Color Atlas of Nerve Biopsy Pathology

asd GR.ules original-21

COLOR ATLAS of

NERVE BIOPSY PATHOLOGY Shin J. Oh, M.D.

University of Alabama at Birmingham Department of Neurology Birmingham, Alabama

CRC Press Boca Raton London New York Washington, D.C.

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Library of Congress Cataloging-in-Publication Data Oh, Shin J. Color atlas of nerve biopsy pathology / by Shin J. Oh p.; cm. Includes bibliographical references and index. ISBN 0-8493-1676-6 (alk. paper) 1. Nerves--Biopsy--Atlases. I. Title. [DNLM: 1. Nervous System--pathology--Atlases. 2. Biopsy--Atlases. 3. Nervous System Diseases--pathology--Atlases. WI 140 O36c 2001] RC409 .O46 2001 616.8'047'0222--dc21

2001025801 CIP

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe.

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© 2002 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-1676-6 Library of Congress Card Number 2001025801 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper

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Dedication This book is dedicated to my wife, Dr. Myung-Hi Kim Oh, Professor of Pediatrics, University of Alabama at Birmingham, my sons David and Michael, my daughter-in-law Bryn, and my grandson Braden, the newest addition to my family.

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Preface This book is based on my experience with approximately 2500 nerve biopsies collected during the past 30 years at the University of Alabama at Birmingham. Some of the cases that I did not have in my files were contributed by colleagues throughout the world. The nerve biopsy is now a well-established procedure in the regular practice of neurology, and its processing and interpretation have become integral parts of daily practice of pathology and neuropathology. The field of nerve biopsy pathology should, therefore, no longer be regarded as novel or exotic. This book should be useful in the everyday practice of pathologists and neuropathologists on the front lines of tissue diagnosis, as well as for neurologists who take a special interest in sural nerve biopsy pathology and neuromuscular diseases. I take great pride in the fact that this is the first nerve pathology book to introduce the diagnostic value of the extremely useful staining techniques of fresh-frozen sections. I have tried to provide all necessary practical knowledge regarding sural nerve biopsy pathology by means of a color atlas, which is based on commonly available frozen, paraffin, and semithin sections rather than on ultrastructural electron microscopy studies. The first five chapters present basic information on nerve biopsy, including the techniques of obtaining the nerve specimen, processing and staining methods of the biopsied nerve, and specific diagnostic pathological features. The next seven chapters present information on the nerve pathology of each disease in proportion to its commonness and importance for clinical practice from a biopsy standpoint. The clinicopathological correlation is introduced through the presentation of 46 cases which illustrate its value in the daily practice of neurology. I hope this book contains sufficient practical information on nerve pathology so that every practicing pathologist, neuropathologist, and neuromuscular disease specialist will find it an invaluable companion in his or her daily practice.

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Acknowledgments I thank my wife, Dr. Myung-Hi Kim Oh, for the steadfast encouragement and emotional support which she has provided me over a period of many years, from the conception of this book through its final writing. I also thank my administrative assistant, Dr. Mary Ward, for her masterful help in editing the manuscript, and my laboratory technologists, Judy Killian, Cheryl Snyder, Susan Lett, and Debbie Reynolds, for their superb technical assistance in the processing and staining of many hundreds of biopsied nerve specimens. In addition, I want to thank Drs. Yadollah Harati, Cheryl Palmer, and David Simpson, and Professors M.R.G. de Freitas, O.J.M. Nasmundo, N. Roertson, and Il Nam Sunwoo for providing color slides of their own cases. Finally, I thank Carol Hollander, Jonathan Pennell, and Judith Simon Kamin at CRC Press for their help in the production of this book.

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Author Born in Seoul, Korea, Dr. Shin J. Oh is professor of neurology and pathology at the University of Alabama at Birmingham. He serves as director of the Muscle/Nerve Histopathology Laboratory as well as director of the Department of Clinical Neurophysiology and the Electromyography and Evoked Potentials Laboratory. During his 30-year tenure at UAB, he established and brought the UAB Neuromuscular Disease Program to national and international prominence, published numerous articles, chapters, and abstracts, on electrodiagnosis and neuromuscular diseases, and trained more than 50 fellows, including many from Korea, Turkey, Japan, Poland, Colombia, and Brazil. He is the author of three EMG text books: Clinical Electromyography: Nerve Conduction Studies (1982 and 1993); Electromyography: Neuromuscular Transmission Study (1988); and Principles of Clinical Electromyography: Case Studies (1998). Dr. Oh serves on several medical advisory and journal review boards and, in recent years, has been an invited lecturer in Australia, Colombia, the Czech Republic, Korea, New Zealand, Turkey, and the United States. His interests include myasthenia gravis, Lambert–Eaton myasthenia syndrome, tarsal tunnel syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), vasculitic neuropathy, and nerve biopsy. His special interest in nerve biopsy led him to recognize early the subacute form of CIDP, chronic sensory demyelinating neuropathy, sensory Guillain–Barré syndrome, multifocal motor-sensory demyelinating neuropathy, and the diagnostic value of sural nerve biopsy in vasculitic neuropathy. Finally, this led him to write the classic paper on the diagnostic usefulness and limitation of sural nerve biopsy, which is the forerunner of this book.

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Table of Contents Chapter 1 General Concepts of Peripheral Neuropathy Classification of Peripheral Neuropathy Basic Pathological Mechanism Axonal Degeneration Wallerian Degeneration Dying-Back Axonal Degeneration Axonal Degeneration in Neuronopathy Secondary Axonal Degeneration Segmental Demyelination Secondary Segmental Demyelination Etiologies of Peripheral Neuropathy Types of Neuropathies Pattern of Involvement Polyneuropathy Mononeuropathy Multiplex Mononeuropathy Systemic Involvement Size of Nerve Fibers Symptoms and Signs Motor Nerve Dysfunction Sensory Nerve Dysfunction Autonomic Nerve Dysfunction Diagnostic Investigations Nerve Conduction Studies and Needle Electromyography Laboratory Studies References Chapter 2 The Nerve Biopsy Indication for the Nerve Biopsy Types of Nerve Biopsy Sural Nerve Biopsy Sequelae of Nerve Biopsy Biopsy of Other Nerves Superficial Peroneal Nerve Biopsy Superficial Radial Nerve Biopsy References Chapter 3 Histological Processing and Staining of the Biopsied Nerve Treatment of the Biopsied Nerve Immediate Care of the Biopsied Nerve

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Processing of the Nerve Paraffin Section Stainings Hematoxylin and Eosin Stain Modified Trichrome Stain Alkaline Congo-Red Stain Frozen Section Stainings Modified Trichrome Stain Hematoxylin and Eosin (H & E) Stain PASH (Periodic Acid Schiff and Hematoxylin) Stain Hirsch-Peiffer Cresyl-Violet Stain Alkaline Congo-Red Stain Processing of the Nerve for Semithin and Electron Microscopy Sections Processing and Embedding Procedure Semithin (0.5 – 1µm) Section Stainings Toluidine Blue and Basic Fuchsin Stain (Paragon Multiple Stain) Toluidine Blue Stain Other Stains Nerve Fiber Teasing Preparation of Nerve for Teasing General Guidelines for Teasing of Fibers Practical Tips for Teasing Fibers Preparing the Slide after Teasing Electron Microscope Study References Chapter 4 Normal Nerve: Histology Age-Related Changes in the Sural Nerve Biopsy References Chapter 5 Specific Diagnostic Pathological Features of Nerve Biopsy Vasculitis Amyloid Deposits Metachromatic Granules Polyglucosan Body Onion-Bulb Formation Inflammatory Cells and Segmental Demyelinatio Inflammatory Cells and Axonal Degeneration Noncaseating Granuloma Necrotizing (Caseating) Granuloma Giant Axons Tomacula Occlusion of Vasa Nervorum Malignant Cells IgM Deposits Segmental Demyelination Axonal Degeneration References

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Chapter 6 Vasculitic Neuropathy Vulnerability of the Peripheral Nerve to Vasculitic Neuropathy Clinical, Electromyographic, and Laboratory Features Diagnostic Sensitivity of Nerve and Muscle Biopsies Pathology of Vasculitic Neuropathy Pathogenesis of Vasculitic Neuropathy Systemic Necrotizing Vasculitides Polyarteritis Nodosa Churg–Strauss Syndrome (Allergic Granulomatosis) Wegener’s Granulomatosis Temporal (Giant Cell) Arteritis Vasculitis Associated with Connective Tissue Diseases Rheumatoid Arthritis Systemic Lupus Erythematosus (SLE) Sjögren’s Syndrome Hypersensitivity Vasculitis (HSV) Nonsystemic Vasculitic Neuropathy Vasculitis in Other Diseases Cases with Vasculitic Neuropathy Case 1: A Patient with Fever of Unknown Etiology for 1 Month Case 2: Numbness in the Right Foot in a Patient with Asthma Case 3: Numbness and Weakness in the Left Leg in a Patient with Endometrial Carcinoma Case 4: Hepatitis C, Cryoglobulinemia, and Vasculitic Neuropathy Case 5: Numbness and Pain in Legs with INH Treatment Case 6: High Sedimentation Rate in a Patient with Subacute Symmetrical Polyneuropathy Case 7: 3-Month History of Mononeuropathy Multiplex Case 8: Guillain–Barré Syndrome? Case 9: Progressive Multifocal Motor and Sensory Deficits over 3 Months References Chapter 7 Inflammatory Demyelinating Neuropathy Pathogenesis of Inflammatory Demyelinating Neuropathies Guillain–Barré Syndrome (Acute Inflammatory Demyelinating Polyneuropathy; AIDP) Variants of GBS Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Multifocal Motor Neuropathy (MMN) Multifocal Motor Sensory Demyelinating Neuropathy (MMSDN) Chronic Sensory Demyelinating Neuropathy (CSDN) Cases of Inflammatory Demyelinating Neuropathy Case 1: Acute Motor Neuropathy with Axonal Neuropathy Case 2: Relapse of GBS Case 3: Acutely Developing "Ileus" Case 4: Subacute Sensory-Motor Neuropathy with 13 Negative Biopsies

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Case 5: Diffuse Areflexia in an MS Patient Case 6: Subacute Sensory-Motor Weakness after a Flu Vaccine Case 7: Uniform Slowing in the Nerve Conduction Study Case 8: Chronic Motor Weakness with Fasciculation and Hyperreflexia Case 9: Flail Arms for 3 Years Case 10: MMN with Sensory Deficits Case 11: Painful Sensory Neuropathy for 5 Years References Chapter 8 Immune-Mediated Neuropathies GM1 Antibody-Positive Neuropathy Anti-MAG Associated Neuropathy Neuropathy Associated with Anti-Hu (ANNA 1) Antibody Neuropathy with Monoclonal Gammopathy Polyneuropathy Associated with Monoclonal Gammopathy of Undetermined Significance (MGUS) Peripheral Neuropathy Associated with Osteosclerotic Myeloma (OSM) Peripheral Neuropathy Associated with Typical Multiple Myeloma (MM) Neuropathy Associated with Waldenström’s Macroglobulinemia (WM) Peripheral Neuropathy with Cryoglobulinemia Cases of Immune-Mediated Neuropathy Case 1: Numbness and Tingling Sensation in the Hands for 12 Years Case 2: Progressive Unsteady Gait for 5 Months in a Smoker Case 3: 2-Month History of Numbness of Hands and Feet in a 68-Year-Old Man Case 4: Progressive Sensory-Motor Neuropathy, Biclonal Gammopathy, Skin Discoloration, Pleural Effusion, and Hepatomegaly for 4 Years Case 5: Progressive Weakness of Legs for 6 Months in a Patient with History of Lymphadenopathy References Chapter 9 Neuropathies with Abnormal Deposits Amyloid Neuropathy Familial Amyloid Polyneuropathy (FAP) Nonfamilial Amyloid Neuropathy Pathology of Amyloid Neuropathy Metachromatic Leukodystrophy (Sulfatide Lipidosis; Arylsulfatidase Deficiency) Polyglucosan Body Neuropathy Fabry’s Disease (Alpha-Galactosidase-A Deficiency) Adrenomyeloneuropathy (AMN) Cases of Neuropathy with Abnormal Deposit Case 1: 6-Month History of Burning Dysesthesia in All Limbs and 4-Year History of Impotence Case 2: Delayed Walking and Hand Tremors in a 27-Month-Old Girl Case 3: A 2-Year History of Parkinsonism, Upper Motor Neuron Signs, and Peripheral Neuropathy

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References Chapter 10 Hereditary Neuropathies Hereditary Motor and Sensory Neuropathies (HMSN) HMSN Type I (Hypertrophic Form of the CMT Disease Including Roussy–Levy Syndrome) Roussy–Levy Syndrome Sex-Linked CMT HMSN Type II (Neuronal Type of CMT; CMT 2) HMSN Type III (Dejerine–Sottas Disease; DSA and DSB) Congenital Hypomyelination Neuropathy Autosomal Recessive CMT (CMT 4; CMT 4B) Hereditary Sensory Neuropathy Type I Hereditary Sensory Neuropathy (Hereditary Sensory Radicular Neuropathy of Denny–Brown; Dominant HSN; HSAN Type I) Type II HSN (Congenital Sensory Neuropathy; Recessively Inherited HSN; HSAN Type II) Hereditary Neuropathy to Pressure Palsy (HNPP) Giant Axonal Neuropathy (GAN) Friedreich’s Ataxia Cases with Hereditary Neuropathy Case 1: Hand-Shaking as an Initial Manifestation of Hereditary Neuropathy Case 2: CMT Patient with Conduction Block Case 3: Autosomal Recessive CMT with Focally Folded Myelin Case 4: 3-Year Worsening of Gait Difficulty, Present Since Early Childhood Case 5: Global Weakness and Sensory Loss in the Entire Left Arm in a Worker’s Compensation Case Case 6: A 31-Year-Old Woman with Numbness and Tingling Sensation in the Legs for 6 Months Case 7: Progressive Walking Difficulty for 19 Months in a Child With Insulin-Dependent Diabetes Mellitus References Chapter 11 Metabolic and Systemic Neuropathies Sarcoid Neuropathy Sensory Perineuritis Leprosy Lymphomatous Neuropathy Diabetic Neuropathy Diabetic Ophthalmoplegia Diabetic Amyotrophy (Diabetic Proximal Neuropathy) Diabetic Sensory Neuropathy Diabetic Polyneuropathy Uremic Neuropathy Alcoholic Neuropathy Hypothyroid Neuropathy

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Vitamin B12 Deficiency Neuropathy Pyridoxine-Induced Sensory Neuropathy Polyradiculoneuropathy in Lyme Disease AIDS Neuropathy Cases of Neuropathy Associated with Systemic Diseases Case 1: Subacute Symmetrical Polyneuropathy for 6 Months Case 2: Subacute Peripheral Neuropathy with White Matter Disease in the Brain MRI Case 3: Neuropathy in a Type I Diabetic with Many Microangiopathy Complications Case 4: 9 Months of Progressive Neuropathy in a 72-Year-Old Woman with Insulin-Dependent Diabetes Mellitus for 15 Years Case 5: Uremic Neuropathy in a Young Patient Whose Two Brothers Had Renal Problems Case 6: Subacute Neuropathy in a Chronic Alcoholic Patient Case 7: Paresthesia of Feet and Abdominal Colic at the Onset of Neuropathy References Chapter 12 Toxic Neuropathies Metal Neuropathies Arsenic Neuropathy Thallium Neuropathy Lead Neuropathy Cisplatinum Neuropathy Drug-Induced Neuropathy Neuropathy Due to Biological Toxins and Vaccines Diphtheritic Neuropathy Vaccine-Induced Neuropathy Toxic Neuropathy Due to Industrial and Environmental Agents Epidemic Toxic Inflammatory Neuropathies Spanish Toxic Oil Syndrome Eosinophilia–Myalgia Syndrome Cases of Toxic Neuropathies Case 1: Subacute Neuropathy in a 19-Year-Old Girl with Possible Anorexia Nervosa Case 2: Progressive Ascending Weakness in the Extremities and Numbness in the Toes for a Few Months Case 3: Subacute Progression of Weakness for 31/2 Months after Swine-Flu Vaccination Case 4: Guillian–Barré Syndrome Following Ingestion of an Unknown Amount of Antifreeze References Chapter 13 Interpretation of Nerve Biopsy References

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General Concepts of Peripheral Neuropathy

Peripheral neuropathy is one of the most common neurological disorders and refers to a disease involving the peripheral nerves, including motor, sensory, and autonomic nerves, with predominant clinical manifestations of weakness, loss of sensation, and muscle wasting. The frequency of peripheral neuropathy is not known, but it is a common feature of many systemic diseases. Diabetes is the most common cause of peripheral neuropathy in adults living in developed countries. Considering that 1.3% of the general population of the United States has diabetes mellitus and that roughly 25% of diabetic patients have peripheral neuropathy, peripheral neuropathy is considered a common disease. In fact, 1 out of 300 individuals has peripheral neuropathy associated with diabetes. This figure excludes other causes of peripheral neuropathy. The most important distinction between the central and peripheral nervous systems is the ability of the peripheral nerves to regenerate after disease or injury. Thus, the chance of clinical improvement is better in peripheral neuropathy than in any central nervous system diseases.

CLASSIFICATION OF PERIPHERAL NEUROPATHY There are two major anatomic components of the peripheral nerves — axons and myelin. Peripheral nerve axons are simply cytoplasmic extensions of the neurons. The axons are responsible for the maintenance and function of the peripheral nerves and derive most of the protein essential for this purpose from the neurons. Along the axons, membrane components, organelles, nutrients, and metabolic products are transported as axoplasm at different velocities in both directions.1 This system renders the axons extremely vulnerable to any metabolic changes in the neurons. Thus, severe damage to the neurons and disruption of proximal axonal integrity result in rapid degeneration of the entire distal portion of the axons. On the other hand, injury to the distal portion of the axons does not result in permanent damage to the neurons; the latter undergo transient swelling and breakdown of the endoplasmic reticulum (chromatolysis), but they usually survive and support regeneration of the damaged axons.2 The myelin of peripheral nerves is derived from the Schwann cells and is dependent on both the Schwann cells and the axons for its continued integrity. Myelin is responsible for the conduction of nerve action potentials along the nerves. This is due to saltatory conduction in myelinated fibers. Schwann cells envelop axons to form unmyelinated and myelinated fibers surrounded by basal lamina. A single Schwann cell occupies each myelinated internode, almost never associating itself with more than one axon.3 Damage to the axons results in the prompt breakdown of myelin but not of the Schwann cells. On the other hand, loss of myelin does not usually result in disruption of the axons. An axon denuded of several segments of myelin simply awaits Schwann cell division and remyelination before resuming normal impulse conduction.4 Depending on which component of the peripheral nerve is predominantly involved in the pathological process, peripheral neuropathy can be classified into two main categories: axonal degeneration and segmental demyelination (Table 1.1). There are also clear pathophysiological differences between axonal degeneration and segmental demyelination, as noted in Table 1.1.

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TABLE 1.1 Pathophysiology of Two Types of Peripheral Neuropathy Type

Axonal Neuropathy

Demyelinating Neuropathy

Primary lesion Pathological process Pathology by teasing preparation Regeneration: mechanism speed Nerve conduction: velocity

Axon Axonal degeneration Myelin ovoids

Myelin Demyelination Segmental demyelination

Axonal sprouting Slow

Remyelination Rapid

Mildly slow: above 30 m/sec Low amplitude

Markedly slow: below 30 m/sec Dispersion: conduction block

(++++)

(-) or (±)

Absent Arsenic, thallium, gold Alcoholic Nutritional Vasculitic Giant axonal Porphyric neuropathy Vitamin B12 Diabetic neuropathy Uremic neuropathy

Present in chronic form Guillain–Barré syndrome CIDP Hypertrophic Metachromatic Tomaculous Leprosy Multifocal motor neuropathy Diphtheric Charcot–Marie–Tooth 1 A

CMAP: Needle EMG: Fibrillation and positive sharp wave Fasciculation Examples:

Abbreviations: CMAP, Compound muscle action potential CIDP, Chronic inflammatory demyelinating polyneuropathy EMG, Electromyography

BASIC PATHOLOGICAL MECHANISM The peripheral nerves have a limited means of reacting to disease, i.e., axonal degeneration and segmental demyelination. It should be pointed out that an element of a minor process may coexist with the predominant process in almost all peripheral neuropathies.

AXONAL DEGENERATION The disease process affects axons primarily by producing axonal degeneration and secondarily by causing breakdown of the myelin sheath. Axonal degeneration is induced by three different mechanisms: (1) axonal degeneration distal to the site of transection of the nerve (Wallerian degeneration); (2) degeneration of the distal axons due to a metabolic derangement throughout the axon (dying-back degeneration; axonopathy) (Figure 1.1); and (3) axonal degeneration following morphologic or metabolic derangement in the neuron cell body (neuronopathy) (Color Figure 1.1).* Wallerian Degeneration The classical description of axonal degeneration following transection of a nerve was provided by Waller in 1850.5 When a nerve is totally transected, continuity of the axon is broken. As in all cells, the * Color insert figures.

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FIGURE 1.1 Mechanism of axonal degeneration and regeneration. Axonal degeneration is induced either by a metabolic derangement either in the neuron cell body (motor neuronopathy) or throughout the axon (dying-back axonal degeneration) (early; arrows). Damage to the neurons and disruption of proximal axonal integrity result in rapid degeneration of the entire distal portion of axon, producing breakdown of the myelin sheath (late). Regeneration occurs with axonal sprouting. (Reproduced with permission from Oh, S.J., Diagnostic usefulness and limitations of the sural nerve biopsy, Yonsei Med. J., 1990;31; 2.)

part of the cytoplasm (axon) separated from the nucleus (neuron) gradually degenerates, producing axonal degeneration in the portion distal to the transection. The cardinal features of Wallerian degeneration are as follows: • It results from transection of an axon. • Paralysis and anesthesia in the distribution of the nerve are immediate, due to the conduction failure of the nerve impulse across the transected segment. • Axons and myelin sheaths degenerate distal to the site of transection. • Conduction over the distal segment fails in 3 or 4 days as the distal nerve becomes inexcitable. • Distal muscles undergo denervation atrophy. • Prominent fibrillation and positive sharp waves occur in distal muscles in 8–14 days. • Nerve cell chromatolysis may occur in severe cases. • A burst of Schwann cell proliferation takes place distal to transection. • Regeneration from the proximal stump begins early but proceeds slowly by the process of axonal sprouting at the rate of 2 or 3 mm per day. • Recovery is variable and depends upon (1) intactness of the neural tube (endoneurium, perineurium, and epineurium) — when the neural tube is intact, regeneration occurs spontaneously and is of excellent quality; (2) the proximo–distal site of injury — the more distal the lesion, the better the recovery; (3) the age of the individual — the younger the patient, the better the recovery; and (4) the closeness of approximation of the severed ends and the degree of adjacent soft-tissue injury — the closer the approximation of the severed ends and the less the degree of adjacent soft tissue injury, the better the recovery.

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Wallerian degeneration occurs following direct trauma to a nerve. In peripheral neuropathy, Wallerian degeneration occurs in vasculitic neuropathy. It is generally believed that in the vasculitides, the nerve fiber damage results from local ischemia severe enough to produce focal axonal damage and distal Wallerian degeneration.6

DYING-BACK AXONAL DEGENERATION Initially, a metabolic abnormality occurs throughout the axons (Color Figure 1.1 and Figure 1.1). Failure of axon transport results in degeneration of vulnerable distal regions of long or large-diameter axons.7 Degeneration appears to advance proximally toward the nerve cell body (dying-back). The clinical effect of this phenomenon is distal symmetrical polyneuropathy. The cardinal features of dying-back axonal degeneration are: • Metabolic abnormalities throughout the axon. • Initial distal axonal change. • Eventual axonal degeneration resembling Wallerian degeneration except that the early ultrastructural changes are spread over a much longer period.8 The myelin sheath breaks down concomitantly with the axon. Secondary demyelination and remyelination may occur more proximally, where the axon is still intact. • Normal or mildly slow conduction until it fails completely. The amplitudes of compound muscle action potential (CMAP) and compound nerve action potential (CNAP) are markedly reduced. • Denervation atrophy in distal muscles. • Prominent fibrillation or positive sharp waves in distal muscles. • Chromatolysis is sometimes present in severe cases. • More indolent and prolonged Schwann cell proliferation than in Wallerian degeneration.9 • Schwann cells and basal lamina tubes remaining in distal nerves and facilitating appropriate peripheral regeneration.

FIGURE 1.2 Mechanism of sensory neuronopathy and regeneration. Sensory neuronopathy is induced by metabolic derangement in the dorsal root ganglion (at onset). Degeneration of these cells is accompanied by fragmentation and phagocytosis of the peripheral-central processes (early). The Schwann cells remain; there is no axonal regeneration (late).

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• Recovery by axonal sprouting that reinnervates denervated muscles. • Slow recovery, proceeding at a rate of 2 or 3 mm per day, sometimes partial, depending on the basis of the neuropathy and its severity. The majority of metabolic and toxic neuropathies are due to this mechanism. Characteristically, the disease is insidious on onset, commences distally, and slowly proceeds toward the neuron cell body, resulting in symmetrical distal polyneuropathy. Axonal Degeneration in Neuronopathy In this process, the primary target of the disease process is in the nerve cell body. (Color Figure 1.1). Either the lower motor neurons or the primary sensory neurons may be affected. Thus, clinical manifestations depend on whether the affected neurons are motor or sensory. When the anterior horn cells are the target of disease, pure motor impairment is the consequence, as noted in poliomyelitis, motor neuron diseases, and the neuronal type of the Charcot–Marie–Tooth disease (HSMN Type II). When dorsal root ganglia cells are the target of disease, a pure sensory neuronopathy syndrome occurs, as in acute sensory neuropathy,10 herpes zoster, carcinomatous sensory neuropathy, and hereditary sensory autonomic neuropathy Type II (Color Figure 1.1 and Figure 1.2). The cardinal features are listed below: • Morphologic or metabolic abnormalities in the motor or sensory neurons. • Pathological changes appearing in the neuronal perikaryon, soon followed by axonal degeneration throughout the length of the axon. Clinically, widespread manifestation is the rule. • Axonal degeneration confined to the nerve that is controlled by the involved neurons: motor nerves in anterior horn cell diseases and sensory nerves in dorsal root ganglia diseases. • Eventual axonal degeneration resembling Wallerian degeneration, though the process is much slower. Myelin sheath breakdown concomitant with that of the axon. • Nerve conduction abnormality depending on the selective nerve cell loss. In anterior horn cell diseases, sensory nerve conduction is normal, and motor nerve conduction shows findings typical of axonal degeneration (motor neuronopathy pattern). In dorsal root ganglia diseases, normal motor nerve conduction and markedly abnormal sensory nerve conduction (sensory neuronopathy pattern), either absent CNAP or markedly reduced CNAP amplitude, are the rule. • In anterior horn cell diseases, prominent denervation atrophy and muscle weakness are the characteristic findings. In dorsal root ganglia diseases, loss of sensation and sensory ataxia reflecting the disappearance of sensory neurons are the usual findings. Sensory syndrome differs depending on the selective involvement of small or large cells in the dorsal root ganglia; pain and temperature are predominantly affected in small cell loss and proprioception is mainly affected in large cell loss. • Prominent fibrillation, positive sharp waves, and fasciculation in distal muscles in anterior horn cell diseases. • Regeneration occurring through collateral sprouting from surviving axons. However, recovery is usually poor.11 This is especially true in sensory neuronopathy.

SECONDARY AXONAL DEGENERATION It is well known that axonal degeneration occurs following severe primary demyelination in human neuropathies12,13 and in experimental demyelinating neuropathy.14 The most likely mechanism is that the Wallerian degeneration is initiated at sites of severe segmental demyelination.12 The electromyography

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test shows prominent fibrillation and positive sharp waves in addition to findings typically seen in segmental demyelination. In the Guillain–Barré syndrome, profuse fibrillations and positive sharp waves within the first four weeks of the illness, indicative of severe axonal degeneration, are associated with a prolonged recovery time and more pronounced residual deficits.15 In the entrapment neuropathies, axonal degeneration over the segment distal to the entrapment site is a well-known observation. This accounts for the minimal motor and sensory nerve conduction abnormalities distal to the entrapment site in entrapment neuropathies.

SEGMENTAL DEMYELINATION About 30 years after Waller’s classic description of axonal degeneration, Gombault16 described segmental demyelination in the nerves of a guinea pig with chronic lead intoxication (Color Figure 1.1 and Figure 1.3). Myelin sheath damage occurred in the internodal segments with sparing of axons. Each segment represented the length of one Schwann cell and its myelin sheath. The cardinal characteristics of segmental demyelination are: • Primary damage of the myelin sheath, leaving the axon intact. • Demyelination, usually beginning at the nodes of Ranvier. Segmental demyelination is induced by various mechanisms, including (1) metabolic damage of Schwann cells, as noted in diphtheric neuropathy; (2) telescoping (intussusception) of myelin, as noted in entrapment neuropathies; (3) edema formation within the myelin sheath, as noted in galactocerebroside neuropathy; and (4) peeling and engulfment of myelin by activated lymphocytes and macrophages, as noted in the Guillain–Barré syndrome. • Segmental demyelination, which may be diffuse, multifocal, or focal. • Conduction block or marked slowing of nerve conduction resulting from segmental demyelination. • Absent or rare fibrillation and positive sharp waves, but fasciculation not uncommon.

FIGURE 1.3 Mechanism of segmental demyelinaton and remyelination. Segmental demyelination is induced by metabolic damage of Schwann cells or peeling and engulfment by activated inflammatory cells (early). This process affects the myelin sheath producing primary segmental demyelination and leaving the axon intact (late). Remyelination occurs with myelination over demyelinated segment. (Reproduced with permission from Oh, S.J., Diagnostic usefulness and limitations of the sural nerve biopsy, Yonsei Med. J., 1990;31; 2.)

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• • • •

No denervation atrophy in muscles. Disuse atrophy occurs if paralysis is prolonged. Chromatolysis of the nerve cell body does not occur. Schwann cell proliferation is not as brisk as in Wallerian degeneration.9 The Schwann cell division and remyelination of the axon forms short internodes of thin myelin in the remyelination process. Once remyelination begins, rapid and usually complete recovery occurs. • In cases of repeated demyelination and remyelination processes, Schwann cells divide again and some of the daughter cells are unable to find a segment of axon to surround. They become detached and form a thin layer around the fibers. Thus, onion bulbs are formed.

SECONDARY SEGMENTAL DEMYELINATION This concept has recently been well documented by Dyck et al.17,18 They described segmental demyelination over many consecutive internodal segments along atrophic axons in Friedreich’s ataxia and uremic neuropathy, taking the view that segmental demyelination is the result of primary axonal degeneration. In contrast to primary demyelination, which tends to show a random distribution of segmental demyelination, secondary demyelination is characterized by segmental demyelination over many consecutive internodes. The needle EMG study shows findings typical of primary axonal degeneration.

ETIOLOGIES OF PERIPHERAL NEUROPATHY The most common known cause of peripheral neuropathy in the United States is diabetes mellitus, followed by chronic alcoholism, whereas in the world as a whole the most common cause is leprosy. For neurology patients, the most common cause of peripheral neuropathy is the Guillain–Barré syndrome (GBS). Despite extensive and costly evaluations, the causes of peripheral neuropathy remain unknown in a substantial number of cases. In 2 studies conducted in the 1980s, the causes were undetermined in only 13 to 24% of cases (Table 1.2). These figures were reported from centers where the sural nerve biopsy is used extensively to identify the cause of peripheral neuropathy. Compared with 52 to 70% in the 1960s, the frequency of unknown causes has decreased over the years. This decrease is due mainly to four factors: (1) greater sophistication of the electrophysiological study of differentiation between axonal neuropathy and demyelinating neuropathy; (2) classification of inflammatory neuropathies such as GBS as a known cause; (3) monoclonal neuropathy and paraneoplastic neuropathy are now known causes of some neuropathies, and (4) increasing use of the nerve biopsy in the work-up for peripheral neuropathy.

TYPES OF NEUROPATHIES Neuropathies can be categorized based on disease mechanisms and the size of involved nerve fibers, as discussed above, the pattern of involvement, and the clinical manifestation of diseases. All of these are helpful for diagnosis, for detection of the cause of neuropathy, and, eventually, for treatment.

PATTERN OF INVOLVEMENT The pattern of involvement can be either polyneuropathy, mononeuropathy multiplex, or mononeuropathy. This distinction is important because it provides the most helpful clinical clue as to the cause of the neuropathy.

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TABLE 1.2 Frequency of Unknown Causes in Peripheral Neuropathy Authors

Case Number 46

Unknown Cause (%) 70

Rose (1960)

80

56

GBS is listed as a known cause.

Prineas (1970)

278

14

GBS is listed as a known cause.

Dyck (1981)

205

24

Inflammatory neuropathy is listed as a known cause.

Fagius (1983)

91

74

Chronic inflammatory or hereditary neuropathies are listed as unknown causes.

519

13

Inflammatory neuropathy is listed as a known cause. All cases had sural nerve biopsy.

Mathews (1956)

McLeod (1984)

Comments GBS is listed as an unknown cause.

Polyneuropathy A polyneuropathy is a symmetrical, distal, usually ascending neuropathy due to involvement of the distal branches of nerves. Stocking-glove dysesthesia is the classic term describing the distribution of sensory impairment. Tingling, numbness, and pain, as well as sensory loss, occur in a symmetrical stocking or glove distribution in the feet or hands. Foot drop is common due to weakness of the lower leg muscles. Mixed sensorimotor polyneuropathy suggests nutritional neuropathy (due to alcoholism, beriberi, vitamin B deficiency, or pernicious anemia), metabolic neuropathy (caused by diabetes mellitus or uremia), and toxic neuropathy. Sensory polyneuropathy suggests a benign idiopathic sensory neuropathy, neuropathy related to diabetes or pernicious anemia, chronic sensory demyelinating neuropathy, and arsenic neuropathy. Sensory ataxic neuropathy is classically seen in paraneoplastic polyneuropathy or Sjögren’s neuropathy. Motor polyneuropathy suggests Guillain–Barré syndrome or chronic inflammatory demyelinating polyneuropath neuropathy (CIDP). Proximal neuropathy is rare and found mostly in inflammatory polyneuropathies such as GBS and CIDP. Cranial neuropathy can produce ophthalmoplegia, and swallowing and speech difficulty. GBS and Lyme disease frequently involve the facial nerves. Respiratory muscle weakness is rare but is one of the most dreadful symptoms of GBS because it is life threatening. Mononeuropathy Multiplex Mononeuropathy multiplex involves two or more nerves in more than one extremity, e.g., left ulnar neuropathy and right peroneal neuropathy. This is classically seen in vasculitic neuropathy. Two other causes of mononeuropathy multiplex are leprosy and diabetes mellitus. A rare cause of this disease is multifocal demyelinating neuropathy, including multifocal motor neuropathy (MMN) and multifocal motor-sensory demyelinating neuropathy (MMSDN). The detection of MMN is especially important because many patients may be misdiagnosed with amyotrophic lateral sclerosis (ALS). MMN is a treatable disease that responds to intravenous immunoglobulin (IVIG) treatment.

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Mononeuropathy The most common cause of mononeuropathy is entrapment neuropathy due to the compression of a nerve in an anatomically narrow area. The best example of this is carpal tunnel syndrome. Certain mononeuropathies are common to certain diseases, for example, femoral neuropathy and ophthalmoplegic neuropathy with pupil sparing in diabetes mellitus, recurrent or bilateral facial nerve palsy in sarcoidosis and Lyme disease, and radial nerve palsy in lead neuropathy.

SYSTEMIC INVOLVEMENT Systemic involvement deals with motor, sensory, autonomic, and mixed neuropathy. Pure motor and sensory neuropathies are described above. Most toxic and metabolic neuropathies are mixed motorsensory neuropathies.

SIZE OF NERVE FIBERS Large-fiber neuropathy is characterized by motor weakness and loss of vibration and position sense. Most neuropathies are large-fiber neuropathies and are thus easily detectable by the nerve conduction study, which usually tests the large fibers of nerves. Small-fiber neuropathy is a painful sensory neuropathy that occurs in diabetes, alcoholism, amyloidosis, leprosy, and AIDS.

SYMPTOMS AND SIGNS MOTOR NERVE DYSFUNCTION When motor nerves are affected, the primary manifestation is weakness. Muscle wasting may follow if the weakness persists. Distal leg weakness produces foot drop, causing patients to trip on their toes because they cannot fully flex their foot as they walk. Proximal leg weakness is most commonly reported as difficulty in getting out of a chair or climbing stairs. Weakness of the hands affects grip and fine coordination, such as that needed for writing or fastening buttons. Proximal weakness of the arms often causes difficulty with such routine chores as carrying groceries and brushing the teeth and hair. Occasionally, cramps or twitching (fasciculation) are described in motor nerve dysfunction. On examination, in addition to muscle weakness, muscle wasting and diminished tone may be seen in motor nerve dysfunction. Reflexes are also diminished or absent because the motor nerve is an efferent limb of the reflex arc. When the cranial nerves are involved, patients may have double vision due to paresis of the eye muscles, as well as swallowing and speech difficulty due to bulbar paresis. When the respiratory muscles are involved, breathing difficulty occurs. This is a life-threatening warning sign because respiratory dysfunction is the killer in peripheral neuropathy.

SENSORY NERVE DYSFUNCTION When sensory nerves are affected, the primary manifestation is abnormal sensation (dysesthesia). This complaint is usually reported as tingling, numbness, dead feeling (like a shot of novocaine), burning, or pain. In fact, pain is the most common complaint that brings patients with peripheral neuropathy to the physician. Patients with significant sensory loss in their feet may complain that they feel like they are walking on sand or are unsteady in a dark room because the visual input that usually compensates for the numbness is absent (sensory ataxia). On examination, decreased or absent pin-prick and temperature sensations are noted when small myelinated fibers are affected (small-fiber neuropathy). Loss of vibration or position sense is prominent when large myelinated fibers are affected (large-fiber neuropathy). Burn scars or unhealed ulcers are signs of severe sensory loss.

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Prominent sensory loss diminishes reflexes because the afferent limb of the reflex arc is sensory. When sensory loss becomes severe, patients may not perceive minor traumas and pressure and may, therefore develop trophic ulcers or arthritis (Charcot joint) without being aware of them. This is common in leprosy, diabetes, and amyloidosis.

AUTONOMIC NERVE DYSFUNCTION As subtle signs of autonomic nerve dysfunction, skin discoloration and hair loss are common findings in peripheral neuropathy. When autonomic nerve dysfunction is severe, the most common complaint is orthostatic manifestations (e.g., light-headedness or syncope on standing). Constipation or diarrhea due to bowel dysfunction, urinary retention caused by bladder dysfunction, and impotence are not uncommon findings. Evaluation of orthostatic blood pressure, measurement of the post-voiding residual in the bladder, and pupillary light response may aid in the identification of autonomic nerve dysfunction. Tonic pupils (large pupils without any light response) are commonly present in severe autonomic nerve dysfunction. Rarely, pseudo-obstruction of the gut occurs due to total paralysis of the gut muscles.

DIAGNOSTIC INVESTIGATIONS The first diagnostic step is to rule out other lower motor neuron diseases which can mimic peripheral neuropathy (Table 1.3) and confirm that the patient has a peripheral neuropathy. The major manifestations of neuropathy are muscle weakness, sensory loss to all modalities, weak or absent reflexes, and trophic changes, as described above. Among these, sensory impairment is the most important clue for peripheral neuropathy. Causes of generalized weakness include anterior horn cell diseases, disorders of the neuromuscular junction (myasthenia gravis), and myopathy. In these diseases, there should not be any sensory loss upon examination because sensory fibers are not damaged.

TABLE 1.3 Differential Clinical Features in Neuromuscular Disorders Anterior Horn Cell

Peripheral Nerves

Neuromuscular Junctions

Muscle

Involved area

Widespread

Distal

Proximal/ oculobulbar

Proximal

Motor or sensory impairment

Motor

Mixed

Motor

Motor

Reflexes

Weak/absent

Weak/absent

Normal

Normal

Other helpful signs

Fasciculation

Disease

Amyotrophic lateral sclerosis

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Myasthenic symptoms Peripheral neuropathy

Myasthenia gravis

Myopathy

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The second step is to decide whether the patient has polyneuropathy, mononeuropathy multiplex, or mononeuropathy. This distinction is important because it will suggest the etiological diagnosis, as described above. The third step is to search for the cause of peripheral neuropathy. In many patients, the cause of peripheral neuropathy is obvious from the medical history and a brief examination, e.g., diabetes or chronic renal failure, and no further investigation is needed. Such diagnosis is easily made by the family physician or internist. However, in some patients, the cause is far from obvious, and further investigation is needed. This should be obtained from a complete history, including any history of drug use or exposure to toxins, and thorough general and neurological examinations. A partial guide to diagnosing peripheral neuropathy is given in Table 1.4. The tips found therein will suggest the need for special laboratory work-up to confirm the cause of neuropathy. This is normally handled by a neurologist. The temporal course of neuropathy varies according to the etiology. With trauma or ischemic infarction, the onset is sudden with the most severe symptoms occurring at the onset. This occurs with diabetic ophthalmoplegia or mononeuropathy in vasculitis. Inflammatory and some metabolic neuropathies have an acute (within a month) or subacute (1–3 months) course extending from days to months. GBS reaches its maximum deficit within four weeks of onset. A chronic course over weeks or months is the hallmark of most toxic and metabolic neuropathies as well as CIDP. A chronic, slowly progressive course over many years occurs with hereditary neuropathy and benign sensory neuropathy. Neuropathies with a relapsing and remitting course include CIDP, toxic neuropathy due to repeated exposure, and porphyria. A clinical assessment should include a careful past medical history, specifically looking for systemic diseases such as diabetes, chronic renal failure, or hypothyroidism that can be associated with neuropathy. Many medications can cause peripheral neuropathy, typically a distal symmetrical axonal sensory-motor neuropathy. Detailed inquiries about drug and alcohol use, as well as exposure to heavy metals and solvents, should be pursued (Table 1.5). Alcohol is one of the most frequently hidden causes of neuropathy. Glue sniffing or exposure to nitrous oxide as a recreational drug can also be a cause of neuropathy. All patients should be questioned regarding HIV risk factors, country of origin (leprosy), diet (vitamin B12 deficiency in a vegetarian), vitamin use (excessive vitamin B6), and the possibility of a tick bite (Lyme disease). Family history is extremely important in the workup of peripheral neuropathy. One study showed that in 42% of cases of peripheral neuropathy with unknown etiology, a hereditary cause was found after careful examination of family history and kin.19 Simply asking patients whether they have a family history of neuropathy is not enough. Instead, specific information should be sought, such as the presence of hammer toes, high arches, weak ankles, gait abnormalities, muscular dystrophy or even multiple sclerosis in the family that would suggest a long-standing or hereditary neuropathy. In Charcot–Marie–Tooth disease, high arches and hammer toes may be the only manifestation among family members. Sometimes, examining close family members is the only way to confirm hereditary neuropathy. The review of systems may provide clues regarding other organ involvement, as seen in rheumatoid diseases, or the presence of an underlying malignancy. A general examination may reveal another medical disease (e.g., diabetes, renal failure, rheumatoid diseases, hypothyroidism, or other autoimmune diseases) that could be the cause of the peripheral neuropathy. Many diseases, AIDS, Lyme disease, leprosy, and vasculitis have a sentinel marker for the disease upon examination (Table 1.4). Orthostatic hypotension without a compensatory rise in heart rate occurs when autonomic fibers are involved. Respiratory rate and vital capacity should be evaluated in GBS to assess for respiratory compromise. The presence of lymphadenopathy, hepatomegaly or splenomegaly, and skin lesions may provide evidence of systemic disease. Pale transverse bands in the nail beds (Mees’ lines) suggest arsenic poisoning. Alopecia may suggest thallium poisoning.

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TABLE 1.4 Helpful Tips in Etiological Diagnosis of Peripheral Neuropathy Family history, pes cavus, “stork-leg” Relapse Acute Alopecia, predominantly sensory neuropathy Painful ophthalmoplegia with sparing of pupil Gum lead line, wrist drop Anesthesic depigmented skin Angiokeratoma, sensory neuropathy Mees’ line, predominantly sensory neuropathy, hyperkeratosis of skin Femoral neuropathy Palpable thick nerves Charcot joint Trophic ulcer, insensitivity to pain Dysautonomia Kaposi sarcoma lymphadenopathy Erythema chronicum migrans, facial palsy Painful small-fiber neuropathy Proximal muscle weakness

Charcot–Marie–Tooth disease Chronic inflammatory demyelinating neuropathy, HNPP Guillain–Barré syndrome, acute intermittent porphyria Thallium neuropathy Diabetes mellitus Lead neuropathy Leprosy Fabry’s disease Arsenic neuropathy Diabetes mellitus Leprosy, Charcot–Marie–Tooth disease 1A Dejerinne–Sottas disease Diabetes mellitus, leprosy Diabetes mellitus, amyloidosis, leprosy, hereditary sensory neuropathy Diabetes mellitus, amyloidosis AIDS neuropathy Lyme disease Diabetes, alcoholism, AIDS, amyloid benign chronic sensory neuropathy Guillain–Barré syndrome, CIDP, diabetic amyotrophy

Source: Reproduced with permission from Oh, S.J., Clinical Electromyography: Case Studies, Williams & Wilkins, Baltimore, MD, 1998.

A thorough neurological evaluation is essential in the work-up of peripheral neuropathy to rule out other neurological disorders which mimic peripheral neuropathy, to confirm peripheral neuropathy, and to determine the type of neuropathy as discussed above. Funduscopic examination may show optic pallor, which is also a symptom of a vitamin B12 deficiency. The examination should include a search for fasciculation, which is the cardinal sign of anterior horn cell disease and a common sign of MMN and, sometimes, CIDP. Severe long-standing neuropathy can result in trophic changes including pes cavus (high arch foot), loss of hair and skin discoloration in affected areas, or ulceration. Unhealed scars are most prominent in diabetes, amyloid neuropathy, leprosy, and hereditary sensory neuropathy. Nerve thickening can be palpated in leprosy, hereditary motor sensory neuropathy (HMSN) Type I, and amyloid neuropathy.

NERVE CONDUCTION STUDIES AND NEEDLE ELECTROMYOGRAPHY The nerve conduction study (NCS) is the most essential part of the work-up in patients with a peripheral neuropathy.20 This study helps confirm peripheral neuropathy, determine the type of neuropathy, localize the site of lesion or entrapment, and follow the course of the disease. The nerve conduction study includes motor and sensory nerve conduction tests. Sensory nerve conduction is a more sensitive index than motor nerve conduction in the diagnosis of peripheral neuropathy.

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Nerve conduction is abnormal in peripheral neuropathy, but it is normal in myopathy and anterior horn cell disease. The nerve conduction study identifies the neuropathy in 76 to 80% of patients with diabetic neuropathy and in 81 to 100% of patients with the Guillain–Barré syndrome.20 It is important to remember that the NCS could be normal in a few patients with mild neuropathy of axonal degeneration. This is especially true in small-fiber neuropathy. In this case, the physician must rely on the needle EMG of distal muscles for evidence of the denervation process or other confirmatory tests for neuropathy such as a sweat test or skin biopsy. The nerve conduction study is also helpful in differentiating between axonal neuropathy and demyelinating neuropathy (Figures 1.4 to 1.6). The hallmark of nerve conduction abnormalities in axonal degeneration is a diminution of the amplitude of the CMAP and CNAP in the presence of normal or near-normal maximal nerve conduction velocity (NCV). On the other hand, the hallmark of nerve conduction abnormalities in demyelinating neuropathy are conduction block, abnormal temporal dispersion (dispersion phenomenon), and marked slowing in the NCV. The nerve conduction study can provide a certain pattern of abnormalities specific enough to be of value in localizing the lesions to specific parts of the nerve and in suggesting the nature of a neuropathy, as discussed above. The best example is the pure sensory neuronopathy pattern: the sensory nerve conduction is markedly abnormal, but the motor nerve conduction is completely normal. This pattern is pathognomonic of a sensory neuronopathy involving the dorsal root sensory ganglia. The NCS is also of some value in the follow-up evaluation of patients recovering from neuropathies, either under specific therapies or spontaneously. It is also of value in the study of families that have a hereditary neuropathy. This is especially true in the detection of asymptomatic cases of hereditary motor and sensory neuropathy I (hypertrophic type of the Charcot–Marie–Tooth (CMT) disease).

A

B

ankle

ankle 1000 µv

500 µv

5 msec 5 msec

knee

knee

C

D 2 µv 3 msec

2 µv 2 msec

FIGURE 1.4 CMAP in axonal neuropathy (arsenic neuropathy). (A) The amplitude of the CMAP in the peroneal nerve is markedly reduced. Terminal latency and motor NCVs are minimally abnormal. (B) Improved CMAP in the peroneal nerve 2 years later. (C) Markedly reduced amplitude and mild slowing of the sensory NCV (34.3 m/sec) over the finger-wrist segment of the median nerve. (D) Reduced amplitude and mild slowing in the sensory NCV (33.3 m/sec) over the finger-wrist segment of the ulnar nerve. (Reproduced with permission from Oh, S.J., Clinical Electromyography. Nerve Conduction Studies, Williams & Wilkins, Baltimore, 1993; 484.)

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8.5

B

20

100 µv 5 msec FIGURE 1.5 CMAP in demyelinating neuropathy. CMAP in segmental demyelination. This is from the posterior ibial nerve at the ankle (A) and the popliteal fossa (B) in a case of hypertrophic neuropathy. The reduced amplitude of the CMAP is due to a marked dispersion phenomenon (duration of the CMAP is 30 msec). Terminal latency is 8.5 msec. Motor NCV is 35.8m/sec. (Reproduced with permission from Oh, S.J., Clinical Electromyography. Nerve Conduction Studies, Williams & Wilkins, Baltimore, 1993; 486.)

27 msec C

17.5 msec B

7 msec 1000µv + 5 msec

A

FIGURE 1.6 Conduction block. Conduction block in segmental demyelination. Median motor nerve conduction in a case of CIDP. (A) Normal amplitude of the CMAP with wrist stimulation. (B) A dramatic reduction in amplitude of the CMAP with elbow stimulation. (C) CMAP with axillary stimulation. Conduction block is clearly seen between wrist and elbow stimulation. The dispersion phenomenon is also observed. The motor NCV is 21.9 m/sec over the wrist-elbow segment and 15.8 m/sec over the elbow-axilla segment. (Reproduced with permission from Oh, S.J., Clinical Electromyography. Nerve Conduction Studies, Williams & Wilkins, Baltimore, 1993; 487.)

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For the entrapment neuropathies, the NCS is the most definite diagnostic test, being positive in 91 to 98% of patients with carpal tunnel syndrome and in 95% of patients with ulnar neuropathy at the elbow. Fortunately, the localized pathology of entrapment neuropathy is segmental demyelination. The absence of CNAP or the slowing of sensory and mixed NCVs, as well as the slowing of motor NCVs in the involved segment, are the classical abnormalities. The needle EMG is very helpful in differentiating denervation process from myopathy and myotonia. In denervation, fibrillation and positive sharp waves (PSWs) are noted at rest. However, it is important to remember that they are not pathognomonic of the denervation process because they are also observed in patients with active myopathy, such as polymyositis. The motor unit potentials (MUPs) are either normal or increased in duration depending on the chronicity of the denervation. In chronic denervation, the collateral sprout from relatively normal axons may innervate denervated muscle fibers, producing high-amplitude and long-duration (HALD) MUPs. On maximal contraction of muscles, the MUPs are reduced in recruitment. In contrast, a different needle EMG pattern is seen in myopathy: MUPs are small in amplitude and short in duration (SASD MUPs, that is, small-amplitude short-duration MUPs) and there is excessive recruitment of MUPs on maximal contraction. In myotonia, the typical dive bomber sound is observed with the waxing and waning of abnormal potentials. The needle EMG is also helpful in identifying the activity of neuropathy. In active (ongoing) denervation, fibrillations and PSWs are prominent with increased polyphasic MUPs and reduced MUP recruitment. On the other hand, in inactive (usually chronic) denervation, fibrillations and PSWs are minimal together with HALD MUPs. In addition, the needle EMG is helpful in distinguishing axonal neuropathy from demyelinating neuropathy. Fibrillations and PSWs, electrophysiological hallmarks of axonal degeneration, are prominent in axonal neuropathy but are absent or scarce in demyelinating neuropathy. Fasciculation or myokymia is a more prominent finding in demyelinating neuropathy.

LABORATORY STUDIES Laboratory tests are most important in confirming the etiology of peripheral neuropathy. The firstline tests should be performed in all patients with suspected peripheral neuropathies (Table 1.5). They may reveal unsuspected causes of neuropathy such as diabetes, rheumatoid disease, vitamin B12 deficiency, hypothyroidism, and monoclonal gammopathy. Considering that all these neuropathies are treatable, it is important to search for these possible causes of neuropathy. The second-line tests are selected depending on the clinical impression, which is based on clinical, electrophysiological, and laboratory data. For example, if monoclonal gammopathy is found in the serum of a patient, then a metastatic bone survey and 24-hour urine immunoelectrophoresis by immunofixation are ordered to differentiate benign monoclonal gammopathy from malignant gammopathy. The spinal fluid evaluation is essential for the diagnosis of GBS, CIDP, and a few other neuropathies. An elevated total protein with fewer than five white blood cells is seen in inflammatory neuropathy (GBS and CIDP). Inflammatory cells are usually increased in AIDS and Lyme disease. Other studies useful in specific clinical contexts are cytology (lymphoma) and specific studies such as Lyme polymerase chain reaction and cytomegalovirus branches chain DNA (polyradiculopathy or mononeuritis multiplex in AIDS). CMT1A DNA duplication or hereditary neuropathy with liability to pressure palsy (HNPP) DNA deletion tests may confirm the specific type of hereditary neuropathy.

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TABLE 1.5 Laboratory Tests for Peripheral Neuropathy Test First-Line Tests CBC, sedimentation rate Renal and liver functions Rheumatoid profiles Blood sugar, fasting 2 hour post-brandial; HbA1C Serum B12 and folate level Thyroid functions Immunoelectrophoresis of serum protein by immunofixation test Second-Line Tests Porphobilinogen in urine Heavy metals in urine Arsenic in hair and nails Hepatitis B antigen Schilling test Antineutrophile cytoplasmic antibody Chest x-ray, cancer survey High CSF protein Increase cell in CSF Serum HIV antibody Serum Borrelia burgdorferi antibody Metastatic bone survey Anti-Hu antibody GM1 and MAG antibody CMT1A DNA duplication test HNPP DNA deletion test

Diagnostic Possibilities

Collagen disease, leukemia, vasculitis Uremic and hepatic neuropathy Collagen disease, vasculitis Diabetes Neuropathy with macrocytosis Hypothyroid neuropathy Dysproteinemia, monoclonal gammopathy lymphoma, amyloidosis

Acute porphyria Lead, arsenic, thallium, mercury Arsenic neuropathy Polyarteritis nodosa Vitamin B12 deficiency Wegener’s granulomatosis Carcinomatous neuropathy Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy Lyme disease, AIDS, paraneoplastic neuropathy AIDS neuropathy Lyme disease Sclerotic multiple myeloma Paraneoplastic neuropathy Autoimmune neuropathy CMT1A neuropathy HNPP

Source: Reproduced with permission from Oh, S.J., Clinical Electromyography: Case Studies, Williams & Wilkins, Baltimore, MD, 1998.

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REFERENCES 1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

19. 20.

Schwartz, J.H., Axonal transport: components, mechanisms, and specificity, Ann. Rev. Neurosci., 2, 467, 1979. Price, D.L. and Proter, K.R., The response of ventral horn neurons to axonal transection, J. Cell Biol. 53, 24, 1972. Berthold, C.H., Morphology of normal peripheral axons, in Physiology and Pathobiology of Axons, Waxman, S.G., Ed., Raven Press, New York, NY, 1978. Raine, C.S., Pathology of demyelination, in Physiology and Pathobiology of Axons, Waxman, S.G., Ed., Raven Press, New York, NY, 1978. Waller, A.V., Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibers, Phil. Trans. Roy. Soc. London B., 140, 423, 1850. Dyck, P.J., Conn, D.J., and Okazaki, H., Necrotizing angiopathic neuropathy. Three-dimensional morphology of fiber degeneration related to sites of occluded vessels, Mayo Clin. Proc., 47, 461, 1972. Spencer, P.S., Sabri, M.I., and Schaumburg, H.H., Does a defect of energy metabolism in the nerve fiber underlie axonal degeneration in polyneuropathies? Ann. Neurol., 5, 501, 1979. Weller, R.O. and Cervos-Navarro, J., Pathology of Peripheral Nerves, Butterworth & Co. Ltd., London, 1977. Asbury, A.K. and Johnson, P.C., Pathology of Peripheral Nerves, W.B. Saunders, Philadelphia, PA, 1978. Sternman, A.B., Schaumberg, H.H., and Asbury, A.K., The acute sensory neuronopathy syndrome: a distinct clinical entity, Ann. Neurol., 7, 354, 1980. Asbury, A.K. and Gilliatt, R.W., The clinical approach to neuropathy, in Peripheral Nerve Disorders, Asbury, A.K. and Gilliatt, R.W., Eds., Butterworth & Co. Ltd., London, 1984, 1. Asbury, A.K., Arnason, B.G., and Adams, R.D., The inflammatory lesion in idiopathic polyneuritis, Medicine, 48, 173, 1969. Dyck, P.J. et al., Chronic inflammatory polyradiculoneuropathy, Mayo Clin. Proc., 50, 621, 1975. Bradley, W.G. and Jennekens, F.G.I., Axonal degeneration in diphtheric neuroapthy, J. Neurol. Sci., 13, 415, 1971. Oh, S.J., Clinical Electromyography: Nerve Conduction Studies, 2nd ed., Williams & Wilkins, Baltimore, MD, 1993. Gombault, A., Contribution á l’étude anatomique de la névrite paraenchymateuse subaigué et chronique — névrite segmentaire péri-axile, Arch. Neurol., (French), 1, 11, 1880. Dyck, P.J., Johnson, W.J., Lambert, E.H., and O’Brien, P.C., Segmental demyelination secondary to axonal degeneration in uremic neuropathy, Mayo Clin. Proc., 46, 400, 1971. Dyck, P.J. and Lais, A.C., Evidence for segmental demyelination secondary to axonal degeneration in Friedreich’s ataxia, in Clinical Studies in Myology, Kakulas, B.K., Ed., Excerpta Medica, Amsterdam, 253, 1973. Dyck, P.J., Oviatt, K.F., and Lambert, E.H., Intensive evaluation of referred unclassified neuropathies yields improved diagnosis, Ann. Neurol., 10, 222, 1981. Oh, S.J., Clinical Electromyography. Nerve Conduction Studies, Williams & Wilkins, Baltimore, 1993.

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CHAPTER 1 Figure 1 Teasing nerve fibers. (1) axonal degeneration: arrows indicate row of myelin ovoids; (2) demyelination: arrows indicate demyelinated segments; (3) tomaculous change: a) thin arrows indicate a demyelinated segment; thick arrows indicate tomaculous change; b) enlarged tomaculous change; (4) giant axons: a) white arrows indicate rows of myelin ovoids. b) arrows indicate axons. (Reproduced with permission from Oh, S. J., Yonsei Med. J., 31, 16, 1990.)

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The Nerve Biopsy

INDICATION FOR THE NERVE BIOPSY If the cause of a neuropathy is known by means of the clinical examination and laboratory tests, a nerve biopsy is not necessary. In many metabolic neuropathies, the patient’s history and laboratory tests are enough to make a definite causative diagnosis. These include diabetic, alcoholic, and uremic neuropathies. In such patients, the nerve biopsy is performed only to study the basic pathophysiology of neuropathy. Even in cases of GBS, the most common form of neuropathy seen by neurologists, the nerve biopsy is not indicated simply because the diagnosis can be made with certainty in most cases on the basis of the clinical, electrophysiological, and spinal fluid findings. The nerve biopsy is clearly indicated in two groups of patients: patients suspected of vasculitis and those with clinically significant peripheral neuropathy without known cause. The sural nerve biopsy is best indicated in patients suspected of having vasculitis, with or without the clinical features of neuropathy (Table 2.1).1 That is because the nerve is more commonly involved than other readily available biopsied tissues such as skin and muscle, and the diagnostic yield of the sural nerve biopsy is high in vasculitis.1 Peripheral neuropathy was reported in 52 to 60% of patients with vasculitis.2, 3 The nerve conduction test was crucial in those patients because it detected neuropathy in asymptomatic patients and because vasculitis was invariably found in the sural nerve when the nerve conduction was abnormal.1 In a recent study of the sural nerve biopsy conducted by our laboratory, we found a diagnostic sensitivity of 39% in 115 patients suspected of having vasculitic neuropathy.4 TABLE 2.1 Diagnostic Usefulness of the Sural Nerve Biopsy

Specific diagnoses Vasculitic neuropathy Hypertrophic neuropathy Inflammatory neuropathy Ischemic neuropathy Amyloid neuropathy Metachromatic neuropathy Sarcoid neuropapthy Leprosy Lymphoma Fabry’s disease Tomaculous neuropathy Amidarone Chronic inflammatory demyelinating polyneuropathy Hereditary neuropathy Total a

Oh (N = 385) 92 (24%) 46 (12%) 27 (7%) 12 (3%) 3 (0.8%) 2 (0.5%) 1 (0.3%) 1 (0.3%)

Midroni (N = 267) 43 (16%) 20 (7.5%) 4 (1.6%) 4 (1.6%)

46 (12%)

2 (0.8%) 1 (0.4%) 2 (0.8%) 1 (0.4%) 3 (1.2%) 3 (1.2%) 51 (19%)

35 (9%) 173 (45%)

12 (4.5%) 106 (40%)

GBS. b Demyelinating neuropathy. This is not necessarily CIDP.

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Schröder (N = 5266) 1200 (23 %) 769 (15%) 124 (2.3%) 116 (2%) a 47 (0.9%) 22 (0.2%)

4 118

(2%)

830 (16%) b 273 (5%) 2303 (44%)

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The reason for performing the sural nerve biopsy in neuropathy without known cause is obvious: it can often point to a definite diagnosis and provide other clinically helpful information in some patients. Even within this group, the nerve biopsy should be confined to patients with a clinically significant neuropathy, the treatment of which can be altered by the potential nerve biopsy finding. Under this guideline, patients with small-fiber neuropathy or mild non-progressive neuropathy are not likely candidates for nerve biopsy. Based on data obtained in 385 sural nerve biopsies performed over a 16-year period (1971–1986), we found clinically helpful or relevant information in 45% of cases5 (Table 2.1). Other investigators reported clinically helpful or relevant information in 27 to 44% of cases.6-8 Specific diagnoses were obtained in 24% of cases, diagnosis of chronic inflammatory demyelinating was confirmed in 12%, and hereditary neuropathy was diagnosed in 9% of cases. Among the specific diagnoses, vasculitic neuropathy was the most common form of neuropathy, accounting for 12% of 385 nerve biopsies. Once a specific diagnosis is made, it dictates the clinical management of the disorder. This is best exemplified in vasculitic neuropathy where steroid and cytotoxic agents are very helpful in inducing remission.9 In chronic inflammatory polyneuropathy, long-term steroid treatment, often over the course of many years, is required.10 Thus, it is essential to confirm such diagnoses with a nerve biopsy before steroids are administered. Confirmation of hereditary neuropathy is helpful in predicting the progression of disease and in genetic counseling of patients. This outlook has changed because of the easy availability of Charcot–Marie–Tooth (CMT) 1A and hereditary neuropathy with liability to pressure palsy (HNPP) DNA testing,11 but nerve biopsies were not clinically helpful in 55% of cases. In another series of tests, a specific diagnosis was made in 16 to 23% of cases, and nerve biopsies were helpful in 40 to 44% of cases.6,12 In the first prospective study of 50 cases, sural nerve biopsies altered the diagnosis in 14% of cases and affected management in 60% of cases.13 The diagnostic sensitivity of the sural nerve biopsy is analyzed in Table 2.2. It is important to recognize that specific diagnoses were made in only 24% of cases. In 55% of cases, the diagnosis of demyelinating or axonal neuropathy was made without further elucidation of any specific cause. In the latter cases, the nerve biopsy findings have to be correlated with the clinical information to reach a final diagnosis. This underlines the importance of exhaustive and detailed clinical examinations in the work-up of neuropathy.

TYPES OF NERVE BIOPSY There are two types of nerve biopsy: fascicular biopsy and whole biopsy. In fascicular biopsy, only a few fascicles of the nerve are biopsied in order to lessen permanent sensory loss and long-term dysesthesia.14 However, studies have shown that there is no significant difference in the areas of sensory loss 5 or more years after sural nerve biopsy in fascicular biopsy compared with whole nerve biopsy.15 Furthermore, fascicular biopsy may fail to show the vasculitic change in the perineurial space in cases TABLE 2.2 Diagnostic Sensitivity of the Sural Nerve Biopsy

Specific diagnosis Demyelinating neuropathy Axonal neuropathies Nonspecific findings Normal

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Oh (N = 385) 92 (24%) 132 (32%) 89 (23%) 62 (16%) 19 (5%)

Midroni (N = 267) 43 (16%)

27 (10%)

Schröder (N = 5266) 1200 (23%) 830 (44%) 1572 (30%)

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of vasculitis because this is where splitting is done in fascicular biopsy.16 This is the most important disadvantage of fascicular biopsy since vasculitis is one of the prime indications for nerve biopsy. Therefore, the author has concluded that there is no justification for fascicular biopsy. Our laboratory routinely performs only whole nerve biopsy, which is practiced in most centers.

SURAL NERVE BIOPSY Biopsies of three different nerves have been described: the radial sensory nerve, the superficial peroneal nerve, and the sural nerve. The sural nerve biopsy is preferable for four reasons: (1) the nerve is easily identifiable and relatively protected from compression injury because it is located behind the lateral malleolus; (2) this nerve is purely sensory, thus producing no motor deficit following biopsy; (3) this nerve is liable to be affected by neuropathy because it is a distal branch of a long nerve; and (4) this nerve is easily tested electrophysiologically. The sural nerve biopsy is not recommended if the nerve conduction is completely normal because the diagnostic yield is small. This policy is based on our experience in a few cases in which normal nerve biopsy was found when the nerve conduction was normal in the sural nerve. One disadvantage of this nerve biopsy is that the sural nerve is not affected if the neuropathy is purely motor. However, in practice, this does not pose a major problem because sensory nerve conduction is often affected, even in a clinically identified motor neuropathy such as GBS or multifocal motor neuropathy.17,18 In a sural nerve biopsy, the patient is placed in the lateral decubitus position and a pillow is placed under the ankle to be biopsied. The skin incision is made under local anesthesia with 1% lidocaine behind the lateral malleolus and halfway between the posterior aspect of the Achilles tendon and the lateral malleolus. This skin incision is extended proximally for 4 to 5 cm, parallel to the Achilles tendon (Color Figure 2.1).* Under the incised skin, the lesser saphenous veins are usually seen. The whitish pearly sural nerve is identified medially under the lesser saphenous veins. When the sural nerve is touched by an instrument, the patient often feels a shooting electrical pain — a definite sign that the structure is the sural nerve. Both the nerve and the veins are superficial to the deep fascia. If the sural nerve is not found easily, the examiner may have gone too deep. Sometimes, a lesser saphenous vein is mistakenly identified as a sural nerve. This can be avoided by carefully inspecting the nerve prior to cutting it, observing the broad angles at which the vein branches in contrast to the narrow angles at which the nerve branches.19 If a vein is cut, the specimen will have a tiny hole through it. Once the sural nerve is identified, the nerve is anesthetized prior to cutting with a small amount of lidocaine a few millimeters proximal to the intended transection site in order to prevent pain when the nerve is cut. Nerve block is tested by gradual gentle clamping of the nerve with a tiny hemostat proximal to the site of transection. Once total anesthesia is achieved, the nerve is firmly clamped proximal to the transection site. This most likely reduces the likelihood of any potential post-biopsy neuralgia. Nevertheless, the patient should be warned that there may be a possible sharp pain at the moment the nerve is cut. Telling this to the patient will improve patient cooperation. Generally, the degree of pain is inversely proportional to the severity of the neuropathy.20 The proximal nerve is lifted gently and cut with sharp dissection distal to the hard clamping. A nerve segment at least 4 cm in length should be obtained with due care in order to avoid any unnecessary trauma to the nerve. The superficial fascia and skin incision is closed using interrupted mattress skin sutures with 4-0 coated vicryl sutures inside and 3-0 nylon sutures outside. An elastic bandage is applied locally to reduce the accumulation of blood and fluid. The patient may be up and about on the same day, but sitting with the leg in a dependent position for long periods, excessive walking, or running are discouraged. Local pain is controlled with mild narcotics. Sutures may be removed in 7 to 10 days. A narcotic painkiller and an antibiotic are prescribed for postoperative care.

* Color insert figures

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SEQUELAE OF NERVE BIOPSY Following the sural nerve biopsy, there is invariably a sensory loss over the lateral aspect of the foot corresponding to the sural nerve territory. This area gradually decreases in size, but a quarter-sized area remains permanently insensitive to pin-prick. Some immediate postoperative pain is not uncommon, having been observed in 30 to 50% of patients.21-23 However, pain gradually diminishes over time.23 Persistent pain has been reported in 19 to 25% of patients8, 23 for 2 years and in 6% of patients after more than 2 years.23 Serious reactions following the sural nerve biopsy are rare. Significant pain or paresthesia was noted in 10% of patients 1 year after the biopsy.21, 22, 24 Asbury and Connolly noted serious side-effects in only 2 of 103 patients: post-traumatic neuroma in 1 and pain in the other.19 Among 385 sural nerve biopsies performed in our laboratory, post-traumatic neuralgia lasted 1 year in 2 cases (0.5%) and delayed wound healing occurred in 4 cases (1%). In those 4 cases, steroids were administered for vasculitic neuropathy or chronic inflammatory demyelinating polyneuropathy immediately after the biopsy, contributing to delayed wound healing. Midroni and Bilbaro reported 2 patients who had significant wound infections and 1 who required resection of neuroma out of a total of 267 biopsies.12 Both patients with severe wound infections had a systemic vasculitis and were treated with steroids. We have not observed any troublesome side-effects in any of our cases 2 years after performing biopsies. In Pollock et al.’s series, there was no long-term pain or paresthesia in any of their cases 5 or more years after a nerve biopsy.15

BIOPSY OF OTHER NERVES SUPERFICIAL PERONEAL NERVE BIOPSY The superficial peroneal nerve is superficially located under the skin in the distal third of the leg and has two sensory branches, the medial (MDC) and intermediate dorsal cutaneous (IDC) nerves (Color Figure 2.1). Thus, this is an ideal site for the nerve biopsy. Kissel and Mendell recommended the following guidelines for biopsy of this nerve:25 The distance from the head of the fibula to the lateral malleolus is determined. This distance is divided into four and three equal segments. An incision is made between the lower one-third and one-quarter distal segmental markings at a point 1.5 to 2 cm anterior to the edge of the fibula (determined by firm palpation of the leg). The superficial peroneal nerve lies above the fascia and can be found in the subcutaneous tissue with minimal dissection, usually along the lateral edge of the fascia. In practice, the superficial peroneal nerve is not readily identifiable as stated because of its tiny size. Thus, the course of this nerve is usually mapped with the nerve conduction study prior to the biopsy. Following removal of the nerve, the fascia within the operative field is opened, revealing the peroneus brevis muscle which is easily accessible for muscle biopsy. Because of the advantage of obtaining the nerve and muscle biopsy under the same incision, Said et al. and Kissel and Mendell prefer the biopsy of this nerve for the diagnosis of vasculitic neuropathy.25, 26 In general, the sural nerve biopsy has a higher diagnostic yield for vasculitis (see Chapter 6). After the biopsy, the patient loses sensation over the territory of the medial or intermediate dorsal cutaneous branches on the dorsum of the foot, depending on which branch is biopsied.

SUPERFICIAL RADIAL NERVE BIOPSY The superficial radial nerve is superficially located under the skin in the distal fourth of the extensor surface of the forearm along the medial border of the radius (Color Figure 2.2). It is ideally located for biopsy. Often, it is buried under the cepahlic veins. In practice, it is not easy to identify this nerve because of its tiny size. Thus, the course of the radial nerve is normally mapped with the nerve

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conduction study prior to a biopsy in order to guarantee the success of the nerve biopsy. The same principle of identification of the nerve is applied as described above. After the biopsy, the patient loses sensation over the territory of the superficial radial sensory nerve, including the first web space.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

Wees, S.J., Sunwoo, I.N. and Oh, S.J., Sural nerve biopsy in systemic necrotizing vasculitis, Am. J. Med., 71, 525, 1981. Frohnert, P.P. and Sheps, S.G., Long-term follow-up study of periarteritis nodosa, Am. J. Med., 43, 8, 1967. Cohen, R.D., Conn, D.L., and Ilstrup, D.M., Clinical features, prognosis, and response to treatment in polyarteritis, Mayo Clin. Proc., 55,1 46, 1980. Claussen, G.C., Thomas, D., Coyne, C., Våsques, LG., and Oh, S.J., Diagnostic value of nerve and muscle biopsy in suspected vasculitis cases, J. Clin. Neuromuscular, 1, 117, 2000. Oh, S.J., Diagnostic usefulness and limitations of the seural nerve biopsy, Yonsei Med. J., 31(1), 1, 1990. Schröder, M., Recommendations for the examination of peripheral nerve biopsies, Virchos Arch., 432, 199, 1998. Argov, X., Steiner, I., and Soffer, D., The yield of sural nerve biopsy in the evaluation of peripheral neuropathies, Acta Neurol. Scand., 79, 243, 1989. Neundörfer, B., Grahmann, F., Engelhart, A., and Harte, U., Postoperative effects and values of sural nerve biopsies: a retrospective study, Eur. Neurol., 30, 350, 1990. Fauci, A.S., Katz, P., Haynes, B.F., and Wolff, S.M., Cyclophosphamide therapy of severe systemic necrotizing vasculitis, New Eng. J. Med., 301, 235, 1979. Oh, S.J., Subacute demyelinating polyneuropathy responding to croticosteroid treatment, Arch. Neurol., 35, 509, 1978. Said, G., Indications and value of nerve biopsy, Muscle and Nerve, 22(12), 1617, 1999. Midroni, G. and Bilbaro, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, MA, 1995. Gabriel, C.M. et al., Prospective study of the usefulness of sural nerve biopsy, J. Neurol. Neurosurg. Psychiatry, 69, 442, 2000. Dyck, P.J. and Lofgren, E.P., Nerve biopsy. Choice of nerve, method, symptoms and usefulness, Med. Clin. North Am., 52, 885, 1968. Pollock, M., Nukada, H., Taylor, P., Donaldson, I., and Carrol, G., Comparison between fascicular and whole sural nerve biopsy, Ann. Neurol., 13, 65, 1983. Dyck, P.J., Conn, D.J., and Okazaki, H., Necrotizing angiopathic neuropathy. Three-dimensional morphology of fiber degeneration related to sites of occluded vessels, Mayo Clin. Proc., 47, 461, 1972. Oh, S.J., Clinical Electromyography, Nerve Conduction Studies, 2nd Ed., Williams & Wilkins, Baltimore, MD, 1993. Corse, A.M., Chaudhry, V., Crawford, T.O., Cornblath, D.R., Kuncl, R.W., and Griffin, J.W., Sensory nerve pathology in multifocal motor neuropathy, Ann. of Neurol., 39(3), 319, 1996. Asbury, A.K. and Connolly, E.S., Sural nerve biopsy: technical note, J. Neurosurg., 38, 391, 1973. Johnson, P.C., Diagnostic peripheral nerve biopsy, Barrow Neurological Institute Q., 1, 2, 1985. Perry, J.R. and Bril, V., Complications of sural nerve biopsy in diabetic versus non-diabetic patients, Can. J. Neurol. Sci., 21, 34, 1994. Solders, G., Discomfort after fascicular sural nerve biopsy, Acta Neurol. Scand., 77, 503, 1988. Flachenecker, P., Janka, M., Goldbrunner, R., and Toyka, K.V., Clinical outcome of sural nerve biopsy: a retrospective study, J. Neurol., 246(2), 93, 1999. Stevens, J.C., Lofgren, E.P., and Dyck, P.J., Biopsy of peripheral nerves, Peripheral Neuropathy, Vol. I, Dyck, P.J., Thomas, P.K., and Lambert, E.H., Eds., W.B. Saunders, Philadelphia, PA, 1975. Said, G., Lacroix-Ciaudo, C., Fujimura, H., Blas, C., and Faux, N., The peripheral neuropathy of necrotizing arteritis: a clinicopathological study, Ann. Neurol., 23, 461, 1988. Kissel, J.T. and Mendell, J.R., Vasculitic neuropathy, Neurol. Clin., 10(3), 761, 1992.

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CHAPTER 2 Figure 1 Sural nerve and superficial peroneal nerve in the anterior-lateral view of the ankle and dorsum of the foot. (Modified from J.C.B. Grant, An Atlas of Anatomy, 6th ed. Williams & Wilkins, Baltimore, 1972.)

CHAPTER 2 Figure 2 Superficial radial sensory nerve in the radial aspect of the wrist. (Modified from J.C.B. Grant, An Atlas of Anatomy, 6th ed. Williams & Wilkins, Baltimore, 1972.)

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Histological Processing and Staining of the Biopsied Nerve

TREATMENT OF THE BIOPSIED NERVE Immediately after removal of the biopsy specimen, the nerve is gently straightened, stretched, and placed on a silicone pad in a dissecting dish for 15 minutes with pins at each end. This step is important for reducing contraction artifact. Asbury and Connolly stretched and applied the nerve to a thin strip of an index card for one minute prior to immersing it in fixatives.1 Dyck and Lofgren suspended the biopsied nerve in the fixative with a tiny weight at one end.2 The nerve is cut into 4 sections with a sharp razor, as described in Figure 3.1, to be processed for paraffin, frozen, semithin, and electronmicroscopic (EM) sections, and for fiber teasing. The piece closest to the transection site should be used for paraffin sections, and the most distal portion should be kept for frozen sections, with the midportions utilized for semithin and EM sections. This distribution is preferred because potential cutting artifacts are not that critical for paraffin sections or nerve fiber teasing, whereas artifact-free sections are essential for semithin and EM sections. All of our specimens for frozen sections are processed first in order to make a fast and definite diagnosis. The nerve specimen is frozen in isopentane cooled to -180°C in liquid nitrogen for 15 seconds. Rapid diagnosis is critical in cases of vasculitis since an immunosuppressive therapy should be instituted as soon as the diagnosis of vasculitis is made. In practice, the diagnosis of vasculitis can be made within 15 to 30 minutes after the biopsy.3 Metachromatic neuropathy can be diagnosed only with frozen sections since metachromatic granules are stained with cresyl-fast violet on frozen sections alone (Table 3.1). Other advantages of the frozen section are easy detection of myelin-digestion chambers and relative ease of preserving the longitudinal sections in a straight alignment. The latter 1.25 1.25

Neutral-buffered formalin

Paraffin section Teasing

H&E Modified trichrome Congo-red

4% glutaraldehyde

4 cm

Isopentane in -180°C liquid N 2

Semithin section Thin section for EM

Toluidine blue or Toluidine blue and basic fuchsin

FIGURE 3.1 Treatment of nerve biopsy specimens.

