protein may be synthesized by the choroid plexus or derive directly from the CNS or its coverings itself.19 The passage of serum proteins across the BBB or the blood–CSF barrier (BCB) depends largely on pinocytosis through capillary endothelial cells or across the choroid plexus epithelial barrier. In most circumstances, the CSF:serum concentration ratio of a given protein originating from the serum is dictated by its size (hydrodynamic radius more so than molecular

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weight) and to some degree by its charge.1,19–21 Most proteins eventually exit the CSF compartment by passing across the arachnoid granulations as fluid is absorbed via macrovesicular transport. Thus, because the net concentration of protein in serum is some 200-fold greater than it is in CSF at steady state (~7.0 gm/dl versus ~35 mg/dl), the protein efflux rate must be 200 times the influx rate. Stated another way, about 0.5% of total protein on average transfers from serum to CSF. This equilibrium takes some time to achieve; in one instance, radiolabeled albumin and gamma-globulin infused intravenously into humans took several days to reach a stable concentration in lumbar CSF.22 Proteins found in CSF at levels much greater than 0.5% of serum concentrations probably undergo some local synthesis within the CNS. As a result, it is incorrect to view CSF as simply an ultrafiltrate of plasma; some proteins derived from serum are present at much greater than the 0.5% proportion described above while others appear uniquely expressed in this compartment. These unique protein constituents of CSF are either made at the choroid plexus, or derive from the meninges or the various neural cell populations themselves. Some of these unique proteins can be measured at very low levels in serum, due to their normal efflux via CSF absorption, and stable CSF concentrations mean that they are actively and continuously produced within the CNS before traversing into the bloodstream. Numerous studies have attempted to link altered production or release of these CNSderived proteins into CSF with various pathological states, but none has achieved much clinical utility to date. There is also little evidence that any known neurological disease causes a significant change in the synthesis of CNS-derived proteins measurable at the level of total protein content (i.e., changes in CSF protein concentrations are driven exclusively by an altered balance of protein influx and efflux rates).

Measurement techniques and normal CSF protein concentrations The total protein concentration of CSF has been measured using various techniques over the years, but most clinical labs currently use some form of colorimetric or turbidometric assay where proteins bind to a substrate that allows for their quantification by spectrophotometry. It should be noted that the accuracy of current methodologies generates differences of up to 5% between individual measurements.1 In terms of normal values, the mean protein concentration of lumbar CSF reported in studies of both normal volunteers and in patients with otherwise normal diagnostic evaluations ranges between 23–38 mg/dl, with the lower and upper limits of this span (2.0 standard deviations in either direction) extending from 9–58 mg/dl.1,23–28 Normal ranges can vary slightly from institution to institution, and it is imperative that the clinician be familiar with those set for the clinical laboratory being used.

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Physiological variables are known to influence CSF protein content, including the developmental maturity of the host (levels are typically lower in infants and young children; see Chapter 5) and the site along the neuraxis from where the sample was obtained. Thus, it is clear from older studies of both infants and normal adults that a substantial concentration gradient of protein exists between the intraventricular, cisternal, and lumbar CSF compartments. In the classic monograph by Merritt and Fremont-Smith,29 CSF from the ventricles was reported to have the lowest protein levels (6–15 mg/dl), while cisterna magna CSF had intermediate concentrations (15–25 mg/dl), and CSF from the lumbar thecal sac had the highest amounts (20–50 mg/dl). While these authors ascribed such a gradient to a general stagnation of the protein turnover processes in the lumbar region,29 more recent studies show that the BCB is also more permeable to proteins in these caudal locations.30,31

Amino acid composition of normal CSF Amino acids are the substrates of all proteins, and several also serve as neurotransmitters or neurotransmitter precursors in the CNS. These compounds are carried across the BBB and BCB via the actions of specific transporters (see Chapter 6). Most studies of CSF amino acid levels have sought to identify changes associated with particular neurological diseases, but many fail to report simultaneous plasma levels or to clarify whether or not measurements were made in the fasting state. In one study of 37 normal volunteers, McGale et al. found that the total concentration of free amino acids in CSF was 826 ± 102 μmol/l, with glutamine alone comprising 67.4% of this total amount (552 ± 69 μmol/l).32 The distribution of individual amino acids required for protein synthesis that were measured in the plasma and lumbar CSF of these individuals is shown in Table 10-1. Another study by Hagenfeldt et al. showed slight gender differences in the CSF:plasma concentration ratios for a few amino acids, as well as a few where the concentration ratios differed between ventricular and lumbar CSF samples.33 Amino acid levels in CSF samples from normal newborn infants can also differ from those in adults, perhaps reflecting some delayed maturation of BBB transport mechanisms.34

Common serum proteins Since many CSF proteins derive from the serum, it is not surprising that early electrophoresis studies showed similar protein expression patterns in samples from these two sites.35 Thus, albumin is the major protein found in both fluid compartments; under normal conditions it constitutes 56–76% of total CSF protein and 52–67% of total serum protein.36 Albumin also exists at a plasma:CSF concentration ratio of 236 that is very similar to the ~200-fold difference in total protein content of the two fluids.19,20,22 Still, the albumin:total protein ratio of CSF often rises as total CSF protein concentration increases, reflecting its

Table 10-1 Cerebrospinal Fluid and Plasma Concentrations of Standard Amino Acids in Normal Adults Mean Concentration (mmol/l) Amino Acid

CSF

Alanine Aspartic acid Arginine Asparagine Cysteine Glutamic acid Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine

31.3 2.3 22.4 13.5 < 2.0 26.1 552.0 5.9 12.3 6.2 14.8 20.8 2.5 9.9 <2.0 29.5 35.5 < 2.0 9.5 19.9

Plasma 328.4 5.3 80.9 111.7 123.7 61.3 641.0 282.7 79.8 76.7 155.3 170.7 27.7 64.0 323.7 139.7 165.5 49.6 73.0 308.6

CSF:Plasma Ratio 0.10 0.43 0.31 0.12 – 0.40 0.86 0.02 0.16 0.09 0.10 0.12 0.10 0.17 – 0.23 0.25 – 0.14 0.07

Adapted from McGale EHF, Pye IF, Stonier C, Hutchinson EC, Aber GM. Studies of the interrelationship between cerebrospinal fluid and plasma amino acid concentrations in normal individuals. J Neurochem 1977;29:291–297; and Hagenfeldt L, Bjerkenstedt L, Edman G, Sedvall G, Wiesel FA. Amino acids in plasma and CSF and monoamine metabolites in CSF: interrelationships in healthy subjects. J Neurochem 1984;42:833–837.

enhanced influx across the BBB relative to other plasma proteins based on its smaller size.37 The next most common serum protein found in CSF, immunoglobulin G (IgG), is present at levels 10-fold lower than albumin and is the third most common protein in CSF (Table 10-2). Several protein constituents have been identified in the other main CSF electrophoretic peaks (i.e., the alpha1-, alpha2-, and beta-globulin fractions; the gamma-globulins are discussed separately below), and most are also found in serum.1,22 Some, however, are much more abundant in CSF, raising the possibility of synthesis within the CNS. Transthyretin (previously known as prealbumin), for example, is made both in the liver and by the choroid plexus; it constitutes 5–6% of total lumbar CSF protein but makes up less than 0.5% of all serum protein.1,19 Likewise, lipocalintype prostaglandin D synthase (L-PGDS, previously known as beta-trace protein) and cystatin C (previously known as gamma-trace protein) together make up some 10% of CSF protein but less than 0.1% of serum protein.1,19 The former is found in normal CSF at levels of 2.0–3.5 mg/dl,1 while the latter normally occurs at 0.4–1.4 mg/dl.19,38,39 Changes in levels of these proteins have been sought as markers of different CNS disease states, although studies have lacked consensus to make the measurements clinically useful at present.

Normal Protein Content of CSF

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Table 10-2 Most Abundant Proteins of Normal Cerebrospinal Fluid in Decreasing Order of Concentration (Top), and the Corresponding Rank Order of the Most Abundant Serum Proteins (Below) Rank

Protein

1 2 3 4 5 6 7 8

Albumin L-PGDS† IgG Transthyretin†† Transferrin Alpha-1-antitrypsin Apolipoprotein E Cystatin C†††

Rank

Protein

1 2 3 4 5 6 7 8

Albumin IgG Beta lipoprotein Alpha lipoprotein Fibrinogen Transferrin Alpha-1-antitrypsin Alpha-2-macroglobulin

Approximate CSF Concentration (mg/dl) 20.0 2.6 2.2 1.7 1.4 0.8 0.8 0.6

% of Total CSF Protein 67 9 7 6 5 3 3 2

% Transfer into CSF* 0.5 3400.0 0.2 6.0 0.6 0.4 6.0 500.0

Approximate Serum Concentration (mg/dl) 4,000 1,000 450 400 300 230 200 140

* Calculated as [ConcentrationCSF/ConcentrationSerum] × 100% †L-PGDS, lipocalin-type prostaglandin-D-synthetase (previously known as beta-trace protein). ††Previously referred to as prealbumin. †††Previously known as gamma-trace protein. Adapted from Thompson EJ. Proteins of the Cerebrospinal Fluid. Analysis and Interpretation in the Diagnosis and Treatment of Neurological Disease, second edition. Amsterdam: Elsevier Academic Press; 2005.

Gamma globulins in the CSF are predominantly, but not exclusively, Ig molecules. Fishman reports that IgG predominates in normal CSF at a mean concentration of 4.6 ± 1.9 mg/dl, while IgA is found at an average level of 0.08 ± 0.05 mg/dl and IgM is typically present around 0.017 ± 0.005 mg/dl.1 Minute amounts of IgD and IgE can be found in normal CSF as well.1,40 The IgG present in normal CSF originates largely from the serum,22 although when normalized to total protein content, IgG levels in CSF (5–12% of total protein) are often less than two-thirds of those in serum (15–18% of total protein).1 Such a discrepancy in this proportion requires that CSF IgG levels be measured in relation to another common plasma protein such as albumin in order to determine whether their rise reflects passive influx across a permeable BBB or local synthesis by plasma cells that have entered the CNS. The simplest means to accomplish this task is by calculating the IgG index, as follows: IgG Index = (IgGCSF/IgGserum) / (AlbCSF/Albserum) Normal values for the IgG index of lumbar CSF have been variably reported to range from 0.34–0.58,41 or to have an upper limit of 0.66 to 0.85.42,43 Fishman makes the important point that CSF contaminated with as little as 0.2% serum (roughly the equivalent of 5,000–10,000 RBCs/mm3) due to a traumatic LP can artificially raise the IgG index, and also that this measure loses reliability when total CSF protein

content is below 25 mg/dl or above 150 mg/dl.1 Similar calculations of an IgA index (normal, 0.14 ± 0.10) or an IgM index (normal, 0.028 ± 0.02) can also be performed.44 Individual laboratories must standardize their own normal indices, and accuracy depends on precision in the measurement of albumin and IgG content of both CSF and serum samples. Finally, qualitative measures of CSF IgG content seek to identify diversity of the gamma-globulin fraction in order to make inferences about intrathecal immune responses. Oligoclonal IgG bands are rarely observed in serum, except in disorders such as multiple myeloma. Zero or one unique oligoclonal band is not uncommon in otherwise normal CSF; two or more that are not found in a paired serum sample signify an abnormal immunological process taking place within the intrathecal space. CSF oligoclonal bands can be observed in a wide variety of infectious, demyelinating, granulomatous, neoplastic, paraneoplastic, and connective tissue disorders affecting the CNS as discussed in various locations throughout this text.

Structural or intracellular proteins of neurons, astroglia, and myelin Beyond proteins such as transthyretin synthesized at the choroid plexus by meningeal cells, others are made within the CNS by various neural cells and can occasionally be found in normal lumbar CSF at low levels. These include the

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Table 10-3 Expression of Common Intracellular Proteins Found in Various Neural Cells Present in Lumbar Cerebrospinal Fluid Concentration (ng/ml) Mean± SD

Source

Protein

Range

Population

Reference

Neurons

14-3-3 NfL NfH NSE

3.10 ± 2.90 0.14 ± 0.03 0.25 ± 0.23 17.30 ± 4.60

0.48 –8.90 0.08 –0.21 0.16 –0.73 4.92 –26.50

non-CJD HC HC HC

45 46 47 48

Astrocytes

GFAP S100B

0.066 ± 0.017 0.20 ± 0.08

0.016 –0.204 0.05 –0.38

HC NV

49 50

Oligodendrocytes

MBP

0.4 ± 0.03

0.08 –0.51

HC

51

NfL, neurofilament light chain; NfH, neurofilament heavy chain; NSE, neuron-specific enolase, GFAP, glial fibrillary acidic protein, MBP, myelin basic protein; non-CJD, demented patients without evidence of Creutzfeldt-Jakob disease; HC, healthy controls (patients undergoing spinal anesthesia); NV, normal volunteers.

intracellular components of neurons (e.g., 14-3-3 protein isoforms, the light and heavy chains of the neurofilament protein (NfL, NfH), neuron-specific enolase (NSE)), as well as those of astrocytes (e.g., glial fibrillary acidic protein (GFAP), S100B protein) and myelin or the myelin-producing oligodendrocytes (e.g., myelin basic protein (MBP)). In many clinical circumstances, evidence of altered CSF expression of one or more of these proteins has been sought as a biomarker of disease in the underlying CNS tissue, and such CSF levels are often compared to those found in samples from non-disease controls. Review of these control data can therefore provide some information regarding expression of these proteins in non-pathological states, although it should be remembered that such control samples are not always acquired from completely normal individuals. Keeping this in mind, these various neuronal and glial proteins are typically present in control CSF at low ng/ml concentrations (Table 10-3). Furthermore, while it is attractive to conceive of their release into CSF as being markers of specific cellular events (neuronal or axonal injury, demyelination, etc.), the clinical utility of such measurements continues to be hotly debated.

Hormones and neuropeptides The principal circulating hormones of plasma (cortisol, insulin, and thyroid hormone) can be found at low levels in CSF, as can those made and released by cells of the anterior pituitary (prolactin, growth hormone, etc.). Various neuropeptides synthesized and released by neurons (now numbering more than 100) may use CSF pathways for dissemination throughout the central neuraxis. Although many of these compounds coexist with classic neurotransmitters, they have unique modes of synthesis, release, and replacement after use. Their signals also play roles in information processing different from that regulated by conventional neurotransmitters, and many appear to be particularly associated with specific behaviors. An abbreviated list of the normal CSF levels of these mediators is provided (Table 10-4); their physiological functions and potential for dysregulation (thus causing altered CSF

levels) during various disease states is beyond the scope of this chapter.

Enzymes and enzyme inhibitors The development of assays to measure the specific function of various catalytic proteins (enzymes) in serum has naturally been applied to the study of other bodily fluids, including CSF. While a vast literature on the subject has ensued, little of relevance has made its way into routine clinical practice. In general, the enzymes present in CSF either derive from the blood, are made and released directly by neural cells, or are secreted by cells present in the meninges or in the CSF compartment itself.1 Regardless of their source, they are typically found at levels much lower than in blood. Banik and Hogan reviewed the subject of CSF enzymes in detail;61 they categorized most into the following groups: (i) glycolytic and mitochondrial enzymes,(ii) neurotransmitter-related enzymes, (iii) lysosomal enzymes, (iv) lipid-metabolizing enzymes, (v) the amino acid- and protein-related enzymes, and (vi) other enzymes. Only a few will be reviewed further here. Lactate dehydrogenase (LDH) exists as five distinct isoforms, and isoenzymes 1 and 2 are preponderant in normal serum, CSF, and brain tissue.1 In one study of 20 adults with headache or back pain and otherwise normal neurological evaluations, total CSF LDH levels were 13 ± 2 U/l.62 Reference values for CSF LDH in a cohort of 15 neonates who underwent LP for suspected meningitis but turned out to have normal findings were 33.5 ± 5.8 U/l.63 Here, nearly 75% of the enzyme activity was exerted by LDH-1 and LDH-2.63 Serial LPs performed in normal full-term neonates showed that CSF LDH levels fell to near normal adult levels before 30 days of life.64 Lysozyme is an enzyme capable of degrading peptidoglycans found in certain bacterial cell walls. It also binds to the surface of these bacteria and facilitates their opsonization by cells of the immune system. In blood, most of the enzyme derives from the cytotoxic granules of PMNs. In CSF, its concentration in normal subjects ranges about

Normal Protein Content of CSF

Table 10-4 Levels of Selected Hormones and Neuropeptides in Normal Cerebrospinal Fluid Category

Mediator

Systemic hormones

Insulin Cortisol Thyroxine (free) Thyroxine (protein bound) Melatonin Growth hormone (GH) Prolactin Thyroid-stimulating hormone (TSH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Adrenocorticotrophic hormone (ACTH) Vasopressin Oxytocin Thyrotropin-releasing hormone (TRH) Somatostatin Growth hormone releasing hormone (GHRH) Corticotropin-releasing hormone (CRH) Endorphin Met-enkephalin Leu-enkephalin Dynorphin Vasoactive intestinal peptide (VIP) Substance P Neuropeptide Y (NPY)

Adenohypophyseal hormones

Posterior pituitary hormones Hypothalamicreleasing factors

Opioid peptides

VIP-glucagon family Tachykinins NPY related family members Natriuretic peptides

Other novel neuropeptides

Brain natriuretic peptide Atrial natriuretic peptide C-type natriuretic peptide Cholecytokinin (CCK) Calcitonin gene-related peptide (CGRP) Hypocretin (Orexin) Cocaine- and amphetamine-related transcript (CART)

Normal CSF Concentration 0.69 ± 0.12 μU/ml 0.73 ± 0.03 ng/ml 0.48 ± 0.49 μg/ml 1.56 ± 1.68 ng/ml 0.14 ± 0.11 nmol/l <1 ng/ml 1–4 ng/ml <2 μU/ml <1 μU/ml <1 μU/ml 20 –80 pg/ml <1.5 –1.8 pg/ml 7–15 pg/ml 2.0±0.6 pg/ml 40–65 pg/ml 29± 2 pg/ml 60 pg/ml 15 pg/ml 5–29 pg/ml <5 pg/ml 30±2 pg/ml 68 pg/ml 25–45 pg/ml 233 ± 10 pg/ml 0.27±0.10 fmol/ml 0.20±0.13 fmol/ml 2.13±0.27 fmol/ml 14 ±3 pmol/ml 4.47 ± 0.68 pmol/l

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retinoic acid, and bilirubin.67 It recently was also shown to bind amyloid beta peptide, thus preventing its aggregation.68 Taken together, however, none of these enzyme assays in CSF has sufficient diagnostic specificity to warrant their use in the clinical arena, despite our expanding knowledge base. Enzyme inhibitors, when considered as a group, are the second most abundant protein type in normal CSF behind albumin.19 Cystatin C binds to and inhibits the cysteine proteases, cathepsins B and D. Alpha-2-macroglobulin blocks trypsin, plasmin, thrombin, and clotting factor X.19 Alpha-1-antitrypsin inhibits trypsin, chymotrypsin, plasmin, thrombin, and elastase.19 Since proteolytic enzymes have been implicated in the initiation and progression of inflammatory and neoplastic diseases of the CNS, it makes teleological sense that there are strong mechanisms in place to inhibit potential tissue destruction related to these types of disorders.

Immune and inflammatory mediators Many soluble inflammatory mediators, including antibodies, cytokines, chemokines, and complement proteins, can be found at varying levels in normal CSF. Intrathecal antibodies in the absence of CNS inflammation are largely derived from the serum and were discussed earlier in this chapter. The cytokines found in normal CSF may derive either from glial cells or from the few infiltrating leukocytes present in the meninges or the subarachnoid space in the absence of disease. When levels of these mediators in normal CSF were examined (mostly as controls in various studies where CSF cytokine concentrations were being examined in different disease processes), most concentrations fell in the low pg/ml range (Table 10-5). Functionally, normal human CSF has measurable anti-

286 ± 34 pg/ml 111 ± 6 pmol/l

Adapted from Refs. 1,19,52–60.

1.0 μg/ml, but numerous reports highlight rises in CSF lyzozyme levels in the setting of both bacterial and neoplastic meningitis.1 Another enzyme, creatine kinase (CK), transfers high-energy phosphate bonds to ATP for eventual release. A brain-specific isoform (CK-BB) is distinct from the muscle subtype, and CK-BB is the main isoform found in CSF. While normal individuals have very low CSF levels (<50 U/l), activity can exceed 10,000 U/l in the setting of severe head trauma or fatal subarachnoid bleeding.65,66 L-PGDS is the most abundant brain-derived protein in CSF. Not only does it catalyze the conversion of prostaglandin (PG) H2 to PGD2, but it also functions as a transporter of small lipophilic molecules such as thyroid hormone,

Table 10-5 Concentrations of Selected Cytokines in Normal Lumbar Cerebrospinal Fluid Cytokine

Concentration ± SEM

Population

IL-1α IL-1β IL-2 IL-4 IL-6

1.28 ± 0.15 ng/ml < 0.1 pg/ml 1.25 ±0.08 ng/ml 6.2 ± 0.8 pg/ml 1.4 ±0.2 pg/ml 3.0 ± 5.0 pg/ml 0.61 ± 0.10 pg/ml 1.3 ±0.3 pg/ml < 2.0 pg/ml 159 ± 10 pg/ml 492 ± 35 pg/ml 0.2 ± 0.1 pg/ml < 2.0 pg/ml 18.0 ± 9.0 ng/ml

NV HC NV HC HC LDD HC HC LDD HC Tension HA HC LDD HC

IL-10 IFN-γ TGF-β1 TNF-α GM-CSF

Reference 69 70 69 71 72 73 74 71 73 70 75 70 73 70

IL, interleukin; IFN, interferon; TGF, transforming growth factor; TNF, tumor necrosis factor; GM-CSF, granulocyte-macrophage colony stimulating factor; NV, normal volunteers; HC, healthy controls; LDD, lumbar disc disease; HA, headache.

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inflammatory properties when tested ex vivo in co-cultures with various leukocyte populations.76,77 To some degree, the immunoregulatory function of normal CSF can be ascribed to the presence of the anti-inflammatory cytokine transforming growth factor (TGF)-beta 1, although other proteins undoubtedly contribute as well.77 Similar in vivo actions of CSF to modulate the function of infiltrating leukocytes are presumed. The chemoattractant cytokines (chemokines) are multifunctional molecules whose main function is to act on chemokine receptors expressed on leukocytes to promote migration along a concentration gradient. The C, CC, CXC, and CX3C subgroups control the migration of distinct leukocyte subsets to coordinate the tissue influx of neutrophils, T cells, B cells, natural killer (NK) cells, and monocyte/macrophages under different physiological and pathophysiological conditions. While many are induced in the CSF of patients with various neuroinflammatory and neuroinfectious diseases, a number of these molecules can be measured in the intrathecal compartment in the absence of disease (Table 10-6). Functionally, however, normal human CSF has only modest chemotactic properties for peripheral blood mononuclear cells in ex vivo cell migration assays, and it contains only low levels of the degradative enzymes required for leukocytes to traverse the BBB.80,81 The complement system is an important innate host defense mechanism. These proteins circulate in inactive forms, but can become rapidly activated to promote phagocytosis, stimulate inflammation, or induce the lysis of microbial pathogens. The classic pathway acts in response to antigen-antibody complexes to aid in the eradication of elements such as viruses or bacteria. The alternative pathway

does not require prior contact with (and thus existing antibodies against) a foreign antigen; instead, activated complement components normally present at low levels bind to antigens which then amplifies further complement protein cleavage and the eventual targeting of coated (“opsonized”) material for phagocytosis or lysis. The complement factors C3, C4, and C9 all are amongst the 25 or 30 most common proteins of normal CSF, each being found at concentrations in the 0.2–3.0 μg/ml range.19,82,83 Activated complement components (C1q, C3a) or a soluble form of the terminal complement complex (SC5b-9), each presumably indicative of some underlying inflammation, are found in normal CSF at concentrations below 10 ng/ml.84,85 Beyond cytokines, other proteins are rapidly released into the circulation in response to inflammation or tissue injury. Termed acute-phase proteins, most are synthesized by the liver and have been proposed to participate in various homeostatic and repair mechanisms. The most commonly measured of these, C-reactive protein and serum amyloid A protein, are found in non-inflammed CSF at concentrations of 7.9 ± 8.3 ng/ml and 4.0 ± 1.7 ng/ml, respectively.86

NEUROTRANSMITTER AND NEUROTRANSMITTER METABOLITES IN NORMAL CSF Biogenic amines The recognition that dopaminergic neurons are lost from the basal ganglia of patients with Parkinson’s disease naturally led to investigation of neurotransmitters and their metabolites in the CSF of patients with many types of

Table 10-6 Concentrations of the Chemoattractant Cytokines (Chemokines) in Normal Lumbar Cerebrospinal Fluid Sub Group C chemokines CC chemokines

CXC chemokines

CX3C chemokines HC, healthy controls.

Chemokine XCL1 CCL1 CCL2 CCL3 CCL4 CCL5 CCL11 CCL17 CCL19 CCL21 CCL22 CXCL1 CXCL7 CXCL8 CXCL10 CXCL11 CXCL12 CX3CL1

Concentration ± SEM (pg/ml) 10.9±2.5 1.0±0.3 576.0±117.0 6.4±0.7 15.6±2.4 2.3±0.6 6.5±1.4 7.2±0.6 118.0±26.0 2.9±1.2 4.3±0.8 1.0±1.7 158.0±53.0 38.4±7.3 74.0±13.0 7.0±0.8 28.2±5.7 27.4±18.8

Population

Reference

HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC

78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 79

Neurotransmitter and Neurotransmitter Metabolites in Normal CSF

neurodegenerative disorders. A parallel literature describing changes in CSF neurotransmitter levels associated with a variety of psychiatric illnesses has also emerged over time, even if findings have been inconclusive if not contradictory in nature. While data from experimental animals suggest that fluctuations in the levels of various monoamine metabolites in CSF generally parallel alterations of the corresponding compound in brain,1 CSF concentrations also depend on the rate of transmitter or metabolite removal from this compartment. Another confounding issue with many of these studies has been the documented concentration gradient in lumbar CSF; for a transmitter such as dopamine (DA) that is present only in certain regions of the brain, sequential fractions of CSF have shown concentrations of its metabolites that increase more that 2-fold simply after the removal of 30 ml of fluid.87 With these provisos in mind, levels of neurotransmitters and their metabolites present in normal CSF samples will be reviewed here. Suffice it to say that changes in these levels have not proven to have much, if any, diagnostic relevance to date. DA and two of its main metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), have recently been measured in lumbar CSF samples using sensitive mass spectrometry methods. In specimens from 10 normal volunteers, Lee et al. reported the mean CSF DA level to be 1.67 ± 0.78 ng/ml (range, 0.29–2.55 ng/ml).88 A study by Kalita et al. using high-performance liquid chromatography (HPLC) documented DA concentrations of 4.50 ± 2.57 ng/ml in 20 control CSF samples.89 This study also reported HVA concentrations of 4.62 ± 1.61 ng/ml and DOPAC levels of 2.82 ± 1.18 ng/ml in these same non-disease specimens.89 A third DA metabolite, 3-methoxytyramine (3-MT), has proven itself to be more difficult to quantify alongside DA in biological specimens. CSF levels of serotonin (5-hydroxytryptamine, 5-HT) and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), have been investigated in the setting of many neurological and psychiatric disorders, and considerable variability between studies has been found. In their report on 14 healthy adult male subjects, Eklundh et al. found CSF 5-HT levels to be 8.9 ± 1.9 pmol/l (1.57 ± 0.33 pg/ml), while 5HIAA was present at concentrations of 404.3 ± 73.0 pmol/l (77.30 ± 13.96 pg/ml).90 5-HT levels also declined nearly 2-fold between subjects in their early twenties and those older than 45 years of age.90 Most studies that have measured norepinephrine (NE) levels in normal CSF have found values ranging from 10 to 300 pg/ml. In general, this represents some 50–60% of the mean plasma concentration (in addition to its role as a central and autonomic neurotransmitter, NE is also made by the adrenal medulla).1 Total CSF NE content can be influenced by dietary intake of foods containing large amounts of monoamines, by the CSF gradient issues described earlier, and by technical issues related to sample collection and storage methodologies. Still, the NE in CSF appears largely

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to derive from the brain; a patient with a pheochromocytoma and a plasma NE level of 9,680 pg/ml had a normal CSF concentration of 200 pg/ml.1 3-Methoxy-4-hydroxyphenylglycol (MHPG) is the major NE metabolite in the brain, and CSF levels are often 40-fold higher than NE.1 Unlike NE, however, MHPG appears more evenly distributed throughout the different levels of the CSF compartment.1

Acetylcholine Studies of CSF acetylcholine (ACh) levels have been limited until recently by technical issues pertaining to the sensitivity and specificity of measurement methodologies and also by the presence of acetylcholinesterase (AChE) in both CSF and brain. As a result, it is not clear that local concentration changes of ACh within the ventricles or over the cerebral convexities may be discernible in lumbar CSF. Still, given reports of low brain ACh levels in Alzheimer’s disease and the widespread clinical use of reversible AChE inhibitors to delay progression of dementia in these patients, there has been resurgent interest in monitoring this transmitter in CSF. Frölich et al. used four different methods to measure CSF ACh levels and, via their preferred technique of HPLC and electrochemical detection, found levels of 6.14 ± 1.39 pmol/ml (897.73 ± 203.23 pg/ml) in lumbar CSF from normal control patients (range, 0.80–12.14 pmol/ml or 116.97–1,774.99 pg/ml).91 The authors concluded, however, that the technique was too cumbersome for widespread clinical application at present.

Amino acid neurotransmitters Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of both the brain and spinal cord. In some brain regions it is released from about one-third of all synapses, meaning that its concentration may exceed those of other neurotransmitters by a significant degree. In a study of chronic migraine patients, Vieira et al. found that CSF GABA levels were 8.46 ± 1.93 nmol/ml (0.87 ± 0.20 μg/ml) in 14 healthy control subjects.92 Molina et al. reported levels of 1.8 ± 0.4 nmol/ml (0.18 ± 0.04 μg/ml) in a cohort of 26 older adults being used as a control population for comparison to levels found in patients with dementia.93 This latter study also measured CSF levels of another important inhibitory amino acid neurotransmitter, glycine, and found that normal CSF contained 6.7 ± 2.2 nmol/ml (0.51 ± 0.16 μg/ml) of this mediator.93 Conversely, glutamate is the main excitatory neurotransmitter of the CNS, and high levels of this mediator actually cause neuronal damage (termed “excitotoxicity”) via actions on multiple glutamate receptor subtypes. This mechanism of cell death is believed to underlie both acute and chronic neurodegeneration in a variety of clinical situations, making measurement of CSF glutamate levels an important avenue

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in the study of neurological disease pathogenesis. In one cohort of 26 older normal adults, lumbar CSF glutamate levels were 24.0 ± 1.2 nmol/ml (3.53 ± 0.18 μg/ml).93 In contrast, Vieira et al. found that CSF glutamate levels were substantially lower at concentrations of 0.109 ± 0.066 nmol/ml (16.04 ± 9.71 ng/ml) in 19 healthy control subjects.94 These and similar divergent values reported in the literature maintain the uncertainty of measuring this transmitter in clinical situations.

measurable affinity for the membrane transporters found at the choroid plexus, and intravenous administration of exogenous fructose causes very little additional entry into CSF.1 Yet because the CSF:plasma fructose concentration ratio under normal conditions exceeds 1.0, it seems likely that this sugar is an end product of brain metabolism. As for mannose, Kusmierz et al. reported that the CSF of 14 healthy adult subjects had concentrations of 1.06 ± 0.24 mg/dl, while their simultaneous plasma mannose levels were 1.37 ± 0.63 mg/dl.96 Like fructose, mannose is not a major energy substrate for the brain.

SUGARS AND CARBOHYDRATES IN NORMAL CSF Polyols Glucose Glucose levels in normal CSF depend entirely on the rates of influx from the plasma on one hand, and on its metabolic utilization by the brain and spinal cord as well as its efflux into venous blood as part of bulk CSF resorption on the other. The mechanisms underlying glucose passage from the circulation into the CNS are reviewed in detail in Chapter 6. Factors regulating brain energy metabolism and substrate utilization are largely beyond the scope of this text. In the setting of normal serum glucose levels (70–120 mg/dl), the glucose concentrations in CSF of otherwise healthy adults will range from 45 to 80 mg/dl (i.e., approximately two-thirds of serum levels). Fishman reports that CSF glucose levels of 40–45 mg/dl are often abnormal, and that values below 40 mg/dl always reflect a pathological state.1 These absolute values are sometimes deceiving, however, as hyperglycemia raises CSF glucose levels and yet may mask a relative fall within the intrathecal compartment. Thus, it is advisable to simultaneously monitor the CSF:serum glucose ratio in addition to absolute glucose concentrations. The normal ratio of 0.6 is subject to much fluctuation due to rapid changes in serum levels, and it typically declines to some degree as serum values rise. Thus, a lower limit to the normal CSF:serum glucose ratio of 0.31 in diabetic patients is accepted.1 Normal glucose concentrations in the extracellular space of the brain are about 20 mg/dl, reflecting a small amount of reserve substrate as a “sink” for both the blood and CSF. Ventricular CSF typically has slightly higher glucose levels than the cisternal fluid, which in turn is slightly higher than at the lumbar level (a total gradient of 10–20 mg/dl between the ventricular and lumbar spaces is the norm).1 Developmental changes in normal CSF glucose levels are discussed in Chapter 5.

Fructose and mannose While the concentration of fructose in normal plasma is relatively low (< 2.0 mg/dl in 29 of 40 healthy fasting adults, and between 2.2–4.6 mg/dl in the remaining 11 individuals), it is consistently somewhat higher in paired lumbar CSF samples (range, 1.8–13.0 mg/dl).95 Fructose has no

Polyols are ubiquitous sugar alcohols, formed by the reduction of aldoses and ketoses during intermediary carbohydrate metabolism. myo-Inositol is involved in signal transduction when released from phospholipids as inositol1,4,5-triphosphate, and mannitol and sorbitol are organic osmolytes. The function of other polyols in mammalian tissues is otherwise unknown, even though studies have gone to substantial lengths to quantify them in normal human plasma and CSF. Shetty et al. reported the following polyol concentrations in the CSF of 12 healthy adults: myo-inositol, 23.97 ± 3.90 μg/ml; 1,5-anhydrosorbitol, 15.32 ± 3.54 μg/ml; arabitol, 3.72 ± 0.87 μg/ml; ribitol, 0.57 ± 0.11 μg/ml; galactitol, 0.33 ± 0.12 μg/ml; sorbitol, 2.37 ± 0.64 μg/ml; and mannitol, 0.84 ± 0.24 μg/ml.97 Similar CSF concentrations have been reported in other studies.96 Furthermore, all of these compounds have CSF:plasma concentration ratios greater than 1.0 (most are above 5.0);97 this indicates that polyols are either being rapidly transported into CSF, or more likely that they are produced within the brain or at the choroid plexus. With the exception of myoinositol, polyols are formed in single-step reductions from their corresponding sugars, meaning that their precursors turn over very rapidly in the brain. An inborn error of metabolism causing high CSF and brain polyol levels and leukoencephalopathy has recently been described.98

THE LIPIDS AND LIPOPROTEINS OF NORMAL CSF Lipids comprise the bulk of the dry mass of the CNS, and they serve many roles in the structure and function of the nervous system. Lipids can also be the target of injury in disease (oxidation, autoimmune damage), and cellular damage may cause their release into the CSF. As a whole, the concentration of total lipid in normal CSF ranges from 10 to 20 μg/ml (Table 10-7).1,99,100 These levels represent some 0.2% of the total lipid content of serum,1 but they reflect diverse compounds such as phospholipids, glycolipids, cholesterols, and specialized signaling lipids such as PGs and other arachadonic acid metabolites. Technological advances have allowed for the identification of individual lipid moieties in

The Lipids and Lipoproteins of Normal CSF

Table 10-7

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Lipid and Lipoprotein Content of Normal Lumbar Cerebrospinal Fluid

Category

Type

Lipid

Concentration

Proportion

10.3–12.5 μg/ml 3.7–6.0 μg/ml

Total lipids Phospholipids Lysolecithin Sphingomyelin Lecithin Cephalin

6.7% 20.3% 54.0% 17.6%

Reference 99,100 99–101 101 101 101 101

Glycolipids 0.65–0.89 μg/ml

Gangliosides

263.0±29.2 pg/ml 97.6±21.7 pg/ml 8.10±4.32 pg/ml 11.4±6.1 pg/ml 5.7±1.9 pg/ml 58.70±10.12 pg/ml 41.6±6.4 pg/ml 80.55±12.56 pg/ml 73.2±19.7 pg/ml 18.0±2.6 pg/ml

102,103 102,103 102,103 102,103 102,103 102,103 102,103 104 99–101 99–101 99–101 106 106 107 106 108 107 106 107 106 108

4.5±2.7 μg/ml 19.8±12.8 μg/ml 12.4±4.7 μg/ml

111 112 113

GM1 GD3 GD1a GD1b GT1b GQ1b Sulfatides

3% 4% 15% 16% 40% 15% 54.3±1.9 pmol/ml 3.1–5.4 μg/ml

Cholesterol Free cholesterol Esterified cholesterol

28–42% 58–72%

Prostaglandins PGD2 PGE2

PGF2α 6-keto-PGF1α

Lipoproteins ApoE

small sample volumes, and these methods have been applied to both normal and diseased CSF samples. Although important advances have been made, none of these measurements yet has well-defined clinical relevance.

Phospholipids Phospholipids can be subdivided into four major categories: (1) lysolecithin and inositol phosphatide, (2) sphingomyelin, (3) phosphatidylserine and phosphatidylethanolamine, and (4) lecithin. The phospholipids of normal CSF represent about 1.5% of the total amount found in serum, and early studies suggested that the composition of phospholipids in both compartments was similar.101 In what still remains a definitive evaluation of the subject, Illingworth and Glover found that normal CSF contained on average 6.0 μg/ml of total phospholipid, some 6.7% of which was lysolecithin, 4.5% was phosphatidylinositol, 3.1% was phosphatidicacid, 20.3% was sphingomyelin, 13.1% was phosphatidylethanolamine, and 54.0% was lecithin.101 While it is generally agreed that both acute and chronic CNS injury can raise total CSF phospholipid content, it is less clear to what degree changes among individual fractions are informative about the pathology of the underlying tissue.

Glycolipids Gangliosides are sialic acid-containing glycosphingolipids highly enriched within the CNS compared to other tissues. Their biosynthetic and metabolic pathways have been well studied, and genetic deficiency of enzymes necessary to degrade certain glycosidic linkages can cause massive ganglioside accumulation in intracytoplasmic lysosomes of neuronal cells (the gangliosidoses). Individual CSF gangliosides have been quantified in both normal and disease states. The total gangliosides content of normal adult CSF has been estimated to range between 0.65 and 0.89 μg/ml.102,103 As to the breakdown of individual ganglioside species in these samples, fractionation assays show a pattern representative of brain ganglioside content. Several studies have reported the following distribution of individual gangliosides in CSF derived from healthy adults: GM1 (3%), GD3 (3%), GD1a (15%), GD1b (16%), GT1b (41%), and GQ1b (16%).102,103 Samples from infants and young children generally reflect this distribution, but may have proportionally higher GD1a and lower GQ1b content compared to adults.103 Sulfatides are sulfated galactocerebrosides synthesized mainly by oligodendrocytes and thus predominate in the myelin sheath around axons. They accumulate within the

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CNS of patients with metachromatic leukodystrophy, and may decline with incipient dementia. In the CSF of nondemented older adults, Han et al. reported that sulfatide concentrations are 54.3 ± 1.9 pmol/ml.104 Since apolipoprotein E (apoE)-containing high-density lipoproteins are the main sulfatide transporters in CSF, the sulfatide mass of CSF was found to depend on the APOE genotype.105 In normal patients homozygous for apoE3, sulfatide content in CSF lipid extracts was 46.4 ± 3.3 nmol/mg apoE.105 In heterozygotes or apoE4 homozygotes, this level was 53.7 ± 4.6 nmol/mg apoE.105

Cholesterol Cholesterol can be found in normal CSF in both its free and esterified forms, usually in approximately a 1:2 ratio (Table 10-7).1 Various studies have measured total CSF cholesterol concentrations (free plus esterified) in a 3.1– 5.4 μg/ml range.99–101 Given that normal serum levels are several hundred-fold higher than this, it is not surprising that pathologically elevated serum levels can increase CSF concentrations to a modest degree.1 Older studies have looked for changes in CSF cholesterol levels in the setting of various neurological disease states, but no consistent patterns have ever emerged.

Prostaglandins PGs are highly reactive lipid compounds derived from essential fatty acids that act via specific receptors to control such diverse physiological functions as vascular reactivity, platlet aggregation, and inflammation. In some circumstances they also mediate pain, and their chronic production may cause oxidative tissue injury. The cyclooxygenase (COX) pathway generates the main PGs, PGD2, PGE2, and PGF2α, via cleavage of arachadonic acid in cell membranes into a common precursor, PGH2. Given epidemiological evidence that COX inhibitors may slow the progression of Alzheimer’s disease, interest in the role of PGs and oxidative injury within the CNS has exploded. As a result, many studies have examined PG concentrations in normal and diseased CSF. Montine et al. reported total CSF eicosanoid levels in normal adult CSF to be 263.0 ± 29.2 pg/ml.106 The breakdown of individual PG concentrations is shown in Table 10-7; in general, PGD2, PGF2α, and 6-keto-PGF1α (the main metabolite of PGI2, also known as prostacyclin) predominate over PGE2.106–108

Lipoproteins The lipoproteins of normal CSF form distinct particles composed of approximately one-third protein, one-third phospholipid, and one-third cholesterol.109 Ex vivo assays using these particles suggest that they act to remove lipids from degenerating cells and deliver lipids to new cells for the purposes of membrane synthesis or lipid storage.109

When isolated from normal CSF, these lipoprotein particles were found to segregate into four distinct classes that differed primarily in their relative content of apolipoproteins A-J.110 ApoE has received the most experimental attention because one of its three allelic variants, apoE4, is linked to an increased risk of Alzheimer’s disease. Many studies have measured apoE levels in CSF; in non-demented agematched control populations, mean concentrations range from 4.5 to 19.8 μg/ml.111–113 When normalized to total protein concentration, Kay et al. reported apoE:total protein ratios in non-disease control CSF of 0.040 ± 0.013.112 Its concentration at more than 6% of serum levels implies intrathecal synthesis.19 Other commonly identified CSF apolipoproteins, apolipoprotein A (apoA)-I and apoA-II, are predominantly derived from the serum.19

IONS AND OTHER SOLUTES OF NORMAL CSF Electrolytes Electrolytes are substances that dissolve in water to generate a solution that can conduct an electrical current. The common ones measured in serum (sodium, potassium, calcium, magnesium, chloride, phosphate, bicarbonate) can also be found in normal CSF. In some cases, CSF levels are held constant across a wide range of serum levels, bespeaking strict underlying control mechanisms, while others vary directly with plasma concentrations. Many are found at levels in CSF somewhat lower than in serum, but a few are consistently higher in the intrathecal space. Only in a few select circumstances have fluctuating CSF electrolyte concentrations been shown to occur in particular neurological diseases, making measurement of CSF levels at present a questionable clinical exercise. As such, data will be reviewed briefly here; the reader is again referred to Fishman’s text on CSF for a more detailed review of this subject.1 Since plasma is some 92% water and CSF is closer to 99% water, a sodium level of 140 mEq/l in each compartment actually represents a concentration of 152 mEq/kg water in plasma and 141 mEq/kg water in CSF.1 Stated another way, the CSF:plasma concentration ratio of sodium is about 0.93.1 In general, sodium (the main osmotically active cation in CSF) levels in CSF vary directly with the serum sodium concentration, albeit with somewhat smaller-magnitude changes. The active secretory processes involved in sodium entry across the choroid plexus were reviewed in Chapter 3. CSF sodium concentrations are also influenced by the ready transfer of water between the two compartments, and by the osmotic forces that work to maintain equal osmolalities between plasma and CSF. Unlike sodium, CSF potassium levels are tightly maintained even in the setting of a significant rise or fall in plasma concentrations. This steady state CSF concentration occurs at about 2.9 mEq/l.114 Since extracellular potassium both has depolarizing effects on neurons and can promote the

Ions and Other Solutes of Normal CSF

swelling of astrocytes,115 the CNS has established precise mechanisms to control interstitial and CSF concentrations of this ion. Thus, even in the setting of subarachnoid bleeding with the large release of potassium into CSF as a result of hemolysis, CSF levels are tightly maintained.116 This bespeaks a highly efficient mechanism to remove potassium from the CSF compartment. Only after death does CSF potassium rise,117 probably due to ATP depletion and failure of sodium-potassium ATPases. Serum calcium is either bound to albumin (30–50%), or is in an ionized, diffusible form (50–70%). In CSF, while normal concentrations (2.3–3.2 mEq/l) may approximate the diffusible fraction found in serum,1 most of the available data suggest that CSF calcium levels are controlled by active transport processes.118 Indeed, they remain steady with the systemic infusion of calcium salts or treatment with calcium chelators, and CNS influx is not influenced by a saturable mechanism controlled by serum levels.119 The CSF calcium level is not particularly affected by diseases of the CNS, and efforts to make such correlations have been largely unrewarding. Magnesium is the sole cation whose concentration in CSF normally exceeds serum levels (2.0–2.5 mEq/l versus 1.5–2.0 mEq/l), and yet massive systemic fluxes have little effect on CSF levels.1 This again points to the existence of potent regulatory mechanisms that keep the CSF magnesium concentration in a narrow, well-defined range. On the other hand, both hypomagnesemia (seizures) and hypermagnesemia (weakness) have notable neurological effects,120 highlighting the important influence of magnesium ions on brain excitability. Regulation of CSF levels to some degree occurs at the choroid plexus, but also is likely to be influenced by glial cells as well.1 Chloride is the principal anion found in the CSF, and, like magnesium, its concentrations there exceed plasma levels. Sambrook et al. reported CSF chloride levels in 40 normal subjects as 119.1 ± 3.3 mEq/l, some 15–20 mEq/l higher than paired serum samples.116 Still, CSF levels generally follow changes in plasma concentrations, suggesting some degree of passive flux between the two compartments. On the other hand, absolute changes in CSF levels are less than the change in plasma, and some ion-specific membrane transport has been demonstrated.1 There has been no convincing clinical utility for the measurement of CSF chloride levels in any known neurological disease state. Inorganic phosphorus in the form of phosphate (PO43−) is found in normal CSF at levels of 1.2–2.0 mg/dl, some 50–60% of expected serum concentrations.1 While there is a somewhat inconsistent relationship between serum and CSF phosphate levels, and no known connection between CSF levels and any specific neurological disease, it has previously been observed that CSF phosphate concentrations increase in direct proportion to total CSF protein levels. Whether this reflects general BBB breakdown or some altered transport process is unknown.

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Bicarbonate is another common electrolyte whose CSF composition will be discussed later in the chapter in the context of normal CSF acid-base balance.

Trace metals There is resurgent interest in the role of iron in brain pathophysiology, and thus in measuring levels of iron and iron-binding proteins in CSF. Free iron is toxic to cells, and thus most tissue iron is bound to ferritin, where it is stored in an inert form. Transferrin is the main iron transport protein of the brain, and thus its level is presumed to reflect the brain’s requirement for iron.121 The high abundance of transferrin receptors at the BBB also suggests that this is an important site for moving iron into the CNS.121 Normal CSF levels of iron have been measured in the range 0.02–0.05 μg/ml.122–124 Transferrin, on the other hand, is the fifth most common protein of CSF,19 and it is present in normal samples at mean levels ranging from 6.7 to 21.7 μg/ml.122–124 Ferritin is found in normal CSF in minute quantities; mean concentrations range between 3.06 and 6.68 ng/ml in several studies.122–124 Since iron, ferritin, and transferrin are found in serum at 100- to 1,000-fold higher levels than in CSF, a traumatic LP can artificially elevate measured values in CSF. Copper may enter the CSF via active transport across the BCB as well as by passive diffusion in both its free and protein-bound forms. Mean normal CSF copper levels are reported to range between 8.67 and 22.50 ng/ml.125–127 In one analysis, the main determinants of CSF copper concentration were measures of BCB integrity and the serum ceruloplasmin concentration.125 Normal CSF ceruloplasmin concentration ranges between 0.8 and 2.2 μg/ml,1,128 which are 100- to 500-fold lower than normal serum levels. In Wilson’s disease, as the serum ceruloplasmin level falls, the high CSF copper concentrations must derive from its over-accumulation within the brain.125 CSF copper levels have thus been proposed as a good measure of chelation therapy, with a goal of lowering it to below 20 ng/ml.129 A wide range of other trace metals (aluminum, boron, silicon, chromium, manganese, zinc, platinum) has been detected in minute quantities in normal CSF. Their respective roles in brain physiology and pathophysiology are poorly understood, and thus the clinical utility behind their measurement remains undefined.

Vitamins Not only are vitamins important co-factors for biochemical reactions in the CNS, but several have also been shown to have antioxidant properties (e.g., vitamins C and E). With increased attention being given to the roles played by oxidative injury in the pathogenesis of neurological disease, vitamin levels in CSF continue to be investigated in a wide range of CNS disorders. In normal CSF, the concentrations

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Table 10-8

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Properties and Composition of Normal CSF

Concentrations of Selected Vitamins in Normal Cerebrospinal Fluid

Descriptor

Name(s)

Vitamin A Vitamin B1 Vitamin B2 Vitamin B3 Vitamin B5 Vitamin B6 Vitamin B7 Vitamin B9 Vitamin B12 Vitamin C Vitamin D

Retinol Thiamine Riboflavin Niacin, niacinamide Pantothenic acid Pyridoxine Biotin Folic acid, folinic acid Cyanocobalamin Ascorbic acid 25-Hydroxyvitamin D 1,25-Dihydroxyvitamin D α-Tocopherol γ-Tocopherol

Vitamin E

Concentration in CSF (mM, Unless Otherwise Noted)

of many water-soluble vitamins exceed those in serum (Table 10-8), and it has now been shown that vitamins enter the CSF both by facilitated diffusion and via active transport mechanisms at the BCB.131,132 Turnover of vitamins from the CSF occurs with their passage into neural cells or with bulk CSF efflux back into the bloodstream. Experimental studies suggest that pools of many individual vitamins turn over in the CSF compartment within hours.131 For the fatsoluble vitamins such as vitamin E, turnover happens much more slowly, and there are powerful homeostatic mechanisms that protect the brain in the setting of systemic deficiency.131 As a potential exogenous antioxidant, oral administration of vitamin E causes CSF (and presumably brain) levels to increase by some 75% over time.137

Metabolic byproducts Ammonia is a metabolic product of amino acid deamination that largely takes place in the gut. It is highly toxic to cells, and thus gets converted to urea or uric acid by the liver for safe transport in the circulation and eventual excretion in the urine. At physiological pH, most ammonia exists in an ionized form and cannot diffuse across membranes. Changes in blood and brain pH probably affect the conversion between its ionized and unprotonated forms to influence ammonia uptake across the BBB and BCB. The CNS detoxifies ammonia by combining it with alphaketoglutarate to generate glutamine; this substance is less volatile in CSF and thus much easier to measure.1 Older studies suggested that the concentration of ammonia in normal CSF (11–37 μg/ml) was approximately one-third to one-half of the concomitant serum arterial level (29–136 μg/ml),138 but more modern assay methods have shown that these results are probably spuriously high due to sample handling issues.139 In normal resting adults, CSF ammonia levels were uniformly found to be below the level of detection of 2 μM with simultaneous serum values of 22 ± 2 μM.140 CSF ammonia levels went as high as 16.1 ± 3.3

0.19 0.36 0.02 0.70 2.0 0.39 0.008 0.068 8.7 pM 232 8.3 ng/ml 25.0 pg/ml 0.029 0.006

CSF:Plasma Ratio 0.19 0.90 0.40 1.40 1.00 1.30 1.33 4.90 0.03 4.10 0.57 0.81 0.001 0.001

Reference 130 131 132 131 131 131 131 133 134 132,133 135 136 136 136

μM with vigorous physical exercise, and post-exercise CSF glutamine levels in these samples were measured at 539 ± 16 μM.140 There was a modest correlation of concentrations between these two compounds.140 In a population of 23 neurological patients without liver disease, the mean CSF ammonia level was 18 μM or 0.31 μg/ml (range, 8–26 μM).139 While there is published literature regarding the various CSF abnormalities associated with uremia and uremic encephalopathy, there is surprisingly little information available about CSF urea levels themselves in either the presence or absence of renal disease. Several older studies, however, would suggest that the concentration of urea in CSF generally parallels that found in serum, albeit at slightly lower overall levels. Bradbury et al. reported that the urea level in the CSF of normal subjects averaged 4.7 mmol/l (equivalent to a blood urea nitrogen value of 13.16 mg/dl, since every molecule of urea has 2 nitrogen atoms each with a molar mass of 14 g/mol), while the parallel mean serum value was 5.4 mmol/l (or 15.2 mg/dl).141 In terms of creatinine, healthy controls had levels of 54.4 ± 10.7 μmol/l (0.62 ± 0.12 mg/dl) found in their CSF, roughly two-thirds of normal serum concentrations.142 Patients with renal insufficiency where circulating levels of this mediator rise show proportional elevations in CSF concentrations of creatinine.143 Its measurement, however, like that of urea, has little clinical utility. Uric acid is the final oxidation product of purine catabolism and is normally excreted by the kidney. Most of the uric acid found in serum is bound to albumin, and changes in plasma levels can occur with high dietary purine intake or impaired renal excretion. The uric acid content of CSF varies directly with serum levels, although it is generally several hundred-fold lower in the intrathecal compartment. In normal infants, CSF uric acid levels have been reported to be 16.32 ± 18.14 μmol/l (0.27 ± 0.30 mg/dl).144 In older children and adults, normal CSF values are 10.40 ± 4.76 μmol/l (0.17 ± 0.08 mg/dl) and 10.22 ± 6.78 μmol/l (0.17 ± 0.11 mg/dl), respectively.144–146

Ions and Other Solutes of Normal CSF

Nucleotides and nucleosides Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messenger molecules important in regulating intracellular energy metabolism via actions on specific protein kinases. Both are highly enriched in the CNS; cAMP is involved in higher cortical functions, while cGMP plays a role in phototransduction. Most studies suggest that normal lumbar CSF in adults contains 15–30 nmol/l of cAMP (Table 10-9),147–153 and one study reports that intraventricular levels may be 2- to 3-fold than lumbar levels.154 Where it has been examined in neurological disease, CSF cAMP levels may be increased in Alzheimer’s disease and meningitis, unchanged in brain tumors, and decreased in acute ischemic stroke, multiple sclerosis, and head trauma.147–153 In control patients, CSF cGMP levels have proven to be more variable, but most studies suggest that they range between 0.1 and 2.0 nmol/l.151,155–158 Levels may be decreased in amyotrophic lateral sclerosis, but are relatively unchanged in the setting of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, meningitis, and brain tumors.149,151,153,155–158 Nucleosides become phosphorylated to become nucleotides, which are the monomers of nucleic acids and several enzymatic cofactors. Many of these compounds can be measured in normal CSF at low levels (Table 10-9).

Abnormal CSF concentrations of some purine and pyrimidine bases have been reported in the setting of hereditary defects in their metabolism. Oxypurines (hypoxanthine, xanthine, and uric acid) are end products of adenosine 5′triphosphate (ATP) breakdown, and their levels may rise in extracellular fluids (including CSF) in response to hypoxia or oxidative stress. Detection of uric acid in CSF may also be viewed as a measure of BBB integrity, since the brain does not contain the enzyme xanthine oxidase, necessary to form it.161 Rising CSF levels of the oxypurines may in some circumstances also reflect underlying glutamate excitotoxicity with ATP degradation and production of oxygen free radicals.146 Normal CSF levels of ATP and guanosine 5′triphosphate (GTP) are low (<1 nmol/l), in part because the fluid contains endogenous hydrolases.162 CSL levels of ATP can rise in the setting of subarachnoid hemorrhage, because the mediator is found at high levels inside erythrocytes.160

Lactate and Pyruvate L-Lactate

is formed during normal anaerobic glycolysis by interconversion from pyruvate via the actions of LDH. Lactate levels in CSF largely reflect its production by the brain; early studies showed that even massively elevated blood levels had little short-term effect on the amount of

Table 10-9 Concentrations of Nucleobases, Nucleosides, Nucleotides, and Cyclic Nucleotides in Normal Lumbar Cerebrospinal Fluid Subgroup

Molecule

Cyclic nucleotides

cAMP

cGMP Nucleobases

Nucleosides

Oxypurines

Adenine Guanine Thymidine Cytosine Uracil Adenosine Guanosine Uridine Cytidine Inosine Hypoxanthine

Xanthine

Nucleotides and deoxynucleotides

AMP ATP GTP IMP

83

Concentration mean ± SD, mean (range) 21.4±3.3 nmol/l 20.2±4.0 nmol/l 4.4±1.2 nmol/l 4.3±2.2 nmol/l 0.24±0.16 nmol/l 0.37 (0.00–10.86) μmol/l 0.58 (0.00–15.71) μmol/l <0.1 μmol/l <0.1 μmol/l 1.12±0.77 μmol/l 0.90 (0.00–19.86) μmol/l 0.12±0.09 μmol/l 0.16 (0.00–1.89) μmol/l 2.12±0.59 μmol/l 0.34±0.20 μmol/l 0.50±0.19 μmol/l 2.47±0.71 μmol/l 3.40±1.40 μmol/l 2.8±0.2 μmol/l 1.73±0.62 μmol/l 2.32±1.01 μmol/l 2.6±0.14 μmol/l 1.80±1.11 μmol/l <1 nmol/l <1 nmol/l 3.19 (0.00–19.70) μmol/l

Population HC NMC AMC AMC HC HCh HCh HC HC HCh HCh HCh HCh HCh HCh HCh HCh HCh HC HCh HCh HC HCh HC HC HCh

Reference 150 151 153 153 158 145 145 159 159 144 145 144 145 144 144 144 144 145 146 144 145 146 145 160 162 145

cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; AMP, adenosine monophosphate, ATP, adenosine 5′-triphosphate; GTP, guanosine 5′-triphosphate; IMP, inosine monophosphate; HC, healthy controls, NMC, non-meningitis controls, AMC, age-matched controls, HCh, healthy children.

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lactate that could be measured in CSF.163 More recently, however, monocarboxylate transporters have been identified that move lactate and pyruvate across cell membranes, including at the BBB and BCB.164 Interest in CSF lactate levels has in part been nurtured by early studies showing high levels in bacterial meningitis, and to a lesser degree in malignant hypertension, cerebral hemorrhage, hepatic encephalopathy, diabetes mellitus, and hypoglycemic coma.1 CSF lactate levels also invariably rise in the setting of very low CSF glucose levels, as the brain is forced to increase its anaerobic glycolysis in order to meet its metabolic demands. The average lactate content of normal lumbar CSF is slightly higher than what is found in paired samples obtained from venous blood,1,163 which is itself slightly higher than arterial levels. Posner and Plum reported CSF lactate levels in normal subjects to be 1.58 ± 0.03 mmol/l, higher than arterial levels of 0.97 ± 0.13 mmol/l.163 Zupping et al. reported CSF lactate levels in control subjects to be 2.03 ± 0.12 mmol/l, which again were higher than blood levels of 1.81 ± 0.14 mmol/l.165 Overall, the consensus normal CSF lactate value derived from multiple studies ranges between 1.1 and 2.2 mmol/l.1 The concentration of lactate relative to pyruvate (L/P ratio) in normal biological fluids is about 20:1, depending on local LDH activity. In the brain, this ratio may reflect the tissue redox state, because as cerebral glycolysis increases, not only do absolute lactate and pyruvate levels in the CSF increase, but the L/P ratio also rises.166 In normal adults, Zupping et al. reported that CSF pyruvate was 0.079 ± 0.004 mmol/l, with an average L/P ratio of 17.6.165 Another group of older control subjects showed values of 0.022 ± 0.007 mmol/l.167 In a large cohort of hospitalized children whose workup for infection or metabolic disease was unremarkable and whose blood lactate levels were normal, total CSF lactate levels averaged 1.5 mmol/l (range, 0.6–2.2 mmol/l), mean pyruvate levels were 0.11 mmol/l (range, 0.059–0.212 mmol/l), and the mean L/P ratio was 13 (range, 7–23).168 In young patients for whom CSF lactate and pyruvate is being measured to exclude an inborn error of metabolism, these authors proposed 90th percentile upper cutoff values of normal to be 1.8 mmol/l for lactate, 0.147 mmol/l (or 147 μmol/l) for pyruvate, and an L/P ratio of 17.168

Pterins and folate metabolites Neopterin and biobterin are the two main metabolites in the tetrahydrobiopterin (BH4) pathway. BH4 is synthesized de novo from GTP through the actions of GTP cyclohydrolase I, an enzyme whose gene is mutated in cases of dopa-responsive dystonia. Deficiencies of BH4 as a group result in various disorders of neurotransmission, since it is a cofactor for aromatic amino acid hydroxylases involved in the biosynthesis of dopamine and serotinin. Interestingly, the activity of GTP cyclohydrolase I is induced by inflammatory cytokines such

as interferon-gamma, making macrophages one of the main producers of neopterin. As such, CSF levels of this mediator have been monitored in both infectious and autoimmune disorders of the CNS, in addition to potential inborn errors of metabolism. In children less than 1 year of age, normal CSF neopterin levels are 12–35 nmol/l and normal CSF biopterin levels range between 15 and 70 nmol/l.169 In older children and adults, normal CSF neopterin levels are 9–20 nmol/l and normal CSF biopterin levels range between 10 and 30 nmol/l.169,170 There is indirect evidence linking the BH4 and folate metabolism pathways. Patients with cerebral folate deficiency have low CSF levels of 5-methyltetrahydrofolate (5MTHF) in the setting of normal plasma folate concentrations. This disorder is believed to result from the generation of autoantibodies against membrane-bound folate receptor present on the choroid plexus.171 Several patients with low levels of 5-MTHF and high levels of neopterin and biopterin in CSF had normalization of all three compounds with folinic acid supplementation.169 A recent study reported standardization of 5-MTHF detection in CSF samples by HPLC and normal reference values in control populations: for patients 0–1 year of age CSF 5MTHF levels were 103 ± 20.4 nmol/l (range, 63–129 nmol/l), for patients 1–3 years of age it was 72 ± 19.1 nmol/l (range, 44–122 nmol/l), and for patients 4–18 years of age normal values were 56 ± 10.7 nmol/l (range, 42–81 nmol/l).172 This corresponded to mean CSF:plasma 5-MTHF ratios of 1.6, 1.4, and 0.9, respectively.172 Folates and cobalamin are both required for the catabolism of homocysteine (HCY) to methionine, and S-adenosylmethionine (from methionine) is the major methyl donor group in the brain. Obeid et al. investigated the role of folate and cobalamin as determinants of CSF HCY levels, and the relationship between plasma and CSF levels of these various metabolites. Normal CSF was found to contain on average 0.09 μmol/l HCY (range, 0.06–0.16 μmol/l), some 120-fold less than in serum.173 Increasing age, low serum folate levels, and high serum HCY concentrations were all independent variables that favored higher CSF HCY levels.173

ACID-BASE BALANCE OF NORMAL CSF The acid-base balance of CSF has been well studied in both clinical and experimental settings, and these data will be overviewed here. Two important provisos, however, must be mentioned: first, that changes in lumbar CSF acid-base status may not reflect local changes within the brain,174 and second, unlike the well-established utility of arterial blood gases in patient management, similar measurements performed on CSF have yet to provide any meaningful therapeutic intervention that impacts clinical outcome. Thus, intrathecal acid-base studies may still only largely serve to inform us about the physiology of the BBB and BCB.

References

Table 10-10 Acid-Base Balance in Cerebrospinal Fluid and Arterial Blood of Healthy Children and Adults Parameter pH

pCO2 (mmHg)

Bicarbonate (mEq/l)

CSF Value

Blood Value

Population

7.326 7.335 7.307 7.328 (C) 7.366 50.2 46.8 43.8 42.9 (C) 40.3 21.5

7.409 7.410 7.428

HA HA HA

7.402 39.5 40.7 38.1

HI HA HA HA

33.6 24.8

HI HA

22.2 24.7

HA HA

20.6

HI

25.8 21.5 22.1 (C) 21.8

Reference 175,176 177 174 174 178 175,176 177 174 174 178 175,176 177 174 174 178

Lumbar CSF samples assayed, except cisteral (C) CSF where noted. HA, healthy adults; HI, healthy infants.

A guiding principle in CSF acid-base balance is that CSF pH remains remarkably stable in the setting of major fluctuations in the pH of arterial blood. Fishman outlines the four main determinants that help maintain the stability of CSF pH: (i) changes in respiratory rate and arterial pCO2, (ii) alterations in cerebral blood flow, (iii) control over CSF bicarbonate concentration, and (iv) the intrinsic buffering capacity of neural tissue itself.1 While it is true that blood pCO2 readily diffuses across membrane barriers surrounding the CNS, bicarbonate transfer at the choroid plexus is a more deliberate and regulated process (reviewed in Chapter 3). These two mediators provide most of the buffering capacity of CSF. Cerebral blood flow is also very pH-dependent, and increased flow can serve to remove both CO2 and hydrogen ions from the brain and CSF. These homeostatic mechanisms mostly come into play in the context of systemic acid-base imbalance, but there are situations where a primary acidosis of the CSF without systemic pH changes can arise. In normal subjects (adults and children), the pH of CSF is slightly less than the arterial blood, while the pCO2 values are slightly higher and the bicarbonate concentrations are quite similar (Table 10-10). Studies comparing the acid-base content of lumbar versus cisternal fluid have shown consistent (albeit slight) differences, probably reflecting variability in local metabolic and hydrogen ion production rates relative to blood flow and clearance differences in tissue adjacent to the two sites.174,179 These regional differences also highlight the fact that lumbar CSF is much slower to reflect acute systemic acid-base changes than cisternal sampling,179 meaning that LP in an acutely ill patient is not likely to provide accurate information about cerebral acid-base status. The reader is referred to

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Fishman’s excellent discussion of CSF acid-base changes in the setting of metabolic acidosis and alkalosis, as well as respiratory acidosis and alkalosis, for more information on this subject.1

CONCLUSIONS This extensive compilation of normal CSF values may be problematic from a number of perspectives, not the least of which is that many of the “control” samples used to generate these data do not derive from neurologically normal individuals, and also that many of the parameters measured are still not part of routine clinical practice. Likewise, some of these data have been gathered from older studies that used outdated analysis methods and that assuredly will need revision if newer technologies are applied. Still, it does not seem farfetched to hypothesize that more precise biochemical characterization of CSF samples will help to unravel the pathogenesis of poorly understood neurological diseases, and that future generations of diagnosticians will employ a broader armamentarium of assays to clarify the nature of their patients’ clinical and radiographic findings. In this light, it is hoped that the efforts required to assemble these data will serve to guide such analyses by providing a more detailed and accurate assessment of what constitutes normal CSF composition. It will be equally interesting to learn what important parameters were left out of this chapter. REFERENCES 1. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System, 2nd ed. Philadelphia: W.B. Saunders; 1992. 2. Simon RP, Abele JS. Spinal-fluid pleocytosis estimated by the Tyndall effect. Ann Intern Med 1978;89:75–76. 3. Barrows LJ, Hunter FT, Banker BQ. The nature and clinical significance of pigments in the cerebrospinal fluid. Brain 1955;78:59–80. 4. Oehmichen M. Cerebrospinal Fluid Cytology: an Introduction and Atlas. Philadelphia: W.B. Saunders; 1976. 5. Oehmichen M, Gruninger H. Cytokinetic studies on the origin of cells in the cerebrospinal fluid. J Neurol Sci 1974;22:165–176. 6. Ransohoff RM, Kivisakk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003;3:569–581. 7. Carrithers MD, Visintin I, Kang SJ, Janeway CA. Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain 2000;123:1092–1101. 8. Cserr HF, Knopf PM. Cervical lymphatics, the blood-brain barrier, and the immunoreactivity of the brain: a new view. Immunol Today 1992;13:507–512. 9. Veerman A, Huismans L, Van Zantwijk I. Storage of cerebrospinal fluid samples at room temperature. Acta Cytol 1985;29:189–190. 10. Aune MW, Becker JL, Brugnara C, et al. Automated flow cytometric analysis of blood cells in cerebrospinal fluid: analytic performance. Am J Clin Pathol 2004;121:690–700. 11. Svenningsson A, Andersen O, Edsbagge M, Stemme S. Lymphocyte phenotype and subset distribution in normal cerebrospinal fluid. J Neuroimmunol 1995;63:39–46.

86

Chapter 10

●

Properties and Composition of Normal CSF

12. Svenningsson A, Hansson GK, Andersen O, Andersson R, Patarroyo M. Stemme S. Adhesion molecule expression in cerebrospinal fluid T lymphocytes: evidence for common recruitment mechanisms in multiple sclerosis, aseptic meningitis, and normal controls. Ann Neurol 1993;34:155–161. 13. Kivisakk P, Trebst C, Liu Z, et al. T cells in cerebrospinal fluid express a similar repertoire of inflammatory receptors in the absence or presence of CNS inflammation: implications for CNS trafficking. Clin Exp Immunol 2002;129:510–518. 14. Kivisakk P, Mahad DJ, Callahan MK, et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci USA 2003;100:8389–8394. 15. Simon RP, Koerper MA. PMNs in normal spinal fluid examined by the cytocentrifuge technique. Ann Neurol 1980;7:380–381. 16. Wilkins RH, Odom GL. Ependymal-choroidal cells in cerebrospinal fluid. Increased incidence in hydrocephalic infants. J Neurosurg 1974;41:555–560. 17. Chen KT, Moseley D. Cartilage cells in cerebrospinal fluid. Arch Pathol Lab Med 1990;114:212. 18. Craver RD, Carson TH. Hematopoietic elements in cerebrospinal fluid in children. Am J Clin Pathol 1991;95:532–535. 19. Thompson EJ. Proteins of the Cerebrospinal Fluid. Analysis and Interpretation in the Diagnosis and Treatment of Neurological Disease, second edition. Amsterdam: Elsevier Academic Press; 2005. 20. Felgenhauer K. Protein size and cerebrospinal fluid composition. Klin Wochenschr 1974;36:66–69. 21. Griffin DE, Giffels J. Study of protein characteristics that influence entry into the cerebrospinal fluid of normal mice and mice with encephalitis. J Clin Invest 1982;70:289–295. 22. Cutler RWP, Watters GV, Hammerstad JP. The origin and turnover of cerebrospinal fluid albumin and gamma globulin in man. J Neurol Sci 1970;10:259–268. 23. Widell S. On the cerebrospinal fluid in normal children and patients with acute bacterial meningoencephalitis. Acta Paediatr 1958;Suppl 115:1–102. 24. Dencker SJ. Variation of total cerebrospinal fluid proteins and cells with sex and age. World Neurol 1962;3:778–780. 25. Tourtellotte WW, Haerer AF, Heller GL. Post-Lumbar Puncture Headaches. Springfield, IL: Charles C. Thomas; 1964. 26. Laterre EC. Les Protéines du Liquide Céphalorachidien a L’état Normal et Pathologique. Bruxelles: Editions Arscia; Paris: Librarie Maloine; 1965:148–161. 27. Cosgrove JB, Agius P. Studies in multiple sclerosis. II. Comparison of the beta-gamma globulin ratio, gamma globulin elevation, and first zone colloidal gold curve in the cerebrospinal fluid. Neurology 1966;16:197–204. 28. Gillard O. Lumbar cerebrospinal fluid total protein in healthy subjects. Acta Neurol Scand 1967;43:526–529. 29. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: W.B. Saunders; 1938. 30. Fishman RA, Ransohoff J, Osserman EF. 1958. Factors influencing the concentration gradient of protein in cerebrospinal fluid. J Clin Invest 37:1419–1428. 31. Weisner B, Bernhardt W. 1978. Protein fractions of lumbar, cisternal, and ventricular cerebrospinal fluid. J Neurol Sci 37:205–214. 32. McGale EHF, Pye IF, Stonier C, Hutchinson EC, Aber GM. Studies of the interrelationship between cerebrospinal fluid and plasma amino acid concentrations in normal individuals. J Neurochem 1977;29:291–297. 33. Hagenfeldt L, Bjerkenstedt L, Edman G, Sedvall G, Wiesel FA. Amino acids in plasma and CSF and monoamine metabolites in CSF: interrelationships in healthy subjects. J Neurochem 1984;42:833–837. 34. Heiblim DI, Evans HE, Glass L, Agbayani MM. Child neurology: amino acid concentrations in cerebrospinal fluid. Arch Neurol 1978;35: 765–768.

35. Werner MA. A combined procedure for protein estimation and electrophoresis of cerebrospinal fluid. J Lab Clin Med 1969;74: 166–173. 36. Schultze HE, Heremans JF. Molecular Biology of the Human Proteins, Volume I. Amsterdam: Elsevier; 1966, pp.732–761. 37. Fishman RA, Ransohoff J, Osserman EF. Factors influencing the concentration gradient of protein in cerebrospinal fluid. J Clin Invest 1958;37:1419–1424. 38. Grubb A. Diagnostic value of analysis of cystatin C and protein HC in biological fluids. Clin Nephrol 1992;38 Suppl:S20–S27. 39. Yamada T, Mukaiyama I, Miyake N, Igari J. Measurement of cystatin C in cerebrospinal fluid. Rinsho Byori 2002;50:613–617. 40. Nerenberg ST, Prasad R, Rothman ME. Cerebrospinal fluid IgG, IgA, IgM, IgD, and IgE levels in central nervous system disorders. Neurology 1978;28:988–990. 41. Tibbling G, Link H, Ohman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385–390. 42. Delpech B, Lichtblau F. Etude quantitative des immunoglobulines G et de l’albumine du liquide céphalo-rachidien. Clin Chim Acta 1972;37:15–23. 43. Olsson JE, Pettersson B. A comparison between agar gel electrophoresis and CSF serum quotients of IgG and albumin in neurological diseases. Acta Neurol Scand 1976;53:308–322. 44. Sharief MK, Hentges R, Thomas E. Significance of CSF immunoglobulins in monitoring neurologic disease activity in Behçet’s disease. Neurology 1991;41:1398–1401. 45. Kenney K, Brechtel C, Takahashi H, Kurohara K, Anderson P, Gibbs CJ. An enzyme-linked immunosorbent assay to quantify 14–3-3 proteins in the cerebrospinal fluid of suspected Creutzfeldt-Jakob disease patients. Ann Neurol 2000;48:395–398. 46. Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C. Patients with amytrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 1996;67:2013–2018. 47. Petzold A, Keir G, Green AJ, Giovannoni G, Thompson EJ. A specific ELISA for measuring neurofilament heavy chain phosphoforms. J Immunol Methods 2003;278:179–190. 48. Casmiro M, Maitan S, De Pasquale F, Cova V, Scarpa E, Vignatelli L; NSE Study Group. Cerebrospinal fluid and serum neuron-specific enolase concentrations in a normal population. Eur J Neurol 2005;12:369–374. 49. Petzold A, Keir G, Green AJ, Giavannoni G, Thompson EJ. An ELISA for glial fibrillary acidic protein. J Immunol Methods 2004;287:169–177. 50. Green AJ, Keir G, Thompson EJ. A specific and sensitive ELISA for measuring S-100B in cerebrospinal fluid. J Immunol Methods 1997;205:35–41. 51. Beems T, Simons KS, Van Geel WJ, De Reus HP, Vos PE, Verbeek MM. Serum- and CSF-concentrations of brain specific proteins in hydrocephalus. Acta Neurochir (Wien) 2003;145:37–43. 52. Bilic E, Bilic E, Rudan I, et al. Comparison of the growth hormone, IGF1, and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls. Eur J Neurol 2006;13:1340–1345. 53. Peskind ER, Wilkinson CW, Petrie EC, Schellenberg GD, Raskind MA. Increased CSF cortisol in AD is a function of APOE genotype. Neurology 2001;56:1094–1098. 54. Zheng W, Lu Y-M, Lu G-Y, Zha Q, Cheung O, Blaner WS. Transthyretin, thyroxine, and retinol-binding protein in human cerebrospinal fluid: effect of lead exposure. Toxicol Sci 2001;61:107–114. 55. Rousseau A, Petren S, Plannthin J, Eklundh T, Nordin C. Serum and cerebrospinal fluid concentrations of melatonin: a pilot study in healthy male volunteers. J Neural Transm 1999;106:883–888. 56. Kaneko T, Shirakami G, Nakao K, et al. C-type natriuretic peptide (CNP) is the major natriuretic peptide in human cerebrospinal fluid. Brain Res 1993;612:104–109.

References

57. Mathe AA, Agren H, Wallin A, Blennow K. Calcitonin gene-related peptide and calcitonin in the CSF of patients with dementia and depression: possible disease markers. Prog Neuro-Psychopharm Biol Psychiatry 2002;26:41–48. 58. Taiwo OB, Russell IJ, Mignot E, et al. Normal cerebrospinal fluid levels of hypocretin-1 (orexin A) in patients with fibromyalgia syndrome. Sleep Med 2007;8:260–265. 59. Altemus M, Jacobson KR, Debellis M, et al. Normal CSF oyxtocin and NPY levels in OCD. Biol Psychiatry 1999;45:931–933. 60. Bjorkqvist M, Leavitt BR, Neilsen JE, et al. Cocaine- and amphetamineregulated transcript is increased in Huntington’s disease. Movement Disorders 2007;22:1952–1954. 61. Banik NL, Hogan EL. Cerebrospinal fluid enzymes in neurological disease. In: Wood JH, ed. Neurobiology of Cerebrospinal Fluid, Vol. 2. New York: Plenum Press; 1983:205–231. 62. Stover JF, Lowitzsch K, Kempski OS. Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases. Neurosci Lett 1997;238:25–28. 63. Nussinovitch M, Prais D, Volovitz B, Amir J, Harel D, Nussinovich A. Reference values for lactate dehydrogenase activity and isoenzyme distribution in cerebrospinal fluid in neonates with fever but no evidence of cerebral disease. Am J Perinatol 2002;19:109–114. 64. Dalens B, Viallard JL, Raynaud EJ, Dastugue B. Enzyme studies and neonatal brain damage. Acta Paediatr Scand 1981;70:743–749. 65. Vazquez MD, Sanchez-Rodriguez F, Osuna E, et al. Creatine kinase BB and neuron-specific enolase in cerebrospinal fluid in the diagnosis of brain insult. Am J Forensic Med Pathol 1995;16:210–214. 66. Coplin WM, Longstreth WT, Lam AM, et al. Cerebrospinal fluid creatine kinase-BB isoenzyme activity and outcome after subarachnoid hemorrhage. Arch Neurol 1999;56:1348–1352. 67. Lescuyer P, Gandini A, Burkhard PR, Hochstrasser DF, Sanchez J-C. Prostaglandin D2 synthetase and its post-translational modifications in neurological disorders. Electrophoresis 2005;26:4563–4570. 68. Kanekiyo T, Ban T, Aritake K, et al. Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid. Proc Natl Acad Sci USA 2007;104:6412–6417. 69. Rapaport MH, McAllister CG, Pickar D, Tamarkin L, Kirch DG, Paul SM. CSF IL-1 and IL-2 in medicated schizophrenic patients and normal volunteers. Schizophr Res 1997;25:123–129. 70. Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003;74:1200–1205. 71. Stoeck K, Bodemer M, Ciesielczyk B, et al. Interleukin 4 and interleukin 10 levels are elevated in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Arch Neurol 2005;62:1591–1594. 72. Steensberg A, Dalsgaard MK, Secher NH, Pedersen BK. Cerebrospinal fluid IL-6, HSP72, and TNF-α in exercising humans. Brain Behav Immun 2006;20:585–589. 73. Brisby H, Olmarker K, Larsson K, Nutu M, Rydevik B. Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica. Eur Spine J 2002;11:62–66. 74. Natelson BH, Weaver SA, Tseng C-L, Ottenweller JE. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clin Diagn Lab Immunol 2005;12:52–55. 75. Li X, Miyajima M, Jiang C, Arai H. Expression of TGF-βs and TGF-β type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus. Neurosci Lett 2007;413:141–144. 76. Pashenkov M, Soderstrom M, Huang YM, Link H. Cerebrospinal fluid affects phenotype and functions of myeloid dendritic cells. Clin Exp Immunol 2002;128:379–387. 77. Taylor AW, Streilein JW. Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation 1996;3:112–118. 78. Franciotta D, Zardini E, Ravaglia S, et al. Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis. J Neurol Sci 2006;247:202–207.

87

79. Rancan M, Bye N, Otto VI, et al. The chemokine fractalkine in patients with severe traumatic brain injury and a mouse model of closed head injury. J Cereb Blood Flow Metab 2004;24:1110–1118. 80. Rupprecht TA, Koedel U, Muhlberger B, Wilske B, Fontana A, Pfister HW. CXCL11 is involved in leukocyte recruitment to the central nervous system in neuroborreliosis. J Neurol 2005;252:820–823. 81. Yushchenko M, Weber F, Mader M, et al. Matrix metalloproteinase-9 (MMP-9. in human cerebrospinal fluid (CSF): elevated levels are primarily related to CSF cell count. J Neuroimmunol 2000;110:244–251. 82. Rodriguez M, Wynn DR, Kimlinger TK, Katzmann JA. Terminal component of complement (C9) in the cerebrospinal fluid of patients with multiple sclerosis and neurologic controls. Neurology 1990;40:855–857. 83. Jongen PJH, Doesburg WH, Ibrahim-Stappers LJM, Lemmens WAJG, Hommes OR, Lamers KJB. Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system. Acta Neurol Scand 2000;101:116–121. 84. Loeffler DA, Brickman CM, Juneau PL, Perry MF, Pomara PN, Lewitt PA. Cerebrospinal fluid C3a increases with age, but does not increase further in Alzheimer’s disease. Neurobiol Aging 1997;18:555–557. 85. Henningsson AJ, Ernerudh J, Sandholm K, et al. Complement activation in Lyme neuroborreliosis – increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS. J Neuroimmunol 2007;183:200–207. 86. Shimetani N, Shimetani K, Mori M. Levels of three inflammation markers, C-reactive protein, serum amyloid A protein and procalcitonin, in the serum and cerebrospinal fluid of patients with meningitis. Scand J Clin Lab Invest 2001;61:657–574. 87. Rapoport SI, Schapiro MB, May C. Reduced brain delivery of homovanillic acid to cerebrospinal fluid during human aging. Arch Neurol 2004;61:1721–1724. 88. Lee J, Huang BX, Yuan Z, Kim H-Y. Simultaneous determination of salsolinol enantiomers and dopamine in human plasma and cerebrospinal fluid by chemical derivatization coupled to chiral liquid chromatography/electrospray ionization-tandem mass spectrometry. Anal Chem 2007;79:9166–9173. 89. Kalita J, Kumar S, Vijaykumar K, Palit G, Misra UK. A study of CSF catecholamine and its metabolites in acute and convalescent period of encephalitis. J Neurol Sci 2007;252:62–66. 90. Eklundh T, Eriksson M, Sjoberg S, Nordin C. Monoamine precursors, transmitters and metabolites in cerebrospinal fluid: a prospective study in healthy male subjects. J Psychiat Res 1996;30:201–208. 91. Frölich L, Dirr A, Götz ME, et al. Acetylcholine in human CSF: methodological considerations and levels in dementia of Alzheimer type. J Neural Transm 1998;105:961–973. 92. Vieira DSS, Naffah-Mazacoratti MG, Zukerman E, et al. Cerebrospinal fluid GABA levels in chronic migraine with and without depression. Brain Res 2006;1090:197–201. 93. Molina JA, Gomez P, Vargas C, et al. Neurotransmitter amino acid in cerebrospinal fluid of patients with dementia with Lewy bodies. J Neural Transm 2005;112:557–563. 94. Vieira DSS, Naffah-Mazacoratti MG, Zukerman E, Senne Soares CA, Cavalheiro EA, Peres MFP. Glutamate levels in cerebrospinal fluid and triptans overuse in chronic migraine. Headache 2007;47:842–847. 95. Wray HL, Winegrad AI. Free fructose in human cerebrospinal fluid. Diabetologia 1966;2:82–85. 96. Kusmierz J, DeGeorge JJ, Sweeney D, May C, Rapoport SI. Quantitative analysis of polyols in human cerebrospinal fluid. J Chromatogr 1989;497:39–48. 97. Shetty HU, Holloway HW, Rapoport SI. Capillary gas chromatography combined with ion trap detection for quantitative profiling of polyols in cerebrospinal fluid and plasma. Anal Biochem 1995;224:279–285. 98. Huck JHJ, Verhoeven NM, Struys EA, Salomons GS, Jakobs C, van der Knaap M. Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 2004;74:745–751.

88

Chapter 10

●

Properties and Composition of Normal CSF

99. Tourtellotte WW, Haerer AF. Lipids in cerebrospinal fluid. XII. In multiple sclerosis and retrobulbar optic neuritis. Arch Neurol 1969;20:605–615. 100. Tichy J, Alling C, Dencker SJ, Svennerholm L. Fatty acid profiles of cerebrospinal fluid lipids in normals and chronic alcoholics. Scand J Clin Lab Invest 1970;25:191–197. 101. Illingworth DR, Glover J. The composition of lipids in cerebrospinal fluid of children and adults. J Neurochem 1971;18:769–776. 102. Trbojevic-Cepe M, Kracun I. Determination of gangliosides in human cerebrospinal fluid by high-performance liquid chromatography and direct densitometry. J Clin Chem Clin Biochem 1990;28:863–872. 103. Trbojevic-Cepe M, Kracun I, Jusic A, Pavlicek I. Gangliosides of human cerebrospinal fluid in various neurologic diseases. J Neurol Sci 1991;105:192–199. 104. Han X, Fagan AM, Cheng H, Morris JC, Xiong C, Holtzman DM. Cerebrospinal fluid sulfatide is decreased in subjects with incipient dementia. Ann Neurol 2003;54:115–119. 105. Han X, Cheng H, Fryer JD, Fagan AM, Holtzman DM. Novel role for apolipoprotein E in the central nervous system. Modulation of sulfatide content. J Biol Chem 2003;278:8043–8051. 106. Montine Tj, Sidell KR, Crews BC,et al. Elevated CSF prostaglandin E2 levels in patients with probable AD. Neurology 1999;53:1495–1498. 107. Vilanova JM, Figueras-Aloy J, Rosello J, Gomez G, Gelpi E, Jimenez R. Arachadonic acid metabolites in CSF in hypoxic-ischemic encephalopathy of newborn infants. Acta Paediatr 1998;87:588–592. 108. Nishino S, Mignot E, Benson KL, Zarcone VP. Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls. Psych Res 1998;78:141–150. 109. Rebeck GW, Alonzo NC, Berezovska O, et al. Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes. Exp Neurol 1998;149:175–182. 110. Koch S, Donarski N, Goetze K,et al. Characterization of four lipoprotein classes in human cerebrospinal fluid. J Lipid Res 2001;42:1143–1151. 111. Hesse C, Larsson H, Fredman P, et al. Measurement of apolipoprotein E (apoE) in cerebrospinal fluid. Neurochem Res 2000;25:511–517. 112. Kay A, Petzold A, Kerr M, Keir G, Thompson E, Nicoll J. Temporal alterations in cerebrospinal fluid amyloid β-protein and apolipoprotein E after subarachnoid hemorrhage. Stroke 2003;34:e240–e243. 113. Kay A, Petzold A, Kerr M, Keir G, Thompson E, Nicoll J. Decreased cerebrospinal fluid apolipoprotein E after subarachnoid hemorrhage. Stroke 2003;34:637–642. 114. Bradbury MWB, Kleeman CR. Stability of the potassium content of cerebrospinal fluid and brain. Am J Physiol 1967;213:519–528. 115. Bourke RS, Nelson KM. Further studies on the K+-dependent swelling of the primate cerebral cortex in vivo: the enzymatic basis of the K+-dependent transport of chloride. J Neurochem 1972;19:663–685. 116. Sambrook MA, Hutchison EC, Aber GM. Metabolic studies after subarachnoid hemorrhage and strikes. II. Serial changes in cerebrospinal fluid and plasma electrolytes and osmolality. Brain 1973;96:191–202. 117. Paulson GW, Stickney D. Cerebrospinal fluid after death. Confin Neurol 1971;33:149–162. 118. Katzman R, Pappius HM. Brain Electrolytes and Fluid Metabolism. Baltimore: Williams and Wilkins; 1973. 119. Tai CY, Smith QR, Rapoport SI. Calcium influx into brain and cerebrospinal fluid are linearly related to plasma ionized calcium concentration. Brain Res 1986;385:227–236. 120. Fishman RA. Neurological manifestations of magnesium metabolism. Arch Neurol 1965;12:562–569. 121. Conner JR, Menzies SL. Cellular management of iron in the brain. J Neurol Sci 1995;134 Suppl:33–44. 122. LeVine SM, Lynch SG, Ou C-N, Wulser MJ, Tam E, Boo N. Ferratin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients. Brain Res 1999;821:511–515.

123. Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP. Abnormalities in CSF concentrations of ferratin and transferrin in restless leg syndrome. Neurology 2000;54:1698–1700. 124. Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J. CSF iron, ferratin and transferrin levels in restless legs syndrome. J Sleep Res 2005;14:43–47. 125. Stuerenburg HJ, Oechsner M, Schroeder S, Kunze K. Determinants of copper concentration in cerebrospinal fluid. J Neurol Neurosurg Psychiatry 1999;67:252–253. 126. Melo TM, Larsen C, White LR, et al. Manganese, copper and zinc in cerebrospinal fluid from patients with multiple sclerosis. Biol Trace Elem Res 2003;93:1–8. 127. Forte G, Bocca B, Senofonte O, et al. Trace and major elements in whole blood, serum, cerebrospinal fluid and urine of patients with Parkinson’s disease. J Neural Transm 2004;111:1031–1040. 128. Paradowski M, Lobos M, Kuydowicz J, Krakowiak M, Kubasiewicz-Ujma B. Acute phase proteins in serum and cerebrospinal fluid in the course of bacterial meningitis. Clin Biochem 1995;28:459–466. 129. Stuerenburg HJ. CSF copper concentrations, blood-brain barrier function, and ceruloplasmin synthesis during the treatment of Wilson’s disease. J Neural Transm 2000;107:321–329. 130. Tabassi A, Salmasi AH, Jalali M. Serum and CSF vitamin A concentrations in idiopathic intracranial hypertension. Neurology 2005;64:1893–1896. 131. Spector R, Johanson CE. Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E. J Neurochem 2007;103:425–438. 132. Spector R, Johanson C. Micronutrient and urate transport in choroid plexus and kidney: implications for drug therapy. Pharm Res 2006;23:2515–2524. 133. Spector R. Micronutrient homeostasis in mammalian brain and cerebrospinal fluid. J Neurochem 1989;53:1667–1674. 134. Nijst TQ, Mevers RA, Schoonderwaldt HC, Hommes OR, de Haan AF. Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia. J Neurol Neurosurg Psychiatry 1990;53:951–954. 135. Balabanova S, Richter HP, Antoniadis G, et al. 25-Hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D in human cerebrospinal fluid. Klin Wochenschr 1984;62:1086–1090. 136. Vatassery GT, Nelson MJ, Maletta GJ, Kuskowski MA. Vitamin E (tocopherols) in human cerebrospinal fluid. Am J Clin Nutr 1991;53:95–99. 137. Vatassery GT, Fahn S, Kuskowski MA. Alpha tocopherol in CSF of subjects taking high-dose vitamin E in the DATATOP study. Neurology 1998;50:1900–1902. 138. Muting D, Heinze J, Reikowski J, Betzien G, Schwarz M, Schmidt FH. Enzymatic ammonia determinations in the blood and cerebrospinal fluid of healthy persons. Clin Chem Acta 1968;19:391–395. 139. Huizenga JR, Teelken AW, Tangerman A, de Jager AE, Gips CH, Jansen PL. Determination of ammonia in cerebrospinal fluid using the indophenol direct method. Mol Chem Neuropathol 1998;34:169–177. 140. Nybo L, Dalsgaard MK, Steensberg A, Moller K, Secher NH. Cerebral ammonia uptake and accumulation during prolonged exercise in humans. J Physiol 2005;563:285–290. 141. Bradbury MWB, Stubbs J, Hughes IE, Parker P. The distribution of potassium, sodium, chloride and urea between lumbar cerebrospinal fluid and blood serum in human subjects. Clin Sci 1963;25:97–105. 142. Swahn CG, Sedvall G. CSF creatinine in schizophrenia. Biol Psychiatry 1988;23:586–594. 143. De Deyn PP, Marescau B, Cuykens JJ, Van Gorp L, Lowenthal A, De Potter WP. Guanidino compounds in serum and cerebrospinal fluid of non-dialyzed patients with renal insufficiency. Clin Chim Acta 1987;167:81–88. 144. Gerrits GPJ, Haagen AAM, De Abreu RA, et al. Reference values for nucleosides and nucleobases in cerebrospinal fluid of children. Clin Chem 1988;34:1439–1442.

References

145. Rodriguez-Nunez A, Cid E, Rodriguez-Garcia J, Camina F, RodriguezSegade S, Castro-Gago M. Neuron-specific enolase, nucleotides, nucleosides, purine bases, oxypurines and uric acid concentrations in cerebrospinal fluid of children with meningitis. Brain Dev 2003;25:102–106. 146. Stover JF, Lowitzsch K, Kempski OS. Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases. Neurosci Lett 1997;238:25–28. 147. Fleischer AS, Rudman DR, Fresh CB, Tindall GT. Concentration of 3′,5′ cyclic adenosine monophosphate in ventricular CSF of patients following severe head trauma. J Neurosurg 1977;47:517–524. 148. Maida E, Kristoferitsch W. Cyclic adenosine 3′,5′ monophosphate in cerebrospinal fluid of multiple sclerosis patients. J Neurol 1981;225:145–151. 149. Cramer H, Schindler E. Cyclic nucleotides in cerebrospinal fluid of patients with intracranial and spinal tumors. Acta Neurol Scand 1982;65:174–181. 150. Papageorgiou C, Gyftaki H, Mavrikakis M, Kesse-Elias M, AlevizouTerzaki V, Kondou I. Cerebrospinal fluid cyclic adenosine 3′,5′monophosphate in cases of severe cerebral ischemia and meningitis. Eur Neurol 1983;22:12–16. 151. Lerche A, Svenson M, Wiik A. Cerebrospinal fluid levels of cyclic nucleotides in meningitis and idiopathic polyneuritis. Acta Neurol Scand 1984;69:168–175. 152. Buttner T, Hornig CR, Busse O, Dorndorf W. CSF cyclic AMP and CSF adenylate kinase in cerebral ischaemic infarction. J Neurol 1986;233:297–303. 153. Martinez M, Fernandez E, Frank A, Guaza C, de la Fuente M, Hernanz A. Increased cerebrospinal fluid cAMP levels in Alzheimer’s disease. Brain Res 1999;846:265–267. 154. Tsang D, Lai S, Sourkes TL, Ford RM, Aronoff A. Studies on cyclic AMP in different compartments of cerebrospinal fluid. J Neurol Neurosurg Psychiatry 1976;39:1186–1190. 155. Volicer L, Beal MF, Direnfeld LK, Marquis JK, Albert ML. CSF cyclic nucleotides and somatostatin in Parkinson’s disease. Neurology 1986;36:89–92. 156. Ikeda M, Sato I, Matsunaga T, Takahashi M, Yuasa T, Murota S. Cyclic guanosine monophosphate (cGMP), nitrite and nitrate in the cerebrospinal fluid in meningitis, multiple sclerosis and Guillain-Barré syndrome. Intern Med 1995;34:734–737. 157. Navarro JA, Jimenez-Jimenez FJ, Molina JA, et al. Cerebrospinal fluid cyclic guanosine 3′5′ monophosphate levels in Parkinson’s disease. J Neurol Sci 1998;155:92–94. 158. Ilecka J. Decreased cerebrospinal fluid cGMP levels in patients with amotrophic lateral sclerosis. J Neural Transm 2004;111:167–172. 159. Eells JT, Spector R. Purine and pyrimidine base and nucleoside concentrations in human cerebrospinal fluid and plasma. Neurochem Res 1983;8:1451–1457. 160. Macdonald RL, Weir BK, Marton LS, et al. Role of adenosine 5′-triphosphate in vasospasm after subarachnoid hemorrhage: human investigations. Neurosurgery 2001;48:854–862.

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161. Al-Khalidi HAS, Chaglassian TH. The species distribution of xanthine oxidase. Biochem J 1965;97:316–320. 162. Naschberger E, Lubeseder-Martellato C, Meyer N, et al. Human guanylate binding protein-1 is a secreted GTPase present in increased concentrations in the cerebrospinal fluid of patients with bacterial meningitis. Am J Pathol 2006;169:1088–1099. 163. Posner JB, Plum F. Independence of blood and cerebrospinal fluid lactate. Arch Neurol 1967;16:492–496. 164. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 1999;343:281–299. 165. Zupping R, Kaasick AE, Ravdam E. Cerebrospinal fluid metabolic acidosis and brain oxygen supply. Studies in patients with brain infarction. Arch Neurol 1971;23:33–38. 166. Siesjo BK. Brain Energy Metabolism. New York: John Wiley & Sons; 1978:607. 167. Parnetti L, Reboldi G, Gallai V. Cerebrospinal fluid pyruvate levels in Alzheimer’s disease and vascular dementia. Neurology 2000;54:735–737. 168. Benoist J-F, Alberti C, Leclercq S, et al. Cerebrospinal fluid lactate and pyruvate concentrations and their ratio in children: age-related reference intervals. Clin Chem 2003;49:487–494. 169. Blau N, Bonafe L, Krageloh-Mann I, et al. Cerebrospinal fluid pterins and folates in Aicardi-Goutieres syndrome. Neurology 2003;61:642–647. 170. Leeming RJ, Blair JA, Melikian V, O’Gorman DJ. Biopterin derivatives in human body fluids and tissues. J Clin Path 1976;29:444–451. 171. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 2005;352:1985–1991. 172. Ormazabal A, Garcia-Cazorla A, Perez-Duenas B, et al. Determination of 5-methyltetrahydrofolate in cerebrospinal fluid of pediatric patients: reference values for a pediatric population. Clin Chim Acta 2006;371:159–162. 173. Obeid R, Kostopoulos P, Knapp J-P, Kasoha M, Becker G, Fassbender K, Herrmann W. Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. Clin Chem 2007;53:326–333. 174. Plum F, Price RW. Acid-base balance of cisternal and lumbar cerebrospinal fluid. N Engl J Med 1973;289:1346–1350. 175. Mitchell RA, Carman CT, Severinghaus JW, Richardson BW, Singer MM, Shnider S. Stability of cerebrospinal fluid pH in chronic acidbase disturbances in blood. J Appl Physiol 1965;20:443–452. 176. Mitchell RA, Herbert DA, Carman CT. Acid-base constants and temperature coefficients for cerebrospinal fluid. J Appl Physiol 1965;20:27–30. 177. Sambrook MA, Hutchinson EC, Aber GM. Metabolic studies in subarachnoid hemorrhage and strokes. I. Serial changes in acid-base values in blood and cerebrospinal fluid. Brain 1973;96:171–190. 178. Hermansen MC, Ellison PH. Cerebrospinal fluid acid-base balance in newborns. Ann Neurol 1982;11:344–346. 179. Siesjo BK. The regulation of cerebrospinal fluid pH. Kidney Int 1972;1:360–374.

CHAPTER

11

Developmental Disorders Constance Smith-Hicks and Gerald V. Raymond

INTRODUCTION Disorders of development may be broadly divided into two groups: those causing psychomotor retardation (developmental delay) and those causing actual neurodevelopmental regression. Many are genetic conditions that cause altered enzymatic activity and abnormal neuronal or glial cell metabolism. Regarding the role of cerebrospinal fluid (CSF) analysis in the diagnosis of neurodevelopmental disorders, some conditions show findings that are essential to establish the diagnosis, while others reveal changes that reflect biochemical findings also present in other tissues. Still, CSF analysis may offer the first clue to such a developmental abnormality. Furthermore, longitudinal studies performed on CSF samples may give important clues to a previously undiagnosed condition. To date, direct biochemical assays performed on CSF have been a standard approach in the diagnosis of many of these diseases. However, other laboratory techniques are being developed which may give important information on the biochemistry of the underlying brain. In this chapter, we will discuss CSF abnormalities as they apply to the diagnosis of disorders of development, with particular emphasis on those diseases where such changes can confirm the disorder in question.

Very low CSF glucose and lactate levels in the absence of hypoglycemia confirmed a defect in CNS glucose transport and led to the identification of defects in the GLUT-1 gene. Since then, two other presentations – mental retardation, dysarthric speech, and intermittent ataxia without seizures and choreoathetosis and dystonia – have been identified.1 An initial diagnosis of Glut-1 deficiency relies on clinical suspicion and CSF evaluation. The CSF glucose concentration is typically less than 40% of the simultaneous serum glucose level. CSF lactate is also usually depressed, albeit to varying degrees. Uptake of 3-O-methyl-D-glucose into erythrocytes is impaired, and this assay can be used to confirm a glucose transporter defect. Genetic evaluation has now demonstrated missense, nonsense, insertion, and deletion mutations in GLUT-1, located on the short arm of chromosome 1. Phenotypic diversity in this disorder has been linked to the variable effects of individual mutations on overall Glut-1 function.1 Interestingly, this carrier is also responsible for the transport of dehydroascorbic acid (the oxidized form of vitamin C) into the brain.3 This molecule can protect cells from oxidative injury in vitro, but its role in the pathogenesis of Glut-1 deficiency is unknown.4

Disorders of electron transport and mitochondrial cytopathies DEVELOPMENTAL DISORDERS WITH PATHOGNMONIC CSF ABNORMALITIES Glucose transporter (Glut-1) deficiency Glucose is the primary source of energy for the central nervous system (CNS) and its presence in the brain is the result of active transport across the blood–brain barrier (BBB). The glucose transporter-1 (Glut-1) protein on cerebrovascular endothelial cells is the main mediator of this process. In 1991, two patients were described with an epileptic encephalopathy that began in the first months of life and caused acquired microcephaly and spasticity.1,2

Disorders of pyruvate metabolism and mitochondrial electron transport commonly result in the accumulation of lactic and pyruvic acid in various tissues and body fluids. The tissues most sensitive to mitochondrial dysfunction are the brain, heart, skeletal muscle, endocrine system, and kidney.5 Because of tissue variability, CSF lactate and pyruvate levels may exceed those in the peripheral circulation (or be elevated when peripheral levels are normal), making it important to assay this fluid in a clinical setting suspicious for such a disorder. The more common mitochondrial disorders include mitochondrial encephalopathy with lactic acidosis and

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stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), Leigh syndrome, pyruvate dehydrogenase deficiency (PDHD), and Kearns-Sayre syndrome. In Kearns-Sayre syndrome, the classic, maternally inherited mitochondrial disorder, CSF protein levels are invariably greater than 100 mg/dl, CSF lactate and pyruvate levels are commonly increased, and CSF folic acid levels are reduced.6–9 In most other mitochondrial disorders, CSF cell counts as well as protein and glucose concentrations are normal despite significant elevations in CSF and serum lactate levels. In one study of patients suspected of having an electron transport chain disorder, CSF and venous blood lactate levels were measured in 11 children aged 0.1–17.5 years compared to 39 age-matched controls. Here, CSF lactate levels were >3.0 mmol/l in 8 of the 11 with electron chain defects (range, 3.0–6.0 mmol/l) and normal in 2 of 11 cases. Control values ranged from 0.8 to 2.2 mmol/l (mean, 1.41 mmol/l).10 Still, it is important to recognize that other disorders not directly associated with defects in energy metabolism may also have elevated CSF lactate levels. Thus, CSF lactic acidosis has been reported in both nonketotic hyperglycinemia and in biotinidase deficiency.10,11

Nonketotic hyperglycinemia Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder of glycine metabolism caused by a defect in the multiprotein glycine cleavage enzyme complex. Glycine, an important inhibitory neurotransmitter, accumulates with devastating consequences. The majority of patients present in the neonatal period with encephalopathy, hypotonia, and myoclonus. Longer-term survivors develop intractable seizures and profound mental retardation. There are also reports of late-onset variants characterized by spasticity, optic atrophy, seizures, and cognitive impairment.12 In classical neonatal NKH, CSF levels of glycine are very elevated. Significant increases in serum glycine levels are often seen as well, although these levels may be normal in affected patients, mandating the need for CSF examination. A CSF/serum glycine ratio of >0.08 is considered diagnostic for the disorder and requires that both samples be obtained simultaneously. In a study by Hamosh and Johnston, 25 cases of confirmed neonatal NKH had mean CSF glycine levels of 368 μmol/l, with a range of 83–1927 μmol/l and a mean CSF/plasma glycine ratio of 0.23 (range 0.07–0.70).13 CSF lactate was found to be elevated in two patients with NKH with levels of 3.5 and 5.8 mmol/l, respectively.10 Diagnostic confirmation may be obtained by DNA analysis.14,15 The enzyme system for cleavage of glycine is confined to the mitochondria and is composed of four protein components. Most patients with NKH have a defect in the glycine decarboxylase subunit, but other mutations have been seen as well.13

3-Phosphoglycerate dehydrogenase deficiency 3-Phosphoglycerate dehydrogenase deficiency is a rare inborn error of serine biosynthesis characterized by hypomyelination, congenital microcephaly, psychomotor retardation, and intractable seizures.16 A diagnosis is made by analyzing CSF amino acid levels, with the characteristic abnormalities best appreciated in the fasting state. The typical pattern reveals low levels of serine, glycine, and 5-methyltetrahydrofolate. de Koning et al. reported findings in two brothers with this disorder. CSF levels of serine were 6 μmol/l and 8 μmol/l (control, 38±2 μmol/l), while CSF glycine levels were 1 μmol/l and 4 μmol/l (control, 7± 2 μmol/l), respectively.17 CSF 5-methyltetrahydrofolate levels were also reduced in each sibling at 24 nmol/l and 5 nmol/l (control, 41–117 nmol/l).17 Other important features were that plasma serine and glycine levels were normal, as were measurements of urine organic acids and amino acids. Treatment with L-serine led to a reduction in seizures.17

Disorders of monoamine neurotransmitter metabolism The monoamine neurotransmitters include serotonin, dopamine, and norepinephrine. Developmental disorders related to aberrant monoamine neurotransmission include the dopa-responsive dystonias (DRD), aromatic L-amino acid decarboxylase deficiency, and tyrosine hydroxylase deficiency.18,19 Also included are disorders related to tetrahydrobiopterin metabolism, a cofactor required for hydroxylation of the aromatic amino acids tyrosine and tryptophan, in the synthesis of dopamine and serotonin. Tetrahydrobiopterin also impacts on the activity of nitric oxide synthase in the oxidation of arginine to nitric oxide, and it is required for hepatic phenylalanine hydroxylation, so certain defects may cause elevations of phenylalanine and one form of phenylketonuria.18 Emphasis here will be placed on those disorders that require CSF analysis for diagnosis. DRDs are genetically heterogeneous disorders caused by mutations in various enzymes involved in the biosynthesis of dopamine: GTP-cyclohydrolase I (GCH1), tyrosine hydroxylase, or sepiapterin reductase (SR). These conditions are characterized by the signs and symptoms related to monoamine neurotransmitter deficiency, the usual being a childhood-onset dystonia that prominently affects gait and shows a beneficial response to L-dopa replacement. The most informative biochemical investigations in patients with DRD are measurement of the pterins (neopterin and biopterin) and neurotransmitter metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), the metabolites of dopamine and serotonin respectively, in CSF (Table 11-1). Both neopterin and biopterin have been found to be significantly reduced in CSF of patients with DRD, while a decrease in the levels of 5-HIAA is a frequent, but not an invariable, finding.19,20 SR deficiency, on the other hand, causes CSF pterin levels to be elevated and results in very low 5-HIAA concentrations (Table 11-1).19,20

Developmental Disorders with Pathognmonic CSF Abnormalities

Table 11-1 CSF Levels of Various Pterin and Monoamine Neurotransmitter Metabolites in Patients with DRD and SR Deficiency Compared to Controls Metabolite (nmol/l)

GCH1 Deficiency (n=13)

Neopterin Biopterin Dihydrobiopterin 5-HIAA HVA HVA/5-HIAA

1.1–6.2 3.1–7.6 Normal 48–97 120–239 Normal

Age-Matched SR Deficiency Controls (n=3) (n=37) Normal 77–83 35–57 4–14 49–111 4.1–12.3

9–20 10–34 14 105–500 210–900 1.5–3.5

(Adapted from Blau N, Bonafe L, Thony B. Tetrahyrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 2001;74:172–185.)

The most common cause of DRD is the autosomal dominant GCH1 deficiency, or Segawa’s disease. Individuals present with a dystonic gait, although torticollis and arm dystonia have also been reported. It is treatable with small oral doses of carbidopa/levodopa. Other forms of DRD are autosomal recessive and usually have an earlier onset, but also generally respond to therapy. Aromatic L-amino acid decarboxylase deficiency is an autosomal recessive disorder involving an enzyme that decarboxylates L-dopa and 5-hydroxytryptophan to make dopamine and serotonin.21 Children present in the first months of life with dystonia, truncal hypotonia, oculogyric crises, autonomic instability, and impaired voluntary movements.21 Here, CSF neurotransmitter metabolites show a characteristic pattern of low HVA and 5-HIAA levels, and high concentrations of 5-hydroxytryptophan and L-dopa. CSF biopterin and neopterin levels are normal.21

Disorders of GABA metabolism Gamma-aminobutyric acid (GABA) is a major inhibitory amino acid neurotransmitter of the CNS. Hereditary impairments of GABA metabolism, typically transmitted as autosomal recessive disorders, include GABA transaminase (GABA-T) deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency, and homocarnosinosis.22–24 These disorders share common clinical features including developmental delay/regression, hypotonia, encephalopathy, and seizures. A diagnosis of GABA-T deficiency is suggested when CSF amino acid analysis shows a significant elevation of both GABA and β-alanine levels. Plasma concentrations can be high as well, but not typically to the same degree. The diagnosis is confirmed by measuring GABA-T activity in the liver or in lymphocytes isolated from whole blood.22–24 SSADH deficiency causes defective conversion of GABA to succinic acid resulting in accumulation of gammahydroxybutyrate (GHB). Levels of this metabolite are increased up to 1,200-fold in CSF, but high concentrations are also found in plasma and urine.22–24 Specialized proton magnetic resonance spectroscopy (MRS) techniques have

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confirmed elevated brain levels of GABA and GNB in both gray and white matter of patients with this disorder.25 This technique can therefore serve as a non-invasive means to both diagnose the disease and to monitor the effectiveness of treatment interventions. Although no standard therapy at present exists, vigabatrin (an irreversible inhibitor of GABA-T) can decrease CSF GHB levels by more than 70% compared to pretreatment baselines.26 Homocarnosine is a brain-specific dipeptide of GABA and histidine. Patients with homocarnosinosis, likely due to hereditary carnosinase deficiency, develop progressive spastic paraparesis between 6 and 29 years of age accompanied by mental deterioration and abnormal retinal pigmentation.22,23,27 These patients have high homocarnosine and normal carnosine levels in CSF.23 Pyridoxine-dependent epilepsy, another rare autosomal recessive disorder, presents with seizures in the neonatal period. These events are unresponsive to the classic anticonvulsants, but they rapidly cease when intravenous pyridoxine is administered. A proposed link to GABA biosynthesis was that pyridoxal 5′-phosphate (PLP, the main active form of pyridoxine in humans) is a cofactor for the reaction that converts glutamate to GABA. Still, CSF levels of both GABA and glutamate have been inconclusive in these patients, and recent studies have instead shown that pipecolic acid (PA) consistently accumulates in the plasma and CSF of patients with this condition.28,29 This, in turn, has led to a clarification of the biochemical and genetic basis for this disorder: mutations of the gene encoding antiquitin causes its loss of function as an α-amino adipic semialdehyde (AASA) dehydrogenase in the cerebral lysine degradation pathway.30 This causes accumulation of piperideine-6-carboxylic acid (P6C) that inactivates PLP. Thus, elevated plasma, urine, and CSF levels of both PA and AASA prior to treatment with pyridoxine support the diagnosis and select patients for analysis of the antiquitin gene.

Collection of CSF for neurotransmitter-related studies The manner in which CSF is collected, processed, and stored in the diagnostic evaluation of suspected neurotransmitterrelated disorders is of particular importance for a variety of reasons. Samples should be frozen immediately on dry ice because many compounds are both highly labile and present in such small quantities that alterations secondary to degradation may dramatically affect the interpretation of results. Thus, tetrahydrobiopterin rapidly oxidizes to other species, while artifactual increases in free GABA levels may occur due to hydrolysis of homocarnosine. The lysis of any contaminating blood cells can accelerate the oxidation of the neurotransmitter metabolites, so samples should be centrifuged immediately and transferred to a new tube before freezing.19,23 Another issue pertains to the rostral–caudal gradient of many neurotransmitters and their increasing

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concentration in CSF as more sample is withdrawn from the lumbar thecal sac. For this reason, it is essential for certain assays that the same fraction of CSF be used for each metabolite analyzed, and that results be compared against age-matched reference ranges established using the same collection criteria.

biopterin (4.1 nmol/l; normal range, 10–30 nmol/l), as well as a reduced HVA concentration (266 nmol/l; normal range, 311–871 nmol/l) and suppressed HVA/5-HIAA ratio (1.21; normal, 1.5–3.5).33 This raises questions about whether low CSF pterins and impaired dopamine turnover are important secondary manifestations of LINCL.

DEVELOPMENTAL DISORDERS WITH ASSOCIATED CSF ABNORMALITIES

Menkes’ kinky hair disease

Among the many known neurodevelopmental disorders, a few show CSF changes that are highly associated with the condition even though such changes are of uncertain pathogenic significance. These include disorders such as AicardiGoutières syndrome (AGS), Menkes disease, and neuronal ceroid lipofuscinosis (NCL). Neurochemical abnormalities have also been found in the CSF of more static disorders such as Rett syndrome, Fragile X syndrome, and Down syndrome. These findings are not needed for diagnosis but it is hoped might give insight into the underlying pathogenesis of these conditions and those like them.

Aicardi-Goutières syndrome AGS is an autosomal recessive disease with onset in the first year of life. Clinical features include microcephaly, developmental delay, spasticity, seizures, and extrapyramidal signs.31 Radiographic and neuropathological studies reveal calcification in the white matter and deep gray nuclei. The CSF in AGS shows a chronic low-grade lymphocytosis (>5 cells/mm3) without evidence of infection and an elevated level of alpha-interferon (>30 U/ml).31 Blau et al. reported a phenotypic variant seen in three infants with onset before 6 months of age who all had clinical and radiographic features of the disease, but in whom CSF studies demonstrated normal cell counts and interferon levels.32 Serial samples from these patients were compared to three children with classic AGS aged 7–15 months and two age-matched controls. In both the classic and the variant cases, levels of neopterin and biopterin were elevated and concentrations of 5-methyltetrahydrofolate were reduced in CSF compared to controls.32 Furthermore, long-term treatment with folinic acid resulted in clinical recovery and normalization of CSF folate and pterin levels in one patient and clinical improvement in another, suggesting that a chronic activation of the tetrahydrobiopterin pathway is an early pathogenic event in this disorder.32

Late infantile neuronal ceroid lipofuscinosis Late infantile neuronal ceroid lipofuscinosis (LINCL) is characterized by myoclonic seizures and psychomotor regression. Barisic et al. reported a case of a child with classic LINCL where CSF analysis revealed very low levels of neopterin (7.3 nmol/l; normal range, 9–30 nmol/l) and

Menkes’ kinky hair disease is an X-linked disorder of copper metabolism. Boys present in the first weeks of life with neurological degeneration, kinky hair, and failure to thrive, and most progress to an early death. CSF catecholamine levels are distinctively abnormal, possibly because dopamine beta-hydroxylase requires copper to catalyze the conversion of dopamine to norepinepherine. In one study, plasma and CSF levels of catecholamine levels were measured in 10 patients ranging from 9 days to 27 months of age.34,35 Compared to controls, mean CSF levels of dopamine, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), and the catecholamine precursor dihydroxyphenylalanine (DOPA) were higher, while CSF levels of norepinephrine were normal and those of its neuronal metabolite dihydroxyphenylglycol (DHPG) were reduced.34 Most notably, the ratios of DOPA:DHPG and DOPAC:DHPG in CSF of Menkes’ disease patients were invariably increased, suggesting that this neurochemical pattern may serve as a biomarker against which the influence of future therapies can be judged.34,35

Pervasive development/autistic spectrum disorders Autism is a very common neurodevelopmental disorder characterized by impaired social, behavioral, and communication skills. It can be associated with mental retardation and epilepsy, and its symptoms are seen in as many as 10% of patients with specific genetic syndromes such as Rett syndrome and Fragile X syndrome. Most patients, however, do not have a diagnosed etiology. In a study by Vargas et al., CSF samples from six autistic patients aged 3–10 years were evaluated using a cytokine protein array system in comparison with samples from nine control patients without any evidence of CNS inflammatory disease. These data showed that multiple inflammatory mediators including monocyte chemoattractant protein (MCP)-1 (12-fold), interferon-gamma (232.5-fold), transforming growth factor (TGF)-beta2 (31-fold), and interleukin (IL)-8 (6-fold) among several others were significantly increased in the CSF of the autistic patients.36 In combination with neuropathological evidence of microglial and astrocytic activation in the brains of other patients found at the time of autopsy, these authors proposed that innate immune reactions may play a pathogenic role in autism and that future therapy might be aimed at modifying this neuroglial response within the brain.36,37

References

Other studies suggest that disturbances in serotonin homeostasis may play a role in the pathogenesis of autism. Ramaekers et al. described a novel neurodevelopmental syndrome with autistic features that is responsive to 5-hydroxytryptophan and carbidopa treatment.38 Five boys with hypotonia, delayed developmental milestones, learning deficits, and short attention spans underwent CSF neurotransmitter evaluation. CSF 5-HIAA values were 51–65% lower compared to age-matched controls, while tryptophan, 5-hydroxytryptophan, dopamine metabolites, as well as biopterin and neopterin levels were uniformly normal.38

NEUROIMAGING OF CSF METABOLITES Proton MRS techniques have confirmed altered brain levels of neurotransmitters and neurotransmitter metabolites in developmental disorders.25 Recently, however, this specialized imaging technique has been used to non-invasively measure select metabolic byproducts in ventricular CSF. In a child with a rare molybdenum cofactor deficiency syndrome, Nagae-Poetscher et al. recently demonstrated the ability to measure select metabolites including lactate, acetone, and an unusual compound, propan-1,2-diol, in CSF more readily than in brain, with levels that were corroborated by ex vivo analyses.39 Although the use of this technique is still in its very early stages, it promises a robust method to longitudinally and non-invasively measure multiple CSF metabolites in a clinically useful format.

CONCLUSIONS Despite exciting advances in genetics and neuroimaging, the utility of CSF examination in the diagnosis of neurodevelopmental disorders continues to be demonstrated. While many of the disorders discussed here may be diagnosed by specific biochemical or genetic evaluation of other fluid or tissues, the proper application of CSF assays provides a powerful screen to direct the clinician to the appropriate genetic test. For disorders that still lack a specific DNA test, CSF provides access to biochemical mediators that closely reflect the disordered pathways in the underlying brain. REFERENCES 1. Wang D, Pascual JM, Yang H, et al. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 2005;57:111–118. 2. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325:703–709. 3. Agus DB, Gambhir SS, Pardridge WM, et al. Vitamin C crosses the bloodbrain barrier in the oxidized form through the glucose transporters. J Clin Invest 1997;100:2842–2848. 4. KC S, Carcamo JM, Golde DW. Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J 2005;19:1657–1667.

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5. Wallace DC. Mitochondrial defects in neurodegenerative disease. Ment Retard Dev Disabil Res Rev 2001;7:158–166. 6. Pineda M, Ormazabal A, Lopez-Gallardo E, et al. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol 2006;59:394–398. 7. Kuriyama M, Suehara M, Marume N, et al. High CSF lactate and pyruvate content in Kearns-Sayre syndrome. Neurology 1984;34: 253–255. 8. Dougados M, Zittoun J, Laplane D, et al. Folate metabolism disorder in Kearns-Sayre syndrome. Ann Neurol 1983;13:687. 9. Allen RJ, DiMauro S, Coulter DL, et al. Kearns-Sayre syndrome with reduced plasma and cerebrospinal fluid folate. Ann Neurol 1983;13:679–682. 10. Hutchesson A, Preece MA, Gray G, et al. Measurement of lactate in cerebrospinal fluid in investigation of inherited metabolic disease. Clin Chem 1997;43:158–161. 11. Grunewald S, Champion MP, Leonard JV, et al. Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics 2004;35:211–216. 12. Hoover-Fong JE, Shah S, Van Hove JLK, et al. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology 2004;63:1847–1853. 13. Hamosh A, Johnston MV. Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS et al., eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:2065–2078. 14. Kure S, Kato K, Dinopoulos A, et al. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. Hum Mutat 2006;27:343–352. 15. Applegarth DA, Toone JR. Glycine encephalopathy (nonketotic hyperglycinemia): comments and speculations. Am J Med Genet A 2006;140:186–188. 16. Jaeken J, Detheux M, VanMaldergem L, et al. 3-Phosphoglycerate dehydrogenase deficiency and 3-phosphoserine phosphatase deficiency: inborn errors of serine biosynthesis. J Inherit Metab Dis 1996;19:223–226. 17. de Koning TJ, Duran M, Dorland L, et al. Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency. Ann Neurol 1998;44:261–265. 18. Swoboda KJ, Hyland K. Diagnosis and treatment of neurotransmitterrelated disorders. Neurol Clin 2002;20:1143–1161. 19. Hyland K. The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 2003;54(Suppl 6): S13–S17. 20. Blau N, Bonafe L, Thony B. Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 2001;74:172–185. 21. Swoboda KJ, Saul JP, McKenna CE, et al. Aromatic L-amino acid decarboxylase deficiency – overview of clinical features and outcomes. Ann Neurol 2003;54(Suppl 6):S49–S55. 22. Jakobs C, Jaeken J, Gibson KM. Inherited disorders of GABA metabolism. J Inherit Metab Dis 1993;16:704–715. 23. Pearl PL, Gibson KM. Clinical aspects of the disorders of GABA metabolism in children. Curr Opin Neurol 2004;17:107–113. 24. Pearl PL, Capp PK, Novotny EJ, et al. Inherited disorders of neurotransmitters in children and adults. Clin Biochem 2005;38:1051–1058. 25. Ethofer T, Seeger U, Klose U, et al. Proton MR spectroscopy in succinic semialdehyde dehydrogenase deficiency. Neurology 2004;62:1016–1018. 26. Jaeken J, Casaer P, deCock P, et al. Vigabatrin in GABA metabolism disorders. Lancet 1989;1:1074. 27. Gjessing LR, Sjaastad O. Homocarnosinosis: a new metabolic disorder associated with spasticity and mental retardation. Lancet 1974;2:1028. 28. Plecko B, Hikel C, Korenke GC, et al. Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics 2005;36:200–205.

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29. Plecko B, Stockler-Ipsiroglu S, Paschke E, et al. Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol 2000;48:121–125. 30. Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 2006;12:307–309. 31. Goutières F. Aicardi-Goutières syndrome. Brain Dev 2005;27:201–206. 32. Blau N, Bonafe L, Krageloh-Mann I, et al. Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome: a new phenotype. Neurology 2003; 61:642–647. 33. Barisic N, Logan P, Pikija S, et al. R208X mutation in CLN2 gene associated with reduced cerebrospinal fluid pterins in a girl with classic late infantile neuronal ceroid lipofuscinosis. Croat Med J 2003;44:489–493. 34. Kaler SG, Goldstein DS, Holmes C, et al. Plasma and cerebrospinal fluid neurochemical pattern in Menkes’ disease. Ann Neurol 1993;33:171–175.

35. Kaler SG, Gahl WA, Berry SA, et al. Predictive value of plasma catecholamine levels in neonatal detection of Menkes’ disease. J Inherit Metab Dis 1993;16:907–908. 36. Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005;57:67–81. 37. Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry 2005;17: 485–495. 38. Ramaekers VT, Senderek J, Hausler M, et al. A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa. Mol Genet Metab 2001;73:179–187. 39. Nagae-Poetscher LM, McMahon M, Braverman N, et al. Metabolites in ventricular cerebrospinal fluid detected by proton magnetic resonance spectroscopic imaging. J Magn Reson Imaging 2004; 20:496–500.

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Disorders of Intracranial Pressure and Cerebrospinal Fluid Circulation Robin K. Wilson and Michael A. Williams

INTRODUCTION Two common disorders of cerebrospinal fluid (CSF) circulation that patients can develop are adult hydrocephalus (AH) and idiopathic intracranial hypertension (IIH). Much less frequently, intracranial hypotension may also occur. Chapter 3 and Chapter 4 review the normal physiology of CSF circulation and intracranial pressure (ICP), respectively. This chapter will focus on the diagnosis and pathophysiology of AH and IIH. Chapter 28 will address the medical and surgical management of these disorders. Intracranial hypotension that commonly presents with headache is covered in Chapter 19. Although AH and IIH differ in their epidemiology, clinical presentation, risk factors, and neuroimaging findings, both disorders may improve following CSF diversion via surgically implanted shunts. Furthermore, even though the physiological disruptions that lead to AH and IIH remain controversial,1,2 formal guidelines to diagnose and treat patients with both disorders now exist.3–6

PATHOPHYSIOLOGY OF CSF CIRCULATION AND PRESSURE DISORDERS In the normal brain, a balance between CSF production and CSF resorption maintains CSF pressure (Pcsf) in the range of 6–20 cmH2O.7 Disorders of CSF circulation arise when this equilibrium is disrupted, either by obstructing normal CSF flow patterns or by perturbing the production/ resorption balance. Obstructed CSF flow can occur at anatomic narrowings in the ventricular system, including the foramina of Monro, the third ventricle, the Sylvian aqueduct, the fourth ventricular outlets or even within the subarachnoid space itself. Impaired CSF resorption across the arachnoid granulations is by far the most common derangement leading to communicating hydrocephalus. Indeed, the overproduction of CSF has been linked to

hydrocephalus only in rare cases of choroid plexus hyperplasia or choroid plexus papilloma;8–11 chronic communicating hydrocephalus is usually associated with a reduced rate of CSF production.12 Causes of obstructed or impaired CSF resorption and flow include tumors, cysts, scarring, adhesions, and accumulation of blood degradation products following hemorrhage. The ability of the ventricular space to maintain Pcsf homeostasis with alterations of both cerebral blood and CSF volume during the normal cardiac and respiratory cycles depends on the property of compliance.13,14 Intracranial compliance is thus defined as the change in ventricular volume following a change in Pcsf.15 Decreased intracranial compliance in AH may result from physical changes to the brain parenchyma caused by vascular disease, particularly small vessel ischemic changes known to be associated with AH.16–18 Pcsf homeostasis is also influenced by interstitial brain fluid, intracellular edema, brain volume changes due to expansive processes such as hemorrhage and tumor or to shrinkage from atrophy, and changes in vascular diameter leading to changes in cerebral blood volume. The interaction of these diverse variables may explain why increased Pcsf can be associated with two clinically distinct disorders treated by CSF diversion, one with enlarged ventricles (AH) and another with normal to small ventricles (IIH). In obstructive hydrocephalus, the pathophysiology is quite straightforward. Obstructed CSF circulation leads to CSF accumulation proximal to the blockage, causing ventriculomegaly and increased Pcsf. In communicating forms of hydrocephalus, impedance of CSF flow through the subarachnoid space or impaired CSF resorption at the arachnoid granulations leads to fluid accumulation within the ventricles, with increased Pcsf during the phase of active ventricular enlargement. Hakim explained ventricular dilatation in AH by recalling Pascal’s law (force = pressure × area),19,20 and speculated that transiently increased intraventricular pressure initiates the ventricular enlargement

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process. However, as ventricular surface area increases, the Pcsf necessary to sustain a constant outward force is correspondingly lower. Thus, a normal CSF pressure may be recorded during a lumbar puncture (LP) in the context of enlarged ventricles, suggesting previously elevated Pcsf. With IIH, disordered CSF circulation is not the primary pathophysiological mechanism leading to elevated Pcsf. Rather, the mechanism is more likely to be impaired cerebral venous outflow, leading to hypertension within the intracranial dural venous sinuses.21–23 Predisposing factors include dural sinus thrombosis, congenital anomalies of venous anatomy, and acquired alterations to this venous anatomy following head or neck surgery. Regardless of cause, increased venous sinus pressure raises the Pcsf required for CSF resorption across the arachnoid granulations, often over 25 cmH2O.3 Impaired cerebral venous outflow results not only in dural venous hypertension, but it also increases cerebral venous blood volume, thus expanding the brain parenchyma itself and preventing ventricular enlargement.24,25 Although IIH is often treated with acetazolamide to decrease CSF production, there is no convincing evidence of such increased production in untreated patients.3,26 ICP represents the combined effects of the cerebrovascular circulation and intracranial compliance on Pcsf, and the detection of abnormal Pcsf patterns can be used to infer the presence of pathophysiological states. With every cardiac cycle, the pulsatile inflow of arterial blood volume and the transmitted arterial pressure wave results in a Pcsf pulsation. When compliance mechanisms are intact (cerebral venous outflow is normal and flow of CSF between the cranial and spinal subarachnoid spaces via the foramen magnum is intact), this CSF pulse amplitude ranges from 0.1 to 0.5 cmH2O.7 Lundberg was the first to characterize ICP waveforms by performing continuous intracranial CSF pressure monitoring in 143 patients with tumors, hemorrhages, and head trauma.27 He described three patterns, now known as A, B and C waves. A-waves, also called plateau waves, are acute elevations of ICP over 68 cmH2O, typically lasting 5 to 20 min.7,28 These waves represent near exhaustion of intracranial compliance mechanisms.29 Near-plateau waves are similar to A-waves, but do not exceed 68 cmH2O.28 B-waves are brief rhythmic or semi-rhythmic pressure elevations occurring at a frequency of 0.5 to 2 cycles per minute.15,28 In spontaneously breathing patients, they often occur with Cheyne-Stokes respirations.30,31 B-waves are most likely the result of variations of cerebral blood volume caused by hypercapnea- or hypoxia-induced cerebral vasodilatation during the apneic phase of periodic breathing. Thus they likely represent intact cerebrovascular autoregulation in the setting of reduced intracranial compliance. Though A- and B-waves are primarily associated with acute, life-threatening increases in ICP, these patterns are both also associated with AH and IIH, particularly during sleep.15 Even patients with otherwise normal CSF

circulation may have brief periods of Pcsf fluctuation similar to B-waves, but their prolonged occurrence suggests a pathological condition.32 C-waves are low-amplitude waves, synchronous with variations in blood pressure, and are thought to be of limited pathological significance.33 The identification of elevated or abnormal Pcsf patterns by continuous recording is more accurate than the measurement of single opening pressure (OP) at the time of an LP. In our clinical experience, a stable OP is rarely observed for longer than 20–30 s. Indeed, it represents a minimal and a potentially unrepresentative sample of overall Pcsf. Furthermore, because most patients are awake during an LP, it is possible for patients with AH or IIH to have normal pressure during an LP, and yet show A- or B-waves with Pcsf monitoring during sleep.

ADULT HYDROCEPHALUS In 1965, Hakim and Adams described a syndrome of progressive cognitive decline, gait impairment, and urinary incontinence in the context of ventricular dilatation and normal Pcsf measurement during LP, a condition subsequently referred to as normal pressure hydrocephalus (NPH).19,20,34 While this is certainly the best-known syndrome of hydrocephalus in adults, we now use the term AH to refer to a spectrum of conditions in adults of any age where Pcsf can range from truly low, to normal, to pathologically elevated. As a result, AH includes congenital or acquired disorders presenting after the age of 18; symptomatic (decompensated) or asymptomatic (compensated); communicating or obstructive; and idiopathic or secondary in etiology.35–38 In patients with AH syndromes, the appropriate diagnostic pathway includes a detailed history, a careful neurological examination, and a brain imaging study. An international study group published guidelines for the diagnosis and management of idiopathic NPH (INPH) in 2005. 4–6,39

Predisposing events While AH can be either idiopathic (2/3) or secondary to many predisposing conditions (1/3), there is little observable difference in the clinical presentation.40 Secondary AH may follow meningitis, encephalitis, head injury (including concussion), subarachnoid hemorrhage, or other processes that cause inflammation in the subarachnoid space. Since hydrocephalus may develop years after the original injury, these risks factors should be carefully sought in the patient’s history.36 Furthermore, previously compensated congenital hydrocephalus can manifest as symptomatic AH at any time in adulthood. Cases of idiopathic AH are presumed to have underlying causes similar to secondary AH, although predisposing events have been forgotten or were asymptomatic at the time they occurred. Asymptomatic AH patients are occasionally identified after cerebral imaging

Adult Hydrocephalus

undertaken for other reasons unexpectedly reveals ventricular enlargement. If neurological deficits are not observed in these cases, the disorder is considered compensated. Chronic compensated hydrocephalus occasionally decompensates,36 so patients should be counseled and periodically reevaluated for relevant signs and symptoms.

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remembering appointments, and dispensing medications. Neuropsychological tests can determine the severity of the dementia and help to clarify whether there is a predominance of subcortical features.

Testing CSF physiology in AH Neuroimaging findings Since the cerebral ventricles may enlarge with normal aging, it can be difficult to identify hydrocephalus in older patients based on imaging alone unless an obstructive cause is clearly seen. Magnetic resonance imaging (MRI) findings supportive of AH include rounding of the lateral and third ventricles, upward bowing and thinning of the corpus callosum, and pulsation artifact (flow void) in the Sylvian aqueduct.41–43 Periventricular hyperintensities (PVH) can be seen on MRI with either vascular dementia or AH, and these disorders often present with similar symptoms.17,44,45 In one study of AH patients with abundant PVH, improvement of symptoms following shunt placement correlated with a reduction of PVH.45,46 This implies that some of these imaging abnormalities are due to pathophysiological processes such as transependymal flow of CSF. Still, there are no imaging techniques available at present that reliably predict a patient’s response to CSF drainage or shunt surgery; testing of CSF physiology is needed to make this determination for nearly all patients.4,47,48

Symptomatic AH Though classically viewed as presenting with a triad of dementia, incontinence, and gait instability, the clinical presentation of AH varies widely from patient to patient. In the appropriate radiographic context, it is not necessary for a given patient to have the complete triad of symptoms before proceeding with further evaluation.4,47,48 Most AH patients have symptoms for several years before coming to medical attention.47 Common mobility changes include reduced gait velocity, shorter stride length, broader base, difficulty turning, decreased foot clearance, external rotation of the feet, and poor dynamic equilibrium.49,50 Some patients present with the classic “magnetic gait” consisting of a wide base with tiny shuffling steps that have a minimal clearance from the floor. Severely impaired patients may be unable to walk, stand, or move easily in bed. Rating scales such as the Tinetti Assessment Tool are useful measures of both gait and balance function over time.51,52 Urinary symptoms appear to be associated with a hyperreflexic bladder.53,54 Most patients complain of urinary frequency, urgency, and near-incontinence rather than frank incontinence. From a cognitive standpoint, AH causes a primarily subcortical dementia.55–57 Patients may notice difficulty getting tasks completed, as their organizational and multitasking abilities decline.35 Family members often have assumed such tasks as managing finances, shopping,

There are the three main techniques used to diagnose AH by assessing CSF physiology: (1) measurement of CSF outflow resistance, (2) continuous Pcsf monitoring, and (3) evaluation of clinical response to temporary CSF removal. CSF outflow resistance (Rout) measurement involves infusing artificial CSF into the lumbar subarachnoid space via a spinal needle while recording CSF pressure simultaneously at a second site. This enables a determination of both plateau pressure and Rout.58 The prospective Dutch NPH study evaluated this diagnostic tool, and demonstrated that an Rout value above 18 mmHg/ml/min predicted shunt responsiveness, though some patients with lower Rout values also improved significantly after shunting.44 A recent study found plateau pressure to be a more sensitive criterion for predicting shunt responsiveness than Rout.59,60 Drawbacks of this procedure include the need for multiple puncture sites as well as specialized equipment and software for data analysis. AH produces a variety of Pcsf waveform abnormalities.61,62 Most AH patients have normal baseline Pcsf measurements punctuated by B-waves and A-waves, particularly during sleep.62–64 The presence of an unstable wave form during >10% of sleep time predicted a beneficial response to shunting, but this finding was not as accurate as assessing the clinical response to CSF drainage. Continuous Pcsf monitoring can be accomplished via intraventricular or lumbar catheters attached to an external transducer, or by means of ventricular, subdural, or intraparenchymal solid state transducers.64 Current INPH Guidelines recommend determining the clinical response to CSF removal by large-volume LP or continuous CSF drainage via spinal catheter before proceeding to shunt surgery,5 as significant symptomatic improvement following large-volume CSF drainage can predict a beneficial response to shunting.48,65–68 One advantage of LP is that the procedure can be performed in the outpatient setting with the safe removal of 40–50 ml of CSF at one time. Fifteen to twenty minutes after the procedure, patients should be encouraged to sit up and walk around because their response to CSF removal cannot be assessed if they remain supine. A physician should evaluate the patient before and after the LP; surgical decisions should not rely solely on the patient’s or the family’s assessment, which can be biased by a desire for improvement. While it is widely believed that patients with AH get immediately better after the LP, our experience is that most responses are delayed. We therefore evaluate patients 4–6 h after the procedure. A positive response can be used to recommend shunt surgery; however, the absence of an

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overt response following an LP does not exclude the possibility of hydrocephalus.5 Continuous drainage of CSF via a spinal catheter creates a more sustained and controlled simulation of the effects of a shunt on the brain without requiring shunt surgery.69 Controlled CSF drainage via spinal catheter is more sensitive than a large volume LP (50–100%, compared to 26–61%), and it has a high positive predictive value for shunt responsiveness (80–100%).5 This is particularly true for patients with multiple potential causes of impaired cognition, gait, or urinary control, as a trial of continuous external CSF drainage helps to identify the proportional contribution of hydrocephalus to the symptoms. Lack of improvement after controlled CSF drainage means shunt surgery is unlikely to benefit the patient.48,64 CSF drainage via spinal catheter requires hospitalization, and even at experienced centers the risk of catheter-associated infection is 2–4%.48,64

decubitus position, (3) normal CSF composition, (4) no hydrocephalus, mass, structural, or vascular lesion on brain imaging, and (5) no other identifiable cause of increased Pcsf.74 Although funduscopic examination usually reveals papilledema, 5% of patients do not have this finding.26,28,78,79 Other supporting signs include abducens nerve palsy, reduced visual fields, visual loss, and optic atrophy in longstanding cases.74 Use of the terms “pseudotumor cerebri” and “benign intracranial hypertension” is now discouraged.80–82

Epidemiology The incidence of IIH is 0.9/100,000 in the general population and 3.5/100,000 in women 15–44 years old.3,83–85 IIH most commonly occurs in obese women between the ages 20 and 44 years, where it has an incidence of 19.3/100,000. It is rare in patients over age 45.86 Men and children may also be affected, and both sexes are equally at risk before puberty.