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1.5

Frozen section

H&E Modified trichrome PASH Congo-red Cresyl-fast-violet

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is critical in recognizing segmental demyelination. These benefits are all achieved in sections stained with modified trichrome4 and Hemotoxylin and Eosin (H & E) stain with Harris hematoxylin.5 A rough estimate of the population of myelinated fibers is possible with modified trichrome staining on frozen sections, which shows the normal nerve fascicles filled with myelinated fibers (see Chapter 4). Paraffin sections are needed to identify amyloid by Congo-red staining and to delineate the detailed structures of cells and vessels (Table 3.1). In the past, when semithin EM sections were unavailable, the population of myelinated fibers, the distribution of the nerve fibers according to fiber diameter, and the relationship between the axon diameter and myelin diameter could be studied with paraffin sections stained with Kulschistky’s stain, which stains myelin black (see Chapter 4). Myelinated fibers are now stained red with modified trichrome on paraffin sections,6 giving an overview of the population of myelinated fibers and, sometimes, of myelin-digestion chambers in severe axonal neuropathy. The semithin EM section has been most commonly used for peripheral nerve pathology in recent years. This section is best for detailed study of the axon–myelin relationship, for identifying onion-bulb formations and clustering of regenerated fibers, and for calculating the density of myelinated fibers (Table 3.1). The semithin EM section is also the only reasonably sure means of detecting thinly myelinated fibers (remyelination). Nerve fiber teasing is superior for documenting segmental demyelination and also allows recognition of nerve fibers with myelin ovoids (axonal degeneration) in a quantitative manner (Table 3.1). With teasing of nerve fibers, one can study the relationship between internode length and fiber diameter. Teasing is not practical because of the time-consuming nature of the technique. However, teasing is the only way to recognize the nature of neuropathy in mild cases when studying other sections has not been informative. The electronmicroscopic study is essential for studying unmyelinated fibers because it is the only means of identifying unmyelinated fibers in the peripheral nerve (Table 3.2). Selective loss of unmyelinated fibers has been identified by such studies in amyloid neuropathy, Fabry’s disease, and small-fiber diabetic neuropathy. EM studies also played a pivotal role in recognizing the widely spaced myelin (WSM) in myelin associated glycoprotein (MAG)-positive neuropathy and uncompacted myelin lamellae (UML) in POEMS (polyneuropathy-organomegaly-endocrinopathy-M-protein-skin change). In rare storage diseases such as Krabbe’s disease, Battern–Kufs disease, adrenoleucodystrophy, Farber’s disease, Tangier’s disease, or Niemann–Pick disease, the EM study shows the distinct ultrastructural features of storage inclusion which are helpful in diagnosing such diseases.7,8 There are several excellent books and articles on this subject which readers can consult for more detailed information.

IMMEDIATE CARE OF THE BIOPSIED NERVE The procedure for caring for the nerve immediately after biopsy is as follows. The nerve is stretched gently and secured with a pin at each end on a silicon pad in a dissecting dish or on a waxed plate for 15 minutes. The nerve specimen is cut into three pieces: 1.5 cm for the frozen section, 1.25 cm for the semithin and EM sections, and 1.25 cm for paraffin sections and nerve teasing (Figure 3.1). For teasing, a nerve fixed in 4% glutaraldehyde can also be used.

PROCESSING OF THE NERVE Processing of the nerve for the frozen sections takes place as follows. The nerve specimen is cut into two pieces, one-third for the transverse section and two-thirds for the longitudinal section. The nerve

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TABLE 3.1 Advantages and Disadvantages of Tissue Sections Section Type Frozen section

Advantage Rapid diagnosis Population of myelinated fibers (modified trichrome) Detection of myelin digestion chambers (modified trichrome) Cresyl-fast-violet stain for metachromatic material Oil red O stain for lipid Relative ease of preserving the longitudinal sections straight for segmental demyelination Immunofluorescent studies Paraffin section Details of cells and anatomical structure Semithin section Population of myelinated fiber Detection of thinly myelinated fibers Detection of clustering of regenerated fibers Detection of onion-bulb formation Axon–myelin relationship EM section The only test for the unmyelinated fibers Widely spaced myelin (WSM) Uncompacted myelin lamellae (UML) Schwann cell inclusions Macrophage-induced demyelination or axonal change Teasing fiber Best method for differential diagnosis for axonal neuropathy vs. demyelinating neuropathy

Disadvantage Details of cells are not clear

Artifact is unavoidable Details of cells are not clear

Special training

Too much time

TABLE 3.2 Diagnosis by the Ultrastructural EM Study Pathological Features Loss of unmyelinated fibers Macrophage mediated demyelination Widely spaced myelin (WSM) Uncompacted myelin lamella (UML) Schwann cell inclusions and demyelination Tuffstone inclusions Needle-like inclusion of GLDb Lipid inclusions Banana body Pi body-like cytosomes Lysosomal inclusions (myelinoid bodies) Schwan cell inclusion and axonal degeneration Lipid storage in perineurium a b

Diagnosis Small-fiber neuropathya Inflammatory demyelinating neuropathy MAG/IgM neuropathy POEMS neuropathy Metachromatic leucodystrophy Krabbe’s disease Nieman pick Farber’s disease Adrenoleukodystrophy Toxic neuropathies due to Amidarone, perhexiline, chloroquine Fabry’s disease

Amyloidosis, Fabry’s disease, small-fiber diabetic neuropathy. GLD, globoid cell leucodystrophy.

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specimen is then oriented correctly for the transverse and longitudinal sections on the OCT medium and covered with the OCT medium. The nerve must be frozen in a -180°C isopentane solution cooled in liquid nitrogen for 15 seconds and then cut at 10 µm by the cryostat using an antiroller plate. The cut sections are picked up on glass slides. The sections are stained with H & E, modified trichrome, PASH, cresyl-fast violet, and Congo-red stains. For paraffin sections, the nerve is processed in the following way. The nerve is fixed in a neutral buffered formalin solution (Formalde-Fresh 10% solution from Fisher Scientific Co.; cat. #SF94-4).* It is then cut into two pieces, one-third for the transverse section and two-thirds for the longitudinal section. Sections are cut at 5 µm, except for Congo-red stain, which should be cut at 8 to 10 µm, and are then stained with H & E, modified trichrome, and Congo-red stains. When processing the nerve for semithin sections, the nerve is fixed in buffered 4% glutaraldehyde solution** for 24 hours and is then dehydrated, osmicated, and embedded in resin. The nerve is cut at 1 µm by the EM microtome for the transverse sections and, if possible, for the longitudinal sections.

PARAFFIN SECTION STAININGS HEMATOXYLIN AND EOSIN STAIN Deparaffinize and hydrate slides to water. Stain in Harris hematoxylin (modified Harris hematoxylin from Richard Allen Co., cat. # 72711) for 5 minutes. Wash in warm running tap water for 10 minutes. Differentiate in acid alcohol (0.5–1% HCl in 70% alcohol) by 2 dips. Rinse in tap water. Dip in ammonia water for 2 minutes and rinse in tap water. Place in eosin Y (eosin Y from Richard Allen Co., cat. #7111) for 2 minutes and rinse in tap water. Dehydrate in alcohol, clear in xylene, and coverslip using permount. The results appear as follows: Nuclei — dark blue Eosinophil granules — bright orange red Thick elastic fibers — deep pink Myelin — pink Red blood cells — bright orange red Cytoplasm — pink Collagen — light pink

MODIFIED TRICHROME STAIN 9 Deparaffinize and hydrate slides to water. Place in Bouin’s fixative (LabChem Inc. LC, cat. #117902) for 30 minutes at 56°C at room temperature. Wash well in running water to remove all yellow color. Stain nuclei with Gill’s hematoxylin† (Surgipath Gill’s II formula, cat. #01520) for 5 minutes. Wash in tap water for 2 minutes. Stain in Gomori’s trichrome solution†† (Richard Allen Co., cat. #88031) for 30 minutes to 1 hour. Rinse in 0.5% acetic water for 20 seconds. If the stain is too dark, decolorize in * Neutral buffered formalin solution: 40% formaldehyde, 100 ml; distilled water (DW), 900 ml; acid sodium phosphate monohydrate, 4 gm; anhydrous disodium phosphate, 6.5 gm. ** 4% glutaraldehyde solution: Sorensen’s phosphate buffer, 2.5 ml; DW, 7.5 ml; 8% glutaraldehyde, 10 ml. For Sorensen’s phosphate buffer, consult a later section of this book. † Gill’s hematoxylin solution: DW, 730 ml; ethylene glycol, 250 ml; hematoxylin, anhydrous powder (C.I. 75290), 2 gm; sodium iodate, 0.2 gm; aluminum ammonia sulfate, 17.6 gm; glacial acetic acid, 20 ml. †† Gomori’s trichrome solution: Fast Green FCF, 0.3 gm; Chromotrope 2 R, 0.6 gm; phosphotungstic acid, 0.6 gm; glacial acetic acid, 1 ml; DW, 100 ml. Dissolve above ingredients in glass beaker using the magnetic stirrer until all ingredients are dissolved. Adjust pH to 3.4 with 0.l N HCl or NaOH. Store at room temperature.

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1% acetic water plus 0.7% phosphotungstic acid solution. Dehydrate, clear in xylene, and coverslip, using permount. Results appear as follows: Myelin — red Connective tissue — green Nuclei — blue

ALKALINE CONGO-RED STAIN Sections are cut at 8 to 10 µm. Deparaffinize and hydrate slides to water. Stain nuclei in Harris hematoxylin for 5 minutes. Wash with tap water for 31/2 minutes. Rinse in distilled water for 2 minutes. Differentiate in acid alcohol solution for 30 seconds. Wash in tap water for 21/2 minutes, and then rinse in distilled water for 2 minutes. Dip in 50% alcohol for 30 seconds. Stain in buffered Congo-red solution* for 1 hour. Dehydrate, clear in xylene, and coverslip, using permount. Sections are examined using crossed Polaroid filters; red-stained amyloid deposits show bright green birefringence. Results appear as follows: Nuclei — blue Amyloid — deep pink to red Elastic fiber — pink to red

FROZEN SECTION STAININGS MODIFIED TRICHROME STAIN 10,11 Stain in Gill’s hematoxylin for 5 minutes. Wash in warm running water to remove excess stain. Stain in Gomori’s trichrome stain for 20 minutes. Wash in warm running water until clear. Do not overrinse. Dehydrate in graded alcohols and xylene. Mount in permount. The results are as follows: Myelin — red Axon — green Nuclei — dark blue

HEMATOXYLIN AND EOSIN (H & E) STAIN Stain in Harris hematoxylin (modified Harris hematoxylin from Richard Allen Co., cat. #72711) for 5 minutes. Wash in warm running tap water for 10 minutes. Place sections in 0.5% ammonium water for 2 minutes. Rinse in warm water for 5 minutes. Stain in eosin for 1 to 2 minutes. Wash in warm running tap water until water is clear. Dehydrate in graded alcohols and xylene. Mount in permount. Results appear as follows: Nuclei — dark blue Myelin — purple Cells with basophilia — varying shades of blue * Congo-red solution: Congo-red C.I. 22120, 0.5 gm; buffered solution at pH 10, 50 ml; absolute alcohol, 50 ml. Dissolve the Congo-red in the buffer solution. Then add the absolute alcohol. This solution is stable for 6 months at room temperature. Alkaline buffer solution, pH 10.0. 0.1 M glycine (7.51 gm in 1000 ml DW), 30 ml; 0.1 M NaCl (NaCl 5.85 gm in 1000 ml DW), 30 ml; 0.2 M sodium hydroxide (4 gm of sodium hydroxide in 1000 ml DW), 40 ml.

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PASH (PERIODIC ACID SCHIFF AND HEMATOXYLIN) STAIN Put the section in Carnoy’s fixative* for 5 minutes. Wash until clear with distilled water. Put in 0.5% periodic acid** for 5 minutes. Wash until clear with distilled water. Put in Schiff’s solution† (Sigma, cat. #S-5133) for 10 minutes. Wash in warm, running tap water for 10 minutes. Counterstain in Gill’s hematoxylin for 5 minutes. Wash in warm running tap water for 10 minutes. Dehydrate in graded alcohols and xylene. Mount in permount. Results appear as follows: PAS positive sustances such as amyloid, basal laminae, polyglucosan body — red or magenta Nuclei — dark blue

HIRSCH–PEIFFER CRESYL-VIOLET STAIN Stain for 3 minutes in 1% aqueous cresyl-fast violet acetate.†† Blot the sections dry after rinsing in water. Dehydrate, clear, and mount. Results appear as follows: Sulphatide — golden brown Normal myelin — purple

ALKALINE CONGO-RED STAIN See the Congo-red stain for the paraffin section. Cut at 10 µm. Follow the Congo-red staining procedure for the paraffin section with two differences: begin at step 2 and stain in buffered Congo-red stain for 45 minutes. Sections are examined using crossed Polaroid filters; red-stained amyloid deposits show bright green birefringence. Results are as follows: Nuclei — blue Amyloid — deep pink to red Elastic fiber — pink to red Myelin — blue-purple

PROCESSING OF THE NERVE FOR SEMITHIN AND ELECTRON MICROSCOPY SECTIONS Always fix the nerve in 4% glutaraldehyde for at least 24 hours before dehydration and embedding.

PROCESSING AND EMBEDDING PROCEDURE Put tissue into Sorensen’s phosphate buffer‡ for 10 minutes, three times, each time in a new buffer solution. Place sample in a 1:1 mixture of 1% osmium tetroxide and the phosphate buffer for 2 hours and * Carnoy’s fixative: absolute alcohol, 60 ml; chloroform, 30 ml; glacial acetic acid, 10 ml. Mix all together in a dry glass bottle and store in glass bottle at room temperature. ** 0.5% periodic acid: periodic acid, 0.5 g; DW, 100 ml. Dissolve all in a glass bottle and store at room temperature. † Schiff’s solution: basic fuchsin, 1 g; DW, 200 ml; l N HCl, 20 ml; anhydrous Na bisulfite, 1 g. To dissolve basic fuchsin in DW in a glass flask, boil with stirring. Cool to 50°C and filter. Add HCl and cool to 250°C. Add Na bisulfite very carefully. Keep in the dark for 2 days. Filter and store in dark bottle in refrigerator. †† 1% aqueous cresyl-fast violet acetate solution: cresyl-fast acetate, 1 g; DW, 100 ml. Mix with the aid of low heat, filter, and store in the cabinet. Solution is good for 6 months. ‡ Sorensen’s phosphate buffer: A solution: 17.6 gm sodium phosphate monobasic in 500 ml DW. B solution: 28.4 gm sodium phosphate dibasic in 500 ml DW. For 100 ml of Sorensen’s phosphate buffer: 13.0 ml A solution and 87 ml B solution.

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30 minutes. Wash tissue with distilled water. Pour on and off. Place in 50% alcohol, 70% alcohol, and 80% alcohol for 10 minutes each. Place in 95% alcohol for 10 minutes twice. Place in 100% alcohol for 10 minutes, 3 times. Place in a 1:1 mixture of 100% alcohol and propylene oxide solution for 10 minutes, 4 times. Fix in a 1:1 mixture of propylene oxide and Spurr resin for at least 6 hours. Tissue can stay in this solution for up to 24 hours. Place in 100% Spurr resin (Electronmiscroscopy Science, Spurr Resin Kit 49001). Tissue should stay in this solution for at least 24 hours but can stay indefinitely. Embed in 100% Spurr resin and place into a 65°C oven for 24 hours.

SEMITHIN (0.5–1 µm) SECTION STAININGS After embedding, cut the nerve at 1 µm with the EM microtome for transverse sections, which are the most important. Once the transverse cut is made, attempt to cut the nerve for longitudinal sections. Often, it is not easy to cut the nerve for the longitudinal section. Always cut tissue at a slant to maintain the correct orientation.

TOLUIDINE BLUE AND BASIC FUCHSIN STAIN (PARAGON MULTIPLE STAIN) Pick up the sections on a drop of distilled water on a clean glass slide. Use a saturated chloroform swab to remove wrinkles from the sections. Gently wave the swab back and forth until the sections spread. Do not touch sections with swab. Heat gently to dry. With the aid of low heat on a hot plate, flood sections with Paragon multiple stain solution** and sprinkle sodium borate lightly over staining. Staining is complete when a green sheen covers the staining surface. Wash well in warm water and flush slides with absolute alcohol. Store slides in an upright position in a slide spacer. Do not mount to avoid any wrinkling. Results appear as follows: Collagen — magenta to pink Cytoplasm — blue Nuclei — dark blue Myelin — very dark blue to black

TOLUIDINE BLUE STAIN Everything is the same as above except a 1% toluidine blue solution† is used. The results appear as follows: Collagen — pale blue Cytoplasm — pale blue Nuclei — dark blue Myelin — very dark blue to black

** Paragon multiple stain: Toluidine blue, 1.095 gm; basic fuchsin, 0.405 gm; 50% alcohol, 150 ml. Add all ingredients together, stir well, and filter before use. Store at room temperature. † 1% toluidine blue solution: 1 gm toluidine blue in 100 ml DW.

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OTHER STAINS Thionin and acridine orange, thionine and basic fuchsin, methyline blue and basic fuchsin,10 and p-Phenylenediamine11 stains can also be used for staining the semithin section. Details of the staining procedure are available in the referenced literature.

NERVE FIBER TEASING For the teasing of nerve fibers, the nerve is fixed in a neutral buffered formalin solution (Formalde-Fresh 10% solution from Fisher Scientific Co.; cat. # SF94-4)* in our laboratory. We prefer formalin fixation because we can choose the time of teasing at our convenience. Other laboratories prefer fixation in glutaraldehyde.17, 11,** The teasing of one nerve fiber from beginning to end requires a minimum of 3 days. Thus, it is always important to plan ahead for the teasing of nerve fibers.

PREPARATION OF NERVE FOR TEASING Find the original sample and pour on two changes of Sorensen’s phosphate buffer for one hour each. With a pair of forceps, place most of the original sample in the second container. Pour just enough 1% osmic acid in the second container to cover the sample. Place a lid on the container, and write the number of pieces in the container on the lid. Any fat in the sample will begin to dissolve, sometimes causing the osmic acid solution to become opaque. Without knowing how many pieces are in the solution, it may be impossible to determine whether all samples have been removed. Allow the tissue to sit in the container for 36 to 48 hours. It is virtually impossible to overstain the sample with osmic acid, so it is better to allow as much time as is practical than to remove the sample after only 24 hours. We do not recommend more than 48 hours, however, because the nerve becomes too hard to tease. After 48 hours, fill another container with diluted glycerol. Remove the stained samples from the original container, and place them in the water/glycerol mixture.† Allow the container to sit for at least 24 hours. The samples can be stored in glycerol indefinitely, and, in general, the longer they sit there, the softer and, thus, easier to tease they will be.

GENERAL GUIDELINES FOR TEASING OF FIBERS Two slides are placed on the stage of a dissecting microscope. One serves as a work surface on which the intact nerve rests in a pool of glycerin, and the other receives the teased individual fibers. With a pair of curved, pointed forceps (such as jeweler’s forceps), strip off the softened epineurium and perineurium onto lightly glycerinated glass slides under a dissecting microscope into several bundles of fascicles. Under higher magnification, subdivide the bundles of fascicles into smaller-sized bundles until single myelinated fibers can be identified. Gently pull a single fiber or a few fibers from the parent strand with forceps and drag them onto the receiving slide in a thin trail of glycerin. After five fibers have been placed on the receiving slide, apply a cover slip (see Figure 3.2).

* Neutral buffered formalin solution: 40% formaldehyde, 100 ml; DW, 900 ml; acid sodium phosphate monohydrate, 4 gm; anhydrous disodium phosphate, 6.5 gm. ** Asbury’s glutaraldehyde fixation: The nerve is fixed for one hour in 0.1 M phosphate-buffered 3.6% glutaraldehyde. After two 15 minute buffer washes, the nerve is immersed in 0.1 M phosphate-buffered 2% osmium tetroxide for 4 to 6 hours. After two further washes, the tissue is placed in 66% glycerin in water for at least 12 hours and is then stored in 100% glycerin at 4°C. Material can be held this way for 6 months or more without recognizable tissue alteration. † Glycerol and DW mixed in a ratio of 1:1 by volume.

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FIGURE 3.2 From left to right and from top to bottom, consecutive steps in fiber teasing: a fascicle of nerve, fixed in glutaraldehyde or formalin and osmium tetroxide, lying in pool of glycerin on glass slide; proximal ends are grapsed and fascicles are pulled apart; epineurium and perineurium are stripped off; strands of fibers are pulled apart; from separated strands of nerve, a single teased fiber is slide onto an adjacent slide as described in the text; teased fibers in place under cover slip. (With permission from Dyck, P.J., Peripheral Neuropathy, Dyck, P.J., Thomas P.K., and Lambert E.H. Eds., W.B. Saunders, Philadelphia, 1975.)

PRACTICAL TIPS FOR TEASING FIBERS* It is not necessary to place a minute drop of glycerol between the slides when transferring the fiber from one slide to another. In fact, this drop has a tendency to slip through the crack between the slides and ruin the microscope stage. In any case, glycerol is likely to get on the stage, which can be cleaned off with alcohol if it becomes bothersome. Note that the stage can be scratched, just like a pair of glasses. Therefore, use only a soft cloth like Kleenex to clean the stage. The forceps can leave the surface of the slide while holding a fiber. It is not important that the tip of the forceps touch the stage, but the far end of the nerve fiber must touch the stage, thus pulling the fiber straight while it is being dragged from one slide to another. In practice, it is virtually impossible to tease a truly single fiber from any nerve sample. A single fiber is very fragile and is liable to break as it is transferred from one slide to another. Instead, it is more practical to collect groups of two or three fibers as one fiber and then transfer this group intact to the second slide. Remember, however, that a group of more than a few fibers will be almost impossible to interpret, as one will not be able to trace the individual fibers under a light microscope. It is virtually impossible to randomly sample fibers in the manner outlined in this chapter without a lot of experience with this technique, and it is not worth the effort. A simple, easier method for * These tips were prepared by Dr. David Oh, who worked on nerve-teasing as an undergraduate student project.

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random selection is this: for each slide, pull one thick strand off the entire sample, and then tease off five fibers from various parts of the strand (this will involve splitting the strand into many smaller sections, because fibers must be obtained from the middle as well as the edge of the thick strand). Repeat this process with new slides until you have 11 slides (50 fibers, with 1 slide left over just in case). Since each fiber is actually a group of 2 or 3 (see above), the total number of fibers ready for analysis will usually exceed 100. Be careful about concentrating too much on the most visible fibers in the sample. Demyelinated fibers are relatively difficult to see and tease, but must be considered in any valid analysis. Therefore, in difficult situations (on the 5–20 fiber level), use the “right hand rule.” Grab the fibers on the right regardless of their visibility or condition. Using this rule leads to a very random sampling of fibers in any situation. Make sure you are using the sharpest pair of forceps available.

PREPARING THE SLIDE AFTER TEASING When preparing the slide, first place a drop of Surgipath Acrytol or similar mounting medium on the cover slip. Use a very small drop, as a large drop will spread out too quickly, dislodging the nerve fibers and ruining the slide. Then align the cover slip so the center of the drop is over the center of the fiber, and drop it on the slide. Do not press on the cover slip, as this, too, will dislodge the fibers. Label the slide and let it sit by itself for 24 hours. Finally, seal the edge of the slip with your fingernail polish.

ELECTRON MICROSCOPE STUDY For the ultrastructural electron microscope study of a nerve, one has to follow standard procedures and techniques. The general guidelines on this subject are given by King.10

REFERENCES 1. 2.

Asbury, A.K. and Connolly, E.S., Sural nerve biopsy: technical note, J. Neurosurg., 38, 391, 1973. Dyck, P.J. and Lofgren, E.P., Nerve biopsy. Choice of nerve, methods, symptoms, and usefulness, Med. Clin. North Am., 52, 885, 1968. 3. Oh, S.J., The nerve conduction and sural nerve biopsy helpful in rapid diagnosis of vasculitis, Neurology, 35 (S1), 240, 1985. 4. Harati, Y. and Matta, K., Gomori trichrome stain, Arch. Neurol., 36, 454, 1979. 5. Oh, S.J., Diagnostic usefulness and limitations of the sural nerve biopsy, Yonsei Med. J., 31(1), 1, 1990. 6. Grunnet, M.L., Gomori’s trichrome stain. Its use with myelin sheaths, Arch. Neurol., 35, 692, 1978. 7. Dyck, P.J., Karnes, J., Lais, A., Lofgren, E.P., and Stevens, J.C., Pathologic alterations of the peripheral nervous system of humans, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds.,W.B. Saunders, Philadelphia, PA, 1984, 760. 8. Midroni, G. and Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, MA, 1995. 9. Engel, W.K. and Cunningham, G.C., Rapid examination of muscle tissue. An improved trichrome method for fresh-frozen biopsy sections, Neurology, 13, 919, 1963. 10. King, R., Atlas of Peripheral Nerve Biopsy, Arnold, London, UK, 1999. 11. Asbury, A.K. and Johnson, P.C., Pathology of Peripheral Nerve, W.B. Saunders, Philadelphia, PA, 1978.

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Normal Nerve: Histology

Grossly, the sural nerve looks like a pearly white cord and measures 2 to 3 mm in diameter. Thus, it resembles angel-hair pasta. It is usually adhered to some loose adipose tissue. In general, the superficial peroneal and radial nerves are smaller than the sural nerve in diameter. There are three compartments in the nerve: the epineurium, perineurium, and endoneurium. Five to fifteen nerve fascicles are usually present in the sural nerve (Color Figure 4.1),* surrounded and bound by connective tissue in the epineurium (Color Figures 4.2 and 4.3). The epineurium makes up approximately one-half of the cross-section area of the nerve. The most important structures in the epineurium are arterioles and venules because these are the vessels most often involved in vasculitic neuropathy. One or two arterioles are found in the epineurium, and their diameters range from 30 to 300 µm. Pacinian corpuscles are rarely observed in the epineurium. Midroni et al. observed this in only 3 of nearly 700 consecutive cases. Apparently, a few mononuclear cell infiltrates were found around the vessels in the epineurium of normal nerves.1,2 Dyck stated that it is not always easy to decide whether the degree of perivascular infiltration is abnormal.1 Again, one has to judge such findings in correlation with the clinical findings. Other cell types normally seen in the epineurium include fibroblasts and mast cells. The perineurium separates the endoneurium of the nerve fascicle from the epineurium. The endoneurium contains nerve fibers, Schwann cells, and blood vessels, together with bundles of endoneurial collagen fibers oriented longitudinally along the nerve fascicles. Ninety percent of the cell nuclei in the endoneurium belong to Schwann cells; the rest of the cells are mainly fibroblasts and capillary endothelium. Occasional mast cells are also present in the endoneurium. A regular light microscope does not reliably detect and identify scattered lymphocytes in normal nerves. Thus, if scattered lymphocytes are definitely observed under the light microscope, this should be interpreted as abnormal. A few recent studies have found a few leukocytes in normal nerves using Leukocyte Common Antigen (LCA) immunohistochemical staining.3,4 There were no immunopositive T- or Bcells.5 As a practical guideline, Midroni stated that a few (three to four on cross-section) LCA-positive cells randomly dispersed throughout the endoneurium of an average fascicle do not necessarily indicate abnormality.2 However, cuffing around an endoneurial vessel is always regarded as a significant marker of inflammation. Total endoneurial area in the distal sural nerve ranges from 0.65 to 1.26 mm 2.6 Myelinated fibers and their Schwann cells account for 24 to 36% of this total cross-sectional area, and unmyelinated fibers and their Schwann cells account for 11 to 12%. Eighty percent of the Schwann cells are associated with nonmyelinated axons. The nonmyelinated fibers are nearly four times as numerous (approximately 30,000 per square millimeter of nerve) as the myelinated fibers (average 8000 per square millimeter). Nonmyelinated fibers have a range of 0.5 to 3.0 µm in a unimodal distribution but are reliably demonstrated only by electron microscopy. Myelinated fibers have a range of external diameter (axon plus myelin sheath) of 2 to 17 µm and show bimodal distribution with peaks at 5 µm and 13 µm. The thickness of the myelin sheath is proportional to axon diameter in the semithin sections (Color Figure 4.4) and Kultschitzky’s stained paraffin sections (Color Figure 4.5). As a rough guide, the ratio of the diameter of an axon without myelin to that of a fully myelinated axon, called the G-ratio, is normally 0.5 to 0.7. Most histologically normal axons over 3 µm in diameter should have a myelin sheath. If there is no myelin sheath in axons over 3 µm in diameter, one can interpret them as denuded axons (demyelinated axons). This G-ratio is not applicable in the frozen or paraffin * Color insert figures. ©2002 CRC Press LLC

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sections because the axon is not mostly visible, and axons are smaller in diameter when visible (Color Figures 4.6 and 4.7). In the frozen and paraffin sections, myelinated fibers fill the entire area of the nerve fascicle (Color Figures 4.8–4.11). Frozen and paraffin sections tend to predominantly show the large-diameter fibers. Sometimes axons can be identified in the center (Color Figures 4.6 and 4.7). On the other hand, in semithin sections, myelinated fibers of varying diameter can easily be seen in transverse sections of the normal sural nerve (Color Figure 4.12). In semithin sections, one can easily recognize the separation of myelinated fibers and two populations of myelinated fibers. Cylindrical hyaline bodies (Renault bodies) occur in the endoneurium (Color Figures 4.13–4.15) as a normal variant and should not be interpreted as abnormal. Renault bodies appear round or ellipsoid in cross-section and are 30 to 200 µm in diameter, lightly eosinophilic, and lightly stained with toluidine blue and Alcian blue, but not with PAS or Congo-red stains. Renault bodies are found in approximately 2 to 7.5% of sural nerve biopsies.2,7,8

AGE-RELATED CHANGES IN THE SURAL NERVE BIOPSY Age-related changes occur at childhood and old age (Figure 4.1). In view of the smaller endoneurial area at birth, fiber density is clearly highest at this time,9 though the total number of myelinated fibers in the sural nerve at birth is smaller, roughly half of the adult value.10 Thus, myelinated fibers are densely packed, and intervening endoneurial collagen forms compact bundles with little space between adjacent collagen fibrils. Unmyelinated fibers contain 10 or more axons. Axon diameter and myelin thickness are below adult values at birth, but the G-ratio is above normal, indicating relative hypomyelination.11,12 Thus, to the inexperienced eye, normal nerves at birth may look like demyelinating neuropathy compared to the normal myelinated population for adults. With increasing age, there is an obvious increase in the size and separation of myelinated fibers.10,13 These changes are most marked during the first few years. During this period there is a progressive increase in the thickness of the myelin sheath in relation to the axon diameter, but a few large fibers have relatively thin myelin sheaths. By the age of 5, axon diameters reach adult values, with final adjustments in myelin thickness continuing for at least 10 years. Midroni recommended 10 years of age as a convenient but rough guideline for the age at which the human sural nerve reaches histologic maturity. The increase in myelin sheath thickness and axon diameter appears complete by the second decade. During the next three or four decades, the amount of endoneurial collagen increases slightly, but there is only occasional evidence of axonal degeneration or demyelination.10 Changes due to aging are obvious from about 60 years of age; there is an obvious reduction in the density of myelinated fibers.10,14,15 The depletion is most prominent for large myelinated fibers.10 In one study of 79 sural nerves, the average large myelinated fiber density decreased by almost 46% from the third to the ninth decade.14 Fascicles contained an occasional degenerating axon as well as scattered regeneration clusters and remyelinated fibers. Also present in moderate numbers were fine- or medium-sized axons with disproportionately thick myelin sheaths. The amount of endoneurial collagen increased, and individual collagen fibrils appeared to be more widely separated. Many unmyelinated fibers showed banding of Schwann cell processes associated with loss of axons. From the sixth decade onward, the vasa nervorum showed increasing reduplication of the endothelial and pericytic basement membranes, but the membranes did not appear to be thickened. In older subjects there was obvious thickening of the perineurial basement membranes. It is, therefore, obvious that one has to be careful in interpreting the nerve biopsy from older patients. Unless the abnormality is obvious, one should not interpret the findings as abnormal in this age group. In patients with minimal abnormalities, changes could well be due to aging and, thus, clinical correlation is essential.

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FIGURE 4.1 Age-related changes. Transverse sections of sural nerves at 5 months (A) 10 years (B) 30 years (C) and 67 years (D). With increasing age there is a reduction in the density of myelinated fibers, an increase in axonal caliber and myelin sheath thickness, and an increase in the amount of endoneurial collagen. In (D) there are scattered fibers with inappropriately thin sheaths, probably remyelinated, myelin sheath irregularities, and clusters of regenerated fibers (arrows). Bar 25 µm. (With permission from Jacobs, J.M. and Love, S., Qualitative and quantitative morphology of human sural nerve at different ages. Brain, 1985, 108:900–901.)

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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Dyck, P.J., Pathologic alterations of the peripheral nervous system of man, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., and Lambert, E.H., Eds., W.B. Saunders, Philadelphia, PA, 1975, 296. Midroni, G. and Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, MA, 1995. Kerkoff, A. et al., Inflammatory cells in the peripheral nervous sytem in motor neuron disease, Acta Neuropathol., 85, 560, 1993. Hanovar, M. et al., A clinicopathological study of the Guillain–Barré syndrome: nine cases and literature review, Brain, 114, 1245, 1991. De la Monte, S.M. et al., Peripheral neuropathy in the acquired immunodeficiency syndrome., Ann. Neurol. 23, 485, 1988. Behse, F., Morphometrric studies on the human sural nerve, Acta Neurol. Scand., S132, 1, 1990. Bergouignan, F.X. and Vital, C., Occurrence of Renault bodies in a peripheral nerve, Arch Pathol. Lab. Med., 108, 330, 1984. Weis, J., Alexianu, M.E., Heide, G., and Schroder, J.M., Renault bodies contain elastic fiber components, J. Neuropathol. Exp. Neurol., 52, 444, 1993. Ouvier, R.A., McLeod, J., and Conchin, T., Morphometric studies of sural nerve in childhood, Muscle and Nerve, 10, 47, 1987. Jacobs, J.M. and Love, S., Qualitative and quantitative morphology of the human sural nerve at different ages, Brain, 108, 897, 1985. Schroder, J.M., Bohl, J., and Brodda, K., Changes of the ratio between myelin thickness and axon diameter in the human developing sural nerve, Acta Neuropathol., 84, 416, 1992. Ferriere, G., Denef, J.F., Rodriguez, J., and Guzzeta, F., Morphometric studies of normal sural nerve in children, Muscle and Nerve, 8, 697, 1983. Schellens, R.L.L.A. et al., A statistical approach to fiber diameter distribution in human sural nerve, Muscle and Nerve, 16, 1342, 1993. Tohgi, H., Tsukagoshi, H., and Toyokura, Y., Quantitative changes with aging in normal sural nerves, Acta Neuropathol., 38, 213, 1977. O’Sullivan, D.J. and Swallow, M., The fiber size and content of the radial and sural nerves, J. Neurol. Neurosurg. Psychiat., 31, 464, 1968.

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CHAPTER 4 Figure 1 Five fascicles in a sural nerve. Each fascicle is filled with red myelinated fibers. Frozen section. Modified trichrome stain. (40 × magnification.)

CHAPTER 4 Figure 3 Three compartments in a normal nerve: epineurial space (ep), perineurium (p), endoneurial space (en); subperineurial space (sps); arteriole (a). Each fascicle is filled with red myelinated fibers. This is normal. Paraffin section. Modified trichrome stain. (100 × magnification.)

CHAPTER 4 Figure 2 Three compartments in a nerve: epineurial space (EP), perineurium (P), and endoneurial space (EN); arteriole (A); vein (V). This nerve had ten fascicles, four of which are visible here. Semithin section. Toluidine blue/basic fuchsin. (100 × magnification.)

CHAPTER 4 Figure 4 Normal sural nerve. G-ratio in one myelinated fiber (arrow) is 0.6. Semithin section. Toluidine blue and basic fuchsin. (400 × magnification.)

CHAPTER 4 Figure 5 Normal sural nerve. G-ratio in one myelinated fiber (arrow) is 0.5. Paraffin section. Kultschitzky’s stain. (400 × magnification.)

CHAPTER 4 Figure 6 Normal sural nerve. Axon is visible as a dot in the center of myelinated fibers. Axon is rarely visible in the paraffin section; lm means largediameter fiber; sm means small-diameter fiber; a stands for axon. Paraffin section. Modified trichrome stain. (400 × magnification.)

CHAPTER 4 Figure 7 Normal sural nerve. Axon (a) is somewhat larger in the frozen section than the paraffin section. Again, the axon is rarely visible in the frozen section; sm means small myelinated fiber and lm means large myelinated fiber. Frozen section. Modified trichrome stain. (400 × magnification.)

CHAPTER 4 Figure 8 Entire nerve fascicle is filled with red myelinated fibers in normal nerve. Frozen section. Modified trichrome stain. (100 × magnification.)

CHAPTER 4 Figure 10 Normal sural nerve. Entire nerve fascicle is filled with red large-diameter myelinated fibers in the longitudinal cut. Frozen section. H & E stain (200 × magnification.)

CHAPTER 4 Figure 9 Normal sural nerve. Myelinated fibers are stained as purple. Frozen section. H & E stain (200 × magnification.)

CHAPTER 4 Figure 11 Normal sural nerve. Entire nerve fascicle is filled with red large-diameter myelinated fibers in the longitudinal cut. Curved distortion (arrow) of the specimen is unavoidable in the paraffin section. Modified trichrome stain. (200 × magnification.)

CHAPTER 4 Figure 12 Normal sural nerve. Varying diameter fibers are clearly identifiable in the semithin section. Semithin section. Toluidine blue and basic fuchsin. (200 × magnification.)

CHAPTER 4 Figure 13 Renault’s body (double arrow) in the endoneurial space. Semithin section. Toluidine blue and basic fuchsin. (200 × magnification.)

CHAPTER 4 Figure 14 Renault’s body (arrow) in the endoneurial space in the longitudinal cut. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 4 Figure 15 Four Renault bodies (arrows) in each nerve fascicle in the transverse cut. Frozen section. H & E stain. (100 × magnification.)

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Specific Diagnostic Pathological Features of Nerve Biopsy

There are some pathological features that are diagnostic of the specific neuropathy in the nerve biopsy. These will be discussed here in the order of specificity. More detailed information on specific pathlogical features is available in the chapters dealing with the specific subjects.

VASCULITIS Vasculitis in the sural nerve biopsy is diagnostic of vasculitic neuropathy and vasculitis. Vasculitis is histologically characterized by the intramural infiltration of inflammatory cells and fibrinoid necrosis of vessel walls. Vasculitis is usually observed in small arterioles in perineurial or epineurial spaces. Peripheral neuropathy is common in systemic vasculitides. Neuropathy is present in 60% of cases of polyarteritis nodosa and in 64% of cases of the Churg–Strauss syndrome.1,2 Vasculitis tends to involve medium- and small-sized arteries in many systemic vasculitides. Since the vasa nervorum in the peripheral nerve fall directly into the spectrum of small-sized arteries and arterioles, it is not surprising that peripheral neuropathy is a common manifestation of systemic vasculitides. As discussed above, whole nerve biopsy should be performed in suspected cases of vasculitic neuropathy. The sural nerve biopsy should be done before any steroid treatment is initiated. It is necessary to cut multiple sections from different levels of the specimen since vasculitis is multifocal and segmental. It has been our repeated experience that only a few sections of the biopsied nerve show the diagnostic change. To render a definite diagnosis of vasculitic neuropathy, the unmistakable histological features of vasculitis must be present: active, inactive, or healed necrotizing changes and infiltration of inflammatory cells within the vessel wall (Color Figures 5.1 and 5.2).* Perivascular infiltration of inflammatory mononuclear cells without intramural necrosis or cellular infiltration is an early and mild change in vasculitis.3 This alone is not enough to diagnose vasculitis because similar effects are observed in inflammatory neuropathies. However, there are some histological features which are helpful in differentiating these disorders: in vasculitic neuropathies, axonal degeneration is the predominant finding, whereas in inflammatory neuropathy, segmental demyelination and endoneurial inflammatory cells are typical findings. Thus, the diagnosis of probable vasculitis is made when perivascular infiltrations of inflammatory cells are present together with axonal degeneration if the clinical findings are compatible with vasculitis.4 Various patterns of degeneration of fibers are noted, ranging from central fascicular degeneration to selective nerve fascicular degeneration depending upon the severity of the neuropathy. Central fascicular degeneration is typical of ischemic neuropathy and is seen in vasculitic neuropathy.5 Selective nerve fascicular degeneration has been observed predominantly in vascular neuropathy. Any combination of these changes may be found in a single sural nerve biopsy in cases of vasculitic neuropathy. In recent years, nonsystemic vasculitic neuropathy (NSVN) has been reported. In this disorder, vasculitis is confined to the peripheral nerve, sparing other organs. Thus, a nerve biopsy is critical. Without nerve biopsy, vasculitis cannot be reliably differentiated from other rapidly progressive neuropathies because many cases of NSVN appear symmetrical and serological markers are usually absent. There are two ideas about nature of NSVN: it is either an organ-specific vasculitis6,7 vs. a mild form of systemic vasculitis.8,9 * Color insert figures. ©2002 CRC Press LLC

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Rarely, vasculitic neuropathy is reported in association with cancer (paraneoplastic vasculitic neuropathy),10-12 Lyme disease,13,14 AIDS,15,16 sarcoidosis, Hepatitis C, and diabetes mellitus.

AMYLOID DEPOSITS Amyloid deposits in the nerve biopsy are diagnostic of amyloid neuropathy and amyloidosis. The nerve biopsy is the diagnostic test of choice in any suspected cases of amyloid neuropathy. The combined nerve and muscle biopsy is recommended because, in rare cases, amyloid is positive in the muscle biopsy whereas it is negative in the nerve biopsy. The hallmark of amyloid neuropathy is amyloid in the nerve. Amyloid is histochemically Congored positive and green birefringent after Congo-red with polarized light (Color Figures 5.3 and 5.4). Thus, Congo-red staining of a biopsy specimen which is then examined by polarizing microscopy is the single best procedure for the diagnosis of amyloid.17 Using fresh-frozen sections, Trotter and Engel were able to demonstrate amyloid quickly and clearly using crystal-violet stain in biopsied muscles in ten cases of amyloid neuropathy, whereas amyloid deposits were rarely observed in the biopsied nerves.18 Crystal-violet staining is used on frozen sections to screen for amyloidosis, but the presence of amyloidosis is either confirmed or ruled out on paraffin sections with Congo-red stain in every biopsied nerve. Three patterns of amyloid deposits are found in the peripheral nerve: (1) amyloid deposit in extraneural connective tissue, (2) widespread endoneurial amyloid deposit, and (3) amyloid deposit within the walls of vasa nervorum both in epineurial and endoneurial spaces. The predominant nerve degeneration in amyloid neuropathy is axonal degeneration, involving smaller diameter fibers.

METACHROMATIC GRANULES The presence of metachromatic granules in the nerve is diagnostic of metachromatic neuropathy and metachromatic leukodystrophy (MLD). Metachromatic leukodystrophy is a rare autosomal recessive disorder characterized by the accumulation of galactosyl-3-sulfate (sulfatide) in the brain, kidney, gallbladder, and peripheral nerve. Four forms of MLD have been recognized: late infantile, juvenile, adult, and multiple sulfatase deficiency. The enzyme, arylsufatase A, is deficient in the first three forms. Its assay in blood leucocytes and cultured skin fibroblasts is used as a standard diagnostic test. The nerve biopsy constitutes a rapid and reliable procedure for the diagnosis of MLD when biochemical assay is not possible. Metachromatic granules are demonstrable in all cases. For demonstration of metachromatic granules, the biopsied nerve should be stained on frozen sections since metachromatia is best demonstrable with acidified cresyl-violet stain (Color Figures 5.5 and 5.6).19 Metachromatic granules are accumulated in the perinuclear cytoplasm of Schwann cells, within macrophages, and in the vicinity of endoneurial capillaries. These metachromatic granules are stained brown instead of purple or blue with cresyl-violet or toluidine blue. They are also PAS-positive and methyl-blue positive. These metachromatic granules are demonstrated in all forms of MLD, including multiple sulfatase deficiency.

POLYGLUCOSAN BODY Many polyglucosan bodies in the nerve biopsy are diagnostic of polyglucosan body disease (PGBD): such as adult polyglucosan body disease (APGBD), Lafora’s disease, and Type IV glycogenosis, if the typical clinical constellations of such diseases are present. A nerve biopsy is the diagnostic test of choice in any suspected case of APGBD. The hallmark of APGBD is the presence of a polyglucosan body in the central and peripheral nervous sytems (Color Figures 5.7 and 5.8). Polyglucosan body (PGB) is a generic name referring to Lafora body, corpora amylacea, and all other similar structures.

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A polyglucosan body is stained pale blue with the modified trichrome stain, basophilic with H & E, metachromatic with toluidine blue, and strongly positive with PAS before and after amylase and with iodine.Typically, the bodies are intra-axonal, round, range from 5 to 70 µm in diameter, and usually occur in myelinated fibers. In the nerve, many huge distended axons with polyglucosan bodies and thin myelin sheaths have been observed in all studied cases.20-23 Teased nerves show a “string of beads” appearance because of an ellipsoid dilatation of an axon due to a polyglucosan body and axonal degeneration. One or two PGBs in the nerve biopsy are a nonspecific finding without any pathological implication. Thus, many polyglucosan bodies are required for diagnosing PGBD. Because PGBs have been reported in other neuropathies, the clinical constellation of APGBD is required for the diagnosis of this disease.

ONION-BULB FORMATION The pathological hallmark of hypertrophic neuropathy is onion-bulb formation (Color Figures 5.9 and 5.10). This term refers to the concentric laminated layers surrounding the nerve fiber as viewed in the transverse section. These concentric layers of flat cell processes are arranged primarily around demyelinated or normal myelinated fibers. Most cell processes are Schwann cells. They are surrounded by basement membrane, and some contain nonmyelinated axons. In electron microscopy, these laminated layers represent the intertwined and attenuated Schwann cell processes. Though onion-bulb formation is discernable in the frozen section, it is best detected in the semithin section. When advanced, it is detectable even in the paraffin section. One way to identify onion-bulb formation in the paraffin section is to look for an increased number of Schwann cell nuclei. In advanced cases, onion-bulb formation is usually associated with prominent endoneurial and subperineurial spaces, a decreased number of myelinated fibers, and thin myelin. Thickening of the nerve may occur in hypertrophic neuropathy, due in part to the increased collagen content and cellularity of the nerve bundle. There is also often an increase in mucosubstance in the endoneurium. In severe cases, the enlarged nerves are palpable through the skin, and at biopsy they may appear grey and gelatious macroscopically due to the large amounts of endoneurial mucosubstance.24 Pathogenetically, onionbulb formation is indicative of repeated demyelination and remyelination.25 Thus, hypertrophic neuropathy itself is indicative of demyelinating neuropathy. The presence of onion-bulb formation is diagnostic of hypertrophic neuropathy. Thus, hypertrophic neuropathy represents a pathological diagnosis observed in many clinical entities. Among these, the hypertrophic type of the Charcot–Marie–Tooth disease (hereditary motor sensory neuropathy [HMSN] type I) is best known. In Roussy–Levy syndrome, Dejerinne–Sottas disease (HMSN type III), congenital hypomyelinative neuropathy, and Refsum’s disease (HMSN type IV), onion-bulb formation is the most prominent finding in the biopsied nerve. In CIDP, onion-bulb formation is seen in 11 to 43% of cases.26,27 Onion-bulb formation is also observed in hypertrophic mononeuropathy, which is characterized by focal enlargement of a single peripheral nerve.28 Hypertrophic mononeuropathy is different from generalized hypertrophic polyneuropathy because of the following characteristics: (1) it is sporadic; (2) only one site is involved; (3) it can be adequately excised and does not recur; and (4) it lacks systemic extraneural manifestations.28

INFLAMMATORY CELLS AND SEGMENTAL DEMYELINATION The presence of inflammatory cells in the nerve fibers and segmental demyelination is diagnostic of inflammatory demyelinating neuropathy. In inflammatory demyelinating neuropathy, the inflammatory cells in the endoneurial space are specific to this type of neuropathy, which is the type of neuropathy most commonly encountered in the practice of neurology. Inflammatory neuropathy is classified into two main categories: acute and chronic.

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Acute inflammatory demyelinating polyneuropathy (AIDP), better known as the Guillain-Barré syndrome (GBS), is a well-known entity. In contrast to the ubiquitous presence of inflammatory cells in the peripheral nerve in the autopsy series in GBS, inflammatory cells are unfortunately not commonly observed in the nerve biopsy.29 Inflammatory cells were observed in 41% of the cases in our series and in 33% of cases in the study performed by Prineas.30 The presence of inflammatory cells in the endoneurial space is the most specific finding indicative of inflammatory neuropathy (Color Figure 5.11). Inflammatory cells are distinctly mononuclear, composed of both small and large lymphocytes. Plasma cells are scattered among the lymphocytes. In some cases, perivascular infiltration of lymphocytes is seen only in the epineurial space. The most consistent finding in the sural nerve biopsy in GBS is segmental demyelination, as demonstrated by our series and Prineas’s study.33 This is best observed in the teased fibers, semithin sections, and longitudinal sections of the frozen section (Color Figure 5.12). Chronic inflammatory demyelinating polyneuropathy (CIDP) is considered a separate clinical entity on the basis of subacute progression of polyneuropathy, marked nerve conduction abnormalities, a high rate of relapse, and responsiveness to steroid treatment.26,27,31,32 There are two forms of CIPD: the monophasic form and the relapsing form.26 The diagnosis of CIDP is based on the typical clinical features such as subacute progression of polyneuropathy, high CSF protein, and marked nerve conduction abnormalities indicative of demyelinating neuropathy. The sural nerve biopsy is recommended for all patients with this disorder for the reasons as described in Chapter 7. The pathological hallmark of CIDP is primary demyelination, the most constant finding in the sural nerve biopsy (Color Figure 5.12). The presence of inflammatory cells, an expected feature in inflammatory neuropathy, is a rare occurrence, observed in about 20 to 30% of cases. When present, inflammation is not as prominent a feature as in GBS.33 Usually, perivascular infiltration in the epineurial space is more common than endoneurial infiltration of cells. AIDP and CIDP were reported as the most frequently observed neuropathies in acquired immune deficiency syndrome (AIDS) due to the HIV virus.15,34,35 CIDP was also reported in a single case of HTLV I myelopathy, another retroviral disease.36 CIDP is a well-known feature of many dysproteinemic neuropathies associated with osteosclerotic myeloma, benign monoclonal gammopathy, and Waldenström’s macroglobulinemia.

INFLAMMATORY CELLS AND AXONAL DEGENERATION The presence of inflammatory cells in the nerve fibers and axonal neuropathy is diagnostic of inflammatory axonal neuropathy. In inflammatory axonal neuropathy, inflammatory cells are characteristically observed in the epineurial space (Color Figures 5.13 and 5.14). This is in contrast to inflammatory demyelinating neuropathy, in which endoneurial inflammatory cells are known to occur more specifically. Inflammatory axonal neuropathy is classically observed in vasculitic neuropathy. Certainly, in vasculitic neuropathy, definite pathological evidence of vasculitis is required to make the diagnosis. However, in roughly one-third of patients with vasculitic neuropathy, definite pathological features of vasculitis were lacking.37,38 In those cases, the diagnosis of probable vasculitic neuropathy was made on the basis of inflammatory axonal neuropathy. This is especially true in nonsystemic vasculitic neuropathy. In Dyck’s series, inflammatory axonal neuropathy was the most common finding in the sural nerve biopsy in nonsystemic vasculitic neuropathy.39 Inflammatory axonal neuropathy has also been observed in paraneoplastic neuropathy, sensory perineuritis, toxic oil syndrome, and eosinophilic myalgic syndrome.

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NONCASEATING GRANULOMA The presence of noncaseating granuloma in the nerve is diagnostic of sarcoid neuropathy and sarcoidosis once leprosy has been ruled out by the acid fast baccilus (AFB) stain. In sarcoidosis, microscopic granulomata were found in muscle in up to 60% of patients with active sarcoidosis, while peripheral nerve involvement was less than 1% in sarcoidosis.40,41 Thus, a muscle biopsy is the procedure of choice for diagnosis of sarcoidosis if skin or lymph node biopsy is not diagnostic. Sarcoid granuloma is classically a noncaseating granuloma consisting of epithelioid cells, Langhan’s giant cells, and lymphocytes (Color Figure 5.15). No organisms are found in sarcoid granuloma. Noncaseating granuloma has been observed primarily in the epi- and perineurial spaces.42-44 Granuloma in the endoneurium was reported in only one case.45 Granulomatous periangitis and panangitis were observed in the epi- and perineurial spaces in four cases.42-44 In practice, the combined muscle and nerve biopsy is recommended in patients clinically suspected of sarcoid neuropathy for two reasons: the diagnostic yield is high in muscle biopsy, as described above, and granuloma was not always observed in biopsied nerves possibly because of the sampling error. In three of four patients with sarcoid neuropathy, in our series, the sural nerve biopsy did not show classical granuloma.

NECROTIZING (CASEATING) GRANULOMA Necrotizing granulomatous neuropathy is diagnostic of neuropathy secondary to leprosy. Leprosy is an infectious disease caused by Mycobacterium leprae and characterized by its skin and peripheral nerve lesions. Mycobacterium leprae is the only bacterium which invades peripheral nerves in man and animals. It is classified into two polar types, tuberculoid and lepromatous, and a borderline (dimorphous, intermediate) type possessing some characteristics of each polar type. In addition, there is an indeterminate type of mycobacterium which has not established itself into any of the three types mentioned above. The pathological features in a nerve are different according to the type of leprosy involved.46,47 In indeterminate leprosy, the nerve shows lymphocytic infiltration in the endoneurial and perineurial space. In tuberculoid leprosy, noncaseating or caseating granulomatous lesions are the most prominent features. Granuloma can be found in the epi- and perineurial spaces as well as in the endoneurial space. Caseation may occur and produce large abscesses within the nerve. With healing, the nerve shows fibrosis and hyalization in the endoneurium and thick perineurial and epineurial sheaths. Bacilli are scanty and, when present, are almost always in the nerve. In lepromatous leprosy, the perineurial and endoneurial infiltration of macrophages and Schwann cells with AFB bacilli (foamy cells) and inflammatory cells is the cardinal feature (Color Figure 5.16). Massive bacilli are found in these foamy cells. In severe cases, the epineurium may be infiltrated by huge numbers of foamy cells, especially around blood vessels. With time, endoneurial fibrosis occurs. Intraneurial microabscesses may be present in either type, especially during an attack of erythema nodosum. In dimorphous leprosy, granuloma and endoneurial foamy cells are present. In all of these cases, the pathological diagnosis of leprosy should be made on the demonstration of acid-fast bacilli in the nerve using the Fite method (Color Figure 5.17).48 In a majority of cases, the diagnosis of leprosy is usually made by observation of typical skin lesions and the presence of acid-fast bacilli from the skin smear or the skin biopsy. The nerve biopsy is imperative for the diagnosis of primary neuritic leprosy in which neuropathy is the sole clinical manifestation without typical skin lesions or a positive skin smear. In those cases, the skin biopsy from anesthesic areas may fail to show histological changes suggestive of leprosy.49 In 77 patients with peripheral neuropathy without any known causes in a leprosy-endemic area, Jacob and Mathai were able to confirm leprosy in 49.4% of cases by performing a nerve biopsy of the cutaneous nerve

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near the neurological deficit: the superficial radial sensory nerve in patients with “glove” anesthesia and the superficial peroneal or sural nerve in patients with “stocking” anesthesia.49 This study clearly shows the important diagnostic role of the biopsy of the cutaneous nerve in primary neuritic leprosy.

GIANT AXONS Giant axons in the nerve are diagnostic of giant axonal neuropathy and certain toxic neuropathies. Giant axonal neuropathy is seldom familial and is classically accompanied by sensory neuropathy and curly hair.50,51 Giant axons have been reported in certain toxic neuropathies: glue-sniffer’s neuropathy, huffer’s neuropathy, and toxic neuropathy induced by n-hexane, methyl n-butyl ketone, acrylamide, and disulfiram.52-57 N-hexane and methyl n-butyl ketone are widely used as solvents and as components of lacquers, glues, and glue and lacquer thinners. Huffer’s neuropathy is peripheral neuropathy due to “huffing” of lacquer thinner. Thus, glue-sniffer’s neuropathy and huffer’s neuropathy are, in essence, due to inhalation of n-hexane or methyl n-butyl ketone. In disulfiram neuropathy, carbon disulfide, a metabolite of disulfiram, is responsible for giant axons. Giant axonal swelling represents a focal mass of neurofilaments surrounded by thin myelin. Swelling ranges from two to three times the original diameter of the fibers and is usually associated with increased paranodal gap (Color Figures 5.18 and 5.19). The axons may reach a diameter of 50 µm but typically range from 20 to 30 µm. Giant axonal swelling is best seen as “green swollen axons” in the transerve sections with the modified trichrome stain on frozen sections and as “swollen axons” in semithin sections. Axonal degeneration is the predominant feature of these neuropathies.

TOMACULA Tomacula (Latin for sausages) in the nerve biopsy are diagnostic of tomaculous neuropathy. In 1975, Madrid and Bradley coined this term in four patients: two with recurrent familial brachial plexus neuropathy, one with a pressure-sensitive neuropathy, and one with a chronic distal sensorimotor neuropathy predominantly affecting the arms.58 Tomacula refer to the focal sausage-shaped swellings of myelin sheaths, best seen in the teased nerves. However, tomacula can easily be detected on the frozen sections as red sausage-shaped swollen myelin in the longitudinal sections and red swollen myelin in the transverse sections. There is no accompanying axonal swelling (Color Figures 5.20 and 5.21). Tomacula measured up to 27 µm in diameter and from 80 to 250 µm in length in Madrid and Bradley’s cases.58 Within the tomacula, the myelin sheath had an increased number of lamellae, two or three times the normal number in the thickest myelin sheath of a normal nerve.71 Tomaculous neuropathy was first described in 1975 by Behse et al. in six patients with hereditary neuropathy with liability to pressure palsies (HNPP).59 So far, all nerve biopsies from patients with hereditary pressure neuropathy and recurrent familial mononeuropathy or brachial plexus neuropathy have exhibited tomaculous neuropathy.60-63 This neuropathy has also been described in a few cases of HMSN I (CMT 1A), HMSN with myelin outfolding (CMT 4B), IgM paraproteinemic neuropathy, and CIDP.64 Segmental demyelination is the unform finding in these cases. Onion-bulb formation is seen in some cases. Tomaculous neuropathy represents demyelinating neuropathy and is most commonly and typically seen in HNPP and familial recurrent brachial plexopathy.

OCCLUSION OF VASA NERVORUM Occlusion of the small arterioles and capillaries in the nerve is diagnostic of ischemic neuropathy and is observed in diabetic neuropathy, vasculitic neuropathy, and arteriosclerotic neuropathy (Color Figure 5.22).

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Recent reports suggest ischemia as one possible factor in the pathogenesis of diabetic polyneuropathy.65,66 In contrast, ischemia does seem to be important in the pathogenesis of diabetic ophthalmoplegia and proximal asymmetrical diabetic neuropathy.67-69 In vasculitic neuropathies, occlusion of the arterioles may occur due to endothelial and intramural inflammation and proliferation, as discussed above. Ischemia may be responsible for ischemic neuropathy due to severe arteriosclerosis.70 Small arterioles and capillaries in the perineurial and epineurial spaces show occlusion due to extensive fibrotic thickening and hyalization (Color Figure 5.14). In vasculitis, inflammatory cells may be present (Color Figures 5.1 and 5.2). Because of the anatomical distribution of the blood supply, ischemia produces degeneration of nerve fibers in a certain section of nerves, producing central fascicular degeneration (depopulation of fiber in the center of a fascicle) and selective nerve fascicular degeneration (depopulation of fibers in one or two fascicles). Thus, central fascicular degeneration and selective nerve fascicular degeneration are used as the histological markers of ischemic neuropathy.

MALIGNANT CELLS The presence of maligant cells in the nerve fiber is indicative of lymphomatous neuropathy (Color Figure 5.23). This is because neoplastic neuropathy is essentially confined to hematological malignancy including lymphoma, lymphomatous granulomatosis, leukemia, and myeloma. The infiltrating cells have all the characteristics of malignant cells: mitotic figures, pleomorphism, and atopia. A diffuse massive infiltration of all peripheral nerve compartments is most typical of lymphomatous neuropathy. In this type of neuropathy, a tendency toward perivascular cuffing commonly occurs, and, sometimes, a striking angiocentricity of the tumor cells is present, as typically observed in lymphomatoid granulomatosis. When malignant cells are seen in a nerve biopsy, B- and T-cell markers can confirm a lymphoid malignancy. The presence of a monoclonal population of infiltrative cells is inferred when the vast majority of the cells belong to a single lymphocyte subset in the bone marrow or peripheral blood cells. That is because the amount of tissue required for the immunotyping of cells is not available on a routine nerve specimen, and thus, an immunotyping of monoclonality is done with bone marrow or peripheral blood cells by using flow cytometry.

IgM DEPOSITS IgM deposits have been the most important exception to the general lack of diagnostic usefulness of immunohistochemical and immunofluorescent techniques in nerve biopsy (Color Figure 5.24). IgM deposits in the myelin sheath or endoneurium are diagnostic of IgM paraproteinemic neuropathy, including anti-MAG neuropathy. IgM deposits in myelin sheaths are specific for IgM-associated neuropathy, being positive in 40 to 80% of patients with this neuropathy, usually in the presence of antiMAG activity.71 This was not reported in IgG- or IgA-associated neuropathies. Endoneurial deposits of IgM are also specific for IgM-associated neuropathy in that they have been reported only in several cases of Waldenström’s macroglobulinemia and a few cases of IgM MGUS neuropathy.72 Usually, in patients with endoneurial IgM deposits, the nerve lesions are mainly axonal, and anti-MAG activity is usually absent.73 IgM deposits can be demonstrated by either immunofluorescent staining on the frozen sections or immunohistochemical staining on the paraffin sections.

SEGMENTAL DEMYELINATION Segmental demyelination in the nerve is diagnostic of demyelinating neuropathy (Color Figure 5.25). The classic example of demyelinating neuropathy is inflammatory neuropathy, either acute or chronic. In inflammatory neuropathy, inflammatory cells are often present in the nerve to make this

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diagnosis possible. Another example is hereditary hypertrophic neuropathy. However, there are many demyelinating neuropathies which are neither inflammatory nor hereditary. In those cases, segmental demyelination is the sole finding in the nerve without any histological clue for the exact etiology. Thus, the etiology for neuropathy should be sought by conducting other tests. Segmental demyelination can best be observed in teased nerves (Color Figure 5.26). Demyelination can also be diagnosed by a thin myelin sheath in proportion to axon diameter in the semithin sections, onion-bulb formation, or tomaculous change. In the longitudinal cuts of frozen sections, segmental demyelination can rarely be observed when the nerve is well stretched and the cut plane is uniformly flat. Segmental demyelination in the nerve is diagnostic of nonspecific demyelinating neuropathy if other histological features diagnostic of specific neuropathies are lacking.

AXONAL DEGENERATION Axonal degeneration in the nerve is diagnostic of axonal neuropathy. Nutritional, alcoholic, vitamin deficiency, and most toxic neuropathies are the best examples. In these neuropathies, there is no histological feature indicative of a specific diagnosis, which should be made on the basis of other findings. Axonal degeneration can best be diagnosed by the presence of myelin-digestion chambers in the frozen sections and myelin ovoids in teased nerves (Color Figures 5.27 and 5.28). Axonal degeneration is indirectly diagnosed by the presence of giant axons in the nerve and is also expressed by small clusters of small axons with thin myelin (axonal regeneration). This is most readily observed in the semithin transverse sections and represents repeated axon degeneration and regeneration.74 In smoldering axonal degeneration, axon atrophy may be the sole finding indicative of axonal degeneration. Axon atrophy is best observed with electron microscopy by smaller axon diameter in proportion to normal myelin thickness. Except for giant axonal and vasculitic neuropathies, most axonal neuropathies do not have any characteristic histological features in the nerve indicative of etiology. Thus, in these neuropathies, etiology should be sought by conducting other tests.

REFERENCES 1. 2.

Frohnert, P.P. and Sheps, S.G., Long-term follow-up study of periarteritis nodosa, Am. J. Med., 43, 8, 1967. Chumbley, L.C., Harrison, E.G., and DeRemee, R.A., Allergic granulomatosis and angiitis (Churg– Strauss syndrome). Report and analysis of 30 cases, Mayo Clin. Proc., 52, 477, 1977. 3. Dyck, P.J., Conn, D.J., and Okazaki, H., Necrotizing angiopathic neuropathy. Three-dimensional morphology of fiber degeneration related to sites of occluded vessels, Mayo Clin. Proc., 47, 461, 1972. 4. Wees, S.J., Sunwoo, I.N., and Oh, S.J., Sural nerve biopsy in systemic necrotizing vasculitis, Am. J. Med., 71, 525, 1981. 5. Harati, Y. and Niakan, E., Clinical significance of selective nerve fascicular degeneration on sural nerve biopsy specimen, Arch. Pathol. Lab. Med., 110, 195, 1986. 6. Dyck, P.J., Benstead, T.J., Conn, D.L., Stevens, J.C., and Windebank, A.J., Non-systemic vasculitic neuropathy, Brain, 110,843, 1987. 7. Davies, L., Spies, J., Pollard, J., and McLeod, J., Vasculitis confined to peripheral nerves, Brain, 19, 1441, 1996. 8. Kissel, J.T., Vasculitis of the peripheral nervous system, Semin. Neuro., 4, 361, 1994. 9. Said, G., Lacroix-Ciaudo, C., Fujimura, H., Blas, C., and Faux, N., The peripheral neuropathy of necrotizing arteritis: a clinicopathological study, Ann. Neurol., 23, 461, 1988. 10. Johnson, P.C., Roak, L.A., Hamilton, R.H., and Laguna, J.F., Paraneopalstic vasculitis of nerve, a remote effect of cancer, Ann. Neurol., 5, 437, 1979.

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11. Vincent, D., Dubas, F., Hauw, J.J., Bodeau, P., L’Hermitte, F., Buge, A., and Castaigne, P., Nerve and muscle microvasculitis, J. Neuro. Neurosurg. Psychiatry, 49, 1007, 1986. 12. Oh, S., Slaughter, R., and Harrell, L., Paraneoplastic vasculitic neuropathy: a treatable neuropathy, Muscle and Nerve, 14, 152, 1991. 13. Vallat, J.M., Hugon, J., Lubveau, M., Leboutet, M.J., Dumas, M., and Desproges-Gotteron, R., Tick-bite meningoradiculoneuritis: clinical, electrophysiologic, and histologic findings in 10 cases, Neurology, 37, 749, 1983. 14. Camponovo, F. and Meier, C., Neuropathy of vasculitic origin in a case of Garin-Bannwarth syndrome with positive borrelia antibody response, J. Neurol., 233, 6972, 1986. 15. Dalakas, M.C., and Pezeschkpour, G.H., Neuromuscular diseases associated with human immunodeficiency virus infection, Ann. Neurol., 23, S38, 1988. 16. Lange, D.J., Britton, C.B., Younger, D.S., and Hays, A.P., The neuromuscular manifestations of human immunodeficiency virus infections, Arch. Neurol., 45, 1084, 1988. 17. Cohen, A.S., The diagnosis of amyloidosis, in Laboratory Diagnostic Methods in the Rheumatic Diseases, Cohen. A.S. Ed., 2nd ed, Little, Brown & Co., Boston, 1975, 375. 18. Trotter, J.L. and Engel, W.K., Amyloidosis with plasma cell dyscrasia, Arch. Neurol., 34, 209, 1977. 19. Olsson, Y. and Sourander, P., The reliablity of the diagnosis of metachromatic leudodystrophy by peripheral nerve biopsy, Acta Pediatr. Scand., 58, 15, 1969. 20. Robitaille, Y., Carpenter, S., Karpati, G., and DiMauro, S., A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes. A report of four cases and a review of occurrence of polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing, Brain, 103, 315, 1980. 21. Vos, A.J.M., and Joosten, E.M.G., and Gabreels-Festen, A.A.W.M., Adult polyglucosan body disease: clinical and nerve biopsy findings in two cases, Ann. Neurol., 13, 440, 1983. 22. Busard, H.S.L.M. et al., Polyglucosan disease in sural nerve biopsies, Acta Neuropathol., 80, 554, 1990. 23. Robertson, N.P., Wharton, S., Anderson, J., and Scolding, N.J., Adult polyglucosan body disease associated with an extrapyramidal syndrome, J. Neurol., Neurosurg. Psychiatry, 65(5), 788, 1998. 24. Weller, R.O. and Herzoz, I., Schwann cell lysosomes in hypertrophic neuropathy and in normal human nerve, Brain, 93, 347, 1970. 25. Dyck, P.J., Expeprimental hypertropohic neuropathy. Pathogenesis of onion-bulb formations produced by repeated tourniquet applications, Arch. Neurol., 21, 73, 1969. 26. Oh, S.J., Subacute demyelinating polyneuropathy responding to corticosteroid treatment, Arch. Neurol., 35, 509, 1978. 27. Prineas, J.W. and McLeod, J.G., Chronic relapsing polyneuritis, J. Neurol. Sci., 27, 427, 1976. 28. Peckham, N.H., O’Boynick, P.L., Meneses, A., and Epes, J.J., Hypertrophic mononeuropathy: a report of two cases and review of the literature, Arch. Pathol. Lab. Med., 106, 534, 1982. 29. Asbury, A.K., Arnason, B.G.W., and Adams, R.D., The inflammatory lesion in idiopathic polyneuritis; its role in pathogenesis, Medicine, 48, 173, 1969. 30. Prineas, J.W., Acute idiopathic polyneuritis. An electron miscroscope study, Lab. Invest., 26, 133, 1972. 31. Dyck, P.J., Lais, A.C., Ohtya, M., Bastron, J.A., Okazaki, H., and Groover, R.V., Chronic inflammatory polyradiculoneuropathy, Mayo Clin. Proc., 50, 621, 1975. 32. Dalakas, M.C. and Engel, W.K., Chronic relapsing (dysimmune) polyneuropathy. Pathogenesis and treatment, Ann. Neurol., S9, 134, 1981. 33. Dyck, P.J. and Arnason, B., Chronic inflammatory demyelinating polyradiculoneuropathy, in Peripheral Neuropathy, Vol. 2, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 2101. 34. Lipkin, W.I., Parry, G.J., Kiprov, D., and Abrams, D., Inflammatory neuropathy in homosexual men with lymphadenopathy, Neurology, 33, 1479, 1985. 35. Cornblath, D.R., McArthur, J.C., Kennedy, P.G., Witte, A.S., and Griffin, J.W., Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotrophic virus type III infection, Ann. Neurol., 21, 32, 1987. 36. Said, G. et al., Inflammatory lesions of peripheral nerve in a patient with human T-lymphoctrophic virus type I-associated myelopathy, Ann. Neurol., 24, 275, 1988.

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37. Claussen, G.C., Thomas, D., Goyne, C., Vázquez, L.G., and Oh, S.J., Diagnostic value of nerve and muscle biopsy in suspected vasculitis cases, J. Clin. Neuromusc. Dis., 1, 117, 2000. 38. Oh, S.J., Vasculitic neuropathy, in Vasculitis, Ball, G.V. and Bridges, S.L. Eds., Oxford University Press, UK, 2001, (in press). 39. Dyck, P.J., Benstead, T.J., Conn, D.L., Stevens, J.C., and Windebank, A.J., Non-systemic vasculitic neuropathy, Brain, 110, 843, 1987. 40. Silverstein, A. and Siltzbach, L.E., Muscle involvement in sarcoidosis, Arch. Neurol., 21, 235, 1969. 41. Delany, P., Neurological manifestations in sarcoidosis: review of the literature with a report of 23 cases, Ann. Intern. Med., 87, 336, 1977. 42. Oh, S.J., Sarcoid polyneuropathy: a histologically proved case, Ann. Neurol., 7, 178, 1979. 43. Vital, C., Aubertin, J., Ragnault, M., Amigues, H., Mouton, L., and Bellance, R., Sarcoidosis of the peripheral nerve: a histological and ultrastructural study of two cases, Acta Neuropathol., 58, 111, 1982. 44. Gellacit, G., Gilbertoni, M., Mancini, A., Nemci, R., Volpi, G., Merelli, E., and Vacca, G., Sarcoidosis of the peripheral nerve: clinical, electrophysiological and histological study of two cases, Eur. Neurol., 23, 459, 1984. 45. Nemi, R., Balassi, G., Latove, N., Sherman, W.H., Olarte, M.R., and Hays, A.P., Symmetric sarcoid polyneuropathy: analysis of a sural nerve biopsy, Neurology, 31, 1217, 1981. 46. Weddell, A.G.M. and Pearson, J.M.H., Leprosy; histopathologic aspects of nerve involvement, in Topics on Tropical Neurology, Hohnbrook, R.W., Ed., F.A. Davis Co., Philadelphia, PA, 1975, 17. 47. Sabin, T.D. and Swift, T.R., Leprosy, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., and Lambert, E.H., Eds., W.B. Saunders Co., Philadelphia, PA, 1975, 1166. 48. Fite, G.L., Cambre, P.J., and Turner, M.H., Procedure for demonstrating lepra bacilli in paraffin sections, Arch. Pathol., 43, 624, 1947. 49. Jacbo, M. and Mathi, R., Diagnostic efficacy of cutaneous nerve biopsy in primary neuritic leprosy, Int. J. Lepr., 56, 56, 1988. 50. Berg, B.O., Rosenberg, S.H., and Asbury, A.K., Giant axonal neuropathy, Pediatrics, 49, 894, 1972. 51. Jones, M.Z., Nigro, M.A., and Bare, P.S., Familial “giant axonal neuropathy,” J. Neuropathol. Exp. Neurol., 38, 324, 1979. 52. Korobkin, R. et al., Glue-sniffing neuropathy, Arch. Neurol., 32, 158, 1975. 53. Oh, S.J. and Kim, J.M., Giant axonal swelling in “Huffer’s” neuropathy, Arch. Neurol., 33, 583, 1976. 54. Ansbacger, K.E., Bosche, E.P., and Cancilla, P.A., Disulfiram neuropathy: a neurofilamentous distal axonopathy, Neurology, 32, 424, 1982. 55. Allen, N., Mendell, J.R., Billmaier, D.J., Fontaine, R.E., and O’Neill, J., Toxic polyneuropathy due to methyl n-butyl ketone. An industrial outbreak, Arch. Neurol., 32, 209, 1975. 56. Rizzujto, W., Terzian, H., and Galiazzo-Rizzuto, S., Toxic polyneuropathies in Italy due to leather cement poisoning in shoe industries. A light and electron microscopic study, J. Neurol. Sci., 31, 343, 1977. 57. Davenport, J.G., Farrell, D.F., and Sumi, S.M., ‘Giant axonal neuropathy’ caused by industrial chemicals: neurofilamentous axonal masses in man, Neurology, 26, 919, 1976. 58. Madrid, R. and Bradley, W.G., The pathology of neuropathies with focal thickening of the myelin sheath (Tomaculous Neuropathy). Studies on the formation of the abnormal myelin sheath, J. Neurol. Sci., 25, 415, 1975. 59. Behse, F., Buchthal, F., Carlsen, F., and Knappeis, G.G., Hereditary neuropathy with liability to pressure palsies; electrophysiological and histopathological aspects, Brain, 95, 777, 1972. 60. Earl, C.J., Fullerton, P.M., Wakerfield, G.S., and Schutta, H.S., Hereditary neuropathy, with liability to pressure palsies; a clinical and electrophysiological study of four families, Q. J. Med., 33, 481, 1964. 61. Fewings, J.D., Blumbergs, P.C., Mukherjee, T.M., and Hallpike, J.F., Tomaculous neuropathy: Hereditary predisposition to pressure palsies, Aust. N.Z. J. Med., 15, 598, 1985. 62. Meier, C. and Moll, C., Hereditary neuropathy with liability to pressure palsies: report of two families and review of the literature, J. Neurol., 228, 73, 1982. 63. Pellissier, J.F. et al., Neuropathies tomaculaires: etude histolopathologique et correlations electrocliniques dans 10 cas, Rev. Neurol., 143, 263, 1987. 64. Sanders, S., Ourrier, R.A., McLeod, J.G., Nicholson, G.A., and Pollard, J.D., Clinical syndromes associated with tomacula or myelin swellings in sural nerve biopsy, J. Neurol. Neurosurg. Psychiatry, 68, 483, 2000.

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65. Dyck, P.J., Karnes, J.L., O’Brien, P., Okazaki, H., Lais, A., and Engelstad, J., The spatial distribution of fiber loss in diabetic polyneuropathy sugggests ischemia, Ann. Neurol., 19, 440, 1986. 66. Johnson, P.C., Doll, S.C., and Cromery, D.W., Pathogenesis of diabetic neuropathy, Ann. Neurol., 19, 450, 1986. 67. Asbury, A.K., Aldredge, H., Hershberg, R., and Fisher, C.M., Oculomotor palsy in diabetes mellitus: a clinico-pathologic study, Brain, 93, 555, 1970. 68. Dreyfus, P.M., Hakim, S., and Adams, R.D., Diabetic ophthalmoplegia, Arch. Neurol. Psychiatry, 77, 337, 1957. 69. Raff, M.C., Sangalang, V., and Asbury, A.K., Ischemic mononeuropathy multiplex associated with diabetes mellitus, Arch. Neurol., 18, 487, 1968. 70. Eames, R.A. and Lange, L.S., Clinical and pathological study of ischemic neuropathy, J. Neurol. Neurosurg. Psychiat., 30, 215, 1967. 71. Young, K.B. et al., The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinemia. Comparative, clinical, immunological, and nerve biopsy findings, J. Neurol., 238, 383, 1991. 72. Vital, A. and Vital, C., Immunoelectron identification of endoneurial IgM deposits in four patients with Waldenström’s macroglobulinemia: a specific ultrastructural pattern related to the presence of cryoglobulin in one case, Clin. Neuropathol., 12, 49, 1993. 73. Dubas, F., Pouplard-Barthelaix, A., Delestre, F., and Emile, J., Polyneuropathies avec gammapathies monoclonale IgM. 12 cas, Rev. Neurol., 143, 670, 1987. 74. Schroeder, J.M., Die Hyperneurotisation buengnerscher baender bei der experimenellen isoniazid-neuropathie: phasenkonstrast und electronmikroskopische Untersuchungen, Virchoes Arch. Zellpath., Abt B, 1, 131, 1968.

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CHAPTER 5 Figure 1 Active vasculitis. Fibrinoid necrosis and intramural infiltration of mononuclear cells of intimal and muscular layers of arterioles in the epineurial space. Almost total occlusion of vessels due to intimal thickening. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 5 Figure 2 Inactive vasculitis. Intramural red blood cells and mononuclear inflammatory cells in a thickened arteriole in the epineurial space. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 5 Figure 3 Amyloid. Congo-red material (arrow) in the wall of tiny vein in the epineurial space. Paraffin section. Alkaline Congo-red stain. (200 × magnification.)

CHAPTER 5 Figure 4 Bright apple-green birefringence of Congo-red material under the polarizing filter. Paraffin section. Alkaline Congo-red stain. (200 × magnification.)

CHAPTER 5 Figure 5 Metachromatic granules are stained as dirty yellow in the perivascular area in the endoneurial vessel. Dirty yellow granules represent metachromasia. The normal color for this stain is blue. Frozen section. Thionine stain. (400 × magnification.)

CHAPTER 5 Figure 7 Polyglucosan body (blue arrow): pearly body with laminated rings and greenish core. Red arrow indicates myelin digestion chambers in one myelinated fiber. Paraffin section. Modified trichrome stain. (400 × magnification.)

CHAPTER 5 Figure 6 Scattered metachromatic granules in the endoneurial space are stained brown instead of normal purple color. Frozen section. Cresylfast violet stain. (400 × magnification.)

CHAPTER 5 Figure 8 Diffuse loss of myelinated fibers. One axon contains a large polyglucosan body (approximately 30 µm) with a round profile in transverse section. It has a laminated appearance with a slightly denser core. The surrounding myelin sheath is thinned. Semithin section. Toulidine blue and acridine orange. (600 × magnification.) (Courtesy of Dr. N.P. Robertson, University Hospitals of Wales, Cardiff, Wales.)