Assessment of response to a CSF drainage trial Gait dysfunction is the AH symptom most likely to improve following temporary CSF drainage, either by LP or spinal catheter.50,70 Improvement in gait scoring scales, increased speed of ambulation over a defined distance, or reduced need for walking aids in response to CSF drainage predicts similar improvement following shunt surgery.67 Urinary symptoms also improve in a substantial percentage of shunted patients; 65% reported moderate to marked subjective improvement in one recent study.70 It is more difficult to assess a change in bladder control following an LP, but patients may notice a significant change during a 3-day CSF drainage trial. If urinary symptoms persist after shunt surgery, a co-existing urinary disorder should be sought. Reports of cognitive improvement following shunting for AH have been mixed. Some studies show little or no change, even in those patients who report benefits in gait and bladder function.71–73 Other studies show that about half of patients have measurable improvement defined as at least one standard deviation increase in verbal memory and recall, psychomotor speed, and motor precision on formal testing conducted 3 months after shunt surgery.55,56

IDIOPATHIC INTRACRANIAL HYPERTENSION IIH is a clinical syndrome of headache and visual symptomatology, associated with papilledema, increased Pcsf, and normal or small ventricles on brain imaging studies.3,26,74–77 The disorder carries a significant risk of permanent visual impairment or blindness if it is not diagnosed and treated properly. Current diagnostic criteria include: (1) signs and symptoms that only reflect intracranial hypertension or papilledema, (2) elevated Pcsf measured via LP in lateral

Clinical presentation Permanent visual loss is the most serious consequence of untreated IIH.3,26,75,87 As such, evaluation and treatment should focus on the careful documentation of visual impairment and the prevention of its progression.88–90 Up to 50% of patients referred to tertiary centers for treatment of IIH develop moderate-to-severe vision loss during the course of the disease.88,91,92 Common field defects detected by automated perimetry include an enlarged blind spot, inferonasal field loss, and generalized field constriction.26,82 Occasionally, papilledema does not resolve despite resolution of symptoms and improvement of visual fields.82 The headache may be generalized or retro-orbital, episodic or chronic, and is commonly aggravated with straining or coughing. As many as 50% of IIH patients also have a second cause of headache, such as migraine or analgesic overuse headache, and need to be treated for both.93

Secondary IIH IIH may be secondary to medications, obstructed cerebral venous outflow, or systemic illness. Medications commonly associated with secondary IIH are tetracycline, minocycline, corticosteroid therapy or withdrawal, vitamin A, and vitamin A derivatives.82,88,94 Factors that predispose to impaired cerebral venous outflow include pregnancy, hypercoagulable disorders, dehydration, systemic lupus erythematosus, malignancy, sarcoidosis, and prior radical neck surgery.95–98 Predisposing medical conditions include renal failure, iron-deficiency anemia, chronic obstructive pulmonary disease, pulmonary hypertension, and Addison’s disease.99 If the workup reveals secondary intracranial hypertension, the underlying cause should be treated. Venous sinus thrombosis may require anticoagulation.87

References

Predisposing medications should be discontinued if possible, in addition to other IIH treatments.100,101

Neuroimaging studies Current methods used to diagnose IIH include MRI plus magnetic resonance venography (MRV) or contrast-enhanced computed tomography (CT) plus CT venography.26,74,97 MRI demonstrates normal or small ventricles, and no major structural or vascular lesions; MRV shows normal venous sinus anatomy.74 MRV may reveal sinovenous stenosis in secondary IIH. Catheter angiography with venous imaging may be helpful if the results derived from less-invasive techniques are ambiguous.74,87

CSF dynamics Following the imaging evaluation, an LP should be performed in suspected IIH to assess Pcsf. Patients should be positioned in the lateral decubitus position with straightened legs.3 In adults, Pcsf less than 20 cmH2O is considered normal, while readings of greater than 25 cmH2O are consistent with IIH.74 Pressures between 20 and 25 cmH2O are ambiguous; if clinical suspicion is high, treatment can be started with careful follow-up.3,26 If signs and symptoms progress despite treatment, a repeat LP can be performed.74 Since patients with IIH can have variable Pcsf over time, prolonged Pcsf monitoring via a spinal catheter may help to reveal abnormal Pcsf waveforms, especially in patients without obvious papilledema.28 Some patients experience headache relief following the LP, but others can develop typical low-pressure symptoms.3,87 CSF should be removed not only to reduce Pcsf, but also for laboratory evaluation to rule out CNS infection or malignancy.3,26 CSF should always be analyzed for cell counts, protein and glucose content, bacterial, fungal, and mycobacterial cultures, cryptococcal antigen, and cytopathology.3 The CSF composition in IIH is uniformly normal.74 An occasional patient with chronic daily headache and no papilledema will experience temporary headache relief following an LP or will be found to have an OP above 25 mmH2O.28 A trial of weight loss for obese patients and medical treatment for IIH may be attempted, but since IIH without papilledema (IIHWOP) is rare, further evaluation prior to any consideration of surgical intervention may be necessary. Continuous Pcsf monitoring via a lumbar catheter can reveal B-waves, plateau waves, or near-plateau waves in patients who turn out to have IIHWOP and may respond to shunt surgery.28

INTRACRANIAL HYPOTENSION The diagnosis and pathophysiology of intracranial hypotension is covered in Chapter 19. Management of these patients is discussed in Chapter 28.

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CONCLUSIONS Altered CSF recirculation and pressure dynamics can result in the clinical syndromes of AH and IIH. Although these two disorders produce divergent clinical features and are associated with very different brain imaging findings, they both require careful assessment of CSF pressures for diagnosis and may respond to therapeutic CSF diversion via a surgically implanted shunt. Consensus data would suggest that basic CSF composition is normal in both of these disorders, and that the main disturbance lies at the level of CSF resorption in most of these patients. As a result, we would argue that these are brain diseases, and not CSF disorders, per se. Yet one future goal is to develop an improved molecular understanding of these resorption disturbances that may be reflected in the CSF. This could lead to diagnostic tools that would improve our capacity to properly select patients who are the most suitable for shunt surgery. REFERENCES 1. Segal MB. The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cell Mol Neurobiol 2000;20:183–196. 2. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 2004;45:545–552. 3. Friedman DI. Pseudotumor cerebri. Neurol Clin 2004;22:99–131. 4. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM. Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery 2005;57:S4–S16. 5. Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PM. The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. Neurosurgery 2005;57:S17–S28. 6. Bergsneider M, Black PM, Klinge P, Marmarou A, Relkin N. Surgical management of idiopathic normal-pressure hydrocephalus. Neurosurgery 2005;57:S29–S39. 7. Fishman RA. Cerebrospinal Fluid in Disease of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992. 8. Fujimoto Y, Matsushita H, Plese JP, Marino R. Hydrocephalus due to diffuse villous hyperplasia of the choroid plexus. Case report and review of the literature. Pediatr Neurosurg 2004;40:32–36. 9. Aziz AA, Coleman L, Morokoff A, Maixner W. Diffuse choroid plexus hyperplasia: an under-diagnosed cause of hydrocephalus in children? Pediatr Radiol 2005;35:815–818. 10. Fujimura M, Onuma T, Kameyama M, et al. Hydrocephalus due to cerebrospinal fluid overproduction by bilateral choroid plexus papillomas. Childs Nerv Syst 2004;20:485–488. 11. Milhorat TH, Hammock MK, Davis DA, Fenstermacher JD. Choroid plexus papilloma. I. Proof of cerebrospinal fluid overproduction. Childs Brain 1976;2:273–289. 12. Silverberg GD, Heit G, Huhn S, et al. The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology 2001;57:1763–1766. 13. Marmarou A, Shulman K, LaMorgese J. Compartmental analysis of compliance and outflow resistance of the cerebrospinal fluid system. J Neurosurg 1975;43:523–534. 14. Marmarou A, Shulman K, Rosende RM. A nonlinear analysis of the cerebrospinal fluid system and intracranial pressure dynamics. J Neurosurg 1978;48:332–344. 15. Davson H, Segal MB. Physiology of the CSF and Blood-Brain Barriers. New York: CRC Press; 1996.

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Disorders of Intracranial Pressure and CSF Circulation

16. Greitz D. Radiological assessment of hydrocephalus: new theories and implications for therapy. Neurosurg Rev 2004;27:145–165. 17. Krauss JK, Regel JP, Vach W, et al. White matter lesions in patients with idiopathic normal pressure hydrocephalus and in an age-matched control group: a comparative study. Neurosurgery 1997;40:491–496. 18. Krauss JK, Regel JP, Vach W, Droste DW, Borremans JJ, Mergner T. Vascular risk factors and arteriosclerotic disease in idiopathic normal-pressure hydrocephalus of the elderly. Stroke 1996;27:24–29. 19. Hakim S. Algunas observaciones sobre la presion del LCR. Sindrome hidrocefalico en el adulto con “presion normal” del LCR. Thesis No. 957, Javeriana University School of Medicine, Bogota, Columbia, 1964. 20. Hakim S, Adams RD. The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. Observations on cerebrospinal fluid hydrodynamics. J Neurol Sci 1965;2:307–327. 21. King JO, Mitchell PJ, Thompson KR, Tress BM. Cerebral venography and manometry in idiopathic intracranial hypertension. Neurology 1995; 45:2224–2228. 22. Karahalios DG, Rekate HL, Khayata MH, Apostolides PJ. Elevated intracranial venous pressure as a universal mechanism in pseudotumor cerebri of varying etiologies. Neurology 1996;46:198–202. 23. Higgins JN, Cousins C, Owler BK, Sarkies N, Pickard JP. Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting. J Neurol Neurosurg Psychiatry 2003;74:1662–1666. 24. Milhorat TH. Classification of the cerebral edemas with reference to hydrocephalus and pseudotumor cerebri. Childs Nerv Syst 1992; 8:301–306. 25. Malm J, Kristensen B, Markgren P, Ekstedt J. CSF hydrodynamics in idiopathic intracranial hypertension: a long-term study. Neurology 1992;42:851–858. 26. Binder DK, Horton JC, Lawton MT, McDermott MW. Idiopathic intracranial hypertension. Neurosurgery 2004;54:538–551. 27. Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Acta Psychiatr Scand 1960;36(Suppl 149):1–193. 28. Torbey MT, Geocadin RG, Razumovsky AY, Rigamonti D, Williams MA. Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache. Cephalalgia 2004;24:495–502. 29. Czosnyka M, Smielewski P, Piechnik S, et al. Hemodynamic characterization of intracranial pressure plateau waves in head-injury patients. J Neurosurg 1999;91:11–19. 30. Kjallquist A, Ponten U, Siesjo BK. Respiratory and cardiac changes during rapid spontaneous variations of ventricular fluid pressure in patients with intracranial hypertension. Acta Neurol Scand 1964;40:291–317. 31. Cooper R, Hulme A. Intracranial pressure and related phenomena during sleep. J Neurol Neurosurg Psychiatry 1966;29:564–570. 32. Newell DW, Aaslid R, Stooss R, Reulen HJ. The relationship of blood flow velocity fluctuations to intracranial pressure B waves. J Neurosurg 1992;76:415–421. 33. Dunn LT. Raised intracranial pressure. J Neurol Neurosurg Psychiatry 2002;73(Suppl 1):23–27. 34. Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH. Symptomatic occult hydrocephalus with “normal” cerebrospinal-fluid pressure. A treatable syndrome. N Engl J Med 1965;273:117–126. 35. Cowan JA, McGirt MJ, Woodworth G, Rigamonti D, Williams MA. The syndrome of hydrocephalus in young and middle-aged adults (SHYMA). Neurol Res 2005;27:540–547. 36. Edwards RJ, Dombrowski SM, Luciano MG, Pople IK. Chronic hydrocephalus in adults. Brain Pathol 2004;14:325–336. 37. Chahlavi A, El-Babaa SK, Luciano MG. Adult-onset hydrocephalus. Neurosurg Clin N Am 2001;12:753–760. 38. Larsson A, Stephensen H, Wikkelso C. Adult patients with “asymptomatic” and “compensated” hydrocephalus benefit from surgery. Acta Neurol Scand 1999;99:81–90. 39. Klinge P, Marmarou A, Bergsneider M, Relkin N, Black PM. Outcome of shunting in idiopathic normal-pressure hydrocephalus and the value of

40. 41.

42.

43. 44. 45.

46.

47.

48. 49.

50. 51. 52. 53. 54.

55. 56.

57.

58.

outcome assessment in shunted patients. Neurosurgery 2005; 57:S40–S52. Krauss JK, Halve B. Normal pressure hydrocephalus: survey on contemporary diagnostic algorithms and therapeutic decision-making in clinical practice. Acta Neurochir (Wien) 2004;146:379–388. Segev Y, Metser U, Beni-Adani L, Elvan C, Reider-Groswasser II, Constantini S. Morphometric study of the midsagittal MR imaging plane in cases of hydrocephalus and atrophy and in normal brains. AJNR Am J Neuroradiol 2001;22:1674–1679. Qureshi AI, Williams MA, Razumovsky AY, Hanley DF. Magnetic resonance imaging, unstable intracranial pressure and clinical outcome in patients with normal pressure hydrocephalus. Acta Neurochir Suppl 1998;71:354–356. Grossman R, Yousem D. Neuroradiology, The Requisites. 2nd ed. Philadelphia: Mosby; 2003. Boon AJ, Tans JT, Delwel EJ, et al. Dutch Normal-Pressure Hydrocephalus Study: the role of cerebrovascular disease. J Neurosurg 1999;90:221–226. Tullberg M, Hultin L, Ekholm S, Mansson JE, Fredman P, Wikkelso C. White matter changes in normal pressure hydrocephalus and Binswanger disease: specificity, predictive value and correlations to axonal degeneration and demyelination. Acta Neurol Scand 2002;105:417–426. Tullberg M, Jensen C, Ekholm S, Wikkelso C. Normal pressure hydrocephalus: vascular white matter changes on MR images must not exclude patients from shunt surgery. AJNR Am J Neuroradiol 2001;22:1665–1673. McGirt MJ, Woodworth GF, Coon AL, Thomas G, Williams MA, Rigamonti D. Diagnosis, treatment, and analysis of long-term outcomes in idiopathic normal-pressure hydrocephalus. Neurosurgery 2005;57:699–705. Marmarou A, Young HF, Aygok GA, et al. Diagnosis and management of idiopathic normal-pressure hydrocephalus: a prospective study in 151 patients. J Neurosurg 2005;102:987–997. Stolze H, Kuhtz-Buschbeck JP, Drucke H, Johnk K, Illert M, Deuschl G. Comparative analysis of the gait disorder of normal pressure hydrocephalus and Parkinson’s disease. J Neurol Neurosurg Psychiatry 2001;70:289–297. Stolze H, Kuhtz-Buschbeck JP, Drucke H, et al. Gait analysis in idiopathic normal pressure hydrocephalus – which parameters respond to the CSF tap test? Clin Neurophysiol 2000;111:1678–1686. Tinetti ME. Performance-oriented assessment of mobility problems in elderly patients. J Am Geriatr Soc 1986;34:119–126. Raiche M, Hebert R, Prince F, Corriuenu H. Screening older adults at risk of falling with the Tinetti balance scale. Lancet 2000;356: 1001–1002. DuBeau CE. Interpreting the effect of common medical conditions on voiding dysfunction in the elderly. Urol Clin North Am 1996;23:11–18. Gerstenberg T, Andersen JT, Klarskov P, Ramirez D, Hald T. Detrusor hyperreflexia and detrusor sphincter incooordination and conductance to cerebrospinal fluid outflow in normal pressure hydrocephalus. Acta Neurol Scand 1982;65:296–302. Duinkerke A, Williams MA, Rigamonti D, Hillis AE. Cognitive recovery in idiopathic normal pressure hydrocephalus after shunt. Cogn Behav Neurol 2004;17:179–184. Thomas G, McGirt MJ, Woodworth G, et al. Baseline neuropsychological profile and cognitive response to cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Disord 2005;20:163–168. van Harten B, Courant MW, Scheltens P, Weinstein HC. Validation of the HIV Dementia Scale in an elderly cohort of patients with subcortical cognitive impairment caused by subcortical ischaemic vascular disease or a normal pressure hydrocephalus. Dement Geriatr Cogn Disord 2004;18:109–114. Albeck MJ, Borgesen SE, Gjerris F, Schmidt JF, Sorensen PS. Intracranial pressure and cerebrospinal fluid outflow conductance in healthy subjects. J Neurosurg 1991;74:597–600.

References

59. Kahlon B, Sundbarg G, Rehncrona S. Lumbar infusion test in normal pressure hydrocephalus. Acta Neurol Scand 2005;111:379–384. 60. Hussey F, Schanzer B, Katzman R. A simple constant-infusion manometric test for measurement of CSF absorption. II. Clinical studies. Neurology 1970;20:665–680. 61. Nornes H, Rootwelt K, Sjaastad O. Normal pressure hydrocephalus. Long-term intracranial pressure recording. Eur Neurol 1973;9:261–274. 62. Borgesen SE, Gjerris F. The predictive value of conductance to outflow of CSF in normal pressure hydrocephalus. Brain 1982;105:65–86. 63. Pickard JD, Lye RH, Teasdale G. Intraventicular pressure waves – the best predictive test for shunting in normal pressure hydrocephalus. In: Intracranial Pressure IV. New York: Springer-Verlag; 1980:498–510. 64. Williams MA, Razumovsky AY, Hanley DF. Evaluation of shunt function in patients who are never better, or better than worse after shunt surgery for NPH. Acta Neurochir Suppl 1998;71:368–370. 65. Hebb AO, Cusimano MD. Idiopathic normal pressure hydrocephalus: a systematic review of diagnosis and outcome. Neurosurgery 2001;49:1166–1184. 66. Mori K. Management of idiopathic normal-pressure hydrocephalus: a multiinstitutional study conducted in Japan. J Neurosurg 2001;95:970–973. 67. Meier U, Konig A, Miethke C. Predictors of outcome in patients with normal-pressure hydrocephalus. Eur Neurol 2004;51:59–67. 68. Sand T, Bovim G, Grimse R, Myhr G, Helde G, Cappelen J. Idiopathic normal pressure hydrocephalus: the CSF tap-test may predict the clinical response to shunting. Acta Neurol Scand 1994;89:311–316. 69. Williams MA. Spinal catheter insertion via seated lumbar puncture using a massage chair. Neurology 2002;58:1859–1860. 70. Poca MA, Mataro M, Del Mar M, Arikan F, Junque C, Sahuquillo J. Is the placement of shunts in patients with idiopathic normal-pressure hydrocephalus worth the risk? Results of a study based on continuous monitoring of intracranial pressure. J Neurosurg 2004;100:855–866. 71. Savolainen S, Hurskainen H, Paljarvi L, Alafuzoff I, Vapalahti M. Five-year outcome of normal pressure hydrocephalus with or without a shunt: predictive value of the clinical signs, neuropsychological evaluation and infusion test. Acta Neurochir (Wien) 2002;144: 515–523. 72. Tromp CN, Staal MJ, Kalma LE. Effects of ventricular shunt treatment of normal pressure hydrocephalus on psychological functions. Z Kinderchir 1989;44 (Suppl 1):41–43. 73. Vanneste JA. Diagnosis and management of normal-pressure hydrocephalus. J Neurol 2000;247:5–14. 74. Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic intracranial hypertension. Neurology 2002;59:1492–1495. 75. Galvin JA, Van Stavern GP. Clinical characterization of idiopathic intracranial hypertension at the Detroit Medical Center. J Neurol Sci 2004;223:157–160. 76. Giuseffi V, Wall M, Siegel PZ, Rojas PB. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study. Neurology 1991;41:239–244. 77. Wall M. The headache profile of idiopathic intracranial hypertension. Cephalalgia 1990;10:331–335. 78. Wang SJ, Silberstein SD, Patterson S, Young WB. Idiopathic intracranial hypertension without papilledema: a case-control study in a headache center. Neurology 1998;51:245–249. 79. Lipton HL, Michelson PE. Pseudotumor cerebri syndrome without papilledema. JAMA 1972;220:1591–1592.

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80. Corbett JJ. Increased intracranial pressure: idiopathic and otherwise. J Neuroophthalmol 2004;24:103–105. 81. Digre KB. Not so benign intracranial hypertension. BMJ 2003;326:613–614. 82. Friedman DI, Jacobson DM. Idiopathic intracranial hypertension. J Neuroophthalmol 2004;24:138–145. 83. Durcan FJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri. Population studies in Iowa and Louisiana. Arch Neurol 1988;45:875–877. 84. Kesler A, Gadoth N. Epidemiology of idiopathic intracranial hypertension in Israel. J Neuroophthalmol 2001;21:12–14. 85. Radhakrishnan K, Ahlskog JE, Cross SA, Kurland LT, O’Fallon WM. Idiopathic intracranial hypertension (pseudotumor cerebri). Descriptive epidemiology in Rochester, Minn, 1976 to 1990. Arch Neurol 1993;50:78–80. 86. Bandyopadhyay S, Jacobson DM. Clinical features of late-onset pseudotumor cerebri fulfilling the modified dandy criteria. J Neuroophthalmol 2002;22:9–11. 87. Mathews MK, Sergott RC, Savino PJ. Pseudotumor cerebri. Curr Opin Ophthalmol 2003;14:364–370. 88. Corbett JJ, Savino PJ, Thompson HS, Kansu T, Schatz NJ, Orr LS, Hopson D. Visual loss in pseudotumor cerebri. Follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol 1982;39:461–474. 89. Rowe FJ, Sarkies NJ. Visual outcome in a prospective study of idiopathic intracranial hypertension. Arch Ophthalmol 1999;117:1571. 90. Rowe FJ, Sarkies NJ. Assessment of visual function in idiopathic intracranial hypertension: a prospective study. Eye 1998;12:111–118. 91. Hung HL, Kao LY, Huang CC. Ophthalmic features of idiopathic intracranial hypertension. Eye 2003;17:793–795. 92. Orcutt JC, Page NG, Sanders MD. Factors affecting visual loss in benign intracranial hypertension. Ophthalmology 1984;91:1303–1312. 93. Friedman DI, Rausch EA. Headache diagnoses in patients with treated idiopathic intracranial hypertension. Neurology 2002;58: 1551–1553. 94. Friedman DI. Medication-induced intracranial hypertension in dermatology. Am J Clin Dermatol 2005;6:29–37. 95. Padeh S, Passwell JH. Systemic lupus erythematosus presenting as idiopathic intracranial hypertension. J Rheumatol 1996;23: 1266–1268. 96. Owler BK, Parker G, Halmagyi GM, et al. Pseudotumor cerebri syndrome: venous sinus obstruction and its treatment with stent placement. J Neurosurg 2003;98:1045–1055. 97. Sylaja PN, Ahsan NV, Radhakrishnan K, Sankara P, Kumar S. Differential diagnosis of patients with intracranial sinus venous thrombosis related isolated intracranial hypertension from those with idiopathic intracranial hypertension. J Neurol Sci 2003;215:9–12. 98. Farb RI, Vanek I, Scott JN, et al. Idiopathic intracranial hypertension: the prevalence and morphology of sinovenous stenosis. Neurology 2003;60:1418–1424. 99. Digre KB, Corbett JJ. Idiopathic intracranial hypertension (pseudotumor cerebri): a reappraisal. Neurologist 2001;7:2–6. 100. Kesler A, Goldhammer Y, Hadayer A, Pianka P. The outcome of pseudotumor cerebri induced by tetracycline therapy. Acta Neurol Scand 2004;110:408–411. 101. Ang ER, Zimmerman JC, Malkin E. Pseudotumor cerebri secondary to minocycline intake. J Am Board Fam Pract 2002;15:229–233.

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13

Diseases of the Spine and Spinal Cord Katherine P. Thomas and Douglas A. Kerr

INTRODUCTION Cerebrospinal fluid (CSF) analysis can be a useful aid in the diagnosis of many spinal disorders. In some situations, such as when cytologically atypical cells are found accompanying a known spinal cord mass, it can provide a definitive diagnosis. In other cases, CSF findings can narrow the differential diagnosis by suggesting that a given spinal disease is neoplastic, vascular, infectious, inflammatory, or degenerative in nature. In this chapter, we will first review how different CSF findings relate to diseases of the spine and spinal cord in order to assist the clinician in creating a differential diagnosis. Next, we will discuss the range of CSF findings associated with specific spine and spinal cord disorders. We will not emphasize those diseases with clinical manifestations elsewhere in the neuraxis, even if the spinal cord is prominently involved, as the CSF findings associated with these conditions are covered elsewhere in this text.

CSF FINDINGS IN APPROACHING THE PATIENT WITH A KNOWN SPINAL DISEASE Pleocytosis An elevated CSF white blood cell (WBC) count is commonly associated with infection or inflammation of the nervous system. In cases where a CSF pleocytosis accompanies acute or chronic spinal cord dysfunction, a variety of serologic and CSF assays for infectious pathogens should be obtained (Table 13-1). In the absence of a defined infection, the presence of an elevated CSF WBC count may suggest an inflammatory or a demyelinating disorder. Such patients should be evaluated for systemic inflammatory disorders known to have CNS manifestations (systemic lupus erythematosus (SLE), Sjögren’s syndrome, or sarcoidosis) and for multifocal inflammatory central nervous system (CNS) disease (neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM), or multiple sclerosis (MS)).1

Inflammation isolated to the spinal cord is often termed transverse myelitis (TM) and is diagnosed by established criteria.2 Acute TM can have many different infectious or inflammatory causes.1 Likewise, patients with paraneoplastic myelopathies, spinal cord tumors, spinal vascular malformations, and even isolated vasculitis of the spinal cord can have a low-grade mononuclear cell CSF pleocytosis.3–7

Erythrocytosis In most cases, vessels at the base of the brain are the source of subarachnoid hemorrhage (SAH); a spinal source is identified in less than 1% of these events. In patients with myelopathy, vascular malformations such as an arteriovenous malformation (AVM) or arteriovenous fistula (AVF) can be the source of SAH.8 Spinal cavernous angiomas, by contrast, usually have no extramedullary component and have not been reported to cause SAH. Spinal trauma can also cause SAH. Although in some cases the causative event is severe and obvious, in others it may be less apparent.8–11 For example, whiplash injury or an axial loading injury (where the victim of a fall lands directly on his or her feet) may result in SAH. Still, external trauma is rarely implicated in spinal SAH.12–14 Primary spinal tumors, particularly those of the conus medullaris or cauda equina,15 and other less common causes including coagulopathy, periarteritis nodosa, SLE, hypertension, coarctation of the aorta, and Beçhet’s disease can cause spinal SAH.16 Spontaneous spinal subarachnoid hematoma, in which no apparent source of bleeding is ever identified, has been reported in a handful of cases.13,16–19

Elevated protein concentration Elevated CSF protein concentration is the most common CSF abnormality found in patients with spine or spinal cord diseases. It occurs in the majority of patients with spinal cord tumors, paraneoplastic myelopathies, radiation

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Table 13-1 Relevant Laboratory Tests in Evaluating for an Infectious Etiology of a CSF Pleocytosis in the Setting of an Acute or a Chronic Non-compressive Myelopathy Pathogen-specific antibodies (serum) Viruses (HIV, HTLV-1) Bacteria (Lyme disease, syphilis, Mycoplasma pneumoniae) Pathogen-specific antibodies (CSF) Bacteria (Lyme, syphilis) Pathogen-specific nucleic acids (CSF) Viruses (HSV-1/2, VZV, CMV, EBV, HHV-6, enteroviruses) Bacteria (Mycoplasma pneumoniae) Cultures (CSF) Bacteria (Listeria monocytogenes) Viruses (enteroviruses)

myelopathies, vascular malformations, epidural abscesses, syringomyelia with spinal block, and spinal cord trauma (Table 13-2). It is also elevated in approximately 50% of patients with TM,1 and it has been associated with epidural hematomas and at least one case of primary spinal cord vasculitis.7,20 The frequency and expected range of CSF protein elevation in individual diseases of the spine and spinal cord will be reviewed below.

Elevated CSF pressure Spinal tumors may occasionally cause elevated lumbar CSF pressure and can even be associated with papilledema and signs of elevated intracranial pressure (ICP).21 Other spinal

causes of elevated lumbar CSF pressure include other mass lesions of the cord, SAH from vascular malformations, epidural abscesses or hematomas, and enlarging syrinx cavities. Since CSF production can occur to some degree in the spinal region, this may help explain why lumbar CSF pressure can be elevated with disorders that selectively involve this area.

Decreased CSF pressure Lumbar CSF may occasionally be difficult to obtain, suggesting a block of CSF flow from the cerebral cisterns. The existence of spinal block can be determined by magnetic resonance imaging (MRI), or by performing Queckenstedt’s maneuver (no respiratory variation in CSF pressure as visualized in the attached manometer). If spinal block is suggested, CSF removal should be aborted since this may worsen any pressure gradient between the compartments above and below the lesion. Such a gradient may precipitate a downward herniation of neural tissue. In addition to decreased pressure, CSF caudal to the site of a block often has a markedly elevated protein concentration, since fluid is still being reabsorbed while the proteins remain. This is referred to as Froin’s syndrome. The presence of spinal block suggests a mass lesion such as an epidural abscess or hematoma, herniated intervertebral disc, or a tumor rostral to the lumbar cistern. Spinal stenosis, an expanding syrinx, radiation-induced spinal cord injury, or an aggressive inflammatory disorder resulting in spinal cord swelling can also occasionally cause spinal block.

Table 13-2 Total Protein Content and White Blood Cell Counts in the CSF of Patients With Diseases of the Spine and Spinal Cord Number of Cases Leukocytes (per mm3)

Total Protein (mg/dl) Total (n) <50

>50

50–100

>100

<5

≥5

<10

≥10

25 14 20 11

6 3 5 8

188 53 41 12 343

5 6 10 0 7

Tumors: Extramedullary/intradural tumors Intramedullary tumors Extradural tumors Meningeal infiltration

31 17 25 19

5 6 6 8

26 11 19 11

7 3 4 5

19 8 15 6

2 106 17 2 130 170 193 59 51 12 350

0 13 6 1 0 65 158 49 13 4 295

2 93 11 1 130 65 35 10 38 8 55

0

2

7 0 14

4 1 116

32 9 18 6 52

3 1 20 2 3

Other disease processes: Radiation myelopathy Angioma, AVM Spinal cord infarction Vasculitis Epidural abscess Transverse myelitis Spondylitic myelopthy Syringomyelia, congenital lesion Trauma Cord compression (unknown cause) Lumbar disc disease

(Data adapted from References 1, 5, 8, 23, 48, 49, 51–58, and 73.)

80 17 1

26 0 1

99

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Diseases of the Spine or Spinal Cord

Other markers Many other specific markers have been sought in the CSF of patients with spinal cord tumors, spondylitic myelopathy, and spinal cord trauma, but most lack a defined clinical utility in individual patients. One possible exception, however, has been the detection of the 14-3-3 protein in the CSF of patients with acute TM.22 Detection of these ordinarily cytoplasmic neuronal proteins in CSF samples obtained at clinical nadir accurately predicted a poor long-term clinical outcome in a small cohort of patients. Current CSF biomarker discovery efforts continue to focus on the identification of protein expression patterns that predict future clinical events such as reversibility of deficits or response to therapy in spinal cord patients.

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of neurological deficits is a potential complication of a lumbar puncture (LP) performed below the level of a complete spinal block. The procedure is best avoided if this situation is suspected. Recent studies have documented spinal block via myelography. The reported incidence of partial or total block caused by primary spinal tumors ranges from 76.5% (among 196 varied tumors) to 100% (among 88 meningiomas) using this technique.25–28 As mentioned, these patients also tend to have elevated CSF protein levels. For example, one study of 95 patients with spinal cord tumors showed that 88 (93%) had CSF protein levels above 40 mg/dl.25 In another study of 66 patients with spinal neurofibromas, the average CSF protein was 410 mg/dl (range, 20–2,900 mg/dl).26 Details regarding this CSF parameter will be discussed below.

DISEASES OF THE SPINE OR SPINAL CORD Elevated ICP and papilledema

Hemorrhage from spinal tumors, although rare, is usually associated with ependymomas of the conus medullaris or cauda equina.15 Of the 28 tumors responsible for SAH reviewed by Guidetti and Fortuna, 16 were ependymomas and six were neurinomas.23 Only six of these lesions were situated above the conus medullaris or cauda equina. Three caused hemorrhage confined to a short segment of subarachnoid space while the remainder caused more diffuse bleeding. Other spinal tumors presenting with SAH have been reported, including one series of six spinal hemangioblastomas and another of 21 spinal schwannomas.8,24

Increased ICP and papilledema as a consequence of a spinal tumor is rare.21 Among 54 tumors with such findings reviewed by Matzkin et al. in 1992, the majority occurred in the lower thoracic or lumbar region.29 Forty percent were ependymomas, 11% were schwannomas, and 7% each were gliomas, meningiomas, and neurofibromas.29 Other case reports describe papilledema with tumors at varying levels of the spinal neuraxis. The proposed pathogenesis with cervical tumors is straightforward; CSF flow is obstructed at the foramen magnum by rostral extension of the tumor. Theories to explain intracranial hypertension in lower cord lesions, however, have long been debated. One explanation proposes that accumulating CSF proteins and protein degradation products cause increased pressure via a hydrostatic process. For tumors not associated with increased CSF protein levels, the lesion itself may cause pooling of CSF in the lumbar thecal sac, thereby compromising the so-called “lumbosacral elastic reservoir.” In this situation, any further change in CSF volume leads to a rapid rise in ICP from back pressure.30 Other theories to explain the cause of increased ICP in the absence of elevated CSF protein levels involve dissemination of tumor cells, production of mucinous material, secondary hemorrhage, and venous stasis all causing impaired CSF flow.29–35

Spinal block

Cellularity

Spinal block due to a spinal tumor occurs more frequently in the thoracic region because of the narrow anteroposterior diameter of the spinal canal at these levels. In Guidetti and Fortuna’s series, intramedullary tumors obstructed CSF flow later in the disease course than extramedullary tumors.23 Among more advanced tumors, 85–90% of extramedullary lesions caused complete or partial block, while only 75% of intramedullary tumors did so. Normal CSF flow dynamics with evidence of a myelographic block suggests a dysembryogenetic tumor or a lipoma, whereas a dry tap suggests a large tumor of the conus or cauda equina.23 It should always be kept in mind that worsening

The cell counts in CSF associated with primary spinal tumors were reviewed by Laterre and are summarized in Table 13-2.4 For most tumors, a low-grade mononuclear cell pleocytosis is notable, but not specific. This finding may or may not accompany an elevated protein level, but a retrospective study of 503 spinal cord tumors showed that only 6% of cases (30 of 503) were associated with both a normal CSF cell count and a normal CSF protein level.36 Careful study of cellular morphology may provide diagnostic insight in cases of spinal neoplasms, particularly in chronic meningeal syndromes caused by leukemic or carcinomatous meningitis.21 In general, abnormal CSF cytology is more

Spinal cord tumors The CSF findings associated with spinal cord tumors vary with tumor type, location, and stage. In 1975, Guidetti and Fortuna reviewed the published literature on spinal cord tumors. Of 4,674 reported cases, some 20% were intramedullary (mostly gliomas and ependymomas), 50% were divided equally between meningiomas and neurofibromas, and the remaining 30% of cases covered a wide range of other tumor types.23 The wide range of CSF abnormalities associated with various spinal tumors are summarized here.

Bleeding

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likely to be found with spinal compared to brain neoplasms, especially when the tumor has a prominent extramedullary component.

Protein concentration The increase in CSF protein content associated with spinal tumors is also summarized in Table 13-2. A few generalizations about the relationship between tumor type and location and CSF protein level can be made. At one extreme is Froin’s syndrome, a condition where CSF protein concentration is so high that the sample spontaneously clots. For nearly a century this phenomenon has been explained via defective CSF recirculation with impaired outflow from the lumbar thecal sac. It has since been demonstrated that abnormal permeability of meningeal vessels, in part due to compression by the tumor, contributes to this effect.36 Furthermore, Froin’s syndrome is much more likely to occur when a block is caused by a lumbar lesion than by a cervical lesion, regardless of tumor type.21 That protein concentrations below the level of a tumor are higher than those above the tumor was also recognized long ago. Additionally, as lumbar CSF protein content increases, the relative concentration of albumin also rises. In 21 normal patients studied by Hill et al., total protein in the lumbar space averaged 31.3 ± 9.5 mg/dl, 49.5 ± 6.5% of which was albumin. In six patients with partial block, total protein averaged 55.0 ± 5.4 mg/dl, 56.8 ± 4.3% of which was albumin. In six patients with complete block, the average total protein was 416.5 ± 241.0 mg/dl, and the percentage of albumin was 53.5 ± 5.4%.37 These investigators proposed that below a spinal block, low molecular weight proteins are the first to pass through vessels walls into the subarachnoid space. As each protein equilibrates at its own rate, its amount and composition in lumbar CSF would be dependent on the length of time the block has been present. In the final stages of disease, the fluid would resemble serum.37 Since these studies, it has been proposed that the differences in protein concentration above and below a tumor causing spinal block are also attributable to abnormal permeability of vessel walls within the lumbar cavity leading to small capillary hemorrhages that spill blood directly into the CSF.21 Guidetti and Fortuna found the highest CSF protein concentrations in neurinomas and intramedullary tumors (330–12,000 mg/dl), with lower, but still elevated, levels in meningiomas (160–5,000 mg/dl) and other extradural growths.23 Subsequent reports of protein levels in 66 spinal neurofibromas (mean, 410 mg/dl), 51 spinal ependymomas (mean, 2,462 mg/dl), and 22 oligodendrogliomas (mean, 1,397 mg/dl) show trends among other tumor types.26–28,38 Still, many authors have reported cases of spinal tumors with normal CSF protein levels. This CSF parameter, however, is much more commonly abnormal than the CSF cell count.

routine clinical settings. In various studies, it has been noted that enolase enzymes, serotonin, 5-hydroxyindoleacetic acid, melatonin, and gamma-GTP are increased in the CSF of patients with spinal tumors compared to controls.39–41 Glial fibrillary acidic protein (GFAP), S-100, and myelin basic protein (MBP) levels are also increased in CSF in cases of tumoral compression of the cord.42 Ribonuclease activity in CSF, normally 269 ± 95 units/ml, was found to be consistently elevated above 550 units/ml in cases of tumors causing spinal cord compression.43 Overall, while clinical-radiographic-biochemical studies seek to link these CSF markers with disease outcome, their clinical utility at present remains unclear.

Paraneoplastic myelopathy Necrotizing myelopathy is the only paraneoplastic syndrome exclusively limited to the spinal cord. It has been associated with lymphomas, leukemias, and small cell lung cancers. Necrotizing myelopathy is extremely rare, with only a handful of cases reported in the medical literature. It is a rapidly progressive syndrome that typically presents as acute spinal shock with flaccid paraparesis, a sensory level, and sphincter disturbances. The CSF of these patients commonly shows a leukocytosis with a high protein content.3 The syndrome has not been consistently linked with a known anti-neuronal antibody, so serological screening of patients with a fulminant cord syndrome suspicious for this disorder is difficult. Unfortunately, a diagnosis is usually confirmed at autopsy.

Radiation myelopathy With current focusing techniques, the spinal cord is no longer the inadvertent target of radiation injury being used for other tumors and thus radiation myelopathy typically develops only on the heels of therapy for a spinal cord tumor itself. However, it can be very difficult to distinguish radiation myelopathy from the sequelae of the original lesion. Older studies suggest that a normal myelogram and a normal CSF protein level exclude a recurrent or metastatic tumor in favor of a radiation-induced lesion,44 and that 75% of patients with radiation myelopathy have a negative myelogram.45 Among the few cases reported in the literature where CSF data were provided, one describes a patient diagnosed with thoracic radiation myelopathy with a normal myelogram and a normal CSF protein level.46 Two other cases describe patients with elevated CSF protein levels (124 mg/dl in one and spontaneously coagulating CSF in the other) and complete spinal block.44,45

Other markers

Spinal angiomas and arteriovenous malformations

Other CSF markers associated with spinal cord tumors have been investigated, although most are not useful in

Although angiomas, AVFs, and AVMs are the most frequent spinal causes of SAH, most vascular malformations of the

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spine do not present with bleeding. Aminoff reviewed 60 cases of patients who presented with symptoms eventually leading to a diagnosis of spinal AVM or angioma. Only 10 of these patients presented with bloody or xanthochromic CSF suggestive of SAH.5 Of the remaining 50 patients, the CSF was abnormal in 38 (76%). Of these 38 patients, 35 had protein levels higher than 50 mg/dl (the highest being 520 mg/dl), and 11 had WBC counts greater than 5 cells/mm3.5 Four of these 11 patients with a CSF pleocytosis had undergone LP soon after an acute episode of worsening.5 Response to Queckenstedt’s maneuver was recorded in 17 patients, and only one had evidence of obstruction.5 Another study of 60 patients with spinal AVMs confirmed these general findings of high protein, a mild pleocytosis, and normal pressure.6 Additional data can be found in Table 13-2. Riche et al. reviewed 38 pediatric cases of spinal AVM. The CSF was hemorrhagic in 21 patients, showed an elevated protein level in eight patients, and was normal in six patients.47 Finally, an association of spinal AVM with elevated CSF immunoglobulin (Ig) G levels was recently suggested. In a retrospective study of 270 patients with high CSF IgG concentrations, three were eventually diagnosed with spinal AVMs.48 At least four other cases of elevated CSF IgG levels in patients with spinal AVMs have been reported.49

spinal cord have been reported, although the CSF findings were different in each one. In one case, CSF analysis revealed 123 WBC/mm3 and a protein concentration of 52 mg/dl.7 In the other, the CSF revealed no cells and a protein level of 38 mg/dl.53

Other vascular disorders of the spinal cord Spinal cord infarction

Transverse myelitis

Infarction of the spinal cord occurs much less commonly than in the brain. CSF analysis was normal in the two published cases of spinal cord infarction, one due to arterial obstruction and the other to venous outflow impairment.50,51

Epidural hematoma Epidural hematomas are often associated with trauma, malignancies, or blood dyscrasias, and they can even be the consequence of LP or another epidural procedure. The CSF findings reported in this disorder have been neither clear nor consistent. In 1961, Plagne reported a series of patients with spinal block identified via Queckenstedt’s maneuver. Here, the CSF protein was elevated to a maximum level of 100 mg/dl, but cytoalbuminological dissociation was not consistently present as a CSF lymphocytosis occasionally occurred as well.20 In a meta-analysis of 613 patients, Kreppel et al. reported nonspecific findings in the CSF of patients with epidural hematomas.52 While the CSF was usually clear, in some cases xanthochromia was observed. Likewise, CSF protein was usually elevated but sometimes normal. Results of Queckenstedt’s test varied widely (from less than 50% to 100% positive) among individual case series.52

Vasculitis Isolated cerebral vasculitis is a well known but very rare condition. Two cases of isolated vasculitis restricted to the

Epidural abscess Spinal epidural abscesses are severe, generally pyogenic, infections that require emergent surgical intervention to avoid permanent neurological deficits. Although there is a theoretical role for LP to exclude an associated meningitis in suspected cases, there is also the very real risk of seeding the subarachnoid space with bacteria if the spinal needle passes through an area of active infection. Thus, many authors recommend that LP be avoided in cases of suspected epidural abscess and the diagnosis (and decision to intervene surgically) be based solely on spinal MRI findings. In a meta-analysis of 915 patients with spinal epidural abscesses, 130 cases had CSF data available. The average CSF protein was 538 mg/dl (range, 17–5,100 mg/dl) and levels were always above 50 mg/dl.54 Surprisingly, this paper did not report on CSF cellularity in this disorder, but case reports and small case series suggest that a pleocytosis can be absent or present with a roughly equal likelihood.

TM is focal inflammation within a defined region of the spinal cord. The disorder may be idiopathic or associated with an underlying infectious or immunological process. It is usually monophasic, but 5–10% of patients will have recurrent clinical episodes.1,2 A thorough CSF analysis is of central importance in fulfilling published diagnostic criteria, with a pleocytosis and/or an elevated IgG index supporting the diagnosis.2 In the largest series reported to date, 71 of 170 patients (42%) with idiopathic TM had a CSF pleocytosis (mean, 38 cells/mm3; range, 0–950 cells/mm3), and 85 of 170 (50%) had increased protein concentrations (mean, 75 mg/dl).1 Patients with recurrent TM were more likely to have CSF oligoclonal bands (OCBs) in their CSF compared to those with monophasic syndromes.1 Still, these individuals are less likely to have unique OCBs compared to patients whose disease disseminates to the brain, such as in MS. Patients with TM and positive CSF OCBs are also more likely to have an underlying connective tissue disease as a cause of their disorder.1

Spondylitic myelopathy The expected CSF profile in cervical spondylitic myelopathy can be found in Table 13-2. Typical findings include a normal or mildly elevated protein level without a pleocytosis. Of 193 patients in Laterre’s series, only three had CSF protein levels of greater than 100 mg/dl and only five had a cell count of more than 10 cells/mm3.4 Romano et al. suggested

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that the combination of arterial hypertension and chronic cervical cord compression, findings that often co-exist in patients with spondylitic myelopathy, may lead to spontaneous SAH with an associated rise in CSF protein content.55 More recently, other CSF markers associated with spondylosis have been investigated. Asahara et al. and Yumite et al. both found that CSF levels of nitric oxide metabolites were significantly higher in patients with cervical stenosis than in controls.56,57 Laurent et al. noted higher levels of hyaluronan in the CSF of patients with spinal stenosis.58 Cartilagederived retinoic acid-sensitive protein, a molecule expressed during chondrogenesis, and chondrex, a protein secreted by chondrocytes and fibroblasts, have also been found to be elevated in CSF from patients with spinal stenosis.59,60 Still, there are no data at present to suggest that levels of these various substances correlate in any way with clinical outcome.

mean, 125 mg/dl), and was extremely high in the six patients who had a complete spinal block.69 Rarely, hydrocephalus can result following spinal cord injury. Joseph et al. reported such a case in a patient with a cervical stab wound.70 The authors proposed that the injury caused bleeding into the basal cisterns, leading to impaired CSF absorption by the arachnoid villi over the hemispheres and communicating hydrocephalus.70 Other groups have sought potential CSF markers indicative of spinal cord injury. The BB isoform of creatine kinase, GFAP, neurofilament protein, and S-100 have all been found to be increased in the CSF of patients with acute spinal cord injury.71–73 Several of these studies suggest that the presence of neuronal proteins in the CSF of these patients correlates with a poorer clinical recovery over time.

CONCLUSIONS Syringomyelia Syringomyelia is a cavitary expansion of the spinal cord that often produces a progressive myelopathy. More than half of cases are associated with Chiari malformations; the remainder are idiopathic, associated with spinal tumors, or develop following trauma. It is generally agreed that CSF composition in syringomyelia depends on the presence or absence of cord expansion leading to a spinal block. In the presence of block, lumbar CSF protein levels are invariably elevated; without it, protein is more commonly in the normal range.61,62 When the composition of the syrinx fluid is examined in comparison to lumbar CSF, high protein levels within the cavity should point to the possibility of an intramedullary neoplasm.63–66 Conversely, if the syrinx protein content is similar to or less than levels found in the lumbar thecal sac, syringohydromyelia (syringomyelia where the syrinx cavity is in continuity with the fourth ventricle) is suggested.67 Finally, in the event that spinal block in syringomyelia patients is tested by the Queckenstedt maneuver, neck position is important in interpreting the results. In 10 patients with known syringomyelia, the test failed to demonstrate block in all patients with their necks extended but it was positive in all patients with their necks in flexion.68

Spinal trauma Vertebral fracture and dislocation of the vertebral column are the most common causes of traumatic spinal cord injury. Travlos et al. compared CSF data from 51 patients with either unstable spinal fractures or dislocations without bony injury all of whom had associated neurological deficits. A CSF pleocytosis was uncommon (only 10 of 51 patients had pleocytosis with a mean WBC count of 29 cells/mm3), but this finding was more likely in samples obtained within the first 7 days of injury.69 Conversely, CSF protein levels were elevated in most cases (38 of 51 patients,

Analysis of CSF in a patient with an acute or chronic myelopathy can help to clarify an underlying diagnosis. In particular, the identification of inflammatory changes (CSF pleocytosis, high IgG index, positive OCBs) can lead to the diagnosis of disorders that are appropriately treated with immunomodulatory or immunosuppressive therapies. Future studies aim to identify specific biomarkers of clinical outcome or response to treatment. REFERENCES 1. Krishnan C, Kaplin AI, Deshpande DM, et al. Transverse myelitis: pathogenesis, diagnosis and treatment. Front Biosci 2004;9: 1483–1499. 2. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002;59:499–505. 3. Hauser SL, Ropper AH. Diseases of the spinal cord. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005:1136–1140. 4. Laterre EC. Cerebrospinal fluid. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Vol. 19. Amsterdam: North-Holland; 1975:125–138. 5. Aminoff MJ. Spinal Angiomas. Oxford: Blackwell Scientific; 1976:54–68. 6. Tobin WD, Layton DD. The diagnosis and natural history of spinal cord arteriovenous malformations. Mayo Clin Proc 1976;51: 637–646. 7. Ropper AH, Ayata C, Adelman L. Vasculitis of the spinal cord. Arch Neurol 2003;60:1791–1794. 8. Parmar H, Pang BC, Lim CC, et al. Spinal schwannoma with acute subarachnoid hemorrhage: a diagnostic challenge. Am J Neuroradiol 2004;25:846–850. 9. Murata K, Nishio A, Nishikawa M, et al. Subarachnoid hemorrhage and spinal root injury caused by acupuncture needle-case report. Neurol Med Chir (Tokyo) 1990;30:956–959. 10. Lesoin F, Rousseaux M, Besson R, et al. Post-traumatic subarachnoid hemorrhage of the cauda equina. Acta Neurol Belg 1985;85:166–170. 11. Fobe JL, Nishikuni K, Gianni MA. Evolving magnetic resonance spinal cord trauma in child: from hemorrhage to intradural arachnoid cyst. Spinal Cord 1998;36:864–876.

References

12. Harris W. Two cases of spontaneous hemorrhachis or intrameningeal spinal hemorrhage, one cured by laminectomy. Proc R Soc Med 1911;5:115–122. 13. Pau A, Brambilla M, Cossu M, et al. Spinal subarachnoid hematoma of unknown aetiology. A case report. Neurosurgery 1991;34: 151–153. 14. Gupta SK, Dhir JS, Khosla VK. Traumatic spinal subarachnoid hematoma: report of a case with MRI. Surg Neurol 1997;48: 189–192. 15. Runnels JB, Hanbury JW. Spontaneous subarachnoid hemorrhage associated with spinal cord tumor. Case report. J Neurosurg 1974; 40:252–254. 16. Komiyama M, Yasui T, Sumimoto T, et al. Spontaneous spinal subarachnoid hematoma of unknown pathogenesis: case reports. Neurosurgery 1997;41:691–694. 17. Hiyama H, Shimizu T, Yato S, et al. Widespread spontaneous spinal subarachnoid hematoma. Case report. Neuol Med Chir (Tokyo) 1990; 30:842–847. 18. Plotkin R, Ronthal M, Froman E. Spontaneous spinal subarachnoid hemorrhage. Report of 3 cases. J Neurosurg 1966;25:287–293. 19. Sunada I, Akano Y, Kidosaki Y, et al. Spontaneous spinal subarachnoid hematoma – case report. Surg Neurol 1995;44:133–136. 20. Plagne R. L’hématome extra-dural rachidien non traumatique (hématome épidural spontané). Thèse pour le Doctorat en Médecine (Diplôme d-Etat). Université de Clermont, Faculté mixte de Médecine et de Pharmacie, 1961. 21. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: Saunders; 1992:309–311. 22. Irani DN, Kerr DA. 14-3-3 protein in the cerebrospinal fluid of patients with acute transverse myelitis. Lancet 2000;355:901. 23. Guidetti B, Fortuna A. Differential diagnosis of intramedullary and extramedullary tumors. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Vol. 19. Amsterdam: North-Holland; 1975:51–75. 24. Minami M, Hanakita J, Suwa H, et al. Cervical hemangioblastoma with a past history of subarachnoid hemorrhage. Surg Neurol 1998; 49:278–281. 25. Okladnikov GI. Cerebrospinal fluid dynamics in tumors of the spinal cord and cauda equina. Zh Nevropatol Psikhiatr Im S S Korsakova 1986;86:1051–1054. 26. Levy WJ, Latchaw J, Hahn JF, et al. Spinal neurofibromas: a report of 66 cases and a comparison with meningiomas. Neurosurgery 1986; 18:331–344. 27. Levy WJ, Bay J, Dohn D. Spinal cord meningioma. J Neurosurg 1982; 57:804–812. 28. Sonneland PR, Scheithauer BW, Onofrio BM. Myxopapillary ependymoma. A clinicopathologic and immunocytochemical study of 77 cases. Cancer 1985;56:883–893. 29. Matzkin DC, Slamovits TL, Genis I, et al. Disc swelling: a tall tail? Surv Opthalmol 1992;37:130–136. 30. Costello F, Kardon RH, Wall M, et al. Papilledema as the presenting manifestation of spinal schwannoma. J Neuro-Opthalmol 2002; 22:199–203. 31. Oikawa S, Kyoshima K, Takamae T, et al. Multiple spinal neurinomas presenting visual disturbance as the initial symptom: case report. Surg Neurol 1992;38:309–314. 32. Tanaka K, Waga S, Shimosaka S. Papilledema and spinal cord tumors. Surg Neurol 1988;29:462–466. 33. Glasauer FE. Thoracic and lumbar intraspinal tumours associated with increased intracranial pressure. J Neurol Neurosurg Psychiatry 1964;27:451–458. 34. Ammerman BJ, Smith DR. Papilledema and spinal cord tumors. Surg Neurol 1975;3:55–57. 35. Breen LA. Disc edema and peripheral neuropathy. Surv Opthalmol 1994;38:467–474. 36. Wieczorek V, Seifferth G, Pothe H, et al. Normal cerebrospinal fluid findings in spinal tumors – an analysis of 503 cases. Psychiatr Neurol Med Psychol 1989;41:609–613.

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37. Hill NC, Goldstein NP, McKenzie BF, et al. Cerebrospinal fluid proteins, glycoproteins and lipoproteins in obstructive lesions of the central nervous system. Brain 1959;82:581–593. 38. Fortuna A, Celli P, Palma L. Oligodendrogliomas of the spinal cord. Acta Neurochir (Wein) 1980;52:305–329. 39. Royds JA, Davies-Jones GA, Lewtas NA, et al. Enolase isoenzymes in the cerebrospinal fluid of patients with diseases of the nervous system. J Neurol Neurosurg Psychiatry 1983;46:1031–1036. 40. Makarov AI, Pomnikov VG, Sheludchenko FI. Serotonin and its metabolites in the cerebrospinal fluid and blood of patients with tumors of the spinal cord. Zh Vopr Neirokhir Im N N Burdenko 1985;5:12–15. 41. Akimov GA, Zinchenko VA, Kalashnikov AV, et al. Activity of gamma-glutamyltranspeptidase in spinal fluid in diseases of the nervous system. Zh Nevropatol Psikhiatr Im S S Korsakova 1985;85:1767–1770. 42. Anderson RE, Winnerkvist A, Hansson LO, et al. Biochemical markers of cerebrospinal ischemia after repair of aneurysms of the descending and thoracoabdominal aorta. J Cardiothorac Vasc Anesth 2003;17:882–889. 43. Rabin EZ, Weinberger V, Tattrie B. Ribonuclease activity of human cerebrospinal fluid. Can J Neurol Sci 1977;4:125–130. 44. Fogelholm R, Haltia M, Andersson LC. Radiation myelopathy of cervical spinal cord simulating intramedullary neoplasm. J Neurol Neurosurg Psychiatry 1974;37:1177–1180. 45. Palmer JJ. Radiation myelopathy. Brain 1972;95:109–122. 46. Kasperek S, Weglarz A, Panasiewicz M. Thoracic radiation myelopathy. Neurol Neurochir Pol 1993;27:583–588. 47. Riche MC, Modenesi-Freitas J, Dijindjian M, et al. Arteriovenous malformations (AVM) of the spinal cord in children. A review of 38 cases. Neuroradiology 1982;22:171–180. 48. Didgar M, Gille M, Declercq I, et al. Intramedullary cavernous angiomas and cerebrospinal fluid oligoclonal IgG bands. J Neurol 2000;247:970–971. 49. Cohen O, Biran I, Steiner I. Cerebrospinal fluid oligoclonal IgG bands in patients with spinal arteriovenous malformation and structural central nervous system lesions. Arch Neurol 2000;57:553–557. 50. Gonzalez-Ordonez AJ, Uria DF, Ferreiro D, et al. Spinal cord infarction and recurrent venous thrombosis in association with estrogens and the 20210A allele of the prothrombin gene. Neurologia 2001;16: 434–438. 51. Hughes JT. Venous infarction of the spinal cord. Neurology 1971;21: 794–800. 52. Kreppel D, Antoniadis G, Seeling W. Spinal hematoma: a literature survey with meta-analysis of 613 patients. Neurosurg Rev 2003;26:1–49. 53. Feasby TE, Ferguson GG, Kaufmann JC. Isolated spinal cord arteritis. Can J Neurol Sci 1975;2:143–146. 54. Reihsaus E, Waldbaur H, Seeling W. Spinal epidural abscess: a meta-analysis of 915 patients. Neurosurg Rev 2000;23:175–204. 55. Romano A. Marsella M, Swamy N, et al. Cervical subarachnoid hematoma of unknown origin: case report. Acta Neurochir (Wien) 1999;141:1115–1117. 56. Asahara H, Yokoi I, Tamada K, et al. Increased cerebrospinal fluid nitrite and nitrate levels in patients with lumbar spondylosis. Res Commun Mol Pathol Pharmacol 1996;91:77–83. 57. Yumite Y, Takeuchi K, Harada Y, et al. Concentration of nitric oxide (NO) in spinal fluid of chronic spinal disease. Acta Med Okayama 2001;55:219–228. 58. Laurent UB, Laurent TC, Hellsing LK, et al. Hyaluronan in human cerebrospinal fluid. Acta Neurol Scand 1996;94:194–206. 59. Natsume N, Kondo S, Matsuyama Y, et al. Analysis of cartilage-derived retinoic acid-sensitive protein in cerebrospinal fluid from patients with spinal diseases. Spine 2001;26:157–160. 60. Tsuji T, Matsuyama Y, Natsume N, et al. Analysis of chondrex (YLK-40, HC gp-39) in the cerebrospinal fluid of patients with spine disease. Spine 2002;27:732–735.

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61. Barnett HJ, Foster JB, Hudgson P. Syringomyelia. Philadelphia: W.B. Saunders; 1973:148–151. 62. Hall PV, Lindseth RE, Turner ML, et al. Alterations in cerebrospinal fluid dynamics in syringomyelia, hydromyelia, and myelomeningocele. In: Wood JH, ed. Neurobiology of Cerebrospinal Fluid. New York: Plenum Press; 1980:895–911. 63. Lohle PN, Wurzer HA, Hoogland PH, et al. The pathogenesis of syringomyelia in spinal cord ependymoma. Clin Neurol Neurosurg 1994;96:323–326. 64. Landan I, Gilroy J, Wolfe DE. Syringomyelia affecting the entire spinal cord secondary to primary spinal intramedullary central nervous system lymphoma. J Neurol Neurosurg Psychiatry 1987;50:1533–1535. 65. Helle TL, Britt RH, Colby TV. Primary lymphomas of the central nervous system. J Neurosurg 1984;60:94–103. 66. Henry JM, Heffner RR, Dillard SH, et al. Primary malignant lymphomas of the central nervous system. Cancer 1974;34:1292–1302. 67. Gardner WJ. Hydrodynamic mechanism of syringomyelia: its relationship to myelocele. J Neurol Neurosurg Psychiatry 1965;28:247–259.

68. Tachibana S, Iida H, Yada K. Significance of positive Queckenstedt test in patients with syringomyelia associated with Arnold-Chiari malformations. J Neurosurg 1992;76:67–71. 69. Travlos A, Anton HA, Wing PC. Cerebrospinal fluid cell count following spinal cord injury. Arch Phys Med Rehab 1994;75: 293–296. 70. Joseph G, Johnston RA, Fraser MH, et al. Delayed hydrocephalus as an unusual complication of a stab injury to the spine. Spinal Cord 2005;43:56–58. 71. Pasaoglu A, Pasaoglu H. Enzymatic changes in the cerebrospinal fluid as indices of pathological change. Acta Neurochir 1989; 97:71–76. 72. Guez M, Hildingsson C, Rosengren L, et al. Nervous tissue damage markers in cerebrospinal fluid after cervical spine injuries and whiplash trauma. J Neurotrauma 2003;20:853–858. 73. Brisby H, Olmarker K, Rosengren L, et al. Markers of nerve tissue injury in the cerebrospinal fluid in patients with lumbar disc herniation and sciatica. Spine 1999;24:742–746.

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Neurodegenerative and Movement Disorders Jennifer L. Berkeley and Richard J. O’Brien

INTRODUCTION Most neurodegenerative diseases, and dementias in particular, are diagnosed on clinical grounds. Beyond the history and physical examination, however, further work-up may include a cranial computed tomography (CT) or magnetic resonance imaging (MRI) scan to evaluate for neoplasm or hydrocephalus and to assess the pattern of brain atrophy, if present. Routine lab testing may also be used to screen for metabolic abnormalities, vitamin B12 deficiency, thyroid dysfunction and, in high-risk patients, syphilis or human immunodeficiency virus (HIV) infection. Lumbar puncture (LP) and cerebrospinal fluid (CSF) evaluation, on the other hand, are not considered a routine part of the work-up for most neurodegenerative disorders. Recent practice guidelines published by the American Academy of Neurology recommend LP in the evaluation of demented patients only in the following settings: (1) suspicion of metastatic cancer, (2) suspicion of central nervous system (CNS) infection, (3) positive serologic screen for syphilis, (4) imaging changes consistent with hydrocephalus, (5) age less than 55 years, (6) rapid clinical progression or unusual features of dementia, (7) immunosuppression, or (8) suspicion of CNS vasculitis.1

APPROACH IN A PATIENT WITH DEMENTIA Abnormalities in the routine analysis of CSF samples from a demented patient could suggest an etiology other than a neurodegenerative disease. Thus, an elevated white blood cell (WBC) count might suggest HIV infection, Lyme disease, or neurosyphilis, while elevated total protein content might suggest malignancy or vasculitis. Protein levels in the 40–60 mg/dl range have been reported in typical Alzheimer’s disease (AD), and these levels can be higher in AD complicated by stroke.2 However, a CSF protein level above 60 mg/dl in the absence of diabetes or recent stroke

should be thoroughly investigated. In the case of a rapidly progressive dementia suggestive of Creutzfeld-Jacob disease, measurement of CSF 14-3-3 protein level is warranted.

Alzheimer’s disease Despite current recommendations against CSF evaluation in routine cases of dementia, there are measurable CSF changes in samples from patients with AD. Unfortunately, overlap of such changes between mildly demented patients and age-matched normal controls makes them unhelpful in the routine evaluation of a single patient. Given that the pathology of AD consists primarily of tissue accumulation of beta-amyloid peptide (Aβ) and excessively phosphorylated forms of the microtubule-associated protein, tau, levels of these two proteins have been extensively studied in CSF. A large body of literature suggests that the concentrations of these two proteins change in the CSF in AD, commonly showing an increase in the level of tau and a decrease in one isoform of Aβ. Still, given that the accuracy of a clinical diagnosis of AD at academic medical centers is in the range of 80–90%,3,4 the challenge at present is to determine whether CSF assays for tau and beta-amyloid can improve upon these rates. A more pressing area of investigation is whether assays for tau, Aβ, or other biomarkers will help in pre-clinical stages of AD or in determining which patients with mild cognitive impairment (MCI) will progress to AD.

Tau Neurofibrillary tangles, a central pathological feature of AD, are composed of paired helical filaments of tau. Tau is a 68 kDa microtubule-associated protein, which in AD becomes hyperphosphorylated at multiple serine and threonine residues, leading to its aggregation. Aggregates of tau, however, are not unique to AD and can be found in other neurodegenerative diseases such as Pick’s disease, progressive supranuclear palsy (PSP), and corticobasal

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degeneration (CBD). Thus, studies evaluating tau levels in CSF must be able to separate patients with AD from normal controls as well as from those suffering from other neurodegenerative diseases. While none of these dementias is treatable at present, diagnostic accuracy is important as it gives patients and their families a basis in fact for the ongoing disease as well as for expectations regarding the rate of functional decline. Furthermore, as new therapies that target specific pathological processes are developed, diagnostic accuracy will be crucial to establish those patients in whom a treatment is likely to be effective and to accurately enroll patients in clinical trials. A recent meta-analysis of 34 studies examining total CSF tau levels in AD showed a significant difference between AD patients and non-demented age-matched controls. In this analysis, the mean CSF tau concentration was 534 pg/ml in AD patients (n=1,054) and 212 pg/ml in controls (n=2,284).5 Although such differences often proved to be statistically significant, many studies examining tau in AD have also shown notable overlap between the AD and control groups. This limits the clinical utility of this test in individual patients, especially those with mild cases.5,6 There also is no direct association between CSF tau concentrations and clinical severity of disease as measured by the Mini-Mental State Examination (MMSE) score.7–9 CSF tau levels also can differ between AD patients and those with other forms of dementia, including those known to have a tau-related neuropathology. In the largest study comparing CSF tau levels in patients with dementias of multiple etiologies completed to date, significant differences were found between AD patients and those with frontotemporal dementia (FTD), vascular dementia (VD), Lewy body dementia (LBD), and other neurologic diseases.10 CSF tau levels proved to be elevated in VD and LBD, though not to the same extent as in AD. They were not elevated above controls in subjects with FTD.10 This study also examined whether measuring tau phosphorylation at threonine 231 (p-tau231) improved the ability to distinguish between these neurodegenerative diseases. Measuring p-tau231 did, in fact, help differentiate AD from FTD as well as AD from healthy controls.10 Thus, measurement of CSF tau levels, particularly p-tau231, may eventually prove to be clinically useful to distinguish between AD and other dementing illnesses. At present, however, normal CSF tau levels do not preclude a diagnosis of AD.

Beta-amyloid Amyloid plaques, another main pathological feature of AD, are composed of aggregations of Aβ, a breakdown product of the intracellular amyloid precursor protein (APP). When APP is processed by a series of intracellular enzymes known as secretases, several Aβ fragments of different lengths and solubilities are produced. The major plaque-forming cleavage products of APP are peptides of either 40 or 42 amino acids, known as Aβ40 and Aβ42, respectively. Early studies of amyloid breakdown products in the CSF of AD patients

did not distinguish between the individual peptide fragments and no significant differences were seen in total CSF levels of Aβ between AD patients and controls.11–13 With the development of specific antibodies that distinguish between peptides ending at amino acids 40 and 42, however, the ability to quantify each specific fragment in the CSF has generated some interesting results. Aβ42 is a more insoluble fragment than Aβ40 and it may form the nidus of the amyloid plaques. CSF Aβ42 levels have been found to be lower in AD patients when compared to age-matched non-demented controls, and several possible explanations for this finding have been proposed. First, Aβ is secreted by healthy neurons, and as cells die or become dysfunctional with disease progression, less Aβ is generated. Second, as Aβ accumulates in plaques, less of the fragment is available for diffusion into the CSF. Finally, a decrease in CSF Aβ levels may reflect abnormal protein transport processes that are at the heart of the disease. This latter point is particularly important for future research. The Aβ peptide is produced at high levels under normal circumstances. It is not clear whether the production increases, decreases or stays the same in subjects with sporadic AD. More importantly, while some Aβ is hydrolyzed by endogenous proteases in the brain such as neprilysin, the vast majority of brain Aβ reaches the blood stream, where it is degraded by the liver. Whether Aβ reaches the blood stream through CSF flow or is transported into the blood across specialized transport molecules embedded within brain capillaries is not known. Moreover, how Aβ reaches the CSF from deep within the brain interstitium is also an unknown. In a meta-analysis of 17 studies, 15 showed statistically significant differences in CSF Aβ42 levels between AD and controls, with means of 554 pg/ml and 979 pg/ml, respectively.5 Some studies have calculated the Aβ42 to Aβ40 ratio, with some reporting an increased ability to distinguish between AD and controls.14 Once again, however, despite the fact that the differences in the CSF Aβ42 to Aβ40 ratio between AD patients and controls reached statistical significance, there was too much overlap between groups to make this a useful test in individual patients. Furthermore, there are limited data in cases of MCI, where the overlap with controls appears to be even greater. As in the case of tau, there is no strong correlation between CSF Aβ42 levels and the degree of dementia as measured by the MMSE.15,16 Finally, as a practical matter, it turns out that Aβ levels are technically difficult to measure, and factors such as the type of tube in which the sample is collected (polypropylene is recommended), the storage conditions, characteristics of the detecting antibody, and the number of freeze/thaw cycles can all greatly influence the final Aβ levels.15,17

Combination assays Given that CSF concentrations of both tau and Aβ42 are altered in AD patients, combining the two assays was hypothesized to increase diagnostic sensitivity and specificity.

Approach in a Patient with Dementia

Several studies have taken this combined analysis approach, and in most the sensitivity for AD detection was >70% while the specificity varied depending on the group to which the AD patients were being compared (see Table 14-1). Unfortunately, however, most of these studies lacked a gold standard diagnostic assay such as post mortem examination. Moreover, the issue is not how these tests work in isolation, but whether they add anything to the clinical evaluation of patients and how they perform in the mildest (and most uncertain) cases. A major concern with all these studies is that most diagnoses were made without any neuropathological confirmation. Clearly, the sensitivity and specificity of these CSF assays would be affected by misdiagnosis. In one study where all diagnoses were confirmed at autopsy, CSF tau had a sensitivity of 85% and a specificity or 84% in distinguishing AD patients from cognitively normal controls using a cutoff of 234 pg/ml.6 However, using tau to distinguish AD patients from those with FTD or LBD had a sensitivity of 72% and specificity of 69%.6 Interestingly, Aβ measurements did not add any extra diagnostic value in this study.

Other CSF markers While most studies examining the CSF of AD patients have focused on Aβ and tau, a variety of other biomarkers have been identified that may eventually prove to be even more useful in distinguishing AD from other dementing illnesses. To illustrate newer approaches being used, one study screened CSF samples from pathologically confirmed AD cases using proteomic methodologies in comparison with specimens from both healthy and other neurological disease

Table 14-1

117

controls. Using two-dimensional protein gel electrophoresis (2DE) to separate all the proteins in each sample and determine their relative abundance, and then tandem timeof-flight mass spectrometry to identify individual proteins isolated from each 2DE gel spot, a group of 23 proteins were identified that reliably distinguished AD from nonAD samples (sensitivity 94%, specificity 94%).18 This CSF “proteome” then reliably distinguished blinded CSF samples with comparable sensitivity and specificity as a validation of its accuracy. This approach raises the possibility that such CSF biomarkers may be useful in the diagnosis of AD.

Mild cognitive impairment Many studies show that routine CSF analysis adds little diagnostic value once a patient has overt clinical evidence of dementia. However, there is a large group of patients who are cognitively impaired yet do not meet diagnostic criteria for dementia in whom early therapeutic intervention could prove most beneficial. As such, there is an intense search for biological markers that predict which patients with MCI will progress to AD. Given that the pathological processes in AD are thought to start long before clinical symptoms become apparent, it is likely that Aβ and tau concentrations are abnormal in CSF during the period of MCI. Indeed, several studies do suggest that elevated CSF tau levels and decreased CSF Aβ levels in MCI patients predict future conversion to AD,19 while others have shown that only the p-tau231 levels correlate with the progression of MCI to AD.20 In one recent study of 137 MCI patients and 39 age-matched controls, the combined use of CSF Aβ42, total-tau, and p-tau181 levels yielded a

Sensitivity and Specificity of Combined CSF Ab42 and Total Tau Levels in the Diagnosis of AD

Study

Sensitivity

Hulstaert (1999)

85%

Schoonenboom (2004) Andreasen (2001)

72% 94% 88%

Kanai (1998) Tapiola (2000)

71% 50%

Galasko (1998)

77%

Motter (1995) Sunderland (2003) Riemenschneider (2002)

Specificity

Comparison

59% 92%

87% 86% 58% 93% 100% 89% 67% 48% 83% 95% 85% 93% 65% 100% 89%

AD vs. C AD vs. OND AD vs. NAD AD vs. FTD AD vs. PS AD vs. C AD vs. LBD AD vs. VD AD vs. C AD vs. C AD vs. NAD AD vs. C AD vs. NAD AD vs. C AD vs. C

92% 85%

95% 85%

AD vs. C AD vs. FTD

Reference 34

35 36

37 38 39 40 5 41

AD, Alzheimer’s disease; C, normal control; OND, other neurological diseases; NAD, non-AD dementia; FTD, frontotemporal dementia; LBD, Lewy body dementia; PS, psychiatric disorders; VD, vascular dementia. (Adapted from Verbeek MM, De Jong D, Kremer HP. Brain-specific proteins in cerebrospinal fluid for the diagnosis of neurodegenerative diseases. Ann Clin Biochem 2003;40:25–40.)

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sensitivity of 95% and a specificity of 83% for the detection of incipient AD among MCI patients.21 Thus, there is some promise that CSF analyses may yield useful diagnostic assays that could identify early patients and guide them into therapeutic trials.

MOVEMENT DISORDERS Parkinson’s disease and other a-synucleinopathies Like AD, Parkinson’s disease (PD) is also characterized pathologically by abnormal protein accumulation in the brain. In this case, α-synuclein aggregates into intraneuronal inclusions called Lewy bodies within dopaminergic neurons of the substantia nigra. In multi-system atrophy (MSA), which in its early stages can resemble PD, α-synuclein is present in characteristic glial cytoplasmic inclusions. While it is possible to measure α-synuclein in CSF, levels are unchanged in PD patients compared to normal controls and are not clinically useful.22 Still, other CSF markers have been proposed to be able to make the more relevant distinction of PD from MSA, and several studies suggest that the combined measurement of the noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and various axonal proteins, including neurofilament light and heavy chains, can separate PD and MSA samples with reasonable sensitivity and specificity.23,24 Furthermore, CSF Aβ42 concentrations may aid in the discrimination of these two disorders, as levels are decreased in MSA only.25 As is the case in AD, none of these substances has proven to be useful in monitoring the clinical progression of PD or in the response to treatment. Each, however, is an area of active investigation.

Cerebellar ataxias Slowly progressive cerebellar ataxia in adulthood can represent diseases that have an inherited, toxic, metabolic, paraneoplastic, infectious, autoimmune, or idiopathic basis. Routine CSF studies are obviously more relevant in some (i.e., infectious, autoimmune, paraneoplastic) than in other (i.e., inherited, toxic, metabolic) of these disorders. Still, among the hereditary spinocerebellar ataxias, several studies have shown diminished levels of biogenic amines and increased levels of oxidative stress markers in CSF that start to shed light on disease mechanisms.29–31 Falling concentrations of HVA, in particular, track with disease progression, supporting its further study in these diseases.29 One study suggests that CSF neurotransmitter metabolite and axonal protein levels can discriminate the cerebellar form of MSA from idiopathic late-onset cerebellar ataxia.32

CONCLUSIONS Routine CSF analyses in most cases of dementia and among the more common movement disorders are normal and do not typically aid in the diagnosis or management of these patients. Still, there are defined situations in demented patients where a complete CSF analysis is indicated.1 Recent molecular diagnostic tools have shown us that there are specific substances found in the CSF of patients with disorders such as AD, and careful clinicopathological correlations suggest that the detection of these compounds may allow for the identification of patients in the earliest stages of this disease. From the standpoint of understanding disease pathophysiology, there may also be lessons to be learned through the careful analysis of CSF specimens. REFERENCES

Huntington’s disease Huntington’s disease (HD) is an autosomal dominant disorder characterized by chorea, behavioral disturbances, dementia, and motor impersistence. A diagnosis is made by genetic testing that reveals an expansion of a CAG repeat in the huntingtin gene found on chromosome 4. CSF analysis is not a routine undertaking in these patients, but it has been used to elaborate on disease pathogenesis. One study showed that CSF levels of the dopamine metabolite homovanillic acid (HVA) were reduced compared to normal individuals, PD patients, and those with a variety of other neurological diseases.26 This suggested that reduced dopamine neurotransmission might account for the clinical finding of bradykinesia in HD patients. More recently, CSF samples from HD patients have shown increased transglutaminase activity, possibly reflecting higher levels of a similar process within the disease tissue itself.27 These reactions crosslink proteins, rendering them highly insoluble, and this may help to explain how the mutant huntingtin protein is neurotoxic.28

1. Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, Small GW, Miller B, Stevens JC. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1143–1153. 2. Hammerstrom DC, Zimmer B. The role of lumbar puncture in the evaluation of dementia: the University of Pittsburgh Study. J Am Geriatr Soc 1985;33:397–400. 3. Lim A, Tsuang D, Kukull W, et al. Clinico-neuropathological correlation of Alzheimer’s disease in a community-based case series. J Am Geriatr Soc 1999;47:564–569. 4. Mirra SS. Neuropathological assessment of Alzheimer’s disease: the experience of the Consortium to Establish a Registry for Alzheimer’s Disease. Int Psychogeriatr 1997;9(Suppl 1):263–272. 5. Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer’s disease. JAMA 2003;289:2094–2103. 6. Clark CM, Xie S, Chittams J, et al. Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol 2003;60:1696–1702. 7. Munroe WA, Southwick PC, Chang L, et al. Tau protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer’s disease. Ann Clin Lab Sci 1995;25:207–217.

References

8. Sunderland T, Wolozin B, Galasko D, et al. Longitudinal stability of CSF tau levels in Alzheimer patients. Biol Psychiatry 1999;46:750–755. 9. Vigo-Pelfrey C, Seubert P, Barbour R, et al. Elevation of microtubuleassociated protein tau in the cerebrospinal fluid of patients with Alzheimer’s disease. Neurology 1995;45:788–793. 10. Buerger K, Zinkowski R, Teipel SJ, et al. Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. Arch Neurol 2002;59:1267–1272. 11. Chong JK, Miller BE, Ghanbari HA. Detection of amyloid beta protein precursor immunoreactivity in normal and Alzheimer’s disease cerebrospinal fluid. Life Sci 1990;47:1163–1171. 12. Henriksson T, Barbour RM, Braa S, et al. Analysis and quantitation of the beta-amyloid precursor protein in the cerebrospinal fluid of Alzheimer’s disease patients with a monoclonal antibody-based immunoassay. J Neurochem 1991;56:1037–1042. 13. Southwick PC, Yamagata SK, Echols CL Jr, et al. Assessment of amyloid beta protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer’s disease. J Neurochem 1996;66:259–265. 14. Lewczuk P, Esselmann H, Otto M, et al. Neurochemical diagnosis of Alzheimer’s dementia by CSF Abeta42, Abeta42/Abeta40 ratio and total tau. Neurobiol Aging 2004;25:273–281. 15. Andreasen N, Hesse C, Davidsson P, et al. Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol 1999;56:673–680. 16. Mehta PD, Pirttila T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM. Plasma and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer disease. Arch Neurol 2000;57:100–105. 17. Schoonenboom NS, Mulder C, Vanderstichele H, et al. Effects of processing and storage conditions on amyloid beta (1–42) and tau concentrations in cerebrospinal fluid: implications for use in clinical practice. Clin Chem 2005;51:189–195. 18. Finehout EJ, Franck Z, Choe LH, Relkin N, Lee KH. Cerebrospinal fluid proteomic biomarkers for Alzheimer’s disease. Ann Neurol 2006 Dec 13; [Epub ahead of print]. 19. Hampel H, Teipel SJ, Fuchsberger T, et al. Value of CSF betaamyloid1–42 and tau as predictors of Alzheimer’s disease in patients with mild cognitive impairment. Mol Psychiatry 2004;9:705–710. 20. Buerger K, Teipel SJ, Zinkowski R, et al. CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 2002;59:627–629. 21. Hansson O, Zetterberg, H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–234. 22. Borghi R, Marchese R, Negro A, et al. Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci Lett 2000;287:65–67. 23. Abdo WF, De Jong D, Hendriks JC, et al. Cerebrospinal fluid analysis differentiates multiple system atrophy from Parkinson’s disease. Mov Disord 2004;19:571–579. 24. Abdo WF, Bloem BR, Van Geel WJ, Esselink RA, Verbeek MM. CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson’s disease. Neurobiol Aging 2006 May 5; [Epub ahead of print]. 25. Holmberg B, Johnels B, Blennow K, Rosengren L. Cerebrospinal fluid Abeta42 is reduced in multiple system atrophy but normal in

26. 27.

28.

29.

30. 31.

32. 33. 34. 35. 36. 37.

38. 39.

40. 41.

119

Parkinson’s disease and progressive supranuclear palsy. Mov Disord 2003;18:186–190. Garcia Ruiz PJ, Mena MA, et al. Cerebrospinal fluid homovanillic acid is reduced in untreated Huntington’s disease. Clin Neuropharmacol 1995;18:58–63. Jeitner TM, Bogdanov MB, Matson WR, et al. N(episilon)(gamma-L-glutamyl)-L-lysine (GGEL) is increased in cerebrospinal fluid of patients with Huntington’s disease. J Neurochem 2001;79:1109–1112. Martin A, Romito G, Pepe I, et al. Transglutaminase-catalyzed reactions responsible for the pathogenesis of celiac disease and neurodegenerative diseases: from basic biochemistry to clinic. Curr Med Chem 2006;13:1895–1902. Higgins JJ, Harvey-White JD, Nee LE, Colli MJ, Grossi TA, Kopin IJ. Brain MRI, lumbar CSF monoamine concentrations, and clinical descriptors of patients with spinocerebellar ataxia mutations. J Neurol Neurosurg Psychiatry 1996;61:591–595. Botez MI, Young SN. Biogenic amine metabolites and thiamine in cerebrospinal fluid in herido-degenerative ataxias. Can J Neurol Sci 2001;28:134–140. Ihara Y, Takata H, Tanabe Y, Nobukuni K, Hayabara T. Influence of repetitive transcranial magnetic stimulation on disease severity and oxidative stress markers in the cerebrospinal fluid of patients with spinocerebellar degeneration. Neurol Res 2005;27: 310–313. Abdo WF, van de Warrenburg BP, Munneke M, et al. CSF analysis differentiates multiple-system atrophy from idiopathic late-onset cerebellar ataxia. Neurology 2006;67:474–479. Verbeek MM, De Jong D, Kremer HP. Brain-specific proteins in cerebrospinal fluid for the diagnosis of neurodegenerative diseases. Ann Clin Biochem 2003;40:25–40. Hulstaert F, Blennow K, Ivanoiu A, et al. Improved discrimination of AD patients using beta-amyloid(1–42) and tau levels in CSF. Neurology 1999;52:1555–1562. Schoonenboom NS, Pijnenburg YA, Mulder C, et al. Amyloid beta(1–42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease. Neurology 2004;62:1580–1584. Andreasen N, Minthon L, Davidsson P, et al. Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001;58:373–379. Kanai M, Matsubara E, Isoe K, et al. Longitudinal study of cerebrospinal fluid levels of tau, A beta1–40, and A beta1–42(43) in Alzheimer’s disease: a study in Japan. Ann Neurol 1998;44: 17–26. Tapiola T, Pirttila T, Mikkonen M, et al. Three-year follow-up of cerebrospinal fluid tau, beta-amyloid 42 and 40 concentrations in Alzheimer’s disease. Neurosci Lett 2000;280:119–122. Galasko D, Chang L, Motter R, et al. High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998;55:937–945. Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995;38:643–648. Riemenschneider M, Wagenpfeil S, Diehl J, et al. Tau and Abeta 42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002;58:1622–1628.

CHAPTER

15

Neuromuscular Diseases Brett M. Morrison and John W. Griffin

INTRODUCTION Neuromuscular diseases are classically divided by localization into disorders that involve cranial and spinal motor neurons, spinal nerve roots, nerve plexuses, peripheral nerves, neuromuscular junctions, and/or muscles. The evaluation of cerebrospinal fluid (CSF) composition is not routinely needed to help facilitate a diagnosis of a suspected neuromuscular disease. Rather, electromyography, nerve conduction studies, and/or nerve and muscle biopsies are often of greater diagnostic importance. Nevertheless, CSF findings can provide important supplemental data in the evaluation of these patients. Alterations in CSF composition have been reported in a variety of neuromuscular diseases due to the transudation of serum proteins, the release of intracellular substances from degenerating cells, the recruitment of inflammatory cells, and/or the production of cytokines and other signaling molecules.

MOTOR NEURON DISORDERS Amyotrophic lateral sclerosis A clinical diagnosis of amyotrophic lateral sclerosis (ALS) is made in the setting of a combined upper and lower motor neuron signs and/or symptoms present in multiple regions of the body.1,2 Although no specific alterations are seen in the CSF of patients with ALS, several non-specific indicators of intrathecal inflammation and breakdown of the blood–brain barrier (BBB) have been reported. In one study of 33 patients with ALS, 46% of patients had mildly elevated CSF albumin levels, 18% had an increased CSF immunoglobulin (Ig) G index, and 9% had unique detectable oligoclonal bands.3 Another study demonstrated that 25% of ALS patients had CSF total protein levels of greater than 50 mg/dl and 12% had detectable oligoclonal bands.4 Finally, increased levels of complement and of monocyte chemoattractant protein-1 (MCP-1), a chemokine

involved in the recruitment of macrophages, have been found in the CSF of patients with ALS.5,6 In addition to these inflammatory markers, levels of substances such as the excitatory amino acid neurotransmitter, glutamate, breakdown products of structural components of neurons such as neurofilament proteins, and even viral nucleic acids have been investigated in the CSF of ALS patients for both their diagnostic value as well as to clarify the underlying mechanisms of motor neuron degeneration. Thus, elevated CSF glutamate levels, which may be due to reduced function of specific glutamate transporters on astrocytes, have been known for some time.7,8 Although not necessarily useful for the diagnosis of ALS, this finding has shed significant light on the role of glutamate-mediated excitotoxicity in motor neuron degeneration. Other potential CSF biomarkers of ALS include the neurofilament light-chain protein and 3-nitrotyrosine, but abnormal levels of these peptides have been found in less than 50% of patients with ALS and therefore do not serve a useful diagnostic purpose.9,10 Lastly, despite virus-specific nucleic acid sequences not being causally linked to ALS,11,12 investigators have used polymerase chain reaction (PCR)-based techniques to search for them as possible markers for ALS.13–15 The results of these studies have been mixed; one study demonstrated the presence of enterovirus RNA in the CSF of ALS patients,13 while several others have been unable to confirm such a link.14,15 Given the propensity of certain enteroviruses to infect spinal motor neurons (see below), the possibility of a viral link to ALS has remained a subject of ongoing investigation.

Poliomyelitis and poliomyelitis-like syndromes Vaccination has dramatically reduced the incidence of poliomyelitis worldwide, and viral causes of acute flaccid paralysis are now more commonly linked with non-polio enteroviruses as well as flaviviruses including West Nile virus (WNV) and Japanese encephalitis virus (JEV).16

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JEV is endemic in India, China, and Southeast Asia. Although the infection most commonly presents with meningoencephalitis, it has also been reported to cause acute flaccid paralysis.16 A diagnosis is confirmed by detecting virus-specific IgM antibodies or JEV antigens in the CSF. Antigen testing is particularly important in the first week of infection, as virus-specific IgM may only be detected in 50% of JEV cases during this period. Other CSF abnormalities include an elevated white blood cell (WBC) count in 68% of patients (mean 146 cells/mm3, range 11–800 cells/mm3) and an elevated total protein content 57% of the time (range 48–152 mg/dl).17 In the USA, WNV is the most common viral cause of acute flaccid paralysis. Infections now occur throughout the continental USA, Canada, and Mexico between April and November. Most are asymptomatic; about 1% of infected individuals develop a nonspecific flu-like syndrome or a gastrointestinal illness, and only a fraction of these patients develop subsequent neurological manifestations including meningoencephalitis and/or acute flaccid paralysis.18,19 Similar to JEV infection, the paralysis is acute, asymmetric, and most commonly mistaken for GuillainBarré syndrome (GBS). Likewise, diagnosis of WNV infection of the central nervous system (CNS) is confirmed by isolating WNV-specific IgM antibodies in the CSF, or by finding such antibodies in the serum of a patient with abnormal CSF and an acute neurological illness. Other CSF abnormalities at presentation include an elevated WBC count in more than 95% of patients (mean 229 cells/mm3, range 0–2600 cells/mm3), with at least 50% neutrophils on the initial WBC differential in over one-third of cases.19,20 Furthermore, the CSF total protein content is elevated almost all the time (mean 117 mg/dl, range 24–292 mg/dl), with a concentration of 100 mg/dl in almost half of encephalitis patients.19,20

PLEXUS DISORDERS Brachial plexopathy Brachial plexus lesions are usually defined by their anatomic location rather than by a specific disease process. Still, two etiologies that deserve attention with respect to alterations of CSF composition are neoplastic plexopathies and neuralgic amyotrophy. Neoplastic plexopathy does not refer to a single disease process, as there are multiple mechanisms by which malignancies can affect the brachial or lumbar plexuses.22 These include direct invasion or compression of the plexus by a surrounding solid tumor (e.g., breast or lung cancer in the brachial plexus, gastrointestinal or gynecologic cancer in the lumbar plexus), diffuse infiltration from meningeal carcinomatosis (e.g., hematological malignancies), or via radiation damage. The CSF profile in each of these situations may help to clarify the underlying pathophysiology. Thus, while all three scenarios may cause elevated CSF protein content, flow cytometry and cytopathology are invaluable in the diagnosis of any malignancy that invades into the subarachnoid space. There is some consensus that while a single LP may be relatively low-yield, three largevolume samples can be diagnostic of intraspinal malignancy in approximately 95% of cases.23,24 Another important cause of brachial plexus dysfunction is neuralgic amyotrophy, also commonly referred to as Parsonage-Turner syndrome. This disorder is characterized by acute onset of pain in the shoulder and arm, followed by weakness, sensory loss, and atrophy in the involved limb.25 Brachial plexus inflammation triggered by a parainfectious process is proposed to be the underlying cause. Although CSF studies in neuralgic amyotrophy are usually normal, one study demonstrated high CSF protein levels in four of 35 patients and a lymphocytic pleocytosis in one of 35 individuals.26

Stiff person syndrome Stiff person syndrome (SPS) is a rare disorder characterized by involuntary muscular rigidity and episodic spasms. It is believed to have an autoimmune pathogenesis, as antibodies that react to glutamic acid decarboxylase (GAD) or to ampiphysin have been linked to this disorder.2 These antibodies may target spinal interneurons, lessening their inhibitory effect on spinal motor neurons. Dalakas et al. studied the CSF of 15 patients with SPS, and compared findings with those from patients with diabetes or other autoimmune diseases. While the CSF cell count, oligoclonal bands, and IgG index were normal in all 15 patients with SPS, antibodies against GAD-65 were detected in the CSF of 10 out of 15 cases.21 These intrathecal antibodies were proposed to provide further evidence for the autoimmune pathogenesis of this disorder. A lumbar puncture (LP) is unnecessary for diagnosis, however, because these autoantibodies are also found in the serum of affected individuals.

NERVE ROOT AND PERIPHERAL NERVE DISORDERS Acquired demyelinating polyneuropathies The spectrum of GBS is now generally felt to include acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and Fisher syndrome.27 These disorders share a common clinical presentation with rapidly progressive weakness and loss of reflexes evolving over several weeks, as well as an autoimmune pathogenesis involving antibody responses against components of the myelin sheath and axon membranes, including gangliosides.27,28 The diseases can be linked to preceding infections in two-thirds of patients, including ones caused by cytomegalovirus, Epstein-Barr virus, and Campylobacter jejuni. A chronic form of disease, known as chronic inflammatory demyelinating polyneuropathy (CIDP), has clinical

Nerve Root and Peripheral Nerve Disorders

features similar to GBS, except that its progression lasts for greater than 2 months.29,30 The exact pathogenetic relationship between the acute and chronic disorders is unclear. Searching for altered CSF composition is useful in the diagnosis of both GBS and CIDP. The classic triad of findings in GBS – weakness, areflexia and elevated CSF protein – were first reported by Guillain, Barré, and Strohl in 1916.31 The CSF changes in this disorder were termed “cytoalbuminologic dissociation,” reflecting an elevation of CSF protein, frequently greater than 100 mg/dl, with minimal or no elevation in the number of CSF leukocytes. The initial CSF results should be interpreted cautiously, however, as only 50% of patients with GBS have an elevated CSF protein concentration at presentation.27,32 The mean CSF protein level reaches a maximum at 16–30 days from symptom onset, ranging from 140 to 213 mg/dl in one cohort,32 at which time 90% of patients demonstrate an elevation of CSF protein.28 The absence of CSF leukocytes was historically used to exclude a diagnosis of poliomyelitis, which was previously a major cause of acute flaccid paralysis. With the worldwide reduction in the incidence of this disorder, the absence of leukocytes is now important to rule out other causes of acute flaccid paralysis such as WNV, non-polio enteroviruses, Lyme disease, human immunodeficiency virus (HIV) infection, and neurosarcoidosis. An exception to the cytoalbuminologic dissociation occurs in HIV-associated GBS, where there may be up to 50 leukocytes/mm3 in the CSF.33 A recent area of GBS research involves the identification of pathogenic autoantibodies directed against components of the myelin sheath or the axolemma, including the gangliosides GM1, GD1a, and GD1b, in the CSF.34–37 Ganglioside-like epitopes have been found on the surface of certain Campylobacter strains, and molecular mimicry has been invoked to explain how such infections might trigger a subsequent immune-mediated demyelinating neuropathy by generating cross-reactive antibodies. Animal models have now demonstrated that these anti-ganglioside antibodies can directly cause nerve degeneration, and this provides an experimental format to test novel treatment approaches for these diseases.38 In contrast to CSF changes in GBS that do not reliably occur until after the first week of symptoms, there is no delay in the development of CSF changes among CIDP patients. As such, CSF analysis is an extremely valuable diagnostic undertaking in suspected cases of CIDP. In one study of 63 patients with CIDP, CSF protein levels were elevated in 86% of patients at presentation (mean, 127 mg/dl; range, 26–515 mg/dl), while a pleocytosis occurred in only 8% of these cases (range, 7–42 cells/mm3).34 For this reason, and to rule out meningeal carcinomatosis as the cause of the neuropathy, many patients with suspected CIDP undergo a CSF analysis. Due to the rarity of the disorder, few studies have reported on CSF findings in the Fisher variant of GBS. In one recent study of 123 patients, however, CSF protein

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concentrations rose with similar kinetics and to levels similar to those reported in other cases of GBS.39 Thus, only 25% of patients demonstrated an elevated CSF protein concentration within the first week, but this percentage increased to 84% by 3 weeks following symptom onset.39 Beyond this non-specific CSF finding, several studies have shown an association between Fisher syndrome and the presence of anti-GQ1b antibodies.38,39 Thus, in one study of 123 patients, 85% had serum antibodies directed against GQ1b, a ganglioside present on peripheral nerves, and changes were found early in the course of disease.39 Unfortunately, this finding has not proven to be entirely specific for the Fisher variant, as it also can be seen in AIDP with ataxia and in Bickerstaff encephalitis.38 Furthermore, while the anti-GQ1b antibody test is now commercially available, the results usually take several weeks to return and therefore are only useful in confirming a diagnosis suspected on clinical grounds. Another acquired demyelinating polyneuropathy occurs in the setting of monoclonal gammopathy of undetermined significance (MGUS). In one study that evaluated this disorder, 23 of 26 (88%) of patients with an IgM gammopathy and a demyelinating polyneuropathy had an elevated CSF protein content (mean, 103 mg/dl; range, 41–284 mg/dl).40 In those patients with IgA or IgG gammopathies and demyelinating polyneuropathies, 18 of 21 (86%) demonstrated elevated CSF protein levels (mean, 100 mg/dl; range, 16–580 mg/dl).40 Similar results were confirmed in two smaller cohorts with this disease.41,42

Diabetic neuropathy The peripheral nervous system (PNS) manifestations of diabetes mellitus can present as a distal symmetric sensory neuropathy, a mononeuropathy, a mononeuropathy multiplex, an autonomic neuropathy, or a plexopathy.43 With respect to CSF changes in these disorders, the mean CSF protein content in a study of 26 patients with diabetic neuropathy was 92.5 mg/dl.44 Nineteen of these 26 patients (73%) had CSF protein levels greater than 70 mg/dl, while 10 of 26 (38%) had protein levels greater than 100 mg/dl. In this same cohort, no patient had an elevated CSF IgG index, although four of 26 had detectable CSF oligoclonal bands.44 Findings of elevated CSF protein levels in diabetic neuropathy should be interpreted with caution, however, as elevated protein content has also been reported in diabetics without any clinical or electrophysiological evidence of neuropathy.45 Still, CSF protein levels in diabetics without neuropathy are lower than those reported in diabetics with neuropathy. In one study, less than 25% of diabetics without neuropathy had CSF protein concentrations greater than 50 mg/dl (range, 18–87 mg/dl), while more than 80% of those with neuropathy had levels greater than 50 mg/dl (range, 18–176 mg/dl).45,46 Other CSF changes were not reported in these cohorts.

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Hereditary neuropathies Hereditary neuropathies represent a diverse group of disorders that may present in children, but also are often not identified until adulthood. Diagnosis is difficult as there are diverse clinical presentations, variable disease penetrance, and sporadic cases resulting from de novo gene mutations.47 Specific attention will be given to the CSF profile of three such diseases: Charcot-Marie-Tooth (CMT) disease, acute intermittent porphyria (AIP), and amyloidosis. CMT is the most prevalent hereditary peripheral neuropathy. It represents a diverse group of disorders with more than 24 genetically distinct forms.48 Electrophysiological studies demonstrate either a demyelinating (CMT1) or an axonal (CMT2) pattern. In patients who have de novo mutations and no family history, the main diagnostic considerations are CIDP and polyneuropathy associated with MGUS. For this reason, many patients who turn out to have CMT undergo both serum protein electrophoresis and an LP. In CMT, patients uniformly demonstrate a normal routine CSF profile that distinguishes them from CIDP.47 AIP is a rare, autosomal dominant disease that results from reduced activity of the enzyme porphobilinogen deaminase, causing elevated porphobilinogen levels in urine and serum. Clinically, the disease manifests as acute episodes of crampy abdominal pain, constipation, and both CNS and PNS involvement.2 Peripheral manifestations are of an acute neuropathy that can mimic GBS. Patients are typically asymptomatic between episodes. During these asymptomatic periods, the CSF protein level is normal and oligoclonal bands are absent.49 In contrast, two-thirds of patients demonstrate elevated CSF protein levels without increases in cellularity during acute attacks.50 Still, the

Table 15-1

degree of protein elevation is much less in AIP than in GBS and can often distinguish these disorders. Another hereditary neuropathy is familial amyloid polyneuropathy. Initial clinical presentation is that of a small-fiber neuropathy with paresthesias and neuropathic pain. Motor involvement becomes evident later and can be profoundly disabling. Diagnosis is usually made by genetic analysis, although support may come from nerve conduction studies or nerve biopsy. Similar to CMT, the utility of LP is largely to exclude other causes of peripheral neuropathy and the CSF is uniformly normal.51

DISEASES OF MUSCLE AND THE NEUROMUSCULAR JUNCTION In general, CSF analysis is not an important tool in the diagnosis of most muscle diseases and neuromuscular junction disorders. The limited published information on the CSF findings in the inflammatory myopathies, myasthenia gravis, and the muscular dystrophies is presented here.

Myopathies The inflammatory myopathies (polymositis, dermatomyositis, inclusion body myositis) all cause myalgias, elevated serum creatine kinase levels, proximal muscle weakness, and inflammation on muscle biopsy. Muscle pathology, in particular, can usually distinguish between the three diseases.52 In the only published series where CSF findings were reported, no abnormalities in cytology, albumin levels, IgG index, or total protein content were found in patients with inclusion body myositis.53

Expected CSF Profiles in Selected Neuromuscular Disorders Protein Level >50 mg/dl (% of patients)

Mean Protein Level (mg/dl)

Range Protein Level (mg/dl)

Pleocytosis (range, cells/mm3 or % of patients >5 cells/mm3)

ALS

25%

67

24–178

Neuralgic amyotrophy WNV

11% 95%

44 117

21–122 24–292

3% >95% (0–2600)

50% 90% 86%

140 213 127

25–242 44–1333 26–800

6% (0–54) 2% (0–11) 8% (7–42)

25% 84% 88% 86%

34 84 103 100

25–45 55–130 41–284 16–580

73% 67%

93 74

54–197 52–122

GBS - initial - after 2 wks CIDP Fisher variant - initial - after 3 wks MGUS neuropathy - IgM - IgG or IgA Diabetic neuropathy Myotonic dystrophy

0%

Other Findings 9–12% OCB, 18% IgG index

WNV-specific IgM, 0–50% PMNs 11% OCB 21% OCB 18% OCB

8% 6% 0% 0% None None

Refs. 3,4

25 19,20

28,32,58 28,32,59 34,60 39,61 39,61 40 40

15% OCB

44 56,57

References

Myasthenia gravis Myasthenia gravis is a disorder characterized by fatigable muscular weakness. The pathogenesis of the disease is well understood to be due to the abnormal production of antibodies against the nicotinic acetylcholine receptor.54 While very few studies of the CSF findings in myasthenics have been reported, one cohort of 46 patients demonstrated no measurable alteration in cell count, total protein level, or IgG index.55

Muscular dystrophies The muscular dystrophies are a heterogeneous group of disorders that include Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, limb-girdle dystrophy, and fascioscapular-humeral dystrophy. With respect to the CSF profiles in these disorders, none demonstrates alterations in cell counts, and the majority have no alterations in total protein content.56 One exception appears to be myotonic dystrophy; 66% of patients in one small study appeared to have mildly elevated CSF protein levels. The source of this protein appeared to be elevated CSF immunoglobulin levels, perhaps bespeaking an immunological pathogenesis.57

CONCLUSIONS As demonstrated by the expected CSF profiles found in these various disorders (Table 15-1), the utility of CSF analysis in the diagnosis of neuromuscular disease remains limited. Although CSF protein content is reliably elevated in several neuromuscular disorders, these results are often not specific enough to help in such processes as distinguishing the individual causes of a peripheral neuropathy. Future studies may identify new CSF biomarkers that will assist clinicians with the diagnosis of neuromuscular diseases. REFERENCES 1. Tandan R. Clinical features and differential diagnosis of classical motor neuron disease. In: Williams AC, ed. Motor Neuron Disease. London: Chapman and Hall; 1994:3–28. 2. Adams R, Victor M, Ropper A. Principles of Neurology. New York: McGraw-Hill; 1997. 3. Apostolksi S, Nikolic J, Bugarski-Prokopljevic C, Meletic V, Pavlovic S, Filipovic S. Serum and CSF immunological findings in ALS. Acta Neurol Scand 1991;83:96–98. 4. Younger DS, Rowland LP, Latov N, et al. Motor neuron disease and amyotrophic lateral sclerosis: relation of high CSF protein content to paraproteinemia and clinical syndromes. Neurology 1990;40: 595–599. 5. Annunziata P, Volpi N. High levels of C3c in the cerebrospinal fluid from amyotrophic lateral sclerosis. Acta Neurol Scand 1985;72:61–64. 6. Baron P, Bussini S, Cardin V, et al. Production of monocyte chemoattractant protein-1 in amyotrophic lateral sclerosis. Muscle Nerve 2005;32:541–544. 7. Rothstein JD, Tsai G, Kuncl RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 1990;28:18–25.

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8. Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 1992;326:1464–1468. 9. Rosengren LE, Karlsson J-E, Karlsson, J-O, Persson LI, Wikkelso C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 1996;67:2013–2018. 10. Shaw PJ, Williams R. Serum and cerebrospinal fluid biochemical markers of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1 Suppl 2:S61–S67. 11. Kelley-Geraghty DC, Jubelt B. Viruses and motor neuron disease: the viral hypothesis lives. In: Williams AC, ed. Motor Neuron Disease. London: Chapman and Hall; 1994:587–602. 12. Jubelt B, Lipton HI. Persistent scientists do not find persisting enteroviruses. Neurology 2004;62:1250–1251. 13. Berger MM, Kopp N, Vital C, Redl B, Aymard M, Lina B. Detection and cellular localization of enterovirus RNA sequences in spinal cord of patients with ALS. Neurology 2000;54:20–25. 14. Walker MP, Schlaberg R, Hays AP, Bowser R, Lipkin WI. Absence of echovirus sequences in brain and spinal cord of amyotrophic lateral sclerosis patients. Ann Neurol 2001;49:249–253. 15. Nix WA, Berger MM, Oberste MS. Failure to detect enterovirus in the spinal cord of ALS patients using a sensitive RT-PCR method. Neurology 2004;62:1372–1377. 16. Solomon T, Kneen R, Dung NM, et al. Poliomyelitis-like illness due to Japanese encephalitis virus. Lancet 1998;351: 1094–1097. 17. Desai A, Chandramuki A, Gourie-Devi M, Ravi V. Detection of Japanese encephalitis virus antigens in the CSF using monoclonal antibodies. Clin Diag Virol 1994;2:191–199. 18. Jeha LE, Sila CA, Lederman RJ, Prayson RA, Isada CM, Gordon SM. West Nile virus infection: A new paralytic illness. Neurology 2003;61:55–59. 19. Saad M, Youssef S, Kirschke D, et al. Acute flaccid paralysis: the spectrum of a newly recognized complication of West Nile virus infection. J Infect 2005;51:120–127. 20. Tyler KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters BK. CSF findings in 250 patients with serologically confirmed West Nile meningitis and encephalitis. Neurology 2006;66;361–365. 21. Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57:780–784. 22. Beghi E, Kurland LT, Mulder DW, Nicolosi A. Brachial plexus neuropathy in the population of Rochester, Minnesota, 1970–1981. Ann Neurol 1985;18:320–323. 23. Grisold W, Piza-Katzer H, Jahn R, Herczeg E. Intraneural nerve metastasis with multiple mononeuropathies. J Peripher Nerv Syst 2000;5:163–167. 24. Grossman SA, Krabek MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999;25:103–119. 25. Rubin DI. Neuralgic amyotrophy: clinical features and diagnostic evaluation. Neurologist 2001;7:350–356. 26. Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial plexus neuropathy. Arch Neurol 1972;27:109–117. 27. Hughes RA, Cornblath DR. Guillain-Barré syndrome. Lancet 2005;366:1653–1666. 28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med 1992;326:1130–1136. 29. Busby M, Donaghy M. Chronic dysimmune neuropathy. J Neurol 2003;250:714–724. 30. Sander HW, Latov N. Research criteria for defining patients with CIDP. Neurology 2003;60(suppl 3):S8–S15. 31. Guillain G, Barré JA, Strohl A. Sur un syndrome de radiculo neurite avec hyperalbuminose du liquide cephalo-rachidien sans reaction cellulaire: remarques sur les caracteres cliniques et graphiques des reflexes tendineux. Bull Mem Soc Med Hosp Paris 1916;40:1462–1470.

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32. McFarland HR, Heller G. Guillain-Barré disease complex. A statement of diagnostic criteria and analysis of 100 cases. Arch Neurol 1966;14:196–201. 33. Cornblath DR, McArthur JC, Kennedy PG, Witte A, Griffin JW. Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann Neurol 1987;21:32–40. 34. Rotta FT, Sussman AT, Bradley WG, Ayyar DR, Sharma KR, Shebert RT. The spectrum of chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 2000;173:129–139. 35. Simone IL, Annunziata P, Maimone D, Liguori M, Leante R, Livrea P. Serum and CSF anti-GM1 antibodies in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 1993;114:49–55. 36. Kimura F, Ito T, Yuki N, et al. Longitudinal study of cerebrospinal fluid (CSF) class-specific antibodies against Campylobacter jejuni and GM1 ganglioside in Guillain-Barré syndrome. Intern Med 1995;34: 1009–1114. 37. Odaka M, Yuki N, Tatsumoto M, Tateno M, Hirata K. Ataxic GuillainBarré syndrome associated with anti-GM1b and anti-GalNAc-GD1a antibodies. J Neurol 2004;241:24–29. 38. Willison HJ. The immunobiology of Guillain-Barré syndromes. J Periph Nerv Syst 2005;10:94–112. 39. Nishimoto Y, Odaka M, Hirata K, Yuki N. Usefulness of anti-GQ1b IgG antibody testing in Fisher syndrome compared with cerebrospinal fluid examination. J Neuroimmunol 2004;148:200–205. 40. Gosselin S, Kyle RA, Dyck PJ. Neuropathy associated with monoclonal gammopathies of undetermined significance. Ann Neurol 1991; 30:54–61. 41. Dalakas MC, Engel WK. Polyneuropathy with monoclonal gammopathy: studies of 11 patients. Ann Neurol 1981;10:45–52. 42. Kelly JJ, Adelman LS, Berkman E, Bhan I. Polyneuropathies associated with IgM monoclonal gammopathies. Arch Neurol 1988;45: 1355–1359. 43. Llewelyn JG. The diabetic neuropathies: types, diagnosis, and management. J Neurol Neurosurg Psychiatry 2003;74: 15–19. 44. Pascoe MK, Low PA, Windebank AJ, Litchy WJ. Subacute diabetic proximal neuropathy. Mayo Clin Proc 1997;72: 1123–1132.

45. Kutt H, Hurwitz LJ, Ginsburg SM, McDowell F. Cerebrospinal fluid protein in patients with diabetes mellitus. Trans Am Neurol Assoc 1960;85: 217–218. 46. Kutt H, Hurwitz LJ, Ginsburg SM, McDowell F. Cerebrospinal fluid protein in patients with diabetes mellitus. Arch Neurol 1961;4:31–36. 47. Pareyson D. Diagnosis of hereditary neuropathies in adult patients. J Neurol 2003;250:148–160. 48. Shy ME. Charcot-Marie-Tooth disease: an update. Curr Opin Neurol 2004;17:579–585. 49. Bylesjo I, Brekke O, Prytz J, Skjeflo T, Salveson R. Brain magnetic resonance imaging white-matter lesions and cerebrospinal fluid finding in patient with acute intermittent porphyria. Eur Neurol 2004;51:1–5. 50. Latorre G, Munoz A. Acellular cerebrospinal fluid with elevated protein level in patients with acute intermittent porphyria. Arch Intern Med 1989;149:1695. 51. Adams D. Hereditary and acquired amyloid neuropathies. J Neurol 2001;248;647–657. 52. Younger DS. The myopathies. Med Clin N Am 2003;87:899–907. 53. Lindberg C, Persson LI, Bjorkander J, Oldfors A. Inclusion body myositis: clinical, morphological, physiology and laboratory findings in 18 cases. Acta Neurol Scand 1994;89:123–131. 54. Drachman DB. Myasthenia gravis. N Engl J Med 1994;330:1797–1810. 55. Thorlacius S, Aarli JA. The cerebrospinal fluid in myasthenia gravis. Acta Neurol Scand 1985;72:432–436. 56. Hirase T, Araki S. Cerebrospinal fluid proteins in muscular dystrophy patients. Brain Dev 1984;6:10–16. 57. Kjellin KG, Stibler H. Isoelectric focusing and electrophoresis of cerebrospinal fluid proteins in muscular dystrophies and spinal muscular atrophies. J Neurol Sci 1976;27:45–57. 58. Siden A, Kjellin KG. Isoelectric focusing of CSF proteins in known or probable infectious neurological diseases and the Guillain-Barré syndrome. J Neurol Sci 1979;42:139–153. 59. Link H, Wahren B, Norrby E. Pleocytosis and immunoglobulin changes in cerebrospinal fluid and herpesvirus serology in patients with Guillain-Barré syndrome. J Clin Microbiol 1979;9:305–316. 60. Bouchard C, Lacroix C, Plante V, et al. Clinicopathologic findings and prognosis in chronic inflammatory demyelinating polyneuropathy. Neurology 1999;52:498–503. 61. Berlit P, Rakicky J. The Miller Fisher syndrome. Review of the literature. J Clin Neuroophthalmol 1992;12:57–63.

CHAPTER

16

Isolated Seizures and Epileptic Disorders Adam L. Hartman and Eileen P. G. Vining

INTRODUCTION Seizures can be the presenting manifestation of such diverse central nervous system (CNS) disorders as meningitis, intracerebral hemorrhage, stroke, or brain tumor. A lumbar puncture (LP) often can help to diagnose these conditions, especially when initial brain imaging studies are normal. A common dilemma facing clinicians is when to perform an LP in a patient with isolated or recurrent seizures, and, if the procedure is undertaken, how to distinguish an idiopathic seizure disorder from a more serious underlying condition based on the cerebrospinal fluid (CSF) profile. In other words, what CSF findings can reasonably be attributed to the seizure itself, and what changes are indicative of some underlying pathology that caused the seizure to occur? This chapter will focus on the CSF findings that accompany idiopathic seizure disorders. The expected CSF profiles in defined conditions such as infections or cerebrovascular disorders that present with seizures are covered in separate chapters in this volume.

METHODOLOGICAL ISSUES A wide variety of CSF abnormalities have been reported in patients with seizures. This diversity of findings may in part relate to the fact that early studies investigating this subject often failed to distinguish those individuals with seizures due to underlying illnesses from those with idiopathic seizures. In contrast, more recent reports have benefited from the use of improved methods to detect underlying infections, vascular events, and malignancies, and thus have more precisely defined the various patient populations in question. One can therefore easily imagine how differences among the populations being studied could have an important impact on the resultant CSF findings. Table 16-1 outlines a general differential diagnosis of isolated, new-onset seizures.

An LP undertaken in such a patient is usually done to exclude one of these conditions, especially infection or subarachnoid hemorrhage.

PATHOPHYSIOLOGY The blood–brain barrier (BBB) is commonly breached in experimental seizure paradigms, thereby allowing circulating factors potential access to the CSF. The concentration of ions and small molecules, in particular, increases in the CSF soon after seizures in many of these models. One autoradiographic study in rats showed that an amino acid analog not ordinarily capable of crossing the BBB could be found in various brain regions following experimental status epilepticus (SE) and temporal lobe epilepsy.1,2 A similar ultrastructural study of generalized seizures in adult rats demonstrated increased BBB permeability to molecules such as albumin, Evans blue dye, and horseradish peroxidase.3 Here, the primary transport mechanism across the BBB was found to be micropinocytosis in small blood vessels dilated beyond their normal size. Systemic hypertension also facilitated this transport across the BBB, since passage was greatly limited when hypertension was controlled.3 A related phenomenon was observed in a magnetic resonance imaging (MRI) study of a patient with a history of daily complex partial seizures over 3 weeks. Post-ictal imaging showed enhancement of both anterior mesiotemporal cortices (areas that coincided closely with EEG abnormalities), suggesting increased BBB permeability as a direct result of the seizures.4 This enhancement resolved on a repeat study after the seizures were controlled. Together, these experimental studies demonstrate that BBB permeability can be temporarily but significantly altered following seizure activity, and, by extension, that post-ictal CSF composition may also reflect these permeability changes.

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Table 16-1 Underlying Causes of Isolated, New-Onset Seizures Epilepsy (idiopathic seizures) Intracranial hemorrhage (subarachnoid, subdural, intraparenchymal) Infection (bacterial, viral, fungal) Malformations of cortical development Malignancy Metabolic* Non-epileptic seizures Stroke Toxic ingestion Trauma *Including inborn errors of metabolism.

COMMON CEREBROSPINAL FLUID CHANGES FOLLOWING SEIZURES IN PATIENTS OF ALL AGES Cellularity A common clinical conundrum is whether an elevated CSF white blood cell (WBC) count following a seizure indicates some underlying pathological process or is simply the result of the seizure itself. In part, this question arises because peripheral WBC counts often increase after a seizure. Demargination of immature neutrophil band forms also can be observed in post-ictal WBC differentials obtained from the peripheral blood. Still, whether an

analogous process consistently occurs in the CSF has been the subject of many studies. Table 16-2 and Table 16-3 summarize data from multiple studies where CSF cell counts and WBC differentials have been examined soon after seizures in cohorts of patients without confirmatory evidence of CNS infection. The caveat of heterogeneity among study populations is once again emphasized in drawing general conclusions from these data. Clinicians should also consult the age-stratified standard reference values of their own diagnostic laboratory when findings from an individual patient are reviewed. A large study of patients with SE showed that 10% of patients (4 of 40) without a confirmed acute insult to explain the seizure (e.g., stroke, infection, or alcohol withdrawal) had an abnormal post-ictal CSF WBC count.5 Two of these four patients had total CSF counts greater than 5 cells/mm3 (maximum, 28 cells/mm3), while two others had polymorphonuclear cells (PMNs) detected but less than 5 cells/mm3 total. Of these four patients, one was a child suspected to have a degenerative disease and another had a history of subacute head trauma. Of the two remaining patients with no previously known CNS disease, the highest CSF WBC count was 8 cells/mm3. Conversely, among patients with new SE and known acute CNS disease (e.g., meningitis, stroke, trauma, or metabolic derangement), the prevalence of a CSF pleocytosis was 20% (19 of 98 patients).5 One limitation of this study is that the subtype of SE (e.g., convulsive, partial, nonconvulsive) was not reported.

Table 16-2 Total Cerebrospinal Fluid White Blood Cell Counts in Patients with Recent Seizures and no Evidence of CNS Infection Study Population

Sample Size

Neonates < 40 wk 40–43 wk > 43 wk

12 10 15

Pediatric status epilepticus

64

Febrile seizures Pediatric inpatient Hospital service < 6 wk 6 wk–3 months 3–6 months 6–12 months > 12 months Children with different seizure subtypes Complex febrile Status epilepticus Non-febrile

Mean (SD) (cells/mm3) 7 (5) 6 (5) 2 (2) 13.6 (7.3)

Range (cells/mm3) 2–20 0–20 0–5

45

2.1 (2.2)

0–13

1.9 (2.1)

0–11

22 17 18 29 21

Pediatric hospital (inpatient and ER) < 4 months > 4 months

7 55

Adults

65

Ref. 19 19 19

8–25

107

111 57 63

Upper %ile (cells/mm3)

17 7.02

(95th)

16 15

3.37 (75th) 3.00 (75th) 2.94 (75th) 1.75 (75th) 1.83 (75th)

15 15 15 15 15

2.2 (3.2) 1.5 (1.9) 1.9 (2.7)

0–19 0–9 0–13

8.2 (95th) 6.5 (95th) 8.1 (95th)

14 14 14

3.86 (3.89) 1.75 (1.84)

0–12 0–8

7.80 (90th) 4.00 (90th)

13 13

10.2 (24.4)

0–71

9

129

Common CSF Changes following Seizures in Patients of all Ages

Table 16-3 Infection

Cerebrospinal Fluid Neutrophil Counts in Patients with Recent Seizures and no Evidence of CNS

Study Population

Mean (SD) (cells/mm3)

Range (cells/mm3)

Upper %ile (cells/mm3)

Mean (SD) (% PMNs)

Range (% PMNs)

Ref.

Neonates < 40 weeks 40–43 weeks > 43 weeks

3 (2) 3 (3) 2 (2)

1–6 0–12 0–5

37 52 48

12–43 0–75 0–100

19 19 19

Pediatric status epilepticus

2.87 (3.21)

1–14

32.6 (18.9)

12–64

17

Febrile seizures

0.21 (0.48)

0–7

9.2 (18.8)

0–72

16

Children with different seizure subtypes Complex febrile Status epilepticus Non-febrile

0.7 (1.3) 0.3 (0.7) 0.1 (0.3)

0–8 0–3 0–1

4 (95th) 3 (95th) 1 (95th)

22.1 (19.7) 17.4 (13.6) 12.9 (10.9)

0–67 0–47 0–31

14 14 14

Pediatric hospital (inpatient and ER) < 4 months > 4 months

0.02 (0.03) 0.01 (0.03)

0–0.09 0–0.18

0.06 (90th) 0.02 (90th)

Adults

4.6 (19.7)

0–55

Another study of young adults being evaluated in an epilepsy monitoring unit (none of whom had acute causes for their seizures) performed CSF examinations in the acute phase after various types of seizures. This study demonstrated that a pleocytosis of more than 5 WBCs/mm3 was found in three of 27 specimens (11%) when the LP was performed within 72 h of the last ictal event.6 The maximum WBC count was 12 cells/mm3, and there were never more than 2% PMNs. The seizure types resulting in a pleocytosis included simple, complex partial, and generalized tonic-clonic; patients with atonic and myoclonic seizures did not have a pleocytosis. Of the 27 patients in this study, 10 had idiopathic epilepsy, eight had a history of febrile seizures, and the remaining nine had distant underlying etiologies (meningitis, stroke, or head trauma). A post-ictal pleocytosis was more common within 12 h of the last seizure. A question not answered by this study is whether focal seizures can produce the same CSF findings as generalized seizures. One report of two patients with epilepsia partialis continua documented normal CSF WBC counts in both cases.7 A number of older studies that examined the CSF of patients with underlying etiologies for seizures are described here for comparison purposes. Because these studies were done before technologies such as MRI and polymerase chain reaction (PCR) came into common clinical use, their conclusions may not be directly comparable to more modern investigations. In one demonstrative example, evidence for seizures directly causing a CSF pleocytosis came from a patient admitted with ascites due to alcoholic cirrhosis who subsequently experienced a flurry of generalized seizures.8 One day prior to this event, his CSF was examined in response to a change in his mental state and was found to be normal. Immediately following his

13 13 53.5 (38.2)

0–100

9

seizures, however, he had 80 WBCs/mm3 in his CSF; serial LPs showed progressively decreasing WBC counts over the next 2 days.8 In another published review of patients with SE, not all of whom underwent LP in the post-ictal period, CSF cell counts ranged from 0 to 71 WBCs/mm3 immediately following the event.9 Among the 65 patients who underwent LP and in whom infection was excluded, 12 individuals (18%) had a pleocytosis of greater than 5 cells/mm3 (mean, 10.2 cells/mm3; range, 0–71 cells/mm3).9 Another series examined CSF cell counts after 98 generalized tonic-clonic seizures, but excluded individuals if a cause for a pleocytosis was immediately apparent.10 Only two patients had counts greater than 5 cells/mm3, but the highest count was 65 cells/mm3. The study showing the highest rate of patients with a post-ictal CSF pleocytosis also included a higher proportion of patients with chronic alcoholism.11 Data from this combined retrospective and prospective study showed that 31 of 102 patients (30%) had unexplained CSF cell counts greater than 5 cells/mm3 (mean, 72 cells/mm3; range, 3–464 cells/mm3) within 48 h of presentation; 57% also had a predominance of PMNs in the initial sample.11 Still, these cases were selected because the patients had undergone LP and CSF data were available; the study did not include all patients who presented with seizures and therefore the findings may not reflect a representative population. In summary, data derived from studies conducted primarily in adults suggest that a mild CSF pleocytosis may occur immediately following a seizure in a subset of patients (5–10%) and can be attributed to the seizure itself. In general, a high CSF WBC count and a significant proportion of PMNs are unusual following seizures. It is therefore incumbent on the clinician to investigate such a laboratory abnormality in any patient with new-onset seizures, as it is

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more likely to reflect a potentially treatable underlying disorder. There is scant evidence to suggest that one type of seizure is more likely to produce CSF abnormalities than another. The fact that post-ictal CSF WBC counts can vary quite widely among studies likely reflects differences in methodologies, rather than any biologically based phenomenon.

Protein concentration Table 16-4 compiles data from various studies that examined total CSF protein content after seizures. In one series of patients with SE, three of eight patients with abnormal CSF had slightly elevated protein levels (range, 48–58 mg/dl).9 Similar elevations were also noted in other studies, but many included patients with underlying risk factors for seizures, making it difficult to discern what was specifically due to the seizures themselves. Elevated CSF protein levels were associated with diabetes and high CSF erythrocyte counts in some studies,8,11 but were normal in others.10 One study noted an elevated protein level (range, 48–77 mg/dl) in 25% of the CSF samples from patients with epilepsy.6 Taken together, the available data suggest that the majority of patients with seizures have normal CSF protein levels in the acute post-ictal period. Confounding explanations were available for most of those patients with mild CSF protein elevations, making it hard to attribute the finding to the seizures themselves. Still, experimental data on post-ictal BBB permeability provide a potential basis to understand how such changes might occur.

Glucose concentration Glucose levels in CSF can be influenced by the integrity of the BBB, concomitant CNS infection, and by the body’s

own stress response.12 Mild systemic hyperglycemia can occur in patients shortly after a seizure, raising the question of whether this can cause hyperglycorrhacia itself. Conversely, certain infections can cause hypoglycorrhachia, so the effect of the seizure may be difficult to discern. Most of the patients in one series had elevated CSF glucose levels shortly after a seizure, but many also received dextrose infusions at the time of initial medical intervention.9 As such, decreased CSF glucose levels may have been masked. Another study found no significant difference in CSF-to-serum glucose ratios in patients with and without CSF pleocytosis after seizures of varying etiologies, including alcohol withdrawal and vascular disease.11 Serum glucose levels were not provided in most other studies, making it difficult to assess the relevance of CSF glucose levels that were reported. Based on available data, it does not appear that seizures alter CSF glucose levels out of proportion to serum glucose concentrations (Table 16-5).

CEREBROSPINAL FLUID CHANGES FOLLOWING SEIZURES IN NEONATES AND CHILDREN Cellularity Some case series have looked at CSF WBC counts in infants and children with seizures to determine whether there are post-ictal changes specifically in younger patients (see Table 16-2 and Table 16-3). One study retrospectively examined the CSF from 62 children with various types of idiopathic seizures; those with underlying neurological diseases and with traumatic LPs were excluded.13 All samples were obtained within 24 h of the last seizure. Only four of these 62 patients (6%) had a CSF pleocytosis, defined as a count greater than 5 cells/mm3. For the subset of patients under 4 months of age (n=7), the range of WBC was 0–12 cells/mm3,

Table 16-4 Cerebrospinal Fluid Protein Concentrations in Patients with Recent Seizures and no Evidence of CNS Infection Study Population Neonates < 40 weeks 40–43 weeks > 43 weeks

Sample Size 12 10 15

Mean (SD) (mg/dl) 116.1 (30.6) 81.6 (23.5) 47.9 (13.1)

Range (mg/dl)

95th %ile (mg/dl)

63–173 45–165 33–67

Ref. 19 19 19

Febrile seizures

61

20.4 (6.8)

11–34

22

Febrile seizures

45

19 (14)

10–41

16

111 57 63

30 (50) 26 (19) 29 (20)

8–419 0–116 9–115

73 (95th) 54 (95th) 68 (95th)

14 14 14

Pediatric hospital (inpatient and ER) < 4 months > 4 months

7 55

53 (32) 20 (11)

9–93 9–52

92 (90th) 36 (90th)

13 13

Adults

65

44.6 (18.8)

Children with different seizure subtypes Complex febrile Status epilepticus Non-febrile

12–99

9

CSF Changes following Seizures in Neonates and Children

Table 16-5 Cerebrospinal Fluid Glucose Concentrations in Patients with Recent Seizures and no Evidence of CNS Infection Study Population Children with different seizure subtypes Complex febrile Status epilepticus Non-febrile Adults

Sample Size

Mean (SD) (mg/dl)

Range (mg/dl)

Ref.

111 57 63

83 (22) 93 (34) 70 (21)

20–178 7–175 32–130

14 14 14

65

114 (52.3)

52–204

9

with the 90th percentile at 7.8 cells/mm3. For those patients older than 4 months (n=55), the range was 0–8 cells/mm3, with the 90th percentile at 4 cells/mm3. Two other important points came out of this study. First, two patients with a pleocytosis but no clinical or culture evidence of meningitis turned out to have positive CSF enteroviral PCRs suggesting subclinical viral meningitis. Since no other study has used enteroviral PCR assays in this fashion, the incidence of a post-ictal pleocytosis attributed solely to seizures may be overestimated elsewhere. Second, there was no difference in the CSF cell counts found in patients with prolonged seizures versus self-limited events, perhaps refuting the concept of a “dose-effect” that might be expected if seizures were the direct cause of the cellular influx. Patients with complex febrile seizures (i.e., those lasting longer than 15 min, those having focal features, or those recurring within 24 h) may have a greater likelihood of developing epilepsy in the future compared to patients with simple febrile seizures. A study of infants aged 2–24 months showed that the range of CSF WBC counts was 0–19 cells/mm3 in those patients with complex febrile seizures.14 Infants with SE had between 0 and 9 cells/mm3 in the CSF, while those with non-febrile seizures had 0–13 cells/mm3. Samples were not analyzed by PCR, although nearly 10% of these patients also had clinical evidence of gastroenteritis, making enteroviral infection a possibility for some of these individuals. This, of course, leaves open the question of the cause of the CSF pleocytosis in the setting of these complex febrile seizures. Importantly, seizure duration again did not correlate with the magnitude of the CSF pleocytosis. These findings add further support to the notion that the severity of the seizure does not correlate with the CSF WBC count. One study compared the CSF profiles of febrile children sick enough to warrant a CSF examination who presented with and without seizures.15 Patients with positive CSF bacterial and viral cultures were excluded from the analysis. There were no statistically significant differences in the CSF WBC counts between the two groups. Indeed, the mean CSF WBC count was 1.9 cells/mm3 for patients with seizures (n=107) and 2.8 cells/mm3 for those without

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seizures (n=266). Only six of the 107 patients with seizures (5.6%) had a CSF cell count of greater than 5 cells/mm3. A related issue is whether children with confirmed systemic illnesses and seizures can have simultaneous CSF abnormalities. A series of 375 febrile children from an era before the widespread availability of the Hemophilus influenzae vaccine who had negative CSF bacterial and viral cultures included a subgroup (n=45) who presented with seizures.16 Other subgroups included infants with possible sepsis and those with a confirmed parameningeal source of infection (e.g., otitis media, mastoiditis). The 95th percentile of the CSF WBC count in the 45 children with seizures was 7.02 cells/mm3, including an average of 55% PMNs. In other words, only 5% of this subgroup had abnormal total WBC values, but over half had an elevated number of PMNs in their WBC differentials. The authors concluded that fever without a known source leading to seizures may sometimes cause a few PMNs to accumulate in the CSF. Furthermore, the patient’s clinical presentation, not the actual CSF WBC count or the proportion of PMNs, should govern further management. Thus, the best clinical judgment should always be applied when faced with this situation in an individual patient, knowing that very early meningitis can produce a similar CSF profile without a large number of cells. Close clinical observation of these patients is indicated. A study of 64 CSF samples obtained from children with SE showed that only seven with a pleocytosis did not have an underlying infectious or inflammatory process, although three of these patients were febrile at presentation.17 Total CSF cell counts in this group ranged from 8 to 25 cells/mm3. In contrast, 13 of 20 children had pleocytosis in a smaller study of idiopathic SE (range, 0–16 WBC/mm3; mean, 3 cells/mm3); nearly one-third of that group had one PMN on the differential.18 In summary, it appears that a low-grade CSF pleocytosis may occur post-ictally in some children with idiopathic seizures. Still, as more sensitive molecular diagnostic assays become available, new explanations for these seizures are being found.

Protein concentration A wide range of CSF protein concentration has been found in infants and children with seizures (Table 16-4). In one pediatric study, the range of protein values was 9–93 mg/dl in patients under 4 months of age and 9–52 mg/dl among older patients.13 Regarding different seizure subtypes, patients with complex febrile seizures had a protein range of 8–419 mg/dl, those with SE were between 0 and 116 mg/dl, and those with nonfebrile seizures ranged from 9 to 115 mg/dl.14 The values in patients with systemic illnesses showed that children with seizures had a mean protein concentration of 19 mg/dl, well within the normal range.16 In summary, there may be mild elevations of CSF protein content in children with seizures. Attempts to correct

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these findings based on the presence of CSF red blood cells (RBCs) were not undertaken.

Glucose concentration With the caveats mentioned earlier, some studies have looked at CSF glucose levels in children with seizures (Table 16-5). The study of patients with complex febrile seizures showed glucose levels ranging from 20 to 178 mg/dl, while those with SE had a glucose levels between 7 and 175 mg/dl and those with nonfebrile seizures had glucose levels of 32–130 mg/dl.14 The study of children with systemic illness showed that five of 45 of patients (11%) with seizures had a CSF:peripheral glucose ratio below 0.5.16 Unlike most adult studies, these patients did not all receive intravenous glucose during their presentation. Still, methodological problems preclude firm conclusions about CSF glucose concentrations in these patients.

CEREBROSPINAL FLUID CHANGES IN OTHER SEIZURE AND EPILEPSY SYNDROMES IN NEONATES AND CHILDREN Neonatal seizures The neonatal population with seizures presents a unique challenge, since the underlying causes for seizures in this group are more diverse than in older children. Common etiologies include self-limited conditions (e.g., benign familial neonatal convulsions), various injury and developmental abnormalities (e.g., hypoxic-ischemic encephalopathy, severe malformations of cortical development), and metabolic disorders (e.g., urea cycle disorders, amino acidopathies, pyridoxine dependency) in addition to the more common causes seen in older patients (e.g., drug effects, meningitis, intracranial hemorrhage, electrolyte abnormalities, stroke). Furthermore, clinical convulsive activity does not always correlate with electrographic abnormalities in this population, and some infants have electrographic abnormalities with no clinical correlate. This makes the identification and classification of neonatal seizures a challenge in itself. Regarding the investigation of CSF abnormalities in neonates with seizures (and no associated infectious, hypoxic, metabolic, or hemorrhagic disorder), one study showed CSF WBC counts of less than 20 cells/mm3 in patients less than 43 weeks post-conception and counts of less than 5 cells/mm3 thereafter.19 Importantly, both culture and viral PCR were used in this study as the gold standard to exclude infection. Unfortunately, however, more than one-third of neonates less than 43 weeks post-conception with confirmed viral infections also had values below this 20 cells/mm3 cutoff (range 2–49 cells/mm3). Infants beyond the 43 weeks post-conception age with CNS viral infections had a CSF WBC range of 4–18 cells/mm3. All had normal CSF glucose and protein concentrations. Thus, given the significant overlap of

laboratory values among normal and virally infected neonates with seizures, absolute cutoffs cannot be established to distinguish viral infection in this age group. Still, as the ability to detect pathogens improves, more data should become available in this population.

Febrile seizures The CSF profile in children with complex febrile seizures has already been discussed. One case series of 50 children with routine febrile seizures documented normal CSF protein levels and no cells in all patients.20 Furthermore, in seven of these individuals (14%), CSF glucose levels actually exceeded those of serum, with no relationship to the frequency, duration, or type of seizure encountered. Hyperglycorrhacia was also noted in another group of children with first-time febrile seizures, all of whom underwent LP.21 Over 20% of these patients had CSF glucose levels above 150 mg/dl.21 The mean serum glucose level on admission was greater than 120 mg/dl in this study, but the mean fasting blood glucose level after admission was only 66 mg/dl.21 This is one of a number of studies that have noted hyperglycemia in febrile seizures. All of these children had normal CSF calcium and magnesium levels, despite the fact that three patients had mild hypocalcemia.21 Questions surrounding a potential post-ictal breach of the BBB in children with febrile seizures were addressed by quantifying CSF proteins of varying sizes.22 This study showed that nearly 20% of children had elevated CSF levels of both albumin and α2-microglobulin (e.g., the smallest and largest of the molecules studied) in the post-ictal period. Interestingly, CSF levels of immunoglobulin (Ig) G molecules were not elevated in these patients, and there was no evidence of intrathecal IgG synthesis in this population. Other studies have reported that total CSF protein concentration can be depressed in children with febrile seizures.23 In conclusion, slightly elevated CSF WBC counts and mild hyperglycorrhacia rarely may be seen in a subset of children with febrile seizures, but these parameters remain normal in most patients. In this respect, there is no conclusive evidence that CSF findings in febrile seizures are different from those in children with other types of seizures.

Infantile spasms Infantile spasms (IS) are a unique seizure type occurring in infants that often reflect a catastrophic underlying disorder. The etiologies of this condition vary widely, but can include malformations of cortical development, neurophakomatoses, and inborn errors of metabolism. One study compared CSF proteins in children with IS (n=50) to both normal controls (n=41) and children with acute aseptic meningitis (n=16).24 Children in the IS group had normal cranial imaging or a wide variety of structural abnormalities. These patients all had normal CSF cell counts.

References

Many, however, had high CSF levels of serum proteins such as albumin that reflected BBB breakdown. These changes were more severe in the subgroup with symptomatic IS (i.e., with a known underlying cause) rather than infants with cryptogenic IS. After treatment with adrenocorticotropic hormone (ACTH) or dexamethasone, levels of serum proteins normalized in CSF samples, perhaps reflecting a reestablishment of more normal BBB permeability. Thus, it remains debatable whether the effects of treatment on CSF composition reflect changes to the underlying pathology or to the seizures themselves.

BLOOD–BRAIN BARRIER PATHOLOGY IN THE PATHOGENESIS OF EPILEPSY The BBB may directly contribute to pathology that causes epilepsy and results in notable CSF abnormalities. One obvious example occurs in patients with congenital deficiency of the glucose transporter-1 (GLUT-1) protein, a major means by which glucose is brought into the CNS. These individuals have both hypoglycorrhacia and seizures.25 Patients with GLUT-1 deficiency can be treated with the ketogenic diet, which may provide an alternative fuel source to the brain, or generate other biochemical changes that have an anticonvulsant effect.26 An example of seizures related to BBB disruption is Rasmussen syndrome, a progressive epileptic disorder associated with neuropathological evidence of significant CNS inflammation. Clinically, patients experience focal seizures (including epilepsia partialis continua), progressive hemiplegia, and radiographic evidence of progressive cortical or subcortical atrophy along with hyperintensities on T2-weighted MRI scans.27 The CSF of these patients may be normal or abnormal, but it should always be assayed to exclude other diagnoses such as infection or neoplasm.27 Although the pathogenesis of this disabling condition that afflicts children and young adults is poorly understood, one hypothesis is that BBB disruption exposes the immune system to novel antigens which then serve to perpetuate an ongoing inflammatory process.28 Anti-inflammatory therapies (e.g., high-dose corticosteroids, intravenous immunoglobulin, plasma exchange, cyclophosphamide) can ameliorate the seizures, but the only curative therapy remains hemispherectomy.27 Biopsy may be misleading, as inflammation can be patchy and result in false-negative findings.29

SUMMARY CSF abnormalities as measured in most clinical diagnostic laboratories are extremely uncommon after idiopathic seizures. While some laboratory data support the notion that there can be transient alterations in CSF protein and glucose content after seizures, the mechanisms involved

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and the sequelae of these events remain poorly understood. A CSF pleocytosis following a seizure is also uncommon and its meaning is less clear in the setting of the otherwise normal patient. Still, abnormal findings in the CSF of a patient with new-onset seizures mandate further investigation, as these can reveal underlying pathologies that are treatable in nature. From a more mechanistic standpoint, abnormalities in BBB endothelial transporters are associated with various epilepsy syndromes, as are inflammatory conditions such as Rasmussen syndrome. In the appropriate clinical context, these abnormalities need to be considered in the differential diagnosis of patients presenting with unexplained seizures. REFERENCES 1. Padou V, Boyet S, Nehling A. Changes in transport of [14-C] α-aminoisobutyric acid across the blood-brain barrier during pentylenetetrazol-induced status epilepticus in the immature rat. Epilepsy Res 1995;22:175–183. 2. Leroy C, Roch C, Koning E, Namer IJ, Nehlig A. In the lithiumpilocarpine model of epilepsy, brain lesions are not linked to changes in blood-brain barrier permeability: an autoradiographic study in adult and developing rats. Exp Neurol 2003;182:361–372. 3. Petito CK, Schaefer JA, Plum F. Ultrastructural characteristics of the brain and blood-brain barrier in experimental seizures. Brain Res 1977;127:251–267. 4. Horowitz SW, Merchut M, Fine M, Azar-Kia B. Complex partial seizure-induced transient MR enhancement. J Comput Assist Tomog 1992;16:814–816. 5. Barry E, Hauser WA. Pleocytosis after status epilepticus. Arch Neurol 1994;51:190–193. 6. Devinsky O, Nadi NS, Theodore WH, Porter RJ. Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures. Ann Neurol 1988;23:402–403. 7. Gaggero R, Ferraris PC, De Negri M. CSF anomalies in children affected by Epilepsia Partialis Continua (EPC). Neuropediatrics 1990;21:143–145. 8. Schmidley JW, Simon RP. Postictal pleocytosis. Ann Neurol 1981;9: 81–84. 9. Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980;69:657–666. 10. Edwards R, Schmidley JW, Simon RP. How often does a CSF pleocytosis follow generalized convulsions? Ann Neurol 1983;13:460–462. 11. Prokesch RC, Rimland D, Petrini JL, Fein AB. Cerebrospinal fluid pleocytosis after seizures. S Med J 1983;76:322–327. 12. Simon RP. Physiologic consequences of status epilepticus. Epilepsia 1985;26(Suppl 1):S58–S66. 13. Wong M, Schlaggar BL, Landt M. Postictal cerebrospinal fluid abnormalities in children. J Pediatr 2001;138:373–377. 14. Rider LG, Thapa PB, Del Beccaro MA, et al. Cerebrospinal fluid analysis in children with seizures. Pediatr Emerg Care 1995;11:226–229. 15. Portnoy JM, Olson LC. Normal cerebrospinal fluid values in children: another look. Pediatrics 1985;75:484–487. 16. Carraccio C, Blotny K, Fisher MC. Cerebrospinal fluid analysis in systemically ill children without central nervous system disease. Pediatrics 1995;96:48–51. 17. Dunn DW. Status epilepticus in children: etiology, clinical features, and outcome. J Child Neurol 1988;3:167–173. 18. Woody RC, Bolyard K, Yamauchi T. Cerebrospinal fluid pleocytosis in childhood idiopathic status epilepticus. Ann Neurol 1986;20:427. 19. Mustonen K, Uotila L, Laitinen R, Koskiniemi M. CSF findings in neonates with seizures; infectious and noninfectious. J Perinat Med 2003;31:69–74.

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20. Yachha SK, Patwari A, Bhan S, Hussain A, Singh D. Cerebrospinal fluid and blood glucose levels in febrile convulsions. Indian Pediatr 1981;18:117–119. 21. Rutter N, Smales ORC. Calcium, magnesium, and glucose levels in blood and CSF of children with febrile convulsions. Arch Dis Child 1976;51:141–143. 22. Siemes H, Siegert M, Hanefeld F. Febrile convulsions and blood-cerebrospinal fluid barrier. Epilepsia 1978;19: 57–66. 23. MacDougall LG. Low cerebrospinal fluid protein in African children with febrile convulsions. Arch Dis Child 1962;37:309–313. 24. Siemes H, Siegert M, Aksi F, Emrich R, Hanefeld F, Scheffner D. CSF protein profile in infantile spasms. Influence of etiology and ACTH or dexamethasone treatment. Epilepsia 1984;25: 368–376.

25. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325:703–709. 26. Oby E, Janigro D. The blood-brain barrier and epilepsy. Epilepsia 2006;47:1761–1774. 27. Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128:454–471. 28. Vining EP. Struggling with Rasmussen’s Syndrome. Epilepsy Curr 2006;6:20–21. 29. Pardo CA, Vining EP, Guo L, Skolasky RL, Carson BS, Freeman JM. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 2004;45:516–526.

CHAPTER

17

Connective Tissue, Endocrine, Toxic, and Psychiatric Disorders Katherine B. Peters and David N. Irani

INTRODUCTION Neurological symptoms can be the heralding manifestation of an underlying connective tissue disorder, or they can represent one facet of these complex, multi-organ diseases. Direct nervous system involvement is somewhat less common in most patients with endocrinological disorders, but this possibility must still be considered in certain clinical situations. The interface between psychiatry and neurology has been appreciated for many years, but very little is known about how psychiatric illnesses affect the structure and function of central nervous system (CNS) tissues or the composition of the surrounding cerebrospinal fluid (CSF). Finally, it has been increasingly appreciated that a number of systemic drug and chemical exposures can sometimes produce what appear to be idiosyncratic inflammatory responses within the CNS. This chapter will review our state of knowledge regarding the CSF profiles that occur in patients with various known connective tissue, endocrine, and psychiatric disorders, as well as with some of the more common drug- and chemical-induced meningitic syndromes. The CSF findings associated with other systemic metabolic and nutritional conditions will be reviewed in Chapter 18.

CONNECTIVE TISSUE DISORDERS Systemic lupus erythematosus Systemic lupus erythematous (SLE) is a progressive autoimmune syndrome manifested by multiple circulating autoantibodies that usually cause a widespread, multi-organ disease. Cross-sectional studies report that as many as 75% of patients with SLE will have some neurological component to their illness.1–5 Neurobehavioral and neuropsychiatric symptoms are most common, but other manifestations can include seizures, aseptic meningitis, stroke, transverse myelitis, dementia, and cranial neuropathies.1–5

Furthermore, peripheral nervous system (PNS) involvement can result in acute or chronic polyneuropathies or single or multiple mononeuropathies.1–5 The most frequent abnormal CSF profile found in SLE patients, a lymphocytic pleocytosis with elevated total protein content, occurs in about half of individuals who undergo a spinal fluid examination (Table 17-1).1,5–8 Among these patients, protein levels in excess of 100 mg/dl are usually found only in cases of neuropathy or myelopathy.5 Likewise, white blood cell (WBC) counts above 50/mm3 in the absence of documented bacterial or fungal meningitis are unusual.5 A few isolated cases have presented with a predominance of polymorphonuclear (PMN) cells in the CSF, but most studies identify lymphocytes and monocytes as the main infiltrating cell types.5,9 The presence of a pleocytosis may not always indicate active CNS lupus, as increased CSF cellularity can be found in some patients without any overt neurological signs or symptoms.9 CSF glucose levels are almost invariably normal in individuals with SLE.5 The presence of intrathecal immunoglobulins (Ig) has been extensively documented in patients with active CNS SLE. In one study of 13 such patients, increased CSF IgG, IgA, and IgM indices were correlated with the presence of active neurological involvement in comparison to paired samples obtained from seven patients with SLE but no known CNS disease.10,11 All three of these CSF Ig indices fell when symptoms came under control following acute treatment, most notably the IgM index.10 Still, while this measurement may be a marker of the response to treatment, it remains less reliable as a predictor of active CNS involvement. Many studies have attempted to correlate the neuropsychiatric manifestations of SLE with levels of other immune system proteins in the CSF of affected patients. Antigenspecific autoantibodies including anti-neuronal antibodies, anti-ribosomal P protein antibodies, anti-ganglioside antibodies, anti-cardiolipin antibodies, anti-DNA antibodies, antinuclear antibodies, anti-SSA/Ro antibodies, and anti-SSB/La

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Table 17-1

●

Connective Tissue, Endocrine, Toxic, and Psychiatric Disorders

Common CSF Characteristics of Patients with Selected Connective Tissue Disorders Disorder

Normal CSF (% patients) > 5 WBC/mm3 (% patients) Cells/mm3, range % Lymphocytes in CSF Protein > 50 mg/dl (% patients) CSF/serum glucose < 0.5 (% patients) IgG index > 0.6 (% patients) Oligoclonal bands (% patients) References

SLE

PACNS

WG

BD

VKH

SS

50 27–32 20–110 85 30–48 5–10 30 25–42 1–11,18

33–50 25–50 10–150 90–100 33 Rare Rare Rare 55–57

? ? 10–100 90–100 50 10 Rare Rare 52,53

25–30 50–60 0–1,100 50 60 5 73 16–20 37,38,48

10–20 80–90 6–700 75 75 0–5 5 5 75–80

70–75 25–30 0–70 90 40–60 Rare 10 5–15 82–85

SLE, systemic lupus erythematosus; PACNS, primary arteritis of the CNS; WG, Wegener’s granulomatosis; BD, Behçet’s disease; VKH, Vogt-Koyanagi-Harada disease; SS, Sjogren’s syndrome.

antibodies have all been detected in the CSF of some patients with neuropsychiatric lupus,6,9–19 but none has held up as a robust predictor of this clinical phenotype. Other markers of inflammation including the cytokines, interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, and interferon-alpha; complement proteins, C3 and C4; matrix metalloproteinase-9; soluble forms of the adhesion molecules, VCAM-1, ICAM-1 and L-selectin; and metabolites of nitric oxide all have been studied in the CSF of patients with SLE and neuropsychiatric involvement.15,20–35 Many are selectively increased in the CSF of patients with CNS involvement, and some even decline with effective therapy, but none is yet in routine clinical use. Prolactin has also been investigated as a potential marker for CNS lupus,27,36 but its exact role in disease pathogenesis and how well it predicts active CNS disease remain unknown.

Behçet’s disease Behçet’s disease (BD) is an autoimmune illness characterized by uveitis and oral and genital skin ulcerations. Some years after onset, neurological manifestations also commonly become apparent.37 The term “Neuro-Behçet’s disease” (NBD) encompasses aseptic meningitis, meningoencephalitis, a small vessel inflammatory brain disease leading to focal CNS deficits, and cerebral vein thrombosis.37,38 The CSF profile in patients with NBD shows a mixed CSF pleocytosis, and about two-thirds of patients have elevated protein content (Table 17-1). Inflammatory cells infiltrating the CSF have a higher proportion of PMNs compared with other connective tissue disorders.37,38 Abnormal CSF immunoglobulin levels occur in most patients, and, like SLE, can fluctuate with clinical disease activity. As with other autoimmune conditions of the CNS, a number of specific inflammatory markers have been identified in the CSF of patients with NBD. Proteins such as IL-6, β2-microglobulin, anti-cardiolipin antibodies, macrophage inflammatory protein-1 alpha, macrophage migration inhibitory factor, and soluble Fas ligand may increase in the CSF of patients with this disorder.39–46 In one case,

antibodies cross-reactive to mycobacterial and normal cellular heat shock proteins were found in the CSF of NBD patients, shedding some light on how an immune response elicited against an infectious pathogen might cause autoimmunity.47 In cases of cerebral vein thrombosis that are associated with BD, patients can have elevated CSF pressures in addition to inflammatory changes.48–50 Finding a high opening pressure should prompt an investigation of the venous anatomy of these patients.

Polyarteritis nodosa As an inflammatory condition of small and medium-sized arteries, polyarteritis nodosa (PAN) can affect many tissues, including the skin, joints, gastrointestinal tract, kidneys, and nervous system. The most common neurological manifestation of PAN is peripheral neuropathy, usually in the form of a painful mononeuritis multiplex. As with other vasculitic neuropathies, the CSF in these patients, when sampled, can show a high protein content but does not usually have a significant pleocytosis.40 There are also documented cases of CNS involvement in PAN causing aseptic meningitis or a focal or diffuse meningoencephalitis.51 These patients, by definition, have a pleocytosis with a mixed cellular composition, but usually a predominance of mononuclear cells.51 The frequency of abnormal CSF immunoglobulin levels in these patients is not known. Similar to other autoimmune conditions, IL-6 can be elevated in the CSF of patients with PAN, although its pathogenic significance is unclear.40

Wegener’s granulomatosis Wegener’s granulomatosis (WG) is a disease of granulomatous inflammation, necrosis, and vasculitis that most commonly involves the kidneys and respiratory tract. Nervous system pathology in WG causes peripheral and cranial neuropathies, usually in a patchy multiple mononeuropathy-type pattern. Cranial neuropathies in WG patients invariably occur as a result of chronic meningitis accompanied by a lymphocytic CSF pleocytosis.52

Connective Tissue Disorders

These patients can also have detectable anti-neutrophilic cytoplasmic antibodies (ANCA) in CSF that can serve as a diagnostic marker for this disorder.53 Spread of granulomatous inflammation to the meninges in WG can result in impaired CSF resorption leading to communicating hydrocephalus.54 Accordingly, the ventricles are large on brain imaging studies in this situation, and CSF opening pressure may be elevated.

Primary arteritis of the CNS Isolated CNS vasculitis, most commonly referred to as primary arteritis of the CNS (PACNS), is a rare, heterogeneous disorder. Most patients come to attention with focal or multifocal deficits that result from inflammation of small intracranial vessels and infarctions, but headache is the most common symptom. In the few, larger series of cases, CSF abnormalities are found in only half to twothirds of patients with PACNS.55–57 Abnormalities include increased protein levels with a mild lymphocytic pleocytosis, but immunoglobulin abnormalities are rare (Table 17-1). One study suggested that elevated CSF levels of neurofilament light-chain protein and glial fibrillary acidic protein could serve as markers of tissue injury in CNS vasculitis.58

Giant cell (temporal) arteritis Giant cell arteritis (GCA) is characterized by granulomatous inflammation of medium to large extracranial arteries, particularly the temporal artery that can lead to anterior ischemic optic neuropathy. Common clinical features of GCA include jaw claudication, scalp tenderness, headaches, and visual changes. A diagnosis is rendered in the setting of an elevated erythrocyte sedimentation rate by means of temporal artery biopsy; CSF analysis is rarely performed unless the clinical setting is unusual. In these rare cases, protein content is normal or modestly elevated and cellular infiltration is limited. As with several other vasculitides, CSF from patients with temporal arteritis may contain increased levels of IL-6.40

Rheumatoid arthritis/Still’s disease In rheumatoid arthritis (RA), chronic synovial inflammation leads to debilitating joint and spine disease. In these cases, CSF analysis may show an elevated protein concentration in one-third of patients with spine involvement, but is otherwise normal.59 Still’s disease is considered as a systemic variant of juvenile RA, but also can present in adults. Patients have spiking fevers, a characteristic rash, arthritis, and other manifestations of systemic inflammation (lymphadenopathy, pericarditis, etc.). In both Still’s disease and RA, aseptic meningitis with a neutrophilic pleocytosis and CSF protein levels in excess of 100 mg/dl can occur.60–66 Intrathecal antibody synthesis is not reported in these patients.64 Most episodes are self-limited and recover spontaneously or with symptomatic therapy.

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Sweet’s syndrome In Sweet’s syndrome (acute febrile neutrophilic dermatosis), patients develop fever and painful erythematous skin plaques; neurological involvement is uncommon. Recently, however, recognition of a handful of such patients has led to the description and diagnostic criteria for what is now called Neuro-Sweet disease.67–71 The clinical phenotype is one of acute aseptic meninigits or meningoencephalitis in a patient with Sweet’s syndrome. The typical CSF profile shows a neutrophilic pleocytosis with a normal glucose value and a normal or slightly elevated protein concentration.67–71 There are no known serological markers available; a diagnosis depends on clinical features and biopsy findings of the skin lesions.

Kawasaki’s disease Kawasaki’s disease (KD) is a childhood disorder of unknown etiology characterized by acute fever, rash, mucocutaneous changes, lymphadenopathy, and coronary lesions including aneurysms secondary to vasculitis. Because of the fever, CSF is usually evaluated to search for infectious etiologies. In one recent series of 46 patients, 18 of 46 (39.1%) had a pleocytosis, one of 46 (2.2%) had a glucose level less than 45 mg/dl, and eight of 46 (17.4%) had protein concentrations greater that 50 mg/dl in the CSF.72 Of those patients with a CSF pleocytosis, the mean white cell count was 22.5 cells/mm3 (range, 7–320 cells/mm3), and on average 6% of these cells were neutrophils (range, 0–79%).72 Based on this and other studies, one concludes that aseptic meningitis is relatively common in children with KD.

Vogt-Koyanagi-Harada disease Vogt-Koyanagi-Harada (VKH) disease is a rare disorder characterized by inflammatory involvement of the eye (uveitis, retinal pigmentary changes), hair and skin (alopecia, vitiligo, poliosis), meninges (headache), and sometimes the brain itself and the cranial nerves that arise from it (personality change, seizures, hearing impairment). The disorder is frequently associated with CSF abnormalities, even in the absence of overt neurological involvement.73 In this “uveomeningitic” syndrome, some 80–90% of patients show a mononuclear cell CSF pleocytosis ranging from 6 to 700 cells/mm3, with two-thirds having cell counts in excess of 100 cells/mm3.74–78 In most cases the CSF protein level is normal or mildly elevated (50–75 mg/dl), and it rarely exceeds 200 mg/dl. The CSF glucose concentration is normal, and while intrathecal immunoglobulins are reported, the frequency of this finding is not known. A small handful of cases show modest increases in lumbar CSF pressure.74–78 Recent investigations have focused more attention on the nature of the cells that infiltrate the CSF in VKH. Several studies have shown that macrophages with

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basophilic granules containing melanin are a frequent component of the pleocytosis, and some investigators have gone as far as to suggest that this is specific for VKH and reflects some immunopathogenic mechanism.79,80 In terms of the chemotactic signals that recruit mononuclear cells to the CNS in VKH, CSF levels of the chemokines CXCL10 (IP-10) and CCL17 (TARC) are elevated, and CSF levels of CCL2 (MCP-1) are suppressed, compared to controls.81 Whether or how these mediators actually drive the disease is unknown.

Sjogren’s syndrome The clinical picture of Sjogren’s syndrome (SS) involves xerostomia (dry mouth) and xerophthalmia (dry eyes) due to chronic inflammation involving the salivary and lacrimal glands. Even though the CNS is rarely involved, manifestations including aseptic meningitis, meningoencephalitis, neuropsychiatric syndromes, and acute or chronic myelopathies have been documented.82 When CNS disease is present, the CSF commonly reflects leptomeningeal involvement with a pleocytosis and elevated protein content.82 Further studies have shown a mixed cellular infiltrate in SS patients, with lymphocytes, plasma cells, and large atypical-appearing monocytes all present.83,84 The CSF protein usually ranges between 50 and 100 mg/dl, and intrathecal IgG and/or oligoclonal bands are sometimes found.82,85 In a few cases of patients with primary SS and distal sensory symptoms, antibodies have been found in the CSF that specifically bind to dorsal root ganglia neurons. This implies that the dorsal root ganglionitis in SS is mediated by humoral autoimmunity.86 Recently, anti-SSA autoantibodies have been identified in the CSF of SS patients with CNS disease, suggesting that these antibodies could be a biomarker of CNS involvement.87

Hashimoto’s thyroiditis (hypothyroidism with circulating anti-thyroglobulin and/or anti-thyroperoxidase antibodies) can have a neurological illness termed Hashimoto’s encephalopathy (HE). In HE, patients can have protean neurological (tremor, seizures, myoclonus, focal deficits) and/or neuropsychiatric (dementia, encephalopathy, coma) symptoms.90,91 In several recent reviews, HE cases were identified and CSF profiles were reported. These studies suggest that about one-quarter of patients have a pleocytosis of >5 WBC/mm3, and only a few cases (2–3%) will have >100 WBC/mm3.91,92 On the other hand, most patients have CSF protein levels above 50 mg/dl, and about 20% will have measurements above 100 mg/dl.91,92 One recent study reported that anti-thyroid antibodies were produced intathecally in HE patients, suggesting a role in the diagnosis of HE.93 As the titer did not correlate with disease severity, however, their pathogenic role in the neurological manifestations remains unclear.93

Cushing’s disease/Nelson’s syndrome In patients with Cushing’s disease, low levels of corticotrophin-releasing hormone (CRH) and adrenocorticotrophin hormone (ACTH) are secreted in the CSF.94 Patients with this disorder who undergo bilateral adrenalectomy can develop Nelson’s syndrome, a condition that results in skin hyperpigmentation, high plasma ACTH levels, and growth of an existing pituitary tumor or the de novo development of a new one. If investigated, CSF levels of ACTH are also elevated in patients with this disorder.95,96

Diabetes mellitus

Scleroderma causes progressive systemic fibrosis with deposition of collagen. While the skin is primarily affected, other organ systems, including the kidneys, gastrointestinal tract, lungs, heart, and genitourinary system, can be involved. With chronic tissue fibrosis and inflammation, peripheral neuropathies can develop. There have only been a few documented cases of CNS disease; in one case of disease localized to the head, CSF IgG levels were elevated but the fluid was otherwise unremarkable.88

Glucose concentrations in CSF, similar to those in serum, are increased in diabetic patients.97 Likewise, CSF lactate levels are measurably higher in diabetic patients, and they become particularly elevated in those patients treated for hypoglycemic coma.98,99 While CSF pH can drop during severe diabetic ketoacidosis, the magnitude of change is significantly less than in serum.100 CSF bicarbonate decreases with diabetic ketoacidosis, while CSF sodium, chloride, and potassium levels remain in a normal range.101 Diabetes can predispose to many PNS abnormalities, and those such as diabetic amyotrophy or chonic inflammatory demyelinating polyneuropathy that involve proximal nerve roots commonly cause elevated CSF protein levels with no increase in the WBC count.102–105

ENDOCRINE DISORDERS

Pituitary apoplexy

Scleroderma

Hypothyroidism/Hashimoto’s thyroiditis The CSF protein level can be increased in patients with hypothyroidism. One study suggested that CSF albumin and CSF IgG were both increased during overt hypothyroidism but not with subclinical disease.89 Patients with

Pituitary apoplexy, acute destruction of the pituitary gland via hemorrhage or infarction, can mimic bacterial meningitis or subarachnoid hemorrhage. The CSF can contain increased numbers of WBCs and/or red blood cells (RBCs), and patients typically complain of headache, nuchal rigidity, and fever.106–109 Evaluation with MRI can help to identify a

Drug- and Chemical-Induced Meningitis

process that involves the pituitary gland, and the laboratory confirmation of endocrine dysfunction adds to the data provided by CSF studies.

Acromegaly/idiopathic growth hormone deficiency Patients with acromegaly due to growth hormone (GH)secreting pituitary tumors have high GH levels in their CSF.110,111 For patients who receive GH replacement therapy due to a deficiency state, several studies have shown that CSF levels increase modestly with chronic treatment.112 In this case, a high concentration of GH receptors at the choroid plexus suggests a possible receptor-mediated transcytosis mechanism for passage into the CSF.112

Hyperparathyroidism Patients with hyperparathyroidism sometimes undergo CSF examination because of the psychiatric symptoms associated with the illness. In one case report, a hyperparathyroid patient had an elevated CSF protein and a mononuclear cell pleocytosis that resolved after correction of the hypercalcemia.113 In larger cohorts of patients, increased ionized calcium and decreased levels of the monoamine metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), have been measured in the CSF of patients with hyperparathyroidism and psychiatric symptoms.114–116 Following parathyroid surgery and normalization of serum and CSF calcium levels, these neurotransmitter metabolites reverted to a normal range, suggesting a cause-and-effect relationship with the calcium homeostasis abnormalities.115,116

Other disorders Multiple endocrine disorders, including Cushing’s disease, hypo- and hyperthyroidism, adrenal insufficiency, hypoparathyroidism, and treatment with thyroid and growth hormone, have all been implicated in the occasional cause of increased CSF opening pressure and pseudotumor cerebri (see Chapter 12).

PSYCHIATRIC DISORDERS Many studies over the years have attempted to correlate various specific CSF findings with features of psychiatric illnesses. The most solid observations to date (even though they are still far from being clinically useful) involve measuring levels of monoamine neurotransmitter metabolites and components of the hypothalamic-pituitary-adrenal (HPA) axis in these disorders. Many reports have suggested that patients with depression, schizophrenia, borderline personality disorder, violent behavior, and suicidal tendencies all have somewhat lower than expected CSF concentrations

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of the monoamine metabolite 5-HIAA, the main metabolite of serotonin.117–121 Since selective serotonin reuptake inhibitors are an important class of drugs used to treat various psychiatric illnesses, it makes some sense that altered metabolism of this particular neurotransmitter would be found in the CSF of patients with these conditions. Still, how these measurements could be used in the diagnosis of, or to establish a prognosis in, individual patients remains unknown. Another example involves CRH, a peptide neurohormone made by the hypothalamus that acts on the pituitary to produce corticotropin (ACTH), which in turn stimulates the adrenal cortex to make cortisol. This pathway represents one of the main stress responses in the body, but CRH is also made by other cells of the CNS and acts throughout the brain in a pleiotropic manner. Disrupted HPA axis activity in general (i.e., hypercortisolism), and altered CRH actions in particular, have been observed in patients with depression, anxiety, and post-traumatic stress disorder.122–124 In depression, a number of studies have shown that CSF CRH levels are inappropriately high given plasma cortisol levels, and that CSF CRH levels fall in response to clinical improvement following antidepressant therapy.125–127 Further study of CSF levels of CRH and other neuropeptide hormones in depression and other psychiatric disease may in the future shed important light on the pathogenesis of these disorders.

DRUG- AND CHEMICAL-INDUCED MENINGITIS A variety of medications can trigger aseptic meningitis and therefore cause significant changes in CSF composition. The usual clinical scenario is that signs and symptoms suspicious of such an event begin within hours after drug ingestion, but cases have been reported as far out as several weeks following exposure. Patients develop the usual features of aseptic meningitis, but may additionally experience pruritus, periorbital and facial edema, and mild confusion. The severity of the episodes is variable, but signs and symptoms usually abate rapidly after drug exposure is stopped. Recurrence can occur if the subject is challenged again with the inciting agent. The rarity of the disorder suggests that it is idiosyncratic in nature, and hypersensitivity mechanisms are presumed to be involved. Most cases occur in otherwise healthy individuals, but an underlying connective tissue disorder such as SLE may predispose to the development of this condition.128–130 A recent review of the subject systemically compiled all MEDLINE documented drug-induced aseptic meningitis cases (Table 17-2).128 The most commonly implicated medications were nonsteroidal anti-inflammatory drugs (NSAID), certain antimicrobial agents, intravenous immunoglobulin (IVIg), and monoclonal antibodies against the CD3 receptor on T cells (OKT3). The CSF in druginduced meningitis reveals a pleocytosis that can have a

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Table 17-2

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Connective Tissue, Endocrine, Toxic, and Psychiatric Disorders

Common CSF Characteristics of Patients with Drug-Induced Meningitis Drug Group

CSF Parameter Cells/mm3,

median (range) Lymphocyte-predominant pleocytosis (% patients) Neutrophil-predominant pleocytosis (% patients) Glucose (mg/dl), median (range) Protein (mg/dl), median (range)

NSAID

Antibiotics

280 (8–5,000) 24 73 57 (27–109) 124 (25–857)

147 (8–19,000) 24 73 61 (43–156) 120 (24–390)

IVIg 651 (16–3,500) 14 78 58 (19–80) 56 (15–450)

OKT3 80 (8–3,850) 37 58 72 (49–132) 66 (27–112)

NSAID, nonsteroidal anti-inflammatory drugs; IVIg, intravenous immunoglobulin; OKT3, monoclonal antibodies against the CD3 receptor on T cells. (Data adapted from Moris G, Garcia-Monco JC. The challenge of drug-induced aseptic meningitis. Arch Int Med 1999;159:1185–1994.)

predominance of either PMNs or mononuclear cells, and not infrequently has a measurable proportion of eosinophils. Total cell counts can range from 10 to 10,000 WBC/mm3, although most cases have 200–400 WBC/mm3 detected. Protein content ranges from normal up to as high as 500 mg/dl, and CSF glucose levels are usually normal or modestly depressed. Intrathecal antibody synthesis is highly variable.128 The fact that OKT3 and IVIg infusions both can precipitate these reactions raises the interesting question of whether acute immune suppression somehow predisposes to these significant meningeal reactions. Nevertheless, the routine CSF findings in patients with drug-induced meningitis do not easily distinguish them from individuals with infectious illnesses, so empiric antimicrobial coverage is appropriate until CSF culture results are available. Several recent reviews provide excellent additional information on this disorder.128,131,132 Beyond the systemic effects of many medications, clinicians should always be concerned about the possibility of either acute or chronic meningitis following the intrathecal injection of any drug or chemical agent. In extreme circumstances, this chemical meningitis can cause a reaction with the lower spinal cord and adjacent lumbar spinal nerve roots, resulting in adhesive arachnoiditis. Intrathecal anesthetics, antibiotics, chemotherapies, and radiographic contrast agents; epidural corticosteroids; local surgical interventions such as the removal of a lumbar disc; even the intravascular placement of an aneurysm coil can occasionally elicit these reactions.133–142 In acute reactions, the CSF shows a pleocytosis that can range from 10 to 10,000 WBC/mm3, and the composition of the cellular infiltrate can be lymphocytic, granulocytic, and may even contain some eosinophils. The protein content is usually elevated, albeit to varying degrees. In only a few cases is the glucose concentration depressed, and cultures are invariably sterile. In those patients with chronic adhesive arachnoiditis, CSF obtained from a loculation can have a very high protein content (Froin’s syndrome) and flow may be impaired or there may be evidence of complete manometric block with unobtainable pressure recordings. With radiographic contrast media, the presence of blood in the CSF appears to increase the likelihood of developing arachnoiditis following the injection.

CONCLUSIONS Changes in CSF composition occur with considerable frequency in patients with connective tissue disorders, and they can sometimes be found in the setting of certain endocrine disorders and rarely following the systemic exposure to particular medications or the intrathecal dosing of drugs or other chemical agents. Even psychiatric disorders are now being investigated and monitored by means of careful biochemical analysis of CSF samples. From the standpoint of the practicing clinician, it is important to be familiar with these changes because they can impact on the decision to alter a patient’s therapy. In connective tissue disorders where clinical disease can fluctuate, the intensity of immunosuppression may need to be adjusted in the setting of active CNS involvement exposed following CSF analysis. Knowing what to look for and when to look for it will help to avoid long-term disease morbidity.

REFERENCES 1. Warnatz K, Peter HH, Schumacher M, et al. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Ann Rheum Dis 2003;62:50–57. 2. West SG. Neuropsychiatric lupus. Rheum Dis Clin N Am 1994;20:129–158. 3. Kaell AT, Shetty M, Lee BCP, Lockshin MD. The diversity of neurologic events in systemic lupus erythematosus. Prospective clinical and computed tomographic classification of 82 events in 71 patients. Arch Neurol 1986;43:273–276. 4. Bresnihan B. CNS lupus. Clin Rheum Dis 1982;8:183–195. 5. Johnson RT, Richardson EP. Neurological manifestations of systemic lupus erythematosus. Medicine 1968;47:337–369. 6. West SG, Emien W, Wener MH, Kotzin BL. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med 1995;99:153–163. 7. Abel T, Gladman DD, Urowitz MB. Neuropsychiatric lupus. J Rheumatol 1980;7:325–333. 8. Christenson RH, Behlmer P, Howard JF Jr, Winfield JB, Silverman LM. Interpretation of cerebrospinal fluid protein assays in various neurologic diseases. Clin Chem 1983;29:1028–1030. 9. Carr RI, Harbeck RJ, Hoffman AA, Pirofsky B, Bardana EJ. Clinical studies on the significance of DNA:anti-DNA complexes in the systemic circulation and cerebrospinal fluid (CSF) of patients with systemic lupus erythematosus. J Rheumatol 1975;2:184–193.

References

10. Hirohata S, Hirose S, Miyamoto T. Cerebrospinal fluid IgM, IgA, and IgG indexes in systemic lupus erythematosus. Their use as estimates of central nervous system disease activity. Arch Intern Med 1985;145: 1843–1846. 11. Hirohata S, Taketani T. A serial study of changes in intrathecal immunoglobulin synthesis in a patient with central nervous system systemic lupus erythematosus. J Rheumatol 1987;14:1055–1057. 12. Golombek SJ, Graus F, Elkon KB. Autoantibodies in the cerebrospinal fluid of patients with systemic lupus erythematosus. Arthritis Rheum 1986;29:1090–1097. 13. Pereira RM, Yoshinari NH, De Oliveira RM, Cossermelli W. Antiganglioside antibodies in patients with neuropsychiatric systemic lupus erythematosus. Lupus 1992;1:175–179. 14. Mevorach D, Raz E, Steiner I. Evidence for intrathecal synthesis of autoantibodies in systemic lupus erythematosus with neurological involvement. Lupus 1994;3:117–121. 15. Yeh TS, Wang CR, Jeng GW, et al. The study of anticardiolipin antibodies and interleukin-6 in cerebrospinal fluid and blood of Chinese patients with systemic lupus erythematosus and central nervous system involvement. Autoimmunity 1994;18:169–175. 16. Isshi K, Hirohata S. Differential roles of the anti-ribosomal P antibody and antineuroal antibody in the pathogenesis of central nervous system involvement in systemic lupus erythematosus. Arthritis Rheum 1998;41:1819–1827. 17. Lai NS, Lan JL. Evaluation of cerebrospinal anticardiolipin antibodies in lupus patients with neuropsychiatric manifestations. Lupus 2000; 9:353–357. 18. Baraczka K, Lakos G, Sipka S. Immunoserological changes in the cerebrospinal fluid and serum in systemic lupus erythematosus patients with demyelinating syndrome and multiple sclerosis. Acta Neurol Scand 2002;105:378–383. 19. Greenwood DL, Gitlis VM, Alderuccio F, Sentry JW, Toh BW. Autoantibodies in neuropsychiatric lupus. Autoimmunity 2002;35:79–86. 20. Lebon P, Lenoir GR, Fischer A, Lagrue A. Synthesis of intrathecal interferon in systemic lupus erythematosus with neurological complications. Br Med J 1983;287:1165–1167. 21. Winfield JB, Shaw M, Silverman LM, Eisenberg RA, Wilson HA, Koffler D. Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction. Am J Med 1983;74:837–844. 22. Hirohata S, Miyamoto T. Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum 1990;33:644–649. 23. Jongen PJ, Boerbooms AM, Lamers KJ, Raes BC, Vierwinden G. Diffuse CNS involvement in systemic lupus erythematosus: intrathecal synthesis of the 4th component of complement. Neurology 1990;40:1593–1596. 24. Alcocer-Varela J, Aleman-Hoey D, Alarcon-Segovia D. Interleukin-1 and interleukin-6 activities are increased in the cerebrospinal fluid of patients with CNS lupus erythematosus and correlate with local late T-cell activation markers. Lupus 1992;1:111–117. 25. Shiozawa S, Kuroki Y, Kim M, Hirohata S, Ogino T. Interferon-alpha in lupus psychosis. Arthritis Rheum 1992;35:417–422. 26. Tsai CY, Wu TH, Tsai ST, et al. Cerebrospinal fluid interleukin-6, prostaglandin E2 and autoantibodies in patients with neuropsychiatric systemic lupus erythematosus and central nervous system infections. Scand J Rheumatol 1994;23:57–63. 27. Jara LJ, Irigoyen L, Ortiz MJ, Zazueta B, Bravo G, Espinoza LR. Prolactin and interleukin-6 in neuropsychiatric lupus erythematosus. Clin Rheumatol 1998;17:110–114. 28. Baraczka K, Pozsonyi T, Szongoth M, et al. A study of increased levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) in the cerebrospinal fluid of patients with multiple sclerosis and systemic lupus erythematosus. Acta Neurol Scand 1999;99:95–99. 29. Trysberg E, Carlsten H, Tarkowski A. Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 2000;9:498–503.

141

30. Baraczka K, Nekam K, Pozsonyi T, Jakab L, Szongoth M, Sesztak M. Concentration of soluble adhesion molecules (sVCAM-1, sICAM-1 and sL-selectin) in the cerebrospinal fluid and serum of patients with multiple sclerosis and systemic lupus erythematosus with central nervous involvement. Neuroimmunomodulation 2001;9:49–54. 31. Svenungsson E, Andersson M, Brundin L, et al. Increased levels of proinflammatory cytokines and nitric oxide metabolites in neuropsychiatric lupus erythematosus. Ann Rheum Dis 2001;60: 372–379. 32. Dellalibera-Joviliano R, Dos Reis ML, Cunha Fde Q, Donadi EA. Kinins and cytokines in plasma and cerebrospinal fluid of patients with neuropsychiatric lupus. J Rheumatol 2003;30:485–489. 33. Jonsen A, Bengtsson AA, Nived O, et al. The heterogeneity of neuropsychiatric systemic lupus erythematosus is reflected in lack of association with cerebrospinal fluid cytokine profiles. Lupus 2003;12:846–850. 34. Okamoto H, Katsumata Y, Nishimura K, Kamatani N. Interferoninducible protein 10/CXCL10 is increased in the cerebrospinal fluid of patients with central nervous system lupus. Arthritis Rheum 2004;50:3731–3732. 35. Trysberg E, Blennow K, Zachrisson O, Tarkowski A. Intrathecal levels of matrix metalloproteinases in systemic lupus erythematosus with central nervous system engagement. Arthritis Res Ther 2004;6:R551–R556. 36. Jara LJ, Vera-Lastra O, Miranda JM, Alcala M, Alvarez-Nemegyei J. Prolactin in human systemic lupus erythematosus. Lupus 2001;10:748–756. 37. Serdaroglu P. Behçet’s disease and the nervous system. J Neurol 1998;245:197–205. 38. Kidd D, Steuer A, Denman AM, Rudge P. Neurological complications in Behçet’s syndrome. Brain 1999;122:2183–2194. 39. Wang CR, Chuang CY, Chen CY. Anticardiolipin antibodies and interleukin-6 in cerebrospinal fluid and blood of Chinese patients with neuro-Behçet’s syndrome. Clin Exp Rheumatol 1992;10:599–602 40. Hirohata S, Tanimoto K, Ito K. Elevation of cerebrospinal fluid interleukin-6 activity in patients with vasculitides and central nervous system involvement. Clin Immunol Immunopathol 1993;66:225–229. 41. Miyagishi R, Kikuchi S, Fukazawa T, Tashiro K. Macrophage inflammatory protein-1 alpha in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases. J Neurol Sci 1995;129:223–227. 42. Hirohata S, Isshi K, Oguchi H, et al. Cerebrospinal fluid interleukin-6 in progressive Neuro-Behçet’s syndrome. Clin Immunol Immunopathol 1997;82:12–17. 43. Kawai M, Hirohata S. Cerebrospinal fluid beta(2)-microglobulin in neuro-Behçet’s syndrome. J Neurol Sci 2000;179:132–139. 44. Niino M, Ogata A, Kikuchi S, Tashiro K, Nishihira J. Macrophage migration inhibitory factor in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis and neuro-Behçet’s disease. J Neurol Sci 2000;179:127–131. 45. Aoyama-Hayashi E, Matsuda T, Ohya N, et al. Soluble Fas ligand levels in cerebrospinal fluid in neuro-Behçet’s disease. Adv Exp Med Biol 2003528:389–391. 46. Saruhan-Direskeneli G, Yentur SP, Akman-Demir G, Isik N, Serdaroglu P. Cytokines and chemokines in neuro-Behçet’s disease compared to multiple sclerosis and other neurological diseases. J Neuroimmunol 2003;145:127–134. 47. Tasci B, Direskeneli H, Serdaroglu P, Akman-Demir G, Eraksoy M, Saruhan-Direskeneli G. Humoral immune response to mycobacterial heat shock protein (hsp)65 in the cerebrospinal fluid of neuro-Behçet patients. Clin Exp Immunol 1998;113:100–104. 48. Swerdlow RH, Hanna GR. Behçet’s disease: presentation with sagittal sinus thrombosis diagnosed noninvasively. Headache 1996;36: 115–118. 49. Ascaso FJ, Rodriguez A, Cristobal JA. Cranial hypertension as first manifestation of Behçet’s disease: a case report. Doc Ophthalmol 2002;105:291–299.

142

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●

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50. Limotai C, Phanthumchinda K. Cerebral venous sinus thrombosis in Behçet’s disease: a case report. J Med Assoc Thai 2004; 87:845–849. 51. Paula De Carvalho Panzeri Carlotti A, Paes Leme Ferriani V, Tanuri Caldas C, et al. Polyarteritis nodosa with central nervous system involvement mimicking meningoencephalitis. Pediatr Crit Care Med 2004;5:286–288. 52. Jinnah HA, Dixon A, Brat DJ, Hellmann DB. Chronic meningitis with cranial neuropathies in Wegener’s granulomatosis. Case report and review of the literature. Arthritis Rheum 1997;40:573–577. 53. Spranger M, Schwab S, Meinck HM, et al. Meningeal involvement in Wegener’s granulomatosis confirmed and monitored by positive circulating antineutrophil cytoplasm in cerebrospinal fluid. Neurology 1997;48:263–265. 54. Scarrow AM, Segal R, Medsger TA Jr, Wasko MC. Communicating hydrocephalus secondary to diffuse meningeal spread of Wegener’s granulomatosis: case report and literature review. Neurosurgery 1998;43:1470–1473. 55. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 1988;67:20–39. 56. Calabrese LH, Furlan AJ, Gragg LA, Ropos TJ. Primary angiitis of the central nervous system: diagnostic criteria and clinical approach. Clev Clin J Med 1992;59:293–306. 57. Stone JH, Pomper MG, Roubenoff R, Miller TJ, Hellmann DB. Sensitivities of noninvasive tests for central nervous system vasculitis: a comparison of lumbar puncture, computed tomography, and magnetic resonance imaging. J Rheumatol 1994;21:1277–1282. 58. Nylen K, Karlsson JE, Blomstrand C, Tarkowski A, Trysberg E, Rosengren LE. Cerebrospinal fluid neurofilament and glial fibrillary acidic protein in patients with cerebral vasculitis. J Neurosci Res 2002;67:844–851. 59. Ludwig AO, Short CL, Bauer W. Rheumatoid arthritis as a cause of increased cerebrospinal fluid protein. N Engl J Med 1943;228:306–310. 60. Markenson JA, McDougal JS, Tsairis P, Lockshin MD, Christian CL. Rheumatoid meningitis: a localized immune process. Ann Intern Med 1979;90:786–789. 61. Garrote FJ, Marco J, Obeso G, Rodriguez E, del Ser T. Aseptic meningitis and focal central nervous system involvement in a case of adult onset Still’s disease. J Rheumatol 1993;20:765–767. 62. Marie I, Levesque H, Perraudin N, Cailleux N, Lecomte F, Courtois H. Aseptic meningitis and cranial nerve palsy revealing adult-onset Still’s disease. Clin Infect Dis 1999; 29:220–221. 63. Sisselman SG. Adult onset Still’s disease presenting as aseptic meningitis in a young healthy female. Del Med J 1999;71:181–184. 64. Blockmans DE, Knockaert DC, Bobbaers HJ, et al. Still’s disease can cause neutrophilic meningitis. Neurology 2000;54:1203–1205 65. Kato T, Hoshi K, Sekijima Y, et al. Rheumatoid meningitis: an autopsy report and review of the literature. Clin Rheumatol 2003;22:475–480. 66. Tabak F, Tanverdi M, Ozaras R, et al. Neutrophilic pleocytosis in cerebrospinal fluid: adult-onset Still’s disease. Intern Med 2003;42:1039–1041. 67. Furukawa F, Toriyama R, Kawanishi T. Neutrophils in cerebrospinal fluid of a patient with acute febrile neutrophilic dermatosis (Sweet’s syndrome). Int J Dermatol 1992;31:670–671. 68. Martinez E, Fernandez A, Mayo J, Manrique P, Collazos J. Sweet’s syndrome associated with cerebrospinal fluid neutrophilic pleocytosis. Int J Dermatol 1995;34:73–74. 69. Noda K, Okuma Y, Fukae J, et al. Sweet’s syndrome associated with encephalitis. J Neurol Sci 2001;188:95–97. 70. Nobeyama Y, Kamide R. Sweet’s syndrome with neurologic manifestation: case report and literature review. Int J Dermatol 2003;42:438–443. 71. Hisanaga K, Iwasaki Y, Itoyama Y, and the Neuro-Sweet Disease Study Group. Neuro-Sweet disease: clinical manifestations and criteria for diagnosis. Neurology 2005;64:1756–1761. 72. Dengler LD, Capparelli EV, Bastian JF, et al. Cerebrospinal fluid profile in patients with acute Kawasaki disease. Pediatr Infect Dis J 1998;17:478–481.

73. Perry HD, Font RL. Clinical and histopathologic observations in severe Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1977;83:242–254. 74. Lubin JR, Loewenstein JI, Frederick AR. Vogt-Koyanagi-Harada syndrome with focal neurologic signs. Am J Ophthalmol 1981;91:332–341. 75. Inomata H, Kato M. Vogt-Koyanagi-Harada disease. In: Mckendall RR, ed. Handbook of Clinical Neurology. Vol. 12. Viral Disease. Amsterdam: Elsevier Science; 1989:611–626. 76. Ikeda M, Tsukagoshi H. Vogt Koyanagi Harada disease presenting as meningoencephalitis. Eur Neurol 1992;32:83–85. 77. Kamondi A, Szegedi A, Papp A, Seres A, Szirmai I. Vogt-Koyanagi-Harada disease presenting initially as aseptic meningoencephalitis. Eur J Neurol 2000;7:719–722. 78. Brazis PW, Stewart M, Lee AG. The uveo-meningeal syndromes. Neurologist 2004;10:171–184. 79. Nakamura S, Nakazawa M, Yoshioka M. Melanin-laden macrophages in cerebrospinal fluid in Vogt-Koyanagai-Harada syndrome. Arch Ophthalmol 1996;114:1184–1188. 80. Takeshita T, Nakazawa M, Murakami K, Tamai M, Nakamura, S. A patient with longstanding melanin-laden macrophages in cerebrospinal fluid in Vogt-Koyanagi-Harada syndrome. Br J Ophthalmol 1997;81:1114. 81. Miyazawa I, Abe T, Narikawa K, et al. Chemokine profile in the cerebrospinal fluid and serum of Vogt-Koyanagi-Harada disease. J Neuroimmunol 2005;158:240–244. 82. Niemela RK, Hakala M. Primary Sjogren’s syndrome with severe central nervous system disease. Semin Arthritis Rheum 1999;29:4–13. 83. de la Monte SM, Hutchins GM, Gupta PK. Polymorphous meningitis with atypical mononuclear cells in Sjogren’s syndrome. Ann Neurol 1983;14:455–461. 84. de la Monte SM, Gupta PK, Hutchins GM. Polymorphous exudates and atypical mononuclear cells in the cerebrospinal fluid of patients with Sjogren’s syndrome. Acta Cytol 1985;29:634–637. 85. Alexander EL, Lijewski JE, Jerdan MS, Alexander GE. Evidence of an immunopathogenic basis for central nervous system disease in primary Sjogren’s syndrome. Arthritis Rheum 1986;29:1223–1231. 86. Satake M, Yoshimura T, Iwaki T, Yamada T, Kobayashi T. Anti-dorsal root ganglion neuron antibody in a case of dorsal root ganglionitis associated with Sjogren’s syndrome. J Neurol Sci 1995;132:122–125. 87. Megevand P, Chizzolini C, Chofflon M, Roux-Lombard P, Lalive PH, Picard F. Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogren’s syndrome with central nervous system involvement. Eur Neurol 2007;57:166–171. 88. Luer W, Jockel D, Henze T, Schipper HI. Progressive inflammatory lesions of the brain parenchyma in localized scleroderma of the head. J Neurol 1990;237:379–381. 89. Nystrom E, Hamberger A, Lindstedt G, Lundquist C, Wikkelso C. Cerebrospinal fluid proteins in subclinical and overt hypothyroidism. Acta Neurol Scand 1997; 95:311–314. 90. Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW. Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment. J Neurol 1996;243:585–593. 91. Tamagno G, Federspil G, Murialdo G. Clinical and diagnostic aspects of encephalopathy associated with autoimmune thyroid disease (or Hashimoto’s encephalopathy). Intern Emerg Med 2006;1:15–23. 92. Chong JY, Rowland LP, Utiger, RD. Hashimoto encephalopathy: syndrome or myth? Arch Neurol 2003;60:164–171. 93. Ferracci F, Bertiato G, Moretto G. Hashimoto’s encephalopathy: epidemiologic data and pathogenetic considerations. J Neurol Sci 2004;217:165–168. 94. Kling MA, Roy A, Doran AR, et al. Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing’s disease and major depression: potential clinical implications. J Clin Endocrinol Metab 1991;72:260–271. 95. Kleerekoper M, Donald RA, Posen S. Corticotrophin in cerebrospinal fluid of patients with Nelson’s syndrome. Lancet 1972;1:74–76. 96. Ullrich I, Lizarralde G. Nelson’s syndrome: case report and review of the literature. South Med J 1977;70:1444–1446.

References

97. Powers WJ. Cerebrospinal fluid to serum glucose ratios in diabetes mellitus and bacterial meningitis. Am J Med 1981;71:217–220. 98. Lester A, Stilbo I, Bartels P, Bruun B. Value of CSF lactate in the differential diagnosis between bacterial meningitis and other diseases with meningeal involvement. Acta Pathol Microbiol Immunol Scand 1985;93:21–25. 99. Yao H, Sadoshima S, Nishimura Y, et al. Cerebrospinal fluid lactate in patients with diabetes mellitus and hypoglycaemic coma. J Neurol Neurosurg Psychiatry 1989;52:372–375. 100. Ohman JL Jr, Marliss EB, Aoki TT, Munichoodappa CS, Khanna VV, Kozak GP. The cerebrospinal fluid in diabetic ketoacidosis. N Engl J Med 1971;284:283–290. 101. Marks CE Jr, Goldring RM, Vecchione JJ, Gordon EE. Cerebrospinal fluid acid-base relationships in ketoacidosis and lactic acidosis. J Appl Physiol 1973;35:813–819. 102. Seddon PC, Smith CS. Adolescent diabetic amyotrophy. Acta Paediatr Scand 1988;77:937–939. 103. Ogawa K, Sasaki H, Kishi Y, et al. A suspected case of proximal diabetic neuropathy predominantly presenting with scapulohumeral muscle weakness and deep aching pain. Diabetes Res Clin Pract 2001;54:57–64. 104. Romedenne P, Mukendi R, Stasse P, Indekeu P, Buysschaert M, Colin IM. An unusual neuropathy in a diabetic patient: evidence for intravenous immunoglobin-induced effective therapy. Diabetes Metab 2001;27:155–158. 105. Sharma KR, Cross J, Farronay O, Ayyar DR, Shebert RT, Bradley WG. Demyelinating neuropathy in diabetes mellitus. Arch Neurol 2002;59:758–765. 106. Bjerre P, Lindholm J. Pituitary apoplexy with sterile meningitis. Acta Neurol Scand 1986;74:304–307. 107. Haviv YS, Goldschmidt N, Safadi R. Pituitary apoplexy manifested by sterile meningitis. Eur J Med Res 1998;3:263–264. 108. Valente M, Marroni M, Stagni G, Floridi P, Perriello G, Santeusanio F. Acute sterile meningitis as a primary manifestation of pituitary apoplexy. J Endocrinol Invest 2003; 26:754–757. 109. Jassal DS, McGinn G, Embil JM. Pituitary apoplexy masquerading as meningoencephalitis. Headache 2004;44:75–78. 110. Coculescu M, Simionescu L, Constantinovici A, et al. High level of human growth hormone (HGH) in cerebrospinal fluid patients with pituitary tumors. J Clin Endocrinol Metab 1976;43:97–106. 111. Rolandi E, Perria C, Cicchetti V, et al. Pituitary hormone concentrations in cerebrospinal fluid in patients with prolactin and growth hormone-secreting tumors. J Neurosurg Sci 1982;26:173–178. 112. Coculescu M. Blood-brain barrier for human growth hormone and insulin-like growth factor-I. J Pediatr Endocrinol Metab 1999;12:113–124. 113. Argov Z, Melamed E, Katz S. Hyperparathyroidism presenting with unusual neurological features. Eur Neurol 1979;18:338–340. 114. Balabanov S, Tollner U, Richter HP, Pohlandt F, Gaedicke G, Teller WM. Immunoreactive parathyroid hormone, calcium, and magnesium in human cerebrospinal fluid. Acta Endocrinol 1984;106:227–233. 115. Joborn C, Hetta J, Rastad J, Agren H, Akerstrom G, Ljunghall S. Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in primary hyperparathyroidism. Biol Psychiatry 1988;15;23:149–158. 116. Joborn C, Hetta J, Niklasson F, et al. Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the blood-brain barrier function in primary hyperparathyroidism. Psychoneuroendocrinology 1991;16:311–322. 117. Agren H. Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid: I. General patterns. Psychiatry Res 1980;3:211–223. 118. Brown GL, Linnoila MI. CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. J Clin Psych 1990;51(Suppl):31–43. 119. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994;40:288–295.

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120. Abi-Dargham A, Laruelle M, Aghajanian GK, Charney D, Krystal J. The role of serotonin in the pathophysiology and treatment of schizophrenia. J Neuropsych Clin Neurosci 1997;9:1–17. 121. Asberg M. Neurotransmitters and suicidal behavior. The evidence from cerebrospinal fluid studies. Ann N Y Acad Sci 1997;836: 158–181. 122. Plotsky PM, Owens MJ, Nemeroff CB. Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr Clin North Am 1998;21:293–307. 123. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999;160:1–12. 124. Kasckow JW, Baker D, Geracioti TD. Corticotropin-releasing hormone in depression and post-traumatic stress disorder. Peptides 2001;22:845–851. 125. Wong ML, Kling MA, Munson PJ, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropinreleasing hormone. Proc Natl Acad Sci USA 2000;97:325–330. 126. Nikisch G, Agren H, Eap CB, Czernik A, Baumann P, Mathe AA. Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram. Int J Neuropsychopharmacol 2005;8:403–410. 127. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Aging Res Rev 2005;4:141–194. 128. Moris G, Garcia-Monco JC. The challenge of drug-induced aseptic meningitis. Arch Int Med 1999;159:1185–1994. 129. Ostensen M, Villiger PM. Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus. Lupus 2001;10:135–139. 130. Horizon AA, Wallace DJ. Risk:benefit ratio of nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus. Expert Opin Drug Saf 2004;3:273–278. 131. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf 2000;22:215–226. 132. Nettis E, Calogiuri G, Colanardi MC, Ferrannini A, Tursi A. Drug-induced aseptic meningitis. Curr Drug Targets Immune Endocr Metabol Disord 2003;3:143–149. 133. Plumb VJ, Dismukes WE. Chemical meningitis related to intrathecal corticosteroid therapy. South Med J 1977;70:1241–1243. 134. Gutknecht DR. Chemical meningitis following epidural injections of corticosteroids. Am J Med 1987;82:570. 135. Chamberlain MC, Kormanik PA, Barba D. Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases. J Neurosurg 1997;87:694–699. 136. Fukushima T, Sumazaki R, Koike K, et al. A magnetic resonance abnormality correlating with permeability of the blood-brain barrier in a child with chemical meningitis during central nervous system prophylaxis for acute leukemia. Ann Hematol 1999;78:564–567. 137. Barami K, Sood S, Ham S, Canady A. Chemical meningitis from bile reflux in a lumbar-gallbladder shunt. Pediatr Neurosurg 1998;29:328–330. 138. Hoeffel C, Gaucher H, Chevrot A, Hoeffel JC. Complications of lumbar puncture with injection of hydrosoluble material. J Spinal Disord 1999;12:168–171. 139. Bender A, Elstner M, Paul R, Straube A. Severe symptomatic aseptic chemical meningitis following myelography: the role of procalcitonin. Neurology 2004;12;63:1311–1313. 140. Harding SA, Collis RE, Morgan BM. Meningitis after combined spinalextradural anaesthesia in obstetrics. Br J Anaesth 1994;73:545–547. 141. Nishimura C, Tsubokawa K, Kasama S, Otagiri T. Two cases of chemical meningitis following spinal anesthesia. J Anesth 2001;15:111–113. 142. Meyers PM, Lavine SD, Fitzsimmons BF, et al. Chemical meningitis after cerebral aneurysm treatment using two second-generation aneurysm coils: report of two cases. Neurosurgery 2004;55:E1222–E1227.

CHAPTER

18

Nutritional and Metabolic Disorders L. Christine Turtzo and David N. Irani

INTRODUCTION Changes in the composition of cerebrospinal fluid (CSF) have been investigated in many nutritional and metabolic disorders of humans. Likewise, the roles played by substances derived from the diet as biochemical co-factors and by electrolyte and metal ions have been clarified in a variety of neurological disease states. Our current understanding of the CSF abnormalities found in various nutritional and metabolic disorders affecting the nervous system will be reviewed below, with particular emphasis on vitamin deficiency states, disorders resulting from abnormal concentrations of various electrolyte and metal ions, abnormalities found in the setting of renal or hepatic failure, and those occurring with disturbances of acid–base balance. A discussion of the CSF changes associated with the more common inborn errors of metabolism is covered in Chapter 11, while those found in the setting of other toxic disorders are reviewed in Chapter 17.

VITAMIN DEFICIENCY DISORDERS Vitamin A Vitamin A deficiency can present in infants with bulging of the fontanelle indicative of increased intracranial pressure (ICP).1 In children with cystic fibrosis, a condition frequently associated with the malabsorption of fat-soluble vitamins such as vitamin A, low serum vitamin A levels have been linked with papilledema and elevated opening pressure (OP) at the time of lumbar puncture (LP).2,3 Animal models of chronic hypovitaminosis A have provided experimental evidence that directly links serum vitamin A deficiency with elevated CSF pressure, mostly due to diminished absorption of CSF.4–9 The possibility of vitamin A deficiency should always be investigated in at-risk patients with unexplained evidence of elevated ICP.

Vitamin B1 (Thiamine) In healthy individuals, the concentration of thiamine and thiamine monophosphate is somewhat higher in CSF than it is in serum, although low CSF concentrations generally correlate with low serum levels.10 Transport of thiamine into the brain and CSF likely occurs from the plasma by facilitated diffusion across brain capillaries. Decreased CSF thiamine concentrations have been documented in patients with Friedreich’s ataxia, olivopontocerebellar atrophy, and spastic ataxia of Charlevoix-Saguenay when compared to age-matched controls.11,12 Other studies have suggested that thiamine and thiamine monophosphate levels are decreased in the CSF of patients with cerebellar ataxias of a variety of origins.13 Unfortunately, the utility of thiamine supplementation in all these situations remains unclear. Decreased levels of thiamine monophosphate were found in the CSF of two patients with Wernicke’s encephalopathy related to chronic alcohol abuse.14 In another study of 59 patients with chronic malnutrition and peripheral neuropathy due to alcoholism, decreased CSF levels of thiamine were also reported.15 One study investigating the CSF of five thiamine-deficient patients showed that CSF thiamine and 5-hydroxyindoleacetic acid levels were both decreased, and that CSF levels of both molecules increased after systemic thiamine replacement.16 Still, a patient with chronic alcoholism and malnourishment developed an acute axonal polyneuropathy where systemic thiamine deficiency was present but the CSF level was normal.17 Another case reported on an elderly woman who presented with a chronic neuropathy in the setting of both thiamine and folate deficiencies, where the only reported CSF abnormality was an elevated total protein concentration.18 In cases of systemic thiamine deficiency leading to polyneuropathy among the Xavante people, CSF examinations were normal.19 Thus, in suspected cases of thiamine deficiency (Wernicke-Korsakoff syndrome, post-gastrectomy, etc.), the CSF should be normal in the majority of patients, with only a subset showing

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modest protein elevations. A total protein level above 100 mg/dl or a CSF pleocytosis should prompt a search for a complicating illness. In 33 patients with Alzheimer’s disease, the mean CSF levels of thiamine diphosphate, thiamine monophosphate, free thiamine, and total thiamine did not differ from those of age-matched controls, despite the finding of decreased plasma thiamine levels in the Alzheimer’s group.20 Low free thiamine levels were reported in both the plasma and CSF of 24 patients with Parkinson’s disease compared to age-matched controls.21 Likewise, a study of 11 epileptic patients treated chronically with phenytoin observed that lower CSF and blood thiamine levels were detected compared to 23 healthy controls.22 In summary, the role of thiamine replacement to treat Wernicke’s encephalopathy is clear, and the corresponding rise in CSF thiamine levels suggests that brain repletion is what actually is beneficial.16 Whether there is any role for thiamine supplementation in patients with other neurological disorders where low serum or CSF thiamine levels have been observed is not known.

Vitamin B6 (pyridoxine) The biochemical underpinnings of infantile pyridoxinedependent seizures, where seizures are rapidly controlled by systemic pyridoxine administration, are poorly understood. The disorder does not, however, appear to involve a defect in the metabolism or uptake of pyridoxine in the central nervous system (CNS).23 In one patient with pyridoxine-dependent seizures, CSF levels of glutamate were recorded at 200-times normal at a time when the patient was not supplemented with vitamin B6, but rapidly normalized following replacement therapy.24 Yet in another such patient, CSF glutamate levels were not elevated either before or after treatment.25 Pipecolic acid was found to be higher in the CSF of two pyridoxine-dependent seizure patients compared to controls with non-pyridoxinedependent epilepsy.26 In a study of 27 patients with nonpyridoxine-dependent epilepsy treated long-term with both phenytoin and phenobarbital, increased CSF levels of vitamin B6 were found in comparison to healthy controls.27 Finally, a single case of juvenile spinocerebellar degeneration with low levels of vitamin B6 in both serum and CSF has been reported.28 Both pyridoxine deficiency (either due to lack of dietary intake or secondary to chronic treatment with drugs such as isoniazid or hydralizine) and pyridoxine oversupplementation can cause a peripheral neuropathy. In the few cases of this disorder where CSF findings have been described, routine analyses (cell counts, protein levels, etc.) have uniformly been normal. CSF vitamin B6 levels were not reported in these patients.15 High concentrations of pyridoxine are directly toxic to sensory neurons in vitro, so the absence of measurable change in the CSF with in vivo toxicity is not surprising.

In summary, the evidence to date implicates pyridoxine in the pathogenesis of certain types of epilepsy, although not through a defect in its direct entry into the CNS or its complete absence from the CSF. The exact mechanism by which pyridoxine supplementation controls seizures and whether and how to measure its effects in the CSF is unclear at the present time. Previous data have implicated a defect in the actions of glutamic acid decarboxylase, a pyridoxinedependent enzyme, but recent studies have been contradictory.23–25 Both deficient and toxic levels of pyridoxine cause neuropathy, but neither state alters the composition of CSF.

Vitamin B12 (cobalamin) Patients with low serum vitamin B12 levels demonstrate high levels of methylmalonic acid in both their serum and CSF.29 Indeed, such patients can have CSF:serum methylmalonic acid ratios that are more than 3-times higher than in individuals with normal serum vitamin B12 levels.30 Conversely, patients with vitamin B12 deficiency also have low CSF levels of 5-hydroxyindoleacetic acid.31 Lower than average vitamin B12 levels have been observed in the CSF of patients with both Alzheimer’s disease and multiple sclerosis compared to healthy controls.32 While the pathophysiological significance of these changes is unclear, patients with clinically definite multiple sclerosis who are treated with high-dose methylprednisolone exhibit significant drops in CSF levels of folate and vitamin B12 following their infusions as compared to before them.33 This suggests that these parameters at least track with the CNS inflammation in this disorder, even if they are not directly involved in disease pathogenesis. Subacute combined degeneration (SCD) is a primary demyelinating disorder of the CNS resulting from cobalamin or methyltetrahydrofolate deficiency, where function of the methyl-transfer pathway is disrupted.34 In patients with SCD due to an underlying cobalamin deficiency, CSF levels of cobalamin and epidermal growth factor (EGF) are low, while CSF homocysteine and tumor necrosis factor-alpha (TNF-α) levels are high compared with controls.35 The CSF total protein level in patients with SCD can range from 28 to 115 mg/dl, with a mean of 49 mg/dl.35 In a cohort of patients with SCD reported by Merritt and Fremont-Smith, 11 of 50 individuals had elevated CSF protein levels ranging between 45 and 95 mg/dl, and two of 50 had a low-grade pleocytosis of up to 10 cells/mm3 (all mononuclear).36 Oligoclonal bands were uniformly negative and the immunoglobulin (Ig) G index was consistently normal (0.29–0.59) in these patients.35,36 In cobalamin-deficient rats with central demyelination, treatment not only with supplemental vitamin B12, but also with antibody against CD40 (a TNF-α family member), restored myelin ultrastructure.37 This suggests that inflammatory mediators induced by cobalamin deficiency may contribute to the pathogenesis of SCD. Low CSF levels of S-adenosylmethionine (SAM) have been found in patients with SCD, and vitamin B12 replacement

Vitamin Deficiency Disorders

therapy can result in clinical improvement, evidence of central remyelination, and reversal of low CSF SAM levels back into the normal range.38 A 16-year-old girl with 5, 10-methylenetetrahydrofolate reductase deficiency and a peripheral neuropathy who had undetectable CSF levels of SAM prior to the initiation of betaine monohydrate therapy increased her CSF SAM level to normal after 24 months of treatment and showed improvement of both her muscle weakness and her gait abnormality.39 In conclusion, most of the plasma biochemical abnormalities associated with vitamin B12 deficiency (high methylmalonic acid and homocysteine levels) can also be found in the CSF, and further, inflammatory mediators such as TNF-α and soluble CD40 that may actually contribute to the demyelination seen in SCD are also elevated in this CNS compartment. Otherwise, most SCD patients have normal routine CSF studies, with only 20% having a modest protein elevation and fewer than 5% having a low-grade mononuclear cell pleocytosis. As with other deficiency states, systemic repletion improves neurological symptoms and reverses low CSF levels.

Folate One patient with a slowly progressive neurological syndrome characterized by hearing loss, distal spinal muscular atrophy, pyramidal tract dysfunction, and cerebellar signs has been described in association with severely depressed CSF concentrations of folate and folate binding protein but normal serum and red blood cell folate levels.40 A handful of patients with the Kearns-Sayre syndrome were shown to have markedly reduced CSF folate levels in the presence of normal serum folate concentrations; one who was being treated with phenytoin for seizures had both low serum and CSF folate levels.41 The mechanism by which central folate deficiency develops in these patients is not known, nor is it understood whether or how these low CSF folate levels actually contribute to disease pathogenesis. A 2-year-old girl with 5,10-methylenetetrahydrofolate deficiency who developed SCD of the spinal cord as well as a leukoencephalopathy prior to her death was shown to have markedly reduced CSF, serum, and red blood cell folate concentrations, but a normal serum vitamin B12 level.42 Intrathecal treatment with the anti-folate chemotherapeutic agent, methotrexate, not surprisingly results in decreased CSF levels of both folate and SAM.43 After 3 weeks of systemic folate replacement therapy, 23 patients with low or low–normal CSF folate concentrations all demonstrated significantly higher CSF levels.44 In patients with mild cognitive impairment associated with folate deficiency, 7–11 months of systemic folate supplementation resulted in measurable neuropsychiatric improvement.45 A 48-year-old woman with a relapsing radial nerve palsy after repeated diarrheal illnesses who had low serum and CSF folate levels also showed marked improvement in her neuropathy after folate supplementation.46

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Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with low CSF levels of the active folate metabolite, 5-methyltetrahydrofolate, but normal folate metabolism elsewhere in the body.47 Children with CFD were given oral supplementation with folinic acid with some clinical improvement.48 Recently, these patients were found to have high-affinity autoantibodies against membrane-bound folate receptors present on the choroid plexus.49 These antibodies presumably inhibit the transfer of folate from plasma into the CSF to cause the CFD disorder. Taken together, current data indicate that systemic supplementation with folate or folinic acid in certain disease states can increase CSF folate and 5-methyltetrahydofolate levels and, at least to some degree, improve the various neurological symptoms associated with the underlying deficiency disorders.

Vitamin C (ascorbic acid) Levels of ascorbic acid in the CSF of patients with senile dementia were found in one study to be 30% of those in healthy controls.50 Likewise, decreased CSF:plasma vitamin C ratios or reduced overall CSF vitamin C levels have been found in Alzheimer’s patients compared to age-matched non-demented controls.51–53 An actual role in disease pathogenesis is less clear; in one study of 10 patients with Alzheimer’s disease who were given supplemental vitamin C, both plasma and CSF levels normalized after treatment, but measurable clinical changes in cognitive function were not consistently observed.54 Still, its documented function as an antioxidant has fueled continued interest in the role of vitamin C in this disorder. Regarding its role in other neurological disorders, lower levels of ascorbic acid were found in both plasma and CSF of patients with septic encephalopathy and with Creutzfeldt-Jakob disease.55,56 Low CSF ascorbic acid levels have also been reported in patients with head trauma, brain tumors, and hydrocephalus.57 Infants and children with severe traumatic brain injury have also been noted to have decreased CSF ascorbic acid levels.58 The precise clinical significance of lower CSF ascorbic acid levels found in these various neurological disorders is not known. Prevailing hypotheses continue to focus on the role of oxidative injury in disease pathogenesis and on vitamin C as an antioxidant.

Vitamin D The vitamin D metabolites 25-hydroxyvitamin D, 24, 25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D are all detectable in the CSF of normal, healthy adults.59 Further, a vitamin D-dependent calcium-binding protein known as calbindin-D can also be detected in this compartment, and levels of this protein are elevated in the CSF of patients with cerebellar lesions or with cerebrovascular disease.60

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Still, the role of CSF vitamin D metabolites in these and other neurological disorders is not currently understood.

Vitamin E (alpha- and gamma-tocopherol) The two main biologically active forms of vitamin E are alpha-tocopherol and gamma-tocopherol; the former is usually about 4-times more abundant in both plasma and CSF than the latter.61 Unlike the water-soluble vitamins, vitamin E metabolites bind avidly to lipoproteins and are typically found in CSF at levels about 1000-fold less than in plasma.61 Vitamin E deficiency (either due to a congenital absence of a binding protein or as an acquired defect due to intestinal malabsorption) can produce a variety of neurological manifestations, most notably a progressive spinocerebellar syndrome. Routine analysis of CSF in these rare patients is uniformly normal. In other disorders, patients with Alzheimer’s disease have been reported to have decreased CSF levels of vitamin E compared to controls,62,63 and both plasma and CSF levels increase with supplementation.54 Lower CSF levels of alpha-tocopherol have also been documented in patients with Parkinson’s disease, with higher levels reported in those patients on dopaminergic therapy compared to those who were not.64 In 16 schizophrenic patients with tardive dyskinesia, lower CSF levels of vitamin E were observed in comparison to schizophrenics without tardive dyskinesia or to normal controls.65 On the other hand, there were no significant differences noted in the CSF vitamin E levels of patients with amyotrophic lateral sclerosis or multiple sclerosis compared to controls.66,67 In summary, based on the paucity of current data, it is difficult to draw many firm conclusions about the significance of CSF levels of vitamin E in the diagnosis and management of most neurological diseases. Supplementation in vitamin E deficiency, however, raises CSF levels and improves neurological symptoms.

hair changes, often accompanied by encephalopathy. Marasmus is the chronic form of this disorder and causes apathy and growth failure. One study showed that ammonia levels were elevated in the CSF of children with either type of protein-calorie malnutrition, and to some degree the magnitude of this rise correlated with the severity of the associated mental status changes.69 In another study, activities of two particular enzymes, glutamic-oxalacetic transaminase and lactate dehydrogenase, were elevated in the CSF of children with marasmus or kwashiorkor.70 Since these enzymes facilitate the conversion of certain amino acids into glucose via the citric acid cycle, these findings are believed to represent an effort on the part of the brain to maintain its energy sources.

METALS AND OTHER IONS Calcium Calcium levels in CSF are kept relatively constant in the setting of either acute or chronic changes in ionized or total serum calcium concentrations. This homeostasis appears to depend on an active, carrier-mediated transport process; there is limited passive diffusion of ionized calcium from serum into CSF.71–74 Experimentally, the infusion of a calcium-depleted artificial CSF into the subarachnoid space of sheep results in continuous muscle tremors and hyperpnea.75 Clinically, however, CSF calcium levels are not significantly altered in most diseases of the nervous system where they have been examined, although this has not been widely investigated. It is perhaps noteworthy here that hyperparathyroidism (resulting in serum hypercalcemia) is a rare cause of pseudotumor cerebri by an unknown mechanism.61 Accordingly, measurement of CSF calcium levels has little utility in clinical practice at present.

Magnesium Vitamin K There are limited clinical data regarding the CSF changes in patients with vitamin K abnormalities. This may in large part be a consequence of the coagulopathy associated with vitamin K deficiency, which would be considered a contraindication to LP. A single case report exists in the literature regarding a breast-fed infant who did not receive any vitamin K prophylaxis at birth, who presented with signs of elevated ICP.68 LP revealed bloody CSF, and the patient subsequently died from complications of her coagulopathy.

OTHER NUTRITIONAL STATES Protein-calorie malnutrition Protein-calorie malnutrition is separated into two forms, kwashiorkor and marasmus. Kwashiorkor is a state of acute, severe protein-calorie malnutrition resulting in edema and

Relatively few data exist on the composition of CSF in states of magnesium excess or deficiency in humans, despite numerous studies in animals. Rats fed a magnesiumdeficient diet that was severe enough to produce neurological symptoms had dramatically lower levels of both plasma and CSF magnesium.76 Similar decreases in CSF magnesium concentrations have been reported in cows and sheep with experimentally induced hypomagnesemic tetany 77–79. Still, like calcium, there appears to be a strong homeostatic mechanism that keeps CSF magnesium levels relatively constant, since sheep fed low-magnesium diets that were not severe enough to result in symptomatic deficiency had CSF magnesium levels no different than controls.80 Likewise, there was little change noted in the CSF magnesium levels of diet-induced hypomagnesemia in rats in the absence of neurological symptoms.81,82 The choroid plexus is the main site where CSF magnesium concentration is regulated.83 When serum calcium

Metals and Other Ions

levels rise, magnesium shifts from the CSF and other extracellular fluids into bone, often precipitating severe neurological symptoms in individuals with preexisting magnesium deficiency.84 Ventriculo-lumbar perfusion techniques in sheep have shown that instilling synthetic CSF with a low magnesium concentration results in tetany.75 Symptoms can be reversed with synthetic CSF having a normal magnesium concentration.75 Systemic repletion of magnesium into diet-induced hypomagnesemic calves resulted in increased plasma levels within 5 min and higher CSF concentrations within 30 min of the infusion.85 The effects of serum hypermagnesemia on CSF were reported in a few studies in animals and humans. In humans with acute traumatic brain injury in whom hypermagnesemia was induced via peripheral administration of magnesium sulfate for 24 h, total and ionized CSF magnesium levels were increased by only 15% and 11%, respectively.86 Likewise, intravenous infusion of magnesium to serum levels that were 700% above normal resulted in only a 20% increase in CSF magnesium concentration in several animal studies.87,88 Still, because both hypermagnesemia (paralysis) and hypomagnesemia (seizures) have important neurological sequelae related to neuronal excitability, an important role in the regulation of CSF and brain extracellular magnesium levels is proposed.89

Potassium Potassium ions can alter neuronal excitability by depolarizing membranes, and high extracellular potassium concentrations can produce astroglial swelling.61 Thus, as with other ions, it makes sense that there are mechanisms in place to maintain a strict stability of CSF potassium levels despite extreme systemic hypokalemia or hyperkalemia.90 In one small study, CSF potassium concentrations in patients remained at 2.9 mEq/l, despite acute changes to serum potassium levels varying from 1.6 to 7.1 mEq/l.90 In less severe but more chronic hypokalemia or hyperkalemia ranging from 3.4 to 5.8 mEq/l, CSF potassium concentrations also remained between 2.7 and 3.9 mEq/l.91 Even in subarachnoid hemorrhage, where a large amount of potassium is released into the CSF as a result of hemolysis, there is no significant rise in CSF potassium concentration.92 This finding indicates the presence of a highly efficient mechanism to regulate CSF potassium levels.76 Only in a rare patient with a large cerebral infarction does the CSF potassium level transiently rise, presumably due to massive release from damaged cells and saturation of the equilibration mechanisms.92 In contrast to the above findings, CSF potassium levels rise quickly after death.93,94 In a post mortem analysis of 157 subjects at autopsy, CSF potassium levels ranged from 5.6 to 40 mEq/l, with the interval after death correlating strongly with the magnitude of CSF potassium level increase.95

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Sodium Data on CSF sodium concentrations during systemic hyponatremia and hypernatremia are mostly derived from experimental studies in animals. In dogs, CSF sodium levels varied directly with changes in plasma concentrations.96 With the induction of acute hypernatremia in cats, CSF sodium concentrations rose over a period of approximately 60 min, but never quite reached plasma levels.61,97 Thus, these data are in stark contrast to potassium levels, which are much more tightly buffered in CSF. Given that sodium is the predominant osmotically active cation in CSF, it is logical that its concentration more closely parallels plasma levels in order to facilitate the transfer of water between the two compartments. In addition, because plasma and CSF sodium levels appear to parallel one another in both experimental models and human disease states, there seems to be little clinical utility from the measurement of CSF sodium in routine clinical practice.

Chloride CSF chloride levels are normally 15–20 mEq higher than in serum, and these may fall slightly in the setting of very high total CSF protein levels.61 The CSF chloride typically follows what is happening in the serum with both hyperchloremia and hypochloremia, but the magnitude of this change is blunted compared to the systemic compartment. Although many earlier studies attempted to correlate CSF chloride levels with various disease states, the data in aggregate now suggest that there is limited utility to the measurement of this parameter in routine clinical practice.61 The use of drugs to decrease CSF formation (carbonic anhydrase inhibitors, loop diuretics) also blocks the movement of both sodium and chloride from plasma into CSF (see Chapter 3).

Copper Patients with Menkes syndrome, an X-linked inherited disorder of copper deficiency, have a defective coppertransporting ATPase that results in the impaired absorption of sufficient dietary copper from the gastrointestinal tract.98 These patients uniformly develop neurological involvement,98 and both plasma and CSF samples show decreased copper concentrations as well as increased dihydroxyphenylalanine:dihydoxyphenylglycol and dihydroxyphenylacetic acid:dihydoxyphenylglycol ratios, indicating partial deficiency of the copper-dependent enzyme dopamine-beta-hydroxylase.99 A single Menkes patient who was treated with copper-histidine infusions showed normal CSF copper concentrations after treatment.100 Patients with Wilson’s disease have an autosomal recessive disorder of copper metabolism where high plasma copper concentrations are due to low circulating levels of the copperbinding protein, ceruloplasmin. This leads to deposition in the brain and subsequent neuropsychiatric symptoms.

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Wilson’s disease patients have 2–3-fold elevated levels of free copper in their CSF, and these concentrations can decrease slowly following treatment with D-penicillamine.101 After the initiation of chelation therapy, normalization of CSF copper concentrations in one study of patients with cerebral involvement took an average of 47 months.102 Indeed, the monitoring of CSF copper concentrations has been utilized as a method to detect early noncompliance with therapy in patients with Wilson’s disease.101,103 Another study investigating factors that influenced CSF copper levels found that in the presence of an intact blood–CSF barrier (as would be expected in Wilson’s disease), raised CSF copper levels must somehow originate from the brain itself.104 These investigators concluded that a therapeutic target for the CSF copper concentration in this disorder should be at least 30% below the upper limit of the normal range.104

Iron The majority of CSF iron is bound to transferrin, and iron levels in this compartment are some 10,000-fold lower than in serum.61 Aceruloplasminemia is an inherited disorder of iron metabolism in which there is no ceruloplasmin ferroxidase activity, resulting in the accumulation of iron in the brain and visceral organs.105 In aceruloplasminemic patients, there are high free iron levels in both serum and CSF, and these elevated levels are associated with higher rates of lipid peroxidation in the CNS.106 Preterm infants with post-hemorrhagic ventricular dilatation have elevated CSF levels of non-protein-bound iron in comparison to control preterm infants.107 Since free iron catalyzes the generation of hydroxyl radicals, it has been proposed that the white matter damage seen in many young patients with these intraventricular hemorrhages is incurred via the formation of these destructive mediators.107 Finally, a patient with rheumatoid arthritis who was given the iron-chelating drug desferrioxamine, along with the anti-emetic prochlorperazine, developed an acute reversible metabolic encephalopathy.108 His CSF showed decreased levels of loosely bound (catalytic) iron and increased levels of catalytic copper, total iron, and various byproducts of lipid peroxidation, all of which returned to normal as he improved.108

Lead Limited data in humans indicate that lead levels in serum and CSF are quite independent of each other.109,110 Rats with chronic lead exposure administered via their drinking water had elevated CSF concentrations of magnesium and reduced CSF levels of transthyretin, a protein made by the choroid plexus.111 Analysis of paired serum and CSF samples from humans also demonstrated an inverse correlation between lead and transthyretin concentrations in CSF.110

There are surprisingly limited data available on CSF findings in humans with toxic lead exposure. In one study of children with lead encephalopathy, CSF analysis showed an increased OP, elevated total protein concentration, and a mononuclear pleocytosis of 30–100 cells/mm3 in more than half of patients.61,112 This latter finding has understandably caused confusion with a variety of infectious processes.

Manganese Studies in rats have shown that the lateral choroid plexus is the main site that regulates manganese entry into the CSF, with saturation due to systemic manganese toxicity resulting in leakage of the element into the CSF and subsequent accumulation in CNS tissues.113 Chronic manganese exposure in rats produced toxic manganese levels in both blood and CSF, as well as increased CSF iron concentrations.114 Manganese poisoning in humans (mostly from the mining or processing of manganese ore) causes irritability, behavioral disturbances, and months later an extrapyramidal syndrome.115 Recently, intrathecal injection of manganese chloride into spinal cord-injured mice led to selective uptake by damage tissues and provided a precise quantification of the amount of injury as assessed by magnetic resonance imaging.116

Zinc Zinc is an essential nutrient whose homeostasis within the CNS is regulated at the blood–brain and blood–CSF barriers.117 Entry of systemic zinc into the CSF of rats occurs over an interval of days as assessed using isotopic zinc, and dietary zinc deprivation results in increased net uptake of zinc into the CSF of these animals.118 Zinc levels in the CSF are increased in some patients with subarachnoid hemorrhage, while they are lowered in patients with Alzheimer’s disease compared to controls, despite normal serum zinc levels.119,120

DISORDERS ASSOCIATED WITH RENAL OR HEPATIC FAILURE Uremia Renal failure can lead directly to uremic encephalopathy, and the treatment of uremia with dialysis can occasionally cause either acute or chronic encephalopathic states. Older studies report CSF abnormalities in a substantial proportion of uremic patients. In a cohort of patients with uremia of different causes, Madonick et al. reported the presence of a pleocytosis of >5 leukocytes/mm3 in 25 of 62 patients (range, 6−250 cells/mm3), although the magnitude of the cellular infiltrate seemed unrelated to the degree of azotemia.121 Another study by Schreiner and Maher showed that CSF protein content exceeded 60 mg/dl in 30 of 52 uremic patients; 19 of these individuals had levels

Acid–Base Balance

above 80 mg/dl, and the concentration was over 100 mg/dl in 11 cases.122 This protein increase was later shown to be the result of generalized blood–brain barrier (BBB) breakdown via an unknown mechanism.123 As for urea, its concentration in normal CSF is usually about 90% of that found in serum.124 Furthermore, even when serum levels become dramatically elevated due to impaired renal clearance, the CSF:serum concentration ratio of 0.9 does not appreciably change.125 Following hemodialysis, however, serum levels are rapidly reduced and the concentration ratio rises.125 As urea is an osmotically active solute, this creates a gradient that favors fluid accumulation in the brain and elevated ICP and it may account for the so-called dialysis disequilibrium syndrome. More recent studies have also implicated the accumulation of several guanidino compounds in CSF as being potential mediators of both epileptic and neurocognitive deficits associated with uremic encephalopathy.126

Liver Failure Acute deterioration of liver function is commonly associated with altered mental status in affected patients, and many of these individuals deteriorate as a result of brain edema to the point of fatal ICP elevation. Cases of acute liver failure are therefore commonly associated with an elevated OP if LP is performed in this setting.127 The mechanisms underlying brain edema in acute liver failure have been exhaustively reviewed by Vaquero and Butterworth; high CSF and brain levels of both glutamine and ammonia cause visible swelling of astrocytes, and along with increased cerebral blood flow, this occurrence causes high ICP with effacement of cortical sulci as well as brain herniation through the foramen magnum.128 Additional factors such as altered extracellular levels of branched amino acids and the related neurotransmitters derived from them, as well as inflammatory mediators, are likely contributing factors.128 Increased permeability of the BBB itself is probably not involved.128 These pathophysiologic insights into brain edema are now reflected in several new experimental interventions being tested in humans; trials of ammonialowering therapies, hypothermia, plasmaphoresis, among other approaches, may help to mitigate the complications of high ICP in patients awaiting liver transplantation.128 Although very few studies have otherwise reported on the routine composition of CSF in the setting of acute liver failure, the scarce data available suggest that findings are normal regardless of CSF pressure dynamics. Chronic liver failure, in contrast, is generally not associated with elevated ICP but instead can produce the syndrome of hepatic encephalopathy (HE). Here, portal hypertension causes blood to bypass its normal detoxification in the liver via the formation of collateral channels, resulting in tremor, ataxia, dysarthria, and variable clouding of the sensorium. Ammonia and a variety of other circulating mediators are implicated in the pathogenesis of

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this disorder. The most prominent changes in CSF composition in the setting of HE are elevated levels of ammonia, glutamine, alpha-ketoglutaramate, and lactate.61 Most blood ammonia is found in an ionized form; only 10% is un-ionized and able to cross the BBB. There it combines with alpha-ketoglutarate to produce glutamine; this substance is more stable, easier to measure, and thus more relevant to consider in the setting of suspected HE. Normal CSF levels of glutamine are 10.4 ± 4.0 mg/dl (range, 5−23 mg/dl). In patients with liver disease but without encephalopathy CSF, glutamine levels are 18.0 ± 8.8 mg/dl (range, 6−51 mg/dl), and in patients with clinical evidence of HE, CSF glutamine levels are 46.4 ± 18.5 mg/dl (range, 11−96 mg/dl).129,130 Values over 35 mg/dl are almost always associated with some degree of encephalopathy, making it a useful diagnostic test in patients with confusional states.61 Other routine CSF parameters are generally normal in the setting of HE, although some studies suggest that total protein content may sometimes be elevated.61 The occasional finding of significant HE in the setting of normal serum and CSF ammonia levels has driven a search for other compounds that might be the actual substrates of this clinical syndrome. Previous studies reported on the presence of high CSF levels of “endogenous” benzodiazepine activity in patients with HE,131,132 but more recent investigations have not confirmed these findings.133 A single study identified high plasma and CSF levels of the delta opioid receptor ligand, met-enkephalin, in a cohort of HE patients, raising the prospect that opioid receptor antagonists might be a therapeutic option in this disorder.134 In summary, it seems reasonable to conclude that further study is required to better understand the pathogenesis of this complex condition.

ACID–BASE BALANCE Homeostatic mechanisms help to maintain a stable CSF pH despite wide fluctuations in systemic arterial pH. These mechanisms include alterations of respiratory rate (thus controlling arterial carbon dioxide tension), changes in cerebral blood flow, regulation of CSF bicarbonate levels, and endogenous buffering by the brain itself. In practice, however, the study of CSF acid–base balance has proven to be of limited clinical utility because assays may not truly reflect what is happening within the brain, and, unlike arterial blood gasses, they have not been shown to be important to patient management.61,135 The reader is referred to the scholarly work of Fishman for a more complete review of CSF acid–base physiology.61

Systemic disorders Metabolic acidosis (i.e., uremia, diabetic ketoacidosis), metabolic alkalosis (i.e., chronic vomiting and volume contraction), respiratory acidosis (i.e., emphysema, extreme obesity),

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and respiratory alkalosis (i.e., head injury, pregnancy, congestive heart failure) all change systemic arterial pH but cause limited changes to CSF pH. Rapid adjustments of CSF bicarbonate levels and CSF carbon dioxide tensions help to mitigate significant pH changes. In these situations, bicarbonate is mobilized by active transport at the choroid plexus and from glial cells. Changes in cerebral blood flow (highly pH-dependent) help to carry away excessive amounts of carbon dioxide.

Primary CSF acidosis Metabolic changes directly affecting the brain can produce a CSF acidosis without any changes in arterial pH or in the arterial blood gasses. Such findings have been documented in patients with subarachnoid hemorrhage, head trauma, stroke, and bacterial meningitis.61 In many of these cases, central pH changes reflect increased CSF lactate levels that result from a shift to anaerobic glycolysis. Normal lumbar CSF has a slightly higher concentration of lactic acid than arterial blood, and most studies report a normal concentration range of 10 to 20 mg/dl (1.1–2.2 mEq or mmol/l) for this substance.61 In subarachnoid hemorrhage, primary CSF acidosis is maximal 4–6 days after the ictus, and CSF lactate levels can be elevated 3–4-fold. All patients in one study with low CSF pH had elevated lactate levels, but some cases of elevated CSF lactate had normal pH.136 In purulent meningitis caused by bacterial or fungal pathogens, the CSF lactate is invariably elevated, sometimes ranging as high as 100 mg/dl (11 mmol/l) prior to the initiation of therapy.61 Still, overlap with the lactate levels found in cases of aseptic meningitis have rendered this parameter more limited in its clinical utility.61,137 The CSF lactate level has also proven useful in the evaluation of patients with congenital lactic acidosis and neurological disorders associated with respiratory-chain defects and mitochondrial DNA mutations.138

CONCLUSIONS A number of systemic vitamin deficiency states produce neurological manifestations, and systemic vitamin replacement invariably increases CSF levels as these substances are actively transported across the choroid plexus. Otherwise, routine CSF analyses in these states are usually normal, although a few patients with cobalamin deficiency can have high CSF protein levels or a small number of mononuclear cells, and vitamin A-deficient individuals can have high ICP. Ions and metals are also tightly regulated in the CNS, and changes in the serum levels of most do not produce dramatic fluctuations in CSF concentrations. Renal and hepatic failure produce clinical pictures of encephalopathy, often with measurable changes in CSF pressure dynamics and composition. Still, as with CSF ion and acid–base balance, there has yet to be any significant clinical utility associated

with the measurement of these substances in the CSF of most patients.

REFERENCES 1. Bass MH, Fisch GR. Increased intracranial pressure with bulging fontanel. A symptom of vitamin A deficiency in infants. Neurology 1961;11:1091–1094. 2. Abernathy RS. Bulging fontanelle as presenting sign in cystic fibrosis. Vitamin A metabolism and effect on cerebrospinal fluid pressure. Am J Dis Child 1976;130:1360–1362. 3. Lucidi V, Di Capua M, Rosati P, Papadatou B, Castro M. Benign intracranial hypertension in an older child with cystic fibrosis. Pediatr Neurol 1993;9:494–495. 4. Mahant L, Eaton HD. Effect of chronic hypovitaminosis A on water metabolism in the weanling rat. J Nutr 1976;106:1817–1826. 5. Millen JW, Dickson AD. The effect of vitamin A upon the cerebrospinalfluid pressures of young rabbits suffering from hydrocephalus due to maternal hypovitaminosis A. Br J Nutr 1957;11:440–446. 6. Millen JW, Woollam DH. The relationship between hypovitaminosis A and the cerebrospinal-fluid pressure in the chick: an experimental study. Br J Nutr 1956;10:355–363. 7. Woollam DH, Millen JW. Effect of vitamin A deficiency on the cerebrospinal fluid pressure of the chick. Nature 1955;175:41–42. 8. Eaton HD. Chronic bovine hypo- and hypervitaminosis A and cerebrospinal fluid pressure. Am J Clin Nutr 1969;22:1070–1080. 9. Frier HI, Gorgacz EJ, Hall RC, Gallina AM, Rosseau JE, Eaton HD, Nielsen SW. Formation and absorption of cerebrospinal fluid in adult goats with hypo- and hypervitaminosis A. Am J Vet Res 1974;35: 45–55. 10. Tallaksen CM, Bohmer T, Bell H. Concentrations of the water-soluble vitamins thiamin, ascorbic acid, and folic acid in serum and cerebrospinal fluid of healthy individuals. Am J Clin Nutr 1992;56: 559–564. 11. Pedraza OL, Botez MI. Thiamine status in inherited degenerative ataxias. J Neurol Neurosurg Psychiatry 1992;55:136–137. 12. Botez MI, Young SN. Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias. Can J Neurol Sci 2001;28:134–140. 13. Poloni M, Mazzarello P, Laforenza U, Caramella C, Patrini C. Thiamin contents of cerebrospinal fluid, plasma and erythrocytes in cerebellar ataxias. Eur Neurol 1992;32:154–158. 14. Tallaksen CM, Bell H, Bohmer T. Thiamin and thiamin phosphate ester deficiency assessed by high performance liquid chromatography in four clinical cases of Wernicke encephalopathy. Alcohol Clin Exp Res 1993;17:712–716. 15. Dastur DK, Santhadevi N, Quadros EV, et al. The B-vitamins in malnutrition with alcoholism. A model of intervitamin relationships. Br J Nutr 1976;36:143–159. 16. Botez MI, Young SN, Bachevalier J, Gauthier S. Thiamine deficiency and cerebrospinal fluid 5-hydroxyindoleacetic acid: a preliminary study. J Neurol Neurosurg Psychiatry 1982;45:731–733. 17. Vandenbulcke M, Janssens J. Acute axonal polyneuropathy in chronic alcoholism and malnutrition. Acta Neurol Belg 1999;99: 198–201. 18. Fukatsu R, Tamura T, Miyachi T, et al. [Chronic neuropathy, a high level of protein in cerebrospinal fluid, and vitamin B1 and folate deficiency in a patient with normal-pressure hydrocephalus]. Nippon Ronen Igakkai Zasshi 1997;34:521–528. 19. Vieira Filho JP, Oliveira AS, da Silva MR, Amaral AL, Schultz RR. [Polyneuropathy deficiency among Xavante indians.] Rev Assoc Med Bras 1997;43:82–88. 20. Molina JA, Jimenez-Jimenez FJ, Hernanz A, et al. Cerebrospinal fluid levels of thiamine in patients with Alzheimer’s disease. J Neural Transm 2002;109:1035–1044.

References

21. Jimenez-Jimenez FJ, Molina JA, Hernanz A, et al. Cerebrospinal fluid levels of thiamine in patients with Parkinson’s disease. Neurosci Lett 1999;271:33–36. 22. Botez MI, Joyal C, Maag U, Bachevalier J. Cerebrospinal fluid and blood thiamine concentrations in phenytoin-treated epileptics. Can J Neurol Sci 1982;9:37–39. 23. Baxter P. Pyridoxine-dependent seizures: a clinical and biochemical conundrum. Biochim Biophys Acta 2003;1647:36–41. 24. Baumeister FA, Gsell W, Shin YS, Egger J. Glutamate in pyridoxinedependent epilepsy: neurotoxic glutamate concentration in the cerebrospinal fluid and its normalization by pyridoxine. Pediatrics 1994;94:318–321. 25. Goto T, Matsuo N, Takahashi T. CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine action in seizure control. Brain Dev 2001;23:24–29. 26. Plecko B, Stockler-Ipsiroglu S, Paschke E, Erwa W, Struys EA, Jakobs C. Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol 2000;48: 121–125. 27. Dastur DK, Dave UP. Effect of prolonged anticonvulsant medication in epileptic patients: serum lipids, vitamins B6, B12, and folic acid, proteins, and fine structure of liver. Epilepsia 1987;28:147–159. 28. Abe K, Hirono N, Udaka F, Kameyama M, Fujita M. [Juvenile spinocerebellar degeneration with low vitamin B6 concentration both in serum and cerebrospinal fluid]. Nippon Naika Gakkai Zasshi 1988;77:1896–1897. 29. van Asselt DZ, Karlietis MH, Poels PJ, de Jong JG, Wevers RA, Hoefnagels WH. Cerebrospinal fluid methylmalonic acid concentrations in neurological patients with low and normal serum cobalamin concentrations. Acta Neurol Scand 1998;97:413–416. 30. Stabler SP, Allen RH, Barrett RE, Savage DG, Lindenbaum J. Cerebrospinal fluid methylmalonic acid levels in normal subjects and patients with cobalamin deficiency. Neurology 1991;41:1627–1632. 31. Botez MI, Young SN, Bachevalier J, Gauthier S. Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal fluid. Ann Neurol 1982;12:479–484. 32. Nijst TQ, Wevers RA, Schoonderwaldt HC, Hommes OR, de Haan AF. Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia. J Neurol Neurosurg Psychiatry 1990;53: 951–954. 33. Frequin ST, Wevers RA, Braam M, Barkhof F, Hommes OR. Decreased vitamin B12 and folate levels in cerebrospinal fluid and serum of multiple sclerosis patients after high-dose intravenous methylprednisolone. J Neurol 1993;240:305–308. 34. Surtees R. Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain. J Inherit Metab Dis 1993;16:762–770. 35. Scalabrino G, Carpo M, Bamonti F, et al. High tumor necrosis factor-alpha [corrected] levels in cerebrospinal fluid of cobalamindeficient patients. Ann Neurol 2004;56:886–890. 36. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: WB Saunders; 1938. 37. Veber D, Mutti E, Galmozzi E, et al. Increased levels of the CD40:CD40 ligand dyad in the cerebrospinal fluid of rats with vitamin B12 (cobalamin)-deficient central neuropathy. J Neuroimmunol 2006;176:24–33. 38. Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 1991;338:1550–1554. 39. Kishi T, Kawamura I, Harada Y, et al. Effect of betaine on S-adenosylmethionine levels in the cerebrospinal fluid in a patient with methylenetetrahydrofolate reductase deficiency and peripheral neuropathy. J Inherit Metab Dis 1994;17:560–565. 40. Wevers RA, Hansen SI, van Hellenberg Hubar JL, Holm J, Hoier-Madsen M, Jongen PJ. Folate deficiency in cerebrospinal fluid associated with a

41. 42.

43.

44. 45. 46. 47. 48.

49. 50. 51. 52.

53.

54. 55.

56. 57. 58. 59. 60.

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defect in folate binding protein in the central nervous system. J Neurol Neurosurg Psychiatry 1994;57:223–226. Allen RJ, DiMauro S, Coulter DL, Papadimitriou A, Rothernberg SP. Kearns-Sayre syndrome with reduced plasma and cerebrospinal fluid folate. Ann Neurol 1983;13:679–682. Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ. Subacute combined degeneration of the cord, dementia and parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 1986;49:920–927. Quinn CT, Griener JC, Bottiglieri T, Arning E, Winick NJ. Effects of intraventricular methotrexate on folate, adenosine, and homocysteine metabolism in cerebrospinal fluid. J Pediatr Hematol Oncol 2004;26:386–388. Botez MI, Bachevalier J. The blood-brain barrier and folate deficiency. Am J Clin Nutr 1981;34:1725–1730. Botez MI, Botez T, Maag U. The Wechsler subtests in mild organic brain damage associated with folate deficiency. Psychol Med 1984;14:431–437. Botez MI, Peyronnard JM, Berube L, Labrecque R. Relapsing neuropathy, cerebral atrophy and folate deficiency. A close association. Appl Neurophysiol 1979;42:171–183. Ramaekers VT, Blau N. Cerebral folate deficiency. Dev Med Child Neurol 2004;46:843–851. Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 2002;33:301–308. Ramaekers VT, Rothenberg SP, Sequeira JM, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 2005;352:1985–1991. Barabas J, Nagy E, Degrell I. Ascorbic acid in cerebrospinal fluid – a possible protection against free radicals in the brain. Arch Gerontol Geriatr 1995;21:43–48. Quinn J, Suh J, Moore MM, Kaye J, Frei B. Antioxidants in Alzheimer’s disease – vitamin C delivery to a demanding brain. J Alzheimers Dis 2003;5:309–313. Cupello A, Rapallino MV, Tabaton M, Lunardi GL. A simple, inexpensive, and precise spectrophotometric method for evaluating the concentration of ascorbic acid in CSF samples: data from different neurological pathologies. Int J Neurosci 2002;112:1337–1345. Glaso M, Nordbo G, Diep L, Bohmer T. Reduced concentrations of several vitamins in normal weight patients with late-onset dementia of the Alzheimer type without vascular disease. J Nutr Health Aging 2004;8:407–413. Kontush A, Mann U, Arlt S, et al. Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer’s disease. Free Radic Biol Med 2001;31:345–354. Voigt K, Kontush A, Stuerenburg HJ, Muench-Harrach D, Hansen HC, Kunze K. Decreased plasma and cerebrospinal fluid ascorbate levels in patients with septic encephalopathy. Free Radic Res 2002;36:735–739. Arlt S, Kontush A, Zerr I, et al. Increased lipid peroxidation in cerebrospinal fluid and plasma from patients with Creutzfeldt-Jakob disease. Neurobiol Dis 2002;10:150–156. Brau RH, Garcia-Castineiras S, Rifkinson N. Cerebrospinal fluid ascorbic acid levels in neurological disorders. Neurosurgery 1984;14:142–146. Bayir H, Kagan VE, Tyurina YY, et al. Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Res 2002;51:571–578. Balabanova S, Richter HP, Antoniadis G, et al. 25-Hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D in human cerebrospinal fluid. Klin Wochenschr 1984;62:1086–1090. Kiyosawa K, Mokuno K, Takahashi A, Murakami N, Kato K. [Cerebrospinal fluid levels of 28 kDa calcium-binding protein in patients with neurological diseases]. Rinsho Shinkeigaku 1992;32:388–392.

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61. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992.. 62. Jimenez-Jimenez FJ, de Bustos F, Molina JA, et al. Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer’s disease. J Neural Transm 1997;104:703–710. 63. Kontush K, Schekatolina S. Vitamin E in neurodegenerative disorders: Alzheimer’s disease. Ann N Y Acad Sci 2004;1031:249–262. 64. Buhmann C, Arlt S, Kontush A, et al. Plasma and CSF markers of oxidative stress are increased in Parkinson’s disease and influenced by antiparkinsonian medication. Neurobiol Dis 2004;15:160–170. 65. Brown K, Reid A, White T, et al. Vitamin E, lipids, and lipid peroxidation products in tardive dyskinesia. Biol Psychiatry 1998;43:863–867. 66. de Bustos F, Jimenez-Jimenez FJ, Molina JA, et al. Cerebrospinal fluid levels of alpha-tocopherol in amyotrophic lateral sclerosis. J Neural Transm 1998;105:703–708. 67. Jimenez-Jimenez FJ, de Bustos F, Molina JA, et al. Cerebrospinal fluid levels of alpha-tocopherol in patients with multiple sclerosis. Neurosci Lett 1998;249:65–67. 68. Ryan CA, Gayle M. Vitamin K deficiency, intracranial hemorrhage, and a subgaleal hematoma: a fatal combination. Pediatr Emerg Care 1992;8:143–145. 69. Abo-Hussein SA, Hussein ZM, Farag SI, Shebl SS, el-Melegy S, Akhnoukh S. A profile of ammonia-urea values in blood and cerebrospinal fluid in children with protein energy malnutrition. J Trop Med Hyg 1984;87:237–240. 70. Metwalli OM, Ismail S, El-Hawary Z. Lactate dehydrogenase and transaminase activities in the cerebrospinal fluid of protein-energy malnourished children. Z Ernahrungswiss 1977;16:163–166. 71. Oppelt WW, Owens ES, Rall DP. Calcium exchange between blood and cerebrospinal fluid. Life Sci 1963;41:599–605. 72. Graziani L, Escriva A, Katzman R. Exchange of calcium between blood, brain, and cerebrospinal fluid. Am J Physiol 1965;208:1058–1064. 73. Graziani LJ, Kaplan RK, Escriva A, Katzman R. Calcium flux into CSF during ventricular and ventriculocisternal perfusion. Am J Physiol 1967;213:629–636. 74. Tai CY, Smith QR, Rapoport SI. Calcium influxes into brain and cerebrospinal fluid are linearly related to plasma ionized calcium concentration. Brain Res 1986;385:227–236. 75. Allsop TF, Pauli JV. Responses to the lowering of magnesium and calcium concentrations in the cerebrospinal fluid of unanesthetized sheep. Aust J Biol Sci 1975;28:475–481. 76. Alloui A, Begon S, Chassaing C, et al. Does Mg2+ deficiency induce a long-term sensitization of the central nociceptive pathways? Eur J Pharmacol 2003;469:65–69. 77. Allsop TF, Pauli JV. Magnesium concentrations in the ventricular and lumbar cerebrospinal fluid of hypomagnesaemic cows. Res Vet Sci 1985;38:61–64. 78. McCoy MA, Hutchinson T, Davison G, Fitzpatrick DA, Rice DA, Kennedy DG. Postmortem biochemical markers of experimentally induced hypomagnesaemic tetany in cattle. Vet Rec 2001;148:268–273. 79. McCoy MA, Bingham V, Hudson AJ, et al. Postmortem biochemical markers of experimentally induced hypomagnesaemic tetany in sheep. Vet Rec 2001;148:233–237. 80. Sims MH, Bell MC, Ramsey N. Electrodiagnostic evaluation of hypomagnesemia in sheep. J Anim Sci 1980;50:539–546. 81. Chutkow JG. Magnesium and calcium in the cerebrospinal fluid of the rat. Proc Soc Exp Biol Med 1968;128:555–558. 82. Chutkow JG, Meyers S. Chemical changes in the cerebrospinal fluid and brain in magnesium deficiency. Neurology 1968;18:963–974. 83. Reed DJ, Yen MH. The role of the cat choroid plexus in regulating cerebrospinal fluid magnesium. J Physiol 1978;281:477–485. 84. Langley WF, Mann D. Central nervous system magnesium deficiency. Arch Intern Med 1991;151:593–596. 85. Reynolds CK, Bell MC, Sims MH. Changes in plasma, red blood cell and cerebrospinal fluid mineral concentrations in calves during magnesium depletion followed by repletion with rectally infused magnesium chloride. J Nutr 1984;114:1334–1341.

86. McKee JA, Brewer RP, Macy GE, et al. Analysis of the brain bioavailability of peripherally administered magnesium sulfate: a study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med 2005;33:661–666. 87. Kemeny A, Boldizsar H, Pethes G. The distribution of cations in plasma and cerebrospinal fluid following infusion of solution of salts of sodium, potassium magnesium and calcium. J New Drugs 1961;7:218–227. 88. Oppelt WW, MacIntyre I, Rall DP. Magnesium exchange between blood and cerebrospinal fluid. Am J Physiol 1963;205:959–962. 89. Fishman RA. Neurological manifestations of magnesium metabolism. Arch Neurol 1965;12:562–569. 90. Bradbury MW, Kleeman CR. Stability of the potassium content of cerebrospinal fluid and brain. Am J Physiol 1967;213:519–528. 91. Bradbury MW, Stubbs J, Hughes IE, Parker P. The distribution of potassium, sodium, chloride and urea between lumbar cerebrospinal fluid and blood serum in human subjects. Clin Sci 1963;25: 97–105. 92. Sambrook MA, Hutchinson EC, Aber GM. Metabolic studies in subarachnoid haemorrhage and strokes. II. Serial changes in cerebrospinal fluid and plasma urea electrolytes and osmolality. Brain 1973;96:191–202. 93. Fraschini F, Muller E, Zanoboni A. Post-mortem increase of potassium in human cerebrospinal fluid. Nature 1963;198:1208. 94. Paulson GW, Stickney D. Cerebrospinal fluid after death. Confin Neurol 1971;33:149–162. 95. Naumann HN. Cerebrospinal fluid electrolytes after death. Proc Soc Exp Biol Med 1958;98:16–18. 96. Fishman RA. Factors influencing the exchange of sodium between plasma and cerebrospinal fluid. J Clin Invest 1959;38:1698–1708. 97. Pape L, Katzman R. Effects of hydration on blood and cerebrospinal fluid osmolalities. Proc Soc Exp Biol Med 1970;134:430–433. 98. Kaler SG. Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. Am J Clin Nutr 1998;67:1029S–1034S. 99. Kaler SG, Goldstein DS, Holmes C, Salerno JA, Gahl WA. Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease. Ann Neurol 1993;33:171–175. 100. Kollros PR, Dick RD, Brewer GJ. Correction of cerebrospinal fluid copper in Menkes kinky hair disease. Pediatr Neurol 1991;7:305–307. 101. Hartard C, Weisner B, Dieu C, Kunze K. Wilson’s disease with cerebral manifestation: monitoring therapy by CSF copper concentration. J Neurol 1993;241:101–107. 102. Stuerenburg HJ. CSF copper concentrations, blood-brain barrier function, and coeruloplasmin synthesis during the treatment of Wilson’s disease. J Neural Transm 2000;107:321–329. 103. Stuerenburg HJ, Eggers C. Early detection of non-compliance in Wilson’s disease by consecutive copper determination in cerebrospinal fluid. J Neurol Neurosurg Psychiatry 2000;69: 701–702. 104. Joergstuerenburg H, Oeshsner M, Schroeder S, Kunze K. Determinants of the copper concentration in cerebrospinal fluid. J Neurol Neurosurg Psychiatry 1999;67:253–254. 105. Miyajima H, Takahashi Y, Kono S. Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals 2003;16:205–213. 106. Miyajima H, Adachi J, Kohno S, Takahashi Y, Ueno Y, Naito T. Increased oxysterols associated with iron accumulation in the brains and visceral organs of acaeruloplasminaemia patients. Q J Med 2001; 94:417–422. 107. Savman K, Nilsson UA, Blennow M, Kjellmer I, Whitelaw A. Nonprotein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation. Pediatr Res 2001;49:208–212. 108. Blake DR, Winyard P, Lunec J, et al. Cerebral and ocular toxicity induced by desferrioxamine. Q J Med 1985;56:345–355. 109. Manton WI, Malloy CR. Distribution of lead in body fluids after ingestion of soft solder. Br J Ind Med 1983;40:51–57.

References

110. Zheng W, Lu YM, Lu GY, Zhao Q, Cheung O, Blaner WS. Transthyretin, thyroxine, and retinol-binding protein in human cerebrospinal fluid: effect of lead exposure. Toxicol Sci 2001;61:107–114. 111. Zheng W, Shen H, Blaner WS, Zhao Q, Ren X, Gaziano JH. Chronic lead exposure alters transthyretin concentration in rat cerebrospinal fluid: the role of the choroid plexus. Toxicol Appl Pharmacol 1996;139: 445–450. 112. Ludwig GD. Lead poisoning. In: Goldensohn ES, Appel SH, eds. Scientific Approaches to Clinical Neurology. Philadelphia: Lea and Febiger; 1977:1346–1373. 113. Ingersoll RT, Montgomery EB Jr, Aposhian HV. Central nervous system toxicity of manganese. I. Inhibition of spontaneous motor activity in rats after intrathecal administration of manganese chloride. Fundam Appl Toxicol 1995;27:106–113. 114. Zheng W, Zhao Q, Slavkovich V, Aschner M, Graziano JH. Alteration of iron homeostasis following chronic exposure to manganese in rats. Brain Res 1999;833:125–132. 115. Crossgrove J, Zheng W. Manganese toxicity upon overexposure. NMR Biomed 2004;17:544–553. 116. Takeda A. Manganese-enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice. Magn Reson Med 2006;55:1124–1131. 117. Takeda A. Movement of zinc and its functional significance in the brain. Brain Res Brain Res Rev 2000;34:137–148. 118. Kasarskis EJ. Zinc metabolism in normal and zinc-deficient rat brain. Exp Neurol 1984;85:114–127. 119. Palm R, Hallmans G. Zinc concentrations in the cerebrospinal fluid of normal adults and patients with neurological diseases. J Neurol Neurosurg Psychiatry 1982;45:685–690. 120. Molina JA, Jimenez-Jimenez FJ, Aguilar MV, et al. Cerebrospinal fluid levels of transition metals in patients with Alzheimer’s disease. J Neural Transm 1998;105:479–488. 121. Madonick MJ, Berke K, Schiffer I. Pleocytosis and meningeal signs in uremia: report on sixty-two cases. Arch Neuro Psychiat 1950;64:431–436. 122. Schreiner G, Maher JG. Uremia: Biochemistry, Pathogenesis and Treatment. Springfield, Illinois: Charles C. Thomas; 1961:234–269. 123. Raskin NH, Fishman RA. Neurologic disorders in renal failure. N Engl J Med 1976;294:143–148. 124. Bradbury MWB, Stubbs J, Hughes IE, Parker P. The distribution of potassium, sodium, chloride and urea between lumbar cerebrospinal fluid and blood serum in human subjects. Clin Sci 1963;25:97–105.

155

125. Funder J, Wieth JO. Changes in cerebrospinal fluid composition following hemodialysis. Scand J Clin Lab Invest 1967;19: 301–312. 126. De Deyn PP, D’Hooge R, Van Bogaert PP, Marescau B. Endogenous guanidino compounds as uremic neurotoxins. Kidney Int Suppl 2001;78:S77–S83. 127. Liu GT, Urion DK, Volpe JJ. Cerebral edema in acute hepatic failure: clinicopathologic correlation. Pediatr Neurol 1993;9:224–226. 128. Vaquero J, Butterworth RF. Mechanisms of brain edema in acute liver failure and impact of novel therapeutic interventions. Neurol Res 2007;29:683–690. 129. Hourani BT, Hamlin EM, Reynolds TB. Cerebrospinal fluid glutamine as a measure of hepatic encephalopathy. Arch Int Med 1971;127:1033–1036. 130. Plum F. The CSF in hepatic encephalopathy. Exp Biol Med 1971;4:34–41. 131. Rothstein JD, McKhann G, Guarneri P, Barbaccia ML, Guidotti A, Costa E. Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy. Ann Neurol 1989;26:57–62. 132. Mullen KD, Szauter KM, Kaminsky-Russ K. "Endogenous" benzodiazepine activity in body fluids of patients with hepatic encephalopathy. Lancet 1990;336:81–83. 133. Perney P, Butterworth RF, Mousseau DD, et al. Plasma and CSF benzodiazepine receptor ligand concentrations in cirrhotic patients with hepatic encephalopathy: relationship to severity of encephalopathy and to pharmaceutical benzodiazepine intake. Metab Brain Dis 1998;13:201–210. 134. Yurdaydin C, Karavelioglu D, Onaran O, Celik T, Yasa MH, Uzunalimoglu O. Opioid receptor ligands in human hepatic encephalopathy. J Hepatol 1998;29:796–801. 135. Plum F, Price RW. Acid-base balance in cisternal and lumbar cerebrospinal fluid. N Engl J Med 1973;289:1346–1350. 136. Sambrook MA, Hutchinson EC, Aber GM. Metabolic studies in subarachnoid hemorrhage and strokes. I. Serial changes in acid-base balance in blood and cerebrospinal fluid. Brain 1973;96: 171–190. 137. D’Souza E, Mandal BK, Hooper J, Parker L. Lactic acid concentration in cerebrospinal fluid and differential diagnosis of meningitis. Lancet 1978;2:579–580. 138. Stacpoole PW, Bunch ST, Neiberger RE, et al. The importance of cerebrospinal fluid lactate in the evaluation of congenintal lactic acidosis. J Pediatr 1999;134:99–102.

CHAPTER

19

Headache Syndromes Jennifer Huffman, Ai Sakonju, and Jason D. Rosenberg

INTRODUCTION This chapter will review the cerebrospinal fluid (CSF) abnormalities associated with various headache syndromes. Topics covered will include a discussion of the signs and symptoms associated with headache that should prompt lumbar puncture (LP), CSF parameters that should be investigated in the setting of headache, the expected CSF profiles found in primary headache disorders, and the CSF findings associated with secondary headache disorders. Headache is a vexing clinical problem because it is so common and because it can reflect either benign or serious underlying pathologies. The International Headache Society (IHS) recently published guidelines specifying 14 main categories of headache.1 In contrast to an idiopathic, primary headache (migraine, tension, and cluster), a secondary headache is defined as being a symptom of other underlying medical disorder. In practice, some 10% of patients who present to an emergency room with headache have a potentially serious underlying disorder.2–4 Yet whether emergent or subacute, certain signs and symptoms should prompt further diagnostic evaluation. A thorough history and physical examination often leads to an neuroimaging study and an LP with complete CSF analysis to clarify the underlying etiology.

SIGNS AND SYMPTOMS THAT SHOULD PROMPT LUMBAR PUNCTURE IN A HEADACHE PATIENT It is essential to consider when and when not to perform an LP in the setting of headache. The careful practitioner can often diagnose secondary causes of headache that require specialized treatment based on a careful CSF analysis, while knowledge of the CSF findings associated with primary or less serious causes of secondary headache can provide reassurance to the headache patient. For any headache complaint, consensus guidelines agree on key associated elements that should prompt further investigation (Table 19-1).5–10

Not surprisingly, this literature emphasizes causes of non-traumatic headache that can be detected by cranial computed tomography (CT) or magnetic resonance imaging (MRI) scans. It should be remembered, however, that there are serious central nervous system (CNS) disorders that present with acute headache and normal neuroimaging findings.11 In this situation, LP has been used to identify certain potentially dangerous causes of headache. Conversely, only limited data are available to clarify the CSF abnormalities associated with non-traumatic causes of headache in non-urgent care settings. Consequently, most of the knowledge with regards to the CSF findings in specific headache disorders is limited to serious secondary causes of headache such as subarachnoid hemorrhage

Table 19-1 Signs and Symptoms of Headache that should Prompt Further Investigation for an Underlying Cause Abnormal neurological exam, particularly with focal findings 3,5,6–8,9,10* Age >55 years 3,7,9 Acute onset 3,7,10 Occipitonuchal location 3 First or worst headache of life 5,9,10 Sudden increased frequency/severity 5,6,9,10 New headache with history of cancer 5,9 New headache with history of immunodeficiency 5,7,9 Headache with mental status changes 5,7,8,10 Headache with fever, neck stiffness, and meningeal signs 5,9,10 History of headache causing awakening from sleep 6** Papilledema 8 Progressive or new persistent daily headache 9,10 Chronic daily headache 9 Headaches always on the same side 9 Headaches not responding to treatment 9 Seizures 9 *No prior documentation of similar migraine. **Could occur with migraine or cluster headaches.

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(SAH) and meningitis. For these disorders, CSF findings are well defined and fairly predictable. It is often helpful to consider headache in terms of the underlying pathophysiology that causes pain; such a paradigm can help the practitioner develop a differential diagnosis, determine whether an LP will be helpful, and even to anticipate specific CSF abnormalities. Generally speaking, headache pain can originate from extracranial or intracranial pain-sensitive structures. The intracranial contents can be separated into parenchymal, vascular, and CSF components. Any increase in the volume of one of these components must occur at the expense of the volume of the other two in order to maintain normal intracranial pressure (ICP). The mechanics of shifting intracranial contents can induce headache by traction, compression, or irritation of painsensitive structures. Using this model, the etiologies of secondary headache can be categorized by the type of mechanical changes they induce. An additional category of headaches secondary to disturbed blood–brain barrier (BBB) or vascular integrity completes the paradigm, allowing typical CSF findings in each situation to be more easily understood (Table 19-2). Despite impressive changes in intracranial mechanics, not all serious headache diagnoses are associated with abnormal CSF, and even fewer are associated with specific CSF profiles that serve to identify all patients with a given disorder. Unfortunately, there are no current evidence-based guidelines about when to perform an LP in a headache patient. However, the circumstances where an LP is the standard of care in the evaluation of the underlying cause of headache are reviewed below.

Table 19-2

Suspected subarachnoid hemorrhage in the setting of a non-diagnostic cranial CT scan Headache induced by SAH is typically severe and abrupt, commonly described as a “thunderclap” headache or the “worst headache of life.” While the first diagnostic test of choice in this situation is cranial CT without contrast, a small proportion of cases present with normal or nondiagnostic imaging findings.12 If the clinical suspicion of SAH remains high, it is imperative to perform an LP. A positive tap will show an increase in the number of red blood cells (RBC), and if performed at least 12 h after headache onset, xanthochromia will also be present.13 A full discussion of the CSF profile expected in SAH is outlined in Chapters 25 and 29.

Headache in the setting of fever The possibility of infectious meningitis must always be excluded in patients who present with any combination of headache, meningismus, and fever, especially if there is any change in mental status. The expected CSF profiles in these disorders are covered in Chapters 20, 21, and 23.

Headache possibly due to idiopathic intracranial hypertension (pseudotumor cerebri) Headache is the single most common manifestation of pseudotumor cerebri. The diagnosis is rendered via the identification of elevated ICP as evidenced by a high opening pressure on LP performed in the lateral decubitus position. Given the risk of permanent visual loss in this disorder, the

Urgent or Emergent Causes of Secondary Headache and their Associated CSF Findings

Underlying Pathology 1. Disturbed BBB/meningeal/vascular integrity ● Bacterial meningitis ● Viral meningitis ● Viral encephalitis ● Vasculitis ● Arterial dissection 2. Mass effect, parenchymal ● Brain tumor ● Acute hemispheric stroke ● Brain abscess 3. Mass effect, blood ● Subdural hematoma ● Subarachnoid hemorrhage ● Intraparenchymal hemorrhage ● Cerebral vein thrombosis 4. Mass effect, CSF ● Hydrocephalus ● Pseudotumor cerebri

High OP (%)

Other CSF Findings (~% of cases)

90% 20% 50% 0% 0%

●

75% 50% 50%

●

75% 75% 75% >90%

●

<25%** 100%

●

*Present in numbers beyond what would be expected from the bleeding itself. **Pressure waveforms are abnormal in ~75% of patients with prolonged monitoring.

● ● ● ●

● ●

● ● ●

●

Low glucose (95%), high protein (90%), many polymorphonuclear WBCs (100%) Normal glucose (99%), high protein (25%), moderate mononuclear WBCs (100%) High protein (50%), low to moderate mononuclear WBCs (100%) High protein (75%), low mononuclear WBCs (60%) Normal (90%), few RBCs (10%) High protein (70%), few to many WBCs (33%) High protein (30%), few to moderate WBCs (33%) High protein (75%), low glucose (20%), few to many WBCs (70%) Normal (75%), few RBCs (25%), high protein (25%) Many RBCs (100%), moderate WBCs (33%)* Moderate to many RBCs (80%), high protein (50%) Few WBCs (25%), high protein (25%) Normal (90%), high protein (10%) Normal (100%)

CSF Profiles in Primary Headache Disorders

importance of a careful ophthalmological evaluation for papilledema in every headache patient cannot be overemphasized. The pathophysiology of this disorder is covered in detail in Chapter 12. Management approaches are discussed in Chapter 28.

Subacute or progressive headache in the immunocompromised patient Headache is often the harbinger of underlying CNS infection in the immunocompromised patient. CSF analysis can often confirm this possibility once a mass lesion is excluded by neuroimaging. Expected CSF profiles in these disorders are reviewed in Chapters 23 and 30.

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More commonly, LP is performed in atypical cases (especially in the setting of any key elements listed in Table 19-1) to help rule out a secondary cause. Routine CSF studies in primary headache disorders should be normal, although there is no published literature validating the predictive value of a negative LP in terms of ruling out an underlying condition or in confirming a primary headache disorder. Although some current research seeks to investigate a connection between migraine and CSF levels of specific neurotransmitters, the diagnostic utility of these findings in routine clinical practice is not yet realized. This section summarizes the current data regarding standard and experimental CSF studies in selected headache disorders.

Migraine ESSENTIAL CSF INVESTIGATIONS IN THE SETTING OF HEADACHE Once a decision to perform an LP in a headache patient is made, the procedure itself should be carefully planned. A preceding neuroimaging study (CT or MRI) is always advised, and the indication for the procedure (evaluation for possible infection or elevated ICP, for example) carefully documented. It is imperative to measure the opening pressure (OP) in every headache patient. The subject should be positioned in the lateral decubitus position with legs extended and the abdomen relatively relaxed. A pressure above 20 cm of CSF is generally considered abnormal and, in this setting, withdrawal of CSF to the point where the pressure falls below this level often produces significant headache relief. It is also worth noting that an OP below 6 cm of CSF may also be abnormal and can account for headache in certain patients (see below). All CSF samples should be sent for routine studies including measurement of protein and glucose concentrations, cell counts and differential, Gram stain and bacterial culture. If infection is strongly suspected, additional samples should be sent for detection of viral nucleic acids by polymerase chain reaction (PCR) assays, various microbial antigens, and smears and cultures for fungi, mycobacteria, and parasites. In the setting of possible intracranial tumor or carcinomatous meningitis, a sizable CSF sample should be sent for cytopathologic and flow cytometric analysis. It is always prudent to refrigerate an additional aliquot of the CSF sample for further testing if routine studies reveal unexpected findings. Patients should always be questioned about changes in headache severity or character following the procedure.

CSF PROFILES IN PRIMARY HEADACHE DISORDERS The indications for an LP in the setting of an obvious primary headache disorder are often unclear, although a few conditions may be associated with abnormal CSF cellularity.

Migraine is the most studied primary headache disorder, in large part because it is so common and so disabling. Migraine affects an estimated 18% of women and 6% of men in the USA.14 It is a clinical diagnosis made over time after the appropriate exclusion of other headache etiologies. The use of LP in the diagnosis of migraine is not standard practice, and if a patient meets established criteria with a normal physical examination, no further studies are recommended.1,6 However, when an LP in the setting of migraine is performed, there is some evidence that the OP can be elevated. Kovacs et al. found peak pressures of 30 cm of CSF during a migraine but only 10 cm of CSF in between attacks.15 However, if the CSF composition is otherwise abnormal, a diagnosis of migraine should be reconsidered.16,17 Initial reports of a CSF lymphocytosis in the setting of migraine invariably occurred in association with transient neurological symptoms and, in accordance with IHS criteria, now fulfill the case definition for a disorder known as Headache with Neurologic Deficits and cerebrospinal fluid Lymphocytosis (HaNDL) rather than migraine.1 This unique secondary headache syndrome is reviewed separately below. Several prior studies have investigated the relationship between various neurotransmitters and neurotransmitter metabolites in CSF and the pathophysiology of migraine headaches, in both the acute and chronic phases of disease. Experimental results are not conclusive, but some studies suggest that migraineurs have abnormal levels of gamma-aminobutyric acid, glycine, glutamine, taurine, 5-hydroxyindoleacetic acid, and homovanillic acid in CSF compared to controls.15,18–23 While this avenue of research may shed further light on migraine pathophysiology, it is not clinically useful at present. Most current studies investigating headache mechanisms in migraine focus on chemical changes in blood sampled from the carotid system or the jugular vein rather than CSF.24–26

Other primary headache disorders Neither tension headache nor cluster headache has been associated with abnormal CSF findings, although there is

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not a wealth of published data on this issue in either condition. There are, however, two primary headache disorders where case reports document abnormal CSF: sporadic hemiplegic migraine27 and basilar-type migraine.28 Upon further review of the sporadic hemiplegic migraine cases, however, some may well represent instances of the newly defined HaNDL syndrome,29 discussed in more detail below. There is one case of basilar-type migraine causing recurrent coma as demonstrated by “spasm” of the basilar artery on cerebral angiography.28 This patient presented with repeated episodes of confusion and decreased mental status that rapidly progressed to coma. During these events, the CSF white blood cell (WBC) count ranged from 6 to 190 cells/mm3, and protein content was documented in the range 524–877 mg/dl.28 According to current criteria, this case is distinguished from HaDNL by the absence of motor weakness. Familial hemiplegic migraine (FHM) has also occasionally been associated with a CSF pleocytosis.1 This disorder is a heritable migraine variant that causes motor weakness along with visual, sensory, or speech disturbances. To meet the case definition, a first- or second-degree relative must have experienced similar attacks. The exact frequency, magnitude, and duration of the CSF pleocytosis in FHM is not documented in the medical literature.

CSF PROFILES IN SECONDARY HEADACHE DISORDERS Headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL) In 1981, Bartleson et al. described seven patients who experienced self-limited episodes of headache associated with focal neurological deficits and a CSF pleocytosis.16 These cases were unusual in that none of the patients had a prior history of migraine and all had limited recurrences over 1–12 weeks. The most frequent neurological symptoms were unilateral tingling or numbness, weakness, and speech disturbances when the dominant hemisphere was involved. CSF abnormalities included mildly elevated OP ranging from 20 to 29 cm of CSF, a mononuclear cellpredominant pleocytosis ranging from 40 to 233 WBC/mm3, and elevated total protein content ranging from 70 to 184 mg/dl. CSF glucose levels were uniformly normal. These abnormalities promptly returned to normal during asymptomatic periods. Extensive testing for infectious etiologies was negative in all cases. In 1995, Berg et al. added another seven patients to what was then a total of 33 reported cases and coined the term Headache with Neurologic Deficits and CSF Lymphocytosis (HaNDL).29 Six of these seven patients experienced recurrent episodes over a maximum interval of 42 days. Symptoms again included transient hemiparesis, hemisensory changes, and speech disturbance when the left

hemisphere was involved. The CSF profiles included an OP of 17.5–33 cm of CSF, a lymphocytic pleocytosis ranging from 41 to 188 WBC/mm3, and total protein content ranging from 62 to 247 mg/dl. Gomez-Aranda et al. published a case series of 50 additional patients who experienced recurrent, but self-limited, transient neurological symptoms associated with headache and abnormal CSF profiles.17 Another 10 patients were reported by Chapman et al., bringing the total number of reported cases to 100 patients.30 The demographics and salient features of these cases are summarized in Table 19-3. Formal diagnostic criteria for HaNDL are now defined but the etiology of the syndrome remains unknown.1

Mollaret’s meningitis Mollaret’s meningitis is a rare form of benign, recurrent aseptic meningitis characterized by the appearance of a particular mononuclear cell in the CSF during the first few days of the illness. The syndrome was first described by the French physician Mollaret in 1944.31 Clinical presentation of a Mollaret’s episode is similar to more typical aseptic meningitis with headache, photophobia, meningismus, myalgias, and occasional fever, nausea, and vomiting. Attacks usually resolve without treatment or sequelae within 5–7 days, but they tend to recur within 3–5 years. Several case reports document episodes occurring over two decades,32–33 and one patient had more than 30 discrete recurrences.34 Mollaret’s meningitis has been characterized by unique abnormalities found on serial CSF examinations. In the original description of three patients with recurrent episodes of meningitis over a 15-year period, the CSF was notable for a leukocytosis and an unusual cell type originally thought to be of endothelial origin.31 These cells have a unique bean-shaped nucleus with nuclear clefts and a “footprint” appearance (Fig. 19-1). They are most typically found in CSF obtained within 24 h of presentation, and can easily be missed if the LP is delayed. Kwong et al.

Table 19-3

Summary of HaNDL Cases16,17,29,30

History Sex Age Family Hx of migraine Personal Hx of migraine Number of episodes Hemiparesis Hemiparesthesia Aphasia

59% male, 41% female 7–52 years 41% 24% 1–27 61% of episodes 82% of episodes 51% of episodes

CSF Profile Opening pressure Mononuclear leukocytes* Protein Glucose *Primarily lymphocytes, less likely monocytes.

10–40 cm of CSF 10–760 cells/mm3 20–250 mg/dl Normal

CSF Profiles in Secondary Headache Disorders

Figure 19-1 CSF Papanicolau stain from a patient with a third episode of Mollaret’s meningitis. Arrows point to examples of “footprint” Mollaret cells. (Courtesy of A. Sakonju, Department of Neurology, and M. Srodon, Clinical Pathology Laboratories, The Johns Hopkins Hospital.)

reported a case of a patient with classic symptoms and three discrete episodes of aseptic meningitis. 35 The CSF was examined for Mollaret cells at weekly intervals from the time of presentation through the second and third episodes. These analyses revealed that the proportion of cytologically atypical cells was highest early in disease, comprising 15–34% of the total cells on the first day of hospitalization and falling to 0–6% of total cells after 1 week.35 Indeed, Mollaret cells are replaced by a more typical lymphocytic pleocytosis within 24 h of symptom onset. However, one case report documents the detection of Mollaret cells on hospital day 5.36 Finally, although these cells are considered to be pathognomonic of Mollaret’s meningitis, they have been reported in sarcoidosis, uveomeningoencephalitic syndrome (Vogt-Koyanagi-Harada syndrome), and Behçet’s disease.34 A recent cytomorphological analysis of CSF samples from 14 patients with Mollaret’s meningitis demonstrated

Table 19-4

CSF cells with deeply lobated or clefted nuclei.34 So-called “ghost cells” (friable cells with partially degenerated cellular structures), neutrophils, and plasma cells were found in half of these samples. Mononuclear cells with cytoplasmic pseudopods were found in 25% of cases, while the classic “footprint” cells were only seen 25% of the time. These proportions are similar to ones reported by Kwong et al. where CSF obtained on the first day of illness showed 15–34% cellular atypia.35 Overall, the CSF typically shows a pleocytosis of at least 10 WBC/mm3, with a reported range of 11–711 WBC/mm3. The WBC differential is predominantly monocytic, ranging from 84 to 100%.34 These values change rapidly over time, so the timing of CSF acquisition relative to symptom onset in these patients must be taken into account. Mildly elevated CSF protein levels (50–100 mg/dl) have been reported in Mollaret’s meningitis, but glucose levels are uniformly normal and a search for bacterial or fungal pathogens is always negative. Intriguingly, an increasing number of case reports have associated the presence of herpes simplex virus (HSV) type 1 or type 2 DNA in CSF with recurrent aseptic meningitis as detected by PCR.37–40 In one case series, 10 of 11 patients who met clinical criteria for Mollaret’s meningitis but had no Mollaret cells detected in the CSF were positive for HSV-2 DNA by PCR.38 In the largest series of 58 patients with Mollaret’s meningitis, only six had CSF that tested negative for both HSV-1 and HSV-2 by PCR; 49 cases were positive for HSV-2.40 The CSF profile in Mollaret’s meningitis is summarized in Table 19-4.