CHAPTER 5 Figure 9 Onion-bulb formations (OBF) are visible around every red myelinated fiber. Thin lines surrounding myelinated fibers represent proliferated Schwann cell processes. There is about a 50% loss of myelinated fibers. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 5 Figure 11 Scattered mononuclear inflammatory cells in the endoneurial space (double arrows). Perivascular collections of inflammatory cells in the endoneurial space (arrow). These are typically seen in inflammatory demyelinating neuropathy. Paraffin section. H & E stain. (200 × magnification. )

CHAPTER 5 Figure 10 Onion-bulb formation (OBF) is recognized by many fine lines around nerve fibers with varying myelin thickness. Red arrow indicates denuded axon (demyelination) and blue arrow indicates OBF without any recognizable axon. Some fibers with OBF have more than one Schwann cell nucleus. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 5 Figure 12 Remyelinated fibers in chronic inflammatory demyelinating polyneuropathy. About 50% of myelinated fibers are remyelinated fibers (blue arrow) characterized by a thin myelin sheath in proportion to axon diameter. Red arrow indicates normal myelinated fibers. Yellow arrow indicates thinly myelinated fibers with two Schwann cell nuclei and tiny OBF. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 5 Figure 13 Perivascular lymphocytes in the epineurial space in a case of vasculitic neuropathy. Paraffin section. H & E stain. (200 × magnification. )

CHAPTER 5 Figure 14 Myelin-digestion chambers (arrows) in the longitudinal cut. Frozen section is indicative of axonal degeneration. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 5 Figure 15 Noncaseating granuloma (arrow) with many epithelioid cells and mononuclear inflammatory cells in the subperineurial space. Arrow head indicates another granuloma in the subperineurial space. No granuloma or inflammatory cell is present in the endoneurium itself in the middle. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 5 Figure 16 Foamy cells in the endoneurium, diagnostic of leprosy (arrows). The entire field is replaced by fibrosis. No myelinated fiber is noted. Semithin section. Toluidine blue stain. (Courtesy of Professor I. Sunwoo, Yonsei University Medical School, Seoul, Korea.)

CHAPTER 5 Figure 17 Mycobacterium leprae. Many acid-fast bacilli (bright red rods or globs) in the foamy cells. Paraffin section. Wade-Fite stain. (Courtesy of Dr. Y. Harati, Baylor Medical College, Houston, TX.)

CHAPTER 5 Figure 19 Giant axon. The dark line represents an axon in the nerve fiber (red arrow). The giant axon (blue arrow) is characterized by a hazelcolored center marked as a dark line. The diameter of the giant axon is 10 times that of the axon. Paraffin section. Glees and Marsland’s silver stain. (400 × magnification.)

CHAPTER 5 Figure 18 Three giant axons are visible in one nerve fascicle. Normally, the axon is stained green as a dot in the middle of red myelinated fibers. The giant axon is easily identified here as a green center surrounded by thin red myelin. Giant axons are three times larger in diameter than normal fibers. The population of myelinated fibers is minimally decreased. Frozen section. Modified trichrome. (200 × magnification.) (With permission from Oh, S.J, Yonsei Med. J., 31, 20, 1990.)

CHAPTER 5 Figure 20 Tomaculous formation. Red sausage-like myelin swelling (red arrow) represents tomaculous formation near the node of Ranvier. The diameter is twice that of normal myelinated fibers. There is also a moderate decrease in the population of myelinated fibers. (With permission from Oh, S.J., Yonsei Med. J., 31, 22, 1990.)

CHAPTER 5 Figure 21 Tomaculous formation with thick myelin layers is noted in the center of the figure. The axon area is extremely small due to thick myelinated layers. Semithin section. Toluidine blue stain. (400 × magnification.)

CHAPTER 5 Figure 23 Malignant cells. Many atypical cells are scattered in the epi- and endoneurial spaces of the nerve. Intramural infiltration of atypical cells is obvious (arrowhead). The infiltrating cells have all the characteristics of malignant cells: mitotic figures, pleomorphism, and atopia. This patient had lymphomatous neuropathy caused by natural killer cell lymphoma. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 5 Figure 22 Occlusion of a tiny arteriole in the subperineurial space in a case of diabetic neuropathy. Near occlusion of an endoneurial arteriole due to arteriosclerotic endothelial thickening. There are a few scattered red myelinated fibers, indicating a decreased population of myelinated fibers. Paraffin section. Gomori trichrome (200 × magnification.)

CHAPTER 5 Figure 24 IgM deposits in the myelin sheaths in a patient with MAG-positive neuropathy. Immunofluorescent stain for IgM outlines all myelinated fibers. Frozen section. Immunofluorescent stain for IgM. (200 × magnification.)

CHAPTER 5 Figure 26 Segmental demyelination (A and B) and paranodal demyelination (C and D) in the teased nerve. CHAPTER 5 Figure 25 Demyelination and remyelination. Blue arrow indicates one denuded axon (demyelinated fiber), and red arrow indicates one thinly myelinated fiber (remyelinated fiber). Inflammatory cells are scattered in the endoneurial space. There is also a decrease in the population of myelinated fibers. Semithin section. Toluidine blue and basic fuchsin. (200 × magnification.)

CHAPTER 5 Figure 27 Axonal degeneration. Moderate (60%) loss of myelinated fibers. Many myelin digestion chambers (empty spaces, ghost fibers) are noted in the endoneurium, indicating axonal degeneration. Frozen sections. Modified trichrome. (100 × magnification.)

CHAPTER 5 Figure 28 Axonal degeneration. All myelinated fibers are undergoing myelin breakdown indicative of axonal degeneration. Semithin section. Toluidine blue. (400 × magnification.)

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Vasculitic Neuropathy

Peripheral neuropathy is common in many systemic necrotizing vasculitides (SNV) (Table 6.1) and, thus, is an important clinical manifestation of SNV. When peripheral neuropathy is caused by necrotizing vasculitis, it is called vasculitic neuropathy. Peripheral neuropathy is due to ischemic damage of nerves as a result of occlusion of blood vessels associated with an inflammatory process in the vessel walls in the vasa nervorum. This can occur either as a manifestation of multisystem involvement in SNV or as an independent disease process such as nonsystemic vasculitic neuropathy. Although vasculitic neuropathy is relatively rare, recognizing it is important because it is potentially treatable.

VULNERABILITY OF THE PERIPHERAL NERVE TO VASCULITIC NEUROPATHY The hallmark of all SNVs is “vasculitis,” or inflammation and necrosis of the blood vessels. Vasculitis tends to involve medium- and small-sized arteries in SNV. Since the vasa nervorum in the peripheral nerve fall directly into the spectrum of small-sized arteries and arterioles, it is not surprising that peripheral neuropathy is a common manifestation of SNV. The vessels responsible for vasculitic neuropathy are predominantly the arterioles of the epineurium, which typically have a diameter ranging from 30 to 300 µm.1,2 Peripheral nerves have a rich anastomotic blood supply through two functionally distinct vascular systems: the extrinsic system composed of the epineurial vessels and regional arteries, arterioles, and venules, and the intrinsic system of the longitudinal microvessels within the fascicles themselves. These two systems are linked by a complex network of interconnecting vessels that provide high blood flow in the baseline state.3,4 This rich blood supply, along with the capacity of nerves to function relatively well with anaerobic metabolism, makes peripheral nerves relatively resistant to ischemia. Only with extensive involvement of the vasa nervorum does ischemic damage occur in the nerves. On the other hand, some characteristics of the endoneurial vessels actually render nerves susceptible to ischemia. The endoneurial capillaries are larger and more widely spaced, particularly in the central fascicular regions, than in other tissues.5,6 In addition, endoneurial vessels have a poorly developed smooth muscle layer3 and, thus, peripheral nerves have almost no capability to autoregulate blood flow and are susceptible to the small changes in perfusion pressure that may occur with a vasculitic process. Because of this vulnerability, a central fascicular fiber loss occurs in vasculitic neuropathy and is regarded as a typical pathological feature of ischemic neuropathy.1

CLINICAL, ELECTROMYOGRAPHIC, AND LABORATORY FEATURES In addition to the signs and symptoms of neuropathy, there are usually features of an underlying associated systemic disease in vasculitic neuropathy due to SNV. Common systemic symptoms are fever, anorexia, weight loss, and fatigue.7,8 Skin rash and ulcers, myalgia, arthralgia, Raynaud’s phenomenon, and photosensitivity are less common systemic manifestations. Systemic symptoms have been observed in 82 to 94% of cases.7,9 Systemic symptoms usually develop at the same time as vasculitic

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neuropathy and may precede vasculitic neuropathy by a mean duration of 24 weeks. In nonvasculitic neuropathy, systemic features are absent by definition.8,10,11 Peripheral neuropathy in SNV is manifested in various forms: mononeuropathy, plexus neuropathy, mononeuropathy multiplex, asymmetrical polyneuropathy, and symmetrical polyneuropathy.7,12 Mononeuropathy multiplex has been regarded as the classic clinical manifestation in vasculitic neuropathy and as the most common neurological abnormality in polyarteritis nodosa (PAN).12 In Ford and Siekert’s series, 54% of patients had mononeuropathy multiplex.13 In Gullivan et al.’s recent series, mononeuropathy multiplex was reported in 70% of 182 cases of PAN.14 Cohen, Conn, and Ilstrup even used mononeuropathy multiplex as a criterion in the diagnosis of polyarteritis nodosa.15 Since mononeuropathy multiplex can be due to multiple causes, especially with the introduction of multifocal motor and motor-sensory demyelinating neuropathies, this practice is no longer justifiable. In fact, multifocal demyelinating neuropathy is more common than vasculitic mononeuropathy multiplex in our clinic. In 1981, our study showed that symmetrical and asymmetrical polyneuropathies are common.7 Since then, it has been well accepted that there are three main patterns of neuropathy (mononeuropathy multiplex, asymmetrical polyneuropathy, and symmetrical polyneuropathy), though the relative frequency varies from study to study. A recent review of the reports on the frequency of these three patterns confirmed our initial finding that polyneuropathy (asymmetrical or symmetrical) is more common, observed in 55% of cases.12 The classical pattern of mononeuropathy multiplex was seen in only one-third of patients. Recognition of this concept is important because vasculitic

TABLE 6.1 Frequency of Vasculitic Neuropathy or Peripheral Neuropathy in Systemic Diseases Diseases

Prevalence

Frequency of Neuropathy (%)

Primary vasculitic diseasesa Polyarteritis nodosa Churg–Strauss syndrome Wegener’s granulomatosis Giant cell artertis

Rare Rare Rare Common in elderly

52–60 64–69 11–21 5–14

Rheumatoid diseasesb Rheumatoid arthritis Systemic lupus erythematosus Sjögren’s syndrome Progressive systemic sclerois

Common Common Common Uncommon

10 2–21 10–15 1.5

Other conditions with vasculitis Crygolobulinaemia Malignancy HIV infection Lyme disease

Rare Common Variable Variable

50 Rare 2 <1

(a) Neuropathy is due to vasculitic neuropathy. (b) Frequency of peripheral neuropathy. Not all cases of neuropathy are due to vasculitic neuropathy.

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neuropathy should not be ruled out simply due to the absence of mononeuropathy multiplex. On several occasions, the clinical features of mononeuropathy multiplex were observed early in the course, only to see it gradually give way to a severe symmetric polyneuropathic picture as the illness progressed. In some vasculitides, cranial nerves are frequently affected: ischemic optic neuropathy in temporal arteritis and trigeminal neuropathy in progressive systemic sclerosis. Nerve conduction studies are vital to the work-up of patients with suspected systemic vasculitis for two reasons: (1) adequate nerve conduction tests can detect asymptomatic peripheral neuropathy — according to our review,12,16 9 to 14% of patients had no clinical signs indicative of peripheral neuropathy; and (2) abnormal sural nerve conduction is an excellent marker for the demonstration of vasculitis on biopsy of this nerve. In our experience, in almost all patients in whom the sural nerve conduction was abnormal, vasculitic neuropathy was diagnosed by sural nerve biopsy.7,16 Thus, it is recommended that abnormal sural nerve conduction be used as a guide for the nerve biopsy.12 Sensory nerve conduction was more often affected in this disorder than motor nerve conduction. The degree of slowing of sensory and motor NCVs was minimal. The needle EMG showed typical denervation patterns: prominent fibrillation and positive sharp waves, normal or long-duration MUPs, and reduced interference patterns. These electrophysiological findings are indicative of peripheral neuropathy with predominant axonal degeneration.17 There is no specific laboratory marker for the SNV or vasculitic neuropathy. Thus, the laboratory evaluation is directed toward identifying the underlying causes of vasculitis or a serologic abnormality that may point toward a specific vasculitic syndrome. The most important laboratory test in SNV is the erythrocyte sedimentation rate (ESR); an elevated ESR is the most consistent and common abnormality in SNV. It is invariably elevated in the PAN group of SNV, Wegener’s granulomatosis, and temporal arteritis and, therefore, is useful diagnostically in these disorders.18 According to Dahlberg et al,19 previously described combinations of anemia, elevated sedimentation rate, abnormal creatinine, and hematuria remain useful for screening purposes. Elevation of serum immunoglobulin is frequently seen in SNV. Cryoglobulin is rarely detected in patients with vasculitic neuropathy due to cryoglobulinemia. A vasculitic neuropathy is common in all forms of cryoglobulinemia, occurring in about half the patients.20 This combination is especially true in connection with hepatitis C.21 Hepatitis B antigen has been reported positive in about one-third of patients with SNV. Antinuclear antibody (ANA) and rheumatoid factor are positive in roughly one-third of cases of SNV and are especially helpful in diagnosing systemic lupus erythematosus (SLE) or rheumatoid arthritis as causes of SNV. In HIV patients, vasculitic neuropathy is rare, usually occurring before the development of AIDS.22 A few patients with Lyme disease have also been reported to have mononeuritis multiplex with a vasculitis demonstrated pathologically.23 In recent years, antineutrophile cytoplasmic antibodies (ANCA) have been helpful in either diagnosing or monitoring disease activity in different vasculitic syndromes.24 In up to 97% of cases of Wegener’s granulomatosis (WG), cANCA (cytoplasmic) was positive. Importantly, pANCA (perinuclear) is only rarely found in patients with WG. Savage et al. reported that cANCA has also been found in some patients with other SNVs,25 most of whom have also been positive for pANCA. Chalk26 studied this issue in connection with vasculitic neuropathy, performing ANCA tests in 166 consecutive patients referred for evaluation of peripheral neuropathy. ANCA was found in 4 of 6 patients with vasculitic neuropathy and also in 6 of 44 patients with inflammatory or immunologically mediated neuropathies. On this basis, Chalk concluded that in patients being evaluated for peripheral neuropathy, the utility of ANCA as a simple serologic test for vasculitic neuropathy is limited by nonspecificity. On the other hand, ANCA was positive in two-thirds of patients with vasculitic neuropathy and, thus, can be used as additional corroborative data for vasculitic neuropathy. In nonsystemic vasculitic neuropathy, ESR is frequently elevated but is usually less than 50 mm/hour. Other serologic studies are usually normal, although an occasional nonspecific abnormality is identified. Cerebrospinal fluid (CSF) is usually normal in vasculitic neuropathy, except for mild elevation of protein in one-third of

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patients. On the other hand, abundant cells and high protein are the classical CSF pattern in HIV vasculitic neuropathy.27

DIAGNOSTIC SENSITIVITY OF NERVE AND MUSCLE BIOPSIES The sural nerve biopsy is best indicated in patients suspected of having vasculitis, with or without the clinical features of neuropathy. This is because the nerve is more commonly involved than other readily available biopsied tissues such as skin and muscle, and the diagnostic yield of the sural nerve biopsy is high in vasculitis. Among the specific diagnoses, vasculitic neuropathy was the most common form of neuropathy, found in 12% of 385 nerve biopsies.28 The diagnostic sensitivity of nerve and muscle biopsies depends solely on the selection criteria used for patients. Among those with suspected SNV or vasculitic neuropathy, the diagnostic sensitivity averages 30% for the nerve biopsy in contrast to 16% for the muscle biopsy.12,16 Among patients with confirmed vasculitic neuropathy, the diagnostic sensitivity averages 71% for the nerve biopsy and 45% for the muscle biopsy.12 These findings indicate the superiority of the nerve biopsy to the muscle biopsy. In our series, the nerve biopsy was significantly superior statistically to the muscle biopsy in diagnostic sensitivity among patients with suspected SNV or vasculitic neuropathies.16 Among six studies, five (all except Said’s study29) showed a higher diagnostic sensitivity of the nerve biopsy over the muscle biopsy. However, the muscle biopsy can give a more specific diagnosis of vasculitis than the nerve biopsy in a few cases.16 Previous studies also found that adding muscle biopsy to the nerve biopsy increased the positive diagnostic yield by 6 to 25%.9,29 On the basis of these findings, the combined biopsy of nerve and muscle is widely advocated when considering vasculitis as a differential diagnosis. We usually do the sural nerve biopsy together with a biopsy of the anterior tibialis or gastrocnemius muscle. Another method is to perform the nerve biopsy first and, depending on the findings in the nerve, consider adding the muscle biopsy later. To increase the diagnostic yield in vasculitic neuropathy, the following guidelines are recommended. The sural nerve should first be tested electrophysiologically and the more abnormally impaired sural nerve biopsied. In practice, when the sural nerve conduction is normal, electrophysiological testing of the superficial peroneal and superficial radial sensory nerves as alternative nerves to biopsy is recommended. Whole nerve biopsy should be obtained. There is no place for fascicular nerve biopsy in patients suspected of vasculitic neuropathy because the vasa nervorum, which are the major vessels involved in this disorder, are located in the epineurial and perineurial space, and fascicular biopsy may not contain the involved vasa nervorum. The sural nerve biopsy should be done before steroid treatment is initiated. Though this is not well documented, it seems prudent to perform the sural nerve biopsy first because steroid treatment may alter the histological features of vasculitis. It is necessary to cut multiple sections from different levels of the specimen since vasculitis is multifocal and segmental. It has been our repeated experience that only a few sections of the biopsied nerve show the diagnostic change. According to Said,30 characteristic lesions may be present on segments of the arteries as short as 50 µm. Thus, in cases of suspected vasculitic neuropathy, we recommend cutting and staining as many sections of the biopsied nerve as possible.

PATHOLOGY OF VASCULITIC NEUROPATHY To render a definite diagnosis of vasculitic neuropathy, the unmistakable histological features of vasculitis must be present: active, inactive, or healed necrotizing changes and infiltration of inflammatory cells within the vessel wall. Several histological types of arterial changes are described in vasculitic neuropathy.16 Perivascular infiltration of inflammatory mononuclear cells occurs without any intramural necrosis or cellular infiltration (Color Figure 6.1).* This is an early and mild arterial insult according to Dyck.1 * Color insert figures. ©2002 CRC Press LLC

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This finding alone is not enough to diagnose vasculitis because a similar finding is observed in inflammatory neuropathies, especially in acute forms. However, there are some histological features which are helpful in differentiating these disorders: in vasculitic neuropathies, axonal degeneration is the predominant finding, whereas in inflammatory neuropathies, segmental demyelination and endoneurial inflammatory cells are typical findings. An exception has been found in vasculitic neuropathy associated with HIV: inflammatory cells are often present in the endoneurial space, and small endoneurial blood vessels are affected.30 Thus, we made a diagnosis of probable vasculitis (Type III lesion) when perivascular infiltrates of inflammatory cells were present together with active axonal degeneration, selective nerve fascicular degeneration, or central fascicular degeneration (see below) if the clinical findings were compatible with vasculitis.7 Active vasculitis represents acute vasculitic changes which are characterized by fibrinoid necrosis of the intimal and muscular layers with the intramural and perivascular infiltrates of inflammatory cells, polymorphonuclear leukocytes, lymphocytes, and eosinophils (Color Figure 6.2). In the acute stage of vasculitis, polymorphonuclear leukocytes may be prominent, but lymphocytes usually predominate in the vessel wall and perivascular area. Eosinophils occur in vasculitis of various etiologies, but marked eosinophilic infiltration suggests Churg–Strauss syndrome.31,32 Together with these cardinal findings, dissolution of the internal elastic membrane and edema or thickening of the adventitia are typically found (Color Figure 6.3). Active vasculitis represents Type I lesion in our classification. With the active vasculitic process, hemorrhage may occur in the necrotic area as well as in the surrounding tissue, sometimes in a perineurial or subperineurial crescentic pattern (Color Figure 6.4). An inactive vasculitis represents chronic vasculitic changes characterized by the concentric fibrous scarring and thickening of the intima and muscular layer with minimal intramural and perivascular infiltrates of inflammatory cells, lymphocytes, and plasma cells (Color Figure 6.5). Splitting and actual overgrowth of the internal elastic membrane usually accompany this lesion, which we classified as a Type II lesion.7 Healed vasculitic lesions are indicative of previous severe injury to the arterial wall. They are characterized by perivascular and intramural fibrosis with fragmentation of the internal elastic membrane and narrowing, occlusion, and calcification of the lumen or recanalization of the previously occluded lumen (Color Figure 6.6). Hemosiderin-laden macrophages indicative of old hemorrhaging may cluster in a periadvential location (Color Figure 6.7). There are no perivascular or intramural inflammatory cells. This lesion may mimic arteriosclerotic lesion. However, careful study of the vessels with connective tissue and elastin stains helps differentiate between these two different processes. Fragmentation of the internal elastic membrane is suggestive of healed vasculitis. Midroni occasionally observed miniature bundles of aberrant regenerating axons, reminiscent of a traumatic neuroma in vasculitis.32 Schroeder drew attention to the reactive proliferation of capillaries that can occur in the epineurium after a vascular insult, although this observation is not specific to vasculitis .33 Thus, these findings should be regarded as clues suggestive of the presence of remote vasculitis but not indicative or diagnostic of vasculitis. Axonal degeneration is the predominant pattern and is due to the ischemic damage to the nerve (Color Figures 6.8 and 6.9).7,9,34 Said et al. observed axonal degeneration in an average of 65% of nerve fibers.29 The degree of axonal degeneration depends on the activity of the vasculitic process. Prominent axonal degeneration is invariably seen with active vasculitic lesions and is best observed in the longitudinal cuts on frozen sections (Color Figures 6.10 and 6.11). In the later stages of disease, the process of axonal degeneration is more complete, and few, if any, fibers remain. Various patterns of degeneration of fibers are noted, ranging from central fascicular degeneration1 to selective nerve fascicular degeneration (SNFD),35 depending upon the severity of neuropathy. According to Dyck et al., central fascicular degeneration is characterized by a selective loss of myelinated fibers in the center of the fascicles of nerve and is typical of ischemic neuropathy (Color Figure 6.12).1 SNFD is characterized by the loss of greater than 50% of nerve fibers in some fascicles with

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intact nerve fibers in other fascicles; it is also typical of ischemic neuropathy because it results from the occlusion of arterioles that supply blood to the involved fascicle.35 According to our experience, SNFD can be sectional or total. Sectional SNFD represents a selective loss of nerve fibers in one section of the nerve fascicle without any nerve fiber loss in other sections of nerve fascicles (Color Figure 6.12). Total SNFD represents a selective loss of nerve fibers in the entire nerve fascicle (Color Figures 6.13 and 6.14). It should be emphasized that any combination of these changes may be found in a single sural nerve biopsy, indicating an ongoing process.9 In most cases studied, the nerve lesions appeared to result from the summation of lesions of different ages of blood vessels.36 In an autopsy series,1,34 all these changes were seen along the course of an involved peripheral nerve. Dyck et al.1 stated that chronic changes are usually seen in nerves of patients with long-standing, nonprogressive neuropathy and in acute lesions in patients with clinically acute neuropathy. It is not possible to diagnose specific vasculitic syndromes from nerve biopsy specimens. In general, the caliber of involved vessels may allow one to assign a given biopsy to one of two broad groups.37 Vasculitic involvement of larger (100–250 µm) epineurial arterioles is a typical feature of PAN, Churg–Strauss syndrome, Wegener’s granulomatosis, and rheumatoid vasculitis, whereas predominant involvement of smaller (<100 µm) epineurial arterioles is more suggestive of Sjögren’s syndrome, SLE, and nonsystemic vasculitis of the nerve.37 Involvement of epineurial veins occurs more commonly in Wegener’s granulomatosis and Churg–Strauss syndrome than in PAN.38 Vasculitis of endoneurial vessels is uncommon and would theoretically be classified with the hypersensitivity vasculitides according to Midroni and Bilbao.32 In HIV-induced vasculitic neuropathy, mononuclear cells are often present in the endoneurial space, and vasculitic change is seen more often in endoneurial vessels.27,39 Although a definite histological diagnosis of vasculitis in the nerve should be based on the demonstration of active or inactive vasculitis (Type I and II lesions), the concept of probable vasculitis in the nerve is introduced because the definite criteria of vasculitis are too stringent for clinical utility in vasculitic neuropathy. In about one-quarter of patients with vasculitic neuropathy, the definite criteria of vasculitic neuropathy are lacking and, therefore, the diagnosis of vasculitic neuropathy cannot be made on this basis alone.16 This is most likely due to the lack of medium- and small-sized arteries in the nerve, which are predominantly involved in SNV. Although the exact diagnostic criteria of of probable vasculitis may differ from author to author, one consensus has emerged: perivascular infiltration (cuffing) of inflammatory cells (Type III lesion) must be present (Color Figure 6.1). This finding alone is not sufficient for the diagnosis of vasculitis because it is a nonspecific finding in nerve pathology. This is especially true in the context of inflammatory demyelinating polyneuropathy. Predominant axonal degeneration favors vasculitis, whereas segmental demyelination and endoneurial inflammatory cells favor inflammatory demyelinating polyneuropathy. Because of this, we recommend that perivascular infiltration of inflammatory cells and axonal degeneration (Color Figures 6.8–6.11) and/or central fascicular degeneration or SNFD (Color Figures 6.12–6.14) be considered the minimal diagnostic criteria for probable vasculitis. Over the years, several studies have shown that the criteria of probable vasculitic neuropathy can be safely used for the clinical diagnosis of vasculitic neuropathy. Three studies showed that all patients with probable vasculitis were proven to have vasculitic neuropathy. In Wees’ report 7 of one patient with Type III nerve biopsy, celiac angiography showed typical microaneurysms indicative of PAN. In Dyck’s 13 cases of probable vasculitic neuropathy, vasculitis was confirmed by liver and kidney biopsies and post-mortem findings.10 In Hawke’s series, vasculitis was confirmed in each case by muscle biopsy, kidney biopsy, and autopsy.9

PATHOGENESIS OF VASCULITIC NEUROPATHY It is generally accepted that the nerve fiber degeneration in this disorder is ischemic in nature secondary to vasculitis in the vasa nervorum.1,40 However, there are some different opinions with regard

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to the appearance of the consequent nerve alteration following ischemia. Dyck et al. did not believe that infarction occurs in the nerve.1 Their view was based on a detailed study of the involved nerves in rheumatoid vasculitic neuropathy, which did not reveal any evidence of infarcts (if infarction is defined as a circumscribed area of necrosis of all cellular elements leading to liquefaction with a border of macrophages such as occurs in the brain). They maintained that the infarcts of nerves described by Kernohan and Woltman were not infarcts but, more likely, were Renault’s corpuscles.41 On the other hand, Ashbury and Johnson took the view that frank infarct necrosis of the nerve does occur in vasculitic, amyloid and diabetic neuropathies, as shown in their illustrations.40 The pattern of neuropathic involvement in vasculitic neuropathy depends on the extent and temporal progression of the vasculitis-induced ischemic changes.42 Mononeuropathy multiplex, the classical pattern of neuropathy in vasculitic neuropathy, is due to lesions in larger vessels leading to whole-nerve trunk infarction in random vasculitic involvement of nerves scattered throughout the body (Color Figure 6.15). On the other hand, asymmetrical polyneuropathy (overlapping mononeuropathy multiplex) results from an increasing confluence of mononeuropathy multiplex or the simultaneous patchy discrete infarction of smaller vessels in many individual peripheral nerves, together with superimposed mononeuropathy due to damage of whole-nerve trunks. Symmetrical polyneuropathy is a consequence of a more diffuse peripheral nerve ischemia due to multiple small lesions which are more likely to affect longer nerves. The classical theory of the pathogenesis of immune-mediated vasculitis is that immune-complex deposition in blood vessel walls leads to activation of inflammatory mechanisms and infiltration of polymorphonuclear leukocytes with subsequent tissue necrosis producing the pathological picture of leukocytoclastic reaction.43 Recent studies confirmed that this mechanism is also operative in vasculitic neuropathy: immunofluorescent evidence exists for immune complex involvement in 72 to 100% of the biopsies.8,9,44 This mechanism has been questioned recently by Kissel, who found that in vascular lesions, the cellular infiltrates were composed predominantly of T-cells and macrophages (Color Figure 6.16).8 On the basis of these findings, Kissel suggested a cytotoxic T-cell-mediated process as a primary mechanism of vascular damage in peripheral nerve vasculitis.

SYSTEMIC NECROTIZING VASCULITIDES POLYARTERITIS NODOSA Classic polyarteritis nodosa (PAN) is a pivotal disease of SNV involving small- and medium-sized arteries producing systemic symptoms and multiple organ involvement. The predominantly involved organs are the peripheral nerves, kidney, gastrointestinal tract, and liver. The lung and spleen are characteristically not involved. The lesions tend to be segmental with a predilection for bifurcations and branching of arteries. A characteristic feature of polyarteritis nodosa is multiple microaneurysms in medium-sized arteries in the renal, hepatic, and visceral vasculature by angiography. It is believed that this finding is virtually pathognomonic of classic polyarteritis nodosa. Clinically, peripheral neuropathy is reported in 52 to 60% of patients with polyarteritis nodosa.13,45 The clinical and laboratory features are the same as described above. In recent years, the prognosis of this disorder has improved with the introduction of cytotoxic agents in addition to the conventional steroid treatment with longterm remission in 90% of patients.14,46 The best histological study of the nerve in this disorder is found in the classic paper by Lovshin and Kernohan.34 They studied the various nerves from autopsy cases with polyarteritis nodosa and described almost all the features noted above. One feature they did not describe was SNFD.1,35 There are no giant cells or granuloma in arterial lesions.

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CHURG–STRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS) The Churg-Strauss syndrome (allergic granulomatosis) is clinically similar to PAN, with the exception of prominent pulmonary symptoms including asthma and eosinophilia. Pathologically there is necrotizing vasculitis of small arterioles and veins with extravascular granulomas, as well as infiltration of vessels and perivascular tissue with eosinophils. The lungs, peripheral nerves, and skin are most frequently involved.47 As in classical PAN, peripheral neuropathy is a frequent manifestation, involved in 64 to 69% of cases.47,48 The histopathological description of the peripheral nerve in this syndrome is rare. The vasculitic features in the peripheral nerve are not different from those in PAN,49,50 with one exception — prominent eosinophilic infiltrations in some cases 31,32 and occasional in one case.51 Perineurial granulomatous lesions were seen in only one case.50

WEGENER’S GRANULOMATOSIS Wegener’s granulomatosis is characterized by necrotizing granulomatous lesions of the respiratory tracts, a focal glomerulonephritis, and systemic necrotizing vasculitis. In recent years, antineutrophil cytoplasmic antibodies (ANCAs) have been helpful in either diagnosing or monitoring disease activity in Wegener’s granulomatosis.52 In up to 97% of cases of Wegener’s granulomatosis, cANCA was positive, but pANCA was only rarely found in patients with WG. The frequency of peripheral nerve involvement in Wegener’s granulomatosis is 11 to 21%.53,54 Cranial neuropathy and peripheral neuropathies are most common. Contiguous extension of granulomatous inflammation from primary sites in the nasopharynx through the walls of the nasal cavity and paranasal sinuses to the orbit or the middle fossa is responsible for the cranial neuropathy.55 Peripheral neuropathy is due to vasculitic neuropathy (Color Figure 6.17).55,56 No granuloma or giant cells were noted. Thus, the pathology of the peripheral nerves is indistinguishable from that found in PAN.56 Neuropathy has responded to cyclophosphamide therapy as the disease itself responds.55,58

TEMPORAL (GIANT CELL) ARTERITIS Temporal arteritis is well recognized by its classic complex of fever, anemia, high sedimentation rate, muscle pain, and headaches in people over 50 years of age. Polymyalgia rheumatica, a syndrome characterized by muscle pain, periarticular pain, and morning stiffness, is considered a form of temporal arteritis.59 The temporal artery is characteristically involved in temporal (giant cell) arteritis. Temporal artery biopsy generally establishes the diagnosis, but because of the segmental nature of the histological findings, multiple sections from the biopsied specimen should be studied. Histologically, temporal arteritis is characterized by mononuclear cell inflammatory infiltration with giant cell formation involving large- and medium-sized arteries (Color Figure 6.18). Ischemic optic neuropathy is a well-known complication of temporal arteritis, occurring in 36 to 58% of patients. However, peripheral neuropathy has been described in 14% of 166 consecutive cases with biopsyproven temporal arteritis.60 It is now well established that these peripheral neuropathies are due to necrotizing vasculitis, with or without giant cells, involving neural vessels of all sizes in cases of clear-cut temporal arteritis (Color Figure 6.19).32

VASCULITIS ASSOCIATED WITH CONNECTIVE TISSUE DISEASES In contrast to the primary vasculitides discussed above, the vasculitides associated with connective tissue diseases occur secondary to the primary connective tissue diseases. Thus, vasculitis is not the most prominent cause of neuropathy in most connective tissue diseases.

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RHEUMATOID ARTHRITIS Vasculitic cause of neuropathy in rheumatoid arthritis is relatively rare. However, rheumatoid vasculitis is the second most common cause of vasculitic neuropathy in most series.37,61 Vasculitic neuropathy in rheumatoid arthritis is a subacute fulminating sensorimotor neuropathy found most commonly in malignant rheumatoid arthritis; it shows a poor prognosis. The basis of this neuropathy is a widespread vasculitis in the nerve, indistinguishable from polyarteritis nodosa. Even though vasculitis in muscle in rheumatoid arthritis has the tendency to involve small arteries in contrast to medium-sized arteries in polyarteritis nodosa,62 vasculitis in the sural nerve is indistinguishable between rheumatoid arthritis and polyarteritis nodosa (Color Figure 6.20).63

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) This disease is characterized by the generation of pathogenic autoantibodies and immune complexes which cause immunologically mediated damage to multiple organs, most notably the kidney, skin, and joints. In the blood vessels, SLE can produce vasculitis with subsequent vasculitic neuropathy (Color Figure 6.21). Vasculitic neuropathy in SLE is uncommon but usually has the clinical appearance of a mixed sensorimotor neuropathy with sensory symptoms dominant, although classical mononeuropathy multiplex may also been seen.63 The nerve biopsy finding may be that of intimal thickening with perivascular inflammatory infiltrates, but classical vasculitis is also commonly seen.64-66 Immunofluorescent staining for immunoglobulin deposition in blood vessel walls is usually negative.66

SJÖGREN’S SYNDROME The diagnosis of Sjögren’s syndrome was made in a patient with objective evidence of any two of the following: dry eyes, dry mouth, and an associated connective tissue disease. Peripheral neuropathy was reported in 10 to 15% of cases67 and was predominantly sensory with mild distal and trigeminal sensory neuropathy. In the largest series of nerve biopsies from patients with Sjögren’s syndrome and neuropathy, necrotizing vasculitis was found in 8 of 11 biopsies and perivascular inflammation of small arterioles and venules was found in 3 biopsies.68 A similar observation was made by Molina et al.67 Sensory neuropathy with severe ataxia has also been reported with Sjögren’s syndrome due to dorsal root ganglionitis (diagnosed by dorsal root ganglion biopsy).69

HYPERSENSITIVITY VASCULITIS (HSV) This term refers to a large and heterogenous group of clinical syndromes with predominantly smallvessel involvement, usually in the skin, and associated with a recognizable precipitating event or exposure. The classic hypersensitivity vasculitis (HSV) is usually self-limiting, resolving itself within 1 to 3 weeks of antigen exposure. This syndrome includes cutaneous vasculitis, drug-induced allergic vasculitis, postinfectious vasculitis, serum sickness, Henoch–Schonlein purpura, and some cases of essential mixed cryoglobulinemia. Over the past 10 years, the causes of HSV have been expanded to include infections (Lyme disease, HIV, leprosy, and Chagas disease), drugs (amphetamines and cocaine), and neoplasm.70 Diagnosis of HSV is based on vasculitic involvement of small-diameter capillaries, arterioles, and venules (microvasculitis). Peripheral neuropathy is rare in the hypersensitivity vasculitides. The sural nerve biopsy findings range from necrotizing vasculitis40 to microvasculitis.71

NONSYSTEMIC VASCULITIC NEUROPATHY Vasculitis confined to the peripheral nerve is termed nonsystemic vasculitic neuropathy (NSVN). This entity was recognized in 1985 when Kissel reported 4 cases of NSVN among 16 cases of biopsyproven vasculitic neuropathy.65

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NSVN is not rare, occurring in 25% of cases of vasculitic neuropathy.10,11,72 There is no difference in the types of neuropathy seen in NSVN and SVN. Dyck observed that there were some pathological differences between NSVN and SVN.10 In NSVN, smaller perineurial arterioles were more often involved, the severity of pathology was less, and probable vasculitis (perivascular infiltration of cells without intramural infiltration of cells or fibrinoid necrosis) was found to be more common. Dyck believed that an underlying indolent necrotizing vasculitis of the small epineurial arterioles appeared to be responsible. However, Davies et al.11 did not observe such a difference. They observed the main vasculitic features predominantly in the epineurial arterioles, similiar to SVN. Both SVN and NSVN showed axonal degeneration as the predominant pathological finding and selective nerve fascicular degeneration or central fascicular degeneration as ischemic changes. In laboratory findings, clinically significant serological abnormalities are absent by definition. One exception is a high sedimentation rate, which is positive in 35 to 50% of cases.10,65 In NSVN, the nerve biopsy is critical. Without a nerve biopsy, vasculitis cannot be reliably differentiated from other rapidly progressive neuropathies because many cases of NSVN appear symmetrical and serological markers are usually absent. There are two thoughts as to the nature of NSVN: it is either an organ-specific vasculitis10,11 or a mild form of systemic vasculitis.29,73

VASCULITIS IN OTHER DISEASES Vasculitic neuropathies associated with neoplasm and hepatitis C are discussed in the presentation of cases. Vasculitic neuropathy associated with other diseases will be discussed in the appropriate chapters.

CASES WITH VASCULITIC NEUROPATHY CASE 1: A PATIENT WITH FEVER OF UNKNOWN ETIOLOGY FOR 1 MONTH Case Presentation A 55-year-old male was admitted to the Infectious Disease Service with chief complaints of persistent fever, sweating, arthralgia, and myalgia for 1 month. He carried the diagnosis of rheumatoid arthritis because of arthralgia, active synovitis in the joints, a positive RF at 1:80, and hypertension for 1 year. Previous work-ups showed mild anemia, leucocytosis, high sedimentation rate (68 mm/hr), and normal CPK. Urinalysis revealed hematuria, proteinuria, and pyuria, which were treated with antibiotics with no reduction of fever. Normal tests included serologic tests for unknown fever, intravenous pyelogram (IVP), CT, and ultrasound scans of the abdomen, and chest x-ray. Abnormal physical findings were an ill-looking male with a temperature of 101°F and a blood pressure of 160/95. Neurological examination was normal except for absent ankle jerk. The attending physician ordered the nerve conduction study (NCS) immediately after admission, and it was performed within 2 hours. The NCS showed diffuse axonal neuropathy with no sensory CNAP in the sural nerve. Case Analysis On the basis of the history of systemic symptoms and laboratory findings, the attending physician’s diagnostic impression was systemic vasculitis of polyarteritis nodosa. Prompt NCS confirmed asymptomatic peripheral neuropathy, and a sural nerve biopsy was then immediately performed in the EMG laboratory. The histological diagnosis of vasculitis was made on the frozen section (Color Figure 6.22) within 30 minutes after the nerve biopsy and 4 hours after admission.

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Sural Nerve Biopsy A Type I vasculitic lesion (Color Figure 6.23) with scattered red blood cells was seen in all layers. In other areas of the section, Type II and III vasculitic features with splitting of the outer layer of arterioles were visualized. Myelin-digestion chambers were prominent in the longitudinal cuts. There was also total SNFD (Color Figure 6.13). Diagnosis of vasculitic neuropathy was confirmed by the frozen section 4 hours after admission. Final Diagnosis The final diagnosis was systemic vasculitis of polyarteritis nodosa. Treatment and Outcome High-dose steroids (IV solu-medrol followed by oral prednisone) and oral cyclophosphamide treatment were given with a gradual improvement in the patient’s neuropathy as a result. Comments Asymptomatic vasculitic neuropathy was first reported in 1981. Among 17 patients with systemic necrotizing vasculitis (SNV), there were 7 (41%) who did not show any clinical signs of peripheral neuropathy. The symptoms experienced by these patients were myopathy in two patients, generalized weakness in three patients, and no complaints of weakness in two patients. The last 2 (12)% of the patients had only systemic symptoms and laboratory findings suggestive of periarteritis nodosa, which led to the nerve conduction study. In all these patients, a diffuse neuropathy was detected by the NCS and vasculitis was confirmed by the sural nerve biopsy. Subsequent studies confirmed the existence of asymptomatic vasculitic neuropathy in 6 to 14% of reported cases.29,74 The nerve conduction study is the only way to detect asymptomatic neuropathy. Once asymptomatic neuropathy is found, then the nerve biopsy in the involved nerve can confirm the diagnosis of vasculitic neuropathy. We found this practice extremely helpful for the rapid tissue diagnosis of SNV, and it is probably the most cost-effective method of diagnosis.

CASE 2: NUMBNESS IN THE RIGHT FOOT IN A PATIENT WITH ASTHMA Case Presentation A 40-year-old man with a long history of recurrent sinusitis and nasal polyps developed severe asthma in October 1980. In April 1981, he developed numbness along the lateral aspect of his right foot, which then spread to his right knee, left forearm, and left foot. These sensory symptoms were gradually accompanied, over the next 6 weeks, by asymmetric weakness in the upper and lower extremities. A general physical examination was unremarkable. Neurological examination revealed asymmetric polyneuropathy: diffuse areflexia, decreased sensation to pin-prick below the wrists and ankles, marked weakness in the left forearm and hand, moderate weakness in the right hand, and weakness in the plantar extensors and flexors, marked in the right and moderate in the left. Abnormal laboratory findings were leucocytosis (14,300/mm3) with 29% eosinophils, high serum IgE, and ESR, 34 mm/hr. The NCS showed a severe diffuse axonal neuropathy with absent CNAP response in the sural nerve. Case Analysis Clinical features were suggestive of the Churg–Strauss syndrome (CSS): asthma, hypereosinophilia, and vasculitis. The patient’s neuropathy progressed from mononeuropathy multiplex to asymmetrical

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polyneuropathy. This pattern of progression of neuropathy over a 6-week period is strongly suggestive of 2 diseases: multifocal motor sensory demyelinating neuropathy or vasculitic neuropathy. Axonal neuropathy in the NCS favors vasculitic neuropathy. A sural nerve biopsy is the next logical step. Sural Nerve Biopsy The biopsy revealed active necrotizing vasculitis in small arterioles in the epineurial space, which was best seen in the longitudinal cuts (Color Figure 6.24); total loss of myelinated fibers in one nerve fascicle, representing total SNFD, and marked axonal degeneration that was characterized by many MDCs. In the involved arterioles, fibrinoid necrosis was noted in the intima. The entire muscular and adventitial layers were infiltrated with inflammatory cells. These were predominantly eosinophilic cells mixed with a few lymphocytes (Color Figure 6.25). A few eosinophilic cells were also noted around small vessels in the endoneurial and perineurial spaces. Granulomatous (epithelioid and giant cell) lesions were not observed. Final Diagnosis The final diagnosis was systemic vasculitic syndrome of CSS. Treatment and Outcome High dose prednisone was administered for two weeks. Further neurological deterioration ensued. At this point, cyclophosphamide was added to prednisone. Gradual improvement was noted over a 2-year period, even with a tapering dose of prednisone and cyclophosphamide. Two years later, all medications were discontinued. The patient was asymptomatic, except for mild right ulnar motor neuropathy and areflexia. Comments This patient had all the diagnostic features of CSS: asthma, hypereosinophilia, and necrotizing vasculitis. CSS is clinically similar to PAN, with the exception of prominent pulmonary symptoms and eosinophilia. Extravascular necrotizing granulomata are a feature of CSS but not PAN. Marked eosinophilic infiltration in the sural biopsy in this case represents the most classical pathological feature of vasculitic neuropathy in CSS.

CASE 3: NUMBNESS AND WEAKNESS IN THE LEFT LEG IN A PATIENT WITH ENDOMETRIAL CARCINOMA Case Presentation A 55-year-old extremely obese pediatrician with a 1-year history of metastatic endometrial carcinoma and successful treatment with high-dose progesterone noticed numbness and lancinating pain below her left knee 8 months after the diagnosis of cancer. This was followed by a left foot drop within 2 weeks and similar, though less severe, sensory complaints and weakness below the right knee. Initial examination showed asymmetric sensorimotor polyneuropathy. The patient had bilateral foot drop due to weakness of the plantar extensors and flexors (worse on the left), pin-prick loss up to the mid-calf, a mild proprioception and vibration loss in the feet, and areflexia in the legs. Abnormal laboratory findings were a high sedimentation rate (69 mm/hr) and CSF protein (135 mg/dl). The NCS and needle EMG showed diffuse axonal neuropathy.

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Case Analysis In view of the patient’s history of cancer, paraneoplastic neuropathy was suspected. High CSF protein suggested polyradiculoneuropathy. A sural nerve biopsy was performed in order to document paraneoplastic inflammatory axonal neuropathy. Sural Nerve Biopsy The biopsy showed microvasculitis characterized by perivascular mononuclear cells and a few intramural mononuclear cells in the capillary of the epineurial space (Color Figure 6.26). Sectional and total SNFD (Color Figure 6.14) and prominent myelin-digestion chambers indicative of axonal degeneration were observed. Larger epineurial arterioles were not involved. Final Diagnosis The final diagnosis was paraneoplastic vasculitic neuropathy. Treatment and Follow-up Because of the patient’s marked obesity, she was treated with cyclophosphamide alone. Within 15 months of treatment, she recovered well, with a minimal neurological deficit in her feet. Comments Our patients had all the prominent features that characterize paraneoplastic vasculitic neuropathy (PVN): asymmetrical sensorimotor polyneuropathy, electrophysiological findings of axonal degeneration, high sedimentation rate and spinal fluid protein, microvasculitis, and axonal degeneration of nerve fibers upon nerve biopsy, all in the presence of overt or occult carcinoma. PVN is rare. So far, only 13 cases have been reported.71 Diverse cancers have been reported in association with PVN, the most common being small-cell lung cancer and lymphoma. Malignancy was found within 18 months before or after the diagnosis of neuropathy. The neuropathy was usually subacute and progressive. Symmetrical polyneuropathy was the most common pattern of neuropathy, followed by asymmetrical polyneuropathy and mononeuropathy multiplex. Other paraneoplastic syndromes were rarely associated with PVN. The most prominent abnormal laboratory findings were high ESR and a high CSF protein. The NCS was typical of axonal degeneration. Nerve biopsy showed microvasculitis in two-thirds of cases and necrotizing vasculitis in one-third of cases. Vasculitis was also common in the muscle biopsy. Unlike other paraneoplastic sensory neuropathy, anticancer treatment and cyclophosphamide with or without steroids led to definite neurological improvement in two-thirds of patients with PVN.

CASE 4: HEPATITIS C, CRYOGLOBULINEMIA, AND VASCULITIC NEUROPATHY Case Presentation A 42-year-old white female diagnosed with hepatitis B in 1973 (which subsequently turned out to be hepatitis C) and cryoglobulinemia in 1994 was treated with interferon alfa starting in 1995. With interferon treatment, she experienced episodes of numbness in her feet lasting 1 month. For the 6 months prior to this study, she noted a persistent numbness on the lateral aspect of her right foot and, most recently, in the lateral aspect of her left foot as well. Abnormal neurological findings included a loss of pin-prick sensation over the right and left sural nerve territories and diminished ankle and knee reflexes. The NCS confirmed right and left sural neuropathy.

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Case Analysis This patient had classical mononeuropathy multiplex in a setting of hepatitis C and cryoglobulinemia. This triad of findings is typical of vasculitic neuropathy associated with hepatitis C. Histological diagnosis should be confirmed by the sural nerve biopsy. Sural Nerve Biopsy The surval nerve biopsy showed prominent total SNFD, Type I active vasculitis (Color Figure 6.27) in a tiny arteriole in the epineurial space, and massive perivascular collections of mononuclear cells in the epineurial space (Color Figure 6.28). In one nerve fascicle with a normal population of myelinated fibers, some scattered myelin digestion chambers were noted. Final Diagnosis The biopsy confirmed the original diagnosis. This patient was diagnosed with vasculitic neuropathy associated with hepatitis C and cryoglobulinemia. Treatment and Follow-up The patient’s neuropathy was stabilized with a small dose of cyclophosphamide. No obvious improvement was noted. Comments A hepatitis C patient has vasculitis, usually in a setting of cryoglobulinemia. Thus, this patient had the classical syndrome. However, she was unusual in two respects: (1) she had vasculitic neuropathy while on treatment with interferon-alfa, and (2) she had sensory mononeuropathy multiplex. The association of hepatitis C, cryoglobulinemia, and mononeuropathy multiplex has rarely been reported. According to Apartis et al.,75 among 15 patients with mixed cryoglobulinemia and peripheral neuropathy, 10 had a positive hepatitis C serology. Necrotizing vasculitis was found in two of nine biopsies from the HCV+ patients, and interferon-alfa apparently improved peripheral neuropathy in two. There were a few more cases of hepatitis C–induced vasculitic neuropathy that showed an improvement with interferon-alfa. Thus, our case is unusual in that the initial onset of neuropathy occurred during interferon-alfa treatment. There has been a general consensus that sensory polyneuropathy in rheumatoid arthritis is not due to vasculitic neuropathy.2 Since the first report of one patient with symmetrical sensory polyneuropathy and rheumatoid arthritis who had a definite vasculitis in the sural nerve biopsy,7 several cases of sensory vasculitic neuropathy have been reported.10,63,76,77 In our recent analysis of a series of SNV, there were 8 instances (18%) of sensory polyneuropathy among 44 vasculitic neuropathy cases. These findings indicate that a sensory polyneuropathy does not rule out vasculitic neuropathy, as previously thought, and can, in fact, be due to vasculitic neuropathy.

CASE 5: NUMBNESS AND PAIN IN LEGS WITH INH TREATMENT Case Presentation A 36-year-old male had 6 months of treatment with INH for positive PPD test when he developed numbness and pain in both legs. This was thought to be due to INH-induced peripheral neuropathy. With vitamin B6 replacement, the symptoms in his left leg disappeared. However, he continued to have a sharp lancinating pain in his right foot for 3 years. As part of a lawsuit against a pharmaceutical company for the INH-induced neuropathy, he sought a neurological consultation. The NCS

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showed an absence of sensory CNAP in his right sural nerve and mildly prolonged terminal latencies in his peroneal nerves. All other neuropathy work-ups were normal. His lawyer requested the sural nerve biopsy to confirm the drug-induced axonal neuropathy. Examination at the UAB a few months after the biopsy showed Tinel’s sign at his ankle in the posterior tibial nerve and hyperesthesia over the right medial plantar nerve territory. The NCS confirmed medial plantar neuropathy but no evidence of diffuse neuropathy. Case Analysis Though the temporal development of symptoms was suggestive of INH-induced neuropathy, the asymmetrical improvement was unusual for drug-induced neuropathy. Considering the absence of right sural nerve response in the NCS and medial plantar neuropathy by the clinical examination, this patient had sensory mononeuropathy multiplex, which, in retrospect, is typical of vasculitic neuropathy. Sural Nerve Biopsy The population of myelinated fibers was relatively normal. There were a few scattered myelin digestion chambers in the longitudinal cuts. A Type I feature (active vasculitis) (Color Figure 6.29) was obvious in the hugely enlarged arteriole in the epineurial space. Fibrinoid necrosis and intramural infiltration of mononuclear cells were prominent in the upper portion of the vessel. There was also a perivascular collection of mononuclear cells (Type III) around a tiny vessel in the upper portion. Final Diagnosis Nonsystemic vasculitic neuropathy was the final diagnosis. Treatment and Follow-up One course of steroids over 3 months was tried without any clinical improvement. His course has been stable over the past 10 years. The patient still has right tarsal tunnel syndrome (TTS). Comments This case represents the classical example of nonsystemic vasculitic neuropathy: lack of any systemic involvement and benign prognosis without treatment in the presence of active vasculitic features in the sural nerve biopsy.

CASE 6: HIGH SEDIMENTATION RATE IN A PATIENT WITH SUBACUTE SYMMETRICAL POLYNEUROPATHY Case Presentation A 59-year-old man with no prior medical issues except for heavy smoking was evaluated for an 8-month history of burning pain and numbness in both his feet. His symptoms began with numbness in the toes and gradually worsened to involve his feet entirely. At the time of evaluation, the pain was aggravated by prolonged sitting and was incapacitating to the point that he was unable to keep his desk job. He denied any orthostatic symptoms but complained of erectile dysfunction. Abnormal neurological findings were mild weakness in the plantar extensors, absent ankle jerk, and sensory loss below the mid-calf level. The NCS and EMG showed a diffuse sensory motor axonal peripheral neuropathy with active denervation in the anterior tibialis and gastrocnemius muscles. All work-ups for peripheral neuropathy were normal except for a high sedimentation rate of 60 mm/hr.

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Case Analysis This patient had a subacute case of symmetrical sensory-motor polyneuropathy. The NCS showed diffuse axonal neuropathy. There was no clinical clue suggestive of an etiology, but the elevated sedimentation rate suggested the possibility of vasculitic neuropathy. Sural Nerve Biopsy A Type I vasculitic lesion was observed in the small arterioles in the epineurial space (Color Figure 6.30). There was also a collection of many inflammatory cells in the perineurial and endoneurial space (Color Figures 6.30 and 6.31). It is extremely unusual to see endoneurial inflammatory cells in vasculitic neuropathy. Epineurial inflammatory cells are common in inflammatory demyelinating neuropathy. Final Diagnosis The final diagnosis was vasculitic neuropathy. Treatment and Follow-up The patient was treated with a high dose of prednisone and cyclophosphamide with a gradual improvement in his neuropathy. Treatment with small-doses of prednisone and cyclophosphamide was maintained for 5 years to keep his neuropathy under control. He developed a cyclophosphamideinduced nonreversible pan-cytopenia and died 6 years later. Comments This case represents a case of vasculitic neuropathy in subacute symmetrical polyneuropathy. Symmetrical polyneuropathy is characterized by an ascending, distal, symmetrical, “stocking-glove” type sensory loss with flaccid distal weakness. The classical examples of symmetrical polyneuropathy are metabolic and alcoholic neuropathies. Thus, vasculitic neuropathy is not usually considered a cause in the differential diagnosis in this clinical setting. Over the past 2 decades, however, repeated studies have shown that vasculitic neuropathy can be a cause of symmetrical polyneuropathy. In fact, a symmetrical polyneuropathy pattern is seen in one-third of patients with vasculitic neuropathy. If this occurs as the end result of extensive mononeuropathy multiplex, it is easier to understand the pathogenesis of symmetrical polyneuropathy. However, such a history is lacking in most patients. Thus, it is most likely that symmetrical polyneuropathy is a consequence of a more diffuse peripheral nerve ischemia due to multiple small lesions which are more likely to affect longer nerves. A symmetrical polyneuropathy presentation represents the most difficult diagnostic challenge for clinicians because of a low index of suspicion of vasculitic neuropathy as a diagnostic possibility. In fact, in Hawke’s series,9 patients with mononeuropathy multiplex had a shorter period (mean 9.2 weeks) before diagnosis was made than patients with symmetrical polyneuropathy (mean 20.4 weeks) or asymmetrical polyneuropathy (31.6 weeks).

CASE 7: 3-MONTH HISTORY OF MONONEUROPATHY MULTIPLEX Case Presentation A 61-year-old woman with chronic idiopathic bronchiectasis for more than 30 years developed an intermittent numbness of her left foot 3 months prior to the study. This was followed by occasional dragging of her left foot. Neurologic evaluation confirmed bilateral peroneal neuropathy and

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recommended bilateral peroneal nerve release at the fibular head. This was performed, and the patient experienced worsening left foot drop. While in the hospital, the patient began to notice tingling and numbness in her left hand, which was soon followed by weakness. No systemic symptom was present. Abnormal neurological findings were mild weakness in the right arm, moderate weakness in the right leg, and marked weakness in the left foot. Sensory loss was present in the left median and right ulnar nerve territory and below the right ankle and left knee. Ankle reflexes were absent. Abnormal laboratory findings were a sedimentation rate of 31 mm/hr and leucocytosis. An NCS showed diffuse axonal neuropathy. Case Analysis This patient had the most classical history of vasculitic neuropathy: mononeuropathy multiplex culminating in asymmetrical polyneuropathy. For obvious reasons, the surgical decompression of the peroneal nerve was a failure. The sedimentation rate was mildly elevated. The NCS ruled out multifocal motor and sensory demyelinating neuropathy. Thus, all the findings were strongly indicative of vasculitic neuropathy. Sural Nerve Biopsy An almost total loss of myelinated fibers was observed. Prominent myelin digestion chambers indicative of axonal degeneration were observed. No definite active (Type I) or inactive vasculitic (Type II) feature was noted. In the epineurial space, there was only perivascular cuffing of mononuclear cells (Type III) in two tiny vessels. However, the muscle biopsy from the anterior tibialis muscles showed active vasculitic features (Type I) in two arterioles in the perimysial space (Color Figure 6.32) and inflammatory myopathic features in the surrounding areas (Color Figure 6.33). Final Diagnosis Vasculitic neuropathy was the final diagnosis. Treatment and Follow-up A combined therapy of cyclophosphamide and steroids was recommended. No follow-up information was available in regard to the outcome. Comments In this case, the nerve biopsy showed probable vasculitic features suggestive of vasculitic neuropathy, but the diagnosis of definite active vasculitis was made by the muscle biopsy. In our series, in 3 of 115 suspected cases of vasculitis in which both nerve and muscle biopsies were performed, the muscle biopsy was more specific and resulted in a definite diagnosis, increasing the diagnostic yield from 29 to 31%.16 On the basis of this, we recommend the combined biopsy of nerve and muscle when considering vasculitis as a differential diagnosis.

CASE 8: GUILLAIN–BARRÉ SYNDROME? Case Presentation A 66-year-old female with a history of undifferentiated connective tissue disease was transferred to the UAB with a diagnosis of GBS. She had a history of viral gastroenteritis that had occurred 3 weeks prior to her transfer. Ten days before that, she had back pain and numbness in her legs. Over

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the first 7 days at UAB, weakness in her legs developed and progressed until she was unable to walk. Neurological examination showed weakness of all four limbs (worse distally and in the legs), absent knee and ankle reflexes, and decreased pin-prick sensation in the hands and feet. An MRI scan of the entire spine was normal. A CSF test showed a protein level of 77 mg/dl and 6 WBC/mm.3 An NCS revealed a severe diffuse axonal peripheral neuropathy with a needle EMG showing widespread denervation. Except for a positive ANA (nucleolar pattern) at 1:640, all laboratory findings were negative. Case Analysis This patient had all the classical findings of GBS: antecedent infection, acute quadriplegia, and high CSF protein. The only exception was axonal neuropathy in the NCS, whereas classically, GBS is characterized by demyelinating neuropathy. The history of undifferentiated connective tissue disease (CTD) and positive ANA were the clues suggesting other causes for her neuropathy. Sural Nerve Biopsy The biopsy showed perivascular collections of inflammatory cells in the small capillaries in the epineurial space and prominent myelin-digestion chambers (Type III lesion) (Color Figure 6.34). Final Diagnosis The final diagnosis was vasculitic neuropathy. Treatment and Follow-up The patient was treated with azathioprine and prednisone and a course of plasma exchange (for the erroneous diagnosis of GBS). Her muscle strength was moderately improved at the time of discharge. Comments This case is the second in our earlier paper78 reporting vasculitic neuropathy mimicking GBS. Aggressive diagnostic procedures of muscle and nerve biopsy for two atypical features led us to the correct diagnosis. In systemic lupus erythematosus (SLE), GBS and CIDP are known to occur.79 According to Rechtenhand,79 unlike post-infectious polyneuropathy, the Guillain-Barré type neuropathy in SLE is generally more gradual in its evolution, mimicking CIDP. Vasculitis was clearly documented in Goldberg’s case, which meets the diagnostic criteria of the Guillain-Barré syndrome.80 However, in other cases, demyelination was clearly documented. Kissel suggested that the mechanism of the Guillain–Barré syndrome and CIDP in SLE may be due to a pathogenic antinerve antibody or some other autoimmune mechanism.

CASE 9: PROGRESSIVE MULTIFOCAL MOTOR AND SENSORY DEFICITS OVER 3 MONTHS Case Presentation A 68-year-old man with a history of bladder cancer (4 years earlier) and rheumatoid arthritis for 7 months, which was treated with steroids with a relatively good response, developed progressive weakness of the right arm which lasted for 3 months. Seven months earlier, he had experienced numbness in his right hand, which was thought to be due to carpal tunnel syndrome (CTS) and was treated with decompression surgery without any benefit. At the time of evaluation, he complained of mild weakness of the legs and worsening shortness of breath, which was due to right diaphragmatic

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paralysis following a prior surgery for an abdominal aorta. The patient was referred to UAB to rule out motor neuron disease. At that time the patient was on portable oxygen. Abnormal neurological findings were mild weakness in the right deltoid, biceps, triceps, and hand muscles and in the left biceps and right and left iliopsoas muscles; trace ankle and triceps reflexes; decreased pin-prick sensation below the right mid-shin; absent vibration in the toes; decreased vibration in the ankle; and decreased position sense in the toes. Abnormal laboratory findings included a high sedimentation rate (100 mm/hr), positive RF at 1:160, positive ANA at 1:640, positive ENA at 1:114, positive SS-A/Ro at 180, and positive sulfatide autoantibody at 2513. pANCA and cANCA were negative. An EMG study showed myopathy in the proximal muscles and diffuse axonal peripheral neuropathy. Case Analysis This patient developed CTS around the time of diagnosis of rheumatoid arthritis. Even though his condition was fairly well controlled with prednisone and gold therapy, he developed multifocal weakness. The first neurologist suggested motor neuron disease, which was clearly ruled out by the presence of a sensory abnormality with a thorough neurological exam. Multifocal motor and sensory deficits clearly suggested the possibility of multifocal motor and sensory demyelinating neuropathy, but this was ruled out by the NCS, which showed axonal neuropathy. In view of the patient’s history, multifocal deficits, and EMG data, paraneoplastic or vasculitic etiology was considered. Laboratory findings strongly favored a vasculitic etiology. Sural Nerve and Muscle Biopsy There was a minimal decrease in the population of myelinated fibers and a few myelin-digestionchambers in the semithin as well as frozen sections (Color Figure 6.35). There were perivascular collections of mononuclear cells and macrophages in the small vessels in the epineurial space (Color Figure 6.36). A deltoid muscle biopsy showed Type II fiber atrophy. Final Diagnosis The final diagnosis was vasculitic neuropathy associated with rheumatoid arthritis. Treatment and Follow-up With prednisone and cytoxan therapy for 1 year, the patient was completely normal, including his respiratory insufficiency. He no longer needed the portable or stationary oxygen therapy. Comments Classically, vasculitic neuropathy is commonly seen in long-standing malignant rheumatoid arthritis. Thus, this case is exceptional. The sural nerve biopsy showed a Type III vasculitic lesion. Unlike case 7 above, the muscle biopsy did not show any histological feature of vasculitis. The diagnosis of probable vasculitic neuropathy was made on the basis of perivascular collections of inflammatory cells and axonal degeneration. The patient was treated with prednisone and cytoxan with a good outcome. This case illustrates the usefulness of the concept of probable vasculitis in the nerve biopsy, which occurs in about one-quarter of patients with vasculitic neuropathy, as discussed above. This finding is unique to the nerve biopsy and is most likely due to the lack of small- and medium-sized arteries in the nerve, which are predominantly involved in systemic necrotizing vasculitis.

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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

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Dyck, P.J., Conn, D.L., and Okazaki, H., Necrotizing angiopathic neuropathy: three-dimensional morphology of fiber degeneration related to sites of occluded vessels, Mayo Clin. Proc., 47, 461, 1972. Conn, D.L. and Dyck, P.J., Angiopathic neuropathy in connective tissue disease, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 2027. McManis, P.G., Low, P.A., and Lagerlund, T.D., Microenvironment of nerve: blood flow and ischemia, in Peripheral Neuropathy, 3rd Ed., Dyck, P.J. and Thomas, P.K., Eds., W.B. Saunders, Philadelphia, PA, 1993, 453. Slady, J.T., Greenberg, J.H., and Brown, M.J., Regional perfusion in normal and ischemic rat sciatic nerves, Ann. Neurol., 17, 191, 1985. Bell, M.A. and Weddell, A.G.M., A descriptive study of the blood vessels of the sciatic nerve in the rat, man and other mammals, Brain, 107, 871, 1984. Bell, M.A. and Weddell, A.G.M., A morphometric study of intrafascicular vessels of mammalian sciatic nerve, Muscle and Nerve, 7, 524, 1984. Wees, S.J., Sunwoo, I.N., and Oh, S.J., Sural nerve biopsy in systemic necrotizing vasculitis, Am. J. Med., 71, 525, 1981. Kissell, J.T., Eiethman, J.L., Omerza, J., Rammohan, K.W., and Mendell, J.R., Peripheral nerve vasculitis: immune characterization of the vascular lesions, Ann. Neurol., 25, 291, 1989. Hawke, S.H.B., Davies, L., Pamphlett, R., Guo, Y.P., Pollard, J.D., and McLeod, J.G., Vasculitic neuropathy. A clinical and pathological study, Brain, 114, 2175, 1991. Dyck, P.J., Benstead, T.J., Conn, D.L. Stevens, J.C., and Windebank, A.J., Non-systemic vasculitic neuropathy, Brain, 110, 843, 1987. Davies, L., Spies, J., Pollard, J. and McLeod, J., Vasculitis confined to peripheral nerves, Brain, 119, 1441, 1996. Oh, S.J., Vasculitic Neuropathy, in Vasculitis, Ball, G.V., and Bridges, S.L., Eds., Oxford University Press, Oxford, UK, 2000, in press. Ford, R. and Siekert, R., Central nervous system manifestations of periarteritis nodosa, Neurology, 15, 114, 1965. Guillevein, L., et al., Treatment of polyarteritis nodosa and Churg–Strauss syndrome. A meta-analysis of 3 prospective controlled trials including 182 patients over 12 years, Ann. Méd. Int., 15, 467, 1992. Cohen, R., Conn, D., and Ilstrup, D., Clinical features, prognosis, and response to treatment in polyarteritis, Mayo Clin. Proc., 55, 146, 1980. Claussen, C.G. et al., Diagnostic value of nerve and muscle biopsy in suspected vasculitic cases, J. Clin. NMD, 1, 117, 2000. Oh, S.J., Clinical Electromyography: Nerve Conduction Studies, Williams & Wilkins, Balimore, MD. 1993. Haynes, B.F., Allen, N.B., and Fauci, A.S., Diagnostic and therapeutic approach to the patient with vasculitis, Med. Clin. North Am., 70, 355, 1986. Dahlberg, P., Lockhart, J., and Overholt, E., Diagnostic studies for systemic necrotizing vasculitis: sensitivity, specificity, and predictive value in patients with multisystem disease, Arch. Intern. Med., 149, 161, 1989. Garcin, R. et al., Sur les formes multinevritiques et polynevritiques de la perarterite noueuse; etude de 7 observations inedites, Ann. Med., 56, 113, 1955. Khella, S.L. et al., Hepatitis C infection, cryoglobulinemia, and vasculitic neuropathy. Treat-ment with interferon alfa: case report and literature review, Neurology, 45(3), 407, 1995. Calabrese, L.H. et al., Systemic vasculitis in association with human immuno-deficiency virus infection, Arth. Rheum., 32, 569, 1989. Meier, C., Grahmann, F., Engelhat, A., and Dumas, M., Peripheral nerve disorders in lyme borreliosis: nerve biopsy studies in eight cases, Acta Neuropathol., 79, 271, 1989. Staud, R. and Williams, R.C., Antineurtrophilic cytoplasmic antibodies (ANCA) and vasculitis, Comp. Ther., 20, 623, 1994. Savage, C.O., Winerrls, C.G., Jones, S.J., Marshall, P., and Lockwood, C., Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis, Lancet, 1, 1389, 1987. Chalk, C.H., Homburger, H.A., and Dyck, P.J., Anti-neutrophil cytoplasmic antibodies in vasculitis peripheral neuropathy, Neurology, 43(9), 1826, 1993.

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27. Said, G. et al., Necrotizing arteritis in patients with inflammatory neuropathy and immunodeficiency virus infection, Neurology, 37(51) (abstract), 176, 1987. 28. Oh, S.J., Diagnostic usefulness and limitations of the sural nerve biopsy, Yonsei Med. J., 31, 1, 1990. 29. Said, G., Lacroix-Ciaudo, C., Fujimura, H., Blas C., and Faux, N., The peripheral neuropathy of necrotizing arteritis: a clinicopathological study, Ann. Neurol., 23, 461, 1988. 30. Said, G., Vasculitic neuropathy, Baillieres Clin. Neurol., 4(3), 489, 1995. 31. Oh, S.J., Herrara, G., and Spalding, D.M., Eosinophilic vasculitic neuropathy in the Churg–Strauss syndrome, Arth. Rheum., 29, 1173, 1986. 32. Midroni, G. and Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, 1995. 33. Schroeder, J.M., Proliferation of epineural capillaries and smooth muscle cells in angiopathic peripheral neuropathy, Acta Neuropathol., 72, 29, 1986. 34. Loveshin, L.L. and Kernohan, J.W., Peripheral neuritis in periarteritis nodosa: a clinicopathological study, Arch. Intern. Med., 82, 321, 1948. 35. Harati, Y. and Niakan, E., Clinical significance of selective nerve fascicular degeneration on sural nerve biopsy specimen, Arch. Pathol. Lab. Med., 110, 195, 1986. 36. Fujimura, H., Lacroix, C., and Said, G., Vulnerability of nerve fibers to ischemia. A quantitative light and electron microscope study, Brain, 114, 731, 1991. 37. Chalk, C.H., Dyck, P.J., and Conn, D.L., Vasculitic neuropathy, in Diseases of the Peripheral Nervous System, Dyck, P.J. et al., Ed., W.B. Saunders, Philadelphia, PA, 1993, 1424. 38. Lie, J., Illustrated histopathologic classification criteria for selected vasculitis syndromes, Arth. Rheum., 33, 1074, 1990. 39. Calabrese L.H., Estes, M., and Ken-Lieberman, B. et al., Systemic vasculitis in association with human immunodeficiency virus infection, Arth. Rheumat. 32, 569, 1989. 40. Asbury, A.K. and Johnson, P.C., Pathology of the Peripheral Nerve, W.B. Saunders, Philadelphia, PA, 1978. 41. Kernohan, J.W. and Woltman, H.W., Periarteritis nodosa: a clinicopathologic study with special reference to nervous system, Arch., Neurol. Psychiatry, 39, 655, 1938. 42. Fathers, E. and Fuller, G.N., Vasculitic neuropathy, Br. J. Hosp. Med., 55(10), 643, 1996. 43. Fauci, A.S., Haynes, B.F., and Katz, P., The spectrum of vasculitis: clinical, pathologic, immunologic and therapeutic considerations, Ann. Int. Med., 89, 660, 1978. 44. Panegyres, P.K., Blumbergs, P.C., Leong, A.S.Y., and Bourne, A.J., Vasculitis of peripheral nerve and skeletal muscle: clinopathological correlation and immunopathogenic mechanisms, J. Neurol. Sci., 100, 193, 1990. 45. Frohnert, P.P. and Sheps, S.G., Long-term follow-up study of periarteritis nodosa, Am. J. Med., 43, 8, 1967. 46. Fauci, A.S., Kataz, P., Ahynes, B.F., and Wolff, S.M., Cyclophosphamide therapy of severe systemic necrotizing vasculitis, New Eng. J. Med., 301, 235, 1979. 47. Chumbley, L.C., Harrison, E.G., DeRemee, R.A., Allergic granulomatosis and angiitis (Churg–Strauss syndrome). Report and analysis of 30 cases, Mayo Clin. Proc., 52, 477, 1977. 48. Churg, J. and Strauss, L., Allergic granulomatois, allergic angiitis, and periarteritis nodosa, Am. J. Pathol., 27, 277, 1951. 49. Merazzi, R. et al., Peripheral nerve involvement in Churg–Strauss syndrome, J. Neurol., 239, 317, 1992. 50. Inoue, A., Koh, C.S., Tsukada, N., and Yanagisawa, N., Allergic granulomatous angiitis and peripheral nerve lesions, Inter. Med., 31, 989, 1992. 51. Weinstein, J.M. et al., Churg–Strauss syndrome (allergic granulomatous angiitis). Neurophthalmologic manifestations, Arch. Ophthalmol., 101, 1217, 1983. 52. Staud, R. and Williams, R.C., Antineurtrophiclic cytoplasmic antibodies (ANCA) and vasculitis, Comp. Ther., 20, 623, 1994. 53. Drachman, D.A., Neurological complications of Wegener’s granulomatosis, Arch. Neurol., 8, 145, 1963. 54. Anderson, J.M., Jamieson, D.G., and Jefferson, J.M., Non-healing granuloma in the nervous system, Q. J. Med., 174, 309, 1975. 55. Nishino, H. et al., Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic, Ann. Neurol., 33, 4, 1993. 56. Stern, G.M., Hoffbranch, A.V., and Urich, H., The peripheral nerves and skeletal muscles in Wegener’s granulomatosis: a clinicopathological study of four cases, Brain, 88, 151, 1965.

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57. MacFayden, D.J., Wegener’s granulomatosis with discrete lung lesions and peripheral neuritis, Can. Med. Assoc. J., 83, 760, 1960. 58. Fauci, A.S., Hayunes, B.F., Katz, P., and Wolff, S.M., Wegener’s granulomatosis: prospective and therapeutic experiences with 85 patients for 21 years, Ann. Intern. Med., 98, 76, 1983. 59. Fauchald, P., Rygvold, O., and Oystese, B., Temporal arteritis and polymyalgia rheumatica. Clinical and biopsy findings, Ann. Intern. Med., 77, 845, 1972. 60. Whisnant, J.P., Peripheral neuropathic syndromes in giant cell (temporal) arteritis, Neurology, 38, 685, 1988. 61. Olney, R.K., AAEM Minimonograph #38: Neuropathies in connective tissue disease, Muscle Nerve, 15, 531, 1992. 62. Sokoloff, L., Wilens, S.L., and Bunium, J.J., Arteritis of striated muscle in rheumatoid arthritis, Am. J. Pathol., 27, 157, 1951. 63. Puechal, X. et al., Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients, Arth. Rheum., 38(11), 1618, 1995. 64. Hughes, R.A.C., Cameron, J.S., Hall, S.M., Heaton, J., Payan, J., and Teoh, R., Multiple mononeuropathy as the initial presentation of systemic lupus erythematosus-nerve biopsy and response to plasma exchange, J. Neurol., 228, 239, 1982. 65. Kissel, J.T., Slivka, A.P., Warmolts, J.R., and Mendell, J.R., The clinical spectrum of necrotizing angiopathy of the peripheral nervous system, Ann. Neurol., 18, 251, 1985. 66. McCombe, P.A., McLeod, J.G., Pollard, J.D., Guo, Y.P., and Ingall, T.J., Peripheral sensorimotor and autonomic neuropathy associated with systemic lupus erythematosus: clinical, pathological and immunological features, Brain, 110, 533, 1987. 67. Molina, R., Provost, T.T., and Alexander, E.L., Peripheral inflammatory vascular disease in Sjögren’s syndrome, Arth. Rheum., 28, 1341, 1985. 68. Mellgren, S.L., Conn, D.L., Stevens, J.C., and Dyck, P.J., Peripheral neuropathy in primary Sjögren’s syndrome, Neurology, 39, 390, 1989. 69. Griffin, J.W., Cornblath, D.R., and Alexander, E., Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren’s syndrome, Ann. Neurol., 27, 304, 1990. 70. Calabrese, L.H. et al., The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis, Arth. Rheum., 33, 1108, 1990. 71. Oh, S.J., Paraneoplastic vasculitis of the peripheral nervous system, Neurol. Clin., 15, 849, 1997. 72. Said, G., Lacroix-Ciaudo, C., Fujimura, H., Blas, C., and Faux, N., The peripheral neuropathy of necrotizing arteritis: a clinicopathological study, Ann. Neurol., 23, 461, 1988. 73. Kissel, J.T., Vasculitis of the peripheral nervous system, Semin. Neurol., 14, 361,1994. 74. Bouche, P., Léger, J.M., Travers, M.A., Cathala, H.P., and Castaigne, P., Peripheral neuropathy in systemic vasculitis: clinical and electrophysiologic study of 22 cases, Neurology, 36, 1598, 1986. 75. Apartis, E. et al., Peripheral neuropathy associated with essential mixed cryoglobulinaemia: a role for hepatitis C virus infection?, J. Neurol. Neurosurg. Psychiatry, 60, 661, 1996. 76. Moore, P.M. and Fauici, A.S., Neurologic manifestations of systemic vasculitis, Am. J. Med., 71, 517, 1981. 77. Lacomis, D., Giuliani, M.J., Steen, V., and Powell, H.C., Small fiber neuropathy and vasculitis, Arth. Rheum., 40(6), 1173, 1997. 78. Suggs, S.P., Thomas, T.D., Joy, J.L., Lopez-Mendez, A., and Oh, S.J., Vasculitic neuropathy mimicking Guillain–Barré syndrome, Arth. Rheum., 33, 975, 1992. 79. Rechthand, E., Cornblath, D.R., Stern, B.J., and Meyerhoff, J.O., Chronic demyelinating polyneuropathy in systemic lupus erythematosus, Neurology, 34, 1375, 1984. 80. Goldberg, M. and Chitanondh, H., Polyneuritis with albuminocytologic dissociation in the spinal fluid in systemic lupus erythematosis, Am. J. Med., 27, 342, 1959.

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CHAPTER 6 Figure 1 Perivascular cuffing of inflammatory cells. Perivascular collection of mononuclear inflammatory cells (Type III lesion) in a small vessel in the epineurial space. There is no intramural infiltration of inflammatory cells or fibrinoid necrosis. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 6 Figure 3 Active vasculitis with recanalization of occluded lumen, discontinuous elastica (arrow head), edema in the adventitia, and prominent intramural infiltration of mononuclear cells producing fibrinoid necrosis. In the surrounding nerve fascicles (arrow), there is obvious loss of myelinated fibers. Paraffin section. Modified trichrome. (100 × magnification.)

CHAPTER 6 Figure 2 Active vasculitis (Type I lesion) in a larger arteriole in the epineurial space. Arteriole is greatly enlarged in size due to active vasculitic process. The normal structure of the arteriole is completely destroyed by the prominent intramural infiltration of mononuclear cells and fibrinoid necrosis of muscular and adventitial layers and near occlusion due to an intimal thickening. One nerve fascicle (arrow) is noted in the right upper corner. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 4 Active vasculitis with hemorrhage in the intimal layer associated with fibrinoid necrosis and intramural lymphocytes in the muscular layer in the small arterioles in muscle biopsy. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 5 Inactive vasculitis (Type II lesion). Thickened intimal and muscular layers and a few scattered intramural inflammatory cells in the muscular and adventitial layers of a small arteriole in the epineurial space, representing an inactive vasculitis. The involved arterioles are larger in size than the noninvolved arterioles next to them due to an inactive vasculitic process. Paraffin section. H & E stain. (100 × magnification.)