Spontaneous intracranial hypotension With our growing understanding of CSF pressure and flow dynamics and with advances in the quality and availability of MRI, both low and high CSF pressure syndromes are recognized as important causes of headache. One such condition, pseudotumor cerebri, is discussed separately in Chapter 12. This section will focus on headache secondary

Summary of CSF Findings in Mollaret’s Recurrent Aseptic Meningitis

CSF Feature

Range (% of cases)

Opening pressure RBC count WBC count

Normal (50%), elevated to 20–40 cm of CSF range (50%) Normal (100%) >10 WBC/mm3 (100%)

Comments

● ●

Protein concentration Glucose concentration Pathognomonic cell type

Other cytomorphological features

Normal (25%), mildly elevated to 50–100 mg/dl range (75%) Normal (>95%), mildly depressed to 40–60 mg/dl range (<5%) ● Mollaret cells: appearance described with classic “footprint” morphology (25%)34, with clefted or lobulated nuclei (100%)34,35 ● ● ●

Viral DNA

161

● ● ●

“Ghost” cells (50%) PMNs or plasma cells (45%) Cells with cytoplasmic pseudopods (25%) HSV-2 PCR+ (85%)40, (10%)34 HSV-1 PCR+ (<1%)40 HSV culture+ (<10%)37–40

● ●

●

●

Monocytic cells if sample obtained <24 h of symptom onset Lymphocytic predominance after 24 h of symptoms

Mollaret cells are believed to be of monocytic origin Cells are common early in clinical episode, disappear within 3–5 days Ghost cells are friable, partially degenerated cellular structures

Presence of HSV-2 DNA has been reported in the past two decades, but causation remains to be determined

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to CSF hypotension, operationally defined in adults as an OP measurement on recumbent LP of less than 6.0 cm of CSF. While this syndrome is most certainly a disorder of ICP, it is discussed here as an important, treatable, and often neglected cause of chronic daily headache that usually presents without other accompanying symptoms.41 Intracranial hypotension can arise from a variety of causes (Table 19-5). Headaches associated with low CSF pressure have recently been separated into three categories: post-dural puncture headaches, CSF fistula headaches, and headaches attributed to spontaneous (or idiopathic) low CSF pressure.1 While pain is common to all these syndromes, the headache of spontaneous intracranial hypotension (SIH) typically develops without a recognized precipitant and with few accompanying symptoms, and thus is often mistaken for a primary headache disorder.41 Despite the fact that SIH is usually benign and self-limited, the disorder can persist for months or even years. There are no prospective studies to clarify the epidemiology of this disorder; it is likely uncommon but not rare, and it may be increasingly identified as awareness of the condition grows and with the application of modern neuroimaging studies. An excellent review of SIH has recently been published by Mokri.42 The following discussion briefly covers the range of clinical findings, pathophysiology, diagnostic approaches, associated CSF findings, and therapeutic options in SIH. The clinical presentation of SIH is varied. In many instances, low CSF pressure may be asymptomatic. However, the classic presentation of SIH is that of a postural headache similar to a post-LP headache, i.e., worse with erect posture, Valsalva maneuver, cough, strain, or jugular venous compression. Relief is characteristically obtained by lying down, even briefly. Still, it is important to distinguish this feature from that of a chronic migraine; in SIH, relief comes with the change in position alone, whereas in migraine, symptoms may improve with any reduction of activity but especially with sleep. For operational purposes, the IHS defines orthostatic headache as one that occurs or is worsened less than 15 min after assuming an upright position, and disappears or improves less than 30 min after returning to recumbency.1

Table 19-5 Differential Diagnosis of CSF Hypotension ● ● ● ● ● ●

●

●

Faulty technique (needle not directly in the thecal sac) Spinal subarachnoid block (tumor, disc, or inflammation) Severe dehydration Known CSF fistula Post-LP Lesion causing rhinorrhea (frontal, ethmoid, sphenoid sinuses or cribiform plate; injuries secondary to head trauma, pituitary tumor, or skull-base surgery) Lesion causing otorrhea (temporal bone; injury secondary to trauma, surgery, or congenital labyrinthine malformation) Spontaneous intracranial hypotension

Uncommonly, SIH can manifest as a chronic daily headache or mimic other types of acute headache, including SAH. Cases have even been reported where there is no clear postural component whatsoever. Indeed, SIH may be a significant subset of what might otherwise be characterized by IHS criteria as a new, persistent daily headache.41 Suspicion of SIH should be raised when a patient can pinpoint the onset of a new headache to an exact date, especially if there was any antecedent trauma (motor vehicle accident, fall, or even a violent sneeze). Our concept of the pathophysiology of SIH has evolved over time. Prior hypotheses focused on decreased CSF production and/or increased CSF resorption. The current theory, however, holds that small CSF leaks may form spontaneously in patients, causing low CSF pressure due to loss outstripping production. Certain patients may be predisposed to the development of these small dural tears, perhaps due to abnormalities of connective tissue,43 including Marfan’s syndrome.44 Some patients may actually form meningeal diverticula following otherwise relatively minor, unrecognized trauma. CSF leaks may occur at any portion of the central neuraxis, from brain to sacrum, but are most common in the thoracic region.45,46 Patients who chronically drain CSF into the nasal cavity and oropharynx via the skull base may have rhinorrhea or post-nasal drip in the absence of meningitis.45,47,48 While small dural tears typically result in continuous CSF leaks, there may also be dynamic or intermittent leakage to account for those patients who present with normal CSF pressures on their initial diagnostic LP. Mokri proposes that the main symptomatology of SIH results not from low CSF pressure per se, but from the accompanying low CSF volume causing traction and/or distortion of the various pain-sensitive structures surrounding the brain.42 Such traction on the meninges and dural veins, or a compensatory dilatation of these veins in response to decreased CSF volume, produces the typical pachymeningeal enhancement seen on cranial MRI.42 This can also produce actual tearing of the bridging veins and result in subdural hygromas or hematomas. Thus, a diagnosis of SIH is based on the presence of headache (classically orthostatic), CSF pressure <6 cm of CSF, and characteristic findings on gadolinium-enhanced cranial MRI. Other studies that sometimes aid in the diagnosis of SIH can include radioisotope cisternography and thoracic myelography.49 The most striking and consistent MRI finding is diffuse pachymeningeal enhancement following gadolinium administration. Many scans may also show downward displacement of the brain, including herniation of the cerebellar tonsils (resembling a Chiari I malformation), flattening of the optic chiasm, and decreased size of the basal cisterns and ventricles.42,45 Some 40–70% of scans also show evidence of subdural fluid collections, including hygromas and hematomas.45,50 Radioisotope cisternography can raise suspicion for a leak if there is premature disappearance of tracer over the

References

cerebral convexities or early appearance of the tracer in the bladder.42 Still, the procedure may have a 30% falsenegative rate.51 The most common site of CSF leaks is at the level of the thoracic spine, although they also commonly occur at the skull base (resulting in CSF rhinorrhea), or the temporal bone (resulting in CSF otorrhea).42 Recent studies advocate the use of spinal MRI with gadolinium to search for CSF leak sites in SIH cases without abnormalities on brain MRI.52 This approach may help localize a leakage site by finding an isodense extradural fluid collection.53 The role of LP in the diagnosis SIH remains controversial. The risk of worsening symptoms or even precipitating brain herniation through the foramen magnum by removing lumbar CSF is unknown, but remains a possibility. When subdural fluid collections seem to be exerting mass effect or where downward brain descent is obvious on MRI, it may be advisable to avoid the procedure altogether. When undertaken, every effort should be made to minimize risk (i.e., small volumes should be removed using a fine-gauge needle). It should be kept in mind that the LP itself may cause subsequent meningeal enhancement, thus confounding the interpretation in cases where the MRI follows the LP. Once a decision is made to perform an LP, the OP must be carefully measured and documented. The pressure in SIH is typically low, but it can range from normal (due to the phenomenon of intermittent CSF leaks mentioned above) to not measurable.54 Unlike the normal situation, lumbar CSF pressure may actually be lower if the SIH patient is upright, with gravitation toward the median range when recumbent.55 It is imperative that the patient is recumbent when the OP is obtained; the practitioner should be familiar with the equipment and procedure, as falsely low pressures can be the result of incomplete penetration of the spinal needle into the lumbar subarachnoid space. The seminal paper describing the CSF findings in SIH is a case series of 24 patients reported by Mokri et al.45 Excluding five patients who had over-drainage due to surgical shunts, the OP was not measurable or <4 cm of CSF in 11 of 19 patients. Of the 18 patients who had multiple taps, all had clear CSF on at least one occasion. Xanthochromia was seen in five of 19 individuals, protein levels were greater than 100 mg/dl in nine of 19 patients, cell counts greater than 10 WBC/mm3 occurred in seven of 19 cases (range, 0 to 222 WBC/mm3), and erythrocyte counts ranged from 2 to 36 cells/mm3. Glucose levels were always normal in non-diabetic individuals, and CSF cytology and bacteriology was consistently negative.45 In another series by Ferrante et al., CSF protein levels were elevated in seven of 12 SIH patients, reaching a maximum of 125 mg/dl.56 Only a minimal pleocytosis was noted in two of 12 cases, with a maximum of 8 WBC/mm3. Information on xanthochromia and erythrocyte counts was not provided. In summary, the CSF in SIH shows a high protein level in up to 50% of cases, along with a mild to moderate pleocytosis, variable erythrocyte counts, and

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normal glucose and bacteriology studies. Xanthochromia is not recurrent when multiple taps are done on the same individual. The mainstay of treatment for SIH is bed rest, which usually results in complete resolution of symptoms over a few weeks. No relapses were reported in a case series of 12 patients treated in such a conservative manner.56 For patients who fail conservative management, an autologous epidural blood patch may be attempted, either as a sitedirected injection or via a “blind” lumbar procedure. This may directly tamponade the leak or act at a distance. Patching often has a dramatic, immediate effect, with an overall success rate of 70–100%.57 Occasionally, however, the blood patch will need to be repeated.46 Long-term follow-up generally reveals sustained improvement, but dural leaks may recur in a few patients. In these cases, repeat patching is indicated. Alternative therapies proposed in case reports include steroids,58 caffeine and theophylline,59 oral and intrathecal hydration,46, 60–62 intrathecal injection of dextran63 and intrathecal infusions of fibrin glue64 or Factor XIII.65 Fibrin glue, a preparation that mimics the final stages of blood coagulation, has recently been reported to be successful in site-directed percutaneous CT-guided injection in a case when repeat epidural blood patches failed.64 Surgical plugging or closure of the tear can be considered in select cases, although exploration of the site is risky and recurrence of surgically repaired tears is not rare.66 REFERENCES 1. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain. Cephalagia 2004;Suppl 1:1–160. 2. Perkins AT, Ondo W. When to worry about headache: head pain as a clue to intracranial disease. Postgrad Med 1995;98:197–208. 3. Ramirez-Lassepas M, Espinosa CE, Cicero JJ, Johnston KL, Cipolle RJ, Barber DL. Predictors of intracranial pathologic findings in patients who seek emergency care because of headache. Arch Neurol 1997;54:1506–1509. 4. Kahn CE, Sanders GD, Lyons EA, Kostelic JK, MacEwan DW, Gordon WL. Computed tomography for nontraumatic headache: current utilization and cost-effectiveness. Can Assoc Radiol J 1993;44:189–193. 5. Field AG, Wang, E. Evidence based emergency medicine: evaluation and diagnostic testing. Emerg Med Clin N Am 1999;17:127–152. 6. Silberstein, SD. AAN Practice Parameter: Evidence-Based Guidelines for Migraine Headache (An Evidence-Based Review) 2000;1–11. 7. Jagoda AS, Dalsey WC, Fairweather PG. Clinical policy: critical issues in the evaluation and management of patients presenting to the emergency department with acute headache. Ann Emerg Med 2002;39:234–244. 8. Sobri M, Lamont AC, Alias NA, Win NM. Red flags in patients presenting with headache: clinical indications for neuroimaging. Br J Radiol 2003;76:532–535. 9. Evans RW. Headaches. In: Evans RW, ed. Diagnostic Testing in Neurology. Philadelphia: WB Saunders; 1999:2–6. 10. Cortelli P, Cevoli S, Nonino F, et al. Evidence-based diagnosis of nontraumatic headache in the emergency department: a consensus statement on four clinical scenarios. Headache 2004;44:587–595.

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11. Dodick D. Headache as a symptom of ominous disease. Postgrad Med 1997;10:46–50,55–56,62–64. 12. Edlow JA, Wyer PC. How good is a negative cranial computed tomograhic scan result in excluding subarachnoid hemorrhage? Ann Emerg Med 2000;36:506–516. 13. Vermeulen M, Hasan D, Blijenberg BG, Hijdra A, van Gijn J. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry 1989;52:826–828. 14. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001;41:646–657. 15. Kovacs K, Bors L, Tothfalusi L, et al. Cerebrospinal fluid (CSF) investigations in migraine. Cephalalgia 1989;9:53–57. 16. Bartleson JD, Swanson JW, Whisnant JP. A migrainous syndrome with cerebrospinal fluid pleocytosis. Neurology 1981;31: 1257–1262. 17. Gomez-Aranda F, Canadilas F, Marti-Masso JF, et al. Pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis. A report of 50 cases. Brain 1997;120:1105–1113. 18. Peres MFP, Zuckerman E, Senne Soares CA, Alonso EO, Santos BF, Faulhaber MH. Cerebrospinal fluid glutamate levels in chronic migraine. Cephalalgia 2004;24:735–739. 19. Rothrock JF, Mar KR, Yaksh TL, Golbeck A, Moore AC. Cerebrospinal fluid analysis in migraine patients and controls. Cephalalgia 1995;15:489–493. 20. Kangasneimi P, Sonninen V, Rinne UK. Excretion of free and conjugated 5-HIAA and VMA in urine and concentration of 5-HIAA and HVA in CSF during migraine attacks and free intervals. Headache 1972;12:62–65. 21. Welch K, Chabi E, Bartosh K, Achar VS, Meyer JS. Cerebrospinal fluid (CSF) investigations in migraine. Cephalalgia 1989;9:53–57. 22. Zuckerman E, Minatti-Hannuch SN, da Graca M. Cerebrospinal fluid neurotransmitter amino acids in migraine (abstract). Cephalalgia 1993;13 Suppl:93. 23. Martinez F, Castillo J, Leira R, Prieto JM, Lemma M, Noya M. Taurine levels in plasma and cerebrospinal fluid in migraine patients. Headache 1993;33:324–327. 24. Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V. Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 2000;20:907–918. 25. Friberg L, Olesen J, Lassen NA, Olsen TS, Karle A. Cerebral oxygen extraction, oxygen consumption, and regional cerebral blood flow during the aura phase of migraine. Stroke 1994;25:974–979. 26. Friberg L, Olesen J, Olsen TS, Karle A, Ekman R, Fahrenkrug J. Absence of vasoactive peptide release from brain to cerebral circulation during onset of migraine with aura. Cephalalgia 1994;14:47–54. 27. Motta E, Rosciszewska D, Miller K. Hemiplegic migraine with CSF abnormalities. Headache 1995;35:368–370. 28. Frequin ST, Linssen WH, Pasman JW, Hommes OR, Merx HL. Recurrent prolonged coma due to basilar artery migraine. A case report. Headache 1991;31:75–81. 29. Berg M, Williams L. The transient syndrome of headache with neurologic deficits and CSF lymphocytosis. Neurology 1995;45:1648–1654. 30. Chapman KM, Szczygielski BI, Toth C, et al. Pseudomigraine with lymphocytic pleocytosis: a calcium channelopathy? Clinical description of 10 cases and genetic analysis of the familial hemiplegic migraine gene CACNA1. Headache 2003;43:892–895. 31. Mollaret P. Benign recurrent pleocytic meningitis and its presumed causative virus. J Nerv Ment Dis 1952;116:1072–1080. 32. Mirakhur B, McKenna M. Recurrent herpes simplex type 2 virus (Mollaret) meningitis. J Am Board Fam Pract 2004;17:303–305. 33. Tyler KL, Adler D. Twenty-eight years of benign recurring Mollaret’s meningitis. Arch Neurol 1983;40:42–43. 34. Chan TY, Parwani AV, Levi AW, Ali SZ. Mollaret’s meningitis: cytopathologic analysis of fourteen cases. Diagn Cytopathol 2003;28:227–231.

35. Kwong YL, Woo E, Fong PC, Yung RW, Yu YL. Mollaret’s meningitis revisited: report of a case with a review of the literature. Clin Neurol Neurosurg 1988;90:163–167. 36. Ellerin TB, Walsh SR, Hooper DC. Recurrent meningitis of unknown aetiology. Lancet 2004;363:1772. 37. Picard FJ, Dekaban GA, Silva JL, Rice GP. Mollaret’s meningitis associated with herpes simplex type 2 infection. Neurology 1993;43:1722–1725. 38. Tedder DG, Ashley R, Tyler KL, Levin MJ. Herpes simplex virus infection as a cause of benign recurrent lymphocytic meningitis. Ann Intern Med 1994;121:334–338. 39. Jensenius M, Myrvang B, Storvold G, Bucher A, Hellum KB, Bruu AL. Herpes simplex virus type 2 DNA detected in cerebrospinal fluid of 9 patients with Mollaret’s meningitis. Acta Neurol Scand 1998;98:209–212. 40. Dylewski JS, Bekhor S. Mollaret’s meningitis caused by herpes simplex virus type 2: case report and literature review. Eur J Clin Microbiol Infect Dis 2004;23:560–562. 41. Schievink WI. Misdiagnosis of spontaneous intracranial hypotension. Arch Neurol 2003;60:1713–1718. 42. Mokri B. Low cerebrospinal fluid pressure syndromes. Neurol Clin N Am 2004;22:55–74. 43. Schievink WI, Gordon OK, Tourje J. Connective tissue disorders with spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery 2004;54:65–70, discussion 70–71. 44. Rosser T, Finkel J, Vezina G, Majd M. Postural headache in a child with Marfan syndrome: case report and review of the literature. J Child Neurol 2005;20:153–155. 45. Mokri B, Peipgras DG, Miller GM. Syndrome of orthostatic headaches and diffuse pachymeningeal gadolinium enhancement. Mayo Clin Proc 1997;72:400–413. 46. Sencakova D, Mokri B, McClelland RL. The efficacy of epidural blood patch in spontaneous CSF leaks. Neurology 2001;57:1921–1923. 47. Brown NE, Grundfast KM, Jabre A, Megerian CA, O’Malley BW, Rosenberg SI. Diagnosis and management of spontaneous cerebrospinal fluid-middle ear effusion and otorrhea. Laryngoscope 2004;114:800–805. 48. Ommaya AK, Di Chiro G, Baldwin M, Pennybacker JB. Non-traumatic cerebrospinal fluid rhinorrhoea. J Neurol Neurosurg Psychiatry 1968;31:214–225. 49. Chiapparini L, Ciceri E, Nappini S, et al. Headache and intracranial hypotension: neuroradiological findings. Neurol Sci 2004;25:S138–S141. 50. Ferrante E, Wetzl R, Savino A, Citterio A, Protti A. Spontaneous cerebrospinal fluid leak syndrome: report of 18 cases. Neurol Sci 2004;25:S293–S295. 51. Schievink W, Meyer F, Atkinson J, Mokri B. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. J Neurosurg 1996;84:598–605. 52. Chen CJ, Lee TH, Hsu HL, Tseng YC, Wang YC, Wang LJ. Spinal MR findings in spontaneous intracranial hypotension. Neuroradiology 2002;44:996–1003. 53. Rabin BM, Roychowdhury S, Meyer JR, Cohen BA, LaPat KD, Russell EJ. Spontaneous intracranial hypotension: spinal MR findings. AJNR Am J Neuroradiol 1998;19:1034–1039. 54. Mokri B, Hunter SF, Atkinson JL, Piepgras DG. Orthostatic headaches caused by CSF leak but with normal CSF pressures. Neurology 1998;51:786–790. 55. Miller JD. Volume and pressure in the craniospinal axis. Clin Neurosurg 1975;22:76–105. 56. Ferrante E, Savino A, Sances G, Nappi G. Spontaneous intracranial hypotension syndrome: report of twelve cases. Headache 2004;44:615–622. 57. Rozec B, Guillon B, Desal H, Blantoeil Y. Early blood-patch for spontaneous intracranial hypotension: a correspondence. Can J Anesth 2004;51:944–945.

References

58. Gentile S. Giudice RL, Martino PD, Rainero I, Pinessi L. Headache attributed to spontaneous low CSF pressure: report of three cases responsive to corticosteroids. Eur J Neurol 2004;11: 849–851. 59. Vilmig ST, Titus F. Low cerebrospinal fluid pressure. In: Olesem J, Tfelt-Hansen P, Welch KM, eds. The Headache. New York: Oxford University Press; 2001:417–433. 60. Rice GG, Dabbs CH. The use of peridural and subarachnoid injections of saline solution in the treatment of severe postspinal headaches. Anesthesiology 1950; 11:17–23. 61. Usubiaga JE, Usubiaga LE, Brea LM, Goyena R. Effect of saline injections on epidural and subarachnoid space pressures and relation to postspinal anesthesia headache. Anesth Analg 1967;46: 293–296.

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62. Gibson BE, Wedel DJ, Faust RJ, Petersen RC. Continuous epidural saline infusion for the treatment of low CSF pressure headache. Anesthesiology 1988;48:789–791. 63. Aldrete JA. Persistent post-dural-puncture headache treated with epidural infusion of Dextran. Headache 1994;34:265–267. 64. Gladstone JP, Nelson K, Patel N, Dodick DW. Spontaneous CSF leak treated with percutaneous CT-guided fibrin glue. Neurology 2005;64:1818–1819. 65. Ishihara S, Fuki S, Otani N, et al. Evaluation of spontaneous intracranial hypotension: assessment on IC monitoring and radiological imaging. Br J Neurosurg 2001;15:239–241. 66. Schievink WI, Maya MM, Riedinger M. Recurrent spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. J Neurosurg 2003;99:840–842.

CHAPTER

20

Bacterial Infections Arun Venkatesan and Diane E. Griffin

INTRODUCTION In bacterial infections of the central nervous system (CNS), cerebrospinal fluid (CSF) findings are considered essential to establish the diagnosis, identify the causative organism, and direct antibiotic therapy. Here, we discuss the CSF findings in a variety of CNS bacterial infections, including bacterial meningitis, brain abscess, brainstem encephalitis, spinal epidural abscess, and Whipple’s disease. Infections caused by mycobacterial and spirochetal pathogens are discussed in Chapter 23.

that it returned to normal upon recovery.6 In a more recent review of 296 episodes of community-acquired bacterial meningitis, the opening pressure was over 400 mmH2O in one-fifth of cases.7 In this series, it was not possible to reliably predict which patients would have an elevated OP based on clinical features, since only half of those with opening pressures over 400 mmH2O were obtunded or comatose.7 Among children, lumbar CSF OP is also commonly elevated in the setting of bacterial meningitis. Noting that the upper limit of normal CSF pressure varies with age, Minns et al. found that 33 of 35 infants and children with bacterial meningitis had elevated opening pressures, with a median pressure of 15 mmHg (or 204 mmH2O).8

BACTERIAL MENINGITIS The major pathogenic agents responsible for acute bacterial meningitis vary with the age of the patient, but include Streptococcus pneumoniae, Neisseria meningitids, Haemophilus influenzae, group B streptococci, and Listeria monocytogenes.1–5 Largely independent of the causative agent, however, the CSF findings in acute bacterial meningitis are often quite similar. As discussed below, the major determinants of the CSF profile include the interval between the onset of infection and the lumbar puncture (LP), the severity of the infection, the clinical setting in which the infection was acquired, and the immune status of the patient.

Opening pressure The CSF opening pressure (OP) is typically increased in bacterial meningitis. In Merritt and Fremont-Smith’s classic review of the CSF findings in over 150 cases of acute bacterial meningitis, the CSF OP was greater than 200 mmH2O in 90% of cases, and over 500 mmH2O in 15% of cases.6 These authors noted that the pressure was more likely to be normal if the LP was performed early in the course of the disease, that it rose in parallel with disease progression, and

Cell count At the time of first LP in bacterial meningitis, the CSF usually shows a marked pleocytosis of between 1,000 and 10,000 white blood cells (WBC)/mm3. The range of findings in 152 cases of meningitis described by Merritt and Fremont-Smith in 1937 is shown in Table 20-1. Only rarely do patients have CSF WBC counts of less than 100 cells/mm3 or greater than 20,000 cells/mm3.6 Findings are remarkably similar, regardless of the causative organism. In a large series of more than 1,000 cases of bacterial meningitis conducted at the Municipal Contagious Diseases Hospital in Chicago between 1954 and 1978, CSF cell counts were similar to those described by Merritt and Fremont-Smith. Here, more than 90% of patients had a CSF WBC count greater than 100 cells/mm3 on the initial LP.1 Findings reported in a more recent review, composed of patients who presented to two hospitals in Alberta, Canada, between 1985 and 1996, suggest that the cellular abnormalities in CSF during bacterial meningitis have not changed significantly over the past 50 years (Table 20-2).2 Polymorphonuclear leukocytes (PMNs) predominate in the CSF of patients with acute bacterial meningitis. PMNs usually account for 90–95% of the total WBC count; in

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Table 20-1

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Bacterial Infections

Initial Lumbar CSF Findings in Patients with Acute Purulent Meningitis from the Pre-antibiotic Era Number of Patients Meningococcus

Pneumococcus

Streptococcus

Staphylococcus

Haemophilus Influenzae

% of All Patients

Cellularity (cells/mm3) <100 100–1,000 1,000–10,000 10,000–20,000 >20,000

1 5 39 11 6

0 3 31 2 0

0 7 27 2 1

1 2 8 1 1

0 1 4 0 0

1 12 72 10 5

1 7 39 7 10

0 2 29 6 3

1 7 23 8 0

1 3 4 1 0

0 0 5 0 0

2 12 64 14 8

13 38 2 5 3

12 19 3 1 2

8 19 3 4 5

0 8 2 0 1

2 3 0 1 0

23 57 6 7 7

Protein Content (mg/dl) <45 45–100 100–500 500–1,000 1,000–2,000 Glucose Content (mg/dl) <10 10–40 40–50 50–60 >60

(Reprinted with permission from Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: W. B. Saunders, 1938.)

fewer than one-quarter of cases do PMNs comprise less than 80% of the total CSF pleocytosis.2,4 As discussed below, however, the CSF WBC count and differential may change markedly with ongoing antibiotic therapy.

Glucose content The CSF glucose concentration at time of first LP in acute bacterial meningitis is usually moderately to severely reduced (Tables 20-1 and 20-2). In three-quarters of cases it is under 50 mg/dl, and in one-quarter of cases it is below 10 mg/dl.2,6 Several confounding factors can affect the interpretation of this CSF parameter. The glucose level will be spuriously low if the sample is not analyzed promptly, due to ongoing cellular metabolism when a purulent fluid remains at room temperature for an extended period. On the other hand, CSF glucose will be elevated in the setting of concomitant systemic hyperglycemia. To correct for this impairment, many authors have investigated the role of the CSF:serum glucose ratio in the diagnosis of bacterial meningitis. In one study of 217 patients with confirmed bacterial meningitis, the median ratio was 0.29 (normal being >0.60),9 while in another study a ratio below 0.31 best differentiated patients with acute bacterial meningitis from diabetic patients with other medical disorders.10 Although CSF glucose concentrations can occasionally be depressed in patients with acute meningitis due to a viral cause, this finding is quite a reliable predictor of an underlying bacterial infection in the proper clinical setting.

Protein content The CSF protein content is almost always elevated in bacterial meningitis (Tables 20-1 and 20-2). Several studies have shown that protein levels are increased at least to some degree in more than 95% of patients, and its absolute value is over 80 mg/dl in more than 80% of patients.2,6,7 Protein values of greater than 1,000 mg/dl, reported in 8% of cases in Merritt and Fremont-Smith’s review, were often associated with spinal subarachnoid block. Importantly, several studies have reported an association between elevated CSF protein content and a poorer outcome in acute bacterial meningitis. Weiss and colleagues reported higher mortality (47%) when the CSF protein content was above 280 mg/dl, compared to below this level (0%).11 More recently, a prospective study of 100 patients with bacterial meningitis demonstrated that CSF protein content was 5-times higher (median, 587 mg/dl) in patients with severe neurologic deficits following acute meningitis compared to those left with no detectable neurologic deficits (median, 124 mg/dl).12

Gram stain The Gram stain continues to be the most rapid and accurate test for the early diagnosis of bacterial meningitis. Older studies suggested that the initial Gram stain is negative in up to one-quarter of patients with confirmed bacterial meningitis.1 More recently, however, centrifugation of samples to concentrate bacteria and inflammatory cells by 100–1000-fold has increased the sensitivity of CSF

Bacterial Meningitis

Table 20-2 Initial CSF Findings in 103 Episodes of Acute Bacterial Meningitis in Adults, 1985–1996* Turbidity Cloudy Clear Unknown

Number of Patients 80 18 5

Pleocytosis (cells/mm3) <100 100–999 ≥1,000 Unknown

10 35 56 2

Percent Neutrophils <50 50–79 80 Unknown

9 7 74 13

Glucose Content (mg/dl) ≤50 >50 Unknown

72 30 1

169

not advocated, since a positive result rarely alters therapy and because the test rarely adds to information already provided by the Gram stain. However, such testing can be helpful when a patient has received antibiotics before the LP, when the Gram stain is unrevealing but bacterial meningitis continues to be suspected on clinical grounds, or when the CSF is otherwise nondiagnostic.15,16

Broth culture Methods to culture CSF for bacteria, including streaking samples on to sheep blood and chocolate agar plates and incubating them in 3–5% CO2, have changed very little over the past decades. Many laboratories also inoculate CSF into enriched broth media to supplement agar plate cultures, purportedly to increase the rate of pathogen recovery. Several retrospective studies, however, have suggested that organisms recovered from broth cultures only are likely to be contaminants, and therefore such data should affect treatment decisions only in the case of shunt-associated meningitis, as discussed below.14,17,18

Protein Concentration (mg/dl) ≤45 46–199 ≥200 Unknown

1 33 67 2

Gram Stain Positive Negative

48 55

Culture Positive Negative

66 37

Gram Stain + Culture One or both positive Both negative

74 29

* Excludes post-neurosurgery patients; includes both community-acquired (n=90) and nosocomial (n=13) cases. (Data adapted from Hussein AS, Shafran SD. Acute bacterial meningitis in adults: a 12-year review. Medicine 2000;79:360–368.)

Gram stain.13 Thus, in a review of 2,635 CSF samples from adult patients where 56 were positive for bacterial or fungal pathogens by culture, Gram stain revealed the causative organism in 48 (88%) cases. If patients who had already received effective antimicrobial therapy prior to LP were excluded, the CSF Gram stain proved to be 92% sensitive. False-positive stains were reported in only three of these 2,635 samples (0.1%).14 Data such as these confirm the value of this procedure in the diagnosis of acute bacterial meningitis.

Bacterial antigen screens The routine use of bacterial antigen detection methodologies for the diagnosis of acute bacterial meningitis is generally

Differentiating bacterial from viral (“aseptic”) meningitis Although CSF examination often provides immediate confirmation of bacterial meningitis, the “classic” CSF profile is not present in a sizeable number of cases. The Gram stain may be negative in up to one-fourth of patients, and other routine CSF investigations are not diagnostic in 30–40% of cases.9 Which CSF parameters then best distinguish bacterial meningitis from aseptic meningitis? Spanos et al. found that the median CSF WBC count in bacterial meningitis was 1,195 cells/mm3, while in viral meningitis it was 100 cells/mm3. These authors concluded that a CSF WBC count greater than 2,000 cells/mm3 was a relatively specific but a somewhat insensitive predictor of a bacterial etiology.9 Likewise, while the CSF WBC differential typically shows a higher percentage of PMNs in bacterial meningitis than in aseptic meningitis, the test does not reliably distinguish the two disorders. Indeed, several studies have found too much overlap in the percentage of PMNs between bacterial and aseptic meningitis for this parameter to be a clinically useful predictor of etiology.9,19 The value of CSF protein and glucose levels in predicting the etiology of meningitis has also been examined. Spanos and colleagues found that a protein level of 220 mg/dl was highly predictive of bacterial meningitis, but also that this parameter was not often clinically useful, since only 17% of patients had levels this high.9 Similarly, a glucose level below 34 mg/dl, though strongly predictive of bacterial meningitis, was only present in 24% of patients in their cohort.9 The CSF:blood glucose ratio has a stronger predictive value in distinguishing bacterial from aseptic meningitis. The median CSF:blood glucose ratio was 0.29 in 217 patients with bacterial meningitis, while it was

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0.61 in 205 patients with aseptic meningitis. A CSF:blood glucose ratio below 0.25 was found in 44% of patients with bacterial meningitis, but was present in less than 1% of patients with aseptic meningitis.9 Because no single routine CSF parameter can reliably distinguish bacterial from aseptic meningitis, several investigators have attempted to develop multivariate approaches based on a combination of CSF measurements. Spanos et al. identified four independent variables for predicting the likelihood of bacterial meningitis: CSF PMN count, CSF:blood glucose ratio, age, and month at the time of disease onset. By combining these variables in a predictive model, a much better separation of aseptic from bacterial meningitis was achieved (Fig. 20-1).9 This model has since been prospectively validated by several groups,20,21 and others have developed similar multivariate models that distinguish bacterial from aseptic meninigitis.20,22 Still, such models have yet to be fully incorporated into routine clinical practice, where the current strategy continues to presume a diagnosis of bacterial meningitis with the empiric initiation of therapy until CSF cultures return negative. Finally, CSF levels of a variety of other mediators have been investigated in an attempt to reliably distinguish bacterial meningitis from aseptic meningitis. Such markers include lactate, lipopolysaccharide binding protein (LBP), and inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8. The clinical utility of most of these assays still

Age, y

remains limited, since they lack specificity and are often very costly to perform. However, some attention has been focused on the measurement of CSF lactate, which is almost invariably elevated during acute bacterial and most forms of fungal meningitis. A recent comparison demonstrated that a CSF lactate of >3.5 mmol/l exhibits high sensitivity (89–100%) and specificity (96–100%) in discriminating untreated bacterial meningitis from aseptic meningitis.23 Of the inflammatory cytokines, IL-1β and IL-6 levels were almost as reliable as CSF lactate in predicting a bacterial etiology of meningitis.23

CSF changes in bacterial meningitis following antibiotic treatment How does the CSF profile change in bacterial meningitis after the initiation of antibiotic therapy? In general, although the yield of a positive CSF Gram stain and/or culture is likely to be reduced, prior treatment for up to 48 h typically does not alter the number or composition of CSF leukocytes. If prior treatment is prolonged, however, the CSF WBC count may decrease and become predominantly mononuclear in nature. The glucose content may also begin to normalize and appear only mildly depressed. Thus, with prolonged antibiotic therapy, the CSF profile may acquire characteristics compatible with tuberculous, fungal, or viral meningitis.1,9,24

Probability of ABM vs AVM

Month

Glucose ratio

B

0.05 Reading line

Reading line

0.10 0.15

12

12 m

5000

A 0.20

4000

75 Figure 20-1 Nomogram for estimating the probability of acute bacterial meningitis (ABM) versus acute viral meningitis (AVM) meningitis. Step 1: place a ruler on the reading lines for the patient’s age and the month of presentation and mark the intersection with line A. Step 2: place a ruler on the values for CSF:serum glucose ratio and total CSF PMN count and mark the intersection with line B. Step 3: use a ruler to join the marks on lines A and B to determine the probability of ABM versus AVM using the central scale. (Reprinted with permission from Spanos A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989;262: 2700–2707.)

70

1 Feb

1 Feb

1 Mar

1 Jan

0.25

6m 18

1 Apr 0m

55 50

35

1 Nov

1 Jun

1 Oct

1 Jul

1 Sep

1 Aug

1 Aug

5

10

15

30 25 22

1 May

2y

45 40

1 Dec

22

.95 .80 .60 .40 .20 .05

.99

0.30

.90

0.35

2000 1500

.70 .50 .30 .10

1000 0.40 500 400 300 200

0.45

.01 0.50

100 50

0.55 A

20

3000 2500

65 60

Total PMN count/mm3 11000 10000 9000 8000 7000 6000

10 5

≥0.60 B

0

Bacterial Meningitis

Table 20-3 CSF Findings after Successful Antibiotic Treatment of Bacterial Meningitis Parameter Total Leukocytes (cells/mm3) Polymorphonuclear cells (%) Glucose (mg/dl) CSF/serum glucose ratio Protein (mg/dl)

Median 17 0 52 0.56 38

Range 0–480 0–98 16–130 0.19–0.86 11–552

Table 20-4 CSF Findings in Acute Meningitis Due to Listeria monocytogenes or Other Bacterial Pathogens Listeria Other Bacteria (n=43) (n=459)* (% of patients) (% of patients)

Number of Patients 157 138 142 62 121

(Data adapted from Durack DT, Spanos A. End-of-treatment spinal tap in bacterial meningitis. JAMA 1982;248:75–78.)

Examination of CSF after completion of a full course of antibiotic treatment for bacterial meningitis, routinely performed in the past, has provided insight into the temporal course of CSF changes in this disease.25–27 In a study of 163 patients with successfully treated bacterial meningitis who had an end-of-treatment LP on the first or second day after the completion of therapy, a wide range of cell counts, glucose concentrations, and protein levels was noted (Table 20-3). Notably, post-treatment CSF WBC counts were less than 5 cells/mm3 in only 28% of cases, while counts of 40 cells/mm3 or more occurred in 32% of cases, and levels greater than 100 cells/mm3 were seen in 15% of cases.25 PMNs were still present in CSF in 38% of cases, and these cells constituted the majority of the remaining pleocytosis 6% of the time. Glucose levels were also not a good predictor of success of treatment. In 8% of cases, the CSF glucose level continued to be below 40 mg/dl, and 13% of the time the CSF:serum glucose ratio was still less than 0.4. Indeed, routine CSF studies failed to identify the only two patients who proved to be unsuccessfully treated.25 Therefore, a post-treatment LP is not routinely recommended, unless a relapse of infection is suspected on clinical grounds.

Listeria meningitis Due in part to the fact that Listeria monocytogenes is an obligate intracellular pathogen, the CSF profile found in Listeria meningitis and meningoencephalitis can have several important differences when compared to acute bacterial meningitis caused by other pathogens.28 Patients with these infections typically have significantly fewer WBCs and lower protein concentrations in CSF than patients with infections caused by other pathogens, and there may be a trend towards lower percentages of PMNs and less hypoglycorrhachia (Table 20-4). Furthermore, the CSF Gram stain can present a source of diagnostic confusion. The Gram stain is negative in two-thirds of cases of Listeria meningitis, and, when microorganisms are detected, they are often falsely identified as Gram-positive cocci.7,28 These CSF findings, combined with the observation that up to 40% of patients have no signs of meningeal irritation on admission, may lead to a delay in the diagnosis of Listeria meningitis.

171

WBC Count (cells/mm3) 0–99 100–5,000 >5,000

9.3 90.7 0.0

12.9 61.0 26.1**

4.7 37.2 58.1

2.0 24.4 73.6

2.3 67.4 30.2

5.4 41.4 53.2**

32.6

48.1

Percent Neutrophils 0–19 20–79 >79 Protein Concentration (mg/dl) 0–45 46–199 >199 Glucose (mg/dl) <40

* Adults hospitalized at Massachusetts General Hospital, 1962–1988. ** p<0.05. (Data adapted from Mylonakis E, Hohmann EL, Calderwood SB. Central nervous system infection with Listeria monocytogenes: 33 years' experience at a general hospital and review of 776 episodes from the literature. Medicine 1998;77:313–336.)

Enterococcal meningitis Early reports of the CSF findings in enterococcal meningitis emphasized a relatively diminished CSF cellular response, with CSF leukocyte counts often less than 200 cells/mm3.29 More recent reports, however, have not confirmed these findings, noting that the CSF leukocyte count is greater than 200 cells/mm3 in the majority of cases. Thus, it appears that CSF findings in enterococcal meningitis are consistent with those seen during meningitis caused by other bacterial pathogens.30

Bacterial meningitis in the setting of HIV infection CSF profiles in HIV-infected individuals with bacterial meningitis have not been clearly defined, and it seems likely that such values can vary with the degree of immunosuppression in these individuals. In one series of 25 HIVseropositive patients with acute bacterial meningitis in Zimbabwe, measured CSF abnormalities were highly variable from patient to patient. Overall, however, such individuals were far more likely to have fewer CSF WBCs (50% of patients had fewer than 100 cells/mm3), a mononuclear cell predominance, and elevated CSF protein content compared to the CSF of HIV-seronegative patients with bacterial meningitis (Table 20-5).31 Because this pattern overlaps with those seen in tuberculous or fungal meningitis, both of which are much more common in HIV-infected patients, an accurate diagnosis can be delayed in this population. Although no HIV-infected patient with

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Table 20-5 CSF Findings During Acute Bacterial Meningitis in 25 HIV-Seropositive Patients Number of Patients*

Percent of Patients

Total Leukocytes (cells/mm3) 0–5 6–99 ≥ 100

1 9 10

5.0 45.0 50.0

15 7 1

65.2 30.4 4.3

5 19

20.8 79.2

0 22

0.0 100.0

% Neutrophils 0–19 20–79 ≥ 80 Glucose (mg/dl) ≥ 39.6** < 39.6 Protein (mg/dl) < 45 ≥ 45

* Data not available for every patient. ** Normal cutoff value of 2.2 mmol/l (=39.6 mg/dl). (Data adapted from Hakim JG, Gangaidzo IT, Heyderman RS, Mielke J, Mushangi E, Taziwa A, Robertson VJ, Musvaire P, Mason PR. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 2000;14:1401–1407.)

bacterial meningitis had completely normal routine CSF studies in this series, one-fifth had normal glucose contents and one patient (4%) had a normal CSF leukocyte count.

Bacterial meningitis in other settings of impaired host immunity Although bacterial meningitis without a CSF pleocytosis can occur early in the course of the illness in patients with normal immune function, such findings are more common in those individuals with impaired immunity. In a review of 50 consecutive cases of bacterial meningitis, Fishbein et al. noted six patients with CSF WBC counts of 5 cells/mm3 or lower.32 Three of these patients were heavy alcoholics, two had Hodgkin’s disease, and one was an otherwise normal octogenarian. The CSF glucose content was nearly normal and the CSF protein level was only moderately elevated in all six of these patients, suggesting a poor meningeal inflammatory response. Gram stain revealed bacteria in four of six of these cases.32

Bacterial meningitis following neurosurgical procedures The rate of bacterial meningitis following neurosurgical procedures ranges from 0.5 to 6.0%, depending upon the type of procedure performed and whether perioperative antibiotics were used.33 However, distinguishing bacterial meningitis from the transient, aseptic, and steroid-responsive

chemical meningitis that occurs in many post-neurosurgical patients can be a challenge. Several studies have compared the CSF profiles of patients in the post-neurosurgical setting. Ross et al. found that the mean CSF WBC count was lower in post-neurosurgical chemical meningitis compared to bacterial meningitis (1,000 cells/mm3 vs. 6,000 cells/mm3), and that PMNs accounted for a higher proportion of CSF WBC in bacterial meningitis versus aseptic meningitis (81% vs. 61%). Significant overlap between the two groups, however, made useful distinctions difficult. Likewise, while the CSF glucose level tended to be lower and the protein content tended to be higher in bacterial meningitis, such differences did not reach statistical significance.34 A more recent study comparing the CSF characteristics of 70 post-neurosurgical patients with chemical or bacterial meningitis confirmed that there is a significant overlap between the two groups in their routine CSF studies, although a CSF WBC count above 7,500 cells/mm3 or a glucose content below 10 mg/dl were found in several cases of bacterial meningitis but never with post-surgical chemical meningitis.35 Given this significant degree of overlap and the low yield of Gram stain (20%) in cases of post-neurosurgical bacterial meningitis, several studies have focused on alternative diagnostic tests to rapidly and reliably distinguish bacterial from chemical meningitis. In a retrospective study of 73 neurosurgical patients, Lieb et al. found that a CSF lactate concentration of >4 mmol/l had a sensitivity of 88% and a specificity of 98% for the diagnosis of bacterial meningitis, and that CSF lactate was a better predictor of this condition than the CSF:blood glucose ratio.36 LopezCortes and colleagues measured various inflammatory cytokines in the CSF of post-neurosurgical patients with meningitis, and found that while TNFα, IL-1β, and IL-6 levels were all higher in bacterial meningitis than in aseptic meningitis, IL-1β was most useful, as concentrations above 90 pg/ml had a 90% sensitivity and a 95% specificity for identifying a bacterial process.37,38

Shunt-associated meningitis Infections of CSF shunts used to treat hydrocephalus are most commonly due to skin flora, including coagulasenegative Staphylococcus, Staphylococcus aureus, and Propionibacterium acnes.39–41 Diagnosing these infections can be a challenge, as both the clinical presentation and CSF findings are highly variable from patient to patient. Overall, the CSF glucose content in this setting is least helpful, as it is often normal during obvious shunt infection.33 The CSF WBC count is somewhat more useful; among symptomatic patients with shunts and a CSF WBC count above 100 cells/mm3 in a sample aspirated from the device, 89% had positive cultures demonstrating the shunt infection.41 Still, routine CSF indices can be completely normal in the context of an infected shunt. Therefore, a positive bacterial culture in the setting of a normal CSF cell

Spinal Epidural Abscess

count, protein, and glucose levels should prompt further action and not automatically be dismissed as a contaminant.33 Furthermore, although CSF plate cultures remain the gold standard methodology for detecting shunt infection, one recent study demonstrated that four of 16 cases of shuntassociated meningitis (25%) would have been missed if broth culture had not also been performed. This has led to the recommendation that CSF always be inoculated into broth in cases of suspected shunt infection.14 Finally, it is customary to first obtain CSF directly from a shunt if infection is suspected, as lumbar CSF often does not reflect the predominantly intraventricular nature of these infections.39–41

BACTERIAL BRAIN ABSCESS The CSF findings in patients with brain abscesses vary considerably, depending on whether the lesion is acute or chronic, its degree of encapsulation, and whether an associated meningitis or cerebritis is present.24,42–44 A CSF pleocytosis, often with a PMN predominance, is generally present in the early stages after the abscess forms, and then declines as encapsulation ensues. If the inflammatory process is truly localized, then the CSF may be entirely normal and cultures remain negative. On the other hand, spread of infection to the leptomeninges or the ventricles will cause a reduced CSF glucose content and a more robust CSF pleocytosis.6 The CSF changes reported in five large studies of brain abscesses are summarized in Table 20-6. Table 20-6 Lumbar CSF Changes Associated with Bacterial Brain Abscesses Number of Patients

Percent of Patients

38 35 26 99

38 35 26

61 81 71 213

29 38 33

26 38 44 108

24 35 41

89 23 112

79 21

Pressure (mmH20) <200 200–300 >300 Total WBC Count (cells/mm3) <5 5–100 >100 Total Protein (mg/dl) <50 50–100 >100 Total

Recently, the polymerase chain reaction (PCR) method has been applied in an effort to improve the diagnostic yield of CSF studies in cases of suspected brain abscess. Indeed, PCR appears to serve as a useful adjunct to routine CSF cultures. In 11 patients with confirmed bacterial brain abscesses, broad-range bacterial PCR performed by amplifying shared prokaryotic genes was positive in seven cases, including two patients who had each received more than 5 days of preoperative antibiotics and had negative CSF bacterial cultures.45 In one additional case, the CSF culture was positive for Fusobacterium sp. while the PCR was negative, and in two other cases both PCR and culture were negative.45 PCR may therefore be especially useful when patients have been exposed to preoperative antibiotics or when the infection is caused by more fastidious organisms.

BRAINSTEM ENCEPHALITIS Several bacterial pathogens, including Listeria monocytogenes, Staphylococcus sp., Streptococcus sp., and Propionibacterium acnes, have been reported to cause focal infections of the brainstem without the usual encapsulation of an abscess. A diagnosis of Listeria brainstem encephalitis is particularly challenging because the associated CSF findings can be so benign. CSF glucose content is typically normal, while protein concentration is modestly elevated (46–99 mg/dl) in 85% of cases.46,47 The mean CSF WBC count was 237 cells/mm3 in one case series; however, one-fifth of confirmed cases had no pleocytosis at all.46,47 The leukocyte differential typically does not help to define a bacterial cause, since mononuclear or polymorphonuclear cells may predominate. Likewise, CSF Gram stain is usually negative. Initial CSF cultures are positive in onethird of cases, and, even with repeated CSF acquisition, only 41% of samples yield a confirmed organism.46,47 Staphylococcus sp. and Streptococcus sp. also cause focal abscesses of the brainstem, and CSF characteristics are similar to those reported in these lesions described earlier.48,49 P. acnes typically causes a chronic, low-grade brainstem infection, often associated with normal CSF cell counts, glucose, and protein content. Repeated cultures are usually necessary to make a diagnosis.50

SPINAL EPIDURAL ABSCESS

Glucose (mg/dl) >40 <40 Total

173

(Reprinted with permission from Fishman R. Cerebrospinal Fluid in Diseases of the Nervous System, second ed. Philadelphia: W. B. Saunders, 1992.)

Several reasons are cited for why LP should be avoided in cases of suspected spinal epidural abscess (SEA). In the setting of infection adjacent to but outside the subarachnoid space, LP may cause the spread of bacteria to this compartment, resulting in meningitis. In addition, CSF analysis often does not facilitate a diagnosis of SEA. For these reasons, MRI of the spine with gadolinium, which allows for direct visualization of the abscess cavity, has become the diagnostic procedure of choice in cases of suspected SEA.51

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Prior to the advent of MRI, however, CSF analysis was often performed in these patients. As in other parameningeal infections, wide variability in the CSF findings can be found. In one series of 43 cases of SEA, the CSF WBC count ranged from 0 to 27,000 cells/mm3 with a median of 40 cells/mm3 and a strong tendency towards a PMN predominance. Still, the CSF WBC count was normal in 25% of these patients.52 An elevated CSF protein concentration was the most common abnormality; the median value was 239 mg/dl, and levels were normal in only 10% of patients.52 Hypoglycorrhachia occurred in approximately one-quarter of patients, while the Gram stain was uniformly negative in all specimens analyzed. Although CSF cultures were positive in 25% of specimens, blood cultures were also positive in all these patients.52 In those cases where an accompanying bacterial meningitis was found, however, CSF WBC counts were higher and glucose contents lower, as would be expected. In the rare instance where the abscess itself is aspirated during an attempted LP, the WBC count of the acquired specimen can exceed 500,000 cells/mm3.53

CNS WHIPPLE’S DISEASE Whipple’s disease is a multi-system, infectious disease predominantly affecting the gastrointestinal tract and joints, with occasional involvement of the CNS. Because the causative bacterium, Tropheryma whipplei, has only recently been identified and cultured,54 and because routine CSF findings in this disorder are nonspecific,55 a laboratory diagnosis of CNS Whipple’s disease rests on CSF cytology and PCR analyses. Examination for periodic acid schiff (PAS)-positive granules within the cytoplasm of CSF-derived histiocytes has been the conventional diagnostic test for Whipple’s disease for many years. The sensitivity of this approach has been reported to exceed 80%, and it increases with multiple CSF examinations. However, since cytologic analysis is technique-dependent and interpretation can be difficult, PCR methodologies have recently been applied to the diagnosis of CNS Whipple’s disease. Recent studies have shown that the sensitivity of CSF PCR for T. whipplei-specific DNA sequences approaches that of cytology; the former has now become the diagnostic test of choice for CNS Whipple’s disease. Furthermore, CSF PCR may be a useful method to monitor the effects of antibiotic treatment, as it converts from positive to negative after successful therapy.56

CONCLUSIONS As discussed, CSF findings are essential to establish the diagnosis, identify the causative organism, and direct antibiotic therapy in many bacterial infections of the CNS. With conditions such as acute bacterial meningitis,

in particular, results of CSF analyses are absolutely required to optimally manage patients. Conventional microbiological assays such as Gram stain and plate and broth cultures form the main diagnostic tools, but emerging technologies such as PCR should significantly improve both the rate and accuracy of bacterial identification. This will very likely translate into improved patient outcomes. REFERENCES 1. Geiseler PJ, Nelson KE, Levin S, Reddi KT, Moses VK. Communityacquired purulent meningitis: a review of 1,316 cases during the antibiotic era, 1954–1976. Rev Infect Dis 1980;2:725–745. 2. Hussein AS, Shafran SD. Acute bacterial meningitis in adults: a 12-year review. Medicine 2000;79:360–368. 3. Schuchat, A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 1997;337:970–976. 4. Sigurdardottir B, Bjornsson OM, Johsdottir KE, Erlandsdottir H, Gudmundsson S. Acute bacterial meningitis in adults. A 20-year review. Arch Intern Med 1997;157:425–430. 5. Spach DH, Jackson LA. Bacterial meningitis. Neurol Clin 1999;17:711–735. 6. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: WB Saunders; 1938. 7. Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults: a review of 493 episodes. N Engl J Med 1993;328: 21–28. 8. Minns RA, Engleman HM, Stirling H. Cerebrospinal pressure in pyogenic meningitis. Arch Dis Child 1989;64:814–820. 9. Spanos A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989;262:2700–2707. 10. Powers WJ. Cerebrospinal fluid to serum glucose ratios in diabetes mellitus and bacterial meningitis. Am J Med 1981;71:217–220. 11. Weiss W, Figueroa W, Shapiro WH, Flippin HF. Prognostic factors in pneumococcal meningitis. Arch Intern Med 1967;120:517–524. 12. Schutte CM, van der Meyden CH. A prospective study of Glasgow Coma Scale (GCS), age, CSF-neutrophil count, and CSF-protein and glucose levels as prognostic indicators in 100 adult patients with meningitis. J Infect 1998;37:112–115. 13. Shanholtzer CJ, Schaper PJ, Peterson LR. Concentrated gram stain smears prepared with a cytospin centrifuge. J Clin Microbiol 1982;16:1052–1056. 14. Dunbar SA, Eason RA, Musher DM, Clarridge JE 3rd. Microscopic examination and broth culture of cerebrospinal fluid in diagnosis of meningitis. J Clin Microbiol 1998;36:1617–1620. 15. Maxson S, Lewno MJ, Schutze GE. Clinical usefulness of cerebrospinal fluid bacterial antigen studies. J Pediatr 1994;125:235–238. 16. Perkins MD, Mirrett S, Reller LB. Rapid bacterial antigen detection is not clinically useful. J Clin Microbiol 1995;33:1486–1491. 17. Morris AJ, Wilson SJ, Marx CE, Wilson ML, Mirrett S, Reller LB. Clinical impact of bacteria and fungi recovered only from broth cultures. J Clin Microbiol 1995;33:161–165. 18. Sturgis CD, Peterson LR, Warren JR. Cerebrospinal fluid broth culture isolates: their significance for antibiotic treatment. Am J Clin Pathol 1997;108:217–221. 19. Negrini B, Kelleher KJ, Wald ER. Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics 2000;105:316–319. 20. Hoen B, Viel JF, Paquot C, Gerard A, Canton P. Multivariate approach to differential diagnosis of acute meningitis. Eur J Clin Microbiol Infect Dis 1995;14:267–274. 21. McKinney WP, Heudebert GR, Harper SA, Young MJ, McIntire DD. Validation of a clinical prediciton rule for the differential diagnosis of acute meningitis. J Gen Int Med 1994;9:8–12.

References

22. Bonsu B, Harper MB. Differentiating acute bacterial meningitis from acute viral meningitis among children with cerebrospinal fluid pleocytosis: a multivariable regression model. Pediatr Infect Dis J 2004;23:511–517. 23. Kleine TO, Zwerenz P, Zofel P, Shiratori K. New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF). Brain Res Bull 2003;61:287–297. 24. Fishman R. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992. 25. Durack DT, Spanos A. End-of-treatment spinal tap in bacterial meningitis. JAMA 1982;248:75–78. 26. Jacob J, Kaplan RA. Bacterial meningitis: limitations of repeated lumbar puncture. Am J Dis Child 1977;131:46–48. 27. Schaad UB, Nelson JD, McCracken GH. Recrudescence and relapse in bacterial meningitis of childhood. Pediatrics 1981;67:188–195. 28. Mylonakis E, Hohmann EL, Calderwood SB. Central nervous system infection with Listeria monocytogenes: 33 years’ experience at a general hospital and review of 776 episodes from the literature. Medicine 1998;77:313–336. 29. Koorevaar CT, Scherpenzeel PG, Neijens HJ, Derksen-Lubsen G, Dzoljic-Danilovic G, de Groot R. Childhood meningitis caused by enterococci and viridans streptococci. Infection 1992;20:118–121. 30. Pintado V, Cabellos L, Moreno S, Meseguer MA, Ayats J, Viladrich PF. Enterococcal meningitis: a clinical study of 39 cases and review of the literature. Medicine 2003;82:346–364. 31. Hakim JG, Gangaidzo IT, Heyderman RS, et al. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 2000;14:1401–1407. 32. Fishbein DB, Palmer Dl, Porter KM, Reed WP. Bacterial meningitis in the absence of CSF pleocytosis. Arch Intern Med 1981;141:1369–1372. 33. Kaufman BA, Tunkel AR, Pryor JC, Dacey RG Jr. Meningitis in the neurosurgical patient. Infect Dis Clin North Am 1990;4:677–701. 34. Ross D, Rosegay H, Pons V. Differentiation of aseptic and bacterial meningitis in postoperative neurosurgical patients. J Neurosurg 1988;69:669–674. 35. Forgacs P, Geyer CA, Freidberg SR. Characterization of chemical meningitis after neurological surgery. Clin Infect Dis 2001;32: 179–185. 36. Leib SL, Boscacci R, Gratzl O, Zimmerli W. Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood glucose ratio for the diagnosis of bacterial meningitis following neurosurgery. Clin Infect Dis 1999;29:69–74. 37. Lopez-Cortes LF, Marquez-Arbizu R, Jimenez-Jimenez LM, et al. Cerebrospinal fluid tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8 as diagnostic markers of cerebrospinal fluid infection in neurosurgical patients. Crit Care Med 2000;28: 215–219. 38. Brown EM. Infections in neurosurgery: using laboratory data to plan optimal treatment strategies. Drugs 2002;62:909–913.

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39. Bayston R. Hydrocephalus shunt infections. J Antimicrob Chemother 1994;34(Suppl A):75–84. 40. Morris A, Low DL. Nosocomial bacterial meningitis, including central nervous system shunt infections. Infect Dis Clin North Am 1999;13:735–750. 41. Schoenbaum SC, Gardner P, Shillito J. Infections of cerebrospinal fluid shunts: epidemiology, clinical manifestations, and therapy. J Infect Dis 1975;131:543–552. 42. Carey ME, Chou SN, French LA. Experience with brain abscess. J Neurosurg 1972;36:1–9. 43. Kiser JL, Kendig JH. Intracranial suppuration: a review of 139 consecutive cases with electron-microscopic observations on three. J Neurosurg 1963;20:494–511. 44. Samson DS, Clark K. A current review of brain abscess. Am J Med 1973;54:201–210. 45. Kupila L, Rantakokko-Jalava K, Jalava J, et al. Aetiological diagnosis of brain abscesses and spinal infections: application of broad range bacterial polymerase chain reaction analysis. J Neurol Neurosurg Psychiatry 2003;74:728–733. 46. Armstrong RW, Fung PC. Brainstem encephalitis (rhomboencephalitis) due to Listeria monocytogenes: case report and review. Clin Inf Dis 1993;16:689–702. 47. Bartt R. Listeria and atypical presentations of Listeria in the central nervous system. Semin Neurol 2000;20:361–373. 48. Hall WA. Infectious lesions of the brain stem. Neurosurg Clin N Am 1993;4:543–551. 49. Kashiwagi S, Abiko S, Aoki H. Brainstem abscess. Surg Neurol 1987;28:63–66. 50. Camarata PJ, McGeachie RE, Haines SJ. Dorsal midbrain encephalitis caused by Propionibacterium acnes. J Neurosurg 1990;72: 654–659. 51. Reishaus E, Waldbaur H, Seeling W. Spinal epidural abscess: a meta-analysis of 915 patients. Neurosurg Rev 2000;232: 175–204. 52. Daurouiche RO, Hamill Rj, Greenberg SB, Weathers SW, Musher DM. Bacterial spinal epidural abscess: review of 43 cases and literature survey. Medicine 1992;71:369–385. 53. Baker AS, Ojemann RG, Swartz MN, Richardson EP Jr. Spinal epidural abscess. N Engl J Med 1975;293:463–468. 54. Maiwald M, von Herbay A, Fredricks DN, Ouverney CC, Kosek JC, Relman DA. Cultivation of Tropheryma whipplei from cerebrospinal fluid. J Infect Dis 2003;188:801–808. 55. Gerard A, Sarrot-Reynauld F, Liozon E, et al. Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine 2002;81:443–457. 56. von Herbay A, Ditton HJ, Schuhmacher F, Maiwald M. Whipple’s disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology 1997;113:434–441.

CHAPTER

21

Viral Infections Benjamin M. Greenberg

INTRODUCTION Evaluation for infection is one of the most common indications to perform a lumbar puncture (LP) and cerebrospinal fluid (CSF) analysis. Still, CSF studies used in the setting of suspected central nervous system (CNS) viral infection have historically been hampered by a relative inability to identify a causative agent in a rapid and reliable manner. Indeed, before the widespread availability of polymerase chain reaction (PCR) based methodologies, a diagnosis of viral meningitis or viral encephalitis relied on insensitive culture methods or on serologic tests. Since the advent of PCR, our ability to detect viral agents has dramatically improved, even if it still falls short of ideal. Novel technologies such as multiplex PCRs have begun to allow the screening of CSF samples for multiple viruses simultaneously, but there are still many viral pathogens not readily detectable via these methods. This chapter outlines current knowledge of the CSF profiles and analysis methodologies for viral agents in the setting of common syndromes indicative of CNS viral infection.

ACUTE VIRAL MENINGITIS Background Viral meningitis is responsible for some 36,000 annual hospital admissions in the USA that collectively cost some 300 million dollars per year.1 The true incidence of this disorder is likely much higher due to the underreporting of milder cases that do not even come to medical attention. Viral meningitis can occur sporadically or in epidemics. Among all cases of “aseptic” meningitis, an underlying etiology is identified only 55–70% of the time;2,3 responsible agents commonly include the enteroviruses (EVs), arthropodborne viruses (arboviruses), herpesviruses, lymphocytic choriomeningitis virus (LCMV), and mumps virus. When a viral pathogen is identified in acute meningitis, EVs make

up some 85–90% of the isolates.1,3 Once a patient seeks medical care, an LP confirms the presence of CSF inflammation and facilitates a determination of the underlying etiology.

General findings When viral meningitis as a distinct entity is compared to other causes of meningitis, several unique CSF characteristics can be discerned. Individual pathogens, however, may produce laboratory findings very different from one another. In general, CSF from a patient with viral meningitis shows a pleocytosis, a normal or mildly elevated total protein concentration, and a normal glucose level. Classic teaching holds that a preponderance of lymphocytes in the CSF predicts a viral etiology while a polymorphonuclear neutrophil (PMN) predominance occurs with bacterial infection, yet recent data dispute this distinction. In one retrospective review of 158 pediatric meningitis cases, an average white blood cell (WBC) count of 391 cell/mm3, an average PMN percentage of 52.6%, an average glucose concentration of 55.4 mg/dl, and an average total protein level of 61.5 mg/dl were found in all cases of confirmed viral origin.4 This disputes the notion that a PMN predominance as a sole distinguishing feature accurately discriminates viral from bacterial meningitis. Still, the identification of a CSF protein content greater than 220 mg/dl all but rules out a virus as the etiology of meningitis.5 The usefulness of nucleic acid, culture, and serologic detection methods is highly pathogen-dependent. CSF findings observed in common types of viral meningitis are summarized in Table 21-1. Determining the sensitivity and specificity of new pathogen detection methodologies is also limited by the lack of preexisting gold standard means to establish the specific diagnosis in nearly all CNS viral infections (Table 21-1). Results of PCR-based nucleic acid detection systems depend on multiple factors, including time between symptom onset and CSF sampling as well as the magnitude of the pleocytosis.6 Two new types of assays have also been

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Table 21-1

Summary of the Expected CSF Findings in Common Types of Viral Meningitis

Pathogen

Total WBC Count (cells/mm3)

Proportion of PMN >50%

EV

100–1,000

Often early

HSV-2

100–500

WNV

Protein Level

Glucose Level

Unusual

Normal to mildly elevated Usually elevated

50–500

Common

Mildly elevated

Normal to mildly decreased Normal to mildly decreased Normal

LCMV

5–1,000

Unusual

Elevated

Mumps

100–500

Unusual

Normal to mildly elevated

Normal to mildly decreased Normal to mildly decreased

CSF PCR Sensitivity

CSF PCR Specificity

Accessory Testing

70–100%

50–100%

Unknown

Unknown

50–80%

100%

Unknown

Unknown

70%

100%

Respiratory and stool PCR Cytology for Mollaret cells* Antibody testing in serum, CSF Antibody testing in serum Antibody testing in serum, CSF

* Neither sensitive nor specific for HSV-2 infection. HSV-2, herpes simplex virus type 2; WNV, West Nile virus

developed that can actually identify a number of potential viruses in a single PCR reaction. Multiplex PCR assays contain a mixture of primers specific for different viruses that can amplify sequences under similar reaction conditions. Other assays rely on consensus PCR primer sets that amplify conserved regions found in many viral genomes. A positive result with this latter type of assay requires subsequent testing to specifically identify the exact pathogen involved. These new molecular approaches are discussed in detail in Chapter 34. Other CSF markers have been screened for their ability to differentiate bacterial from viral meningitis and to help avoid unnecessary antibiotic therapy. A partial list of these markers includes lactic acid, interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), IL-8, and IL-1β.7 Multiple studies suggest that a CSF lactic acid level above 5.0 mmol/l effectively rules out viral meningitis.8,9 While inflammatory cytokines have shown some promise in their capacity to differentiate bacterial from viral infections of the CNS, results obtained thus far are too inconsistent for routine clinical use. Some of this variability stems from the fact that individual viruses trigger specific cytokine responses, making a universal virus-specific pattern difficult to discern.10

Pathogen-specific findings Enteroviruses Members of the Picornaviridae family, EVs can be subclassified into the polioviruses, the coxsackieviruses, the echoviruses, and the newer “numbered” EVs. More than 70 total serotypes have now been identified. Most of these infections occur in the summer or early fall months and preferentially affect children. Patients are usually febrile and may have nonspecific complaints such as nausea, anorexia, or upper respiratory symptoms. The CSF in EV meningitis usually contains a pleocytosis of between 100 and 1,000 WBCs/mm3.11,12 There are cases where the cell count ranges into the thousands,13 and others where no pleocytosis is observed at all.14 In one study, over 20% of patients with confirmed EV infections

of the CNS had no pleocytosis.15 While a PMN predominance can be seen early in infection, a lymphocytepredominant pleocytosis after several days is the norm. Thivierge and Delage reported a PMN predominance in 59% of initial CSF analyses.15 Protein concentrations in CSF can be normal or mildly elevated (<100 mg/dl), while glucose levels are normal to mildly decreased (>40 mg/dl).16–18 PCR has become the diagnostic mainstay in EV meningitis. While viruses themselves can often be isolated from the oropharynx, stool, blood, and CSF, cell culture detection is a slow and relatively insensitive technique.19 Likewise, serologic tests are limited by their need for acute and convalescent titers and the requirement to test for specific antibodies against numerous serotypes. PCR-based methods for diagnosing EV infections have been shown to be superior to viral culture in numerous studies.20–22 Still, the sensitivity and specificity of these assays are difficult to quantify if one assumes that PCR techniques are superior to culture methods, because a comparative diagnostic technique is lacking. Despite these limitations, PCR has been reported to be 70–100% sensitive and 50–100% specific for EV meningitis.2,17,20,21,23–25 Similar to the polioviruses (discussed later), EV-71 has been associated with a variety of neurologic conditions, including aseptic meningitis, encephalitis, and acute flaccid paralysis. This viral serotype was first identified in an infant with encephalitis in California in 1969.26 Identification of this pathogen relies on PCR amplification of the virus, followed by genotyping to identify serotypespecific sequences. CSF, however, remains a relatively insensitive medium from which to isolate this virus. In one study, EV-specific nucleotide sequences were amplified in 31.2% of patients with neuroinvasive EV-71 infection, while 100% of respiratory specimens and 87.5% of stool specimens were positive.27

Herpesviruses Among aseptic meningitis patients in whom a viral etiology is identified, herpesviruses are the second most common

Acute Viral Meningitis

cause behind the EVs. This family includes herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), varicella zoster virus (VZV), Epstein Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV6). While aseptic meningitis has been associated with all of these pathogens, HSV-2 is by far the most common cause. HSV-2 has been identified as a cause of benign recurrent aseptic meningitis, also known as Mollaret’s meningitis.28,29 Patients with a first episode of HSV-2 meningitis typically have a lymphocytic pleocytosis, moderately elevated total protein level, and normal glucose content in their CSF. One series of 27 patients reported an average of 431 WBCs/mm3 (mean, 85% lymphocytes), an average protein content of 160 mg/dl, and an average glucose level of 54 mg/dl.30 During episodes of recurrence, cell counts and protein levels tended to be slightly lower when compared to the initial attack, but the profile was similar in individual cases. HSV-2 meningitis in immunocompromised patients presents in a clinical fashion similar to episodes in immunocompetent hosts, but the disease may reveal a somewhat different CSF profile in this setting. In one small series, immunocompromised patients with HSV-2 meningitis had an average CSF cell count of 74 WBCs/mm3 (mean, 97% lymphocytes) and a mean protein level of 72 mg/dl. More than half these patients had hypoglycorrachia, defined as a CSF glucose concentration less than 50% of the simultaneous blood glucose level.31 A diagnosis of HSV-2 meningitis has also been aided by the development of PCR-based detection assays. Once again, however, there is no established gold standard comparison test to allow for accurate determination of sensitivity and specificity in the setting of acute meningitis. In recurrent “aseptic” meningitis, HSV-2 has consistently been identified as the most common underlying cause using nucleic acid detection strategies.32 Still, while all of the herpesviruses have been occasional causes of isolated viral meningitis, as a group they are rarely found in this clinical setting.33–35

Arboviruses Numerous viruses transmitted to humans by mosquitoes or ticks cause neurological disease. West Nile virus (WNV) has become the most common cause of arboviral meningitis in the USA. This pathogen belongs to the Flaviviridae family and can cause fever, aseptic meningitis, encephalomyelitis, and/or acute flaccid paralysis. Still, fewer than 1% of infected patients develop neuroinvasive disease; most are asymptomatic or have a febrile illness only.36 Patients with WNV meningitis have the classic CSF profile associated with viral meningitis. In the largest published case series, Tyler et al. reviewed the CSF findings in 174 cases. More than 97% of patients had a pleocytosis greater than 5 WBCs/mm3, and 63% had between 51 and 500 WBCs/mm3.37 A PMN predominance (>50% of the cells) was identified in half of their cases, making it an unreliable marker of bacterial versus WNV infection.37

179

Over 90% of patients had elevated CSF protein content (> 40 mg/dl), but only 16% had values greater than 100 mg/dl.37 In this study, the average CSF glucose concentration was 65 mg/dl.37 Overall, these findings were similar to ones reported in a smaller study published several years earlier.38 Abnormal cells, similar to Mollaret cells, have been identified in the CSF of a few patients with confirmed WNV meningitis.39 A definitive diagnosis of WNV neuroinvasive disease depends on identification of the virus by culture, antigen capture, or nucleic-acid-based methodologies, or by the detection of an antiviral immune response using serological assays. Due to safety concerns among laboratory personnel, viral culture is now rarely used.36 Identification of viral nucleic acids in blood samples is relatively insensitive in the setting of acute meningitis, due to waning of the viremia once neurological symptoms develop. When applied to CSF, however, PCR-based assays have a specificity reported to approach 100% and a sensitivity ranging from 57 to 70%.40 Still, the identification of virus-specific antibodies in the serum, CSF, or both using enzyme-linked immunosorbent assays (ELISA) remains the principal means of diagnosis until nucleic-acid-based strategies gain wider use. Several issues must be considered when interpreting results of WNV serologies. First, while nucleic-acid-based detection has a very high specificity, antibodies against the flaviviruses commonly cross-react with one another. Thus, a patient being screened for WNV can have a false positive result in the setting of prior St. Louis encephalitis, Japanese encephalitis, dengue, or yellow fever infections or with prior vaccination against one of these pathogens.36 A confirmatory plaque reduction neutralization assay (a test that requires the use of infectious virus and thus specialized biocontainment facilities) ensures a precise serological diagnosis. Second, the kinetics of the antibody response against WNV differs from that against most other viral pathogens. While most viral infections rapidly induce specific immunoglobulin (Ig) M antibodies that then quickly disappear, followed by the generation of a longerlived IgG response, this is not the case in WNV infection. Here, antiviral IgM antibodies can persist in both serum and CSF for substantial periods.41 Tardei et al. described 93 patients with WNV meningitis, 19% of whom had IgM antibodies detected in the CSF at the time of diagnosis, while 80% had virus-specific IgM found in either the serum or CSF.42 In some of these patients, IgM antibodies actually appeared in the CSF prior to the serum, making antibody testing in both compartments critical.42 The persistence of antiviral antibodies, while well documented, is not well understood. Whether this is due to persistent viral replication at a low level, or some other immunological reason, is unclear.

Lymphocytic choriomeningitis virus LCMV is an arenavirus spread to humans from rodents via contact with the urine, feces, or saliva of infected animals.

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Patients commonly present with aseptic meningitis, but there are no unique clinical or laboratory features specific for this illness that aid in diagnosis. Studies outlining the CSF findings in LCMV meningitis are limited, but in general reveal a pleocytosis with a mononuclear cell predominance ranging up to 3,000 WBCs/mm3.43 A single case reported a persistent eosinophilia in both the peripheral and CSF compartments in the setting of a suspected LCMV aseptic meningitis,44 but this particular finding has not been reported since. CSF protein is usually elevated, and in some cases can be greater than 200 mg/dl.43 A low CSF:serum glucose ratio has been described, but is not universally observed.43 Diagnosis is based on serologic testing of serum samples via immunofixation assays. A reverse transcriptase PCR assay has been developed for potential use in CSF, but prospective data to establish its sensitivity and specificity are not yet available.45

Mumps virus Mumps virus, a paramyxovirus, is spread from person to person via infected saliva. It most commonly causes parotitis, with orchitis occurring in approximately 10–20% of infected men. Some 1–5% of patients infected with mumps virus will develop aseptic meningitis.46,47 Rates of mumps meningitis, however, have declined dramatically since the advent of an effective antiviral vaccine. In one Japanese study, rates of meningitis were compared before and after mumps vaccination. Here, a 1.24% incidence among patients with naturally acquired mumps was observed, compared to a rate of 0.05% among vaccinated patients.46 Nevertheless, there are documented cases of mumps meningitis developing following vaccination.48 This disease is heralded by typical aseptic meningitis features. A pleocytosis is almost always present, with an average CSF WBC count in the 100–500 cells/mm3 range.10,49 The CSF protein concentration is usually normal to mildly increased, and the CSF glucose is usually normal even though reports of hypoglycorrachia exist.50,51 A definitive diagnosis of mumps meningitis relies on isolation of the virus, detection of virus-specific nucleic acid sequences, or serologic studies. Most patients will have evidence of virusspecific IgM and IgG antibodies in the serum, with many patients also having evidence of intrathecal antibody synthesis.49,52 One study validated the use of RT-PCR technology on clinical specimens and documented a sensitivity of 70% and a specificity of 100% when applied to CSF samples.53

determinant of disease for the vector-borne pathogens; while Japanese encephalitis virus causes more than 20,000 deaths per year throughout Asia, it is unheard of in the Western hemisphere due to the restricted habitat of its principal mosquito vector.56 In the USA, HSV-1/2, VZV, EVs, WNV, and influenza are the most common viruses isolated from patients with sporadic forms of viral encephalitis.54,57,58 In the appropriate clinical and radiographic setting,59 CSF analysis undertaken in these patients will confirm the presence of intrathecal inflammation and may potentially identify an underlying viral pathogen.

General findings A diagnosis of viral encephalitis is often a two-step process. First, a suspected patient is confirmed to have inflammatory CSF consistent with an underlying viral infection. Second, the CSF is analyzed by means of tissue culture, antigen and antibody detection methods, and nucleic acid amplification assays in a search for a specific pathogen. Glucose levels in CSF are usually within normal limits, but hypoglycorrachia has occasionally been reported in some instances of viral infections of the CNS (Table 21-2).59–64 As in viral meningitis, many cases of viral encephalitis have an increased CSF protein levels; two-thirds will have moderate increases up to 100 mg/dl.54 The majority of patients with viral encephalitis will also have some degree of a lymphocytic pleocytosis, but there is extreme variability in total WBC counts, varying from 0 to 1,200 cells/mm3.54 Of 170 patients with confirmed or probable viral encephalitis enrolled in the California Encephalitis Project, the median CSF cell count was 70 WBCs/mm3.58 Still, 15% of patients had normal CSF at the initial LP, with no correlation to the underlying etiology. The continued clinical or radiographic suspicion of acute viral encephalitis mandates a second CSF sampling within 24–48 h for a given patient if the initial specimen is non-diagnostic. Findings observed in common types of viral encephalitis are summarized in Table 21-3.

Pathogen-specific findings Herpes simplex encephalitis While there are many reports of documented herpes simplex encephalitis (HSE) in the setting of normal initial CSF analyses, the prototypical patient will have a

VIRAL ENCEPHALITIS

Table 21-2 Viral Infections of the CNS Associated With Hypoglycoracchia

Background

Enteroviruses Herpes simplex virus Human immunodeficiency virus Lymphocytic choriomeningitis virus Mumps virus Varicella zoster virus

While systemic viral infections are common, symptomatic viral infections of the brain parenchyma itself are exceptionally rare. One study in Finland estimated viral encephalitis to occur at a rate of 1.4 cases per 100,000 persons per year.54,55 Geography, however, is a major

Viral Encephalitis

Table 21-3

Summary of the Expected CSF Findings in Common Types of Acute Viral Encephalitis

Pathogen

Total WBC Count (cells/mm3)

Proportion of PMN >50%

EV

0–1,000

Unusual

HSV-1

0–1,000

Unusual

VZV

0–500

WNV

0–500

Protein Level

Glucose Level

CSF PCR Sensitivity

CSF PCR Specificity

Accessory Testing

Normal

Unknown

Unknown >95%

20–90%

90–100%

Common

Elevated

Normal to mildly decreased Normal to mildly decreased Normal

>95%

Unusual

Normal to elevated Normal to elevated Elevated

50–80%

100%

Respiratory and stool PCR Antibody testing in serum, CSF Antibody testing in serum, CSF* Antibody testing in serum, CSF

181

* Often determined as the CSF:serum antibody index.

mononuclear cell pleocytosis and modestly elevated total protein content.65,66 In one study, the median CSF cell count among 40 patients with confirmed HSE was 42 WBCs/mm3, ranging from 0 to 975 WBCs/mm3.58 Only five patients in this study were documented to have HSE caused by HSV-2, and the CSF cell counts were significantly higher in this group (median, 726 WBCs/mm3; range, 389–1,250 cells/mm3.58 Six Danish patients with HSV-2 encephalitis had an average WBC count of 146 WBCs/mm3 (range, 2–270 WBCs/mm3).67 The pleocytosis typically diminishes with antiviral treatment, but it may not return to normal for some time. Thus, it can persist at a low level for weeks or even months, despite appropriate treatment and clinical improvement on the part of the patient.68 The median CSF protein level in patients with confirmed HSE was 70 mg/dl (range, 15–297 mg/dl) in one study, while the median CSF glucose concentration in this cohort was 69 mg/dl (range, 39–112 mg/dl).58 Hypoglycorrachia is rare in adults with HSE, but it has been reported in neonatal cases.61,69 While it is widely held that HSE is commonly associated with the presence of red blood cells (RBCs) in the CSF due to the hemorrhagic nature of the underlying pathology, this finding is neither sensitive nor specific for this infection.70 The presence of persistent RBCs in both the first and fourth CSF collection tube has been observed in up to 40% of patients with proven HSE.71 Care should be taken, however, as this sign is not universal among HSE patients, and rarely this finding can be seen with other CNS infections (e.g., anthrax).72 Prior to the advent of nucleic-acid-based detection methods, significant effort had gone into the development of various antiviral antibody detection systems in suspected HSE. Several methods (immunoblots, ELISAs) were tested for their capacity to identify intrathecal synthesis of virusspecific antibodies. Early work also compared CSF levels of these markers to those in serum, often using the CSF:serum albumin ratio as a correction coefficient. However, this antibody index (AI) artificially lowered the sensitivity of the test by not accounting for a polyclonal, non-antigen-specific antibody response generated in the CSF during inflammatory events within the CNS. This polyclonal response artificially

lowers the AI and has led to false negative results.73 Still, when appropriate corrections were applied, the HSV AI in the setting of suspected HSE was quite sensitive, albeit not particularly specific.73–76 Thus, an elevated HSV AI can be seen in patients with VZV infections of the CNS and in patients with multiple sclerosis (MS).73–75,77 Oligoclonal banding with antibodies specific for HSV has been reported in the setting of encephalitis, but prospective studies to determine whether this reaction persists are lacking.78–80 Yet unlike the elevated CSF IgG synthesis rate in autoimmune diseases such as MS which produce widely polyclonal antibodies, the elevated production of antibodies in HSE is much more virus-antigen-specific.74 PCR on concentrated CSF specimens has become the mainstay in the diagnosis of HSE. The sensitivity and specificity of PCR against the previous method of direct brain biopsy in suspected HSE exceed 95%.81,82 This sets the standard for nucleic acid detection in the setting of CNS viral infection. The sensitivity and specificity for the CSF HSV PCR are so high that even in a clinical situation where a low pretest probability of HSE exists (<5%), a positive CSF PCR yields a greater than 80% post-test probability of the disease.83 These statistics, however, only apply to adults being evaluated for HSE. In the setting of neonatal infection, the CSF HSV PCR has an estimated sensitivity of 70–100%.84 Multiple groups have developed consensus PCR primers and multiplex PCR assays in various attempts to increase the efficiency of testing in the setting of probable encephalitis. Consensus PCR assays amplify conserved DNA sequences among multiple herpesvirus family members (HSV-1, HSV-2, EBV, CMV, VZV, and HHV6).85–87 In contrast, multiplex PCR assays combine different primer sets into one reaction, each specific for a different virus.88–90 These methods are currently being tested in experimental studies, and confirmatory sensitivity and specificity compared to the standard single virus PCR assays are still unavailable. With adequate antiviral therapy in HSE, the rate of positive HSV PCR decreases over time, usually beginning after a full week of therapy.29,82,91 Some authors recommend routine surveillance of patients after 2 weeks of treatment with a second LP and PCR test. If positive,

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continuing therapy has been recommended.29,92,93 The relapse rate in adults treated with acyclovir is low (<2%), but may range between 5 and 26% in the pediatric population.29,94,95 Whether or not a patient with clinical and/or radiographic evidence of relapse and a subsequently negative CSF HSV PCR represent recrudescence of infection or post-infectious inflammation is unknown.

Varicella zoster virus encephalitis Use of the term VZV encephalitis, while referenced in many articles and books, may be a misnomer. It is actually unusual for patients to have neurological disease from direct VZV infection of neurons or glial cells. Rather, most individuals experience symptoms due to the compromise of cerebrovascular endothelial vessels and/or infection of choroidal cells.96 Neurological syndromes are often, but not always, accompanied by cutaneous manifestations of either primary infection or reactivation (i.e., chickenpox or shingles).97 CNS involvement by VZV may cause acute cerebellar ataxia, ascending myelitis, granulomatous angiitis, and the Ramsay Hunt syndrome (facial palsy, herpes zoster oticus, and vertigo). One review of 23 cases of VZV encephalitis demonstrated a mild lymphocytic pleocytosis in 21 cases (range, 7–260 WBCs/mm3), and normal to modestly elevated total protein levels in most patients (maximum, 76 mg/dl).98 In contrast, Jemsek et al. reviewed 12 cases where the mean CSF cell count was 155 WBCs/mm3 (range, 1–800 WBCs/mm3), and the average CSF protein level was 246 mg/dl (range, 48–960 mg/dl).99 While the glucose concentration of CSF is usually normal in VZV encephalitis, there have been rare reports of hypoglycorrachia.100 In the setting of concomitant HIV infection, interpreting CSF results becomes even more difficult. Often these patients will have no pleocytosis at all, or an alternative explanation for the elevated CSF WBC count is simultaneously uncovered.101 The presence of oligoclonal bands in the CSF of patients with VZV encephalitis has been documented to occur in at least one-third of patients, usually a week or more after the onset of symptoms.102,103 Indeed, intrathecal antibodies directed against viral antigens can be used to confirm a diagnosis of VZV encephalitis, even when the CSF PCR assay is negative. While patients previously exposed to VZV will have measurable antiviral IgG titers in their serum, the presence of significant CSF antibody titers outside the setting of an active CNS VZV infection is distinctly unusual. In two series, the presence of anti-VZV IgG antibodies in the CSF was more sensitive than PCR in the diagnosis of VZV encephalitis.103,104 Indeed, even before the routine availability of PCR testing, antibodies to the viral membrane antigens were commonly detected in the CSF of patients with VZV encephalitis.99 Thus, a definitive diagnosis of CNS VZV infection relies on the detection of viral nucleic acids as well as serologic testing. Still, determining the sensitivity and specificity of PCR assays again has been difficult due to a lack of a

diagnostic gold standard for comparison purposes and because of complex clinical situations that often involve multiple co-infections. When compared to serologic testing, CSF VZV PCR assays have a sensitivity that ranges between 28 and 83%.103–105 Specificity of PCR in controlled settings has been reported as 100% (i.e., no amplification of other herpesviruses using VZV-specific probes), but it is hard to determine specificity without a comparative diagnostic test. Patients with cutaneous reactivation of VZV infection (i.e., shingles) often have positive CSF VZV PCR reactions, even without any other evidence of active CNS involvement.96 Thus, in a clinically convincing situation, a positive CSF VZV PCR can be used as confirmatory evidence of CNS disease, but alternative diagnostic modalities should also be pursued.

Enteroviral encephalitis Among patients with evidence linking a particular pathogen to acute encephalitis, EVs are identified in 5–25% of cases.54,57,58 For the 43 patients in the California Encephalitis Project with confirmed EV encephalitis, the median CSF cell count was 100 WBCs/mm3 (range, 0–1,080 WBCs/mm3). The median CSF protein level was 54 mg/dl (range, 16–881 mg/dl), and the median glucose level was 67 mg/dl (range, 38–159 mg/dl).58 Other literature regarding the CSF findings in EV encephalitis is limited. Two Chinese studies provided evidence that PCR is more sensitive than culture for diagnosis, but most of the reports used to establish sensitivity and specificity numbers were conducted in patients with EV meningitis.23,83,106,107 The EV-71 serotype has been associated with a higher rate of encephalitis, specifically a focal brainstem infection. Patients can present with isolated brainstem dysfunction or can have concomitant autonomic dysregulation and pulmonary edema. One cohort of 57 children with EV-71 brainstem encephalitis in Taiwan identified an average CSF WBC count of 131 cells/mm3, normal CSF glucose content, and normal to mildly elevated CSF protein (average, 39.3 mg/dl).108 Patients with X-linked agammaglobulinemia are particularly susceptible to a chronic EV meningoencephalitis.109,110 While the incidence of this disease has been greatly reduced by the treatment of patients with intravenous immunoglobulin, cases associated with therapeutic B cell depletion following treatment with rituximab have been reported.111 In this setting, patients develop headache, lethargy, seizures, and a constellation of abnormal neurological signs.109,110 The few cases reported in the literature show a low-grade mononuclear cell CSF pleocytosis (10–25 WBC/mm3), elevated protein level (75–150 mg/dl), and consistently positive CSF EV PCR.109–111 Most CSF viral isolates turn out to be echoviruses.110

West Nile virus encephalitis The largest review to date of the CSF findings among patients with WNV encephalitis was published in 2006.

Myelitis, Spinal Motor Neuronopathies, and Polyradiculitis Due to Viruses

Among 76 patients with encephalitis, details regarding CSF cellularity was available in 73: four (5.3%) had normal CSF WBC counts, 17 (22.4%) had 5–50 WBCs/mm3, 46 (60.5%) had between 51 and 500 WBCs/mm3, and 6 (7.9%) had greater than 500 WBCs/mm3.37 Twenty-eight (36.9%) of these patients had 50% or greater PMNs at presentation, and 36 (47.4%) had a protein concentration greater than 100 mg/dl.37 No patient had a CSF glucose level below 40 mg/dl.37 In the California Encephalitis Project cohort, there were 19 cases of confirmed WNV encephalitis. Here, the median CSF cell count was 67.5 WBCs/mm3 (range, 0–468 WBCs/mm3), the median CSF protein level was 86.0 mg/dl (range, 71–300 mg/dl), and the median CSF glucose concentration was 83.0 mg/dl (range, 47–192 mg/dl).58 A specific diagnosis depends on serological and nucleic acid detection assays, as described in the earlier section on WNV meningitis.

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and Chapter 24. In contrast, acute viral infections of the spinal cord causing long tract or white matter damage are rare (Table 21-4). Pathogens implicated in these events include HSV-2, VZV, EBV, CMV, and EVs.118–123 The bestdescribed syndrome of viral myelitis is caused by HSV-2, which can be either relatively benign or, in the setting of underlying human immunodeficiency virus (HIV) infection, a highly necrotizing disease process. With more benign HSV-2 myelitis, the CSF typically shows a lymphocytic pleocytosis between 10 and 200 WBC/mm3. In patients with the necrotizing myelopathy, the CSF may show a striking pleocytosis with >5,000 WBC/mm3 and a PMN predominance. The protein content is almost invariably elevated (range, 5–430 mg/dl), and oligoclonal bands are observed 10–15% of the time. Viral DNA is detected by PCR in a high proportion of these cases when assayed within 14 days after symptom onset, after which time serological studies on CSF are often more useful.

Rabies Rabies virus transmission to humans occurs via the bite of an infected animal (e.g., dog, bat, raccoon, fox, skunk, or cat) or via the inhalation of aerosolized droplets of saliva from these animal vectors (e.g., spelunking in caves containing rabid bats). There are two major clinical presentations for rabies in humans, the encephalitic form and the paralytic form. While the encephalitic form often manifests classic features such as hydrophobia, the paralytic form can be confused with the Guillain-Barré syndrome. The CSF formulation found in patients with rabies infections is relatively nondescript. It can range from completely normal to a profile having a mild lymphocytic pleocytosis accompanied by a modestly elevated CSF protein content.112 A definitive diagnosis prior to autopsy can be difficult, but is based on finding viral antigens at accessory sites, such as by immunofluorescent staining of skin samples.113 An ELISA to detect rabies antigen in brain, saliva, and CSF was developed to allow for the rapid identification of human and animal rabies cases post mortem.114 The same research team applied its test to a separate cohort of 30 CSF samples from suspected paralytic rabies patients and documented 76.6% sensitivity and 100% specificity compared to autopsy results.115 Small studies have confirmed the potential for PCR-based assays to detect rabies RNA in saliva or CSF, but serial testing is required in order to increase the sensitivity, probably due to the intermittent shedding of virus from infected cells.116

MYELITIS, SPINAL MOTOR NEURONOPATHIES, AND POLYRADICULITIS DUE TO VIRUSES Myelitis Transverse myelitis is usually either a post-infectious phenomenon or one that occurs in the setting of an underlying systemic autoimmune disorder.117 The CSF findings associated with these disorders are covered in Chapter 13

Spinal motor neuronopathy Viral infection of anterior horn cells, causing motor neuronopathy, is the basis of one the largest public health efforts in history. The scourge of poliomyelitis has all but been eliminated as part of a worldwide eradication program relying on mass immunization. In the past, 1–2% of patients infected with poliovirus developed a non-paralytic aseptic meningitis with a CSF profile similar to patients with non-polio enteroviral meningitis.124 Some 0.1–1.0% of these patients developed paralytic poliomyelitis. These patients presented with asymmetric weakness, usually Table 21-4

Viral Etiologies of Acute Myelitis

DNA viruses Herpesviruses Herpes simplex virus-2 Varicella zoster virus Cytomegalovirus Human herpesviruses-6 and -7 Epstein Barr virus RNA viruses Flaviviruses West Nile virus Japanese encephalitis virus St. Louis encephalitis virus Dengue virus Orthomyxoviruses Influenza A virus Paramyxoviruses Measles virus Mumps virus Picornaviruses Coxsackieviruses A and B Echoviruses Enterovirus-70 and -71 Hepatitis A virus Polioviruses-1, -2, and -3

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affecting the legs more than arms, sometimes progressing to involve the respiratory musculature. Studies documenting the CSF findings in paralytic poliomyelitis were mainly published before 1960. In most, patients were defined as having a normal CSF WBC if the total cell count was below 10/mm3. Using this cutoff value, 10–20% of patients had a normal CSF WBC count, while the remaining 80–90% had a mononuclear cell pleocytosis of up to 220 WBC/mm3.125 Some 40–75% of patients had an elevated CSF protein content, ranging as high as 164 mg/dl.125 It is not surprising, then, that several case series have reported on poliomyelitis patients being misdiagnosed as having the Guillain-Barré syndrome based on a clinical presentation of ascending weakness and the presence of CSF cytoalbuminological dissociation.126 For many years, confirming a diagnosis of poliomyelitis relied on cell culture methods. The virus could often be isolated from CSF, but was more consistently found in fecal specimens. An antibody capture assay performed on CSF from patients with acute poliomyelitis yielded an 85% sensitivity in detecting virus-specific IgM antibodies.127 Now there are poliovirus-specific PCR primers, although most labs still detect these pathogens using pan-EV primers. There are no sensitivity or specificity data available to validate this technology in the setting of acute poliomyelitis. As of 1999, WNV has become the leading cause of paralysis via infection of anterior horn cells. Patients with WNV-induced acute flaccid paralysis typically present with lower extremity weakness, often (but not always) in the setting of meningeal or encephalitic symptoms. The CSF findings in these patients are variable. In one study, CSF WBC counts ranged between 0 and 2,600 cells/mm3, with an average of 229 cells/mm3.128 CSF protein levels ranged between 24–234 mg/dl, with an average concentration of 117 mg/dl.128 A specific diagnosis relies on the same serologic and nucleic acid studies discussed earlier for WNV meningitis.

Polyradiculitis Viral polyradiculitis is most commonly seen in HIV-infected patients, and CMV is by far the most common cause. Patients present with subacute leg weakness, saddle pain, and bowel and bladder dysfunction. The CSF findings in CMV polyradiculitis are unique when compared to other CNS viral infections in the HIV-positive population. Here, the average CSF WBC count is 651 cells/mm3 with an average PMN percent of 68%.129 This strong PMN predominance often erroneously points towards a bacterial process. Likewise, the average CSF protein has been reported to be 228 mg/dl, and the average CSF:serum glucose ratio is below 0.5.129 Definitive identification of CMV as a causative agent relies on PCR methodologies. Cultures are insensitive, and serologic studies are not helpful because most cases of CMV polyradiculitis are due to reactivated latent infections and thus antiviral IgM and IgG

already exist. The CSF PCR for CMV, on the other hand, has a reported sensitivity and specificity of 92% and 94%, respectively.130,131

CHRONIC VIRAL INFECTIONS Retroviruses are the main chronic viral infections of the CNS. This section will review the CSF findings associated with two of these disorders: human T-cell lymphotrophic virus-1 (HTLV-1) associated myelopathy (HAM, also known as tropical spastic paraparesis, TSP, or a combination thereof, HAM/TSP) and HIV infection.

Human T-cell lymphotrophic virus-1 HAM/TSP is characterized by a slowly progressive spastic paraparesis. Affected patients manifest lower extremity weakness, spasticity, hyperreflexia, and urinary dysfunction. Sensation and upper extremity strength are usually intact. One retrospective review of 213 patients documented a mean CSF cell count of 6.4 WBCs/mm3.132 In this cohort, only 10% of patients actually had a CSF pleocytosis (>5 WBCs/mm3). A separate study reviewed the CSF findings in 81 patients with HAM/TSP and noted a pleocytosis in 26% of cases and an elevated CSF protein in 42% of individuals.133 Patients with this disorder will often have positive oligoclonal bands (40–95%), and elevated myelin basic protein (60%), within the CSF.133,134 While textbooks and articles also refer to the presence of flower-like cells (lobulated lymphocytes) in the CSF, the documented incidence of this finding is strikingly small.135,136 A diagnosis of HAM/TSP is confirmed in a patient with the appropriate clinical presentation and a positive serum viral titer. The CSF can be screened for the presence of virus by nucleic acid detection strategies, and antibodies can also be quantified in this compartment. While over 95% of patients will have a positive anti-HTLV-1 ELISA in the CSF, only 83% will have evidence of intrathecal antibody synthesis (an elevated CSF:serum antiviral AI).133 Identification of proviral DNA via PCR is useful in confirming a diagnosis of HAM/TSP. Puccioni-Sohler et al. reported a sensitivity of 93% and a specificity of 85% in the CSF for this disorder.133 A smaller study identified a higher virus copy number in the CSF compared to the serum,137 and an increased CSF viral load over time has been correlated with clinical progression.138 Small, uncontrolled studies have identified potential CSF markers of disease progression, including elevated ferritin and S100-beta.139 Another unique feature about the CSF from patients with HAM/TSP is the intrathecal accumulation of a subset of lymphocytes. Various studies have implicated CD8+ T cells that are activated against the HTLV-1 protein, Tax, in the pathogenesis of HAM/TSP, and indeed, the number of these cells within the CSF increases over time.140,141 While not routinely studied during the

References

Table 21-5

185

CSF Profiles Associated With Common Neurological Manifestations of HIV Infection

Stage of disease

Patents w. pleocytosis (%)

WBC count, range (mean) (cells/mm3)

Acute seroconversion (meningitis) Chronic infection (asymptomatic) AIDS dementia complex

25–40

0–200 (87)

15–20

0–50 (15)

20–30

0–70 (22)

Vacuolar myelopathy

15–20

0–45 (14)

CSF viral load (log10 copies/ml)

Protein level

Glucose level

Normal to mildly elevated Normal to mildly elevated Normal to mildly elevated

Normal to mildly low

0–5

Normal

0–6

Normal

2–6*

Normal

0–4†

Normal to mildly elevated

* Level can correlate with dementia severity; the absence of detectable HIV RNA makes ADC unlikely. † No correlation with the presence or severity of myelopathic symptoms or findings.

diagnostic evaluation of a patient, this finding is important for our understanding of the pathogenesis of this disorder.

Human immunodeficiency virus While there are many CSF changes known to occur in the setting of opportunistic CNS infections in HIV-infected individuals (reviewed in Chapter 23), HIV itself can also cause neurological disease and altered CSF composition (Table 21-5). The two main clinical CNS syndromes mediated directly by HIV are dementia and vacuolar myelopathy (VM). Patients with the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC), described shortly after the first description of AIDS,142 experience declines in cognition, motor function, and behavior. Here, CSF findings include a pleocytosis in 20–30% of patients with mononuclear cell counts up to 70 WBCs/mm3, and elevated CSF protein levels in two-thirds of patients (range, 45–200 mg/dl).143 While several studies have reported increased anti-HIV antibody titers and high viral loads in the CSF of patients with ADC, this finding does not strictly correlate with the presence of dementia.144,145 There are data correlating CSF viral load with the severity of AIDS dementia, but in the era since the implementation of highly active antiretroviral therapy (HAART), reliable CSF markers for the response of ADC to treatment have not been identified.146,147 Regarding surrogate biomarkers for the development or progression of ADC, a number of CSF substances have been studied. While neurofilament light chain (NF-L) protein levels may correlate with the severity of the condition, a predictive marker with reasonable sensitivity or specificity has yet to be identified.148 One study found that 78% of patients with ADC had an elevated CSF NF-L level 2 years prior to the onset of symptoms, but this elevation was also seen in one-third of patients who did not develop dementia.149 Another group identified elevated levels of vitamin E and a specific triglyceride in the CSF of HIV patients at highest risk for dementia.150 These markers both presumably relate to the proposed oxidative stress pathogenesis model for the ADC.151,152

The characteristic pathology seen in HIV-associated VM is quite common at autopsy, ranging between 15 and 55% of unselected cases.153,154 Clinically, however, prevalence of the disease is much lower. Routine CSF analysis in VM patients usually reveals a mild lymphocytic pleocytosis and an elevated CSF protein content. Yet, unlike ADC, there does not seem to be any correlation with CSF viral load.155 Two studies have noted elevated CSF levels of TNF-α in patients with VM, in keeping with the hypothesis that neural degeneration in these disorders may occur as a result of local activation of microglial cells that harbor the virus.155,156

CONCLUSIONS Viral infections of the CNS pose unique challenges to clinicians. These syndromes can often have significant clinical overlap, and the identification of an underlying pathogen may or may not be possible. While the advent of nucleic acid detection systems holds significant promise for increasing diagnostic yields, its success so far has been limited to a few specific pathogens. Given the added overlap in CSF profiles between immune mediated and infectious entities, much work is needed to improve our diagnostic capabilities. Determining that a patient is suffering from a viral, bacterial, fungal, mycobacterial, or non-infectious process is the first step in determining appropriate care. Identification of specific viral agents within the CSF early in the course of an illness would be helpful for directing therapy and avoiding unnecessary tests.

REFERENCES 1. Khetsuriani N, Quiroz ES, Holman RC, Anderson LJ. Viral meningitisassociated hospitalizations in the United States, 1988–1999. Neuroepidemiology 2003;22:345–352. 2. Kupila L, Vuorinen T, Vainionpaa R, Hukkanen V, Marttila RJ, Kotilainen P. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology 2006;66:75–80. 3. Rotbart HA. Viral meningitis. Semin Neurol 2000;20:277–292.

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4. Negrini B, Kelleher KJ, Wald ER. Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics 2000;105:316–319. 5. Spanos A, Harrell FE Jr, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989;262:2700–2707. 6. Davies NW, Brown LJ, Gonde J, et al. Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections. J Neurol Neurosurg Psychiatry 2005;76:82–87. 7. Kleine TO, Zwerenz P, Zofel P, Shiratori K. New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF). Brain Res Bull 2003;61:287–297. 8. Lindquist L, Linne T, Hansson LO, Kalin M, Axelsson G. Value of cerebrospinal fluid analysis in the differential diagnosis of meningitis: a study in 710 patients with suspected central nervous system infection. Eur J Clin Microbiol Infect Dis 1988;7:374–380. 9. Bailey EM, Domenico P, Cunha BA. Bacterial or viral meningitis? Measuring lactate in CSF can help you know quickly. Postgrad Med 1990;88:217–223. 10. Ichiyama T, Maeba S, Suenaga N, Saito K, Matsubara T, Furukawa S. Analysis of cytokine levels in cerebrospinal fluid in mumps meningitis: comparison with echovirus type 30 meningitis. Cytokine 2005;30:243–247. 11. Dagan R, Jenista JA, Menegus MA. Association of clinical presentation, laboratory findings, and virus serotypes with the presence of meningitis in hospitalized infants with enterovirus infection. J Pediatr 1988;113:975–978. 12. Gorgievski-Hrisoho M, Schumacher JD, Vilimonovic N, Germann D, Matter L. Detection by PCR of enteroviruses in cerebrospinal fluid during a summer outbreak of aseptic meningitis in Switzerland. J Clin Microbiol 1998;36:2408–2412. 13. Miller SA, Wald ER, Bergman I, DeBiasio R. Enteroviral meningitis in January with marked cerebrospinal fluid pleocytosis. Pediatr Infect Dis 1986;5:706–707. 14. Mulford WS, Buller RS, Arens MQ, Storch GA. Correlation of cerebrospinal fluid (CSF) cell counts and elevated CSF protein levels with enterovirus reverse transcription-PCR results in pediatric and adult patients. J Clin Microbiol 2004;42:4199–4203. 15. Thivierge B, Delage G. Infections of the central nervous system caused by enterovirus: 223 cases seen at a pediatric hospital between 1973 and 1981. Can Med Assoc J 1982;127:1097–1102. 16. Sathish N, Scott JX, Shaji RV, et al. An outbreak of echovirus meningitis in children. Indian Pediatr 2004;41:384–388. 17. Carrol ED, Beadsworth MB, Jenkins N, et al. Clinical and diagnostic findings of an echovirus meningitis outbreak in the north west of England. Postgrad Med J 2006;82:60–64. 18. Bernit E, de Lamballerie X, Zandotti C, et al. Prospective investigation of a large outbreak of meningitis due to echovirus 30 during summer 2000 in Marseilles, France. Medicine (Baltimore) 2004;83:245–253. 19. Sawyer MH. Enterovirus infections: diagnosis and treatment. Curr Opin Pediatr 2001;13:65–69. 20. Guney C, Ozkaya E, Yapar M, Gumus I, Kubar A, Doganci L. Laboratory diagnosis of enteroviral infections of the central nervous system by using a nested RT-polymerase chain reaction (PCR) assay. Diagn Microbiol Infect Dis 2003;47:557–562. 21. Mohamed N, Elfaitouri A, Fohlman J, Friman G, Blomberg J. A sensitive and quantitative single-tube real-time reverse transcriptase-PCR for detection of enteroviral RNA. J Clin Virol 2004;30:150–156. 22. Romero JR. Reverse-transcription polymerase chain reaction detection of the enteroviruses. Arch Pathol Lab Med 1999;123:1161–1169. 23. Verstrepen WA, Bruynseels P, Mertens AH. Evaluation of a rapid realtime RT-PCR assay for detection of enterovirus RNA in cerebrospinal fluid specimens. J Clin Virol 2002;25 Suppl 1:S39–S43. 24. Archimbaud C, Mirand A, Chambon M, et al. Improved diagnosis on a daily basis of enterovirus meningitis using a one-step real-time RT-PCR assay. J Med Virol 2004;74:604–611. 25. Monpoeho S, Coste-Burel M, Costa-Mattioli M, et al. Application of a real-time polymerase chain reaction with internal positive control for

26. 27. 28. 29. 30. 31.

32. 33. 34.

35. 36. 37. 38. 39. 40.

41. 42.

43. 44. 45.

46.

detection and quantification of enterovirus in cerebrospinal fluid. Eur J Clin Microbiol Infect Dis 2002;21:532–536. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 1974;129:304–309. Perez-Velez CM, Anderson MS, Robinson CC, et al. Outbreak of neurologic enterovirus type 71 disease: a diagnostic challenge. Clin Infect Dis 2007;45:950–957. Kupila L, Vainionpaa R, Vuorinen T, Marttila RJ, Kotilainen P. Recurrent lymphocytic meningitis: the role of herpesviruses. Arch Neurol 2004;61:1553–1557. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s. Herpes 2004;11 Suppl 2:57A-64A. Bergstrom T, Vahlne A, Alestig K, Jeansson S, Forsgren M, Lycke E. Primary and recurrent herpes simplex virus type 2-induced meningitis. J Infect Dis 1990;162:322–330. Mommeja-Marin H, Lafaurie M, Scieux C, Galicier L, Oksenhendler E, Molina JM. Herpes simplex virus type 2 as a cause of severe meningitis in immunocompromised adults. Clin Infect Dis 2003;37: 1527–1533. Tedder DG, Ashley R, Tyler KL, Levin MJ. Herpes simplex virus infection as a cause of benign recurrent lymphocytic meningitis. Ann Intern Med 1994;121:334–338. Fujimoto H, Asaoka K, Imaizumi T, Ayabe M, Shoji H, Kaji M. Epstein-Barr virus infections of the central nervous system. Intern Med 2003;42:33–40. Leveque N, Galambrun C, Najioullah F, Bleyzac N, Pages MP, Bertrand Y. Two cases of varicella zoster virus meningitis found in pediatric patients after bone marrow transplantation despite valaciclovir prophylaxis and without skin lesions. J Med Virol 2006;78:514–516. Rafailidis PI, Kapaskelis A, Falagas ME. Cytomegalovirus meningitis in an immunocompetent patient. Med Sci Monit 2007;13:CS107–CS109. Davis LE, DeBiasi R, Goade DE, et al. West Nile virus neuroinvasive disease. Ann Neurol 2006;60:286–300. Tyler KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters BK. CSF findings in 250 patients with serologically confirmed West Nile virus meningitis and encephalitis. Neurology 2006;66:361–365. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003;290:511–515. Procop GW, Yen-Lieberman B, Prayson RA, Gordon SM. Mollaret-like cells in patients with West Nile virus infection. Emerg Infect Dis 2004;10:753–754. Lanciotti RS, Kerst AJ, Nasci RS, et al. Rapid detection of West Nile virus from human clinical specimens, field-collected mosquitoes, and avian samples by a TaqMan reverse transcriptase-PCR assay. J Clin Microbiol 2000;38:4066–4071. Roehrig JT, Nash D, Maldin B, et al. Persistence of virus-reactive serum immunoglobulin m antibody in confirmed West Nile virus encephalitis cases. Emerg Infect Dis 2003;9:376–379. Tardei G, Ruta S, Chitu V, Rossi C, Tsai TF, Cernescu C. Evaluation of immunoglobulin M (IgM) and IgG enzyme immunoassays in serologic diagnosis of West Nile Virus infection. J Clin Microbiol 2000;38: 2232–2239. Barton LL, Hyndman NJ. Lymphocytic choriomeningitis virus: reemerging central nervous system pathogen. Pediatrics 2000;105:E35. Chesney PJ, Katcher ML, Nelson DB, Horowitz SD. CSF eosinophilia and chronic lymphocytic choriomeningitis virus meningitis. J Pediatr 1979;94:750–752. Park JY, Peters CJ, Rollin PE, et al. Development of a reverse transcription-polymerase chain reaction assay for diagnosis of lymphocytic choriomeningitis virus infection and its use in a prospective surveillance study. J Med Virol 1997;51:107–114. Nagai T, Okafuji T, Miyazaki C, et al. A comparative study of the incidence of aseptic meningitis in symptomatic natural mumps patients and monovalent mumps vaccine recipients in Japan. Vaccine 2007;25:2742–2747.

References

47. Bjorvatn B, Skoldenberg B. [Meningitis in mumps and orchitis in Stockholm during 1955–1976 — an epidemiological background for a vaccination policy]. Lakartidningen 1978;75:2295–2298. 48. Waxman MA, Abrahamian FM, Talan DA, Moran GJ, Pinner R. Update on emerging infections from the Centers for Disease Control and Prevention. Multistate outbreak of mumps — United States, January 1–May 2, 2006. Ann Emerg Med 2006;48:332–336. 49. Kacprzak-Bergman I, Zaleska I, Jasonek J. Specific humoral immunity in mumps meningitis in children. Med Sci Monit 2001;7:977–981. 50. Cintado Bueno C, Aguilera Llovet MA, Menendez Ruiz M, Macias Mardones P, Gayoso Gomez F, Torronteras Santiago R. [Hypoglycorrhachia in mumps meningitis (author’s transl)]. An Esp Pediatr 1978;11:547–552. 51. Rodriguez-Vidigal F, Redondo L, Aguilar FJ, Vera A, Munoz-Sanz A. [Lymphocytic meningitis by mumps virus: epidemiologic, clinical, serologic and evolutive analysis of 28 cases]. Enferm Infect Microbiol Clin 1999;17:176–179. 52. Forsberg P, Fryden A, Link H, Orvell C. Viral IgM and IgG antibody synthesis within the central nervous system in mumps meningitis. Acta Neurol Scand 1986;73:372–380. 53. Uchida K, Shinohara M, Shimada S, et al. Rapid and sensitive detection of mumps virus RNA directly from clinical samples by real-time PCR. J Med Virol 2005;75:470–474. 54. Rantalaiho T, Farkkila M, Vaheri A, Koskiniemi M. Acute encephalitis from 1967 to 1991. J Neurol Sci 2001;184:169–177. 55. Whitley R, Lakeman AD, Nahmias A, Roizman B. DNA restrictionenzyme analysis of herpes simplex virus isolates obtained from patients with encephalitis. N Engl J Med 1982;307:1060–1072. 56. Solomon T. Recent advances in Japanese encephalitis. J Neurovirol 2003;9:274–283. 57. Koskiniemi M, Rantalaiho T, Piiparinen H, et al. Infections of the central nervous system of suspected viral origin: a collaborative study from Finland. J Neurovirol 2001;7:400–408. 58. Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis 2006;43:1565–1577. 59. Steiner I, Budka H, Chaudhuri A, et al. Viral encephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 2005;12:331–343. 60. Chan CW, Tam KM, To WK, Law TC, Kwan WK. Hypoglycorrhachia in herpes zoster associated encephalitis of an immunocompetent young male: an unusual presentation. J Neurol 2005;252:987–988. 61. White CB, Bass JW. Low CSF glucose and high protein levels in neonatal herpes simplex meningoencephalitis. J Pediatr 1986;109:911–913. 62. Wilfert CM. Low CSF sugar in mumps. N Engl J Med 1969;281:106. 63. Farinelli M, Camera M, Del Bono V, Fiorelli MA, Panavese C, Valguarnera F. [Hypoglycorrhachia as an early sign of central nervous system infection caused by HIV]. Medicina (Firenze) 1989;9:44–45. 64. Ratzan KR. Viral meningitis. Med Clin North Am 1985;69:399–413. 65. Avkan Oguz V, Yapar N, Sezak N, et al. [Two cases of herpes encephalitis with normal cerebrospinal fluid findings]. Mikrobiyol Bul 2006;40:93–98. 66. Razavi B, Razavi M. Herpes simplex encephalitis – an atypical case. Infection 2001;29:357–358. 67. Omland LH, Vestergaard BF, Wandall JH. Herpes simplex virus type 2 infections of the central nervous system: A retrospective study of 49 patients. Scand J Infect Dis 2008;40:59–62. 68. Rosler A, Pohl M, Braune HJ, Oertel WH, Gemsa D, Sprenger H. Time course of chemokines in the cerebrospinal fluid and serum during herpes simplex type 1 encephalitis. J Neurol Sci 1998;157:82–89. 69. Toth C, Harder S, Yager J. Neonatal herpes encephalitis: a case series and review of clinical presentation. Can J Neurol Sci 2003;30:36–40. 70. Whitley RJ, Soong SJ, Linneman C Jr, Liu C, Pazin G, Alford CA. Herpes simplex encephalitis. Clinical Assessment. JAMA 1982;247:317–320. 71. Kamei S, Takasu T, Otani S, Mochizuki Y. [Cerebrospinal fluid findings in 108 Japanese cases of herpes simplex encephalitis]. Rinsho Shinkeigaku 1989;29:131–137.

187

72. Lanska DJ. Anthrax meningoencephalitis. Neurology 2002;59: 327–334. 73. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 1991;37:1153–1160. 74. Jacobi C, Lange P, Reiber H. Quantification of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response. J Neuroimmunol 2007;187:139–146. 75. Monteyne P, Albert F, Weissbrich B, et al. The detection of intrathecal synthesis of anti-herpes simplex IgG antibodies: comparison between an antigen-mediated immunoblotting technique and antibody index calculations. European Union Concerted Action on Virus Meningitis and Encephalitis. J Med Virol 1997;53:324–331. 76. Denne C, Kleines M, Dieckhofer A, et al. Intrathecal synthesis of anti-viral antibodies in pediatric patients. Eur J Paediatr Neurol 2007;11:29–34. 77. Schultze D, Weder B, Cassinotti P, Vitek L, Krausse K, Fierz W. Diagnostic significance of intrathecally produced herpes simplex and varizella-zoster virus-specific antibodies in central nervous system infections. Swiss Med Wkly 2004;134:700–704. 78. Ceroni M, Camana C, Franciotta DM, et al. Specific activation of B-cell clones within the central nervous system in course of herpes simplex encephalitis. Boll Soc Ital Biol Sper 1990;66:1223–1230. 79. Monteyne P, Laterre EC, Sindic CJ. Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2: determination by polymerase chain reaction and detection of intrathecal virus-specific oligoclonal antibodies. Acta Neurol Belg 1997;97:233–239. 80. Tang JW, Coward LJ, Davies NW, et al. Brain stem encephalitis caused by primary herpes simplex 2 infection in a young woman. J Neurol Neurosurg Psychiatry 2003;74:1323–1325. 81. Chaudhuri A, Kennedy PG. Diagnosis and treatment of viral encephalitis. Postgrad Med J 2002;78:575–583. 82. 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. 83. Debiasi RL, Tyler KL. Molecular methods for diagnosis of viral encephalitis. Clin Microbiol Rev 2004;17:903–925. 84. Kimberlin D. Herpes simplex virus, meningitis and encephalitis in neonates. Herpes 2004;11 Suppl 2:65A-76A. 85. Bouquillon C, Dewilde A, Andreoletti L, et al. Simultaneous detection of 6 human herpesviruses in cerebrospinal fluid and aqueous fluid by a single PCR using stair primers. J Med Virol 2000;62: 349–353. 86. Calvario A, Bozzi A, Scarasciulli M, et al. Herpes Consensus PCR test: a useful diagnostic approach to the screening of viral diseases of the central nervous system. J Clin Virol 2002;25 Suppl 1:S71–S78. 87. Minjolle S, Michelet C, Jusselin I, Joannes M, Cartier F, Colimon R. Amplification of the six major human herpesviruses from cerebrospinal fluid by a single PCR. J Clin Microbiol 1999;37:950–953. 88. Casas I, Klapper PE, Cleator GM, Echevarria JE, Tenorio A, Echevarria JM. Two different PCR assays to detect enteroviral RNA in CSF samples from patients with acute aseptic meningitis. J Med Virol 1995;47:378–385. 89. Casas I, Tenorio A, de Ory F, Lozano A, Echevarria JM. Detection of both herpes simplex and varicella-zoster viruses in cerebrospinal fluid from patients with encephalitis. J Med Virol 1996;50:82–92. 90. Casas I, Tenorio A, Echevarria JM, Klapper PE, Cleator GM. Detection of enteroviral RNA and specific DNA of herpesviruses by multiplex genome amplification. J Virol Methods 1997;66:39–50. 91. Skoldenberg B. Herpes simplex encephalitis. Scand J Infect Dis Suppl 1996;100:8–13. 92. Cinque P, Cleator GM, Weber T, Monteyne P, Sindic CJ, van Loon AM. The role of laboratory investigation in the diagnosis and management

188

93.

94. 95. 96. 97. 98. 99.

100. 101. 102.

103.

104. 105.

106.

107.

108.

109. 110. 111.

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of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry 1996;61:339–345. Cinque P, Vago L, Marenzi R, et al. Herpes simplex virus infections of the central nervous system in human immunodeficiency virus-infected patients: clinical management by polymerase chain reaction assay of cerebrospinal fluid. Clin Infect Dis 1998;27:303–309. De Tiege X, Rozenberg F, Des Portes V, et al. Herpes simplex encephalitis relapses in children: differentiation of two neurologic entities. Neurology 2003;61:241–243. Ito Y, Kimura H, Yabuta Y, et al. Exacerbation of herpes simplex encephalitis after successful treatment with acyclovir. Clin Infect Dis 2000;30:185–187. Gilden D. Varicella zoster virus and central nervous system syndromes. Herpes 2004;11 Suppl 2:89A-94A. Koskiniemi M, Piiparinen H, Rantalaiho T, et al. Acute central nervous system complications in varicella zoster virus infections. J Clin Virol 2002;25:293–301. Johnson R, Milbourn PE. Central nervous system manifestations of chickenpox. Can Med Assoc J 1970;102:831–834. Jemsek J, Greenberg SB, Taber L, Harvey D, Gershon A, Couch RB. Herpes zoster-associated encephalitis: clinicopathologic report of 12 cases and review of the literature. Medicine (Baltimore) 1983; 62:81–97. Pujadas R, Fernandez-Monras F, Sort MD, Jane J. [Hypoglycorrhachia in varicella zoster meningoencephalitis]. Med Clin (Barc) 1987;88:432–433. Brown M, Scarborough M, Brink N, Manji H, Miller R. Varicella zoster virus-associated neurological disease in HIV-infected patients. Int J STD AIDS 2001;12:79–83. Burgoon MP, Hammack BN, Owens GP, Maybach AL, Eikelenboom MJ, Gilden DH. Oligoclonal immunoglobulins in cerebrospinal fluid during varicella zoster virus (VZV) vasculopathy are directed against VZV. Ann Neurol 2003;54:459–463. Gregoire SM, van Pesch V, Goffette S, Peeters A, Sindic CJ. Polymerase chain reaction analysis and oligoclonal antibody in the cerebrospinal fluid from 34 patients with varicella-zoster virus infection of the nervous system. J Neurol Neurosurg Psychiatry 2006;77:938–942. Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology 2007;68:1069–1073. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz C. Detection of varicella-zoster virus DNA by polymerase chain reaction in the cerebrospinal fluid of patients suffering from neurological complications associated with chicken pox or herpes zoster. J Clin Microbiol 1991;29:1513–1516. Li A, Chen Z, Liu Q. [Detection of enterovirus RNA in cerebrospinal fluid from patients with aseptic meningitis and encephalitis and its clinical significance]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2001;15:371–373. Yang XH, Yan YS, He AH, Chen QJ, Zhang YH. [Molecular identification and genetic analysis of an echovirus 19-associated epidemic of aseptic encephalitis]. Zhonghua Liu Xing Bing Xue Za Zhi 2006;27:375–378. Wang SM, Lei HY, Su LY, et al. Cerebrospinal fluid cytokines in enterovirus 71 brain stem encephalitis and echovirus meningitis infections of varying severity. Clin Microbiol Infect 2007;13: 677–682. McKinney RE, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987;9:334–356. Misbah SA, Spickett GP, Ryba PC, et al. Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol 1992;12:266–270. Padate BP, Keidan J. Enteroviral meningoencephalitis in a patient with non-Hodgkin’s lymphoma treated previously with rituximab. Clin Lab Haematol 2006;28:69–71.

112. Hemachudha T, Laothamatas J, Rupprecht CE. Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 2002;1:101–109. 113. Rupprecht CE, Hanlon CA, Hemachudha T. Rabies re-examined. Lancet Infect Dis 2002;2:327–343. 114. Vasanth JP, Madhusudana SN, Abhilash KV, Suja MS, Muhamuda K. Development and evaluation of an enzyme immunoassay for rapid diagnosis of rabies in humans and animals. Indian J Pathol Microbiol 2004;47:574–578. 115. Muhamuda K, Madhusudana SN, Ravi V, Desai A. Presence of rabies specific immune complexes in cerebro-spinal fluid can help in ante-mortem diagnosis of human paralytic rabies. J Clin Virol 2006;37:162–167. 116. Wacharapluesadee S, Hemachudha T. Nucleic-acid sequence based amplification in the rapid diagnosis of rabies. Lancet 2001;358: 892–893. 117. Krishnan C, Kaplin AI, Deshpande DM, Pardo CA, Kerr DA. Transverse myelitis: pathogenesis, diagnosis and treatment. Front Biosci 2004;9: 1483–1499. 118. Junker AK, Roland EH, Hahn G. Transverse myelitis and Epstein-Barr virus infection with delayed antibody responses. Neurology 1991;41:1523–1524. 119. Iwamasa T, Yoshitake H, Sakuda H, et al. Acute ascending necrotizing myelitis in Okinawa caused by herpes simplex virus type 2. Virchows Arch A Pathol Anat Histopathol 1991;418:71–75. 120. Grant AD, Fox JD, Brink NS, Miller RF. Detection of varicella-zoster virus DNA using the polymerase chain reaction in an immunocompromised patient with transverse myelitis secondary to herpes zoster. Genitourin Med 1993;69:273–275. 121. Folpe A, Lapham LW, Smith HC. Herpes simplex myelitis as a cause of acute necrotizing myelitis syndrome. Neurology 1994;44:1955–1957. 122. Jadoul C, Van Goethem J, Martin JJ. Myelitis due to coxsackievirus B infection. Neurology 1995;45:1626–1627. 123. Marriage SC, Booy R, Hermione Lyall EG, et al. Cytomegalovirus myelitis in a child infected with human immunodeficiency virus type 1. Pediatr Infect Dis J 1996;15:549–551. 124. De Jesus NH. Epidemics to eradication: the modern history of poliomyelitis. Virol J 2007;4:70–82. 125. Witte JJ, Henderson DA. The cerebrospinal fluid in type 3 poliomyelitis. Am J Epidemiol 1966;83:189–195. 126. Yohannan MD, Ramia S, al Frayh AR. Acute paralytic poliomyelitis presenting as Guillain-Barré syndrome. J Infect 1991;22: 129–133. 127. Roivainen M, Agboatwalla M, Stenvik M, Rysa T, Akram DS, Hovi T. Intrathecal immune response and virus-specific immunoglobulin M antibodies in laboratory diagnosis of acute poliomyelitis. J Clin Microbiol 1993;31:2427–2432. 128. Saad M, Youssef S, Kirschke D, et al. Acute flaccid paralysis: the spectrum of a newly recognized complication of West Nile virus infection. J Infect 2005;51:120–127. 129. Anders HJ, Goebel FD. Cytomegalovirus polyradiculopathy in patients with AIDS. Clin Infect Dis 1998;27:345–352. 130. Gozlan J, el Amrani M, Baudrimont M, et al. A prospective evaluation of clinical criteria and polymerase chain reaction assay of cerebrospinal fluid for the diagnosis of cytomegalovirus-related neurological diseases during AIDS. AIDS 1995;9:253–260. 131. Arribas JR, Clifford DB, Fichtenbaum CJ, Commins DL, Powderly WG, Storch GA. Level of cytomegalovirus (CMV) DNA in cerebrospinal fluid of subjects with AIDS and CMV infection of the central nervous system. J Infect Dis 1995;172:527–531. 132. Nakagawa M, Izumo S, Ijichi S, et al. HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings. J Neurovirol 1995;1:50–61. 133. Puccioni-Sohler M, Rios M, Carvalho SM, et al. Diagnosis of HAM/TSP based on CSF proviral HTLV-I DNA and HTLV-I antibody index. Neurology 2001;57:725–727.

References

134. Ohta M, Ohta K, Nishimura M, Saida T. Detection of myelin basic protein in cerebrospinal fluid and serum from patients with HTLV-1associated myelopathy/tropical spastic paraparesis. Ann Clin Biochem 2002;39:603–615. 135. Osame M, Matsumoto M, Usuku K, et al. Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells. Ann Neurol 1987;21:117–122. 136. Ijichi S, Ijichi N, Yamano Y, Hall WW, Osame M. Reflux of HTLV-I infected lymphocytes from the privileged compartment(s) to peripheral blood flow in patients with HTLV-I-associated myelopathy. J Mol Med 1998;76:117–125. 137. Lezin A, Olindo S, Oliere S, et al. Human T lymphotropic virus type I (HTLV-I) proviral load in cerebrospinal fluid: a new criterion for the diagnosis of HTLV-I-associated myelopathy/tropical spastic paraparesis? J Infect Dis 2005;191:1830–1834. 138. Takenouchi N, Yamano Y, Usuku K, Osame M, Izumo S. Usefulness of proviral load measurement for monitoring of disease activity in individual patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. J Neurovirol 2003; 9:29–35. 139. Regner A, Bianchini O, Jardim C, Menna-Barreto M. HTLV-I-associated myelopathy: are ferritin, S100beta protein, or guanine nucleotides CSF markers of disease? J Neurovirol 2002;8:64–67. 140. Greten TF, Slansky JE, Kubota R, et al. Direct visualization of antigenspecific T cells: HTLV-1 Tax11–19- specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc Natl Acad Sci USA 1998;95:7568–7573. 141. Kubota R, Nagai M, Kawanishi T, Osame M, Jacobson S. Increased HTLV type 1 tax specific CD8+ cells in HTLV type 1-asociated myelopathy/tropical spastic paraparesis: correlation with HTLV type 1 proviral load. AIDS Res Hum Retroviruses 2000;16:1705–1709. 142. Snider WD, Simpson DM, Nielsen S, Gold JW, Metroka CE, Posner JB. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 1983;14:403–418. 143. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Ann Neurol 1986;19:517–524. 144. Arendt G, Nolting T, Frisch C, et al. Intrathecal viral replication and cerebral deficits in different stages of human immunodeficiency virus disease. J Neurovirol 2007;13:225–232.

189

145. Trujillo JR, Navia BA, Worth J, et al. High levels of anti-HIV-1 envelope antibodies in cerebrospinal fluid as compared to serum from patients with AIDS dementia complex. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12:19–25. 146. McArthur JC, McClernon DR, Cronin MF, et al. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 1997;42:689–698. 147. Brew BJ, Pemberton L, Cunningham P, Law MG. Levels of human immunodeficiency virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage. J Infect Dis 1997;175:963–966. 148. Abdulle S, Mellgren A, Brew BJ, et al. CSF neurofilament protein (NFL) — a marker of active HIV-related neurodegeneration. J Neurol 2007; 254:1026–1032. 149. Gisslen M, Hagberg L, Brew BJ, Cinque P, Price RW, Rosengren L. Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis 2007;195:1774–1778. 150. Bandaru VV, McArthur JC, Sacktor N, et al. Associative and predictive biomarkers of dementia in HIV-1-infected patients. Neurology 2007; 68:1481–1487. 151. Steiner J, Haughey N, Li W, et al. Oxidative stress and therapeutic approaches in HIV dementia. Antioxid Redox Signal 2006;8: 2089–2100. 152. Opii WO, Sultana R, Abdul HM, Ansari MA, Nath A, Butterfield DA. Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2’,3’-dideoxycytidine (ddC): relevance to HIV-dementia. Exp Neurol 2007;204:29–38. 153. Dal Pan GJ, Glass JD, McArthur JC. Clinicopathologic correlations of HIV-1-associated vacuolar myelopathy: an autopsy-based case-control study. Neurology 1994;44:2159–2164. 154. Petito CK, Navia BA, Cho ES, Jordan BD, George DC, Price RW. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 1985;312:874–879. 155. Geraci A, Di Rocco A, Liu M, et al. AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid. Neurology 2000; 55:440–442. 156. Tan SV, Guiloff RJ, Henderson DC, Gazzard BG, Miller R. AIDSassociated vacuolar myelopathy and tumor necrosis factor-alpha (TNF alpha). J Neurol Sci 1996;138:134–144.

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22

Transmissible Spongiform Encephalopathies Benjamin M. Greenberg and Richard T. Johnson

INTRODUCTION Transmissible spongiform encephalopathies (TSEs) are a family of related disorders affecting both humans and animals, characterized by a relentlessly progressive and unique spongy degeneration of the brain that results in rapid neurological deterioration and death. Included in the spectrum of human TSEs are classic Creutzfeldt-Jakob disease (CJD), the newly identified variant form of CJD (vCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, fatal familial insomnia (FFI), and kuru. The worldwide incidence of CJD averages between 0.5 and 2.0 cases/million population/year.1–5 Some 85% of classic CJD cases occur sporadically, while the remaining 15% are familial disorders with an autosomal dominant mode of inheritance. CJD can also be spread unintentionally from human to human via cornea transplantation, dural grafting, or treatment with cadaveric human pituitary growth hormone.6–10 vCJD was first reported in Great Britain in 1996.11–13 Over 150 cases of this disorder have now been confirmed.14 The vCJD outbreak has been linked to human consumption of meat products containing bovine spongiform encephalopathy (BSE)-infected neural tissue.15

CLINICAL BACKGROUND Human TSEs have heterogeneous clinical presentations. Classic CJD typically presents later in life as a rapidly progressive dementia associated with myoclonus and ataxia. Magnetic resonance imaging (MRI) studies of the brain may reveal abnormal signal intensity in the basal ganglia and cerebral cortex on diffusion weighted imaging.16,17 The electroencephalogram (EEG) often reveals periodic sharp waves.18 vCJD has several notable differences from the classic form of sporadic CJD including a younger age of onset and a longer disease duration. Early clinical features

of vCJD also include psychiatric manifestations and prominent cerebellar ataxia.19 Diagnostic confirmation typically requires pathological confirmation of spongiform neuropathology along with the deposition of a protease-resistant form of the normal cellular prion protein (PrP).

CEREBROSPINAL FLUID FINDINGS IN HUMAN TSEs Routine analysis of cerebrospinal fluid (CSF) samples from patients with TSEs is usually normal in terms of cell count as well as total protein and glucose concentrations. Still, a variety of more specific CSF assays have been analyzed for their capacity to conclusively identify a spongiform brain pathology without the need for obtaining an actual tissue specimen. Published literature on routine and experimental CSF findings as they pertain to the human TSEs will be reviewed here.

Cell count The white blood cell (WBC) count in CSF samples from patients with confirmed CJD is almost always normal. In one review of specimens obtained from a cohort of patients being evaluated for dementia, the CSF profile of those patients with confirmed CJD was analyzed separately. While 76% of specimens (39 of 51) were completely normal (normal cell count and total protein level), 4% of samples (two of 51) had a mild pleocytosis.20 In these two cases, the CSF WBC counts were 14 cells/mm3 and 15 cells/mm3, respectively.20 The WBC differential was not provided.20 Our own experience suggests that a CSF pleocytosis is rare enough in CJD that its presence in a patient with a rapidly progressive dementia should prompt further screening for an alternative explanation.

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Total protein content Similar to the cellular profiles of CSF samples derived from patients with CJD, total protein content is also usually in the normal range. Previous studies suggest that only 20% of patients ultimately diagnosed with CJD can have even mildly elevated CSF protein levels.20,21 Among this subset of patients, protein elevations ranging between 50 and 100 mg/dl have been reported.

Glucose content To our knowledge, there are no published reports showing abnormal CSF glucose levels in any patient with a confirmed TSE.

Prion protein Several studies have attempted to identify mutant (i.e., protease-resistant) PrP in the CSF of patients with suspected CJD. This has been undertaken in an effort to develop an ante mortem, CSF-based diagnostic assay specific for human TSEs that would obviate the need for a brain biopsy. Unfortunately, such attempts have not yet generated practical tools with clinically useful sensitivities or specificities. One study undertaken by the United States National Prion Disease Surveillance Center analyzed the CSF from 18 patients with confirmed sporadic CJD, three patients with vCJD, and 12 patients initially suspected of having CJD but who ultimately were found to have other diseases. In this study, three different antibodies against PrP were used in immunoblot assays, and four PrP-specific antibodies were used in an enzyme-linked immunosorbent assay (ELISA) protocol.22 Disappointingly, no significant differences were found in the CSF PrP levels between CJD patients and controls.22 Thus, although finding protease-resistant PrP deposited in brain tissue is pathognomonic for a TSE, the same does not seem to apply to CSF specimens.

14-3-3 proteins The most widely studied surrogate markers for CJD measured in CSF have been the 14-3-3 proteins. These proteins are ubiquitous, highly conserved species with seven closely related isoforms that all are about 30 kilodaltons in size.23 The normal biological functions of these proteins within the central nervous system (CNS) are still a matter of some controversy. Five isoforms that are highly abundant in the brain have been found to bind to a variety of cytoplasmic proteins, suggesting a role as intracellular chaperones.23,24 The highest CNS expression of 14-3-3 occurs in neuronal synapses.25 Its link to CJD was first reported when investigators found this protein in CSF samples from patients with sporadic CJD using 2-dimensional protein electrophoresis.26 Since this original publication, a multitude of studies have retrospectively and prospectively examined

the sensitivity and specificity of various CSF-based 14-3-3 assays as a tool to identify CJD. Reported sensitivities range from 87% to 97%, and the specificities range from 87% to 100%.26–31 Still, elevated CSF levels of 14-3-3 proteins have been reported in patients with ischemic stroke, bacterial meningitis, transverse myelitis, viral encephalitis, hypoxic brain damage, intracerebral metastasis, and metabolic encephalopathy.32,33 The largest study published to date analyzed CSF 14-3-3 protein levels in European patients with suspected CJD as part of a multinational disease surveillance program. It included 1,826 samples from patients with confirmed TSEs and 1,108 disease-negative controls. Western blot analysis proved to have an 84.5% sensitivity for detecting TSEs (88.8% if cases were limited to sporadic CJD) as well as an 83.6% specificity.34 Still, the sensitivity and specificity of using elevated CSF 14-3-3 levels to diagnose CJD depends on the patient population being studied. When all patients with dementia are included in the study population, the usefulness of the assay diminishes.35 Even when its use is restricted to patients with dementia evolving over less than 1 year, there can be a significant false-positive rate.36 False-negative CSF 14-3-3 protein detection results have also been documented to occur in the setting of sporadic CJD. This false-negative rate appears to depend on disease duration. Thus, if screened early or very late in the course of sporadic CJD, the CSF 14-3-3 protein level may not be elevated.36 Given these findings, as well as elevated CSF levels of 14-3-3 protein in various other neurologic conditions, many now consider this assay to be a general marker of neuronal destruction and not a specific tool for the identification of CJD. In this light, CSF 14-3-3 protein is a poor screening test for TSEs. Even in the clinical context of a rapidly evolving dementia, care must be taken when using this assay as the sole means for diagnosing CJD. 14-3-3 assays in CSF are even less useful in screening for vCJD as compared to sporadic CJD; one study found increased CSF levels in only 77% of vCJD patients compared to 91% of sporadic CJD patients.31 In the largest study to date, only 40% of patients with confirmed vCJD had elevated CSF 14-3-3 protein levels.34 Among those patients with a genetically determined prion disease, usefulness of the CSF 14-3-3 assay seems to depend on the underlying mutation. In patients with the E200K PrP mutation, CSF 14-3-3 levels were elevated in 93% of cases.37,38 Conversely, in patients with FFI, 14-3-3 protein levels in CSF were not elevated.38 Interestingly, the E200K mutation produces a rapidly progressive phenotype that mimics sporadic CJD, while FFI has a more prolonged disease course. Hence, the rate of neuronal destruction in a given TSE seems to be a critical determinant of associated CSF 14-3-3 protein levels. In this light, regardless of the specific TSE suspected on clinical grounds, 14-3-3 protein assays in CSF have a more questionable role as the sole determinant of an accurate diagnosis and must be interpreted with caution.