CHAPTER 6 Figure 7 Healed vasculitis. Thickened wall of epineurial small arterioles with hemosiderin in the intimal layer, representing old hemorrhage, and total occlusion of lumen of arterioles due to thickened intimal layer. PASH. (200 × magnification.)

CHAPTER 6 Figure 6 Healed vasculitis. Marked narrowing of lumen of small arteriole in the epineurial space due to thickened intima and muscular layers. No inflammatory cells are visible. Other areas of this section showed inactive vasculitic changes. Paraffin. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 8 Many myelin ovoids typical of active axonal degeneration are obvious. Arrow indicates one of many myelin ovoids. Arrow head indicates one of many myelin-digestion chamber. Semithin EM section. (200 × magnification.)

CHAPTER 6 Figure 9 Active axonal degeneration in two teased fibers characterized by myelin ovoids of various sizes (arrowheads). Successive segments of teased nerve fibers from top to bottom.

CHAPTER 6 Figure 10 Active axonal degeneration in the longitudinal section. Prominent myelin-digestion chambers (arrow indicates one of them) indicative of axonal degeneration in one nerve fascicle. Arrow head indicates one myelin ovoid. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 6 Figure 11 Active axonal degeneration in the transverse section. Prominent myelindigestion chambers (arrow indicates one of them) indicative of active axonal degeneration in one nerve fascicle. (200 × magnification.)

CHAPTER 6 Figure 12 Sectional selective nerve fiber degeneration (SNFD) indicative of ischemic neuropathy in vasculitic neuropathy. Loss of myelinated fibers in a wedge-shaped section of one nerve fascicle (arrowhead) with central fascicular degeneration is due to occlusion of the vasa nervorum supplying blood to this section of the fascicle. Myelinated fibers are stained red. The normal number of myelinated fibers is noted in the lower half of the fascicle. Frozen section. Modified trichrome. (100 × magnification.)

CHAPTER 6 Figure 13 SNFD indicative of ischemic neuropathy in vasculitic neuropathy in the longitudinal section. Total SNFD: total loss of myelinated fibers in one nerve fascicle (arrows). In the lower nerve fascicle, a few myelin-digestion chambers indicating active axonal degeneration are also observed. Frozen section. Modified trichrome. (100 × magnification.)

CHAPTER 6 Figure 15 Polyneuropathy vs. mononeuropathy multiplex and their pathogenetic mechanisms in vasculitic neuropathy. (A) Mononeuropathy multiplex (green area): right peroneal, left ulnar, and right superficial radial sensory neuropathy. Blue area of the nerve represents the ischemic degeneration in vasculitic neuropathy. (B) Asymmetrical polyneuropathy due to more patch damage in the scattered nerves, but not corresponding to the named nerves. Red areas represent a milder degree of involvement; (C) Symmetrical polyneuropathy, which is more likely to affect longer nerves.

CHAPTER 6 Figure 14 SNFD in the transverse section. Two small nerve fascicles are totally devoid of any myelinated fibers (total SNFD) (double arrowheads), while one larger nerve fascicle has sectional SNFD (arrowhead) with a normal number of relatively well preserved myelinated fibers in most areas of the nerve fascicle. (200 × magnification.)

CHAPTER 6 Figure 16 Most intramural mononuclear cells are T-cells. Frozen section. CD4 marker stain. (200 × magnification.)

CHAPTER 6 Figure 17 Type I vasulitic lesion with total occlusion of arterioles in the epineurial space. Many myelin-digestion chambers (arrow heads) are obvious in the nerve fascicle. Frozen section. H & E stain. In the frozen sections, myelin-digestion chambers are often detectable on H & E stain. (100 × magnification.)

CHAPTER 6 Figure 18 Temporal arteritis. Type I vasculitic lesion in the temporal artery. Prominent intimal thickening with narrowing of the lumen of the artery and fibrinoid necrosis of the muscular layer with many inflammatory cells and giant cells (arrowhead). Paraffin section. H & E stain. (Courtesy of Dr. Cheryl Palmer.)

CHAPTER 6 Figure 19 Type I vasculitic lesions with total occlusion of arteriole in the perimysial space. Many nearby muscle fibers (arrow) show subtle changes of myopathy (purple-tinged smear in muscle fibers) with internal nuclei. Frozen section. H & E stain. (100 × magnification.)

CHAPTER 6 Figure 20 Type I vasculitic lesion with near-total occlusion of the arteriole between two nerve fascicles. Also, a prominent perivascular collection of mononuclear cells (arrow). Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 21 Three different features in three tiny arterioles in the same epineurial space: long arrow indicates normal, short arrow indicates a Type I vasculitic lesion, and arrowhead, indicates a Type II inactive vasculitic lesion. (200 × magnification.)

CHAPTER 6 Figure 22 Type I lesion with total occlusion of vessel lumen due to the fibrinoid necrosis of intima and muscular layers. Details of pathological features are obscured because of frozen section. Frozen section. PASH. (100 × magnification.)

CHAPTER 6 Figure 23 Type I vasculitic lesion with scattered red blood cells in all layers. One nerve fascicle shows minimal decrease in the population of myelinated fibers. Paraffin section. Modified trichrome. (200 × magnification.)

CHAPTER 6 Figure 24 Type I lesion with neartotal occlusion of the arteriole’s lumen in the epineurial space. One nerve fascicle is indicated with an arrow. Arrowhead indicates a collection of many eosinophilic leucocytes (see Figure 6.25). Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 25 Higher magnification of Figure 6.24 showing many eosinophilic leucocytes (with reddish cytoplasm) among many infiltrating inflammatory cells in the walls of arteriole. Paraffin section. H & E stain. ( 400 × magnification.)

CHAPTER 6 Figure 27 Type I vasculitic lesions in the upper smaller arterioles in the longitudinal cut. Lower larger arterioles are not affected by the vasculitic process. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 26 Microvasculitis in a tiny capillary in the epineurial space. Arrow indicates nerve fascicle. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 28 Type III vasculitic lesion: prominent collections of small mononuclear cells in the perivascular area (double arrow heads). There are no intramural inflammatory cells in the wall of the small arteriole in the epineurial space (arrow). Paraffin section. H & E stain. (100 × magnification.)

CHAPTER 6 Figure 29 Type I vasculitic lesion: prominent intramural infiltration of inflammatory cells is in the muscular and adventitial layers in the larger arterioles in the epineurial space. There is also microvasculitis in the tiny arterioles (arrow head). Frozen section. PASH. (100 × magnification.)

CHAPTER 6 Figure 30 Type I vasculitic lesion (arrow) with near-total occlusion of the vessel in the tiny arteriole in the epineurial space and prominent perineurial collections of mononuclear cells (arrowhead). Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 31 Invasion of mononuclear cells into the endoneurial space from the perineurial space (see Figure 6.30) through the fragmented segment of the wall of the nerve fascicle. Endoneurial inflammatory cells are extremely rare in vasculitic neuropathy. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 32 Type I vasculitic lesion in the arteriole in the perimysial space. In a nearby area, there are histological features of inflammatory myopathy: endomyisial inflammatory cells and some muscle fibers undergoing regeneration and phagocytosis. Frozen section. H & E stain. (100 × magnification.)

CHAPTER 6 Figure 33 Myositis in an area distant from vasculitic arterioles. Endomysial mononuclear inflammatory cells with a few muscle fibers undergoing regeneration (arrow). Sometimes, myositic features are seen without vasculitic features. Frozen section. H & E stain. (200 × magnification.)

CHAPTER 6 Figure 35 Minimal decrease in the population of myelinated fibers is obvious. The arrow indicates one nerve fiber undergoing active axonal degeneration (MDC). Arrowheads indicate two of many clusters of regenerating axon sprouting. Semithin section. (200 × magnification.)

CHAPTER 6 Figure 34 Perivascular collections of inflammatory cells in a small vessel in the epineurial space (Type III). Notice the relatively normal population of myelinated fibers in lower nerve fascicle, but the decreased population of myelinated fibers in one nerve fascicle (arrow). Paraffin section. Modified trichrome. (200 × magnification.)

CHAPTER 6 Figure 36 Perivascular collection of inflammatory cells in a small vessel in the epineurial space (Type III). Double arrows indicate perivascular collections of macrophages and inflammatory cells. Notice the lack of any inflammatory cells in a small arteriole. Paraffin sections. H & E stain. (200 × magnification.)

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Inflammatory Demyelinating Neuropathy

Inflammatory demyelinating neuropathy is the type of neuropathy most commonly encountered in the practice of neurology. This is because most patients with diabetic or alcoholic neuropathies, the most common forms of neuropathy, are usually taken care of by non-neurologists. Inflammatory neuropathies are classified into two main categories: acute and chronic. Acute inflammatory demyelinating neuropathy, better known as the Guillain–Barré syndrome (GBS), is a well-known entity. In Western countries, GBS is the most frequent cause of acute paralytic illness since poliomyelitis has become uncommon. The prime example of chronic inflammatory demyelinating neuropathy is chronic inflammatory demyelinating polyneuropathy (CIDP). Multifocal motor neuropathy (MMN) has received the most attention in the past decade and is now considered a separate clinical entity. The existence of multifocal motor sensory demyelinating neuropathy (MMSDN) as a separate disease has been debated. A sensory variant of CIDP has also been well recognized in recent years. The hallmark of inflammatory neuropathy, as the name implies, is the presence of inflammatory cells in the endoneurial space of the nerve (Color Figure 7.1).* Although inflammatory cells are commonly observed in autopsy series, they are not a common feature in the sural nerve biopsy (see below). This raises some question as to the validity of the designation “inflammatory neuropathy.” However, many believe that inflammatory cells are primarily responsible for the macrophageinduced demyelination in these neuropathies (Color Figure 7.2),1 which are, therefore, classified as inflammatory demyelinating neuropathies. The typical clinical features of inflammatory neuropathy are a widespread or multifocal neuropathy and nerve conduction features of demyelination. CSF albuminocytological dissociation is the cardinal feature of GBS and CIDP. Axonal forms of GBS and CIDP (see cases below) have also recently been reported. Although the clinical features are similar to those of GBS and CIDP, the electrophysiological and pathological features are characterized by axonal degeneration. Thus, by definition, these are not classified as inflammatory demyelinating neuropathy. This subject will be discussed as a case presentation later in this chapter.

PATHOGENESIS OF INFLAMMATORY DEMYELINATING NEUROPATHIES It is generally believed that GBS is a cell-mediated autoimmune neuropathy, analogous to experimental allergic neuritis (EAN). In EAN, the pathogenetic mechanism has been well delineated. Immunization with the P2 protein of the peripheral nerve induces the sensitized T-cells (transformed lymphocytes) into the nerve fascicle. The sensitized T-cells attract macrophages to peripheral nerves and activate macrophages in the initiation of primary demyelination of myelin. A similar mechanism has been proposed in GBS.1-3 It is generally believed that the pathogenesis of CIDP is similar to that of GBS.4,5 This notion has been reinforced by two factors: some animals with EAN follow a chronic progressive or relapsing course, and recurrent EAN was induced by the reinoculation of P2 protein in animals that recovered from the first EAN.7 Onion-bulb formation, which is a characteristic finding in CIDP, is abundant in most nerves examined in recurrent EAN.6 * Color insert figures.

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In GBS, the mechanism of demyelination has been well worked out ultrastructurally by Prineas,7 who showed findings identical to those occurring in EAN.8 According to him, primary demyelination occurs in the circumscribed areas infiltrated with inflammatory cells, confirming the previous reports.2,9 This primary demyelination is initiated largely by macrophages, which penetrate the Schwann cell basement membrane around nerve fibers and strip what appears to be normal myelin away from the body of the Schwann cell and off the axon, subsequently phagocytizing and digesting the stripped myelin fragments. This demyelinating mechanism appears to be common in GBS, CIDP, and EAN,8,10 supporting the cell-mediated autoimmune mechanism in inflammatory neuropathies. Extensive studies in regard to circulating demyelinating antibodies in GBS and CIDP have been disappointing.3,5 No reliable circulating antibodies have been consistently found in either disease. Current evidence suggests that GBS and CIDP result from an immune attack on myelin and/or Schwann cells, involving humoral factors, lymphocytes, and macrophages. Accompanying axonal damage may be a secondary phenomenon. We do not fully understand the exact mechanisms underlying demyelination in GBS and CIDP. Clinical experience of the effectiveness of plasmapheresis and IVIG treatment in GBS and CIDP, and of the effectiveness of immunotherapies in CIDP, clearly supports such a mechanism. However, why there is such a clear difference in steroid responsiveness in GBS and CIDP is a mystery.

GUILLAIN–BARRÉ SYNDROME (ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY; AIDP) The Guillain–Barré syndrome is characterized by acute ascending polyneuropathy.3 Progressive and usually symmetrical motor weakness, combined with hyporeflexia, is the cardinal clinical feature. In about 70% of these cases, there is a history of some viral or other illness 2 to 4 weeks prior to the onset of neuropathy. Paralysis is maximal by 1 week in more than half, by 3 weeks in 80%, and by 1 month in 90%.11 We believe that the diagnosis of CIDP is more appropriate if the progression of paralysis is longer than 4 weeks.12 Facial diplegia and respiratory paresis are frequent. Recovery begins 1 to 4 weeks after the illness has reached its peak. The majority of patients make a complete functional recovery, but the mortality rate of this disorder is about 5%. Death is usually due to complications associated with respiratory failure. Recurrences occur in approximately 3% of cases. CSF shows a classical albuminocytological dissociation in most patients. However, CSF may be normal during the first few days after onset. Electrophysiological studies have been useful in diagnosing this disorder. Nerve conduction abnormalities are observed in 81 to 100% of patients.13 Although a wide spectrum of nerve conduction abnormalities is observed, diffuse slowing of conduction accompanied by a dispersion phenomenon and conduction block indicative of demyelination is the most common pattern. The diagnosis of GBS is based on typical clinical features of (1) acute progression of diffuse polyneuropathy; (2) high CSF protein; and (3) nerve conduction abnormalities indicative of demyelinating neuropathy. In a majority of cases, the diagnosis of GBS can usually be established without any difficulty. However, in some cases, because of atypical features, the diagnosis of GBS is difficult. Diagnostic criteria of GBS were published in 1978.11 Nerve biopsy is seldom indicated in classic cases of GBS. We do recommend the nerve biopsy in atypical cases of GBS and in relapsing GBS. In atypical cases, the reason for the sural nerve biopsy is obvious. Since our experience suggests that relapsing GBS is responsive to long-term steroid therapy, we recommend the sural nerve biopsy before initiation of steroid treatment for histological confirmation of this disorder. The pathology of the peripheral nerves in autopsied cases of GBS has been well described in three classic papers. Haymaker and Kernohan described the histological findings in 50 fatal cases of GBS in their classic paper.14 Their study showed that: (1) the main pathology in GBS was in the more proximal part of the peripheral nerve, (2) the most prominent changes were noted in the region where ©2002 CRC Press LLC

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the motor and sensory roots join to form the spinal root, and (3) the majority of findings in the central nervous system were restricted to changes secondary to damage to peripheral nerve fibers. Thus, this study established GBS as a polyradiculoneuropathy. In view of the early edema followed by the late demyelination and axonal degeneration and inflammatory changes in these cases, the inflammatory cells were regarded as part of the reparative process. Krucke,9 in a personal series of seven fatal cases, found early serous exudation, most prominent where the anterior and posterior roots entered the dural sac, and inflammatory cells in all cases. He concluded that edema was always part of an inflammatory reaction. Thus, his study established GBS as an inflammatory neuropathy. In a 1969 landmark study of 19 cases of idiopathic polyneuritis including 3 cases of CIDP, Asbury, Arnason, and Adams2 reported that: (1) the common denominator in all 19 cases was mononuclear inflammatory infiltration of the peripheral nerve from the earliest stages of disease; (2) all levels of the peripheral nerve were vulnerable to attack, from the roots to the distal portion of the nerve; (3) segmental demyelination was the predominant form of nerve fiber damage and occurred in zones corresponding to the areas of inflammatory cells; and (4) the 3 slowly evolving cases (CIDP) were pathologically indistinguishable from the more rapidly evolving cases (GBS). Thus, this study established that GBS and CIDP represent a spectrum of inflammatory demyelinating neuropathy. In the 1970s and 1980s, Prineas reported macrophage-induced demyelination as the basic mechanism of demyelination in GBS in the extensive electronmicroscopic study.1,7 In our series and three others on the sural nerve biopsy in GBS (Table 7.1),7,15,16 the most consistent finding was primary demyelination (Color Figures 7.3–7.6). This is in strong contrast to the autopsy findings. Histological evidence of primary demyelination was best observed in the teasing fibers and the semithin plastic sections, and rarely in the longitudinal sections of the frozen nerve. When primary demyelination was observed together with inflammatory cells in the same nerve section, it occurred near the inflammatory cells. Onion-bulb formation, which is a common finding in

TABLE 7.1 Histological Features in the Sural Nerve Biopsy in GBS Histologic feature

Prineas 7a GBS (N = 9) Loss of myelinated fibers 6 Endoneurial or subneurial edema 2 Mononuclear cells 3 Endoneurial (6) Perivascular Primary demyelination 5 (6) a Onion bulb formation (1) Axonal degeneration Mixed Normal

2 (4)

Hughes2 (N = 10) 3

Oh GBS (N = 17) 12

Oh Recurrent GBS (N = 7) 6

4 (40%) 3 4 7

7 (41%) 1 7 15

4 (57%) 4 3 5 1

8

4

1

2

0

Brechenmacher3 (N = 65)

7 (N = 57) 5 (57) b 2 (63)

(10)

a

Nine sural nerve biopsies and one spinal root. Numbers in parenthesis represent the number of cases under the ultrastructural EM study. Six had primary demyelination associated with invasion of internodes by mononuclear cells. Two had vesicular degeneration of myelin. Degeneration of myelin sheaths into fine osmiophilic debris occurred in five. b

The ultrastructural study showed primary demyelination or remyelination in 63, altered axons in 10, and inflammatory cells (lymphocytes, macrophages, and some rare plasma cells) in 57.

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CIDP, was not observed in classical GBS. In our series, it was observed in one case of recurrent GBS. Recurrent GBS is now considered a variant of CIDP (see case below). The next most frequent finding in the sural nerve biopsy in GBS is inflammatory cells. In contrast to the ubiquitous presence of inflammatory cells in the peripheral nerve in the autopsy series, inflammatory cells are unfortunately not commonly observed in sural nerve biopsies. They were observed in 41% of the cases (7 of 17) in our series and 33% in Prineas’ series.7 The presence of inflammatory cells in the endoneurial space is the most specific finding indicative of inflammatory demyelinating neuropathies (Color Figures 7.7 and 7.8). This is a cardinal feature which distinguishes inflammatory demyelinating neuropathies from vasculitic neuropathies. Thus, it is a desirable histopathological feature in GBS. Endoneurial inflammatory cells are usually present together with the inflammatory cells in the epineurial space. In some cases, perivascular infiltration of lymphocytes is seen only in the epineurial space (Color Figure 7.9). In those cases, the histological differentiation from vasculitic neuropathies should be made on the basis of other available findings. In vasculitic neuropathy, axonal degeneration is the predominant feature. Inflammatory cells are distinctly mononuclear, composed mainly of both small and large lymphocytes. Plasma cells are scattered among the lymphocytes. In the most intense cases, polymorphonuclear leukocytes are admixed with lymphocytes. These cells are usually present in a perivenular and pericapillary space. It has been stated that low-grade perivascular inflammation may persist for many months and even years after clinical recovery.31 In that regard, it is interesting that the most abundant inflammatory cells were seen in the recurrent GBS patient in our series who had had the first attack 14 years previously. One wonders why inflammatory cells are not common in the sural nerve biopsy in this disorder. We believe that this is due to the less common involvement of the sural nerve in GBS. The sural nerve may be the last target of GBS because it is distally located and sensory in nature. It should also be pointed out, that autopsy series represent the most severe form of the disease in contrast to that commonly seen in biopsy. Depopulation of large myelinated fibers, a nonspecific finding indicative of peripheral neuropathy, is another common finding in the sural nerve biopsy. This is based on gross observations rather than on quantitative analysis. Subependymal edema was observed in one-third of the patients in Prineas’ series.7 Frozen sections in our series do not show any impressive subependymal edema. Axonal degeneration was observed in 23% of cases in ours and Prineas’ series,7 but in Hughes’ series,13 axonal degeneration was found in 80% of cases. Axonal degeneration is usually present together with severe demyelination. Thus, we believe that axonal degeneration in these cases is secondary to primary demyelination. In summary, the sural nerve biopsy in GBS shows (1) segmental demyelination as the most consistent finding and (2) endoneurial and epineurial mononuclear cells in about 33 to 41% of patients.

VARIANTS OF THE GBS Acute panautonomic neuropathy is characterized by acute severe sympathetic and parasympathetic impairment with relative or complete preservation of somatic motor and sensory function. CSF protein is high in some cases.17 Incomplete recovery is the usual outcome. A sural nerve biopsy was reported in eight cases, with normal findings in three, small perivascular inflammatory cells in the epineurial space in one,17 and reduction of myelinated fibers in three, with predominant involvement of small myelinated fibers. In one case, there was a selective loss of small myelinated and unmyelinated nerve fibers, explaining dysautonomia.18 In one case of acute autonomic and sensory neuropathy, the sural nerve biopsy revealed marked axonal degeneration of myelinated as well as unmyelinated fibers (see below).19 That patient had absent sensory nerve potential in the presence of normal motor and mixed nerve conduction. Sural nerve findings were best explained as Wallerian

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degeneration following widespread ganglionopathy. In a fatal case of acute dysautonomia, Stoll et al. showed inflammatory infiltrates within the autonomic and sensory ganglia and, to a lesser extent, in the nerve roots, spinal cord, and brainstem.20 At the very least, this case strengthens the theory that acute autonomic neuropathy represents a type of inflammatory polyneuropathy. Miller–Fisher syndrome of acute ophthalmoplegia, ataxia, and areflexia, described by Fisher in 1956, is generally considered a variant of the Guillain–Barré syndrome. It is accompanied by a high CSF protein level and has a benign course. It is now well-established that GQ1b antibody is specific for this disorder. Because of the benign nature of the disease, detailed neuropathological studies are rare. In one fatal case of Miller–Fisher syndrome, the classical pathological findings of the Guillain–Barré syndrome were observed: a patchy but extensive recent segmental demyelination and scanty perivascular mononuclear cells.21 We have not as yet been able to find any report describing the sural nerve biopsy in this disorder. In one case of the relapsing form of Miller–Fisher syndrome, the sural nerve biopsy showed segmental demyelination.22 The sensory variant of GBS is characterized by acute development of pure sensory neuropathy, high CSF protein, demyelination in the nerve conduction study, and monophasic improvement.23 Some patients have profound sensory ataxia.24 So far, peripheral nerve pathology has not been reported in this variant.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP) The chronic form of the Guillain–Barré syndrome has been well-known for years. Until Austin reported a remarkable case of recurrent polyneuropathy with dramatic response to various corticosteroid agents, this disease was not considered a separate disease entity.25 In the past 3 decades, CIDP has been clearly recognized as a separate entity on the basis of subacute progression of polyneuropathy, marked nerve conduction abnormalities, a high rate of relapse, and positive response to steroid treatment.5 The distinction between GBS and CIDP is imperative due to the differing prognoses and therapeutic approaches (Table 7.2).12 Though the relapsing nature of this disease has been emphasized, it is important to know that there are two distinct forms of CIDP: monophasic and relapsing polyneuropathy. According to Oh’s study, monophasic polyneuropathy was noted in 40% of patients.12 The diagnosis of CIDP is based on the typical clinical features of (1) subacute progression of diffuse polyneuropathy, (2) high CSF protein level, and (3) marked nerve conduction abnormalities

TABLE 7.2 Different Features of GBS and CIDP Features Onset Antecedent infection Cranial nerve deficit Respiratory failure CSF NCV Response to steroids Response to IVIG and PE Relapse

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Guillain–Barré Syndrome Acute; peak deficit in less than 4 weeks Present in 70% of cases Common Not uncommon High protein Normal or slightly slow in 50% of cases; markedly slow in 50% Not proven Yes Rare

CIDP Subacute or chronic; peak deficit in more than 4 weeks Absent Rare Rare High protein Markedly slow Yes Yes Common

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indicative of demyelinating neuropathy. According to our experience, this disorder cannot be diagnosed without electrophysiological confirmation. We recommend the sural nerve biopsy in all patients with this disorder for two reasons: (1) to confirm the demyelinating nature of the disease and (2) to rule out other polyneuropathies that can mimic this disorder. We believe that this histological confirmation is essential before treatment is initiated in these patients in view of the long-term commitment to steroids or immunosuppressors which are potentially life-endangering. There are some experts who disagree with this view.26,27 The pathological hallmark of CIDP is primary demyelination (Table 7.3 and Color Figures 7.10 and 7.11). It is this feature, most constant and important in the sural nerve biopsy, which confirms the clinical diagnosis. This is best shown by the presence of thinly myelinated fibers in the semithin sections. Onion-bulb formation (Color Figures 7.12 and 7.13), a histological feature of chronic demyelination and remyelination, is a rarely observed feature in the sural nerve biopsy and is best observed on semithin sections. The presence of mononuclear cells, an expected feature in inflammatory neuropathy, is a rarer occurrence than in GBS in general (Table 7.3). When present in inflammatory neuropathy inflammation is not as prominent a feature as in GBS.5 Usually, perivascular infiltration in the epineurial space is more common than endoneurial infiltration of mononuclear cells (Color Figures 7.14 and 7.15), which is best recognized on longitudinal sections (Color Figure 7.14). The percentage of mononuclear cells in the sural nerve biopsy varies from 1128,29 to 65%.52 Midroni et al. used the immunohistochemical marker staining for identification of leukocytes, which may explain their figure of 65%.26 In our series, there were inflammatory cells in 27% of cases. Dyck stated that in occasional nerves, mononuclear cells were seen to lie within the intima and the media,4 but he did not see medial necrosis, intimal proliferation, arterial occlusion, hemorrhage, or hemosiderin-laden macrophages adjacent to the small arterioles. This observation is important in the differentiation between inflammatory neuropathies and vasculitic neuropathy. Loss of myelinated fibers is not easily observed by quantitative analysis10 because the fiber counting includes many small remyelinated fibers. However, the gross observation of these nerves shows a patchy depopulation of the large myelinated fibers in most cases in our series. In studies of the distribution of fibers by diameter,the majority of cases showed a normal bimodal distribution of fiber diameter,10 while some cases revealed a pronounced reduction in the number of large-diameter myelinated fibers.12 Endoneurial or subperineurial edema, which was considered by Austin to be an important histological finding in his patient with chronic relapsing polyneuropathy, was observed in some cases (Color Figure 7.16). Axonal degeneration was observed in 5 to 25% of cases in most series and was most likely secondary to primary demyelination. Dyck et al. described degeneration into myelin ovoids as the most frequent abnormality in the teased nerve fibers in the sural nerve biopsy.4 They assumed that the brunt of the pathological process in roots and proximal parts of nerves caused transection of nerve fibers and subsequently produced Wallerian degeneration in a distal nerve. Contrary to the widely observed finding, Midroni also observed axonal degeneration as the most common or sole feature in 24% of cases.26 On the basis of his observation, Dyck5 stated that sural nerve biopsy is often not as helpful as one might hope in the diagnosis of CIDP. We disagree with Dyck in that the sural nerve biopsy shows an unmistakable picture of demyelination in a majority of patients with this disorder, thus confirming the diagnosis of demyelinating neuropathy. It is interesting to note that in the autopsy series, the most prominent histological feature was mononuclear cell infiltrates in the nerves, mostly in the spinal roots or proximal nerves, according to the nature of the autopsy. This discrepancy from the sural nerve biopsy may represent the greater severity of disease and the proximal location of the studied segment in the autopsy series.

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TABLE 7.3 Histological Features of Sural Nerve Biopsy and Autopsies in CIDP

5

slight 0 10 (44%) 12 (52%) 7*c

Oh (N = 110) 89 (81%) 2

Barohn28 (N = 56)

Small 29 (N = 19)

30 (27%) 6 (26%) 30 (27%) 12 (11%) 86 (78%) g 18 (16%) g 18 2

6 (11%) 6 (5%)

2 (11%)

? 27 (48%) 12 (21%)

4 (21%) 5 (26%) 3 (16%)

10 (18%)

16 (37%)

Krendal 79 (N = 14)

Bouchard 80 (N = 95)

Autopsiesa (N = 11) 1 2

18 (19%)

8 (73%) 6 (55%) 1

33 (65%)*d 4 (29%) 5 (36%) 7 (50%)

a

Eleven cases were collected from Borit (1971), Dyck (1975), Mathews (1970), Thomas (1969), and Torvik (1977)

b

In the epi- or perineurial space

c

Epoxy section showing axonal degeneration in two cases and axonal regeneration in five cases

d

LCA is used for identification of inflammatory cells

e

Primary demyelination alone in 4, axonal degeneration alone in 12, and mixed findings in 34 cases

f

Teased nerve fibers

g

This represents the predominant finding

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Midroni 26 d (N = 51)

10 (20%) 38 (75%) e 46 (88%) 34 (67%) 1

17 (18%) 68 (72%) 5 20 (21%)

3

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6 14 (54%) 4 6 (N = 24) f 6 (N = 24)

Prineas 10 (N = 23) 7 7

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Loss of myelinated fibers Endoneurial or subneurial edema Mononuclear cells Endoneurial Perivascularb Onion-bulb formation Primary demyelination Axonal degeneration Mixed Normal

Dyck 4 (N = 26)

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MULTIFOCAL MOTOR NEUROPATHY (MMN) Multifocal motor neuropathy (MMN) is characterized by asymmetrical motor weakness primarily involving the upper extremities, multifocal motor conduction block, high anti-GM1 antibody titer, non-responsiveness to steroid treatment, and good response to cyclophosphamide and intravenous immunoglobulin.30-32 Often, this entity resembles amyotrophic lateral sclerosis because of fasciculations and increased reflexes. It is now well established that conduction block or high GM1 titer is not a sine qua non of diagnosis. All data suggest that MMN is an autoimmune neuropathy on the spectrum of chronic inflammatory demyelinating neuropathy. Auger et al.33 provided the earliest pathological evidence of demyelinating neuropathy in MMN in a mixed nerve from a proximal ulnar nerve biopsy: patches of thinly myelinated large axons, onion-bulb formation (OBF), and only minimal nerve fiber loss. Kaji et al.34 reported pathological findings at the site of conduction block in a medial pectoral nerve from the lower trunk of the brachial plexus: subperineurial edema, slight thickening of the perineurium, many extremely thinly myelinated fibers in the center of the nerve fascicle, and small onion-bulb formation. The sural nerve biopsy in 17 reported cases showed mild demyelinating neuropathy with many thinly myelinated nerve fibers as the predominant feature (Color Figure 7.17), even though the sural nerve conduction was normal.30 Miniature onion-bulb formation (identified only by the ultrastructural EM study) was observed in all 11 cases in Corse’s series.35 Endoneurial inflammatory cells were reported in only one case.36 Active demyelination was reported in 3 cases, and regeneration cluster was reported in 4 of 11 cases in Corse’s series.35 In MMN, there have been two reports of autopsy findings.38,39 Adams’ patient had progressive lower motor neuron syndrome over a 6-year period, with motor conduction block in many motor nerves and high anti-GM1 ganglioside antibody titers. Autopsy showed a predominantly proximal motor radiculoneuropathy with multifocal IgG and IgM deposits on nerve fibers associated with loss and central chromatolysis of spinal motor neurons. No inflammatory cells or histological evidence of demyelination was documented. Oh’s patient had progressive motor weakness with exaggerated reflexes over a 5-year period, with motor conduction block but normal anti-GM1 ganglioside titer. Oh’s case is unique in that it is the first autopsied case of MMN with histological documentation of inflammatory demyelinating neuropathy in the motor roots and cranial nerves. Demyelination was clearly documented by the segmental demyelination in the teased nerve fibers and the semithin section. In both cases, there were extensive IgG and IgM deposits in the nerve, supporting an autoimmune mechanism of MMN. Thus, the autopsy findings are almost identical to those in CIDP, suggesting a close relation between the two entities. However, the sural nerve biopsy showed mild demyelinating neuropathy without inflammatory cells.

MULTIFOCAL MOTOR SENSORY DEMYELINATING NEUROPATHY (MMSDN) Multifocal motor sensory demyelinating neuropathy (MMSDN) is characterized by subacute or chronic progression of multifocal motor-sensory neuropathy over months or years, commonly starting in the upper extremities, elevated spinal fluid protein, demyelination in the NCS, and good steroid responsiveness during the progressive stage of the disease. Clinically, the features are almost identical to those of MMN, except for an additional sensory deficit and steroid responsiveness. We believe that this is a distinctly different entity from either CIDP, as generally accepted, or MMN, and it may be an intermediate link between CIDP and MMN. Adams et al. reported 2 patients who had characteristically multiple asymmetrical motor and sensory neuropathy progressing over 9 to 15 years, a mass over the neck area due to prominent inflammatory cells and onion-bulb formations, and steroid responsiveness.39 Bradley et al. reported a patient with a 5-year history of asymmetrical motor and sensory polyneuropathy with a supraclavicular mass (prominent onion-bulb formations and inflammatory cells), multifocal conduction blocks, ©2002 CRC Press LLC

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reduced sensory CNAP, and steroid responsiveness.40 The sural nerve biopsy showed mild mixed axonal degeneration and demyelination without inflammatory cells. Van den Berg-Vos reported prominent infiltration of inflammatory cells in the biopsy from the brachial plexus in one patient, which was identified by an MRI scan.41 The sural nerve biopsy in 30 reported cases showed demyelinating neuropathy as the cardinal feature40-44 (Color Figure 7.18): demyelinating neuropathy was observed in 26 (87%) of 30 cases. Inflammatory cells were present in 6 (21%) of 29 cases (Color Figure 7.19). Onion-bulb formation was not reported. Axonal degeneration was reported in 7 of 13 cases as a secondary change in Oh’s series.44

CHRONIC SENSORY DEMYELINATING NEUROPATHY (CSDN) Chronic sensory demyelinating neuropathy (CSDN), a sensory variant of CIDP, is characterized by subacute or chronic progression of pure sensory neuropathy, high spinal fluid protein in the majority of cases, electrophysiological evidence of demyelination affecting motor as well as sensory nerve fibers, and good response to immunotherapy in the progressive phase.23,45 The sural nerve biopsy showed a definite demyelinating neuropathy (see below). In eight sural nerve biopsies, there were no inflammatory cells or onion-bulb formation. In five cases, a definite decrease in the population of myelinated fibers was noted. Loss of myelin was the most prominent finding in the longitudinal cuts of nerve on the frozen sections. In two cases, a few myelin-digestion chambers were observed, indicating mild axonal degeneration. In three cases, semithin sections showed evidence of demyelination: remyelinated fibers in 3 and demyelination in 1. Teased nerve fiber preparation showed segmental demyelination in 18 to 33% of teased fibers in 4 cases and axonal degeneration in 0 to 4% in 2 cases. The latest analysis in our series showed inflammatory cells in 1 of 20 biopsies and onion-bulb formation in 3 cases (Color Figure 7.20).

CASES OF INFLAMMATORY DEMYELINATING NEUROPATHY CASE 1: ACUTE MOTOR NEUROPATHY WITH AXONAL NEUROPATHY Case Presentation A 56-year-old female with SLE was admitted to a local hospital for progressive difficulty ambulating for 1 week. Several weeks prior to admission, she had a sinus infection and fever, which were treated with Tavist-D. Abnormal neurological examination at the time of admission showed pure motor weakness in the legs and diffuse areflexia. The CSF protein level was 46 mg/dl. The NCS did not show any evidence of peripheral neuropathy upon admission. Because of the SLE diagnosis, she was initially treated with a high dose of Solu-medrol. Her weakness gradually worsened, producing total quadriplegia, bulbar palsy, and facial diplegia. A second NCS a week later showed pure motor polyneuropathy. The CSF protein level was 58 mg/dl. The patient was treated with IVIG but developed respiratory failure and required intubation. She was transferred to UAB for plasma exchange. An NCS performed at the UAB showed severe axonal motor neuronopathy (low CMAP amplitude) with widespread fibrillations and PSW. Sensory nerve conduction was normal except for a low CNAP amplitude in one sural nerve conduction. Case Analysis This patient had a classic history of GBS with antecedent infection, progressive motor weakness, and minimal elevation of CSF protein. Surprisingly, the NCS did not show any evidence of demyelinating neuropathy, but instead showed severe axonal motor neuronopathy with almost normal sensory ©2002 CRC Press LLC

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nerve conduction. The main reason for performing a nerve biopsy was to rule out vasculitic neuropathy in view of the medical history of SLE. Vasculitic neuropathy has been known to mimic GBS.46 Sural Nerve Biopsy Findings No vasculitis was found. The population of myelinated fibers was relatively normal. Frozen sections showed scattered MDC (Color Figure 7.21). Semithin sections showed myelin ovoids (Color Figure 7.22). These findings were diagnostic of axonal neuropathy. There was no histological feature of demyelinating neuropathy. Final Diagnosis AMAN (axonal form of GBS) was the final diagnosis. Treatment and Follow-up One course of plasma exchange was given. Because she showed no improvement, the patient was placed on a ventilator with tracheostomy and fed through PEG. During her 4-month period of hospitalization, she showed a slow but steady improvement to the degree that she could breathe by herself, swallow some food, and move her limbs. Comments The diagnosis of GBS was well established in this patient: acute motor paralysis within 2 days and elevated spinal fluid protein following antecedent infection. The low CMAP and widespread fibrillations and PSW on the first two tests are indicative of axonal neuropathy in electrophysiological terms. Thus, the diagnosis of the axonal form of GBS is well-justified. Clinical features in this case were also similar to those seen among Chinese children with acute motor neuropathy (AMAN), which was considered an axonal form of GBS.47,48 Normal sensory nerve conduction and F-wave and delayed CSF protein elevation are typical of AMAN. Relatively rapid recovery was the rule in AMAN, but in this case, the recovery was slow and protracted. AMAN is also associated with a high frequency of GM1 antibodies and Camphobactor jejuni.49 GBS with serum IgG GM1 antibody was predominantly characterized by motor neuropathy,50,51 axonal neuropathy in the NCS, poor prognosis, and high association of Camphobactor jejuni infection.51 The pathological findings in 7 patients with AMAN studied within 18 days of onset were characterized by Wallerian-like degeneration of variable severity, with only minimal inflammation or demyelination, and the presence of frequent para-axonal and occasional intra-axonal macrophages in the large motor fibers, suggesting macrophage-induced axonal degeneration as the primary pathologic process.52 Acute motor-sensory axonal neuropathy (AMSAN), the motor-sensory type of the axonal form of GBS, was reported. Pathologically, findings similar to those seen in AMAN were observed in the motor and sensory fibers.53 This case is different than the original case of axonal GBS reported by Feasby et al., in which both motor and sensory nerves were electrophysiologically unexcitable early in the illness. It is possible that Feasby et al.’s case may represent the most severe form of axonal GBS.54,55 There are some experts who claim that the axonal form of GBS is really due to the axonal change secondary to severe demyelination.55,56 Berciano et al. reported two cases of axonal GBS with autopsy findings of segmental demyelination, axonal degeneration, widespread endoneurial lipid-laden macrophage infiltrates, remyelination, and clusters of small regenerating fibers in the roots in one case57 and extensive, almost pure, macrophage-associated demyelination with occasional T-lymphocytes in the roots and axonal degeneration with some denuded axons remaining in the distal peripheral nerve in the other.58 They concluded that axonal damage in axonal GBS is secondary to demyelination.57

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CASE 2: RELAPSE OF GBS Case Presentation In November 1983, a 28-year-old male reported low back pain followed by burning paresthesia in the feet and ascending weakness of the legs to the degree that he was not able to walk for a 3-week period. Three weeks prior to the initial onset of low back pain, he had what he thought was a stomach virus. Abnormal findings were facial diplegia, mild weakness in the arms, moderate weakness in the iliopsoas, mild weakness in other leg muscles, and areflexia. His CSF protein level was 486 mg/dl. A diagnosis of GBS was made. He was immediately started on prednisone — 100 mg each day. Over the next 2 weeks, there was a gradual improvement to the degree that he was able to walk with a cane. With gradual tapering of prednisone, the patient had two relapses of GBS in January and April 1984; each time, maximum paralysis occurred within a few days and was worse than before. At the worst relapse, in April, the patient was quadriplegic with diplopia and bulbar paresis. After both relapses, he improved with a high dosage of prednisone and continued on 80 mg of prednisone daily. Examination in August 1984 showed normal muscle strength, areflexia all over, and decreased pinprick sensation in his toes. An NCS revealed marked demyelinating neuropathy with markedly prolonged terminal latencies (36 msec in the median and 58 msec in the peroneal nerves) and markedly slow NCV (20–30 m/sec). Case Analysis This patient had classical GBS: acutely developing predominantly motor weakness, areflexia, high CSF protein, antecedent infection, and rapid recovery. What is atypical in classical GBS is the recurrence of symptoms. In view of this unusual feature, a nerve biopsy was needed to confirm the clinical impression of disease and rule out other relapsing causes of neuropathy: toxic neuropathy due to repeated exposure to toxins and undertreated vasculitic neuropathy. Sural Nerve Biopsy The population of myelinated fibers was minimally decreased. There were prominent perivascular collections of mononuclear inflammatory cells in the epineurial space (Color Figure 7.23), as well as some thinly myelinated fibers, indicating inflammatory demyelinating neuropathy (Color Figure 7.24). Final Diagnosis Recurrent GBS was the final diagnosis. Treatment and Follow-up Over the next 10 years, this patient was kept on a small maintenance dosage of prednisone daily without any major relapse. He had three minor relapses involving numbness of the hands and feet, one following kidney-stone surgery and two after the flu. These relapses were controlled with a temporary increase of his prednisone dose. The last NCS 10 years after the initial GBS still showed a terminal latency of 20 to 25 msec. Comments This patient was treated with prednisone for GBS before a controlled study showed steroids to be ineffective in GBS. Clearly, two relapses of acutely developing neuropathy occurred when the prednisone dose was being tapered downward, and continued prednisone therapy eventually controlled ©2002 CRC Press LLC

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the relapses. Whether the initial relapses in this case were related to prednisone therapy is not clear. Recurrence of GBS is rare, occurring in only 3% of cases, and it can occur either shortly or long after the first episode. In this case, once the diagnosis of recurrent GBS was made, the disease behaved like CIDP,59 especially with regard to steroid responsiveness.60 Grand’Maison et al. differed from this view in that recurrent GBS was found to be distinctively different from CIDP, with rapid onset of symptoms with subsequent complete or near-complete recovery, high incidence of antecedent illness, lack of an apparent response to immunosuppressive therapy, and normal CSF protein levels at the onset of a recurrence.59 The sural nerve findings were somewhat different between recurrent GBS and CIDP: inflammatory cells were present in 57% of cases of recurrent GBS as compared to 27% of cases in CIDP. In this sense, recurrent GBS is similar to classical GBS. In 2 cases, Grand’Maison et al. observed inflammatory cells in 2 cases, onion-bulb formation in one, axonal degeneration in 1, and thinly myelinated fibers in both.59

CASE 3: ACUTELY DEVELOPING “ILEUS” Case Presentation A 9-year-old boy began having headaches, intermittent fever, and lassitude 2 weeks prior to an initial neurological evaluation.61 Three days after the onset of symptoms, an exploratory laparotomy was performed because of progressive severe vomiting and abnormal distention and pain. Nothing was found except for some mesenteric adenitis. Because of persistent postoperative pneumonia, the patient was transferred to UAB one week after surgery. Abnormal findings were corneal ulceration and nonreactive pupils, total loss of pain and temperature sensation over the entire body with preservation of light touch, marked proprioception loss, loss of vibration distally in the extremities, and diffuse areflexia. Motor examination was normal. The patient’s mouth was dry. Lacrimation was absent. There was no spontaneous voiding of urine or bowel. Sweating was patchy and scanty. The CSF protein level was 130 mg/dl. An NCS showed absent sensory CNAP with normal mixed CNAP and motor NCS. Case Analysis This patient developed acute “ileus” 2 weeks after a flu-like episode. The exploratory laparotomy confirmed that this patient had pseudo-obstruction of his gut due to autonomic neuropathy. Examination confirmed autonomic and sensory neuropathy and high CSF protein. The NCS showed sensory neuronopathy, indicative of dorsal root sensory ganglia. Sural Nerve Biopsy No identifiable large or small myelinated fibers were identified in either the modified trichrome stains or semithin sections. Numerous myelin-digestion chambers were present in the longitudinal cut (Color Figure 7.25). Final Diagnosis The final diagnosis was acute autonomic and sensory neuropathy (AASN). Treatment and Follow-up Initially, the patient required central hyperalimentation. In 4 months, a PEG was tolerated. Gradually, dysautonomia disappeared over 18 months, but marked loss of proprioception and pain persisted.

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Comments Autonomic neuropathy may be a feature of acute or chronic peripheral neuropathy. Diabetic and amyloid neuropathies are known to be frequently associated with dysautonomic neuropathy. These were ruled out in this case by the clinical history and by laboratory and biopsy results. Another diagnostic consideration is botulism. An acute dysautonomia may be a striking finding or even the sole feature in this disease. Clinically, the sensory abnormalities in the present case ruled out botulism. Our patient had the classic features of AASN, a variant of GBS. Since our report, there have been several well-documented cases of AASN. Their clinical features are rather typical: acutely developing dysautonomic and sensory neuropathy, high CSF protein, sensory neuronopathy by the NCS, and usually good recovery from dysautonomia but incomplete recovery of sensory abnormalities.62 The major lesion in AASN is present in the dorsal root ganglion neurons, ganglioneuronopathy. The sural nerve biopsy shows severe axonal neuropathy.

CASE 4: SUBACUTE SENSORY-MOTOR NEUROPATHY WITH 13 NEGATIVE BIOPSIES Case Presentation A 40-year-old male with a recent diagnosis of pyoderma gangrenosum, for which he was taking 10 mg of prednisone per day, first noticed mild hearing loss in his left ear 3 months prior to the UAB evaluation. Three or 4 weeks later, he developed numbness and tingling in his feet, soon followed by weakness of the legs and, later, the arms. An extensive evaluation at a famous midwestern clinic showed diffuse pial enhancement but no intramedullary lesions on an MRI of the spinal cord. Biopsies of the stomach, liver, skin, conjunctiva, bone marrow, spinal cord, and pia/arachnoids were negative. Myopathy on the EMG led to a quadriceps muscle biopsy which showed inflammatory myopathy. Abnormal findings from our evaluation (during the 4th month) included decreased hearing in the left ear, mild weakness in the legs (worse distally), decreased pin-prick sensation up to the wrists and mid-thighs, absent vibration on the toes and ankles, decreased vibration in the knees bilaterally, absent position sense in the toes, and absent ankle reflex. The only abnormal laboratory finding was a high CSF protein (201 mg/dl). An NCS showed mild peripheral neuropathy. However, the right sural nerve conduction showed 36.7 m/sec with 2 peaks in the CNAP. Case Analysis Thirteen biopsies did not show any definite etiology for his hearing loss. The patient had hearing loss and subacute sensory-motor peripheral neuropathy. An NCS showed mild axonal neuropathy. The only evidence of demyelination was the presence of two peaks in the sensory CNAP in the sural nerve, a sure indication of demyelination. Clearly, the diffuse pial enhancement in the MRI and high CSF protein indicated polyradiculopathy. CIDP with hearing loss was suspected. Sural Nerve Biopsy The sural nerve biopsy showed inflammatory demyelinating neuropathy: a moderate decrease (30% loss) in the population of myelinated fibers and a few perivascular inflammatory cells in the perineurial and endoneurial spaces (Color Figure 7.26). No obvious thinly myelinated fibers were observed on the semithin section. Teasing of nerve fibers revealed segmental demyelination in 40% of fibers, confirming demyelinating neuropathy (Color Figure 7.27). Final Diagnosis CIDP with the VIIIth cranial nerve involvement was the final diagnosis.

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Treatment and Follow-up The patient was treated with IVIG and prednisone with definite improvement in neuropathy but minimal improvement in hearing. Shortly thereafter, he developed cryptococcal meningitis, which led to discontinuation of prednisone. He experienced a relapse of neuropathy, which was finally controlled with cyclosporin. The patient needed a cochlear implant to restore some hearing. Comments This patient fulfilled the criteria for the diagnosis of CIDP: monophasic progressive sensorimotor neuropathy over 6 months, elevated CSF protein, demyelinating nerve conduction, and inflammatory demyelination upon nerve biopsy. Although CIDP has been associated with a variety of cranial nerve abnormalities including diplopia, ptosis, facial numbness, jaw weakness, facial weakness, bulbar weakness, and tongue weakness in a few cases, the VIIIth cranial nerve involvement is extremely rare. This is in contrast to GBS, in which the VIIth cranial nerve is commonly involved. As far as the VIIIth cranial nerve is concerned, there was 1 reported case of vestibular dysfunction in CIDP and IgG kappa monoclonal gammopathy in which a striking synchronization between CIDP and vestibulopathy was well-documented over a 6-year period.63 Thus, our case is unique. It is possible that the VIIIth nerve involvement in CIDP is rare because of its peculiarity of myelin: it has central myelin for the majority of its length, except for a short distal segment which has peripheral myelin.

CASE 5: DIFFUSE AREFLEXIA IN AN MS PATIENT Case Presentation A 42-year-old man experienced progressive weakness of the right lower extremity for 6 months.64 Over a 10-year period, he experienced 3 episodes of weakness and numbness of the right lower extremity, each lasting a few weeks. Family medical history was not significant. Abnormal neurological findings were euphoria, bilateral optic pallor, bilateral internuclear ophthalmoplegia, mild weakness in the right upper and lower extremities and in the left lower leg, Babinski sign, areflexia, decreased position sense in the toes of the right foot, mild intention tremor in the finger-to-nose test on the right, and absent superficial abdominal reflexes. Spinal fluid showed high protein of 162 mg/dl, of which 12.5% was gamma globulin. Myelogram up to the foramen magnum was normal. The patient was treated with a 10-day course of ACTH (80 U daily), after which complete remission of symptoms occurred. He had another relapse of weakness which again responded well to another course of ACTH treatment. Case Analysis This patient had the classic history and findings of multiple sclerosis (MS) which responded to ACTH treatment. In MS, it is extremely unusual to have diffuse areflexia. In an effort to explain the areflexia, an NCS was ordered. This test showed severe demyelinating neuropathy with markedly prolonged terminal latency 2 to 4 times the normal, NCV < 50% of the normal mean, and dispersion phenomenon. This raised a question as to whether this patient had leukodystrophy with peripheral neuropathy or CIDP with MS. Sural Nerve Biopsy A characteristic onion-bulb formation was observed (Color Figure 7.28). There was a moderate decrease in the population of myelinated fibers. Almost all the teased nerve fibers revealed segmental demyelination. Onion-bulb formation secondary to a proliferation of Schwann cell processes was confirmed by an electron microscopy study (Figure 7.1). There was no metachromatic substance. ©2002 CRC Press LLC

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FIGURE 7.1 Onion-bulb formation. Two Schwann cell nuclei and numerous processes surround the myelin membrane with minimal alterations and an intact axon. Bar, 1 µm. Electronmicrograph.

Treatment and Follow-up Over the next several years, the patient had a classic pattern of relapse and remission which responded to ACTH treatment, but with gradual neurological deterioration. Comments There are two diseases characterized by relapsing and remitting CNS symptoms and hypertrophic neuropathy: Refsum’s disease and metachromatic leukodystrophy. Metachromatic leukodystrophy was ruled out by the absence of metachromatic substance in the sural nerve, and Refsum’s disease was ruled out by the normal serum phytanic acid level. We believed this patient had MS and CIDP. Rubin et al.65 reported two patients with a combination of MS and demyelinating neuropathy, and five such cases were found in the literature. Out of four biopsied nerves, onion-bulb formation was reported in three. Lassen et al. reported a case of acute MS without any clinical features of peripheral neuropathy but with autopsy findings of widespread demyelination and inflammatory cells in the nerve root.66 Multifocal demyelinating neuropathy has also shown CNS demyelination. No onionbulb formation was found.67 Schoene et al., in a postmortem examination of four cases, observed onion-bulb formation in the nerve roots, proximal peripheral nerves, and some cranial nerves.68 An MRI scan of the brain in 16 patients with CIDP revealed periventricular and brain stem MS-like lesions in 6 cases (38%).69 Three of these had definite clinical and laboratory evidence of MS. There is no question that MS and CIDP can occur together in a few patients. Most likely, this is due to the

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common cross-antigen which produces the demyelinating process in the peripheral and central nervous systems. This conclusion is supported by observation in relapsing experimental allergic encephalomyelitis in which a characteristic demyelinating neuropathy was well documented after repeated clinical relapses.70

CASE 6: SUBACUTE SENSORY-MOTOR WEAKNESS AFTER A FLU VACCINE Case Presentation Four days after receiving a flu-shot, a 56-year-old female developed tingling, numbness, and pain in her feet. Over the next 21/2 month period, these sensory symptoms spread to her thighs, and weakness of the legs developed. For the following 2 weeks prior to examination, numbness and weakness had been noted in her arms and she had mild swallowing difficulty. She was not able to ambulate. Abnormal findings were mild weakness in the proximal arm and distal leg muscles, moderate weakness in the distal arm and proximal leg muscles, pin-prick loss up to the mid-thighs, vibration loss in the knees, position sense loss in the toes, and diffuse areflexia. Abnormal laboratory findings were high CSF protein (86 mg/dl) and ESR (55 mm/hr). All other laboratory work-ups for neuropathy were normal. Her pain was controlled with narcotics. An NCS/EMG showed no evidence of demyelination but did show severe axonal motor-sensory neuropathy with lumbar polyradiculopathy. Case Analysis The patient’s history, abnormal neurological findings, and high CSF protein were typical of CIDP. Thus, we expected the NCS to confirm a demyelinating neuropathy. However, it showed severe axonal neuropathy with polyradiculopathy. In view of the high ESR, vasculitis should be ruled out by the nerve biopsy. Sural Nerve Biopsy A moderate decrease in the population of myelinated fibers was noted. There were no inflammatory cells or vasculitic changes. Modified trichrome staining showed many myelin-digestion chambers (Color Figure 7.29). Semithin sections revealed myelin ovoids, clusters of tiny nerve fibers, and many macrophages (Color Figure 7.30). These changes are indicative of active axonal degeneration. Treatment and Follow-up The patient was treated with IVIG and high-dose prednisone with initial improvement. She later had a severe relapse of neuropathy which eventually responded to plasma exchange twice a year. The patient was on azathioprine and 20 mg of prednisone as a maintenance dose. Comments In the past 5 years, there have been a few reports describing the axonal form of CIDP. Clinical features of these patients are similar to those of CIDP except for the lack of demyelination in the NCS and nerve biopsy. Chroni et al.71 reported a patient with chronic relapsing axonal neuropathy with a 3-year history of sensory-motor neuropathy, normal CSF protein, axonal neuropathy by the NCS, and good response to steroids and azathioprine. A sural nerve biopsy showed mild axonal neuropathy. Uncini et al. reported five cases of chronic progressive motor polyneuropathy, high CSF protein in four cases, axonal neuropathy by the NCS, and good response to steroids. Sural nerve conduction was normal in all cases, and sural nerve biopsy was normal in one case. Thus, the diagnosis of an axonal form of CIDP was based on the nerve conduction data. Morino reported another case of chronic relapsing

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axonal neuropathy with a high CSF protein and response to steroids.72 Oh73 reported seven cases of chronic neuropathy that clinically mimicked CIDP. CSF protein was elevated in all seven cases. EMG studies revealed axonal neuropathy in all seven cases and polyradiculopathy in six cases. The sural nerve biopsy showed axonal neuropathy in five cases, inflammatory cells in one case, and axonal loss in one. Unlike the axonal form of GBS, all cases responded well to immunotherapy. The main question was whether the disease was completely due to primary axonal degeneration or secondary to the primary demyelinating process at the roots. This has not been completely resolved pathologically.

CASE 7: UNIFORM SLOWING IN THE NERVE CONDUCTION STUDY Case Presentation A 34-year-old female had experienced numbness circumferentially in her lower leg from the knee down for 4 months when she began to notice weakness in her feet. Family history was negative. She had never been able to walk on her heels, even as a child. Abnormal neurological findings were mild weakness and atrophy of the hand intrinsic muscles, 4 MRC strength in the anterior tibialis muscles, diminished pin-prick sensation below the ankles, absent vibratory and position sense on the toes, absent reflexes, and pes cavus. The patient’s CSF protein level was 28 mg/dl. An NCS showed demyelinating neuropathy with uniform slowing of motor NCV (16–12 m/sec in the forearm and 23–18 m/sec in the upper arm in the median and ulnar nerves, respectively). No conduction block or temporal dispersion was noted. Case Analysis Pes cavus, an inability to walk on the heels since childhood, normal CSF protein, and uniform slowing of the NCS were all strongly indicative of hereditary motor sensory neuropathy (HMSN). Uniform slowing in the NCS is considered typical of hereditary demyelinating neuropathy. The 4-month history of numbness and weakness would be unusual for HMSN. It was hoped that the nerve biopsy would show inflammatory cells, which are definite evidence of CIDP. Sural Nerve Biopsy Moderate loss of myelinated fibers was noted (Color Figure 7.31). Many onion-bulb formations were noted. There were a few perivascular inflammatory cells in the epineurial space. Special cell marker staining identified only a few T-cells but many B-cells (Color Figure 7.32). Thus, the diagnosis of inflammatory demyelinating neuropathy was made. Final Diagnosis The final diagnosis was CIDP with inflammatory hypertrophic neuropathy. Treatment and Follow-up A blood test for CMT 1A (duplication of PMP 22) was negative. This patient was treated with IVIG and azathioprine. We preferred azathioprine over steroids because of the patient’s obesity. She improved gradually over a few months. Comments The distinction between CIDP and HMSN can be challenging. In the NCS, the classic pattern of CIDP is non-uniform slowing with frequent conduction block and dispersion phenomenon. Blood tests are helpful in diagnosing some cases of HMSN: duplication of PMP 20 for CMT 1A, connexin

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32 for sex-linked CMT, and deletion of PMP 22 for HNPP. In CIDP, a few cases have been known to have hypertrophic neuropathy without any inflammatory cells. In our series, there were 7 cases of hypertrophic neuropathy among 110 patients who had sural nerve biopsy. We reported 3 cases of CIDP with uniform nerve conduction slowing, hypertrophic neuropathy, and negative blood tests. Inflammatory cells in the nerve biopsy in the first case, an increased IgG synthesis and oliogoclonal bands in the CSF in the second case, and monoclonal gammopathy in the blood test in the third case were critical indicators for CIDP. On histological grounds alone, the distinction between CIDP and HMSN is not easy. Midroni26 listed histological features that favor CIDP over HMSN: (1) non-uniform involvement within and between fascicles, (2) macrophage-mediated myelin-stripping, (3) perivascular lymphocytes, especially in endoneurium, (4) signs of active demyelination (less reliable in children) including numerous naked axons, scattered endoneurial macrophages, and Schwann cell mitosis, and (5) a bimodal myelin fiber-diameter histogram. King74 maintained that the varying size of onion-bulb formations favors the diagnosis of CIDP. In our case, the immunohistological study of cells was crucial in distinguishing CIDP from HMSN.

CASE 8: CHRONIC MOTOR WEAKNESS WITH FASCICULATION AND HYPERREFLEXIA Case Presentation A 68-year-old male had painful muscle cramps in his left arm with weakness of his left hand 5 years before the initial evaluation.38 Muscle cramps soon spread to his entire body. Gradually, weakness was noted in his left leg, right leg, and left hand, in that order. For 6 months, there was rapid deterioration of his condition with weight loss, muscle cramps, and twitching, walking difficulty, and a bad taste in his mouth. Abnormal neurological findings were atrophy of the hand and lower leg muscles, mild weakness and fasciculations in the thighs and shoulder girdle muscles, decreased vibration in the toes, brisk reflexes, weakness of the left wrist flexor, and asymmetrical weakness in the leg muscles, worse on the right and distally. An NCS showed demyelinating neuropathy with conduction block in peroneal and posterior tibial nerves and absent sensory CNAP in all sensory nerves. CSF protein levels were not examined. GM1 and MAG autoantibodies were negative. Case Analysis This patient was referred to UAB with an initial diagnosis of ALS because of widespread fasciculations, pure motor weakness, and brisk reflexes. Certainly, the history and neurological findings were typical of ALS. Decreased vibration in the toes was thought to be age-related. However, the NCS showed more than motor neuronopathy, a typical finding in ALS. It showed, instead, demyelinating neuropathy with conduction block and absent sensory CNAP. In ALS, sensory CNAP is classically normal. Sural Nerve Biopsy A minimal decrease in the population of myelinated fibers and the presence of many thinly myelinated fibers, indicative of demyelination, were noted. Final Diagnosis Multifocal motor neuropathy was the final diagnosis. Treatment and Follow-up The patient was treated with a high dose of prednisone with some improvement in muscle twitching and cramps. He suffered sudden respiratory failure during the night and died. An autopsy revealed an ©2002 CRC Press LLC

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FIGURE 7.2 Teased nerve fibers in the ventral roots of lumbosacral nerves. A and B represent segmental demyelination, and C and D represent paranodal widening between the arrows. Osmium tetroxide, (100 × magnification.) (Reprinted with permission from Neurology, 45, 1829, 1995.)

inflammatory demyelinating polyradiculoneuropathy in the motor cranial nerves and motor roots of peripheral nerves (Color Figure 7.33 and Figure 7.2). Comments MMN can mimic ALS because of hyperreflexia, fasciculation, and pure motor weakness, as suspected initially in this case. However, there are distinct differences between MMN and ALS: demyelinating neuropathy exists in MMN and motor neuronopathy exists in ALS. Prior to this report, there was one report of autopsy findings in MMN.37 That patient had a progressive lower motor neuron syndrome over a 6-year period with motor conduction block in many motor nerves and high antiGM1 autoantibody titers. An autopsy showed predominantly proximal motor radiculoneuropathy with multifocal IgG and IgM deposits on the nerve fibers, associated with a loss and central chromatolysis of spinal motor neurons. There were no inflammatory cells or histological evidence of demyelination. Our case is unique, with histological documentation of inflammatory demyelinating neuropathy in the motor roots and cranial nerves. Thus, autopsy findings in our case are almost identical to those in CIDP, suggesting a close relationship between the two entities. Our case is negative for GM1 antibody. GM1 antibody is not sine qua non for the diagnosis of MMN, as discussed above.

CASE 9: FLAIL ARMS FOR 3 YEARS Case Presentation A 45-year-old female experienced cramping in her hands 3 years prior to examination. This was soon followed by progressive weakness and wasting of the proximal muscles of the arms, which had progressed distally over the previous 3 years. In the 1 year prior to examination, the patient had difficulty with leg weakness, particularly in going up hills and climbing stairs. She complained of cramping in her legs, which improved with rest, but she denied any speech or swallowing difficulty.

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Abnormal findings were classical flaccid “flail arms” with marked wasting and weakness of the entire musculature of the arms and hands, mild weakness in the iliopsoas muscles, absent triceps and biceps reflexes, 3+ knee jerks, and 2+ ankle jerks. Fasciculations were sought but not detected. The EMG/NCS showed widespread fibrillation and PSW in three limbs with some HALD MUPs, prolonged terminal latency, mildly slow motor NCV, and absent F-waves in the motor NCS and normal sensory NCS. Her creatinephosphokinase (CPK) was elevated at 488 units. Case Analysis The referring neurologist suspected an inflammatory myopathy on the basis of elevated CPK, fibrillations, and PSW. Flail arms are supposed to be pathognomomic of ALS. Brisk knee reflexes and needle EMG findings are typical of ALS, and mild CPK elevation is also common in ALS. Thus, the initial diagnostic impression was ALS. One atypical finding was the absence of any fasciculations. The motor NCS was not typical of motor neuronopathy seen in ALS, but suggested a distal demyelinating neuropathy. Sural Nerve Biopsy A muscle biopsy showed a combination of denervation and inflammatory myopathy (Color Figure 7.34). A sural nerve biopsy 3 years later revealed a minimal decrease in the population of myelinated fibers, the presence of many thinly myelinated fibers, and perivascular collections of inflammatory cells in the epineurial space (Color Figure 7.35). Treatment and Follow-up The patient was treated with prednisone and IVIG for two years. At the beginning, she showed a mild but definite improvement in muscle strength, and the disease progression was arrested. After the second year, there was a gradual worsening of motor functions involving the legs. Finally, she began to notice breathing difficulty. An NCS 3 years after the initial visit showed mild slowing in the sural nerve for the first time, although no sensory symptom was observed. Comments This patient represents a case of MMN without conduction block. It taught us that the classical flail arm syndrome does not always necessarily represent ALS. Inflammatory demyelinating neuropathy was finally confirmed by the sural nerve biopsy 3 years later. Another significant finding in this case is the presence of inflammatory cells in the muscle biopsy. This may suggest that the inflammatory process in CIDP basically represents a systemic autoimmune inflammatory disease. We now have three such cases. A diagnosis of polymyositis was made by a famous midwestern clinic on the basis of needle EMG and muscle biopsy in one such case (Case 4). That patient turned out to have CIDP with VIIIth cranial nerve involvement. When treated with immunotherapies, he had complete remission except for a residual hearing loss.

CASE 10: MMN WITH SENSORY DEFICITS Case Presentation A 36-year-old male began to notice tingling numbness over his right forearm 6 months before his initial examination, followed by a tingling sensation in his left arm below the elbow and gradual onset of weakness in both arms. For 1 month, he also noticed tingling sensations on the bottom of his right foot, and then his left foot, and weakness of his right leg. Abnormal neurological findings were moderate atrophy in the right and left forearm flexor surfaces; fasciculations in the intrinsic hand muscles; ©2002 CRC Press LLC

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asymmetrical weakness in the right arm, left forearm, right lower leg, and left anterior tibialis muscles; decreased pin-prick sensation in both hands and feet; markedly decreased vibration in the toes and ankles; absent position sense in the fingers and on the left great toe; absent ankle and knee reflexes at the ankles; and decreased reflexes in the triceps and biceps. Abnormal laboratory findings were normal CSF protein and mildly elevated GM1 and asialo-GM1 autoantibody. An NCS showed demyelinating neuropathy with conduction block in median, ulnar, peroneal, and posterior tibial nerves. Sensory and mixed CNAPs were absent in ulnar and median nerves. Case Analysis This patient had subacute multifocal sensory motor neuropathy with initial sensory complaints in the arm. CSF protein was normal, but GM1 autoantibody levels were elevated. Thus, except for the sensory component, this case had all the typical findings of MMN. Clinically, this patient had MMSDN. Sural Nerve Biopsy There was a small perivascular collection of inflammatory cells in the epineurial space (Color Figure 7.36) in the paraffin section. No endoneurial cells were found. Semithin sections showed many thinly myelinated fibers and a few denuded axons, indicating demyelinating neuropathy (Color Figure 7.37). Final Diagnosis The final diagnosis was multifocal motor sensory demyelinating neuropathy (MMSDN). Treatment and Follow-up With high daily prednisone treatment, the patient returned to normal within four months and maintained his normal status with less prednisone. He has had one relapse of mild weakness of the hip flexors, which was again controlled with prednisone. Since then, the patient has been symptom-free with low-dose prednisone. Comments This patient represents a case of MMSDN experiencing good recovery with steroid treatment. As discussed above, the features of MMSDN are almost identical to MMN, except for an additional sensory deficit and steroid responsiveness. In MMSDN, GM1 antibody is rarely positive and spinal fluid protein is more often elevated as compared with MMN. All 5 cases in Lewis’s paper,75 which has often been quoted as the first paper on MMN, showed sensory symptoms and findings. Thus, this condition is sometimes called Lewis–Sumner syndrome.

CASE 11: PAINFUL SENSORY NEUROPATHY FOR 5 YEARS Case Presentation A 58-year-old female with a 12-year history of Crohn’s disease and a permanent ileostomy for 3 years developed burning pain in her feet 5 years prior to our evaluation, while taking metronidazole for Crohn’s disease. Metronidazole was discontinued, but the pain and numbness in her feet persisted and gradually worsened, eventually involving her legs up to the knees. Abnormal neurological findings were 1+ reflex in the ankles, decreased pin-prick sensation below the mid-calf level, decreased vibration at the knees, absent vibration in the ankles and toes, and position loss in the toes. Muscle strength was normal. All laboratory studies were normal, including a spinal fluid protein of 19 mg/dl. A needle EMG showed acute and chronic denervation in the intrinsic foot muscles. Abnormal NCS ©2002 CRC Press LLC

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findings were a low CMAP amplitude and abnormal temporal dispersion in peroneal and posterior tibial nerves and absent superficial peroneal CNAP. Marked slowing to the degree of demyelination was demonstrated by the near-nerve needle sensory NCS of the plantar nerve. Case Analysis At first, the history suggested metronidazole-induced sensory neuropathy. However, the sensory neuropathy persisted even with discontinuation of medication. Clearly, the NCS was the pivotal clue indicative of demyelinating neuropathy and suggested the definite possibility of chronic sensory demyelinating neuropathy (CSDN). Sural Nerve Biopsy The sural nerve biopsy showed moderate reduction in the population of myelinated fibers, many thinly myelinated fibers, a few denuded axons, and a macrophage (Color Figure 7.38). Final Diagnosis The final diagnosis was chronic sensory demyelinating neuropathy. Treatment and Follow-up With IVIG treatment and low-dose prednisone, this patient’s painful sensory neuropathy was well controlled. Comments Chronic painful sensory neuropathy in the elderly is usually unknown in etiology and benign in course. This neuropathy is the most common type of neuropathy in many neuromuscular disease centers and has been a therapeutic challenge to clinicians because of the lack of an effective regimen for often unbearable pain.76 Thus, it is imperative to find any treatable cause in chronic painful sensory neuropathy. CSDN is the most common treatable form of chronic sensory neuropathy in our clinic. CSDN is usually strongly suggested by the definite demonstration of demyelination in the motor as well as sensory nerve conduction study. Sural nerve biopsy confirms the demyelinating neuropathy. CSDN responds to immunotherapy, including IVIG treatment, during the progressive phase of disease.77 Gorson and Ropper treated seven patients with idiopathic distal small fiber neuropathy with IVIG and reported that 3 had near-complete resolution of their burning pain with one course of IVIG infusion, and one had partial improvement.117 The rationale for IVIG treatment in these patients is not clear. None of the patients had any electrophysiological evidence of demyelinating neuropathy or high spinal-fluid protein.

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Prineas, J.W,. Pathology of the Guillain–Barré syndrome, Ann. Neurol., Suppl. 9, 6, 1981. Asbury, A.K., Arnason, B.G., and Adams, R.D., The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis, Medicine, 48, 173, 1969. Arnason, B.G., Acute inflammatory demyelinating polyradiculoneuropathies, in Peripheral Neuropathy, Vol. 2, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 2050. Dyck, P.J., Lais, A.C., Ohtya, M., Bastron, J.A., Okazaki, H., and Groover, R.V., Chronic inflammatory polyradiculoneuropathy, Mayo Clin. Proc., 50, 621, 1975.

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Dyck, P.J. and Arnason, B., Chronic inflammatory demyelinating polyradiculoneuropathy, in Peripheral Neuropathy, Vol. 2, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 2101. Pollard, J.D., King, R.H.M., and Thomas, P.K., Recurrent experimental allergic neuritis. An electron microscope study, J. Neurol. Sci., 24, 365, 1975. Prineas, J.W., Acute idiopathic polyneuritis. An electron microscope study, Lab. Invest., 26, 133, 1972. Lampert, P.W., Mechanism of demyelination in experimental allergic neuritis. Electron microscopic studies, Lab. Invest., 20, 127, 1969. Krucke, W., Die primar-entzundliche Polyneuritis unbekannter Ursache, in Handbuch des Speziellens Pathologishen Anatomie und Histologie, Vol 13, Erkrankungen der Peripheren Nerven, Lubarsch, O., Henke, F.J. and Rossle, G., Eds., Springer-Verlag, Berlin, 1955, 164. Prineas, J.W. and McLeod, J.G., Chronic relapsing polyneuritis, J. Neurol. Sci., 27, 427, 1976. Asbury, A.K., Arnason, B.G., Karp, H.R., and McFarlin, D.F., Criteria for diagnosis of Guillain–Barré syndrome, Ann. Neurol., 3, 565, 1978. Oh, S.J., Subacute demyelinating polyneuropathy responding to corticosteroid treatment, Arch. Neurol., 35, 509, 1978. Oh, S.J., Clinical Electromyography. Nerve Conduction Studies. Williams & Wilkins, Baltimore, MD, 1993. Haymaker, W. and Kernohan, J.W., The Landry–Guillain–Barré syndrome. A clinicopathologic report of fifty fatal cases and a critique of the literature, Medicine, 28, 59, 1949. Hughes, R., Atkinson, P., Coates, P., Hall, S., and Leibowitz, S., Sural nerve biopsies in Guillain-Barré syndrome: axonal degeneration and macrophage-associated demyelination and absence of cytomegalovirus genome, Muscle and Nerve, 15, 568, 1992. Brechenmachyer, C., et al., Guillain–Barré syndrome: an ultrastructural study of peripheral nerve in 65 patients, Clin. Neuropathol., 6, 19, 1987. Suarez, G.A., Fealety, R.D., Camillerit, M., and Low, P.A., Idiopathic autonomic neuropathy: clinical, neurophysiolgic, and follow-up studies on 27 patients., Neurology, 44, 1675, 1994. Low, P.A., Dyck, P.J., Lambert, E.H., Brimijoin, W.S., Trauytmann, J.C., Lalagelada, J.R., Fealey, R.D., and Barrett, D.M., Acute panautonomic neuropathy, Ann. Neurol., 13, 412, 1983. Colan, R.V., Snead, C., Oh, S.J., and Kashlan, B., Acute autonomic and sensory neuropathy, Ann. Neurol., 8, 441, 1980. Stoll, G., Thomas, C., Reiners, K., Schober, R., and Hartung, H.P., Encephalo-myelo-radiculo-ganglionitis presenting as pandysautonomia, Neurology, 41, 723, 1991. Phillips, M.S., Stewart, S., and Anderson, J.R., Neuropathological findings in Miller–Fisher syndrome, J. Neurol. Neurosurg. Psychiatry, 47, 492, 1984. Kaplan, J.G., Schaumburg, H.H., and Sumner, A., Relapsing ophthalmoparesis-sensory neuropathy syndrome, Neurology, 35(4), 595, 1985. Oh, S.J., Joy, J.L., and Kuruoglu, R., Chronic sensory demyelinating neuropathy: chronic inflammatory demyelinating polyneuropathy as a pure sensory neuropathy, J. Neurol. Neurosurg. Psychiatry, 55, 677, 1992. Sternman, A.B., Schaumbauer, H.H., and Asbury, A.K., The acute sensory neuropathy syndrome: a distinct clinical entity, Ann. Neurol., 7, 354, 1980. Austin, J.H., Recurrent polyneuropathies and their corticosteroid treatment. With five-year observations of a placebo-controlled case treated with with corticotrophin, cortisone, and prednisone, Brain, 81, 157, 1958. Midroni, G. and Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, MA, 1995. Molenaar, D.S., Vermeulen, M., and de Haan, R., Diagnostic value of sural nerve biopsy in chronic inflammatory demyelinating polyneuropathy, J. Neurol. Neurosurg. Psychiatry, 64, 84, 1998. Barohn, R. J. et al., Chronic inflammatory demyelininating polyradiculoneuropathy, Arch. Neurol., 46, 878, 1989. Small, G.A. and Lovelace, R.E., Chronic inflammatory demyelinating polyneuropathy, Semin. Neurol., 13, 303, 1994. Parry, G. and Clarks, S., Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease, Muscle and Nerve, 11, 103, 1988.

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31. Sumner, A.J., Separating motor neuron diseases from pure motor neuropathies, Adv. Neurol., 56, 399, 1991. 32. Pestronk, A., Motor neuropathies, motor neuron disorders, and antiglycolipid antibodies, Muscle and Nerve, 14, 927, 1991. 33. Auer, R., Bell, R., and Lee, M., Neuropathy with onion bulb formations and pure motor manifestation, Can. J. Neurol. Sci., 24, 194, 1989. 34. Kaji, R. et al., Pathological findings at the site of conduction block in multifocal motor neuropathy, Ann. Neurol., 33, 152, 1993. 35. Corse, A.M., Chaudhry, V., Crawford, T.O., Cornblath, D.R., Kuncl, R.W., and Griffin, J.W., Sensory nerve pathology in multifocal motor neuropathy, Ann. Neurol., 39(3), 319, 1996. 36. Krarup, C., Stewart, J., Sumner, A., Pestronk, A., and Lipton, S., A syndrome of asymmetric limb weakness with motor conduction block, Neurology, 40, 118, 1990. 37. Adams, D., Kuntzer, T., Steck, A., Lobrinum, A., Janzer, R., and Regli, F., Motor conduction block and high titers of anti GM1 ganglioside antibodies: pathological evidence of a motor neuropathy in a patient with lower motor neuron syndrome, J. Neurol. Neurosurg. Psychiatry, 56, 982, 1993. 38. Oh, S.J., Claussen, G.C., Odabasi, Z., and Palmer, C.P., Multifocal demyelinating motor neuropathy: pathologic evidence of inflammatory demyelinating polyradiculoneuropathy, Neurology, 45(10), 1828, 1995. 39. Adams, R.D., Asbury, A.K., and Michelsen, J.J., Multifocal pseudohypertrophic neuropathy, Trans. Am. Neurological Assoc., 9, 30, 1965. 40. Bradley, W., Bennett, R., Good, P., and Little, B., Proximal chronic inflammatory neuropathy with multifocal conduction block, Arch. Neurol., 45, 451, 1988. 41. Van den Berg-Vos, R. M. et al., Multifocal inflammatory demyelinating neuropathy, Neurology, 54, 26, 2000. 42. Lewis, R.A., Sumner, A.J., Brown, M.J., and Asbury, A.K., Multifocal demyelinating neuropathy with persistent conduction block, Neurology, 32, 958, 1982. 43. Saperstein, D. S. et al., Multifocal acquired demyelinating sensory and motor neuropathy: the Lewis–Sumner syndrome, Muscle and Nerve, 22(5), 560, 1999. 44. Oh, S.J., Claussen, G.C., and Kim, D.S., Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy?, JPNS, 2, 362, 1997. 45. Oh, S.J., Joy, J.L., Sunwoo, I., and Kuruoglu, R., A case of chronic sensory demyelinating neuropathy responding to immunotherapies, Muscle and Nerve, 15, 255, 1992. 46. Suggs, S.P., Thomas, T.D., Joy, J.L., Lopez-Mendez, A., and Oh, S.J., Vasculitic neuropathy mimicking Guillain–Barré syndrome, Arth. Rheum., 35, 975, 1992. 47. McKhann, G.M., Cornblath, D.R., and Griffin, J.W., Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China, Ann. Neurol., 33, 333, 1993. 48. McKhann G.M. et al., Clinical and electrophysiological aspects of acute paralytic disease of children and young adults in northern China, Lancet, 338, 593, 1991. 49. Ho, T.W. et al., Guillain–Barré syndrome in northern China: relationship to Camphobacter jejuni infection and anti-glycolipid antibodies, Brain, 118, 597, 1995. 50. Nobile-Orazio, E. et al., Guillain–Barré syndrome associated with high titers of anti-GM1 antibodies, J. Neurol. Sci., 109, 1992. 51. Visser, L.H. et al., Guillain–Barré syndrome without sensory loss (acute motor neuropathy). A subgroup with specific clinical, electrodiagnostic and laboratory features. Dutch Guillain–Barré study group, Brain, 118(Pt. 4), 841, 1995. 52. Griffin, J.W. et al., Guillain–Barré syndrome in northern China: the spectrum of neuropathologic changes in clinically defined cases, Brain, 118, 577, 1995. 53. Griffin, J.W., Li, C.Y., Ho, T.W., Tian, M., Gao, C.Y., Xue, P., Mishu, B., Cornblath, D.R., Macko, C., McKahann, G.M., and Asbury, A.K., Pathology of the motor-sensory axonal Guillain–Barré syndrome, Ann. Neurol., 39, 17, 1996. 54. Feasby, T.E., Gilbert, J.J., Brown, W.F., Bolton, C.F., and Hahn, A.F., An acute axonal form of Guillain–Barré polyneuropathy, Brain, 109, 1115, 1986. 55. Feasby, T.E., Hahn, A.F., Brown, W.F., Bolton, C.F., Gilbert, J.J., and Koopman, W.J., Severe axonal degeneration in acute Guillain–Barré syndrome: evidence of two different mechanisms?, J. Neurol. Sci., 116, 185, 1993.