References

Neuron-specific enolase Neuron-specific enolase (NSE) is one of five isomers of the glycolytic enzyme enolase. It is localized within central and peripheral neurons as well as in neuroendocrine cells, but not in glial cells. Like the 14-3-3 proteins, this enzyme can be released into the CSF when neurons are injured. Commercial immunoassays are available to measure NSE concentrations in both CSF and serum. NSE has been evaluated as a possible marker of a variety of medical conditions, including post-anoxic brain injury and certain malignancies.39–41 Several studies have examined the utility of measuring CSF NSE levels in the diagnosis of human TSEs. In one cohort of patients with autopsy-confirmed CJD, a CSF level of NSE greater than 35 ng/ml had a sensitivity of 80% and a specificity of 92% for the diagnosis when compared to patients with other dementing processes.20 In a second larger study, CSF NSE levels were measured in patients with suspected CJD. Using a cutoff of 25 ng/ml as the upper limit of normal, a sensitivity of 79.7% and a specificity of 91.5% was established.28 Finally, in the largest study to date, the sensitivity of a positive CSF NSE assay was 73% and the specificity was 95% for the diagnosis of sporadic CJD.34 However, this sensitivity dropped to 24% when vCJD cases were analyzed and was only 60% in the setting of familial CJD.34 Thus, the routine measurement of CSF NSE levels in screening for human TSEs is limited by its sensitivity. Given its greater specificity, however, the assay could be useful as a confirmatory test in the setting of a suspected sporadic CJD diagnosis.

S-100B protein S-100B is an acidic, calcium-binding protein that is abundant in glial cells, particularly astrocytes.42 Similar to NSE, S-100B has been evaluated as a marker of nervous system damage in a variety of conditions, including melanoma, nerve sheath tumors, traumatic brain injury, anoxic injury, and blood–brain barrier disruption.41,43–46 Three large studies have analyzed the usefulness of measuring CSF S-100B levels in establishing the diagnosis of sporadic CJD. In one study that used a cutoff value of 2.5 ng/ml, a sensitivity of 94.2% and a specificity of 85.4% was achieved.28 In a second study, a cutoff value of 8 ng/ml resulted in a sensitivity of 84.2% and a specificity of 90.6% for the diagnosis of CJD.42 In the third, and largest, study to date, investigators found a sensitivity of 82% for both sporadic and familial CJD and a sensitivity of 62% for vCJD.34 Various ELISA kits are commercially available for measuring S-100B concentrations in clinical samples. Given these sensitivities and specificities, however, the routine use of this marker to diagnose human TSEs cannot be advised.

states, however, the tau protein may undergo modification via phosphorylation that can result in its aggregation. These phosphorylated tau aggregates are toxic to neurons. This phosphorylation process occurs in a number of neurological disorders, the most common of which is Alzheimer’s disease, collectively known as the “tauopathies.” Two studies have examined the role of measuring tau levels in CSF in establishing a diagnosis of CJD. In one study, 40 patients with suspected CJD were separated into two groups, definite CJD (n=21) and “other dementing processes” (n=19), based on autopsy findings.47 Among the definite CJD patients, CSF tau levels ranged from 1,533 to 27,648 pg/ml.47 In contrast, patients with other dementing processes had CSF tau levels that ranged from 233 to 1,769 pg/ml.47 Using a cutoff value of 1,530 pg/ml, the sensitivity for diagnosing CJD was 100% and the specificity was 94.7%.47 A second larger study analyzed CSF from 297 patients with suspected CJD where ultimately 109 patients had pathologically confirmed CJD, 55 had probable CJD, 39 had possible CJD, eight had genetically mediated CJD, one had an iatrogenic TSE, and 85 had other dementing illnesses.48 In the subset of pathologically confirmed CJD cases, CSF tau levels ranged from 150 to 35,360 pg/ml. If a cutoff value of 1,300 pg/ml was applied, the sensitivity for a CJD diagnosis was 94% and the specificity proved to be 90%.48 The largest study to date using a 1,300 pg/ml cutoff calculated an 86% sensitivity for CSF tau in sporadic CJD, 82% sensitivity for hereditary CJD, and a 24% sensitivity for vCJD.34 The sensitivity of CSF tau in identifying vCJD increased to 86% if the cutoff value was lowered to 500 pg/ml.34 Thus, in the clinical setting of suspected CJD, a CSF tau level above 1,300 pg/ml would be supportive of the diagnosis, but could not rule out other conditions.

CONCLUSIONS Although routine CSF studies (cell count, protein and glucose concentrations) are usually normal in human TSEs, emerging data now suggest that certain neuronal and glial proteins can be found in the CSF at higher than expected levels in many patients with classic CJD. Although none of these markers has yet proven to be uniquely specific for CJD, their frequent detection strongly validates the approach of looking for disease-specific biomarkers in CSF samples. We fully expect that future studies will identify protein biomarkers with high enough sensitivities and specificities that will allow for the accurate and noninvasive diagnosis of human TSEs. REFERENCES 1.

Tau protein Tau is a protein that binds to and stabilizes neuronal microtubules under physiological conditions. In certain pathological

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2.

Brown P, Cathala F, Raubertas RF, Gajdusek DC, Castaigne P. The epidemiology of Creutzfeldt-Jakob disease: conclusion of a 15-year investigation in France and review of the world literature. Neurology 1987;37:895–904. Haltia M, Kovanen J, Goldfarb LG, Brown P, Gajdusek DC. Familial Creutzfeldt-Jakob disease in Finland: epidemiological, clinical,

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3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

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pathological and molecular genetic studies. Eur J Epidemiol 1991; 7:494–500. Knight R. Creutzfeldt-Jakob disease: clinical features, epidemiology and tests. Electrophoresis 1998;19:1306–1310. Mollenhauer B, Zerr I, Ruge D, et al. [Epidemiology and clinical symptomatology of Creutzfeldt-Jakob disease]. Dtsch Med Wochenschr 2002;127:312–317. Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 2000;47:575–582. Boutoleau C, Guillon B, Martinez F, Vercelletto M, Faure A, Feve JR. Iatrogenic Creutzfeldt-Jakob disease subsequent to dural graft: persisting risk after 1987. Eur J Neurol 2003;10:521–523. Hammersmith KM, Cohen EJ, Rapuano CJ, Laibson PR. CreutzfeldtJakob disease following corneal transplantation. Cornea 2004;23: 406–408. Mitrova E, Belay G. Creutzfeldt-Jakob disease risk in Slovak recipients of human pituitary growth hormone. Bratisl Lek Listy 1999;100:187–191. Sato T. [Infectious prion disease: CJD with dura mater transplantation]. Rinsho Shinkeigaku 2003;43:870–872. Shimizu S, Hoshi K, Muramoto T, et al. Creutzfeldt-Jakob disease with florid-type plaques after cadaveric dura mater grafting. Arch Neurol 1999;56:357–362. Gordon N. New variant Creutzfeldt-Jakob disease. Int J Clin Pract 1999;53:456–459. Horby P. Variant Creutzfeldt-Jakob disease: an unfolding epidemic of misfolded proteins. J Paediatr Child Health 2002;38:539–542. Irani DN. The classic and variant forms of Creutzfeldt-Jakob disease. Semin Clin Neuropsychiatry 2003;8:71–79. Beghi E, Gandolfo C, Ferrarese C, et al. Bovine spongiform encephalopathy and Creutzfeldt-Jakob disease: facts and uncertainties underlying the causal link between animal and human diseases. Neurol Sci 2004;25:122–129. Will R. Variant Creutzfeldt-Jakob disease. Folia Neuropathol 2004; 42(Suppl A):77–83. Shiga Y, Miyazawa K, Sato S, et al. Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease. Neurology 2004;63:443–449. Mendez OE, Shang J, Jungreis CA, Kaufer DI. Diffusion-weighted MRI in Creutzfeldt-Jakob disease: a better diagnostic marker than CSF protein 14-3-3? J Neuroimaging 2003;13:147–151. Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14–3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000;55:811–815. Will RG, Ward HJ. Clinical features of variant Creutzfeldt-Jakob disease. Curr Top Microbiol Immunol 2004;284:121–132. Zerr I, Bodemer M, Racker S, et al. Cerebrospinal fluid concentration of neuron-specific enolase in diagnosis of Creutzfeldt-Jakob disease. Lancet 1995;345:1609–1610. Brown P, Gibbs CJ Jr, Rodgers-Johnson P, et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994;35: 513–529. Wong BS, Green AJ, Li R, et al. Absence of protease-resistant prion protein in the cerebrospinal fluid of Creutzfeldt-Jakob disease. J Pathol 2001;194:9–14. Takahashi Y. The 14-3-3 proteins: gene, gene expression, and function. Neurochem Res 2003;28:1265–1273. Fu H, Subramanian RR, Masters SC. 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol 2000;40:617–647. Aitken A, Collinge DB, van Heusden BP, et al. 14-3-3 proteins: a highly conserved, widespread family of eukaryotic proteins. Trends Biochem Sci 1992;17:498–501. Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14–3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996;335:924–930. Lemstra AW, van Meegen MT, Vreyling JP, et al. 14-3-3 testing in diagnosing Creutzfeldt-Jakob disease: a prospective study in 112 patients. Neurology 2000;55:514–516.

28. Beaudry P, Cohen P, Brandel JP, et al. 14-3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord 1999;10:40–46. 29. Collins S, Boyd A, Fletcher A, et al. Creutzfeldt-Jakob disease: diagnostic utility of 14-3-3 protein immunodetection in cerebrospinal fluid. J Clin Neurosci 2000;7:203–208. 30. Green AJ. Use of 14-3-3 in the diagnosis of Creutzfeldt-Jakob disease. Biochem Soc Trans 2002;30:382–386. 31. Green AJ, Ramljak S, Muller WE, Knight RS, Schroder HC. 14-3-3 in the cerebrospinal fluid of patients with variant and sporadic CreutzfeldtJakob disease measured using capture assay able to detect low levels of 14–3-3 protein. Neurosci Lett 2002;324:57–60. 32. Zerr I, Bodemer M, Gefeller O, et al. Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 1998;43:32–40. 33. Bonora S, Zanusso G, Raiteri R, et al. Clearance of 14-3-3 protein from cerebrospinal fluid heralds the resolution of bacterial meningitis. Clin Infect Dis 2003;36:1492–1495. 34. Sanchez-Juan P, Green A, Ladogana A, et al. CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2006;67:637–643. 35. Satoh J, Kurohara K, Yukitake M, Kuroda Y. The 14-3-3 protein detectable in the cerebrospinal fluid of patients with prion-unrelated neurological diseases is expressed constitutively in neurons and glial cells in culture. Eur Neurol 1999;41:216–225. 36. Van Everbroeck B, Quoilin S, Boons J, Martin JJ, Cras P. A prospective study of CSF markers in 250 patients with possible Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2003;74:1210–1214. 37. Rosenmann H, Meiner Z, Kahana E, et al. Detection of 14-3-3 protein in the CSF of genetic Creutzfeldt-Jakob disease. Neurology 1997;49:593–595. 38. Collins S, Boyd A, Fletcher A, Gonzales MF, McLean CA, Masters CL. Recent advances in the pre-mortem diagnosis of Creutzfeldt-Jakob disease. J Clin Neurosci 2000;7:195–202. 39. Ghayumi SM, Mehrabi S, Doroudchi M, Ghaderi A. Diagnostic value of tumor markers for differentiating malignant and benign pleural effusions of Iranian patients. Pathol Oncol Res 2005;11: 236–241. 40. Schoerkhuber W, Kittler H, Sterz F, et al. Time course of serum neuronspecific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke 1999;30:1598–1603. 41. Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 2003;34:2881–2886. 42. Otto M, Stein H, Szudra A, et al. S-100 protein concentration in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurol 1997;244:566–570. 43. Ghanem G, Loir B, Morandini R, et al. On the release and half-life of S100B protein in the peripheral blood of melanoma patients. Int J Cancer 2001;94:586–590. 44. Ingebrigtsen T, Waterloo K, Jacobsen EA, Langbakk B, Romner B. Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. Neurosurgery 1999;45:468–475; discussion 475–466. 45. Marchi N, Rasmussen P, Kapural M, et al. Peripheral markers of brain damage and blood-brain barrier dysfunction. Restor Neurol Neurosci 2003;21:109–121. 46. Kanner AA, Marchi N, Fazio V, et al. Serum S100beta: a noninvasive marker of blood-brain barrier function and brain lesions. Cancer 2003;97:2806–2813. 47. Otto M, Wiltfang J, Tumani H, et al. Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 1997;225:210–212. 48. Otto M, Wiltfang J, Cepek L, et al. Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2002;58:192–197.

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Mycobacterial, Fungal, Spirochetal, and Parasitic Infections Anita Venkataramana and Justin C. McArthur

INTRODUCTION Careful study of the cerebrospinal fluid (CSF) is critical in the diagnosis of all central nervous system (CNS) infections. Although tuberculous, fungal, spirochetal, and parasitic infections involving the CNS remain relatively rare in the USA, they have become more prevalent in the wake of the acquired immunodeficiency syndrome (AIDS) epidemic and the expanded use of chronic immunosuppressive therapies. In developing countries, many of these infections also occur in otherwise immunocompetent individuals. CNS involvement by these pathogens is often the result of spread from an extracerebral site of infection, so a systemic approach to diagnosis is imperative. This chapter will review the CSF profiles associated with the most common mycobacterial, fungal, spirochetal, and parasitic infections of the CNS in both immunocompetent and immunocompromised individuals.

MYCOBACTERIAL INFECTIONS OF THE NERVOUS SYSTEM Tuberculous meningitis Tuberculosis (TB) is a global scourge responsible for some 2 million annual deaths worldwide. Its prevalence has been rising again in the wake of the AIDS epidemic, and the emergence of multi-drug-resistant strains has raised major public health concerns. Other hosts at risk for TB beyond AIDS patients include the elderly, immigrants from highrisk countries, those living in crowded or inner-city residential areas, alcohol and drug users, and patients requiring the prolonged use of corticosteroids and other immunosuppressive agents as a result of transplantation or autoimmune disease. Invasion of the subarachnoid space causing meningitis is by far the most common manifestation of TB involving the CNS, but focal infections that create space-occupying lesions of the brain and spinal cord are also observed.

Routine cerebrospinal fluid findings The development of chronic meningitis symptoms in endemic areas usually heralds tuberculous meningitis (TBM). Fewer than half of both children and adults with confirmed disease have a known history of prior TB infection. Routine CSF analysis should include tests to exclude other causes of chronic meningitis such as partially treated bacterial meningitis, as well as cryptococcal, cysticercal, and carcinomatous meningitis. Initial results show the expected elevated white blood cell (WBC) count, high protein content, and low glucose concentration. When a tube of spinal fluid is allowed to settle, a characteristic “cobweb” coagulum may form at the top of the specimen due to the high fibrinogen content in the sample.1 Acid-fast bacilli (AFB) may become entangled in this formation, and smears and cultures should incorporate this part of the sample if it is observed to occur.2 Opening pressure (OP) at the time of the initial lumbar puncture (LP) in patients with TBM is elevated in 40–70% of cases, usually in the range 20–40 cm H2O.7,13 It should be kept in mind that such readings are not a completely reliable means to assess the patency of the CSF recirculatory pathways; spinal block may result in lower OP readings even in the setting of obstructive hydrocephalus and elevated intracranial pressure (ICP).14 No study has convincingly shown that an elevated OP at the time of clinical presentation predicts a more adverse disease outcome, although some reports lean towards such an association.13 A moderate CSF pleocytosis is characteristic of TBM (Table 23-1). Most series report that 90–100% of patients with confirmed disease have more than 5 WBC/mm3 present in their initial samples, although some investigators have proposed that patients co-infected with human immunodeficiency virus (HIV) may be somewhat more likely to not have a pleocytosis.14 The total number of cells is rarely above 300 WBC/mm3, although reports of counts in excess of 8,000/mm3 exist (Table 23-1). The initial WBC differential usually reveals a mixture of polymorphonuclear and

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Table 23-1 Routine Cerebrospinal Fluid Findings in Case Series of Definite or Presumed Tuberculous Meningitis Number of Patients 18 19 16 19 45 20*

WBC (/mm3) Median (Range)

Protein (mg/dl) Median (Range)

283 (23–1030) 177 (8–900) 63 (9–520) 200 (0–960) 162 (0–8600) 212 (0–678)

206 (84–1340) 158 (51–1000) 190 (55–950) 159 (20–980) 151 (35–2900) 288 (121–1152)

Glucose (mg/dl) Median (Range)

Reference

18 (7–66) 45 (20–145) 40 (13–108) 40 (11–146) 35 (7–189) 34 (11–115)

3 4 5 6 7 8

*All HIV-seropositive patients.

mononuclear cells, but this profile transitions to a mononuclear cell predominance over the first few weeks of therapy. Plasma cells are found in the CSF later in infection, and a few cases have documented as many as 20% eosinophils present.14 Raised total protein content and depressed overall glucose levels are the norm in the CSF of patients with TBM (Table 23-1). Both findings tend to worsen slowly over time in untreated patients.14 Hypoglycorrhachia has been correlated with a more advanced stage of clinical disease, and CSF glucose levels tend to be somewhat lower in culturepositive cases compared to those diagnosed on clinical grounds.5,7 Total CSF protein levels are usually in the 150–200 mg/dl range, although levels above 1,000 mg/dl are occasionally observed in the setting of spinal block. Again, somewhat higher concentrations are found in culture-proven rather than clinically defined cases.5,7

Microbiology Direct smears of CSF identify AFB in 10–80% of cases, although most studies suggest that smear-positivity rates comprise some 25–30% of all culture-proven cases (Table 23-2). Techniques used to increase the yield of CSF smears include staining of the coagulum, when present, as well as centrifugation of large CSF volumes onto a single slide in order to stain a large aliquot at once. Repeated sampling is

Table 23-2 Frequency of Positive Cerebrospinal Fluid Acid-Fast Bacilli Smears in Patients with Culture-Proven Tuberculous Meningitis Number of CultureProven Cases 9 19 18 43 50 24†

Smear-Positive, Number (Percent) 2 (22%) 2 (11%) 3 (17%) 37 (86%)* 26 (52%) 7 (29%)

*Four separate CSF specimens examined per patient. †Children only.

Reference 4 6 7 9 10 11

also used in this regard; one study reported an 86% positive smear rate when up to four samples per patient were examined,9 but this high rate has never been duplicated by other investigators. Definitive proof of TBM requires the isolation of M. tuberculosis in CSF culture. This gold standard test, however, is not always the definitive benchmark one expects. Hence, many studies have shown that culturepositivity rates may not even exceed 50% among cohorts of patients (Table 23-3). Presumptive false-negative CSF cultures are common enough that many clinicians make a diagnosis of TBM based on a consistent clinical and CSF profile, evidence of TB elsewhere in the body, a positive purified protein derivative (PPD) skin test, and/or an obvious clinical response to empiric anti-mycobacterial therapy.14 Higher yields are again obtained with repeated CSF sampling, but fully 20% of these patients still have negative cultures.9 When combined with the required interval of at least several weeks before mycobacterial cultures can be formally identified as positive, clinicians are routinely required to make empiric judgments about therapy based on other clinical and laboratory parameters.

Adenosine deaminase activity Adenosine deaminase (ADA) converts adenosine (or deoxyadensine) into inosine (or deoxyinosine) and

Table 23-3 Frequency of Positive Cerebrospinal Fluid Cultures in Clinically Diagnosed Cases of Tuberculous Meningitis Number of Clinically Diagnosed Cases* 18 16 45 58 57† 237†

Culture-Confirmed, Number (Percent) 7 (39%) 4 (25%) 18 (40%) 50 (86%) 24 (42%) 84 (35%)

Reference 3 5 7 10 11 12

*Consistent clinical and CSF profile, evidence of TB elsewhere in the body, positive PPD, response to anti-mycobacterial therapy, and/or autopsy diagnosis. †Children only.

Fungal Infections of the Nervous System

ammonia via the actions of two main isoenzymes, ADA1 and ADA2.15 Its activity has been associated primarily with T lymphocytes in humans.15 Elevated pleural, pericardial, and peritoneal ADA levels have previously been associated with TB infection of these cavities,14 raising some hope that it could be a useful marker of TBM when assayed in the CSF. One study reported a sensitivity of 100% and specificity of 99% in identifying 21 patients with TBM,16 although others have had less successful results, with particular difficulty in distinguishing TBM from viral and bacterial meningitis.17,18 At best, it seems that CSF ADA level measurement is useful as an adjunct tool in the early diagnosis of TBM.

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in the CNS at the time of hematogenous dissemination from the site of primary infection. A small tubercle forms as the cell-mediated immune response develops, but, instead of rupturing into the subarachnoid space causing a basilar meningitis, lesions continue to grow and wall themselves off from the brain parenchyma via a dense fibrous capsule. The lesions then present clinically as single or multiple intracranial mass lesions, often causing seizures, focal deficits, and elevated ICP. In this setting, CSF analysis may be contraindicated due to the risk of causing a pressure gradient and compartment shift. However, older studies suggest that the fluid, when assayed, may show an elevated total protein concentration but otherwise be unremarkable.31

Polymerase chain reaction Polymerase chain reaction (PCR) is an increasingly reliable test for the rapid diagnosis of TBM.19–21 Various studies report sensitivities above 85% in high-probability cases.22,23 A nested PCR test is useful to maximize sensitivity when the volume of CSF submitted for microbiological analysis is low,24 giving rapid results with 90% sensitivity and 100% specificity in one cohort of 100 samples.25 This test was found to be consistently negative in all non-TB patients.24,25 A semi-automated method for detecting M. tuberculosis sequences is now available in a standardized commercial kit. While originally designed to test respiratory specimens, subsequent studies on CSF samples showed a sensitivity and specificity of 60% and 100%, respectively.26 Application of PCR-based detection methodologies on CSF samples from patients co-infected with HIV showed high sensitivity and specificity, and furthermore the test turned consistently negative in patients who were responding to therapy, but remained positive in patients who succumbed to disseminated TB.27 This suggests that PCR assays on CSF may become useful in monitoring treatment responsiveness.

Proinflammatory cytokines Inflammatory mediators including cytokines, chemokines, and matrix metalloproteinases (MMP) are found at high levels in the CSF during TBM.28–30 While concentrations of many of these factors fall over the course of disease following treatment, others remain elevated for many months after therapy is completed.28,29 Levels of cytokines and chemokines have not been correlated with response to therapy, but higher CSF levels of MMP-2 and MMP-9 are both associated with the development of late neurological complications (cranial nerve palsies, spinal arachnoiditis, hydrocephalus) compared to TBM patients without these associated laboratory findings.30

Tuberculomas TB infection of the CNS can sometimes take the form of focal abscesses instead of overt meningitis. The pathogenesis of these infections is similar to TBM; organisms lodge

FUNGAL INFECTIONS OF THE NERVOUS SYSTEM Cryptococcal meningitis Cryptococcus neoformans is an encapsulated yeast that most commonly causes clinical disease among patients with AIDS. Cryptococcal meningitis (CM) also occurs in HIV-seronegative individuals with reticuloendothelial malignancies or lymphoproliferative disorders, in patients on chronic immunosuppressive therapy, and in the setting of sarcoidosis.32,33 Its invasion of the CNS is associated with considerable morbidity and mortality, often due to its propensity to cause elevated ICP. Indeed, CM patients may require frequent LPs to reduce ICP and alleviate the effects of brain swelling. A complete CSF analysis is imperative in suspected CM, both to identify the fungus and to exclude other opportunistic infections.

Routine cerebrospinal fluid findings Various studies suggest that the CSF WBC count in CM can range from 0 to 3,700 cells/mm3 (Table 23-4). Levels tend to be significantly lower in HIV-seropositive individuals, where up to 50% of patients with proven CM can actually have normal CSF WBC counts at the time of diagnosis.36 Differential counts show a preponderance of lymphocytes, and total protein levels are usually elevated while CSF glucose concentrations can either be normal or depressed.37 An India ink examination of the CSF shows yeast forms in 70–90% of untreated AIDS patients with CM due to higher pathogen loads, but may be positive in only 50% of the non-AIDS population (Table 23-5).37

Serology and antigen detection Antibodies against C. neoformans are not useful in the diagnosis of CM. Conversely, immunological detection of cryptococcal polysaccharide antigen in serum and CSF by rapid latex agglutination tests or enzyme immunoassays has a sensitivity in excess of 90% and, at titers above 1:4 dilutions, a high specificity for the disorder (Table 23-5). In asymptomatic HIV-infected patients, serum antigenemia identifies early cryptococcal disease and mandates both

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Table 23-4 Meningitis

Routine Cerebrospinal Fluid Findings in both AIDS- and Non-AIDS-Associated Cryptococcal

OP (cm H2O)

WBC count (cells/mm3)

Glucose (mg/dl)

Protein (mg/dl)

NA 36 (9−60) NA NA NA NA

11 (0−45) 8 (0−3700) 22 NR 47 (11−542)* 10 (0−181)

40.7 43 (2−81) 50.4 NR 37 (12−67)* 41 (18−81)

85.1 45.6 42.7 NR 92 (39−211)* 101 (37−239)

India Ink (% positive) 87.5 NA 25.5 82.5 62.5* 72

Antigen titer 1:100−1:10,000 NA 1:16−1:64 1:0−1:524,288 1:1−1:1024* 1:16−1:2048

Culture (% positive)

Reference

60 67 82 NR 100* 100

34 35 39 41 45 46

OP, WBC count, glucose, and protein values presented are median (range), where available. NA, not assessed; NR, not reported. *Immunocompetent patients.

a CSF examination and antifungal treatment.38 CSF antigen titers above 1:1,024 correlate with a high organism burden by quantitative culture methods and are a marker of poor prognosis. These titers often fall in the setting of successful antifungal therapy, but serial measurements are generally felt to be of little clinical value in the management of individual patients due to variability in the rate of response.39 There are reports of occasional false negative cryptococcal antigen detection assays, particularly among non-HIV-associated patients, making the diagnosis hard to exclude in certain settings.40

Cultures Cryptococcus neoformans isolated from blood or CSF produces white mucoid colonies on many types of culture media, often within 72 h after plating. While the pathogen can grow at 37°C, culture temperatures of 30–35°C are optimal.37 Specific identification is then based on biochemical tests such as urease production, or via DNA-based methodologies. Serotyping by means of specific monoclonal antibodies can distinguish among the five isolates, although such distinctions have little clinical utility. Despite the relative ease of culture, positive fungal growth is reported in only 60–80% of clinically suspected cases (Tables 23-4 and 23-5).

Response to Therapy Pathogen clearance from the CSF is the gold standard readout of treatment response in CM. Therapy with amphotericin B alone (0.7 mg/kg/day) has been shown to sterilize CSF fungal cultures at rates of 51% after 2 weeks.41 Nephrotoxicity may be problematic for some patients, and a formulation where amphotericin B is incorporated into liposomes allows for the delivery of much larger doses (4 mg/kg/day) with reduced renal complications.42 In a small study of AIDS-associated CM, this lipid formulation resulted in significantly earlier CSF culture conversion than conventionally administered therapy.42 Other studies in both HIV and non-HIV populations have shown that treatment with amphotericin B (0.7 mg/kg/day) in combination with flucytosine (100 mg/kg/day) is associated with CSF sterilization at 2 weeks in 60–90% of individuals.41,43 Additional investigation of culture methodologies have shown that CSF cryptococcal colony-forming units (CFU) can be measured in a semi-quantitative manner, thus allowing for more accurate assessment of fungicidal activity of drug regimens.43 It is also clear from these studies that initial CSF CFU count is an important predictor of outcome.43 Other determinants of survival include CSF opening pressure of more than 60 cm H2O, and an initial Glasgow Coma Scale (GCS) score of less than 13.35

Table 23-5 Cerebrospinal Fluid Microbiology and Pathogen-Specific Immunodiagnostics in Common Forms of Fungal Meningitis Organism Cryptococcus neoformans Candida sp. Coccidioides immitis Histoplasma capsulatum Blastomyces dermatitidis Aspergillus sp.

Positive Smear (%) 75−90% (AIDS); 30–50% (non-AIDS) 40% 5−10% <5% <5% <5%

Positive Culture (%)

Pathogen-Specific Diagnosis in CSF

Best Sensitivity

Adjunctive Tests

References

60−80%

Antigen

98−100%

Serum antigen

36−39,45,48

50% 25−35% 50% 10−20% 20−30%

Antibody, antigen, (PCR) Antibody Antibody, antigen Antibody Antigen, antibody, PCR

50% 80−100% >90% Unknown 75−80%

Blood culture Serum antibody Urine antigen None Serum Antigen

48−54,80 48,55−60 61–66 67−70 71−80

Fungal Infections of the Nervous System

The prognostic value of cryptococcal antigen titers in both serum and CSF was reviewed in a pooled analysis from two prospective clinical trials in AIDS-related CM. No correlation with eventual outcome was found using serum cryptococcal antigen titers in the acute phase of illness, but CSF antigen titers did decrease in most individuals who responded to therapy.39 Sustained CSF antigen titers can identify those individuals who may be likely to relapse, and, as mentioned, higher initial CSF titers have been associated with higher mortality.39 This value should therefore be monitored to help guide treatment response. Still, CSF culture conversion remains the primary means of assessing treatment response.

Adjunctive tests Vascular endothelial growth factor (VEGF) is an important determinant of blood–brain barrier (BBB) permeability, and it has been shown to contribute to the pathogenesis of a variety of CNS disorders associated with vascular disruption and cerebral edema. VEGF can be produced by macrophages, neutrophils, lymphocytes, and smooth muscle cells in response to a variety of inflammatory stimuli, including cryptococcal antigens.44 One study showed that VEGF levels were elevated in 41 of 95 (43%) CSF samples from patients with CM (range, <20–160 pg/ml), but in none of 27 CSF specimens from healthy control patients undergoing spinal anesthesia for various surgical procedures.44 Further studies need to determine whether levels can be correlated with clinical outcomes in order to establish its usefulness in the clinical arena.

Candidal meningitis Candida species are part of normal human microbial flora and rarely cause disease unless host defenses are impaired. Neutropenia is a major risk factor for invasive Candida infections,47 and CNS spread occurs via hematogenous dissemination (especially among infants and newborns) and in the setting of prior CNS trauma or instrumentation (especially ventriculostomy or ventricular shunts).48 Meningitis is the most common presentation in neonates, while CNS Candida infection in adults often presents with brain abscesses rather than diffuse subarachnoid involvement. While C. albicans is the most frequent species isolated, C. tropicalis, C. glabrata, and C. lusitaniae also occasionally cause CNS infection. The CSF formulation in Candida meningitis is typical of most forms of fungal meningitis.48 Patients often have a mixed pleocytosis of 50–200 WBC/mm3, usually with fewer than 50% polymorphonuclear neutrophils (PMN). As with CM, more severely immunocompromised patients may have normal CSF findings, even in the setting of high pathogen loads.49 The same can be observed in neonates.50 CSF protein levels can be as high as 100 mg/dl, and CSF glucose is modestly low in 60% of cases. Fungal smears are somewhat unreliable and should not be used to exclude the

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presence of Candida (Table 23-5).50,51 One study reported a 40% positivity rate of fungal staining of CSF in cultureproven cases.52 Conversely, fungal cultures of CSF for Candida may be positive in up to 80% of meningitis cases after only a few days of growth.48,50,51 Standard blood cultures also can support the growth of Candida sp. in this setting and should not be overlooked. With macroabscesses of the brain parenchyma, CSF studies may not reveal biochemical alterations or yield positive cultures. It is essential to maintain a high clinical index of suspicion in the setting of chronic immunosuppression or past neurosurgical procedures, and to look assiduously in other sites such as blood and urine to confirm a diagnosis. Immunodiagnostics to detect Candida antigen mannan in CSF is promising, but has not been extensively studied (Table 23-5). One study found that 4 of 5 patients with culture-proven candidal meninigitis also had detectable CSF antigen.53 PCR for candidal DNA sequences has not proven to be useful.54 Even with prompt antifungal treatment, CSF changes can persist for several months and do not indicate disease recurrence or the need for further treatment.

Coccidioidal meningitis Coccidioides immitis is an infectious, dimorphic fungus that inhabits dry soil and thus is endemic to the southwestern USA as well as parts of Mexico and Central and South America. Fungal spores dispersed from the soil get inhaled, causing primary pulmonary infection. The majority of such patients remain asymptomatic, and in less than 0.2% of primary infections does the organism disseminate outside the respiratory tract. Up to one-third of these extrapulmonary cases present with meningitis, and the CNS is frequently the only site of dissemination.48 This typically occurs several months after primary infection.48,55 Both immunocompetent and immunosuppressed individuals are at risk for infection. Coccidioidal meningitis can be fatal within a few months to beyond 3 years after infection.56 The CSF profile in coccidioidal meningitis typically shows a lymphocytic pleocytosis, an elevated protein concentration, and a modestly low glucose level that resembles other chronic meningeal processes. Coccidioides, however, is unique among the major CNS fungal pathogens in causing an eosinophilic meningitis; up to 70% of cases have some CSF eosinophilia, and in a significant proportion of these cases the counts exceed 10 cells/mm3.57 Occasional cases show hyphae directly in CSF, allowing the early initiation of antifungal therapy.58 Likewise, only one-third to one-half of patients have positive CSF cultures, and the slowly growing pathogen may take 2–4 weeks to appear on culture plates (Table 23-5).59 For Coccidioides immitis, elevated serum titers (>1:32) of complement-fixing antibodies (CFA) are the hallmark of disseminated disease. Still, patients with coccidioidal meningitis as the sole manifestation of extrapulmonary involvement may have relatively low serum CFA titers.

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CSF will show detectable CFA titers in ~70% of patients with early coccidioidal meningitis, and this value approaches 100% as the infection progresses (Table 23-5).48 Conversely, CSF titers are negative in the absence of meningitis, even if the patient has high serum levels associated with extraneural disease. The CFA in CSF generally parallel the course of meningeal disease, so their titer can be used to follow the response to treatment. Relapse, however, is heralded by the early return of a pleocytosis and elevated protein concentration well before the antibody titer rises. Finally, antibodies against a specific antigen of Coccidioides immitis have been found in the CSF by enzyme-linked immunosorbent assay (ELISA) in a high proportion of patients with meningitis, even when CFA assays are negative.60 With broader use, this assay may supplant the measurement of CFA as the preferred diagnostic test for coccidioidal meningitis.

Histoplasmosis Histoplasma capsulatum is another soil fungus, this time endemic in midwest regions of the USA, particularly the Ohio and Mississippi Valleys. The high prevalence of positive skin tests of people living in endemic areas indicates that primary pulmonary infection is usually asymptomatic. In the rare case of hematogenous dissemination outside the lungs, the CNS is involved 10–20% of the time. Such dissemination often occurs in the setting of impaired cell-mediated immunity, now most commonly with AIDS.48 Chronic meningitis is the usual manifestation of CNS spread, although focal abscesses have also been reported. The CSF profile in CNS histoplasmosis is reminiscent of other fungal infections with a mononuclear cell pleocytosis, moderately high protein levels, and normal-to-low glucose levels.61–63 The organism is almost never identified on direct smears of CSF (concentrated or otherwise), and it can be difficult to isolate on routine fungal culture. Most studies report that no more than 50% of clinically suspected cases yield positive cultures,48,61 although the fungus is sometimes isolated in blood cultures.48 More reliable proof of CNS histoplasmosis comes from the detection of fungus-specific antibodies in CSF; one study showed that 89% of CSF samples were positive even when the culture confirmed a diagnosis in only 22% (Table 23-5).64 Some cross-reactivity with other fungal pathogens may occur with this assay,64 but additional CSF antibody testing for other organisms often resolves this finding. Finally, disseminated histoplasmosis should not be identified solely by CSF analysis – it is vital to look in other organs to establish the diagnosis. The most practical method detects an H. capsulatum polysaccharide antigen in the urine (positive if the value is >2.0 U). This occurs in 90% of patients with widespread disease.65 Antigen has since been found in the CSF of 40% of patients with Histoplasma meningitis in one series.66

Blastomycosis Blastomyces dermatitidis is a dimorphic fungus endemic in the USA from the lower Mississippi Valley up into the mid-Atlantic and North Central States. As with other soil fungi, primary infection occurs in the lungs following inhalation. Disseminated infection causes supperative, granulomatous lesions in a variety of sites including lung, skin, bone, and the CNS. The latter is invaded up to onethird of the time, and most patients with CNS blastomycosis have infection documented at other sites.48,67 Unlike many other fungal infections, immune deficiency is not a clear-cut predisposing factor for dissemination. CNS invasion is heralded by meningitis, although some patients develop blastomycoma (focal abscesses). The CSF in blastomycotic meningitis shows a pleocytosis, either with a lymphocyte or neutrophil predominance, as well as elevated protein and low glucose levels.68,69 Cultures are notoriously unreliable and most often negative. CSF examined by direct microscopy may rarely reveal the fungus, but smears are also usually unhelpful. Some authors report a higher rate of positive cultures when CSF is obtained from the ventricles or cisterns.68,69 Pathogen isolation is still the only means to establish a definitive diagnosis, although newer serological tests are in development.

Cerebral aspergillosis Aspergillus species are ubiquitous molds found in soil, water, and decaying vegetation. Nine species are identified as causing CNS disease in humans, but the majority of cases are due to infection by A. fumigatus. Airborne spores typically gain entry into the lungs, and intracranial spread occurs by direct extension from the sinuses or by hematogenous dissemination. Invasive disease is most common among neutropenic hosts, but it can also occur in the setting of a variety of other chronic illnesses that compromise immune function. CNS spread usually results in single or multiple brain abscesses, but diffuse meningitis can also occur. Because of its rarity, CSF characteristics in these settings have not been well described. In the setting of focal brain abscesses, the CSF can be nonspecifically abnormal (elevated OP, normal–low glucose levels and increased protein content, low-grade pleocytosis) or completely normal.70 Some authors have argued that the presence of red blood cells (RBC) in the CSF of a patient with a brain abscess is suggestive of cerebral aspergillosis.71 Fungal smears and culture of CSF are rarely positive in this setting (Table 23-5).72 Conversely, a sandwich ELISA has been developed that can detect Aspergillus galactomannan. While the test has been used primarily on serum samples to detect disseminated aspergillosis, it has been increasingly applied to other body fluids in single reported cases and small case series.73–75 Among patients with cerebral involvement, CSF levels of the galactomannan antigen were significantly higher than in serum.74 In a single patient who appeared to respond to antifungal

Spirochetal Infections of the Nervous System

therapy, a corresponding decrease in CSF antigen levels was seen.76 Well-designed prospective studies are needed to validate the utility of these measurements. With Aspergillus meningitis, the CSF formulation is typically that of most forms of fungal meningitis.48 Patients often have a mixed pleocytosis of 50–200 WBC/mm3, usually with fewer than 50% PMNs. As with CM, more severely immunocompromised patients may have totally normal CSF in response to infection. Protein levels are generally elevated, and glucose concentrations are very commonly reduced to some degree.48 Smears of CSF remain relatively low yield, but fungal cultures are somewhat more commonly positive than with Aspergillus abscesses. In this setting, galactomannan assays may yield positive fungal antigen levels, and PCR has been used to detect fungal DNA.78–80 Both of these methods yield more sensitive results than detection of fungal-specific IgG.78 Both nested and real-time PCR assays have an emerging role in the rapid identification of fungal pathogens such as Aspergillus in CSF.79,80

SPIROCHETAL INFECTIONS OF THE NERVOUS SYSTEM Syphilis Symptomatic involvement of the CNS by Treponema pallidum can occur any time beyond the primary stage of infection (chancre). A systemic spirochetemia often seeds the CNS via hematogenous dissemination early on, and neuroinvasion can either be asymptomatic or manifest itself as clinically apparent neurosyphilis. Progression through the various stages of syphilis can be accelerated in the setting of coexistent HIV infection, and the two diseases share many pathophysiological features and often confound the management of the other. CSF abnormalities are common in syphilis, and evidence of systemic syphilis infection is invariably an indication to perform an LP. Indeed, CSF examination is reasonable in order: (a) to provide diagnostic information for patients with clinical findings suspicious of neurosyphilis, (b) to diagnose asymptomatic neurosyphilis in a patient with untreated systemic infection, and/or (c) to follow the response to treatment in patients with documented CNS involvement. The CSF profiles associated with different neurosyphilis syndromes will be reviewed here.

Asymptomatic neurosyphilis Untreated systemic syphilis is commonly associated with CNS invasion that may at some point produce overt neurological symptoms. Hence, positive syphilis serology is a well-defined reason to perform a CSF examination, since proven CNS involvement has important treatment implications. Early studies conducted during the pre-antibiotic era suggested that patients with established secondary syphilis and normal CSF findings were at little to no risk of

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developing subsequent neurosyphilis.81,82 Conversely, one study prospectively followed 123 syphilis patients with asymptomatic CNS involvement, dividing them into cohorts based on the degree of their CSF abnormalities. Whereas only 2 of 7 (14%) in Group I and 5 of 73 (7%) in Group II went on to develop neurological progression, 12 of 36 (33%) in Group III progressed to overt parenchymatous neurosyphilis.82 More recently, Lukehart et al. used T. pallidum isolation procedures on CSF (inoculation into rabbit testes) to re-evaluate the frequency of CNS invasion in a cohort of untreated syphilis patients and to correlate pathogen isolation with other, more readily performed CSF laboratory tests.83 Treponemes were isolated from 12 of 40 (30%) of patients with primary or secondary syphilis and 0 of 18 (0%) patients with latent syphilis (although 5 of these 18 patients with latent disease had positive CSF Venereal Disease Research Laboratory (VDRL) assays).83 Of the 12 patients from whom T. pallidum was cultivated, 4 (33%) had otherwise normal CSF cell counts, total protein concentrations, and CSF VDRL assays.83 This strongly suggests that routine CSF analysis underestimates the frequency of patients with asymptomatic neurosyphilis. Likewise, because the CSF VDRL is positive in only 75–80% of patients with symptomatic neurosyphilis, treatment can be initiated if the clinical index of suspicion is high but the CSF VDRL is negative. The CSF fluorescent treponemal antibody absorption test (FTA-ABS) is more often reactive in syphilis than the CSF VDRL, but it also can be positive in patients who have never had syphilis.84 Thus, most clinicians agree that a negative CSF FTA-ABS effectively rules out neurosyphilis, but it should not alone form the basis for diagnosis. Newer methodologies such as PCR detection of T. pallidum sequences in CSF remain under active development but are yet unproven in the clinical arena. Current standards advocate that patients with any two of the following features be treated for presumptive neurosyphilis: (a) CSF pleocytosis of >8 WBC/mm3, (b) CSF protein level >50 mg/dl, and (c) reactive CSF VDRL.

Syphilitic meningitis Overt meningitis occurs in fewer than 2% of patients in the setting of secondary syphilis. It can be accompanied by focal findings, seizures, hydrocephalus, and cranial neuropathies.85 In a cohort of 80 syphilis patients with the clinical syndrome of acute meningitis, 79 (99%) had a pleocytosis in excess of 10 WBC/mm3 (mean, 67 WBC/mm3), 62 (78%) had a CSF protein > 50 mg/dl (mean, 87 mg/dl), and 44 (55%) had CSF glucose <45 mg/dl.85 Unlike the other neurosyphilis syndromes, these patients tend to do relatively well over time and typically resolve their deficits (with the exception of cranial nerve deficits such as hearing loss that commonly persist) following antibiotic treatment. Treatment also effectively blocks clinical progression to parenchymatous neurosyphilis.84

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Meningovascular syphilis

Neurosyphilis in HIV-infected individuals

Meningovascular syphilis develops in up to 15% of patients with CNS involvement, usually months to several years after primary infection. It can be the presenting manifestation of disease or occur in patients after ineffective prior therapy. Focal deficits arise due to a prominent arteritis that accompanies active meningeal inflammation. All vascular territories of the CNS can be involved, but the middle cerebral artery is affected in nearly two-thirds of cases.84,86 In patients with overt ischemic infarctions, CSF abnormalities are common when the fluid is examined.86 Most cases reveal a mononuclear cell pleocytosis (20–50 WBC/mm3) and elevated total protein content (70–150 mg/dl). Peripheral serologies are invariably reactive, and the CSF VDRL is commonly positive.84,86

As sexually transmitted diseases, HIV and syphilis often coexist in the same host. Numerous case reports document dramatic presentations of neurosyphilis in HIV seropositive individuals, frequently as a manifestation of benzathine penicillin failure.84 Furthermore, both diseases commonly cause CSF abnormalities, often leaving clinicians in a dilemma as to the cause of the findings noted on CSF examination. Most studies suggest that while underlying HIV infection does not necessarily increase the risk of CNS invasion by syphilis, HIV-infected patients more commonly have a CSF pleocytosis in early syphilis infection,83 and they are more likely to relapse after penicillin G therapy.89

Response to therapy Parenchymatous neurosyphilis General paresis and tabes dorsalis are the two late-stage forms of neurosyphilis that directly involve the CNS parenchyma. Both typically occur many years after primary infection. General paresis is a chronic, progressive spirochetal meningoencephalitis that produces a wide spectrum of neurocognitive and neurobehavioral findings. Examination of the CSF helps to establish the diagnosis since it is reported to be abnormal in 100% of cases.87 In this setting, as with other neurosyphilis syndromes, a mononuclear cell pleocytosis, elevated total protein content, and reactive serological tests for syphilis are the norm.87 Tabes dorsalis produces a typical syndrome of ‘lightning pains’ that develop in multiple nerve root distributions, accompanied later by patchy anesthesia and decreased proprioception. Patients develop a characteristic shuffling gait, and neuropathological studies reveal major degeneration in the dorsal columns of the spinal cord. Unlike general paresis where CSF abnormalities are uniformly found, only about one-half of patients with tabes dorsalis have demonstrable CSF findings. In a series of 100 patients, Merritt et al. found a pleocytosis (>5 WBC/mm3) in exactly 50 individuals and elevated CSF protein levels in 53 cases.88 The prevalence of CSF abnormalities tended to be lower in those patients who had received some prior therapy for syphilis compared to those who had not.88

Gummatous neurosyphilis Gumma may occur at any stage of syphilis and develop virtually anywhere in the CNS. These rare lesions produce signs and symptoms of an expanding mass lesion. CSF findings may include a mononuclear cell pleocytosis, elevated total protein content, and/or reactive serological tests, although the prevalence of these abnormalities in gummatous neurosyphilis is unknown due to the rarity of the disorder. The lesions, and presumably the CSF abnormalities that accompany them, respond to antibiotic therapy.84

The desired outcome of therapy for neurosyphilis depends in part on the manifestations of disease. Among infected patients with asymptomatic CSF abnormalities, the main goal is to normalize the laboratory values and to prevent the progression to clinically overt disease. In a large cohort of such patients, the CSF cell count appeared to be the most sensitive indicator of penicillin response. Thus, 89% of 454 patients with an initial CSF cell count >10 WBC/mm3 had normal values at a follow-up LP 1 year later.90 Among 235 of these patients with high CSF protein values, 69% had normalized at 1 year after therapy.90 The serological response to therapy, on the other hand, was dissociated from the responsiveness of CSF parameters; neither the presence nor the rate of serological response accurately predicted resolution of CSF values to treatment.90 Still, CSF abnormalities may be a more reliable indicator of response to therapy than changes in clinical findings.

Lyme disease Borrelia burgdorferi is the microorganism responsible for Lyme disease; it is transmitted to humans via the bite of Ixodes tick vectors. Much like what occurs with syphilis, peripheral inoculation is followed by local replication and hematogenous dissemination to secondary sites, including the skin, heart, joints, eye, and nervous system. Neurological involvement can rarely occur without the characteristic skin lesions or joint findings,91 and variability in serological testing often results in over-diagnosis and treatment. Early CNS involvement, occurring in about one-quarter of North American patients but closer to onehalf of European cases, is usually heralded by meningitis and cranial neuropathies. Less frequently found are syndromes of multilevel radiculitis, plexitis, myelitis, and even mild encephalitis. Late disease, generally occurring a year or more after illness onset, can manifest as an encephalomyelitis or an encephalopathy. CSF abnormalities are important in establishing the diagnosis and in monitoring the response to treatment.

Parasitic Infections of the Nervous System

Lyme meningitis Meningitis is the most common neurological event that occurs in the setting of early Lyme dissemination. It typically follows the characteristic erythema migrans (EM) skin lesion by 2–10 weeks, but a preceding rash is reported in fewer than half of cases.91 In this clinical setting, the CSF is invariably abnormal. OP is usually normal, but it may be elevated as high as 50 cm H2O.91 A brisk pleocytosis as high as 4,000 WBC/mm3 can occur, although most patients have 100–200 WBC/mm3 found in their initial sample.91 The WBC differential is predominantly lymphocytic in nature (>90% lymphocytes in three-quarters of patients), and plasma cells may constitute up to 10% of the infiltrate.91 Total protein content increases in direct proportion to the duration of symptoms, and is usually found to vary in the range 100–300 mg/dl.91 Values as high as 1,300 mg/dl, however, have been reported.91 The CSF glucose content is usually normal, but it falls below half the serum concentration in 20% of patients, and levels as low as 12 mg/dl are known.91 These CSF abnormalities subside 4–8 weeks after meningeal symptoms begin, even without treatment, but values may not return fully to normal for 3–4 months. Immunoglobulin abnormalities are common in the CSF of patients with Lyme meningitis. High total levels of IgG, IgM, and IgA are reported in 75–90% of patients, and oligoclonal bands are found in 9 out of 10 cases of over 3 weeks duration.91 In terms of B. burgdorferi-specific antibodies, positive CSF IgM or IgG by ELISA occurs in 75–100% of cases and is similarly related to disease duration. These findings may persist for years after the meningitis has resolved, even without any further evidence of disease activity. Conversely, in the setting of negative CSF anti-B. burgdorferi antibodies, a positive serum titer and a CSF pleocytosis, in the absence of a better alternative explanation, prompt many specialists to consider antibiotic treatment for individuals living in endemic areas.

Cranial neuropathies Cranial neuropathies occur in approximately 60% of patients with early disseminated Lyme disease, and some 80–90% of these events involve one or both facial nerves. Nearly half are also accompanied by polyradiculoneuritis. Patients usually become symptomatic within 3–4 weeks after EM first appears.91 Routine CSF analysis of these patients shows a mononuclear cell pleocytosis in more than 80% of cases. Pathogen-specific antibodies are found in the serum and CSF of most patients at the time symptoms develop, but this response can be delayed up to 6 weeks in selected individuals.92,93

Peripheral nervous system abnormalities Some Lyme patients develop severe radicular pain, paresthesias, and motor weakness within weeks after EM develops. This is commonly, but not universally, associated with signs and symptoms of meningitis (75%) and/or cranial neuropathies (60%).91 More than 90% of these patients have

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a lymphocyte-predominant CSF pleocytosis, and the total CSF protein can be significantly elevated, particularly among patients with illnesses reminiscent of Guillain-Barré syndrome.94 These CSF abnormalities typically improve in parallel with the recovery of motor and sensory symptoms, usually over a period of several months.91

Central nervous system parenchymal abnormalities Direct involvement of the brain and/or spinal cord is a rare complication of CNS Lyme disease, but various syndromes are reported both in the early dissemination period and as a late complication of infection.91 Thus, some 50% of meningitis patients also develop emotional lability, poor concentration, somnolence, and behavioral changes, while other patients can have an isolated partial transverse myelitis. In the late stages of disease a chronic encephalomyelitis has been reported in 0.5% of European patients; these individuals develop gradually progressive or stuttering neurological deficits that often suggest a diagnosis of multiple sclerosis. The CSF is almost always abnormal in these patients, with a pleocytosis of 200–2,000 WBC/mm3, protein level of 100–500 mg/dl, multiple IgG oligoclonal bands, and easily detected anti-B. burgdorferi antibodies.91 Response to antibiotic therapy is generally better among patients treated sooner into their illness, and CSF changes generally track in parallel with the clinical picture. A more difficult but less dramatic situation arises in occasional North American patients who complain of impaired cognitive function (memory, concentration, problem solving, etc.) accompanied by depression, irritability, and paresthesias. A CSF pleocytosis is found in only 5–10% of such cases, but total CSF protein may be increased 20–40% of the time, and anti-B. burgdorferi antibodies have been described in 40–80% of individuals affected by this more encephalopathic process.91 Occasional reports also suggest the presence of B. burgdorferi antigens and DNA in CSF samples.95,96 At least one study has suggested that patients with these CSF abnormalities may be more likely to respond to treatment, but management remains controversial.97

PARASITIC INFECTIONS OF THE NERVOUS SYSTEM Systemic parasitic infections are common in developing countries, but many also occur in travelers or recent immigrants to developed regions of the world. Individuals who develop CNS involvement by these pathogens often have evidence of systemic disease. In general, routine CSF studies in these patients may be abnormal but are not conclusive, and a diagnosis rests more commonly on specific serological assays or laboratory demonstration of the parasite in other clinical samples. Nevertheless, this section will review the CSF findings associated with more common parasitic infections that involve the CNS.

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Cerebral malaria Although definitions vary, cerebral malaria is generally considered to represent any new CNS finding that develops in a patient infected with Plasmodium falciparum. Almost invariably it develops in individuals with pronounced multi-organ involvement due to systemic infection with the parasite. Despite a long and extensive history of investigation, the pathogenesis of CNS involvement in malaria remains incompletely understood. Histological studies show extensive packing of cerebral capillaries by parasitized erythrocytes, and gross study of fatal cases shows swelling, congestion, and hemorrhage throughout the brain. The underlying molecular basis for neurological dysfunction is unclear, but it does not involve direct invasion or infection by P. falciparum. Instead, a combination of impaired oxygen transport and local production of soluble proinflammatory mediators have been implicated.98 A laboratory diagnosis of malaria is established by direct microscopic examination of blood smears stained with Giemsa stain.98 Most cases of cerebral malaria are associated with extensive parasitemia, although prior treatment with antimalarial agents can sometimes reduce peripheral parasitemia to the point where infected erythrocytes are difficult to find. Examination of the CSF in suspected cases of cerebral malaria is most useful to exclude other causes of acute encephalopathy. In malaria, the CSF is clear and the OP is less than 20 cm H2O in greater than 80% of cases.98 Microscopy of centrifuged and stained CSF is normal, and there are rarely more than 10 WBC/mm3 present.98,99 Cell counts up to 150 WBC/mm3 have occasionally been described.99 Nearly all of the cells present in the CSF during cerebral malaria are lymphocytes, and the presence of neutrophils should suggest an alternative diagnosis. The total protein content may be slightly elevated, sometimes reaching a level of 150 mg/dl.98 The CSF:serum glucose ratio is invariably normal.98 Hypoglycemia is common in malaria, and serum levels should be checked to exclude this event as a cause of neurological decline. CSF cultures should be sent to exclude bacterial meningitis, which is common in the same parts of the world where malaria is prevalent.

Neurocysticercosis A myriad of clinical syndromes collectively known as neurocysticercosis result when the larval forms of the pork tapeworm, Taenia solium (Cysticercus cellulosae and C. racemose), gain access to the human CNS. The epidemiology and pathogenesis of this complex disease are reviewed elsewhere.100 Once the cysticerci enter the human host, they have a predilection to lodge in the CNS, eyes, and striated muscle. They then pass through a defined life cycle in target tissues, with neurological symptoms occurring anywhere from 1 to 30 years after the original infection. Beyond asymptomatic disease, defined clinical syndromes of neurocysticercosis include primarily parenchymal,

subarachnoid, intraventricular, spinal, or ocular involvement. CSF abnormalities associated with the more common of these varied disorders will be reviewed here.

Parenchymal neurocysticercosis When cysticerci spread to the brain, they commonly lodge at the grey-white junction. The resulting cysts can be alive or dead when they become symptomatic; the latter commonly are calcified and easily visualized by cranial computed tomography (CT). Seizures, focal neurological deficits, and altered mental status are the most common neurological sequelae. A diagnosis is based on clinical, radiographic, and serological findings. Among large cohorts, routine CSF analysis is abnormal in 40–80% of neurocysticercosis patients.101–103 A CSF WBC count above 10 cells/mm3 occurs in 10–53% of all infected individuals,101,102 and many of these cells can be neutrophils in early stages of disease.103 Later, the infiltrate becomes mostly mononuclear in nature, but many patients also show a significant proportion of eosinophils.103 Total CSF protein is elevated in 10–30% of patients,100–102 while mild hypoglycorrhachia (<45 mg/dl) is seen 25% of the time.102,103 Very low CSF glucose levels (<10 mg/dl) are possible, and these patients have higher morbidity and mortality in some series.102,103 Intrathecal synthesis of immunoglobulins has been demonstrated in a few small series of patients with neurocysticercosis. One study showed high CSF IgG synthesis rates in 83% of patients, with unique oligoclonal bands not found in matched serum samples present 67% of the time.104 Another study suggested that high CSF IgG levels occur more commonly in those patients with active cysts rather than inactive or calcified lesions.105 CSF is also important for pathogen-specific antibody and antigen detection assays. An ELISA for anticysticercal IgM shows good specificity of 95% and sensitivity of 87% in the CSF of patients with active forms of neurocysticersosis.106 Complement fixation assays are positive in 83% of patients with active inflammation, but only 22% of patients without it.107 Both assays can be used together to improve overall sensitivity and specificity.

Subarachnoid and intraventricular neurocysticercosis Cysticercal seeding of the subarachnoid space usually presents with meningitis and elevated ICP. Large lesions that form at the base of the brain cause a variety of specific signs and symptoms dictated by their precise neuroanatomical location. Intraventricular cysts occur commonly in this form of neurocysticercosis, frequently causing either fixed or intermittent obstructive hydrocephalus. While the CSF composition in these cases may by similar to parenchymal neurocysticercosis, disease in these locations must be considered in the setting of disruption of CSF flow dynamics.

References

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Spinal neurocysticercosis

Cerebral toxoplasmosis in AIDS

Spinal involvement in neurocysticercosis is less frequent than are intracranial lesions. Extramedullary lesions are most common in the cervical area and are believed to result from cysticerci migrating from the cranial subarachnoid space.

CNS toxoplasmosis has become one of the most common and most important opportunistic infections in patients with AIDS. Nearly all of these cases are due to reactivation of chronic latent infection, so most patients have serological evidence of prior exposure.108 Disease typically develops after the CD4 lymphocyte count falls below 100/mm3; prospective cohorts suggest that 20–40% of patients in this situation develop toxoplasmic encephalitis in the next 12–18 months.108 Most patients develop single or multiple enhancing brain lesions on neuroimaging studies; the lesions can be asymptomatic at discovery or associated with subacute focal findings or general decline. Analysis of CSF in this setting is either contraindicated due to the presence of surrounding edema and compartment shift, or not particularly helpful in establishing the diagnosis. When examined, the CSF may reveal a few mononuclear cells, normal-to-high protein content, and normal glucose concentrations.108 A diagnosis is suggested by the presence of either anti-Toxoplasma antibodies or Toxoplasma-specific DNA sequences in CSF,109,110 neither of which are in widespread clinical use. Instead, patients with suspicious clinical and radiographic features are often treated empirically for toxoplasmosis and followed over time for change in the size of their brain lesions on enhanced cranial magnetic resonance imaging (MRI) scans.

Toxoplasmosis Toxoplasma gondii is an important intracellular protozoan pathogen of both humans and animals. Although most human infections are asymptomatic, T. gondii can invade the CNS causing four clinically defined syndromes: (a) meningoencephalitis during primary infection of an immunocompetent host, (b) encephalitis and chorioretinitis following transplacental infection of the fetus, (c) chorioretinitis with either primary infection or reactivated infection in an adult, and (d) intracerebral mass lesions or encephalitis in an immunocompromised host.

Primary infection of an immunocompetent host Transmission of T. gondii to humans occurs in the setting of eating undercooked meats or inadvertent ingestion of oocysts present in cat feces. The prevalence of seropositivity in humans varies greatly from place to place, but can range from 20 to 80% among adults.108 Symptomatic CNS infection is rare during primary infection of normal hosts. Some 10% of people develop lymphadenopathy and a mononucleosis-like illness.108 Very rare cases of CNS infection can develop in the context of disseminated infection with multi-organ failure or in isolation. The latter may be either multifocal abscesses or diffuse encephalitis, without or with simultaneous chorioretinitis. In this setting, the CSF shows a mild mononuclear cell pleocytosis, elevated protein content, and normal glucose level. The diagnosis is made by showing rising serum and CSF anti-Toxoplasma antibodies.108

Congenital toxoplasmosis Congenital toxoplasmosis preferentially involves the eyes and brains of infected infants. The classic presentation is one of hydrocephalus, intracranial calcification, and chorioretinitis, although the severity of findings is variable and may range from profound involvement at birth to mild findings much later in life. In one prospective screening of 7,500 infants, 10 were found to have congenital toxoplasmosis based on persistently positive serologies.109 Only one of these children had clinical evidence suggestive of congenital toxoplasmosis, but one other had subclinical chorioretinitis identified by careful ophthalmoscopic examination.109 In eight of these children who underwent LP, CSF abnormalities were uncovered in all of them. Findings were most notable for a high mononuclear cell pleocytosis and elevated total protein content.109 More recently, PCR has proven useful in detecting Toxoplasma-specific DNA sequences in these CSF samples.110

CONCLUSIONS Neurological involvement occurs commonly with many tuberculous, fungal, spirochetal, and parasitic infections, and CSF analysis can help clarify the underlying nature of these illnesses and often may serve to guide therapy. These infections have become more prevalent in the wake of the AIDS epidemic and the expanded use of chronic immunosuppressive therapies, making an improved understanding of the laboratory abnormalities that occur in hosts with these infections imperative. Future advances in rapid molecular diagnostics should increase the role of CSF analyses in these settings.

REFERENCES 1. Boyd W. Physiology and Pathology of the Cerebrospinal Fluid. New York: Macmillan; 1920. 2. Holt DE, Howland J. The Diseases of Infancy and Childhood, 9th edition. New York: D Appleton; 1926. 3. Barrett-Connor E. Tuberculous meningitis in adults. South Med J 1967;60:1061–1067. 4. Haas EJ, Madhavan T, Quinn EL, Cox F, Fisher E, Burch K. Tuberculous meningitis in an urban general hospital. Arch Int Med 1977;137:1518–1521. 5. Traub M, Colchester ACF, Kingsley DPE, Swash M. Tuberculosis of the central nervous system. Q J Med 1984;53:81–100. 6. Klein NC, Damsker B, Hirschman SZ. Mycobacterial meningitis: retrospective analysis from 1970–1983. Am J Med 1985;79:29–34.

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7. Ogawa SK, Smith MA, Brennessel DJ, Lowy FD. Tuberculous meningitis in an urban medical center. Medicine 1987;66:317–326. 8. Schutte CM. Clinical, cerebrospinal fluid and pathological findings and outcomes in HIV-positive and HIV-negative patients with tuberculous meningitis. Infection 2001;29:213–217. 9. Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979;241:264–268. 10. Kent SJ, Crowe SM, Yung A, Lucas CR, Mijch AM. Tuberculous meningitis: a 30-year review. Clin Inf Dis 1993;17:987–994. 11. Sumaya CV, Simek M, Smith MHD, Seidemann MF, Ferriss GC, Rubin W. Tuberculous meningitis in children during the isoniazid era. J Pediatr 1975;87:43–49. 12. Lincoln EM, Sewell EM. Tuberculosis in Children. New York: McGraw-Hill; 1963. 13. Singhal BS, Bhagwati SN, Syed AH, Laud GW. Raised intracranial pressure in tuberculous meningitis. Neurology (India) 1975; 23:32–39. 14. Zuger A, Lowy FD. Tuberculosis. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd edition. Philadelphia: Lippincott-Raven; 1997:417–443. 15. Sullivan JL, Osborne WRA, Wedgwood RJ. Adenosine deaminase activity in lymphocytes. Br J Haematol 1977;37:157–158. 16. Ribera E, Martinez-Vazquez JM, Ocana I, Segura RM, Pascual C. Activity of adenosine deaminase in cerebrospinal fluid for the diagnosis and follow-up of tuberculous meningitis in adults. J Infect Dis 1987;155:603–607. 17. Donald PR, Malan C, Schoeman JF. Adenosine deaminase as a diagnostic aid in tuberculous meningitis. J Infect Dis 1987;156:1040–1041. 18. Chotmongkol V, Teerajetgul Y, Yodwut C. Cerebrospinal fluid adenosine deaminase activity for the diagnosis of tuberculous meningitis in adults. Southeast Asian J Trop Med Public Health 2006;37:948–952. 19. Shankar P, Manjunath N, Mohan KK, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991;337:5–7. 20. Lin JJ, Harn HJ, Hsu YD, Tsao WL, Lee HS, Lee WH. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction assay of cerebrospinal fluid. J Neurol 1995;242:147–152. 21. Desai MM, Pal RB. Polymerase chain reaction for the rapid detection of tuberculous meningitis. Indian J Med Sci 2002;56:546–552. 22. Seth P, Ahuja GK, Bhanu NV, et al. Evaluation of polymerase chain reaction for rapid diagnosis of clinically suspected tuberculous meningitis. Tuber Lung Dis 1996;77:353–357. 23. Rafi A, Naghily B. Efficiency of polymerase chain reaction for the diagnosis of tuberculous meningitis. Southeast Asian J Trop Med Public Health 2003;34:357–360. 24. Caws M, Wilson SM, Clough C, Drobniewski F. Role of IS6110-targeted PCR, culture, biochemical, clinical, and immunological criteria for diagnosis of tuberculous meningitis. J Clin Microbiol 2000;38:3150–3155. 25. Liu PY, Shi ZY, Lau YL, Hu BS. Rapid diagnosis of tuberculous meningitis by a simplified nested amplification protocol. Neurology 1994;44:1161–1164. 26. Bonington A, Strang JI, Klapper PE, et al. TB PCR in the early diagnosis of tuberculous meningitis: evaluation of the Roche semi-automated COBAS Amplicor MTB test with reference to the manual Amplicor MTB PCR test. Tuber Lung Dis 2000;80:191–196. 27. Scarpellini P, Racca S, Cinque P, et al. Nested polymerase chain reaction for diagnosis and monitoring treatment responses in AIDS patients with tuberculous meningitis. AIDS 1995;9:895–900. 28. Mastroianni CM, Paoletti F, Lichtner M, D’Agostino C, Vullo V, Delia S. Cerebrospinal fluid cytokines in patients with tuberculous meningitis. Clin Immunol Immunopathol 1997;84:171–176. 29. Mastroianni CM, Lancella L, Mengoni F, et al. Chemokine profiles in the cerebrospinal fluid during the course of pyogenic and tuberculous meningitis. Clin Exp Immunol 1998;114:210–214.

30. Lee KY, Kim EH, Yang WS, et al. Persistent increase of matrix metalloproteinases in cerebrospinal fluid of tuberculous meningitis. J Neurol Sci 2004;220:73–78. 31. Sibley WA, O’Brien JL. Intracranial tuberculomas: a review of the clinical features and treatment. Neurology 1956;6:157–165. 32. Eng RH, Bishburg E, Smith SM, Kapila R. Cryptococcal infections in patients with acquired immune deficiency syndrome. Am J Med 1986;81:19–23. 33. Ennis DM, Saag MS. Cryptococcal meningitis in AIDS. Hosp Pract 1993;28:99–112. 34. Chaka W, Heyderman R, Gangaidzo I, et al. Cytokine profiles in cerebrospinal fluid of human immunodeficiency virus-infected patients with cryptococcal meningitis: no leukocytes despite high interleukin-8 levels. J Infect Dis 1997;176:1633–1636. 35. Pitisuttithum P, Tansuphasawadikul S, Simpson AJ, Howe PA, White NJ. A prospective study of AIDS-associated cryptococcal meningitis in Thailand treated with high-dose amphotericin B. J Infect 2001;43:226–233. 36. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in acquired immunodeficiency syndrome. N Engl J Med 1989;321:794–799. 37. Bicanic T, Harrison TS. Cryptococcal meningitis. BMJ 2005;72:99–118. 38. Feldmesser M, Harris C, Reichberg S, Khan S, Casadevall A. Serum cryptococcal antigen in patients with AIDS. Clin Infect Dis 1996;23:827–830. 39. Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1994;18:789–792. 40. Berlin L, Pincus JH. Cryptococcal meningitis. False negative antigen test results and cultures in non-immunosuppressed patients. Arch Neurol 1989;46:1312–1316. 41. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997;337:15–21. 42. Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (AmBisome) compared to amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997;11:1463–1471. 43. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomized trial. Lancet 2004;363:1764–1767. 44. Coenjaerts FE, van der Flier M, Mwinzi PN, et al. Intrathecal production and secretion of vascular endothelial growth factor during cryptococcal meningitis. J Infect Dis 2004;190:1310–1317. 45. Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis 1995;20:611–616. 46. Moosa MY, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (HIV)-positive and HIVnegative patients. Clin Infect Dis 1997;24:131–134. 47. Parker JC Jr, McCloskey JJ, Lee RS. The emergence of candidosis. The dominant postmortem cerebral mycosis. Am J Clin Pathol 1978;70:31–36. 48. Perfect JR, Durack DT. Fungal Meningitis. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, second edition. Philadelphia: Lippincott-Raven; 1997:721–739. 49. Casado JL, Quereda C, Corral I. Candidal meningitis in HIV-infected patients. AIDS Patient Care STDS 1998;12:681–686. 50. Fernandez M, Moylett EH, Noyola DE, Baker CJ. Candidal meningitis in neonates: a 10-year review. Clin Infect Dis 2000;31:458–463. 51. Chen TL, Chen HP, Fung CP, Lin MY, Yu KW, Liu CY. Clinical characteristics, treatment and prognostic factors of candidal

Pathophysiology

52. 53.

54.

55. 56. 57. 58. 59. 60.

61. 62.

63. 64. 65. 66. 67. 68. 69. 70.

71. 72. 73.

meningitis in a teaching hospital in Taiwan. Scand J Infect Dis 2004;36:124–130. Sanchez-Portocarrero J, Perez-Cecilia E, Corral O, Romero-Vivas J, Picazo JJ. The central nervous system and infection by Candida species. Diagn Microbiol Infect Dis 2000;37:169–179. Verduyn Lunel FM, Voss A, Kuijper EJ, et al. Detection of the Candida antigen mannan in cerebrospinal fluid specimens from patients suspected of having Candida meningitis. J Clin Microbiol 2004;42:867–870. Ralph ED, Hussein Z. Chronic meningitis caused by Candida albicans in a liver transplant recipient: usefulness of the polymerase chain reaction for diagnosis and monitoring treatment. Clin Infect Dis 1996;23:191–192. Bouza E, Dreyer JS, Hewitt WL, Meyer RD. Coccidioidal meningitis: An analysis of thirty-one cases and review of the literature. Medicine 1981;60:139–172. Vincent T, Galgiani JN, Huppert M, Salkin D. The natural history of coccidioidal meningitis: VA-Armed Forces cooperative studies, 1955–1958. Clin Infect Dis 1993;16:247–254. Ragland AS, Arsura E, Ismail Y, Johnson R. Eosinophilic pleocytosis in coccidioidal meningitis: frequency and significance. Am J Med 1993;95:254–257. Zepeda MR, Kobayashi GK, Appleman MD, Navarro A. Coccidioides immitis presenting as a hyphal form in cerebrospinal fluid. J Natl Med Assoc 1998;90:435–436. Meyer PR, Hui AN, Biddle M. Coccidioides immitis meningitis with arthroconidia in cerebrospinal fluid: report of the first case and review of the arthroconidia literature. Hum Pathol 1982;13:1136–1138. Galgiani JN, Peng T, Lewis ML, Cloud GA, Pappagianis D. Cerebrospinal fluid antibodies detected by ELISA against a 33-kDa antigen from spherules of Coccidioides immitis in patients with coccidioidal meningitis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group. J Infect Dis 1996;173:499–502. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system. Medicine 1990;69:244–260. Mawhorter SD, Curley GV, Kursh ED, Farver CE. Prostatic and central nervous system histoplasmosis in an immunocompetent host: case report and review of the prostatic histoplasmosis literature. Clin Infect Dis 2000;30:595–598. Saccente M, McDonnell RW, Baddour LM, Mathis MJ, Bradsher RW. Cerebral histoplasmosis in the azole era: report of four cases and review. South Med J 2003;96:410–416. Wheat J, French M, Batteiger B, Kohler R. Cerebrospinal fluid Histoplasma antibodies in central nervous system histoplasmosis. Arch Intern Med 1985;145:1237–1240. Wheat J. Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine 1997;76:339–354. Wheat LJ, Kohler RB, Tewari RP, Garten M, French ML. Significance of Histoplasma antigen in the cerebrospinal fluid of patients with meningitis. Arch Intern Med 1989;149:302–304. Witorsch P, Utz JP. North American blastomycosis: a study of 40 patients. Medicine 1968;47:169–200. Gonyea EF. The spectrum of primary blastomycotic meningitis: a review of central nervous system blastomycosis. Ann Neurol 1978;3:26–39. Kravitz GR, Davies SF, Eckman MR, Sarosi GA. Chronic blastomycotic meningitis. Am J Med 1981;71:501–505. Sepkowitz K, Armstrong D. Space-occupying fungal lesions. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, second edition. Philadelphia: Lippincott-Raven; 1997:741–762. Meyer RD, Young LS, Armstrong D, Yu B. Aspergillosis complicating neoplastic disease. Am J Med 1973;54:6–15. Jinkins JR, Siqueira E, Al-Kawi MZ. Cranial manifestations of aspergillosis. Neuroradiology 1987;29:181–185. Verweij PE, Dompeling EC, Donnelly JP, Schattenberg AV, Meis JF. Serial monitoring of Aspergillus antigen in the early diagnosis of invasive

74. 75. 76. 77. 78. 79. 80.

81. 82. 83.

84. 85. 86. 87. 88. 89. 90.

91. 92. 93. 94. 95. 96. 97.

207

aspergillosis. Preliminary investigations with two samples. Infection 1997;25:86–89. Viscoli C, Machetti M, Gazzola P, et al Aspergillus galactomannan antigen in the cerebrospinal fluid of bone marrow recipients with probable cerebral aspergillosis. J Clin Microbiol 2002;40:1496–1499. Klont RR, Mennink-Kersten MA, Verweij PE. Utility of Aspergillus antigen detection in specimens other than serum specimens. Clin Infect Dis 2004;39:1467–1474. Machetti M, Zotti M, Veroni L, et al. Antigen detection in the diagnosis and management of a patient with probable cerebral aspergillosis treated with voriconazole. Transpl Infect Dis 2000;2:140–141. McGinnis MR. Detection of fungi in cerebrospinal fluid. Am J Med 1983;75:129–138. Verweij PE, Brinkman K, Kremer HP, Kullberg BJ, Meis JF. Aspergillus meningitis: diagnosis by non-culture-based microbiological methods and management. J Clin Microbiol 1999;37:1186–1189. Hummel M, Spiess B, Kentouche K, et al. Detection of Aspergillus DNA in cerebrospinal fluid from patients with cerebral aspergillosis by a nested PCR assay. J Clin Microbiol 2006;44:3989–3993. Schabereiter-Gurtner C, Selitsch B, Rotter ML, Hirschl AM, Willinger B. Development of novel real-time PCR assays for detection and differentiation of eleven medically important Aspergillus and Candida species in clinical specimens. J Clin Microbiol 2007;45:906–914. Merritt HH. The early clinical and laboratory manifestations of syphilis of the central nervous system. N Engl J Med 1940;223:446–450. Moore JE, Hopkins HH. Asymptomatic neurosyphilis. VI. The prognosis of early and late asymptomatic neurosyphilis. JAMA 1936;95:1637–1641. Lukehart SA, Hook EW III, Baker-Zander SA, Collier AC, Critchlow CW, Handsfield HH. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 1988;109:855–861. Hook EW III. Syphilis. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd edition. Philadelphia: Lippincott-Raven; 1997:669–684. Merritt HH, Moore M. Acute syphilitic meningitis. Medicine 1935;14:119–183. Holmes MD, Brant-Zawadzki MM, Simon RP. Clinical features of meningovascular syphilis. Neurology 1984;34:553–556. Simon RP. Neurosyphilis. Arch Neurol 1985;42:606–613. Merritt HH, Adams RD, Solomon HC. Neurosyphilis. New York: Oxford University Press; 1946. Malone JL, Wallace MR, Hendrick BB, et al. Syphilis and neurosyphilis in a human immunodeficiency virus type-1 seropositive population: evidence for frequent serologic relapse after therapy. Am J Med 1995;99:55–63. Hahn RD, Cutler JC, Curtis AC, Gammon G, Heyman A, Johnwick E. Penicillin treatment of asymptomatic central nervous system syphilis. II. Results of therapy as measured by laboratory findings. Arch Dermatol 1956;74:367–377. Reik L Jr. Lyme disease. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd edition. Philadelphia: Lippincott-Raven; 1997:685–718. Olsson I, Engervall K, Asbrink E, Carlsson-Nordlander B, Hovmark A. Tick-borne borreliosis and facial palsy. Acta Otolaryngol 1988;105:100–107. Reik L. Neurologic aspects of North American Lyme disease. In: Coyle PK, ed. Lyme Disease. St. Louis: Mosby-Year Book; 1993:101–112. Sterman AB, Nelson S, Barclay P. Demyelinating neuropathy accompanying Lyme disease. Neurology 1982;32:1302–1305. Coyle PK, Deng Z, Schutzer SE, et al. Detection of Borrelia burgdorferi antigens in cerebrospinal fluid. Neurology 1993;43:1093–1097. Keller TL, Halperin JJ, Whitman M. PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology 1992;42:32–42. Halperin JJ, Krupp LB, Golightly MG, Volkman DJ. Lyme-borreliosisassociated encephalopathy. Neurology 1990;40:1340–1343.

208

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●

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98. Cegielski JP, Warrell DA. Cerebral Malaria. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd edition. Philadelphia: Lippincott-Raven; 1997:765–784. 99. White NJ, Warrell DA. The management of severe malaria. In: Wernsdorfer WH, McGregor I, eds. Malaria: Principles and Practices of Malariology. Edinburgh: Churchill Livingstone; 1988:865–888. 100. Cameron ML, Durack DT. Helminthic infections. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd edition. Philadelphia: Lippincott-Raven; 1997:845–878. 101. Wei GZ, Cun-jiang L, Jia-mei M, Ming-chen D. Cysticercosis of the central nervous system. A clinical study of 1,400 cases. Chin Med J 1988;101:493–500. 102. McCormick GF, Zee C, Heiden J. Cysticercosis cerebri. Review of 127 cases. Arch Neurol 1982;39:534–539. 103. McCormick GF. Cysticercosis - review of 230 patients. Bull Clin Neurosci 1985;50:76–101. 104. Miller BL, Staugaitis SM, Tourtellotte WW, et al. Intra-blood-brain barrier IgG synthesis in cerebral cysticercosis. Arch Neurol 1985;42:782–784. 105. Espinoza B, Ruiz-Palacios G, Tovar A, Sandoval MA, Plancarte A, Flisser A. Characterization by enzyme-linked immunosorbent assay of the humoral immune response in patients with neurocysticerosis and

106. 107. 108. 109.

110.

111.

its application in immunodiagnostics. J Clin Microbiol 1986;24:536–541. Rosas N, Sotelo J, Nieto D. ELISA in the diagnosis of neurocysticercosis. Arch Neurol 1986;43:353–356. Sotelo J, Guerrero V, Rubio F. Neurocysticercosis: a new classification based on active and inactive forms. Arch Intern Med 1985;145:442–445. Dukes CS, Luft BJ, Durack DT. Toxoplasmosis. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd edition. Philadelphia: Lippincott-Raven; 1997:785–806. Alford CA Jr, Stagno S, Reynolds DW. Congenial toxoplasmosis: clinical, laboratory, and therapeutic considerations, with special reference to subclinical disease. Bull NY Acad Med 1974;50:160–181. Cassaing S, Bessieres MH, Berry A, Berrebi A, Fabre R, Magnaval JF. Comparison of two amplification sets for molecular diagnosis of toxoplasmosis by real-time PCR. J Clin Microbiol 2006;44: 720–724. Potasman I, Resnick L, Luft BJ, Remington JS. Intrathecal production of antibodies against Toxoplasma gondii in patients with toxoplasmic encephalitis and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;108:49–51.

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24

Inflammatory and Demyelinating Disorders Irene Cortese and Peter A. Calabresi

INTRODUCTION Non-infectious inflammatory and demyelinating diseases of the central nervous system (CNS) are commonly associated with abnormal cerebrospinal fluid (CSF) composition, including a lymphocyte predominant pleocytosis, variably increased total protein content, markers of blood–brain barrier (BBB) disruption, and evidence of abnormal intrathecal antibody responses. To this end, both qualitative and quantitative measures of inflammation are commonly examined in the CSF of patients suspected of having one of these disorders. After briefly reviewing the mechanisms associated with antibody accumulation in the CSF and the various techniques used to measure these changes, this chapter will provide an overview of the CSF abnormalities associated with the most common primary inflammatory and demyelinating disorders of the CNS (multiple sclerosis (MS), optic neuritis (ON), transverse myelitis (TM), neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM)). The CSF profile associated with CNS involvement in the setting of sarcoidosis will also be considered. The reader is referred to Chapter 17 for details related to the CSF abnormalities in common systemic connective tissue disorders.

MEASUREMENT OF INTRATHECAL ANTIBODY RESPONSES Under physiological conditions, most proteins enter the CSF by passage across the blood–CSF barrier (BCB). Molecular size and plasma concentration are two main factors that determine the concentration of a given protein in this compartment. Immunoglobulins (Ig), for example, are large molecules that are found in CSF at low levels relative to plasma. Both the absolute concentrations of IgG in CSF, as well as its relative proportion compared to albumin or total protein levels, can rise as the BCB becomes more permeable during

acute or chronic CNS inflammation. Three overlapping mechanisms account for the CSF IgG levels found during an inflammatory process of the CNS: an existing component found under physiological conditions, a locally synthesized component that accumulates due to intrathecal production, and a component that results from enhanced transudation across an abnormally permeable BCB.1,2 The CSF albumin index (AI), calculated as albuminCSF/ albuminserum×103, provides a simple measure of BBB leakiness; albumin is not synthesized in the CNS, and its detection in CSF is exclusively due to its passage from the serum. Under physiological circumstances, the concentration of albumin in CSF equilibrates at approximately 0.5% of the level found in serum (AI~5.0). Increased CSF albumin concentrations occur with increased permeability of the BBB, but also to some degree with advancing age (Table 24-1). Similarly, the concentration of IgG found in the CSF of normal subjects is approximately 0.25% of that in the serum.2 During CNS inflammation, however, CSF IgG content can preferentially increase over serum levels, reflecting intrathecal synthesis. There are a number of methods used to quantify the amount of locally synthesized IgG in the CSF, each requiring its own assumptions and each with its own constraints. The Tourtellotte formula is a quantitative measurement of IgG synthesis rate inside the BBB; it is based on the proportional crossing of serum IgG and albumin across the BBB. Reiber and Felgenhauer’s formula is an empirically derived quantification of intrathecal IgG synthesis based on differences in permeability between an intact and a damaged BBB. Other formulas include Schuler and Sagar’s formula, the Log IgG index, the Extended IgG index, and the IGGPROD.3 A detailed review of the derivation of these formulas goes beyond the scope of this chapter. The most common method used to estimate intrathecal IgG synthesis in routine clinical practice is the IgG index, calculated as (IgGCSF/IgGserum)/(albuminCSF/albuminserum).

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Table 24-1 Normal Cerebrospinal Fluid Albumin Index (AI) as a Function of Patient Age Age Range 17–30 31–40 41–50 51–60 >60

Normal AI Range 1.7–5.7 1.8–6.8 2.0–7.2 2.1–8.9 3.2–9.0

Most clinical laboratories consider an abnormal CSF IgG index to be greater than 0.70–0.75, although defined upper limits of normal for this parameter range from 0.66 to 0.85 (see Chapter 10). All formulas used to quantify intrathecal IgG are, to some extent, influenced by the presence of BBB damage.4 Still, the IgG index gives valid quantitative determinations even in this setting, and it is generally considered sufficient, together with qualitative determinations of intrathecal Ig synthesis detailed below, for identifying CNS inflammation.3–5 Qualitative evidence of intrathecal Ig production is demonstrated by detecting unique oligoclonal bands (OCBs) in CSF not found in the serum. When CSF or serum proteins are separated by electrophoresis, the Ig fraction can be specifically stained by immunofixation or immunoblotting; distinct banding patterns can be revealed in this setting, referred to as OCBs. Most laboratories consider a positive OCB designation as the presence of two or more distinct bands in the CSF that are not present in a corresponding serum sample. Most OCBs are IgG, although some can be IgM and rarely IgA. Five general electrophoretic patterns of Ig can be detected in CSF (Fig. 24-1): (a) no bands, (b) bands found only in the CSF with no serum correlate, (c) identical bands in the CSF and serum with several additional bands seen only in the CSF, (d) identical bands in both the CSF and serum (mirror pattern), and (e) a pattern consistent with a monoclonal gammopathy. Only the second and third of these patterns

are considered positive for OCB. Of note, the detection of OCB can be masked in the presence of severe BBB disruption, probably due to the ingress of polyclonal IgG from the serum with consequent dilution of the intrathecally synthesized IgG.4 Currently, isoelectric focusing (IEF) performed on agarose gels, followed by immunoblotting for Ig, is considered the gold standard method for detecting OCB. Older techniques that do not utilize IEF, or that require preparative steps such as CSF concentration, yield lower sensitivity and specificity and a recent consensus statement concluded these should no longer be used.1,6

MULTIPLE SCLEROSIS MS is an inflammatory, demyelinating disorder of the CNS that is a leading cause of disability in young adults. Clinically, MS most commonly presents as a relapsingremitting disorder (RRMS) that over time evolves into a secondary-progressive phase of disease (SPMS) associated with the slow accumulation of disability. Approximately 10% of cases, however, have slowly progressive disease from the onset without acute relapses (primary progressive MS; PPMS).7,8 CSF analysis plays an important role in the diagnosis of this disease. According to the widely accepted McDonald criteria, CSF examination can be used to confirm a diagnosis of MS when the clinical and radiographic data are not definitive (Table 24-2).9,10 Currently, there are no reliable CSF biomarkers to track disease progression or response to treatment. Being adjacent to the parenchyma, however, it is hypothesized that changes in CSF composition might eventually be identified that will reflect ongoing disease and/or repair processes. Although many specific candidate markers remain under investigation, none has achieved widespread clinical use. Still, such studies should continue to shed light on the pathogenesis of this complex neuroimmunological disorder. Conventional and experimental CSF profiles found in MS will be discussed here.

Figure 24-1 Five general electrophoretic patterns of immunoglobulins can be detected in CSF (left lane) compared to the serum (right lane): (a) no bands detected in either sample, (b) bands found only in the CSF with no serum correlate, (c) identical bands present in the CSF and serum with several additional bands seen only in the CSF, (d) identical bands detected in both the CSF and serum (mirror pattern), and (e) a restricted pattern consistent with a monoclonal gammopathy. Of these, only the second and third patterns are interpreted as positive for OCB.

Multiple Sclerosis

Table 24-2 Role of Cerebrospinal Fluid Analysis in the Diagnosis of Multiple Sclerosis Disease With Progression From Onset 1. One year of disease progression (retrospectively or prospectively determined), plus 2. Two (2) of the following: a. Positive brain MRI (≥9 T2 lesions, or ≥4 T2 lesions with a positive VEP) b. Positive spinal cord MRI (≥2 focal T2 lesions) c. Positive CSF analysis (IEF evidence of ≥2 OCBs, elevated IgG index, or both) Two or More Clinical Attacks, Objective Clinical Evidence of One Lesion 1. Two or more MRI-detected lesions consistent with MS, but scans that do not fulfill criteria for dissemination in space*, plus 2. Positive CSF analysis (IEF evidence of ≥2 OCBs, elevated IgG index, or both) One Clinical Attack, Objective Clinical Evidence of One Lesion 1. MRI scans that meet full criteria for dissemination in space*, or two or more MRI-detected lesions consistent with MS, plus positive CSF analysis (IEF evidence of ≥2 OCBs, elevated IgG index, or both), and 2. MRI evidence of dissemination in time*, or second clinical attack See Ref. 10 for the complete MS diagnostic criteria. *See Ref. 10 for current MRI criteria of disease dissemination in space and time. MRI, magnetic resonance imaging; VEP, visual evoked potential; CSF, cerebrospinal fluid; IEF, isoelectric focusing; OCB, oligoclonal bands; IgG, immunoglobulin G.

Cell count The CSF cell count is typically normal or only mildly elevated in most MS patients.11 A CSF pleocytosis (defined as >5 WBCs/mm3) has been reported in anywhere from 13 to 62% of randomly selected cases,12,13 although most large cohorts suggest only one-third of cases exhibit this finding. A CSF cell count above 50 WBC/mm3 should prompt consideration of an alternative diagnosis such as an infectious or neoplastic disorder of the CNS.12,14 When white blood cells (WBC) are present, there is usually a predominance of lymphocytes, although other cell types can occasionally be identified as well (see below). The relationship between a CSF pleocytosis and clinical disease features has been extensively investigated in MS, but no consistent correlations have been found. A few studies suggest that a pleocytosis can be identified more frequently in MS patients during clinical disease exacerbations as compared to cases in remission,13,15 especially in women and in younger patients.13 The highest mean numbers of CSF mononuclear cells have been found in those patients with the least disability, as well as those with shorter disease duration or earlier disease onset. Conversely, low CSF leukocyte counts are more typically associated with longer disease durations.15 Detailed longitudinal studies in individual patients are rare. Immunophenotyping of lymphocytes in the CSF of MS patients has revealed that about two-thirds are CD4+T cells.16,17 Thus, the CD4+/CD8+ ratio is usually

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elevated, often as high as 4.0. Mature B cells typically constitute only 2.5–5.0% of the total CSF cell population.16,17 Low numbers of plasma cells are reported in the CSF of up to 97% of MS patients, most frequently in cases of longer duration.13 Despite these interesting trends, lymphocyte phenotyping has no defined role in the routine diagnosis of MS at present because it lacks diagnostic specificity. Up to 5–10% of CSF cells in MS patients are of nonlymphoid origin. One study of 47 patients with MS found no CSF neutrophils,18 while another study using electron microscopy of the CSF sediment revealed the presence of rare neutrophils, even if there was no correlation with the clinical phase of disease.19 Rarely, a higher proportion of neutrophils can be found in the CSF of patients with hyperacute demyelinating syndromes. Myeloid and plasmacytoid dendritic cells have been reported to constitute up to 0.3–0.6% of CSF cell populations in MS patients.20 The majority of non-lymphoid cells in the CSF, however, remain uncharacterized. A correlation between gadolinium-enhancing lesion volume on cranial magnetic resonance imaging (MRI) scans and CSF WBC count has been described.21 Similarly, an elevated CSF WBC count correlated with subsequent MRI disease activity.21 In this study, having >5 WBCs/mm3 found in the CSF was associated with a greater risk of developing gadolinium-enhancing lesions over the next 1–2 years, as well as with a higher number of clinical relapses during the first year after the CSF analysis was performed.21

Total protein and glucose content The total CSF protein concentration is within normal limits in two-thirds of patients with MS and is mildly increased (50–70 mg/dl) in the other third.15 A CSF protein level in excess of 70 mg/dl is uncommon, and levels above 100 mg/dl should prompt reconsideration of the diagnosis to include infectious, connective tissue, and neoplastic diseases. As is the case in normal individuals, the major protein represented in CSF during MS is albumin; its absolute value in one study during disease (23.47 mg/dl) was slightly higher compared to healthy controls (17.81 mg/dl).22 Still, CSF albumin levels are within normal limits among the majority (76.7%) of MS patients.23 Other studies have suggested that any increase in total CSF protein content in the setting of MS is largely attributable to its increased content of IgG (1.5 mg/dl in healthy individuals vs. 5.7 mg/dl in MS patients).22 A more detailed discussion of the analysis of CSF Ig content in MS will follow below. Elevated total protein content can be found in MS patients with severe disability and longer durations of the disease, an observation that remains significant even when corrected for age.2,15 In one study, evidence of high molecular weight protein transudation was found in 100% of patients with PPMS, in 93% of patients with SPMS, but only in 18% of patients with RRMS.2

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Glucose levels are invariably normal in the CSF of MS patients.1

Measures of blood–brain barrier integrity In practice, measures traditionally used to demonstrate impaired BBB integrity are more commonly used to exclude alternative diagnoses rather than to support a diagnosis of MS. Although careful neuropathology studies suggest that there is chronic, diffuse BBB damage in MS on top of acute, focal BBB disruptions in areas of active demyelination,24–26 measures such as the AI are reported to be normal in more than 90% of patients.27 Thus, an AI in the range of 5.0–7.0 is generally seen in patients with MS, although marked increases in this parameter are rarely seen.1 Clinically, such BBB disturbances have been associated with longer disease durations and higher degrees of neurological disability.28,29

Immunoglobulin measurements Evidence of an active intrathecal humoral immune response is the most specific routine CSF finding used to support of a diagnosis of MS. As described above, three components may contribute to the IgG found in the CSF in MS: a physiological component (3–12% of total CSF protein), a component due to transudation across an abnormally permeable barrier, and a locally synthesized component. Since the total protein concentration of CSF is rarely elevated in MS, transudation of large amounts of IgG across a very permeable barrier is unlikely.2 The immunoglobulin measurements of CSF are both qualitative and quantitative; these measurements are used together to demonstrate intrathecal antibody synthesis. While absolute IgG concentrations can be increased in MS, demonstrating intrathecal synthesis relies on a normalized measure such as the IgG index. The IgG index is increased in approximately 82–91% of MS patients.2,11 Indeed, along with the qualitative detection of more than one unique OCB, elevation of this quantitative parameter continues to be an important part of the recently revised diagnostic criteria for MS.9,10 The presence of multiple OCBs in the CSF not found in the serum represents a qualitative demonstration of an intrathecal antibody response. With IEF performed on agarose gels followed by immunoblotting, two or more OCBs are found in the CSF of more than 95% of MS patients.12,14 The specificity of such a finding for an MS diagnosis is reported to be approximately 87%,30 but since the presence of OCBs is used to establish a diagnosis of MS in clinically suspected cases, these high figures may be somewhat biased. Even in childhood MS, OCBs have been demonstrated in up to 92% of patients.31 Attempts to correlate the IgG index value or the number of OCBs with clinical and MRI features in MS patients have not led to consistent findings across multiple studies.

Some suggest that patients with higher CSF IgG concentrations or higher IgG indices have a greater level of disability or are more likely to experience subsequent clinical deterioration.2 These reports, however, remain unconfirmed. In contrast, no correlation between CSF IgG concentration and the time from onset of the last relapse has been found.2 In terms of disease duration, some studies have suggested that CSF gammaglobulin levels tend to be low early in the course of MS, rising to a plateau and then falling among patients who have been afflicted more than 15 years.2 Again, however, consistent findings are lacking to the degree that such information can be applied to therapeutic decision-making in an individual patient. The OCB pattern in a given patient tends to persist over periods ranging from 7 to 12 years,31 and it is not significantly affected by immunomodulatory or immunosuppressive treatment. Small studies have found some correlation between intrathecal IgG synthesis rate and lesion burden on cranial MRI,32,33 as well as between IgG index and T2 lesion load;34 again these findings remain unconfirmed. Another recent study suggested that an elevated IgG index correlates with African-American ethnicity, but not with other demographic or clinical features.35 In summary, an abnormal IgG index and/or the presence of multiple unique OCBs in CSF can support a diagnosis of MS, but their absolute values hold no added clinical or prognostic significance.36,37 Abnormal Ig fractions other than IgG can also be found in the CSF of MS patients. Oligoclonal IgM can be detected in the CSF of 30–55% MS cases.11 Some investigators have suggested that IgM OCB might predict more recent or active immunological stimulation and thus an unfavorable disease course,38 but this has not been confirmed. Conversely, intrathecal IgA is distinctly uncommon in MS.11 Free kappa light chain (FKLC) portions of the Ig molecule have been detected in the CSF of up to 60% of MS patients.39 These FKLC levels appear to remain relatively stable over time, and concentrations are not significantly affected by various disease-modifying treatments.39 An abnormal light chain ratio in the CSF of MS patients has also been described, with a predominance of IgGκ over IgGλ bands.5 Finally, the antigenic specificities of antibodies found in the CSF of MS patients are largely unknown. Anti-viral and anti-myelin antibodies enriched in the CSF compared to the serum have both been demonstrated, but these rarely correspond to OCBs. Such assessments are not used in routine diagnosis.

OCB-negative MS An occasional patient with clinically definite MS (CDMS) lacks evidence of intrathecal IgG synthesis; one study of 1,422 MS patients found that 5.5% did not have detectable OCBs in the CSF.40 Although the absence of such a finding has been identified as one of five “red flag” features that should cast doubt on the diagnosis, post-mortem studies

Multiple Sclerosis

have confirmed that OCBs may be absent in pathologically confirmed MS cases. Several studies have suggested that the absence of CSF OCBs is associated with a relatively benign disease course and possibly a delayed progression from a clinically isolated syndrome (CIS) to CDMS,38,41 although other studies have not been able to establish such correlation.39,40 One report found that 50% of OCBnegative patients developed OCB over a mean follow-up interval of 4 years.41 Other suggestions of differences linked to OCB-negative MS patients reported in the literature (most of which do not reach statistical significance nor have been confirmed) include: a higher proportion of men, a higher representation of PPMS, older age at disease onset, and a lower number of MRI abnormalities.40 Such OCB-negative patients may benefit less from treatment with interferon compared to OCB-positive patients;42 this finding has not been validated and the OCB status alone should not guide therapeutic decisions. In summary, OCBs are not absolutely necessary for making a diagnosis of MS, and clinical and radiographic differences between OCB-positive and OCB-negative MS patients remain to be confirmed.

CSF profiles during relapses and remissions It is well known that MS patients without significant disability may have widespread CNS involvement by MRI. Moreover, widespread and active CNS inflammation may be evident by gadolinium enhancement on MRI with no clinical correlation. By extension, one would not expect a clear association between CSF changes and active clinical symptoms.2 Still, numerous groups have noted some change in total CSF WBC count between relapse and remission among individual patients.43 Some 48–67% of patients were found to have a CSF pleocytosis when examined within 2 months after a relapse, compared to only 30–33% when CSF analysis was delayed beyond 2 months after the last clinical attack. Entirely negative findings have also been reported in this regard.2 Studies attempting to correlate MRI and CSF parameters have shown a significant link between the number of gadolinium-enhancing MRI lesions and the total CSF WBC count.34 The total protein content of CSF has not been found to vary in relation to clinical exacerbation or remission. The IgG index or other quantitative measures of relative IgG concentration may fluctuate somewhat during the course of the disease, but again without a clear correlation between relapse and remission.44,45 The OCB pattern does not typically change with clinical exacerbation or remission.45

Comparing CSF profiles between RRMS, PPMS and SPMS No single marker (CSF or otherwise) has been reliably associated with a particular subtype or phase of MS; the values of individual parameters for CSF overlap too much

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to be useful as discriminating tools. Still, a CSF pleocytosis may be more frequent in RRMS (93%) compared to PPMS (50%) in several small studies.18,28 Similarly, median leukocyte numbers were reported to be higher in RRMS (11.0 WBC/mm3) than in PPMS (5.4 WBC/mm3) in one of these reports,28 but not the other.18 Conversely, elevated CSF protein levels were more common in PPMS compared to RRMS (31% vs. 15%), with slightly higher absolute median values in PPMS (37 mg/dl) than in RRMS (33 mg/dl).18 This difference was largely attributed to higher CSF IgG levels, which were more common (75% vs. 63%) and had higher absolute value (7.1 mg/dl vs. 4.2 mg/dl) in PPMS compared to RRMS.18 The IgG index was not found to be significantly different between the two MS subtypes.18 Raised CSF IgG levels and higher IgG indices were, however, correlated with a greater degree of disability.2,18 An increased AI has also been reported in SPMS compared to RRMS, suggesting that damage to the BBB is more diffuse in this phase of disease.46

Effect of MS treatments on CSF composition No CSF marker to date has been identified that either predicts or reflects a given patient’s response to treatment. Serial lumbar puncture (LP), therefore, does not have a defined role in the management of most MS patients beyond their utility in facilitating an initial diagnosis. Thus, data regarding changes in CSF composition following the initiation of immunomodulatory therapy are scarce.

Methylprednisolone High-dose intravenous methylprednisolone (IVMP) therapy is the standard treatment for MS relapses – it speeds the rate of recovery, normalizes BBB permeability, and suppresses gadolinium enhancement on MRI in and around acutely demyelinated lesions.47 One study showed that high-dose IVMP (1,000 mg/day) slightly diminished the proportion of patients with a CSF pleocytosis 10 days later (51.4% vs. 42.2%).47 Studies that have investigated the effects of shorter courses and lower doses of corticosteroids have not consistently found significant treatment effects on CSF cell counts.32,47 Similarly, the IgG index was reported to improve following treatment with IVMP by one group,48 but this finding was not confirmed in another study.47 When a reduction of the CSF IgG index was found, a return to pretreatment levels occurred within 30 days for 50% of the patients, and by 147 days for all of the subjects in this cohort.32 As mentioned, the CSF OCB pattern has consistently been found to remain stable over time, even in the setting of ongoing immmunomodulatory or immunosuppressive treatment.11

Interferon Interferon beta-1a is an approved immunomodulatory treatment for RRMS. This drug was found to significantly

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reduce total CSF WBC counts over an observation period of 104 weeks compared to pretreatment baseline.21 No treatment-related effect on the CSF IgG index, FKLC level, or OCB number was described, all of which remained stable over the course of the study.21

Natalizumab Natalizumab is a humanized monoclonal antibody that binds to and blocks the function of the α4-integrin adhesion molecule expressed by all WBCs except neutrophils. The drug was designed to prevent the extravasation of leukocytes into tissues by preventing their interactions with its cognate ligand, vascular cell adhesion molecule 1 (VCAM-1). Leukocyte cell counts and phenotypes have been tracked in the CSF of treated MS patients. These studies showed that the numbers of CD4+ and CD8+ T cells, CD19+ B cells, and CD138+ plasma cells were significantly lower in CSF following treatment, and that these values remained persistently depressed for up to 6 months after the cessation of treatment.49 It was further observed that the CD4+/CD8+ ratio of T cells in the CSF was decreased in treated patients, but normalized by 6 months after therapy was discontinued. It is therefore hypothesized that natalizumab impairs immune surveillance within the CNS, perhaps accounting for the increased risk for opportunistic infection with JC virus observed in treated patients.50

Research findings The search for CSF biomarkers able to reliably diagnose MS, distinguish between clinical subtypes, and predict the future course of disease is an active area of research. To date, however, no single marker has been sufficiently correlated with current or future disease-related events. The data remain contradictory for many of the markers under investigation, perhaps in part due to a lack of standardized measurement techniques.51,52 Nevertheless, various CSF markers have been proposed to identify such pathological processes as parenchymal inflammation, demyelination, BBB disruption, neuroaxonal loss, gliosis, and remyelination. Other markers are sought as specific diagnostic tools to distinguish MS from other related neurological disease. Some of these data will be reviewed here.

Proposed markers of demyelination and remyelination Levels of the myelin protein, myelin basic protein (MBP), have been reported increased in the CSF of some 80% of MS patients during acute relapses, and these levels may remain elevated for a period of 5–6 weeks after the clinical attack.53 CSF MBP levels are also raised in approximately 40% of patients with non-relapsing, progressive disease.53 Still, finding high MBP levels in the CSF (>5 ng/ml) does not necessarily imply the presence of a primary demyelinating disorder, since any significant white matter pathology may cause the release of myelin degradation products into

the subarachnoid space. As such, MBP should be considered a non-specific marker of tissue damage.54 Other proteins have been measured in CSF as markers of demyelination, but with little clinical relevance ascribed at present. In one study, patients with progressive MS showed lower CSF levels of neural cell adhesion molecule (N-CAM) than non-disease controls; levels in RRMS patients during acute disease relapses did not differ from controls, while in the weeks following an exacerbation, N-CAM levels showed significant increases, in step with clinical improvement.54 Although MRI data were not available for correlation, these data suggest that this marker could reflect the remyelination process.

Proposed markers of neuroaxonal loss Recent histopathological studies suggest that axonal damage is a frequent event within active MS lesions,55 and many have hypothesized this could be the cellular substrate of irreversible disease progression known to occur in this disease.56,57 As a result, numerous neuroaxonal proteins have been sought in the CSF of MS patients as potential markers of this cellular injury process and as possible predictors of future clinical disease progression. Conflicting reports exist in the medical literature at present regarding the expression and utility of these CSF markers in different MS populations. Elevated CSF levels of actin, tubulin, neurofilament light chain (NF-L), neurofilament heavy chain (NF-H), neuron-specific enolase (NSE), tau, microtubuleassociated phosphoprotein, and 14-3-3 protein constitute only a partial list of markers implicated in some clinical event in MS pathogenesis.53,58–61 While some are touted as risk factors that predict the conversion of CIS patients to CDMS, others are proposed as indicators or even predictors of increased disease severity among existing MS patients.31,53,62 Recently, a molecule known to inhibit axonal regrowth, Nogo-A, was selectively found in the CSF of RRMS and SPMS patients and was hypothesized to reflect a failure of axonal regeneration within the CNS.63 At this point, while an exciting concept, none of these CSF biomarkers has proven themselves to be reliable enough for use in routine clinical practice.

Proposed markers of inflammation Numerous inflammatory markers have been measured in the CSF of MS patients: studies find high levels of soluble adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), VCAM-1, L-selectin, platelet/endothelial cell adhesion molecule-1 (PECAM-1), and E-selectin);64–68 skewed cytokine profiles with preferentially elevated type-1 T cell-derived cytokines (TNF-α, IL-1β, IFN-γ, IL-2, IL-6, and IL-12) and relatively decreased type-2 T cell cytokines (IL-4, IL-10, and TGF-β);68 elevated chemokines (CCL5, CXCL10, CCL2, CXCL12, CXCL13, CCL19, and CCL21);68 increased oxidation products of nitric oxide;68–70 high β-2-microglobulin levels;71 variable changes in C3 and C4 concentrations;72 and high isoprostane, Fas, neopterin,

Optic Neuritis and Other Clinically Isolated Syndromes

αB-crystallin, and matrix metalloprotease-9 (MMP-9) levels.54,73–75 All of these mediators are proposed in some way to be involved in MS pathogenesis, but none yet has any clinically relevant role in clarifying the diagnosis or in guiding therapy.

Autoantibodies Autoantibodies reactive against a variety of self antigens (CNS and otherwise) have been identified in the CSF of MS patients, including ones that are specific for MBP, myelinassociated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein, transaldolase, β2-glycoprotein I, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, heterogeneous nuclear ribonucleoprotein B1, as well as anti-nuclear antibodies (ANA) and anti-cardiolipin antibodies.73,76,77 Early reports that anti-MOG antibodies were increased in patients with CIS, RRMS, and SPMS, but not PPMS, have not been subsequently confirmed in either serum or CSF samples.78 Their respective roles in disease pathogenesis versus simply being markers of cellular injury remain unknown.

T cell subsets Studies of the precise phenotype and functional properties of T cells in the CSF of MS patients have long been pursued as a means to understand the inflammatory process going on behind the BBB. Some of these studies have shown that CD4+ T cells found in the CSF of MS patients are predominantly of a central memory phenotype, expressing high levels of the chemokine receptors, CCR7 and CXCR3.79,80 Conversely, there are decreased numbers of naive CD4+ T cells in CSF, especially during active disease.81,82 Recently, enrichment of the CD25hiFoxP3+ regulatory CD4+ T cell population has also been described in the CSF,83 and highly differentiated CD8+ T cells and memory B cells are found at higher levels in this compartment compared to the periphery.84,85

Proteomics studies Proteomics is the large-scale study of protein expression in biological samples. This unbiased approach to characterize protein phenotypes has been applied to CSF samples from MS patients with the goal of identifying disease biomarkers and/or proteins with pathogenic relevance. Different methods include two-dimensional protein electrophoresis, which separates individual proteins based on their size and isoelectric point, and more sophisticated approaches using various forms of mass spectrometry.86 Proteomics studies of CSF samples have led to the construction of protein expression maps in both MS and various other CNS inflammatory diseases. Several proteins identified in this manner appear uniquely expressed in MS, including CRTAC-1B (a cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a cell signaling glycoprotein), and autotoxin T (a phosphodiesterase).87 Other proteomics studies have

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identified alpha-1-antitrypsin, alpha-1-acid glycoprotein, haptoglobin, transferrin, transthyretin, cystatin C, neurotrimin, chromogranin B, and prostaglandin D synthase as being elevated in the CSF of MS patients compared to controls.73 The significance of these proteins remains to be clarified, but it is hoped that an MS-specific protein expression pattern can eventually be identified for use as a diagnostic tool, as well as to shed more light on disease pathogenesis.

OPTIC NEURITIS AND OTHER CLINICALLY ISOLATED SYNDROMES Some 85% of patients who develop MS first experience an acute or subacute episode of symptoms attributable to a single CNS lesion. This presentation is referred to as a CIS. Acute monosymptomatic ON is the most common and best-studied CIS, representing 21% of all these events.88 While CIS patients with abnormal cranial MRI imaging are known to be at greater risk of conversion to clinically definite MS, CSF abnormalities have a predictive value in this early setting as well. Thus, ON patients with evidence of inflammation in the CSF (raised WBC count, multiple unique OCBs, or both) have a 49% risk of a subsequent MS conversion over the next 15 years, compared to a 23% rate among those with normal CSF.89 The CSF findings in acute monosymptomatic ON of all etiologies will be reviewed here.

Cell count A CSF pleocytosis occurs in 28–38% of all patients with acute monosymptomatic ON.90 Median values reported in the literature vary between 3 and 7 WBCs/mm3, and actual ranges between 0 and 134 WBCs/mm3.90 One study found that when the LP was performed early (6–17 days after onset of symptoms), 57% of patients had mononuclear pleocytosis.91 In contrast, when the procedure was delayed (18–293 days after onset), the proportion decreased to 34% of cases.91 In this same study, a mononuclear cell pleocytosis was the only CSF abnormality found in 4 out of 59 patients.91 Similar to MS, the highest cell counts were observed in the younger patients.92 Most of these cells were mononuclear in origin (lymphocytes and monocytes), but a small proportion was polymorphonuclear neutrophils (PMNs).90 There is no consensus as to the prognosis for visual recovery, response to corticosteroid treatments, or likelihood of conversion to MS based on the magnitude or phenotype of the cellular infiltrate in the CSF of patients with isolated ON.

Total protein and glucose content Total protein and glucose levels in CSF, as well as CSF to serum albumin quotient, are almost always normal in acute monosymptomatic ON.90,93,94

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Immunoglobulin measurements The IgG index has been reported to be elevated in anywhere from 17 to 100% of acute ON patients, ranging as high as 1.8 in some studies.90,93,95 Some 36–76% of patients with acute monosymptomatic ON or other CIS are found to have multiple unique OCBs in their CSF.93–96 Thus, both are common but not universal findings in this situation.

Other abnormalities Elevated levels of MBP have been described in the CSF of about one-third of patients with isolated ON.90,93 However, these measurements have no role in the routine diagnostic process nor do they carry any known prognostic significance.

Predictive value of CSF for conversion to CDMS One or more CSF abnormalities are found in 79% of patients with acute monosymptomatic ON who go on to develop CDMS in studies that follow individuals over the long term. The IgG index and presence of multiple unique OCBs are considered the most specific CSF findings, while a mononuclear pleocytosis is considered somewhat less specific.92 The presence of OCBs is the second strongest predictor of subsequent conversion to CDMS, after the presence of one or more white matter lesions on cranial MRI scans.88 One study found that during a follow-up period of 6–36 months, 28% of ON patients converted to CDMS; 94% of these individuals had had CSF OCB on their initial examination.91 FKLCs were reported in the CSF of 27% of ON patients, more than half of whom went on to develop MS over the next 2 years.95

Various factors predict recurrent disease, including multifocal lesions within the spinal cord, demyelinating lesions in the brain by MRI, the presence of CSF OCBs, known underlying mixed connective tissue disorder, or positive serum autoantibodies (most notably SS-A). Preliminary studies suggest that patients with persistently abnormal CSF cytokine profiles, which are admittedly not a part of a routine CSF analysis, may also be at risk for recurrent TM; these results await validation.98 Finally, acute partial TM and acute complete TM may be distinct entities with somewhat different underlying causes and prognoses. Compared to partial TM, complete TM patients appear less likely to relapse and have very low transitional rate to CDMS.100 This section will discuss typical CSF findings in acute TM.

Cell count A CSF pleocytosis is described in 20–42% of all TM patients. Total WBC counts range between 0 and 950 WBC/mm3, typically with a lymphocytic predominance.98,101–105 Reliable data addressing the typical differential WBC count or any longitudinal fluctuation of cell counts in response to disease progression, resolution, or treatment are lacking in the literature.

Total protein and glucose content An increased total protein level in CSF is described in 42–50% of TM patients. Mean protein levels range between 22 and 1,120 mg/dl.97,98,101,105 With regard to glucose levels, one study reported that an increased CSF glucose level (above 3.45 mmol/l or 62 mg/dl) was associated with a worse functional outcome.106 Typically, however, CSF glucose levels are normal.

ACUTE TRANSVERSE MYELITIS Immunoglobulin measurements Acute transverse myelitis (TM) refers to any immunemediated process causing neural injury to the spinal cord with a defined rostral level. It can occur in the setting of multifocal CNS disease such as MS, during systemic inflammatory diseases such as connective tissue disorders, or as an isolated, idiopathic entity. This latter category accounts for approximately 10–45% of all TM cases.97 Most occur as an isolated episode, although TM can relapse up to 20% of the time.98 In the clinical setting of an acute myelopathy, the demonstration of inflammation by CSF analysis, with a pleocytosis or an elevated IgG Index, or via gadolinium enhancement on spinal MRI is diagnostic of TM.98 Routine CSF studies are reported to be abnormal in up to 94% of acute TM cases.99 Should the inflammatory criteria not be met at symptom onset, it is recommended that an MRI and LP be repeated 2–7 days later. Symptoms commonly stop progressing after 2–3 weeks, following which both CSF and MRI abnormalities stabilize and then begin to resolve.98

OCBs have been described in the CSF of 0–17% of all TM patients at the time of acute presentation.97,101,102 Their presence, of either an IgG or an IgM isotype, is associated with an increased risk of subsequently developing CDMS.107 When only partial TM syndromes are considered, OCB were found in 90% of patients who subsequently went on to develop MS over a mean follow up interval of 35 months, compared to 36.4% in patients who did not.108 In contrast, patients with complete TM rarely exhibited CSF OCB.109 An elevated IgG index (>0.7) has been reported in 20–46% of patients.102,106

Predictive value of CSF for conversion to CDMS Acute partial TM may be the initial manifestation of MS. The utility of an abnormal brain MRI scan in predicting long-term outcome in the context of acute TM has been

Neuromyelitis Optica (Devic’s Disease)

studied, and, like acute ON, such radiographic changes render patients high risk for developing MS. In the setting of a normal brain MRI scan, however, CSF analysis can provide useful predictive data. Thus, longitudinal studies report that some 10–33% convert to CDMS over a followup period of up to 5 years.110 Most of these patients developed MS within 16 months, and, in one study, nobody developed MS after 24 months.110 Here, 55% of patients with partial TM had abnormal CSF defined by the presence of two or more CSF OCBs or an elevated IgG index, or both; all patients who developed MS had abnormal CSF. Thus, an abnormal CSF predicted a 53% conversion rate to MS within 2 years of onset.110

Other biomarkers Recently, several authors have found that detecting 14-3-3 proteins in the CSF of patients with acute TM acquired at the time of clinical nadir accurately predicted an adverse long-term neurological outcome.98,101,111,112 Further studies will need to confirm these findings. From the standpoint of the pathogenesis of this rare and poorly understood disorder, there are data to suggest that elevated CSF levels of the inflammatory cytokine, IL-6, are found in many cases of acute TM.98 Studies in experimental animals suggest that this mediator is pathogenic in the spinal cord, and, by extension, that it may contribute to neurodegeneration in humans.

NEUROMYELITIS OPTICA (DEVIC’S DISEASE) NMO is characterized by severe episodes of inflammatory demyelination, with or without clinical recovery, largely restricted to the optic nerves and spinal cord. Diagnostic criteria proposed in 1999 laid out three absolute requirements: optic neuritis, acute myelitis, and no symptoms implicating other CNS regions. To enhance specificity, fulfillment of at least one of three major supportive criteria was required: (1) brain MRI at disease onset is normal or does not fulfill MS imaging criteria; (2) spinal cord MRI shows a lesion extending over at least three vertebral segments; and (3) CSF reveals at least 50 WBC/mm3 or at least 5 PMNs/mm3. The recent description of a highly specific serum biomarker for NMO (NMO-IgG), representing antibodies reactive to the aquaporin-4 (AQP4) water channel, has extended the clinical spectrum of NMO to include somewhat more limited forms of the disease such as recurrent, longitudinal extensive TM and recurrent ON. Therefore, new diagnostic criteria for NMO have been proposed that incorporate this biomarker, replacing CSF abnormalities as a major supportive criterion. The new criteria also allow for the presence of demyelinating changes outside the optic nerve and spinal cord.113,114 Some 34–50% of NMO patients have a normal CSF profile at their initial presentation.115,116 The most common abnormality is a CSF

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pleocytosis; since significant cellularity is reported only within 4 weeks of symptom onset, sampling during acute disease exacerbations may yield a higher sensitivity.113,117

Cell count A CSF pleocytosis of >50 WBC/mm3 or >5 PMNs/mm3 in the appropriate clinical context supports a diagnosis of NMO.113 Mean total CSF WBC counts reported in the literature fall between 28 and 57 WBC/mm3 (range, 0–2,645 WBC/mm3).118,119 Total CSF PMN counts can range between 1 and 2,169 cells/mm3.118 With longitudinal CSF examinations, fluctuation in the magnitude of the pleocytosis has been reported, with increased cellularity generally occurring with clinical relapses.120 In one study, 26.7% of NMO patients had a pleocytosis greater than or equal to 50 WBC/mm3 during relapse, compared to only 4.4% during remission.121 In this setting, a PMNpredominant pleocytosis, ranging between 74 and 94% of the WBC count, has been reported.117,122 Of interest, when CSF analysis was performed within one week of symptom onset, cell counts were generally lower (range, 20–60 WBC/mm3) than when performed more than 10 days after symptom onset (mean, 60 WBC/mm3; range, 2–200 WBC/mm3).116

Total protein and glucose content Total CSF protein levels are often elevated in NMO patients.119 In one longitudinal study, fluctuations in CSF protein concentration correlated with disease exacerbations, ranging between 209 and 640 mg/dl during relapses, and between 33 and 63 mg/dl during remissions.117 Other studies have reported less striking increases in total protein content, with values above 50 mg/dl in only 17% of patients.121 Of interest, when LPs were performed within 1 week of symptom onset, the protein concentration was lower (50–60 mg/dl) than if performed more than 10 days after symptom onset (mean 104 mg/dl; range, 58– 240 mg/dl);116 hence some of the variability reported in the literature may be related to the timing of CSF analysis. BBB breakdown, as assessed by the AI, has been reported to be abnormal in 16–83% of NMO patients.121,122 This has also been reported to be associated more with the acute phase of the disease.120 CSF glucose levels have largely been normal.116,120

Immunoglobulin measurements The IgG index is elevated in no more than 8% of NMO patients.121 In one longitudinal study, this value varied between a mean of 0.64 during remission and 0.74 during active disease, with a normal value of < 0.70.120 OCBs are also typically absent from the CSF of most NMO patients. Some 14–35% of patients have detectable OCBs on initial examination,118,121–123 but the majority of these individuals

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are negative on subsequent testing.120,121,123 This finding is in stark contrast with the stability of the OCB pattern typically observed in MS.123 Since the antigenic target of the recently identified NMO-IgG biomarker, AQP4, is mainly expressed in the brain and spinal cord, it has been natural to look for the antibody in CSF. Indeed, anti-AQP4 has been detected in the CSF of NMO patients, although only at CSF:serum ratios of approximately 1:500.124 This finding is taken to mean that there is no intrathecal production of the antibody.124 Furthermore, in light of the much lower values found in CSF, biomarker measurement in this compartment is not considered to be of any routine diagnostic value.

Experimental biomarkers NF-H, a putative biomarker of axonal damage in the CNS, was found in one study to be significantly elevated in 25% of CSF samples from patients with NMO.125 The eotaxins (Eo-2 and Eo-3), selective eosinophil chemoattractants and activators, and eosinophil cationic protein, an eosinophil granule protein, have all been found at elevated levels in the CSF of NMO patients.126 Likewise, the number of cells secreting IgM antibodies specific for MOG is also higher in this disorder.126 These findings have no role in routine diagnosis of NMO at the present, even if they do shed some interesting light on disease pathogenesis.

ACUTE DISSEMINATED ENCEPHALOMYELITIS ADEM is a multifocal, usually monophasic, inflammatory demyelinating disorder of the CNS, commonly triggered by preceding infection or vaccination. It can occur at any age, but is more frequent in children than adults. More rapidly progressive, fulminant variants (acute hemorrhagic leukoencephalitis) occur in 1–2% of children.127 In adults, as many as 30–35% of cases first presenting as ADEM subsequently evolve into typical MS, with clear dissemination in both space and time over a follow-up period of about 3 years; in children, the conversion to MS occurs in 10–15% of patients.128 Abnormalities of CSF content have been reported in some 20–30% of pediatric ADEM patients and in 50–80% of adults.129–131 These data will be reviewed here.

cells have been found in the CSF of 65% of cases.130 One study found that among 20 patients with severe ADEM requiring intensive care unit admission, 75% had CSF pleocytosis, which were about two-thirds lymphocytes and one-third neutrophils.137 This study probably does not represent typical ADEM, given that a mortality rate of 25% was also reported in this cohort.137 Of note, adverse outcome did not correlate to the CSF findings.137 Another study reported a median value of 1% neutrophils (range, 0–87%); no clinical correlation with the WBC differential was provided.132

Total protein and glucose content In pediatric ADEM patients, approximately 45–60% of patients have an elevated CSF protein level.134 Across pediatric cohorts, median protein concentrations were 32 mg/dl, with a range between 14 and 672 mg/dl.129,132,133 In adults, median CSF protein levels were 63 mg/dl, with a range between 25 and 268 mg/dl.130,136 An abnormal AI has been reported in ADEM, but a low median value of 1.2 was noted in one sizable study.136 Glucose levels can vary between 47 and 269 mg/dl, with a median value of 62 mg/dl.132

Immunoglobulin measurements In children with ADEM, unique OCBs have been detected in CSF in fewer than 30% of cases.88 Only 13% of patients had elevated total CSF IgG levels, and nearly all showed a normal CSF IgG index.88 In adults, OCBs were found in the CSF of nearly 60% of ADEM patients in one study, but other cohorts have reported closer to a 20–30% positivity rate.90,91,94 Furthermore, OCBs tend to disappear from the CSF over time in ADEM.128,134 When positive, intrathecal synthesis of IgG was found in 38%, IgM in 27%, and IgA in 23% of cases.91 A BBB disturbance was found in 23–71% of cases, with a median CSF AI of 7.6 (range, 2.4–28.8).90,94 Thus, intrathecal antibody synthesis occurs in a significant subset of ADEM patients, but certainly at a rate much lower than in MS.

Opening pressure A mildly elevated opening pressure was described in approximately one-third of adult patients with ADEM in one study; the maximal reported value was 33 cm H2O.131

Cell count

Experimental findings

In children with ADEM, a lymphocytic pleocytosis is reported to occur in 39–69% of patients (median, 15–51 WBC/mm3; range, 0–340 WBC/mm3).129,132–135 Similarly in adults, a lymphocytic pleocytosis has been described (median, 30–52 WBC/mm3; range, 3–472 WBC/mm3). 130,136 In adults, one study found that only 25% of patients had a CSF WBC count in excess of 30 cells/mm3.128 Plasma

Elevated levels of numerous growth factors, cytokines, and chemokines have been described in the CSF during ADEM. A partial list includes G-CSF, IFN-γ, IL-6, IL-8, IL10, CXCL1, CXCL7, CXCL10, CCL1, CCL3, CCL5, CCL17, and CCL22.93,94 While it has been suggested that patterns among these individual mediators may aid in the differentiation of ADEM from other inflammatory CNS

Monoclonal Immunoglobulin Bands in CSF

disorders, this has yet to be confirmed. At present, these measurements have no role in routine diagnostic evaluation of suspected ADEM cases.

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cases.140 These OCBs are typically transient when assayed by repeat testing.138

Angiotensin converting enzyme NEUROSARCOIDOSIS Sarcoidosis is a multi-system disease of unknown etiology with a propensity to form granulomatous lesions, particularly in the lungs. Some 5–10% of patients have clinical evidence of CNS disease, although autopsy studies detect occult involvement of the CNS parenchyma or the meninges via histopathological analyses in up to three-quarters of cases. Thus, it is not surprising that some 80% of patients with neurosarcoidosis are found to have abnormal CSF findings.95 Numerous studies have reported normalization of CSF parameters with treatment, so interpretation of laboratory data must account for preceding or ongoing therapy.138

Cell count A CSF pleocytosis has been described in 31–72% of patients with untreated neurosarcoidosis.96,97 Values range between 1 and 235 WBC/mm3 (mean, 61 WBC/mm3), with a mononuclear cell predominance in most patients.96,98 Higher CSF cell counts are typically associated with a greater degree of meningeal involvement.99 A high CD4+/CD8+ ratio has been described in some patients, and a ratio above 5.0 in undiagnosed patients has been proposed to strongly suggest the diagnosis.100,101 Prominent CSF eosinophilia (up to 17% eosinophils) has been reported in a small number of pathologically confirmed cases,102 making neurosarcoidosis a diagnostic consideration in this setting.

Total protein and glucose content Elevated total CSF protein levels have been described in 66–80% of patients with neurosarcoidosis, with values ranging from 25 to 314 mg/dl and a mean concentration of 138 mg/dl.96,97,99,103 Increased AIs are described in about 50% of patients,98,99,103 often with normalization following treatment with steroids or immunosuppressants.103 Glucose levels are decreased in the CSF in 18–31% of patients,97,103 typically to a range of 30–40 mg/dl.104,138 This, again, is more common in patients with prominent meningeal symptoms or with severe disseminated neurosarcoidosis.105

Angiotensin converting enzyme (ACE) is a membrane-bound glycoprotein present at high levels in the epithelioid cells of the granulomas that develop in sarcoidosis. It is thus felt to be a useful marker of systemic sarcoidosis, since serum ACE activity is elevated in 58–88% of all patients. In neurosarcoidosis, serum ACE activity is high in only 23–25% of patients, while CSF ACE activity is reported in 33–58% of patients with otherwise proven CNS involvement.142–144 In one study, a range of 3–21 U/ml was found using a kinetic enzyme method; using a discriminator value of 8 U/ml, the assay had a sensitivity of 55% and a specificity of 94% in a cohort of well-characterized patients.143 Using inhibitorbinding assays, CSF levels of 1.42 U/ml have been reported in neurosarcoidosis.145 A significant correlation was found between CSF ACE activity and total CSF protein levels, while no correlation was found with CSF WBC counts or with serum ACE levels. Values of CSF ACE have been reported to fluctuate in the individual neurosarcoidosis patient in parallel with their neurological signs.142 As such, CSF ACE may be of help in supporting a diagnosis of neurosarcoidosis and, in the individual patient, may be of some help in monitoring disease activity. It is important, however, to recognize that similar elevations can be found in other CNS diseases, such as meningitis; therefore this test must be evaluated in the clinical context together with the full CSF profile.146

Other markers Serum lysozyme is a product of activated monocytes and macrophages and is often elevated during active sarcoidosis, similar to ACE.147 β-2-Microglobulin is present on the surface of all nucleated cells and forms the light chain of Class I HLA antigens; cell turnover is associated with its release into body fluids. β-2-Microglobulin has been found to be elevated in the serum of patients with active sarcoidosis, and declines during steroid treatment, and thus has been proposed as a marker of disease activity.142 Lysozyme and β-2-microglobulin have also been reported to be elevated in the CSF of 75% and 68% of neurosarcoidosis patients, respectively142,145 with ranges between 0.05 and 1.11mg/l and 1.6 and 14.7mg/l.142,145 Their utility as biomarkers of neurosarcoidosis remains to be confirmed.

Immunoglobulin measurements There are varied reports of the CSF IgG index in neurosarcoidosis, with some studies suggesting it can be increased up to 80% of the time.11,139 Unique CSF OCBs have been described in as many as 30–50% of patients,11,140,141 while paired serum and CSF OCBs (mirror pattern), indicative of systemic synthesis, have been described in 18.5% of

MONOCLONAL IMMUNOGLOBULIN BANDS IN CSF Monoclonal immunoglobulin bands in the CSF are not common. In a survey of 1,490 samples, a total of three CSF specimens had a monoclonal immunoglobulin band.

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In this study, one patient had chronic inflammatory demyelinating polyneuropathy, one had B cell lymphoma with an extradural lumbar vertebral mass, and one had lymphomatoid granulomatosis with central nervous system involvement.148 In another study, 6,000 CSF samples were re-examined; in only 33 samples (0.55%) a single band was found in the absence of a corresponding serum band.149 Among these cases, the few patients who had repeated analysis demonstrated a stable monoclonal pattern.149 Of the 20 patients for whom full data were available, seven (35%) had CDMS and another seven (35%) had other white matter diseases of the CNS, including TM and ON. The remaining patients had inflammatory peripheral nerve disease, inflammatory CNS gray matter disease (lupus, paraneoplastic disease), and non-inflammatory CNS disease (torsion dystonia, superficial hemosiderosis).149 A third study found that in 27 cases of monoclonal CSF immunoglobulin bands, nine patients went on to develop an oligoclonal pattern, 13 had a persistent monoclonal pattern, and five lost evidence of intrathecal immunoglobulin synthesis. Of the patients who subsequently developed an oligoclonal pattern, most were diagnosed with CDMS. Among those with persistent monoclonal pattern, there was one CIS suggestive of MS, three cases of CNS infection, one CNS lymphoma, one axonal neuropathy, and seven cases without any other evidence of infection, inflammation, or demyelination.150

CONCLUSIONS Inflammatory and demyelinating diseases of the CNS are very commonly associated with abnormal CSF composition. The most notable findings include a lymphocytic pleocytosis, variably increased total protein content, markers of BBB disruption, and evidence of abnormal intrathecal antibody responses. Accordingly, LP can and should be performed in the clinical and radiographic setting that suggests such a disease process. Ongoing and future studies of CSF composition seem likely to shed further light on the pathogenesis of these disorders, and they may identify unique biomarkers that will eventually serve as reliable diagnostic tools. REFERENCES 1. Freedman MS. Primary progressive multiple sclerosis: cerebrospinal fluid considerations. Mult Scler 2004;10 Suppl 1:S31–S35. 2. Walker RWH, Thompson EJ, McDonald WI. Cerebrospinal fluid in multiple sclerosis: relationships between immunoglobulins, leucocytes and clinical features. J Neurol 1985;232:250–259. 3. Blennow K, Fredman P, Wallin A, et al. Formulas for the quantitation of intrathecal IgG production. Their validity in the presence of blood-brain barrier damage and their utility in multiple sclerosis. J Neurol Sci 1994;121:90–96.

4. Gallo P, Bracco F, Tavolato B. Blood-brain barrier damage restricts the reliability of quantitative formulae and isoelectric focusing in detecting intrathecally synthesized IgG. J Neurol Sci 1988;84:87–93. 5. Hershey LA, Trotter JL. The use and abuse of the cerebrospinal fluid IgG profile in the adult: a practical evaluation. Ann Neurol 1980;8:426–434. 6. Jenkins MA, Cheng L, Ratnaike S. Multiple sclerosis: use of light-chain typing to assist diagnosis. Ann Clin Biochem 2001;38:235–241. 7. Thompson A. Overview of primary progressive multiple sclerosis (PPMS): similarities and differences from other forms of MS, diagnostic criteria, pros and cons of progressive diagnosis. Mult Scler 2004;10:S2–S7. 8. Wolinsky JS, PROMiSe Study Group. The diagnosis of primary progressive multiple sclerosis. J Neurol Sci 2003;206:145–152. 9. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127. 10. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840–846. 11. Reske D, Petereit HF, Heiss WD. Difficulties in differentiation of chronic inflammatory diseases of the central nervous system–value of cerebrospinal fluid analysis and immunological abnormalities in the diagnosis. Acta Neurol Scand 2005;112:207–213. 12. Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 2005;62:865–870. 13. Zeman D, Adam P, Kalistova H, Sobek O, Andel J, Andel M. Cerebrospinal fluid cytologic findings in multiple sclerosis: a comparison between patient subgroups. Acta Cytol 2001;45:51–59. 14. Olsson T. Cerebrospinal Fluid. Ann Neurol 1994;36:S100–S102. 15. Olsson JE, Link H, Muller R. Immunoglobulin abnormalities in multiple sclerosis: relation to clinical parameters: disability, duration and age of onset. J Neurol Sci 1976;27:233–245. 16. Oreja-Guevara C, Sindern E, Raulf-Heimsoth M, Malin JP. Analysis of lymphocyte subpopulations in cerebrospinal fluid and peripheral blood in patients with multiple sclerosis and inflammatory diseases of the nervous system. Acta Neurol Scand 1998;98:310–313. 17. Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 2005;62:258–264. 18. Kleine TO, Zwerenz P, Graser C, Zofel P. Approach to discriminate subgroups in multiple sclerosis with cerebrospinal fluid (CSF) basic inflammation indices and TNF-alpha, IL-1beta, IL-6, and IL-8. Brain Res Bull 2003;61:327–346. 19. Herndon RM, Kasckow J. Electron microscopic studies of cerebrospinal fluid sediment in demyelinating disease. Ann Neurol 1978;4:515–523. 20. Pashenkov M, Huang YM, Kostulas V, Haglund M, Soderstrom M, Link H. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 2001;124:480–492. 21. Rudick RA, Cookfair DL, Simonian NA, et al. Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNb-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. J Neuroimmunol 1999;93:8–14. 22. Kjellin KG, Hallander LB. Determination of CSF proteins by a simple and rapid immunonephelometric method. J Neurol 1980;223:35–42. 23. Eickhoff K, Wikstrom J, Poser S, Bauer H. Protein profile of cerebrospinal fluid in multiple sclerosis with special reference to the function of the blood brain barrier. J Neurol 1977;214:207–215. 24. Barnes D, Munro PM, Youl BD, Prineas JW, McDonald WI. The longstanding MS lesion: a quantitative MRI and electron microscopic study. Brain 1991;114:1271–1280. 25. Vos CM, Guerts JJ, Montagne L, et al Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis. Neurobiol Dis 2005;20:953–960.

References

26. Leech S, Kirk J, Plumb J, McQuaid S. Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis. Neuropathol Appl Neurobiol 2007;33:86–98. 27. Christenson RH, Behlmer P, Howard JF Jr, Winfield JB, Silverman LM. Interpretation of cerebrospinal fluid protein assays in various neurologic diseases. Clin Chem 1983;29:1028–1030. 28. Baum K, Nehrig C, Girke W, Brau H, Schorner W. Multiple sclerosis: relations between MRI and CT findings, cerebrospinal fluid parameters and clinical features. Clin Neurol Neurosurg 1990;92:49–56. 29. Sellebjerg F, Christensen M, Neilsen PM, Fredericksen JL. Cerebrospinal fluid measures of disease activity in patients with multiple sclerosis. Mult Scler 1998;4:475–479. 30. Schneider R, Euler B, Rauer S. Intrathecal IgM-synthesis does not correlate with the risk of relapse in patients with a primary demyelinating event. Eur J Neurol 2007;14:907–911. 31. Rinker JR, Trinkaus K, Cross AH. Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis. Neurology 2006;67:1288–1290. 32. Baumhefner RW, Tourtellotte WW, Syndulko K, Staugaitis A, Shapshak P. Multiple sclerosis intra-blood-brain-barrier IgG synthesis: effect of pulse intravenous and intrathecal corticosteroids. Ital J Neurol Sci 1989;10:19–32. 33. Brandao CO, Ruocco HH, Farias AS, et al. Intrathecal immunoglobulin G synthesis and brain injury by quantitative MRI in multiple sclerosis. Neuroimmunomodulation 2006;13:89–95. 34. Wang HY, Matsui M, Saida T. Immunological disturbances in the central nervous system linked to MRI findings in multiple sclerosis. J Neuroimmunol 2002;125:149–154. 35. Rinker JR, Trinkaus K, Naismith RT, Cross AH. Higher IgG index found in African American versus Caucasians with multiple sclerosis. Neurology 2007;69:68–72. 36. Thompson EJ, Freedman MS. Cerebrospinal fluid analysis in the diagnosis of multiple sclerosis. Adv Neurol 2006;98:147–160. 37. Walsh MJ, Tourtellotte WW. Temporal invariance and clonal uniformity of brain and cerebrospinal IgG, IgA, and IgM in multiple sclerosis. J Exp Med 1986;163:41–53. 38. Annunziata P, Giorgio A, De Santi L, et al. Absence of cerebrospinal fluid oligoclonal bands is associated with delayed disability progression in relapsing-remitting MS patients treated with interferonbeta. J Neurol Sci 2006;244:97–102. 39. Koch M, Heersema D, Mostert J, Teelken A, De Keyser J. Cerebrospinal fluid oligoclonal bands and progression of disability in multiple sclerosis. Eur J Neurol 2007;14:797–800. 40. Imrell K, Landtblom AM, Hillert J, Masterman T. Multiple sclerosis with and without CSF bands: clinically indistinguishable but immunogenetically distinct. Neurology 2006;67:1062–1064. 41. Zeman AZ, Kidd D, McLean BN, et al. A study of oligoclonal band negative multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60:27–30. 42. Polman C, Kappos L, Freedman MS, et al. Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta1b. J Neurol 2008;255:1–10. 43. Matsui M, Araya S, Wang HY, Matsushima K, Saida T. Differences in systemic and central nervous system cellular immunity relevant to relapsing-remitting multiple sclerosis. J Neurol 2005;252:908–915 44. Olsson JE, Link H. Immunoglobulin abnormalities in multiple sclerosis. Arch Neurol 1973;28:392–399. 45. Rifai N, Christenson RH, Gelman BB, Silverman LM. Changes in cerebrospinal fluid IgG and apolipoprotein E indices in patients with multiple sclerosis during demyelination and remyelination. Clin Chem 1987;33:1155–1157. 46. Jongen PJ, Lamers KJ, Doesberg WH, Lemmens WA, Hommes OR. Cerebrospinal fluid analysis differentiates between relapsing-remitting and secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;63:446–451.