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56. Triggs, W.J. et al., Motor nerve inexcitability in Guillain–Barré syndrome: the spectrum of distal conduction block and axonal degeneration, Brain, 115, 1291, 1992. 57. Berciano, J., Coria, F., Monton, F., Calleja, J., Figols, J., and Lafarga, M., Axonal form of Guillain–Barré syndrome: evidence for macropahge-associated demyelination, Muscle and Nerve, 16, 744, 1993. 58. Berciano, J. et al., Fulminant Guillain–Barré syndrome with universal inexcitability of peripheral nerves: a clinicopathological study, Muscle and Nerve, 20, 846, 1997. 59. Grand’Maison, F., Feasby, T.E., Hahn, A.F., and Koopman, W.J., Recurrent Guillain–Barré syndrome. Clinical and laboratory features, Brain, 115, 1093, 1992. 60. Thomas, P., Lscelles, R., Hallpike, J., and Hower, R., Recurrent and chronic replasing Guillain–Barré polyenuritis, Brain, 92, 589, 1969. 61. Colan, R.V., Snead, C., Oh, S.J. and Kashlan, B., Acute atuonomic and sensory neuropathy, Ann. Neurol. 8, 441, 1980. 62. Yasuda, T. et al., Clinico-pathological features of acute autonomic and sensory neuropathy: a long-term follow-up, J. Neurol., 242, 623, 1995. 63. Frohyman, E.M., Rusa, R., Mark, A.S., and Cornblath, D.R., Vestibular dysfunction in chronic inflammatory demyelinating polyneuropathy, Ann. Neurol. 39, 529, 1996. 64. Ro, Y.I., Alexander, B., and Oh, S.J., Multiple sclerosis and hypertrophic demyelinating peripheral neuropathy, Muscle and Nerve, 6, 312, 1983. 65. Rubin, M., Karpati, G., and Carpenter, S., Combined central and peripheral neuropathy, Neurology, 37, 1287, 1987. 66. Lassmann, H., Budka, H., and Schnaberth, G., Inflammatory demyelinating polyradiculitis in a patient with multiple sclerosis, Arch. Neurol., 38, 99, 1981. 67. Naganuma, M., Shima, K., Matsumotor, A., and Tashiro, K., Chronic multifocal demyelinating neuropathy associated with central nervous system demyelination, Muscle and Nerve, 14, 953, 1991. 68. Schoene, W.C., Carpenter, S., Behan, B.O., and Geschwind, N., Onion bulb formations in the central and peripheral nervous system in association with multiple sclerosis and hypertrophic polyneuropathy, Brain, 100, 755, 1977. 69. Mendell, J.R., Kolkin, S., Kissel, J.T., Weiss, K.L., Chakeres, D.W., and Rammohan, K.W., Evidence for central nervous sytem demyelination in chronic inflammatory demyelinating polyradiculoneuropathy, Neurology, 37, 1291, 1987. 70. Madrid, R.E. and Wisniewski, H.M., Peripheral nervous system pathology in relapsing experimental allergic encephalomyelitis, J. Neurocytol., 7, 265, 1978. 71. Chroni, E., Hall, S.M., and Hughes, R.A.C., Chronic relapsing axonal neuropathy: a first case report, Ann. Neurol., 37, 112, 1995. 72. Morino, S. and Antonini, G., Another case of chornic relapsing axonal neuropathy, Muscle and Nerve, 19, 533, 1996. 73. Oh, S.J. and Claussen, C.C., Is there chronic immune-mediated axonal polyneuropathy?, Ann. Neurol., 40, 544, 1996. 74. King, R., Atlas of Peripheral Nerve Biopsy, Arnold, London, 1999. 75. Lewis, R.A., Sumner, A.J., Brown, M.J., and Asbury, A.K., Multifocal demyelinating neuropathy with persistent conduction block, Neurology, 32, 958, 1982. 76. Wolfe, G.I. et al., Chronic cryptogenic sensory polyneuropathy: clinical and laboratory characteristics, Arch. Neurol., 56(5), 540, 1999. 77. Oh, S.J. and Claussen, C.C., Intravenous immunoglobulin (IVIG) treatment in chronic sensory demyelinating neuropathy, Neurology, 45(4) A168, 1995. 78. Gorson, K.C. and Ropper, A.H., Idiopathic distal small fiber neuropathy, Acta Neurol. Scand., 92(5), 376, 1995. 79. Krendel, D. et al., Sural nerve biopsy in chronic inflammatory demyelinating polyradiculoneuropathy, Muscle and Nerve, 12, 257, 1989. 80. Bouchard, C., Lacroix, C., Plantae, V., Adams, D., Chedru, F., Guglielmi, J.M., and Said, G., Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy, Neurology, 52, 498, 1999.

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CHAPTER 7 Figure 1 Endoneurial cells in CIDP: many mononuclear inflammatory cells are scattered throughout the endoneurial space. CIDP. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 3 Paranodal widening. Arrow indicates normal paranodal gap. Two arrowheads indicate paranodal widening. CIDP. Frozen section. Modified trichrome. (400 × magnification.)

CHAPTER 7 Figure 2 Macrophage-induced demyelination (arrowhead). Arrow indicates one thinly myelinated fiber (remyelinated fiber). CIDP. Semithin section. Toluidine/basic fuchsin. (1000 × magnification.)

CHAPTER 7 Figure 4 Probable demyelination of large-diameter fibers. Between two normal myelinated fibers (arrowheads), there is an area where the large myelinated fibers are lacking. This is probably due to demyelination. Straightness of nerve fibers in this section guarantees that this section is cut on an equal plane. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 7 Figure 5 Demyelination and remyelination in teased nerve fibers. (A) Two successive segments of teased nerve fibers. (1) and (2) between two arrows indicate segmental demyelination, and (3) paranodal widening. (400 × magnification.) (B) Segment between two arrows indicates paranodal widening, and the segment between two open arrows indicates a remyelinated segment. (100 × magnification.) (C) The segment between two arrows indicates segmental demyelination. (100 × magnification.)

CHAPTER 7 Figure 7 Perivascular cuffing of mononuclear inflammatory cells in the endoneurial space (arrowhead). A few inflammatory cells are scattered nearby in the endoneurial space. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 6 Denuded axon (demyelination). Semithin section. Toluidine blue and basic fuschin.

CHAPTER 7 Figure 8 T-cell marker stain identifies many cells in the endoneurial space. Paraffin section. T-cell marker stain. (200 × magnification.)

CHAPTER 7 Figure 9 Perivascular collections of mononuclear inflammatory cells along the vessels in the epineurial space in the longitudinal cut. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 7 Figure 10 Demyelinating and remyelinating fibers. The long arrowhead indicates a denuded axon (demyelination), and the arrow indicates a thinly myelinated fiber (remyelination). The short arrowhead indicates macrophage near a myelinated fiber. Possible lymphocytes are scattered. Semithin section. Vesicular degeneration of myelin is seen in one myelinated fiber in the right low corner. Toluidine blue/baso fuchsin. (1000 × magnification.)

CHAPTER 7 Figure 11 Demyelinated segment of nerve fiber; segmental demyelination (between two arrows). The arrowhead indicates one normal node of Ranvier. Straightness of nerve fibers in this section guarantees that this section is cut on an equal plane. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 7 Figure 12 Onion-bulb formation. Onion bulb formations are observed in almost all nerve fibers: Onion-bulb formations in the normal myelinated (arrow) as well as thinly myelinated fibers (arrowhead). Semithin section. Toluidine blue. (1000 × magnification.)

CHAPTER 7 Figure 13 Many onion-bulb formations (OBF). One OBF is indicated by the arrowhead. Notice there are two Schwann cell nuclei surrounding this nerve fiber. Also notice the marked reduction of population of myelinated fibers. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 7 Figure 14 Endoneurial and epineurial perivascular inflammatory cells. The arrow indicates some mononuclear inflammatory cells scattered in the endoneurial space, and the arrowhead indicates a perivascular collection of mononuclear inflammatory cells in the epineurial space. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 15 Impressive collection of small mononuclear cells around the vessels in the epineurial space. The arrowhead indicates the endoneurial space where no obvious inflammatory cells are observed. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 16 Prominent endoneurial edema and many scattered mononuclear cells are obvious. The bubbly appearance of myelin (arrow) may represent a vesicular degeneration of myelin in the frozen section. Frozen section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 17 Demyelinating and remyelinating fibers. The arrow indicates a thinly myelinated fiber (remyelinating), and the arrowhead indicates an almost denuded (demyelinating) fiber. Semithin section. Toluidine blue. (1000 × magnification.)

CHAPTER 7 Figure 19 Perivascular collection of mononculear cells in the epineurial space. The arrowhead indicates a histiocyte. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 18 Remyelinating fibers. Prominent reduction of population of myelinated fibers and a few thinly myelinated fibers. The arrowhead indicates one thinly myelinated fiber, and the arrow indicates a cluster of tiny fibers (regenerating axonal sprouting). Semithin section. Toluidine blue/ basic fuchsin. (400 × magnification.)

CHAPTER 7 Figure 20 Onion-bulb formation (OBF). The arrow indicates OBF in one nearly denuded axon (demyelinating). OBF is also observed around a few normal myelinated fibers. Semithin section. Toluidine blue/basic fuchsin. (1000 × magnification.)

CHAPTER 7 Figure 21 Normal population of myelinated fibers. Scattered myelin-digestion chambers (arrowheads). Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 7 Figure 23 Perivascular inflammatory cells in the epineurial space. Paraffin section. Leucocyte common antigen (LCA) stain. (200 × magnification.)

CHAPTER 7 Figure 22 Minimal decrease in the population of myelinated fibers. The arrow indicates one myelin-digestion chamber and the arrowhead indicates a myelin-ovoid. Semithin section. Toluidine blue/basic fuchsin. (400 × magnification.)

CHAPTER 7 Figure 24 Thinly myelinated fibers (arrow) in the longitudinal cut. Semithin section. Toludine blue. (400 × magnification.)

CHAPTER 7 Figure 25 No surviving myelinated fiber is seen here. Many myelin-digestion chambers (arrows) are noted here indicating axonal degeneration. Frozen section. Modified trichrome. (400 × magnification.)

CHAPTER 7 Figure 26 Scattered mononuclear cells in the endo- and epineurial spaces. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 27 Segemental demyelination between arrows in one teased nerve fiber.

CHAPTER 7 Figure 28 Onion-bulb formations (OBF) are identified by more than one Schwann cell nucleus around myelinated fibers. Arrows indicate OBF with more than four Schwann cell nuclei around myelinated fibers. Frozen section. Modified trichrome. (400 × magnification.)

CHAPTER 7 Figure 30 Minimal loss of myelinated fibers and active axonal degeneration. The arrow indicates one lipid-laden macrophage among many scattered macrophages. The arrowheads indicate clusters of regenerating fibers. The diamond indicates myelin ovoids. Semithin section. Toluidine blue and basic fuchsin stain. (400 × magnification.)

CHAPTER 7 Figure 29 MDCs representing active axonal degeneration are obvious. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 7 Figure 31 Moderate loss of myelinated fibers. Onion-bulb formation (OBF) is present in almost all fibers. The arrowhead indicates OBF around normal fibers, the short arrow indicates OBF around thinly myelinated fibers, and the long arrow indicates OBF around the denuded axon. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 7 Figure 32 Many B-cell positive cells in the perivascular area in the epineurial space. Frozen section. B-cell stain.

CHAPTER 7 Figure 33 Many scattered mononuclear cells and macrophages around vessels in the endoneurial space in the ventral root. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 34 Collections of mononuclear cells in the endomysial space near one vessel. Many small atrophic muscle fibers are also seen. Some of these are angular in shape. Frozen section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 35 Almost normal population of myelinated fibers. Thinly myelinated fibers are scattered in the fascicles. The arrow indicates one thinly myelinated fiber. Semithin section. Toluidene blue and basic fuchsin stain. (400 × magnification.)

CHAPTER 7 Figure 36 Minimal but definite perivascular mononuclear cells in the epineurial space in the longitudinal cut. Nerve fascicle is in the upper portion of the figure. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 7 Figure 37 Moderate loss of myelinated fibers. The arrow indicates a denuded axon. The arrowhead indicates thinly myelinated fibers. Semithin section. Toluidine blue and basic fuchsin stain. (400 × magnification.)

CHAPTER 7 Figure 38 Moderate loss of myelinated fibers. The arrow indicates one denuded axon. The arrowhead indicates one of many thinly myelinated fibers; the larger arrow indicates a lipid-laden macrophage. Semithin section. Toluidine blue and basic fuchsin stain. (1000 × magnification.)

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Immune-Mediated Neuropathies

Although vasculitic and inflammatory neuropathies are, in theory, also immune-mediated, they are discussed separately in Chapters 6 and 7. In this chapter, three serum autoantibody positive neuropathies, which were well established in 1990, and dysproteinemic neuropathies (neuropathies associated with paraproteinemia or monoclonal gammopathy), which were well-established in 1980, are included.

GM1 ANTIBODY-POSITIVE NEUROPATHY There are two main neuropathies associated with GM1 antibody: IgM GM1 antibody associated with multifocal motor neuropathy and IgG GM1 antibody associated with axonal Guillain–Barré syndrome (GBS). IgM GM1 antibody was positive in 50 to 80% of cases of multifocal motor neuropathy (MMN). Mild demyelinating neuropathy with many thinly myelinated nerve fibers was the predominant feature in this disorder, even though the sural nerve conduction was normal (Chapter 7). Miniature onion-bulb formation (identified only by the ultrastructural EM study) was observed in all of the 11 cases in Corse et al.’s series.2 IgG GM1 antibody was positive in 42% of patients with acute motor axonal neuropathy (AMAN)3 and in 18 to 42% of patients with GBS.4,5 GBS with positive serum IgG GM1 antibody was characterized predominantly by motor neuropathy,5,6 axonal neuropathy in the NCS, poor prognosis, and high association of Camphobactor jejuni infection.5 The main pathological findings in AMAN were characterized by axonal degeneration of variable severity with only minimal inflammation or demyelination and the presence of frequent para-axonal and occasional intra-axonal macrophages in the large motor fibers, suggesting macrophage-induced axonal degeneration as the primary pathological process.7

ANTI-MAG ASSOCIATED NEUROPATHY This neuropathy is a disease of the elderly, with a clear-cut male predominance and the following distinct features: predominantly sensory abnormality, IgM paraprotein, high CSF protein, and unsatisfactory response to immunotherapies. Anti-MAG (myelin-associated protein) antibody was positive in 50 to 90% of cases of neuropathy and IgM monoclonal gammopathy (usually kappa light chain). Although sensory symptoms were predominant, neuropathy was not necessarily pure sensory neuropathy, with two-thirds of patients having some motor weakness.8 No hematological or bone changes were seen in this neuropathy. Because of cross-reactivity with sulfated glucuronyl paraglobside (SGPG), anti-SGPG was also often positive. The NCS showed a distinct pattern: demyelinating neuropathy with markedly prolonged terminal latency.9,10 The pathological findings in the sural nerve biopsy were characterized by segmental demyelination and widely spaced myelin (WSM).11-13 In all cases, segmental demyelination with many thinly myelinated fibers and concentric Schwann cell processes (onion-bulb formation) were observed (Color Figure 8.1).8* WSM refers to the wide spacing between the separated leaflets of an intermediate line which seemed to contain electrolucent materials. The ultrastructural features of the dense lines remained unchanged. WSM, sometimes restricted to the outermost myelin lamellae of scarce fibers, was present in 96% of cases (Figure 8.1). Immunoglobulin deposits were detected by * Color insert figures. ©2002 CRC Press LLC

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FIGURE 8.1 Electronmicrograph of transverse section through myelinated nerve fiber showing alternating zones of normal and widely spaced myelin (WSM). Sp=Schwann cell process, ax=axon, my=myelin. (With permission from Young, K.B., et al., J. Neurol., 238, 1991.)

immunofluorecence in 68% of cases.8 IgM deposits on the myelin sheath are more specific for antiMAG associated neuropathy, observed in 83 to 100% of cases (Color Figure 8.2 and Color Figure 5.24). The use of immunogold labelling has conclusively demonstrated the localization of IgM and light chain to the separated myelin lamellae.14 According to Midroni, IgM deposits on myelin sheaths in the endoneurium are strongly suggestive of IgM paraproteinemic neuropathy with antibodies against MAG.15

NEUROPATHY ASSOCIATED WITH ANTI-HU (ANNA 1) ANTIBODY The anti-Hu antibody is associated with paraneoplastic syndromes associated with small-cell lung cancer (SCLC). The dominant neurological syndromes associated with the anti-Hu antibody are subacute sensory neuronopathy and paraneoplastic encephalomyelitis (PEM).16 CSF protein levels were elevated in most cases, and pleocytosis was observed in 21% of cases. Nerve conduction (NC) abnormalities are supposed to be typical of a sensory neuronopathy pattern — absent SNAP in the presence of normal motor NC — but minor motor NC abnormality is universal. The sural nerve biopsy has been reported in ten cases.16-20 The most characteristic finding in this neuropathy was axonal degeneration (Color Figure 8.3). Inflammatory cells were observed in the nerve in five cases, in either the endoneurial or epineurial space (Color Figure 8.4). Microvasculitis in the epineurial space without any fibrinoid necrosis was reported in three cases. Superimposed demyelination was reported in only three cases.

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NEUROPATHY WITH MONOCLONAL GAMMOPATHY The prevalence of monoclonal gammopathy increases with age. Benign paraproteinemia was found in 1 to 3% of unselected patients over the age of 50 and increased in an age-dependent fashion.21 The monoclonal antibodies were approximately 60% IgG, 10 to 27% IgM, and the remainder IgA.22 Monoclonal gammopathy is divided into nonmalignant (benign) and malignant gammopathy. Malignant gammopathy includes multiple myeloma, osteosclerotic myeloma, and Waldenström’s macroglobulinemia. The relative incidence of nonmalignant gammopathies was approximately 200 to 1.23 Because prolonged follow-up of these patients with benign monoclonal gammopathy revealed an 11% conversion to a malignant plasma cell dyscrasia, a new designation of monoclonal gammopathy of undetermined significance (MGUS) was proposed.24 Neuropathy associated with malignant and benign gammopathy has been well recognized for many years. In one study, 10% of 279 patients with monoclonal gammopathy were found to have neuropathy of unknown etiology.25 Conversely, 5 to 10% of all patients with idiopathic neuropathy were associated with monoclonal gammopathy.22 Approximately 50% of patients with neuropathy and monoclonal gammopathies (NMG) have IgM M protein, 30% have IgG M protein, and 20% have IgA M protein.26-28 In most patients, neuropathy is associated with MGUS. The clinical and pathological features in MGUS neuropathy depend more on the type of paraprotein (IgM vs. IgG or IgA; light chain vs. whole immunoglobulin) than on the associated disease (Table 3.1). In general, IgM-associated neuropathy includes chronic inflammatory demyelinating polyneuropathy (CIDP) and, thus, demonstrates the classic nerve conduction pattern of demyelinating neuropathy. IgG- or IgA-associated neuropathy, on the other hand, includes CIDP as well as axonal neuropathy. 26,29 Demyelinating neuropathies associated with MGUS of all classes, but particularly IgM, Waldenström’s macroglobulinemia, and osteosclerotic myeloma typically follow an indolently progressive course and frequently respond to immunotherapy treatments.30 In contrast, axonal neuropathies associated with MGUS, multiple myeloma, and primary (AL) amyloidosis have generally shown no response to therapy.30,31 The general pathological features of neuropathy associated with monoclonal gammopathy are as follows (Table 8.1): 1.

2.

3.

4.

Perivascular inflammatory cells are rarely detected in this disorder and in any space in the nerve. Usually these cells are lymphocytes and macrophages. Less frequently, plasmatoid cells are observed (Color Figure 8.5). Segmental demyelination is the pathological hallmark in IgM-associated neuropathy (Color Figure 8.6). This is especially true in anti-MAG antibody associated neuropathy (vida infra). On the other hand, segmental demyelination or axonal degeneration as the predominant feature is equally represented in IgG- or IgA-associated neuropathy.26,29 In monoclonal gammopathy associated with amyloid neuropathy, axonal degeneration is typical. IgM deposits in the myelin sheaths are specific for IgM-associated neuropathy, being positive in 40 to 80% of these cases, usually in the presence of anti-MAG activity (see above).26 This finding was not reported in IgG- or IgA-associated neuropathies. Endoneurial deposits of IgM are also specific for IgM-associated neuropathy in that these were reported only in several cases of Waldenström’s macroglobulinemia and in a few cases of IgM MGUS neuropathy.32 According to Dubas et al.,43 the nerve lesions are mainly axonal and WSM and anti-MAG activity are usually absent in patients with endoneurial IgM deposits. A more specific pathological feature for certain types of paraproteinemic neuropathy is increased periodicity of myelin lamellae: widely spaced myelin (WSM) is highly typical of anti-MAG antibody–associated neuropathy, and uncompacted myelin (UCM) is typical of POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes).

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Nerve Conduction Pattern Demyelinating neuropathy

Normal Normal High High

Axonal neuropathy; amyloid Axonal neuropathy Segmental demyelination Segmental demyelination

Axonal neuropathy Axonal neuropathy Demyelinating neuropathy Demyelinating neuropathy

High Normal

Segmental demyelination Vasculitis

Demyelinating neuropathy Axonal neuropathy

a

In IgG or IgA types, occasionally axonal degeneration is seen

b

Predominantly sensory

c

Multiple myeloma with amyloidosis: see amyloidosis

d

POEMS (Polyneuropathy, organomegaly, endrocrinopathy, M-protein, and skin change).

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CSF Protein Pathology High Segmental demyelination

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Clinical Features Monoclonal gammopathy of undetermined significance CIDP a (MGUS; benign monoclonal gammopathy) Amyloidosis, light chain Sensory-motor b c Multiple myeloma without amyloidosis Sensory-motor Osteosclerotic myeloma including POEMS d CIDP Angiofollicular lymph node hyperplasia CIDP (Castleman’s disease) Waldenström’s macroglobulinernia CIDP Cryoglobulinemic neuropathy Sensory-motor

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Endoneurial, perivascular, and subperineurial masses of PAS-positive, Congo-red negative amorphous material are an infrequent observation and indicate deposits of paraprotein. IgM has been implicated in almost all well-documented cases of non-amyloid immunoglobulin deposition in nerves.15,33-36

POLYNEUROPATHY ASSOCIATED WITH MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) MGUS is the most frequent monoclonal gammopathy associated with peripheral neuropathy. Neuropathy is frequently the first manifestation of MGUS. This neuropathy typically resembles CIDP in most patients, with distal and proximal muscle weakness, large-fiber sensory loss, and high CSF protein levels. Nerve conduction studies show a classic demyelination pattern with markedly slow NCVs. Bromberg et al. did not find any significant differences in the various nerve conduction parameters between classic CIDP and CIDP associated with MGUS.37 No obvious differences emerged between IgM neuropathy and IgG and IgA neuropathy in the clinical, CSF, and electrophysiological features.26,27,29,38,39 However, there is a consensus that demyelination is much more uniform and severe in IgM neuropathy. In IgM neuropathy, segmental demyelination and WSM are the pathological hallmarks in the nerve biopsy (Figure 8.1 and Color Figure 8.6). This is especially true in MAG-positive neuropathy. According to Vital et al.,40 thinly myelinated fibers and onion-bulb formation were observed in 100% of 31 cases, whereas WSM was seen in 25 cases. Yeung et al.41 classified the nerve fiber pathology as mixed neuropathy in 54% of cases, pure demyelinating neuropathy in 41%, and axonal neuropathy in 5%. WML was observed in 56% of cases. IgM immunostaining on the myelin sheath was positive in 79% of cases in Yeung et al.’s series and 55% of cases in Vital et al.’s series.

FIGURE 8.2 Uncompacted myelin lamellae (UML) are present along a semicircumference of the myelin sheath. (12,800 × magnification.) (With permission from Vital, C. et al., Acta Neuropathol., 87, 304, 1994.)

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In 25 patients with IgG neuropathy, the nerve biopsy most commonly demonstrated demyelinating neuropathy in 13 cases, mixed axonal degeneration and demyelination in 8 cases, and pure axonal degeneration in 3 patients.39 IgG immunostaining on the peripheral nerve was reported in less than onethird of the nerve biopsies examined.39 Bleasel et al. reported demyelinating neuropathy with inflammatory cell infiltrates in all five patients with IgG neuropathy and onion-bulb formation in three.39 WSM was not observed in this group.41 In five cases of IgA neuropathy, the nerve biopsy showed axonal degeneration in four cases and mixed demyelination and axonal degeneration in one case.29,41-43 Cell infiltration is an extremely rare finding in MGUS neuropathy: Dalakas and Engel found a few inflammatory cells in two cases of MGUS,44 and Yeung et al. found no cells in 62 cases.41 On the other hand, Bleasel et al. found inflammatory cells in all five cases of IgM neuropathy.39 A minority of patients have a polyneuropathy that electrophysiologically appears to be caused primarily by axonal degeneration (Color Figure 8.7).31,45 This group of patients has predominant IgG and IgA monoclonal gammopathy, lower CSF protein, and mild sensory neuropathy.31 Fewer patients with axonal neuropathy improved with immunomodulating therapy.31 Immunosuppressants have been found to have a minimal to marked beneficial effect in many patients, and plasmapheresis and IVIG have also been effective in a few patients,22 indicating that this polyneuropathy is potentially treatable.

PERIPHERAL NEUROPATHY ASSOCIATED WITH OSTEOSCLEROTIC MYELOMA (OSM) Osteosclerotic myeloma (OSM) differs from multiple myeloma by the absence of anemia or marrow plasmacytosis and the presence of osteosclerotic bone lesions. Osteosclerotic myeloma is unique in its strong association with neuropathy, which occurs in at least 50% of patients and is almost always the presenting manifestation, with subsequent investigation leading to the correct diagnosis.46 The neuropathy resembles subacute demyelinating neuropathy or chronic inflammatory demyelinating polyneuropathy, with, predominantly, motor disability, high CSF protein, and marked nerve conduction abnormalities.46,47 In testing OSM patients, the majority had detectable levels of monoclonal Mprotein (IgG or IgA and nearly always lambda light chain). Some of these patients developed a dramatic POEMS syndrome.48 A skeletal survey showed osteosclerotic lesions in the spine, pelvic bones, and ribs. Open biopsy of suspicious bony lesions is mandatory for the diagnosis. Treatment of solitary lesions with tumorcidal irradiation usually improves the neuropathy.46,49 Nerve conduction studies show a classic demyelinating neuropathy.46 In all of six nerve biopsies, Kelly found demyelination, axonal degeneration, and perivascular inflammatory cells in the epineurium.46 In POEMS, the most striking pathological feature is uncompacted myelinated lamellae (UML) (Figure 8.2).50 UML refers to the uncompactness of Schwann cytoplasm between two lamellae (two halves) of the major dense line. According to Vital et al., UML were present in 19 (86%) of 22 cases and in 1 to 16% of myelinated fibers.50 In Ohnishi’s series, UML were present in over half the cases and in 3 to 8% of myelinated fibers.51 Teased nerve fiber studies showed a mixture of both axonal degeneration and demyelination in eight cases, segmental demyelination alone in 6, and axonal degeneration in three.52 Lymphocytes scattered in the endoneurium were reported in 1 of 62 nerve biopsy cases in the literature, and lymphocytes were found in the spinal roots in 6 of 7 autopsy cases.50 The most prominent pathology in the lymph node biopsy in POEMS is giant lymph node hyperplasia, the features of Castleman’s disease, observed in 63 to 82% of cases.50,52 Castleman’s disease, or angiofollicular lymph node hyperplasia, is a rare lymphoproliferative disorder that can be associated with peripheral neuropathy. Neuropathy in this disease resembles that of osteosclerotic myeloma and POEMS syndrome, being predominantly motor and severely disabling.53 Nerve conduction studies showed a mixture of axonal degeneration and demyelination in some cases53 and demyelinating neuropathy in others.54 A nerve biopsy showed active axonal degeneration with active regeneration in three cases53,55 and demyelination in one case.56 Donaghy et al.’s two cases showed capillary proliferation and endothelial hypertrophy in the epineurium and endoneurium similar to that seen in affected lymph nodes.53 Teased nerves in two cases showed a ©2002 CRC Press LLC

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mixture of axonal degeneration and demyelination.53,56 One case revealed an epineurial infiltrate consisting of macrophages, lymphocytes, and plasma cells occasionally invading the perineurium.56

PERIPHERAL NEUROPATHY ASSOCIATED WITH TYPICAL MULTIPLE MYELOMA (MM) Multiple myeloma (MM) differs from MGUS by the presence of a malignant proliferative clone of plasma cells in the bone marrow biopsy, high or rising paraprotein levels, and multisystem involvement. Neuropathy is estimated to occur in 1 to 13% of all patients with multiple myeloma.57 Peripheral neuropathy associated with multiple myeloma can be divided into two categories: myeloma neuropathy without amyloidosis and myeloma neuropathy with amyloidosis.58 Myeloma neuropathy without amyloidosis is a heterogeneous disorder and bears a close resemblance to carcinomatous neuropathy: sensorimotor neuropathy in two-thirds of patients and sensory or motor neuropathy in the remainder.59 An NCS reveals axonal neuropathy.57 The basic pathological process in peripheral nerves is axonal degeneration (Color Figure 8.8).57 In five cases, Walsh observed generalized loss of fibers of all diameters and axonal degeneration in the teased nerve fibers, but no cellular infiltration, amyloidosis, or vasculitis.57 In 12 cases, Vital et al. observed no cellular infiltrates, abnormal globulin in the endoneurium in one patient with cryoglobulinemia, and axonal degeneration in 10 cases.60 Myeloma neuropathy with amyloidosis is not clinically different from non-hereditary systemic amyloidosis (see Chapter 11). Azar estimated the association of MM with amyloid in 15% of all cases.61 In another series of 236 cases of amyloidosis, 61 (26%) had multiple myeloma.62 Among patients with multiple myeloma and polyneuropathy, about two-thirds had amyloid neuropathy.59 Predominant sensory neuropathy, carpal tunnel syndrome, and autonomic neuropathy are common findings.

NEUROPATHY ASSOCIATED WITH WALDENSTRÖM’S MACROGLOBULINEMIA (WM) Waldenström’s macroglobulinemia differs from IgM MGUS in the amount of circulating paraprotein (greater than 30 g/L in WM) and in the presence of over 10% marrow plasmacytoid lymphocytes. Neuropathy occurs in 25 to 50% of these patients and may precede or follow the systemic manifestation. Anti-MAG antibody was found in 50% of patients with neuropathy.63 Neuropathy in Waldenström’s macroglobulinemia is almost identical to IgM neuropathy in clinical, electrophysiological, and pathological aspects. In most cases, the neuropathy develops after the systemic manifestations. Sensory, sensorimotor, and motor types of neuropathy have all been reported in this disorder.64 In 12 nerve biopsies, the teasing of nerve fibers showed demyelinating neuropathy in all cases; IgM deposits of the myelin sheath were present in all but one patient with the anti-MAG antibody.40 In patients with IgM but not anti-MAG, IgM deposits were not found on the myelin sheath of the sural nerve, but in four patients there was variable staining of IgM deposits in the endoneurial connective tissue. In two cases, PAS-positive but Congo-red negative amorphous materials which were IgM-positive were found in the endoneurium.34,35 WSM was also reported in five cases of WM. In three of ten cases of WM neuropathy, cell infiltrates were observed — in the perineurium in one case and in the endoneurium in two cases.65 These cells were atypical lymphocytes.

PERIPHERAL NEUROPATHY WITH CRYOGLOBULINEMIA Cryoglobulins are circulating proteins that can reversibly precipitate when cooled. There are two types of cryoglobulinemia — essential cryoglobulinemia and secondary cryoglobulinemia — seen in association with collagen vascular diseases, lymphoproliferative diseases, or chronic inflammation. Recently, hepatitis C was found to be associated with cryoglobulinemia.66 Secondary cryoglobulinemia is much more common. The incidence of clinical neuropathy in cryoglobulinemia is about 7 to 19%.67 Characteristically, patients present symptoms of Raynaud’s phenomenon, purpuric skin eruptions, and ulceration of the

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lower limbs. Peripheral neuropathy is predominantly sensory and asymmetrical and is precipitated by cold weather. An NCS shows axonal neuropathy. In cryoglobulinemic neuropathy, vasculitis and axonal degeneration were documented in the nerve up to 75% of biopsies (Color Figure 8.9).68-70 In the absence of vasculitis, a nonspecific inflammatory axonal neuropathy was observed. In three cases, focal deposits of cryoglobulin, staining positive by PAS, were observed in the endoneurium.36,71

CASES OF IMMUNE-MEDIATED NEUROPATHY CASE 1: NUMBNESS AND TINGLING SENSATION IN THE HANDS FOR 12 YEARS Case Presentation A 61-year-old male began to have numbness and tingling in his left hand 12 to 13 years before examination, followed by similar symptoms in his right hand. In the 5 years prior to evaluation, he had numbness and tingling sensations in his right foot, followed by similar complaints in his left foot, spreading further to involve the lower third of his leg. He denied any burning pain, but reported occasional sharp, needle-like sensations extending into his feet. He had no history of diabetes, but he did have a history of moderate ethanol abuse and was told that his neuropathy was due to alcoholism. Normal laboratory studies included ANA, rheumatoid factor, sedimentation rate, folic acid and B12, and a negative urine screen for heavy metal. He had undergone three previous NCS and EMG studies. Examination showed normal muscle strength, mild pes cavus with hammer toes, pin-prick sensation loss below the wrists and mid-calves, loss of position sense in the toes, absent vibratory sensation below the ankles, and absent ankle reflexes, but otherwise normal reflexes. An NCS showed demyelinating neuropathy with disproportionate distal slowing: marked prolonged terminal latency (10 msec for median nerve), minimally slow NCV (34.7 m/sec) and no sensory potentials. Immunoelectrophoresis of serum protein by immunofixation showed IgM monoclonal gammopathy with kappa chain. His CSF protein level was 86 mg/dl with one kappa oligoclonal band. The SGPG autoantibody TLC was positive. SGPG-ELISA: 51200. MAG autoantibody-ELISA. < 800. MAG-autoantibody-Western: positive. Case Analysis This patient had a pure sensory neuropathy for 12 years which was thought to be due to alcoholism. It is dangerous to assume that sensory neuropathy is due to chronic alcoholism simply because of a patient’s history. In fact, the NCS showed a clear-cut demyelinating neuropathy, which is not typical of alcoholic neuropathy. In older patients, it is always important to check for monoclonal gammopathy as a cause of neuropathy because it is one of the major neuropathies in this age group. The NCS showed a typical feature of MAG-positive CSDN with disproportionate distal slowing. Sural Nerve Biopsy A minimal decrease in the population of myelinated fibers was noted. Amyloid was negative. Modifiedtrichrome-stained frozen sections showed areas of demyelination and a few scattered myelin-digestion chambers (MDCs). Semithin sections showed a few nerve fibers with extremely thin myelin (Color Figure 8.10). IgM immunofluorescence staining showed prominent IgM deposits on the myelin sheath (Color Figure 8.11). These findings were typical of IgM-positive demyelinating neuropathy. Final Diagnosis The final diagnosis was anti-MAG antibody–positive CSDN. ©2002 CRC Press LLC

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Treatment and Follow-up With azathioprine and intermittent IVIG treatment, this patient’s neuropathy gradually improved. Comments IgM monoclonal gammopathy (kappa light chain), high CSF protein, demyelinating neuropathy with disproportionate distal slowing, and IgM deposits on the myelin sheath are typical of anti-MAGassociated neuropathy. Our patient’s response to immunotherapy is an exception for this neuropathy, especially in view of his long 12-year history. This neuropathy is known to be resistant to immunotherapy.

CASE 2: PROGRESSIVE UNSTEADY GAIT FOR 5 MONTHS IN A SMOKER Case Presentation A 70-year-o1d woman began to notice low energy and tingling of the toes 5 months before evaluation. The tingling in her toes gradually spread upward to her feet and knees, and, for the 2 months prior to examination, she began to notice some tingling sensation in her hands. The tingling in her toes was also associated with a stabbing pain. For 3 months, she had frequent falls because of an unsteadiness of her legs and she had to walk with a cane. She had been a smoker for a long period of time. Abnormal neurological findings were clear-cut truncal ataxia upon standing, ataxic gait, pinprick sensation loss below the knees, hyperpathic sensation on the thighs, absent vibration in her toes and ankles, absent position sense in her toes and impaired position sense in her ankles, and absent ankle reflexes. Her muscle strength was normal. An NCS showed nearly normal motor NCS but absent sensory CNAP. All other laboratory work-ups for peripheral neuropathy were negative except for an elevated CSF protein and positive anti-Hu antibody in the serum. Case Analysis This patient had progressive subacute ataxic sensory neuropathy. The NCS showed the classical pattern of sensory neuronopathy: normal motor NCS with marked sensory nerve conduction abnormality. These findings were indicative of a lesion in the sensory neurons in the dorsal root (sensory neuronopathy), which is typically seen in anti-Hu antibody–associated neuropathy. Sural Nerve Biopsy Modified trichrome stains showed a marked loss of myelinated fibers and prominent MDC (Color Figure 8.12). Paraffin sections showed a few mononuclear inflammatory cells in the perivascular area in the epineurial space (Color Figure 8.13). These findings were indicative of inflammatory axonal neuropathy. Final Diagnosis The final diagnosis was anti-Hu antibody–associated neuropathy. Treatment and Follow-up All work-ups for small-cell lung cancer were negative. With an aggressive combined therapy of highdose prednisone, azathioprine, and IVIG, her neuropathy improved.

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Comments Anti-Hu antibody is the serological marker for small-cell lung cancer. Thus, we have to assume that small-cell lung cancer may show up later in this patient. The most unusual feature in this patient is her clinical improvement with a combined aggressive immunotherapy. This neuropathy is usually resistant to either cancer therapy or immune therapy.

CASE 3: 2-MONTH HISTORY OF NUMBNESS OF HANDS AND FEET IN A 68-YEAR-OLD MAN Case Presentation Two months prior to examination, a 68-year-o1d man noticed some tingling in his fingers after prolonged use of a chain saw and he later experienced some numbness of both feet, which gradually progressed over the course of 11/2 months. He became mildly unsteady on his feet and the numbness extended up to his ankles. He continued to have occasional numbness and tingling in the fingertips of both hands but no particular pain. Abnormal neurological findings were mild weakness in the gastrocnemius and anterior tibialis muscles, areflexia, decreased vibration, proprioception, and pinprick sensation loss to just above the ankles bilaterally. The patient had mild unsteadiness of gait and was unable to heel-, toe-, or tandem-walk. Romberg was borderline positive. The NCS/EMG showed demyelinating neuropathy (marked prolonged terminal latency, conduction block in many nerves, moderate slowing in NCV). Abnormal laboratory findings were an elevated CSF protein (142 mg/dl) and IgG monoclonal gammopathy (kappa spike). No monoclonal gammopathy was found in the urine. A metastatic bone survey did not show any abnormalities. Case Analysis This patient had a 2-month history of mostly symmetrical sensory neuropathy with minimal motor deficits. Demyelinating neuropathy, high spinal fluid protein, and IgG monoclonal adenopathy were indicative of CIDP associated with monoclonal gammopathy. Sural Nerve Biopsy The biopsy showed a minimal loss of myelinated fibers and many thinly myelinated fibers (Color Figure 8.14), indicative of demyelinating neuropathy. Final Diagnosis CIDP associated with MGUS was the final diagnosis. Treatment and Follow-up Initially, this patient was treated with IVIG, prednisone, and azathioprine with good improvement. Over a 5-year period, he had 2 relapses which were controlled with IVIG. With the third relapse, there was no clear-cut clinical improvement with IVIG treatment. Thus, multiple myeloma work-ups were repeated. There was an increased IgG level in the serum. A 24-hour urine test showed a faint IgG monoclonal band. A repeated metastatic bone survey showed osteolytic lesion in the right humerus, a biopsy of which showed multiple myeloma. A bone marrow study confirmed multiple myeloma by showing 24% plasma cells. Once multiple myeloma was found, azathioprine was switched to melphalan. This, together with intermittent IVIG treatment, again induced a remission of CIDP.

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Comments CIDP can be associated with monoclonal gammopathy of unknown significance (MGUS). This gammopathy was originally called benign because many patients follow a benign course, but extended follow-up revealed a conversion to a malignant plasma dyscrasia within 10 years in 17% and within 20 years in 33% of patients, as noted in this case.72 No significant difference is found in the various nerve conduction parameters between CIDP and CIDP associated with MGUS. Usually, patients with CIDP associated with MGUS respond less well to immunotherapy than those with classical CIDP. Unlike our case, CIDP in myeloma is usually seen in osteosclerotic myeloma. A skeletal survey revealed osteosclerotic lesions in the spine, pelvic bones, and ribs. Open biopsy of suspicious bony lesions is mandatory for confirmation of diagnosis. The treatment of solitary lesions with tumorcidal irradiation usually improves the neuropathy.

CASE 4: PROGRESSIVE SENSORY-MOTOR NEUROPATHY, BICLONAL GAMMOPATHY, SKIN DISCOLORATION, PLEURAL EFFUSION, AND HEPATOMEGALY FOR 4 YEARS Case Presentation A 53-year-o1d woman was initially evaluated in 1988 for numbness of the feet and difficulty walking for 10 months. Abnormal neurological findings were hyperpathia to pin-prick sensation below the ankles, absent vibration in the toes, decreased vibration in the ankles and knees, moderate weakness in the anterior tibialis and gastrocnemius muscles, and diffuse areflexia. The NCS/EMG studies showed a mixed pattern of demyelinating and axonal neuropathy. The patient’s CSF protein level was 145 mg/dl. IgA and IgG lambda paraproteins were found. GM1 and asialo GM1 antibodies were positive. However, paraprotein was absent in the urine. A bone survey did not show any abnormality. Despite prednisone treatment under the diagnosis of CIDP with biclonal gammopathy, the patient’s neuropathy gradually progressed to include foot drop and sensory loss below the knees. Soon diabetes mellitus was found, probably secondary to steroid therapy. In 1989, the patient developed cyanotic discoloration and splinter hemorrhages in her toes and fingers. In 1990, she developed two episodes of pleural effusion. Plasmapheresis did not improve her neuropathy. In 1991, hepatomegaly and splenomegaly were found. In early 1992, the patient had left brachial artery thrombosis. She soon developed a bluish discoloration of the face and hands, ascites and ischemia of the left leg despite IV cytoxan and plasmapheresis and chrambucil treatment. The patient died within a few months due to multiple organ failure. Case Analysis Initially, this patient had all the features of CIDP associated with MGUS. Unlike the classical cases of CIDP, she had positive GM1 and asialo-GM1 antibodies and no response to steroid treatment. Sural Nerve Biopsy The population of myelinated fibers was moderately decreased. Semithin sections showed many areas of demyelination and some MDC in the longitudinal cuts (Color Figure 8.15). Final Diagnosis The final diagnosis was CIDP associated with POEMS. Comments POEMS is the acronym coined by Bardwick et al.48 to facilitate recognition of the most constant features of this multisystem syndrome — polyneuropathy, organo-megaly, endocrinopathy, M-protein, ©2002 CRC Press LLC

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and skin change. This unusual syndrome initially received considerable attention in Japan and has been subsequently described worldwide. Hepatomegaly is often encountered. Gynecomastia and impotence in men, secondary amenorrhoea in women, diabetes mellitus, and hypothyroidism are the most common endocrinopathies. Skin changes include hyperpigmentation, hypertrichosis, diffuse skin thickening, and hemangiomas. Anasarca, pitting edema of the lower limbs, ascites, pleural effusion, weight loss, and finger clubbing are other signs. About one-quarter of reported cases have no detectable bone lesions. In this case, arterial thrombosis in the limb is unusual. This has been reported as a component of POEMS.73

CASE 5: PROGRESSIVE WEAKNESS OF LEGS FOR 6 MONTHS IN A PATIENT WITH HISTORY OF LYMPHADENOPATHY Case Presentation A 54-year-o1d man was presented to a neurologist with progressive weakness of the legs for 6 months which began with weakness in the feet. The patient also complained of some weakness of the hands and a pulling sensation in the legs. An examination showed peripheral neuropathy with areflexia and distal leg weakness. An NCS showed axonal neuropathy with some features of demyelination. Laboratory work-ups showed a high CSF protein level (67 mg/dl), a high sedimentation rate (53 mm/hr), and IgG lambda monoclonal spike in the serum. Bence–Jone protein was negative in the urine. A bone survey was negative. The patient had a history of swollen legs and nephrotic syndrome. Case Analysis High CSF protein and a long history of neuropathy suggested the possibility of CIDP. However, the NCS was more indicative of axonal neuropathy. A high sedimentation rate, IgG lambda monoclonal spike, and history of nephrotic syndrome were indicative of malignant monoclonal gammopathy — primary amyloidosis, multiple myeloma, and lymphoma — as a cause of his neuropathy. The absence of Bence–Jone protein was unusual for multiple myeloma and primary amyloidosis. Sural Nerve Biopsy The population of myelinated fibers was moderately decreased. Perivascular collections of mononuclear cells were noted in the epineurial space (Color Figure 8.16). There were no intramural inflammatory cells. Amyloid was negative. Modified trichrome staining showed scattered MDC in the longitudinal cuts. The semithin section also showed many myelin ovoids typical of axonal neuropathy (Color Figure 8.17). These findings were indicative of inflammatory axonal neuropathy. Treatment and Follow-up The patient was referred to a hemato-oncologist for work-up of malignant monoclonal gammopathy. This physician obtained a 2-year-o1d record which showed that the patient had retroperitoneal and mesenteric adenopathy, a biopsy of which revealed angiofollicular lymph node hyperplasia typical of Castleman’s disease. Chest, abdominal, and pelvic CT scans showed patchy interstitial lung disease with pleural effusions and mild pericardial effusion together with soft tissue masses near the adrenal gland, aorta, and inferior vena cava, consistent with adenopathy. Six months later, a renal biopsy showed primary glomerulonephritis. Final Diagnosis Inflammatory axonal neuropathy due to Castleman’s disease was the final diagnosis.

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REFERENCES 1. 2. 3. 4. 5.

6. 7. 8.

9.

10.

11. 12. 13. 14. 15. 16. 17. 18. 19.

20. 21. 22. 23. 24.

Pestronk, A., Invited review: motor neuropathies, motor neuron disorders, and antiglycolipid antibodies, Muscle and Nerve, 14(10), 927, 1991. Corse, A.M., Chaudhry, V., Crawford, T.O., Cornblath, D.R., Kuncl, R.W., and Griffin, J.W., Sensory nerve pathology in multifocal motor neuropathy, Ann. Neurol., 39(3), 319, 1996. Ho, T.W. et al., Guillain–Barré syndrome in northern China: relationship to Camphobacter jejuni infection and anti-glycolipid antibodies, Brain, 118, 597, 1995. Van den Berg, L., Marrink, J., de Jager, A., de Jong van Imhoff, G., and Latov, N., Anti-GM1 antibodies in patients with Guillain–Barré syndrome, J. Neurol. Neurosurg. Psych., 55, 8, 1989. Visser, L.H., et al., Guillain–Barré syndrome without sensory loss (acute motor neuropathy). A subgroup with specific clinical, electrodiagnostic and laboratory features. Dutch Guillain–Barré study group, Brain, 118(Pt. 4), 841, 1995. Nobile-Orazio, E. et al., Guillain–Barré syndrome associated with high titers of anti-GM1 antibodies, J. Neurol. Sci., 109, 200, 1992. Griffin, J.W. et al., Guillain–Barré syndrome in northern China: the spectrum of neuropathologic changes in clinically defined cases, Brain, 118, 577, 1995. Ellie, E., Vital, A., Steck, A., Boiron, J.M., Vital, C., and Julien, J., Neuropathy associated with “benign” anti-myelin-associated glycoprotein IgM gammopathy: clinical, immunological, neurophysiological pathological findings and response to treatment in 33 cases, J. Neurol. 243(1), 34, 1996. Trojabor, W., Hays, A., Van den Berg, L., Younger, D., and Latove, N., Motor conduction parameters in neuropathies associated with anti-MAG antibodies and other types of demyelinating and axonal neuropathies, Muscle and Nerve, 18, 730, 1995. Kaku, D.A., England, J.D., and Sumner, A.J., Distal accentuation of conduction slowing in polyneuropathy associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside, Brain, 117, 941, 1994. Haffer, D.A., Johnson, D., Kelly, J.J., Panitch, H., Kyle, R., and Winer, H., Monoclonal gammopathy and neuropathy: myelin-associated glycoprotein reactivity and clinical characteristics, Neurology, 36, 75, 1986. Latov, N. et al., Plasma cell dyscrasia and peripheral neuropathy with monoclonal antibody to peripheral nerve myelin, New Eng. J. Med., 303, 618, 1980. Melmud, C. et al., Peripheral neuropathy with IgM kappa monoclonal immunoglobulin directed against myelin-associated glycoprotein, Neurology, 33, 1397, 1983. Lach, B. et al., Immunoelectronmicroscopic localization of monoclonal IgM antibodies in gammopathy associated with peripheral demyelinative neuropathy, Acta Neuropathol., 85, 298, 1993. Midroni, G., and Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, MA, 1995. Dalmau, J., Graus, F., Rosenblum, M.K., and Posner, J.B., Anti-Hu—associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients, Medicine, 71(2), 59, 1992. Eggers, C., Hagel, C., and Pfeiffer, G., Anti-Hu-associated paraneoplastic sensory neuropathy with peripheral nerve demyelination and microvasculitis, J. Neurol. Sci., 155(2), 178, 1998. Sharief, M.K., Robinson, S.F., Ingram, D.A., and Geddes, J.F., and Swash, M., Paraneoplastic painful ulnar neuropathy, Muscle and Nerve, 22(7), 952, 1999. Hirabayashi, H., Hamano, H., Ohnuki, Y., Nitta, M., and Shinohara, Y., Inflammatory sensory ataxic neuropathy presenting with alternating skew deviation on lateral gaze: a case report (transl.), Clin. Neurology, 37(10), 937, 1997. Younger, D., Dalmau, J., Inghirami, G., Sherman, W., and Hays, A., Anti-Hu-associated peripheral nerve and muscle microvasculitis, Neurology, 44, 181, 1994. Kohn, J., Benign paraproteinemia, J. Clin. Pathol., 28 (Suppl. 6), 77, 1976. Latov, N., Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies, Ann. Neurol., 37(1), S32, 1995. Radl, J., Benign monoclonal gammopathy, in Mechanisms in B-cell Neoplasia, Melchers, F., Porter, M., Eds., Springer-Verlag, Berlin, 1985, 221. Kyle, RA., Monoclonal gammopathy of undertermined signficance: natural history in 241 cases, Am. J. Med., 64, 814, 1978.

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25. Kelly, J.J., Kyle, R.A., O’Brien, P.C., and Dyck, P.J., Prevalence of monoclonal protein in peripheral neuropathy, Neurology, 31, 1480, 1981. 26. Yeung, K.B. et al., The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinemia. Comparative, clinical, immunological, and nerve biopsy findings, J. Neurol., 238, 383, 1991. 27. Suarez, G.A. and Kelly, J. Jr., Polyneuropathy associated with monoclonal gammopathy of undetermined significance: further evidence that IgM-MGUS neuropathies are different than IgG-MGUS, Neurology, 43(7), 1304, 1993. 28. Gosaselin, S., Kyle, R.A., and Dyck, P.J., Neuropathy associated with monoclonal gammopathy of undertermined significance, Ann. Neurol., 30, 54, 1991. 29. Nobile-Orazio, E. et al., Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies, Acta Neurol. Scand., 85(6), 383, 1992. 30. Bosch, E.P., and Smith, B.E., Peripheral neuropathies associated with monoclonal proteins, Med. Clin. North Am., 77(1), 125, 1993. 31. Gorson, K.C. and Ropper, A.H., Axonal neuropathy associated with monoclonal gammopathy of undetermined significance, J. Neurol. Neurosurg. Psychiatry, 63(2), 163, 1997. 32. Vital, A. and Vital, C., Immunolectron identification of endoneurial IgM deposits in four patients with Waldenstrπm’s macroglobulinemia: a specific ultrastructural pattern related to the presence of cryoglobulin in one case, Clin. Neuropathol., 12, 49, 1993. 33. Dubas, F., Pouplard-Barthelaix, A., Delestre, F., and Emile, J., Polyneuropathies avec gammapathies monoclonales IgM. 12 cas., Rev. Neurol., 143, 670, 1987. 34. Lamarca, J., Casquero, P., and Pou, A., Mononeuritis multiplex in Waldenström’s macroglobulinemia, Ann. Neurol., 22, 268, 1987. 35. Iwashita, H. et al., Polyneuropathy in Waldenström’s macroglobulinemia, J. Neurol. Sci., 21, 341, 1974. 36. Vital, A., Vital, C., Ragnaud, J.M., Baquey, A., and Aubertin, J., IgM cryoglobulin deposits in the peripheral nerve, Virchows Arch. Pathol. Anat., 418, 83, 1991. 37. Bromberg, M.B., Feldman, E.L., and Albers, J.W., Chronic inflammatory demyelinating polyradiculoneuropathy: comparison of patients with and without an associated monoclonal gammopathy, Neurology, 42, 1157, 1992. 38. Simovic, D., Gorson, K.C., and Ropper, A.H., Comparison of IgM-MGUS and IgG-MGUS polyneuropathy, Acta Neurol. Scand., 97(3), 194 1998. 39. Bleasel, A.F., Hawke, S.H.B., Pollard, J.D., and McLeod, J.G., IgG monoclonal paraproteinemia and peripheral neuropathy, J. Neurol. Neurosurg. Psychiatry, 56, 52, 1993. 40. Vital, A. et al., Polyneuropathy associated with IgM monoclonal gammopathy; immunogical and pathological study in 31 patients, Acta Neuropathol., 79, 160, 1989. 41. Yeung, K.B., Thomas, P.K., and King, R., The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinemia. Comparative, clinical, immunological, and nerve biopsy findings, J. Neurol., 238, 383, 1991. 42. Bosch, E.P., Ansbacher, L.E., Goeken, J.A., and Cancilla, P.A., Peripheral neuropathy associated with monoclonal gammopathy. Studies of intraneural injections of monoclonal immunoglobulin sera, J. Neuropathol. Exp. Neurol., 41, 446, 1982. 43. Bailey, R.O., Ritaccio, A.L., Bishop, M.B., and Wu, A., Benign monoclonal IgA gammopathy associated with polyneuropathy and dysautonomia, Acta Neurol. Scand., 73, 574, 1986. 44. Dalakas, M.C. and Engel, W.K., Polyneuropathy with monoclonal gammopathy: studies of 11 patients, Ann. Neurol., 10, 45, 1981. 45. Kelly, J.J., The electrodiagnostic findings in peripheral neuropathy associated with monoclonal gammopathy, Muscle and Nerve, 6, 504, 1983. 46. Kelly, J.J., Kyle, R.A., Miles, J.M., and Dyck, P.J., Osteosclerotic myeloma and peripheral neuropathy, Neurology, 33, 202, 1983. 47. Iwashita, H., Ohnishi, A., Asada, M., Kanazawa, Y., and Kuroiwa, Y., Polyneuropathy, skin hyperpigmentation, edema, and hypertrichosis in localized osteosclerotic myeloma, Neurology, 27, 675, 1977. 48. Bardwick, P.A. et al., Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrin-opathy, M-protein and skin change: the POEMS syndrome, Medicine, 59, 311, 1980. 49. Read, D. and Warlow, C., Peripheral neuropathy and solitary plasmacytoma, J. Neurol. Neurosurg. Psychiatry, 41, 177, 1978. ©2002 CRC Press LLC

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50. Vital, C. et al., Uncompacted myelin lamellae in polyneuropathy, organomegaly, endocrn-opathy, M-protein and skin changes syndrome. Ultrastructural study of peripheral nerve biopsy from 22 patients, Acta Neuropathol., 87, 302, 1994. 51. Ohnishi, A., Geographical patterns of neuropathy: Japan, in Peripheral Nerve Disorders. A Practical Approach, Asbury, A.K. and Gilliatt, R.W., Eds., Butterworths, London, 1984, 303. 52. Nakanish, T. et al., The Crow–Fukase syndrome: a study of 102 cases in Japan, Neurology, 34, 712, 1984. 53. Donaghy, M. et al., Peripheral neuropathy associated with Castleman’s disease, J. Neurol. Sci., 89(2–3), 253, 1989. 54. Fernandez-Torre, J.L., Polo, J.M., Calleja, J., and Berciano, J., Castleman’s disease associated with chronic inflammatory demyelinating polyradiculoneuropathy: a clinical and electrophysiological follow-up study, Clin. Neurophysiol., 110, 1133, 1999. 55. Scherokman, B., Vukelja, S., and May, E., Angiofollicular lymph node hyperplasia and peripheral neuropathy. Case report and literature review, Arch. Intern. Med., 151, 789, 1991. 56. Case records, Massachusetts General Hospital, Case 32, New Eng. J. Med., 311, 388, 1984. 57. Walsh, J.C., The neuropathy of multiple myeloma: an electrophysiological and histological study, Arch. Neurol., 25, 404, 1971b. 58. Victor, M., Banke, B.Q., and Adams, R.D., The neuropathy of multiple myeloma, J. Neurol. Neurosurg. Psychiatry, 21, 73, 1958. 59. Kelly, J.J., Kyle, R.A., Miles, J.M., O’Brien, P.C., and Dyck, P.J., The spectrum of peripheral neuropathy in myeloma, Neurology, 31, 24, 1981. 60. Vital, C., Vallat, J.M., Deminiere, C., Loubet, A., and Leboutet, M.J., Peripheral nerve damage during multiple myeloma and Waldenström’s macroglobulinemia. An ultrastructural and immunopathologic study, Cancer, 50, 1491, 1982. 61. Azar, H.A., Amyloidosis and plasma cell disorders, in Multiple Myeloma and Related Disorders, Vol. 1, Azar, H.A. and Potter, M., Eds., Harper and Row, Hagerstown, MD, 1973, 328. 62. Kyle, R.A. and Bayard, E.D., The Monoclonal Gammopathies, C.C. Thomas, Springfield, IL, 1976. 63. Nobile-Orazio, E. et al., Peripheral neuropathy in macroglobulinemia: incidence and antigen-specificity of M protein, Neurology, 37, 1506, 1987. 64. McLeod, J.G. and Walsh, J.C., Peripheral neuropathy asociated with lymphomas and other reticuloses, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., and Lambert, E.H., Eds., W.B. Saunders, Philadelphia, PA, 1975, 1314. 65. Vital, C., Vallat, J.M., Deminiere, C., Loubet, A., and Leboutet, M.J., Peripheral nerve damage during multiple myeloma and Waldenström’s macroglobulinemia. An ultrastructural and immunopathologic study, Cancer, 50, 1491, 1982. 66. Apartis, E. et al., Peripheral neuropathy associated with essential mixed cryoglobulinaemia: a role for hepatitis C virus infection?, J. Neurol. Neurosurg. Psychiatry, 60(6), 661, 1996. 67. Logothetis, J., Kennedy, W.R., Ellington, A., and Williams, R.C., Cryoglobulinemic neuropathy: incidence and clinical characteristics, Arch. Neurol., 19, 389, 1968. 68. Gemignani, F., Pavesi, G., Fiocchi, A., Manganelli, P., Ferraccioli, G., and Marbini, A., Peripheral neuropathy in essential mixed cryoglobulinaemia, J. Neurol. Neurosurg. Psychiatry, 55, 116, 1992. 69. Garcia-Bragado, F., Fernandez, J.M., Navarro, C., Villar, M., and Bonaventura, I., Peripheral neurpoathy in essential mixed cryoglobulinemia, Arch. Neurol., 45, 1210, 1988. 70. Vital, C. et al., Peripheral neuropathy with essential mixed cryoglobulinemia: biopsies from 5 cases, Acta Neuropathol., 75, 605, 1988. 71. Vallat, J.M., Desproges-Gotteron, R., Leboutert, M.J., Loubet, A., Gualde, N., and Treves, R., Cryglobulinemic neuropathy: a pathological study, Ann. Neurol., 8, 179, 1980. 72. Kyle, R.A., Monoclonal proteins in neuropathy, Neurol. Clin., 10, 713, 1992. 73. Lesprit, P. et al., Acute arterial obliteration: a new feature of the POEMS syndrome?, Medicine, 75(4), 226, 1996.

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CHAPTER 8 Figure 1 Segmental demyelination: thinly myelinated (remyelinating) fibers in about 50% of large-diameter fibers. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 8 Figure 2 IgM deposit on myelin sheath. Myelin sheath of myelinated fibers is stained dark (blue arrow) with IgM antibody immunohistochemical staining (top panels). Myelinated fibers (yellow arrows) are identified by the modified trichrome (bottom panels) stain. Paraffin section. IgM immunohistochemical stain. (100 × magnification.)

CHAPTER 8 Figure 3 Axonal degeneration. Many myelin-digestion chambers (one of them indicated by an arrow) are noted in almost all myelinated fibers. Inflammatory cells are scattered in the endoneurial space, especially in the upper section. Paraffin section. Gomori trichrome stain. (200 × magnification.)

CHAPTER 8 Figure 5 Perivascular inflammatory cells in the epineurial space. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 8 Figure 4 Many mononuclear inflammatory cells in the endoneurial space. Arrow indicates one of the “ghost fibers” as a result of myelin-digestion chambers. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 8 Figure 6 Segmental demyelination. Moderate loss of large-diameter fibers and a few thinly myelinated fibers (remyelinating) are obvious. The arrow indicates a small onion-bulb formation. The arrowhead indicates one denuded axon (demyelination). Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 8 Figure 7 Axonal degeneration: many scattered myelin-digestion chambers. Marked loss of population of large-diameter fibers is obvious. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 8 Figure 8 Active axonal degeneration: many myelin ovoids (arrowhead) and active myelin breakdowns (arrow). There is also a minimal loss of myelinated fibers. Semithin section. Toluidine blue. (200 × magnification.)

CHAPTER 8 Figure 9 Active vasculitis in an epineurial arteriole. Fibrinoid necrosis is prominent in the intimal layer of the arteriole (arrow). The arrowhead indicates one nerve fascicle. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 8 Figure 10 Minimal loss of myelnated fibers. One thinly myelinated (remyelinating) fiber is indicated by an arrow. Semithin section. Toluidine blue and basic fuchsin. (400 × magnification.)

CHAPTER 8 Figure 11 IgM deposit on myelin sheaths. Myelin sheath of almost all large-diameter myelinated fibers is clearly stained with IgM antibody immunofluorescence staining (arrow). Frozen section. IgM antibody immunofluorescence stain. (200 × magnification.)

CHAPTER 8 Figure 13 Perivascular collection of mononuclear cells in the epineurial space (arrows). H & E stain. (200 × magnification.)

CHAPTER 8 Figure 12 Active axonal degeneration: many myelin ovoids. Almost all myelinated fibers are undergoing active axonal degeneration. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 8 Figure 14 Segmental demyelination: many thinly myelinated fibers of large and intermediate diameter fibers. Moderate loss of population of myelinated fibers is present. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 8 Figure 15 Mixed axonal degeneration and segmental demyelination. Arrow 1 indicates a myelin breakdown, and arrow 2 indicates a myelin ovoid. The arrowhead indicates a thinly myelinated fiber. Moderate loss of myelinated fibers is also present. Semithin section. Toluidine blue. (200 × magnification.)

CHAPTER 8 Figure 17 Active axonal degeneration. The arrow indicates the largest myelin ovoid. Almost total loss of large-diameter fibers is obvious. Semithin section. Toluidine blue and basic fuchsin. (200 × magnification.)

CHAPTER 8 Figure 16 Perivascular infiltration of a few mononuclear cells in the epineurial space (arrow). H & E stain. (200 × magnification.)

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Neuropathies with Abnormal Deposits

There are many neuropathies with abnormal deposits. Most of them are rare and require ultrastructural electron microscopic study, which is beyond the scope of this book. Readers can find an excellent treatise on this subject in several books.1-3 Amyloid neuropathy, metachromatic neuropathy, polyglucosan body neuropathy, Fabry’s disease, and adrenomyeloneuropathy are discussed in this chapter because these disorders can be diagnosed confidently without any ultrastructural electron microscopic study.

AMYLOID NEUROPATHY Amyloid is a fibrillary substance made of beta-pleated proteins.4 Amyloid is relatively insoluble and resistant to proteolysis in vivo, so its deposition in tissue tends to be permanent. Amyloid neuropathy is a consequence of amyloid deposits in the nerve. Amyloid neuropathy is broadly divided into two major categories: familial and nonfamilial (Table 9.1). Nonfamilial amyloid neuropathy includes (1) primary amyloidosis (immunoglobulin light chair derived; AL), including myeloma-associated amyloidosis, and (2) secondary amyloidosis (amyloid A; AA), associated with chronic disease. Even though each type of amyloid neuropathy has distinct clinical features (Table 9.1), they often share certain common characteristic features because of selective involvement of small fibers and involvement of other organs: sensory neuropathy, dysautonomia, and other system involvements. Sensory neuropathy is usually characterized by dissociated sensory loss, with pain and temperature sensations most affected. Dysautonomia includes impotence, diarrhea, postural hypotension, and pupillary abnormality. Systemically, the kidney, heart, and liver are often involved.

FAMILIAL AMYLOID POLYNEUROPATHY (FAP) Familial amyloidosis is characterized by peripheral neuropathy in the majority of cases. In Gertz et al.’s series, 83% of patients with familial amyloidosis had peripheral neuropathy at the time of diagnosis. Cardiomyopathy was present in 27% and autonomic neuropathy was present in 33% of cases.5 Thus, neuropathy is the most disabling clinical feature in familial amyloidosis. FAP is classified into four types depending upon the clinical features : Type I (Andurade; Portuguese),6 Type II (Rukavian; Indiana),7,8 Type III (Van Allen; Iowa),9 and Type IV (Meretoja; Finnish).10 The major circulating proteins as a cause in FAP are now known (see Table 9.1): transthyretin in types I and II, apolipoprotein A1 in type III, and gelsolin in Type IV. Mutant transthyretin (TTR) is implicated in most cases of FAP. Approximately 20 mutant TTRs have been linked to disease. In one study, TTR mutations were detected in 29 of 32 patients with familial amyloidosis.5 An autosomal dominant inheritance pattern is also seen in all types. However, a positive family history was initially obtained in as few as 50%,11 but with further inquiry, this percentage was increased to 83%.5 Previously, clinical patterns formed the sole basis for differentiating one type of FAP from another. Now, more accurate molecular genetic testing of leukocyte DNA is available and can be performed even in asymptomatic individuals. Abnormal immunoglobulins are not present in the blood or urine in individuals with FAP. Nerve conduction findings are typical of axonal degeneration,12 predominantly involving sensory fibers. In Type I FAP, the most prominent nerve conduction abnormality is a markedly abnormal sensory CNAP in ©2002 CRC Press LLC

Types

Secondary type associated with chronic disease

Common Mutation

Except for the onset at an older age, the clinical features and NCS are the same as familial Type I amyloidosis

Transthyretin

TTR Met 30

Type II (Rukavian): Upper limb form Onset: Middle age.

Carpal tunnel syndrome and vitreous opacity. Relatively benign NCS: Typical carpal tunnel findings

Transthyretin

TTR Tyr 77

Type III (Van Allen): Generalized form Onset: Fourth decade.

Progressive painful distal sensorimotor polyneuropathy NCS: Not reported

Apolipoprotein

Point mutation in apolipoprotein A1 gene

Gelsolin

Point mutation in gelsolin gene

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Sensory neuropathy of the leg (preferentially involving pain and temperature) and autonomic neuropathy NCS: The markedly abnormal CNAP (either absent potential or reduced amplitude) in the presence of a normal or mildly slow motor NCV

.

Type IV (Meretoja): Cranial nerve form Multiple cranial nerve palsy Onset: Third decade. and lattice corneal dystrophy. NCS: Not reported

a

This includes amyloidosis associated with multiple myeloma and Waldenström’s macroglobulinemia.

Types I and II are both produced by point mutation in a serum protein, TTR; more than 40 mutations have been described. Met 30 mutation is most common, and Tyr 77 mutation is the second most prevalent. b

Abbreviation: NCS, nerve conduction study ©2002 CRC Press LLC

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Familial amyloidosisb Type I (Andurade): Lower limb form Onset:Third decade.

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Nonfamilial amyloidosis Primary typea

Clinical Features

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TABLE 9.1 Molecular and Genetic Classification of Amyloidosis

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the presence of a normal or mildly slow motor NCV. In Type II FAP, typical findings of carpal tunnel syndrome are observed. Correct diagnosis of familial amyloidosis is important both for genetic counseling and early recommendation of liver transplantation, an effective treatment modality for familial amyloidosis.13 Previously, FAP was diagnosed by the presence of endoneurial amyloid deposits on the nerve biopsy and positive family history. The sural nerve biopsy was positive in 87 to 95% of patients with amyloid neuropathy.5,14 At present, the diagnosis of FAP can also be made by the positive TTR reactivity of amyloid deposits in the sural nerve and by molecular DNA testing.5 In asymptomatic or presymptomatic carriers, the sural nerve biopsy may be normal. Thus, at present, molecular genetic testing has emerged as the pivotal test for familial amyloidosis.

NONFAMILIAL AMYLOID NEUROPATHY In nonfamilial amyloidosis, the amyloid fibril appears homologous to the terminal region of an immunoglobulin light chain,15 indicating a close relationship between amyloid and light chain (lambda and kappa) immunoglobulins. In primary amyloidosis, the neuropathy resembles Type I hereditary neuropathy clinically and electrophysiologically. In nonfamilial neuropathy, however, onset is later, and bladder and rectal incontinence may be more delayed than in the inherited variety.16 Neuropathy is characterized by painful distal symmetrical sensorimotor neuropathy with prominent autonomic features. Loss of pain and temperature sensation is frequently more striking than loss of position sense. The most important test for differentiation from familial amyloidosis is the immunoelectrophoresis of serum protein, because a monoclonal protein can be detected in two-thirds of patients, while it is negative in familial amyloidosis.17 Systemic manifestations include common renal insufficiency with proteinuria, abnormal protein electrophoretic patterns in the serum in about two-thirds of patients and in the urine in 90%, monoclonal proteins in approximately 90% of patients when both serum and urine are studied, and increased plasma cells on bone marrow examination in about twothirds of patients.17,18 The nerve conduction findings are consistent with axonal degeneration.16,19 Diagnosis depends on the histological demonstration of amyloid. Rectal biopsy may be the safest and most convenient procedure, with a 61 to 82% chance of identifying amyloids.18 When neuropathy is present, amyloid is found in 86 to 100% of biopsied sural nerves.16,20 Light-chain positive immunostaining in amyloid is diagnostic of primary amyloidosis. In general, polyneuropathy is not a feature of secondary amyloidosis. Diagnosis of secondary amyloidosis is made on the basis of amyloid in the tissue and serious chronic disease. A few cases of amyloid in the sural nerve in secondary amyloidosis have been reported.1

PATHOLOGY OF AMYLOID NEUROPATHY Biopsy of abdominal fat pad (fine needle aspiration biopsy) or rectal mucosa provides a high-yield and low-morbidity option for primary and familial amyloidosis.5,21 Abdominal fat pad biopsy was positive for amyloid in 72 to 100% of patients with amyloidosis, whereas the rectal mucosa biopsy was positive for amyloid in 69 to 87% of cases.21,22 In contrast, in one large series, skin biopsy was proven as sensitive as nerve biopsy for detection of amyloid in Portuguese FAP.14 In one study, muscle biopsy had a higher diagnostic yield than nerve biopsy, at least in primary amyloidosis: there were no deposits of crystal-violet or Congo-red positive amyloid in or between nerve fibers in contrast to typical crystal-violet positive amyloid in many regions of the endomysium of muscle biopsy in six cases of light-chain amyloid neuropathy.23 In view of this, we recommend a combination of nerve and muscle biopsy for diagnosis of amyloid neuropathy. The hallmark of amyloid neuropathy is amyloid in the peripheral nerve (Color Figures 9.1 and 9.2).* In post-mortem studies, amyloids have been found everywhere in peripheral nerves, including * Color insert figures. ©2002 CRC Press LLC

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dorsal root, sympathetic, and parasympathetic ganglia.24 Widespread amyloid involvement in the autonomic nervous system explains the frequent dysautonomic symptoms in amyloid neuropathy. The predominant nerve degeneration in amyloid neuropathy is axonal degeneration (Color Figure 9.3). This has been clearly documented in teasing preparations 16,25-28 and in semithin sections.28 Certainly, nerve conduction data are consistent with axonal degeneration. It is generally accepted that axonal degeneration in this neuropathy is a result of intrinsic amyloid deposits.25,27,29,30 Coimba and Andrade30 reached the opposite conclusion from their observations of nerve biopsies: nerve fiber degeneration preceded the appearance of the amyloid, considering that fiber degeneration never had a focal character, and amyloid deposits were rare compared with the widespread nerve fiber degeneration. Utilizing contemporary histological techniques, Dyck and Thomas found severe depletion of unmyelinated and small-diameter myelinated fibers, correlating closely with clinical findings of pain and temperature sensory loss and autonomic dysfunction (Color Figure 9.4).25,27 They proposed that this is the consequence of compression of the dorsal root ganglia cells by amyloid deposits. On the other hand, Coimba and Andrade observed that degeneration of unmyelinated fibers appeared to be less widespread than that of myelinated fibers.30 Jedzejowska also observed a striking diminution of the density of myelinated fibers, involving all fiber sizes.26 The definite diagnosis of amyloid neuropathy is based on demonstration of amyloid in the nerve (Color Figure 9.1). Amyloid is histochemically Congo-red positive (Color Figure 9.5) and green birefringence is seen after Congo-red staining is observed with polarized light. Congo-red staining of a biopsy specimen which is then examined by polarizing microscopy is the single best procedure for the diagnosis of amyloid (Color Figure 9.6).31 Congo-red stains elastic tissue and occasionally thick bundles of collagen as well as amyloid. Unless it is properly decolorized, erroneous interpretation may occur. For these reasons, Blum claimed that light microscopic examination has not been as useful on Congo-red stained sections as on sections stained with crystal-violet.32 When the sections are viewed under the polarizing microscope, however, one immediately observes the bright apple-green birefringence of amyloid as distinguished from the white birefringence of collagen. This positive form of birefringence is characteristic of amyloid of all types. As yet, no false-positive green birefringence has been reported. Almost all types of amyloids also give reddish metachromasia with crystal- or methyl-violet (Color Figure 9.7).31,33 This method suffers from the disadvantages of rapid deterioration of the slides and variability in the quality of different batches of the dyes. However, Trottler et al. claimed that, using fresh-frozen sections, they were able to demonstrate amyloids quickly and clearly using crystal-violet stain on the biopsied sural nerve and muscles (Color Figure 9.7).34 Amyloid gives a bright yellow fluorescence with thioflavin T or S stain (Color Figure 9.8).31,33 However, these methods are not specific for amyloid. Thus, because of their high sensitivity, these tests should be used only as a screening device.31,33 Amyloids were found in the sural nerve in most patients with clinical amyloid neuropathy in which the biopsy was performed. In primary amyloid neuropathy, the diagnostic yield was 86 to 100%,16,20 while it was 95% in FAP.14 Thus, it is natural that the sural nerve should be the biopsy of choice in any cases of suspected amyloid neuropathy on clinical grounds. This indicates that in a small percentage of patients with amyloid neuropathy, the sural nerve biopsy is negative. We believe that this is due to the small sample in the nerve. Thus, if clinical suspicion is high and the nerve biopsy is negative, the clinician should consider another biopsy site.35 In Type II hereditary amyloid neuropathy, the most common site for amyloid detection was shown to be the flexor carpi retinaculum.7 Bastian found 2 cases of previously undiagnosed amyloidosis by routine study of flexor retinaculum tissue from 87 consecutive carpal tunnel release procedures.36 Three patterns of amyloid deposition have been found in the peripheral nerves in this disorder:37 1.

Extraneurial connective tissue deposition of amyloid: this is responsible for carpal tunnel syndrome, a common feature of all types of amyloid neuropathy. However, it is more

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common in Type II hereditary neuropathy. It should be stressed that carpal tunnel syndrome may precede generalized amyloidosis by several years and that surgical release usually affords good relief of symptoms. Widespread endoneurial deposition of amyloid: this pattern is most prominent in Types I and III hereditary and primary non-hereditary forms (Color Figure 9.9).38 Amyloid deposition within the walls of the vasa nervorum of both the epineurium and endoneurium: this pattern occurs to some extent in almost all types of amyloid neuropathy, but is most pronounced in and most clearly related to the secondary non-hereditary form with malignant dysproteinemia. (Color Figure 9.9.)37

Immunohistochemical staining for the amyloid major protein can distinguish familial from primary light-chain amyloidosis (Color Figure 9.10). Kappa or lambda light-chain positivity for amyloid is diagnostic of primary amyloid neuropathy, while transthyretin (TTR) positivity for amyloid, is diagnostic of familial amyloid neuropathy. For technical adequacy, serial sections must be stained alternately with Congo-red and immunostain in order to verify that the localization of immunostaining corresponds to sites of amyloid deposit. In the immunohistochemical staining of 39 muscles from patients with amyloid neuropathy, TTR was positive in all 12 FAP cases and light chain positive in all 12 cases with plasma dyscrasia, confirming the high specificity of the immunochemical staining technique. Among 15 patients with sporadic amyloidosis (no family history and no clinicopathologic signs of plasma cell disease), this test showed positive immunostaining for light-chain in 11 cases and for TTR in 3.39 Among 38 sural nerve biopsies, immunostaining was positive for TTR in 11 patients and for light-chain in 15 (lambda in 8 and kappa in 7).11 Among 11 TTR-positive patients, there was no family history in 5 cases while no evidence of circulating paraprotein was found in 2 of 15 light-chain positive patients. These two studies not only confirmed the specificity of these immunohistochemical staining tests, but also demonstrated the value of these tests in identifying familial or primary amyloid neuropathy in “sporadic cases.” Thus, immunostaining can prove critical to diagnosis of a small number of sporadic cases. Unfortunately, in 10 to 30% of cases, this technique is not able to identify the amyloid subtypes.1

METACHROMATIC LEUKODYSTROPHY (SULFATIDE LIPIDOSIS; ARYLSULFATIDASE DEFICIENCY) Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder characterized by the accumulation of galactosyl-3-sulfate (sulfatide) in the brain, kidney, gallbladder, and peripheral nerves. The sulfatide is stained brown by cresyl-violet (Color Figure 9.11) or thionine (Color Figure 9.12) instead of the purple or blue color of normal tissues. This phenomenon, termed metachromasia, is specific for metachromatic leukodystrophy and gives the disease its name. Four forms of MLD have been commonly recognized: late infantile, juvenile, adult, and multiple sulfatase deficiency. The enzyme arylsulfatase A is deficient in the first three forms. Its assay in blood leukocytes and cultured skin fibroblasts is used both as a standard diagnostic test and a means of heterozygote detection. However, such assays give normal results in rare cases of defective arylsulfatase-A activator production.40 The late infantile form is by far the most common and its clinical features develop in four stages.41 Stage 1 manifests in the second year as weakness, hypotonia, areflexia, extensor plantar response, and retardation of mental development. In stage 2, ataxia and hypotonia are more pronounced, flaccid diplegia or tetraplegia arises, and cerebral deficiencies increase. In stage 3, the symptoms of central nervous system deterioration predominate: speech deterioration, apathy, ataxia, and optic atrophy. In stage 4, the patient shows indications of decerebrate rigidity, blindness due to optic atrophy, deafness, and hypertonic seizures. Marked slowing in motor NCVs and absent CNAPs are the rule in the nerve conduction study.12 ©2002 CRC Press LLC

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Diagnosis of MLD does not usually require nerve biopsy. Nerve biopsy is indicated in the following circumstances: (1) when the biochemical assay is not available; (2) when the biochemical tests give falsely negative results; and (3) when a neuropathy is suspected without any detectable CNS disease. Nerve biopsy constitutes a rapid and reliable procedure for the diagnosis of MLD which is preferable to arylsulfatase-A assays on leukocytes and cultured fibroblasts because metachromatic material is probably demonstrable in all cases,41-44 and demonstration of metachromatic granules is diagnostic of MLD (Color Figures 9.11 and 9.12). According to Vos et al.,45 in 7 patients (5 of them suffering from MLD) out of 13 with low arylsulfatase-A activity in the leukocytes (9 MLD patients), adequate interpretation of low arylsulfatase-A activity failed to make a definite diagnosis of MLD. In those cases, a sural nerve biopsy provided essential diagnostic information, correcting one false negative and 2 false positive diagnoses of clinical MLD. For demonstration of metachromatic granules, the biopsied nerve should be stained on frozen sections, since metachromasia is best demonstrable with acidified cresyl-fast violet stain.46 In our laboratory, we routinely use cresyl-fast violet stain on frozen sections in every biopsied nerve. The following findings are characteristic of the peripheral nerve: 1.

2.

3. 4.

5.

There is an accumulation of metachromatic granules of 0.5 to 1 µm in diameter in the perinuclear cytoplasm of Schwann cells — these granules are also seen in Remak cells, within macrophages, and in the vicinity of endoneurial capillaries. These metachromatic granules are stained brown instead of purple or blue with cresyl-fast violet or toluidine blue. They are also PAS-positive and methylene-blue-positive (Color Figure 9.13). These metachromatic granules are also demonstrated in all forms of MLD, including multiple sulfatase deficiency.47 No definite correlation is found between the degree of segmental demyelination and the presence of metachromatic granules.48,49 In semithin sections, there is a reduction in the myelinated fiber population, metachromatically stained granules, many thinly myelinated fibers in relation to the axon diameter, and occasional small onion-bulb formations (Color Figure 9.14). In teased fibers, segmental demyelination and remyelination occur.48,50 With electron microscopy, many types of membrane-bound inclusion materials were reported. Among these, “tuffstone” bodies seems to be most typical of MLD51: myelin figures in Schwann cells and lamellated inclusions corresponding to the metachromatic granules. Both Martin43 and Thomas51 failed to detect any differences in the types of inclusion among the different forms. Some quantitative differences have been described among the various classic forms: demyelination was found to be most pronounced in the late infantile form, while less markedly diminished myelinated fiber density, fewer Schwann cell inclusion macrophages, and more numerous small onion bulbs were noted in the later onset forms.43,51

The presence of metachromatic granules in the sural nerve biopsy is diagnostic of MLD.

POLYGLUCOSAN BODY NEUROPATHY Adult polyglucosan body disease (APGBD) was first reported in 1980.52 Until 1998, some 25 cases of this disease were reported.53 It is characterized by the typical constellation of clinical features: onset in the fifth to seventh decades (88%), peripheral neuropathy (80%), dementia (64%), neurogenic bladder (72%), and upper motor neuron signs (82%).53 Atypical cases present with amyotrophic lateral sclerosis54 or Parkinsonism53 were reported. In one-third of cases of APGBD, there

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was a positive family history. The course of disease was variable, with survival of between 1 and 14 years in reported cases. The nerve conduction study showed axonal neuropathy.55 The pathological hallmark of this entity is a large number of polyglucosan bodies in the central and peripheral nervous system52,56 This disease can be diagnosed by sural nerve biopsy.52,56 Skin biopsy from the axilla in one case showed an abundance of PGB in the myoepithelial cells of apocrine glands.57 Polyglucosan body is a generic name referring to a Lafora body (PGB in neurons), corpora amylacea (PGB in astrocytes), and all other similar structures. In the nerve, many huge distended axons with polyglucosan bodies and thin myelin sheaths were observed in all studied cases of APGBD (Color Figure 9.15).52,53,56,58 The larger bodies measured 50 µm in diameter. Polyglucosan bodies were stained pale blue with the modified trichrome stain, basophilic with H & E, metachromatic with toluidine blue, and strongly positive with PAS (Color Figure 9.16) before and after amylase and with iodine. They were composed predominantly of abnormally branched glycogen (amylopectin), as classically seen in Type IV glycogenosis.52 Teased nerves showed a “string of beads” appearance due to an ellipsoid dilatation of the axon due to a polyglucosan body (Color Figure 9.17) and axonal degeneration. These bodies were also observed in the intramuscular and dermal nerve bundle. Since these bodies increase with aging58,59 as well as with the presence of neuropathy,1 the presence of one or two PCBs is nonspecific without any pathological importance.1 Midroni and Bilbao stated that observation of more than one PGB per nerve fascicle cross-section, of a PGB outside an axon, or of unusually large PGBs (larger than 30 µm) should lead to consideration of APGBD, type IV glycogenosis, and Lafora’s disease,1 and that findings of even a single PGB for a patient under the age of 5 and perhaps under the age of 20, should raise similar suspicions. It was once thought that PGBs were seen in sural nerve biopsy only in APGBD.52,56 However, with time, the bodies were also seen in primary axonal neuropathies,60 demyelinating neuropathy,58 aging,58,59 human diabetes,61 Lafora’s disease,58 and type IV glycogenosis.62 The recent consensus has been that typical clinical manifestations (see above) are essential for the diagnosis of APBGD in addition to the histological findings of many PGBs in the nerve biopsy.53,55

FABRY’S DISEASE (ALPHA-GALACTOSIDASE-A DEFICIENCY) Fabry’s disease is a sex-linked recessive disorder with angiokeratoma, painful neuropathy, diminished sweating, easy thrombotic episodes, and renal failure. It is due to progressive deposition of ceramides, mainly trihexosides, in many tissues including peripheral nerves, as a result of a deficiency of the lysosomal enzyme ceramide trihexosidase (alpha galatocidase A). Clinically, there are no obvious objective findings of peripheral neuropathy except constant dysesthetic pain and occasional episodes of excruciating pain. Motor and sensory nerve conductions were normal in two reports,63,64 while mild slowing in motor nerve conduction was reported in 8 of 12 cases in another report.65 Sensory and autonomic dysfunction in this disorder can be explained by sensory and autonomic neuronal degeneration due to lipid storage in the neurons. This has been verified in post-mortem examinations.64,66,67 Ohnishi and Dyck showed that the small cell neurons in the dorsal root ganglia are selectively infiltrated with lipids, resulting in a ballooned-out appearance.64 Dysautonomic signs including lack of sweating, common in this disorder,68 are due to known lipid deposition in autonomic neurons and correlate well with the loss of unmyelinated fibers in the peripheral nerves. Nerve biopsy is not necessary for the diagnosis of Fabry’s disease because of the characteristic clinical manifestations and the availability of a reliable alpha galactosidase assay in the leukocytes. Skin biopsy readily demonstrates characteristic lipid inclusions. However, when the diagnosis is unsuspected, the nerve biopsy shows a pathognomonic histology.1

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Intracytoplasmic granular lipid inclusions in the perineurium and in the endothelial cells in the endoneurial vessels are the pathognomonic finding for this disorder. These lipid inclusions are birefringent, thus being identified as a “Maltese cross” on the fresh-frozen sections under polarized light microscopy (Figure 9.1),1 also reliably identified as positive with Sudan-black B, oil-red O (Color Figure 9.18), and PAS stains on the frozen sections,63,69 and readily identified as osmophilic lipid in the semithin sections.1 In paraffin sections, these lipid inclusions can be identified only by Kultschitzky’s stain.2 These granular inclusions are observed in all cases and under the electron microscope represent osmophilic lamellar inclusion bodies. Selective loss of small myelinated and unmyelinated fibers. Small myelinated fibers were selectively lost in four of six studied cases, and unmyelinated fibers were lost in four of five cases.70 Teased fibers showed axonal degeneration in 2 to 42% of teased fibers and segmental demyelination in 4 to 19% of fibers.64,71 Ohnishi contended that axonal degeneration is the primary process and segmental demyelination is secondary.64 Plotting of internodal lengths against diameters in teased nerve fibers in one case showed excessive variability of internodal length and uniformly short internodes, indicative of predominant axonal degeneration.

Thus, the combination of the selective loss of small myelinated and unmyelinated fibers with the typical granular lipid inclusions in the perineurial cells and in the endoneurial blood vessels is diagnostic of Fabry’s disease.

FIGURE 9.1 “Maltese cross” birefringence in perineurium (arrows) in Fabry’s disease under polarized light. (With permission from Bilbao, J.M., Ackerman’s Surgical Pathology, 8th ed., Rosai, J., Ed., C.V. Mosby Co., 1995.)

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ADRENOMYELONEUROPATHY (AMN) Adrenomyeloneuropathy (AMN), a variant of adrenoleukodystrophy (ALD), is a sex-linked recessive disorder characterized by adrenal insufficiency, progressive myelopathy, and peripheral neuropathy due to the accumulation of very long-chain fatty acids. Onset typically occurs in the second to fourth decade and the disease is usually progressive. Neuropathy is not a feature of childhood ALD.72 The definite diagnosis of ALD or AMN is made on the assay of very long-chain (26 more carbon) fatty acids in the redcell or whole-plasma lipid. Motor nerve conduction is moderately slow in this disorder.12 Nerve biopsy showed the following: 1. 2. 3. 4.

Loss of myelinated fibers.73-76 Some authors have reported loss of large and small myelinated fibers,73,74 while others have reported only large myelinated fiber loss.76,77 Thin myelin compared with the axon diameter and onion-bulb formation.75,76 Teased fibers showed evidence of chronic demyelination and remyelination. Electron microscopy showed lamellar inclusions in the Schwann cell cytoplasm.74-76

This disorder showed nonspecific demyelinating neuropathy with onion-bulb formation.

CASES OF NEUROPATHY WITH ABNORMAL DEPOSIT CASE 1: 6-MONTH HISTORY OF BURNING DYSESTHESIA IN ALL LIMBS AND 4-YEAR HISTORY OF IMPOTENCE Case Presentation A 60-year-old white male, 6 months prior to evaluation, noticed the onset of dyspnea, especially with exertion, which was initially thought to be cardiac in origin. He underwent cardiac evaluation which was unremarkable. Shortly thereafter, he developed burning dysesthesia in the distal right lower extremity, which subsequently progressed to involve all four extremities. He also had intermittent shock-like sensations in all four extremities. In addition, he described hyperesthesia to clothing or bedsheets. Other history included a 15- to 20-pound weight loss in the preceding 3 to 4 months as well as decreased muscle bulk, but he did not complain of weakness. An MRI of the brain was normal. He was treated with gabapentin, phenytoin, and carbamazepine, all without success. The patient also described light-headedness upon arising to a standing position and severe constipation. In addition he described a 4-year history of impotence for which he received penile injections of pavaverine. A general physical exam was noncontributory. A neurological exam revealed generalized atrophy of muscles and occasional fasciculations in the right deltoid. Motor strength and sensory exam to pinprick, proprioception, and vibration were intact. Reflexes were 2+ and symmetric, and plantar responses were flexor. All laboratory work-ups for peripheral neuropathy including anti-Hu antibody and CSF were negative except monoclonal IgA-lambda light-chain. A bone survey was normal. The NCS/EMG showed predominantly axonal polyradiculoneuropathy with mild slowing in motor and sensory NCV. Case Analysis This patient had a subacute course of weight loss, a history suggestive of painful sensory neuropathy, and nonrevealing neurological examination. Light-headedness upon arising and impotence for 4 years were indicative of autonomic dysfunction. There are two diseases which classically are presented with sensory neuropathy and autonomic neuropathy: diabetes mellitus and amyloidosis. Since ©2002 CRC Press LLC

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diabetes was clearly ruled out by the appropriate studies, there remained a definite possibility of amyloid neuropathy. Paraneoplastic sensory neuropathy was another consideration, though dysautonomia is rarer in this condition. This was ruled out by the chest CT scan and negative anti-Hu antibody. We did muscle and nerve biopsies in this case for two reasons: the possibility of amyloid neuropathy and the remote possibility of vasculitis in view of the weight loss. Sural Nerve and Anterior Tibialis Muscle Biopsies There was a minimal loss (20%) of myelinated fibers with large-diameter fiber sparing and a few scattered myelin-digestion chambers in the frozen section stained with the modified trichrome. Amyloid was apparently absent by the Congo-red stain in the initial evaluation. Muscle biopsy showed scattered angular atrophic fibers which were intensely stained with NADH, indicative of mild denervation. Congo-red material was obvious in the vessel walls in the epimysial space (Color Figure 9.19) and along the perimysial border of the muscle. Evaluation of many more sections of the nerve later showed scattered Congo-red materials in the fatty tissues in the epineurial space in a few sections (Color Figure 9.20). Treatment and Follow-up Bone marrow biopsy showed significant plasmacytosis compatible with multiple myeloma. Despite treatment with melphalan, the patient continued to lose weight and his dysautonomic symptoms (orthostatic hypotension and abdominal distention due to severe constipation) got worse, requiring proamatine. Comments This case represents a situation in which the nerve biopsy was apparently negative and the muscle biopsy was obviously positive for amyloidosis in the initial evaluation. However, the evaluation of more nerve sections documented scattered amyloid in the fatty tissue in the epineurial space in a few sections. This taught us that it is necessary to cut multiple sections from different levels of the specimen since amyloid may be present in a few sections. Thus, in cases of suspected amyloid neuropathy, it is our recommendation to cut and stain as many sections of the biopsied nerve as possible. Clearly, in one study, muscle biopsy had a higher diagnostic yield than nerve biopsy.23 In view of this, we do both nerve and muscle biopsies for diagnosis of amyloid neuropathy, as in this case.

CASE 2 : DELAYED WALKING AND HAND TREMORS IN A 27-MONTH-OLD GIRL Case Presentation A 27-month-old girl was referred to a pediatric neurologist for evaluation of delayed walking and hand tremors. Her birth was uneventful and her early development up to sitting at 6 months of age was normal. She crawled at 1 year and started to stand up without assistance at 18 months. Her mental development was normal. When she attempted to walk, her arms and legs often began to shake and she would fall down. Because of her shaking hands, she frequently spilled food or dropped objects. Family history was remarkable for a maternal second cousin with cerebral palsy and a maternal greataunt who suffered from mental retardation. Abnormal neurological findings were increased tone in the legs, marked dysmetria in the upper and lower extremities, a very wide-based ataxic gait, absent DTRs, and upgoing toes. No telangiectasia was noted. Muscle strength was good. An MRI of the brain was reported to be normal. An NCS showed marked demyelinating neuropathy (8–10 m/sec). Serum alpha-fetoprotein, pyruvate, and lactate were all normal. CPK was also normal.

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Case Analysis The most salient feature in this patient was the combination of CNS and peripheral nerve involvement: ataxia, increased tone, and Babinski signs with absent reflexes. Thus, obvious diagnostic possibilities at this age included metachromatic leukodystrophy, globoid leukodystrophy (Krabbe’s disease), adrenoleukodystrophy, infantile axonal dystrophy, and ataxia telangiectasia. In view of the lack of telangiectasia, ataxic telangiectasia was most likely ruled out. Normal cognition and normal MRI scan of the brain were thought to rule out leukodystrophy. An NCS and EMG were included in the workup in view of the specific pattern of nerve conduction abnormalities seen in these conditions. Following the NCS, the pediatric neurologist ordered a nerve biopsy in desperation for a diagnosis. Sural Nerve Biopsy There was a moderate loss (30%) of myelinated fibers. Scattered granules in the endoneurium were stained as metachromatic by crystal-violet (Color Figure 9.21) and cresyl-fast violet stains. These granules were Congo-red negative. Almost all myelinated fibers were thinly myelinated. Metachromatic granules were seen scattered in the endoneurium with some granules in the Schwann cells and in the macrophages near the endoneurial vessels (Color Figure 9.14). Final Diagnosis Metachromatic leukodystrophy was the final diagnosis. Treatment and Follow-up After the diagnosis of metachromatic leukodystrophy was made by the sural nerve biopsy, the referring pediatric neurologist was not convinced about the diagnosis and checked the arylsulfatase-A level in the leucocytes of the patient. This was found to be 12% of normal. Comments This case represents a situation in which the diagnosis was unsuspected because of the normal MRI scan and the nerve biopsy was diagnostic of metachromatic leukodystrophy. This case demonstrated two lessons: the sural nerve biopsy can confirm the diagnosis of metachromatic leukodystrophy even with a normal MRI scan, and the frozen sections stained with routine cresyl-fast violet may confirm the diagnosis of metachromatic leukodystrophy in unsuspected cases.

CASE 3: A 2-YEAR HISTORY OF PARKINSONISM, UPPER MOTOR NEURON SIGNS, AND PERIPHERAL NEUROPATHY* Case Presentation A 50-year-old woman was presented with a 2-year history of slow and low volume speech and a 1-year history of poor balance, frequent falls, tremor of the right hand, urinary urgency, and impaired concentration and episodic memory.53 She was not able to walk without support around her house and required a wheelchair for longer distances. Abnormal neurological findings were slow, hypomimic speech with a paucity of facial expression, a coarse resting tremor, cogwheel rigidity and bradykinesia. There was wasting of intrinsic hand muscles and muscles below the knees, mild weakness of all ankle movements, and high-arched feet. Light touch and pin-prick sensation were impaired below the knees, and vibration was absent to the mid-shins. DTRs were absent at the ankles and brisk at the knees with bilateral plantar extensor responses. Her gait was slow, festinating, and bradykinetic. *This case was contributed by Dr. N.P. Robertson at the University Hospital of Wales in Cardill, Wales. This case was reported in a paper in the Journal of Neurology, Neurosurgery, and Psychiatry in 1998.53 ©2002 CRC Press LLC

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Formal neuropsychological evaluation suggested frontal lobe dysfunction. A cranial CT was normal and a whole spine x-ray showed moderate degenerative changes. An NCS showed axonal neuropathy. Peripheral neuropathy laboratory work-ups were negative. Case Analysis This patient was presented with Parkinsonism, frontal dementia, peripheral neuropathy, neurogenic bladder, and upper motor neuron signs. This patient had all five common neurological features of APGBD: onset in the fifth to seventh decades, upper motor neuron signs, peripheral neuropathy, neurogenic bladder, and dementia. Thus, APGBD was a definite diagnostic possibility, although Parkinsonism was an unusual presentation. Sural Nerve Biopsy There was a moderate loss of both small and large myelinated fibers and occasional axonal clusters. Several polyglucosan bodies were present: almost one polyglucosan body per fascicle on average, two within some fascicles (Color Figure 9.22 and Figure 9.2). Teased fibers showed a few fibers in late-stage Wallerian degeneration and an occasional polyglucosan body. Final Diagnosis APGBD with axonal neuropathy and a polyglucosan body was the final diagnosis.

FIGURE 9.2 Electronmicrograph demonstrating a myelinated fiber with a polyglucosan body occupying part of the axon. The polyglucosan body has an electron-dense core with a less dense peripheral. (16,300 × magnification.) (Courtesy of Dr. Neil Robertson, University Hospital of Wales, Cardiff, Wales.) ©2002 CRC Press LLC

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Treatment and Follow-up No improvement was noted with an incremental apomorphine test or more prolonged dopamine challenge. Comments Diagnosis of APGBD was made by the association of the appropriate clinical phenotype with excessive numbers of polyglucosan bodies in the nerve biopsy. In this patient, the presence of an axonal neuropathy, mild frontal dementia, upper motor neuron signs, and a history of urinary dysfunction associated with excessive numbers of polyglucosan bodies on the sural biopsy was characteristic of APGBD. This case underlines the diverse clinical presentation of this rare neurological disease and the importance of recognizing the unusual association of clinical features in making the diagnosis. APGBD should be included in the differential diagnosis of Parkinsonism unresponsive to dopaminergic therapy.

REFERENCES 1. 2. 3. 4. 5. 6. 7.

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15. 16. 17.

Midroni, G. and Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, MA, 1995. King, R., Atlas of Peripheral Nerve Biopsy, Arnold, London, UK, 1999. Vital, C. and Vallat, J., Ultrastructural Study of the Human Diseased Peripheral Nerve, 2nd ed., Elsevier, Amsterdam, 1987. Glenner, G.G., Amyloid deposits and amyloidosis: the B-fibrilloses, New Eng. J. Med., 302, 1283, 1980. Gertz, M.A., Kyle, R.A., and Thibodeau, S.N., Familial amylodosis: a study of 52 North American-born patients examined during a 30-year period, Mayo Clin. Proc., 67, 428, 1992. Andrade, C., A peculiar form of peripheral neuropathy. Familiar atypical generalized amyloidosis with special involvement of the peripheral nerves, Brain, 75, 408, 1952. Mahloudji, M., Teasdall, R.D., Adamkiewicz, J.J., Hartmann, W.H., Lambird, P.A., and McKusick, V.A., The genetic amyloidoses, with particular reference to hereditary neuropathic amylodosis, Type II (Indiana or Rukavina type), Medicine, 48, 1, 1969. Rukavina, J.G., Block, W.D., Jackson, C.E., Falls, H.F., Carey, J.H., and Curtis, A.C., Primary systemic amyloidosis: review and an experimental, genetic and clinical study of 29 cases with particular emphasis on the familial form, Medicine, 35, 239, 1956. Van Allen, M.W., Frohlich, J.A., and Davis, J.R., Inherited predisposition to generalized amyloidosis. Clinical and pathlogical study of a family with neuropathy, nephropathy and peptic ulcer, Neurology, 19, 10, 1969. Meretoja, J., Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms, Ann. Clin. Res., 1, 314, 1969. Li, K., Kyle, R.A., and Dyck, P.J., Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy, Am. J. Pathol., 141, 217, 1992. Oh, S.J., Clinical Electromyography: Nerve Conduction Studies, Williams & Wilkins, Baltimore, MD, 1993. Holmgren, G. et al., Clinical improvement and amyloid regresssion after liver transplantation in transthretin amyloidosis, Lancet, 341, 1113, 1993. Guimaraes, A., Pinheiro, A.V., and Leite, I., Sural nerve biopsy in familial amylodotic polyneuropathy: a morphological and morphometrical study, Amyloid and Amylodosis: Proceedings of the 5th International Symposium on Amyloidosis, Om Ospbe, T. et al., Eds., Plenum Press, New York, 1987, 493. Glenner, G.G., Ein, D., and Terry, W.D., The immunoglobulin origin of amyloid, Am. J. Med., 52, 141, 1972. Kelly, J.J., Jr. Kyle, R.A., O’Brien, P.C., and Dyck, P.J., The natural history of peripheral neuropathy in primary systemic amyloidosis, Ann. Neurol., 6, 1, 1979. Gertz, W.A. and Kyle, R.A., Primary systemic amyloidoses — a diagnostic primer, Mayo Clin. Proc., 64, 1505, 1989.

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18. Kyle, R.A. and Bayard, E.D., Amyloidosis: review of 236 cases, Medicine, 54, 271, 1975. 19. Melgaard, B. and Nielsen, B., Electromyographic findings in amyloid polyneuropathy, EEG Clin. Neurophysiol., 17, 31, 1977. 20. Kyle, R.A. and Dyck, P.J., Amyloidosis and neuropathy, in Peripheral Neuropathy, 3rd ed., Dyck, P.J. et al., Eds., W.B. Saunders, Philadelphia, PA, 1993, 1294. 21. Gertz, M.A. et al., Utility of subcutaneous fat aspiration for the diagnosis of systemic amylodosis (immunoglobulin light chain), Arch. Intern. Med., 148, 929, 1988. 22. Westermark, P. and Stenkvist, B., A new method for the diagnosis of systemic amyloidosis, Arch. Int. Med., 132, 522, 1973. 23. Dalakas, M.C. and Engel, W.K., Role of immunoglobulin light chains in the pathogenesis of amyloid polyneurpathy associated with occult plasma cell dyscrasia, Trans. Am. Neurol. Assoc., 104, 227, 1979. 24. Cohen, A.S. and Rubinow, A., Amyloid neuropathy, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lamber, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 1866. 25. Dyck, P.J. and Lamber, E.H., Dissociated sensation in amyloidosis. Compound action potential, quantitative histologic and teased-fiber, and electron microscopic studies of sural nerve biopsies, Arch. Neurol., 20, 490, 1969. 26. Jedzejowska, H., Some histological aspects of amyloid polyneuropathy, Acta Neuropathol., 37, 119, 1977. 27. Thomas, P.K. and King, R.H.M., Peripheral nerve changes in amyloid neurpathy, Brain, 97, 395, 1974. 28. Coimbra, A. and Andrade, C., Familial amyloid polyneuropathy: an electron microscope study of the peripheral nerve in five cases. I. Intersitial changes, Brain, 94, 199, 1971 29. De Navasquez, S. and Trebele, H.A., A case of primary generalized amyloid disease with involvement of the nerves, Brain, 61, 116, 1938. 30. Coimba, A. and Andrade, C., Familial amyloid polyneuroapthy: an electron microscope study of the peripheral nerve in five cases. II. Nerve fiber change, Brain, 94, 207, 1971. 31. Elghetany, M.T. and Saleen, A., Methods for staining amyloid in tissues: a review, Stain Technol., 63, 201, 1988. 32. Blum, A. and Sohar, E., The diagnosis of amyloidosis, Lancet, 1, 721, 1962. 33. Cohen, A.S., The diagnosis of amyloidosis, in Laboratory Diagnostic Methods in the Rheumatic Diseases, Cohen, A.S., Ed., 2nd ed., Little, Brown & Co., Boston, MA, 375, 1975. 34. Trotter, J.L., Engel, W.K., and Ignaszak, T.F., Amyloidosis with plasma cell dyscrasia: an overlooked cause of adult onset sensorimotor neuropathy, Arch. Neurol., 34, 209, 1977. 35. Simmons, A., Balivas, M., Aguilera, A.J., Feldman, E.L., Bromberg, M.B., and Towfighi, J., Low diagnostic yield of sural nerve biopsy in patients with peripheral neurpathy and primary amyloidosis, J. Neurol. Sci., 120, 60, 1993. 36. Bastian, F.O., Amyloidosis and the carpal tunnel syndrome, Am. J. Clin. Pathol., 61, 711, 1974. 37. Asbury, A.K. and Johnson, P.C., Pathology of the Peripheral Nerve, W.B. Saunders, Philadelphia, PA,1978. 38. Rajani, B., Rajani, V., and Prayson, R.A., Peripheral nerve amyloidosis in sural nerve biopsy. A clinicopathologic analysis of 13 cases, Arch. Pathol. Lab. Med., 124, 114, 2000. 39. Dalakas, M.C. and Cunningham, G., Characterization of amyloid deposits in biopsies of 15 patients with “sporadic” (non-familial or plasma cell dyscrasic) amyloid polyneuropathy, Acta Neuropathol., 69, 66, 1986. 40. Hahn, A.F., Gordon, B.A., Gilbert, J.J., and Hinton, G.G., The AB variant of metachromatic leukodystrophy (postulated activator protein deficiency): light and electron microscopic findings in a sural nerve biopsy, Acta Neuropathol., 55, 281, 1981. 41. Hagberg, B. and Svennerholm, L., Laboratory diagnostic tests in metachromatic leucodystrophy, Acta Pediatr., 489, 632, 1959. 42. Cravioto, H., In vivo and in vitro studies of metachromatic leukodystrophy, J. Neuropathol. Exp. Neurol., 26, 157, 1967. 43. Martin, J.J., Ceuterick, C., Mercelis, R., and Joris, C., Pathology of peripheral nerves in metachromatic leukodystrophy: a comparative study of ten cases, J. Neurol. Sci., 53, 95, 1982. 44. Webster, H.F., Schwann cell alteration in metachromatic leukodystrophy: preliminary phase and electron microscopic observations, J. Neuropathol. Exp. Neurol., 21, 534, 1962. 45. Vos, A.J.M. et al., The diagnostic value of sural nerve biopsy in metachromatic leukodystrophy and other conditons with low leukocyte arylsulphatase-A activities, Neuropediatrics, 13, 42, 1982. 46. Olsson, Y. and Sourander, P., The reliability of the diagnosis of metachromatic leukodystrophy by peripheral nerve biopsy, Acta Pediatr. Scand., 58, 15, 1969. ©2002 CRC Press LLC

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47. Haltia, T., Palo, J., Haltia, M., and Ilen, A., Juvenile metachromatic leukostrophy, clinical, biochemical and neuropathological studies in nine new cases, Arch. Neurol., 37, 42, 1980. 48. Dayan, A.D., Peripheral neuropathy of metachromatic leukodystrophy: observations on segmental demyelination and remyelination and the intracellular distribution of sulphatide, J. Neurol. Neurosurg. Psychiatry, 30, 311, 1967. 49. Webster, H.F., Schwann cell alteration in metachromatic leukodystrophy: preliminary phase and electron microscopic observations, J. Neuropathol. Exp. Neurol., 21, 534, 1962. 50. Dyck, P.J., Gutrecht, J.A., Bastron, J.A., Karnes, W.E., and Dale, A.J.D., Histologic and teased fiber measurements of sural nerve in disorders of lower motor and primary sensory neurons, Mayo Clin. Proc., 43, 81, 1968. 51. Thomas, P.K., King, R.H., Kocen, R.S., and Brett, E.M., Comparative ultrastructural observations on peripheral nerve abnormalities in the late infantile, juvenile and late onset forms of metachromatic leukodystrophy, Acta Neuropathol., 39, 237, 1977. 52. Robitaille, Y., Carpenter, S., Karpati, G., and DiMauro, S.D., A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes: a report of four cases and a review of the occurrence of polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing, Brain, 103(2), 315, 1980. 53. Robertson, N.P., Wharton, S., Anderson, J., and Scolding, N.J., Adult polyglucosan body disease associated with an extrapyramidal syndrome, J. Neurol., Neurosurg. Psychiatry, 65(5), 788, 1998. 54. McDonald, T.D., Faust, P.L., Bruno, C., DiMauro, S., and Goldman, J.E., Polyglucosan body disease simulating amyotrophic lateral sclerosis, Neurology, 43(4), 785, 1993. 55. Cafferty, M.S., Lovelace, R.E., Hays, A.P., Servidei, S., Dimauro, S., Rowland, L.P., Polyglucosan body disease, Muscle and Nerve, 14(2), 102, 1991. 56. Vos, A.J.M., Joosten, E.M.G., and Gabreels-Festen, A.A.W.M., Adult polyglucosan body disease: clinical and nerve biopsy findings in two cases, Ann. Neurol., 13, 440, 1983. 57. Busard, H.L. et al., Adult polyglucosan body disease: the diagnostic value of axilla skin biopsy, Ann. Neurol., 29(4), 448, 1991. 58. Busard, H.L. et al., Polyglucosan disease in sural nerve biopsies, Acta Neuropathol., 80, 554, 1990. 59. Bersen, R.A. et al., Polyglucosan bodies in intramuscular motor nerves, Acta Neuropathol., 77, 629, 1989. 60. Carpenter, S. and Karpati, G., Intra-axonal polyglucosan bodies: an unusual lesion of peripheral nerves, Neurology, 26, 369, 1976. 61. Mancardi, G.L. et al., Polyglucosan bodies in the sural nerve of a diabetic patient with polyneuropathy, Acta Neuropathol., 66, 83, 1985. 62. Schröder, J.M. et al., Juvenile hereditary polyglucosan body disease with complete branching enzyme deficiency (type glycogenosis), Acta Neuropathol., 85, 419, 1993. 63. Kocen, R.S. and Thomas, P.K., Peripheral nerve inovlement in Fabry’s disease, Arch. Neurol., 22, 81, 1970. 64. Ohnishi, A. and Dyck, P.J., Loss of small peripheral sensory neurons in Fabry’s disease, Arch. Neurol., 31, 120, 1974. 65. Sheth, K.J. and Swick, H.M., Peripheral nerve conduction in Fabry’s disease, Ann. Neurol., 7, 319, 1980. 66. Case records of Massachusetts General Hospital. Case 2-1984, New Eng. J. Med., 310, 106, 1984. 67. Godoth, N. and Sandbank, U., Involvement of dorsal root ganglia in Fabry’s disease, J. Med. Genet., 20, 309, 1983. 68. Cable, W.J., Dvorak, A.M., Osage, J.E., and Kolodny, E.H., Fabry’s disease: significance of ultrastructural localization of lipid inclusions in dermal nerves, Neurology, 32, 347, 1982. 69. Fukuhara, N., Suzuki, M., Fujita, N., and Tsubaki, T., Fabry’s disease on the mechanism of the peripheral nerve involvement, Acta Neuropathol., 33, 9, 1975. 70. Toyooka, K. and Said, G., Nerve biopsy findings in hemizygous patients with Fabry’s disease, J. Neurol., 244, 464, 1976. 71. Gemignani, F., Marbini, D., Bragaglia, M.M., and Govoni, E., Pathological study of the sural nerve in Fabry’s disease, Eur. Neurol., 23, 173, 1984. 72. Schamburg, H.H. et al., Adrenoleukodystrophy. A clinical and pathological study of 17 cases, Arch. Neurol., 32, 577, 1975. 73. Griffin, J.W., Goren, E., Schaumburg, H., Engel, W.K., and Loriaux, L., Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. I. Clinical and endocrinologic aspects, Neurology, 27, 1107, 1977.

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74. Schaumburg, H.H., Powers, J.M., Raine, C.S., Spencer, P., Griffin, J.W., Prineas, J.W., and Boehme, D., Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. II. General pathologic, neuropathologic, and biochemical aspects, Neurology, 27, 1114, 1977. 75. Julien, J., Vallat, J.M., Vital, C., Lagueny, A., Ferrer, X., and Darriet, D., Adrenomyeloneuropathy; demonstration of inclusions at the level of the peripheral nerve, Eur. Neurol., 20, 367, 1981. 76. Martin, J.J., Lowenthal, A., Ceuterick, C., and Gacoms, H., Adrenomyeloneuropathy. A report on two families, J. Neurol., 226, 221, 1982. 77. Pages, M. and Pages, A.M., Adenomyeloneuropathy. Morphometric and ultrastructural study of the peripheral nerves, Ann. Pathol., 5, 205, 1985.

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CHAPTER 9 Figure 1 Congo-red materials in the epineurial space in the sural nerve. The red arrow indicates Congo-red material at the edge of the epineurial space, and the red arrowhead indicates one of several Congo-red stained materials in the vessel walls of the epineurial space. The green arrow indicates one nerve fascicle. Paraffin section. Alkaline Congo-red stain. (40 × magnification.)

CHAPTER 9 Figure 2 Congo-red material in the sub-perineurial space. Some individual nerve fibers are well recognizable in the endoneurial space. Frozen section. Alkaline Congo-red stain. (200 × magnification.)

CHAPTER 9 Figure 4 Moderate loss of myelinated fibers. Note that many of the remaining myelinated fibers are large-diameter fibers. The arrow indicates two clusters of tiny myelinated fibers indicating regenerating axon sprouting. Semithin section. Toluidine blue and basic fuchsin. (200 × magnification.)

CHAPTER 9 Figure 3 Axonal degeneration. Marked loss of myelinated fibers is obvious. Arrows indicate myelin-digestion chambers, indicating active axonal degeneration. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 9 Figure 5 Congo-red materials in the vessel wall in the epineurial space. Paraffin section. Alkaline Congo-red stain. (200 × magnification.)

CHAPTER 9 Figure 6 Apple-green colored Congored materials (arrow) in a vessel wall in the epineurial space confirming amyloid. In contrast, collagen fibers are colored white. Paraffin section. Alkaline Congored stain under the polarized light. (200 × magnification.)

CHAPTER 9 Figure 7 Brown materials (arrow) between muscle fibers represent metachromasia from the violet-stained muscle fibers. Frozen section. Cresyl-violet stain. (100 × magnification.)

CHAPTER 9 Figure 8 Amyloid: bright yellow fluorescence (arrow) with thioflavin-T stain in the wall of arterioles in the perimysial space in the muscle. (100 × magnification.)

CHAPTER 9 Figure 9 Apple-green amyloid in the endoneurial space (red arrow) and in the wall of the tiny vessel (blue arrow). Alkaline Congo-red stain under the polarized light. (200 × magnification.)

CHAPTER 9 Figure 10 Amyloid: bright red fluorescence positive to antibodies to kappa light chain. See Figure 9.7. Frozen section. Monoclonal antibody to kappa light-chain. (100 × magnification.)

CHAPTER 9 Figure 11 Brown granules (arrows) scattered in the endoneurial space represent metachromatic granules. Nerve fibers are stained light pink. Frozen section. Hirsh–Pfeiffer cresyl-fast violet. (100 × magnification.)

CHAPTER 9 Figure 12 Dark-gray granules in the macrophages (arrow) along the tiny vessels in the endoneurium. Frozen section. Thionine stain. (200 × magnification.)

CHAPTER 9 Figure 13 PAS-positive metachromatic granules in macrophages around the endoneurial vessel. Frozen section. PASH. (200 × magnification.)

CHAPTER 9 Figure 14 Many thinly myelinated fibers (arrowhead). Metachromatic granules in a large macrophage (red arrow). Metachromatic granules in a Schwann cell (blue arrow). Semithin section.

CHAPTER 9 Figure 16 Polyglucosan body with various stains. (A) Pearly with modified trichrome. Notice the central core. Paraffin section. (800 × magnification.) (B) Basophilic with H & E stain. Frozen section. (400 × magnification.) (C) Intensely positive with PASH stain. Frozen section. (400 × magnification.) (D) Green with modified trichrome. Frozen section. (400 × magnification.)

CHAPTER 9 Figure 15 Two polyglucosan bodies (arrows). The red arrow indicates a polyglucosan body with a central core. Semithin section. Toluidine blue and basic fuchsin. (400 × magnification.)

CHAPTER 9 Figure 17 Teased fiber preparation demonstrating an ellipsoid dilation of an axon due to a polyglucosan body. (Courtesy of Dr. N.P. Robertson, University Hospitals of Wales, Cardiff, Wales.)

CHAPTER 9 Figure 18 The lipid deposits of Fabry’s disease (arrows). These inclusions are also PAS-positive and diastase-digestible. Frozen section. ORO. (450 × magnification.)(Reproduced by permission from King, R., Atlas of Peripheral Nerve Pathology, Edward Arnold Ltd, London, UK, 1991.)

A

A

B

B

CHAPTER 9 Figure 19 Amyloid in a vessel wall in the epimysial space in the muscle. (A) Congo-red material; (B) Apple-green colored Congo-red material under the polarized light. Paraffin section. Alkaline Congo-red stain. (100 × magnification.)

CHAPTER 9 Figure 20 Amyloid in the fatty tissue in the epineurial space in the nerve. (A) Congo-red material; (B) Apple-green colored Congo-red material under polarized light. Arrows indicate a small nerve fascicle. Paraffin section. Alkaline Congo-red stain. (100 × magnification.)

CHAPTER 9 Figure 21 Scattered metachromatic granules stained purple with crystal-violet stain. Frozen section. Crystal-violet stain. (200 × magnification.)

CHAPTER 9 Figure 22 Polyglucosan body. Diffuse loss of myelinated fibers. One axon contains a large polyglucosan body (approximately 30 µm) with a round profile in transverse section. It has a laminated appearance with a slightly denser core. The surrounding myelin sheath is thinned. Semithin section. Thione and acridine orange. (600 × magnification.) (Courtesy of Dr. N.P. Robertson, University Hospitals of Wales, Cardiff, Wales).

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Hereditary Neuropathies

Hereditary neuropathies generally have the following characteristics: (1) they are inherited; (2) they are symmetrical and diffuse; (3) they are slowly progressive; (4) their clinical features may differ from family to family; and (5) the inheritance pattern, age of onset, clinical features, and natural course are rather uniform among the affected members within the same family. Because of the wide spectrum of clinical features among the various hereditary neuropathies, it is not easy to classify these disorders into simple categories. Thus, various eponyms have been assigned to these disorders in the past. In 1975, Dyck attempted to classify these disorders on the basis of the inheritance pattern, age of onset, symptomatology, characteristics of nerve conduction, and pathological abnormalities.1 Depending on the predominant symptomatology, Dyck divided hereditary neuropathies into two main categories: hereditary motor and sensory neuropathy (HMSN) and hereditary sensory neuropathy (HSN). The HMSN group was subdivided into seven types and the HSN group into four types. Although this classification is generally accepted, it is still subject to modification and controversy.2-4 In 1984, Dyck renamed HSN hereditary sensory autonomic neuropathy (HSAN) and added one more type to the HSAN group.5 With the major advances in understanding hereditary neuropathies at the molecular genetic level in recent years, there has been a tendency to classify the hereditary neuropathies based on the underlying genetic disorders. Thus, the term Charcot–Marie–Tooth (CMT) disease has become more popular in the literature of genetics. Because a genetic defect has not been found for all of the HMSNs, classifications using only CMT unfortunately do not include all the clinical syndromes (Table 10.1). Thus, both HMSN and CMT classifications are combined in this chapter. With the recent availability of the molecular genetic diagnostic test, the usefulness of nerve biopsy in the diagnosis of hereditary neuropathy has been considerably reduced.

HEREDITARY MOTOR AND SENSORY NEUROPATHIES (HMSN) The predominant symptomatology of HMSN is motor weakness, with lesser impairment of sensory functions. HMSN includes the disorders which have been referred to by the following names: progressive muscular atrophy, CMT disease, Roussy–Levy syndrome, Dejerine–Sottas disease, and Refsum’s disease.

HMSN TYPE I (HYPERTROPHIC FORM OF THE CMT DISEASE INCLUDING ROUSSY–LEVY SYNDROME) CMT disease is the most common hereditary neuropathy. It is usually inherited as an autosomal dominant trait and is characterized clinically by pes cavus (high-arched feet) and marked atrophy of the feet and lower legs, resulting in a “stork-leg” or “inverted champagne bottle–leg” appearance. This neuropathy is slowly progressive. Dyck, Buchthal, Behse, and Harding and Thomas, classified CMT into two types: hypertrophic (HMSN Type I) and neuronal (HMSN Type II).1,7-9 Though there are some differences in clinical features between the two types, it is impossible to differentiate between them on the basis of clinical features alone (Table 10.1). In this regard, the nerve conduction study has been a definite help: slow motor nerve conduction velocity (NCV) is noted in Type I, and normal motor nerve conduction is noted in Type II.10 Bradley et al. claimed that there is an

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Gene Defect

Cardinal Pathological Features

Hereditary Motor and Sensory Neuropathy (HMSN; Charcot–Marie–Tooth Disease [CMT]) Hypertrophic neuropathy; demyelination; onion-bulb formation of Schwann cell processes; palpable nerve in 25% of cases

HMSN II (CMT 2) HMSN IIA (CMT 2A) HMSN IIB (CMT 2B) HMSN IIC (CMT 2C) HMSN lID (CMT 2D) HMSN IIE (CMT 2E) Autosomal dominant Autosomal recessive

Locus on Lp35–p36 Locus on 3q13–q22 Location unknown Locus on 7pI4 Point mutation P0 Location unknown (see under CMT 4)

Axonal degeneration; loss of large diameter fiber; no OBF

HMSN III (Dejerine–Sottas Disease ([DSD]; Congenital Hypomyelination Neuropathy) DSD A DSD B Autosomal dominant DSD Autosomal recessive

Point mutation PMP-22 Point mutation P0 Point mutations PG Locus on 8q23–q24

Hypomyelination/hypertrophic neuropathy, Prominent OBF of Schwan with cell processes and basal cell lamina; absence of myelin sheath; palpable nerve in most cases; CSF protein: elevated

HMSN II (CMT 1B) HMSN (CMT 1C) HMSN (CMT 1D) X-linked (CMT-X1) X-linked (CMT-X2) Autosomal recessive

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Duplication PMP-22 Point mutation PMP-22 Point mutations P0 Location not known Point mutation EGR2 Point mutation connexin-32 Locus on Xq24-q26 (see under CMT 4)

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TABLE 10.1 Classification, Genetic Defect, and Cardinal Pathological Features of Inherited Neuropathiesa

Complex forms of HMSN

Location unknown

Hereditary Sensory and Autonomic Neuropathies (HSAN) HSAN I (dominant sensory neuropathy)

Locus on 9q22.1–q22.3

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) HNPP

Axonal degeneration in the small and intermediate fibers; sparing of large fibers; virtual absence of myelinated fibers

Virtual absence of unmyelinated fibers; marked loss of small myelinated fibers

Deletion PMP-22; point mutation PMP-22; location unknown

Tomaculous neuropathy

Giant Axonal Neuropathy

Locus unknown

Giant axonal neuropathy

Familial Amyloid Polyneuropathies (FAP) TTR-related FAP Apolipoprotein A1-related FAP Gelsolin-related FAP

Mutations transthyretin Mutations apolipo-protein A1 Mutations gelsolin

Amyloid; axonal degeneration

a

This is based on two review articles.6,98

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HSAN II (recessive sensory neuropathy) Location unknown HSAN III (Riley–Day syndrome, Locus on 9q31-33 familial dysautonomia) HSAN IV (congenital sensory neuropathy with anhydrosis) HSAN V (sensory neuropathy with loss of small myelinated fibers)

Hypomyelination, basal lamina onion bulbs; demyelinating, focally folded myelin sheaths; hypomyelinaton, basal lamina OBF; demyelination with poorly developed OBF

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Locus on 8q13–21.l Locus on 11q23.l Locus on 5q23–q33 Locus on 8q24

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CMT 4 (Autosomal Recessive CMT) CMT 4A CMT 4B CMT 4C HMSNL (deafness, Balkan Gypsies)

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Table 10.1 (continued)

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intermediate form showing normal NCV (above 45 m/sec) in the neuronal group, markedly slow NCV (below 25 m/sec) in the hypertrophic group, and moderately slow NCV (25–45 m/sec) in the intermediate group.2,11,12 Although the clinical and electrophysiological features are relatively uniform in autosomal dominant HMSN (CMT 1A), genetic studies have shown that it is genetically heterogeneous, involving at least three known gene defects. These include duplication of PMP22 in CMT 1A, the most common form of HMSN and 70 to 80% of all CMT 1A; P0 mutation in CMT 1B, 4 to 5% of all CMT cases; and connexin 32 mutation in X-linked CMT, nearly 14% of all CMT cases. A review of postmortem findings in 18 cases of CMT disease13 also succeeded in dividing the findings in peripheral nerves into two groups: peripheral nerve degeneration with onion-bulb formation (OBF)13,14 and peripheral nerve degeneration without OBF.15,16 Thus, postmortem findings support the two-type concept. In both groups, similar findings were described in anterior horn cells and dorsal root ganglia: neuronal loss in anterior horn cells in all of seven examined cases and dorsal root ganglia in all of four examined cases. Sural nerve biopsies in HMSN Type I showed the following findings:5,8,11,17,18 1.

2. 3. 4.

Numerous OBFs are the pathological hallmark of HMSN Type 1 (Color Figures 10.1–10.6).* These OBFs are made up of circumferentially directed Schwann cell processes with abundant cytoplasm and a normal content of organelles. Loss of large-diameter fibers5,8 Teased fibers showing extensive segmental demyelination and remyelination Normal fiber density of unmyelinated fibers

A recent study by Low et al. shed more light on the relationship between the histopathological and clinical features:18 1. 2.

3.

There is a considerable variation in the size of OBFs in patients from different kinships, but the appearance is similar in patients from the same kinship. Within the same family, there is a progressive reduction in myelinated fiber density, an increased number of fibers undergoing demyelination, and an increased frequency of OBFs with increasing age. Motor NCV is inversely proportional to the number of onion-bulb lamellae and to the population of demyelinated fibers found on the sural nerve biopsy.

On the other hand, Van Weerden et al.19 reported a large variability in the demyelination and remyelination and OBF in sural nerve biopsies from five affected members of the same kinship. In this disorder, the peripheral nerves are thickened and palpable on clinical examination in only one-quarter of patients.4

ROUSSY–LEVY SYNDROME Roussy–Levy syndrome has the clinical features of both CMT disease (hypertrophic type) and essential tremor. Because of this combination of clinical features, Dyck and Lambert20 classified this syndrome as Type I HMSN. On the other hand, Oelschlager et al.21 believed that this syndrome is a separate nosological entity. As in Type I HMSN, marked slowing of motor NCV has been reported in this condition.10 The biopsy of a musculocutaneous nerve from Roussy and Levy’s original patients22,23 and of a sural nerve in subsequent cases24,25 showed the following characteristics: 1.

A considerable reduction in myelinated fibers, especially of large-diameter fibers

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Conspicuous OBFs formed by overlapping Schwann cell processes together with segmental demyelination Teased fiber preparation showing segmental and paranodal demyelination and remyelination25

Thus, the sural nerve biopsy findings were identical to those described in the hypertrophic type of CMT disease, supporting the hypothesis that this syndrome is a variant of HMSN Type I.

SEX-LINKED CMT Sex-linked CMT disease is characterized by the absence of male–male transmission, a more severe clinical course in males than in females, and slower motor NCV in males, suggesting an X-linked inheritance. Based on the linkage studies, CMT-X can be classified into the more frequent CMT-X1 and the rare CMT-X2. CMT-X1 is caused by point mutations in the connexin-32 gene. Though axonal neuropathy was reported in four cases in two series,26 later studies convincingly showed classic demyelinating neuropathy: many thinly myelinated fibers and many OBFs.27-30 The teased nerve fiber study confirmed demyelination.27,31 Sanders et al.28 compared the nerve biopsy findings in 5 cases of CMT-X vs. 18 cases of CMT 1A. They found that myelin fiber density was significantly lower in CMT-1A than CMT-X1; there was large-diameter fiber loss in both. The myelin sheaths were significantly thinner in CMT-X1, expressed by a high mean G-ratio; OBFs were much more abundant in CMT-1A, and cluster formations were more frequent in CMT-X1.

HMSN TYPE II (NEURONAL TYPE OF CMT; CMT 2) A less common form of CMT disease, this neuropathy has a later onset, less pronounced involvement of the hands, and normal nerve conduction in comparison with Type I HMSN. It is still inherited according to the autosomal dominant pattern. Thickened nerves are not present in this disorder as a rule. The sural nerve findings are characterized by the following (Color Figure 10.7):5,8,11,17 1. 2. 3. 4. 5.

Loss of large-diameter fibers Normal unmyelinated fibers Teased fibers showing axonal degeneration, the most prominent change A majority of studies noted no OBF,8,11,17 but occasional mild OBF was described by Dyck5 Abundant clustering of small myelinated fibers was described by Gherard et al.53

Dyck interpreted these histological studies as indicative of neuronal atrophy and degeneration of peripheral motor and sensory neurons in Type II HMSN. Thus, there are distinct differences in sural nerve pathology between Type I and Type II HMSN. These pathological differences explain the differences in the nerve conduction studies in these disorders. Ben Hamida also observed that histological findings were constant within a given family and claimed that the histological differentiation of types appeared to be more reliable than the clinical differentiation.32 In the intermediate form of CMT disease described by Madrid et al., the sural nerve biopsy showed moderate segmental demyelination with mild OBF, prominent axonal degeneration, and clusters of regenerating myelinated fibers.11

HMSN TYPE III (DEJERINE–SOTTAS DISEASE; DSA AND DSB) The Dejerine–Sottas disease, a recessively inherited disorder, usually begins during infancy or early childhood and is associated with hypertrophic (OBF) neuropathy, thickened nerves, and a markedly

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increased cerebrospinal fluid protein.33,34 Marked slowing of motor NCV has been a consistent finding in this disease.10 The sural nerve biopsy has the following characteristic findings: 1. 2. 3.

Extensive OBFs: OBFs are made of Schwann cell processes in most cases, though in a few cases they are composed of Schwann cell basement membranes.35 Severe loss of large- and intermediate-sized myelinated fibers.33 Teased fibers showing prominent segmental demyelination and remyelination.

Compared with HMSN Type I, this disorder shows a more severe form of hypertrophic neuropathy.36 Dyck and co-workers emphasized the existence of a severe degree of hypomyelination in this disorder and, thus, included congenital hypomyelination neuropathy in HMSN Type III.33 For the sural nerve pathology of other rare forms of HMSN which were not clearly classified, readers should consult other references.37

CONGENITAL HYPOMYELINATION NEUROPATHY Congenital hypomyelination neuropathy (Color Figures 10.8 and Figure 10.1), most likely a variant of HMSN Type III, has clinical features identical to those of Dejerine–Sottas disease except for its onset at birth and the absence of enlarged nerves. It has been postulated that the Schwann cells are incapable of forming myelin in this disorder.38-40 This hypothesis is based on histological findings in the nerve: a virtual absence of myelin sheaths and myelin breakdown. Motor nerve conduction is markedly abnormal: terminal latencies are markedly prolonged, and motor NCVs are markedly slow.10

FIGURE 10.1 Congenital dysmyelinating neuropathy. Dejerine–Sottas: basal lamina rings form a prominent part of these onion bulbs. (With permission from Midroni, G., and Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, 1995.)

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Sural nerve biopsies showed the following findings: 1. 2. 3. 4.

A virtual absence of myelin sheaths in all of 12 reported cases (Color Figure 10.8).38,41-47 Prominent OBF in 8 of 12 reported cases.38,39,41,43,48 OBFs are essentially composed of multiple layers of basement membrane (Figure 10.1). Schwann cell nuclei are also increased.38,39 No evidence of myelin breakdown in 11 of 12 reported cases, with a few exceptions in one case.43 Teased nerve fibers showing no myelin in two studied cases.39,43

Guzzeta et al. compared histological features between congenital hypomyelination neuropathy and Dejeriine–Sottas disease.39 In sharp contrast to findings in congenital hypomyelination neuropathy, they found evidence of segmental demyelination in the already formed myelin in late infantile and juvenile forms (Dejerine–Sottas disease): segmental demyelination in teased nerve fibers, more myelinated fibers with evidence of myelin breakdown, and classic OBFs with prominent Schwann cell processes.

AUTOSOMAL RECESSIVE CMT (CMT 4; CMT 4B) Autosomal recessive CMT disease includes different disorders and a broad spectrum of clinical severity. Three pathological forms are now recognized:49 basal laminar onion bulbs in CMT 4A, focally folded myelin sheaths in CMT 4B,50 and classic onion bulbs in CMT 4C.51 CMT 4A is often associated with delayed milestones, marked muscular distal atrophy rapidly progressing to the proximal parts of the legs and arms, mild sensory loss, and skeletal deformities and scoliosis. Motor NCV is slow. CMT 4B is characterized by a markedly slow motor NCV and by the presence of myelin outfoldings in the nerve biopsy (Color Figure 10.9). CMT 4C is characterized by early onset, with foot deformities and spine deformities, markedly slow motor NCV, and thinly myelinated fibers with extensive small OBF and numerous regenerative clusters. Hereditary motor and sensory neuropathy-Lom (CMT 4L), named after the town where the initial cases were found, was described in Bulgarian gypsies and is characterized by a progressive, severe, sensory motor polyneuropathy with deafness, skeletal and foot deformity, and demyelination with OBF.52

HEREDITARY SENSORY NEUROPATHY Many hereditary sensory neuropathies were described in the past under different names such as Morvan’s syndrome, lumbosacral syringomyelia, and sensory radicular neuropathy. In 1975, Dyck and Ohta classified these disorders into four types: hereditary sensory neuropathy (HSN) Types I–IV.53 However, in 1984, Dyck changed the designation of these disorders to hereditary sensory autonomic neuropathies (HSANs) and added one more type, Type V (Table 10.1).5 Although there have been some objections to this system,4,54 it has now been widely accepted as the standard classification. In recent years, some genetic defects have been identified. The most common form of HSAN is the dominant HSAN Type I, which presents itself in the second decade of life with distal sensory neuropathy. In contrast to Type I, HSAN Types II–V are congenital or infantileonset, in which autonomic abnormalities play a more prominent role, progression is absent or extremely slow, and the inheritance pattern is typically autosomal recessive. The more common forms of HSAN Types I and II are described here, and the sural nerve pathologies of the other types are described in Table 10.1.

TYPE I HEREDITARY SENSORY NEUROPATHY (HEREDITARY SENSORY RADICULAR NEUROPATHY OF DENNY–BROWN; DOMINANT HSN; HSAN TYPE I) This is a rare, dominantly inherited, sensory neuropathy primarily affecting the distal lower extremities. The characteristic clinical features are sensory dissociation (pain and temperature perceptions

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are markedly affected more than touch-pressure sensations), lancinating pain, and subsequent painless ulceration of the feet. The disease is insidious, with the first symptoms manifesting during the second decade of life. The most prominent nerve conduction abnormality is the absence of the sensory or mixed CNAPs in the presence of mildly slow motor NCV.10 The most prominent pathological change was degeneration of the small neurons of the posterior root ganglia in Denny–Brown’s case.55 In addition, he found loss of the smaller myelinated fibers and axonal degeneration in the peripheral nerves, as well as loss of fibers in the dorsal root entry zone and in the posterior columns. Thus, Denny–Brown concluded that degeneration of the dorsal root ganglia neurons is primary. On the other hand, Dyck5 is of the opinion that the distal fibers of peripheral sensory nerves degenerate first. Descriptions of sural nerve biopsy findings are limited.5,56 In Dyck and O’Brien et al.’s cases, teased fibers showed predominant axonal degeneration,5,56 whereas Danon et al.’s one case revealed several ovoids of Wallerian degeneration.57 In Dyck and O’Brien et al.’s cases, a marked loss of unmyelinated fibers and moderate loss of small myelinated fibers with sparing of larger myelinated fibers5,56,57 were noted. In Danon’s three cases, large and small fibers were equally affected. Thus, the sural nerve biopsy findings confirmed the autopsy findings in Denny–Brown’s case.55

TYPE II HSN (CONGENITAL SENSORY NEUROPATHY; RECESSIVELY INHERITED HSN; HSAN TYPE II) Type II HSN is different from Type I HSN in that Type II appears during infancy or early childhood, taking the form of painless blisters, ulcers, and sensory impairment, and touch/pressure is more affected than pain and temperature perception. The nerve conduction findings are identical between Types I and II HSN.10 The sural nerve biopsy shows the following consistent findings:58-62 1. 2. 3.

A virtual absence of myelinated fibers (Color Figure 10.10). A relative preservation of unmyelinated fibers. A teased fiber study showed no myelinated fibers in the several hundred strands of nerve fiber examined.58 In Jedzejowska and Milczrek’s case, predominant axonal degeneration and secondary segmental demyelination were observed.63

Thus, there is a clear histological difference in the sural nerve biopsies between Type I and Type II HSN: a selective loss of unmyelinated fibers in Type I in contrast to a selective loss of myelinated fibers in Type II. On the other hand, there is a considerable clinical overlap.4 In a review of 66 family members with HSN, clinical features other than age at onset appeared identical in HSN I and II.64 In some patients, classification was impossible on clinical grounds.59,60 Thus, Nukuda recommended the nerve biopsy as a means of making a distinction between Types I and II HSN.60 Danon claimed that the nerve biopsy finding has limited value in classification of these disorders.57

HEREDITARY NEUROPATHY TO PRESSURE PALSY (HNPP) Hereditary neuropathy to pressure palsy (HNPP) is a rare disorder characterized by (1) susceptibility to pressure palsies following relatively minor episodes of compression or ischemia; (2) improvement of symptoms within weeks or months; (3) frequent recurrence of pressure palsies; and (4) autosomal dominant inheritance.65 The disorder may present along with recurrent brachial plexus neuropathy. The electrophysiological hallmark is mild demyelinating neuropathy with prolonged distal latency, which is out of proportion to NCV slowing, and focal neuropathy at the entrapment site.66 The classic pattern of nerve conduction abnormalities can also be seen in clinically unaffected

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nerves and in clinically unaffected relatives, possibly identifying individuals at risk of developing this disorder.65 Recent studies concluded that HNPP is caused by a 1.5-Mb deletion in 17p 11.2–12, which spans the same region duplicated in most CMT 1A patients.67 This region encompasses the PMP-22 gene, which is expressed on Schwann cells. A recent European study showed an overall deletion frequency of 84% in 162 patients with HNPP.68 DNA testing can now be used to detect HNPP in individual patients as well as in unaffected family members. With the availability of this test, other heretofore unsuspected phenotypes have been reported.69,70 In one series, 5 other phenotypes in 15 of 99 HNPP patients were described. These include CMT-like polyneuropathy, chronic sensory polyneuropathy, and CIDP-like recurrent polyneuropathy.69 Thus, the role of nerve biopsy in the diagnosis of this disease has diminished considerably. Sural nerve biopsies in HNPP show a characteristic pathology: tomaculous neuropathy.71,72 Features of this neuropathy are as follows: 1.

2.

3. 4.

The most striking finding is focal sausage-shaped thickenings of the myelin sheath (Color Figures 10.11 and 10.15). Tomaculous neuropathy is derived from the Latin tomaculum (sausage). This can be easily detected on the frozen sections as red sausage-shaped swollen myelin in the longitudinal sections and red swollen myelin in the transverse sections (Color Figures 10.11 and 10.12) The diameter of the tomacula is often increased to as much as twice that of the remaining segment (maximally 40 µm).71 In semithin sections, tomacula are represented by giant fibers with unusually thick myelin sheaths and reduced axonal areas (Color Figures 10.13 and 10.14). Thin myelin in proportion to axon diameter (remyelination) is also seen.71,72 OBFs often occur, but not as a dominant feature.65,72 Myelinated fiber density is either normal or slightly reduced.65 In teased fibers, tomacula ranged from 40 to 250 µm in length (Color Figure 10.15). Segmental demyelination and remyelination were consistent findings.65,71,72 With the electron microscope, tomacula are represented by redundant looping of the myelin.

It is worth noting that tomaculous neuropathy may be found in biopsied nerves which are not clinically affected. Precise molecular diagnosis of HNPP, employing interphase-to-color fluorescence in situ hybridization (FISH), is possible by the detection of a 1.5-Mb deletion on chromosome 17b 11.2-12 from the extraction of nuclei from paraffin-embedded and cryofixed sural nerve biopsies.73 Tomaculous neuropathy was noted in 19 of 25 (76%) patients with HNPP74 and have also been described in patients with familial recurrent brachial plexus neuropathy.75,76 Since brachial plexus involvement is not infrequent (accounting for 8% of episodes in one review),65 it is possible that familial recurrent brachial plexus neuropathy is a phenotypic variant of HNPP. Tomaculous neuropathy was also described in a few cases of HMSN I (CMT 1A), HMSN with myelin outfolding (CMT 4B), IgM paraproteinemic neuropathy, and CIDP.77 Thus, tomaculous neuropathy is not synonymous with HNPP, but HNPP should be the diagnostic choice until proven otherwise in the presence of tomaculous neuropathy. The genetic study is now extremely helpful in this regard.

GIANT AXONAL NEUROPATHY (GAN) Giant axonal neuropathy (GAN) was first described by Asbury in 1972.78 Since then, about 30 cases have been reported.79 Common clinical features include early onset, slowly progressive distal polyneuropathy, strikingly curly hair, and soft signs suggestive of CNS involvement — commonly cerebellar signs, mental retardation, extensor plantar responses, and neurogenic bladder.79 Unlike that

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seen in kinky hair disease,80 the hair of patients with this neuropathy does not exhibit pili torti. Normal hair was reported in one case.81 In nerve conduction studies, the prominent finding is abnormal sensory nerve conduction: amplitude either absent or reduced in CNAP with relatively normal motor nerve conduction.10 GAN is considered to be inherited on an autosomal recessive basis.79 At this time, the pathogenesis of this neuropathy is not known. Prineas et al. demonstrated microfilaments within the cytoplasm of many cells including endoneurial fibroblasts, endothelial cells, perineurial cells, and Schwann cells and, therefore, postulated that the neuropathy is a manifestation of a generalized cytoplasmic microfilament disorder.82 A similar observation has been made by others.81-84 Nerve biopsy is recommended in any patient in whom this neuropathy is suspected since it shows a definite diagnostic finding of giant axons (Color Figures 10.16 and 10.19).79 1.

2.

3.

These giant axons are not morphologically different from giant axons found in toxic neuropathies (Color Figures 10.16 and 10.17). However, giant axonal neuropathy shows more dramatic axonal swelling than the toxic neuropathies (Color Figures 10.18 and 10.19).86 Giant axons are scattered in the nerve fascicle and are easily recognizable. They are light-green by modified trichrome on frozen sections and dark on silver staining. Giant axonal change is noted in myelinated as well as unmyelinated fibers. On longitudinal sections, these giant axons are shown as cigar-shaped ballooning, often near a node of Ranvier. At this point, paranodal widening is often visible. Several giant axons, some more than 30 µm in diameter, are surrounded by a thin or fragmented myelin sheath. Under the electron microscope, the giant axons are seen to be packed with neurofilaments. Teased nerve fibers characteristically show single or multiple spindle-shaped or fusiform swellings along axons measuring from 40 to 350 µm in length and 10 to 30 µm in diameter (Color Figure 10.20). Some segmental demyelination may be shown together with giant axons.79,83 No obvious OBFs are recognizable on semithin or paraffin sections. However, occasional small OBFs around giant axons were seen under the electron microscope.

Thus, a definite diagnosis of giant axonal neuropathy can be made by demonstration of giant axons in the nerve biopsy.

FRIEDREICH’S ATAXIA Friedreich’s ataxia is a hereditary disease characterized by onset of ataxia in the first or second decade of life, absence of deep tendon reflexes, loss of proprioception, extensor plantar responses, pes cavus, and kyphoscoliosis. The characteristic nerve conduction abnormalities have been reported as follows: motor nerve conduction is normal, whereas sensory or mixed CNAPs are either absent or reduced in amplitude, indicating the predominant degeneration of dorsal root ganglia.10 The pathology of the sural nerve shows the following abnormalities: 1. 2.

A decrease in the number of myelinated fibers, predominantly large-diameter fibers.87,88 Teased fibers demonstrating segmental demyelination and remyelination.88 Statistical evaluation of this segmental demyelination has shown that its occurrence is highly clustered, as might be expected in secondary segmental demyelination. Using the ratio of the number of myelin lamellae to the perimeter of the axis cylinder, it was found that old internodes had an excessively high ratio and new internodes had a low ratio. These observations led to the conclusion that segmental demyelination in this disorder is secondary to axonal atrophy.

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CASES WITH HEREDITARY NEUROPATHY CASE 1: HAND-SHAKING AS AN INITIAL MANIFESTATION OF HEREDITARY NEUROPATHY Case Presentation A 25-year-old female first noticed tremors in her hands and feet at age 14. Her developmental history was normal. After giving birth to a child at age 18, the patient’s tremors became worse and she began to have cramps in her toes and calf muscles. One year prior to examination, she began to experience decreased sensation in her toes and weakness of her legs, especially in dorsiflexion of her feet. In the 2 years prior to examination, she had 2 surgeries to remove bony spurs from her feet. Her tremors were worse under stress and when she attempted to write. Family history was interesting in that her mother was crippled with “claw hands” and weakness of the feet, her aunt possibly had a similar problem, and her 22-year-old brother had a tremor and weakness of the feet. Abnormal neurological findings were atrophy of intrinsic hand muscles, pes cavus without hammer toes, mild weakness in anterior tibialis, peroneus, and posterior tibial muscles, absent patellar and ankle reflexes, decreased pin-prick sensation below the mid-calf and mid-forearm, and a fine tremor in her hands upon extension of her arms. Vibratory and position senses were normal. No thickened nerves were noted on palpation. A nerve conduction study showed uniform demyelinating motor and sensory polyneuropathy typical of HMSN Type 1 (CMT 1A). Case Analysis It is interesting that the initial presentation of this patient’s neuropathy was essential tremor. Essential tremor in the presence of neuropathy is always due to demyelinating neuropathy, either hereditary or acquired. Her essential tremor was soon followed by weakness of the legs. Examination confirmed the classic findings of chronic neuropathy: pes cavus and distal leg weakness. A strong family history clearly pinpointed the hereditary nature of her neuropathy. Pes cavus and an autosomal dominant family history are strongly suggestive of HMSN (CMT). The presence of essential tremor indicated that we were dealing with HMSN Type I (hypertrophic type of CMT; CMT 1, Roussy–Levy syndrome). Essential tremor is not observed in HMSN Type II (neuronal type of CMT; CMT 2). Sural Nerve Biopsy The biopsy showed moderate decrease (50%) in myelinated fibers (Color Figure 10.21), many onion-bulb formations, and some myelinated fibers with many Schwann cell nuclei. Final Diagnosis HMSN Type I (CMT 1A) and Roussy–Levy syndrome were the final diagnosis. Treatment and Follow-up Two other members of the patient’s family were evaluated. Both had HMSN Type I with uniform demyelinating neuropathy, confirming the hereditary nature of this neuropathy. Over a 10-year period, no significant worsening was noted in the patient’s lower leg strength, and her tremor was well controlled with Inderal and valium.

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Comments Roussy–Levy syndrome resembles CMT in (1) its familial nature, (2) the prevalence of clubfoot, (3) weakness and minimal atrophy of the distal extremity muscles, and (4) some distal sensory loss. It differs from CMT because there is a static tremor of the hands. Dyck and Lambert classified this syndrome as Type I HMSN because they concluded that Roussy–Levy syndrome is nothing more than CMT plus an essential tremor. Nerve biopsy showed hypertrophic neuropathy (numerous onion-bulb formations). Marked slowing of the motor NCV has been reported in this condition. We found that sensory and mixed CNAPs were absent in most patients with this disorder.

CASE 2: CMT PATIENT WITH CONDUCTION BLOCK89 Case Presentation A 32-year-old man had difficulty running and had a high arched foot since childhood. The diagnosis of HMSN I was made in his grandmother, father, and son. He had had progressive weakness in the legs for the 2 years prior to evaluation. Examination showed no strength in the anterior tibialis, moderate weakness in the gastrocnemius muscles, pes cavus, diffuse atrophy in the lower leg, thick peroneal nerve at the fibular head, and sensory impairment below the mid-shin level. An NCS showed uniform slowing (15–20 m/sec) between the segments and nerves with conduction block in the wristelbow segment of the median and the elbow-axilla segment of the ulnar nerves. Case Analysis Uniform slowing in the motor NCS without any conduction block or temporal dispersion is typical of HMSN Type I neuropathy. In this case, even though uniform slowing in the NCV was observed, there was conduction block, indicating the possibility of acquired demyelinating neuropathy. However, there were no clinical data suggestive of acquired demyelinating neuropathy in this case. Sural Nerve Biopsy The biopsy revealed a marked loss of myelinated fibers (Color Figure 10.22). Onion-bulb formations were present in every nerve fiber, regardless of the presence of myelination. No inflammatory cells were found. Final Diagnosis HMSN Type I (CMT 1A) was the final diagnosis. Treatment and Follow-up Recent tests showed PMP-22 duplication, confirming the diagnosis of CMT 1A. Over a follow-up period of 10 years, there has been slow but steady worsening of his neuropathy. Comments Uniform slowing without any conduction block and temporal dispersion are thought to be pathognomonic of hereditary neuropathy. This case showed an exception. In 28% of our cases of hereditary neuropathy, there was conduction block in the ulnar and median nerves. Recent studies have shown that conduction block can occur in hereditary neuropathy due to pressure palsy, Dejerine–Sottas neuropathy, and sex-linked CMT 1A. This case indicates that differentiation between HMSN and chronic inflammatory demyelinating polyneuropathy is not possible with the nerve conduction study alone. A nerve biopsy clearly showed that this patient had HMSN Type I. ©2002 CRC Press LLC

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CASE 3: AUTOSOMAL RECESSIVE CMT WITH FOCALLY FOLDED MYELIN Case Presentation A 33-year-old female had complained of frequent falls and cramping in her calves, especially at night, for the past 11/2 years. During her high school days, it took her twice as long as her peers to run a mile. She did not complain of any sensory impairment. Abnormal neurological findings were mild weakness in her hand intrinsic muscles, marked weakness in anterior tibialis and mild weakness in gastrocnemius muscles, pes cavus, absent patellar and ankle reflexes, decreased triceps and biceps reflexes, and decreased pin-prick sensation below the ankles. An NCS showed uniform slowing of motor NCV at 12 to 24 m/sec. There was no contributory family history. All peripheral neuropathy work-ups were normal, including the spinal fluid. Case Analysis Though the subacute course and demyelinating neuropathy on the NCS suggest CIDP, the presence of pes cavus, delayed milestones, uniform NCV, and normal spinal fluid raises the question of hereditary neuropathy, even without a positive family history. Sural Nerve Biopsy The biopsy showed a moderate loss of myelinated fibers, no inflammatory cells, and prominent onion-bulb formations in the nerve fibers regardless of myelination. In addition, there were moderate numbers of nerve fibers with focally folded myelin (Color Figure 10.23). Treatment and Follow-up PMP-22 duplication was found in the genetic blood test for CMT. Even with this information, family history was lacking. Comments Focally folded myelin has been the pathological hallmark of one form of autosomal recessive CMT: CMT 4B. This was first described in 1977, and since then 18 identical cases have been described.49 The condition is inherited as an autosomal recessive mode, with onset usually in infancy or childhood. Many patients are seriously handicapped. Hand muscles and proximal leg muscles frequently become involved. Diffuse areflexia is the rule, and pes cavus and scoliosis are common. Sensory impairment is marked, and sensory ataxia occurs in many patients. The nerves are not palpable. CSF protein is elevated in some patients. Most patients show a maximum NCV value of 24 m/sec. Nerve biopsy shows many fibers with focally folded myelin in addition to chronic segmental demyelination. Onion-bulb formations are fairly frequent and are composed of thin Schwann cell processes with some double layers. DNA study in some patients did not show PMP-22 duplication. Our case is unique because focally folded myelin was observed in the biopsy in a patient with autosomal recessive CMT, which was shown to be 1A by DNA testing.

CASE 4: 3-YEAR WORSENING OF GAIT DIFFICULTY, PRESENT SINCE EARLY CHILDHOOD Case Presentation A 13-year-old girl was evaluated for gait difficulty in 1992. At 14 months of age she had begun walking, but her mother had noted some clumsiness with frequent falling episodes. At age 2, she was evaluated for flat feet. She continued to have a clumsy gait, and at age 10 she underwent surgery for foot ©2002 CRC Press LLC

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deformity. After the surgery, the patient still reported frequent falls and poor balance. There was a strong family history of foot deformity, though the patient’s grandmother was examined and found to be normal neurologically, with normal NCS. Abnormal findings in the 13-year-old patient were mild foot deformity with hammer toes, difficulty of tandem gait, positive Romberg test, slightly decreased vibration in toes and fingers, total loss of position sense in the toes, absent reflexes, mild hand tremor, mild weakness in the anterior tibialis, and normal strength in the gastrocnemius muscles. There was no pes cavus. An NCS showed a severe uniform slowing in the motor NCV in the range of 5 to 15 m/sec. SGPG autoantibody TLC was positive. DNA testing did not show a PMP-22 duplication or deletion. CSF protein was 86 mg/dl with increased IgG synthesis rate, high IgG level, and monoclonal bands. Case Analysis In view of the onset of neurological problems in infancy, Dejerine–Sottas neuropathy (HMSN Type III) was a definite possibility. NCS findings were compatible with Dejerine–Sottas neuropathy. Two laboratory findings suggested the possibility of acquired demyelinating neuropathy (CIDP): positive SGPG autoantibody and an increased IgG synthesis rate in the CSF with monoclonal bands. Sural Nerve Biopsy The biopsy showed severe loss of myelinated fibers. Numerous ill-defined onion-bulb formations were noted in small myelinated as well as nonmyelinated fibers and were much more prominent on PAS staining. These findings were more typical of congenital hypomyelinative neuropathy (Color Figures 10.24 and 10.25). Final diagnosis CIDP in HMSN Type III was the final diagnosis. Treatment and Follow-up Initial improvement with prednisone and, more recently, slight improvement with cyclosporin were noted. This improved state was sustained for 8 years. No improvement was noted with IVIG. Comments The nerve biopsy clearly showed features typical of congenital hypomyelination neuropathy. Sustained responsiveness to immunotherapies confirmed our initial impression that this patient had CIDP. Thus, we concluded that she had congenital hypomyelination neuropathy together with CIDP. Corticosteroid-responsive inherited neuropathy has been reported.90,91 A history of rapid recent clinical deterioration and an elevated CSF protein may be an indication of cases that will respond to steroids.90 Most likely, those patients have acquired inflammatory neuropathy in a background of inherited neuropathy.91,92 Conduction block and abnormal temporal dispersion, the electrophysiological hallmarks of acquired demyelinating neuropathy, were supportive of acquired inflammatory neuropathy.91 Mononuclear cells in the nerve biopsy are the only definite sign distinguishing CIDP from hereditary neuropathies.91-93 Thus, the nerve biopsy is critical in such cases. In our case, there were no inflammatory cells.