221

47. Wang HY, Matsui M, Araya S, Onai N, Matsushima K, Saida T. Immune parameters associated with early treatment effects of high-dose intravenous methylprednisolone in multiple sclerosis. J Neurol Sci 2003;216:61–66. 48. Frequin ST, Barkhof F, Lamers KJ, Hommes OR, Borm GF. CSF myelin basic protein, IgG and IgM levels in 101 MS patients before and after treatment with high-dose intravenous methylprednisolone. Acta Neurol Scand 1992;86:291–297. 49. Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743–747. 50. Stuve O, Marra CM, Bar-Or A, et al. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 2006;63:1383–1387. 51. Laman JD, Thompson EJ, Kappos L. Body fluid markers to monitor multiple sclerosis: the assays and the challenges. Mult Scler 1998;4:266–269. 52. Jongen PJ, Lamers KJ, Doesberg WH, Lemmens WA, Hommes OR. Cerebrospinal fluid analysis differentiates between relapsing-remitting and secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;63:446–451. 53. Giovannoni G. Multiple sclerosis cerebrospinal fluid biomarkers. Dis Markers 2006;22:187–196. 54. Massaro AR. Are there indicators of remyelination in blood or CSF of multiple sclerosis patients? Mult Scler 1998;4:228–231. 55. Trapp BD, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med (1998) 338(5):278–285. 56. Bjartmar C, Trapp BD. Axonal degeneration and progressive neurologic disability in multiple sclerosis. Neurotox Res 2003;5:157–164. 57. Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 2003;206:165–171. 58. Malmestrom C, Haghighi S, Rosengren L, Andersen D, Lycke J. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 2003;61:1720–1725. 59. Haghighi S, Andersen D, Oden A, Rosengren L. Cerebrospinal fluid markers in MS patients and their healthy siblings. Acta Neurol Scand 2004;109:97–99. 60. Zaffaroni M. Biological indicators of the neurodegenerative phase of multiple sclerosis. Neurol Sci 2003;24:S279–S282. 61. Teunissen CE, Dijkstra C, Polman C. Biological markers in CSF and blood for axonal degeneration in multiple sclerosis. Lancet Neurol 2005;4:32–41. 62. Jongen PJ, Lycklama A, Niejholt G, et al. Cerebrospinal fluid IgM Index correlates with cranial MRI lesion load in patients with multiple sclerosis. Eur Neurol 2007;58:90–95. 63. Jurewicz A, Matysiak M, Raine CS, Selmaj K. Soluble Nogo-A, an inhibitor of axonal regeneration, as a biomarker for multiple sclerosis. Neurology 2007;68:283–287. 64. Baraczka K, Nekam K, Pozsonyi T, Jakab L, Szongoth M, Sesztak M. Concentration of soluble adhesion molecules (sVCAM-1, sICAM-1 and sL-Selectin) in the cerebrospinal fluid and serum of patients with multiple sclerosis and systemic lupus erythematosus with central nervous involvement. Neuroimmunomodulation 2001;9:49–54. 65. Waubant E. Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis. Dis Markers 2006;22:235–244. 66. McDonnell GV, McMillan SA, Douglas JP, Droogan AG, Hawkins SA. Serum soluble adhesion molecules in multiple sclerosis: raised sVCAM-1, sICAM-1 and sE-selectin in primary progressive disease. J Neurol 1999;246:87–92. 67. Elovaara I, Ukkonen M, Leppakynnas M, et al. Adhesion molecules in multiple sclerosis: relationship to subtypes of disease and methylprednisolone therapy. Arch Neurol 2000;57:546–551. 68. Uccelli A, Pedemonte E, Narciso E, Mancardi G. Biological markers of the inflammatory phase of multiple sclerosis. Neurol Sci 2003;24:S271–S274.

222

Chapter 24

●

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69. Drulovic J, Dujmovic I, Mesaros S, Levic Z, Mostarica-Stojokvic M. Raised cerebrospinal fluid nitrite and nitrate levels in patients with multiple sclerosis: no correlation with disease activity. Mult Scler 2001;7:19–22. 70. Yuceyar N, Taskiran D, Sagduyu A. Serum and cerebrospinal fluid nitrite and nitrate levels in relapsing-remitting and secondary progressive multiple sclerosis patients. Clin Neurol Neurosurg 2001;103:206–211. 71. Adachi N. Beta-2-microglobulin levels in the cerebrospinal fluid: their value as a disease marker. Eur Neurol 1991;31:181–185. 72. Jongen PJ, Doesburg WH, Lemmens WA, Hommes OR, Lamers KJ. Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system. Acta Neurol Scand 2000;101:116–121. 73. O’Connor KC, Roy SM, Becker CH, Hafler DA, Kantor AB. Comprehensive phenotyping in multiple sclerosis: discovery based proteomics and the current understanding of putative biomarkers. Dis Markers 2006;22:213–225. 74. Boylan MT, Crockard AD, McDonnell GV, McMillan SA, Hawkins SA. Serum and cerebrospinal fluid soluble Fas levels in clinical subgroups of multiple sclerosis. Immunol Lett 2001;78:183–187. 75. Stoevring B, Vang O, Christiansen M. aB-crystallin in cerebrospinal fluid of patients with multiple sclerosis. Clin Chim Acta 2005;356: 95–101. 76. Kolln J, Ren HM, Da RR, Zhang Y, Olek M, Hilgenberg LG, Smith MA, van den Noort S, Qin Y. Triosephosphate isomerase- and glyceraldehydes-3-phosphate dehydrogenase-reactive autoantibodies in the cerebrospinal fluid of patients with multiple sclerosis. J Immunol 2006;177:5652–5658. 77. Sueoka E, Yukitake M, Iwanaga K, Sueoka N, Aihara T, Kunoda Y. Autoantibodies against heterogeneous nuclear ribonucleoprotein B1 in CSF of MS patients. Ann Neurol 2004;56:778–786. 78. Zadro I, Brinar V, Horvat G, Brinar M. Clinical relevance of antibodies against myelin oligodendrocyte glycoprotein in different clinical types of multiple sclerosis. Clin Neurol Neurosurg 2007;109:23–26. 79. Kivisäkk P, Trebst C, Liu Z, et al. T-cells in the cerebrospinal fluid express a similar repertoire of inflammatory chemokine receptors in the absence or presence of CNS inflammation: implications for CNS trafficking. Clin Exp Immunol 2002;129:510–518. 80. Kivisäkk P, Mahad DJ, Callahan MK, et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol 2004;55:627–638. 81. Oksaranta O, Tarvonen S, Ilonen J, Poikonen K, Reunanen M, Salonen R. T-cell subpopulations in the cerebrospinal fluid and peripheral blood of patients with multiple sclerosis: a follow-up study. Neurology 1996;47:1542–1545. 82. Zaffaroni M, Gallo L, Ghezzi A, Cazzullo CL. CD4+ lymphocyte subsets in the cerebrospinal fluid of multiple sclerosis and non-inflammatory neurological diseases. J Neurol 1991;238:209–211. 83. Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H. Increased frequency of CD4+CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol 2007;147:412–418. 84. Jilek S, Schluep M, Rossetti AO, Le Goff G, Pantaleo G, Du Pasquier RA. CSF enrichment of highly differentiated CD8+ T cells in early multiple sclerosis. Clin Immunol 2007;123:105–113. 85. Harp C, Lee J, Cameron E, Olson G, Frohman E, Racke M, Monson N. Cerebrospinal fluid B cells from multiple sclerosis patients are subject to normal germinal center selection. J Neuroimmunol 2007;183:189–199. 86. Han MH, Hwang SI, Roy DB, et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008;451:1076–1081. 87. D’Aguanno S, Del Boccio P, Bernardini S, Di Ilio C, Frederici G, Urbani A. Electrophoretic separations of cerebrospinal fluid proteins in clinical investigations. Clin Chem Lab Med 2007;45:437–449. 88. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural

89. 90. 91.

92.

93.

94.

95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107.

108. 109.

history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4:281–290. Nilsson P, Larsson EM, Maly-Sundgren P, Perfekt R, SandbergWollheim M. Predicting the outcome of optic neuritis: evaluation of risk factors after 30 years of follow-up. J Neurol 2005;252:396–402. Frederiksen JL, Whitaker JN. Cerebrospinal fluid myelin basic proteinlike material in acute monosymptomatic optic neuritis. Acta Neurol Scand 1996;94:303–309. Soderstrom M, Lindqvist M, Hillert J, Kall TB, Link H. Optic neuritis: findings on MRI, CSF examination and HLA class II typing in 60 patients and results of a short-term follow-up. J Neurol 1994;241:391–397. Frederiksen JL, Larsson HBW, Lesen J. Correlation of magnetic resonance imaging and CSF findings in patients with acute monosymptomatic optic neuritis. Acta Neurol Scand 1992;86:317–322. Frederiksen JL, Sindic CJM. Intrathecal synthesis of virus-specific oligoclonal IgG, and of free kappa and free lambda oligoclonal bands in acute monosymptomatic optic neuritis. Comparison with brain MRI. Mult Scler 1998;4:22–26. Tumani H, Tourtellotte WW, Peter JB, Felgenhauer K. Acute optic neuritis: combined immunological markers and magnetic resonance imaging predict subsequent development of multiple sclerosis. J Neurol Sci 1998;155:44–49. Rolak LA, Beck RW, Paty DW, Tourtellotte WW, Whitaker JN, Rudick RA. Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial. Neurology 1996;46:368–372. Kuhle J, Lindberg RL, Regeniter A, et al. Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF. J Neurol 2007;254:160–168. Pidcock FS, Krishnan C, Crawford TO, Salorio CF, Trovato M, Kerr DA. Acute transverse myelitis in childhood: center-based analysis of 47 cases. Neurology 2007;68:1474–1480. Kaplin AI, Krishnan C, Deshpande DM, Pardo CA, Kerr DA. Diagnosis and management of acute myelopathies. Neurologist 2005;11:2–18. Al Deeb SM, Yaqub BA, Bruyn GW, Biary NM. Acute transverse myelitis: a localized form of postinfectious encephalomyelitis. Brain 1997;120:1115–1122. Scott TF, Kassab SL, Singh S. Acute partial transverse myelitis with normal cerebral magnetic resonance imaging: transition rate to clinically definite multiple sclerosis. Mult Scler 2005;11:373–377. De Seze J, Lanctin C, Lebrun C, et al. Idiopathic acute transverse myelitis: application of the recent diagnostic criteria. Neurology 2005;65:1950–1953. Kim K. Idiopathic recurrent transverse myelitis. Arch Neurol 2003;60:1290–1294. Brinar VV, Habek M, Brinar M, Malojcic B, Boban M. The differential diagnosis of acute transverse myelitis. Clin Neurol Neurosurg 2006;108:278–283. Seifert T, Enzinger C, Storch MK, Pichler G, Fazekas F. Relapsing acute transverse myelitis: a specific entity. Eur J Neurol 2005;12:681–684. Harzheim M, Schlegel U, Urbach H, Klockgether T, Schmidt S. Discriminatory features of acute transverse myelitis: a retrospective analysis of 45 patients. J Neurol Sci 2004;217:217–223. Bruna J, Martinez-Yelamos S, Rubio F, Arbizu T. Idiopathic acute transverse myelitis: a clinical study and prognostic markers in 45 cases. Mult Scler 2006;12:169–173. Bashir K, Whitaker JN. Importance of paraclinical and CSF studies in the diagnosis of MS in patients presenting with partial cervical transverse myelopathy and negative cranial MRI. Mult Scler 2000;6:312–316. Cordonnier C, de Seze J, Breteau G, et al. Prospective study of patients presenting with acute partial transverse myelopathy. J Neurol 2003;250:1447–1452. Scott TF. Nosology of idiopathic transverse myelitis syndromes. Acta Neurol Scand 2007;115:371–376.

References

110. Perumal J, Zabad R, Caon C, et al. Acute transverse myelitis with normal brain MRI: long-term risk of MS. J Neurol 2008;255:89–93. 111. Finsterer J, Voigtlander T. Elevated 14-3-3 protein and axonal loss in immunoglobulin-responsive, idiopathic acute transverse myelitis. Clin Neurol Neurosurg 2002;105:18–22. 112. Irani DN, Kerr DA. 14-3-3 protein in the cerebrospinal fluid of patients with acute transverse myelitis. Lancet 2000;355:901. 113. Wingerchuk DM, Lennon VA, Pittock SM, Luchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–1489. 114. Saiz A, Zuliani L, Blanco Y, Tavolato B, Giometto B, Graus F, SpanishItalian NMO Study Group. Revised diagnostic criteria for neuromyelitis optica (NMO): Application in a series of suspected patients. J Neurol 2007;254:1233–1237. 115. Ghezzi A, Bergamaschi R, Martinelli V, et al. Clinical characterisitics, course and prognosis of relapsing Devic’s Neuromyelitis Optica. J Neurol 2004;251:47–52. 116. Fardet L, Genereau T, Mikaeloff Y, Fontaine B, Seilhean D, Cabane J. Devic’s neuromyelitis optica: study of nine cases. Acta Neurol Scand 2003;108:193–200. 117. Milano E, Di Sapio A, Malucchi S, et al. Neuromyelitis optica: importance of cerebrospinal fluid examination during relapse. Neurol Sci 2003;24:130–133. 118. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999;53:1107–1114. 119. De Seze J, Stojkovic T, Ferriby D, et al. Devic’s neuromyelitis optica: clinical, laboratory, MRI and outcome profile. J Neurol Sci 2002;197:57–61. 120. Piccolo G, Franciotta DM, Camana C, et al. Devic’s neuromyelitis optica: long-term follow-up and serial CSF findings in two cases. J Neurol 1990;237:262–264. 121. Zaffaroni M, The Italian Devic’s Study Group. Cerebrospinal fluid findings in Devic’s neuromyelitis optica. Neurol Sci 2004;25:S368–S370. 122. O’Riordan JI, Gallagher HL, Thompson AJ, et al. Clinical, CSF, and MRI findings in Devic’s neuromyelitis optica. J Neurol Neurosurg Psychiatry 1996;60:382–387. 123. Bergamaschi R, Tonietti S, Franciotta D, et al. Oligoclonal bands in Devic’s neuromyelitis optica and mulitple sclerosis: differences in repeated cerebrospinal fluid examinations. Mult Scler 2004;10:2–4. 124. Takahashi T, Fujihara K, Nakashima I, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 2007;130:1235–1243. 125. Miyazawa I, Nakashima I, Petzold A, Fujihara K, Sato S, Itoyama Y. High CSF neurofilament heavy chain levels in neuromyelitis optica. Neurology 2007;68:865–867. 126. Correale J, Fiol M. Activation of humoral immunity and eosinophils in neuromyelitis optica. Neurology 2004;63:2363–2370. 127. Tenembaum S, Chitnis T, Ness J, Hahn JS, International Pediatric MS Study Group. Acute disseminated encephalomyelitis. Neurology 2007;68 Suppl2:S23–S36. 128. De Seze J, Debouverie M, Zephir H, et al. Acute fulminant demyelinating disease: a descriptive study of 60 patients. Arch Neurol 2007;64:1426–1432. 129. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology 2002;59:1224–1231. 130. Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology 2000;56:1313–1318.

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131. Hollinger P, Sturzenegger M, Mathis J, Schroth G, Hess CW. Acute disseminated encephalomyelitis in adults: a reappraisal of clinical, CSF, EEG and MRI findings. J Neurol 2002;249:320–329. 132. Leake JA, Albani S, Kao AS, et al. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J 2004;23:756–764. 133. Ishizu T, Minohara M, Ichiyama T, et al. CSF cytokine and chemokine profiles in acute disseminated encephalomyelitis. J Neuroimmunol 2006;175:52–58. 134. Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 2000;123:2407–2422. 135. Murthy SN, Faden HS, Cohen ME, Bakshi R. Acute disseminated encephalomyelitis in children. Pediatrics 2002;110:e21. 136. Franciotta D, Zardini E, Ravaglia S, et al. Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis. J Neurol Sci 2006;247: 202–207. 137. Sonneville R, Demeret R, Klein I, et al. Acute disseminated encephalomyelitis in the intensive care unit: clinical features and outcome of 20 adults. Intensive Care Med 2008;34:528–532. 138. Marangoni S, Argentiero V, Tavolato B. Neurosarcoidosis: clinical description of 7 cases with a proposal for a new diagnostic strategy. J Neurol 2006;253:488–495. 139. Borucki SJ, Nguyen BV, Ladoulis CT, McKendall RR. Cerebrospinal fluid immunoglobulin abnormalities in neurosarcoidosis. Arch Neurol 1989;46:270–273. 140. Zajicek JP, Scolding NJ, Foster O, et al. Central nervous system sarcoidosis – diagnosis and management. Q J Med 1999;92:103–117. 141. McLean BN, Miller DH, Thompson EJ. Oligoclonal banding of IgG in CSF, blood-brain barrier function, and MRI findings in patients with sarcoidosis, systemic lupus erythematosus, and Behçet’s disease involving the nervous system. J Neurol Neurosurg Psychiatry 1995;58:548–554. 142. Oksanen V, Gronhagen-Riska C, Tikanoja S, Somer H, Fyhrquist F. Cerebrospinal fluid lysozyme and beta 2-microglobulin in neurosarcoidosis. J Neurol Sci 1986;73:79–87. 143. Tahmoush AJ, Amir MS, Connor WW, et al. CSF-ACE activity in probable CNS neurosarcodosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19:191–197. 144. Jones DB, Mitchell D, Horn DB, Edwards CR. Cerebrospinal fluid angiotensin converting enzyme levels in the diagnosis of neurosarcoidosis. Scot Med J 1991;36:144–145. 145. Oksanen V. New cerebrospinal fluid, neurophysiological and neuroradiological examinations in the diagnosis and follow-up of neurosarcoidosis. Sarcoidosis 1987;4:105–110. 146. Baudin B, Beneteau-Burnat B, and Vaubourdolle M. Angiotensin I-converting enzyme in cerebrospinal fluid and neurosarcoidosis. Ann Biol Clin (Paris) 2005;63(5):475–480. 147. Tomita H, Sato S, Matsuda R, et al. Serum lysozyme levels and clinical features of sarcoidosis. Lung 1999;177:161–167. 148. McCombe PA, Brown NN, Barr AE, Parkin L. Monoclonal immunoglobulin bands in the cerebrospinal fluid. Aust NZ J Med 1991;21:227–229. 149. Ben-Hur T, Abramsky O, River Y. The clinical significance of a single abnormal immunoglobulin band in cerebrospinal fluid electrophoresis. J Neurol Sci 1996;136:159–161. 150. Davies G, Keir G, Thompson EJ, Giovannoni G. The clinical significance of an intrathecal monoclonal immunoglobulin band: a follow-up study. Neurology 2003;60:1163–1166.

CHAPTER

25

Cerebrovascular Disorders Matthew Koenig and Eric M. Aldrich

INTRODUCTION In the past, lumbar puncture (LP) was a major diagnostic tool used in the evaluation of patients with stroke and intracerebral hemorrhage. Indeed, before the routine availability of cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans, examining the cerebrospinal fluid (CSF) for the presence of red blood cells (RBCs) was the primary means of diagnosing subarachnoid hemorrhage (SAH) and intraparenchymal hemorrhage (IPH). Ischemic and hemorrhagic strokes were distinguished from one another by finding xanthochromia or grossly bloody CSF. In ischemic stroke, LP was also routinely used to exclude meningovascular syphilis, a historically common cause of these events. The majority of data reviewed here derive from an era before the routine availability of brain imaging studies. For this reason, autopsy was usually required to confirm ischemic stroke and IPH. This requirement inherently biases the data toward more severe or atypical cerebrovascular presentations. Still, because of the paucity of recent published data on CSF composition in cerebrovascular diseases, we must rely on reports from the past. Since modern brain imaging technologies have become widely available, LP is now reserved for a few specific clinical situations. These include cases where SAH is suspected but not visible on CT. In ischemic stroke, an LP is performed only when there is a clinical suspicion of vasculitis, an underlying infectious process, or meningeal carcinomatosis. Because these conditions are uncommon, many physicians are not familiar with the expected CSF formulation in these diseases. On the other hand, CSF examination is commonly used in the evaluation of acute neurological deficits in a young person, where the differential diagnosis might include both stroke and demyelinating disease. If the LP is delayed for a few days after an ischemic stroke, there is often an inflammatory response with some degree of CSF leukocytosis and a mildly elevated protein content.

Oligoclonal bands and an elevated immunoglobulin (Ig) G index are also not uncommon several days after these events. If the clinician is unfamiliar with the expected CSF composition after a stroke, such data may be mistaken as evidence of an infectious process or even multiple sclerosis. In another common scenario, an LP is performed to evaluate the cause of unexplained fevers in a patient several days after a hypertensive IPH. The CSF in this setting may contain an elevated number of white blood cells (WBCs) with a predominance of polymorphonuclear cells (PMN), elevated total protein content, and a depressed glucose concentration. This may lead to the unnecessary initiation of treatment for suspected bacterial meningitis. The expected CSF findings in a variety of cerebrovascular disorders are described below.

ISCHEMIC STROKE The histological changes that occur in the brain parenchyma over the days and weeks following an acute stroke have been well described. Within 24–72 h, the infarcted tissue is infiltrated by PMNs. After another 72–96 h, macrophages replace many of these PMNs, which may persist for weeks to months as they clear cellular debris. Over subsequent months to years, these inflammatory cells disperse and the infarct becomes encapsulated with a lining of reactive glial cells. Although changes in CSF composition generally parallel these parenchymal pathologies, such alterations are incompletely described in the modern medical literature. Diffusion-weighted MRI has dramatically changed the diagnostic sensitivity and specificity of stroke, as many patients formerly diagnosed with transient ischemic attacks (TIA) now prove to have actual infarctions. Historical data on the composition of CSF in acute ischemic stroke are limited by the exclusion of findings in small strokes misdiagnosed as a TIA and the improper inclusion of data from what were actually small IPHs.

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Table 25-1

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Cerebrovascular Disorders

Composite CSF Findings in Common Cerebrovascular Processes

Opening pressure (cmH2O) RBC count (cells/mm3) WBC count (cells/mm3) Total protein (mg/dl) Glucose (mg/dl)

Ischemic Stroke

IPH

SAH

5% >30 0 0–1,000 (10% >5) 10–560 (50% >45) 20–210 (5% <50)

40% >30 0–900,000 (75% >5) 0–21,000 (10% >5) 5–2,200 (70% >45) 15–113 (10% <50)

70% >30 1,000–3.5 million 5–7,000 (80% >5) 28–1,600 (90% >45) 8–107 (80% <50)

Nevertheless, composite CSF findings in ischemic stroke are summarized in Table 25-1.

Opening pressure Elevated opening pressure (OP) in ischemic stroke depends on the size of infarct, the degree of pre-morbid brain atrophy, and the timing of the LP. Reports of OP after stroke are limited. One series reported 31 patients with ischemic stroke who underwent LP within the first 7 days of symptom onset, most within the first 72 h. The OP was between 20 and 30 mmHg (272–408 mm CSF) in 19% of individuals, >30 mmHg (408 mm CSF) in 6% of cases, and normal in the remaining population.1 In Merritt and Fremont-Smith’s series of 310 autopsy-proven or clinically suspected ischemic stroke patients, 21% had an OP of >20 mmHg (>272 mm CSF), while 4% were between 30 and 40 mmHg (408–544 mm CSF).2 The timing of the LP relative to the ictus was not reported in this series.

Cell count and WBC differential Excessive RBCs and true xanthochromia are not seen in acute ischemic stroke, unless a traumatic LP has occurred. The exception is hemorrhagic conversion of an ischemic stroke, where erythrocytosis or xanthochromia was found in 75% of CSF samples, depending upon the timing of the LP.1 The kinetics of RBC lysis in CSF is similar to that which occurs following primary IPH to be described below. The earliest report of a CSF leukocytosis following ischemic stroke came from Babinski and Gendron, who described a patient with 450 WBCs/mm3 (90% PMNs) 48 h after such an event.3 A second CSF examination performed the following day revealed a decrement to 40 WBCs/mm3, 60% of which were PMNs.3 Aring and Merritt published a series of 56 patients with autopsy-verified ischemic stroke. Antemortem CSF examination revealed 6–50 WBCs/mm3 in 18% of patients, 51–100 WBCs/mm3 in 4% of cases, and >100 WBCs/mm3 in another 7% of individuals.4 The maximum number reported was 3,600 WBCs/mm3. The timing of the LP after symptom onset and the WBC differential were not included in this series, but the authors mentioned that PMNs predominated in most samples. Sörnäs et al. published a series of 92 patients with acute ischemic stroke diagnosed by clinical history, angiography, or autopsy.5 The initial LP was performed within 72 h of symptom onset in all cases. Here, the CSF

of 14% of patients had 5–10 PMNs/mm3 while 11% had >10 PMNs/mm3 and the maximum number was 1,100 PMNs/mm3. On serial CSF examinations, PMNs typically appeared over the first 1–3 days, peaked between day 3 and 5, and normalized after 2 weeks.5 The advent of the cranial CT spurred several case series of CSF composition in ischemic stroke. One group reported 100 consecutive patients with acute ischemic stroke who had an LP within 28 days of ictus, 48% of which were performed within the first week. A hemorrhagic component was excluded by CT. A CSF leukocytosis was reported in 10% of patients, but the exact number of cells and the WBC differential counts were not described.6 Another series reported on 225 ischemic stroke patients who underwent LP within 72 h of symptom onset. Greater than 5 WBCs/mm3 were reported in 8.9% of cases, with a predominance of PMNs in most of these individuals.7 A CSF leukocytosis was more common in patients with superficial strokes than those with deep infarctions.7 Those patients with presumed cardioembolic events were also more likely to have a CSF leukocytosis than strokes of other etiologies.7 In a series of 161 patients with ischemic stroke who underwent LP at a mean of 2.5 days after symptom onset, the mean CSF WBC count was 8 ± 4/mm3 (range 0–550/mm3), and >5 cells/mm3 were found in 12% of cases.8 A higher rate of CSF leukocytosis was reported in 21 patients with hemorrhagic conversion of ischemic stroke, with 35% of these patients presenting with >5 WBCs/mm3. The mean WBC count in these patients was 60 ± 50 cells/mm3 (range 0–940 cells/mm3). 8 The highest CSF leukocytosis ever reported after a stroke was from a patient who had 5,400 WBCs/mm3 in a sample taken 72 h after an ischemic stoke with hemorrhagic conversion.9

Protein concentration Elevated CSF protein concentration is common after ischemic stroke, most likely due to disruption of the blood–brain barrier along with some component of intrathecal antibody synthesis. Strokes occurring near the ventricular surface have been speculated to cause greater CSF protein elevation, but this has never been clearly demonstrated. Carasso et al. reported CSF protein concentrations in 16 patients with ischemic strokes who underwent LP within 72 h of symptom onset.10 Using an upper limit of normal of 45 mg/dl, 44% of patients had elevated CSF protein levels, with a maximum concentration

Ischemic Stroke

of 104 mg/dl.10 Five of these patients, however, had diabetes, which often itself causes elevated CSF protein levels due to radicular demyelination. In another series of 161 patients with ischemic stroke who underwent LP a mean of 2.5 days after symptom onset, the mean CSF protein was 69 ± 40 mg/dl, with a range of 20–470 mg/dl.8 The CSF protein concentration was greater in a series of 21 patients with hemorrhagic conversion after ischemic stroke, with a mean of 114 ± 29 mg/dl and a range of 40–560 mg/dl.8 The time course for normalization of CSF protein levels after stroke has not been delineated, but most authors report normal values 1 month after the ictus. CSF protein concentrations have also been correlated with stroke size and prognosis. Suzuki et al. reported a series of 57 stroke patients who underwent LP within 10 days of symptom onset (mean, 5.7 days). The mean CSF protein was 50.4 ± 23.3 mg/dl (range, 14–133 mg/dl), with a good correlation between higher protein concentration and larger stroke volume on brain CT.11 Another group compared CSF protein concentrations in 42 patients with acute ischemic stroke who underwent LP within 7 days, and six patients with subacute or chronic strokes who underwent LP more than 30 days after their event.12 The median CSF protein level for acute stroke patients was 46.7 mg/dl, with a range of 29.4–219 mg/dl, while the protein concentrations were normal in all 6 patients with remote events.12 In 24 patients who underwent serial LPs, protein concentrations decreased from a median of 51.7 mg/dl on the first day to 46.4 mg/dl on day 5.12 Here, elevated CSF protein concentration was correlated with a greater risk of death or severe disability. Conversely, another study of 312 stroke patients who underwent LP within 7 days showed elevated CSF protein levels in half of patients, but protein concentration did not correlate with stroke severity.13

Glucose concentration There are very few reports of CSF glucose concentrations after ischemic stroke in the published literature. These few reports suggest mild to moderate elevation of CSF glucose concentrations, but they all are marred by a failure to include simultaneous data on serum glucose levels or CSF-to-serum ratios. For the most part, no information is given about the presence of diabetes, the simultaneous use of dextrose-containing intravenous fluids, or the proximity of the LP to meals. In the Merritt and Fremont-Smith series, the mean glucose was 78 mg/dl with a range of 60–133 mg/dl.2 Mrsulja reported CSF glucose concentration in 43 stroke patients who underwent LP within 24 h of symptom onset, excluding patients with known diabetes.14 The mean glucose was 83.9 ± 43.9 mg/dl with a range of 19.8–210.6 mg/dl.14 Serum glucose was not reported. The mean CSF glucose for hospitalized controls without stroke was 33.1 ± 5.8 mg/dl in this study. The time course of CSF glucose elevation was studied by grouping patients into

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4-h intervals after symptom onset. Within 4 h, the mean glucose was 66.4 ± 9.5 mg/dl; it was 90 ± 12.8 mg/dl between 4 and 8 h; 115.2 ± 19.8 mg/dl between 8 and 12 h; 74.7 ± 15.3 mg/dl between 12 and 16 h; and 75.6 ± 15.7 mg/dl between 16 and 24 h.14 In another report of 53 stroke patients undergoing LP within 24 h, CSF glucose was elevated compared to controls throughout the first day.15 The peak mean glucose concentration was 97.2 mg/dl at 7–12 h from symptom onset. The time to normalization of CSF glucose concentration has not been delineated in ischemic stroke.

IgG index The IgG index is used to measure intrathecal antibody synthesis. Because of the frequent presence of inflammatory cells in the CSF after stroke, many studies have investigated cytokine production and inflammatory markers in CSF. Most of these markers remain investigational and are rarely examined in routine clinical practice. The IgG index and the presence of oligoclonal bands, however, are often used as supportive evidence for the diagnosis of multiple sclerosis. Because stroke must occasionally be differentiated from demyelinating disease, it is important to keep in mind the IgG index is often elevated and oligoclonal bands are often detected after ischemic stroke. A series of 57 stroke patients who underwent LP within 10 days of symptom onset demonstrated a range of IgG index values from 0.34 to 0.78, with an upper limit of normal of 0.7.14 The IgG index correlated with stroke volume on head CT, with larger infarcts more likely to have an elevated IgG index. Roström and Link reported a series of 12 patients with CSF oligoclonal bands after ischemic stroke who underwent LP at 1, 3, and 7 days and again between 1 and 3 months after stroke.16 Three quarters of these patients had two or more oligoclonal bands, with a maximum of eight bands found in one patient.16 All bands were of the IgG isotype; no patients had IgA or IgM bands. Only one of 12 patients had bands on the first day after stroke, with most developing between day 2 and 4 after symptom onset. All bands disappeared between day 16 and day 179 in every patient.16 The IgG index was elevated in only one-quarter of patients with oligoclonal bands, with a maximum value of 1.6.16 On the other hand, two studies reported a normal IgG index in all patients with ischemic stroke.13,17

Myelin basic protein Although CSF myelin basic protein (MBP) has proven nonspecific for the diagnosis of multiple sclerosis, it continues to be measured when demyelinating disease is in the differential diagnosis. It is therefore important to appreciate that CSF MBP levels can be elevated in most destructive lesions involving the CNS, including ischemic stroke. In one study of 23 ischemic stroke patients, LPs were performed between day 1 and 3 and again between day 4 and 8 in all patients.18

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Cerebrovascular Disorders

The mean CSF MBP concentration was 4.8 ± 4.0 ng/ml on the first examination and 10.4 ± 11.8 ng/ml on the second examination. CSF from 8 patients with TIA, on the other hand, remained normal on both examinations.18 In stroke patients, the MBP concentration correlated with stroke volume on CT. In another study, 28 ischemic stroke patients underwent LP between 12 and 48 h from symptom onset, at 7 days, and again between 18 and 21 days after the ictus.19 The CSF MBP concentration was normal on the initial examination, elevated after 1 week, and had normalized by 3 weeks.19 Absolute values were not provided.

Tau protein Tau protein is an investigational CSF marker for Alzheimer’s disease (AD). Like S100, neuron-specific enolase, 14-3-3 protein, and other CNS structural proteins, CSF tau tends to be a nonspecific marker of brain injury that spills into the CSF with breakdown of cellular membranes. Because it is often difficult to distinguish vascular dementia from AD on clinical grounds, many investigators have sought more specific CSF markers that distinguish the two disorders. In one study, 26 acute ischemic stroke patients underwent LP on the first day of symptom onset, and again between 2 and 3 days, between 7 and 9 days, at 3 weeks, and between 3 and 5 months. CSF tau was normal on the first day, was elevated between the second and third day, peaked at 1 week, and had normalized between 3 and 5 months.20 The concentration of CSF tau also correlated with stroke volume on CT. A separate series of nine acute stroke patients used the same study design to examine the CSF concentration of tau protein along with phospho-tau, an abnormally phosphorylated form of the protein found in neurofibrillary tangles. In this small study, the CSF tau concentration peaked at 18.7 ± 4.0 pM at 3 weeks and normalized between 3 and 5 months.21 Phospho-tau, on the other hand, remained within the normal range at all time points after stroke, suggesting it may be more specific for AD than total tau.21

a range of 10.2–75 mg/dl.22 The authors speculated that CSF protein elevation may be related to increased vascular permeability in this microangiopathic disease. The cell count was normal in all cases. Oligoclonal bands were present in only one patient, who also had anti-phospholipid antibodies detected in the serum.22

INTRAPARENCHYMAL HEMORRHAGE The profile of CSF after primary IPH parallels the changes seen in ischemic stroke with a few important differences. Just as the accumulation of WBCs in ischemic brain parenchyma is often reflected in the CSF, RBCs and hemoglobin breakdown products are often detected in the CSF of patients with brain hemorrhages. In general, the magnitude of the CSF erythrocytosis and xanthochromia depends on several factors, including the proximity of the hemorrhage to the CSF spaces, the degree of injury to the ventricular wall, the presence of frank extension into the ventricles, and the timing of the LP relative to the ictus. As described with SAH below, there is an expected time course of RBC breakdown in IPH. An excess number of CSF RBCs is present in 75% of primary IPH without direct extension into the ventricles and in 100% of hemorrhages with gross intraventricular extension, provided that the LP is performed within a few days of the hemorrhage.1 RBC hemolysis begins between 12 and 14 h after bleeding, is maximal around the fifth day, and is usually complete after 1–2 weeks.23 In SAH and IPH with intraventricular extension, oxyhemoglobin is metabolized to bilirubin, which can be detected by spectrophotometry or by visual inspection for xanthochromia. In IPH without gross extension into the CSF spaces, oxyhemoglobin is metabolized to methemoglobin within the parenchymal clot and subsequent passage into the CSF.24 CSF methemoglobin has a spectrophotometric absorbance peak distinct from oxyhemoglobin and lends a greenish or muddy discoloration to the CSF rather than the yellowish appearance of true xanthochromia.24

CADASIL Opening pressure Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy leading to strokes and dementia in midadulthood. The disease is characterized by migraine, progressive subcortical dementia, and recurrent strokes and TIAs. The genetic defect involves mutation of the Notch3 gene. Case reports and small case series have reported on a variety CSF abnormalities in CADASIL, including elevated total protein levels, oligoclonal bands, and leukocytoses. The CSF findings were reported in a series of 87 patients with genetically proven CADASIL. A mild elevation in CSF protein concentration was found in 29% of patients, with a mean of 40.4 ± 14.0 mg/dl and

Patients with IPH are more likely to have an elevated OP compared to those with ischemic stroke. Elevated intracranial pressure (ICP) is more likely to occur because of a more sudden increase in intracranial volume from the clot itself compared to the subacute development of edema surrounding a stroke. In one series of 70 patients with autopsy-proven primary IPH, the OP ranged between 30 and 1,100 mm CSF. The OP was greater than 200 mm CSF in 57% of patients, greater than 300 mm CSF 38% of the time, and greater than 400 mm CSF in 19% of individuals.2 In a smaller series of 14 cases of IPH in whom an LP was performed within 4 days of presentation, the OP was normal in 50% of patients, between 200 and 300 mm CSF

Cerebral Venous Thrombosis

15% of the time, and greater than 300 mm CSF in another 35% of individuals.1

Cell count, protein concentration and WBC differential Compared to ischemic stroke, IPH generates a more robust inflammatory cell reaction within the CSF, a higher protein concentration, and even occasional hypoglycorrhachia. This response can sometimes mimic the findings in bacterial meningitis, especially when the LP is performed 3–5 days after the hemorrhage. In a series of 70 autopsy-proven cases of primary IPH, 71% of CSF samples were grossly bloody, 9% were cloudy or xanthochromic, and 20% were clear.2 The number of CSF WBCs was normal or proportional to the number of RBCs in 73% of cases, elevated by 5–10 WBC/mm3 21% of the time, up to 13 WBC/mm3 in two samples, and as high as 50 WBC/mm3, 136 WBC/mm3, and 700 WBC/mm3 in one sample each.2 All of these samples were acquired early after the hemorrhage. Serial LPs were performed in 20 of these patients, and three individuals developed a marked CSF pleocytosis of 531 WBC/mm3, 1,900 WBC/mm3, and 3,600 WBC/mm3, respectively, on the second examination.2 PMNs represented 90% of the CSF WBCs present in all cases. Individuals with the most robust CSF inflammatory reactions were eventually demonstrated to have necrosis of the ventricular wall at autopsy. In this series, the protein concentration was elevated in most of the grossly bloody CSF samples, ranging from 40 to 2,200 mg/dl, but it was less than 75 mg/dl in all but two samples having clear CSF.2 In most cases, the protein concentration was slightly elevated with respect to the number of RBCs. The glucose concentration ranged from 15 to 113 mg/dl in 24 cases, although only two individuals had a glucose concentration less than 50 mg/dl.2 In another case series, 20 patients with primary IPH underwent LP a mean of 2.5 days from symptom onset. The mean CSF RBC count was 92,400 ± 49,000/mm3, with a range of 0–900,000/mm3.8 The CSF WBC count was elevated disproportionately to the RBC count with a mean of 300 ± 150/mm3 and a range of 0–2,900/mm3. Threequarters of patients had greater than 5 WBCs/mm3 present in the CSF. The mean CSF total protein concentration was 42.4 ± 8.6 mg/dl with a range of 5–124 mg/dl.8 In a study of CSF cytology, Sörnäs et al. examined serial samples from 16 patients after the development of lobar hematomas that were verified operatively or by autopsy.5 Here, the CSF WBC count was either normal or proportionate to the RBC count on the first day, peaked at around 1,000 WBC/mm3 on day 3, and had normalized by day 7 in most cases. The majority of samples contained 75–100% PMNs.5 In 34 cases of CT- or autopsy-verified hemorrhages, Norvving and Olsson separated cases into isolated IPH and those with intraventricular extension.25 Among the 23 cases with isolated IPHs, the mean CSF RBC count was 280 ± 92/mm3, CSF mononuclear WBC count of 4.3 ± 1.8/mm3,

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CSF PMNs 1.6 ± 1.4/mm3, and CSF protein of 63 ± 7 mg/dl.25 In the 11 cases with intraventricular extension, the mean CSF RBC count was 51,379 ± 3,308/mm3, CSF mononuclear cells of 48 ± 26/mm3, CSF PMNs 252 ± 210/mm3, and CSF total protein of 263 ± 85 mg/dl.25 In those patients undergoing serial LPs, the CSF PMN count normalized between 8 and 14 days, but the mean CSF protein concentration remained slightly elevated at 56 ± 10 mg/dl by 2 weeks.25

Other specific proteins Fewer studies have evaluated CSF tau or MBP concentrations after primary IPH. In one study of seven patients with hemorrhages, CSF MBP levels were elevated to a mean of 25.0 ± 15.5 ng/ml in samples obtained between 1 and 3 days after presentation.18 This contrasts with acute ischemic stroke, where the elevation of CSF MBP is typically delayed for several days.18 In hemorrhage, the concentration of MBP was also slightly higher on a second CSF sample obtained between 4 and 8 days later. CSF tau concentrations were normal in the initial samples obtained 1 to 3 days after presentation, but were increased slightly to a mean of 3.2 ± 1.6 μg/ml on a second sample obtained 4 to 8 days later.18 This contrasts with ischemic stroke, where CSF tau is often slightly elevated within a few days of presentation and remains elevated for weeks to months.21

Summary In summary, the typical CSF profile following IPH is marked by an elevated RBC count and the presence of xanthochromia in the majority of cases. The WBC count and total protein concentration are initially proportionate to the number of RBCs. Over the next few days, however, there is progressive RBC lysis leading to a disproportionate elevation in the ratio of WBCs to RBCs. In some cases, there is also a significant meningeal inflammatory response that produces an elevated CSF WBC count with a predominance of PMNs, further elevated total protein concentration, and occasional mild hypoglycorrhachia. The CSF profile in IPH typically normalizes within 2 weeks of the hemorrhage. A composite of these CSF findings is outlined in Table 25-1.

CEREBRAL VENOUS THROMBOSIS Thrombosis of cerebral veins may occur as a primary idiopathic event or may be secondary to various thrombophilic states, pregnancy, dehydration, or a septic process involving adjacent structures such as the sphenoid sinus or the mastoid. The composition of CSF during cerebral venous thrombosis has not been well documented. In most cases, these thromboses are associated with some degree of superficial cortical infarction and hemorrhage. Based on this

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pathological finding, it is expected that CSF composition would resemble that seen in ischemic strokes with hemorrhagic conversion. In one study of 31 patients with an angiographically demonstrated cerebral venous thrombosis, 93% had an elevated OP, with a mean of 32 mmHg (435 mmCSF) and range of 24–51 mmHg (326–694 mmCSF).26 The CSF protein concentration and cell counts were elevated in 45% of patients, but the actual values were not provided in this study. Because the superior sagittal sinus has the greatest concentration of arachnoid granulations, it is the major site of CSF resorption. Increased ICP is therefore most likely to occur with extensive thrombosis of the superior sagittal sinus and the lateral sinus, particularly on the right side, which is often larger than the left.27 Intracranial hypertension is also more likely to occur in acute thrombosis rather than with the progressive occlusions that are seen with slowly growing dural-based tumors such as meningiomas.27 In cases of septic cerebral vein thrombosis, the CSF composition resembles that of patients with parameningeal abscesses, with an elevated total WBC count containing a predominance of PMNs, elevated total protein levels, and depressed glucose concentration.27 This condition may also be associated with a positive CSF bacterial culture, although microbiological confirmation of a specific pathogen is not a universal occurrence.

SPONTANEOUS SUBARACHNOID HEMORRHAGE Evaluation of CSF composition in SAH and strategies to distinguish true subarachnoid blood from a traumatic LP are discussed in detail in Chapter 29. SAH due to trauma, the most common cause of subarachnoid bleeding, will be covered in Chapter 27. The remaining SAH typically result from the rupture of a congenital or an acquired aneurysm of the arterial wall. Patients typically present with sudden and severe “thunderclap” headache, nausea, and lethargy. The development of headache, photophobia, and nuchal rigidity can signify an inflammatory response in the meninges that results from the presence of blood products within the subarachnoid space. This meningeal response is also reflected in the composition of CSF, particularly when the LP is delayed by one or more days. As in other cerebrovascular disorders, CSF composition in SAH is influenced by the timing of the LP relative to the ictus. In an early series of 45 cases of spontaneous SAH, the mean initial OP was 330 mm CSF, with a range of 120–700 mm CSF.2 The OP was normal in 27% of cases, between 200 and 500 mm CSF in 69% of patients, and greater than 500 mm CSF 4% of the time.2 It normalized within 2–3 weeks in the majority of patients, but it occasionally remained elevated more than 3 weeks.2 In this series, the CSF was grossly bloody or xanthochromic in all cases and the blood did not clot in the collection tube. Xanthochromia could be determined by visual inspection in as few as 4 h from symptom onset; it increased in intensity over the first

7–9 days, and cleared thereafter.2 Thus, the majority of CSF samples were clear to visual inspection by 21 days after the ictus. The RBC count was elevated in all of these cases of SAH, with a range of 1,000–3,500,000/mm3. It ranged between 1,000 and 10,000/mm3 in 26% of cases, 10,000 to 100,000/mm3 in 42% of patients, 100,000 to 1 million/mm3 23% of the time, and greater than 3 million/ mm3 in 10% of individuals on the initial CSF examination.2 This CSF erythrocytosis resolved within 10–15 days in all cases. The WBC count was initially proportionate to the RBC count in the majority of cases, with a range between 18 and 7,000/mm3.2 As RBCs lysed, the ratio of WBCs to RBCs increased, but the absolute number of WBCs fell steadily over the first several days. In some cases, however, there was a transient increase in the number of WBCs attributed to a sterile meningeal inflammatory reaction to the presence of blood products. PMNs predominated initially, but were gradually replaced by lymphocytes over the next few days. In the majority of cases, the WBC count remained elevated between 5 and 25/mm3 after several weeks, even though all RBC had lysed.2 The early CSF protein concentration is usually elevated in proportion to the number of RBCs following SAH. In the series by Merritt and Fremont-Smith, the majority of CSF samples had a protein concentration between 100 and 1,000 mg/dl with an absolute range of 28–1,600 mg/dl.2 In serial samples, the protein concentration gradually diminished back to normal over 10–15 days. The CSF glucose concentration was measured in all these cases of SAH, but a simultaneous serum glucose value was not reported. The range of CSF glucose concentration was 8–107 mg/dl.2 In half of these cases, the glucose concentration was less than 50 mg/dl, but it rapidly normalized on most subsequent examinations. Only 10% of cases remained below 50 mg/dl on the second LP, and all had normalized by the time of hospital discharge.2 In a later series of 213 patients with angiographically proven spontaneous SAH, the OP was greater than 200 mm CSF in 60% of cases.28 In those patients who underwent LP within 6 h of symptom onset, all samples were grossly bloody but only 20% were xanthochromic by visual inspection after centrifugation. In those patients who underwent LP between 6 and 12 h after symptom onset, all samples were grossly bloody and 65% were xanthochromic. All patients undergoing LP between 12 and 14 h after symptom onset had xanthochromia in this series.28 On cytological analysis, all samples had erythrocytosis if the LP was performed within the first 12 h, and 92% had erythrocytosis between 12 and 24 h from the ictus. By 2 weeks, however, the majority of CSF samples had no detectable RBCs.28 Using spectrophotometry, CSF bilirubin was first detected 10 h from symptom onset, reached a peak by 48 h, and persisted 2–4 weeks later.28 These findings illustrate the natural history of RBC lysis and heme metabolism in the CSF, and the process is described in greater detail in Chapter 29. The CSF WBC count was initially proportionate

References

to the RBC count in this series. The number of mononuclear WBCs increased in the first 3–5 days, after which lymphocytes commonly persisted for several weeks.28 The meningeal response to blood products after aneurismal rupture is believed to play a role in the development of communicating hydrocephalus and vasospasm, the two major delayed complications of SAH. This hypothesis has led to efforts to delineate the specific mediators produced in SAH that drive these events, with the ultimate goal of developing rational pharmacological strategies to block these events. Although several papers have linked elevated CSF levels of cytokines such as IL-6 and subsequent vasospasm, these measurements remain investigational.29,30 In summary, the CSF RBC count is elevated in all cases of SAH who undergo LP within the first few days of symptom onset. After 12 h, the presence of xanthochromia can be detected by visual inspection or by spectrophotometry in the majority of cases. Xanthochromia typically persists for about 2 weeks, but RBCs may disappear from the CSF after 5–7 days. The initial CSF WBC count and protein concentration are usually proportionate to the RBC count on this initial CSF examination if the LP is performed within a day of symptom onset. After 3–5 days, however, the RBCs lyse, causing an elevated total protein concentration and an increase in the relative WBC to RBC ratio. Many patients also display an inflammatory reaction to blood products in the meninges, which manifests itself as a PMN-predominant CSF leukocytosis, elevated total protein concentration, and – in many cases – hypoglycorrhachia. This CSF leukocytosis often lasts for several weeks, long after the RBCs have fully lysed. Table 25-1 again presents composite CSF data in this disorder. REFERENCES 1. 2. 3. 4. 5. 6. 7.

Lee MC, Heaney LM, Jacobson RL, et al. Cerebrospinal fluid in cerebral hemorrhage and infarction. Stroke 1975;6:638–641. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: WB Saunders; 1937:197–203. Babinski J, Gendron A. Leucocytose du liquide céphalo-rachidien au cours du ramollissement de l’écorce cérébrale. Bull Soc Med Hop Paris 1912;33:370–374 Aring CD, Merritt HH. Differential diagnosis between cerebral hemorrhage and cerebral thrombosis. Arch Intern Med 1935;56: 435–456. Sörnäs R, Östlund H, Müller R. Cerebrospinal fluid cytology after stroke. Arch Neurol 1972;26:489–501. Gudmundsson G, Kjellin KG, Mettinger KL, et al. Isoelectric focusing of cerebrospinal fluid proteins in ischemic cerebrovascular disease. J Neurol 1980;222:227–234. De Reuck J, De Coster W, Vander Eecken H. Cerebrospinal fluid cytology in acute ischaemic stroke. Acta Neurol Belg 1985; 85:133–136.

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8. Britton M, Hultman E, Murray V, et al. The diagnostic accuracy of CSF analysis in stroke. Acta Med Scand 1983;214:3–13. 9. Smith BF, Matz R. Cerebrospinal fluid pleocytosis following hemorrhagic cerebral infarction. Am J Med Sci 1983;286:37–39. 10. Carasso RL, Vardi J, Rabay JM, et al. Measurement of prostaglandin E2 in cerebrospinal fluid in patients suffering from stroke. J Neurol Neurosurg Psychiatry 1977;40:967–969. 11. Suzuki S, Kelley RE, Reyes-Iglesias Y, et al. Cerebrospinal fluid and peripheral blood cell response to acute cerebral ischemia. Southern Med J 1995;88:819–824. 12. Palm R, Strand T, Hallmans G. Zinc, total protein, and albumin in CSF of patients with cerebrovascular diseases. Acta Neurol Scand 1986;74:308–313. 13. Lamers KJB, Schoonderwaldt HC, Borkent MV, et al. The effects of acute cerebrovascular disease on serum and cerebrospinal fluid parameters. Clin Neurol Neurosurg 1987;89:23–29. 14. Mrsulja BB, Djuricic BM, Kostic VS, et al. Cyclic AMP in the cerebrospinal fluid of patients with recent cerebral infarction. Eur Neurol 1984;23:201–205. 15. Selakovic V, Jovanovic MD, Jovicic A, et al. Index of lipid peroxidation and glucose utilization in the cerebrospinal fluid in patients with cerebral infarction. Vojnosanit Pregl 2000;57:375–379. 16. Roström B, Link H. Oligoclonal immunoglobulins in cerebrospinal fluid in acute cerebrovascular disease. Neurology 1981;31:590–596. 17. Tarkowski E, Rosengran L, Blomstrand C, et al. Intrathecal release of pro- and anti-inflammatory cytokines during stroke. Clin Exp Immunol 1997;110:492–499. 18. Strand T, Alling C, Karlsson B, et al. Brain and plasma proteins in spinal fluid as markers for brain damage and severity of stroke. Stroke 1984;15:138–144. 19. Aurell A, Rosengren LE, Karlsson B, et al. Determination of S-100 and glial fibrillary acidic protein concentrations in cerebrospinal fluid after brain infraction. Stroke 1991;22:1254–1258. 20. Hesse C, Rosengran L, Vanmechelen E, et al. Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. J Alzheimers Dis 2000;2:199–206. 21. Hesse C, Rosengren L, Andreasen N, et al. Transient increase in total tau but not phosphor-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 2001;297:187–190. 22. Dichgans M, Wick M, Gasser T. Cerebrospinal fluid findings in CADASIL. Neurology 1999;53:233–237. 23. McMenemy WH. The significance of subarachnoid hemorrhage. Proc R Soc Med 1954;47:701–704. 24. Barrows LJ, Hunter FT, Banker BA. The nature and clinical significance of pigments in the cerebrospinal fluid. Brain 1955;78:59–80. 25. Norrving B, Olsson JE. The diagnostic value of spectrophotometric analysis of the cerebrospinal fluid in cerebral hematomas. J Neurol Sci 1979;44:105–114. 26. Daif A, Awada A, Al-Rajeh S, et al. Cerebral venous thrombosis in adults. Stroke 1995;26:1193–1195. 27. Fishman R. Cerebrospinal Fluid in Diseases of the Central Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992:183–252. 28. Walton J. Subarachnoid Hemorrhage. Edinburgh: E & S Livinstone;1956:118–127. 29. Hendryk S, Jarzab B, Josko J. Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurysmal SAH. Neuro Endocrinol Lett 2004;25:141–147. 30. Osuka K, Suzuki Y, Tanazawa T, et al. Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochir 1998;140:943–951.

CHAPTER

26

Neoplastic and Paraneoplastic Disorders Jaishri Blakeley and John J. Laterra

INTRODUCTION Cerebrospinal fluid (CSF) analysis can be an important tool in the evaluation of central nervous system (CNS) malignancies. Although brain tumors are most often identified with either computed tomography (CT) or magnetic resonance imaging (MRI) scans, and while a diagnosis usually requires a tissue biopsy, CSF studies can be diagnostic for select CNS malignancies and are essential in the staging and monitoring of others. Such analyses can also differentiate tumors from other processes such as demyelinating disease, sarcoidosis, or infection. Finally, detecting malignant cells in the CSF of a patient with unexplained symptoms may lead to the diagnosis of a previously unrecognized tumor that has metastasized to the CNS. This chapter will discuss the CSF findings in common adult and pediatric brain tumors as well as in leptomeningeal carcinomatosis. Also included are discussions of the CSF findings associated with paraneoplastic disorders and in patients receiving intrathecal chemotherapy. It bears remembering that because many CNS tumors cause elevated intracranial pressure (ICP), pressure gradients created during a lumbar puncture (LP) may precipitate brain herniation. If elevated ICP is suspected, a careful fundoscopic exam to evaluate for papilledema and review brain imaging is required to evaluate for compartment shift or mass effect prior to CSF acquisition.

PRIMARY ADULT BRAIN TUMORS Much of the literature on the CSF findings in primary brain tumors does not distinguish between intraparenchymal and leptomeningeal-based malignancies or between high- and low-grade tumors. Hence, the true nature of the CSF findings in most primary brain tumors is still largely unknown. There are, however, select situations in adults where CSF analysis is critical. These include: (1) the diagnosis of demyelinating or infectious processes that can mimic brain cancer,

(2) the evaluation for leptomeningeal metastases, (3) the monitoring of patients with known leptomeningeal disease before and after therapy, and (4) the evaluation for primary CNS lymphoma (PCNSL). Immunocytochemical and molecular testing may expand the role of CSF analysis in the diagnosis and monitoring of adult brain cancer in the future. Key CSF findings (opening pressure (OP), cell count, protein and glucose concentrations, cytopathology) depend on the specific type and stage of the tumor, its relative proximity to the subarachnoid space (SAS), and its intrinsic propensity to shed malignant cells. Overall, OP is generally elevated when there is significant mass effect or leptomeningeal involvement. A pleocytosis occurs mostly in advanced high-grade malignancies or with leptomeningeal disease. Protein concentration is either normal or slightly elevated in most cases, but it may exceed 150 mg/dl in high-grade malignancies associated with necrosis and breakdown of the blood–brain barrier (BBB).1 An exception to this rule is acoustic neuromas; these lesions are commonly associated with a total CSF protein content of 100–500 mg/dl in the absence of significant necrosis or inflammation.2,3 CSF glucose levels in patients with primary brain tumors are normal unless there is overt leptomeningeal involvement. In these cases, levels commonly fall below 50 mg/dl. Cytopathology may reveal malignant cells in the CSF with glioblastoma multiforme (GBM), PCNSL, or tumors in close proximity to the ventricular space such as ependymomas (Table 26-1). Distinct CSF abnormalities in tumors such as pineoblastoma, medulloblastoma, and germ cell tumors will be discussed with pediatric brain tumors, as they are rare in adults and there are no differences in the CSF characteristics of these tumors between adults and children.4

Meningiomas Meningiomas are the most common primary brain tumor in adults. Most of these tumors are slow growing and have

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Table 26-1

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Neoplastic and Paraneoplastic Disorders

Summary of CSF Findings in Patients with Malignant Gliomas % of Patients with Abnormal Finding (Abnormal Boundary)

CSF Parameter

Finding (Range)

Opening pressure Protein content

Normal to ≠ (69–384 mm CSF) Normal to ≠ (14–344 mg/dl)

Cellularity

Normal to ≠≠ (0–7,000 cells/mm3)

Glucose content Cytopathology Immunocytochemistry Other CSF markers

Usually normal Normal or positive Positive cytoplasmic GFAP staining of cells Soluble MCP-1 levels Soluble VEGF levels

70% (>200 mm CSF)∗ 37% (45–100 mg/dl) 29% (>100 mg/dl) 32% (5–25 cells/mm3) 8% (>25 cells/mm3) 5–10% (<50 mg/dl)† 7–66% (>1 sample)# Unknown∗∗ 67% (>0.9 ng/ml)†† 58% (>10 ng/ml)††

∗Frequency

may be an overestimate as most tumors are now identified by MRI and this figure was generated in a cohort of patients studied prior to the availability of neuroimaging. leptomeningeal spread. #Variability is determined by a number of factors including (but not limited to) the patient’s age, tumor location, tumor size, tumor grade, source and volume of CSF being analyzed, and analysis methodology used. ∗∗Isolated cases of both positive and negative GFAP immunostaining of CSF-derived cells have been reported in patients with confirmed gliomas. ††Grade III and Grade IV tumors only; no elevation in lower grade tumors compared to CSF from control patients with hydrocephalus or other non-tumor controls. (Data adapted from references 1, 2, 5, 9, 10, 15, 17, 20, 26, 29, 34, 35.) †Suggests

a benign course. Although they commonly disrupt the BBB (as illustrated by their intense contrast enhancement on CT and MRI) and are typically in close proximity to the SAS, they generally do not infiltrate or shed cells into the CSF.5 However, in the rare case of malignant meningioma, CSF analysis can identify metastatic disease. These tumors invade both the brain parenchyma and the leptomeninges,6 and they often metastasize within or outside the central neuraxis.7 Due to the propensity for invasion of the SAS, CSF findings consistent with leptomeningeal involvement (elevated OP, pleocytosis, high protein and decreased glucose concentrations) may be detected. CSF cytopathology in these cases is almost always positive.5–8 Benign meningiomas can also rarely metastasize throughout the neuroaxis.7–9 If a patient with a meningioma undergoes an LP and there are CSF abnormalities, this should raise suspicion of an aggressive tumor that requires more intensive surveillance and therapy.

Gliomas Gliomas account for three-quarters of all malignant brain neoplasms in adults.8 Included in this category are GBM, all grades of astrocytomas and oligodendrogliomas, ependymomas, and mixed gliomas.

General considerations Although many patients with gliomas have normal CSF findings, high-grade gliomas (HGG) or those involving the ventricular or meningeal surfaces may elicit a robust pleocytosis and/or high protein content.2,9 One-third of tumors in these locations metastasize to the leptomeninges and show CSF findings characteristic of leptomeningeal involvement (elevated OP, pleocytosis, high protein and

decreased glucose concentrations, positive cytology).10,11 There is also a rare condition known as primary diffuse leptomeningeal gliomatosis, defined by leptomeningeal involvement in the absence of a primary parenchymal lesion.12 In these cases, CSF findings show a lymphocytic pleocytosis and high protein content, although cytopathology is often non-diagnostic for unclear reasons.12,13 As such, CSF dynamics and composition can be extremely variable in patients with gliomas.

CSF pressure and protein and glucose content In their classic monograph, Merritt and Fremont-Smith provide the most detail about the CSF findings in patients with gliomas.2 In this series of 106 patients (all identified before the availability of CNS imaging), the most common abnormality (~70% of cases) was elevated OP of >200 mm CSF (Table 26-1). The next most common finding in this cohort was an elevated total protein content. Total CSF protein was >100 mg/dl in 29% of glioma patients, and was 45–100 mg/dl in another 37% of cases. Although not accounted for in this study, higher protein levels are now generally associated with higher pathological grades. Such changes are due to the increased passage of plasma proteins into the CSF across an abnormal BBB,1 but CSF gammaglobulins can also be elevated in some glioma patients, suggesting a local inflammatory response to the tumor itself.1,9 Glucose is within normal range in all grades of glioma with the exception of tumors that have spread to the leptomeninges, where it is often <50 mg/dl.1,2,9

CSF cellularity CSF cell counts are often normal in gliomas, although a variable pleocytosis (ranging from 15 to 7,000 cells/mm3) can be seen with high-grade tumors. This is due to local

Primary Adult Brain Tumors

anti-tumor immune responses within the CNS.1,2,9 Although the magnitude of the pleocytosis does not correlate with the presence of malignant cells in the CSF,14 this occurrence can reflect tumors that have metastasized to the leptomeninges.1,15 Red blood cells (RBCs) in the CSF are exceedingly rare in patients with gliomas (and most likely reflect a traumatic LP), but can rarely be associated with oligodendrogliomas.1

Cytopathological findings Malignant glioma cells can spread into the CSF via direct seeding of the SAS by tumors involving the ventricular or meningeal surfaces. This occurs in roughly 20% of adult glioma cases at autopsy.10,15–18 Still, the frequency of positive CSF cytology during life is far more variable, ranging from 7 to 66% (Table 26-1).11,18–20 There is less variability in pediatric glioma cases, with 3–11% of these patients having CSF dissemination at the time of diagnosis.21,22 Hence, children with malignant gliomas often undergo complete imaging of the central neuraxis and a CSF examination early; this workup is now standard in recent pediatric cooperative trials.11,22 On the other hand, survival differences between glioma patients with or without tumor dissemination in the CSF have never been convincingly demonstrated, so this finding may still be of academic value at this time. Several factors contribute to the likelihood of CSF dissemination of gliomas, including tumor location, tumor grade, source of CSF sampled, patient population being studied, and the cytopathology techniques used. Tumors adjacent to ventricular or meningeal surfaces are more likely to shed cells into the CSF.16 High-grade gliomas also have higher rates of subarachnoid seeding than low-grade gliomas,19 although all tumors in close proximity to the SAS can spread into the CSF.23 There may also be molecular features that contribute to CSF dissemination. For example, patients with malignant gliomas carrying PTEN gene mutations (a tumor suppressor gene commonly mutated in GBM) are more likely to have meningeal seeding than those without this mutation.24 It is expected that new immunocytochemical analyses will soon reveal a molecular profile of glioma cells (including their predilection for CSF dissemination) at the time of biopsy. Another factor influencing the frequency of positive CSF cytology is the patient population being investigated. In cohorts of symptomatic patients (usually with hydrocephalus, myelopathy, or radiculopathy), CSF is positive nearly 10-times more frequently than among asymptomatic patients.18,20 When routine cytological examination of CSF cells is positive in patients with gliomas, the findings typically reflect the underlying parenchymal tumor in terms of features such as hyperchromatism, nuclear:cytoplasmic ratio, and frequency of mitoses.9,25 Much work has gone into improving the diagnostic utility of CSF analyses in these cases. Detection of several brain-specific proteins in CSF-infiltrating cells may assist in the diagnosis of glioma.

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Glial fibrillary acid protein (GFAP) is a marker specific for astrocytes and is expressed by most glial tumors. In a series of 12 samples containing malignant cells of unknown type, positive immunostaining of CSF cells for GFAP reliably predicted a subsequent diagnosis of glioma at the time of biopsy.26 Still, it has also been proposed that highly undifferentiated gliomas that are GFAP-negative are more likely to invade the SAS and be shed into the CSF.10,27 In actuality, CSF cytology may be positive in cases both with and without detectable GFAP.10,26 Other immunocytochemical markers are under development that should improve the detection of glioma cells in the CSF in the future.

Soluble CSF markers Selected CSF markers of gliomas and other primary brain tumors are listed in Table 26-2. S-100 protein is found in the cytoplasm of different neural cell types and its release suggests recent cellular destruction. With CNS tumors, CSF S-100 levels are higher with more invasive and aggressive tumors, and they are generally negative with benign tumors such as meningiomas.28 Creatine kinase (CK) levels may also be elevated in the CSF of patients with HGG,28 although this, too, is a general marker of neural cell destruction that is not specific for glioma. Other substances such as monocyte chemoattractant protein-1 (MCP-1) have also been demonstrated to be higher in the CSF of patients with HGG compared to low-grade gliomas,29 while polyamines (markers of proteolysis) are variably elevated in samples from patients with GBM and anaplastic astrocytomas.30–32 Desmosterol (a precursor of cholesterol) is elevated in the CSF with a number of primary brain tumors, malignant gliomas in particular.31 This compound is measured via the “sterol test” where patients take triparanol to inhibit cholesterol synthesis, allowing desmosterol to accumulate.

Table 26-2 Soluble Markers Detectable in the CSF of Adult and Pediatric Patients with Primary Brain Tumors Marker

Associated Tumor Type

GFAP S-100 VEGF Creatine kinase brain fraction (CK-BB) Desmosterol Beta-glucuronidase Neural cell adhesion molecule (N-CAM) Polyamines Neuron-specific enolase (NSE)

Glioma Glioma, medulloblastoma, melanoma Glioma, PCNSL Glioma Glioma PCNSL Medulloblastoma Glioma, medulloblastoma Glioma, craniopharyngioma, medulloblastoma Neuroblastoma Neuroblastoma Germ cell tumors (trophoblast predominant) Germ cell tumors (embryonic/ yolk sac predominant) Pituitary tumors

Nerve growth factor N-myc (amplification) Human chorionic gonadotropin (hCG) Alpha fetoprotein (αFP) ACTH, TSH, GH, prolactin, FSH, LH

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This test is almost uniformly negative in patients without brain tumors, but shows elevated CSF desmosterol levels in 60–80% of patients with primary brain cancer.31 Still, the procedure is cumbersome and has not been fully validated. Neuron-specific enolase (NSE) is of interest as one of the few markers correlated with low-grade gliomas.31 However, it is a non-specific marker of damage to neural or neuroendocrine cells and has also been associated with medulloblastoma, craniopharyngioma and neuroblastoma. Preliminary studies have also suggested that a novel glycoprotein, α-2 Heremans-Schmid glycoprotein, is elevated in the CSF of patients with low-grade gliomas compared to patients with various non-tumor-related neurological disease.33 However, its diagnostic and prognostic significance remains unknown. Levels of angiogenic factors in CSF have been of recent interest, since gliomas exhibit high neovascularization.34 Vascular endothelial growth factor (VEGF), in particular, is a central mediator of angiogenesis in these tumors and is secreted into the CSF.35,36 One study showed that VEGF levels are higher in the CSF of patients with malignant gliomas compared to patients with non-glial tumors such as lymphomas and metastases.36 Similarly, CSF VEGF levels are significantly higher in patients with high-grade rather than low-grade gliomas, although there is substantial overlap in VEGF concentrations between these two groups.34 CSF VEGF levels are also elevated in patients with carcinomatous meningitis and in bacterial meningitis, making it nonspecific for glioma.37,38

Pituitary and suprasellar tumors Although a wide variety of tumors can involve the sella and suprasellar region, the most common are pituitary adenomas and craniopharyngiomas. The pituitary gland is located in the roof of the third ventricle and hence has ready access to the CSF. However, pituitary tumors are almost always benign and rarely shed cells into the CSF. Hence, CSF studies are not routine in the evaluation of pituitary masses and there is limited information known about the CSF findings associated with these tumors. Merritt and Fremont-Smith report that in five cases of pituitary or suprasellar tumors, three had mildly elevated protein levels between 45 and 100 mg/dl and four had OP ranging from 150 to 200 mm CSF.2 These patients were all evaluated prior to the availability of neuroimaging, and it is likely the pressure recordings were related to secondary compression of the third ventricle and associated hydrocephalus. Pituitary tumors that extend into the suprasellar region may cause elevation of one or more of the adenohypophyseal hormones (corticotropin, growth hormone, thyrotropin, prolactin, luteinizing hormone, or follicle stimulating hormone) in the CSF.31 Since these levels fall with successful treatment they can be helpful for monitoring disease, but serum levels also indicate the state of disease and are more easily accessed for serial measurement. On the other hand, CSF studies

may help diagnose rare inflammatory diseases involving the pituitary and sellar region, including sarcoidosis, histiocytosis, and various chronic infections. Pituitary adenomas can transform to carcinomas in <1% of cases.39 There are no distinct clinical or radiographic features of metastatic pituitary tumors, and hence the diagnosis is made when metastases are confirmed either within or outside the CNS. Leptomeningeal involvement is common in these situations, and hence CSF findings may include an elevated OP, a pleocytosis, elevated protein content and/or hypoglycorrhachia, depending on the extent of disease. Craniopharyngiomas are generally benign, cystic tumors of the suprasellar region that arise from remnants of the craniopharyngeal duct. They account for 1–3% of all brain tumors.8 A high proportion are diagnosed in children, and sellar lesions in the pediatric population are more likely to be craniopharyngiomas than pituitary adenomas.40 Although craniopharyngiomas are thought to more actively shed cells than pituitary tumors, positive CSF cytology is a highly variable event.41–43 These tumors rarely metastasize via the CSF, making it uncommon to find evidence of leptomeningeal involvement.44 Notably, cystic craniopharyngiomas can rarely rupture their proteinacious contents into the ventricular or subarachnoid spaces causing a chemical meningitis with elevated CSF cell counts and protein levels.45 Such an event is heralded by acute meningismus along with spontaneous resolution of prior symptoms (such as visual defects) as neighboring structures are suddenly decompressed. In the absence of such a dramatic event, routine diagnostic evaluation for craniopharyngiomas and pituitary adenomas includes a cranial MRI scan, neuro-ophthalmology evaluation, and serum endocrine assessment. CSF analysis can usually be avoided.

Vestibular Schwannomas Vestibular Schwannomas (VS) are tumors that arise from the Schwann cells investing the eighth cranial nerve. They are the most common structural abnormality of the cerebellopontine (CP) angle, and they are benign, slow-growing lesions. They are also associated with multiple CSF findings, the most notable of which is elevated total protein content in the range of 100–500 mg/dl that correlates with tumor size.2,3,46,47 VS are also occasionally associated with obstructive hydrocephalus due to compression of the fourth ventricle or aqueduct of Sylvius. It has also been postulated that these tumors may cause communicating hydrocephalus via elevated protein concentrations and disrupted CSF flow.47,48 Metastases account for <1% of CP angle tumors and can mimic the appearance of VS. Such tumors present with rapid bilateral hearing loss and facial weakness. Schwannomas, in contrast, typically cause gradual unilateral hearing loss. In cases of suspected metastases, CSF cytology may be helpful in confirming the diagnosis.49

Primary Adult Brain Tumors

Primary central nervous system lymphoma PCNSL is a non-Hodgkin’s lymphoma confined to the CNS, typically of B-cell origin. It was previously appreciated to be a very rare primary brain cancer found almost exclusively in patients with severe immunosuppression such as with acquired immune deficiency syndrome (AIDS). However, the incidence of PCNSL in both immunocompetent and immunosuppressed patients has been steadily rising over the last two decades, and lymphomas now account for 3% of all primary adult brain tumors.8,50 CSF abnormalities are common in patients with PCNSL primarily because of its frequent periventricular location, its high mitotic activity, and its strong propensity to spread to the leptomeninges. Elevated protein concentration (>45 mg/dl) is the most reliable finding, being seen in 50–68% of patients with leptomeningeal involvement.51,52 This parameter is inversely correlated with treatment response rate and overall survival in immunocompetent patients.51,53 It often occurs in the absence of positive CSF cytology or a measurable pleocytosis. High CSF cell counts can be seen, and significant elevations suggest leptomeningeal involvement. Similarly, glucose is often normal unless there is leptomeningeal spread, in which case it can range from 7 to 140 mg/dl.54 These data are summarized in Table 26-3. Cytological examination of CSF is extremely valuable in both the diagnosis and monitoring of PCNSL. Since surgical resection is not typically indicated, confirmation of the diagnosis via CSF cytology can obviate the need for a biopsy procedure. CSF cytology can also help distinguish PCNSL from other inflammatory processes. This is particularly important in immunocompromised patients who are at high risk for both PCNSL and cerebral toxoplasmosis, which present with similar neuroimaging findings. Positive cytology has a specificity of 97–100% and provides an accurate and reliable diagnosis. Unfortunately, however, such analyses are hampered by a lack of sensitivity. Only 16–26% of patients with newly diagnosed PCNSL have positive cytology with a single CSF sample, even though

Table 26-3

Finding (Range)

Elevated protein content Pleocytosis Low glucose content Unique oligoclonal bands Cytopathology

19–1,800 mg/dl 0–2,000 cells/mm3 7–157 mg/dl 0–14 ● Monotonous population of lymphoid cells; ● Hyperchromatic nuclei ● β-Glucuronidase; ● Lactate dehydrogenase; ● Monoclonal population by flow cytometry ● Positive EBV PCR (AIDS)

Additional biomarkers

∗At

more than 40% turn out to have leptomeningeal involvement at this time.51–53 This poor sensitivity is in part due to the fact that many patients are placed on corticosteroids early in the disease course. PCNSL is very sensitive to glucocorticoids, and the diagnostic yield of both CSF and tissue biopsy may be substantially reduced following this treatment.52,55 Diagnostic sensitivity is also hampered by difficulty distinguishing reactive lymphocytes from true neoplastic cells by morphology. Biochemical markers such as β-glucuronidase and lactate dehydrogenase (LDH) may be elevated in the CSF and can support a diagnosis of PCNSL, but both are nonspecific.51,52 Immunocytochemistry to quantify B lymphocyte populations substantially improves diagnostic sensitivity,56 and immunophenotyping with flow cytometry further increases the diagnostic yield by differentiating monoclonal B lymphocyte populations from reactive polyclonal lymphocytes even in relatively hypocellular samples.57,58 Hence, flow cytometry analysis of CSF is strongly recommended for any patient with suspected PCNSL. Polymerase chain reaction (PCR)-based detection of immunoglobulin (Ig) heavy chain genes may further contribute to diagnostic accuracy and also allow testing of both lysed CSF samples and specimens with low cellularity.55,59 However, such PCR tests are not yet routinely available for clinical use. The diagnostic yield can be maximized by utilizing all available tests (cytology, immunocytochemistry, flow cytometry, and molecular genetic analysis) as well as by repeated CSF sampling. Several other CSF tests may be helpful to diagnose PCNSL in immunocompromised patients. These tumors are strongly associated with Epstein-Barr virus (EBV) transformation of malignant cells. Thus, EBV PCR in CSF has a high sensitivity and specificity for the diagnosis of PCNSL in HIV-positive patients.60,61 The addition of increased lesion uptake on Thallium-201 single-photon emission computed tomography (SPECT) imaging of the brain further increases the diagnostic accuracy of CSF EBV PCR in PCNSL; both tests together yield a sensitivity of 77%,

Common CSF Abnormalities Found in Patients with Primary Central Nervous System Lymphomas

CSF Parameter

initial diagnosis. (Data adapted from references 51–63.)

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% of Patients with Abnormal Finding (Abnormal Boundary) 67% (>50 mg/dl) 54% (>5 cells/mm3) 10% (<40 mg/dl) 27% (>1) 16–26%∗ 16–26%∗ 50% 67% 74–89% 77%

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a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 86% in HIV-positive patients.62 Although still being validated, this approach may be sufficient to diagnose PCNSL without the need for a tissue specimen.63

PRIMARY PEDIATRIC BRAIN TUMORS Gliomas account for some 56% of all primary brain tumors in children, and most are of lower histological grade.8 Up to 11% of these patients may have CNS dissemination at the time of diagnosis, hence some centers pursue a full evaluation for leptomeningeal disease right away.21,22 Just as in adults, however, there are no uniform CSF findings in pediatric gliomas. In contrast, several other primary tumors that predominate in children do have specific CSF findings. These include medulloblastoma, primitive neuroectodermal tumors (PNET), choroid plexus tumors, ependymomas, and germ cell tumors. Collectively, primary brain cancers of childhood have a high propensity for CSF dissemination, and CSF sampling is a very useful diagnostic procedure.64 Interestingly, the sensitivity of cytology is higher in lumbar versus ventricular samples, making LP the procedure of choice in these patients.65 Results are discussed below and summarized in Table 26-4.

Medulloblastomas and primitive neuroectodermal tumors Medulloblastoma is the second most common brain tumor of children, accounting for 25% of these lesions. CSF findings are of particular importance in medulloblastoma, as LP and CNS imaging results are both critical parts of disease staging.66 If tumor cells are detected in the CSF, patients are considered “high risk” and high-dose craniospinal

Table 26-4

radiation followed by adjuvant chemotherapy is usually proposed. “Average risk” patients are treated with lower doses of radiation to the spine and no adjuvant chemotherapy. CSF findings, therefore, directly impact on clinical management and prognosis. Medulloblastoma is known to disseminate widely throughout the CSF, commonly seeding the leptomeninges and causing elevated CSF protein levels, a pleocytosis, and positive CSF cytology.9 Prayson and Fischler found that medulloblastoma accounted for 21 of 31 (77.4%) cytologypositive CSF samples out of a total of 390 pediatric specimens examined over a 10-year period at one institution.67 Overall, 28–42% of medulloblastomas have positive CSF cytology,19,68,69 and sensitivity goes up to 78% with repeated sampling.68 Importantly, the frequency of positive CSF cytology is temporally related to surgery in that there is a relatively high false-positive rate if samples are obtained within 2 weeks of surgery.19,68 In a series by Balhuizen et al., two of 17 (12%) preoperative samples had positive cytology whereas 10 of 11 (91%) samples from the same cohort were positive in the postoperative period.19 When CSF studies are delayed 2–3 weeks after surgery, positive rates fall to 23%.70 The high rate of post-operative positive CSF cytology is due to tumor shedding at the time of surgery. Hence, LP should be delayed for at least 2 weeks after resection to prevent findings that may result in overly aggressive treatment. Cytologic features of medulloblastoma cells in the CSF include frequent clustering, small anaplastic cells, neurosecretory granules, and pleomorphic nuclei.26,71 Immunostaining shows the cells to be GFAP-negative but positive for synaptophysin in 50% of cases.26 CSF detection of polyamines such as putrescine, spermidine, and spermine has been used successfully to monitor medulloblastoma over time and to diagnose recurrent disease.28,72 Putrescine is the most sensitive polyamine biomarker for medulloblastoma, but it is

Summary of CSF Findings Found in Pediatric Patients with Primary Brain Tumors

Tumor Type

Opening Pressure

Protein Content

Cell Count (Range)

Glucose Content

Cytopathology (% Positive)

Medulloblastoma

Normal or ≠

Usually ≠

Normal

Ependymoma

Normal or ≠

Normal or ≠

12–42% (1 sample) 66–78% (>1 sample) 0–33% (>1 sample)

Choroid plexus papilloma

Normal or ≠∗

Often ≠

Usually ≠ (0–50 cells/mm3) Normal or mildly ≠ (0–19 cells/mm3) Usually ≠ (0–35 cells/mm3)

Germ cell tumors † Pineocytoma and pineoblastoma

Normal or ≠

Normal or ≠

Normal or ≠∗

Often ≠

∗May

produce obstructive or communicating hydrocephalus. reported in only a few cases. ∗∗Exact frequency unknown due to rarity of these tumors. (Data adapted from references 5, 9, 19, 67–69, 71, 76–78, 82–84.) †Data

Usually ≠ (0–87 cells/mm3) Usually ≠ (15–400 cells/mm3)

Normal Normal

Normal

Rare (cells usually show relatively normal choroid or ependymal morphology) 50–75% with multiple samples∗∗

Normal

14–43% (>1 sample)

Primary Pediatric Brain Tumors

not specific for the disorder and may be elevated in other primary CNS malignancies, certain infections, and hydrocephalus.72,73 PNET encompass several cancer types including neuroblastoma and undifferentiated PNET. PNET and medulloblastoma have similar histologic features but recent molecular studies show them to be distinct.74 PNETs and neuroblastomas are both rare, but they are noteworthy because of their high propensity for CNS dissemination and their specific CSF findings. In neuroblastoma, PCR amplification of the N-myc gene in CSF is associated with more advanced disease and a more aggressive course.71 High CSF levels of carcinoembryonic antigen (CEA) have also been reported in patients with neuroblastoma.31 However, CEA is not specific and is also commonly seen with leptomeningeal metastases of systemic tumors. CSF cytologic features of neuroblastomas are similar to those of medulloblastomas and PNET, but neuroblastomas more often show rosette formations.

Ependymomas Ependymal tumors are distinct within the glioma family. Intracranial ependymomas make up roughly 8% of all pediatric brain tumors. Histological grades vary and, although they occur throughout the CNS, the most common location is the fourth ventricle. Due to their proximity to ventricular spaces, they are classically thought to have a high propensity for shedding cells into the CSF. Although initial clinical staging of intracranial ependymomas includes CSF studies and imaging of the neuraxis, the reported rate of positive cytology is only 0–33% at the time of diagnosis or recurrence.19,75,76 Some of this variability is probably due to the inclusion of both low- and high-grade tumors in CSF assessments, as well as sampling before or after surgery. In one study of high-grade ependymomas, only 9% of samples had positive preoperative cytology, but 33% were positive in the postoperative period.19 Similar to medulloblastoma, this may reflect a shedding process that is aggravated by surgical intervention. Notably, in a recent study of the CSF findings in 22 children with recurrent ependymoma, cellularity was normal and cytology was negative in all cases, raising the question of whether CSF analysis adds any benefit over neuroimaging in monitoring for tumor recurrence.76 When seen, the typical cytologic features of ependymoma in the CSF include a highly cellular sample with cuboidal cells, bland-looking oval nuclei, a high nuclear:cytoplasmic ratio, and occasional rosettes.26,71,77 In some cases, prominence of these features distinguishes between ependymoma (low-grade) and anaplastic ependymoma (high-grade).5

Tumors of the choroid plexus Choroid plexus papillomas (CPP) and choroid plexus carcinomas (CPC) account for only 0.5% of primary brain tumors.

239

However, due to their intraventricular location and the nature of the tissue from which they originate, they readily shed cells into the CSF and have implications for the CSF formation process. Total CSF protein content was elevated in two reported cases of CPP (98–114 mg/dl), although published data are scanty enough to preclude clear statements about this parameter with these tumors.9 Cytologically, CPPs can form fronds that may look identical to normal ependymal or choroidal cells and complicate a pathologic diagnosis.5 Normal ependymal and choroidal cells can be shed in the CSF after various CNS interventions or in association with non-tumor conditions such as hydrocephalus. However, high numbers of cells suggest the presence of a CPP, especially in the setting of a midline lesion on brain imaging. Another caveat is that the cells of CPCs are similar to those seen in systemic adenocarcinomas and such tumors may have to be distinguished from metastases from systemic neoplasms.5,9 Since choroid plexus tumors occur predominantly in children and metastases are nearly exclusive to adults, such a distinction is usually straightforward. Choroidal tumors also cause disrupted CSF physiology due to hypersecretion of CSF that can result in symptomatic hydrocephalus resistant to standard shunting procedures. Likewise, the intraventricular mass may itself cause obstruction contributing to hydrocephalus.78

Germ cell tumors Germ cell tumors include germinomas, embryonal carcinomas, yolk sac tumors, choriocarcinomas, and teratomas. Although rare, they commonly release malignant cells into the CSF due both to their deep, midline location in proximity to the ventricular spaces, as well as to an intrinsic shedding potential.5,67 Germinomas are the most common germ cell tumor and have a characteristic cytopathology. Immunocytochemistry may further assist in diagnosis with strong reactivity for placental alkaline phosphatase.71,77 These tumors frequently cause hydrocephalus due to obstruction of the third ventricle. There are few published data regarding the protein content or the cellularity of CSF samples from patients with germ cell tumors. The most important CSF parameters related to these tumors are the markers human chorionic gonadotropin (βHCG) and alphafetoprotein (αFP). βHCG is produced mostly by placental syncytiotrophoblasts, but it can be found in normal CSF at low levels. These levels increase significantly in the setting of choriocarcinomas or with CNS spread of malignant teratomas.28,31 An elevated CSF:plasma βHCG ratio suggests a primary or metastatic embryonal carcinoma or choriocarcinoma.1,28,31 αFP is a major serum protein of the fetus and is a sensitive marker of yolk sac and embryonic brain tumors. However, unlike βHCG, any measure of αFP in the CSF is indicative of tumor. Detection of αFP in the CSF is now so sensitive that recurrence of malignancy can be reliably predicted by CSF αFP in advance of MRI changes or clinical symptoms.28

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Although βHCG may be mildly elevated in some germinomas, significant elevations in CSF βHCG or αFP are diagnostic of non-germinomatous germ cell tumors. In general, higher elevations of βHCG or αFP are associated with more aggressive tumors and a worse prognosis. Both these markers are also found in serum, but increased levels are often first detectable in CSF. This is especially true in cases of early tumor recurrence.31,79 Hence, CSF measurement of βHCG and αFP is required for surveillance of germ cell tumors. Although these markers are specific, their sensitivity in CSF remains variable. In one series, only three of 11 patients (27%) with germinoma, malignant teratoma, choriocarcinoma or pineocytoma had positive tumor markers.80 In another series, however, 42% of patients with pineal region tumors had positive tumor markers.81 Despite this variable sensitivity, βHCG and αFP appear more reliable than cytology for the diagnosis and monitoring of non-germinomatous germ cell tumors.

Pineal tumors The most common tumors of the pineal region are of germ cell origin and the associated CSF findings are discussed above. The less common pineocytomas and pineoblastomas are also associated with frequent shedding of cells into the CSF. LP is routine at the time of diagnosis to assist in staging, as well as later to provide surveillance for recurrence following treatment. Pineoblastomas demonstrate tumor cell shedding into the CSF in 14–43% of cases.82–84 If the CSF cytology is positive, the patient is considered to have disseminated disease and requires both craniospinal radiation therapy and adjuvant chemotherapy. CSF analysis is sensitive for detecting recurrence. Pineoblastomas are also often associated with a significant pleocytosis (15–400 cells/mm3) and elevated protein content in the CSF.9 Cytologic features can readily distinguish these tumors from the less malignant pineocytomas.85 Finally, similar to patients with germ cell tumors, hydrocephalus may occur in 58–90% of patients with pineal region tumors and require a CSF diverting procedure to bypass tumor compression of the aqueduct of Sylvius.86,87

METASTATIC TUMORS Brain metastases Up to 30% of all patients with systemic cancer will experience brain metastasis over the course of their disease.88 The majority occur through hematogenous spread, commonly depositing in the cortex due to the high blood volume delivered to the cerebral hemispheres. The most common solid tumors to metastasize to the brain are breast, lung, and gastric malignancies, as well as melanoma. Other frequent culprits are renal cell carcinoma and tumors of the female genital tract. Although metastases to brain parenchyma are twice as common as metastases

to the leptomeninges, parenchymal lesions only rarely cause abnormalities in the CSF due to limited access to the SAS. Thus, only 2–10% of CSF samples from patients with parenchymal metastases will have positive cytology.19,89 However, all of the solid tumors mentioned above also have the propensity to spread to the leptomeninges causing CSF abnormalities up to 90% of the time. There are few tumor-specific features of leptomeningeal involvement. Rather, there are variable elevations in the cell count and protein concentration with all tumor types. Melanoma is one of the few metastatic tumors that do have unique CSF features, as variable melanin concentrations may cause the CSF to appear tan or brown. Melanoma may also cause the CSF to become viscous.26 The immunocytochemistry of melanoma can show unique staining of cells that are positive for vimentin, S-100 protein, HMB-45, MAGE-3, MART-1, and tyrosinase.26,90 Unlike solid tumors, hematological malignancies (leukemias and lymphomas) are more likely to involve the leptomeninges than the parenchyma.89 Leukemia may, in fact, be the most common tumor type to involve the leptomeninges, and the most notable example is acute lymphoblastic leukemia (ALL). Due to the high propensity to involve the leptomeninges, all patients with ALL are given prophylactic therapy for CNS extension and routinely undergo surveillance CSF examinations. CSF may be normal or show a pattern typical of leptomeningeal involvement. On cytopathology, leukemic cells in the CSF are identified as blasts with high nuclear:cytoplasmic ratios and prominent nucleoli.71 These changes are generally more easily recognized with stains such as Wright-Giemsa or Diff-Quick. In addition, markers of leptomeningeal involvement include fibronectin and terminal deoxynucleotidyl transferase (TdT) that differentiate reactive lymphocytosis from leukemic cells in the CSF.91 Fibronectin levels are reliably increased in the CSF of patients with ALL that has spread to the CNS and is used clinically to document relapse. Normal CSF levels of fibronectin (~2.0 μg/ml) double in the setting of proven CNS relapse of ALL.92 Elevated CSF β2-microglobulin levels suggest increased cellular turnover and have been correlated with CNS involvement by leukemia or lymphoma. This marker may, in fact, predict CNS relapse before clinical symptoms arise. However, CSF β2-microglobulin levels can also increase in other metabolically active diseases, and hence is not a specific finding.28 These markers are summarized in Table 26-5.

Leptomeningeal metastases The leptomeninges consist of the pia and arachnoid mater, membranes which form the inner and outer boundaries of the SAS, respectively. Leptomeningeal metastases occur in up to 8% of patients with systemic solid tumors, in ~15% of patients with systemic hematological tumors, and in 7–66% of patients with primary brain tumors depending on the tumor type.89,93,94 Such leptomeningeal involvement

Metastatic Tumors

Table 26-5 Soluble Markers Detectable in the CSF of Adult and Pediatric Patients with Metastatic Brain Tumors Marker

Associated Tumor Type

β-Glucuronidase Lactate dehydrogenase (LDH) Terminal deoxynucleotide transferase (TdT) β2-Microglobulin Fibronectin Cytokeratin Carcinoembryonic antigen (CEA) VEGF HMB-45 MAGE-3, MART-1, tyrosinase

Leptomeningeal carcinomatosis Lymphoma Leukemia Leukemia, lymphoma Leukemia Carcinoma Solid tumor metastases Leptomeningeal carcinomatosis Melanoma Melanoma

may cause focal neurological deficits, symptoms of elevated ICP due to communicating or obstructive hydrocephalus, or be entirely asymptomatic and discovered only at autopsy. Leptomeningeal carcinomatosis (also referred to as carcinomatous or neoplastic meningitis) is the clinical syndrome defined by involvement of the leptomeninges by tumor cells causing symptoms referable to the cerebral hemispheres, the cranial nerves, and/or the spinal cord or spinal nerve roots. A diagnosis of leptomeningeal spread from any tumor suggests more aggressive disease, often requiring additional therapies and commonly associated with a poorer prognosis. CSF analysis is critical in the identification of leptomeningeal metastases. Common CSF characteristics of leptomeningeal carcinomatosis, regardless of the underlying tumor, include an elevated OP, a pleocytosis, hypoglycorrhachia, and elevated total protein content (Tables 26-6 and 26-7). The elevated protein content and high cell counts are due to inflammation elicited in response to the presence of tumor cells. The low glucose level is attributed to poor membrane transfer of glucose, as well as to increased utilization by metabolically active tumor cells that draw nutrients out of the CSF.1 It is always advisable to monitor CSF cultures in patients with suspected leptomeningeal disease, as the CSF profile can be suspicious for infection and patients often have received therapies that suppress their immune responses and increase susceptibility to a variety of pathogens. Tumors predisposed to hemorrhage (melanoma, thyroid carcinoma, renal cell carcinoma, Table 26-6 Range of Abnormal CSF Findings in Patients with Leptomeningeal Disease CSF Parameter

Finding (Range)

Opening pressure Protein content Cell count Glucose content Positive cytology

60–550 mmH2O 24–2,400 mg/dl 0–1,800 cells∗/mm3 0–225 mg/dl 45–100%†

∗Predominance †Commonly

of lymphocytes and monocytes. requires 2–3 samples (see Table 26-7).

241

choriocarcinoma) that invade the meninges may also cause xanthochromia and/or elevated CSF RBC counts. Oligoclonal bands (OCB) have even been reported in leptomeningeal carcinomatosis as a further reflection of intrathecal inflammation, although the frequency of this finding is unknown.95 Still, the definitive diagnostic step remains the identification of malignant cells in the CSF. In many cases, this can obviate the need for further invasive procedures. The diagnostic sensitivity of CSF cytology in patients with leptomeningeal metastases is 47–90%.19,31,96–99 MRI with contrast of the neuraxis improves this sensitivity (Fig. 26-1),96 although active leptomeningeal involvement can be seen even without contrast administration (Fig. 26-2). An important caveat is that meningeal irritation following an LP may itself cause nonspecific leptomeningeal enhancement on MRI for several days that can be misinterpreted as active leptomeningeal disease. Hence, the MRI should always precede the LP, or the examinations should be separated by days. The wide range of sensitivity that CSF cytology has for the diagnosis leptomeningeal carcinomatosis is due to multiple factors, including the site of CSF sampling, the degree of leptomeningeal involvement, the tumor type, the patients being studied (symptomatic or asymptomatic), and type of pathological examination conducted. Although there is disagreement about the optimal site from which to obtain CSF in pursuit of possible leptomeningeal disease, it is widely recognized that there may be discordance between lumbar and ventricular specimens.19,31,65,100,101 This may relate to the site from which disease originates, with ventricular CSF being more commonly positive in the setting of cranial symptoms and lumbar CSF the preferred source with radicular or spinal symptoms.19,100 Sampling directly from an implanted reservoir has the lowest yield.101 Hence, if CSF from such a reservoir is negative and leptomeningeal involvement is still suspected, LP should be pursued. If lumbar CSF and contrast-enhanced MRI of the neuraxis both do not reveal leptomeningeal disease, ventricular sampling can be considered. Yet despite such as aggressive diagnostic effort, it should be remembered that up to 10% of patients with systemic cancer and leptomeningeal disease proven at autopsy have negative diagnostic testing during life.94,100 Patients with widespread leptomeningeal disease are more likely to have positive CSF cytology than patients with focal deposits.89 Similarly, symptomatic patients are more likely to have positive samples than non-symptomatic patients.98 The sensitivity of testing increases with multiple samplings. Thus, 41–71% of cases were found to have positive cytopathology on the first CSF sample, but 79–100% were positive with repeated sampling.31,97,98,102 However, 9% of patients with confirmed leptomeningeal disease never have positive cytology, despite multiple samplings. Kaplan et al. found somewhat more encouraging results in their review of 63 cases of confirmed leptomeningeal carcinomatosis.

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Table 26-7

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Neoplastic and Paraneoplastic Disorders

Frequency of Abnormal Lumbar CSF Findings in Patients with Leptomeningeal Carcinomatosis

CSF Parameter

Olson et al., 1974

Wasserstrom et al., 1982

Kaplan et al., 1990

Yoshida and Morii, 2005

57% 74% 57% 74%

49% 80% 56% 31%

42% 83% 64% 47%

72% 72% 69% 29%

45% 79%

54% 91%

71% 100%

41% 79%

Pressure >15 cmH2O Protein >50 mg/dl Cellularity >4 cells/mm3 Glucose <50 mg/dl Positive cytology 1 sample >1 sample (Data adapted from references 97–99, 102.)

Seventy-one percent of patients had positive cytology on the first LP and an additional 21% had positive cytology after the second.98 Only 8% of patients required more than two procedures. Findings such as these form the basis for the recommendation that three large-volume (>20 ml) LPs should be analyzed for malignant cells in CSF in patients with suspected leptomeningeal metastases. Overall, 86–92% of these patients should have positive cytology with three lumbar samples. Proper CSF handling is essential for the identification of malignant cells. Samples should be promptly delivered to and prepared by the cytopathology laboratory to avoid autolysis that begins within 1–2 h. The overall cellularity of the sample does not influence whether the cytology will be positive or not.98 Normal inflammatory cells in highly cellular samples may obscure neoplastic ones,26 but they

may also contribute to false-positive readings when reactive lymphocytes are misinterpreted as lymphoma cells.71,89 Recent advances in flow cytometry that allow the quantification of intracellular DNA and RNA levels and cell cycle phases in a mixed population of cells have added diagnostic sensitivity and specificity over standard cytopathology methods.103 Detection of clonal gene rearrangements via PCR has also increased the diagnostic yield in these specimens.104 Finally, immunocytochemistry often is helpful in identifying the origin of abnormal cells when encountered.71,105,106 Such tests can be critical for the 5–11% of patients in whom identification of the malignant cell in the CSF is the first sign of systemic malignancy.5,100,107 CSF biomarkers such as β-glucuronidase, CEA, LDH, CK, and β2-microglobulin can be useful in supporting the

H

Figure 26-1 Post-contrast T1-weighted sagittal cervical spine MRI of an adult with recurrent medulloblastoma (ccircle) with associated postoperative meningoencephalocele. Arrows show areas of enhancement of the leptomeninges (left image). Post-contrast T1-weighted sagittal MRI of the lumbosacral spine showing diffuse tumor involvement altering the signal of the CSF (arrows) and encasing the cauda equina (right image).

Paraneoplastic Disorders

243

Figure 26-2 T1-weighted cranial MRI of a patient with diffuse leptomeningeal and parenchymal involvement from melanoma. Bright signal is seen in the subarachnoid space prior to contrast administration reflecting the shortening caused by high melanin content (left image). Cytopathological analysis of CSF from the same patient shows cells with dysmorphic nuclei with multiple, prominent nucleoli and pronounced cytoplasm with varying degrees of pigment.

diagnoses of leptomeningeal disease (Table 26-5).31,102,108 For example, β2-microglobulin is very helpful in confirming leptomeningeal involvement from hematological malignancies. CEA is useful in the setting of solid tumor metastases and may be notably elevated with breast, colon, and lung metastases.108 VEGF has been shown to be elevated in CSF in cases of leptomeningeal carcinomatosis.38 Moreover, levels of this mediator fell with successful therapy and rose again concurrent with relapse. Validation in large clinical studies will be needed to make these, or other, biomarkers useful clinical surrogates in the diagnosis of leptomeningeal disease.

PARANEOPLASTIC DISORDERS Paraneoplastic neurological disorders (PND) are a collection of syndromes associated with underlying (generally

systemic) malignancies. These conditions are thought to result from an inappropriate immune response to normal regions of the nervous system that are associated with antibodies formed in response to protein antigens expressed on the underlying tumor.109 While the exact roles played by these autoantibodies in the pathogenesis of these disorders is not fully understood, it is agreed that their detection in the serum and CSF has utility as diagnostic markers of the PNDs. Thus, detection of specific autoantibodies in association with a classic PND clinical syndrome (i.e., cerebellar degeneration) can be diagnostic of these disorders. Table 26-8 provides a list of many known PNDs and their associated antibody markers. Patients with PND frequently have evidence of CSF inflammation with a pleocytosis ranging from 3 to 75 cells/mm3 and an elevated protein content ranging from 50 to 100 mg/dl.110,111 Nonspecific markers of neuronal injury such as 14-3-3 protein have also been found to be

Table 26-8 Classic Paraneoplastic Neurological Disorders and Their Associated Autoantibodies and Underlying Malignancies Antibody Marker

Common Associated Malignancies

Associated Neurological Syndrome(s)

Anti-Hu Anti-Yo Anti-Ri

Small-cell lung cancer Gynecologic malignancies (ovarian, breast) Gynecologic malignancies (ovarian, breast), Small-cell lung cancer Testicular cancer, germ cell tumors Hodgkin’s lymphoma Small-cell lung cancer

Encephalomyelitis, cerebellar degeneration, sensory neuropathy, dysautonomia Cerebellar degeneration Cerebellar degeneration, opsoclonus-myoclonus, brainstem encephalitis Limbic encephalitis, brainstem encephalitis Cerebellar degeneration Cerebellar degeneration, Lambert-Eaton myasthenic syndrome Encephalomyelitis, stiff-person syndrome Cancer-associated retinopathy

Anti-Ma Anti-Tr Anti-voltage-gated calcium channel Anti-amphiphysin Anti-recoverin

Breast cancer Small-cell lung cancer

(Data adapted from references 109, 110.)

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elevated in the CSF of patients with confirmed PNDs. Saiz et al. found that 12.5% of their PND patients had detectable 14-3-3 protein in the CSF, and that the pattern of immunoblotting (a double band) distinguished these patients from those with Creutzfeld-Jakob disease (single band).112 While such CSF findings support the diagnosis of a PND, the most useful CSF studies for confirming the diagnosis are elevated total IgG OCB and elevated OCB associated with PND-specific autoantibodies. Elevated CSF levels of total Ig in general and OCB in particular may partially be explained by passage from serum across a disrupted BBB, but the dominant source of antibodies appears to be from de novo intrathecal synthesis. This has been demonstrated by higher CSF than serum concentrations of the antibodies and the presence of increased total and antigen-specific OCB in the CSF, but not in the serum.110,111,113–115 Techniques such as isoelectric focusing have also increased the sensitivity of antibody detection and have helped to confirm that antibody levels may be elevated in the CSF and yet undetectable in the serum.114,115 These findings are of particular clinical interest in the post-treatment period when antibody concentrations are expected to be undetectable in the serum, but may yet persist in the CSF, suggesting the need for further therapy.113 There is also evidence that PNDs with mostly CNS manifestations (e.g., paraneoplastic encephalomyelitis) are more likely to have elevated CSF:serum antibody levels compared to patients with peripheral nervous system involvement (e.g., subacute sensory neuropathy), even when the two clinical syndromes are linked to the same autoantibody (e.g., anti-Hu).116 In summary, CSF studies can be very useful in both the diagnosis and monitoring of patients with PND. There may be general signs of inflammation such as elevated total protein content, high total IgG, and a mild pleocytosis. However, the real value comes in assessment of antigenspecific OCB levels, which are frequently found at higher concentrations and for longer intervals in CSF than in serum.

CEREBROSPINAL FLUID CHANGES IN THE MONITORING OF TREATMENT TOXICITY All treatments for brain and spinal cord tumors have the potential to cause CNS toxicity. The best known of these complications are associated with radiation therapy and include an acute encephalopathy and a delayed leukoencephalopathy/cognitive disorder with or without radiation necrosis. Recognition of these toxicities has led to the use of more focal, lower-dose, and fractionated treatment regimens.117 Systemic and intrathecal chemotherapy is also associated with severe CNS toxicities, including a disseminated necrotizing leukoencephalopathy.118 The most damaging CNS toxicities are seen with the combination of intrathecal chemotherapy and radiotherapy. This phenomenon has been documented in children being treated with preventive intrathecal chemotherapy and concurrent

craniospinal radiation for ALL, and in adults being treated with intrathecal chemotherapy and cranial radiation for primary CNS lymphoma or carcinomatous meningitis.119 The clinical manifestations of disseminated necrotizing leukoencephalopathy (lethargy, dementia, confusion, hemiparesis, aphasia) have been correlated with abnormal CSF findings. Total protein content, α2-macroglobulin levels, and measures of IgG content have all been noted to be elevated during and subsequent to combined intrathecal chemotherapy and radiation therapy.120 CSF levels of myelin basic protein (MBP), a nonspecific marker of oligodendrocyte damage, have been shown to be elevated in children with ALL following combination CNS therapy.121 The microtubule-associated protein, tau, thought to be a marker of neuronal injury, has also been shown to be elevated in the CSF of children with ALL at the time of diagnosis and then to increase further with intrathecal chemotherapy.122 In one of the few studies that directly correlated pathologic CSF changes after intrathecal chemotherapy and/or cranial radiation treatment to clinical toxicity syndromes, Mahoney et al. showed that persistently elevated levels of MBP following treatment were associated with signs and symptoms of progressive leukoencephalopathy.121 Still, although CSF changes such as elevated total protein content or elevated MBP or tau levels can support the clinical suspicion of leukoencephalopathy following intrathecal chemotherapy and/or radiation, there are few studies to support the widespread clinical use of these measures as a means to accurately distinguish between the condition and tumor recurrence. Finally, surgical placement of equipment such as intrathecal catheters and Ommaya reservoirs may themselves be associated with pathologic CSF changes in patients with CNS tumors. Bigner et al. reported the CSF findings of three patients with brain tumors that required placement of a ventricular shunt (ependymoma, astrocytoma, and pineal germinoma).123 Fluid drawn from these devices contained ependymal cells, multinucleated histiocytic giant cells, and, in the case of the patient with germinoma, neoplastic cells at the time of shunt malfunction. These authors stressed the importance of identifying true neoplastic cells suggesting tumor recurrence versus a reactive infiltrate in response to the device itself. As mentioned earlier, the sensitivity for the identification of tumor cells in the CSF is less when samples are taken from an indwelling catheter than from the ventricle or lumbar space directly.100,101 REFERENCES 1. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992. 2. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: WB Saunders; 1938. 3. Thomsen J, Bech P, Nielsen OS. CSF total protein: normal values. A reappraisal and discussion of its value in diagnosis of acoustic neuromas. Acta Otolaryngol 1978;86:359–365.

References

4. Kang JK, Jeun SS, Hong YK, et al. Experience with pineal region tumors. Childs Nerv Syst 1998;14:63–68. 5. Bigner SH, Johnston WW. The cytopathology of cerebrospinal fluid. II. Metastatic cancer, meningeal carcinomatosis, and primary central nervous system neoplasms. Acta Cytologica 1981;25:461–479. 6. Parwani AV, Mikolaenko I, Eberhart CG, Burger PC, Rosenthal DL, Ali SZ. Rhabdoid menigioma: cytopathologic findings in cerebrospinal fluid. Diagn Cytopathol 2003;29:297–299. 7. Chamberlain MC, Glantz MJ. Cerebrospinal fluid-disseminated meningioma. Cancer 2005;103:1427–1430. 8. CBTRUS. Statistical Report: Primary Brain Tumors in the United States, 1997–2001. New York: The Central Brain Tumor Registry of the United States, 2004. 9. Sayk J. The cerebrospinal fluid in brain tumors. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Vol. 16. Amsterdam: North Holland; 1974:360–417. 10. Onda K, Takana R, Takahashi H, Takeda N, Ikuta F. Cerebral glioblastoma with cerebrospinal fluid dissemination: a clinicopathological study of 14 cases examined by complete autopsy. Neurosurgery 1989;25:533–540. 11. Grabb PA, Albright AL, Pang D. Dissemination of supratentorial malignant gliomas via the cerebrospinal fluid in children. Neurosurgery 1992;30:64–71. 12. Yomo S, Tada T, Hirayama S, et al. Primary diffuse leptomeningeal gliomatosis. A case report and review of the literature. J Neurooncol 2007;81:209–216. 13. Dietrich PY, Aapro MS, Rieder A, Pizzolato GP. Primary diffuse leptomeningeal gliomatosis (PDLG): a neoplastic cause of chronic meningitis. J Neurooncol 1993;15:275–283. 14. Sa MJ, Vaz R, Cruz C. Cerebrospinal fluid cytomorphologic findings in 41 intracranial tumors: a retrospective review. Arq Neuropsiquiatr 1995;53:218–226. 15. Arita N, Taneda M, Hayakawa T. Leptomeningeal dissemination of malignant gliomas. Incidence, diagnosis and outcome. Acta Neurochir (Wien) 1994;126:84–92. 16. Nishio S, Korosue K, Tateishi J, Fukui M, Kitamura K. Ventricular and subarachnoid seeding of intracranial tumors of neuroectodermal origin. A study of 26 consecutive autopsy cases with reference to focal ependymal defect. Clin Neuropath 1982;1:83–91. 17. Erlich SS, Davis RL. Spinal subarachnoid metastasis from primary intracranial glioblastoma multiforme. Cancer 1978;42:2854–2864. 18. Yung WA, Horten BC, Shapiro WR. Meningeal gliomatosis: a review of 12 cases. Ann Neurol 1980;8:605–608. 19. Balhuizen JC, Bots G, Schaberg A, Bosman F. Value of cerebrospinal fluid cytology for the diagnosis of malignancies in the central nervous system. J Neurosurg 1978:48:747–753. 20. Awad I, Bay JW, Rogers L. Leptomeningeal metastasis from supratentorial malignant gliomas. Neurosurgery 1986;19:247–251. 21. Heideman RL, Kuttesch J Jr, Gajjar AJ, et al. Supratentorial malignant gliomas in childhood: a single institution perspective. Cancer 1997;80:497–504. 22. Benesch M, Wagner S, Berthold F, Wolff JE. Primary dissemination of high-grade gliomas in children: experiences from four studies of the Pediatric Oncology and Hematology Society of the German Language Group (GPOH). J Neurooncol 2005;72:179–183. 23. Browne TJ, Goumnerova LC, De Girolami U, Cibas ES. Cytologic features of pilocytic astrocytoma in cerebrospinal fluid specimens. Acta Cytologica 2004;48:3–8. 24. Izumoto S, Ohnishi T, Kanemura H, et al. PTEN mutations in malignant gliomas and their relation with meningeal gliomatosis. J Neurooncol 2001;53:21–26. 25. Gondos B. Cytology of cerebrospinal fluid: technical and diagnostic considerations. Ann Clin Lab Sci 1976;6:152–157. 26. Gupta RK, Naram S, Lallu S, Fauck R. Cytodiagnosis of neoplasms of the central nervous system in cerebrospinal fluid samples with an application of selective immunostains in differentiation. Cytopathology 2004;15:38–43.

245

27. Minami T, Kai T, Hirabaru C, et al. A case of cerebral glioblastoma with extensive cerebrospinal fluid dissemination: diagnostic value of immunohistochemical examination and MR imaging. Childs Nerv Syst 1993;9:478–480. 28. Koskiniemi M. Malignancy markers in the cerebrospinal fluid. Eur J Pediatr 1988;148:3–8. 29. Kuratsu J, Yoshizato K, Yoshimura T, Leonard EJ, Takeshima H, Ushio Y. Quantitative study of monocyte chemoattractant protein-1 (MCP-1) in cerebrospinal fluid and cyst fluid from patients with malignant glioma. J Natl Cancer Inst 1993;85:1836–1839. 30. Marton LJ, Heby O, Levin VA, Lubich WP, Crafts CS, Wilson CG. The relationship of polyamines in cerebrospinal fluid to the presence of central nervous system tumors. Cancer Res 1976:36:973–977. 31. Wasserstrom WR, Schwartz MK, Fleisher M, Posner J. Cerebrospinal fluid biochemical markers in central nervous system tumors: a review. Ann Clin Lab Sci 1981;11:239–251. 32. Fulton DS, Levin VA, Lubich WP, Wilson CB, Marton LJ. Cerebrospinal fluid polyamines in patients with glioblastoma multiforme and anaplastic astrocytoma. Cancer Res 1980;40:3293–3296. 33. Ribom D, Westman-Brinkmalm, Smits A, Davidsson P. Elevated levels of alpha-2-Heremans-Schmid glycoprotein in the CSF of patients with low-grade gliomas. Tumor Biol 2003;24:94–99. 34. Peles E, Lidar Z, Simon A, Grossman R, Nass D, Ram Z. Angiogenic factors in cerebrospinal fluid of patients with astrocytic brain tumors. Neurosurgery 2004;55:562–568. 35. Schmidt NO, Westphal M, Hagel C, et al. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 1999;84:10–18. 36. Sampath P, Weaver CE, Sungarian A, Cortez S, Alderson L, Stopa EG. Cerebrospinal fluid (vascular endothelial growth factor) and serologic (recoverin) tumor markers for malignant glioma. Cancer Control 2004;11:174–180. 37. Van der Flier M, Stockhammer G, Vonk GJ, et al. Vascular endothelial growth factor in bacterial meningitis: detection in cerebrospinal fluid and localization in post-mortem brain. J Infect Dis 2001;183:149–153. 38. Stockhammer G, Poewe W, Burgstaller S, et al. Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis. Neurology 2000;54:1670–1676. 39. Pernicone PJ, Scheithauer BW, Sebo TJ, et al. Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 1997;79:804–812. 40. Jagannathan J, Dumont AS, Jane JA. Diagnosis and management of pediatric sellar lesions. Front Horm Res 2006;34:83–104. 41. Packer RJ, Sutton LN, Elterman R, et al. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 1994;81:690–698. 42. Chapman PH, Linggood RM. The management of pineal area tumors: a recent reappraisal. Cancer 1980;46:1253–1257. 43. Sung DI, Harisliadis L, Chang CH. Midline pineal tumors and suprasellar germinomas: highly curable by irradiation. Radiology 1978;128:745–751. 44. Ito M, Jamshidi J, Yamanaka K. Does craniopharyngioma metastasize? Case report and review of the literature. Neurosurgery 2001;48:933–935. 45. Kulkarni V, Daniel RT, Pranatartiharan, R. Spontaneous intraventricular rupture of craniopharyngioma cyst. Surg Neurol 2000;54:249–253. 46. Thomsen J, Saxtrup O, Tos M. Spinal proteins in patients with acoustic neuromas. ORL J Otorhinolaryngol Relat Spec 1982;44:66–71. 47. Bloch J, Vernet O, Aube M, Villemure JG. Non-obstructive hydrocephalus associated with intracranial schwannomas: hyperproteinorrhachia as an etiopathological factor? Acta Neurochir (Wien) 2003;145:73–78. 48. Grainger J, Dias P. Case report: optic disc edema without hydrocephalus in acoustic neuroma. Skull Base Surg 2005;15:83–86. 49. Laing RJ, Smielewski P, Czosnyka M, Quaranta N, Moffat DA. A study of perioperative lumbar cerebrospinal fluid pressure in patients undergoing acoustic neuroma surgery. Skull Base Surg 2000;10:179–185.

246

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50. Olson JE, Janney CA, Rao RD, et al. The continuing increase in the incidence of primary central nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer 2002;95:1504–1510. 51. Ferreri AJM, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: The International Extranodal Lymphoma Study Group Experience. J Clin Oncol 2003;21:266–272. 52. Balmaceda C, Gaynor JJ, Sun M, Torres Gluck J, DeAngelis LM. Leptomeningeal tumor in primary central nervous system lymphoma: Recognition, significance and implications. Ann Neurol 1995;38:202–209. 53. Blay JY, Lassett C, Carrie C, et al. Multivariate analysis of prognostic factors in patients with non-HIV-related primary cerebral lymphoma: a proposal for prognostic scoring. Br J Cancer 1993;67:1136–1141. 54. Lachance DH, O’Neill BP, Macdonald DR, et al. Primary leptomeningeal lymphoma: report of 9 cases, diagnosis with immunocytochemical analysis, and review of the literature. Neurology 1991;41:95–100. 55. Gleissner B, Siehl J, Korfel A, Reinhardt R, Thiel E. CSF evaluation in primary CNS lymphoma patients by PCR of the CDR III IgH genes. Neurology 2002;58:390–396. 56. Li CY, Witzig TE, Phyliky RL, Ziesmer SC, Yam LT. Diagnosis of B-cell non-Hodgkin’s lymphoma of the central nervous system by immunocytochemical analysis of cerebrospinal fluid lymphocytes. Cancer 1986;57:737–744. 57. Hegde U, Filie A, Little RF, et al. High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood 2005;105:496–502. 58. Subira D, Gorgolas M, Castanon S, et al. Advantages of flow cytometry immunophenotyping for the diagnosis of central nervous system non-Hodgkin’s lymphoma in AIDS patients. HIV Med 2005;6:21–26. 59. Hug A, Storch-Hagenlocher B, Haas J, Vogt-Schaden ME, Goldschmidt H, Wildemann B. Single-cell PCR analysis of the immunoglobulin heavy-chain CDR3 region for the diagnosis of leptomeningeal involvement of B-cell malignancies using standard cerebrospinal fluid cytospins. J Neurol Sci 2004;219:83–88. 60. Cinque P, Brytting M, Vago L, et al. Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 1993;342:398–401. 61. Cingolani A, De Luca A, Larocca LM, et al. Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. J Natl Cancer Inst 1998;90:364–369. 62. Antinori A, DeRossi G, Ammassari A, et al. Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol 1999; 17:554–560. 63. Eichler AF, Batchelor TT. Primary central nervous system lymphoma: presentation, diagnosis and staging. Neurosurg Focus 2006;21:E15. 64. Packer RJ, Siegel KR, Sutton LN, Litmann P, Bruce DA, Schut L. Leptomeningeal dissemination of primary central nervous system tumors of childhood. Ann Neurol 1985;18:217–221. 65. Gajjar A, Fouladi M, Walter AW, et al. Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors. J Clin Oncol 1999;17:1825–1828. 66. Packer RJ. Diagnosis, treatment, and outcome of primary central nervous system tumors of childhood. Curr Opin Oncol 1996; 6:240–246. 67. Prayson RA, Fischler DF. Cerebrospinal fluid cytology: an 11-year experience with 5951 specimens. Arch Path Lab Med 1998; 122:47–51. 68. Meyers SP, Wildenhain SL, Chang JK, et al. Postoperative evaluation for disseminated medulloblastoma involving the spine: contrast-enhanced MR findings, CSF cytologic analysis, timing of disease occurrence, and patient outcomes. AJNR Am J Neuroradiol 2000;21:1757–1765.

69. Harrison SK, Ditchfield MR, Waters K. Correlation of MRI and CSF cytology in the diagnosis of medulloblastoma spinal metastases. Pediatr Radiol 1998;28:571–574. 70. Fouladi M, Gajjar A, Boyett JM, et al. Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 1999;17:3234–3237. 71. Bigner S. Cerebrospinal fluid (CSF) cytology: current status and diagnostic applications. J Neuropath Exp Neurol 1992;51:235–245. 72. Marton LJ, Edwards MS, Levin VA, Lubich WP, Wilson CB. Predictive value of cerebrospinal fluid polyamines in medulloblastoma. Cancer Res 1979;39:993–997. 73. Takaue Y, Nishioka K, van Eys J. Evaluation of polyamine levels in cerebrospinal fluid of children with brain tumors. J Neurooncol 1986;3:327–333. 74. Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002;415:436–442. 75. Reni M, Brandes AA, Vavassori V, et al. A multicenter study of the prognosis and treatment of adult brain ependymal tumors. Cancer 2004;100:1221–1229. 76. Poltinnikov IM, Merchant TE. CSF cytology has limited value in the evaluation of patients with ependymoma who have MRI evidence of metastasis. Pediatr Blood Cancer 2006;47:169–173. 77. Chieng DC, Elgert P, Cohen JM, Jhala NC, Cangiarella JF. Cytology of primary central nervous system neoplasms in cerebrospinal fluid specimens. Diag Cytopathol 2002;26:209–212. 78. Pencalet P, Sainte-Rose C, Lellouch-Tubiana A, et al. Papillomas and carcinomas of the choroid plexus in children. J Neurosurg 1998; 88:521–528. 79. Allen JC, Nisselbaum J, Epstein F, Rosen G, Schwartz MK. Alphafetoprotein and human chorionic gonadotropin determination in cerebrospinal fluid. An aid to the diagnosis and management of intracranial germ-cell tumors. J Neurosurg 1979;51:368–374. 80. Berman TR, Plowman SJ, Jones PT. Germ cell tumours. In: Bleehen NM, ed. Tumours of the Brain. New York: Springer-Verlag; 1986:237–252. 81. Kang JK, Jeun SS, Hong YK, et al. Experience with pineal region tumors. Childs Nerv Syst 1998;14:63–68. 82. Fauchon F, Jouvet A, Paquis P, et al. Parenchymal pineal tumors: a clinicopathological study of 76 cases. Int J Radiat Oncol Biol Phys 2000;46:959–968. 83. Lutterbach J, Fauchon F, Schild SE, et al. Malignant pineal parenchymal tumors in adult patients: patterns of care and prognostic factors. Neurosurgery 2002;51:44–56. 84. Lee YK, Wakabayashi T, Yoshida J. Management and survival of pineoblastoma: an analysis of 34 adults from the brain tumor registry of Japan. Neurol Med Chir (Tokyo) 2005;45:132–142. 85. Chang S, Lillis-Hearne PK, Larson DA, Wara WM, Bollen AW, Prados MD. Pineoblastoma in adults. Neurosurgery 1995;37:383–391. 86. Konovalov AN, Pitskhelauri DI. Principles of treatment of the pineal region tumors. Surg Neurol 2003;59:250–268. 87. Yamini B, Refai D, Rubin CM, Frim DM. Initial endoscopic management of pineal region tumors and associated hydrocephalus: clinical series and literature review. J Neurosurg 2004;100:437–441. 88. Norden AD, Wen PY, Kesari S. Brain metastases. Curr Opin Neurol 2005;18:654–661. 89. Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells in cerebrospinal fluid (CSF): the meaning of positive CSF cytology. Neurology 1979;29:1369–1375. 90. Hoon DSB, Kuo CT, Wascher RA, Fournier P, Wang HJ, O’Day SJ. Molecular detection of metastatic melanoma cells in cerebrospinal fluid in melanoma patients. J Invest Dermatol 2001;117:375–378. 91. Casper JT, Lauer SJ, Kirchner PA, Gottschall JL, Camitta BM. Evaluation of cerebrospinal fluid mononuclear cells obtained from children with acute lymphocytic leukemia: advantages of combining cytomorphology and terminal deoxynucleotidyl transferase. Am J Clin Pathol 1983;80:666–670.

References

92. Koskiniemi M, Rajantie J, Rautonen J, et al Fibronectin concentration in cerebrospinal fluid reflects early central nervous system involvement in children with acute lymphoblastic leukemia. Leuk Res 1990;14:449–452. 93. Maroldi R, Ambrosi C, Farina D. Metastatic disease of the brain: extra-axial metastases (skull, dura, leptomeningeal) and tumour spread. Eur Radiol 2005;15:617–626. 94. Jaeckle KA. Neoplastic meningitis from systemic malignancies: diagnosis, prognosis and treatment. Semin Oncol 2006;33:312–323. 95. Zeller JA, Zunker P, Witt K, Schlueter E, Deuschl ML. Unusual presentation of carcinomatous meningitis: case report and review of typical CSF findings. Neurol Res 2002;24:652–654. 96. Straathof CS, de Bruin HG, Dippel DW, Vecht CJ. The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 1999;246:810–814. 97. Olson ME, Chernik NL, Posner JB. Infiltration of the leptomeninges by systemic cancer: a clinical and pathologic study. Arch Neurol 1974;30:122–137. 98. Kaplan J, DeSouza T, Farkash A, et al. Leptomeningeal metastases comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. J Neurooncol 1990;92:225–229. 99. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–772. 100. Chamberlain MC, Kormanik PA, Glantz MJ. A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases. Neuro-oncology 2001;3:42–45. 101. Murray JJ, Greco FA, Wolff SN, Hainsworth JD. Neoplastic meningitis. Marked variations of cerebrospinal fluid composition in the absence of extradural block. Am J Med 1983;75:289–294. 102. Yoshida S, Morii K. Intrathecal chemotherapy for patients with meningeal carcinomatosis. Surg Neurol 2005;63:52–55. 103. Cibas ES, Malkin MG, Posner JB, Melamed MR. Detection of DNA abnormalities by flow cytometry in cells from cerebrospinal fluid. Am J Clin Pathol 1987;88:570–577. 104. Rhodes CH, Glanz MJ, Glanz L, et al. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer 1996;77:543–548. 105. Tani E, Costa I, Svedmeyr E, Skoog L. Diagnosis of lymphoma, leukemia and metastatic tumor involvement of cerebrospinal fluid by cytology and immunocytochemistry. Diagn Cytopathol 1995;12:14–22. 106. Roma AA, Garcia A, Avagnia A, Rescia C, Elsner B. Lymphoid and myeloid neoplasms involving the cerebrospinal fluid: comparison of morphological examination and immunophenotyping by flow cytometry. Diagn Cytopathol 2002;27:271–275. 107. Bigner SH, Johnston WW. The diagnostic challenge of tumors manifested initially by the shedding of cells into the cerebrospinal fluid. Acta Cytologica 1984;28:29–36. 108. Grossman SA, Moynihan TJ. Neoplastic meningitis. Neurol Clin 1991;9:843–856.

247

109. Dalmau JO, Posner JB. Paraneoplastic syndromes. Arch Neurol 1999; 56:405–408. 110. Bataller L, Dalmau JO. Paraneoplastic disorders of the central nervous system: update on diagnostic criteria and treatment. Semin Neurol 2004;24:461–471. 111. Rauer S, Kaiser R. Demonstration of anti-HuD specific oligoclonal bands in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes: qualitative evidence of anti-HuD specific IgG synthesis in the central nervous system. J Neuroimmunol 2000;111:241–244. 112. Saiz A, Graus F, Dalmau J, Pifarra A, Marin C, Tolosa E. Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurologic disorders. Ann Neurol 1999;46:774–777. 113. Blaes F, Strittmatter M, Schwamborn J, et al. Antineuronal antibody-associated paraneoplastic neuropathy in Hodgkin’s disease. Eur J Neurol 1998;5:109–112. 114. Storstein A, Monstad SE, Honnorat J, Vedeler CA. Paraneoplastic antibodies detected by isoelectric focusing in cerebrospinal fluid and serum. J Neuroimmunol 2000;155:150–154. 115. Stich O, Graus F, Rasiah C, Rauer S. Qualitative evidence of anti-Yo-specific intrathecal antibody synthesis in patients with paraneoplastic cerebellar degeneration. J Neuroimmunol 2003;141: 165–169. 116. Vega F, Graus F, Chen QM, Poisson M, Schuller E, Delattre JY. Intrathecal synthesis of the anti-Hu antibody in patients with paraneoplastic encephalomyelitis or sensory neuronopathy: clinical-immunologic correlation. Neurology 1994;44:2145–2147. 117. Keime-Guibert F, Napolitano M, Delattre JY. Neurological complications of radiotherapy and chemotherapy. J Neurol 1998;245:695–708. 118. Sakamaki H, Onozawa Y, Yano Y, et al. Disseminated necrotizing leukoencephalopathy following irradiation and methotrexate therapy for central nervous system infiltration of leukemia and lymphoma. Radiat Meth 1993;11:146–153. 119. Boogerd W, Sande JJ, Moffie D. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate. J Neurol Neurosurg Psychiatry 1988;51: 1277–1283. 120. Siemes H, Rating D, Siegert M, et al. Changes of CSF-protein pattern in children with acute lymphoblastic leukemia during prophylactic central nervous system therapy (Berlin protocol). Med Pediatr Oncol 1980;8:25–34. 121. Mahoney DH, Fernbach DJ, Glaze DG, Cohen SR. Elevated myelin basic protein levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia. J Clin Onc 1984;2:58–61. 122. Van Gool SW, De Meyer GD, Van de Voorde A, Vanmechelen E, Vanderstichele H. Neurotoxicity marker profiles in CSF are not age-dependent but show variation in children being treated for acute lymphoblastic leukemia. Neurotoxicology 2004;25:471–480. 123. Bigner SH, Elmore PD, Dee AL, Johnston WW. The cytopathology of reactions to ventricular shunts. Acta Cytol 1985;29:391–396.

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Nervous System Trauma Wendy Wright and Daniele Rigamonti

INTRODUCTION In clinical practice, cerebrospinal fluid (CSF) is not often collected from patients who have experienced nervous system trauma. After all, such a diagnosis does not depend on CSF analysis, and collection is invasive and sometimes risky in these patients. These issues, along with the broad spectrum of central nervous system (CNS) injuries that follow trauma, limit the availability of data on the expected CSF profiles in these disorders. Even when CSF is examined, its composition will vary widely based on the nature, extent, and timing of the injury. Still, CSF markers have long been sought to help clinicians evaluate the severity of injury, the prognosis for recovery, and the response to various therapeutic interventions.1,2 None of the markers investigated to date has replaced the clinical exam and neuroimaging findings for these purposes. Some markers have suggested theories about mechanisms of primary and secondary neuronal injury in these disorders, however, and perhaps others will serve a more important prognostic role in the future.

TRAUMATIC BRAIN INJURY At least 1.4 million people per year suffer a traumatic brain injury (TBI) in the USA.3 Some 250,000 of these individuals are hospitalized and survive,3 but about one-third are left with some debilitating loss of neurological function.4 TBI is a heterogeneous disorder, and the associated CSF findings are highly variable. CSF dynamics are not usually altered by head injury in the acute setting per se, but significant brain injury is often associated with increased intracranial pressure (ICP). Furthermore, blood accumulating in the ventricular system may prevent CSF reabsorption, and transtentorial herniation may cause cisternal block. Both of these processes can result in obstructive hydrocephalus.5

The CSF changes related to increased ICP and hydrocephalus are discussed in Chapters 4 and 12, respectively. Most patients with a cerebral concussion will have a normal routine CSF profile. In more significant acute head injuries, CSF protein levels may be mildly to moderately elevated once a sample can be safely obtained. If a patient suffers a cerebral contusion, the CSF red blood cell (RBC) count can rise. A mild CSF leukocytosis may also develop secondary to inflammation in the underlying brain parenchyma or in response to RBC breakdown products in the CSF itself. If a large amount of blood violates the subarachnoid or intraventricular space, the CSF RBC count will be dramatically elevated, and the CSF white blood cell (WBC) count will rise to a degree that reflects the normal intravascular RBC:WBC ratio (usually 700:1 to 1,000:1). Glucose levels in CSF may sometimes be mildly elevated after severe head injury.6 Concentrations are highest on the first day after trauma, plateau on days 3–5, and often remain elevated compared to controls even without exogenous glucose administration. Such treatment does not typically raise the CSF glucose concentration, although CSF lactate production may increase in patients receiving systemic glucose.6 The Gram stain and culture of CSF should be negative after a typical closed head injury. While a positive CSF Gram stain or culture may be the result of contamination, a CSF leak should always be sought in trauma patients with these findings (discussed below). Penetrating CNS injuries are more likely to introduce bacteria into the CSF space, thereby resulting in positive bacterial cultures. In clinical practice, lumbar puncture (LP) is not routine in TBI due to the presence of cerebral edema and an increased risk of herniation, but an intraventricular catheter (IVC) may be placed for the purpose of ICP monitoring and/or CSF diversion. In these patients, CSF samples have been studied for the presence of markers of neural damage (discussed below).

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CSF-RELATED COMPLICATIONS OF NERVOUS SYSTEM TRAUMA Spinal fluid leaks Traumatic fracture of the skull base may also cause perforation of the leptomeninges, sometimes allowing CSF to flow from the subarachnoid space out of the nose or ear.7 Thus, after basilar skull fracture or facial trauma, a persistent leak may result in CSF rhinorrhea or otorrhea. Two large series report that the incidence of CSF leak after basilar skull fracture and/or facial trauma to 2.6% and 4.6%, respectively.8,9 The observation of otorrhea or rhinorrhea should alert the clinician to the presence of a CSF leak. Intermittent flow can sometimes be reproduced or increased with provocative maneuvers such as valsalva.7 Still, while clear fluid draining from the ear can safely be assumed to be CSF, determining the etiology of serous nasal discharge is more difficult. Tests such as the “target sign” or the “ring test,” where nasal secretions are examined on a sheet of paper for the presence of a water-density halo indicative of CSF, are not reliable diagnostic maneuvers. Similarly, measuring glucose concentrations in these secretions can have a high false-positive rate; 10 if anything, the laboratory test of choice should be the measurement of β-2 transferrin levels in collected secretions (it is present in CSF and absent in other fluids).11,12 A computed tomography (CT) scan with intrathecal contrast administration (CT cisternography) can help identify the location of the leak, although this procedure is best reserved for situations where surgical repair is being considered.7 Conservative management, often implemented for 5–7 days before invasive treatment is considered, consists of bed rest, head elevation, and sinus precautions (no nose blowing, no valsalva, etc).7,9,13 Antiemetics, antitussives, and stool softeners may also be used to suppress vomiting, coughing, and straining that predisposes to CSF leakage.7 Antibiotics are not routinely recommended in an acute CSF leak; one study suggests that they may actually increase the incidence of meningitis by altering the normal sinus flora.13 If a leak does not subside with conservative measures, then temporary CSF diversion is often implemented via a lumbar drain. This often resolves the leak in approximately 5–10 days.7,9 If CSF diversion is not successful, then surgical repair can be considered. However, repair procedures are generally used more for iatrogenic rather than posttraumatic CSF leaks.7,9 Furthermore, the incidence of meningitis was higher (40% vs. 29%) in one series of patients whose traumatic CSF leaks were surgically repaired compared to those where they were not.8

Meningitis A longstanding conduit between the paranasal sinuses, nasopharynx, or middle ear and the subarachnoid space may allow for the eventual retrograde influx of microbes

and the development of meningitis. The incidence of meningitis in this situation has been reported to range anywhere from 0% to 50%, depending on the series referenced.7,9 Based on cases described from recent military conflicts, the incidence of intracranial infection is about 5% in patients with penetrating head injury, and about half that in patients with closed head injuries.14,15 Prophylactic antibiotics are not recommended in the latter population, but they are often administered to patients with penetrating head traumas. When implemented, antibiotics should cover skin flora, Gram-negative bacteria, and anaerobic pathogens. A 5-day course of prophylactic antibiotics is probably reasonable, and anti-tetanus immunoglobulin is also recommended.14,15 The diagnosis of meningitis should be entertained in any patient who has fever or unexplained neurological decline after head injury. Persistent CSF leak and penetrating trauma are the main predisposing factors for developing meningitis. Once suspected, broad-spectrum antibiotics that penetrate the CNS should be implemented, and CSF samples should be obtained. Routine CSF parameters may sometimes be difficult to interpret since an increase in the cell count and protein concentration can be seen in head injury without infection,16 so the Gram stain and culture are essential to confirm a diagnosis. If cultures are positive, an extended treatment course of 14–21 days should be completed. If CSF cannot be safely sampled due to ICP issues, a 14-day course of prophylactic antibiotics should be given.

Abscesses Patients with penetrating injuries to the CNS run the additional risk of local abscess formation with or without associated meningitis. Intracerebral abscesses are not particularly common, occurring in substantially less than 5% of penetrating head injuries,17 but may occur up to 6–8 weeks after the initial injury.16,17 If a head trauma patient develops sepsis or fever, particularly with headache and/or focal neurological deficits, brain imaging should be repeated and CSF cultured. It should be kept in mind that the yield of positive cultures by LP may be low in these cases, since an encapsulated abscess may not significantly alter CSF content unless it ruptures into the ventricular or subarachnoid space. Treatment of these post-traumatic intracranial abscesses includes intravenous antibiotics, and most also require percutaneous drainage or surgical excision. While surgical intervention has sometimes in the past been deferred if the patient was considered too unstable to undergo open craniotomy, advances in neuroanesthesia and in drainage techniques render the concept of medical management only in these patients rather outdated. The goal of any surgery should be to excise necrotic brain and to remove infected tissue and foreign bodies when accessible, but fragments of bone and metal from high-velocity projectiles such as bullets are often left behind if their removal would likely worsen neurological deficits. Surgical treatment should

CSF Biomarkers in TBI

definitely not be deferred in patients with cerebellar abscesses, those lesions steadily progressing in size, or in abscesses causing worsening mass effect or focal neurological deficits.18 Corticosteroids are often administered if vasogenic edema is felt to contribute to the clinical decline.18

CSF BIOMARKERS IN TBI Following head injury, a variety of specific pathophysiological processes that affect the underlying brain may also influence CSF composition. Some of these processes include direct neuronal or axonal disruption, excitotoxicity, impaired cerebral energy metabolism, oxidative stress, inflammation, and apoptosis. As a result, many intracellular proteins derived from both neurons and glial cells can be released into the CSF with TBI, and levels of inducible proteins such as pro-inflammatory cytokines can also rise in this compartment.19,20 A number of these proteins have been measured in CSF in an effort to quantify underlying neural injury, and others have been used to study injury mechanisms in experimental models of CNS trauma. While there has been a longstanding search for CSF biomarkers that are easily measured in patient samples and that reliably predict clinical outcome,2 the identification of such biomarkers has remained elusive. Recent studies, however, have made some notable progress in this effort.

Direct disruption of neurons, axons, and glial cells The shear forces that occur in TBI cause direct mechanical rupture of cellular structures such as neurons, axonal processes, glial cells, and blood vessels.21,22 This can lead to a rapid spillage of intracellular proteins into the CSF,21 often causing measurable levels within hours of the event. Because many of these substances reach peak levels by the time the first CSF sample is collected, it is likely that their accumulation is a passive process due to direct damage and not any ongoing secondary injury processes. Indeed, since ICP issues can sometimes prolong the interval to the first CSF sampling, it is difficult to know what the profiles of these substances would look like if they were studied minutes to hours after injury.