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CASE 5: GLOBAL WEAKNESS AND SENSORY LOSS IN THE ENTIRE LEFT ARM IN A WORKER’S COMPENSATION CASE Case Presentation In 1983, a 33-year-old male, not a good historian, apparently developed complete paralysis of his left arm without any pain after a tree fell on his left arm 1 year previously. With weekly injections from a physician, his left arm weakness gradually improved over an 8-month period. Abnormal neurological findings were as follows: absent knee and ankle reflexes; decreased biceps, triceps, and brachioradialis reflexes; mild weakness in the entire left arm muscles; analgesia over the entire left arm below the shoulder; absent position sense in the toes; decreased vibration sense in the wrists, fingers, and iliac bones; and absent vibration sense in the toes, ankles, and knees. The patient had minimal difficulty walking on his heels. An NCS showed demyelinating neuropathy, suggestive of acquired neuropathy. Case Analysis Neurological examination in this worker’s compensation case showed rather functional motor and sensory deficits, as noted in many such patients, giving the impression that this patient did not have any organic neurological disease. The only reliable objective findings indicative of an organic neurological disease were decreased or absent reflexes and abnormal nerve conduction findings. The neuropathy work-up was nonrevealing. Thus, a sural nerve biopsy was done. Sural Nerve Biopsy The biopsy showed a mild decrease in the population of myelinated fibers, a few thinly myelinated fibers, and scattered tomaculous changes (Color Figure 10.26). Final Diagnosis The final diagnosis was hereditary neuropathy with liability to pressure palsy (HNPP). Treatment and Follow-up The remaining neuropathy work-up was negative. After the diagnosis of tomaculous neuropathy was made, the patient told us that his father had been treated by us for CIDP. His father had an asymmetrical polyneuropathy with pes cavus and high CSF protein (170 mg/dl) and had been treated with prednisone with some improvement. His father’s NCS showed nonuniform demyelinating neuropathy with conduction block and dispersion. A review of his biopsy also showed tomaculous neuropathy. Over the next 6-month period, the patient’s neuropathy resolved completely. Comments Except for his functional neurological deficits, our case was classic for HNPP: most likely a brachial plexus neuropathy following a minor injury, positive family history, tomaculous changes in the nerve biopsy, widespread nerve conduction abnormalities even in unaffected nerves, and gradual recovery. Tomaculous neuropathy is classically observed in two disorders: HNPP and recurrent brachial plexus neuropathy. As noted in this patient’s father, polyneuropathy mimicking CIDP has been reported in a few cases. HNPP is a rare disorder characterized by (1) susceptibility to pressure palsies following relatively minor episodes of compression or ischemia; (2) improvement of symptoms within weeks or months; (3) frequent recurrence of pressure palsies; and (4) autosomal dominant inheritance. The disorder may present along with recurrent brachial plexus neuropathy. ©2002 CRC Press LLC

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CASE 6: A 31-YEAR-OLD WOMAN WITH NUMBNESS AND TINGLING SENSATION IN THE LEGS FOR 6 MONTHS Case Presentation Three years before evaluation, a 31-year-old woman had numbness and tingling sensations in her hands, which were thought to be due to carpal tunnel syndrome. Since then, the symptoms had progressed. In the last 6 months before examination, the patient noted numbness and tingling in her legs up to the knees and staggering gait. Family history was negative. Abnormal neurological findings were decreased reflexes, pin-prick sensation loss below her elbows and knees, decreased vibration in her fingers, ankles, and toes, and impaired position sense in her toes. Muscle strength was normal. An NCS/EMG showed diffuse demyelinating neuropathy, with the worst NCV of 29 m/s in the peroneal nerve. CSF findings were normal. All work-ups for neuropathy were normal. Case Analysis The diagnosis of chronic sensory demyelinating neuropathy was made on the basis of subacute progression of sensory neuropathy and nonuniform demyelinating neuropathy in the NCS.94 CSF protein is increased in 70% of cases; thus, normal CSF protein was an exception in this case. Sural Nerve Biopsy A marked loss of myelinated fibers, and many scattered tomaculous changes (Color Figure 10.27) were the biopsy findings. Final Diagnosis The final diagnosis was hereditary neuropathy to pressure palsy manifesting as chronic sensory demyelinating neuropathy. Treatment and Follow-up The patient exhibited unresponsiveness to IVIG and a side-reaction to imuran. Within 2 months, weakness developed in the patient’s anterior tibialis muscles. Subsequent DNA testing showed PMP-22 deletion, confirming the diagnosis of HNPP. Comments In this case, the sural nerve biopsy was the key in making the correct diagnosis. In classic cases of HNPP, the diagnosis can be confirmed by DNA blood tests without a nerve biopsy. With the availability of these tests, other heretofore unsuspected phenotypes have been reported.95,96 In one series, 5 other phenotypes in 15 of 99 HNPP patients were described. These include CMT-like polyneuropathy, chronic sensory polyneuropathy, and CIDP-like recurrent polyneuropathy.95 Mouton et al.95 reported two cases of chronic sensory polyneuropathy. Thus, ours is the third case in the literature. Unlike the majority of patients with CSDN, the patient did not respond to IVIG. This was because she had HNPP.

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CASE 7: PROGRESSIVE WALKING DIFFICULTY FOR 19 MONTHS IN A CHILD WITH INSULIN-DEPENDENT DIABETES MELLITUS 97 Case Presentation This 101/2-year-old black male was the product of parental consanguinity. The prenatal history and developmental milestones were unremarkable. A maternal first cousin had insulin-dependent diabetes mellitus, and the boy was diagnosed with that disease at 3 years of age. At 8 years old, he was evaluated for a progressive gait disturbance he had experienced for the previous 19 months. Examination showed a short height (< 5th percentile), normal hair texture, nasal speech, waddling gait, marked weakness in anterior tibialis and gastrocnemius muscles, absent reflexes, and loss of vibration in his fingers and toes. An NCS showed a marked abnormality indicative of diffuse axonal peripheral neuropathy. His CSF protein level was normal. Case Analysis The pediatric endocrinologist thought that the neuropathy was not due to diabetes because of a lack of sensory involvement. Motor neuropathy is commonly seen in CIDP. However, the NCS and CSF findings were not supportive of this diagnosis. Thus, a nerve biopsy was ordered. Sural Nerve Biopsy Frozen sections showed a moderate decrease in the population of myelinated fibers and giant axons. Giant axons were surrounded by either thin myelin or no myelin (Color Figure 10.28). By electron microscopy, the giant axons were found to be composed uniformly of neurofilaments. There was no thickening of basal lamina in the endoneurial vessels, as commonly seen in diabetic neuropathy. Final Diagnosis Giant axonal neuropathy was the final diagnosis. Comments Our patient had the characteristic features of giant axonal neuropathy based upon the age of onset, parental consanguinity, and pathognomonic axonal changes upon sural nerve biopsy, even though there was no hair abnormality. This is the first report of this neuropathy in an African American. In spite of the limited number of reports, the heterogeneity of giant axonal neuropathy has been documented by reports of a more slowly progressive course in Tunisian kindred, a congenital form with a rapidly progressive course, and a form with predominant central nervous system manifestations. In addition, children with giant axonal neuropathy were reported to have renal tubular acidosis, precocious puberty, and insulin-dependent diabetes.

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4. 5.

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Asbury, A.K. and Johnson, P.C., Pathology of Peripheral Nerve, W.B. Saunders, Philadelphia, PA, 1978. Dyck, P.J., Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 1578. Riley, M.M., Genetically determined neuropathies, J. Neurol., 245, 6, 1998. Buchthal, F. and Behse, F., Peroneal muscular atrophy (PMA) and related disorders. I. Clinical manifestations as related to biopsy findings, nerve conduction and electromyography, Brain, 100, 41, 1977. Behse, F. and Buchthal, F., Peroneal muscular atrophy (PMA) and related disorders. II. Histological findings in sural nerves, Brain, 100, 67, 1977. Harding, A.E. and Thomas, P.K., The clinical features of hereditary motor and sensory neuropathy types I and II, Brain, 103, 259, 1980. Oh, S.J., Clinical Electromyography. Nerve Conduction Studies, Williams & Wilkins, Baltimore, MD, 1993. Madrid, R., Bradley, W.G., and Davis, C.F.J., The peroneal muscular atrophy. Clinical, genetic, electrophysiological and nerve biopsy studies. Part 2. Observations on pathological changes in sural nerve biopsies, J. Neurol. Sci., 32, 91, 1977. Davis, C.J.F., Bradley, W.G., and Madrid, R., The peroneal muscular atrophy syndrome. Clinical, genetic, electrophysiological and nerve biopsy studies. Part 1: Clinical, genetic and electrophysiological findings, J. Genet. Hum., 26, 311, 1978. Smith, T.W., Bahywan, J., Keller, R., and DeGirolami, U., Charcot–Marie–Tooth disease associated with hypertrophic neuropathy. A neuropathologic study of two cases, J. Neuropathol. Exp. Neurol., 39, 420, 1980. Julien, J., Vital, C., Vallat, J.M., Coquet, M., and Li Blanc, M., Maladie de Charcot-Marie et diabéte. Etude clinique, ultrastructurale et autopsique d’une observation, Nouv. Presse Med., 3, 139, 1974. Hughes, J.T. and Brownell, B., Pathology of peroneal muscular atrophy (Charcot–Marie–Tooth disease), J. Neurol. Neurosurg. Psychiatry, 35, 648, 1972. Mathews, T. and Moosey, J., Mixed glioma, multiple sclerosis, and Charcot–Marie–Tooth disease, Arch. Neurol., 27, 263, 1972. Gherard, R., Bouche, P., Escourolle, R., and Hauw, J.J., Peroneal muscular atrophy. Part 2. Nerve biopsy studies, J. Neurol. Sci., 61, 401, 1983. Low, P.A., McLeod, G., and Prineas, J.W., Hypertrophic Charcot–Marie–Tooth disease — light and electron microscope studies of the sural nerve, J. Neurol. Sci., 35, 93, 1978. van Weerden, T.W. et al., Variability in nerve biopsy findings in a kinship with dominantly inherited Charcot–Marie–Tooth disease, Muscle and Nerve, 5, 185, 1982. Dyck, P.J. and Lambert, E.H., Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies, Arch. Neurol., 18, 603, 1968. Oelschlager, R., White, H.M., and Neilshimke, R., Roussy–Levy syndrome: report of kindred and discussion of the nosology, Acta Neurol. Scand., 47, 80, 1971. Lapresle, J., Salisachs, P., and Kremlin-Bicetre, L., Onion bulbs in a nerve biopsy specimen from an original case of Roussy–Levy disease, Arch. Neurol., 29, 346, 1973. Salilsachs, P., Findley, L.J., Codina, M., Torre, P.L., and Martinez-Lage, J.M., Data on three of the original patients of Roussy and Levy (1926), Muscle and Nerve, 5, 663, 1982. Kirel, R.L., Cliffer, K.D., Berry, J., Sung, J.H., and Blond, C.S., Investigation of a family with hypertrophic neuropathy resembling Roussy–Levy syndrome, Neurology, 24, 801, 1974. Barbeir, F., Ragno, F.M., Santoro, C.L., Santoro, L., Corona, M., and Campanella, G., Evidence that Charcot–Marie–Tooth disease with tremor coincides with the Roussy–Levy syndrome, Can. J. Neurol. Sci., 11, 534, 1984. Birouk, N., LeGuern, E., Maisonobe, T., Rouger, H., Gouider, R., Tardieu, S., Gugenheim, M., Routon, M.C., Léger, J.M., Agid, Y., Brice, A., and Bouche, P., X-linked Charcot–Marie–Tooth disease with connexin 32 mutations. Clinical and electrophysiologic study, Neurology, 50, 1075, 1998. Rozear, M.P., Pericak-Vance, M.A., Fischbeck, K., Stajich, J.M., Gaskell, P.C., Krendel, D.A., Graham, D.G., Dawson, D.V., and Roses, A.D., Hereditary motor and sensory neuropathy, X-linked: a half century follow-up, Neurology, 37, 1460, 1987.

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28. Sanders, S., Nocholson, G.A., Ouvrier, R.O., McLeod, J.G., and Pollard, J.D., Charcot–Marie–Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1a) and connexin 32 mutations (CMTX1), Muscle and Nerve, 21, 217, 1998. 29. Fischbeck, K.H., ar-Rushdi, N., Pericak-Vance, M., Rozear, M., Roses, A.D., and Fryns, J.P., X-linked neuropathy; gene localization with DNA probes, Ann. Neurol., 20, 527, 1986. 30. Mostacciuolo, M.L., Müller, E., Fardin, P., Micaglio, G.F., Bardoni, B., Guioli, S., Camerino, G., and Danieli, G.A., X-linked Charcot–Marie–Tooth disease; a linkage study in a large family by using 12 probes of the pericentromeric region, Hum. Genet., 87, 23, 1991. 31. Hahn, A.F., Brown, W.F., Koopman, W.J., and Feasby, T.E., X-linked dominant hereditary motor and sensory neuropathy, Brain, 113, 1511, 1990. 32. Ben Hamida, M., Letaief, R., Ben Hamida, C., and Samoud, S., Les atrophies péroniéres en Tunisie, J. Neurol. Sci., 50, 335, 1981. 33. Dyck, P.J., Lambert, E.H., Sanders, K., and O’Brien, P.C., Severe hypomyelination and marked abnormality of conduction in Dejerine–Sottas hypertrophic neuropathy: myelin thickness and compound action potential of sural nerve in vitro, Mayo Clin. Proc., 46, 432, 1971. 34. Satran, R., Dejerine–Sottas disease revisited, Arch. Neurol. 37, 67, 1980. 35. Joosten, E., Gabreéls, F., Gabreéls-Festen, A., Vrensen, G., Korten, J., and Notermans, S., Electron microscopic heterogeneity of onion-bulb neuropathies of the Dejerine–Sottas type, Acta Neuropathol., 27, 105, 1974. 36. Tredici, S., Petroccioli-Pizzini, M.G., Gergely, A., and Coletti, A., The importance of quantitative electron microscopy in studying hypertrophic neuropathies. A comparison between a case of Dejerine–Sottas (HMSN III) and a case of the hypertrophic form of Charcot–Marie–Tooth disease (HMSN I), Int. J. Tissue React., 6, 267, 1984. 37. Dyck, P.J., Chance, P., Lebo, R., and Carney, J.A., Hereditary motor and sensory neuropathies, in Peripheral Neuropathy, 3rd Ed., Dyck, P.J., Thomas, P.K., Griffin, J.W., Low, P.A., and Poduslo, J.F., Eds., W.B. Saunders, Philadelphia, PA 1993, 1094. 38. Kennedy, W.R., Sung, J.H., and Berry, J.F., A case of congenital hypomyelination neuropathy; clinical, morphological, and chemical studies, Arch. Neurol., 34, 337, 1977 39. Guzzetta, L., Ferriere, G., and Lyon, G., Congenital hypomyelination polyneuropathy: pathological findings compared with polyneuropathies starting later in life, Brain, 105, 395, 1982. 40. Karch, S.B. and Urich, H., Infantile polyneuropathy with defective myelination: an autopsy study, Dev. Med. Child. Neurol., 17, 504, 1975. 41. Lyon, G., Ultrastructural study of a nerve biopsy from a case of early infantile chronic neuropathy, Acta Neuropathol., 13, 131, 1969. 42. Palix, C. and Coignet, J., Un cas de polyneuropathie peripherique neo-natale par amyelisation, Pediatrie, 33, 201, 1978. 43. Moss, R.B., Sriram, S., Kelts, K.A., Forno, L.S., and Lewiston, N.J., Chronic neuropathy presenting as a floppy infant with a respiratory distress, Pediatrics, 64, 459, 1979. 44. Hakamada, S., Kumagai, T., Miyazaki, S., Miyazaki, K., and Watanabe, K., Congenital hypomyelination neuropathy in a newborn, Neuropediatrics, 14, 182, 1983. 45. Ono, J., Senba, E., Okada, S., Abe, J., and Futagi, Y., A case report of congenital hypomyelination, Eur. J. Pediatr., 138, 165, 1982. 46. Ulrich, J. et al., Congenital polyneuropathy: a case with proliferated microfilaments in Schwann cells, Acta Neuropathol., 55, 39, 1981. 47. Towfighi, J., Congenital hypomyelination neuropathy: glial bundles in cranial and spinal nerve roots, Ann. Neurol., 10, 570, 1981. 48. Anderson, R.M., Denniett, X., Hopkins, I.J., Shield, L.K., Hypertrophic interstitial polyneuropathy in infancy: clinical and pathologic features in two cases, J. Pediatr., 82, 619, 1978. 49. Gabreéls-Festen, A. and Gabreéls, F.. Hereditary demyelinating motor and sensory neuropathy, Brain Pathol., 3, 135, 1993. 50. Gambardella, A. et al., Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B), Neurology, 50, 799, 1998. 51. Kessali, M. et al., A clinical, electrophysiologic, neuropathologica, and genetic study of two Algerian families with an autosomal recessive demyelinating form of Charcot–Marie–Tooth disease, Neurology, 48, 867, 1997. ©2002 CRC Press LLC

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52. Kataydjieva, L. et al., Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24, Nat. Genet., 14, 214, 1996. 53. Dyck, P.J. and Ohta, M., Neuronal atrophy and degeneration predominantly affecting peripheral sensory neurons, in: Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., and Lambert, E.H., Eds., W.B. Saunders, Philadelphia, PA, 1975, 791. 54. Thomas, P.K., Hereditary sensory neuropathies, Brain Pathol., 3, 157, 1993. 55. Denny-Brown, D., Hereditary sensory radicular neuropathy, J. Neurol. Neurosurg. Psychiatry, 14, 237, 1951. 56. O’Brien, B., Jackson, R., Tang-Wai, R., Lewis, A.J., and Atauk, E.A., Hereditary sensory neuropathy: a case with pain and temperature dissociation, Can. J. Neurol. Sci., 7, 73, 1980. 57. Danon, M.J. and Carpenter, S., Hereditary sensory neuropathy: biopsy study of an autosomal dominant variety, Neurology, 35(8), 1226, 1985. 58. Ohta, M., Ellefson, R.D., Lambert, E.H., and Dyck, P.J., Hereditary sensory neuropathy type II. Clinical, electrophysiological, histologic and biochemical studies of a Quebec kinship, Arch. Neurol., 29, 23, 1973. 59. Schoene, W.C., Asbury, A.K., Astrom, K.E., and Masters, R., Herditary sensory neuropathy, a clinical and ultrastructural study, J. Neurol. Sci., 11, 463, 1970. 60. Nukuda, H., Pollock, M., and Haas, L.F., The clinical spectrum and morphology of type II hereditary sensory neuropathy, Brain, 105, 647, 1982. 61. Linarelli, L.G. and Prichard, J.W., Congenital sensory neuropathy, Am. J. Dis. Child., 119, 513, 1970. 62. Barry, J.E., Jopkins, J.J., and Neal, B.W., Congenital sensory neuropathy, Arch. of Dis. Child., 49, 128, 1974. 63. Jedzejowska, H. and Milczrek, H., Recessive hereditary sensory neuroapthy, J. Neurol. Sci., 29, 371, 1976. 64. Kondo, K. and Horikawa, Y., Genetic heterogeneity of hereditary sensory neuropathy, Arch. Neurol., 30, 3 36, 1974. 65. Meier, C. and Moll, C., Hereditary neuropathy with liability to pressure palsies. Report of two families and review of the literature, J. Neurol., 228, 73, 1982. 66. Amato, A.A., Gronseth, G.S., Callerame, K.J., Kagan-Hallet, K.S., Bryan, W.W., and Barohn, R.J., Tomaculous neuropathy: a clinical and electrophysiological study in patients with and without 1.5-Mb deletions in chromosome 17p11.2, Muscle and Nerve, 19(1), 16, 1996. 67. Chance, P.F. et al., DNA deletion associated with hereditary neuropathy with liability to pressure palsies, Cell, 72, 143, 1993. 68. Nelis, E. et al., Estimation of the mutation frequencies in Charcot–Marie–Tooth disease type I and hereditary neuropathy with liability to pressure palsies: a European collaborative study, Eur. J. Hum. Genet., 4, 25, 1996. 69. Mouton, P. et al., Spectrum of clinical and electrophysiologic features in HNPP patients with the 17p11.2 deletion, Neurology, 52, 1440, 1999. 70. Kumar, N., Cole, J., and Parry, G.J., Variability of presentation in hereditary neuropathy with liability to pressure palsy results in underrecognition, Ann. N.Y. Acad. Sci., 883, 344, 1999. 71. Behse, F., Buchthal, F., Carlsen, F., and Knappeis, G.G., Hereditary neuropathy with libaility to pressure palsy. Electrophysiological and histopathological aspects, Brain, 95, 777, 1972. 72. Madrid, R. and Bradley, W.G., The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy). Studies on the formation of the abnormal myelin sheath, J. Neurol. Sci., 25, 415, 1975. 73. Liehr, T., Grehl, H., and Rautenstrauss, B., Molecular diagnosis of PMP22-associated neuropathies using fluorescence in situ hybridization (FISH) on archival peripheral nerve tissue preparations, Acta Neuropathol., 94(3), 266, 1997. 74. Windebank, A.J., Inherited recurrent focal neuropathies, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lambert, E.H. and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 1656. 75. Rizzuto, N., Moretto, G., and Galiazzo-Rizzuto, S., Clinical spectrum of the tomaculous neuropathies. Report of 60 cases and review of the literature, J. Neurol. Sci., 14(9), 609, 1993. 76. Pou Serradell, A., De Paiva, V.J., Alameda, F., Lloreta, J., Blasco, R., and Piqueras, A., Familial recurrent paralysis of the brachial plexus. Tomaculous neuropathy (transl.), Rev. Neurolog., 148(2), 123, 1992. 77. Sanders, S., Ourrier, R.A., McLeod, J.G., Nicholson, G.A., and Pollard. J.D., Clinical syndromes associated with tomacula or myelin swellings in sural nerve biopsy, J. Neurol. Neurosurg. Psychiatry, 68, 483, 2000.

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78. Asbury, A.K., Gale, M.K., Cox, S.C., Barinter, J., and Berg, B.O., Giant axonal neuropathy: a unique case with segmental neurofilamentous masses, Acta Neuropathol., 20, 237, 1972. 79. Tandan, R. et al., Childhood giant axonal neuropathy: case report and review of the literature, J. Neurol. Sci., 82, 205, 1987. 80. Menkes, J.H., Alter, M., Steigleder, G.K., Weakley, D.R., and Sung, J.H., A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral degeneration, Pediatrics, 29, 764, 1962. 81. Bolshauser, E., Bishoff, A., and Isler. W., Giant axonal neuroapthy: report of a case with normal hair, J. Neurol. Sci., 31, 269, 1977. 82. Prineas, J.W., Ourvier, R.A., Wright, R.G., Walsh, J.C., and McLeod, J.G., Giant axonal neuropathy — a generalized disorder of cytoplasmic microfilament formation, J. Neuropathol. Exp. Neurol., 35, 458, 1976. 83. Koch, T., Schulte, P., Williams, R., and Lampert, P.W., Giant axonal neuropathy: a childhood disorder of microfilaments, Ann. Neurol., 1, 438, 1977. 84. Gambarelli, D. et al., Giant axonal neuropathy: Involvement of peripheral nerve, myenteric plexus and extra-neural area, Acta Neuropathol., 39, 261, 1977. 85. Carpenter, S., Karpati, G., Andermann, F., Gold, R., and Chir, B., Giant axonal neuropathy. A clinically and morphologically distinct neurologically distinct neurological disease, Arch. Neurol., 31, 312, 1974 86. King, R.H. et al., Axonal neurofilamentous accumulations: a comparison between human and canine giant axonal neuropathy and 2,5-HD neuropathy, Neuropathol. Appl. Neurobiol., 19, 224, 1993. 87. Hughes, J.T., Brownell, B., and Hewer, R.L., The peripheral sensory pathway in Friedreich’s ataxia: an examination by light and electron microscopy of the posterior nerve roots, posterior root ganglia, and peripheral sensory nerves in cases of Friedreich’s ataxia, Brain, 91, 803, 1968. 88. Dyck, P.J. and Lais, A.C., Evidence for demyelination secondary to axonal degeneration in Friedreich’s ataxia, in Clinical Studies in Myology, Kakulas, B., Ed., Excerpta Medica, Amsterdam, 1973, 253. 89. Oh, S.J.. Conduction block in hereditary motor sensory neuropathy, Type I: case report, Muscle and Nerve, 15, 521, 1992. 90. Dyck, P.J., Swanson, C.J., Low, P.A., Bartleson, J.D., and Lambert, E.H., Prednisone-responsive hereditary motor and sensory neuropathy, Mayo Clin. Proc., 57, 239, 1982. 91. Bird, S.J. and Sladky, J.T., Corticosteroid responsive dominantly inherited neuropathy in childhood, Neurology, 41, 437, 1991. 92. Malandrini, A., Villanova, M., Dotti, M.T., and Federico, A., Acute inflammatory neuropathy in Charcot–Marie–Tooth disease, Neurology, 52, 859, 1999. 93. Gabreél-Festen, A.A.W.M. et al., Chronic inflammatory demyelinating polyneuropathy in two siblings, J. Neurol. Neurosurg. Psychiatry, 49, 152, 1986. 94. Oh, S.J., Joy, J.L., Kuruoglu, R., Chronic sensory demyelinating neuropathy: chronic inflammatory demyelinating polyneuropathy as a pure sensory neuropathy, J. Neurol. Neurosurg. Psychiatry, 55, 677, 1992. 95. Mouton, P., Tardieu, S., Guoider, R. et al., Spectrum of clinical and elecrophysiologic features in HNPP patients with the 17p11.2 deletion, Neurology, 52, 1220, 1990. 96. Kumar, N., Cole, J., and Parry, G.J., Variability of presentation in hereditary neuropathy with liability to pressure palsy results in underrecognition, Ann. NY Acad. Sci., 883, 344, 1999. 97. Hoffman, W.H., Carrol, J.E., Perry, G.Y., Hartlage, P.L., Kaminer, S.J., Flowers, N.C., Oh, S.J., and Kelly, D.R., Giant axonal neuropathy in a child with insulin-dependent diabetes mellitus, J. Child. Neurol., 10, 250, 1995. 98. Schenone, A. and Mancardi, G.L., Molecular basis of inherited neuropathies, Current Opinion Neurol. 12, 603, 1999.

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CHAPTER 10 Figure 1 Onion-bulb formations in almost all nerve fibers, regardless of the presence or absence of myelin (red ring). More than two Schwann cell nuclei in the nerve fibers (arrowhead) are indicative of Schwann cell proliferation suggestive of onion-bulb formation. Fine layers of onion-bulb formation are clearly seen in this stain. Paraffin section. Modified trichrome stain. (400 × magnification.)

CHAPTER 10 Figure 2 Increased number of Schwann cell nuclei (arrows), suggestive of onionbulb formations, is the only feature which is clearly seen. Fine layers of onion-bulb formations are not clearly seen in most nerve fibers. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 10 Figure 4 One myelinated fiber surrounded by seven Schwann cell nuclei (arrow) is the only feature suggestive of onion-bulb formations. Frozen section. H & E stain. (400 × magnification.)

CHAPTER 10 Figure 3 Onion-bulb formation. Fine layers of onion-bulb formation around the myelinated fibers (arrow) are clearly visible here. Frozen section. Modified trichrome stain. (1000 × magnification.)

CHAPTER 10 Figure 5 Onion-bulb formations around a normal myelinated fiber (yellow arrow), denuded axon (demyelinated fiber; red arrow), and thinly myelinated (remyelinated; pink arrow) fibers. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 10 Figure 6 Onion-bulb formations around normal myelinated fibers (arrows). Separation between myelinated fibers is also obvious here. Semithin section. Toluidine blue and basic fuchsin stain. (400 × magnification.)

CHAPTER 10 Figure 7 Spotty loss of myelinated fibers in neuronal CMT, otherwise normal findings. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 10 Figure 8 Hypomyelination and amyelination. There are not any fully myelinated fibers. Nerve fibers are either very thinly myelinated (hypomyelination) or nonmyelinated (amyelinated). Notice that layers of onion-bulb formations are not clearly visible. Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 10 Figure 9 Focally folded myelin (arrows). At least two fibers with focally folded myelin are distinctly identifiable here. OBFs are clearly seen. Semithin section. Toluidine blue and basic fuchsin stain. (400 × magnification.)

CHAPTER 10 Figure 10 Severe loss of myelinated fibers in HSN II. Only six myelinated fibers are identifiable in this nerve fascicle. In six other fascicles, there was total loss of myelinated fibers. Paraffin section. Kultschitzky’s hematoxylin stain. (200 × magnification.)

CHAPTER 10 Figure 11 Two “sausage” tomaculous myelin (arrows) on the longitudinal cut. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 12 Four huge tomaculae myelinated fibers (arrows) stand out from other myelinated fibers in the transverse cut. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 13 Tomaculous myelin is obvious in this field. Semithin section. Toluidine blue.

A

CHAPTER 10 Figure 14 Thickened myelin is obvious. Axon is tiny in comparison with hugely thickened myelin. Some fibers have thinly myelinated fibers. Semithin section. Toluidine blue stain. (300 × magnification.)

B

CHAPTER 10 Figure 15 (A) Segmental demyelination in one internodal segment between two thin arrows. Thick arrows indicate “sausage” like tomaculae. (B) Various forms of tomaculous change.

CHAPTER 10 Figure 16 Two giant axons surrounded by myelin sheaths (arrows). Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 17 Two giant axons (arrows) in one fascicle. Population of myelinated fibers is relatively normal in this nerve fascicle. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 19 Giant axons (red arrows) with thinly myelinated fibers. The giant axon is compared with the size of normal axon (yellow arrow). Semithin section. Toluidine blue. (400 × magnification.)

CHAPTER 10 Figure 18 Giant axon in giant axonal neuropathy. Giant axons (arrows) are characterized by green globules which are not surrounded by any red myelin sheath. This is a strong contrast to the giant axons in Figure 10.17. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 20 Arrows indicate two spindle-shaped giant axons in the teased nerve.

CHAPTER 10 Figure 21 Onion-bulb formation in Roussy–Levy syndrome. Moderate decrease in myelinated fibers. The red arrow indicates one of many onion-bulb formations around normal myelinated fibers. The blue arrow indicates three Schwann cell nuclei around myelinated fibers. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 22 Onion-bulb formation in CMT 1A. Marked loss of myelinated fibers. Onionbulb formations are present in every nerve fiber regardless of whether myelin is present or not. Semithin section. Toluidine blue and basic fuchsin. (400 × magnification.)

CHAPTER 10 Figure 23 Three focally myelinated fibers (arrows) in addition to OBF in CMT 1A. Many more fibers show onion-bulb formations. Semithin section. Toluidine blue and basic fuchsin. (400 × magnification.)

CHAPTER 10 Figure 24 Onion-bulb formation in congenital hypomyelination neuropathy. Severe loss of myelinated fibers. Many ill-defined onion-bulb formations surrounded by small or no myelinated fibers (arrows). Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 25 Ill-defined onion-bulb formations are prominently recognized by PASH stain, indicating basal lamina onion-bulb formation. PASH is good for staining basal lamina. Frozen section. PASH stain. (400 × magnification.)

CHAPTER 10 Figure 27 Tomaculous myelin changes (arrows) are only visible here. All other myelinated fibers are lost. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 10 Figure 26 Tomaculous myelin changes in hereditary neuropathy with liability to pressure palsy. Larger tomaculum (red arrow) and smaller one (blue arrow). Semithin section. Toluidine blue. (1000 × magnification.)

CHAPTER 10 Figure 28 Four giant axons in giant axonal neuropathy. Semithin section. Toluidine blue. (400 × magnification.)

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Metabolic and Systemic Neuropathies

The majority of neuropathies due to systemic diseases do not require a nerve biopsy for diagnosis. Diagnosis is made by clinical evaluation and laboratory data. However, there are a few neuropathies which do necessitate a nerve biopsy for confirmation of diagnosis. These include vasculitic neuropathy, sarcoid neuropathy, sensory perineuritis, leprosy, and lymphomatous neuropathy. Vasculitic neuropathy was discussed in Chapter 6.

SARCOID NEUROPATHY Involvement of the central and peripheral nervous systems is well-recognized in sarcoidosis; it is observed in 5% of cases.1 The most frequently affected sites are the cranial nerves, particularly the VIIth nerve, the meninges, and the muscles. Involvement of peripheral nerves is rare, accounting for only 15% of cases with neurological involvement. All types of neuropathies have been reported in sarcoidosis — mononeuropathy, mononeuropathy multiplex, and polyneuropathy — although the most characteristic is mononeuropathy multiplex.1 In such cases, the NCS shows axonal neuropathy. In sarcoidosis, microscopic granulomata are found in muscle in up to 60% of patients with active sarcoidosis, whereas peripheral nerve involvement is less than 1% in this disease.1,2 Thus, muscle biopsy is the procedure of choice for diagnosis of sarcoidosis if a skin or lymph node biopsy is not diagnostic. However, because sarcoidosis was not clinically suspected in most reported cases, the nerve biopsy was ordered to ascertain the unknown cause of neuropathy and was the critical test in the diagnosis of sarcoidosis in those cases.3-6 In 1979, we reported the first case of nerve-biopsy proven sarcoid neuropathy.4 Since then, 12 other biopsy-proven cases of sarcoid polyneuropathy have been reported.3,5-12 Neuropathy was the only manifestation of sarcoidosis in most of these cases. Sarcoid granulomas are classically noncaseating granulomas consisting of epithelioid cells, Langhan’s giant cells, and lymphocytes (Color Figure 11.1).* No organisms are found in sarcoid granulomas. Noncaseating granulomas are mostly observed in the epi- and perineurial spaces. Granulomas in the endoneurium have been reported in only four cases.3,5,10,12 Granulomatous periangiitis and panangiitis (true vasculitis) were observed in the epi- and perineurial spaces in four cases (Color Figure 11.2).4,7,9,11 Axonal degeneration is the predominant feature (Color Figure 11.3). Muscle biopsy showed granulomas in three cases.3,7,10 In practice, we recommend both muscle and nerve biopsies in patients clinically suspected of sarcoid neuropathy for two reasons: the diagnostic yield is high in muscle biopsy, as described above, and granulomas are not always observed in biopsied nerves because of the sampling error.8 In three of four patients with sarcoid neuropathy, the sural nerve biopsy did not show classical granulomas in our series. Noncaseating granulomas in the nerve are diagnostic of sarcoid neuropathy and sarcoidosis once leprosy is ruled out by the AFB stain.

SENSORY PERINEURITIS Asbury et al. reported two cases of sensory perineuritis with a chronic relapsing-remitting course of mononeuropathy multiplex affecting cutaneous sensory nerves. It was characterized by asymmetric painful dysesthesia, sensory loss, and positive Tinel’s sign.13 To date, nine similar cases have been * Color insert figures. ©2002 CRC Press LLC

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reported.14,15 Pure sensory mononeuropathy multiplex is the classic clinical presentation. An NCS showed abnormal sensory nerve conduction in four cases and axonal sensorimotor neuropathy in five. There was good response to steroids in seven of nine treated cases. The hallmark of sural nerve biopsy abnormality was chronic inflammation and fibrosis in the peineurial sheaths of some fascicles. Chronic granulomatous features with epithelioid histiocytes and perineurial fibrosis were found in five cases, and inflammation in the endoneurium was seen in two cases.14 Active lesions were marked by a greatly thickened perineurium and by infiltration by mononuclear cells and histiocytes, creating a somewhat granulomatous appearance with occasional giant cells. Chronic lesions were characterized by severe perineurial fibrosis and a few inflammatory cells. Acid-fast bacilli were absent. Asbury et al.13 concluded that these cases differ from the migrant sensory neuropathy of Wartenberg and represent a distinct entity. On the basis of sural nerve biopsy, there is a possibility that this may be a restricted form of sarcoidosis.16

LEPROSY Leprosy is still the most common neuropathy in the world, occurring primarily in Asia, Africa, and South America. Leprosy is an infectious disease caused by Mycobacterium leprae (M. leprae) and is characterized by skin and peripheral nerve lesions. M. leprae is the only bacterium that invades peripheral nerves in man and animals. The organism proliferates preferentially in cool tissues, 30°C being optimal, and has a particular affinity to the human Schwann cell.17 Leprosy is classified into two polar types, tuberculoid and lepromatous, and a borderline (dimorphous) type possessing some characteristics of each polar type. In addition, there is an indeterminate type which has not established itself into one of the three types. This classification depends on the host’s immunological response to M. leprae infection. Lepromatous leprosy is characterized by the lack of immune responses, minimal inflammatory response, massive quantities of bacterial organisms, and widespread maximal cutaneous nerve damage. The tuberculoid type shows a brisk immune response, intense delayed hypersensitivity-type inflammatory response, rare M. leprae organisms, and localized and circumscribed lesions. Borderline leprosy takes the middle ground between the tuberculoid and lepromatous types with intermediate clinical and pathological features. Borderline leprosy has a tendency to drift toward one of the poles: tuberculoid if treated and lepromatous otherwise. The clinical hallmarks of leprosy are sensory loss caused by superficial neuropathy and skin lesions. Anesthesic depigmented skin lesions are an important finding and should be sought. Other characteristic findings are thickened nerves, trophic ulcers, mutilated digits, and a Charcot joint. In the tuberculoid form, mononeuropathy multiplex is the typical pattern, whereas asymmetrical or symmetrical polyneuropathy is most common in the lepromatous form. Motor involvement occurs in a predictable sequence as a result of nerve trunk damage to those nerves that course close to the skin surface and, hence, are locally cool. Common nerves involved include the ulnar nerve at the elbow, the deep peroneal branch at the ankle, superficial branches of the facial nerve, and the median nerve at the wrist, more or less in that order.18 Since the skin responses are more indicative of the general tissue response, the skin biopsy is the best guide for classification of the disease and treatment choice. This is probably because the nerves are in a protected site: neural architecture hinders the influx of lymphocytes, and organisms within Schwann cells tend not to incite an inflammatory response.17,19 In a majority of cases, the diagnosis of leprosy is made by the typical skin lesion and the presence of acid-fast bacilli from the skin smear obtained by the scrape-incision method. The nerve biopsy is imperative in diagnosing primary neuritic leprosy in which neuropathy is the sole clinical manifestation without typical skin lesions or a positive skin smear. In those cases, skin biopsied from anesthesic areas may fail to show histological changes suggestive of leprosy.20 In 77 patients in a

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leprosy-endemic area who presented with peripheral neuropathy without any known cause, Jacob and Mathai biopsied a cutaneous nerve near the area of neurological deficit.20 The cutaneous branch of the radial nerve was biopsied when “glove-stocking” anesthesia was present, and the sural nerve or superficial peroneal nerve was biopsied when “stocking” anesthesia was present. Leprosy was confirmed in 49.4% of the 77 patients, in 56% of 25 patients with mononeuritis multiplex, in 50% of 40 patients with distal polyneuropathy, and in 65% of 54 patients with thickened nerves. In other patients, vasculitic, hereditary, or chronic inflammatory neuropathy was diagnosed. This study clearly documented the important diagnostic role of the cutaneous nerve biopsy in primary neuritic leprosy. The sural nerve biopsies from 18 patients with leprosy under treatment for varying periods were reviewed.21 The classic histological features were observed in all 8 patients with lepromatous leprosy and in 80% of 10 patients with tuberculoid leprosy. In one of two negative patients, a skin biopsy revealed tuberculoid leprosy. This study showed that the sural nerve biopsy is highly sensitive in the diagnosis of leprosy and that a good histological correlation exists between skin and sural nerve biopsies. The degree of activity of leprosy was reviewed in 59 patients who had sural nerve biopsies.22 There was a relatively good correlation between the activity of leprosy and sural nerve biopsy findings: positive sural nerve biopsy in 75% of 24 patients with active leprosy and in 22% of 32 patients with leprosy inactive for an average of 5.5 years. This study suggests that the sural nerve biopsy may be indicated in apparently inactive cases by examination of skin scrapings if a progressive neurological deficit occurs. Pathological features in the nerve are different according to the type of leprosy.18,23 In indeterminate leprosy, the nerve shows lymphocytic infiltration in the endoneurial and perineurial spaces (inflammatory neuropathy) without any epithelioid cells or foamy macrophages. Mycobacterial stains show few or no organisms. In tuberculoid leprosy, the pathological hallmark is an intense inflammatory noncaseating or caseating granulomatous lesion that severely damages the neural architecture. Granulomas consist of epithelioid histiocytes, multinuclear giant cells, lymphocytes, and plasma cells (Color Figure 11.4). Granulomas are seen in the epi- and perineurial spaces as well as in the endoneurial space. Caseation may occur and produce large abscesses within the nerve. Bacilli are scanty and, when found, are almost always in the nerve. With healing, the nerve shows fibrosis and hyalization in the endoneurium and thick perineurial and epineurial sheaths (Color Figures 11.5 and 11.6). The nerve is enlarged by a fibrotic mass with a markedly thickened perineurium and epineurium infiltrated by exuberant inflammatory cells. In lepromatous leprosy, perineurial and endoneurial infiltration of enlarged macrophages and Schwann cells with M. leprae bacilli (foamy or leprae cells) and inflammatory cells are the cardinal features. Massive bacilli are found in these foamy cells. In severe cases, the epineurium may be infiltrated by huge numbers of foamy cells, especially around blood vessels (Figure 11.7). Granulomatous inflammatory response is minimal. The overall architecture of the nerve is better preserved, although myelinated fibers are increasingly lost until, in the most advanced cases, myelinated fiber loss is total and the entire nerve is replaced by fibrous and hyalin materials. The nerve is enlarged with a thickened perineurium and endoneurium with massive infiltration of bacteria. In the perineurium, foamy cells infiltrate and separate individual layers, there is fibroblast and perineurial cell proliferation, and collagen is deposited, producing a striking “onion-skinning” of the nerve fascicle. Perivascular collections of inflammatory cells are common, but true vasculitis is rare. Intraneurial microabscesses may be present in either type, especially during an attack of erythema nodosum (Color Figure 11.8). In borderline leprosy, there are some pathological features of tuberculoid as well as lepromatous types: characteristically diffusely spread epithelioid histiocytes and easily demonstrable organisms, but no foamy or giant cells. The perineurium appears to be the main site of the disease process with perineurial splitting, edema, thickening, and infiltration of inflammatory cells and histiocytes.23 According to Pearson and Weddell, perineurial cells invade and subdivide the adjacent endoneurium into multiple small microfascicles.24 Segmental demyelination is the predominant feature with thinly myelinated and denuded axons and even occasional onion ©2002 CRC Press LLC

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bulbs.25,26 With progression of the disease, axonal degeneration becomes significant and involves myelinated and unmyelinated fibers. In all of these cases, the pathological diagnosis of leprosy should be made on the demonstration of acid-fast bacilli in the nerve by the Fite method (Color Figure 5.17).27 In tuberculoid leprosy, bacilli may be difficult to demonstrate, requiring a thorough examination of serial sections through the entire tissue block. Polymerase Chain Reaction (PCR) techniques for detection of M. leprae in tissue are now available and have proven extremely sensitive in detecting bacteria.28,29

LYMPHOMATOUS NEUROPATHY The nervous system is involved in 10 to 25% of all cases of lymphoma. Complications of lymphoma include encephalomyelitis, cerebellar degeneration, progressive multifocal leucoencephalopathy (PML), polymyositis, peripheral neuropathy, and opportunistic infections.30 Peripheral neuropathy as a complication of lymphoma is not common, affecting 0.1 to 2% of patients.30 Non-compression peripheral neuropathy may be due to a variety of causes, such as nerve infiltration by lymphomatous cells (neurolymphomatosis), antibody-mediated nerve damage (GBS or CIDP), or vasa nervosum changes caused by cryoglobulins (vasculitis).30 Neurolymphomatosis (NL) is a clinical disorder with signs of peripheral neuropathy confirmed by histopathological evidence of lymphomatous infiltration of the nerves by biopsy or at autopsy.31 A total of 48 patients with NL were reported as of 1999. This disease occurs mostly in individuals over 50 years of age, and in nearly half the patients, the diagnosis is not made until autopsy. This is because the diagnosis was not suspected clinically and the nerve biopsy was not performed. Only one-third of patients had a history of lymphoma at the time of diagnosis. Most patients showed subacute progressive sensorimotor polyneuropathy, cranial neuropathy, mononeuropathy multiplex, or an isolated median or sciatic nerve palsy. The most common EMG abnormality was axonal neuropathy. CSF testing usually showed mildly increased protein and cells; CSF cytology was positive for tumor cells in 40% of tested cases. In most cases reported before 1980, the diagnosis was made at autopsy; since 1980, most diagnoses have been made by nerve biopsy due to the emergence of this procedure as a definitive diagnostic test. In 20 of 48 patients (41%), biopsy of a peripheral nerve was diagnostic of NL. Of 25 nerve biopsies, 20 (80%) showed lymphomatous infiltration of nerve, a pathognomonic finding of NL, and five showed nonspecific findings. This indicates that the nerve biopsy is the diagnostic method of choice for NL. Because the sural nerve, the most commonly selected nerve for biopsy, may not be involved in patients with NL due to the patchy nature of the disease, biopsy of a clinically involved nerve is advised. Recently, the MRI scan has also become a useful tool in identifying involved nerve segments by showing nerve enlargement and possible sites for diagnostic biopsy.32,33 In five patients with mononeuropathy or mononeuropathy multiplex, the MRI documented an enlarged nerve.32-36 Biopsy of the enlarged nerve confirmed the diagnosis of NL in three patients.34-36 The cardinal histological feature of NL is a diffuse, massive infiltration of lymphomatous cells in all three compartments of the nerve (Color Figures 11.9–11.11). Perivascular cuffing of lymphomatous cells is common, and sometimes a striking angiocentricity of the tumor cells is present. Mitosis, pleomorphism, and atypia of the infiltrating cells usually immediately suggest a diagnosis of NL to experienced eyes. However, well differentiated lymphoma cells may prove difficult to distinguish from mature lymphocytes without modern immunophenotyping tests. Flow cytometry is the best means of demonstrating clonality. B- and T-cell markers can confirm a lymphoid malignancy. Lymphomatous tissue from 13 of 20 patients studied by modern immunophenotype methods were stained positive for B-cell markers,31–41 and 6 were positive for T-cell markers.37,41–44

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DIABETIC NEUROPATHY DIABETIC OPHTHALMOPLEGIA Third, fourth, and sixth cranial neuropathies are commonly associated with diabetes. Ophthalmoplegia develops abruptly with pain. Pupils are classically spared. Serial sections along the length of oculomotor nerves in two autopsied cases showed a noninflammatory focal lesion in the intracavenous portion of the nerve: focal demyelination and axon destruction without any evidence of occluded vessel in Dreyfus et al.’s cases,45 and focal central demyelination with arteriosclerotic narrowing of arterioles in Asbury et al.’s case.46 From these, ischemia is considered a likely cause of diabetic ophthalmoplegia.

DIABETIC AMYOTROPHY (DIABETIC PROXIMAL NEUROPATHY) Diabetic amyotrophy is characterized by painful amyotrophy involving pelvic girdle muscles, especially the thighs, occurring in older diabetic patients; high CSF protein; and lumbosacral radiculoplexoneuropathy in the EMG study.47 One study showed microfarcts in the obturator, femoral, sciatic, and posterior tibial nerves and extensive arteriosclerotic changes of small arteriolar and capillary walls.48 Ischemia is a likely cause of diabetic amyotrophy. In recent years, there has been a flurry of reports of inflammatory vasculopathy in this entity. In 1984, Bradley et al. reported three diabetic patients with painful lumbosacral plexopathy, elevation of ESR, and epineurial lymphocyte infiltration in the sural nerve biopsy.49 Said et al.50 reported endoneurial inflammatory cells in 4 patients and vasculitis in the epineurial and/or perineurial vessels and ischemic changes in 2 of 10 patients with painful diabetic proximal neuropathy who had biopsy of the intermediate femoral cutaneous nerve. In ten patients with proximal diabetic neuropathy, Krendal et al.51 reported perivascular lymphocytic infiltrates in the epineurial small vessels in either the femoral cutaneous nerve (two) or the sural nerve (three) (Color Figure 11.12). Younger et al.52 found microvasculitis (inflammatory infiltration of the walls of blood vessels measuring 70 µm or less) with scattered cells in the endoneurium in the sural nerve biopsy in 12 of 20 (60%) patients (4 with distal peripheral neuropathy, 6 with proximal diabetic neuropathy, and 2 with mononeuropathy multiplex) and perivascular lymphocytic infiltration alone in 8 (40%) patients (2 with distal and 6 with proximal diabetic neuropathy). In addition, 3 patients had focal pathology of ischemia. Axonal degeneration was seen in 10 tested nerves. Dyck et al.53 reported ischemic injury (axonal degeneration, multifocal fiber loss, focal perineurial necrosis and thickening, injury neuroma, neovascularization, and swollen fibers with accumulated organelles) in 33 nerve biopsies in this condition and attributed this to microscopic vasculitis (epineurial vascular and perivascular inflammation, vessel wall necrosis, and evidence of previous bleeding). Kelkar et al.54 also reported polymorphonuclear vasculitis affecting epineurial vessels consisting of transmural infiltration of postcapillary venules with polymorphonuclear leuckocytes in 4 of 15 cases and perivasculitis in 6 cases. Thus, these studies showed that inflammatory vasculopathy is observed in 20 to 66% of nerve biopsies in diabetic neuropathy, especially in patients with proximal diabetic neuropathy (diabetic amyotrophy), and that microvasculitis seems to be an uncommon feature of nerve pathology in diabetic neuropathy. These studies also suggested that prednisone and IVIG are effective therapies in these patients. On the basis of these findings, Krendal et al.55 stated that there is a more pervasive contribution of inflammatory and immune-mediated damage to the pathogenesis of diabetic neuropathy than had previously been imagined. On the other hand, genuine necrotizing arteritis of the nerve is rare in patients with diabetic neuropathy.55

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DIABETIC SENSORY NEUROPATHY Three studies showed the predominant loss of small myelinated fibers and unmyelinated fibers in the sural nerve, explaining the pure sensory involvement in this disorder.56-58 In one study, a loss of large and small myelinated fibers was observed.59 In teased nerve fibers, segmental demyelination and axonal degeneration were observed with more fibers showing segmental demyelination in Said et al.’s 5 cases,57 segmental demyelination and axonal degeneration with more fibers showing axonal regeneration were observed in Llewelyn et al.’s 13 cases,59 and axonal degeneration was observed in Brown et al.’s 2 cases.56 Said et al. observed distal degeneration of single fibers with subsequent axonal sprouting from the proximal axon and concluded that severe axonal neuropathy was associated with primary and secondary demyelination.57

DIABETIC POLYNEUROPATHY There is a well accepted consensus that sensory-motor diabetic polyneuropathy is primarily an axonal neuropathy (Color Figure 11.13).58,60-62 The hallmarks of overt diabetic neuropathy are the striking fiber atrophy and loss of myelinated and unmyelinated fibers associated with axonal degeneration and segmental demyelination.63 According to Dyck et al., segmental demyelination in diabetic neuropathy is secondary to axonal degeneration because demyelination and remyelination are less prominent abnormalities than axonal degeneration and many teased fibers have multiple regions of demyelination, as seen in secondary demyelination.62 Metabolic axonopathy is thought to be the primary mechanism of diabetic polyneuropathy.64 Other frequent findings in diabetic neuropathy are the focal loss of myelinated fibers (central fascicular degeneration or selective nerve fascicular degeneration) and vascular abnormality in the endoneurial or epineurial space (thickening, occlusion, medial sclerosis, and even fragmentation of the internal elastica) (Color Figure 11.14).62,65,66 These changes were observed in the sural nerve biopsies of 36 diabetic patients62 and in samples of lumbosacral trunk, posterior tibial, and sural nerves obtained at autopsy compared with those of non-diabetic patients.66 They concluded that diabetic microangiopathy (ischemia) is also important in the development of diabetic neuropathy. In recent years, an inflammatory vasculopathy as a third factor in the pathogenesis of diabetic neuropathy has been proposed, as discussed above. To unify these three mechanisms, Said et al. stated that metabolic factors seem to prevail in distal diabetic neuropathy and mild proximal diabetic neuropathy, whereas a superimposed inflammatory process and ischemic nerve lesions seem responsible for severe forms of proximal diabetic neuropathy.50 Nerve biopsy is not needed in the diagnosis of diabetic neuropathy. However, nerve biopsy is indicated in any diabetic neuropathy if other treatable diseases such as vasculitis, CIDP, or dysproteinemic neuropathy are suspected.67 In diabetic amyotrophy, there may be a place for the nerve biopsy to identify any inflammatory vasculopathy (microvasculitis) which might possibly respond to IVIG or steroid treatment.51,68

UREMIC NEUROPATHY Uremic polyneuropathy is a well-known and frequent complication of chronic renal failure, present in 22 to 26% of patients with that disorder.69 Asbury et al.,70 on the basis of four autopsied cases, originally reported axonal degeneration, maximal distally with sparing of the proximal portions of the nerve, the nerve roots, and the sympathetic ganglia. They considered that the degree of demyelination may have been in excess of the amount of axonal loss, but frank demyelination was not demonstrated. In two autopsied cases, Forno and Alston71 reported a mixture of segmental and axonal degeneration and concluded that these findings were similar to those found by Asbury et al.70

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The sural nerve biopsy showed different patterns of pathology: axonal degeneration,72-74 segmental demyelination,75 and axonal degeneration and segmental demyelination.76-78 Large-diameter fiber loss was a predominant feature,74,77,78 and axon atrophy (axon diameter disproportionately thinner than myelin diameter) was documented by morphometric studies.72,73 Dyck et al. and Said et al. concluded that some segmental demyelination in uremic neuropathy was due to axonal degeneration.73,77 Thus, it is fair to conclude that the predominant pathological process in uremic neuropathy is axonal degeneration involving the large-diameter fibers and that segmental demyelination is secondary to axonal degeneration.

ALCOHOLIC NEUROPATHY Alcoholic neuropathy is one of the most common neuropathies in the U.S. It usually produces a symmetrical polyneuropathy. There is considerable evidence that thiamine deficiency plays an important role in the pathogenesis of alcoholic neuropathy. Three studies clearly established that alcoholic neuropathy is characterized by axonal degeneration (Color Figure 11.15).79-81 In Walsh et al.’s study,79 sural nerve biopsies in 11 patients showed a reduction in the number of fibers of all diameters; the predominant finding in teased nerve fibers was axonal degeneration. In patients with a history of acute onset of peripheral neuropathy, active axonal degeneration was prominent. In contrast, active axonal degeneration was inconspicuous, although regenerating fibers were prominent, in patients without acute symptoms of neuropathy. In Behse and Buchthal’s study,80 sural nerve biopsies in 37 patients showed a loss of small and large fibers in most nerves, retaining a bimodal distribution, an absence of segmental demyelination in teased nerves, and axonal degeneration of myelinated and unmyelinated fibers in electron microscopy (EM) studies. EM studies of the sural nerve in six cases confirmed axonal degeneration.82 In most of the 11 patients with alcoholic neuropathy and trophic ulcers, Said et al.81 noted a reduction of large-diameter fibers and axonal degeneration in teased nerve fibers as the most prominent findings. Increased axonal degeneration was observed distally in two of three studied cases.

HYPOTHYROID NEUROPATHY Hypothyroidism may be a cause of two types of neuropathy: carpal tunnel syndrome and sensory polyneuropathy. In this disease, nerve conduction data are more suggestive of axonal neuropathy with superimposed carpal tunnel syndrome.83,84 In hypothyroid neuropathy, there is disagreement with regard to the pathology of the biopsied nerve. Three recent studies reported axonal degeneration,83-85 although segmental demyelination was previously described.86,87 All studies agree that there is a predominant loss of large-diameter fibers.84,85,87 Though Nickel et al.88 described a mucoid infiltration of the perineurium and endoneurium as the predominant pathological change in the myelin sheaths and axons,88 other studies did not observe any significant accumulation of mucoid material in the nerve.85-87

VITAMIN B12 DEFICIENCY NEUROPATHY Peripheral neuropathy, posterior column signs, and pyramidal tract signs are the classic triad of symptoms of vitamin B12 deficiency, which usually occurs in patients with pernicious anemia, more rarely in those with blind-loop syndrome, after gastric resection, and in vegetarians.89 In all of five studied cases, axonal degeneration was the major finding in biopsied nerves as well as in teased nerve fibers (Color Figure 11.16).90-92 In one case, semithin sections also showed axonal degeneration.93 In two cases, there was a loss of large-diameter fibers, although small-diameter fibers were also affected.92 ©2002 CRC Press LLC

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PYRIDOXINE-INDUCED SENSORY NEUROPATHY A few cases of sensory ataxic neuropathy have been reported after high daily pyridoxin consumption. Sensory nerve action potentials are unobtainable, whereas motor nerve conduction is normal. Sural nerve biopsy in two cases showed widespread axonal degeneration.94 Pyridoxine deficiency, which is almost exclusively due to isoniazid or hydralazine, produces a sensory axonal neuropathy involving myelinated and unmyelinated fibers, with ample regenerative activity in both populations.95

POLYRADICULONEUROPATHY IN LYME DISEASE Lyme disease is caused by a Borrelia burgdorferi spirochete after a tick bite (Ixodes). An erythema chronicum migrans spreading from the bitten area is followed by the neurological triad of: lymphocytic meningitis, cranial neuritis, and radiculoneuritis.96 In Europe, this disease is called Garin–Bujadoux or Bannwarth syndrome. Diagnosis is confirmed by the detection of anti-Borrelia burgdorferi antibodies in the serum. Sural nerve biopsy in ten cases showed inflammatory neuropathy.97 Lymphocytes and plasma cells were seen around many epineurial, perineurial, and endoneurial small vessels. There was no vasculitic change. In addition, axonal degeneration was the predominant finding, in contrast to demyelination in the Guillain–Barré syndrome, which shows a similar inflammatory neuropathy. In one patient with neuropathy and Lyme disease, perivascular collections of lymphocytes were observed in two small epineurial spaces.98 Nerve teasing showed segmental demyelination in 11% of the fibers, axonal degeneration in 6%, and minor abnormalities in 3%. Rarely, vasculitis of the epineurial arterioles with axonal degeneration of nerve fibers was described.99,100 In view of the presence of perivascular inflammatory cells and predominant axonal degeneration in most cases, it is reasonable to classify the neuropathy associated with Lyme disease as inflammatory axonal neuropathy.100-102

AIDS NEUROPATHY Peripheral neuropathy is one of the most common neurological manifestations of acquired immunodeficiency syndrome (AIDS). It may occur in as many as 20% of AIDS patients and in all stages of AIDS infection.103 Various types of peripheral neuropathy have been observed (Table 11.1).104 Multifactorial causes were often responsible for peripheral neuropathy. Midroni and Bilbao6 recommended the following guidelines for the nerve biopsy in HIV-positive patients: (1) no biopsy in typical inflammatory demyelinating neuropathy or distal symmetrical polyneuropathy (DSPN) patients; (2) biopsy in patients with mononeuropathy multiplex in whom aggressive treatment would be considered; and (3) consideration of biopsy for patients with atypical (i.e., very severe or rapidly evolving) DSPN or demyelinating neuropathy. Even in the last two groups of patients, the nerve biopsy is not indicated unless the nerve biopsy finding is vital for decision of alternative effective treatment. Five distinct pathological entities have been noted in the sural nerve biopsies of patients with AIDS: vasculitis, inflammatory demyelinating neuropathy, inflammatory axonal neuropathy, cytomegarovirus neuropathy, and neurolymphomatosis. Vasculitic neuropathy is rare in HIV. Until 1997, 27 cases with necrotizing vasculitis were reported.105 It was sometimes the first manifestation of HIV, but also occurred after AIDS had developed. The predominant manifestation of HIV-vasculitic neuropathy was distal and symmetric polyneuropathy (8 of 18 cases) and asymmetrical polyneuropathy (6 cases) with weight loss, myalgia, weakness, and leg tenderness. Mononeuritis multiplex was least common. In most patients, vasculitic neuropathy was not associated with other organ involvement and was usually monophasic ©2002 CRC Press LLC

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TABLE 11.1 Peripheral Neuropathy in AIDS Type of neuropathy Distal polyneuropathy

Main etiology HIV-related

Inflammatory demyelinating polyneuropathy: GBS/CIDP Progressive polyradiculopathy

Autoimmune Cytomegarovirus

Mononeuropathy multiplex

Vasculitis

Rare etiology Main pathology of nerve Neurotoxic drugs Axonal neuropathy Vitamin B12 deficiency Diffuse infiltrative lymphocytosis Cytomegavirus Inflammatory demyelinating neuropathy Lymphoma Cytomegarovirus Diffuse infiltrative lymphocytosis Autoimmune Vasculitis Cytogemarovirus

without relapse or remission. Pathological studies showed inflammation and fibrinoid necrosis of arteries smaller than those typically affected in systemic necrotizing vasculites (SNV). Endoneurial inflammatory cells were prominent. Active necrotizing lesions did not coexist with healed lesions. GBS and CIDP occur more commonly in early AIDS. The clinical, laboratory, and electrophysiological findings are not different from those of the classic GBS and CIDP except for the presence of pleocytosis in the CSF.106 The nerve biopsy is not different from that of patients with classic GBS and CIDP: the biopsied nerve shows segmental demyelination and mononuclear cell infiltration, abnormal features typical of inflammatory neuropathy.107-110 Inflammatory axonal neuropathy is seen in two types of neuropathies; distal symmetrical polyneuropathy and diffuse infiltrative lymphocytosis syndrome. Distal polyneuropathy, predominantly sensory, is the most common type of neuropathy seen in the late stages of AIDS. CSF tests may show mild elevation of protein and cells. An NCS reveals a distal axonal neuropathy. In 2 series of sural nerve biopsy, an inflammatory axonal neuropathy was found in 67 to 83% of patients and axonal neuropathy was found in the remaining patients.109,110 Diffuse infiltrative lymphocytosis syndrome (DILS) is characterized by persistent CD8 hyperlymphomatosis and multivisceral CD8 T-cell infiltration, which may affect peripheral nerves. Clinically, it resembles Sjögren’s syndrome associated with multivisceral involvement.111 Peripheral nerves usually present acute or subacute, painful, multifocal, or symmetric neuropathy and can improve under either steroid or antiretroviral treatment. An NCS reveals axonal neuropathy. Nerve biopsy invariably shows marked angiocentric CD8 infiltration in the epineurium and endoneurium (Color Figure 11.17), without mural necrosis and abundant expression of HIV p24 protein in macrophages. Cytomegalovirus-associated neuropathy is almost always documented in the setting of late-stage HIV infection. Although polyradiculoneuropathy is considered to be due to the CMV infection,112 multifocal neuropathy was thought to be typical of CMV neuropathy.113 Several patients with CMVproven neuropathy have been reported, all with late-stage HIV infection. A definite diagnosis of CMV neuropathy can be achieved only by finding typical CMV cytopathology: gigantic cells, 30 to 50 µm in diameter, containing intranuclear and intracytoplasmic inclusions characteristic of CMV, with immunostains confirming the organism (Color Figure 11.18). Said et al. stated that multifocal necrotic endoneurial lesions with neutrophilic cell response, which look like multiple endoneurial microabscesses, seem unique to this agent, aiding the diagnosis when characteristic inclusions are not present in the biopsy specimen.113 Neurolymphomatosis must be extremely rare in HIV infection. Gold et al. reported three patients with mononeuropathy multiplex due to HIV-associated lymphoma of the nerve.114 In two patients, lymphoma infiltration of the nerve was confirmed at autopsy, and in the third patient, lymphoma of ©2002 CRC Press LLC

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the nerve was assumed on the basis of large blasts with basophilic cytoplasm, vacuoles, and multiple nucleolei consistent with Burkitt’s lymphoma in the spinal fluid and bone marrow.

CASES OF NEUROPATHY ASSOCIATED WITH SYSTEMIC DISEASES CASE 1: SUBACUTE SYMMETRICAL POLYNEUROPATHY FOR 6 MONTHS Case Presentation A 58-year-old woman had progressive numbness in her lower legs for 6 months and weakness in her legs for 3 months.4 At the time of evaluation, she was not able to rise from a chair or walk without assistance. Abnormal neurological findings were marked weakness in the anterior tibialis, hamstrings, and iliopsoas muscles; mild weakness in the quadriceps; hypesthesia below the knees with vibratory sensation decreased in the knees and absent in the ankles and toes; and absent reflexes. CSF findings were normal. An NCS/EMG showed axonal neuropathy with no motor response in the peroneal and posterior tibial nerves and no sensory response in the sural nerves. Social, medical, and family histories were not contributory. All work-ups were negative except for mild hypercalcemia. Case Analysis This case represents one of the indications for the sural nerve biopsy: to ascertain the unknown cause for subacute neuropathy. Sural Nerve Biopsy The biopsy showed a moderate loss of myelinated fibers and selective nerve fascicular degeneration. The most prominent findings were multiple granulomas in the epineurial and perineurial spaces, granulomatous vasculitis, prominent perivascular collections of inflammatory cells, and many myelin-digestion chambers (Color Figures 11.1–11.3). Acid-fast baccilli, silver, and van Gieson stains did not show any organisms. Final Diagnosis Sarcoid polyneuropathy was the final diagnosis. Treatment and Follow-up With steroid therapy, the patient’s neuropathy improved to normal. Over a 15-year follow-up period, there was no sign of sarcoidosis in any other organ in the body. Muscle biopsy from the anterior tibialis revealed moderate type I fiber grouping and target fibers and one arteriole showing granulomas in the perivascular area. Comments Mazza reported one patient with sarcoid polyneuropathy confined to the arms and described fusiform swellings of the median, radial, and ulnar nerves at autopsy,115 but his case turned out to be due to leprosy.116 Thus, our patient represents the first case of sarcoid polyneuropathy histologically proven by the sural nerve biopsy. In addition to the classic findings of noncaseating granulomas, our case showed granulomatous vasculitis as the most prominent finding in the nerve biopsy.

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CASE 2: SUBACUTE PERIPHERAL NEUROPATHY WITH WHITE MATTER DISEASE IN THE BRAIN MRI Case Presentation A 61-year-old male presented with a 3-month history of numbness in the fingers of both hands, dysesthesia on the chest and anterior thighs, lower-extremity weakness, and ataxic gait. Abnormal neurological findings were decreased vibration sense on bilateral toes and fingers, ataxic gait, slight proximal weakness, and decreased deep-tendon reflexes in the lower extremities. Magnetic resonance imaging (MRI) of the head and entire spine was unremarkable. All work-ups were normal except for a high CSF protein (79 mg/dl). Electrophysiological findings were indicative of myeloradiculopathy. With one course of intravenous methylprednisolone, symptoms were somewhat improved at the time of discharge. In the ensuing month, despite antibiotic treatment for positive Lyme titer, the patient had continued progression of symptoms, including ataxic gait, weakness, fatigue, anorexia with weight loss, insomnia, dysesthesia, and dysarthria. Upon readmission, the patient was nonambulatory and illappearing. Abnormal findings were poor attention, perseveration, bilateral ptosis, dysarthria, hyperactive gag reflex, diffuse weakness with normal tone, postural tremor, truncal and appendicular ataxia, “stocking and glove” pattern of sensory loss, and diminished reflexes throughout. General examination was significant for hepatomegaly. MRI of the head revealed multifocal, nonenhancing, diffuse white matter disease typical of progressive multifocal leukoencephalopathy (PML). Cerebral angiography was normal. Computed tomography of the chest and abdomen revealed patchy atelectasis of the lungs with multiple nonenhancing nodules of the adrenal glands and pancreas. CSF studies showed a protein of 69 mg/dl with high IgG synthesis rate and IgG index. Electrophysiological findings were indicative of both peripheral neuropathy and multifocal central nervous system involvement. Case Analysis In the first 3 months, the patient had spotty symptoms of peripheral and central nervous system involvement which escaped definite diagnosis. At the final admission, the patient clearly had findings indicative of peripheral neuropathy and central nervous system white matter disease. Peripheral neuropathies which are known to be associated with extensive white matter lesions include multiple sclerosis, vasculitis, metachromatic leukodystrophy, Krabbe’s leukodystrophy, and neurolymphomatosis. For obvious reasons, we chose to biopsy the sural nerve and anterior tibialis muscle to reach a definite diagnosis. Sural Nerve and Muscle Biopsies Sural nerve biopsy showed a moderate decrease (60%) in the population of myelinated fibers, prominent myelin-digestion chambers, prominent endoneurial and subperineurial infiltrations of immature lymphoid cells, and some perineurial and perivascular lymphoid cell collections (Color Figure 11.19). In one small arteriole in the epineurial space, there was fibrinoid necrosis with intramural lymphoid cell infiltration in the muscular layer. Morphologically, these cells were similar to bone marrow infiltrates. Muscle biopsy revealed endomysial and perivascular collections of immature lymphoid cells and a few muscle fibers showing granular change, indicative of lymphomatous polymyositis (Color Figure 11.20). Immunophenotyping of cells in bone marrow and nerve biopsy were consistent with NK/T large cell lymphoma.

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Final Diagnosis The final diagnosis was neurolymphomatosis (NL) associated with muscle and cerebral involvement caused by natural killer-cell lymphoma. Treatment and Follow-up The patient died due to multiple organ failure early in the course of high-dose methylprednisolone treatment and prior to initiation of further chemotherapy. Comments Peripheral neuropathy is rare as a complication of lymphoma. The nerve biopsy is definitely the diagnostic test of choice. In most cases reported before 1980, the diagnosis was made at autopsy: among 17 cases, only one case had the diagnosis of NL made by nerve biopsy.117 Since 1980, the nerve biopsy has been the main means of diagnosis of NL: in 19 of 30 (63%) reported cases, the diagnosis was made by the nerve biopsy. This is clearly due to the emergence of the nerve biopsy as a definitive diagnostic test for neuropathy since 1980. Our case demonstrates a combination of several neurologic complications of lymphoma, including lymphomatous sensorimotor axonal polyneuropathy, lymphomatous polymyositis, and probable PML. In our case, although lymphomatous polymyositis and polyneuropathy were biopsy-proven, the diagnosis of PML was not confirmed and central nervous system lymphoma could not be excluded with confidence. A patient with brain lesions similar to those seen in our case was shown to have central nervous system lymphoma, as well as NL, at autopsy.118

CASE 3: NEUROPATHY IN A TYPE I DIABETIC WITH MANY MICROANGIOPATHY COMPLICATIONS Case Presentation A 20-year-old white male patient had a long-standing history of juvenile diabetes mellitus complicated by diabetic nephrotic syndrome, diabetic retinopathy, and hypertension with hypertensive cardiovascular disease. For the few years prior to evaluation, he experienced progressively increasing muscle weakness and atrophy of the lower extremities. Abnormal findings were marked atrophy and weakness of distal muscles and moderate weakness of proximal muscles in both legs, absent knee and ankle reflexes, “stocking-glove” sensory loss below the knees, and a necrotic foul-smelling ulcer on the right heel. X-ray revealed air in the soft tissues of the right foot. An NCS/EMG showed severe diffuse peripheral neuropathy with no response in the peroneal, posterior tibial, and sural nerves. Amputation of the right leg below the knee was performed. Case Analysis Considering many diabetic microangiopathic complications and an unhealing infected ulcer, this patient most likely had ischemic neuropathy. Sural Nerve Biopsy The biopsy showed marked reduction of myelinated fibers by Kulschitsky’s stain and marked smallvessel disease characterized by hyalin thickening of the walls and endothelial proliferation to the degree of marked luminal narrowing in the endothelial arterioles (Color Figure 11.21). Muscle biopsy from the gastrocnemius muscle showed some vascular lesions and fascicular atrophy of the muscle.

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Final Diagnosis Diabetic ischemic (microangiopathic) neuropathy was the final diagnosis. Comments Microangiopathy is a common complication in diabetes mellitus. Regardless of the presence or absence of neuropathy, hyalinization of endoneurial microvessels is a consistent feature of diabetic nerves. The severity of endoneurial microvascular alterations may correlate with the severity of the neuropathy.119 Some epineurial arterioles may show occlusion, medial sclerosis, and even fragmentation of the internal elastica, as noted in our case.62

CASE 4: 9 MONTHS OF PROGRESSIVE NEUROPATHY IN A 72-YEAR-OLD WOMAN WITH INSULIN-DEPENDENT DIABETES MELLITUS FOR 15 YEARS Case Presentation A 72-year-old woman with insulin-dependent diabetes mellitus for 15 years began to fall due to her knee giving way soon after bilateral knee surgery 9 months previously. This was soon followed by foot drop. The patient’s weakness progressed to the point that she required a walker. In the meantime, she also developed tingling/numbness in the feet, which spread to her hands in the 2 months prior to evaluation. She had hypertension, coronary artery bypass, and bilateral femoropopliteal bypass surgery. Abnormal neurological findings were atrophy of anterior tibialis and hand intrinsic muscles, complete paralysis in the anterior tibialis, moderate weakness in the iliopsoas, mild weakness in the quadriceps, hamstrings, and gastrocnemius muscles, decreased pin-prick sensation below the knees, loss of proprioception at the toes and ankles, and absent knee and ankle jerks. A total myelogram showed lumbar and cervical stenosis. All work-ups for peripheral neuropathy, including a serum autoantibody study, were normal except for a high CSF protein (74 mg/dl) with increased IgG synthesis rate and IgG level. An NCS/EMG showed diffuse axonal neuropathy and lumbar polyradiculopathy. Case Analysis Even with cervical and lumbar stenosis on the myelogram, the patient’s neurological problem was correctly identified as neuropathy. NCS/EMG findings were said to be typical of diabetic neuropathy with lumbar polyradiculopathy. Spinal fluid protein is known to be high in diabetic neuropathy. An increased IgG synthesis rate, an IgG level typical of immune response in the spinal fluid, and motor weakness as the initial symptoms were somewhat unusual. This raised the possibility of CIDP, and, thus, a sural nerve biopsy was performed. Sural Nerve Biopsy Biopsy of the surval nerve showed moderate loss (40%) of myelinated fibers, prominent myelin-digestion chambers (Color Figure 11.22), and a few inflammatory cells in the endoneurial space as well as around the vessels in the epineurial space (Color Figure 11.23). No definite fibrinoid necrosis or intramural inflammatory cells were noted. Inflammatory axonal neuropathy was the biopsy diagnosis. Final Diagnosis Inflammatory diabetic neuropathy was the final diagnosis.

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Treatment and Follow-up Muscle biopsy showed severe denervation, but no vasculitis. IVIG treatment followed by imuran therapy brought gradual improvement in her neuropathy. Foot drop and sensory loss below the ankles were the only residual findings 4 years later. The patient needed 150 mg of imuran daily to sustain her improved status even after 4 years of treatment. Comments This patient had inflammatory axonal neuropathy demonstrated by the nerve biopsy. Since this could be an expression of vasculitic neuropathy, we proceeded to do a muscle biopsy, which did not show any evidence of polymyositis or vasculitis. The main question was whether she had diabetic inflammatory neuropathy or the axonal form of CIDP. It is possible that this patient had the axonal form of CIDP in addition to diabetes mellitus. The patient was treated with immunotherapy, which improved her neuropathy. As discussed above, there are several studies advocating an autoimmune mechanism as one factor in diabetic neuropathy, especially in diabetic amyotrophy.

CASE 5: UREMIC NEUROPATHY IN A YOUNG PATIENT WHOSE TWO BROTHERS HAD RENAL PROBLEMS Case Presentation A 29-year-old man developed hypertension a few years prior to evaluation and was found to have proteinuria. One year before examination, because of chronic renal failure, he was placed on hemodialysis. During the 5 months prior to exam, he developed numbness and burning in his feet spreading upward to the knees, with subsequent difficulty walking. He had two brothers with chronic renal failure on hemodialysis but without any complaint of numbness in their feet. The patient had multiple dialysis catheter replacements. Upon neurological examination, abnormal findings were a decreased pin-prick sensation to 10 cm above the ankles, decreased vibration and position sensation in the toes, no strength in the anterior tibialis and moderate weakness in the gastrocnemius muscles, steppage gait, absent ankle reflexes, and 1+ knee reflexes. Peripheral neuropathy work-ups were normal except for a high sedimentation rate (52 mm/hr) and mild anemia. CSF findings were normal. The NCS showed axonal neuropathy. Case Analysis Apparently, this patient was thought to have a hereditary form of kidney disease for which he was placed on chronic hemodialysis without renal biopsy. Clearly, this patient had a subacute symmetrical sensory-motor polyneuropathy which could well be uremic neuropathy. In view of his high sedimentation rate, the referring neurologist ordered a nerve biopsy. Sural Nerve Biopsy The biopsy showed a marked loss of myelinated fibers, prominent myelin-digestion chambers (Color Figure 11.24), and prominent perivascular collections of mononuclear cells. In one arteriole in the epineurial space, prominent intramural infiltration of inflammatory cells and some narrowing of the central canal were observed (Color Figure 11.25). Vasculitic neuropathy was the biopsy diagnosis. Final Diagnosis The final diagnosis was periarteritis nodosa involving the kidney and peripheral nerves.

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Treatment and Follow-up Cytoxan and prednisone therapy improved this patient’s renal function and peripheral neuropathy. Comments This case represents the indication for nerve biopsy in the setting of possible neuropathy due to systemic disease. Even with a common systemic disease like chronic renal failure and diabetes mellitus, it is always important to look for and rule out other possible causes of neuropathy. In this case, a high sedimentation rate prompted the referring neurologist to order a nerve biopsy, which confirmed vasculitic neuropathy. This changed the patient’s treatment. Another lesson from this case is that a symmetrical polyneuropathy does not rule out vasculitic neuropathy, as discussed in Chapter 6.

CASE 6: SUBACUTE NEUROPATHY IN A CHRONIC ALCOHOLIC PATIENT Case Presentation A 22-year-old female alcoholic patient developed tingling/numbness and cramps in her legs 6 months prior to evaluation, followed by walking difficulty. In the 2 months prior to examination, she also noted weakness of her hands and difficulty swallowing and chewing. Abnormal findings were general cachexia; weakness in all four extremities, more prominent in the lower extremities and distally; “stocking-glove” distribution of pin-prick sensation and vibratory sensory loss below the knees and elbows; absent position sense in her toes and ankles; and absent knee and ankle reflexes. All work-ups for peripheral neuropathy, including spinal fluid examination, were negative. An NCS/EMG showed diffuse axonal neuropathy. Case Analysis Certainly, this patient’s history and findings were typical of alcoholic neuropathy. However, other causes for neuropathy should be ruled out in a case such as this one. Sural Nerve Biopsy The biopsy revealed a marked reduction of myelinated fibers, prominent myelin-digestion chambers, and a few ghost fibers indicative of severe axonal degeneration (Color Figure 11.26). Final Diagnosis Alcoholic neuropathy was the final diagnosis. Treatment and Follow-up Despite medical advice, the patient would not abstain from alcohol, and her neuropathy continued to worsen. Comments Alcoholic neuropathy is one of the most common forms of peripheral neuropathy. It is a mixed sensory and motor neuropathy, predominantly involving the distal segments and the legs. Sensory neuropathy is typical in mild cases, with complaints of burning feet or painful paresthesia. The neuropathy develops slowly and recovery is slow. The nerve conduction abnormality is typically characterized by axonal degeneration.

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CASE 7: PARESTHESIA OF FEET AND ABDOMINAL COLIC AT THE ONSET OF NEUROPATHY Case Presentation A 44-year-old male had paresthesia of the feet and abdominal cramps 6 weeks prior to admission. He was given barbiturates at that time and his foot pain got worse. Two weeks later he had difficulty walking. Paresthesia spread to his thighs and hands, and he noted red-colored urine on two occasions. Abnormal neurological findings included wasting of the small muscles of his hands, weakness of the distal muscle groups, “glove and stocking” hypalgesia and hypesthesia, and absent vibratory sensation up to the iliac crest. His gait was broad-based and ataxic, and his Romberg sign was positive. CSF findings were normal. Urine porphobilinogen was elevated. An NCS/EMG showed severe axonal peripheral neuropathy. Case Analysis This patient had two parts of the triad — abdominal pain, psychiatric disorder, and peripheral neuropathy — of neurological crisis in acute intermittent porphyria. Red-colored urine was an important clinical clue indicative of porphyria. Increased urine porphobilinogen content is diagnostic of acute intermittent porphyria. In our case, treatment with barbiturates, which are known to precipitate an acute crisis, aggravated the patient’s neuropathy. Sural Nerve Biopsy The biopsy showed a minimal reduction of the myelinated fibers and many myelin-digestion chambers on the longitudinal cuts typical of axonal degeneration (Color Figure 11.27). Comments Porphyric neuropathy is an acute or subacute, asymmetrical or symmetrical, predominantly motor neuropathy, occurring in three dominantly inherited types of hepatic porphyria — acute intermittent porphyria, hepatic coproporphyria, and variegated porphyria. Two autopsy studies showed widespread nerve fiber degeneration and axonal degeneration in the teased nerve preparation in five patients with acute intermittent porphyria.120,121 Segmental demyelination was not found in any of these cases. Teased nerve fibers in the sural nerve biopsy showed a predominantly axonal degeneration in two cases,122,123 while one other case revealed minimal axonal degeneration and onion-bulb formation.123 These findings suggest that the predominant pathological process in porphyric neuropathy is axonal degeneration.