Glial cell and myelin injury S-100B is a brain-specific calcium-binding protein localized primarily to astroglial cells, and its extracellular release is considered a marker of astroglial cell death.23,24 Levels of S-100B in CSF from non-injured control patients range from <1.0 to 6.8 ng/ml.25 In TBI, the protein reaches peak levels in CSF within 6 h after injury, and higher concentrations are known to correlate with higher ICP at the time of CSF sampling.23 In one study, peak CSF S-100B levels were significantly higher in patients with poor outcomes (62.2±21.8 ng/ml) compared to favorable outcomes

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(21.8±17.7 ng/ml).26 Still, there do not seem to be enough published data at this point to know whether a specific level is useful as a cutoff for prognostic purposes. Likewise, disruption of myelin sheaths will cause levels of myelin basic protein (MBP) to rise in the CSF after head injury. Once again, these levels generally correlate with the degree of disruption, which in turn is determined by the extent of the injury.1 CSF MBP levels have not, however, been shown to be significantly higher in TBI patients with poor outcomes compared to those with more favorable outcomes.26 As a result, most biomarker research has focused on neuronal or axonal proteins as more reliable markers of outcome in TBI.

Neuronal and axonal injury Neuron-specific enolase (NSE) is the γ γ -isoenzyme of enolase, a glycolytic enzyme that converts 2-phosphoglycerate to phosphoenolpyruvate.27,28 NSE is found in high concentrations in neurons and neuroendocrine cells,28 and both serum and CSF levels of NSE have been investigated as markers of neuronal damage in a variety of CNS disorders.29–36 In normal individuals, CSF NSE levels are usually <2 ng/ml.25 In one study of adult patients with TBI, control subjects with non-traumatic CNS disorders and those with mild head injuries did not have significantly elevated CSF NSE levels (median of 8.44 ng/ml and 6.95 ng/ml, respectively).27 In the more severely injured population, the median CSF NSE level was 12.8 ng/ml, although actual levels did not correlate with individual outcomes.27 The explanation offered for this lack of correlation was that damage of critical brain regions caused devastating functional deficits without injuring a large number of neurons.27 Still, a statistically significant correlation between CSF NSE level and the Glasgow Coma Scale score in the acute setting was noted.27 Highest concentrations of CSF NSE in TBI patients have been found within 24 h of injury.21 The BB-isoenzyme of creatine kinase (CK-BB) exhibits brain-specific expression, but it is not normally found in CSF.37 When detected in this compartment, its presence is highly indicative of CNS injury.2 High concentrations of CK-BB are measured in CSF within 24 h of TBI,21 and it is speculated that levels would be even higher if CSF samples were obtained sooner after injury.20 In one series, the mean level of CK-BB in CSF after head injury was 348±406 U/l.37 Higher levels are associated with a poor outcome, but low levels do not always correlate with a more favorable prognosis.37,38 CSF CK-BB is thought to reflect the overall extent of CNS tissue disruption more than the severity of neurological deficits,38 which is also likely the case for many of the other markers already discussed. After neuronal injury, the neuronal microtubule-binding protein, tau, is proteolytically cleaved (C-tau), which is then released from damaged cells. C-tau was not found in the CSF of control patients, but it was measured at levels ranging from 104 to 16,906 ng/ml in one series of patients

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with TBI.39 In this cohort, the mean C-tau level was 3,205 ng/ml in the injury group; unlike some of the other markers already reviewed, peak CSF levels of this protein were reached only on the fourth hospital day.39 In another recent cohort, total tau levels were measured in both serum and ventricular CSF from 39 patients with TBI. This study reported that the protein was not measurable in serum samples after injury, but that high CSF levels (>702 pg/ml) at 48–72 h could discriminate between good versus bad outcomes among survivors after 1 year (83% sensitivity, 69% specificity), and that even higher levels (>2,126 pg/ml) accurately distinguished survivors from those with lethal injuries (100% sensitivity, 81% specificity).40 Data such as these, where absolute cutoff levels have been reasonably well correlated with future clinical outcomes, can now be examined in prospective studies in order to validate their use in clinical decision-making after TBI.

Excitotoxicity Excitotoxicity is postulated to be a key mechanism of secondary neuronal injury after TBI. Experimentally, glutamate, glycine, aspartate, taurine, phosphoethanolamine, and alanine are all released from cells in response to neuronal injury, and each can be measured in CSF.41–43 Clinically, glutamate has been found in higher concentrations in the CSF of adults and children following TBI.41,44 In adults, the normal CSF concentration of glutamate is 1–3 mmol/l. In one series of patients with TBI, CSF glutamate levels peaked at 48 h, and were stiller higher than controls 1 week after injury. In particular, patients with concentrations greater than 7 mmol/l had poorer outcomes.45 Other studies, however, have been unable to correlate CSF glutamate levels with the severity of injury or clinical outcome.46 Other excitotoxins can be measured in the CSF. Quinolinic acid is a macrophage-derived excitotoxin that is postulated to contribute to secondary neuronal damage in a variety of pathological states. In healthy controls, quinolinic acid levels in CSF are normally less than 50 nmol/l, but they increase to 463±128 nmol/l at 72 h after TBI, and are significantly higher in patients who die compared to those who survive.47

pathways,1 and these elevations have been associated with a poor outcome in TBI.44,48 In one case series, CSF lactate levels were highest on the first day after injury and decreased over the next 5 days studied, but remained elevated in those patients with persistent coma.48 In another cohort, CSF lactate levels were higher in TBI patients who received glucose-containing intravenous fluids (2.86 ±0.96 mmol/l) compared to those receiving saline alone (2.30 ±0.47 mmol/l).6 This finding suggests that acutely brain-injured patients should not receive exogenous glucose during the initial management phase of their disease. Lactate levels are also difficult to study if CSF reabsorption is impaired,1 or if there are many RBCs in the CSF, because glycolysis occurring in erythrocytes also elevates CSF lactate values.49 Low CSF pH, mostly driven by increased CNS lactate production, portends a poorer outcome in TBI.48 Normal CSF pH ranged from 7.29 to 7.36 in one non-traumatic control population,50 but in a series of severely head injured patients, all had a CSF acidosis with a nadir ranging from 6.51 to 7.17.51 Interestingly, correction of CSF acidosis by means of the intrathecal administration of sodium bicarbonate may increase cerebral blood flow and improve clinical outcome.52 The brain is particularly vulnerable to oxidative stress.53 ROS can precipitate destruction of membrane lipids through peroxidation reactions, resulting in the generation of markers such as F2-isoprostane that can be recovered from CSF. With severe TBI, CSF levels of F2-isoprostane are acutely increased, then decline over several days.44 For unknown reasons, these levels decrease faster in females, who are hypothesized to tolerate oxidative stress better than males.44 Endogenous antioxidants such as glutathione and ascorbate are thought to buffer the CNS from the damaging effects of ROS, and consumption of these antioxidants is one way that the brain can become susceptible to oxidative injury. Indeed, several studies have shown that ascorbate levels decrease in the CSF after head injury, often reaching a nadir at the time immediately after the event.44,54 Antioxidant reserves may increase over the next several days, but they continue to be depleted throughout the acute injury period.54

Inflammation Impaired energy and oxygen metabolism Markers of energy imbalance and oxidative stress are detectable in the CSF of both adults and children with acute TBI. A state of impaired cerebral energy metabolism is directly related to the severity of TBI,43 and the production of lactate, in particular, may cause a lowering of CSF and brain pH and can potentiate CNS injury. Likewise, reactive oxygen species (ROS) derived from endogenous glial cells and influxing macrophages can also propagate a vicious cycle of neuronal damage.44 High lactate levels in ventricular CSF are indicative of metabolic imbalance as the brain shifts to anaerobic

Traumatic head injury commonly causes an accumulation of neutrophils in the damaged brain parenchyma, and some of these cells accumulate in the CSF and contribute to the pleocytosis that follows TBI. Other studies have identified a variety of inflammatory mediators in the CSF after head injury.19,55 High CSF concentrations of tumor necrosis factor (TNF)-α, leukotrienes, interleukin (IL)-1β, IL-6, IL-8 and IL-10, in particular, have been found.23,56–58 Nitric oxide (NO) metabolites are also elevated in the CSF after trauma, as NO production seems to be induced in the CNS as part of the inflammatory response.59 In this setting, NO is produced by astrocytes, neurons, and microglia,60,61

Limitations and Future Directions

and CSF levels peak between 20 and 28 h after trauma.59 The role of these inflammatory responses in propagating secondary neuronal damage in TBI is unclear; no study has clearly demonstrated improved clinical outcomes in patients who receive some anti-inflammatory intervention. Still, it is tempting to speculate that such processes are pathogenic in TBI given their known capacity to cause neural damage in other disease states.

Apoptosis Apoptosis may be an important mechanism responsible for secondary neuronal damage in TBI. Activation of caspase-3 is a reliable marker of apoptosis, and this protein was found in the CSF of 74% of TBI patients.62 In one study, caspase-3 levels were highest between days 2 and 5 after injury, and then declined thereafter.62 In a rat model of TBI, both calpain and caspase derivatives were detected in CSF in proportion to the amount of neuronal apoptosis present in and around the site of injury.63 Here, these proteins proved to be accurate surrogate markers of an important underlying mechanism of neurodegeneration following focal cortical trauma.63

TBI IN INFANTS AND CHILDREN TBI claims the life of one child every 12 minutes in the USA,41 making it a leading cause of death in this age group.54 Unfortunately, up to 95% of children with severe TBI may be victims of abuse.64 The pathophysiological changes reflected in the CSF of these patients are generally similar to those found in adults. Some substances that increase in the CSF after severe TBI in children include structural proteins (NSE, S-100B),24 excitatory amino acids (glutamate, quinolinic acid),41,65,66 inflammatory mediators (IL-6, IL-8, and IL-10),67,68 markers of apoptotic neuronal death,69,70 and byproducts of oxidative injury.54 As an investigative strategy, there is some interest in trying to use CSF biomarkers to distinguish victims of abuse from those with accidental injuries. In one study, higher initial and peak CSF values of quinolinic acid were found in children with inflicted TBI versus accidental TBI.65 In fact, every patient with inflicted TBI had a peak CSF quinolinic acid concentration greater than 100 nM, while almost no patient with accidental TBI reached this level.65 In another study, CSF NSE levels were 3.5±1.4 ng/ml in control patients, and 117.07±12.02 ng/ml in infants and children with TBI.24 Those patients who were victims of abuse had an initial peak NSE concentration on day 1, followed by a second, higher peak after a median of 63 h. The second peak was sustained for up to 8 days; for some patients, levels were still increasing at the time of last sampling.24 In children with accidental TBI, there was an early peak in CSF NSE at a median of 11 h, but no second peak.24 The second peak in abused children was postulated

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to represent a delayed phase of neuronal death.24 Likewise, CSF glutamate levels were massively increased for a prolonged period in patients with inflicted TBI compared with those with accidental TBI.41 One limitation of studying markers of injury that result from abuse is that TBI patients are not a homogenous population. Higher CSF values in abused children may be due to a higher severity of injury, a younger age, and/or a longer delay in seeking medical care.65 All clinicians must remain vigilant for signs of abuse in children presenting with nervous system trauma,24,65 and the measurement of CSF markers has not been studied thoroughly enough at this time to assess the its efficacy in predicting child abuse.

SPINAL CORD INJURY Spinal cord injury (SCI) has an annual incidence of 15–40 cases per million people in the USA,71 and penetrating trauma is the third most common type of spinal cord injury.72 All penetrating spinal injuries should be surgically explored due to the high risk of dural tear and the need for local debridement.73 Direct physical trauma to the spinal cord will quickly lead to neuronal necrosis, followed by secondary axonal degeneration and apoptosis over a period of days to weeks.71 As with TBI, CSF is not routinely collected in most cases of SCI. Nevertheless, it has been reported that many SCI patients show a mild CSF pleocytosis during the first week, likely reflecting an associated inflammatory response with the cord itself.38 These cells consist primarily of lymphocytes and neutrophils.38 Total CSF protein levels may also be elevated after SCI, depending on the extent of the injury. CSF levels of CK-BB have been investigated in this population and, in one small series, patients with values greater than 10U/L in the acute period did not recover neurological function.38 Other CSF markers examined in SCI include glial fibrillary acidic protein (GFAP), a marker of injured astrocytes, and neurofilament light-chain protein (NF-L), a marker of axonal damage. Both proteins were significantly increased in the CSF of patients with cervical spinal cord damage and prominent neurological deficits, including three of 17 patients with whiplash injury.71 Interestingly, CSF NF-L levels continued to increase throughout the study period, so optimal sampling time remains unclear.71

LIMITATIONS AND FUTURE DIRECTIONS As can be surmised from the preceding pages, there are obvious limitations to the study of CSF from patients with nervous system trauma. Some lie in the collection process itself, and some relate to unanswered questions and even ethical dilemmas in the use and interpretation of such CSF data. As for collecting CSF after TBI, the risks of LP have

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been discussed. If an IVC is required for pressure monitoring, CSF acquisition becomes much more convenient but is still not entirely without risk. Serial sampling via the IVC may increase the risk of introducing bacteria into the collection system, potentially leading to a catheter-related ventriculitis.14,74 The use of CSF biomarkers in TBI and SCI cases is still limited by unresolved questions regarding which markers should be studied and when samples should optimally be collected. The expression of individual proteins in CSF following trauma is a dynamic process, and clear data on expected changes over time are not always available. Further, lumbar and ventricular CSF can vary in composition,19 and the presence of an IVC can itself alter protein levels in the CSF.19,24,75 As already discussed, markers that seek to define the extent of damage may not provide useful prognostic information since small lesions in eloquent locations can produce devastating effects with minimal CSF changes. It also seems likely that reliance on one marker to assess complex cellular and molecular processes will inherently provide clinicians with limited information.20 Having a panel of markers that measure an array of injury phenomena will more likely encapsulate these complex events. Despite these limitations, CSF markers that predict future clinical outcomes continue to be sought in CNS trauma. One useful application in coming years may be to help assess the cellular and molecular response to interventions such as induced hypothermia.76 Furthermore, cerebral microdialysis can be used to measure the parenchymal concentrations of many substances also studied in CSF.77 This should validate the degree to which CSF parameters reflect changes within the brain itself, and the catheters required for these recordings seem to carry less risk of hemorrhage and infection than placement of an IVC.78 Still, microdialysis can only provide information about a few cubic millimeters of brain that surround the catheter, so CSF sampling should provide more complete information about global brain function. Furthermore, because the IVC offers the advantage of therapeutic CSF drainage in cases of increased ICP or obstructive hydrocephalus, it is reasonable to ask scientific questions about what the CSF collected out of the catheter can tell us about what is happening within tissue from which it is draining. REFERENCES 1. Bakay RAE, Sweeny K, Wood H. Pathophysiology of cerebrospinal fluid in head injury: Part 1. Pathological changes in cerebrospinal fluid solute composition after traumatic brain injury. Neurosurgery 1986;18:234–243. 2. Bakay RAE, Sweeny K, Wood H. Pathophysiology of cerebrospinal fluid in head injury: Part 2. Biochemical markers for central nervous system trauma. Neurosurgery 1986;18:376–382. 3. CDC. Traumatic brain injury in the United States: a report to Congress. Atlanta, GA: US Department of Health and Human Services, CDC, National Center for Injury Prevention and Control, 1999.

4. Whiteneck G, Mellick D, Brooks CA, Harrison-Felix C, Terrill MS, Noble K. Colorado Traumatic Brain Injury Registry and Follow-Up System. Denver, CO: Craig Hospital, 2001. 5. Barnes BD, Hoff JT. Radionuclide cisternography after head injury. Arch Neurol 1976;33:21–25. 6. Robertson CS, Goodman JC, Narayan RK, Contant CF, Grossman RG. The effect of glucose administration on carbohydrate metabolism after head injury. J Neurosurg 1991;74:43–50. 7. Sayva A, Taylor MJ, Beatty CW. Management of cerebrospinal fluid leaks involving the temporal bone: report on 92 patients. Laryngoscope 2003;113:50–56. 8. Bernal-Sprekelsen M, Belda-Vazquez C, Carrau RL. Ascending meningitis secondary to traumatic cerebrospinal fluid leaks. Am J Rhinol 2000;14:257–259. 9. Bell RB, Dierks EJ, Homer L, Potter BE. Management of cerebrospinal fluid leak associated with craniomaxillofacial trauma. J Oral Maxillofac Surg 2004;62:676–684. 10. Kirsch AP. Diagnosis of cerebrospinal fluid rhinorrhea: lack of specificity of the glucose-oxidase tape test. J Pediatr 1967;71: 718–719. 11. Ryall RG, Peacock MK, Simpson DA. Usefulness of beta-2 transferrin assay in the detection of cerebrospinal fluid leaks following head injury. J Neurosurg 1992;77:737–739. 12. Reisinger PWM, Hochstrasser K. The diagnosis of CSF fistulae on the basis of detection of beta-2 transferrin by polyacrylamide gel electrophoresis and immunoblotting. J Clin Chem Clin Biochem 1989; 27:169–172. 13. Clemenza JW, Kaltman SI, Diamond DL. Craniofacial trauma and cerebrospinal leakage: a retrospective clinical study. J Oral Maxillofac Surg 1995;53:1004–1007. 14. Aucoin, PJ, Kotilainen HR, Gantz NM, Davidson R, Kellogg P, Stone B. Intracranial pressure monitors. Epidemiologic study of risk factors and infections. Am J Med 1986;80:369–376. 15. Bayston R, de Louvois J, Brown EM, Johnston RA, Lees P, Pople IK. Use of antibiotics in penetrating craniocerebral injuries. Lancet 2000;355:1813–1817. 16. Boque MC, Bodi M, Rello J. Trauma, head injury, and neurosurgical infections. Semin Respir Infect 2000;15:280–286. 17. Tunkell AR, Scheld WM. Acute infectious complications in head trauma. In: Branckman R, ed. Handbook of Clinical Neurology. New York: Elsevier; 1990:317–326. 18. Kao PT, Tseng HK, Liu CP, Su SC, Lee CM. Brain abscess: clinical analysis of 53 cases. J Microbiol Immunol Infect 2003;36: 129–136. 19. Conti A, Sanchez-Ruiz Y, Beretta L, Grandi E, Beltramo M, Alessio M. Proteome study of human cerebrospinal fluid following traumatic brain injury indicates fibrin(ogen) degradation products as trauma-associated markers. J Neurotrauma 2004;21:854–863. 20. Maas AI. Cerebrospinal fluid enzymes in acute brain injury. 1. Dynamics of changes in CSF enzyme activity after acute experimental brain injury. J Neurol Neurosurg Psychiatry 1977;40:655–665. 21. Hardemark HG, Ericsson N, Kotwica Z, et al. S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage. J Neurosurg 1989;71:727–731. 22. Franz G, Beer R, Kampfl A, Engelhardt K, Ulmer H, Deisenhammer F. Amyloid beta 1–42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology 2003;60:1457–1461. 23. Hayakata T, Shiozaki T, Tasaki O, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock 2004;22:102–107. 24. Berger RP, Pierce MC, Wisniewski SR, et al. Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics 2002;109:E31. 25. Persson L, Hardemark HG, Gustafsson J, Rundstrom G, Esscher T, Pahlman S. S-100 Protein and neuron-specific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous system. Stroke 1987;18:911–918.

References

26. Ucar T, Baykal A, Akyuz M, Dosemeci L, Toptas B. Comparison of serum and cerebrospinal fluid protein S-100B levels after severe head injury and their prognostic importance. J Trauma 2004;57:95–98. 27. Ross SA, Cunningham RT, Johnston CF, Rowlands BJ. Neuron-specific enolase as an aid to outcome prediction in head injury. Br J Neurosurg 1996;10:471–476. 28. Marangos PJ, Schmechel D, Zis AP, Goodwin FK. The existence and neurobiological significance of neuronal and glial forms of the glycolytic enzyme enolase. Biol Psychiat 1979;14:563–579. 29. Dauberschmidt R, Marangos PJ, Zinsmeyer J, Bender V, Klages G, Gross J. Severe head trauma and the changes of concentration of neuron-specific enolase in plasma and in cerebrospinal fluid. Clin Chim Acta 1983;131:165–170. 30. Scarna H, Delafosse B, Steinberg R, et al. Neuron-specific enolase as a marker of neuronal lesions during various comas in man. Neurochem Int 1982;4:405–411. 31. Mabe H, Suzuki S, Mase M, Umemara A, Nagai H. Serum neuron-specific enolase levels after subarachnoid hemorrhage. Surg Neurol 1991;36:170–174. 32. Cunningham RT, Young IS, Winder J, et al. Serum neuron specific enolase (NSE) levels as an indicator of neuronal damage in patients with cerebral infarction. Eur J Clin Invest 1991;21:497–500. 33. Karkela J, Bock E, Kaukinen S. CSF and serum brain-specific creatine kinase isoenzyme (CK-BB), neuron specific enolase (NSE), and neural cell adhesion molecule (NCAM) as prognostic markers for hypoxic brain injury after cardiac arrest in man. J Neurol Sci 1993; 116:100–109. 34. Skogseid I, Nordby H, Urdal P, Paus E, Lilleaas F. Increased serum creatine kinase BB and neuron specific enolase following head injury indicate brain damage. Acta Neurochir 1992;115:106–111. 35. Vazquez M, Rodriguez-Sanchez F, Osuna E, et al. Creatine kinase BB and neuron specific enolase in cerebrospinal fluid in the diagnosis of brain insult. Am J Forensic Med Pathol 1995;16:210–214. 36. Yamazaki Y, Yada K, Morii S, Kitahara T, Ohwada T. Diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head trauma. Surg Neurol 1995;43:267–271. 37. Hans P, Born JD, Chapelle JP, Milbouw G. Creatinine kinase isoenzymes in severe head injury. J Neurosurg 1983;58:689–692. 38. Pasaoglu A, Pasaoglu H. Enzymatic changes in the cerebrospinal fluid as indices of pathological change. Acta Neurochir 1989;97: 71–76. 39. Zemlan FP, Jauch EC, Mulchahey JJ, Gabbita SP, Rosenberg WZ, Zuccarello M. C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res 2002;23:131–139. 40. Ost M, Nylen K, Csajbok L, et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 2006;67:1600–1604. 41. Ruppel RA, Kochanek PM, Adelson PD, et al. Excitatory amino acid concentrations in ventricular cerebrospinal fluid after severe traumatic brain injury in infants and children: the role of child abuse. J Pediatr 2001;138:18–25. 42. Seki Y, Kimura M, Mizutani N, Fujita M, Aimi Y, Suzuki Y. Cerebrospinal fluid taurine after traumatic brain injury. Neurochem Res 2005;30:123–128. 43. Cristofori L, Tavazzi B, Gambin R, et al. Early onset of lipid peroxidation after human traumatic brain injury: a fatal limitation for the free radical scavenger pharmacologic therapy? J Invest Med 2001;49:450–458. 44. Wagner AK, Bayir H, Ren D, Puccio A, Zafonte RD, Kochanek PM. Relationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: the impact of age, gender and hypothermia. J Neurotrauma 2004;21:125–136. 45. Zhang X, Qui M, Zhang J, Zhang H, Kang D. Excitatory amino acids in cerebrospinal fluid and their relation with clinical features and outcomes in acute head injury. Chin Med J 1998;111:978–981.

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46. Brown JI, Baker AJ, Konasiewicz SJ, Moulton RJ. Clinical significance of CSF glutamate concentrations following severe traumatic brain injury in humans. J Neurotrauma 1998;15:253–263. 47. Sinz EH, Kochanek PM, Heyes MP, et al. Quinolinic acid is increased in CSF and associated with mortality after traumatic brain injury in humans. J Cereb Blood Flow Metab 1998;18:610–615. 48. Enevoldsen EM, Jensen FT. Cerebrospinal fluid lactate and pH in patients with acute severe head injury. Clin Neurol Neurosurg 1977;80:213–225. 49. Sambrook MA, Hutchinson EC, Aber GM. Metabolic studies on subarachnoid haemorrhage and strokes: I. Serial changes in acid-base values in blood and cerebrospinal fluid. Brain 1973;96:171–190. 50. Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 1991;75:731–739. 51. Shiogai T, Nara I, Saruta K, Hara M, Saito I. Continuous monitoring of cerebrospinal fluid acid-base balance and oxygen metabolism in patients with severe head injury: pathophysiology and treatments for cerebral acidosis and ischemia. Acta Neurochir Suppl 1999;75:49–55. 52. Seitz HD, Ocker K. The prognostic and therapeutic importance of changes in the CSF during the acute stage of brain injury. Acta Neurochir 1977;38:211–231. 53. Shohami E, Beit-Yannai V, Horowitz M, Kohen R. Oxidative stress in closed-head injury: brain antioxidant capacity as an indicator of functional outcome. J Cereb Blood Flow Metab 1997;17:1007–1019. 54. Bayir H, Kagan VE, Tyurin V, et al. Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Res 2002;51:571–578. 55. Vos PE, Lamers KJB, Hendriks JC, et al. Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury. Neurology 2004;62:1303–1310. 56. Schuhmann MU, Mokhtarzadeh M, Skardelly M, Klinge PM, Samii M, Brinker T. Temporal profiles of cerebrospinal fluid leukotrienes, brain edema and inflammatory response following experimental brain injury. Neurol Res 2003;25:481–491. 57. Csuka E, Morganti-Kossman MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-α, TGF-β and blood-brain barrier function. J Neuroimmunol 1999;101: 211–221. 58. Singhal A, Baker AJ, Hare GM, Reinders FX, Schlichter LC, Moulton RJ. Association between cerebrospinal fluid Interleukin-6 concentrations and outcome after severe human traumatic brain injury. J Neurotrauma 2002;19:929–937. 59. Uzan M, Tanriover N, Bozkus H, Gumustas K, Guzel O, Kuday C. Nitric oxide (NO) metabolism in the cerebrospinal fluid of patients with severe head injury: inflammation as a possible cause of elevated NO metabolites. Surg Neurol 2001;56:350–356. 60. Faraci FM, Brian JE. Nitric oxide and the cerebral circulation. Stroke 1994;11:499–506. 61. Feuerstein GZ, Wang X, Barone FC. The role of cytokines in the neuropathology of stroke and neurotrauma. Neuroimmunomodulation 1998;5:143–149. 62. Harter L, Keel M, Hentze H, Leist M, Ertel W. Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury. J Neuroimmunol 2001;121:76–78. 63. Siman R, McIntosh TK, Soltesz KM, Chen Z, Neumar RW, Roberts VL. Proteins released from degenerating neurons are surrogate markers for acute brain damage. Neurobiol Dis 2004;16:311–320. 64. Billmire M, Myers P. Serious head injury in infants: accident or abuse? Pediatrics 1985;75:340–342. 65. Berger RP, Heyes MP, Wisniewski SR, Adelson PD, Thomas N, Kochanek PM. Assessment of the macrophage marker quinolinic acid in cerebrospinal fluid injury after pediatric traumatic brain injury: insight into the timing and severity of injury in child abuse. J Neurotrauma 2004;21:1123–1130.

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66. Bell MJ, Kochanek PM, Heyes MP, et al. Quinolinic acid in the cerebrospinal fluid of children after traumatic brain injury. Crit Care Med 1999;27:493–497. 67. Bell MJ, Kochanek PM, Doughty LA, Adelson PD, Clark RS, Wisniewski SR, DeKoskey ST. Interleukin-6 and Interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children. J Neurotrauma 1997;14:451–457. 68. Whalen MJ, Carlos TM, Kochanek PM, Clark RS, DeKoskey ST, Adelson PD. Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury. Crit Care Med 2000;28:929–934. 69. Clark RS, Kochanek PM, Adelson PD, et al. Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury. J Pediatr 2000;137:197–204. 70. Janesko K, Satchell M, Kochanek PM, Bell MJ, Graham SH. IL-1 converting enzyme (ICE), IL-1, and cytochrome C in CSF after head injury in infants and children. J Neurotrauma 2000;17: 956–963. 71. Guez M, Hildingsson C, Rosengren L, Karlsson K, Toolanen G. Nervous tissue damage markers in cerebrospinal fluid after cervical spine injuries and whiplash. J Neurotrauma 2003;20:853–8.

72. Miller CA. Penetrating wounds of the spine. In: Wilkins RH, Rengachary SS, eds. Neurosurgery. Vol II. San Francisco: McGraw-Hill; 1985:1746–1748. 73. Bhatoe HS, Singh P. Missile injuries of the spine. Neuro India 2003;51:507–511. 74. Mayhall CG, Archer NH, Lamb VA, et al. Ventriculostomy-related infections: a prospective epidemiologic study. N Engl J Med 1984;310:553559. 75. Kruse A, Cesarini KG, Bach FW, Persson L. Increase of neuron-specific enolase, S-100 protein, creatine kinase and creatine kinase BB isoenzyme in CSF following intraventricular catheter implantation. Acta Neurochir 1991;110:106–109. 76. Karibe H, Chen FS, Zarow GJ, et al. Mild intrinsic hypothermia suppresses consumption of endogenous antioxidants after temporal focal ischemia in rats. Brain Res 1994;649:12–18. 77. Winter CD, Pringle AK, Clough GF, Church MK. Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain 2004;127:315–320. 78. Hallstron A, Carlsson A, Hillered L, Ungerstedt U. Simultaneous determination of lactate, pyruvate, and ascorbate in microdialysis samples from rat brain, blood, fat, and muscle using high-performance liquid chromatography. J Pharmacol Methods 1989;22:113–124.

CHAPTER

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Approach to the Patient with Altered Cerebrospinal Fluid Pressure Dynamics Michael A. Williams

INTRODUCTION The diagnosis and pathophysiology of two common disorders presenting with abnormal cerebrospinal fluid (CSF) pressure dynamics and circulation, adult hydrocephalus (AH) and idiopathic intracranial hypertension (IIH), were reviewed in Chapter 12. Likewise, intracranial hypotension due to persistent leakage of CSF that invariably presents with headache has been discussed in Chapter 19. Here, attention will focus on the surgical management of these disorders. Approach to the identification and management of some of the more common complications of these surgical interventions will also be reviewed. Additional description of these CSF diversion devices and the various complications they may produce is provided in Chapter 7.

HISTORICAL PERSPECTIVE The surgical treatment of hydrocephalus has been a challenge for several hundred years. Alexander Monro’s 1783 mongraph, “Observations on the Structure and Function of the Nervous System,” best known for its identification of the foramina between the lateral ventricles and the third ventricle which now bear his name, also describes the surgical treatment of hydrocephalus in a 3-year-old child.1 Monro’s determination that CSF could not be effectively drained from the subarachnoid space of this patient led to the first consideration of an intraventricular removal procedure. An early description of the surgical diversion of CSF by means of an implanted device is found in the 1907 book, “Some Points in the Surgery of the Brain and its Membranes” by Charles Ballance of the National Hospital for the Paralysed and Epileptic, Queen Square, London.2 This device predates the similar Torkildsen shunt described some 40 years later.

In the early 1900s, Walter Dandy at Johns Hopkins first characterized the physiology of communicating and obstructive hydrocephalus in humans,3 and suggested choroid plexotomy,4,5 or surgical fenestration of the floor of the third ventricle as treatment for hydrocephalus.6 In 1947, Arne Torkildsen at the University of Oslo described the now-eponymous Torkildsen shunt for obstructive hydrocephalus.7 This procedure entailed inserting a valveless catheter into the occipital horn of the lateral ventricle and then tunneling it beneath the scalp to drain into the cisterna magna. As a result, CSF could pass from otherwise obstructed ventricles into the subarachnoid space where it could then flow to the arachnoid granulations for resorption. The modern era of hydrocephalus treatment began with John Holter, a machinist from Philadelphia whose son Casey was born with a lumbar myelomeningocele and who developed hydrocephalus after the spinal lesion was surgically closed. Holter designed and built a prototype ventriculoperitoneal (VP) shunt that was later implanted in his son, and became the first successful, commercially manufactured shunt.8,9 He was the first to use silastic tubing as a durable material for shunt components.

MANAGEMENT OF ADULT HYDROCEPHALUS The main approaches for treating patients with hydrocephalus remain surgical in nature; CSF is either diverted via a surgically implanted shunt, or CSF outflow obstruction is corrected by means of endoscopic third ventriculostomy (ETV). There are no published data to demonstrate that pharmacological agents such as carbonic anhydrase inhibitors that decrease CSF production have any effectiveness in AH.10 Consensus guidelines provide an evidence-based review on the selection and use of shunts.11 Put simply, there are no specific criteria for selecting a VP

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shunt over a lumboperitoneal (LP) shunt, nor is there evidence demonstrating that one make or model of shunt valve produces a better outcome than another. While there is a common perception that LP shunts fail more frequently than VP shunts, there is no good literature to support this contention in cases of AH. One retrospective series found that LP shunts were more likely to become obstructed and need replacement than ventricular shunts in the management of IIH.12 While VP shunts are designed to be extremely safe, they do present about a 1% risk of intraoperative brain injury from direct mechanical trauma, hemorrhage, or edema.11 LP shunts, on the other hand, do not require passage of the catheter through the brain, and thus negate this risk. This certainly is a consideration for some patients and neurosurgeons.

Basic principles of shunt function All shunts consist of a proximal catheter inserted in a CSF space (either the ventricle or the lumbar subarachnoid space), a passive valve mechanism (differential pressure valve), and a distal catheter that carries CSF to some extracerebral site for resorption. The peritoneal cavity, the jugular vein, or the intrapleural space are the most common distal sites currently being used. In essence, these shunts are nothing more than tiny plumbing systems; therefore, they are subject to the same types of problems as conventional plumbing, including obstruction, disconnection, or valve malfunction. The proximal catheter of a VP shunt is passed through the brain parenchyma, and ideally the tip will either rest in the frontal horn of the lateral ventricle or pass through the foramen of Monro into the third ventricle. In children, obstruction of the proximal catheter by choroid plexus is common, but this happens much less frequently in adults, where the most common site of shunt obstruction is at the end of the distal catheter.13,14 The proximal catheter of an LP shunt is usually passed into the lumbar subarachnoid space via a Touhy needle, a special spinal needle with a side aperture. The differential pressure valve mechanism attached to the proximal catheter is similar in all shunts. The purpose of these valves is to limit CSF flow; the “resting position” of the valve is in the closed alignment in nearly all shunts. In order for the valve to open, CSF pressure (Pcsf) in the proximal catheter must increase enough to overcome the resistance to flow. CSF will then mechanically displace a mechanism in the valve that allows CSF to flow around and through it into the distal catheter. When CSF volume within the ventricles or lumbar subarachnoid space is reduced, Pcsf in the proximal catheter diminishes, causing the valve to close again and halt further CSF flow. Thus, the flow of CSF through shunts with differential pressure valves is considered to be intermittent rather than continuous. The pressure gradient across the valve necessary to open it is the source of the term “differential pressure” valve.

This gradient represents the difference between the pressure in the proximal catheter (i.e., Pcsf), and the pressure at the outlet of the distal catheter (i.e., the intra-abdominal pressure, central venous pressure, or intrapleural pressure). Thus, shunt obstruction occurs not only with mechanical obstruction of the distal catheter, but also if distal pressure is so high that the pressure differential across the valve cannot cause it to open despite a patent distal catheter. Another mechanism of functional shunt obstruction occurs when the valve setting (i.e., the pressure required to open the valve) is set so high that the patient’s usual pressure gradient is insufficient to cause the valve ever to open. Differential pressure, then, is the fundamental characteristic that governs the flow of CSF through the shunt, no matter whether the patient is supine or vertical. Using a VP shunt as an example, shunt function can be described by the equation, Pcsf = OPV − HP +IAP where Pcsf is the intracranial CSF pressure, OPV is opening pressure of the valve, HP is hydrostatic pressure, and IAP is intra-abdominal pressure. The HP (in cm H2O) is equivalent to the vertical distance between the ventricular catheter and the distal catheter tip. With a supine patient, if the OPV is set at 10 cm H2O, IAP is 0, and HP is 0, then the Pcsf must exceed 10 cm H2O before the valve opens and CSF flows. With this same patient in an upright position having the same OPV of 10 cm H2O, and assuming that IAP will remain close to zero if the patient is thin, the HP will be approximately 30 cm H2O (i.e., the vertical distance from the ventricle to the distal catheter tip), and the Pcsf will turn out to be about −20 cm H2O. This negative Pcsf in the upright position leads to a phenomenon known as siphoning, where more CSF than is desired flows through the shunt. Potential complications of siphoning include low-pressure headaches, nausea, hearing loss, or even ventricular collapse, all from intracranial hypotension. In extreme circumstances, this can lead to the formation of subdural effusions (hygromas) or hematomas. Because AH tends to be a disorder of the elderly who may have concomitant brain atrophy, collapse of the ventricles can result in stretching or disruption of the bridging veins, which then causes a subdural hematoma. One management strategy favored for the care of elderly patients with AH is to avoid the risk of siphoning by using a shunt system with a second valve placed in series with the differential pressure valve. Collectively known as antisiphon devices (ASD), these second valves are designed so that their resistance to flow is highest when the patient is upright, thereby reducing CSF flow through the shunt simply due to the hydrostatic pressure gradient. Most ASDs are also designed so that their resistance to flow is lowest when the patient is supine, hopefully preventing any “extra” resistance to CSF flow in this position.

Management of Adult Hydrocephalus

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Shunt adjustment in clinical practice

Evaluation of possible shunt malfunction

Experience leads one to conclude that shunts rarely function exactly the same way in every patient, and that the theoretical calculations and role of ASDs described above provide only general guidelines.15,16 Once implanted, a given shunt may produce an intracranial Pcsf that is higher than intended, lower than intended (the usual case), or as intended. If the clinical function of the shunt does not seem to match the intended pressure range, Pcsf monitoring through the shunt may be required.17,18 This requires specialized monitoring equipment and direct access to the CSF compartment inside the shunt via a butterfly needle, a process that necessitates a brief hospitalization for the patient. So-called programmable shunts (more appropriately called adjustable shunts) have valves with variable resistance that can be changed using a magnetic mechanism. Thus, the OPV of a programmable shunt can be changed non-invasively in the clinic or office using a hand-held device. As a general rule, higher shunt settings result in higher OPV and less flow, while lower settings result in lower OPV and more flow. The great advantage of an adjustable shunt is that if the initial valve setting does not permit sufficient CSF flow to alleviate the patient’s symptoms, the setting can be lowered in small increments over time, and the patient’s corresponding clinical response can be assessed. Alternately, if flow through the shunt is too great and low pressure symptoms are present, then the shunt setting can be adjusted upwards, thereby reducing the flow through the system. Adjustable shunts have fundamentally changed the treatment paradigm in AH. These devices now allow neurologists and neurosurgeons to intervene longitudinally in the management of this disorder, making it a much more manageable problem. A small subset of AH patients have “low pressure hydrocephalus,” meaning that their Pcsf must be lowered as close to zero as possible when supine, and sometimes must be allowed to become negative when in the upright position.19 These patients cannot be identified in advance; in most instances, they are found only after a shunt with an ASD has been inserted. If a patient does not improve with shunting, assuming that the OPV has already been lowered as much as possible, then the patient may require an even lower Pcsf for their symptoms to resolve. Here, removal of the ASD can be considered if such patients have proven themselves tolerant of low Pcsf without the development of subdural hygromas or hematomas.20,21 Some neurosurgeons and neurologists use the strategy of starting with shunts that lack ASDs, and add them only if patients have clinically significant side effects of over-drainage. There is no evidence to suggest that one management strategy is better than another, except to say that, whatever approach is used, patients should be evaluated at regular intervals to determine whether the desired therapeutic effects are being achieved while side effects are minimized.

Although they are engineered for long-term use, all shunts can malfunction over time, including obstruction, disconnection, or valve failure. Malfunction is the most common complication of shunts in both adults and children.22 Shunt obstruction is the most common form of malfunction, a process that usually occurs somewhere within the shunt catheters and less frequently in the valve itself. Experience in AH suggests that obstruction nearly always occurs in the distal catheter.13 This has important implications for surgical management, because it means that the proximal catheter within the brain and the valve itself rarely have to be removed or replaced, thus significantly reducing the risk of shunt revision surgery compared to the initial insertion procedure. On the other hand, shunt obstruction in children is much more likely to occur in the proximal ventricular catheter. This is because the brain is more compliant in children, and shunt insertion causes a more significant reduction in the size of the ventricles. This brings the choroid plexus or even the walls of the ventricles themselves into close proximity with the fenestrations of the ventricular catheter, potentially blocking the entry of CSF into the shunt system. Recognition of shunt obstruction depends on a keen awareness of the patient’s original symptoms, knowledge of their magnitude of shunt responsiveness to date, and an appreciation of any concomitant conditions that can produce AH-like symptoms. Shunt obstruction in children is more likely to be a life-threatening emergency than it is in adults, mainly because children are more commonly shunted for obstructive hydrocephalus. Shunt obstruction in this setting leads to the intraventricular accumulation of CSF and a rapid rise in intracranial pressure, potentially resulting in a reduction of cerebral blood flow or cerebral herniation. Thus, delayed recognition of shunt obstruction in obstructive hydrocephalus can result in permanent brain injury or brain death. For adults with communicating hydrocephalus, shunt obstruction is usually heralded by the insidious return of the original symptoms over an interval of weeks to months. Fortunately, because most forms of AH are time-tolerant syndromes that respond to treatment even though symptoms may have been present for years, the return of symptoms is rarely an emergency. Nonetheless, it is a problem that is best treated sooner rather than later. The nature of shunt obstruction symptoms should be routinely discussed with patients and their families, given that it is not possible to predict who will experience this complication or when it might occur. For children with suspected shunt malfunction, a cranial computed tomography (CT) scan is usually first obtained to assess the ventricular size. Thereafter, since the proximal and distal catheters of a VP shunt can become disconnected or fractured, plain radiographs of the skull, neck, chest, and abdomen (a “shunt series”) can be used to demonstrate whether this has occurred. In both adults and children,

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another common practice is to depress the shunt reservoir to see how easily it refills. Slow refilling of the shunt reservoir can be a clue that the proximal portion of the shunt system has a partial blockage. However, because in most shunts the reservoir is between the valve and the ventricles, rapid refilling is not a foolproof method to conclude that the shunt is functioning properly since the patient may still have an obstruction of the distal catheter that would not affect refilling of the reservoir.23,24 The next step in adults is usually a radionuclide shunt patency study, a process that involves the injection of a small volume of radioisotope into the shunt reservoir (Fig. 28-1). If a butterfly needle with tubing is used to access the reservoir, then Pcsf can first be estimated by measuring the height of the fluid column in the tubing before injecting the radiotracer. Once the injection is complete, images of the proximal system are obtained every minute for the first 20 minutes. Serial imaging of the body region that contains the distal shunt catheter follows thereafter. Determination of shunt patency is proven when the radionuclide freely diffuses throughout the peritoneal cavity for VP shunts or in the venous system for ventriculo-atrial (VA) shunts (Fig. 28-1). Other factors to consider in the interpretation of these studies include the opening Pcsf, as well as the rates of radionuclide outflow from the reservoir and dispersal throughout the peritoneal cavity. In general, patients who initially improve after shunt surgery but who then experience shunt obstruction have a very good chance of improving after shunt revision surgery.25 The magnitude of recovery, however, may depend on the

number of times the shunt has become obstructed and whether acute or recurrent brain injury has occurred.25,26 Because children are much more likely to be shuntdependent, there is usually little choice in deciding whether to proceed with shunt revision surgery. On the other hand, there is often more flexibility in this decision for adults. Occasionally, elderly patients with AH who have experienced several cycles of shunt insertion or revision with subsequent improvement, followed later by a return of their symptoms, have less and less improvement with each shunt revision. This may be due to the fact that as patients become older, they are more likely to have concomitant disorders that contribute to their symptoms. Some elderly patients ultimately choose to have no more shunt revision surgery. In such circumstances, it is sometimes prudent to reconsider the approach of evaluating for shunt malfunction because the benefit-to-risk ratio of shunt revision surgery can diminish. Instead, it may be more advisable to determine whether the patient is still capable of responding to CSF drainage altogether. Using a technique described by Marvin Bergsneider and colleagues,21 this can be accomplished via the insertion of a temporary spinal catheter for CSF drainage, as is done in some centers for the initial diagnosis of AH. If the patient shows symptomatic improvement with temporary external CSF drainage, then shunt revision surgery can be recommended because it is clear that the patient is still capable of responding. If not, then diagnostic and treatment interventions can be directed elsewhere.

Tracer injected into the shunt bulb and proximal catheter Ventricles

Shunt valve

Ventricles

Shunt valve Tracer evenly dispersed throughout the ventricles, the shunt catheters, and the peritoneal cavity

Peritoneal cavity

Peritoneal cavity

Figure 28-1 Diagram of radionuclide shunt patency evaluation. A small volume of tracer is injected into the shunt reservoir using a butterfly needle, and the tracer passes into the proximal shunt catheter tubing (left panel). Over time, the tracer is imaged as it disperses throughout the shunt tubing, the ventricles, and the abdominal cavity (right panel).

Management of Adult Hydrocephalus

Shunt infection Shunt infection is the most feared complication of shunt surgery because not only is it life-threatening, it is common.26–30 Important risk factors that predispose to subsequent shunt infection, whether in adults or children, are almost always encountered at the time of surgery. Roger Bayston and others have shown that breaks in sterile technique are more common than appreciated, and that improper handling of the shunt system by operating room (OR) personnel, or merely the presence of excessive foot traffic in and out of the OR during the procedure, can result in a higher risk of contamination of the shunt catheter with skin flora.31,32 Thus, exquisite attention to sterile technique during skin preparation as well as gentle handling of the shunt using sterilized instruments rather than gloved hands are all recommended steps. Furthermore, there is evidence to suggest that shaving the scalp causes microscopic abrasions that increase the likelihood of wound contamination, whereas close trimming of the adjacent hair using clippers avoids these abrasions and reduces the risk of shunt infection.33 Another potential complication is that the silicone elastomers from which all shunts are made can provide a microscopic surface for bacterial adhesion and colonization.34,35 Most shunt infections occur within 2–3 months of surgery,31 and it is likely that the initial contamination occurs at the time when it is exposed to the external environment. While the development of an overt meningitis syndrome makes some shunt infections clinically obvious, other presentations can be more insidious, with little more than a subtle worsening of symptoms. There is evidence to suggest that the C-reactive protein (CRP) can be useful as a monitoring test, rising when shunt infection becomes apparent.36 In cases of suspected infection, CSF should be aspirated from the shunt reservoir using meticulous sterile technique, as contamination of the specimen may lead to long-term antibiotic administration, or even shunt revision surgery, that would otherwise be unnecessary. While most organisms will grow in the usual CSF culture medium, special culture techniques may be required for less aggressive, but nonetheless pathogenic, organisms such as Staphylococcus epidermidis or Propionibacterium acnes. Thus, it is often appropriate for the culture to be kept longer than usual, as the rate of bacterial growth is very slow. When shunt infection is demonstrated, there is a prevailing belief that the shunt must be removed, as it is considered almost impossible to sterilize both the inner and outer surfaces of the catheters and valve mechanisms with intravenous (IV) antibiotics. Thus, while bacterial growth can be suppressed, organisms on the shunt surfaces either develop resistance, or extrude a slime layer that protects from the antibiotics, or both, and bacterial growth with re-infection will occur when the antibiotics are stopped. For patients with obstructive hydrocephalus, removal of the shunt will require the patient to be hospitalized so that a temporary

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intraventricular catheter can be inserted for external CSF drainage until the infection is eradicated and a new shunt can be inserted. For patients with communicating hydrocephalus, there is usually no need for external CSF drainage. Thus, prolonged IV antibiotic therapy can be administered outside the hospital. As expected, the hydrocephalus symptoms will probably worsen during this time. The duration of antibiotic administration and the interval between the completion of antibiotics and the insertion of the next shunt is variable from center to center.27

Endoscopic third ventriculostomy Endoscopic third ventriculostomy (ETV) is the other widely accepted surgical intervention for hydrocephalus. As a general rule, ETV is used for obstructive rather than communicating hydrocephalus,37,38 although its use has been reported in AH.39,40 The ETV procedure consists of advancing a fiberoptic endoscope into the lateral ventricle, through the foramen of Monro, into the third ventricle so that, under direct visualization, the membranous floor of the third ventricle can be perforated bluntly, followed by enlargement of the fenestration using a balloon.37 While in theory this is a simple procedure, there is some risk of injuring vascular structures in the subarachnoid space on the opposite side of the floor of the third ventricle (e.g., the basilar artery), or of injuring hypothalamic nuclei if the endoscope or the perforations are misdirected.37,41 The physiologic premise of ETV is that by restoring a route for CSF to exit the ventricles into the subarachnoid space, fluid can then flow over the cerebral convexities to the arachnoid villi for reabsorption. Thus, if the CSF resorptive capacity is impaired, ETV may not be successful in treating hydrocephalus, and a shunt may eventually be necessary. Nonetheless, a common decision-making strategy is to consider that it is better to treat a patient’s hydrocephalus without a shunt than with a shunt, thus avoiding the long-term risks associated with an implanted device. ETV is therefore often attempted first for obstructive hydrocephalus. In a retrospective series of ETV in adults with obstructive hydrocephalus, the time to treatment failure with ETV was shorter for patients whose hydrocephalus had first been treated with a shunt and then underwent an ETV, as compared to patients whose first intervention was the ETV.42 When first reintroduced more than a decade ago, there was great optimism that ETV would be highly successful and have a lower treatment failure rate than with shunts. Longitudinal research in Canada, however, has shown that the 1-year ETV success rate is 65% (i.e., that it has a 1-year failure rate of 35%), and its 5-year success rate is 52% in a predominantly pediatric patient population.43 The primary determinant of outcome in children was age, with higher failure rates in neonates and infants.43 In a large series of adults in Germany, the rate of

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symptomatic improvement following ETV was 69%, although underlying hydrocephalus etiology was an important determinant of outcome.38 The highest success rate was for obstructive hydrocephalus caused by tumor (81%), followed by aqueductal stensosis (73%), whereas the success rate for AH was only 35%.38 It is important to note that sudden, unexpected death can occur due to incipient occlusion of the fenestrated third ventricular floor.44 It follows, then, that patients with hydrocephalus treated with ETV should have periodic reevaluation. Signs of failure are sometimes subtle and not recognized by patients and families, and careful clinical examination, with particular attention to the original deficits or symptoms of the hydrocephalus, is advisable. In addition, neuroimaging, especially with MRI, can be helpful in determining whether the ETV fenestration remains patent. If thin cuts in sagittal and coronal views are obtained, it is sometimes possible to see the discontinuity in the floor of the third ventricle. Alternately, cardiac-gated cine phase contrast CSF flow studies can be used to identify the flow of CSF back and forth through the fenestration.

MANAGEMENT OF IDIOPATHIC INTRACRANIAL HYPERTENSION Many of the same principles used in the management of patients with AH are also applicable for patients with IIH. The major difference between the two disorders is that medical therapy exists for IIH. It is appropriate to invoke the general principle of using medical management before surgical management, unless there is a need for urgent or emergent escalation to surgical therapy. Medical management usually involves starting treatment with acetazolamide, which is considered first-line therapy, and instituting aggressive weight loss.45,46 Topiramate has emerged as a second-line medical therapy with very little scientific evidence behind it; although a recent open-label randomized trial found topiramate as effective as acetazolamide,47 the mechanism of its effect remains unclear. In patients with papilledema or changes in visual fields and visual acuity, the response to therapy can be monitored with objective examination measures, and frequent evaluations are recommended to prevent unrecognized or incipient visual loss. Surgical interventions are usually indicated by the development of severe papilledema or progressive visual impairment, where failure to treat expeditiously and effectively could result in permanent visual impairment or blindness. The headaches associated with IIH can be debilitating, but headache alone is not usually considered an indication for urgent surgical management of IIH. Emergency lumbar puncture is often done to reduce CSF pressure, although in some circumstances insertion of a temporary spinal catheter to permit continuous CSF

drainage until surgical intervention can be arranged. One advantage of the spinal catheter is that, as long as CSF drains, the CSF pressure is reduced, whereas with lumbar puncture there is the potential that healing of the dural puncture site would permit occult CSF pressure elevation. Provided that neuroimaging shows no focal lesions or mass effect, there is virtually no risk of cerebral herniation when performing a lumbar puncture in IIH, despite the fact that Pcsf may exceed 30–50 mmHg. Inadequate or delayed reduction of CSF pressure can result in permanent, and sometimes complete, visual loss, and lumbar puncture should not be delayed for fear of herniation. The accepted surgical treatment of IIH is insertion of a shunt, in either the lumbar or ventricular configuration.12,45 An alternate surgical intervention is optic nerve sheath fenestration (ONSF).45,46,48 Endovascular stenting of the dural venous sinuses is an emerging intervention for patients whose IIH has been demonstrated to be directly linked to cerebral venous hypertension secondary to stenosis of the dural venous sinuses.49–51 There have been few studies directly comparing outcomes of these treatment modalities, although it has been suggested that there is better documentation of visual outcomes for ONSF than for shunting or stenting because ONSF is performed by ophthalmologists.52 The headaches associated with IIH can be debilitating, but headache is not usually considered an indication for surgical management of IIH. An uncommon presentation of IIH is IIH without papilledema (IIHWOP), which essentially consists of chronic daily headache. This disorder is difficult to diagnose, although continuous CSF pressure monitoring via temporary spinal catheter has been utilized as a method to demonstrate unstable and elevated CSF pressure waveforms. Their presence can be used to recommend shunt surgery, which essentially is surgical management of headache.45,53 An additional diagnostic consideration for patients with suspected IIH is sleep apnea. Particularly for obese patients, chronic, undiagnosed sleep apnea may be an underlying etiology for the headaches, or it may be an explanation for patients whose visual exam improves but who still have persistent headaches. Patients with IIH and IIHWOP should routinely be referred to headache specialists to assist in the management of their pain syndromes. Patients with IIH deserve careful attention and regular follow-up visits. Especially when there is papilledema or visual impairment, frequent visits are necessary to ensure that medical management is effective. Patients who undergo surgical management should also have regular follow-up, as each of the surgical interventions can fail, with resultant return of CSF pressure elevation. The recently published Iowa experience suggests that at least 1 out of 6 patients with IIH is at risk for long-term recurrence, and thus IIH should be considered a chronic and sometimes relapsing disorder.54

References

MANAGEMENT OF SPONTANEOUS INTRACRANIAL HYPOTENSION Because it invariably presents with headache, the diagnosis, pathophysiology, and management of spontaneous intracranial hypotension has been covered in detail in Chapter 19. From the discussion here, it should be added that symptomatic intracranial hypotension can occur in patients who have shunts for either hydrocephalus or IIH. The risk of over-drainage and subdural effusions in the elderly population with hydrocephalus because of concomitant cerebral atrophy has already been discussed. In young and middle-aged adults with hydrocephalus, or in adults with IIH, over-drainage via the shunt may not be evident on routine neuroimaging. A common scenario is an adult who has had a shunt since childhood, or at least one that is more than 8–10 years old. Depending on the materials used to construct the shunt valve, it is possible that aging of the mechanism may cause the valve to become less flexible, and even to stick in the open position causing chronic overdrainage. Diffuse meningeal enhancement on MRI scan is seen in this population, just as with spontaneous intracranial hypotension. It can be helpful to monitor the CSF pressure via the shunt reservoir to demonstrate the physiologic need for shunt revision surgery.18 For adults who have programmable shunts and low-pressure symptoms, the management may be as simple as changing the shunt setting to a higher pressure.

CONCLUSIONS The approach to patients with AH, IIH, and low CSF pressure syndromes can be complex. Optimal management invariably requires close collaboration between neurologists, neurosurgeons, and ophthalmologists, and it is imperative that patients be closely followed both before and after a surgical intervention is undertaken. Even in the most practiced hands in specialized centers, complications of the various CSF diversion procedures can still occur. If not recognized promptly, these events can cause significant morbidity or mortality. On the other hand, proper diagnosis and management of conditions such as IIH can prevent irreversible vision loss, and the appropriate shunting of patients with AH can appreciably improve quality of life. Thus, these disorders require thoughtful diagnostic evaluation and close longitudinal care for their optimal management. REFERENCES 1. Monro A. Observations on the Structure and Functions of the Nervous System. Printed for and sold by William Creech and by T. Cadell, P. Elmsley, J. Murray, and T. Longman, London; 1783.

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2. Ballance CA. Some Points in the Surgery of the Brain and its Membranes. London: Macmillan and Company; 1907. 3. Dandy WE, Blackfan KD. An experimental and clinical study of internal hydrocephalus. JAMA 1913;61:2216–2217. 4. Dandy WE. Extirpation of the choroid plexus of the lateral ventricles in communicating hydrocephalus. Ann Surg 1918;6:569–579. 5. Goodrich JT. Reprint of “The Operative Treatment of Communicating Hydrocephalus” by Walter E. Dandy, M.D. 1938. Childs Nerv Syst 2000;16:545–550. 6. Dandy WE. The Brain. Hagarstown, MD: W.F. Prior; 1942. 7. Torkildsen A. Ventriculocisternostomy. A Palliative Operation in Different Types of Non-Communicating Hydrocephalus. Oslo: Johan Grundt Tanum; 1947. 8. Baru JS, Bloom DA, Muraszko K, Koop CE. John Holter’s shunt. J Am Col Surg 2001;192:79–85. 9. Boockvar JA, Loudon W, Sutton LN. Development of the Spitz-Holter valve in Philadelphia. J Neurosurg 2001;95:145–147. 10. Williams MA, McAllister JP, Walker ML, et al. Priorities for hydrocephalus research: report from an NIH-sponsored workshop. J Neurosurg 2007;107:345–357. 11. Bergsneider M, Black PMcL, Klinge P, Marmarou A, Relkin R. Surgical management of idiopathic normal-pressure hydrocephalus. Neurosurgery 2005;57:S29–S39. 12. McGirt MJ, Woodworth G, Thomas G, Miller N, Williams M, Rigamonti D. Cerebrospinal fluid shunting for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term outcomes. J Neurosurg 2004;101:627–632. 13. Friedman K, Thomas G, Rigamonti D, Williams M. Role of ventricular shunt scintigraphy as a predictor of surgical outcomes in patients with adult hydrocephalus. Presented at the 90th Scientific Assembly and Annual Meeting of the Radiological Society of North America, November 28–December 3, 2004, Chicago, IL. 14. Drake JM, Sainte-Rose C. The Shunt Book. Cambridge, MA: Blackwell Science; 1995. 15. Czosnyka Z, Czosnyka M, Richards HK, Pickard JD. Laboratory testing of hydrocephalus shunts – Conclusion of the U.K. Shunt Evaluation Programme. Acta Neurochir 2002;144:525–538. 16. Bergsneider M, Yang I, Hu X, McArthur DL, Cook SW, Boscardin WJ. Relationship between valve opening pressure, body position, and intracranial pressure in normal pressure hydrocephalus: paradigm for selection of programmable valve pressure setting. Neurosurgery 2004;55:851–859. 17. Geocadin RG, Varelas PN, Rigamonti D, Williams MA. Continuous intracranial pressure monitoring via shunt reservoir to assess suspected shunt malfunction in adult hydrocephalus. Neurosurg Focus 2007;22:E10. 18. Eide PK. Quantitative analysis of continuous intracranial pressure recordings in symptomatic patients with extracranial shunts. J Neurol Neurosurg Psychiatry 2003;74:231–237. 19. Pang D, Altschuler E. Low-pressure hydrocephalic state and viscoelastic alterations in the brain. Neurosurgery 1994;35:643–656. 20. Lesniak M, Clatterbuck R, Rigamonti D, Williams MA. Low pressure hydrocephalus and ventriculomegaly: hysteresis, non-linear dynamics and the benefits of CSF diversion. Br J Neurosurg 2002;16:555–561. 21. Bergsneider M, Peacock WJ, Mazziotta JC, Becker DP. Beneficial effect of siphoning in treatment of adult hydrocephalus. Arch Neurol 1999;10:1224–1229. 22. Drake JM, Kestle JR, Milner R, et al. Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus. Neurosurgery 1998;43:294–303. 23. Piatt JH Jr. Pumping the shunt revisited. A longitudinal study. Pediatr Neurosurg 1996;25:73–76. 24. Sood S, Canady AI, Ham SD. Evaluation of shunt malfunction using shunt site reservoir. Pediatr Neurosurg 2000;32:180–186.

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25. Williams MA, Razumovsky AY, Hanley DF. Evaluation of shunt function in patients who are never better, or better then worse after shunt surgery for NPH. Acta Neurochir 1998;71 Suppl:368–370. 26. Gupta N, Park J, Solomon C, Kranz DA, Wrensch M, Wu YW. Long-term outcomes in patients with treated childhood hydrocephalus. J Neurosurg 2007;106 Suppl:334–339. 27. Kestle JR, Garton HJ, Whitehead WE, Drake JM, Kulkarni AV, Cochrane DD, Muszynski C, Walker ML. Management of shunt infections: a multicenter pilot study. J Neurosurg 2006;105:177–181. 28. Whitehead WE, Kestle JR. The treatment of cerebrospinal fluid shunt infections. Results from a practice survey of the American Society of Pediatric Neurosurgeons. Pediatr Neurosurg 2001;35:205–210. 29. Marmarou A, Young HF, Aygok GA, Sawauchi S, Tsuji O, Yamamoto T, Dunbar J. Diagnosis and management of idiopathic normal-pressure hydrocephalus: a prospective study in 151 patients. J Neurosurg 2005;102:987–997. 30. McGirt MJ, Coon AL, Thomas G, Woodworth G, Williams MA, Rigamonti D. Diagnosis, treatment and analysis of long-term outcomes in idiopathic normal pressure hydrocephalus. Neurosurgery 2005;57:699–705. 31. Kulkarni AV, Drake JM, Lamberti-Pasculli M. Cerebrospinal fluid shunt infection: a prospective study of risk factors. J Neurosurg 2001;94:195–201. 32. Pople IK, Bayston R, Hayward RD. Infection of cerebrospinal fluid shunts in infants: a study of etiological factors. J Neurosurg 1992;77:29–36. 33. Tanner J, Woodings D, Moncaster K. Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev 2006 Jul 19;3:CD004122. 34. Livnia GY, Yuhas Y, Ashkenazi S, Michowiz S. In vitro bacterial adherence to ventriculoperitoneal shunts. Pediatr Neurosurg 2004;40:64–69. 35. Braxton EE, Ehrlich GD, Hall-Stoodley L, et al. Role of biofilms in neurosurgical device-related infections. Neurosurg Rev 2005;28:249–255. 36. Schuhmann MU, Ostrowski KR, Draper EJ, et al. The value of C-reactive protein in the management of shunt infections. J Neurosurg 2005;103:223–230. 37. Schroeder HWS, Oertel J, Gaab MR. Endoscopic treatment of cerebrospinal fluid pathway obstructions. Neusurgery 2007;60(Suppl 1):S44–S52. 38. Oertel JMK, Schroeder HWS, Gaab MR. Third ventriculostomy for treatment of hydrocephalus: results of 271 procedures. Neurosurg Q 2006;16:24–31. 39. Meier U, Zeilinger FS. Shunt-operation versus endoscopic ventriculostomy in normal-pressure hydrocephalus; diagnostics and outcome. Neurosurg Q 2003;13:179–185.

40. Gangemi M, Maiuir F, Buonamassa S, Colella G, de Devitiis E. Endoscopic third ventriculostomy in idiopathic normal pressure hydrocephalus. Neurosurgery 2004;55:129–134. 41. Schroeder HWS, Niendorf W-R, Gaab MR. Complications of endoscopic third ventriculostomy. J Neurosurg 2002;96:1032–1040. 42. Woodworth G, McGirt MJ, Thomas G, Williams MA, Rigamonti D. Prior CSF shunting increases the risk of endoscopic third ventriculostomy failure in the treatment of obstructive hydrocephalus in adults. Neurol Res 2007;29:27–31. 43. Drake JM. Endoscopic third ventriculostomy in pediatric patients: the Canadian experience. Neurosurgery 2007;60:881–886. 44. Hader WJ, Drake J, Cochrane D, Sparrow O, Johnson ES, Kestle J. Death after late failure of third ventriculostomy in children. J Neurosurg 2002;97:211–215. 45. Skau M, Brennum J, Gjerris F, Jensen R. What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalalgia 2006;26:384–399. 46. Acheson JF. Idiopathic intracranial hypertension and visual function. Br Med Bull 2006;79–80:233–244. 47. Çelebisoy N, Gökçay F, Sirin H, Akyürekli Ö. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand 2007;116:322–327. 48. Agarwal MR, Yoo JH. Optic nerve sheath fenestration for vision preservation in idiopathic intracranial hypertension. Neurosurg Focus 2007;23:E7. 49. Owler BK, Parker G, Halmagyi GM, et al. Pseudotumor cerebri syndrome: venous sinus obstruction and its treatment with stent placement. J Neurosurg 2003;98:1045–1055. 50. Donnet A, Metellus P, Levrier O, et al. Endovascular treatment of idiopathic intracranial hypertension: Clinical and radiologic outcome of 10 consecutive patients. Neurology 2008;70;641–647. 51. Friedman DI. Cerebral venous pressure, intra-abdominal pressure, and dural venous sinus stenting in idiopathic intracranial hypertension. J Neuroophthalmol 2006;26:61–64. 52. Feldon SF. Visual outcomes comparing surgical techniques for management of severe idiopathic intracranial hypertension. Neurosurg Focus 2007;23:E6. 53. Torbey MT, Geocadin RG, Razumovsky AY, Rigamonti D, Williams MA. Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache. Cephalalgia 2004;24:495–502. 54. Shah VA, Kardon RH, Lee AG, Corbett JJ, Wall M. Long-term follow-up of idiopathic intracranial hypertension: the Iowa experience. Neurology 2008;70;634–640.

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Approach to the Patient with Bloody or Pigmented Cerebrospinal Fluid Matthew Koenig

INTRODUCTION The presence of red blood cells (RBCs) or abnormal pigmentation in the cerebrospinal fluid (CSF) is a vexing clinical problem. In one common scenario, a patient undergoes a lumbar puncture (LP) for evaluation of headache and examination of the CSF reveals either an elevated number of RBCs or xanthochromia. The physician is then left with the difficult task of sorting out whether the data indicate subarachnoid hemorrhage (SAH) or simply a “traumatic tap.” This dilemma is not to be taken lightly; the evaluation of SAH often leads to cerebral angiography, an invasive procedure with potential morbidity. On the other hand, dismissing blood in the CSF as being due to a traumatic procedure could result in fatal rebleeding from an unrecognized cerebral aneurysm. The vascular anatomy surrounding the lumbar cistern and the physiological behavior of heme proteins in the CSF will be discussed here.

VASCULAR ANATOMY OF THE LUMBAR CISTERN The presence of RBCs in the CSF has often been falsely accounted for by injury to Batson’s epidural venous plexus, which was initially believed to lie both anteriorly and posteriorly to the lumbar thecal sac. Careful anatomic study, however, has shown that four major longitudinal epidural veins lie anterior to the spinal canal, but none is posterior to the thecal sac.1 Furthermore, post mortem studies suggest that the most common cause of a traumatic LP is injury to radicular arteries and veins that are closely opposed to nerve roots exiting the lateral aspect of the spinal cord.2 Subarachnoid bleeding may be extensive after a traumatic LP, with rare reports of blood refluxing all the way back into the lateral ventricles of supine patients to a degree that mimics intraventricular hemorrhage.3 Another rare cause of repeated traumatic LP is the presence of an

unsuspected vascular abnormality, such as a dural arteriovenous fistula, next to the lumbar cistern.

METABOLISM OF HEME PIGMENTS IN CSF The normal lifespan of RBCs in circulation is approximately 120 days. In CSF, however, RBCs lyse much more rapidly. Because of historical descriptions that reported deformed RBCs in the CSF of patients with SAH, RBC lysis was erroneously attributed to osmolarity differences between CSF and peripheral blood. Subsequent studies, however, have demonstrated that such osmolarity differences are minimal, and current theories regarding rapid RBC lysis in CSF are based on the absence of plasma proteins that stabilize the RBC membrane.4 Oxyhemoglobin from RBC lysis can be detected by spectrophotometry in CSF within 2 h of experimental SAH. This release is nonspecific and can occur both in vivo and ex vivo when the processing of samples is delayed.5 Oxyhemoglobin concentrations reach maximal levels in CSF within 36 h after SAH and gradually decline over the subsequent 7–10 days.6 The presence of oxyhemoglobin in centrifuged CSF samples lends a red, pink, or orange coloration to the fluid when present in sufficient quantities. The conversion of heme to bilirubin, on the other hand, is an enzyme-dependent process that only occurs in vivo. Heme metabolism in the CSF depends on the enzymatic activity of heme oxygenase that is found in macrophages present in the leptomeninges.7 Heme oxygenase activity is maximal at 12 h after SAH, the approximate time when bilirubin can also first be detected in the CSF. In this clinical setting, bilirubin reaches maximal levels 48 h after bleeding, and may persist for up to 2–4 weeks.8 CSF bilirubin includes both glucuronyl-conjugated and unconjugated forms, both of which are largely bound by albumin. The presence of bilirubin in centrifuged samples lends a yellow

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coloration to the CSF – the infamous “xanthochromia” – if present in sufficient quantities. Another heme pigment occasionally detected in CSF is methemoglobin, a compound that imbues a brownish coloration to centrifuged CSF. The clinical significance of methemoglobin detection in CSF during the evaluation of SAH is unclear, but it has been described in patients with encapsulated subdural hemorrhages as well as old loculated intracerebral hemorrhages.5

TRAUMATIC TAP OR SUBARACHNOID HEMORRHAGE? The first test performed to exclude SAH in the evaluation of a patient with sudden-onset headache is cranial computed tomography (CT). The reported sensitivity of a noncontrast head CT scan for detecting SAH in the first 24 h of symptoms ranges from 92 to 98% in various studies.9 This sensitivity declines to about 50% after 5 days. An LP is often performed in those patients with a negative or an equivocal head CT in whom SAH remains a clinical concern. The typical rationale for the procedure is to exclude an aneurismal “sentinel leak” too small to be detected on CT but nevertheless portending an increased risk of a major hemorrhage over the coming hours to weeks. Because most patients in this situation undergo CT imaging within the first 24 h of symptom onset, very few patients with true aneurismal subarachnoid bleeding are actually diagnosed by LP. This procedure, however, is routinely performed on patients with severe or atypical headaches and a normal CT. A significant proportion of these patients will have blood inadvertently introduced into the CSF by the procedure itself, leading to the common clinical conundrum of sorting out the small handful of true positives from the larger number of traumatic false positives. The stakes in this situation are high, because thorough evaluation of subarachnoid blood requires a cerebral angiogram to exclude an aneurysm. Angiography carries the potential morbidities of contrast nephropathy, iatrogenic stroke, and even retroperitoneal hemorrhage. It is also expensive, labor-intensive, and not always available in the community. Furthermore, small incidental cerebral aneurysms are present in 1–2% of the general population. The decision to treat an incidental aneurysm less than 7 mm in the setting of a probable traumatic tap is a complex one. On the other hand, missing a sentinel aneurismal leak can be a fatal oversight. Although the term “traumatic tap” is often invoked to describe the presence of RBCs in CSF, there actually is no standard definition of this entity. Visible pink discoloration requires at least 400 cells/mm3 be present in CSF,10 but several reports use more arbitrary definitions such as the presence of 500 or 1,000 cells/mm3 to define a traumatic tap. Using such definitions, the incidence of a traumatic tap varies between 10 and 20% of all procedures.10,11 Some 70% of all CSF samples have >1 RBC cells/mm3 in the final

tube of CSF collected. By the same token, true SAH and sentinel aneurismal leaks may present with as few as several hundred RBCs/mm3 in the CSF.4 Techniques to reliably distinguish a traumatic tap from a true SAH have been poorly validated in prospective studies, but the most popular methods are discussed below.

THE “THREE-TUBE” TEST The “three-tube” test is predicated on the assumption that blood introduced into the CSF via a traumatic tap will progressively clear as more CSF is removed. If cell counts are performed on three sequential tubes of CSF, then the RBC count should diminish in each sample. In SAH, on the other hand, blood is presumably evenly dispersed throughout the CSF and should not clear over time. This test has been validated in several small series where clearance of RBCs was able to distinguish a traumatic tap from a true hemorrhage.12,13 Thus, in situations in which the first sample is blood-tinged and subsequent tubes demonstrate no RBCs, the results can reliably be attributed to a traumatic tap. By the same token, when the first tube contains no RBCs but manipulation of the spinal needle or patient movement induces hemorrhage in subsequent tubes, these results may also be attributed to a traumatic tap.4 The more common scenario of partial clearance of RBCs, where the number of cells in the final tube is diminished compared to the first tube but still remain in the hundreds or thousands per mm3, is more perplexing. In order to maximize the potential specificity of the “three-tube” test, only 0.5 ml of CSF should be collected in the first tube when the sample is grossly bloody. Subsequent tubes should contain 5 or more ml, and the final tube should be submitted for a cell count. Even in cases of normal CSF appearance, the first and last tubes should be routinely submitted for cell count, because even CSF that seems clear to the naked eye may still contain several hundred RBCs/mm3.

VISUAL INSPECTION FOR XANTHOCHROMIA The term xanthochromia was initially used to describe the yellowish discoloration of centrifuged CSF that contains bilirubin. As with many medical terms, xanthochromia has since been expanded to include any bloody, brownish, or even cloudy CSF sample. Many labs report xanthochromia based on simple visual inspection of uncentrifuged samples. In the USA, visual inspection for xanthochromia is widely practiced,14 while in Europe xanthochromia is largely determined by spectrophotometry. In best practice, visual inspection for xanthochromia is performed as follows: 3 or more ml of CSF from the final tube should immediately be centrifuged at >2000 rpm for 5 min and placed in a clear glass tube. An equal volume of water should be placed in an identical tube and the two samples should be compared

Spectrophotometry for Xanthochromia

against a pure white backdrop – such as a sheet of paper – in natural lighting. This protocol is rarely followed, so visual inspection can be poorly standardized and fraught with problems. The basis for xanthochromia is the generation of bilirubin via the action of heme oxygenase, a process that can take up to 12 h to occur. In the vast majority of true SAH where the CSF is obtained within the first few days of symptom onset, the presence of intact RBCs and oxyhemoglobin can obscure the yellowish hue of bilirubin. Centrifugation is therefore required to remove intact cells and cellular debris, so the supernatant alone can be examined. Uncentrifuged samples and samples obtained within 12 h after symptom onset cannot be used to reliably exclude SAH. This conclusion was convincingly demonstrated in a study of patients with known SAH who underwent LP. Patients tapped within 6 h of symptom onset all had bloody CSF, but only 20% had xanthochromia by visual inspection.8 Xanthochromia was seen in 65% of samples taken between 6 and 12 h, and in 100% of those samples obtained between 12 h and 14 days.8 On the other hand, faint xanthochromia can also be seen in the supernatant of CSF with heavy blood contamination due to a traumatic tap. This situation may occur when >100,000 RBCs/mm3 are present.4 Similarly, when there is a delay in processing CSF obtained via a traumatic tap, a small amount of oxyhemoglobin in the supernatant may appear faintly yellow instead of pink.4 Visual inspection may also falsely identify xanthochromia when the CSF is contaminated with other pigments. This situation has been reported in patients taking rifampin for treatment of tuberculosis, excessive carotinoid intake from fad dieting, high total CSF protein concentration, or hepatic jaundice.1 Elevated CSF protein levels may cause yellowish discoloration of the CSF because of the presence of albumin-bound bilirubin; this usually requires a protein concentration in excess of 150 mg/dl.4 Discoloration may be seen at lower protein concentrations if the patient also has jaundice. Such high protein concentrations are commonly seen in spinal block (Froin’s syndrome), radicular demyelination, carcinomatous meningitis, intracranial neoplasms, and cryptococcal or tuberculous meningitis. In jaundice, the gradient of serum-to-CSF bilirubin is unpredictable – ranging from 1:10 to 1:100 in adults – but 10–15 mg/dl of total serum bilirubin is required for visible discoloration of the CSF to occur.4 Brownish discoloration of the CSF has also been rarely reported in melanomarelated meningeal carcinomatosis.15

SPECTROPHOTOMETRY FOR XANTHOCHROMIA Formal guidelines issued in the UK recently recommended abandoning visual inspection for xanthochromia and instead proposed standard spectrophotometric definitions for CSF xanthochromia.16 Using spectrophotometry to distinguish a traumatic tap from true SAH relies on the

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different absorption spectra of the major CSF pigments. This report recommended waiting at least 12 h after symptom onset to obtain CSF, and then sending only the last tube for immediate processing and spectrophotometric analysis. After centrifugation at >2,000 rpm for 5 min, the supernatant is scanned between wavelengths of 350 and 650 nm. Oxyhemoglobin produces a broad peak at 450–460 nm and bilirubin produces an absorption peak at 413–415 nm.17 Methemoglobin produces a broad peak between 403 and 410 nm.17 The net bilirubin absorbance is calculated using the Chalmers method, where a predicted baseline forms a tangent to the scan between 350 and 400 nm and again between 430 and 530 nm.18 The absorbance of the scan is then measured above the baseline at 476 nm to determine the net bilirubin absorbance.18 The absorbance of the oxyhemoglobin peak is similarly measured to determine the net oxyhemoglobin absorbance. The presence of oxyhemoglobin and bilirubin is then used to determine the probability of SAH. When both are absent at 12 or more hours, SAH is excluded.17,18 When oxyhemoglobin is present and bilirubin is absent, the results are indeterminate. When both are present or only bilirubin is present, SAH is probable. If the serum bilirubin is >20 mg/dl or CSF protein >100 mg/dl, adjustments must be made to account for contamination of the CSF by serum bilirubin.17 A study of CSF spectrophotometry in 111 patients with known SAH diagnosed by CT reported a sensitivity of 100% after 12 h and 90% within 3 weeks of symptom onset.19 A higher number of false positives occurs when centrifugation is delayed, because ex vivo hemolysis results in oxyhemoglobin contamination. Because the bilirubin peak is a shoulder off the broader oxyhemoglobin peak, excess oxyhemoglobin from very traumatic taps may produce a false-positive peak in the bilirubin absorbance range. Such false positives were reported in six of 27 patients without SAH in one series.20 False positives from blood contamination are unlikely, however, when the sample contains <400,000 RBCs/mm3 and is centrifuged within 15 min.21 Most studies used to validate spectrophotometry were performed in patients with known SAH as demonstrated by CT. This population does not routinely undergo LP, which is usually reserved for patients with normal CTs and the clinical suspicion of a sentinel leak or hemorrhage more than 24 h earlier. In a study of 253 patients with the clinical suspicion of SAH and negative CT, spectrophotometry successfully identified the two patients with true SAH (100% sensitivity) but suffered from a high number of false positives (75.2% specificity).22 Because of the large prevalence of false positives over true positives in this CT-negative population, the positive predictive value of spectrophotometry was only 3.3%.22 Even more troubling, a study of 24 CT-negative patients who underwent angiography demonstrated that spectrophotometry had a sensitivity of only 80%, missing two of 10 patients with true subarachnoid blood even though CSF had been obtained more than 12 h after symptom onset.9

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FERRITIN Measuring CSF ferritin concentration is an experimental technique to demonstrate SAH. Local production of ferritin has been seen in brain necrosis.23 CSF ferritin levels remain elevated for several weeks after intracranial hemorrhage, rendering this assay potentially useful in diagnosing remote CNS bleeding.9 The reference CSF ferritin concentration is <12 μg/l in normal controls. In a study of 24 CTnegative patients undergoing angiography to rule out SAH, ferritin levels in CSF obtained more than 12 h after symptom onset were elevated in 100% of patients with true SAH, including two patients with negative bilirubin spectrophotometry.9 There were three false positives in this cohort, yielding a specificity of 78%.9 It is important to note, however, that this study was not designed to separate SAH from traumatic tap, and CSF RBC counts were not described. Another small study compared CSF ferritin concentrations in patients with known SAH against artificial blood contamination of CSF.24 Simulated traumatic taps did not elevate ferritin concentrations at RBC counts <45,000/mm3. Artificial blood contamination did elevate CSF ferritin levels when the samples were incubated for more than a week or when RBC counts of >450,000/mm3 were used. All seven patients with SAH demonstrated elevated CSF ferritin levels, but the timing of CSF collection from the ictus was not reported.24 One false-negative ferritin measurement was reported at 16 h from symptom onset in a study of 12 cases of known SAH.25

D-DIMER Another experimental procedure used to distinguish SAH from a traumatic tap is measurement of CSF D-dimer concentration. D-dimer is an attractive target for study because it is released by recently clotted blood, as would occur in SAH, but not by intact RBCs due to a traumatic tap. In one initial report, an elevated CSF D-dimer level was found in all six patients with true SAH but was absent in all 14 patients with traumatic taps and all 20 patients with normal CSF.26 In this study, the sensitivity and specificity of D-dimer were greater than visual inspection for xanthochromia and the three-tube test. This sensitivity appears to decrease with time after subarachnoid bleeding, however, as demonstrated by an excessive false-negative rate in CT-negative patients presenting more than 4 days after symptom onset.25 A high false-positive rate has also been reported.27 At this point, the CSF D-dimer test should still be considered investigational.

CRENATED ERYTHROCYTES AND CLOT FORMATION Examinations of CSF RBC morphology and CSF clot formation are tests largely of academic and historical interest

that have not been validated for either the diagnosis or the exclusion of SAH. Crenated RBCs were reported in some early studies of CSF after SAH.28 Fresh bleeding from a traumatic tap should yield intact RBCs, whereas cells bathed in CSF for several hours undergo progressive deterioration. This is manifest by altered cellular morphology with irregular outlines and blebs. Still, such morphological changes remain an unreliable means of distinguishing SAH from traumatic tap. One report proposed comparing the mean corpuscular volume (MCV) of CSF and peripheral RBCs, where a smaller MCV would be found in a true hemorrhage compared to a traumatic tap.29 Similarly, RBCs that have undergone prolonged exposure to CSF should be unable to clot because of defibrination. This can be tested clinically when frankly bloody CSF is obtained; a few milliliters of fluid are allowed to settle in the collection tube for several minutes and are then examined for clot formation. Clotting usually requires >200,000 RBCs in the sample.4 Thus, the presence of clot can be an indicator of a traumatic tap but its presence or absence has not been validated to diagnose or exclude SAH.

CONCLUSIONS Distinguishing the traumatic tap from bleeding that results from a true SAH remains a challenging clinical dilemma. Ironically, advances in neuroimaging have made the interpretation of CSF data more difficult by increasing the pre-test probability that blood in the CSF was induced by the LP itself. The small number of patients with true CT-negative SAH compared to the larger number of traumatic taps significantly decreases the positive predictive value of even the most specific test for blood in the subarachnoid space. Even though a number of CSF markers for subarachnoid bleeding continue to be investigated, it seems unlikely that a single assay will ever be proven specific and reliable enough to diagnose or exclude SAH in all cases. Past being prologue, it is more likely that advances in imaging technology will continue to drive this field and lessen the indications for LP in suspected SAH. A few general conclusions can be drawn from the data presented here. First, within the first 24 h of even the smallest subarachnoid bleeds, at least several hundred RBCs/mm3 will be present in the CSF. If no RBCs are present within this time frame, then there is no SAH. Second, if a high number of RBCs are present in the first tube but completely clear by the final tube, the results can be safely attributed to a traumatic tap. Third, the release of bilirubin into the CSF from RBC lysis is unreliable in less than 12 h after the ictus, and the absence of xanthochromia – by any measurement standard – does not exclude SAH in this time frame. If non-reassuring CSF is obtained prior to the 12 h interval, then another LP should be done in the next 12–24 h to rule out xanthochromia, or if the clinical history is suggestive the patient should proceed directly to angiography.

References

Fourth, if a patient complains of having had symptoms suggestive of sentinel SAH between 24 h and 2 weeks prior to presentation, the CSF RBC count may be normal, but xanthochromia will reliably be found by either visual inspection or spectrophotometry. Fifth, although most texts continue to recommend repeat LP at a higher interspace to exclude traumatic tap, the specificity of this procedure has not been rigorously studied. It also bears mentioning that if the first LP actually introduced blood into the lumbar subarachnoid space and there is a significant delay in performing the second procedure, then the CSF profile will closely emulate a true SAH. Finally, in addition to the RBC count, it is important to calculate the ratio of white blood cells (WBCs) to RBCs present in CSF samples. Although the standard RBC:WBC ratio of 700:1 is frequently cited as a tool to correct for the number of leukocytes in the evaluation of suspected meningitis, it also has relevance in the evaluation of bloody CSF. The presence of hemorrhage in the CSF induces a delayed inflammatory response, with elevated polymorphonuclear cells after 1 day and mononuclear cells after 3–5 days.8 This relative lymphocytosis may persist for weeks. This phenomenon is discussed in greater detail in Chapter 25. In the evaluation of a patient with a severe headache, however, it is important to remain vigilant for alternative diagnoses. The presence of true CSF hemorrhage in a patient with headache and a normal CT scan can also be a presenting feature of hemorrhagic anthrax meningitis or herpes simplex encephalitis. In the absence of a systemic inflammatory response, the observant physician will be cued to these diagnoses by an elevated ratio of CSF white blood cells in a patient with bloody CSF. REFERENCES 1. Fishman R. Cerebrospinal Fluid in Diseases of the Central Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992:183–252. 2. Breuer AC, Tyler HR, Marzewski DJ, et al. Radicular vessels are the most probable source of needle-induced blood in lumbar puncture: significance for the thrombocytopenic cancer patient. Cancer 1982;49:2168–2172. 3. Stubgen JP. Intraventricular blood after “traumatic” lumbar puncture: a report of two cases. Childs Nerv Syst 1995;11:492–493. 4. Shah KH, Edlow JA. Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage. J Emerg Med 2002;23:67–74. 5. Barrows L, Hunter F, Banker B. The nature and clinical significance of pigments in the cerebrospinal fluid. Brain 1955;78:59–79. 6. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: WB Saunders; 1937:197–203. 7. Roost KT, Pimstone NR, Diamond I, et al. The formation of cerebrospinal fluid xanthochromia after subarachnoid hemorrhage. Enzymatic conversion of hemoglobin to bilirubin by the arachnoid and choroids plexus. Neurology 1972;22:973–977. 8. Walton J. Subarachnoid hemorrhage. Edinburgh: E & S Livingstone; 1956:118–127. 9. O’Connell DM, Watson ID. Definitive angiographic detection of subarachnoid haemorrhage compared with laboratory assessment of

10. 11.

12. 13. 14.

15. 16.

17. 18. 19. 20.

21.

22. 23. 24.

25.

26. 27. 28. 29.

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intracranial bleed in CT-negative patients. Ann Clin Biochem 2003;40:269–273. Shah K, Richard K, Nicholas S, et al. Incidence of traumatic lumbar puncture. Acad Emerg Med 2003;10:151–154. Eskey CJ, Ogilvy CS. Fluoroscopic-guided lumbar puncture: decreased frequency of traumatic tap and implications for the assessment of CT-negative acute subarachnoid hemorrhage. Am J Neuroradiol 2001;22:571–576. Buruma O, Janson H, Den Bergh F, et al. Blood-stained cerebrospinal fluid: traumatic puncture or hemorrhage. J Neurol Neurosurg Psychiatry 1981;44:144–147. Tourtellotte WW, Somers JF, Parker JA, et al. A study of traumatic lumbar punctures. Neurology 1958;8:129–134. Judge B. Laboratory analysis of xanthochromia in patients with suspected subarachnoid hemorrhage: a national survey. In Scientific Assembly, American College of Emergency Physicians. Philadelphia: 2000:14–18. el-Mallakh RS. CSF evaluation in neurologic diseases. Am Fam Physician 1987;35:112–118. UK National External Quality Assessment Scheme for Immunochemistry Working Group. National guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage. Ann Clin Biochem 2003;40:481–488. Cruickshank AM. CSF spectrophotometry in the diagnosis of subarachnoid haemorrhage. J Clin Pathol 2001;54:827–830. Chalmers AH. Cerebrospinal fluid xanthochromia testing simplified. Clin Chem 2001;47:147–148. Vermeulen M, Hasan D, Blijenberg BG, et al. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry 1989;52:826–828. Fahie-Wilson MN, Park DM. Spectrophotometric analysis of CSF in suspected subarachnoid haemorrhage – what should we look for? In: Martin SM, Halloran SP, eds. Proceedings of the XVI International Congress on Clinical Chemistry, 8–12 July 1996, London. London: Association of Clinical Biochemists; 1996:85. Smith LA, Cruickshank AM. Subarachnoid haemorrhage or traumatic tap? In: Martin SM, ed. Proceedings of the ACB National Meeting, 17–21 May 1999, Manchester. London: Association of Clinical Biochemists; 1999:61. Wood MJ, Dimeski G, Nowitzke AM. CSF spectrophotometry in the diagnosis and exclusion of spontaneous subarachnoid haemorrhage. J Clin Neurosci 2005;12:142–146. Keir G, Tasdemir N, Thompson EJ. Cerebrospinal fluid ferritin in brain necrosis: evidence for local synthesis. Clin Chim Acta 1993;216:153–166. Wick M, Fink W, Pfister W, et al. Ferritin in cerebrospinal fluid differentiation between central nervous system haemorrhage and traumatic spinal puncture. J Clin Pathol 1988;41: 809–814. Page KB, Howell SJ, Smith CML, et al. Bilirubin, ferritin, D-dimers and erythrophages in the cerebrospinal fluid of suspected subarachnoid hemorrhage but negative computed tomography scans. J Clin Pathol 1994;47:986–989. Lang DT, Berberian LB, Lee S, Ault M. Rapid differentiation of subarachnoid hemorrhage from traumatic lumbar puncture using the D-dimer assay. Am J Clin Pathol 1990;93:403–405. Morgenstern LB, Luna-Gonzalez H, Huber JC, et al. Worst headache and subarachnoid hemorrhage: prospective computed tomography and spinal fluid analysis. Ann Emerg Med 1998;32:297–304. Matthews WF, Frommeyer WB. The in vitro behavior of erythrocytes in human cerebrospinal fluid. J Lab Clin Med 1955;45:508–515. Yurdakök M, Kocabas CN. CSF erythrocyte volume analysis: a simple method for the diagnosis of traumatic tap in newborn infants. Pediatr Neurosurg 1991–92:17;199.

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30

Approach to the Patient with a Cerebrospinal Fluid Pleocytosis Jeffrey A. Rumbaugh and Avindra Nath

INTRODUCTION Numerous causes may underlie a cerebrospinal fluid (CSF) pleocytosis. While determining the magnitude of the pleocytosis and the relative predominance of neutrophils versus lymphocytes can be a helpful first step, the differential diagnosis usually cannot be adequately narrowed based on the CSF formulation alone. The skilled clinician must instead use the entire clinical presentation in considering the various diagnostic possibilities. Thus, the acuity of the illness is one important clinical characteristic that helps to identify the underlying disorder. Other ancillary tests, including disease-specific markers in both the serum and CSF as well as imaging modalities to directly visualize central nervous system (CNS) structures, are also helpful. This chapter provides a general approach to understanding the possible etiologies of a CSF pleocytosis. It should go without saying that one must tailor such a general approach to best meet the challenges presented by each individual patient.

NORMAL CEREBROSPINAL FLUID CELLULARITY The normal white blood cell (WBC) count of CSF ranges from 0 to 5 cells per cubic millimeter (mm3).1 These few lymphocytes and monocytes reflect normal immune surveillance of the CNS. A normally processed CSF sample should not contain any polymorphonuclear (PMN) cells, although by concentrating a large volume of CSF via centrifugation, a single PMN may sometimes be identified. Therefore, even if the total WBC count is 5 cells/mm3 or less, a CSF specimen should be considered abnormal if the WBC differential associated with that count includes two or more PMNs.1–3

ACUTE NEUTROPHILIC PLEOCYTOSIS The patient with an acute neurological illness and a CSF pleocytosis containing a predominance of PMNs must be

assumed to have bacterial meningitis until proven otherwise. Symptoms of bacterial meningitis include fever, headache, nausea, vomiting, irritability, and lethargy. Clinical signs include evidence of meningeal irritation, often accompanied by focal neurological deficits. The course is frequently a fulminant one, with rapid deterioration leading to coma, respiratory failure, and death over a period of hours to days. Therefore, any patient having a clinical presentation and CSF formulation even remotely compatible with bacterial meningitis should be promptly treated with antibiotics, keeping in mind that clinical features may be atypical in young children and the elderly. A CSF sample showing a pleocytosis that contains more than 33% neutrophils, with a protein concentration of greater than 100 mg/dl and a glucose level less than 50% of the serum glucose level, is strongly suggestive of bacterial meningitis.2,4,5 This formulation should almost always prompt the institution of broad-spectrum antibiotic coverage. Indeed, in the proper clinical setting, the initiation of treatment should not even be delayed by the time necessary to obtain CSF (i.e., the two events should happen simultaneously). The role of brain imaging prior to CSF examination in suspected bacterial meningitis is fraught with controversy, and the issue is discussed in detail in Chapter 8. Other than a careful Gram stain, there are no current diagnostic tests that are both rapid and reliable enough to identify a specific causative organism on which to base initial treatment decisions.5 The main utility of tests such as bacterial antigen screens is therefore is to confirm the initial clinical diagnosis and to allow adjustment of the initial therapeutic interventions. There are only a few exceptions to the general association between a neutrophilic CSF pleocytosis and bacterial infection. Some bacteria, such as Listeria monocytogenes, can cause a lymphocytic CSF pleocytosis. Therefore, if the clinical presentation is consistent with acute bacterial meningitis the patient should be treated as such, even if CSF analysis shows a relative predominance of lymphocytes over neutrophils. Factors that increase the likelihood of

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listerial infection include age less than 30 days or over 60 years and preexisting immunosuppression, but this pathogen can cause disease in patients of any age group or health status.6 On the other hand, a neutrophilic CSF pleocytosis may sometimes occur in response to viral and not bacterial CNS infection, especially if the CSF sample is obtained very early in the course of the illness. In such cases, the CSF glucose concentration is usually normal, while the protein is often elevated but generally below 100 mg/dl. Recent reports have focused attention, in particular, on a predominance of PMN WBCs in the CSF of up to half of patients with West Nile virus neuroinvasive disease.7,8 In patients with acquired immunodeficiency syndrome (AIDS), flaccid lower extremity weakness and areflexia prompting a CSF examination can reveal neutrophils indicative of cytomegalovirus (CMV) polyradiculitis.9 Indeed, even in the absence of AIDS, occasional GuillainBarré syndrome-like illnesses are now recognized with a neutrophilic CSF pleocytosis.10 Finally, fungal or mycobacterial infections of the CNS can recruit neutrophils into the CSF, and there are case reports indicating that disorders such as Kawasaki disease, Sjogren’s syndrome, hemorrhagic stroke, neuro-Behçet’s disease, and acute febrile neutrophilic dermatosis (Sweet’s syndrome) may cause a CSF pleocytosis with a predominance of neutrophils. Another condition that closely resembles acute bacterial meningitis from both a clinical and laboratory standpoint is the chemical meningitis that occurs in patients with underlying connective tissue disorders who are treated with the non-steroidal anti-inflammatory drug ibuprofen.11

INFECTIOUS ETIOLOGIES OF A LYMPHOCYTIC PLEOCYTOSIS Viral meningoencephalitis is the most common cause of a lymphocytic CSF pleocytosis in a patient with some acute illness. Common symptoms of viral meningitis include headache, fever, and meningismus. If an encephalitic component is also present, there may be varying degrees of altered consciousness, seizures, and focal neurological deficits. These patients will generally not appear as ill as someone with bacterial meningitis, although distinction on clinical grounds alone is difficult and not advised. A complete CSF examination is the most important means to establish a diagnosis of viral meningoencephalitis. The WBC count typically ranges from 10 to 1000 cells/mm3, but it is usually less than 300 cells/mm3 and composed primarily of mononuclear cells. Still, there may be a predominance of PMN leukocytes during the first 48 h of disease, particularly with infections caused by enteroviruses, herpes viruses, and arboviruses.5 The CSF glucose concentration is usually normal, but it can be decreased with infections caused by lymphocytic choriomeningitis virus.5

The protein content is normal to mildly elevated.5 Distinguishing between the many viruses that cause aseptic meningoencephalitis can be difficult based on the clinical presentation and routine CSF profile alone. Polymerase chain reaction (PCR) assays for viral nucleic acids, viral cultures, measurement of anti-viral antibody titers in acute and convalescent serum samples, systemic manifestations, and epidemiological features are all important factors that help to determine the causative pathogen.12,13 Contrary to common belief, many viruses that cause meningoencephalitis can be isolated from CSF, pharynx swabs, urine, and/or stool during the acute illness.5,12,13 Likewise, a 4-fold increase in antibody titers between acute and convalescent serum samples, and/or the presence of specific antibody within the CSF, would be strongly supportive of a specific diagnosis.5,12,13 Detecting viral nucleic acid sequences in the CSF using PCR is the most sensitive and rapid diagnostic test currently available for the identification of most common viral pathogens that infect the CNS.5 These assays are now widely available for enteroviruses and many human herpes viruses.5,14,15 For enteroviral meningitis, viral PCR is twice as likely to be positive as a routine viral culture.16,17 Because of their high sensitivity and specificity, such assays are a cornerstone in the evaluation of patients with an acute lymphocytic CSF pleocytosis. This is particularly true in individuals with a focal encephalitis who may be infected with herpes simplex virus and respond to intravenous acyclovir therapy. In the setting of a more chronic disorder, a lymphocytic CSF pleocytosis of infectious origin is usually due to fungal, tuberculous, or spirochetal infection of the CNS (Fig. 30-1). Most fungal infections can be diagnosed by India ink staining and fungal culture of the CSF, along with rapid immunological detection assays for cryptococcal polysaccharide antigen, histoplasma polysaccharide antigen, and Coccidiodes immitis complement fixation antibodies.5,18 Tuberculous meningitis is diagnosed by acid-fast bacilli smear and culture of the CSF, PCR for Mycobacterium tuberculosis, and a tuberculin skin test.19 It should be borne in mind that such diagnoses frequently require multiple, large-volume CSF collections to increase diagnostic yield; these organisms typically cause a basilar meningitis and may not always be present in sufficient numbers in the lumbar thecal sac.5 In immunocompromised individuals, however, these organisms may be easier to recover because of a higher pathogen load that develops in the setting of impaired immune clearance. Spirochetal causes of a chronic lymphocytic pleocytosis include CNS Lyme disease and neurosyphilis.20,21 The most useful tests to identify these infections seek to identify pathogen-specific antibodies in both serum and CSF; for Lyme, tests for antibodies against Borrelia burgdorferi by enzyme-linked immunosorbent assay (ELISA) and Western blot confirm disease, and for neurosyphilis, the serum rapid plasma reagin (RPR) test and fluorescent treponemal antibody absorption (FTA-Abs)

Non-infectious Etiologies of a Lymphocytic Pleocytosis

275

CSF

Lymphocytes

Neutrophils

Urgent Rx for bacterial meningitis

Eosinophils

Acute

Chronic

Non-infectious etiology suspected

Clinical suspicion for bacteria (i.e., Listeria)

Clinical and radiographic suspicion for infection

See Figure 30-2

Various helminths

Blood cx, CSF GS and cx

AFB smear and cx, Mtb PCR, PPD

Bacteria confirmed

India ink, fungal cx, crypto Ag, histo Ag, coccidio Ab

Early viral meningoencephalitis suspected (enterovirus, HSV, CMV, WNV)

Lyme Ab, VDRL

Parasites

TB confirmed Coccidiomycosis Fungus confirmed

Bacteria confirmed

CSF viral PCR, cx, Ab; acute and convalescent serologies; viral cx from CSF, pharynx, stool

Virus confirmed Figure 30-1 Approach to the diagnosis of a patient with a CSF pleocytosis of infectious origin. Abbreviations used: Ab, antibody; AFB, acid-fast bacilli; Ag, antigen; CMV, cytomegalovirus; coccidio, Coccidiodes immitis; crypto, Cryptococcus neoformans; CSF, cerebrospinal fluid; cx, culture; GS, Gram stain; histo, Histoplasma capsulatum; HSV, herpes simplex virus; Mtb, Mycobacterium tuberculosis; PCR, polymerase chain reaction; PPD, purified protein derivative; Rx, treatment; TB, tuberculosis; VDRL, venereal disease research laboratory; WNV, West Nile virus.

as well as the CSF Venereal Disease Research Laboratory (VDRL) test are all reactive.

NON-INFECTIOUS ETIOLOGIES OF A LYMPHOCYTIC PLEOCYTOSIS Beyond infections, neoplastic, granulomatous, autoimmune, and toxic disorders may all cause lymphocytes and monocytes to accumulate in the CSF (Fig. 30-2). Table 30-1 lists some of the most common infectious and non-infectious etiologies of a chronic, lymphocytic CSF pleocytosis. A number of these disorders are discussed in detail here.

Neoplastic and paraneoplastic disorders Non-Hodgkin’s lymphoma is the leading cause of cancerrelated death in people between the ages of 20 and 40.22

Patients typically present with constitutional symptoms including fever, night sweats, weight loss, and lymphadenopathy. Approximately 10% of patients with non-Hodgkin’s lymphoma will develop leptomeningeal metastases,23 and the CSF of these patients will typically demonstrate a lymphocytic pleocytosis. These mature lymphocytes are recruited as an immune reaction to the malignant cells, and on routine microscopic evaluation they can mask detection of the malignant sub-population. Hence, CSF samples obtained in this clinical setting should be analyzed for cytology as well as by flow cytometry. Flow cytometry identifies various cell surface markers that not only distinguish malignant from non-malignant cells, but can also help to define the specific type of lymphoma. These assays may therefore also have important therapeutic implications.24 Measurement of CSF cytokine levels can also be useful in these disorders. Interleukin (IL)-10 is not normally detected in CSF, but it is produced by many

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CSF

Lymphocytes

Eosinophils Malignancy

Chronic Serum/CSF ACE, CXR/chest CT, lymph node biopsy

Neurosarcoidosis

Serum vasculitis markers, brain MRI, leptomeningeal/ brain biopsy

Vasculitis (see Table 30-2)

Clinical suspicion for malignancy

Medications

Flow cytometry, cytopathology, CSF cytokines, biopsy

Clinical suspicion for demyelination

Neoplastic meningitis

Other

Paraneoplastic disorder, toxin/ medications

Eosinophilic leukemia, lymphoma

CSF IgG index, OCBs; brain/cord MRI

Ciprofloxacin, ibuprofen, various intrathecal therapies Indwelling hardware

VP shunt Hypereosinophilic syndrome

Demyelination confirmed Figure 30-2 Approach to the diagnosis of a patient with a CSF pleocytosis of non-infectious origin. Abbreviations used: ACE, angiotensin-converting enzyme; CSF, cerebrospinal fluid; CT, computed tomography; CXR, chest X-ray; IgG, immunoglobulin G; MRI, magnetic resonance imaging; OCBs, oligoclonal bands; VP, ventriculoperitoneal.

lymphoma cells. In contrast, high CSF levels of IL-6 are seen in a variety of non-malignant, inflammatory disorders. Therefore, a CSF IL-10 to IL-6 ratio of greater than 1.0 is strongly suggestive of a lymphomatous meningitis, while a ratio less than 1.0 is suggestive of a non-malignant etiology.25 Leptomeningeal metastasis from solid tumors is referred to as carcinomatous meningitis. Adenocarcinomas and malignant melanoma are the most common types of solid tumors to metastasize in this manner. Such patients frequently present with signs of meningeal irritation,

Table 30-1 Etiologies of a Chronic Lymphocytic CSF Pleocytosis Infectious

Non-Infectious

Viral meningoencephalitis Fungal meningitis Tuberculosis CNS Lyme disease Neurosyphilis

Malignancy CNS lymphoma Lymphomatous/leukemic meningitis Carcinomatous meningitis Paraneoplastic encephalitis CNS vasculitis Neurosarcoidosis Demyelinating disease Medications/toxins

including headache, nausea, vomiting, and some degree of meningismus. Cranial nerve palsies are also common, most frequently affecting cranial nerves III–VIII. Papilledema may also be observed. Lower extremity weakness, sensory abnormalities, and loss of reflexes can also occur due to cellular infiltration of nerve roots. The upper extremities are often spared; gravity tends to settle the malignant cells at the base of the brain and in the thecal sac.26 In addition to a mixed pleocytosis that may include lymphocytes, monocytes, PMNs, and “atypical” cells, the opening pressure and total protein content are typically elevated in these patients. The CSF must be sent for cytologic analysis; the diagnostic gold standard is the identification of malignant cells in the CSF.27 To improve the diagnostic yield, multiple, largevolume CSF collections must be analyzed over time. Paraneoplastic syndromes affecting the nervous system very commonly produce a mild lymphocytic CSF pleocytosis (10–40 WBC/mm3), a slightly elevated CSF protein content (50–100 mg/dl), and an increased immunoglobulin G (IgG) index. Various anti-neuronal antibodies can be found in the serum and/or CSF of many of these patients.28 The antibodies associated with each individual clinical syndrome and each type of cancer are discussed in detail in Chapter 26. It bears remembering, however, that the neurological

Non-infectious Etiologies of a Lymphocytic Pleocytosis

manifestations and CSF abnormalities associated with paraneoplastic disorders can precede the diagnosis of the underlying malignancy, so there is a role in screening for antibodies even in the absence of a confirmed cancer.

Granulomatous disorders Sarcoidosis can present with protean systemic and neurological symptoms. While less than one-quarter of patients will have CNS involvement over the course of their disease, this can be the presenting disease manifestation in almost half of these cases.29 Thus, if neurosarcoidosis is suspected, pulmonary involvement should be sought as the lungs as well as the hilar and mediastinal lymph nodes are commonly affected. In addition to a lymphocytic pleocytosis, the CSF protein concentration is typically elevated, the glucose concentration is normal or mildly depressed, the IgG index is elevated, and oligoclonal bands are often present in neurosarcoidosis patients.30–32 Angiotensin-converting enzyme (ACE) levels may be elevated in both serum and CSF, although an elevated CSF ACE level has a sensitivity of only 24% for this diagnosis (the specificity, however, is 95%).33 A definitive diagnosis of sarcoidosis requires the pathological identification of non-caseating granulomas in affected tissue. Positive specimens are typically obtained via transbronchial biopsy of an adjacent lymph node identified by chest computed tomography (CT) or positron emission tomography (PET) imaging. Such systemic involvement accompanied by inflammatory CSF is presumptive evidence for neurosarcoidosis and sufficient to treat the patient as such.

Autoimmune disorders The CNS vasculitides are a poorly understood group of very rare neurological disorders. Clinical presentation is heterogeneous, but may include headache, encephalopathy, cognitive decline, recurrent small vessel stroke, and cranial nerve palsies. Table 30-2 lists the most common CNS vasculitides that cause a lymphocytic CSF pleocytosis.

Table 30-2 Vasculitides Affecting the CNS and Likely to Cause a CSF Pleocytosis Primary Vasculitis

Secondary Vasculitis

Isolated angiitis of the CNS Takayasu’s arteritis Giant cell arteritis Churg Strauss vasculitis Wegener’s granulomatosis Polyarteritis nodosa Behçet’s disease Kawasaki’s arteritis Rheumatoid arthritis Systemic lypus erythematosis Sjogren’s disease

Cryoglobulinemia Malignancy Medications/toxins Infections Hepatitis B virus Tuberculosis Human immunodeficiency virus Varicella zoster virus Herpes simplex virus Fungi

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Most cases will have some associated clinical, pathological, or serological evidence of systemic vasculitis. An obvious exception is isolated angiitis of the CNS, in which there are no systemic manifestations of vasculitis and serological tests are typically normal.34 CSF examination will be abnormal in 75–90% of patients with CNS vasculitis and will typically show a lymphocyte predominant pleocytosis with an elevated protein concentration and normal glucose content. The CSF WBC count will rarely exceed 200 cells/mm3. Cranial magnetic resonance imaging (MRI) scans will be abnormal in well over 90% of these cases. Imaging will typically demonstrate ischemic lesions in multiple vascular distributions of different ages.35 A normal CSF examination in a patient with a normal cranial MRI scan makes CNS vasculitis exceedingly unlikely, but even if only one of these two tests is abnormal, it still could be a conceivable diagnosis.36 A combined leptomeningeal and brain biopsy must be done to confirm CNS vasculitis. Although biopsy is positive in only 75–80% of autopsy-confirmed cases, the procedure is still the most sensitive and specific test available.36,37 Demyelinating diseases of the CNS, such as multiple sclerosis (MS), transverse myelitis (TM), and acute disseminated encephalomyelitis (ADEM), are frequently associated with a lymphocytic pleocytosis in the CSF. A CSF examination is often used to confirm a diagnosis of MS, especially in situations where the clinical and/or MRI findings are atypical.38,39 In this disease, unique oligoclonal bands and an increased IgG index are found in the CSF of 85–90% of confirmed cases.38–41 Otherwise, the fluid typically shows a moderately increased WBC count (usually 8–20 cells/mm3 and almost always below 100 cells/mm3) and normal to mildly elevated total protein content. Once identified, the intrathecal IgG typically persists for life. The WBCs found in the CSF of MS patients consist mainly of CD3+ T lymphocytes (in a 3:1 ratio of CD4+ to CD8+ cells), and, during active disease, are often blasts.41 One study reports that a higher proportion of B cells may predict a more fulminant future clinical course.41 Acute TM can resemble a spinal cord exacerbation of MS, and inflammatory CSF with a predominance of lymphocytes is certainly an important diagnostic feature of this disorder.42 Nevertheless, the CSF in acute TM typically shows a lower rate of intrathecal IgG synthesis compared to MS and it almost always lacks oligoclonal bands.43–46 Furthermore, once the acute clinical episode and the pathological enhancement seen on spinal MRI subside, the pleocytosis also resolves and there are no long-term markers of inflammation detected. Clinical recurrence is rare, but detection of the newly described neuromyelitis optica-IgG (NMO-IgG) marker in the serum may be a harbinger of future inflammatory demyelinating events in these patients.44 ADEM is differentiated from MS based mostly on its clinical presentation and MRI features, which by definition are both acute and often widely disseminated throughout the central neuraxis. However, the CSF findings in ADEM

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also commonly differ from other demyelinating diseases in that CSF WBC counts higher than 100 cells/mm3 are not unusual, and that a significant proportion of these cells may be PMNs, especially early in the disease course. Additionally, the CSF IgG index is rarely elevated in ADEM, and oligoclonal bands are frequently transient and often disappear on follow-up testing.47 Not unexpectedly, however, both the clinical and laboratory spectra of this disorder are broad, and the CSF profile in a patient with multifocal cranial MRI lesions often does not adequately discriminate ADEM from MS.

Toxic disorders Certain medications can also cause an aseptic meningitis picture with a CSF pleocytosis, usually lymphocytic in nature. The most common offending agents include nonsteroidal anti-inflammatory drugs, sulfa antibiotics, intravenous immunoglobulin, and isoniazid.48 Drug-induced aseptic meningitis can manifest across a wide clinical spectrum from mild headache to fever and meningismus to significant alteration in consciousness, and it can begin anywhere from minutes to months after the initiation of the offending agent. The CSF WBC count can range from being slightly elevated to as high as hundreds or even thousands of cells/mm3. The CSF protein content is usually elevated, but the glucose level is invariably normal. Clinical response to drug discontinuation is usually rapid.48

for 10 days if started in the first 72 h of infection. After 3 days, tissue damage is usually so extensive that treatment is ineffective.51–54 Coccidiodes immitis, a fungus endemic to southwestern regions of the USA, is another common cause of eosinophilic meningitis. Meningitis occurs in 50% of patients with disseminated disease (usually manifest as a pulmonary disease due to the inhalation of spores aerosolized from the soil), and 70% of individuals with coccidiodal meningitis have a CSF eosinophilia. In up to a third of cases, the initial clinical presentation of Coccidiodes infection will be with meningitis.55,56 Other less common causes of CSF eosinophilia include malignancy, medications, and indwelling intraventricular catheters.50 The most common malignancies that produce this finding are lymphoma and eosinophilic leukemia. The most frequently implicated medications include any intrathecally administered drug, as well as oral nonsteroidal anti-inflammatory agents and ciprofloxacin. The hardware responsible is primarily ventriculoperitoneal shunts. Finally, idiopathic hypereosinophilic syndrome can cause an eosinophilic meningitis. This rare disease, in which eosinophils infiltrate numerous tissues, can cause multi-organ damage and death. It is not uncommon for these patients to manifest a wide range of neurological symptoms due to the infiltration of the brain and CSF by eosinophils.57

CEREBROSPINAL FLUID BASOPHILIA CEREBROSPINAL FLUID EOSINOPHILIA A predominance of eosinophils in the CSF suggests a parasitic infection of the CNS until proven otherwise. Eosinophilic meningitis is defined as the presence of ≥10 eosinophils/mm3 of CSF, or when eosinophils comprise ≥10% of the total CSF leukocyte count.49 Important history in these patients includes recent travel, exposure to raccoons or possibly contaminated soil, and the presence of migratory tissue swellings, rash, arthralgia, and adenopathy. Helminths are the most common parasites to cause eosinophilic meningitis worldwide. Meningitis caused by these organisms has been recently reviewed.50 Most of these organisms are not endemic to the USA, with the exception of the raccoon ascarid, Baylisascaris procyonis. This organism is present throughout the USA, with the highest prevalence in the Midwest, Northeast, and West Coast regions. It is transmitted via a fecal-to-oral route by individuals who have recently handled infected raccoons or soil contaminated with raccoon feces. Infected patients generally have systemic symptoms, as the organism disseminates throughout the body. The larvae can often be found in the CSF, brain, blood, eyes, and liver. The Centers for Disease Control recommend treatment with albendazole

Accumulation of basophils in the CSF is exceedingly rare. However, CSF basophilia may occur in children with acute lymphoblastic leukemia, where mature basophils are often accompanied by eosinophils.58,59 These cells are thought to be responding to the meningeal infiltration of leukemic cells. A basophilic meningitis has also been reported in a single case of CNS varicella zoster virus infection.60

THE TRAUMATIC LUMBAR PUNCTURE When both erythrocytes and leukocytes are recovered from a CSF sample, the question will frequently arise as to whether the leukocytes are present as a result of an underlying infectious or inflammatory process or were unintentionally introduced into the CSF from the bloodstream during the lumbar puncture. A distinction can often be made by directly comparing the ratios of erythrocytes to leukocytes in both the CSF and the peripheral blood. If WBCs were introduced into the CSF from the peripheral blood, the ratio should be the same in both specimens. If this ratio is lower in CSF, then the excess WBCs must have been present in the CSF prior to the procedure.

References

EMPIRIC THERAPY FOR A CHRONIC CEREBROSPINAL FLUID PLEOCYTOSIS If a patient with a chronic, unexplained CSF pleocytosis is deteriorating, then initiating some empiric therapy may be required.61 Most infections that fall into this category will respond to either anti-tuberculosis or anti-fungal therapy. Most non-infectious disorders will respond to empiric corticosteroid therapy. If there are clinical indicators to favor one category over the other, then the appropriate choice can be made based on those indicators. If no such indicators are found, then many clinicians choose to start with corticosteroids alone. Regardless of which approach is chosen, it is critical to monitor the patient’s clinical and laboratory status after therapy is initiated. If the patient improves the initial choice is validated, but if the patient deteriorates, it is imperative to discontinue that intervention and consider switching to the alternative therapeutic approach. A repeat CSF examination can often be informative in this difficult situation, using the magnitude of the CSF pleocytosis as the principal indicator of success or failure.

CONCLUSIONS Most clinicians will have a differential diagnosis in mind for their patient even as they decide that a CSF analysis is needed. Thus, the results of a CSF examination are not interpreted in isolation, but rather are used to further narrow the diagnostic possibilities in a given clinical situation. Important clues to the possible etiologies underlying a CSF pleocytosis include whether the clinical condition is acute or chronic, and whether the pleocytosis is predominantly lymphocytic or neutrophilic in nature. While it may be broadly helpful to determine whether there is any evidence to suggest an infectious versus non-infectious process, the pleocytosis itself is not likely to aid in this distinction. Otherwise, the approach to a given patient with a CSF pleocytosis should be guided by the particular clinical, radiographic, and laboratory details that are uncovered. Although not meant to be all-encompassing, hopefully the discussion provided here will help to prevent any major diagnostic oversights.

REFERENCES 1. Conly JM, Ronald AR. Cerebrospinal fluid as a diagnostic body fluid. Am J Med 1983;75:102–108. 2. Bonadio WA. The cerebrospinal fluid: physiologic aspects and alterations associated with bacterial meningitis. Pediatr Infect Dis J 1992;11:423–431. 3. Dougherty JM, Roth RM. Cerebral spinal fluid. Emerg Med Clin North Am 1986;4:281–297. 4. Skipper BJ, Davis LE. Ascertaining hypoglycorrhachia in an acute patient. Am J Emerg Med 1997;15:378–380.

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5. Thomson RB, Jr., Bertram H. Laboratory diagnosis of central nervous system infections. Infect Dis Clin North Am 2001;15:1047–1071. 6. Lorber B. Listeriosis. Clin Infect Dis 1997;24:1–11. 7. Davis LE, DeBiasi R, Gonde DE, et al. West Nile virus neuroinvasive disease. Ann Neurol 2006;60:286–300. 8. Tyler KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters BK. CSF findings in 250 patients with serologically confirmed West Nile meningitis and encephalitis. Neurology 2006;66;361–365. 9. Miller RF, Fox JD, Thomas P, et al. Acute lumbosacral polyradiculopathy due to cytomegalovirus in advanced HIV infection: CSF findings in 17 cases. J Neurol Neurosurg Psychiatry 1996;61:456–460. 10. Berciano J, Berciano MT, Lafarga M. Cerebrospinal fluid pleocytosis with neutrophil leukocytes in Guillain-Barré syndrome. Eur J Neurol 2004;11:645–646. 11. Rodriguez SC, Olguin AM, Miralles CP, Viladrich PF. Characteristics of meningitis caused by Ibuprofen: report of 2 cases with recurrent episodes and review of the literature. Medicine (Baltimore) 2000;85;214–220. 12. Toltzis P. Viral encephalitis. Adv Pediatr Infect Dis 1991;6:111–136. 13. Rubeiz H, Roos RP. Viral meningitis and encephalitis. Semin Neurol 1992;12:165–177. 14. Ramers C, Billman G, Hartin M, Ho S, Sawyer MH. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 2000;283:2680–2685. 15. Yamamoto T, Nakamura Y. A single tube PCR assay for simultaneous amplification of HSV-1/-2, VZV, CMV, HHV-6A/-6B, and EBV DNAs in cerebrospinal fluid from patients with virus-related neurological diseases. J Neurovirol 2000;6:410–417. 16. Henquell C, Chambon M, Bailly JL, et al. Prospective analysis of 61 cases of enteroviral meningitis: interest of systematic genome detection in cerebrospinal fluid irrespective of cytologic examination results. J Clin Virol 2001;21:29–35. 17. Corless CE, Guiver M, Borrow R, et al. Development and evaluation of a “real-time” RT-PCR for the detection of enterovirus and parechovirus RNA in CSF and throat swab samples. J Med Virol 2002;67:555–562. 18. McGinnis MR. Detection of fungi in cerebrospinal fluid. Am J Med 1983;75:129–138. 19. Monteyne P, Sindic CJ. The diagnosis of tuberculous meningitis. Acta Neurol Belg 1995;95:80–87. 20. Pachner AR. Early disseminated Lyme disease: Lyme meningitis. Am J Med 1995;98:30S–43S. 21. Singh AE, Romanowski B. Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. Clin Microbiol Rev 1999;12:187–209. 22. Theodossiou C, Schwarzenberger P. Non-Hodgkin’s lymphomas. Clin Obstet Gynecol 2002;45:820–829. 23. Recht LD. Neurologic complications of systemic lymphoma. Neurol Clin 1991;9:1001–1015. 24. Moriarty AT, Wiersema L, Snyder W, Kotylo PK, McCloskey DW. Immunophenotyping of cytologic specimens by flow cytometry. Diagn Cytopathol 1993;9:252–258. 25. Whitcup SM, Stark-Vancs V, Wittes RE, et al. Association of interleukin-10 in the vitreous and cerebrospinal fluid and primary central nervous system lymphoma. Arch Ophthalmol 1997;115: 1157–1160. 26. Little JR, Dale AJ, Okazaki H. Meningeal carcinomatosis. Clinical manifestations. Arch Neurol 1974;30:138–143. 27. Glantz MJ, Cole BF, Glantz LK, et al. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer 1998;82:733–739. 28. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543–1554. 29. Stern BJ, Krumholz A, Johns C, Scott P, Nissim J. Sarcoidosis and its neurological manifestations. Arch Neurol 1985;42:909–917. 30. Borucki SJ, Nguyen BV, Ladoulis CT, McKendall RR. Cerebrospinal fluid immunoglobulin abnormalities in neurosarcoidosis. Arch Neurol 1989;46:270–273.

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31. Scott TF, Seay AR, Goust JM. Pattern and concentration of IgG in cerebrospinal fluid in neurosarcoidosis. Neurology 1989;39:1637–1639. 32. Kinnman J, Link H. Intrathecal production of oligoclonal IgM and IgG in CNS sarcoidosis. Acta Neurol Scand 1984;69:97–106. 33. Dale JC, O’Brien JF. Determination of angiotensin-converting enzyme levels in cerebrospinal fluid is not a useful test for the diagnosis of neurosarcoidosis. Mayo Clin Proc 1999;74:535. 34. Calabrese LH. Vasculitis of the central nervous system. Rheum Dis Clin North Am 1995;21:1059–1076. 35. Wynne PJ, Younger DS, Khandji A, Silver AJ. Radiographic features of central nervous system vasculitis. Neurol Clin 1997;15:779–804. 36. Stone JH, Pomper MG, Roubenoff R, Miller TJ, Hellmann DB. Sensitivities of noninvasive tests for central nervous system vasculitis: a comparison of lumbar puncture, computed tomography, and magnetic resonance imaging. J Rheumatol 1994;21:1277–1282. 37. Kadkhodayan Y, Alreshaid A, Moran CJ, Cross DT, Powers WJ, Derdeyn CP. Primary angiitis of the central nervous system at conventional angiography. Radiology 2004;233:878–882. 38. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–231. 39. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127. 40. Rudick RA, Schiffer RB, Schwetz KM, Herndon RM. Multiple sclerosis. The problem of incorrect diagnosis. Arch Neurol 1986;43:578–583. 41. Cepok S, Jacobsen M, Schock S, et al. Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 2001;124:2169–2176. 42. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59:499–505. 43. Krishnan C, Kaplin AI, Pardo CA, Kerr DA, Keswani SC. Demyelinating disorders: update on transverse myelitis. Curr Neurol Neurosci Rep 2006;6:236–243. 44. Pittock SJ, Lucchinetti CF. Inflammatory transverse myelitis: evolving concepts. Curr Opin Neurol 2006;19:363–368. 45. Jeffery DR, Mandler RN, Davis LE. Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Arch Neurol 1993;50: 532–535. 46. Deuskar NJ, Thakare JP, Gore MM, Wadia RS, Ghosh SN. Cerebrospinal fluid immunoglobulins in acute transverse myelitis. Indian J Med Res 1983;77:854–860.

47. Kesselring J, Miller DH, Robb SA, et al. Acute disseminated encephalomyelitis. MRI findings and the distinction from multiple sclerosis. Brain 1990;113(Pt 2):291–302. 48. Moris G, Garcia-Monco JC. The challenge of drug-induced aseptic meningitis. Arch Intern Med 1999;159:1185–1194. 49. Kuberski T. Eosinophils in cerebrospinal fluid: criteria for eosinophilic meningitis. Hawaii Med J 1981;40:97–98. 50. Lo Re V 3rd, Gluckman SJ. Eosinophilic meningitis. Am J Med 2003;114:217–223. 51. Huff DS, Neafie RC, Binder MJ, De Leon GA, Brown LW, Kazacos KR. Case 4. The first fatal Baylisascaris infection in humans: an infant with eosinophilic meningoencephalitis. Pediatr Pathol 1984;2: 345–352. 52. Fox AS, Kazacos KR, Gould NS, Heydemann PT, Thomas C, Boyer KM. Fatal eosinophilic meningoencephalitis and visceral larva migrans caused by the raccoon ascarid Baylisascaris procyonis. N Engl J Med 1985;312:1619–1623. 53. Cunningham CK, Kazacos KR, McMillan JA, Lucas JA, McAuley JB, Wozniak EJ, Weiner LB. Diagnosis and management of Baylisascaris procyonis infection in an infant with nonfatal meningoencephalitis. Clin Infect Dis 1994;18:868–872. 54. Stephenson J. Raccoon parasite an emerging health concern. JAMA 2002;288:2106, 2109–2110. 55. Ismail Y, Arsura EL. Eosinophilic meningitis associated with coccidioidomycosis. West J Med 1993;158:300–301. 56. Ragland AS, Arsura E, Ismail Y, Johnson R. Eosinophilic pleocytosis in coccidioidal meningitis: frequency and significance. Am J Med 1993;95:254–257. 57. Weingarten JS, O’Sheal SF, Margolis WS. Eosinophilic meningitis and the hypereosinophilic syndrome. Case report and review of the literature. Am J Med 1985;78:674–676. 58. Fasipe F, Bestak M, Green NS. Recurrent central nervous system acute lymphoblastic leukemia associated with cerebrospinal fluid eosinophilia and basophilia: a proposed cytokine-mediated mechanism. Pediatr Hematol Oncol 2003;20:31–37. 59. Budka H, Guseo A, Jellinger K, Mittermayer K. Intermittent meningitic reaction with severe basophilia and eosinophilia in CNS leukaemia. J Neurol Sci 1976;28:459–468. 60. Courtade M, Viguier A, Sailler L, Busato F, Corberand J, Caratero C. Varicella-zoster virus basophilic meningitis: a case report. Cytopathology 2003;14:91–92. 61. Anderson NE, Willoughby EW. Chronic meningitis without predisposing illness — a review of 83 cases. Q J Med 1987;63:283–295.

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Approach to the Patient with Abnormal Cerebrospinal Fluid Glucose Content Brett M. Morrison

INTRODUCTION As with many other tissues, glucose is the principal source of energy for the brain. Without it, the brain must switch to using ketones to fuel its metabolic requirements. This switch is less efficient for most biochemical reactions and often leads to a situation where energy demands outstrip energy supplies. Disorders that reduce cerebrospinal fluid (CSF) glucose content, the main source of brain glucose, can thus have many deleterious effects on central nervous system (CNS) function. For this reason, mechanisms of glucose entry into the CNS are important to understand, not the least because they may provide eventual therapeutic targets to mitigate neural injury. This chapter will review the mechanisms involved in glucose influx into and efflux from the CSF, and then cover common clinical conditions where low CSF glucose levels are known to occur. Elevated CSF glucose concentrations will not be specifically addressed, as this state has no known pathological significance for the CNS and occurs only in the setting of elevated serum glucose levels. It should also be kept in mind that the rationale behind determining a CSF:serum glucose ratio is that normal or even elevated absolute CSF glucose levels may still be pathologically low in the setting of significant hyperglycemia.

MECHANISMS OF NORMAL CSF GLUCOSE INFLUX AND EFFLUX Glucose is a polar molecule that is soluble in water but unable to pass through lipid membranes. For this reason, it requires a transmembrane carrier in order to cross the blood–brain barrier (BBB). The choroid plexus is the primary site of glucose transport into the CSF, and the main transmembrane protein that mediates this transport process from blood is the glucose transporter type 1 (GLUT1). GLUT1 belongs to a family of 12 glucose transporters, but

is the only one present in the choroid plexus.1 This makes it the sole means of transporting glucose into the CSF. Transport is an energy-independent process, as glucose actually moves down a concentration gradient. This contrasts with glucose transport into other tissues such as the intestinal tract, renal tubules, and skeletal muscle that requires co-transport with sodium ions (Na+) in order to concentrate glucose at levels higher than in blood. These other transporters require the establishment of a Na+ gradient to drive the co-transporter for Na+ and glucose, and this gradient is generated by the energy-dependent Na+/K+ ATPase.1 The GLUT1 gene encodes a protein with a predicted structure having 12 transmembrane domains, thus providing a physical pore through which glucose can pass into the CSF. Evidence for the central role of GLUT1 in this transport process comes from studies of patients with glucose transporter deficiency resulting from mutation of the GLUT1 gene.2,3 To date, some 30 different mutations have been found in individuals with this disorder.1 These patients typically present with epilepsy, developmental delay, acquired microcephaly, incoordination, and spasticity in infancy.1,4 On laboratory testing, they typically have CSF glucose levels in the range of 30 mg/dl, but uniformly have normal CSF lactate levels. As will be discussed below, the ratio of CSF to serum glucose concentration is the most sensitive measure of decreased CSF glucose levels, and this ratio is markedly reduced in patients with GLUT1 deficiency. These findings suggest that other transporters do not meaningfully compensate for the absence of GLUT1, and that GLUT1 is the primary, if not the sole, glucose transporter into the brain.1,4 Because glucose transport into the CSF is energyindependent, it requires a concentration gradient to move between blood and CSF. In normal human subjects, the expected ratio of CSF to serum glucose is approximately 0.6, and this ratio remains constant through a large range of serum glucose levels.5,6 Still, at very high serum glucose levels, GLUT1-facilitated transport becomes saturated and

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the CSF:serum glucose ratio falls. Thus, it may reach 0.5 with serum glucose concentrations of 500 mg/dl, and it can slip to 0.4 when the serum glucose level approaches 700 mg/dl.7 Clinicians should also recognize that fluctuations in serum glucose concentrations do not translate into immediate changes in CSF glucose levels. Rather, these changes may take up to 4 h to reach equilibrium.8 The CSF:serum glucose ratio is therefore also determined by the kinetics of glucose influx and efflux through the basolateral and apical membranes of the choroid plexus.6 From the CSF, glucose moves down another concentration gradient into the interstitial fluid of the brain and finally into neurons, which themselves have very low levels of free glucose due to their rapid aerobic metabolism.9 In this way, much of the glucose present in the CSF is absorbed into the CNS parenchyma. Any remaining glucose returns to the bloodstream with other CSF components at the arachnoid granulations and along the extracranial lymphatics via bulk flow resorptive mechanisms.

concentrations, suggesting that increased anaerobic glycolysis by cellular elements in close proximity to the CSF is responsible for these shifts.12 Increased CNS glucose utilization can occur as a result of higher metabolic demands by neurons or glial cells, or via increased consumption by infectious pathogens, tumor cells, or inflammatory cells that infiltrate the meninges or the brain. Indeed, most experimental data that address this issue in purulent meningitis models point to leukocytes or the effects of leukocyte products on adjacent neural cells, rather than the bacteria themselves, as the main cause of increased CSF glucose utilization.13 Thus, while total change in CSF glucose level may be determined by multiple overlapping or even divergent mechanisms in any given disease state, the frequent association of elevated CSF lactate with low CSF glucose strongly supports increased utilization as the main determinant of this change.

Meningeal infections ABNORMAL CSF GLUCOSE LEVELS IN DISEASE STATES Unlike elevations in CSF protein concentration or high CSF cell counts, the differential diagnosis for a patient with a low CSF:serum glucose ratio is quite limited. This ratio, rather than the actual concentrations themselves, is critical, as it remains constant through a wide range of serum glucose levels in normal subjects. Reduced CSF:serum glucose ratios are always abnormal, and levels below 0.5 require immediate evaluation. Pathologies that produce low CSF:serum glucose ratios, including infections, cancer, and certain inflammatory diseases, all share a prominent diffuse meningeal component of disease.

Mechanisms underlying decreased CSF glucose levels A reduced CSF:serum glucose ratio can occur due to impaired glucose transport into the CSF or as a result of increased glucose utilization within the CNS. Reduced transport is mostly found in patients with hereditary GLUT1 dysfunction,1 but early experimental studies in animal models of meningitis suggested that active glucose transport across the BBB becomes impaired as the infections progress.8,10,11 In these same experimental models, however, this impaired active CNS glucose entry was more than overcome by a passive diffusion of glucose from the blood due to BBB breakdown.8,10,11 Thus, impaired transport seems only conceivable as an explanation for low CSF glucose levels in the setting of an intact BBB and no concomitant evidence of increased utilization. More recent investigations have demonstrated that measured drops in CSF and brain interstitial glucose levels are commonly accompanied by increased CSF lactate

Meningitis caused by bacteria, fungi, and tuberculosis commonly reduces the CSF:serum glucose ratio. Certain parasitic and viral infections of the CNS may less frequently lower this parameter. Most cases of bacterial meningitis in adults are caused by Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes. Infants also develop bacterial meningitis from group B streptococci and Escherichia coli. With the possible exception of Listeria, CSF analysis in untreated cases of acute bacterial meningitis in adults almost uniformly demonstrates a CSF:serum glucose ratio below 0.33. In the classic series of Merritt and Fremont-Smith, only 22 of 154 patients (14%) had CSF glucose levels above 50 mg/dl, and 35 of 154 patients (23%) had levels below 10 mg/dl.14 Likewise, in one Canadian study, 72 of 103 patients (70%) had CSF glucose concentrations less than 50 mg/dl; most of the remaining patients turned out to have listerial meningitis.15 Other case series confirm that CSF glucose levels below 20 mg/dl are common.16 Regarding the predictive value of low CSF glucose levels, a CSF:serum glucose ratio less than 0.23 in patients with acute meningitis was found to have a positive predictive value of greater than 99% for a bacterial process.17 Indeed, a glucose concentration this low may be more predictive of disease than an absolute value of 40 mg/dl, a level previously considered a more reliable cutoff.18 In terms of outcome, most studies have concluded that the CSF glucose level does not carry any major predictive value.17 As a marker of treatment response, one study of 116 children with Haemophilus influenzae meningitis showed that low CSF glucose levels returned to normal in most patients within 48 h of initiating antibiotic treatment.19 Occasional reports, however, suggest that the CSF glucose level may remain depressed for 7–10 days after other parameters have returned to normal.13 Given that some 15% of patients with acute bacterial meningitis can have CSF glucose levels above 50 mg/dl,13,14 it must be

Abnormal CSF Glucose Levels in Disease States

concluded that a reduced CSF glucose level is not always a sensitive indicator of disease. Therefore, other CSF characteristics such as the presence of neutrophils should also be used to predict a bacterial process. Other bacterial pathogens that cause more chronic forms of meningitis include Borrelia burgdorferi and Treponema pallidum, the agents of Lyme disease and syphilis, respectively. Although CSF glucose levels in these infections are not typically altered to the same degree as in acute bacterial meningitis, patients with Lyme meningitis as a group have significantly lower CSF glucose concentrations than those with meningitis due to viral causes.20 Indeed, a study from Sweden reported that 33% of patients with chronic Lyme meningitis had a CSF:serum glucose ratio below 0.5.21 Similarly, some 40–45% of patients with syphilitic meningitis may have reduced CSF glucose levels as defined by concentrations that fall below 40 mg/dl.14,22 More recent studies have clarified that reduced CSF glucose levels occur more commonly in neurosyphilis patients who are co-infected with HIV.22,23 The CSF glucose levels in this group were almost 50% lower when compared with those found in patients without HIV co-infection.22 With the exception of immunocompromised patients and neonates, fungal meningitis is rare. Many fungi can cause meningitis, but case reports that include data on CSF glucose levels are infrequent. In general, these infections cause a moderate decrease in CSF glucose levels to the 20–40 mg/dl range in a half to two-thirds of patients, although this parameter can be normal early in the course of infection and may never decline in a proportion of patients.13 In one published series of neonatal candidal meningitis, Fernandez et al. noted that most cases had CSF glucose levels in the normal range, with a mean of 95 mg/dl; only five of 21 infants had CSF glucose levels below 45 mg/dl.24 This study, however, did not report on concurrent serum glucose levels and therefore the CSF:serum glucose ratio could not be calculated. In contrast, two earlier case series of candidal meningitis in adults demonstrated the potential for decreased CSF glucose levels during these infections.25,26 Other CNS fungal infections that commonly depress CSF glucose levels include coccidioidal and cryptococcal meningitis.27,28 In patients with AIDS, however, cryptococcal infection of the CNS can be associated with completely normal CSF findings.28 In the USA, tuberculous meningitis occurs most commonly in children and immunocompromised adults. This infection characteristically, but not invariably, depresses the CSF glucose level. In one study of children with this disorder, the mean CSF:serum glucose ratio was determined to be 0.29.29 In another report of 100 patients admitted with CSF culture-positive Mycobacterium tuberculosis infection, the mean admission CSF glucose level was 23 mg/dl.30 As with acute bacterial meningitis, there is no convincing evidence to suggest that this CSF parameter impacts on clinical outcome from infection.13 As a predictive indicator, however, a low CSF glucose level in combination with a

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lymphocytic pleocytosis and an elevated CSF opening pressure should lead to the initiation of therapy for presumptive tuberculous meningitis.31 Up to 80% of viral meningitis cases are caused by enteroviruses, although a large number of other viral pathogens can also cause acute aseptic meningitis. Although cytomegalovirus, lymphocytic choriomeningitis virus, and mumps virus may be exceptions, the vast majority of viral meningitis cases do not have altered CSF glucose levels.32,33 In one study of 43 cases of acute aseptic meningitis in Germany, not a single occurrence of a reduced CSF glucose level was demonstrated.34 In another study of acute meningitis, only 3.7% of aseptic cases demonstrated a reduced CSF glucose level.35 Still, it should probably be kept in mind that the CSF in very early viral meningitis sometimes demonstrates a low CSF glucose level as a result of neutrophils that may be a transient component of the inflammatory infiltrate. Empiric antibiotic coverage until CSF culture results are available is justified in this situation.

Malignancy With an incidence of 3–5%, carcinomatous meningitis is not an uncommon complication of many malignant tumors.36 The cancers most associated with such meningeal involvement include gliomas, sarcomas, lymphomas, leukemias, melanomas, and adenocarcinomas.37,38 Carcinomatous meningitis is diagnosed by demonstrating the presence of tumor cells in the CSF, although a single lumbar puncture will have positive cytology in only about 50% of cases. Still, if a single lumbar puncture demonstrates a normal opening pressure, cell count, protein and glucose level, and a negative cytology, the probability of having leptomeningeal metastases has been estimated to be less than 5%.39 Given these data, it is important to thoroughly analyze the CSF in a patient with possible carcinomatous meningitis. As had been reported previously,36,40,41 a recent review demonstrated reduced CSF glucose levels in approximately 40% of patients with carcinomatosis meningitis.38 Further support for the diagnostic utility of this parameter comes from a treatment study that found increasing CSF glucose levels were a sign of a positive treatment response.42 Similar to the mechanisms invoked with infectious pathogens, tumor cells are highly metabolically active and appear to depress CSF glucose concentrations by increasing utilization of this substrate at the expense of brain and CSF levels.

Non-infectious inflammatory disorders In addition to infectious pathogens and tumor cells, metabolically active inflammatory cells that collect in the subarachnoid space may also lead to reduced CSF glucose levels. This inflammation can be either primary, such as in systemic lupus erythematosus (SLE) with CNS involvement or in neurosarcoidosis,43 or secondary to such processes as

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Table 31-1 Expected Changes in CSF Glucose Concentration with Various Infectious, Inflammatory, or Neoplastic Disorders of the CNS

Disease Bacterial meningitis Syphilitic meningitis –without HIV –with HIV/AIDS Lyme disease Fungal meningitis TB meningitis Viral meningitis Leptomeningeal carcinomatosis Systemic lupus erythematosus Neurosarcoidosis Subarachnoid hemorrhage

Patients (%) with Low CSF Glucose Concentration (<40 mg/dl or CSF:Serum Ratio <0.33)

Mean CSF Glucose Concentration or CSF:Serum Ratio

Expected Range of CSF Glucose Concentration

References

70–95%

27–44 mg/dl

1–89 mg/dl

13–16,35,53

20–42% 35–43% 12–15% 42–60% 74–100%

46 mg/dl 38 mg/dl 58 mg/dl 32–41 mg/dl 23 mg/dl 0.29 0.59

10–87 mg/dl 11–67 mg/dl 20–120 mg/dl 7–76 mg/dl 8–100 mg/dl 0.02–0.61 15–100 mg/dl 0.45–0.90 1–132 mg/dl 34–109 mg/dl 22–79 mg/dl 24–87 mg/dl

13,14,22,54 13,22,2 13,20,21 13,24,25,28 13,29–31 13,29,35 13,34,35,52 34,52 36,38,41 13,43,46 13,47 14,44,48,49 13,44

0–4% 47–56% 8% 18% 12%

subarachnoid hemorrhage or chemical meningitis.44,45 Gibson and Meyers found that 8% of SLE patients with involvement of the nervous system had CSF glucose levels of less than 45 mg/dl.46 Similarly, in a study of 57 patients with neurosarcoidosis, 18% had CSF glucose levels that were measured below 40 mg/dl.47 Finally, by combining the results of three separate studies of non-traumatic subarachnoid hemorrhage, one can conclude that approximately 12% of patients develop a transiently depressed CSF glucose level immediately following the bleeding event.21,48,49 In most of these cases, the sugar concentration reached a nadir 4–8 days after the ictus, and was typically back in the normal range within 2–3 weeks.49 In addition, low CSF glucose was reported in a patient who developed aseptic meningitis after having received two intrathecal injections of methylprednisolone.50 The mechanism of reduced glucose in the CSF of patients with either primary or secondary inflammation is likely similar to that of infections and tumors, involving consumption of glucose by metabolically active inflammatory cells with or without increased anaerobic glycolysis by the adjacent CNS tissue.

CONCLUSIONS As described throughout this chapter and as summarized in Table 31-1, there are a number of other causes of reduced CSF glucose levels in addition to acute bacterial meningitis. Although still somewhat controversial and not universally accepted within the scientific community, most studies suggest that increased glucose utilization is the primary mechanism that causes lowering of CSF glucose concentrations. Thus, while reduced glucose transport has been observed in some experimental models of meningitis, this deficit is more than made up by increased passive influx

44 mg/dl 51–58 mg/dl 44 mg/dl 59 mg/dl 0.43

across a disrupted BBB.8 In addition, the elevated CSF lactate level that commonly accompanies a low CSF glucose level strongly suggests that increased anaerobic metabolism contributes to these changes. Instead of absolute concentration, a reduced CSF:serum glucose ratio is the most important diagnostic parameter that can be followed. Low brain glucose levels are deleterious to neuronal and axonal function and survival,51 and thus it is important to continue investigation into the mechanisms that regulate CSF and brain glucose content.

REFERENCES 1. Pascual JM, Wang D, Lecumberri B, et al. GLUT1 deficiency and other glucose transporter diseases. Eur J Endocrinology 2004;150:627–633. 2. De Vivo DC, Trifiletti RR, Jacobsen RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325:703–709. 3. Seidner G, Alvarez MG, Yeh JI, et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain hexose carrier. Nature Genetics 1998;18:188–191. 4. Klepper J. Impaired glucose transport into the brain: the expanding spectrum of glucose transporter type 1 deficiency syndrome. Curr Opin Neurol 2004;17:193–196. 5. Fishman RA. Studies of the transport of sugars between blood and cerebrospinal fluid in normal states and in meningeal carcinomatosis. Trans Am Neurol Assoc 1963;88:114–118. 6. Redzic ZB, Segal MB. The structure of the choroid plexus and the physiology of the choroid plexus epithelium. Adv Drug Delivery Rev 2004;56:1695–1716. 7. Powers WJ. Cerebrospinal fluid to serum glucose ratios in diabetes mellitus and bacterial meningitis. Am J Med 1981;71:217–220. 8. Fishman RA. Carrier transport of glucose between blood and cerebrospinal fluid. Am J Physiol 1964;206:836–844. 9. Csaky TZ, Rigor BM. A concentrative mechanism of sugars in the choroid plexus. Life Sci 1964;18:931–936.

References

10. Prockop LD, Fishman RA. Experimental pneumococcal meningitis. Arch Neurol 1968;19:449–455. 11. Menkes JH. The causes for low spinal fluid sugar in bacterial meningitis: another look. Pediatrics 1969;44:1–3. 12. Guerra-Romero L, Tauber MG, Fournier MA, Tween JH. Lactate and glucose concentrations in brain interstitial fluid, cerebrospinal fluid, and serum during experimental pneumococcal meningitis. J Infect Dis 1992;166:546–550. 13. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992. 14. Merritt HH, Fremont-Smith R. The Cerebrospinal Fluid. Philadelphia: WB Saunders; 1938. 15. Hussein AS, Shafran SD. Acute bacterial meningitis in adults: a 12-year review. Medicine 2000;79:360–368. 16. Bonsu BK, Harper MB. Accuracy and test characteristics of ancillary tests of cerebrospinal fluid for predicting acute bacterial meningitis in children with low white blood cell counts in cerebrospinal fluid. Acad Emerg Med 2005;12:303–309. 17. Spanos A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989;262:2700–2707. 18. Silver TS, Todd JK. Hypoglycorrhachia in pediatric patients. Pediatrics 1976;58:67–71. 19. Valmari P, Peltola H, Kataja M. Cerebrospinal fluid white cell, glucose and protein changes during the treatment of Haemophilus influenzae meningitis. Scand J Infect Dis 1986;18:39–43. 20. Lakos A. CSF findings in Lyme meningitis. J Infect 1992;25:155–161. 21. Stiernstedt GT, Skoldenberg BR, Vandvik B, et al. Chronic meningitis and Lyme disease in Sweden. Yale J Biol Med 1984;57:491–497. 22. Katz DA, Berger JR, Duncan RC. Neurosyphilis. A comparative study of the effects of infection with human immunodeficiency virus. Arch Neurol 1993;50:243–249. 23. Carmo RA, Moura AS, Christo PP, Morandi AC, Oliveira MS. Syphilitic meningitis in HIV-patients with meningeal syndrome: report of two cases and review. Brazilian J Infect Dis 2001;5:280–287. 24. Fernandez M, Moylett EH, Noyola DE, Baker CJ. Candidal meningitis in neonates: a 10-year review. Clin Inf Dis 2000;31:458–463. 25. Bayer AS, Edwards JE, Seidel JS, Guze LB. Candida meningitis. Report of seven cases and review of the English literature. Medicine (Baltimore) 1976;55:477–486. 26. Voice RA, Bradley SF, Sangeorzan JA, Kauffman CA. Chronic candidal meningitis: an uncommon manifestation of candidiasis. Clin Infect Dis 1994;19:60–66. 27. Johnson RH, Einstein HE. Coccidioidal meningitis. Clin Infect Dis 2006;42:103–107. 28. Bicanic T, Harrison TS. Cryptococcal meningitis. Br Med Bull 2005;72:99–118. 29. Farinha NJ, Razali KA, Holzel H, Morgan G, Novelli VM. Tuberculosis of the central nervous system in children: a 20 year survey. J Infect 2000;41:61–68. 30. Kilpatrick ME, Girgis NI, Yassin MW, Abu el Ella AA. Tuberculous meningitis – clinical and laboratory review of 100 patients. J Hyg (Lond) 1986;96:231–238. 31. Leonard JM, Des Prez RM. Tuberculous meningitis. Infect Dis Clin North Am 1990;4:769–787. 32. Jacobson RE. Hypoglycorrhachia in mumps meningoencephalitis. N Engl J Med 1969;280: 1362.

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33. Ratzan KR. Viral meningitis. Med Clin North Am 1985;69: 399–413. 34. Nowak DA, Boehmer R, Fuchs H-H. A retrospective clinical, laboratory, and outcome analysis in 43 cases of acute aseptic meningitis. Eur J Neurol 2003;10:271–280. 35. Karandanis D, Shulman JA. Recent survey of infectious meningitis in adults: review of laboratory findings in bacterial, tuberculosis, and aseptic meningitis. South Med J 1976;69:449–457. 36. Zeller JA, Zunker P, Witt K, Schlueter E, Deuschl G. Unusual presentation of carcinomatous meningitis: case report and review of typical CSF findings. Neurol Res 2002;24:652–654. 37. Budka H, Pilz P, Guseo A. Primary leptomeningeal sarcomatosis. Clinicopathological report of six cases. J Neurol 1975;211: 77–93. 38. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999;25:103–119. 39. Reuler JB, Meier D. Leptomeningeal carcinomatosis with normal CSF features. Arch Intern Med 1979;139:237–238. 40. Sumi SM, Leffman H. Primary intracranial leptomeningeal glioma with persistent hypoglycorrhachia. J Neurol Neurosurg Psych 1968;31:190–194. 41. Balm M, Hammach J. Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol 1996;53:626–632. 42. Fathallah-Shaykh HM, Zimmerman C, Morgan H, Rushing E, Schold SC, Unwin DH. Response of primary leptomeningeal melanoma to intrathecal recombinant interleukin-2. A case report. Cancer 1996;77:1544–1550. 43. Provenzale J, Bouldin TW. Lupus-related myelopathy: report of three cases and review of the literature. J Neurol Neurosurg Psych 1992;55:830–835. 44. Vincent FM. Hypoglycorrhachia after subarachnoid hemorrhage. Neurosurgery 1981;8:7–14. 45. Dughly ME, Dhopesh VP. Hypoglycorrhachia does not necessarily indicate infection. Br J Clin Pract 1989;43:182–183. 46. Gibson T, Meyers AR. Nervous system involvement in systemic lupus erythematosus. Ann Rheum Dis 1976;35:398–406. 47. Gaines JD, Eckman PB, Remington JS. Low CSF glucose level in sarcoidosis involving the central nervous system. Arch Intern Med 1970;125:333–336. 48. Medonick MJ, Savitsky N. Spinal fluid sugar in subarachnoid hemorrhage. J Nerv Ment Dis 1948;108:45–53. 49. Troost BT, Walker JE, Cherington M. Hypoglycorrhachia associated with subarachnoid hermorrhage. Arch Neurol 1968;19:438–442. 50. Plumb VJ, Dismukes WE. Chemical meningitis related to intrathecal corticosteroid therapy. South Med J 1977;70:1241–1243. 51. Dolinak D, Smith C, Graham DI. Hypoglycaemia is a cause of axonal injury. Neuropathol Appl Neurobiol 2000;26:448–453. 52. Bottner A, Daneschnejad S, Handrick W, Schuster V, Liebert UG, Kiess W. A season of aseptic meningitis in Germany: epidemiologic, clinical and diagnostic aspects. Pediatr Infect Dis J 2002;21: 1126–1132. 53. Gieseler PJ, Nelson KE, Levin S, Reddi KT, Moses VK. Communityacquired purulent meningitis: A review of 1316 cases during antibiotic era, 1954–1976. Rev Infect Dis 1980;2:725–745. 54. Traviesa DC, Prystowsky SD, Nelson BJ, Johnson KP. Cerebrospinal fluid findings in asymptomatic patients with reactive fluorescent treponemal antibody absorption tests. Ann Neurol 1978;4:524–530.

CHAPTER

32

Approach to the Patient with Abnormal Cerebrospinal Fluid Protein Content Jaishri Blakeley and David N. Irani

INTRODUCTION Increased cerebrospinal fluid (CSF) total protein concentration has been recognized as an indicator of pathology in the nervous system for as long as the lumbar puncture (LP) has been part of routine clinical practice. Although relatively nonspecific, it is a sensitive marker of disease and carries great diagnostic importance.1 Advances in neuroimaging, identification of novel genetic markers, and development of new molecular diagnostics and proteomic methods to assess both CSF and serum are all under active investigation to improve diagnostic accuracy for common and clinically challenging neurological diseases. The recent surge of interest in proteomic methods and molecular diagnostics, in particular, has reaffirmed the importance of evaluating CSF proteins in many of these conditions. This chapter will review the interpretation of abnormal CSF protein values in many neurological disease states. Consideration of such findings will first be framed in the context of what proteins are normally present in the CSF and where they derive from, and then how and why protein levels change in the setting of different types of nervous system pathology.

PROTEIN CONTENT OF NORMAL CEREBROSPINAL FLUID Normal CSF values The protein composition of normal CSF was extensively reviewed in Chapter 10. To assist in the review of common clinical situations associated with altered CSF protein levels, however, some of these data will be readdressed here. First, the mean total protein concentration of lumbar CSF reported in various studies of both normal volunteers and patients with otherwise unremarkable diagnostic evaluations ranges between 23 and 38 mg/dl.1–6 The lower and upper limits of this normal range (2.0 standard deviations in either

direction) extend from 9 to 58 mg/dl.1–6 Defined normal values are based on these data but can also vary from institution to institution; it is imperative that the clinician be familiar with those set for the clinical laboratory being used. Furthermore, it should be remembered that limitations in the accuracy of current methodologies generate differences of up to 5% from measurement to measurement.1 Physiological variables known to influence CSF protein content include the developmental maturity of the host (levels are typically lower in infants and young children) and the site along the neuroaxis from where the sample was obtained. In general, total protein concentrations are lowest within the ventricles, higher in the cisterna magna, and highest in the lumbar thecal sac. All of these factors must be considered when interpreting measured values in a given patient.

Normal sources of CSF proteins Most proteins found in normal CSF are derived from the serum, although some are synthesized by the choroid plexus or within the brain itself. The passage of serum proteins across the blood–brain barrier (BBB) or the blood– CSF barrier (BCB) depends largely on their pinocytosis through capillary endothelial cells or across the choroid plexus epithelial barrier. In most circumstances, the CSF: serum concentration ratio of a given protein originating from the serum is dictated by its size (hydrodynamic radius more so than molecular weight) and to some degree by its charge.1,7,8 On the other end, proteins leave the CSF compartment by passing across the arachnoid granulations as CSF is absorbed via macrovesicular transport. Thus, at steady state, because the net concentration of protein in serum is some 200-fold greater than it is in CSF (~7.0 gm/dl versus ~35 mg/dl), the protein efflux rate must be 200-times the influx rate. This equilibrium takes some time to achieve. For example, one study showed that radiolabeled γ-globulin infused intravenously into humans took 3–6 days to reach a stable concentration in lumbar CSF.9

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Approach to Abnormal CSF Protein Content

Other less abundant protein constituents of CSF are either made at the choroid plexus (e.g., transthyrein, transferrin), or derive from various neural cells themselves (e.g., tau protein, myelin basic protein, glial fibrillary acidic protein) (Table 32-1). Some of these proteins can be measured at very low levels in serum due to their efflux via normal CSF absorption. In general, stable CSF levels over time indicate that such proteins are actively and continuously produced within the central nervous system (CNS). Numerous studies have attempted to link altered production or release of these CNS-derived proteins into CSF with various pathological states, but none has achieved any significant clinical utility to date. Although specific proteins change their concentration in the setting of neurological disease, there is little evidence that any CNS disease causes a change in the synthesis of CNS-derived proteins that is measurable at the level of total protein content. In other words, changes in total CSF protein levels seen in disease states are driven largely by disrupted protein migration (altered influx and efflux rates) rather than altered brain production. Excessive release of intracellular proteins from neural cells into CSF, however, can sometimes be used as an indicator of cellular pathology.

Normal protein constituents of CSF While CSF and serum express many proteins in similar proportions, previous electrophoresis studies have demonstrated some notable differences.8,10 The most apparent changes are a prominent prealbumin (transthyretin) peak in CSF not typically seen in serum, a distinct tau fraction in Table 32-1 Specific Proteins in the Cerebrospinal Fluid and Some Neurological Disorders Associated with Them Protein

Associated Condition

Neuronal and Glial Proteins Tau NSE S-100 beta 14-3-3

AD, PD, FTD, intracranial hemorrhage, encephalitis CJD, head trauma Hypoxia, head trauma, CJD, MS CJD, TM, MS, stroke, head trauma

Leptomeningeal Proteins Beta-trace Cystatin C

CSF leak HIV dementia, ALS

MS, chronic HIV Lyme disease, CNS lymphoma

Other Serum Proteins Transthyretin ACE

CHANGES TO AND SOURCES OF CEREBROSPINAL FLUID PROTEINS IN NEUROLOGICAL DISEASE Low CSF total protein levels When CSF protein levels fall below the lower limit of normal (usually considered to be less than 20 mg/dl), it almost invariably occurs as a result of accelerated protein efflux out of the CSF compartment. Even severe declines in total serum protein levels to below 4.0 gm/dl do not appreciably reduce CSF protein concentrations.1 Common situations in which lumbar CSF protein values may fall below 20 mg/dl include normal infants and children less than 2 years of age, or in adult patients with acute water intoxication, untreated hyperthyroidism, idiopathic intracranial hypertension (pseudotumor cerebri), certain forms of leukemia, and after undergoing large-volume CSF drainage procedure or in the setting of a persistent CSF leak (Table 32-2).1,17,18 Increased intracranial pressure is

Table 32-2 Common Causes of Low Cerebrospinal Fluid Total Protein Concentration Physiological

Immune Surveillance Proteins IgG IgM

CSF that appears between the beta and gamma peaks (also not found in serum), a proportionally lower γ-globulin fraction in CSF, and very low levels of glycoproteins and lipoproteins in the CSF compared to serum.1,10 More recently, highly sensitive proteomic methodologies have been used to separate CSF proteins for identification and quantification in a much more rigorous manner.11,12 Although results vary based on the particular analysis method used and the quality of the samples being analyzed, more than 2,500 unique proteins have been identified in human CSF samples.13–15 At this level of resolution, however, many of these individual proteins are not expressed in every specimen. Thus, fewer than 10% of the proteins identified in one study were common to all samples analyzed.13 This suggests that the protein constituents of CSF can be highly variable from person to person, even when total protein concentrations are similar. The most common CSF proteins are discussed in greater detail in Chapter 10. The reader is also referred to a scholarly text on the subject.16

ALS Sarcoidosis

NSE, neuron-specific enolase; ACE, angiotensin converting enzyme; AD, Alzheimer’s disease; PD, Parkinson’s disease; FTD, frontotemporal dementia; CJD, Creutzfeldt-Jakob disease; MS, multiple sclerosis; TM, transverse myelitis; HIV, human immunodeficiency virus; ALS, amyotrophic lateral sclerosis.

Infants and children <2 years of age Pathophysiological Acute water intoxication Untreated hyperthyroidism Idiopathic intracranial hypertension (pseudotumor cerebri) Leukemic meningitis Large volume CSF drainage (iatrogenic) Persistent CSF leak Increased intracranial pressure

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Changes to and Sources of Cerebrospinal Fluid Proteins in Neurological Disease

believed to cause low CSF protein levels by accelerating the rate of bulk CSF efflux across the arachnoid granulations without affecting the rate of protein influx from serum.1

It is more common with lower rather than upper spinal lesions (i.e., more concentrated loculations), and it can occur with any form of intramedullary or extramedullary pathology that causes complete spinal block. The total protein content of CSF may sometimes be elevated without obvious disruption of the BBB or BCB. For example, patients with diabetic neuropathy (particularly those with polyradiculoneuropathy) are known to have CSF protein levels ranging as high as 224 mg/dl.1 No clear focal BBB disruption has ever been identified in this situation, and altered protein handling may be responsible rather than the diabetes mellitus itself. However, there is increasing evidence that some diabetes-related neuropathies (particularly the proximal neuropathies) may have an inflammatory component as they are clinically very similar to chronic inflammatory demyelinating polyneuropathy (CIDP) (including elevated CSF protein).21 Finally, CSF protein may be elevated in the setting of blood in the subarachnoid space. This can occur in the setting of intracranial hemorrhages or, far more commonly, in the setting of a traumatic LP where blood has been inadvertently introduced into the CSF sample. In these cases, an estimate that the protein concentration will be elevated by 1 mg/dl for every 100 red blood cells/mm3 has been proposed to ‘correct’ for the effect of RBC on the total CSF protein concentration value. These changes are more fully described in Chapter 29.

Increased CSF total protein levels Elevations in total CSF protein content can range from mild (50–75 mg/dl) to extreme (>1,000 mg/dl), and such changes have been reported in a wide variety of neurological disorders (Table 32-3). Particularly common are conditions causing increased BBB or BCB permeability in the setting of normal or impaired protein absorption from CSF back into the systemic circulation. Indeed, rising CSF protein levels may themselves slow further protein absorption in a positive-feedback loop. This mechanism likely contributes to the dramatic CSF protein elevation seen in various forms of purulent meningitis.1,19 In addition to meningitis, extreme elevations in CSF total protein content occur with spinal arachnoiditis and spinal cord tumors causing complete spinal block. Froin’s syndrome occurs whenever there is loculated CSF (typically found below the level of a block) that is prone to clotting in the tube after it is removed from the subarachnoid space.20 This finding reflects the passage of sufficient fibrinogen from the serum into the CSF to permit clotting, and it typically occurs only when total protein concentration exceeds 1,000 mg/dl.

Table 32-3 Total Protein Content of Lumbar CSF From 4,157 Patients with Various Common Neurological Disorders Normal (n) Diagnosis (n) Purulent meningitis (157) Tuberculous meningitis (253) Poliomyelitis (158) Neurosyphilis (890) Brain tumor (182) Spinal cord tumor (36) brain abscess (33) Aseptic meningitis (81) Multiple sclerosis (151) Polyneuritis (211) Idiopathic epilepsy (793) Cerebral thrombosis (300) Cerebral hemorrhage* (247) Uremia (53) Myxedema (51) Head trauma† (474) Acute alcoholism (87) Total (4157)

<45 mg/dl 3 2 74 412 56 5 9 37 102 107 710 199 34 31 12 255 80 2158

Increased (n) 45−75 mg/dl 7 30 44 258 45 4 15 20 36 33 80 78 41 13 28 84 5 821

75−100 mg/dl 12 37 16 102 22 3 3 7 9 17 2 13 32 8 3 43 2 331

100−500 mg/dl 100 172 24 117 57 14 6 17 4 44 1 10 95 1 8 73 0 743

Range (mg/dl) >500 mg/dl 32 12 0 1 2 10 0 0 0 10 0 0 45 0 0 19 0 134

Low

High

21 25 12 15 15 40 16 11 13 15 7 17 19 19 30 10 13

2220 1142 366 4200 1920 3600 288 400 133 1430 200 267 2110 143 242 1820 88

Average 418 200 70 68 115 425 69 77 43 74 31 46 270 57 71 100 32

*Usually the first of several CSF results reported. †Usually due to the admixture of blood in the CSF. (Adapted from Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992; and Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: W.B. Saunders; 1938.)

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Pathological patterns of CSF proteins Modern protein analysis methodologies are moving ever closer to the goal of finding specific CSF protein expression profiles (i.e., biomarkers) that occur in particular disease states (discussed below and in Chapter 34). Past investigations have used various electrophoretic methodologies to identify more generalized protein expression patterns in disease that diverge from what is seen in normal samples. There are three basic mechanisms by which individual proteins become elevated in the CSF: (1) decreased absorption back into the circulation, (2) increased intrathecal production, and/or (3) leakage across the BBB or BCB due to very high serum levels (i.e., in paraproteinemias such as multiple myeloma).22 Detailed analysis of both serum and CSF protein levels can help determine whether a given CSF protein is present due to leakage across an injured BBB or due to intrathecal production. In addition, inflammatory cells attracted in the setting of acute illness may increase CSF protein concentrations, and areas of focal inflammation can result in CSF flow abnormalities that lead to variable concentrations of protein throughout the CSF compartment.

ABNORMAL CEREBROSPINAL FLUID PROTEIN CONTENT IN PARTICULAR CLINICAL SITUATIONS OR DISEASE STATES Analysis of total CSF protein content is abnormal in many clinical settings (Table 32-3). A more precise and detailed assessment of specific proteins in CSF, such as with highly sensitive proteomic methods, has not yet been validated in specific disease processes and thus is not yet in routine clinical use. Still, international laboratories are now starting to provide protein analysis panels for CSF that assess the status of BBB integrity, quantify intrathecal antibody production, and measure multiple putative markers of CNS tissue destruction.22,23 By providing such an integrated analysis of these various parameters on a single form, it is felt that diagnostic accuracy can be improved.22 Although formal validation of such a comprehensive methodology remains to be completed, such reports do reflect the growing sophistication in the analysis of CSF proteins. Additional markers of specific disease processes (discussed below) could then easily be added to further increase diagnostic specificity. Common clinical situations in which total and specific CSF proteins may be used to help guide the differential are reviewed here, and have been covered in multiple chapters elsewhere in this text.

Acute infection of the central nervous system Acute infections of the CNS include meningitis, encephalitis, abscess, and ventriculitis. CSF protein concentrations may be variably elevated in all of these infections, but are

most significantly with bacterial meningitis. Mechanisms include: (1) BBB dysfunction allowing entry of serum proteins, (2) impaired absorption of proteins due to abnormal CSF flow, (3) increased intrathecal immunoglobulin production and/or, (4) elevations of other acute inflammatory mediators, including cytokines.23 A common clinical dilemma in CNS infection involves distinguishing viral from bacterial meningitis. CSF protein levels in bacterial meningitis often range between 100 and 500 mg/dl, and they can be higher in more than 20% of cases independent of the causative pathogen. Indeed, normal CSF protein levels are found in less than 2% of cases of acute bacterial meningitis.24 Furthermore, protein elevations above 280 mg/dl have been associated with increased mortality in bacterial meningitis.25,26 In contrast, the CSF protein may be normal or only moderately increased in viral meningitis. Hence, in the clinical setting of acute meningitis, CSF protein levels above 200 mg/dl are highly suggestive of a bacterial rather than a viral etiology. Proteomic analysis of CSF in the setting of acute meningitis has yet to be reported, although elevations of specific proteins have been documented. For example, 14-3-3 protein isoforms have been shown to increase in the CSF in the setting of acute bacterial, but not aseptic, meningitis.27 Higher mortality has also been associated with a failure to clear these proteins from the CSF.27 Other markers that are elevated in the CSF during acute meningitis include β-glucuronidase, S-100 β, cortisol, glutamate, and lactate.26,28–31 Similar to 14-3-3, the degree to which these mediators are elevated may be associated with increased mortality. The association between mortality and elevated CSF total protein levels or specific protein markers in acute meningitis may be due to overall impairment of CSF motility causing elevated intracranial pressure, or may simply reflect a more fulminant infection, local inflammatory response, and/or underlying nervous system injury. Bacterial infections that extend into the brain parenchyma cause meningoencephalitis, and viruses cause most cases of pure encephalitis. Here, CSF protein levels are variable, but generally stay in the range 50–80 mg/dl. Although polymerase chain reaction (PCR) for viral DNA is the most sensitive and specific means to detect herpes simplex virus (HSV) in CSF, virus-specific antibodies are still investigated in many centers and can be paired with serum samples to clarify the stage of disease. In the setting of several CNS viral infections, CSF:serum antibody ratios can be used both to make a diagnosis and to determine the degree of recovery from the acute illness. This is most commonly done in herpes simplex encephalitis where HSV-specific antibodies are detected some 8–12 days after the onset of symptoms and persist for 1–3 months after the resolution of disease. Importantly, virus-specific antibodies found in CSF allow accurate and rapid diagnosis even in the setting of normal total protein values.22 Similar protein profiles may be seen in with other viruses, including varicella-zoster virus (VZV) and West Nile virus (WNV). In these diseases,

Abnormal Cerebrospinal Fluid Protein Content in Particular Clinical Situations or Disease States

total protein content is variably elevated, intrathecal immunoglobins (IgM and IgG) are increased, and pathogenspecific antibodies are detectable.22,32 Increasingly, however, DNA-specific PCR techniques are replacing the detection of pathogen-specific antibodies in the CSF. Still, in the setting of recurrent or progressive disease (such as relapsing herpes encephalitis), or for diseases with limited availability of PCR testing (such as for WNV), CSF:serum antibody ratios can be helpful.

Chronic HIV infection of the central nervous system Human immunodeficiency virus (HIV) commonly spreads to the CNS early in infection, and some HIV RNA can be identified in the CSF of almost every patient throughout the course of disease.33 Other CSF analyses have played a prominent role in the effort to distinguish the many causes of neurological disease that occur in HIV-infected patients. With reference to CSF total protein content during HIV infection, levels vary depending on the stage of disease and past exposure to antiretroviral therapy. Acute seroconversion is often associated with an aseptic meningitis and mildly elevated total protein content in the range 50–100 mg/dl. After these inflammatory changes subside, however, CSF protein levels commonly return to normal. Thereafter, some correlation between viral load and total protein concentration of CSF can be made. Thus, if highly active antiretroviral therapy (HAART) is stopped, total CSF protein levels as well as CSF viral load may both increase in parallel with clinical progression of neurological symptoms. Patients with more advanced HIV disease are at risk for opportunistic infections of the CNS, and CSF protein levels often rise significantly in these settings. Such increases may occur via disruption of the BBB in the setting of superimposed acute infection. However, the sources of CSF proteins in chronic HIV infection are not clear. Specific protein markers have been identified in HIVassociated neurological disease, and many are proposed to assist in the diagnosis of suspected HIV encephalitis. These include β-2 microglobulin (B2M), neopterin, quinolinic acid, MCP-1, vitamin D binding proteins, clusterin, gelsolin, complement C3, procollagen, C-endopeptidase enhancer 1, and cystatin C.34 Neopterin and MCP-1 are markers of macrophage activation, a process linked with active intrathecal HIV replication. Elevated levels of both markers have been associated with symptomatic neurological disease, ranging from encephalopathy to neuropathy. Neopterin, in particular, may be a sensitive marker of acute neurological disease.35 HIV-infected macrophages also release soluble Fas (sFas) which may participate in astrocyte injury. sFas has been shown to be elevated in the CSF of patients with HIV versus controls, and correlates with the degree of dementia among HIV-infected patients.36 B2M is a component of all major histocompatibility complex

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(MHC) class I molecules and has been investigated as a marker of acute inflammation in various disease states, including cancer and infection. Patients with HIV dementia have significantly elevated CSF B2M levels compared to HIV positive patients without dementia.37 Dissociation between serum and CSF B2M levels suggests that it is produced intrathecally in patients with active HIV dementia. Although these CSF markers can be helpful when applied as a composite, many normalize in patients treated with HAART even with persistent neurological deficits.38,39 Work continues in looking for a cohort of CSF markers that will best help to identify those HIVinfected patients at highest risk for neurological disease, as well as to differentiate HIV from other factors as the causative agent of neurological symptoms in these complex patients.

Inflammatory demyelinating disease Analysis of CSF proteins can greatly assist in the evaluation of suspected demyelinating diseases of the CNS. Oligoclonal bands (OCB), in particular, are a very common finding with the central inflammation that occurs both during and after acute demyelination. Multiple studies have shown that elevated IgG levels in CSF relative to serum, indicative of intrathecal antibody production, occur with high frequency in patients with confirmed multiple sclerosis (MS) compared to controls. Moreover, these elevated levels may persist long after an acute episode of demyelination has resolved. Across multiple series, OCBs have been detected in the CSF of >95% of patients with confirmed MS,40–42 making it almost an obligatory CSF parameter in the diagnosis of this disorder.23 Furthermore, CSF OCBs have been correlated with MRI manifestations of MS and the clinical course of disease.42,43 Nevertheless, it should be kept in mind that they are not specific for demyelinating disease, and they must always be interpreted with careful consideration of the overall clinical and radiographic picture. Additional CSF protein markers may provide further diagnostic certainty in suspected MS. Kappa light chain bands (KLCB) are commonly associated with IgG synthesis, but can also occur independently of OCB. Their presence in CSF is further evidence of intrathecal antibody production and can add further diagnostic specificity in cases of suspected MS.44 Elevated CSF IgM has been identified in pediatric MS cases as well as adults early in their disease course.41,45 Other markers under investigation include anti-myelin antibodies, soluble MHC class I (sHLA-I) and class II (sHLA-II) molecules, interleukin (IL)-10, intermediate neurofilaments (NfM), and intercellular adhesion molecule-1 (ICAM-1).44 These observations raise the possibility of developing a menu of protein biomarkers that will ultimately help guide both diagnosis and therapy throughout the course of MS. These and other markers are discussed at greater length in Chapter 24.

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Other forms of CNS demyelinating disease (acute disseminated encephalomyelitis (ADEM), optic neuritis (ON)) are generally associated with only modest increases in total CSF protein levels, with a few notable exceptions. Rare cases of ADEM occur as a fulminant, necrotizing hemorrhagic leukoencephalitis associated with significantly elevated CSF protein levels. OCB are generally rare in the setting of ADEM, and this difference may help to differentiate it from MS. In contrast, the β-1-globulin fraction of CSF may be higher in ADEM than in MS.46 In isolated ON, CSF total protein levels are generally normal or only minimally elevated and OCB are only rarely detected. When detected in monosymptomatic patients, progression to MS should be closely monitored. In one series, all cases of ON with detectable CSF OCB also had abnormalities found on brain MRI and correlated strongly with the subsequent development of MS.47

Demyelinating polyradiculoneuropathies Elevated CSF total protein levels are virtually pathonogmonic for the Guillain-Barré Syndrome (GBS) in a patient with rapidly progressive weakness, areflexia, and normal sensation. Albuminocytological dissociation, defined as an elevated CSF protein level in the absence of a pleocytosis, is a cardinal laboratory hallmark of GBS. That said, CSF total protein levels vary in GBS based on the timing of CSF sampling relative to symptom onset. Despite the absence of a cellular infiltrate, immunoglobulins are frequently detected in the CSF during acute GBS, even in the face of ongoing debate regarding their site of origin (peripheral versus intrathecal). In this setting, an elevated total IgG level, and to a lesser extent a high IgG index, is more common than finding multiple unique OCBs.48 Hence, it is felt that the elevated IgG seen in GBS may largely occur due to the entry of serum immunoglobulins across a disrupted BBB and BCB.48 CIDP is, as its name implies, a long-term disorder with electrophysiological and pathological similarities to GBS. There also is overlap in the associated CSF parameters between GBS and CIDP, including albuminocytological dissociation and total protein levels almost always in excess of 45 mg/dl. Furthermore, anti-GM1 antibodies (IgG and IgM) have been detected in the CSF of 48–55% of patients with both GBS and CIDP.49 Cyclooxygenase-2 (a proinflammatory protein) also has been found at high levels in the CSF of patients with both GBS and CIDP.50 However, there are some differences in CSF protein markers between GBS and CIDP. Patients with GBS, for example, have high CSF levels of cytokines such as macrophage-colony stimulating factor that are not seen in CIDP.51 Identification of these protein markers has improved our overall understanding of the pathophysiology of GBS and CIDP, even though they have not yet been prospectively validated for routine use in clinical care.

Neurocognitive disorders Intense investigation to identify diagnostic markers for the various neurodegenerative diseases that cause progressive cognitive decline is under way. Thus, as potential diseasemodifying therapies become available for testing, the early discrimination of Alzheimer’s disease (AD) from related dementing conditions has become a high clinical priority. In addition to novel imaging strategies and plasma markers, much effort to identify CSF-based assays that distinguish between the various neurocognitive disorders and to monitor response to therapies is being spent. As many of these neurodegenerative diseases overlap considerably in their clinical presentations, such advances would be of major clinical importance. In almost all of these degenerative diseases, the abnormal proteins that get deposited in the brain are also identified in CSF that is otherwise of normal composition. Specifically, cell counts and total protein and glucose levels are invariably normal in AD and related progressive dementias. Still, alterations in important proteins related to disease pathophysiology have been identified in CSF, and significant progress has been made in the field of AD. Proteomic analyses have revealed more than 50 potential CSF biomarkers associated with AD, with the most important being the tau protein (both total and phosphorylated forms) and varying fragments of the amyloid beta protein (Aβ42).52,53 Tau is found in the CSF when there is neuronal damage of all forms. In contrast, CSF Aβ42 levels typically decrease in the setting of AD, as the protein fragment is progressively sequestered within the amyloid plaques. In one prospective analysis, CSF levels of these two proteins in patients with mild cognitive impairment were found to predict future development of AD.54 The usual pattern observed is elevation of both total and phosphorylated tau and a decrease of the Aβ42 fragment.54,55 This finding has been seen across multiple studies and has been correlated with clinical outcome.56 The sensitivity of tau and Aβ42 levels (often reported as Aβ42/phosphorylated-tau ratio) for predicting AD is 80–90% and specificity of 85–90% is reported across multiple studies.54,56 Such investigations are not yet routine in clinical practice, although validation of these CSF biomarkers is ongoing in the setting of prospective trials, and are likely to be of significant clinical importance in the near future. Importantly, these markers are increasingly used as criteria for inclusion in clinical trials for AD.57 Caveats that may alter the sensitivity of these studies include diurnal variation in the protein concentrations and variable sensitivity of assays.58 These limitations should be considered carefully before such markers are applied in widespread clinical practice. Changes in CSF levels of tau and Aβ42 can also be seen in other forms of progressive dementia, even though they are less well validated than in AD.54 Recent investigations have sought to identify CSF protein biomarkers for diseases such as Parkinson’s disease or Huntington’s disease with limited success. Markers investigated for Parkinson’s

References

disease include elevated CSF levels of a-synuclein, oxidized coenzyme Q-10, and the protein DJ-1 as well as low levels of a-tocopherol.59–61 These results are not applicable in routine clinical use.

6. 7. 8.

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that results in paralysis and death over an average of 3–5 years. There is no single definitive diagnostic test, and the exact pathophysiology remains incompletely understood. To enhance our understanding of the mechanisms of disease, to identify novel therapeutic targets, and to assist in diagnosis, CSF parameters have been extensively studied in ALS. Here, the total CSF protein tends to be within the normal range, and, if elevated, rarely exceeds 100 mg/dl. In one study, only 36% of patients had a protein level greater than 45 mg/dl.1 Recently, proteomic analyses have identified three markers that when measured together appear to be specific for ALS: transthyretin (decreased), cystatin C (decreased), and a carboxy-terminal fragment of the neuroendocrine protein, 7B2 (increased).62 These initial findings may add diagnostic accuracy to a disease that is currently difficult to confirm. However, the sensitivity and specificity of these proteins for ALS deserves prospective validation.

CONCLUSIONS

9. 10. 11. 12. 13.

14. 15.

16. 17. 18.

The CSF total protein value has long been used as a sensitive, but nonspecific, marker of CNS disease. Elevated levels remain one of the most common laboratory findings in these settings, and recognizing common patterns of protein elevation can assist in accurate clinical diagnosis. Recent advances in the technology of proteomics allow the increasingly accurate identification of protein biomarkers in CSF that are specific for particular disease states. Efforts are now focused on the accurate detection of these proteins and the validation of their diagnostic utility. Ultimately, such discoveries will enhance clinical diagnostic accuracy and improve our understanding of the pathophysiology of many CNS diseases.

19.

20. 21. 22. 23. 24.

REFERENCES

25.

1. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders; 1992. 2. Widell S. On the cerebrospinal fluid in normal children and in patients with acute bacterial meningo-encephalitis. Acta Paediatr Suppl 1958;47:1–102. 3. Tourtellotte WW, Haerer A, Heller G, Somers JE. Post-Lumbar Puncture Headaches. Springfield, IL: Charles C. Thomas, 1964. 4. Gilland O. Lumbar cerebrospinal fluid total protein in healthy subjects. Acta Neurol Scand 1967;43:526–529. 5. Cosgrove JB, Agius P. Studies in multiple sclerosis. II. Comparison of the beta-gamma globulin ratio, gamma globulin elevation, and first-zone

26. 27. 28. 29.

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colloidal gold curve in the cerebrospinal fluid. Neurology 1966; 16:197–204. Dencker SJ. Variation of total cerebrospinal fluid proteins and cells with sex and age. World Neurol 1962;3:778–781. Felgenhauer K. Protein size and cerebrospinal fluid composition. Klin Wochenschr 1974;52:1158–1164. Griffin DE, Giffels J. Study of protein characteristics that influence entry into the cerebrospinal fluid of normal mice and mice with encephalitis. J Clin Invest 1982;70:289–295. Cutler RW, Watters GV, Hammerstad JP. The origin and turnover rates of cerebrospinal fluid albumin and gamma-globulin in man. J Neurol Sci 1970;10:259–268. Werner M. A combined procedure for protein estimation and electrophoresis of cerebrospinal fluid. J Lab Clin Med 1969;74:166–173. Hühmer AF, Biringer RG, Amato H, Fonteh AN, Harrington MG. Protein analysis in human cerebrospinal fluid: Physiological aspects, current progress and future challenges. Dis Markers 2006;22:3–26. Yuan X, Desiderio DM. Proteomics analysis of prefractionated human lumbar cerebrospinal fluid. Proteomics 2005;5:541–550. Wenner BR, Lovell MA, Lynn BC. Proteomic analysis of human ventricular cerebrospinal fluid from neurologically normal, elderly subjects using two-dimensional LC-MS/MS. J Proteome Res 2004;3:97–103. Romeo MJ, Espina V, Lowenthal M, Espina BH, Petricoin EF, Liotta LA. CSF proteome: A protein repository for potential biomarker identification. Expert Rev Proteomics 2005;2:57–70. Pan S, Zhu D, Quinn JF, et al. A combined dataset of human cerebrospinal fluid proteins identified by multi-dimensional chromatography and tandem mass spectrometry. Proteomics 2007;7:469–473. Thompson EJ. Proteins of the Cerebrospinal Fluid. New York: Elsevier Academic; 2005. Greer M. Management of benign intracranial hypertension (pseudotumor cerebri). Clin Neurosurg 1968;15:161–174. Paulson GW. Low value for protein in the spinal fluid of leukemic patients. Confin Neurol 1968;30:337–340. Prockop LD, Fishman RA. Experimental pneumococcal meningitis. Permeability changes influencing the concentration of sugars and macromolecules in cerebrospinal fluid. Arch Neurol 1968;19:449–463. Froin G. Inflammations méningées avec réactions chromatique, fibrineuse et cytologique du liquide céphalo-rachidien. Gazette des Hôpitaux 1903;76:1005–1006. Sharma KR, Cross J, Farronay O, Ayyar DR, Shebert RT, Bradley WG. Demyelinating neuropathy in diabetes mellitus. Arch Neurol 2002;59:758–765. Reiber H, Peter JB. Cerebrospinal fluid analysis: Disease-related data patterns and evaluation programs. J Neurol Sci 2001;184:101–122. Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: A consensus statement. Arch Neurol 2005;62:865–870. Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: W.B. Saunders; 1938. Weiss W, Figueroa W, Shapiro WH, Flippin HF. Prognostic factors in pneumococcal meningitis. Arch Intern Med 1967;120:517–524. Baird DR, Whittle HC, Greenwood BM. Mortality from pneumococcal meningitis. Lancet 1976;2:1344–1346. Lu CH, Chang WN, Chang HW, et al. The value of serial cerebrospinal fluid 14–3-3 protein levels in adult community-acquired bacterial meningitis. QJM 2008;101:225–230. Beratis NG, Eliopoulou MI, Syrogiannopoulos GA. Beta-glucuronidase in the diagnosis of bacterial meningitis and response to treatment. Acta Paediatr 2003;92:1272–1276. Spinella PC, Donoghue A, Rajendra A, Drott HR, Dominguez TE, Helfaer M. Cerebrospinal fluid levels of S-100beta in children and its elevation in pediatric meningitis. Pediatr Crit Care Med 2004;5:53–57.

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30. Holub M, Beran O, Dzupova O, et al. Cortisol levels in cerebrospinal fluid correlate with severity and bacterial origin of meningitis. Crit Care 2007;11:R41. 31. Spranger M, Krempien S, Schwab S, Maiwald M, Bruno K, Hacke W. Excess glutamate in the cerebrospinal fluid in bacterial meningitis. J Neurol Sci 1996;143:126–131. 32. Jeha LE, Sila CA, Lederman RJ, Prayson RA, Isada CM, Gordon SM. West Nile virus infection: A new acute paralytic illness. Neurology 2003;61:55–59. 33. Price RW, Epstein LG, Becker JT, et al. Biomarkers of HIV-1 CNS infection and injury. Neurology 2007;69:1781–1788. 34. Rozek W, Ricardo-Dukelow M, Holloway S, et al. Cerebrospinal fluid proteomic profiling of HIV-1-infected patients with cognitive impairment. J Proteome Res 2007;6:4189–4199. 35. Brew BJ, Bhalla RB, Paul M, et al. Cerebrospinal fluid neopterin in human immunodeficiency virus type 1 infection. Ann Neurol 1990;28:556–560. 36. Towfighi A, Skolasky RL, St Hillaire C, Conant K, McArthur JC. CSF soluble fas correlates with the severity of HIV-associated dementia. Neurology 2004;62:654–656. 37. McArthur JC, Nance-Sproson TE, Griffin DE, et al. The diagnostic utility of elevation in cerebrospinal fluid beta 2-microglobulin in HIV-1 dementia. multicenter AIDS cohort study. Neurology 1992;42:1707–1712. 38. McArthur JC, McDermott MP, McClernon D, et al. Attenuated central nervous system infection in advanced HIV/AIDS with combination antiretroviral therapy. Arch Neurol 2004;61:1687–1696. 39. Cysique LA, Brew BJ, Halman M, et al. Undetectable cerebrospinal fluid HIV RNA and beta-2 microglobulin do not indicate inactive AIDS dementia complex in highly active antiretroviral therapy-treated patients. J Acquir Immune Defic Syndr 2005;39:426–429. 40. Rudick RA, Cookfair DL, Simonian NA, et al. Cerebrospinal fluid abnormalities in a phase III trial of avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. J Neuroimmunol 1999;93:8–14. 41. Villar LM, Masjuan J, Sadaba MC, et al. Early differential diagnosis of multiple sclerosis using a new oligoclonal band test. Arch Neurol 2005;62:574–577. 42. Link H, Huang YM. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: An update on methodology and clinical usefulness. J Neuroimmunol 2006;180:17–28. 43. Sharief MK, Thompson EJ. The predictive value of intrathecal immunoglobulin synthesis and magnetic resonance imaging in acute isolated syndromes for subsequent development of multiple sclerosis. Ann Neurol 1991;29:147–151. 44. Luque FA, Jaffe SL. Cerebrospinal fluid analysis in multiple sclerosis. Int Rev Neurobiol 2007;79:341–356. 45. Pohl D, Rostasy K, Reiber H, Hanefeld F. CSF characteristics in earlyonset multiple sclerosis. Neurology 2004;63:1966–1967. 46. Chopra B, Abraham R, Abraham A. CSF beta-1 globulin—a potential marker in differentiating multiple sclerosis and acute disseminated encephalomyelitis: A preliminary study. Neurol India 2002;50:41–44.

47. Rolak LA, Beck RW, Paty DW, Tourtellotte WW, Whitaker JN, Rudick RA. Cerebrospinal fluid in acute optic neuritis: Experience of the optic neuritis treatment trial. Neurology 1996;46:368–372. 48. Mata S, Galli E, Amantini A, Pinto F, Sorbi S, Lolli F. Anti-ganglioside antibodies and elevated CSF IgG levels in guillain-barre syndrome. Eur J Neurol 2006;13:153–160. 49. Simone IL, Annunziata P, Maimone D, Liguori M, Leante R, Livrea P. Serum and CSF anti-GM1 antibodies in patients with guillain-barre syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 1993;114:49–55. 50. Hu W, Mathey E, Hartung HP, Kieseier BC. Cyclo-oxygenases and prostaglandins in acute inflammatory demyelination of the peripheral nerve. Neurology 2003;61:1774–1779. 51. Sivieri S, Ferrarini AM, Lolli F, et al. Cytokine pattern in the cerebrospinal fluid from patients with GBS and CIDP. J Neurol Sci 1997;147:93–95. 52. Bouwman FH, van der Flier WM, Schoonenboom NS, et al. Longitudinal changes of CSF biomarkers in memory clinic patients. Neurology 2007;69:1006–1011. 53. Simonsen AH, Hansson SF, Ruetschi U, et al. Amyloid beta1–40 quantification in CSF: Comparison between chromatographic and immunochemical methods. Dement Geriatr Cogn Disord 2007;23:246–250. 54. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: A follow-up study. Lancet Neurol 2006;5:228–234. 55. Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of betaamyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995;38:643–648. 56. Wallin AK, Blennow K, Andreasen N, Minthon L. CSF biomarkers for Alzheimer’s disease: Levels of beta-amyloid, tau, phosphorylated tau relate to clinical symptoms and survival. Dement Geriatr Cogn Disord 2006;21:131–138. 57. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734–746. 58. Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: Implications for a diagnostic and therapeutic biomarker. Neurology 2007;68:666–669. 59. Buhmann C, Arlt S, Kontush A, et al. Plasma and CSF markers of oxidative stress are increased in Parkinson’s disease and influenced by antiparkinsonian medication. Neurobiol Dis 2004;15:160–170. 60. Isobe C, Murata T, Sato C, Terayama Y. Increase of oxidized/total coenzyme Q-10 ratio in cerebrospinal fluid in patients with Parkinson’s disease. J Clin Neurosci 2007;14:340–343. 61. Waragai M, Nakai M, Wei J, et al. Plasma levels of DJ-1 as a possible marker for progression of sporadic Parkinson’s disease. Neurosci Lett 2007;425:18–22. 62. Ranganathan S, Williams E, Ganchev P, et al. Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis. J Neurochem 2005;95:1461–1471.

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Clinically Relevant Lessons Learned from Animal Models David N. Irani

INTRODUCTION Studies undertaken in experimental animal models have taught many important lessons about the pathogenesis of human neurological diseases. Some of these studies have focused on the analysis of cerebrospinal fluid (CSF) dynamics or composition as a means to understand or treat the disorder in question, although, regrettably, data derived from these studies have not always come to the attention of clinicians who diagnose and treat the related problems in humans. In this chapter, some of the more clinically relevant lessons learned through the analysis of CSF samples from experimental animals will be presented. The explicit goals here are to remind clinicians of both the utility and limitations of the various assays they perform on human samples, and to stimulate new thinking as to how novel CSF-based assays can be brought from the laboratory to the clinic and the hospital ward where they can benefit human patients.

INFECTIOUS DISEASE MODELS Acute bacterial meningitis Given the high morbidity and mortality of acute bacterial meningitis in humans, animal models have been developed in order to study pathogenetic and pathophysiologic mechanisms, to evaluate the pharmacokinetic and antimicrobial properties of antibiotics in the central nervous system (CNS), and to search for novel adjuvant treatment strategies.1 In a rat model of pneumococcal meningitis, high CSF concentrations of matrix metalloproteinases (MMPs) and tumor necrosis factor-alpha (TNF-α) were found to correlate closely with increased levels of cortical neuronal injury among infected animals.2 Furthermore, treatment of animals with pharmacological inhibitors of both MMP activity and TNF-α formation could synergize with conventional antibiotics to reduce CSF levels of these inflammatory mediators and improve survival and long-term

cognitive outcome.2,3 Even when more clinically relevant anti-inflammatory compounds were used, lower CSF levels of TNF-α were associated with both enhanced survival and improved auditory outcome compared to animals given antibiotics alone.4 While these data may not yet prove a direct cause-and-effect relationship between CSF levels of these particular inflammatory mediators and irreversible cortical damage (i.e., they may simply be markers of inflammatory injury), they do point strongly to a role for host responses in disease pathogenesis. As such, they are driving a new push to develop adjuvant treatment strategies that target detrimental inflammatory responses for use in humans with related infections. From the standpoint of the pathogens that cause bacterial meningitis, teichoic acid (TA) and lipoteichoic acid (LTA) are both cell wall components of Streptococcus pneumoniae. These substances can be measured in CSF, and higher concentrations are known to correlate with more severe neurological sequelae and greater mortality in humans with meningitis caused by this pathogen.5 In a rabbit model of pneumococcal meningitis, antibiotic treatment regimens that more effectively lowered CSF levels of TA and LTA were associated with improved clinical outcomes and less histological and biochemical evidence of neuronal destruction in underlying brain tissue.6–8 Both of these bacterial components drive the production of hydroxyl radicals and glutamate, which are important downstream effectors of neuronal injury in this model.8 As a result, their identification provides a potential new CSF biomarker of outcome in pneumococcal meningitis, and they may represent specific new therapeutic targets in this disease.

Viral encephalitis In a mouse model of mosquito-borne alphavirus encephalitis, a pleocytosis composed primarily of T cells was quantified in the CSF of infected animals over time.9 Interestingly, while the kinetics of cell accumulation in the

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CSF compartment showed robust inflammation in the first few days of infection, the response was already subsiding as perivascular inflammation in brain parenchyma was reaching its peak.9 Furthermore, the inflammatory cells identified in brain tissue were a much more heterogeneous population of T cells, B cells, and monocytes.9 By extrapolating these findings to related infections that occur in humans, the data would suggest that monitoring the magnitude and composition of the CSF pleocytosis could potentially provide misleading information as to the nature of the underlying host response within the brain itself (the actual site of CNS pathology). While this would not impact on actual treatment decisions for humans with these infections (antiviral agents active against these particular viruses are still lacking), it could be misleading in terms of predicting the course of clinical disease. In the macaque-based simian immunodeficiency virus (SIV) model used to study human immunodeficiency virus (HIV)-associated neurological disease, high CSF viral loads were shown to correlate with both the magnitude of the underlying encephalitis and the actual CNS viral load found in the brains of infected animals.10 Furthermore, when serial CSF samples were obtained from macaques before necropsy, levels of interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and 14-3-3 protein were all confirmed as reliable predictors of more severe encephalitis and more extensive neuronal injury.11,12 While CSF-based studies have long been used to track the status of CNS disease in HIV-infected individuals, data from these animal models have more convincingly shown the relationship between individual CSF mediators and what is occurring at a histopathological level in the underlying brain itself.

NEURODEGENERATIVE DISEASE MODELS Alzheimer’s disease Autosomal dominant forms of Alzheimer’s disease (AD) in humans have been linked to known mutations in the amyloid precursor protein (APP) and presenilin (PS) genes, where the resulting mutant proteins acquire toxic properties that lead to pathogenic APP cleavage into Aβ fragments which themselves oligomerize and get deposited to form amyloid plaques within the brain.13 Transgenic mice that express these mutant APP and PS genes within the CNS have been generated, and the animals develop synaptic abnormalities, cognitive deficits, and accelerated CNS Aβ amyloidosis.14 Studies in these transgenic mice reveal that CSF levels of Aβ fragments reliably increase prior to the initiation of amyloid deposition within brain tissue;15 levels then plateau and actually begin to decline as plaques develop, suggesting a dynamic equilibrium between the plaque (insoluble) and the CSF (soluble) forms of this protein.16,17 Furthermore, drugs which inhibit aberrant APP cleavage into pathogenic Aβ fragments by blocking an enzyme known as γ-secretase can reduce CSF levels of Aβ,

regardless of whether plaques have already formed within the brain or not.18 This finding suggests that CSF Aβ levels may be a valuable measure of local γ-secretase activity within the CNS. Finally, systemic administration of anti-Aβ antibodies has been shown to reduce amyloid pathology in the CNS of transgenic animals,19 raising hopes that a similar approach could eventually be used in humans. Subsequent data regarding the CNS penetration of these antibodies are mixed; one study reported that antibody-treated animals had measurable CSF levels of antibody:Aβ complexes, suggesting that antibodies may help to sequester Aβ in a soluble form within the CNS,20 while another failed to find antibody in the CNS but did show that systemic treatment increased CSF levels of free Aβ, suggesting an indirect clearance mechanism.21 Taken together, these findings suggest novel theories of how normal Aβ turnover within the CNS may be disrupted in AD, and they offer insight into how CSF assays may eventually reveal pre-symptomatic evidence of incipient AD pathology in susceptible individuals. Indeed, clinical studies now show that elevated CSF levels of Aβ fragments in patients with mild cognitive impairment may predict the conversion to AD with some degree of accuracy.22

Motor neuron disease Excessive levels of the excitatory amino acid neurotransmitter, glutamate, have been strongly implicated in chronic neurodegeneration, including the destruction of motor neurons in the spinal cords of patients with sporadic amyotrophic lateral sclerosis (ALS). This may occur via dysfunction or loss of astrocytic glutamate reuptake proteins that normally buffer extracellular glutamate concentrations. Indeed, CSF samples derived from patients with confirmed ALS show high levels of glutamate and one of its metabolites, N-acetyl-aspartate, compared to controls.23 Some cases of familial ALS are caused by defined mutations of the copper-zinc superoxide dismutase (SOD1) gene, and transgenic mice bearing these mutant human SOD1 genes develop slowly progressive weakness and a motor neuron pathology highly reminiscent of human ALS.14 A handful of studies have investigated CSF samples derived from these SOD1 transgenic animals; in one case CSF glutamate levels were normal, both before and during the accumulation of motor neuron pathology, even though expression of glutamate transporters in the ventral horn of the spinal cord progressively declined as clinical deterioration ensued.24 Here, the lack of CSF changes in the pre-symptomatic period calls into question whether excitatory amino acids play a primary role in motor neuron degeneration in familial ALS. Since SOD is a major antioxidant defense mechanism, attention has focused on the roles played by reactive oxygen and nitrogen species in the neuronal injury that occurs in human ALS and in SOD1 transgenic mice. CSF levels of oxidized nitric oxide products are elevated in sporadic ALS patients and in SOD1 transgenic animals.25,26

Disorders of CSF Recirculation, Intracranial Pressure, and Brain Fluid Homeostasis

This finding in mice was directly correlated with an increase in the number of neurons specifically in motor regions of the CNS that contained nitrated and oxidized proteins when compared to both non-motor regions as well as nontransgenic controls.26 This suggests that products of nitric oxide synthesis in CSF could define a pathogenic event in the motor cortex and ventral horn of the spinal cord and serve as a surrogate marker of disease onset and progression. If confirmed, such a marker could be used in eventual therapeutic clinical trials as a surrogate outcome measure.

METABOLIC AND NUTRITIONAL DISEASE MODELS Hepatic encephalopathy Hepatic encephalopathy (HE) is a neuropsychiatric disorder that ranges in severity from mild confusion to deep coma in the setting of either acute or chronic liver failure. Its underlying pathogenesis remains poorly understood, but investigators have proposed for some time that increased gamma-aminobutyric acid (GABA)-ergic tone, an inhibitory neurotransmitter within the CNS, is an important predisposing event. This hypothesis is based in part on the anecdotal improvement of some patients following treatment with flumazenil, a highly selective benzodiazepine (BDZ) antagonist that acts at the GABA receptor complex. Since then, novel endogenous BDZ receptor ligands were detected in the CSF and brain tissue of humans with HE, suggesting that their production may be a possible mechanism of disease.27 Animal models, however, have largely refuted this hypothesis and have shed new light on this disorder. HE can be induced in animals by hepatectomy, liver devascularization procedures, or hepatotoxins, causing high serum and CSF ammonia levels.28 In these experimental settings, not only are there no alterations in the density and/or affinity of GABA-A receptors for radiolabeled benzodiazepines in brain tissue, but studies have also identified non-BDZ GABA-A receptor complex modulators, including a novel group of compounds known as neurosteroids, that are more likely candidate disease mediators.29 These animal models have also identified new therapeutic candidates that act as partial inverse agonists at the GABA receptor complex and produce a much clearer benefit to disease outcome when compared to flumazenil.29 Another important contribution made by animal models of HE has been to clarify a role for blood–brain barrier (BBB) permeability and brain edema in disease pathogenesis. Not only are these events important contributors to outcome in experimental models of acute liver failure,30 but studies also show that interventions which protect affected animals are closely correlated with their ability to limit brain swelling and to lower CSF concentrations of ammonia, often without changing serum levels.31,32 These data suggest that the blood–brain and blood–CSF barriers may be novel therapeutic targets in humans with HE.

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Cobalamin deficiency Prolonged vitamin B12 (cobalamin) deficiency leads to the characteristic and well known human neurological disorder known as subacute combined degeneration (SCD), a prototypical myelinolytic disease.33 Gastrectomized rats become progressively cobalamin-deficient due to loss of intrinsic factor, and these animals develop overt neurological symptoms and spinal cord demyelination that is highly reminiscent of SCD and that responds to cobalamin replacement.34 Importantly, high CSF levels of TNF-α were found in these cobalamin-deficient animals, and the intrathecal administration of anti-TNF-α antibodies substantially improved the demyelinating pathology, while CSF infusion of TNF-α itself into non-gastrectomized animals reproduced these changes.35 Other inflammatory and neurotrophic mediators were simultaneously dysregulated in the CSF of cobalamin-deficient animals; low IL-6, and epidermal growth factor (EGF) levels, and high CD40:CD40 ligand dyad complex levels were also found.36–38 Based on these observed changes, recent studies have gone back to examine levels of these mediators in the CSF of humans with SCD. In keeping with the animal model, human cobalamin deficiency results in low EGF and high TNF-α levels in CSF.39 Although a cause-and-effect relationship between these findings and the disease manifestations remains formally unproven, these data highlight novel mechanisms of non-inflammatory demyelination and possible new approaches in the treatment of SCD.

DISORDERS OF CSF RECIRCULATION, INTRACRANIAL PRESSURE, AND BRAIN FLUID HOMEOSTASIS Communicating hydrocephalus Acquired communicating adult hydrocephalus (AH) is a progressive disorder, typically affecting older individuals, where presumed abnormalities in CSF absorption lead to altered CSF pressure dynamics and gradual ventricular enlargement. Common neurological symptoms include gait disturbance, cognitive impairment, and urinary incontinence.40 Although some patients have a prior history of CNS trauma, infection, or hemorrhage, most cases are idiopathic in nature.40 In mice, intrathecal injection of the pleiotropic cytokine transforming growth factor-beta 1 (TGF-β1) results in a subacute and progressive ventricular dilatation that causes animals to stop gaining weight and become more lethargic in their behavior.41 These hydrocephalic animals have no microscopic evidence of CSF outflow obstruction, but instead show increased cellularity and fibrosis throughout the leptomeninges with narrowing of the intrameningeal CSF spaces.41,42 As a result, CSF flow dynamics are altered; an intrathecally injected contrast agent is delayed in its absorption and passage to cervical lymph nodes in these animals, and the resulting elevations of intraventricular pressure lead to the development of

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ventricular enlargement.42 Subsequent investigations in transgenic mice that overexpress TGF-β1 show similar neuropathological findings and reinforce the important role of this mediator in the pathogenesis of experimental hydrocephalus.43 To make correlations with AH in humans, investigators have recently studied CSF derived from a cohort of these patients with particular reference to the amount of TGF-β1, 2, and 3, as well as TGF-β type II receptor found in these samples. These data confirmed that CSF levels of both TGF-β1 and the TGF-β type II receptor were elevated in AH patients compared to controls.44 Thus, not only do these findings validate the experimental models, but they also provide important insights into disease pathogenesis in humans and they uncover potential new treatment approaches to be explored in the future.

beyond those causing brain edema or increased CSF volume via impaired absorption (hydrocephalus) discussed above. In the CNS, aquaporin-1 (AQP1) is located exclusively at the apical membrane of the choroid plexus, suggesting an important role in CSF production.49 Mice rendered deficient in AQP1 have significantly lower ICP compared to controls as a result of both reduced CSF production and lower central venous pressure.49 Therefore, these animals tolerate a variety of focal and diffuse brain insults that cause high ICP to a much greater degree than controls.49 Although relatively under-investigated at present, data such as these suggest that AQP1 inhibition may become a novel therapeutic option for the management of elevated ICP caused by many different neurological disorders.

Brain edema

CSF-BASED THERAPEUTICS IN EXPERIMENTAL ANIMAL MODELS

Brain edema is a significant contributor to the morbidity and mortality associated with many common neurological disorders. Still, therapies to combat this problem, primarily surgical decompression and hyperosmolar agents, were introduced more than 70 years ago and new strategies have been slow to develop. In part, this delay may be due to our limited understanding of the molecular events involved in brain fluid homeostasis. Discovery of the aquaporin family of water channels, however, has provided many new insights into the molecular mechanisms of membrane water permeability.45 Aquaporin-4 (AQP4) is concentrated in perivascular and subpial membrane domains of brain astrocytes at the BBB and blood–CSF barrier, and mice rendered deficient in AQP4 have significantly improved survival due to reduced cytotoxic brain edema in models of acute water intoxication and ischemic stroke.46 Yet this same protein, however, actually removes excess brain water at ependymal barriers; AQP4 knockout mice were found to have increased brain edema in experimental models of vasogenic edema.47 In terms of the actual in vivo detection of brain edema, this same AQP4 knockout mouse model has been used to characterize a noninvasive technique based on near-infrared light scattering that efficiently and accurately measures brain water content independent of cerebral blood flow, blood oxygenation, and blood flow-related changes in intracranial pressure (ICP).48 Given that such water content changes could be imaged even before ICP began to rise, the eventual clinical application of such a method appears high.48 Taken together, these findings suggest the AQP4 may be an important new therapeutic target in developing improved strategies to treat both cytotoxic and vasogenic brain edema.

Elevated intracranial pressure Elevated ICP can be the dynamic result of any disorder affecting the CSF, cerebral blood, and/or brain tissue compartments. Thus, it encompasses clinical problems

Conventional pharmacological agents (antimicrobials, antineoplastics, anesthetics, etc.) have been injected into the CSF of experimental animals and have subsequently gone on to extensive intrathecal use in humans. These data will not be reviewed here. Instead, focus will turn to the use of novel intrathecal agents in experimental settings to appreciate how future therapies in humans might be used to target specific molecular pathways or even to affect repair or regeneration inside the CNS.

Monoclonal antibody-based therapies Humanized monoclonal antibodies have come to the therapeutic forefront in recent years, particularly in an effort to target specific cell populations or cell–cell interactions involving the immune system. In mice with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), the intrathecal injection of neutralizing antibody against Fas ligand was shown to reduce brain inflammation and autoimmune myelin breakdown during acute EAE episodes.50 This approach raises the prospect of treating new MS exacerbations without altering systemic immunity. In mutant APP transgenic mice, the intraventricular injection of anti-Aβ antibody potently reversed the effects of incipient Aβ deposition,51 raising the prospect of being able to treat AD in a similar manner without concerns about inefficient antibody transit across the BBB. Finally, in a rat model of spinal cord trauma, intrathecal infusion of antibodies against the Nogo-A, a myelin protein known to inhibit neurite outgrowth, was able to cause Nogo-A expression to decline throughout the length of the spinal cord and to facilitate both clinical and histological evidence of recovery.52,53 Together, these data demonstrate that antibodies against CNS cell surface proteins can reach their antigens through the CSF and induce their downregulation.

References

Antisense oligodeoxynucleotides Antisense oligodeoxynucleotides (ODNs) bind messenger RNA molecules in a sequence-specific manner preventing their translation and thus knocking down expression of the encoded protein product. Novel therapies based on this strategy are currently under investigation in various neoplastic, inflammatory, and infectious diseases. In a rat model of middle cerebral artery occlusion, the intraventricular injection of an ODN specific for intercellular adhesion molecule-1 (ICAM-1) prevented ischemia-induced ICAM1 protein expression and reduced total infarct volume by more than 50%.54 A corresponding benefit in the mean neurological deficit score was also seen, and this neuroprotective effect proved to be independent of any change in local cerebral blood flow or systemic hemodynamics.54 More recent studies compared the efficacy of small interfering RNAs (siRNAs) against ODNs in knocking down the expression of specific brain proteins following CSF infusion; in one case ODNs were more clearly taken up by neural cells expressing the protein in question.55 Given preliminary success in these and other experimental systems, it seems likely that such a strategy will undergo further testing with an eye towards its eventual movement into human trials.

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Intraventricular infusion of NSCs has been undertaken with some success in various animal models, including those of intracerebral hemorrhage (ICH) and excitotoxic brain damage in neonates. In rats with collagenase-induced ICH, one research group showed that transplantation of neuronal lineage-committed NSCs into the contralateral ventricle resulted in the appearance of graft-derived neurons around the hematoma cavity and in adjacent subependymal areas 28 days later.60 Similarly, neonatal mice with excitotoxic forebrain injuries showed migration and differentiation of intraventricularly administered NSCs at the site of injury with processes that appeared to integrate into existing neuronal circuits.61 In a somewhat different approach, other investigators have recently shown that intraventricular infusion of growth factors known to promote NSC proliferation and differentiation could promote the histological and functional repair of motor cortex in a rat model of stroke by activating endogenous neural precursors in the subventricular zone.62 Cortical regeneration and functional recovery occurred even when the growth factor administration was delayed up to 7 days after lesion formation, highlighting the potential clinical relevance of such an approach in humans.62 These and other findings support the further investigation of intraventricular CSF as a means to deliver cell-based therapies to the injured brain.

Cell-based therapies Implantation of exogenous neural stem cells (NSCs) has gained significant attention as a potential strategy to promote regeneration and repair within the CNS following a variety of insults. Still, the scientific issues behind such a strategy remain daunting; obstacles related to the delivery, dissemination, survival, differentiation, integration, and control of aberrant proliferation of these cells must all be understood before this approach is considered truly viable for the treatment of human neurological disease. In experimental animal models, the inoculation of NSCs into various CSF compartments has been investigated as a delivery and dissemination technique for disorders affecting both the brain and spinal cord. In a rat spinal cord contusion injury model, cells injected into the fourth ventricle or cisterna magna were found to disseminate widely within the spinal subarachnoid space of paralyzed animals, to survive as clusters on the pial surface of the cord, to preferentially migrate into the sites of injury, to differentiate into functional glial cells, to integrate into the surrounding tissue, and to survive for many months.56–58 In a rat model of diffuse motor neuron injury, CSF-infused embryonic germ cell derivatives migrated into the spinal cord parenchyma of paralyzed animals, and some then differentiated into cells with the phenotype of mature motor neurons and extended axonal processes into the sciatic nerve.59 Most importantly, these transplanted rats partially recovered motor function over a period of 12–24 weeks.59 Together, these data validate CSF delivery in cell-based treatment approaches for various forms of spinal cord disease.

CONCLUSIONS Studies in experimental animal models have demonstrated the utility of analyzing CSF dynamics and composition in order to clarify the pathogenesis of many types of neurological disease. Other avenues of investigation have shown the expanding benefit of using CSF spaces for the delivery of novel treatments to the injured or diseased CNS. The studies reviewed here (undoubtedly only a fraction of the literature published on the subject) hopefully serve to clarify how new diagnostic and treatment approaches can begin to move from the experimental setting in the laboratory to the clinic and hospital ward where they can benefit humans with related diseases.

REFERENCES 1. Koedel U, Pfister HW. Models of experimental bacterial meningitis. Role and limitations. Infect Dis Clin North Am 1999;13:549–577. 2. Leib SL, Leppert D, Clements J, Tauber MG. Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis. Infect Immun 2000;68:615–620. 3. Leib SL, Clements J, Lindberg RL, et al. Inhibition of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis. Brain 2001;124:1734–1742. 4. Meli DN, Coimbra RS, Erhart DG, et al. Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis. Infect Immun 2006;74:3890–3896.

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5. Schneider O, Michel U, Zysk G, Dubuis O, Nau R. Clinical outcome in pneumococcal meningitis correlates with CSF lipoteichoic acid concentrations. Neurology 1999;53:1584–1587. 6. Trostdorf F, Reinhart RR, Schmidt H, et al. Quinupristin/dalfopristin attenuates the inflammatory response and reduces the concentration of neuron-specific enolase in the cerebrospinal fluid of rabbits with experimental pneumococcal meningitis. J Antimicrob Chemother 1999;43:87–94. 7. Gerber J, Pohl K, Sander V, Bunkowski S, Nau R. Rifampin followed by ceftriaxone for experimental meningitis decreases lipoteichoic acid concentrations in cerebrospinal fluid and reduces neuronal damage in comparision to ceftriaxone alone. Antimicrob Agents Chemother 2003;47:1313–1317. 8. Bottcher T, Ren H, Goiny M, et al. Clindamycin is neuroprotective in experimental Streptococcus pneumoniae meningitis compared with ceftriaxone. J Neurochem 2004;91:1450–1460. 9. Moench TR, Griffin DE. Immunocytochemical identification and quantitation of the mononuclear cells in the cerebrospinal fluid, meninges, and brain during acute viral encephalitis. J Exp Med 1984;159:77–88. 10. Zink MC, Suryanarayana K, Mankowski JL, et al. High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol 1999;73:10480–10488. 11. Mankowski JL, Queen SE, Clements JE, Zink MC. Cerebrospinal fluid markers that predict SIV CNS disease. J Neuroimmunol 2004; 157:66–70. 12. Helke KL, Queen SE, Tarwater PM, et al. 14-3-3 protein in CSF: an early predictor of SIV CNS disease. J Neuropathol Exp Neurol 2005; 64:202–208. 13. Price DL, Tanzi RE, Borchelt DR, Sisodia SS. Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 1998;32:461–493. 14. Wong PC, Cai H, Borchelt DR, Price DL. Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 2002;5: 633–639. 15. Liu L, Herukka SK, Minkeviciene R, van Groen T, Tanila H. Longitudinal observation on CSF Abeta42 levels in young to middle-aged amyloid precursor protein/presenilin-1 doubly transgenic mice. Neurobiol Dis 2004;17:516–523. 16. DeMattos RB, Bales KR, Parsadanian M, et al. Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer’s disease. J Neurochem 2002;81:229–236. 17. Liu L, Tapiola T, Herukka SK, Heikkila M, Tanila H. Abeta levels in serum, CSF, and brain, and cognitive deficits in APP+PS1 transgenic mice. Neuroreport 2003;14:163–166. 18. Barten DM, Guss VL, Corsa JA, et al. Dynamics of beta-amyloid reductions in brain, cerebrospinal fluid, and plasma of amyloid precursor protein transgenic mice treated with a gamma-secretase inhibitor. J Pharmacol Exp Ther 2005;312:635–643. 19. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer’s disease. Nat Med 2000;6:916–919. 20. Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer’s disease model. Nat Neurosci 2002;5:452–457. 21. Levites Y, Smithson LA, Price RW, et al. Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer’s disease mouse models. FASEB J 2006;20:E2002–E2014. 22. Hansson O, Zetterberg H, Buchhave P, Londros E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow up study. Lancet Neurol 2006;5:228–234. 23. Rothstein JD, Tsai G, Kuncl RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 1990;28:18–25.

24. Bendotti C, Tortarolo M, Suchak SK, et al. Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J Neurochem 2001;79:737–746. 25. Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, Isobe C. Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic forms of amyotrophic lateral sclerosis. Neurosci Lett 1999;260:204–206. 26. Liu D, Bao F, Wen J, Liu J. Mutation of superoxide dismutase elevates reactive species: comparison of nitration and oxidation of proteins in different brain regions of transgenic mice with amytrophic lateral sclerosis. Neuroscience 2007;146:255–264. 27. Olasmaa M, Rothstein JD, Guidotti A, et al. Endogenous benzodiazepine receptor ligands in human and animal hepatic encephalopathy. J Neurochem 1990;55:2015–2023. 28. Bhatnagar A, Majumdar S. Animal models of hepatic encephalopathy. Indian J Gastroenterol 2003;22 Suppl:S33–S46. 29. Ahboucha S, Butterworth RF. Role of endogenous benzodiazepine ligands and their GABA-A-associated receptors in hepatic encephalopathy. Metab Brain Dis 2005;20:425–437. 30. Eizavaga F, Scorticati C, Prestifilippo JP, et al. Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered. World J Gastroenterol 2006;12:1367–1372. 31. Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF. L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 1999;30:636–640. 32. Chatauret N, Rose C, Therrien G, Butterworth RF. Mild hypothermia prevents cerebral edema and CSF lactate and ammonia accumulation in acute liver failure. Metab Brain Dis 2001;16:95–102. 33. Scalabrino G. Subacute combined degeneration one century later. The neurotrophic action of cobalamin (vitamin B12) revisited. J Neuropathol Exp Neurol 2001;60:109–120. 34. Tredici G, Buccellato FR, Cavaletti G, Scalabrino G. Subacute combined degeneration in totally gastrectomized rats: an ultrastructural study. J Submicrosc Cytol Pathol 1998;30:165–173. 35. Buccellato FR, Miloso M, Braga M, et al. Myelinolytic lesions in spinal cord of cobalamin-deficient rats are TNF-alpha-mediated. FASEB J 1999;13:297–304. 36. Scalabrino G, Nicolini G, Buccellato FR, et al. Epidermal growth factor as a local mediator of the neurotrophic action of vitamin B(12) (cobalamin) in the rat central nervous system. FASEB J 1999;13:2083–2090. 37. Scalabrino G, Corsi MM, Veber D, et al. Cobalamin (vitamin B(12)) positively regulates interleukin-6 levels in rat cerebrospinal fluid. J Neuroimmunol 2002;127:37–43. 38. Veber D, Mutti E, Galmozzi E, et al. Increased levels of the CD40:CD40 ligand dyad in the cerebrospinal fluid of rats with vitamin B12 (cobalamin)-deficient central neuropathy. J Neuroimmunol 2006;176:24–33. 39. Scalabrino G, Carpo M, Bamonti F, et al. High tumor necrosis factoralpha levels in the cerebrospinal fluid of cobalamin-deficient patients. Ann Neurol 2004;56:886–890. 40. Wilson RK, Williams MA. Normal pressure hydrocephalus. Clin Geriatr Med 2006;22:935–951. 41. Tada T, Kanaji M, Kobayashi S. Induction of communicating hydrocephalus in mice by intrathecal injection of human recombinant transforming growth factor-beta 1. J Neuroimmunol 1994;50:153–158. 42. Moinuddin SM, Tada T. Study of cerebrospinal fluid flow dynamics in TGF-beta 1 induced chronic hydrocephalic mice. Neurol Res 2000;22:215–222. 43. Crews L, Wyss-Coray T, Masliah E. Insights into the pathogenesis of hydrocephalus from transgenic and experimental animals. Brain Pathol 2004;14:312–316. 44. Li X, Miyajima M, Jiang C, Arai H. Expression of TGF-betas and TGF-beta type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus. Neurosci Lett 2007;413:141–144.

References

45. King LS, Agre P. Pathophysiology of the aquaporin water channels. Annu Rev Physiol 1996;58:619–648. 46. Manley GT, Fujimura M, Ma T, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 2000;6:159–163. 47. Papadopoulos MC, Manley GT, Krishna S, Verkman AS. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 2004;18:1291–1298. 48. Thiagarajeh JR, Papadopoulos MC, Verkman AS. Noninvasive early detection of brain edema in mice by near-infrared light scattering. J Neurosci Res 2005;80:293–299. 49. Oshio K, Watanabe H, Song Y, Verkman AS, Manley GT. Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 2005;19:76–88. 50. Okuda Y, Sakoda S, Fujimura H, Nagata S, Yanagihara T, Bernard CC. Intrathecal administration of neutralizing antibody against Fas ligand suppresses the progression of experimental autoimmune encephalomyelitis. Biochem Biophys Res Commun 2000;275:164–168. 51. Chauhan NB, Siegel GJ. Reversal of amyloid beta toxicity in Alzheimer’s disease model Tg2576 by intraventricular anti-amyloid beta antibody. J Neurosci Res 2002;69:10–23. 52. Liebscher T, Schnell L, Schnell D, et al. Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann Neurol 2005;58:706–719. 53. Weinmann O, Schnell L, Ghosh A, et al. Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A. Mol Cell Neurosci 2006;32:161–173. 54. Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides

55. 56. 57.

58.

59. 60. 61.

62.

303

is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 2004;35:179–184. Senn C, Hangartner C, Moes S, Guerini D, Hofbauer KG. Central administration of small interfering RNAs in rats: a comparison with antisense oligonucleotides. Eur J Pharmacol 2005;522:30–37. Wu S, Suzuki Y, Kitada M, et al. New method for transplantation of neurosphere cells into injured spinal cord through cerebrospinal fluid in rat. Neurosci Lett 2002;318:81–84. Wu S, Suzuki Y, Noda T, et al. Immunohistochemical and electron microscopic study of invasion and differentiation in spinal cord lesion of neural stem cells grafted through cerebrospinal fluid in rat. J Neurosci Res 2002;69:940–945. Bai H, Suzuki Y, Noda T, et al. Dissemination and proliferation of neural stem cells on the spinal cord by injection into the fourth ventricle of the rat: a method for cell transplantation. J Neurosci Methods 2003;124:181–187. Kerr DA, Lldo J, Shamblott MJ, et al. Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury. J Neurosci 2003;23:5131–5140. Nonaka M, Yoshikawa M, Nishimura F, et al. Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats. Neurol Res 2004;26:265–272. Mueller D, Shamblott MJ, Fox HE, Gearhart JD, Martin LJ. Transplanted human embryonic germ cell-derived neural stem cells replace neurons and oligodendrocytes in the forebrain of neonatal mice with excitotoxic brain damage. J Neurosci Res 2005;82:592–608. Kolb B, Morshead C, Gonzalez C, et al. Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab 2007;27:983–997.

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Future Directions in Cerebrospinal Fluid Analysis David N. Irani

INTRODUCTION Analysis of cerebrospinal fluid (CSF) samples, usually collected via lumbar puncture (LP), has been a mainstay in the diagnostic evaluation of patients with neurological disorders for more than a century. Still, most of the routine laboratory assays performed on CSF samples have not changed very dramatically over this period, even as our understanding of central nervous system (CNS) disease pathogenesis has virtually exploded. In the previous chapter, new approaches to CSF analysis being undertaken in various experimental animal models of neurological disease were reviewed, with the goal of provoking some thought as to how clinicians might expand their diagnostic repertoire using these specimens to aid humans with related disorders. Here, I will discuss several exciting new directions in CSF analysis that are on the horizon and will be pursued in the foreseeable future. In particular, I submit that the fields of broad-spectrum infectious disease screening, disease biomarker discovery, and metabolic imaging of the CSF compartment will each likely have important clinical impact in the coming decades.

INFECTIOUS DISEASE SCREENING Development of DNA microarrays, where the expression of literally tens of thousands of human genes can be surveyed in a single hybridization reaction, has revolutionized our thinking about disease pathogenesis and diagnosis in many fields, perhaps most notably in cancer and autoimmunity. Because these assays lend themselves to both automation and high-throughput analysis, their success has stimulated the development of chip-based methodologies for detecting individual proteins and antigen-specific antibodies as well. Furthermore, as the genomic sequences of more and more infectious organisms are solved, the concept of developing molecular screening arrays for the

simultaneous detection of many pathogen-specific nucleic acid sequences or proteins in clinical specimens has gained significant traction. Pioneering studies involving these broad-spectrum infectious disease diagnostic assays, mostly as they apply to CSF, are reviewed here.

Nucleic acid-based assays While the development of polymerase chain reaction (PCR)-based methodologies for detecting and quantifying viral nucleic acids in CSF has been a major advance in the diagnosis of CNS infections,1,2 these tests remain costly and relatively labor-intensive because multiple steps are involved and only one pathogen is detected at a time. Recent advances in PCR technology and primer design, however, have allowed for the creation of newer assays that amplify conserved DNA sequences among multiple related pathogens in a single reaction. Thus, for the six major human herpes viruses (herpes simplex virus (HSV)-1 and HSV-2, cytomegalovirus (CMV), EpsteinBarr virus (EBV), varicella-zoster virus (VZV), and human herpes virus-6 (HHV-6)), multiplex PCR assays compare favorably with individual virus-specific PCR tests in terms of sensitivity and specificity when performed on CSF samples.3,4 Beyond efficiency and cost, this approach has the added benefit of detecting co-infections that might otherwise be overlooked unless all the individual PCR assays are routinely requested. Even more recent studies now show that when multiplex PCR amplification assays are coupled with a microarraybased detection strategy, CSF samples can be screened for the presence of nucleic acid sequences specific for 13 common viruses that cause meningitis and encephalitis.5,6 Once validated against the current gold standard of single-virus PCR, it is not hard to conceive of how these pathogen microarrays will likely become the next major advance in CSF-based diagnostics for suspected viral infections of the CNS.

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A similar approach is being used to detect common bacterial pathogens that cause acute meningitis in humans. This strategy takes advantage of the fact that sequence data are available for genes contained in the 16S ribosomal DNA (rDNA) region of nearly all bacteria known to be pathogenic in humans. Universal PCR primers specific for highly conserved sequences have been designed to amplify long stretches of the 16S rDNA region from any of these bacterium, and then individual pathogen-specific DNA sequences internal to this amplified PCR product can be detected by either direct sequencing or via hybridization to custom oligonucleotide probes.7,8 The design of these individual bacteria-specific probes has now lent itself to a chip-based detection format that could seemingly come into future clinical practice; a 16S rDNA microarray for the identification of 20 common bacterial causes of meningitis in humans has recently been developed.9 In a study of 100 CSF samples from 87 patients with suspected bacterial meningitis, 29 specimens from 16 patients were positive for bacteria by routine culture methods.9 All 29 of these specimens were also positive as assessed by 16S rDNA PCR without any false positives, and the causative organism was correctly identified in 26 of 29 samples, including one instance where the patient was infected with two pathogens simultaneously.9 Because these assays can be completed in a matter of 5–6 h (compared to 24–72 h for a routine bacterial culture) and do not require specialized detection equipment, their prospect for routine clinical application appears high once all the individual detection probes have been optimized and validated in larger prospective studies. In an amazing advance in this field, a recent paper reported on the creation and use of a panmicrobial oligonucleotide microarray containing 29,495 individual gene targets; this single chip has redundant probes for all 1,710 vertebrate virus species known (including all reported viral isolates), as well as 135 bacterial, 73 fungal, and 63 parasitic genera.10 In assays performed on clinical specimens (serum, urine, nasopharyngeal aspirates, and bronchoalveolar lavage fluid) from a cohort of patients with a variety of infectious diseases, this array routinely confirmed the presence of viruses and bacteria that were identified by other methods.10 It also implicated Plasmodium falciparum in an unexplained fatal case of hemorrhagic fever that had not yielded a specific diagnosis when samples were screened for other more likely suspected pathogens.10 This early study suggests that such a tool may provide unprecedented opportunities for infectious disease diagnosis and surveillance, both within the CNS once it is optimized for the analysis of CSF samples and otherwise.

(Toxoplasma gondii) antigens onto separate regions of nitrocellulose membranes and using this substrate to screen CSF samples for specific immunoglobulin (Ig) G and IgM antibodies to all six pathogens simultaneously in a Western blot-type format.11 The test proved to have good sensitivity in a cohort of 51 samples, and, because it could be completed in less than 24 h, the authors proposed that a negative result could be a useful screening tool for patients.11 Whole proteins or peptide fragments robotically spotted at high densities onto solid phase arrays could also theoretically be used to screen clinical samples for the presence of multiple antigen-specific antibodies. Here, labeled secondary antibodies are used for detection purposes much like a conventional enzyme-linked immunosorbent assay (ELISA), but these broad-spectrum arrays are advantageous compared to the traditional ELISA from the perspective of throughput, convenience, and cost. Several have been fabricated, and, although none has yet been directly applied to the analysis of CSF samples and reported in the published literature, first-generation assays can detect serum IgG and IgM antibodies to a variety of viral and bacterial antigens. In particular, one array simultaneously detects antibodies against T. gondii, rubella virus, CMV, and HSV-1 and -2 (all of the so-called TORCH infections that are important causes of congenital infection) with a high concordance to the more conventional ELISA-based measurement of these individual molecules.12,13 Still, having convenient quantities of recombinant proteins derived from many human pathogens for use in such assays has lagged far behind the availability of genomic sequences from these organisms, creating a bottleneck in the construction of broader-range infection-based protein arrays. A new, high-throughput PCR recombination cloning and expression platform, however, now allows for the in vitro production of literally hundreds of gene products using standard laboratory procedures. This means that the proteome of an entire viral pathogen, for example, can be expressed and spotted onto a single array, thus conceivably allowing for a comprehensive scan of humoral immune responses in potentially infected (or vaccinated) individuals. In the first demonstration of the feasibility of this approach, the serological responses of both experimental animals and humans were characterized following vaccinia virus immunization using a whole vaccinia protein array.14 It is foreseeable that other pathogen-specific protein chips could eventually be generated to undertake a similar screening approach to survey CSF samples for the presence of a wide variety of anti-viral, anti-bacterial, and anti-fungal antibodies in a rapid, accurate, and sensitive manner.

Antibody-based detection methods Protein microarrays One recent study reported on the efficacy of blotting viral (HSV-1 and -2, VZV, CMV, measles) and protozoal

Various attempts using antibodies to detect pathogenspecific antigens in CSF samples have met with only partial success and mixed acceptance over time. While latex agglutination assays to identify bacterial capsular polysaccharides

Disease Biomarker Discovery

as a rapid screen for bacterial meningitis have not proven to have much clinical utility,15 similar assays to detect cryptococcal antigens have shown high sensitivity and significant clinical usefulness in the identification of patients with cryptococcal meningitis.16 Multiplexing these affinitybased detection methods into antibody arrays, however, has proven to be a technical challenge for a variety of reasons. Not only are well-characterized antibodies suitable for such a purpose in short supply, but also those that are available have affinities for their respective antigens that vary over many orders of magnitude. Likewise, the pathogenspecific proteins to be assayed in a given clinical sample would also presumably be present over a wide concentration range, and each would have different physiochemical properties, making optimization of the binding conditions for each antibody-antigen pair an onerous task. Perhaps not surprisingly, current attempts to produce antibody arrays have mostly resulted in low multiplex systems (i.e., 8–20 spot arrays). None has been developed specifically for the detection of infectious pathogens, but a few commercial products can measure cytokine levels in CSF samples in order to profile local CNS immune responses that occur during various infectious and inflammatory diseases.

DISEASE BIOMARKER DISCOVERY At the broadest level, a biomarker is any physical measurement that can be used as an indicator or predictor of a particular biological state. In medicine, biomarkers are often measured substances whose detection indicates a particular disease, or whose change in expression correlates with the progression of a particular disease or with the response to a given treatment. Once validated, biomarkers can be used to assess disease risk, to diagnose disease, to predict future disease activity, or to tailor treatment in an individual patient. Much effort has already gone into the identification of CSF biomarkers for various neurological diseases, particularly those disorders with unpredictable clinical courses or that lack specific diagnostic tests. This field has exploded in recent years, and it is not risky to predict that future advances will continue to be made. Some of the most promising recent work in this area will be reviewed here.

Biomarkers of disease outcome For some neurological diseases, a diagnosis is not particularly difficult to establish but variability in the clinical course makes it hard to predict the short- or long-term outcome for an individual patient. This holds true for both acute illnesses where functional recovery can be uncertain, as well as for chronic diseases that are known to fluctuate over time or to progress at different rates. In the acute setting, the degree of clinical improvement for an individual patient often relates to the extent of irreversible neuronal

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damage that has occurred. Furthermore, it has now been recognized that proteins released from degenerating neurons act as surrogate markers of acute brain or spinal cord damage, and that such proteins can be detected and quantified in CSF.17 Laboratory data show that the profiles of released proteins can differ based on the underlying mechanism of neuronal injury (apoptosis, necrosis, excitotoxicity, etc.), but also that a subset of cytoplasmic and axonal proteins can be detected with all types of neurodegeneration.17 A number of recent studies have investigated the utility of measuring CSF levels of these substances during the acute phase of disease as a predictor of subsequent clinical outcome or recovery.

Acute transverse myelitis In idiopathic acute transverse myelitis (ATM), the development of focal inflammation in the spinal cord can lead to profound neurological deficits that reach a clinical nadir in a matter of hours to a few days. Nearly half of these patients progress to complete paraplegia.18 Natural history studies have shown that clinical recovery from this stage can be highly variable; in the absence of any anti-inflammatory intervention about one-third of patients recover with little to no sequelae, one-third make a partial recovery with moderate long-term disability, and one-third are left with profound deficits.18,19 Although recent reports suggest that a subset of these patients can respond to aggressive immunotherapy,20 predicting recovery in an individual patient can be difficult. Analysis of CSF samples obtained from patients with ATM at the time of clinical nadir, however, shows that immunodetection of the neuronal protein 14-3-3 occurs exclusively in patients who show little to no clinical recovery.21 It is assumed that CSF accumulation of this protein reflects irreversible neuronal or axonal injury in the spinal cord as a by-product of local tissue inflammation, and thus serves as a useful prognostic indicator in this disorder.

Hypoxic-ischemic coma and traumatic brain injury Traditionally, the prognosis for patients having incurred brain injury following cardiac arrest or as a result of trauma has been dictated by clinical examination findings. Recently, however, there has been a push to seek biochemical markers that might assist in prognostication for these patients. While the measurement of neuronal proteins in serum has shown inconsistent results, several studies suggest that elevated CSF levels of such proteins as neuron-specific enolase (NSE), brain-specific isoform of creatine kinase (CK-BB), S-100B, and neurofilament (NFL) can, at least to some degree, be correlated with eventual outcome. In surviving cardiac arrest patients, CSF levels of NFL measured in the first 2 weeks after the clinical event in one cohort of 22 patients correlated directly with coma duration and

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coma depth and inversely with Glasgow Outcome Scale (GOS) and Mini-Mental Status Examination scores at 1 year follow-up.22 In a group of 48 patients with severe traumatic brain injury (TBI) and Glasgow Coma Scale (GCS) scores below 9 at presentation, ventricular CSF levels of S-100B were significantly higher in those patients with unfavorable outcomes at 6–9 months compared to those with more favorable recoveries as assessed by the GOS.23 Serum levels of S-100B in the acute setting were not different between these outcome groups, suggesting that intrathecal measurements must be made in order to draw meaningful outcome conclusions.23 A similar set of findings was recently reported in a cohort of 88 pediatric TBI patients where CSF NSE and S-100B levels were used, although subgroup analyses did not confirm any correlation in those patients below 4 years of age.24 While much work in this field is still required, there is some preliminary reason to conclude that CSF biomarkers may be useful in predicting outcome for patients following cardiac arrest or with TBI.

Disease-specific biomarkers While some CSF biomarkers have been investigated as predictors of disease outcome, others have been sought as diagnostic surrogates for conditions that otherwise must be defined on clinical grounds alone. In these settings, attention has focused not on the measurement of a single mediator in CSF, but rather on the simultaneous assessment of multiple substances (mostly proteins) that might serve as a “diagnostic signature” for the disease in question. This approach has been greatly advanced by the fields of proteomics and bioinformatics, where new tools have recently become available to quantify thousands of proteins in a given sample simultaneously, and then to sift through all the data using computer algorithms in order to compare the proteomes of multiple samples and identify common expression patterns. These techniques have been used to identify serum biomarkers for particular types of cancer with astonishing accuracy, and success in the oncology field has fueled the application of these technologies in the analysis of CSF samples. A few of the brightest examples of these studies are reviewed here.

Amyotrophic lateral sclerosis A diagnosis of amyotrophic lateral sclerosis (ALS) is based on defined clinical and electrophysiological criteria; there is no laboratory marker specific for the disease, and such investigations are usually undertaken to exclude other disorders that can mimic ALS.25 As a result, it is not uncommon for the disease to have undergone substantial progression before a diagnosis is confirmed. Eventual progress in therapeutic clinical trials for this disorder, however, will require that ALS patients be identified at much earlier stages of disease in order to prevent the insurmountable loss of motor neurons. To seek a specific biomarker for this

disorder, investigators have used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-MS) to characterize the CSF proteome of patients with ALS and disease-related controls. This method first captures subclasses of proteins on solid substrates based on certain physicochemical characteristics, and then it generates quantitative mass profiles (spectra) of the captured proteins that are used for comparison purposes. In discovery studies, SELDI-MS analysis identified three protein species (4.8-, 6.7-, and 13.4-kDa) that were all significantly lower in concentration in the CSF of patients with ALS (n=36) compared to controls (n=21).26 Using a combined “threeprotein” model, this analysis then correctly identified ALS samples with 95% accuracy, 91% sensitivity, and 97% specificity, even when the biomarker was used prospectively on a second cohort of blinded samples from patients with relatively short durations of disease.26 Purification and sequencing of the three proteins in question allowed for the formulation of hypotheses about their respective roles in disease pathogenesis, but, even without knowing the identity of these proteins, the biomarker itself presents new possibilities in providing diagnostic certainty to ALS patients, and it may even become a surrogate marker for disease progression that could be useful in future clinical trials.

Mild cognitive impairment As currently understood, the pathogenic processes in Alzheimer’s disease (AD) begin years before clinical onset and only become apparent as a threshold of neuronal damage is crossed. The first symptoms, most often manifest as impaired episodic memory, are commonly referred to as the syndrome of mild cognitive impairment (MCI). Using emerging clinical diagnostic criteria,27 patients with MCI are estimated to convert to overt AD at a rate of 8–15% per year.28 Still, many MCI patients can remain clinically stable over time and are presumed to manifest symptoms only as part of normal aging. In this setting, a means to identify those MCI patients who will progress to AD would allow clinicians to apply and test disease-modifying therapies at a point where interventions would be most likely to succeed. Indeed, using a panel of ELISA assays to measure CSF levels of β-amyloid1–42, total tau, and phosphorylated tau proteins, investigators can now identify those patients with progressive MCI, although specificity for AD compared to other forms of dementia still remains an issue.29,30 In a recent study using SELDI-MS to analyze CSF samples from 113 patients with MCI and 28 age-matched controls, a panel of 17 proteins was identified whose levels in aggregate reliably distinguished the 57 patients who progressed to AD over a 6-year follow-up interval compared to the 56 patients with stable MCI.31 Four of these proteins were down-regulated and 13 were up-regulated in the MCI-AD group; five were purified and sequenced but the identity of 12 others remains unreported.31 Among the identified proteins (all elevated in the MCI-AD cohort versus the stable MCI group) were ubiquitin, a phosphorylated

References

C-terminal fragment of osteopontin, β2-microglobulin (β2M), and the C3a and C4a complement proteins.31 Not only do these findings have implications for our understanding of AD pathogenesis (particularly an early inflammatory component given the high β2M and complement levels), but they also suggest that CSF-based assays may soon be useful in the prospective identification of early AD patients. Given the expanding epidemiology of this disorder, a reliable diagnostic tool that can be used for patients in early disease stages is urgently needed to spearhead future therapeutic clinical trials.

IMAGING OF THE CSF COMPARTMENT Given the importance that various imaging methodologies now play in the diagnosis and management of patients with nervous system disorders, I felt that imaging of the CSF compartment deserved its own place in this text and it was separately reviewed in Chapter 9. One important point these authors illustrated was how new magnetic resonance imaging (MRI) methods can be applied to improve our understanding of normal and abnormal patterns of CSF flow. Here I will take the next step to highlight emerging and experimental MRI and magnetic resonance spectroscopy (MRS) techniques as they apply to CSF. In particular, the possibility of noninvasive measurement of CSF pressure dynamics and CSF content is explored.

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response to ventriculoperitoneal shunt surgery using a noninvasive imaging measurement method is worthy of aggressive further investigation.

Metabolic imaging of CSF content The technique of magnetic resonance spectroscopy (MRS) can certainly be applied to biological fluids as well as tissues, and the resulting spectra can provide a metabolic fingerprint of the specimen in question. Still, while MRS has previously been used to analyze CSF samples ex vivo,34 such imaging in vivo has generally been limited by metabolite concentrations below the threshold of detection using these relatively insensitive methodologies.35 In some cases, however, proton MRS may demonstrate elevated metabolite signals in ventricular CSF that are either not visible or much less prominent than in brain parenchyma.36 Here, increased CSF signal relative to brain was proposed to be due to either higher actual concentrations of the substrate in question or increased sensitivity of detection in CSF because of longer T2 relaxation times that occur in a lowerviscosity substrate.36 Extensions of this technology are spawning the field of “metabonomics” that may very well be used to characterize CSF composition in a noninvasive manner for both clinical and research purposes.37

CONCLUSIONS Noninvasive measurement of CSF pressure dynamics Intracranial pressure physiology was reviewed in Chapter 4, and the roles played by the measurement of pressure dynamics in the diagnosis and management of patients with disorders of CSF pressure and flow were discussed in Chapter 12 and Chapter 28. In all of these situations, such measurements require the physical placement of a needle or a catheter into some region of the intrathecal space in order to make pressure recordings. These procedures, while often routine in the hands of practiced clinicians, are not totally without risk. Indwelling intraventricular or lumbar catheters, in particular, are prone to serious infectious complications. As such, it would be advantageous to develop a noninvasive means to make similar pressure recordings in an accurate manner. Recently, echo planar MRI sequences have been successfully used to detect CSF pressure oscillations,32 particularly those originally referred to as B-waves by Lundberg.33 Interestingly, these dynamic pressure changes could be detected in both the intracranial and intraspinal CSF compartments, and they were noted in both normal volunteers and patients with adult hydrocephalus.32 While the technique clearly requires further refinement in that the amount of B-waves detected in symptomatic individuals was still rather low, the promise of finding abnormal CSF pressure dynamics in patients with hydrocephalus that might eventually predict a beneficial

The fields of research described above represent only a few very exciting examples of future directions that may be taken in CSF analysis. While it is, of course, difficult to clearly discern how research and clinical directions will evolve in this area over the coming decades, it seems that technology is providing new tools that could potentially revolutionize neurological disease diagnostics in a variety of areas. It will be interesting to look back in 10–20 years to see to what degree these new developments have impacted their respective fields. REFERENCES 1. Lakeman FD, Whitley RJ, National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. J Infect Dis 1995;171:857–863. 2. Huang C, Chatterjee NK, Grady LJ. Diagnosis of viral infections of the central nervous system. N Engl J Med 1999;340:483–484. 3. Minjolle S, Michelet C, Jusselin I, Joannes M, Cartier F, Colimon R. Amplification of the six major human herpesviruses from cerebrospinal fluid by a single PCR. J Clin Microbiol 1999;37:950–953. 4. Markoulatos P, Georgopoulou A, Siafakas N, Plakokefalos E, Tzanakaki G, Kourea-Kremastinou J. Laboratory diagnosis of common herpesvirus infections of the central nervous system by a multiplex PCR assay. J Clin Microbiol 2001;39:4426–4432. 5. Boriskin YS, Rice PS, Stabler RA, et al. DNA microarrays for virus detection in cases of central nervous system infection. J Clin Microbiol 2004;42:5811–5818.

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6. Jaaskelainen AJ, Piiparinen H, Lappalainen M, Koskiniemi M, Vaheri A. Multiplex-PCR and oligonucleotide microarray for detection of eight different herpesviruses from clinical specimens. J Clin Virol 2006;37:83–90. 7. Greisen K, Loeffelholz M, Purohit A, Leong D. PCR primers and probes for the 16S rRNA gene of most species of pathogenic bacteria, including bacteria found in cerebrospinal fluid. J Clin Microbiol 1994;32:335–351. 8. Wilson K, Blitchington R, Greene R. Amplification of bacterial 16S ribosomal DNA with polymerase chain reaction. J Clin Microbiol 1990;28:1942–1946. 9. Liu Y, Han J-X, Huang H-Y, Zhu B. Development and evaluation of 16S rDNA microarray for detecting bacterial pathogens in cerebrospinal fluid. Exp Biol Med 2005;230:587–591. 10. Palacios G, Quan P-L, Jabado OJ, et al. Panmicrobial oligonucleotide array for diagnosis of infectious diseases. Emerg Infect Dis 2007; 13:73–81. 11. Morris P, Davies NWS, Keir G. A screening assay to detect antigenspecific antibodies within cerebrospinal fluid. J Immunol Meth 2006; 311:81–86. 12. Mezzasoma L, Bacarese-Hamilton T, Di Cristina M, Rossi R, Bistoni F, Crisanti A. Antigen microarrays for serodiagnosis of infectious diseases. Clin Chem 2002;48:121–130. 13. Bacarese-Hamilton T, Mezzasoma L, Ardizzoni A, Bistoni F, Crisanti A. Serodiagnosis of infectious diseases with antigen microarrays. J Appl Microbiol 2004;96:10–17. 14. Davies DH, Liang X, Hernandez JE, et al. Profiling the humoral immune response to infection by using proteome microarrays: high-throughput vaccine and diagnostic antigen discovery. Proc Natl Acad Sci USA 2005;102:547–552. 15. Perkins MD, Mirrett S, Reller LB. Rapid bacterial antigen detection is not clinically useful. J Clin Microbiol 1995;33:1486–1491. 16. Antinori S, Radice A, Galimberti L, Magni C, Fasan M, Parravicini C. The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis. J Clin Microbiol 2005;43:5828–5829. 17. Siman R, McIntosh TK, Soltesz KM, Chen Z, Neumar RW, Roberts VL. Proteins released from degenerating neurons are surrogate markers for acute brain damage. Neurobiol Dis 2004;16:311–320. 18. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59:499–505. 19. Ropper AH, Poskanzer DC. The prognosis of acute and subacute transverse myelopathy based on early signs and symptoms. Ann Neurol 1978;4:51–59. 20. Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, Kerr DA. Idiopathic transverse myelitis. Corticosteroids, plasma exchange, or cyclophosphamide. Neurology 2007;68:1614–1617.

21. Irani DN, Kerr DA. 14-3-3 protein in the cerebrospinal fluid of patients with acute transverse myelitis. Lancet 2000;355:901. 22. Rosen H, Karlsson JE, Rosengren L. CSF levels of neurofilament is a valuable predictor of long-term outcome after cardiac arrest. J Neurol Sci 2004;221:19–24. 23. Ucar T, Baykal A, Akyuz M, Dosemeci L, Toptas B. Comparison of serum and cerebrospinal fluid protein S-100b levels after severe head injury and their prognostic importance. J Trauma 2004;57:95–98. 24. Shore PM, Berger RP, Varma S, et al. Cerebrospinal fluid biomarkers versus Glasgow Outcome Scale in pediatric traumatic brain injury: the role of young age and inflicted injury. J Neurotrauma 2007;24:75–86. 25. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2003;344:1688–1700. 26. Pasinetti GM, Ungar LH, Lange DJ, et al. Identification of potential CSF biomarkers in ALS. Neurology 2006;66:1218–1222. 27. Artero S, Petersen R, Touchon J, Ritchie K. Revised criteria for mild cognitive impairment: validation within a longitudinal population study. Dement Geriatr Cogn Disord 2006;22:465–470. 28. DeCarli C. Mild cognitive impairment: prevalence, prognosis, aetiology, and treatment. Lancet Neurol 2003;2:15–21. 29. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–234. 30. Andreasen N, Blennow K. CSF biomarkers for mild cognitive impairment and early Alzheimer’s disease. Clin Neurol Neurosurg 2005;107:165–173. 31. Simonsen AH, McGuire J, Hansson O, et al. Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment. Arch Neurol 2007;64:366–370. 32. Friese S, Hamhaber U, Erb M, Klose U. B-waves in cerebral and spinal cerebrospinal fluid pulsation measurement by magnetic resonance imaging. J Comput Assist Tomogr 2004;28:255–262. 33. Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Acta Psychol Neurol Scand 1960;36:149–193. 34. Petroff OA, Yu RK, Ogino T. High-resolution proton magnetic resonance analysis of human cerebrospinal fluid. J Neurochem 1986;47: 1270–1276. 35. Barker PB, Lee RR, McArthur JC. AIDS dementia complex: evaluation with proton MR spectroscopic imaging. Radiology 1995;195:58–64. 36. Nagae-Poetscher LM, McMahon M, Braverman N, et al. Metabolites in ventricular cerebrospinal fluid detected by proton magnetic resonance spectroscopic imaging. J Magn Reson Imaging 2004;20:496–500. 37. Holmes E, Tsang TM, Tabrizi SJ. The application of NMR-based metabonomics in neurological disorders. NeuroRx 2006;3:358–372.

Index Page numbers for figures have suffix f, those for tables have suffix t A abscesses 173, 173t, 250 absorptive-mediated transportation 36 acetylcholine 77 acid–base balance 84–85, 85t, 151 primary CSF acidosis 152 systemic disorders 151–152 acquired demyelinating polyneuropathies 122–123 acromegaly 139 acute disseminated encephalomyelitis 218 acute intermittent porphyria 124 acute neutrophilic pleocytosis 273 acute transverse myelitis 216–217 biomarkers 307 adenosine deaminase 196 adherens junctions 34, 35f adult hydrocephalus 100–102 animal models 299 drainage trials 102 management 259–264 neuroimaging findings 101 predisposing events 100 symptomatic 101 testing CSF physiology 101–102 See also shunts; third ventriculostomy Aicardi-Goutières syndrome 96 albumin 72 albumin index 209, 210t Alzheimer’s disease animal models 298 biomarkers 117, 308 CSF evaluation 115–116, 117t amines 76–77 amino acids in CSF 72, 72t neurotransmitters 77 transport 37, 37t ammonia 82 amyloidosis 124 amyotrophic lateral sclerosis 121, 293 animal models 298 biomarkers 121, 308 anatomy choroid plexus 6–7 circumventricular organs 7 CSF compartment 5–10 lumbar cistern 267 meninges 6 neuroimaging 63–67 perivascular spaces 7 subcommissural organ 7 ventricular system 5 angiomas 110

angiotensin converting enzyme 219 animal models Alzheimer’s disease 298 antisense oligodeoxynucleotides 301 bacterial meningitis 297 brain edema 300 cell-based therapies 301 cobalamin deficiency 299 communicating hydrocephalus 299 elevated intracranial pressure 300 hepatic encephalopathy 299 monoclonal antibody-based therapies 300 motor neuron disease 298 viral encephalitis 297–298 antibiotics meningitis treatment 170, 171t antibody accumulation 209–210 antibody-based detection methods 306–307 anti-siphon devices 260 apoptosis 253 arachnoid mater 6 arachnoid villi 14–15, 14f arboviruses 179 aspergillosis 200 astrocytes 35 autistic spectrum disorders 96 autoimmune syndromes and pleocytosis 277 systemic lupus erythematous (SLE) 135 axonal injury 251 B bacterial infections 167–174 brain abscess 173, 173t brainstem encephalitis 173 spinal epidural abscess 173 Whipple’s disease 174 See also meningitis basal lamina 35 basophilia 278 Behçet’s disease 136 beta-amyloid 116 bilirubin (CSF) children and infants 28 biomarkers 307–308 biopterins 84 blastomycosis 200 blood–brain barrier 33–42, 34f cellular anatomy 34–36 and epilepsy 133 glucose transport 281 gross anatomy 33

blood–brain barrier—Cont’d immune system 40–42 ion regulation 30 metabolic activity 39 multiple sclerosis 212 protein transport 71, 287 transport mechanisms 35–39, 36f volume regulation 39 blood–CSF barrier 33–42 cellular anatomy 34–36 dynamic regulation 35 epithelial features 35 general anatomy 8, 33 metabolic activity 39 protein transport 71, 287 transport mechanisms 35–39 blood gases influence on ICP 24f bloody/pigmented CSF management approach 267–271 brachial plexopathy 122 brain abscess 173, 173t brain edema 300 brain herniation 59 brainstem encephalitis 173 brain trauma 249 broth culture 169 C CADASIL 228 calcium disease states 148 normal CSF levels 81 carbonic anhydrase 13 carcinomatous meningitis 276 carrier mediated efflux 36 cell count bacterial meningitis 167 Creutzfeld-Jakob disease 191 infants 28, 29t ischemic stroke 226 normal 273 seizures 128, 130 spinal diseases 109 cellular constituents of CSF 70–71 analysis methodologies 70 leukocyte counts 70 physiological turnover 70 central nervous system immune surveillance 40 infection as indication for lumbar puncture 55 leukocyte entry 40 cerebellar ataxias 118

312

Index

cerebral folate deficiency 147 cerebral venous thrombosis 229–230 cerebrospinal fluid (CSF) cellular constituents 70–71 circulation in adults 5 anatomical routes 8 neuroimaging 64–65 composition, see composition of CSF CSF:serum glucose ratio 282 developmental changes 27–29 drainage complications 48–49 techniques 47–48 homeostasis 41 leakage 65 macroscopic features 7 normal properties and composition 69–85 physiological functions 9, 11–17 pigmentation 69 pregnancy-related CSF changes 29–30, 30t pressure dynamics, see pressure dynamics of CSF production during childhood 27–28 general anatomy 7 physiology 12–14 protein content 71–76 See also proteins pulsations 20 recirculation 14 resorption 4–16 general anatomy 8–9 sampling, history 3–4 solutes 12t structural correlates 9 turbidity 69 viscosity 69 volume 12 volumes required for assays 56 xanthochromia 69 See also examination, monitoring, and diversion techniques; composition of CSF; neuroimaging; pressure dynamics of CSF cerebrovascular disorders 225–231 CADASIL 228 cerebral venous thrombosis 229–230 intraparenchymal hemorrhage 228–229 ischemic stroke 225–228 spontaneous subarachnoid hemorrhage 230 Charcot-Marie-Tooth disease 124 chemotherapy 65 childhood CSF dynamics and composition 27–29, 28t, 29t neoplastic disorders 238–240 seizures 130–133 traumatic brain injury 253 chloride normal levels 81 variability 149 cholesterol 80

choroid plexus anatomy 6–7 cellular anatomy 12 CSF secretion 13–14, 13f glucose transport 281 tumors 240 circulation of CSF anatomical routes 8 disorders 99–103 pathophysiology 99–100 See also adult hydrocephalus; idiopathic intracranial hypertension neuroimaging 64–65 normal adult 5 circumventricular organs 7 cisternal puncture 47, 57 cobalamin deficiency 299 complications lumbar drains 48–49 lumbar puncture 57–59 ventircular drains 49–51 composition of CSF acid–base balance 84–85, 85t after ventricular shunt placement 51 carbohydrates 78 in children and infants 28, 29t during pregnancy 29 electrolytes 80 folate 84 ion regulation 39 ions 81–82 lactate 83 lipids 78–80, 79t lipoproteins 78–80, 79t metabolic byproducts 82 neuroimaging 66–67, 67f, 309 neurotransmitters 76–78 normal 12 nucleotides 83, 83t protein content 71–76 pyruvate 83 sugars 78 trace metals 81 vitamins 81–82, 82t volume regulation 39 See also glucose; proteins connective tissue disorders 135–138, 136t Behçet’s disease 136 giant cell (temporal) arteritis 137 Kawasaki’s disease 137 polyarteritis nodosa 136 primary arteritis of the CNS 137 rheumatoid arthritis 137 scleroderma 138 Sjogren’s syndrome 138 Sweet’s syndrome 137 systemic lupus erythematous 135 Vogt-Koyanagi-Harada 137 Wegener’s granulomatosis 136 contraindications lumbar puncture 46, 55–56, 56t copper abnormal levels 149 normal concentration 81 cranial nerve dysfunction 60 creatine kinase 251 Creutzfeld-Jakob disease 191–193

cryptococcal meningitis CSF findings 197, 198t cultures 198 serology 197 CSF compartment access in infants 28 neuroimaging 63–67 normal anatomy 5–10 Cushing’s disease 138 cyclic adenosine monophosphate (cAMP) 83 cyclic guanosine monophosphate (cGMP) 83 cystatin C 72 D D-dimer 270 dementia patients 115 demyelinating disorders, see inflammatory and demyelinating disorders developmental disorders 93–97 with associated CSF abnormalities Aicardi-Goutières syndrome 96 autistic spectrum disorders 96 late infantile neuronal ceroid lipofuscinosis (LINCL) 96 Menkes’ kinky hair disease 96 collection of CSF 95 neuroimaging CSF metabolites 97 with pathognmonic CSF abnormalities electron transport disorders 93 GABA metabolism disorders 95 glucose transporter (Glut-1) deficiency 93 mitochondrial cytopathies 93 monoamine neurotransmitter metabolism disorders 94 nonketotoic hyperglycinemia 94 3-phosphoglycerate dehydrogenase deficiency 94 diabetes mellitis CSF composition 138 diabetic neuropathy 123 diagnostic tests 57 differential pressure 260 DNA microarrays 305 dopamine 77 dopa-responsive dystonias 94, 95t dura mater 6 E eclampsia 30 efflux transport systems 38 electrolytes 80 electron transport disorders 93 encephalitis brainstem 173 CSF proteins 290 viral, see viral infections encephalomyelitis 218 endocrine disorders 138–139 acromegaly/idiopathic growth hormone deficiency 139 Cushing’s disease/Nelson’s syndrome 138 diabetes mellitus 138 hyperparathyroidism 139

Index

endocrine disorders—Cont’d hypothyroidism/Hashimoto’s thyroiditis 138 pituitary apoplexy 138 endocytosis 36 enteroviruses encephalitis 182 meningitis 178 enzymes in CSF 74 eosinophilia 278 ependymomas 239 epiliptic disorders 127–133 blood–brain barrier 133 pyridoxine-dependent epilepsy 95 See also seizures erythrocytes 70 erythrocytosis 107 examination, monitoring, and diversion techniques cisternal puncture 47 ICP monitoring devices 51 lateral cervical puncture 47 lumbar catheters 47 lumbar puncture 45–46, 55–60 lumboperitoneal shunts 47 for neurotransmitter-related studies 95 third ventriculostomy 51 ventricular drains and shunts 49–51 excitotoxicity 252 F facilitated diffusion 36 fatal familial insomnia 191 febrile seizures 132 ferritin 270 folates deficiency disorders 147 normal CSF content 84 fructose 78 fungal infections 197–201 blastomycosis 200 candidal meningitis 199 cerebral aspergillosis 200 coccidioidal meningitis 199 cryptococcal meningitis 197–199 histoplasmosis 200 future research directions 305–309 antibody-based detection methods 306–307 biomarkers 307–308 imaging 309 nucleic acid-based assays 305–306 protein microarrays 306 G gamma-aminobutyric acid (GABA) 77 GABA metabolism disorders 95 germ cell tumors 239 Gerstmann-Sträussler-Scheinker syndrome 191 giant cell (temporal) arteritis 137 glial cell injury 251 gliomas 234, 234t glucose abnormal levels 282, 284t bacterial meningitis 168, 282 cancers 283

glucose—Cont’d following seizure 130, 131t, 132 inflammatory disorders 283–284 ischemic stroke 227 management approach 281–286 meningeal infections 282–283 CSF content 78, 282 CSF:serum glucose ratio 282 transport 37, 93, 281–282 glucose transporters GLUT1 281 deficiency 93 GLUT1 gene 281 glycolipids 79 Gram stain 168 growth hormone deficiency 139 Guillain-Barré syndrome 122, 123 H HaNDL (headache with neurologic deficits and CSF lymphocytosis) 160, 160t Hashimoto’s thyroiditis 138 headaches 157–163 CSF investigations 159 CSF profiles primary headaches disorders 159 secondary headaches disorders 160 HaNDL 160t idiopathic intracranial hypertension 158 immunocompromised patient 159 lumbar puncture 157, 157t Mollaret’s meningitis 160 secondary 157, 158t spontaneous intracranial hypotension 161 subarachnoid hemorrhage 158 headache syndromes 157–163 helminths 278 heme metabolism 267 hepatic encephalopathy 299 hepatic failure 151 hereditary neuropathies 124 herpes viruses viral encephalitis 180 viral meningitis 178 histoplasmosis 200 historical perspectives 3–4 blood–brain barrier 33 intracranial pressure 19 pressure dynamics 259 ventricular drainage 49 HIV 185 animal models 298 CSF profiles 185t CSF proteins 291 and meningitis 171 neurological manifestations 185 and syphilis 201 and tuberculomas 197 homocarnosinosis 95 hormones in CSF 11, 74, 75t human T-cell lymphotrophic virus-1 184 Huntington’s disease 118 hydrocephalus, see adult hydrocephalus; normal pressure hydrocephalus hydrostatic indifference point 24 hyperparathyroidism 139

313

hypertension, see idiopathic intracranial hypertension hypotension, see intracranial hypotension hypothyroidism 138 I idiopathic hypereosinophilic syndrome 278 idiopathic intracranial hypertension 102–103 clinical presentation 102 CSF dynamics 103 epidemiology 102 headaches 158 management 264 neuroimaging 65, 103 secondary 102 imaging, see neuroimaging immune surveillance 40, 70 immune system and blood–brain barrier 40–42, 70 chemokines in CSF 75t cytokines in CSF 75t inflammatory mediators 75–76 immunoglobulin intrathecal synthesis 210, 210f See also inflammatory and demyelinating disorders; multiple sclerosis immunoglobulin G (IgG) concentration 72, 73 IgG index 73, 209, 227 infants CSF dynamics and composition 27–29 infantile pyridoxine-dependent seizures 146 infantile spasms 132 lumbar puncture 28 infectious disease screening future trends 305–307 inflammatory and demyelinating disorders 209–220 acute disseminated encephalomyelitis 218 acute transverse myelitis 216–217 antibody responses 209 biomarkers 218 CSF proteins 291–292 monoclonal immunoglobulin bands 219 neuromyelitis optica 217–218 neurosarcoidosis 219 optic neuritis 215–216 and pleocytosis 277 See also multiple sclerosis inflammation, following trauma 252 inflammatory mediators 75–76 intercellular junctions 34 interferon 213 interstitial fluid 11 intracellular junctions 34 intracranial pressure (ICP) 19–24, 20t animal models 300 definition 19 disorders 99–103 See also adult hydrocephalus; idiopathic intracranial hypertension; intracranial hypotension intracranial compartment 19

314

Index

intracranial pressure (ICP)—Cont’d intracranial compliance 21 monitoring 51, 101 Munro-Kellie doctrine 11, 20 normal physiology 19–24 pulsations 20 spinal cord disorders 108 spinal tumors 109 systemic influences blood flow 23f blood gases 24f body position 24 temperature 24 venous pressure 23 vitamin A deficiency 145 volume–pressure relationships 22–23, 22f, 23f waveforms 20–21, 20f, 21f intracranial compliance 21 intracranial hypotension causes 162t headache 161–163 management 265 neuroimaging 65, 66f intracranial volume 11 intraparenchymal hemorrhage 228–229 ions disorders 148–150 normal CSF content 80–81 regulation 39 iron 150 ischemic stroke 225–228 CSF findings 226t myelin basic protein 227 opening pressure 226 tau protein 228 J Japanese encephalitis virus 122 K Kawasaki’s disease 137 Kearns-Sayre syndrome 94 kuru 171 L lactate 83 late infantile neuronal ceroid lipofuscinosis (LINCL) 96 lateral cervical puncture 47, 57 lead 150 leptomeningeal metastases 240–243, 241t, 242t, 242f, 243f pleocytosis 276 leptomeninges 6 leukocytes CNS entry 40, 70 counts in normal CSF 70 extravasion 41 polymorphonuclear 70 lipids cholesterol 80 glycolipids 79 in normal CSF 78–80, 79t phospholipids 79 prostaglandins 80

lipocalin-type prostaglandin D synthase (L-PGDS) 72 lipoproteins 78–80, 79t lumbar catheters 47 lumbar cistern 267 lumbar drains 47–49 lumbar puncture alternatives 57 in children 28 clinical practice 55–60 complications 57–59, 58t contraindications 46, 55–56, 56t headaches, as indication 157–159, 157t indications 55 patient position 45 pre-procedure considerations 56 spontaneous intracranial hypotension 163 techniques 45–46 volumes required 56 lumboperitoneal shunts 47–50, 260 catheter obstruction 49 See also shunts Lundberg waveforms 21, 22f Lyme disease 202–203 CSF glucose 283 Lyme meningitis 203 lymphocytic choriomeningitis virus 179 lymphocytic pleocytosis 274–276 lymphoma 237 M macromolecule transport 38 magnesium abnormal levels 148–149 normal levels 81 magnetic gait 101 magnetic resonance pulse sequences 63 management approaches abnormal CSF glucose 281–284 altered CSF dynamics 259–265 adult hydrocephalus 259–264 idiopathic intracranial hypertension 264 spontaneous intracranial hypotension 265 bloody/pigmented CSF 267–271 subarachnoid hemorrhage 268 traumatic tap 268 CSF pleocytosis 273–279 malaria, cerebral 204 mannose 78 meninges, anatomy 6 meningiomas 233 meningitis bacterial animal models 297 CSF findings 167–173, 168t, 169t CSF protein 168, 290 Enterococcal meningitis 171 and HIV 171 Listeria meningitis 171 following neurosurgery 172 shunt-associated 172 carcinomatous 276 CSF glucose 282–283 differentiating bacterial and viral 169, 170f, 290 drug/chemical-induced 139–140, 140t

meningitis—Cont’d eosinophilic 278 fungal candidal 199 coccidioidal 199 cryptococcal 197–199 headaches 157 and lumbar drains 48 Lyme 201 Mollaret’s 160, 161f, 161t neuroimaging 67f syphilitic 201 trauma related 250 tuberculous 195–197 viral arboviruses 179 enteroviruses 178 general findings 177, 178t herpes viruses 178 lymphocytic choriomeningitis virus 179 mumps virus 180 Menkes kinky hair disease 96 Menkes syndrome 149 metabolic byproducts, removal 11 metastases, see neoplastic disorders methemoglobin 268 methylprednisolone 213 migraine, CSF profile 159 mild cognitive impairment 117–118, 308 mitochondrial cytopathies 93 Mollaret’s meningitis 160, 161f, 161t monoamine neurotransmitter metabolism disorders 94 monoclonal antibody-based therapies 300 motor neuron disorders amyotrophic lateral sclerosis 121 Japanese encephalitis virus 122 poliomyelitis 121–122 stiff person syndrome 122 West Nile virus 122 movement disorders cerebellar ataxias 118 Huntington’s disease 118 Parkinson’s disease 118 See also neuromuscular diseases multiple sclerosis 210–215 CSF analysis 211–213, 211t CSF protein content 211, 291 Munro-Kellie doctrine 11 muscular dystrophies 125 myasthenia gravis 125 mycobacterial infections tuberculomas 197 tuberculous meningitis 195–197 myelin basic protein 227 myelitis, viral 183, 183t myelography 63 myopathies 124 N natalizumab 214 necrotizing myelopathy 110 Nelson’s syndrome 138 neonatal seizures 130, 132 neoplastic disorders 233–244 brain metastases 240, 241t choroids plexus tumors 239

Index

neoplastic disorders—Cont’d CSF markers 235t, 241t ependymomas 239 germ cell tumors 239 gliomas 234, 234t leptomeningeal metastases 240–243, 241t, 242t, 242f, 243f and lymphocytic pleocytosis 274–276 medulloblastoma 238 meningiomas 233 metastatic tumors 240–243 pineal tumors 240 pituitary and suprasellar tumors 236 primary central nervous system lymphoma 237, 237t primary tumors adult 233–238 pediatric 238–240, 238t treatment toxicity 244 vestibular Schwannomas 236 See also paraneoplastic disorders neopterins 84 nerve root disorders 122 neural stem cells 301 neurocysticercosis 204–205 neurodegenerative disorders 115–118 dementia patients 115 mild congnitive impairment 117 See also Alzheimer’s disease; movement disorders neuroimaging adult hydrocephalus 101 of CSF compartment 63–67, 64f, 65f of CSF composition 66, 67f, 309 of CSF flow dynamics 64–65 of CSF metabolites 97 of CSF pressure dynamics 309 headaches 157 magnetic resonance pulse sequences 63 myelography 63 phase-contrast MR 64 post-myelographic CT 64, 64f radionuclide tracers 64 ventriculography 63 neuroimmunological disorders indication for lumbar puncture 55 neurological disease blood–brain barrier dysfunction 42 neurotransmitters 76–77 neuromuscular diseases 121–125, 125t acquired demyelinating polyneuropathies 122–123 acute intermittent porphyria 124 amyloidosis 124 Charcot-Marie-Tooth disease 124 CSF profiles 124t diabetic neuropathy 123 Guillain-Barré syndrome 122, 123 hereditary neuropathies 124 muscular dystrophies 125 myasthenia gravis 125 myopathies 124 plexus disorders 122 See also motor neuron disorders neuromyelitis optica 217–218 neuronal injury 251 neuron-specific enolase 193, 251

neurosarcoidosis 219 neurotransmitters acetylcholine 77 collection of CSF 95 inactivation 39 monoamine neurotransmitter metabolism disorders 94 in normal CSF 76–77 neutrophilic pleocytosis 273 non-Hodgkin’s lymphoma and lymphocytitic pleocytosis 274 nonketotoic hyperglycinemia 94 norepinephrine 77 normal pressure hydrocephalus 100 neuroimaging 65 See also adult hydrocephalus nucleic acid-based assays 305–306 nucleotides 83, 83t nutritional disorders 145–152 protein-calorie malnutrition 148 See also vitamins O opening pressure bacterial meningitis 167 and headaches 159 infants and young children 28 and intracranial pressure 100 intraparenchymal hemorrhage 228 ischemic stroke 226 measurement 45, 159 tuberculous meningitis 195 optic neuritis 215–216 outflow resistance measurement 101 over-drainage 49, 50–51 P pachymeninges 6 paraneoplastic disorders 243–244 pleocytosis 277 parasitic infections 203–205 Parkinson’s disease 118 pericytes 35 peripheral nerve disorders 122 perivascular spaces 7 P-glycoprotein transporter 38t 3-phosphoglycerate dehydrogenase deficiency 94 phospholipids 79 phosphorus 81 physiological functions of CSF 11–17 pia mater 6 pigmentation 69 pituitary apoplexy 138 pituitary tumors 236 pleocytosis 107, 108t autoimmune disorders 277 basophilia 278 empiric therapy 279 eosinophilia 278 granulomatous disorders 277 lymphocytic 274–276, 275f, 276f, 276t management approach 273–279 neutrophilic 273 following seizure 129 toxic disorders 278 traumatic LP

315

polyarteritis nodosa 136 polymerase chain reaction 4 polymorphonuclear leukocytes 70 polyols 78 polyradiculitis, viral 184 post-partum CSF changes 30 potassium disease states 149 normal CSF levels 80 regulation 39–40 pregnancy changes to CSF dynamics 29–30 pressure dynamics of CSF imaging 309 in infants and children 28, 28t management approach 259–265 during pregnancy 29, 29 See also adult hydrocephalus; idiopathic intracranial hypertension; intracranial pressure; normal pressure hydrocephalus pressure monitoring devices 51 primary arteritis 137 prostaglandins 80 protein microarrays 306 proteins abnormal CSF content 288–293, 289t acute infection 291 Alzheimer’s disease 292 amyotrophic lateral sclerosis 293 bacterial meningitis 168, 290 Creutzfeldt-Jakob disease 191 HIV infection 291 increased total content 289, 289t inflammatory demyelinating disease 291 intraparenchymal hemorrhage 228 ischemic stroke 226 low total content 288, 288t multiple sclerosis 211 neurocognitive disorders 292 pathological patterns 290 following seizure 130, 130t, 131 spinal diseases 107, 108t, 110 amino acids 72, 72t biomarkers 290 chemokines 76t cytokines 75t enzymes 74 hormones 74, 75t inflammatory mediators 75–76 intracellular 73, 74t management approach 287–293 measurement 71 myelin basic protein 227 and neurological disorders 288t neuropeptides 74, 75t neurotransmitters 76 normal CSF content 71–76, 73t, 287–288 14-3-3 proteins 192 prions 192 S-100B protein 193, 251 serum proteins 72, 287 sources 71, 287 tau 115, 193, 228, 292 proteomics 215

316

Index

pseudotumor cerebri, see idiopathic intracranial hypertension psychiatric disorders 139 pterins in dopa-responsive dystonia patients 95t normal CSF content 84 pulsations 20 pyruvate 83 Q Quincke’s maneuver 46 R rabies 183 radiation myelopathy 110 Rasmussen syndrome 133 recirculation of CSF 14 renal disorders 150–151 resorption of CSF 14–16 general anatomy 8–9 rheumatoid arthritis 137 S sarcoidosis 219, 277 S-100B protein 193, 261 Schwannomas 236 scleroderma 138 secretion of CSF 12–14 seizures 127–133 common CSF changes cellularity 128, 128t, 129 glucose concentration 130, 131t protein concentration 130, 130t CSF changes in neonates and children cellularity 130, 128t, 129t glucose concentration 132, 131t protein concentration 131, 130t febrile seizures 132 infantile spasms 132 neonatal seizures 132 pathophysiology 127 underlying causes 128 See also epiliptic disorders shunts adjustment 261 anti-siphon devices 260 differential pressure 260 infection 263 lumboperitoneal 47, 260 malfunction 261, 262f principles 260 ventricular 49, 259–262 Sjogren’s syndrome 138 sodium CSF variability 149 normal levels 80 solutes normal CSF content 80–84 plasma and CSF 12t spectrophotometry 269 spinal block 109 spinal cord injuries 253 spinal disorders 107–112 angiomas 110 CSF findings 107–108, 108t

spinal disorders—Cont’d necrotizing myelopathy 110 radiation myelopathy 110 spinal cord tumors 109–110 spinal motor neuropathy 183 spinal trauma 112 spondylitic myelopathy 111 subarachnoid hemorrhage 107 syringomyelia 112 transverse myelitis 107, 111 vascular disorders 111 spinal epidural abscess 173 spinal fluid leaks 250 spinal nerve root injury 60 spirochetal infections Lyme disease 202–203 syphilis 201–202 spondylitic myelopathy 111 spongiform encephalopathies 191–193 spontaneous intracranial hypotension headache 161–163 management 163, 265 pathophysiology 162 stiff person syndrome 122 Still’s disease 137 subarachnoid cisterns 5 subarachnoid hemorrhage 107, 230 headaches 158 tests 268–270 subcommissural organ 7 suprasellar tumors 236 Sweet’s syndrome 137 α-synuclein 118 syphilis asymptomatic neurosyphilis 201 gummatous neurosyphilis 201 meningovascular 202 parenchymatous neurosyphilis 202 syphilitic meningitis 201 syringomyelia 112 systemic lupus erythematous (SLE) 135 T tau protein Alzheimer’s disease 115–116 Creutzfeld-Jakob disease 193 ischemic stroke 228 thecal sac 6 third ventriculostomy 51, 263–264 three-tube test 268 tight junctions 8f, 34, 35f toxicity, tumor treatment 244 toxoplasmosis 205 trace metals 81 transmissible spongiform encephalopathies clinical background 191 CSF findings 191–193 transport mechanisms amino acids 37, 37t blood–brain and blood–CSF barriers 35–39 efflux transport systems 38 glucose 37, 93 macromolecules 38 P-glycoprotein 38t transthyretin 72

transverse myelitis 107, 111, 216–217 trauma apoptosis 253 excitotoxicity 252 glial cell and myelin injury 251 impaired metabolism 252 in infants and children 253 nervous system trauma 250 neuronal and axonal injury 251 spinal cord injury 253 traumatic brain injury 249, 251, 307 trauma protection 11 traumatic tap 268, 278 trephination 3 tuberculomas 197 tuberculous meningitis adenosine deaminase activity 196 CSF findings 195, 196t microbiology 196, 196t polymerase chain reaction 197 proinflammatory cytokines 197 tumors, spinal cord 109–110 See also neoplastic disorders turbidity of CSF 69 Tyndall’s effect 69 U urea 82, 151 uremia 150–151 V variant Creutzfeld-Jakob disease 191 Varicella zoster virus encephalitis 182 vasculitides 277t ventricular drainage 49–51 ventricular system 5 ventriculitis 50 ventriculography 63 ventriculostomy 51 vesicular drainage 3 viral infections 177–185 encephalitis 180–183 animal models 297 enteroviral encephalitis 182 general CSF findings 180, 180t, 181t herpes simplex encephalitis 180 rabies 183 Varicella zoster virus encephalitis 182 West Nile virus encehpalitis 182 HIV 185 human T-cell lymphotrophic virus-1 184 myelitis 183 polyradiculitis 184 spinal motor neuropathy 183 See also meningitis viscosity 69 vitamin deficiency disorders folate 147 vitamin A 145 vitamin B1 145 vitamin B6 146 vitamin B12 146, 299 vitamin C 147 vitamin D 147

Index

vitamin deficiency disorders—Cont’d vitamin E 148 vitamin K 148 vitamins 81–82, 82t Vogt-Koyanagi-Harada 137 volume–pressure relationship (ICP) 22–23, 22f, 23f volume regulation 39

W waveforms (ICP) 20–21, 20f, 21f Wegener’s granulomatosis 136 West Nile virus 122 encephalitis 182 meningitis 179 Whipple’s disease 174 Wilson’s disease 81, 149

X xanthochromia 69, 268, 269 Z zinc 150

317