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61. Bischoff, A., Diabetic neuropathy. Pathologic anatomy, pathophysiology and pathogenesis on the basis of electronmicroscopic studies, Dtrsch. Med. Wochenschr., 93, 237, 1968. 62. Dyck, P.J., Lais, A., Karnes, J., O’Brien, P., and Rizza, R., Fiber loss is primary and multifocal in sural nerve in diabetic polyneuropathy, Ann. Neurol., 19, 425, 1986. 63. Sima, A.A.F., Diabetic neuropathy — the utility of nerve biopsy, Clin. Neurophysiol., (Suppl. 50), 525, 1999. 64. Sima, A.A.F., Diabetic neuropathy — the present and future of a common but silent disorder, Mod. Pathol., 6, 399, 1993. 65. Dyck, P.J., Karnes, J.L., O’Brien, P., Okazaki, H., Lais, F., and Engelstad, J., The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia, Ann. Neurol., 19, 440, 1986. 66. Johnson, P.C., Doll S.C., and Cromey D.W., Pathogenesis of diabetic neuropathy, Ann. Neurol., 19, 450, 1986. 67. Thomas, P.K., Nerve biopsy, Diabet. Med., 14, 353, 1997. 68. Jaradeh, S.S., Prieto, T.E., and Lobeck, L.J., Progressive polyradiculoneuropathy in diabetes: correlation of variables and clinical outcome after immunotherapy, J. Neurol. Neurosurg. Psychiatry, 67, 607, 1999. 69. Oh, S.J., Clinical Electromyography: Nerve Conduction Studies, 2nd ed., Williams & Wilkins, Baltimore, MD, 1993. 70. Asbury, A.K., Victor, M., and Adams, R.D., Uremic polyneuropathy, Arch. Neurol., 8, 413, 1963. 71. Forno, L. and Alston, W., Uremic polyneuropathy, Acta Neurol. Scand., 43, 640, 1967. 72. Ahonen, R.E., Peripheral neuropathy in remic patients and in renal transplant recipients, Acta Neuropathol., 54, 43, 1981. 73. Dyck, P.J., Johnson, W.J., Lambert, E.H., and O’Brien, P.C., Segmental demyelination secondary to axonal degenertion in uremic neuropathy, Mayo Clin. Proc., 46, 400, 1971. 74. Thomas, P.K., Hollinrake, K., Lascelles, G., O’Sullivan, D.J., Baillod, A., Moorehead, J.F., and Mackenzie, J.C., The polyneuropathy of chronic renal failure, Brain, 94, 761, 1971. 75. Dinn, J.J. and Crane, D.L., Schwann cell dysfunction in uremia, J. Neurol. Neurosurg. Psychiatry, 33, 605, 1970. 76. Dayan, A.D., Gardner-Thorpe, C., Down, P.F., and Gleadle, R.I., Peripheral neuropathy in uremia. Pathological studies on peripheral nerves from 6 patients, Neurology, 20, 649, 1970. 77. Said, G., Boudier, L., Selva, J., Zingraff, J., and Drueke, T., Different patterns of uremic polyneuropathy: clinicopathologic study, Neurology, 33, 567, 1983. 78. Rosales, R.L., Navarro, J., Izumo, S., Osame, M., Naidas, O., Ordinario, A., and Igata, A., Sural nerve morphology in asymptomatic uremia, Eur. Neurol., 28, 156, 1988. 79. Walsh, J.C. and McLeod, J.G., Alcoholic neuropathy: an electrophysiological and histological study, J. Neurol. Sci., 10, 457, 1970. 80. Behse, F. and Buchthal, F., Alcoholic neuropathy: clinical, electrophysiological, and biopsy findings, Ann. Neurol., 2, 95, 1977. 81. Said, G., A clinicopathologic study of acrodystrophic neuropathies, Muscle and Nerve, 3, 491, 1980. 82. Tredici, G. and Minazzi, M., Alcoholic neuropathy: An electron-microscopic study, J. Neurol. Sci., 25, 333, 1975. 83. Nemni, R. et al., Polyneuropathy in hypothyrodism: clinical, electrophysiological and morphological findings in four cases, J. Neurol. Neurosurg. Psychiatry, 50, 1454, 1987. 84. Pollard, J.D., McLeod, J.G., Angel-Honnibal, T.G., and Verheijden, M.A., Hypothyroid polyneuropathy. Clinical, electrophysiological and nerve biopsy findings in two cases, J. Neurol. Sci., 53, 461, 1982. 85. Meir, C. and Bischoff, A., Polyneuropathy in hypothyroidism. Clinical and nerve biopsy study of 4 cases, J. Neurol., 215, 103, 1977. 86. Dyck, P.J. and Lambert, E.H., Polyneuropathy associated with hypothyroidism, J. Neurpathol. Exp. Neurol., 24, 631, 1970. 87. Shirabe, T., Tawara, S., Terao, A., and Araki, S., Myxoedematous polyneuropathy: a light and electron microscopic study of the peripheral nerve and muscle, J. Neurol. Neurosurg. Psychiatry, 38, 241, 1975. 88. Nickel, S.N., Frame, B., Bebin, W., Tourtellotte, W., Parker, A., and Hughes, B.R., Myxoedema neuropathy and myopathy. A clinical and pathological study, Neurology, 8, 511, 1961. 89. Greenfield, J.G. and Carmichael, E.A., The peripheral nerves in cases of subacute combined degeneration of the cord, Brain, 58, 483, 1935.

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90. McLeod, J.G., Walsh, J.C., and Little, J.M., Sural nerve biopsy, Med. J. Aust., 2, 1092, 1969. 91. Kosik, K.S., Mullins, T.F., Bradley, W.G., Tempelis, L.D., and Cretella, A.J., Coma and axonal degeneration in vitamin B12 deficiency, Arch. Neurol., 37, 590, 1980. 92. McCombe, P.A. and McLeod, J.G., The peripheral neuropathy of vitamin B12 deficiency, J. Neurol. Sci., 66, 117, 1984. 93. Bischoff. A. and Meier, L.C., Polyneuropathie bei vitamin-B12 und folsaeuremangel. Klinishe-histpathologische studie mit elektronenmikoroskopischer analyse des nervus suralis, Muench. Med. Wschr., 117, 1593, 1975. 94. Schaumburg, H., Kaplan, J., Winderbank, A., Vick, N., Rasmus, S., Pleasure, D., and Brown, M., Sensory neuropathy from pyridoxin abuse, New Eng. J. Med., 309, 445, 1983. 95. Ochoa, J., Isoniazid neuropathy in man: quantitative electron miscroscope study, Brain, 93, 831, 1970. 96. Pachner, A.R., and Steere, A.C., The triad of neurologic manifestations of Lyme disease: meningitis, cranial neuritis, and radiculoneuritis, Neurology, 35, 47, 1985. 97. Vallat, J.M., Hugon, J., Lubveau, M., Leboutet, M.J., Dumas, M., and Desproges-Gotteron, R., Tick-bite meningoradiculoneuritis: clinical, electrophysiologic, and histologic findings in 10 cases, Neurology, 37, 749, 1987. 98. Halperin, J.J., Litle, B.W., Coyle, P.K., Dattwyler, R.J., Lyme disease: cause of treatable peripheral neuropathy. Neurology, 37, 1700, 1987. 99. Camponovo, F. and Meier, C., Neuropathy of vasculitic origin in a case of Garin-Boujadour-Bannwarth syndrome with positive borrelia antibody response, J. Neurol., 233, 69, 1986. 100. Tezzon, F. et al. Vasculitic mononeuritis multiplex in patients with Lyme disease, Ital. J. Neurol. Sci. 12, 229, 1991. 101. Kirsoferitch, W., et al. Neuropathy associated with acrodermatitis chronica atrophicans, Ann. NY Acad. Sci., 539, 35, 1988. 102. Meier, C., Grahmann, F., Engelhardt, A., and Dumas, M., Peripheral nerve disorders in Lyme-Borreliosis. Nerve biopsy studies from eight cases, Acta Neuropathol., 79, 271, 1989. 103. Parry, G.J., Peripheral neuropathies associated with human immunodeficiency virus infection, Ann. Neurol., 23(Suppl.), S49, 1988. 104. Berger, J.R. and Simpson, D.M., The pathogenesis of diffuse infiltrative lymphocytesosis syndrome. An AIDS-related peripheral neuropathy, Neurology, 50, 855, 1998. 105. Brannagan, T.H., Retroviral-associated vasculitis of the nervous sytem, Neurologic Clinics, 15, 927, 1997. 106. Dalakas, M.C. and Pezeschkpour, G.H., Neuromuscular diseases associated with human immunodeficiency virus infection, Ann. Neurol., 23(Suppl.), S38, 1988. 107. Lipkin, W.I., Parry, G., Kiprov, D., and Abrams, D., Inflammatory neuropathy in homosexual men with lymphadenopathy, Neurology, 35, 1479, 1983. 108. Cornblath, D.R., McArthur, J.C., Kennedy, P.G., Witte, A.S., and Griffin, J.W., Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection, Ann. Neurol., 21, 32, 1987. 109. Vital, A. et al., Morphological findings on peripheral nerve biopsies in 15 patients with human immunodeficiency virus infection, Acta Neuropathol., 83, 618, 1992. 110. Chaunu, M. et al., The spectrum of changes on 20 nerve biopsies in patients with HIV infection, Muscle and Nerve, 12, 452, 1989. 111. Moulignier, A. et al., Peripheral neuropathy in HIV-infected patients with diffuse infiltrative lymphocytosis syndrome (DILS), Ann. Neurol., 41, 438, 1997. 112. Eidelberg, D. et al., Progressive polyradiculopathy in acquired immune deficiency syndrome, Neurology, 36, 912, 1986. 113. Said, G. et al., Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathlogical study, Ann. Neurol., 29, 139, 1991. 114. Gold, J.E., Jimenez, E., and Zalusky, R., Human immunodeficiency virus-related lymphoreticular malignancies and peripheral neurologic disease. A report of four cases, Cancer, 61, 2318, 1988. 115. Mazza, G., Über das multiple benigne Sarkoid der Haut (Boeck), Arch. Dermatol. Syph. Wien., 91, 51, 1908. 116. Matthews, W.B., Sarcoid neuropathy, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 2018.

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117. Vital, C. et al., Polyradiculonévrite au cours d’une leucémie lymphoïde chronique. Etude ultrastructurale d’une biopsie de nerf périphérique. Acta Neuropathol., 32, 169, 1975. 118. Jones, H.R., Schaefer, P.W., and Edgar, M.A., Case Records of Massachusetts General Hospital, New Eng. J. Med., 332, 730, 1995. 119. Malik, R.A. et al., Endoneurial localization of microvascular damage in human diabetic neuropathy, Diabetologia, 36, 454, 1993. 120. Sweeney, V.P., Pathak, M.A., and Asbury, A.K., Acute intermittent porphyria: increased ALA-synthetase activity during an acute attack, Brain, 93, 369, 1970. 121. Cavanagh, J.B. and Mellick, R.S., On the nature of the peripheral nerve lesions associated with acute intermittent porphyria, J. Neurol. Neurosurg. Psychiatry, 28, 320, 1965. 122. Anzil, A.P. and Dozic, S., Peripheral nerve changes in porphyric neuropathy: findings in a sural nerve biopsy, Acta Neuropathol., 42, 121, 1978. 123. Trapani, G.D., Casali, C., Tonali, P., and Topi, G.C., Peripheral nerve findings in hereditary coproporphyria. Light and ultrastructural studies in two sural nerve biopsies, Acta Neuropathol., 63, 96, 1984.

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CHAPTER 11 Figure 1 Noncaseating granuloma (arrow) in the perineurium. A giant cell, epithelioid cells, and lymphocytes are present in a granuloma. This granuloma compressed the endoneurium (arrowhead). Thickened perineurium with lymphocyte infiltration is noted opposite the granuloma. Paraffin section. H & E stain. ( 400 × magnification.)

CHAPTER 11 Figure 3 Axonal degeneration in sarcoid neuropathy. Scattered myelin-digestion chambers (yellow arrows) are indicative of axonal degeneration. The red arrow indicates granuloma in the perineurial space. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 11 Figure 2 Granulomatous panangiitis in sarcoid neuropathy. Prominent granuloma infiltration of the entire vessel wall and total occlusion of vessel in one arteriole in the epineurial space. Double arrows indicate giant cells. Lymphocytes are scattered in the epineurial and perineurial spaces. The arrowhead indicates the nerve fascicle. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 11 Figure 4 Sural nerve of a patient with tuberculous leprosy. A granuloma with epithelioid and giant cells is observed. Paraffin section. H & E stain. (400 × magnification.) (Courtesy of Professors O.J.M. Nascimento and M.R.G. Freitas, Universidad Federal Fluminense, Rio de Janeiro, Brazil.)

CHAPTER 11 Figure 5 Intense fibrosis in the endoneurium, perineurium, and epineurium, replacing the normal structures. Not a single myelinated fiber is present in the endoneurium. Mononuclear inflammatory cell infiltrates are seen in the endoneurial space. Frozen section. Modified trichrome stain. (Courtesy of Professor Y. Harati, Baylor Medical School, Houston, TX.)

CHAPTER 11 Figure 6 Ulnar nerve (biopsy of the dorsal sensory branch of the hand) of a patient with tuberculoid leprosy. Semithin section showing complete loss of endoneurial structures with fibrosis; a small granuloma is seen. Toluidine blue, (200 × magnification.) (Courtesy of Professors O.J.M. Nascimento and M.R.G. Freitas, Universidad Federal Fluminense, Rio de Janeiro, Brazil.)

CHAPTER 11 Figure 7 Sural nerve of a lepromatous leprosy patient. Semithin section showing reduction of the myelinated fiber density. Many foamy cells containing lepra bacilli are seen in the endoneurial vessel walls. Some foamy cells are also noted in the endoneurial space. Semithin section. Toluidine blue stain. (400 × magnification.) (Courtesy of Professors O.J.M. Nascimento and M.R.G. Freitas, Universidad Federal Fluminense, Rio de Janeiro, Brazil.)

CHAPTER 11 Figure 8 Sural nerve of a lepromatous leprosy patient. Intense mononuclear inflammatory reactions in the sural nerve obliterating normal anatomical structures. Paraffin section. H & E stain. (250 × magnification.)

CHAPTER 11 Figure 9 Immature lymphoid cell infiltration in the epineurial, perineurial (arrow), and endoneurial spaces. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 11 Figure 11 Axonal degeneration in neurolymphomatosis. Many myelin-digestion chambers (arrow). Many lymphoid cells (arrowhead) are scattered in the endoneurial space. Moderate loss of myelinated fibers is obvious. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 11 Figure 10 Angiocentric involvement of lymphoid cells in neurolymphomatosis. Intramural immature lymphoid cell infiltration in one small perineurial arteriole in the perineurial space. Notice many immature large lymphoid cells with bizarre shapes and some large lymphoid cells with the nuclei showing fine chromatin. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 11 Figure 12 Perivascular collection of inflammatory cells in diabetic neuropathy. Arrows indicate a perivascular collection of inflammatory cells in two small arterioles in the epineurial space of the sural nerve. Arrowheads indicates two nerve fascicles with total loss of myelinated fibers. Paraffin section. Modified trichrome. (200 × magnification.)

CHAPTER 11 Figure 13 Axonal degeneration in diabetic neuropathy. Scattered myelin-digestion chambers (yellow arrows) are indicative of axonal degeneration. The red arrow points to a normal myelinated fiber. Moderate loss of myelinated fibers is obvious. Frozen section. H & E stain. (200 × magnification.)

CHAPTER 11 Figure 15 Axonal degeneration in alcoholic neuropathy. Almost all myelinated fibers show myelin-digestion chambers. The arrowhead indicates edema in the subperineurial space. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 11 Figure 14 Ischemic neuropathy in diabetic neuropathy. Almost total occlusion of the larger epineurial arteriole characterized by a few recanalized tiny openings in the center, thickened muscular and endothelial layers, and intramural calcium deposits. Minimal loss of myelinated fibers in the nearby nerve fascicles. Frozen section. Modified trichrome. (100 × magnification.)

CHAPTER 11 Figure 16 Large-diameter fiber loss in Vitamin B12 deficiency. No obvious myelin breakdown is observed. However, there are a few clusters (arrow) of tiny, thinly myelinated fibers indicative of axonal regeneration. Semithin section. Toluidine blue.

CHAPTER 11 Figure 17 Nerve biopsy in diffuse infiltrative lymphocytosis syndrome: (a) sheets of lymphoid cells in the epineurium (Masson’s trichrome, 250 × magnification); (b) marked angiocentric CD8 T-cell infiltration in the epineurium, (APPAP, 800 × magnification); (c) endoneurial, predominantly perivascular, CD8 T-cell infiltration (APAAP, 800 × magnification); (d) perivascular cells, presumably macrophages, showing positive p24 immunoreactivity in their cytoplasm (APAAP, 1600 × magnification). (With permission from Moulignier, A. et al., Ann. Neurol., 41, 442, 1997.)

CHAPTER 11 Figure 18 Cytomegalic virus infection in the dorsal root in an AIDS patient. Inflammatory necrosis and intranuclear CMV inclusions (arrow). Paraffin section. H & E stain. (Courtesy of Dr. D.M. Simpson, The Mount Sinai Medical Center, New York.)

CHAPTER 11 Figure 19 Sural nerve biopsy showing obvious endoneurial infiltration of immature lymphoid cells. Paraffin section. H & E stain. (200 × magnification.)

CHAPTER 11 Figure 20 Muscle biopsy showing prominent endomysial infiltration of immature lymphoid cells. Frozen section. H & E stain. (400 × magnification.)

CHAPTER 11 Figure 21 Occlusion of a tiny arteriole in the subperineurial space in diabetic neuropathy (red arrow). Recanalization and thickening of the internal elastica and medial sclerosis are clearly seen. A few intact myelinated fibers are scattered in the field. Paraffin section. Mason trichrome. (200 × magnification.)

CHAPTER 11 Figure 22 Axonal degeneration in diabetic inflammatory neuropathy. Prominent myelindigestion chambers and moderate loss of myelinated fibers are seen. Frozen section. Modified trichrome. (200 × magnification.)

CHAPTER 11 Figure 23 Perivascular inflammatory cells in a tiny vessel in the subperineurial space. A few scattered inflammatory cells are noted in the nearby endoneurial space. Paraffin section. Congored stain. (400 × magnification.)

CHAPTER 11 Figure 24 Axonal degeneration in vasculitic neuropathy. There are many myelin-digestion chambers (red arrow) and many fibers showing myelin breakdown (yellow arrow). There are no normal myelinated fibers. Semithin section. Toluidine blue and basic fuchsin. (400 × magnification.)

CHAPTER 11 Figure 25 Vasculitic change in a small arteriole in the epineurial space. Prominent intramural infiltration of inflammatory cells and some narrowing of the central canal. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 11 Figure 26 Axonal degeneration in alcoholic neuropathy. Prominent myelin-digestion chambers involving all myelinated fibers. Frozen section. Modified trichrome stain. (200 × magnification.)

CHAPTER 11 Figure 27 Axonal degeneration in porphyric neuropathy. Varying degree of axonal degeneration is seen here from a ghost fiber (arrowhead) to a myelin-digestion chamber (arrow). Frozen section. Modified trichrome. (200 × magnification.)

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Toxic Neuropathies

The term toxic neuropathies refers to neuropathies induced by various exogenous substances, which include alcohol, heavy metals, drugs, industrial agents, and vaccines (Table 12.1). It is obvious that the most common form of toxic neuropathy is alcoholic neuropathy. However, since alcoholic neuropathy is considered to be due to a nutritional deficiency, it is discussed under the heading of systemic neuropathies in Chapter 11. The following general principles are applied to toxic neuropathies: 1.

2.

3.

Toxins usually affect axons more than myelin (Table 12.1). This may be due to the fact that maintaining an axon as far as a meter away from a cell body is more complex than maintaining the myelin of a single internode. Thus, the majority of toxins induce simple axonal degeneration. Some induce axonal degeneration through giant axonal, inflammatory, or vasculitic changes. Exceptions to this rule are demyelinating neuropathies due to diphtheric toxin, swine-flu vaccine, or amphiphilic drugs such as amodarone and perhexilene. Because of this selective axon damage, most toxic neuropathies are fiber-length dependent and predominantly affect large axons, producing dying-back neuropathy. This phenomenon explains why most toxic neuropathies are predominantly sensory because the longest peripheral nerve axons in the body are sensory fibers to the toes. Thus, if electrophysiological testing shows a demyelinating neuropathy or motor involvement as the early and predominant clinical feature, the common demyelinating neuropathies such as CIDP should be considered first. The dose and duration of intoxicant exposure are usually correlated with the rate of onset and the severity of the neuropathy. Diphtheric and flu vaccine-induced demyelinating neuropathies are exceptions to this rule, as are individual differences in drug metabolism. The prognosis is usually good if the toxin is withdrawn. Because most toxic neuropathies are axonal neuropathies, recovery is slow, extending over months or years. This principle is critical for the diagnosis of toxic neuropathies: if the neuropathy progresses continuously even after the toxin is withdrawn, other diagnostic possibilities must be considered.

For most toxic neuropathies, the usual diagnostic strategy is to confirm the presence of an axonal neuropathy by clinical examination and electrophysiological testing and to identify a toxic exposure by history, typical clinical features, and/or laboratory tests, if such tests are available. Thus, a nerve biopsy is not usually needed for the diagnosis of toxic neuropathy but may be an important diagnostic tool in more specifically identifying the agents involved (e.g., solvent-induced neuropathy by the presence of giant axons) or ruling out other neuropathies.1

METAL NEUROPATHIES ARSENIC NEUROPATHY Arsenic neuropathy is an age-old neuropathy which occurs in two varieties: a subacute type that appears within weeks of a massive overdose, as in the case of an unsuccessful suicide or homicide attempt, and an insidiously developing type following prolonged low-level exposure, as may occur ©2002 CRC Press LLC

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TABLE 12.1 Toxic Neuropathya Axonal Neuropathy Alcohol Heavy metals Arsenic Thallium Lead in alcoholics Drugs Cisplatinum Disulfiram Ethambutol (optic neuropathy) Gold Isoniazid (pyridoxin antagonist) Nitrofurantoins Mizonidazoleb Thalidomide Vincristine Cholesterol-lowering agent Industrial agents Carbon disulfide Triorthocresyl phosphate (TOCP) (Jamaican ginger palsy) (organophosphorus compounds) Mipafox (organophosphorus compounds) Kepone (small fiber involvement) Giant Axonal Neuropathy Industrial agents n-hexane Methyl n-butyl ketone 2,5 hexanedione Acrylamide Glue-sniffer’s neuropathy Huffer’s neuropathy Carbon disulfide Dimethylaminopropionitrile (DMAPN) Demyelinating Neuropathy Diphtheria toxin (diphtheric neuropath) Swine-flu vaccine Tetanus shot (brachial plexus neuropathy) Lead in animals Trichloroethylenec Perhexiline Amidarone Suramin Inflammatory Neuropathy Drug-induced hypersensitivity vasculitis Neuropathy associated with toxic oil syndrome Eosionphilia–myalgia syndrome These are confirmed histologically. Axonal degeneration and segmental demyelination are observed. Predominantly electrophysiologically axonal degeneration. c Axonal degeneration and segmental demyelination are observed. Predominantly electrophysiologically segmental demyelination. a

b

in industry.2-4 Arsenic neuropathy is predominantly sensory in character. In severe cases, motor weakness is also present. In subacute neuropathy following massive exposure, the patient classically develops severe gastrointestinal symptoms at the time of exposure. Within a few weeks, exfoliative dermatitis appears, as well as a painful sensory neuropathy. In severe cases, motor weakness and ©2002 CRC Press LLC

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FIGURE 12.1 Axonal degeneration: many myelin ovoids indicative of axonal degeneration in the teased nerve fibers.

respiratory failure may occur. The most important findings in the diagnosis of this disorder are Mees’ line (a transverse white line in the nails) and distal sensory neuropathy. A classic sensory axonal neuropathy is characterized electrophysiologically by marked abnormality in sensory nerve conduction in the presence of a mild motor nerve conduction abnormality, thus confirming the predominant involvement of sensory nerves.3 Diagnosis is confirmed by the elevated levels of arsenic in urine, nails, and hair. There is a consensus among previous reports that axonal degeneration is the predominant change in nerves in this disorder. Two early papers in which conventional stains were used showed fragmentation of myelin and disintegration of axons.5,6 All nine of our cases showed active axonal degeneration in the biopsied sural nerve (Color Figures 12.1–12.4).3* In studies of ten other cases, axonal degeneration was reported in the teasing fiber preparation of the biopsied sural nerve in all cases (Figure 12.1).2,7-9 The quantitative analysis of the density of myelinated fibers showed a decrease in nine of 11 cases. While Dyck et al. demonstrated that this occurred equally across the complete range of fiber diameters,8 LeQuesne and Oh showed that the large-diameter fibers were predominantly affected.3,9 In one case, acute axonal degeneration was documented in the first sural nerve biopsy, but regenerative proliferative myelinated fibers were noted in the second sural nerve biopsy after recovery.10 In the first sural nerve biopsy, arsenic was located by laser microprobe mass analysis.

THALLIUM NEUROPATHY Thallium neuropathy is predominantly sensory, although in severe cases, motor weakness may also occur. It may mimic arsenic neuropathy in that both produce acute gastrointestinal distress, hyperkeratosis, and Mees’ line. Alopecia, the hallmark of thallium poisoning, is a constant distinguishing feature which unfortunately appears only 2 to 4 weeks after acute exposure. Thallium poisoning is caused by accidental or intentional ingestion of rodenticides.11 Nerve conduction studies show mild slowing in sensory and motor nerve conduction, indicative of axonal neuropathy.12 Diagnosis can be achieved by urinary thallium estimation. * Color insert figures. ©2002 CRC Press LLC

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Pathological studies of the peripheral nerves in this disorder are limited in number but clearly demonstrate axonal degeneration. Five reports of autopsied cases of thallium poisoning showed prominent axonal degeneration in all peripheral nerves and, in addition, demyelination in the fasciculus gracilis secondary to chromatolytic changes in dorsal root ganglia in two patients.13-15 In four cases, the sural nerve biopsy showed active axonal degeneration.16-18 Semithin sections revealed a decrease in myelinated fiber density, myelin ovoids, and dilated or collapsed myelin sheaths.17 Teased nerve fibers showed linear rows of myelin ovoids. A systemic morphometric analysis of the sural nerve biopsy in two patients revealed a minimal decrease in the density of large and small myelinated fibers, normal fiber density of unmyelinated fibers, linear rows of myelin ovoids in 9 to 62% of teased fibers, and myelin ovoids and dilated or collapsed myelin in the transverse sections of the nerve.17

LEAD NEUROPATHY Unlike other metal neuropathies, lead neuropathy is predominantly a motor neuropathy characterized by wrist drop and occasional foot drop. It can, therefore, mimic motor neuron disease.19,20 Anemia and basophilic stippling are noted in the peripheral blood. Nephropathy and encephalopathy may be present. The gum lead line, if present, is a helpful clue in diagnosis. Lead encephalopathy is more common in children, whereas lead neuropathy is more frequently seen in adults. This disorder is most often found in individuals who work with lead, acetylene torches, batteries, and automobile radiators, as well as in alcoholics who drink lead-contaminated moonshine. Since Gombault’s classic description of segmental demyelination in guinea pigs with chronic lead intoxication, lead neuropathy has been used as a classic example of segmental demyelination.21 Recent studies in rats confirmed demyelinating neuropathy.22,23 However, in guinea pigs, a mixed picture of axonal degeneration and segmental demyelination was found.24 In baboons, no neuropathy could be demonstrated in spite of high blood lead levels for periods of up to 1 year.25 Axonal degeneration is the only well-described pathological alteration in the few previous reports on human nerves from individuals with lead neuropathy. The demyelination which was reported in one case was most likely a secondary feature.26 According to Fullerton’s review,24 axonal degeneration in peripheral nerves has been found on a number of occasions in patients dying from lead poisoning, while segmental demyelination, though specifically sought on at least two occasions, has not been described. Sural nerve biopsy reports on lead neuropathy have been limited in number.24 Oh noted a distinct decrease in the number of nerve fibers and myelin ovoids without segmental demyelination in a fascicular biopsy of the sural nerve in a patient who was a heavy drinker of moonshine whiskey.20 Unfortunately, concurrent alcoholism was a confounding factor in Oh’s case. Unequivocal evidence of mild axonal degeneration in human lead neuropathy was documented by Buchthal and Behse in a sural nerve biopsy in a single case of pure lead neuropathy.27 Biopsy of the sural nerve showed marked loss of large-diameter fibers, but the number of clusters of regenerating fibers and the abnormalities among teased fibers were within normal limits. Dupuy et al. observed a loss of large myelinated fibers and some regenerating clusters in the semithin sections but a mild degree of segmental demyelination and remyelination in teased nerve fibers, in a case of lead neuropathy due to contaminated tap water.26 Both patients had minimal nerve conduction abnormalities compatible with axonal neuropathy.26,27

CISPLATINUM NEUROPATHY Cis-diamine-dichlorplatinum II (cisplatinum) is a new, widely used antineoplastic agent which produces a predominantly sensory neuropathy. Nerve conduction studies showed major abnormalities in sensory nerve conduction in the presence of normal motor nerve conduction.28,29 Thompson28 demonstrated axonal degeneration and secondary myelin breakdown in the sural nerve biopsy from

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four patients who had been treated with cisplatinum alone. Roelfs et al.,29 on the other hand, found a mild decrease in the number of large-diameter fibers, axonal degeneration in some fibers, and segmental demyelination and remyelination in other fibers in teased-nerve-fiber studies of sural nerve biopsies from 10 patients who were treated with cisplatinum plus adriamycin. In five cases, Gastaut et al. reported a loss of large-diameter fibers and typical axonopathic changes with secondary demyelination.30 Thus, the sural nerve biopsy in pure cisplatinum neuropathy is characterized by axonal degeneration.

DRUG-INDUCED NEUROPATHY Various drugs are known to induce peripheral neuropathy during the course of treatment. Some, such as clioquinol and thalidomide, have been withdrawn from clinical use because they produce significant peripheral neuropathy, while others are still used because their therapeutic effects outweigh the side-effect of peripheral neuropathy. Table 12.1 shows a list of drugs responsible for neuropathy. The pathogenesis of drug-induced neuropathy is well known in some drugs but unknown in many others.31 Most drugs responsible for drug-induced neuropathies cause either a pure sensory or a mixed sensorimotor neuropathy.31 Sensory symptoms usually precede any motor disorder. Neurological deficits usually develop first and are most severe distally in the legs. There are a few drugs which cause an almost exclusively motor neuropathy: sulfonamide, amphotericin, imipramine, dapsone and lithium. Autonomic dysfunction is particularly prominent in patients with vincristine neuropathy. Cranial neuropathy can be seen in certain drugs: optic neuropathy in chroramphenicole and ethambutol, and eighth cranial nerves in streptomycin and kanamycin.32 Drug-induced peripheral neuropathies are almost always due to a dose-dependent primary axonal degeneration caused either by toxic reactions or metabolic changes in neurons or their surroundings.33 Axonal degeneration can occur in the sensory neurons, as in pyridoxin- and thalidomide-induced neuropathies. Because drug-induced neuropathies are potentially reversible, the opportunities for histological studies of human peripheral nerves are extremely limited. Thus, the number of drug-induced neuropathies, the pathologies of which have been reported, is relatively small (Table 12.1). Axonal degeneration is the most common pathological process in the peripheral nerves in drug-induced neuropathies. Exceptions have been few; perhexiline, amiodarone, and suramin neuropathies. Said reported segmental demyelination in the sural nerve biopsy in five patients with perhexiline neuropathy,34 Jacobs and Costa-Jussà reported demyelination with only mild axonal loss in two cases of amiodarone neuropathy (Color Figure 12.5).35 An accumulation of lysosomal inclusions characterizes amiodarone neuropathy (Figure 12.2).36 These inclusions appear in great numbers in endothelial cells, perineurial cells, and Schwann cells, especially in non-myelinated Schwann cells. These inclusions are well visualized in semithin toluidine-blue stained sections but are not well retained in paraffin-embedded material. La Rocca et al. reported a suramin-induced polyneuropathy which resembled subacute GBS with conduction block and a high CSF protein.37 Sural nerve biopsy showed axonal degeneration in one case and segmental demyelination in another case. Vasculitis has been shown to be a prominent feature in amphetamine-induced neuropathy.51,52

NEUROPATHY DUE TO BIOLOGICAL TOXINS AND VACCINES DIPHTHERITIC NEUROPATHY In about 10 to 15% of patients with diphtheria, a polyradiculopathy develops.40 There are two distinct syndromes: (1) local neuropathy producing palatal paralysis and paralysis of ocular accommodation,

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FIGURE 12.2 Small arrows point to some of the many inclusions in Schwann cells and endothelial cells. A few degenerating fibers are seen; others show myelin abnormalities (large arrows). The arrowhead indicates an axon with an inappropriately thin myelin sheath. Reduced density of myelinated fibers. (With permission from Jacobs, J.M., Costa-Jussà, F.R., Brain, 108, 756, 1985.)

developing 5 to 12 days after infection, and (2) generalized sensorimotor neuropathy with high CSF protein, developing 30 to 50 days after infection. Nerve conduction studies show moderate slowing consistent with segmental demyelination.12 In such cases, the peripheral neuropathy is due to the diphtheria exotoxin. Diphtheria exotoxin has repeatedly been shown to induce noninflammatory segmental demyelination in animals.40 Local injection of diphtheria exotoxin produces focal demyelination in many fibers following a latent period without the accumulation of lymphocytes or plasma cells. Because diphtheria toxin produces a relatively pure demyelinating neuropathy in animals, it has been regarded as a valid model for demyelinating neuropathy and used extensively as an investigative tool for the morphological and electrophysiological character of segmental demyelination. In human diphtheritic neuropathy, three postmortem studies clearly documented widespread non-inflammatory segmental demyelination of nerve roots and adjacent portions of somatic nerves. The outstanding feature of the lesions was segmental demyelination with preservation of axonal continuity. This was demonstrated in a teased nerve fiber preparation in Myer’s original paper.41 Two previous studies showed that the lesions were consistently concentrated in the dorsal root ganglia and adjacent ventral and dorsal roots.42,43 Among cranial nerves, only the nodose ganglion of the vagus was consistently affected. Peripheral portions of the spinal nerves appear to be largely spared in the acute phase of illness.

VACCINE-INDUCED NEUROPATHY Neuropathy may occur as a complication of immunizations, though that is rare. We became more acutely aware of this entity because of the outbreak of the Guillain–Barré syndrome (GBS) following A/New Jersey influenza vaccination in 1976.44 Three distinct syndromes were reported: (1) GBS, (2) brachial plexus neuropathy, and (3) sensory neuropathy. GBS was the most common form of neuropathy following swine-flu vaccination. The clinical and electrophysiological features were not different from those of classic GBS.45 There are no reports of postmortem findings in patients with vaccine-induced neuropathy. Sural nerve biopsy of two patients with swine-flu-induced neuropathy showed mild demyelinating neuropathy in one case and mild inflammatory demyelinating neuropathy (Color Figures 12.6–12.9),45 which is identical to classical GBS, in the other. Brachial plexus ©2002 CRC Press LLC

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neuropathy was reported after immunization for diphtheria alone, for tetanus alone, with DPT, and with swine-flu vaccine.46 Distal paresthesia with arthralgia is the most common type of complication after vaccination for rubella.46 Most likely the distal paresthesia represents a mild sensory neuropathy, but it has also been considered to be caused by a combination of mild arthritis and neuropathy.46

TOXIC NEUROPATHY DUE TO INDUSTRIAL AND ENVIRONMENTAL AGENTS Among many chemicals deployed in the workplace and present in the general environment, some agents are known to be causes of peripheral neuropathy. Fullerton47 suggested that the following criteria establish the relationship of a suspected toxin to peripheral neuropathy: (1) a characteristic clinical picture, (2) a definite and dose-related exposure, and (3) a neuropathy reproducible in experimental animals. So far, only five substances meet these criteria: hexocarbons, carbon disulfide, triorthocresyl phosphate, acrylamide, and dimethylaminopropionitrile (DMAPN). However, there are other agents that have been consistently associated with human neuropathy but have no documentation of neuropathy in experimental animals as yet. The pathogenesis of these toxic neuropathies is unknown with regard to most agents. In acrylamide, acrylamide monomer is neurotoxic. In hexocarbons, 2,5-hexanedione is responsible for the neurotoxic effects in n-hexane and methyl n-butyl ketone exposure.48 In glue sniffer’s neuropathy, n-hexane used as a solvent in some contact cements is responsible for neuropathy.49 In huffer’s neuropathy, attributed to the huffing of lacquer thinner, methyl ethyl ketone is neurotoxic.50,51 Triorthocresyl phosphate (TOCP) neuropathy results from the adulteration or misuse of TOCP in food, drink, or cooking oil. Prominent outbreaks have occurred in the U.S. from drinking adulterated Jamaica ginger extract (Jake Leg Paralysis)52 and in Morocco due to cooking with contaminated cooking oil.53 In Nigerian neuropathy, ingestion of a large quantity of the cassava plant, which contains a high level of thiocyanate, is responsible for neuropathy.54,55 The most important diagnostic procedure in toxic neuropathy caused by industrial and environmental agents is a detailed occupational and individual history, necessary to identify the possible neurotoxic agents. Once this has been accomplished, it must be ascertained that the clinical features in the given patient are consistent with the reported side-effects of the implicated agents. Only then can the diagnosis of toxic neuropathy be established. Most of these agents produce a sensorimotor polyneuropathy. However, some are known to produce a distinct symptom complex which is helpful in the diagnosis of specific toxic neuropathies (Table 12.1). Nerve conduction studies usually show mild abnormalities in neuropathies of axonal degeneration. However, in many toxic neuropathies characterized pathologically by giant axonal swelling, moderately slow motor nerve conduction is observed. This is due to the widening of the paranodal gap secondary to paranodal giant axonal swelling and subsequent retraction of myelin.49,50 In an effort to establish the diagnostic criteria of toxic neuropathy due to industrial and environmental agents, extensive experiments have been performed with many agents. These have become the main sources of information on the pathology of peripheral neuropathies in these disorders. Among the experimental toxic neuropathies, acrylamide-induced neuropathy is widely viewed as a valid model for the pattern of distal axonal neuropathy induced by many neurotoxic agents.48 The fundamental axonal change is the accumulation of 10-nm neurofilaments, producing giant axonal swelling (Color Figures 12.10–12.13). These accumulations initially appear in the distal regions of large-diameter myelinated axons of peripheral nerves. Nerve terminals may become grossly enlarged by accumulations of neurofilaments. Paranodal accumulations of neurofilaments may cause axonal swelling and subsequent retraction of myelin, sometimes giving an appearance of paranodal demyelination (Color Figure 12.14). Similar giant axonal swelling has been reported in experimental neuropathies due to carbon-disulfide, n-hexane, methyl n-butyl ketone, and DMAPN. ©2002 CRC Press LLC

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Figure not available electronically due to American Medical Association copyright. See printed book to view the figure.

FIGURE 12.3 Electron micrographs of a sural nerve. (A) transverse section, showing swollen axon surrounded by thin or no myelin sheath (1800 × magnification); (B) axoplasma is filled with dense array of neurofilaments (9500 × magnification). (With permission of Oh, S.J., Kim, J.M., Arch. Neurol., 33, 585, 1976.)

On the other hand, the number of well documented pathological studies of human peripheral nerves is rather limited. Giant axonal swelling, the most characteristic finding in these toxic neuropathies, has been reported in human toxic neuropathies due to n-hexane,51,56,57 acrylamide,1 methyl n-butyl ketone,58 and DMAPN.48 In glue-sniffer’s and huffer’s neuropathy, giant axonal swelling and widening of the paranodal gap have been clearly documented in human cases.49-51 Different types of pathology have been reported with other agents: in TOCP, Aring reported simple axonal degeneration in the peripheral nerves in postmortem studies of Jake Leg Paralysis from the 1930s52; in trichloroethyl, Buxton et al. reported extensive axonal degeneration in the trigeminal nerve and its sensory roots.59

EPIDEMIC TOXIC INFLAMMATORY NEUROPATHIES SPANISH TOXIC OIL SYNDROME In 1981, an epidemic of toxic/allergic syndrome caused by ingestion of rapeseed oil denatured with aniline occurred in Spain.60 Myalgias, joint limitations, weight loss, cramps, progressive weakness and wasting due to nerve and muscle involvement, sensory disturbances, and scleroderma-like changes were the main clinical features. Electrophysiological studies showed that the neuromuscular impairments were caused by a slowly progressive mixed axonal neuropathy.61 Nerve biopsy confirmed inflammatory axonal neuropathy. Perivascular inflammation involving epineurial, perineurial, and endoneurial vessels was noted, consisting mostly of lymphocytes and occasional PML, including eosinophils. A particularly striking feature was a tendency toward perineurial inflammation (perineuritis) and perineurial fibrosis.62 Axonal degeneration was the predominant process.

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EOSINOPHILIA–MYALGIA SYNDROME In 1989 and 1990, there was an epidemic of eosinophilia–myalgia syndrome caused by ingestion of contaminated L-tryptophan. Myalgia, eosinophilia in the blood, and scleroderma-like changes were the main clinical features. In one-third of patients, peripheral neuropathy occurred as part of a multisystem syndrome or in isolation.63,64 Electrophysiological studies showed predominantly axonal neuropathy, and nerve biopsies revealed inflammatory axonal neuropathy. Active axonal degeneration was the predominant feature in 12 of 14 cases.64-67 Inflammatory cells, predominantly lymphocytes with some eosinophils in the untreated cases, were reported in all three layers but predominantly in the epineurial space. Freimer et al. reported two cases of demyelinating neuropathy with histological evidence of active demyelination in the nerve biopsy.67 Frank fibrinoid necrosis was not observed. However, inflammatory vasculopathy characterized by luminal narrowing and angioneogenesis was observed in one study (Color Figure 12.15).64 Prominent microvasculitis in the epineurial space was observed in one case.63 Muscle biopsy usually showed inflammatory myopathy.64-66 A vasculitis predominantly involving veins was observed in 5 cases, and a medium-sized arteritis was seen in 1 case out of 11 muscle biopsies.63

CASES OF TOXIC NEUROPATHIES CASE 1: SUBACUTE NEUROPATHY IN A 19-YEAR-OLD GIRL WITH POSSIBLE ANOREXIA NERVOSA Case Presentation During the 5 months preceding admission for evaluation, a 19-year-old female was admitted to local hospitals twice for short episodes of nausea and vomiting which were initially thought to be due to gastroenteritis. She improved while in the hospital but continued to lose weight because of anorexia. The patient was transferred to the psychiatric unit at another hospital for treatment of anorexia nervosa with several psychotrophic medications. One week after admission there, she began to have trouble with lower-extremity weakness and fell several times while on the ward. A bone marrow study was performed for bone marrow suppression during hospitalization. Abnormal neurological findings at the UAB hospital were as follows: mild weakness in the hand grip, proximal leg, and gluteus muscles and moderate weakness in the hamstrings, anterior tibialis, and peroneus muscles; “stocking-glove” dysesthesias of the feet and hands with loss of position and vibration sensation in the toes and moderate sensory impairment in the fingers and ankles; mild atrophy of the anterior tibialis muscles; and absent DTRs. She walked with foot drop. The CSF study was completely normal. When Mees’ line was discovered on the patient’s fingers, arsenic neuropathy was suspected. An EMG study showed acute axonal neuropathy with predominant sensory nerve conduction involvement. Case Analysis Guillain–Barré syndrome was initially suspected because of the progression of neuropathy over a 3-week period following an episode of gastrointestinal illness. However, normal CSF findings and axonal neuropathy in the NCS did not support the diagnosis of GBS. Mees’ line was the critical clue suggestive of arsenic neuropathy. Bone marrow suppression was another indication of toxic neuropathy. Our patient had the classic feature of arsenic neuropathy: subacute mixed sensory-motor polyneuropathy.

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Sural Nerve Biopsy A marked loss of myelinated fibers was noted in the transverse sections. Myelin-digestion chambers were prominent, with many vacuolated ghost fibers. Semithin sections showed active myelin breakdown of various stages (Color Figures 12.16 and 12.17). Final Diagnosis Arsenic neuropathy was the final diagnosis. Treatment and Follow-up The diagnosis of arsenic neuropathy was confirmed by the 24-hour urine, fingernail, and hair testing. The patient gradually improved over a 2-year period. In the meantime, an investigation by law enforcement authorities implicated the girl’s stepmother as the culprit who had poisoned her as well as the stepmother’s two former husbands. Comments Our patient demonstrated the classic feature of arsenic neuropathy: subacute mixed sensory-motor polyneuropathy. Other systemic features of arsenic intoxication included a history of severe gastrointestinal upsets, multiple organ failure, dermatological lesions, and Mees’ line. The most helpful diagnostic finding in arsenic polyneuropathy is the presence of Mees’ line in the fingernails and toenails, observed in 80% of cases. Mees’ line may not be seen in the early stages of neuropathy because it takes 4 to 6 weeks to develop. Arsenic neuropathy in the U.S. is most commonly due to homicidal intent, as noted in our case. The diagnosis of arsenic intoxication is confirmed by 24-hour urinalysis in the acute stage and by fingernail, toenail, and hair analysis in the chronic stage. The most prominent electrophysiological findings are marked abnormalities in the sensory and mixed nerve conduction in the presence of moderate abnormalities in motor conduction. These electrophysiological findings are well supported by the histological observation of axonal degeneration as the predominant process in the sural nerve biopsy.

CASE 2: PROGRESSIVE ASCENDING WEAKNESS IN THE EXTREMITIES AND NUMBNESS IN THE TOES FOR A FEW MONTHS Case Presentation A 20-year-old man reported progressive ascending weakness in his extremities and numbness of the toes for a few months prior to evaluation. At the time of examination, the patient was not able to rise from a chair or walk without assistance. There was marked weakness in plantar extensors and wrist extensors; moderate weakness in plantar flexors, quadriceps, hamstrings, and wrist flexors; and mild weakness in biceps and triceps muscles. Sensory abnormalities were minimal: hyperesthesia over the toes and decreased vibratory sensation in the ankles and toes. Patellar and ankle reflexes were absent, but biceps and triceps reflexes were weakly present. Peripheral neuropathy work-ups were all normal, including a CSF protein of 53 mg/dl. An NCS showed demyelinating neuropathy with markedly prolonged terminal latency, moderate slowing in the motor NCV, and absent sensory nerve potentials. Case Analysis The constellation of subacute progression, predominant motor neuropathy, and demyelinating neuropathy in the NCS was indicative of CIDP. An atypical feature for CIDP was normal CSF protein, which is observed in 25% of CIDP cases. A nerve biopsy was done to confirm the diagnosis of CIDP. ©2002 CRC Press LLC

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Sural Nerve Biopsy Frozen sections showed giant axonal swelling, many myelin-digestion chambers indicative of axonal degeneration, and increased paranodal gaps. The giant axonal swelling was best seen by modified trichrome and Glees–Masland silver stains. Teased nerve fiber preparations showed giant axonal swelling in 7% of fibers, linear rows of myelin ovoids in 7% of fibers, and increased paranodal gaps in 10% of fibers (Color Figures 5.19, 12.3, and 12.10–12.14). Final Diagnosis The final diagnosis was toxic neuropathy due to lacquer thinner (huffer’s neuropathy). Treatment and Follow-up Giant axonal swelling in the nerve biopsy led us to seek the history of exposure to toxins, including glue-sniffing. For 2 years, the patient had been huffing almost daily, in volumes up to 7.5 liters per month, 2 kinds of lacquer thinner. Despite cessation of exposure, his weakness progressed over the next 2 months, followed by gradual improvement for the next 2 years. Comments Around the time this patient was evaluated, Prockop et al.68 reported seven cases of ascending predominant motor polyneuropathy due to inhalation of a lacquer thinner. Of their seven patients, four had respiratory distress and two had bulbar paralysis. Our case confirmed that giant axonal neuropathy is the histological basis of huffer’s neuropathy. This has also been reported in glue-sniffing neuropathy. Most likely, methylbutylketone (MBK) in the commercial grade of MIBK in lacquer thinner was responsible for giant axonal neuropathy in this patient.

CASE 3: SUBACUTE PROGRESSION OF WEAKNESS FOR 31/2 MONTHS AFTER SWINE-FLU VACCINATION Case Presentation A 57-year-old man was admitted to the Neurology Service for progressive weakness in all 4 extremities for 31/2 months. One month after receiving an injection of swine-flu vaccine, he noted numbness and burning sensations on the soles of his feet. This was soon followed by progressive weakness in his legs and arms for 31/2 months. Abnormal neurological findings were mild weakness in the arms and moderate weakness in the leg muscles, worse proximally, diffuse areflexia, and normal sensory functions. CSF protein was 134 mg/dl with increased IgG. An NCS/EMG showed mild demyelinating neuropathy. Case Analysis Subacute progression of predominantly motor weakness, high CSF protein, and demyelinating neuropathy in the NCS are indicative of CIDP. In this case, CIDP developed 1 month after the swine-flu vaccination. Sural Nerve Biopsy There was perivascular infiltration of a moderate number of mononuclear cells in the epineurial space. A minimal decrease in the population of myelinated fibers was also noted. Modified trichrome stain on longitudinal cuts showed an apparent segmental demyelination. Teasing of nerve fibers revealed demyelination in 78% of fibers (see Color Figures 12.6–12.9). ©2002 CRC Press LLC

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Final Diagnosis CIDP associated with swine-flu vaccination was the final diagnosis. Treatment and Follow-up This patient was treated with 100 mg of prednisone and intensive physical therapy in the rehabilitation ward for 11/2 months. Within 2 months, the patient had recovered almost completely. Comments According to our report on seven patients with swine-flu vaccination–induced peripheral neuropathy, many clinical features were similar to those of Guillain–Barré syndrome except for two prominent characteristics: (1) subacute progression of neuropathy was more common in the former group, and (b) subjective sensory symptoms were prominent. NCS abnormalities observed in all cases were almost identical to those seen in GBS. The sural nerve biopsy in two patients showed evidence of inflammatory demyelinating neuropathy. Thus, the electrophysiological and pathological findings in these cases were identical to those of classical GBS, but there were several atypical clinical features.

CASE 4: GUILLAIN–BARRÉ SYNDROME FOLLOWING INGESTION OF AN UNKNOWN AMOUNT OF ANTIFREEZE Case Presentation A 43-year-old man was admitted to a local hospital with acute abdominal pain, severe nausea, vomiting, lethargy, and anuria after ingesting an unknown amount of antifreeze. Initial evaluation disclosed hypertension, an anion gap metabolic acidosis, and renal failure. Urinalysis showed hematuria but no crystals. The patient underwent emergency dialysis. Over the next 7 days, he developed progressive swallowing difficulty, facial diplegia, fixed pupils, and absent gag reflex. CSF was acellular with a high protein (226 mg/dl). He was transferred to the UAB hospital on the 14th day after exposure for possible plasmapheresis under the diagnosis of Guillain–Barré syndrome. Abnormal neurological findings were fixed pupils, severe facial diplegia, bulbar palsy, absent gag reflex, mild weakness in iliopsoas muscles, and decreased ankle reflexes. Laboratory evaluation showed renal failure and high spinal fluid protein (258 mg/dl). An EEG revealed diffuse mild slowing consistent with a metabolic encephalopathy. A nerve conduction study showed a mild sensorimotor peripheral neuropathy with conduction block in the forearm segment in the median nerve. A cranial MRI scan did not show any brainstem abnormalities. Case Analysis Clinical and laboratory findings in this case are similar to those of the descending form of acute inflammatory demyelinating polyneuropathy (Guillain–Barré syndrome). However, a temporal relationship to the ingestion of ethylene glycol (EG), renal failure due to EG poisoning, and cranial neuropathy as the initial manifestation of neuropathy strongly suggest that this patient’s neuropathy was secondary to EG poisoning. Sural Nerve Biopsy Frozen and semithin sections of the sural nerve showed a minimal decrease in the number of myelinated fibers and a few fibers with thin myelin in proportion to axon diameters. Most likely, these latter fibers represent partially demyelinated fibers. Teasing of 83 nerve fibers showed paranodal ©2002 CRC Press LLC

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widening in 16%, segmental demyelination in 28% (Color Figure 12.18), and axonal degeneration in 9.6%. Calcium crystals were absent. Thus, nerve biopsy findings were indicative of a demyelinating neuropathy. Renal biopsy showed acute tubular necrosis with massive intratubular calcium oxalate deposits typical of ethylene glycol poisoning. Final Diagnosis The final diagnosis was ethylene glycol–induced peripheral neuropathy. Treatment and Follow-up Over the next 2 days, despite dialysis, the patient became confused and developed respiratory failure requiring intubation. His condition began to improve on the 7th day of admission and further improvement ensued during the following 6 months. Comments EG poisoning is rare. The diagnosis of EG poisoning is easy when a history of EG ingestion is given. However, in the absence of such a history, the diagnosis of EG poisoning should be considered when any combination of the following signs is present: (1) an apparently intoxicated patient without the odor of alcohol on his breath, (2) coma associated with metabolic acidosis and a large anion gap, (3) calcium oxalate crystals on urinalysis, and (4) an osmodal gap. Most of the classic descriptions of EG poisoning concentrate on metabolic abnormalities and renal failure. Berger and Ayyar reported a case of facial diplegia as a delayed complication of EG poisoning and summarized all known neurological complications of EG poisoning.69 Among the various neurological complications including fixed pupils, decreased visual acuity, ophthalmoplegia, facial diplegia, and bulbar palsy, cranial neuropathy was most commonly reported and, thus, seems to be the classic feature of EG poisoning. The CSF may be abnormal, with high protein as well as pleocytosis. Our patient exhibited many of the classic neurological complications of EG poisoning: initial lethargy and fixed pupils, facial diplegia, and bulbar palsy as a late complication. He also had the CSF abnormalities previously reported in EG poisoning. An NCS and nerve biopsy showed demyelinating neuropathy. Thus, EG-induced neuropathy is not different from the descending form of GBS.

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Davenport, J.G., Farrell, D.F., and Sumi, S.M., Giant axonal neuropathy caused by industrial chemicals, Neurology, 26, 919, 1976. Goldstein, N., McCall, J.T., and Dyck, P.J., Metal neuropathy, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K. and Lambert, E.H., Eds., W.B. Saunders, Philadelphia, PA, 1975, 1227. Oh, S.J., Electrophysiological profile in arsenic neuropathy, J. Neurol., Neurosurg. Psychiatry, 54(12), 1103, 1991. Feldeman, R.G., Niles, C.A., Kelly-Hayes, M., Sax, D.S., Dixon, W.J., Thompson, D.J., and Landau, E., Peripheral neuropathy in arsenic smelter workers, Neurology, 29, 939, 1979. Heyman, A., Pfeiffer, J.B. Jr., Willet, R.W., and Taylero, H.M., Peripheral neuropathy caused by arsenical intoxication, New Eng. J. Med., 254, 401, 1956. Chuttani, P.N., Chawla, L.S., and Sharma, T.D., Arsenical neuropathy, Neurology, 17, 269, 1967. Ohta, M., Ultrastructure of sural nerve in a case of arsenical neuropathy, Acta Neuropathol., 16, 233, 1970. Dyck, P.J., Gutrecht, J.A., Bastron, J.A., Karnes, W.E., and Dale, A.J.D., Histologic and teased fiber measurements of sural nerve in disorders of lower motor and primary sensory neurons, Mayo Clin. Proc., 43, 81, 1968. LeQuesne, P.M. and McLeod, J.G., Peripheral neuropathy following a single exposure to arsenic, J. Neurol. Sci., 32, 437, 1977.

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10. Goebel, H.H., Schmidt, P.F., Bohl, J., Tettenborn, B., Kramer, G., and Gutmann, L., Polyneuropathy due to acute arsenic intoxication: biopsy studies, J. Neuropathol. and Exp. Neurol., 49(2), 137, 1990. 11. Rangel-Guerra, R., Martinez, H.R., and Villarreal, H.J., Thallium poisoning. Experience with 50 patients (transl.), Gaceta Medica de Mexico, 126(6), 487, 1990. 12. Oh, S.J., Clinical Electromyography. Nerve Conduction Studies, Williams & Wilkins, Baltimore, MD, 1993. 13. Cavanagh, J.B., Fuller, N.H., Johnson, H.R.M., and Rudge, P., The effects of thallium salts, with particular reference to the nervous system changes, Q. J. Med., 43, 293, 1974. 14. Kennedy, P. and Cavanagh, J.B., Spinal changes in the neuropathy of thallium poisoning. A case with neuropathological studies, J. Neurol. Sci., 29, 295, 1976. 15. Tanaka, J., Yonezawa, T., and Ureyama, M., Acute thallotoxicosis: neuropathological and spectrophotometric studies on an autopsy case, J. Toxicol. Sci., 3, 325, 1978. 16. Bank, W.J., Pleasure, D.E., Suzuki, K., Nigro, M., and Katz, R., Thallium poisoning, Arch. Neurol., 26, 456, 1972. 17. Limos, L.C., Ohnishi, A., Suzuki, N., Kojima, N., Yoshimura, T., Goto, I., and Kuroiwa, Y., Axonal degneration and focal muscle fiber necrosis in human thallotoxicosis: histopathological studies of nerve and muscle, Muscle and Nerve, 5, 698, 1982. 18. Davis, L.E., Standefere, J.C., Kornfeld, M., Abercrombie, D.M., and Butler, C., Acute thallium poisoning: toxicological and morphological studies of the nervous system, Ann. Neurol., 10, 38, 1981. 19. Boothy, J.A., DeJesus, P.V., and Rowland, L.P., Reversible forms of motor neuron disease: lead “neuritis.” Arch. Neurol., 31, 269, 1974. 20. Oh, S.J., Lead neuropathy: case report, Arch. Phys. Med. Rehabil., 56, 312, 1975. 21. Gombault, M., Contribution a l’étude anatomique de la névite parenchymatuse subaigué et chronique: névite segmentaire péri-axile, Archives Neurologie, 1, 11, 1980. 22. Lampert, P.W. and Schochet, S.S., Demyelination and remyelination in lead neuropathy-electron microscopic studies, J. Neuropathol. Exp. Neurol., 27, 527, 1968. 23. Ohnishi, A., Schilling, K., Bvrimijoin, W.S., Lambert, E.H., Fairbanks, V.F., and Dyck, P.J., Lead neuropathy. 1. Morphometry, nerve conduction, and choline acetyltransferase transport: new finding of endoneurial edema associated with segmental demyelination, J. Neuropathol Exp. Neurol., 36, 499, 1977. 24. Fullerton, P.M., Chronic peripheral neuropathy produced by lead poisoning in guinea-pigs, J. Neuropathol. Exp. Neurol., 25, 214, 1966. 25. Hopkins, A., Experimental lead poisoning in the baboon, Br. J. Ind. Med., 27, 130, 1970. 26. Dupuy, B., Lechevalier, B., Berthelin, C., and Prevot, P., Étude du nerf périphérique dans un cas de neuropathie saturnine, Rev. Neurol., 140, 406, 1984. 27. Buchthal, F. and Behse, F., Electrophysiological and nerve biopsy in men exposed to lead, Br. J. Ind. Med., 36, 135, 1979. 28. Thompson, S.W., Davis, L.E., Kornfeld, M., Hilgers, R.D., and Standefer, J., Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies, Cancer, 54, 1269, 1984. 29. Roelfs, R.I., Hrushesky, W., Rogin, J., and Rosenberg, L., Peripheral sensory neuropathy and cisplatin chemotherapy, Neurology, 34, 934, 1984. 30. Gastauet, J.L. and Pellisssier, J.F., Neuropathie au cisplatine. Étude clinique, électrophysiologique et morphologique, Rev. Neuro., 141, 614, 1985. 31. Argov. Z. and Mastaglia, F.L., Drug-induced peripheral neuropathies, Br. Med. J., 1, 663, 1979. 32. Noone, P., Use of antibiotics, Aminoglycosides, Br. Med. J., 2, 549, 1978. 33. Oslesen, L.L. and Jensen, T.S., Prevention and management of drug-induced peripheral neuropathy, Drug Safety, 6, 302, 1991. 34. Said, G., Perhexiline neuropathby: a clinicopathological study, Ann. Neurol., 3, 259, 1978. 35. Jacobs, J.M. and Costa-Jussà, F.R., The pathology of amiodarone neurotoxicity. II peripheral neuropathy in man, Brain, 108, 753, 1985. 36. Midroni, G., Bilbao, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann, Boston, MA, 332, 1995. 37. La Rocca, R.V., Meer, J., Gilliatt, R.W., Cassidy, J., Myers, C.E., and Dalkas, M.C., Suramin-induced polyneuropathy, Neurology, 40, 954, 1990.

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38. Citron, B.P. et al., Necrotizing angiitis associated with drug abuse, New Eng. J. Med., 283, 1003, 1970. 39. Stafford, C.R. et al., Mononeuropathy multiplex as a complication of amphetamine angiitis, Neurology, 25, 570, 1975. 40. McDonald, W.I. and Kocen, R.S., Diphtheric neuropathy, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lambert, E.H., Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1983, 2010. 41. Meyer, P., Anatomische untersuchungen uber dipththeritische lahmung, Virchows. Arch. Pathol. Anato. Physiol., 85, 181, 1881. 42. Fischer, C.M. and Adams, R.D., Diphtheritic polyneuritis — a pathological study, J. Neuropathol. Exp. Neurol., 15, 243, 1956. 43. Veith, G., Untersuchunger uber die histologie der polyneuritis diphtheerica, Beitr. Pathol. Anat., 110, 567, 1949. 44. Schonberger, L.B., Hurwitz, E.S., Katona, P., Holman, R.C., and Bregman, D.J., Guillain–Barré syndrome: its epidemiology and associations with influenza vaccination, Ann. Neurol., 9(Suppl.), 31, 1981. 45. Oh, S.J. and Kuba, T., The swine-flu vaccination-induced peripheral neuropathy: electrophysiological and histological studies, EEG Clin. Neurophys., 50, 173, 1980. 46. Fenichel, GM., Neurological complications of immunization, Ann. Neurol., 12, 119, 1982. 47. Fullerton, P.M., Toxic chemicals and peripheral neuropathy: clinical and epidemiological features, Proc. R. Soc. Med., 62, 201, 1969. 48. Schaumburg, H.H. and Spencer, P.S., Human Toxic Neuropathy due to industrial agents, in Diseases of the Peripheral Nervous System, by Dyck, P.J., Thomas, P.K., Lambert, E.H., Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1984, 2112. 49. Korobkin, R., Asbury, A.K., Sumner, A.J., and Nielson, S.L., Glue sniffing neuropathy, Arch. Neurol., 32, 158, 1975. 50. Oh, S.J. and Kim, J.M., Giant axonal swelling in “Huffer’s neuropathy,” Arch. Neurol., 33, 583, 1976. 51. Altenkirch, H., Mager, J., Stoltenburg, G., and Helmbrecht, J., Toxic polyneuropathies after sniffing a glue thinner, J. Neurol., 214, 137, 1977. 52. Aring, C.D., The systemic nervous affinity of triorthocresyl phosphate (Jamaican ginger palsy), Brain, 65, 34, 1942. 53. Smith, H.V. and Spalding, J.M.K., Outbreak of paralysis in Morocco due to orthocresyl phosphate poisoning, Lancet, 2, 1019, 1959. 54. Osuntokun, B.O., An ataxic neuropathy in Nigeria, Brain, 91, 215, 1968. 55. Osuntokun, B.O., Aldetoyinbo, A., and Adeuja, A.O.G., Free cyanide levels in tropical ataxic neuropathy, Lancet, 2, 372, 1970. 56. Rizzuto, W., Terzian, H., and Galiazzo-Rizzuto, S., Toxic polyneuropathies in Italy due to leather cement poisoning in shoe industries. A light and electron microscopic study, J. Neurol. Sci., 31, 343, 1977. 57. Shirabe, T., Tsuda, T., Terao, A., and Araki, S., toxic polyneuropathy due to glue sniffing. Report of two cases with light and electron microscope study of the peripheral nerves and muscles, J. Neurol. Sci., 21, 101, 1974. 58. Allen, N., Mendell, J.R., Billmaier, D.J., Fontaine, R.E., and O’Neill, J., Toxic polyneuro-pathy due to methyl n-butyl ketone. An industrial outbreak, Arch. Neurol., 32, 209, 1975. 59. Buxton, P.H. and Hayward. M., Polyneuritis cranialis associated with industrial trichlorethylene poisoning, J. Neurol. Neurosurg. Psychiatry, 30, 511, 1967. 60. Tabuenca, J.M., Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline, Lancet, 2, 567, 1981. 61. Cruz Martinez, A., Pérez-Conde, M.C., Ferrer, M.T., Cantón, R., and Téllez, I., Neuromuscular disorders in a new toxic syndrome: electrophysiological study — a premininary report, Muscle and Nerve, 7, 12, 1984. 62. Ricoy, J.R. et al., Neuropathologic studies on the toxic syndrome related to adulterated rapeseed oil in Spain, Brain, 106, 817, 1983. 63. Kaufman, L.D., Seidman, R.J., and Gruber, B.L., L-triptophan-associated eosinophilic perimysoitis, neuritis, and fasciitis. A clinico-pathologic and laboratory study of 25 patients, Medicine, 69, 187, 1990. 64. Smith, B.E. and Dyck, P.J., Peripheral neuropathy in the eosinophilia–myalgia syndrome associated with L-tryptophan ingestion, Neurology, 40, 1035, 1990. 65. Burns, S.M., Lange, D.J., Jaffe, I., and Hays, A.P., Axonal neuropathy in eosinophilia–myalgia syndrome, Muscle and Nerve, 17, 293, 1994. ©2002 CRC Press LLC

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66. Heilman-Patterson, T.D. et al., Peripheral neuropathy associated with eosinophilia–myalgia syndrome, Ann. Neurol., 28, 522, 1990. 67. Freimer, M.L. et al., Chronic demyelinating neuropathy associated with eosinophilia–myalgia syndrome, J. Neurol. Neurosurg. Psychiatry, 55, 352, 1992. 68. Prokop, L.D., Alt, M., and Tison, J., “Huffer’s” neuropathy, JAMA, 1083, 1974. 69. Berger, J.R. and Ayyar, D.R., Neurological complications of ethylene glycol intoxication, Arch. Neurol., 38, 724, 1981.

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CHAPTER 12 Figure 1 Many myelin-digestion chambers indicative of active axonal degeneration. Double arrows indicate two myelin-digestion chambers. Moderate decrease (60%) in population of myelinated fibers is obvious. Frozen section. Modified trichrome stain. (200 × magnification.)

CHAPTER 12 Figure 2 Many myelin-digestion chambers in the longitudinal cut. The arrow indicates one myelin-digestion chamber. There are two normal myelinated fibers. Frozen section. Modified trichrome stain. (200 × magnification.)

CHAPTER 12 Figure 3 Almost all myelinated fibers are undergoing myelin breakdown indicative of active axonal degeneration. The arrow indicates one fiber undergoing myelin breakdown. Moderate loss (60%) of population of myelinated fibers. Semithin section. Toluidine blue stain. (400 × magnification.)

CHAPTER 12 Figure 4 Prominent myelin-digestion chambers in all myelinated fibers except two normal fibers (yellow arrows). The red arrow indicates edema in the subperineurial space. Frozen section. Modified trichrome stain. (200 × magnification.)

CHAPTER 12 Figure 5 Demyelination in amiodarone-induced neuropathy. Arrows point to thinly myelinated fibers indicative of remyelination. Also, there is a decrease in large-diameter fibers. Semithin section. Toluidine blue and basic fuchsin stain. (400 × magnification.)

CHAPTER 12 Figure 6 Perivascular collection of lymphocytes in an epineurial vessel. The arrow indicates one nerve fascicle. Paraffin section. H & E stain. (400 × magnification.)

CHAPTER 12 Figure 7 Segmental demyelination: demyelination in one internode between arrows. Contiguous to the demyelinated segment, a normal myelinated segment is clearly visible. Marked loss of myelinated fibers is obvious in this nerve fascicle. Frozen section. Modified trichrome stain. (100 × magnification.)

CHAPTER 12 Figure 8 Minimal loss of myelinated fibers in this nerve fascicle. No myelin-digestion chamber is observed. Frozen section. Modified trichrome stain. (200 × magnification.)

CHAPTER 12 Figure 9 Segmental demyelination in the second internode segment. The first and third internode segments are normal.

CHAPTER 12 Figure 10 Three giant axons (arrows) are easily identified here as a green center surrounded by thin red myelin. The giant axon (1 arrow) is three times larger in diameter than in a normal large-diameter fiber. The population of myelinated fibers is minimally decreased. Frozen section. Modified trichrome stain. (400 × magnification.)

CHAPTER 12 Figure 11 Two giant axons (arrows) in one nerve fiber. Notice that the axon is not stained. Arrowheads indicates myelin ovoids. Frozen section. H & E stain. (200 × magnification.)

CHAPTER 12 Figure 12 Four giant axons (arrowhead) in one nerve fiber. Paraffin section. Holmes silver and Luxol fast blue stain. (100 × magnification.)

CHAPTER 12 Figure 14 Giant axon (arrow) and paranodal demyelination (arrowheads) in teased nerve fiber.

CHAPTER 12 Figure 13 Giant axons in the transverse section. Two giant axons are surrounded by a thin myelin sheath (arrowhead) while one giant axon (arrow) has no myelin sheath. Semithin section. Toluidine blue and basic function. (400 × magnification.) (With permission of Oh, S.J., Yonsei Med. J., 31, 20, 1990.)

CHAPTER 12 Figure 15 Perivascular inflammatory infiltrate in eosinophilia–myalgia. Two centrally located epineurial vessels are surrounded by eosinophilic leucocytes (reddish-brown cytoplasm) and mononuclear cells. At the bottom of the field is a small collection of plasma cells. Paraffin section. Congo-red stain. (312 × magnification.) (With permission of Smith, B.E. and Dyck, P.J., Neurology, 40, 1039, 1990.)

CHAPTER 12 Figure 16 Prominent myelin-digestion chambers in almost all nerve fibers. The arrowhead indicates edema in the subperineurial space.

CHAPTER 12 Figure 17 Active myelin breakdown of all myelinated fibers except one (arrow). Semithin section. Toluidine blue stain. (400 × magnification.)

CHAPTER 12 Figure 18 Segmental demyelination (hypomyelination) in the internode segment (1) between the downward arrow, and (2) in the internode segment between the upward arrow.

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Interpretation of Nerve Biopsy

For the pathological evaluation of nerve biopsy, the first task is to assess the adequacy of the sample in terms of size and technical preparation. Once this is determined, the sections must be evaluated systematically. The following guidelines are from the method of interpretation adopted by the UAB muscle and nerve histopathology laboratory. The first step is to evaluate paraffin sections stained with H & E, modified trichrome, and Congo-red in cross and longitudinal sections. Paraffin sections provide the best means of recognizing cell infiltration, vascular changes, and malignant cells (Table 13.1). Even in the hands of the best technologist, however, paraffin sections are subject to distortion of the specimen. The number of fascicles is easily identified on paraffin sections. Inflammatory cells, Schwann cells, granulomata, and vascular changes are assessed with the H & E stain. In general, H & E–stained paraffin sections reveal the nature of cells and vascular changes in detail and are essential in establishing the diagnoses of vasculitis, granuloma, inflammatory neuropathy, and lymphomatous neuropathy. The location of inflammatory cells is helpful in the diagnosis of neuropathies. Inflammatory cells in the epineurial space are usually present around the vessels and can be seen in both inflammatory axonal and demyelinating neuropathies, as well as in vasculitic neuropathies. On the other hand, endoneurial inflammatory cells are strongly indicative of inflammatory demyelinating neuropathy. Perineurial inflammatory cells are commonly observed in lymphomatous neuropathy, leprosy, and sensory perineuritis. H & E stain can suggest onion-bulb formation (OBF) by identifying more than one nucleus around the nerve fiber. This is because three or four Schwann cells may be required to remyelinate each demyelinated segment. However, OBF must be confirmed by other stains. There has been some controversy as to whether an enlarged subperineurial space represents edema or artifact. In this regard, Asbury provided the following guidelines1: an enlarged subperineurial space that is watery-clear should be considered to have resulted from artifactual contraction of the endoneurium away from the perineurium. A slightly widened subperineurial space containing faintly stained interstitial fluid and traversed by thin cytoplasmic processes and collagen fibers should be interpreted as edema and is common in many neuropathies; when that is a prominent feature, it suggests one of the chronic demyelinating neuropathies. The modified trichrome stain on the paraffin sections stains myelinated fibers and is useful in assessing the population of myelinated fibers. In severe axonal degeneration, myelin-digestion chambers (MDC) are identifiable in the longitudinal cuts. However, when a few MDCs are present, they are not easy to identify because of their resemblance to artifacts. OBFs are more easily identifiable because of the appearance of red myelinated fibers in their centers. Thus, when only paraffin sections are available, the modified trichrome stain can, at least, shed some light on the population of myelinated fibers and axonal degeneration in severe cases. Myelinated fibers can also be estimated by Kultschitzky’s stain in the paraffin section. Kultschitzky’s stain, the oldest myelin stain, stains myelin black. One advantage of this stain is that it can identify the varying diameters of myelinated fibers as well as the ratio of axon to full-nerve fiber diameter. However, because of artifacts, the semithin sections are far superior to and more reliable than sections stained with Kultschitzky’s stain in these respects. Luxol-fast blue stain, which is commonly used for the detection of demyelination in the central nervous system, is totally useless for detecting demyelination in the peripheral nerve. It is useful for ©2002 CRC Press LLC

Chapter 13 Final Proof

TABLE 13.1 Pathological Features and Interpretation Diagnostic Possibilities

Inflammation Inflammation Inflammation

Inflammatory demyelinating neuropathy Perineural sensory neuritis; leprosy Inflammatory demyelinating neuropathy Inflammatory axonal neuropathy; vasculitic neuropathy Lymphomatous neuropathy

H & E Stains Inflammatory Cells Endoneurial Perineurial Epineurial (usually perivascular) Malignant cells

Malignancy

Sarcoidosis Leprosy

Vascular change Intramural cell infiltration Fibrinoid necrosis of wall Occlusion Thickening

Vasculitis Vasculitis Ischemia Ischemia

Vasculitic neuropathy Vasculitic neuropathy Ischemic neuropathy Diabetic neuropathy

Modified Trichrome Stain Loss of myelinated fibers Myelin-digestion chamber Onion-bulb formation (OBF) (rarely) Selective nerve fascicular degeneration Central fascicular degeneration

Axonal degeneration Demyelination and remyelination Ischemia Ischemia

Nonspecific neuropathy Axonal neuropathy Hypertrophic neuropathy Ischemic neuropathy Ischemic neuropathy

Congo-red Stain Congo-red materials

Amyloid

Amyloid neuropathy

Ischemia Ischemia

Nonspecific neuropathy Ischemic neuropathy Ischemic neuropathy

Frozen Sections Modified Trichrome Stain Loss of myelinated fibers Selective nerve fascicular degeneration Central fascicular degeneration

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Granuloma Noncaseating Caseating (necrotizing)

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Interpretation

Paraffin Sections

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Histopathological Features

Axonal degeneration Tomacula Giant axon Demyelination and remyelination

Axonal neuropathy Tomaculous neuropathy Giant axonal neuropathy Hypertrophic neuropathy

PAS Stain PAS positive body

Polyglucosan body

Polyglucosan body disease

Cresyl-fast Violet Stain Purple-colored material

Metachromatic granules

Metachromatic neuropathy

Congo-red Stain Congo-red material

Amyloid

Amyloid neuropathy

Semithin Sections Loss of myelinated fibers Loss of large-diameter fibers Loss of small fibers Selective nerve fascicular degeneration Central fascicular degeneration Thinly myelinated fiber Cluster of tiny thinly myelinated fiber Myelin breakdown Swollen axon Onion-bulb formation Thick myelin diameter

Neuropathy Large-fiber neuropathy Small-fiber neuropathy Ischemia Ischemia Remyelination Regeneration (axonal sprouting) Axonal degeneration Giant axon Demyelination and remyelination Tomacula

Nonspecific neuropathy Most toxic or metabolic neuropathy Diabetic; amyloid; Fabry’s disease Ischemic neuropathy Ischemic neuropathy Demyelinating neuropathy Chronic axonal neuropathy Axonal neuropathy Giant axonal neuropathy Hypertrophic neuropathy Tomaculous neuropathy

Teased Nerve Fibers Row of myelin-ovoids Paranodal widening Segmental demyelination Remyelinated segment Sausage-like thickening of myelin

Axonal degeneration Early demyelination Active demyelination Remyelination* Tomacula

Axonal neuropathy Demyelinating neuropathy Demyelinating neuropathy Demyelinating neuropathya Tomaculous neuropathy

a

Exception is axonal regeneration.

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See above — paraffin sections

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H & E Stain

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Myelin-digestion chamber Sausage-like thickening of myelin Swollen axon Onion-bulb formation

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TABLE 13.1 continued

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the qualitative assessment of the population of myelinated fibers, but it should not be used to evaluate segmental demyelination. Congo-red staining can identify amyloid for obvious reasons. In cases where amyloid neuropathy is suspected, as many sections as possible must be cut and stained because amyloid may be present in only a few sections. The second step is to evaluate the frozen sections. In the UAB muscle and nerve histopathology laboratory, frozen sections are stained with H & E, modified trichrome, cresyl-fast violet, PAS, and Congo-red stains. The frozen section is the best technique for recognizing axonal degeneration (Table 13.2). Anatomic structures are much better preserved on frozen sections than on paraffin sections. However, straightening the nerve in the longitudinal cut is not easy, even on frozen sections. Among the available sections, the frozen section provides the best technique for the evaluation of pathology in the longitudinal cut. The cardinal stain on frozen sections is the modified trichrome stain, which can clearly assess the population of myelinated fibers. This is also the best stain for recognizing myelin-digestion chambers, which are easily distinguished on the longitudinal cuts. Tomacula, giant axons, and polyglucosan bodies can readily be identified by the modified trichrome stain. OBFs are also recognizable by their red-tinged myelin surrounded by Schwann cell nuclei and fine Schwann cell proliferation. Selective nerve fascicular degeneration and central fascicular degeneration, two indices of ischemia, are also easily identifiable. Paranodal widening can be seen in the longitudinal cuts. This is recognized when the retraction of myelin occurs from the node of Ranvier with widening of the nodal gap. The axon retains its continuity across the gap in the myelin sheath. However, the recognition of segmental demyelination (myelin loss through the entire internode) is possible only when two nerve fibers are cut on the same plane and stretched straight long enough to show the entire internodal segment. Cresyl-fast violet staining on frozen sections is the only reliable staining technique for identification of a metachromatic substance. If metachromatic leukodystrophy is suspected prior to the surgery, one specimen should be submitted for frozen section examination; otherwise, the nerve biopsy is useless for this purpose. H & E stain reveals inflammatory cell infiltration, granuloma, and Schwann cells. However, frozen sections do not show the cellular details, which can only be assessed by the paraffin sections. PAS staining can easily show polyglucosan bodies. The Congo-red stain has an advantage over the crystal-violet stain in identifying amyloid in that the former can reveal the bright apple-green birefringence of amyloid as distinguished from the white birefringence of collagen on Polaroid film. We routinely perform the Congo-red stain on frozen sections to confirm the diagnosis of amyloidosis. Sometimes, when amyloid is missed on the paraffin section because of a poor staining technique, it can be picked up by the Congo-red stain on the frozen sections. The third step is to evaluate the semithin sections. The semithin section has been well established as the major staining technique in the pathology of peripheral nerves and the best technique for recognizing demyelinating neuropathy. It is the surest method of assessing the population of myelinated fibers and, consequently, the loss of myelinated fibers, including that of selective-diameter fibers, such as large- or small-diameter fibers. Although severe loss of myelinated fibers is easily recognized, a minor depletion of myelinated fibers may not be clearly visible. Appreciating a minor loss of myelinated fibers requires familiarity with the normal for a given age, because a mild degree of myelinated fiber loss accompanies normal aging. The semithin section is the only reliable technique for the identification of extremely thin myelin sheaths in relation to axon size, a hallmark of remyelination (thus, previous demyelination), and denuded axons, a hallmark of demyelination. Recognition of denuded axons (demyelination) is more difficult, even on the semithin section. Normally, nonmyelinated nerve fibers do not exceed 3 µ in diameter, and most fibers are between 0.5 and 2.0 µ.2 If an axon is larger than 3 µ and lacks a myelin sheath, it is safe to interpret it as a demyelinating fiber. The distinction between primary demyelination, as seen in primary demyelinating neuropathies, and secondary demyelination, as seen in axonal degeneration, may be impossible given a single level of nerve to evaluate. If obvious ongoing axonal degeneration is recognized on the other sections, one ©2002 CRC Press LLC

Onion-bulb formation Onion-bulb formation Thinly myelinated fibers

Myelin-digestion chambers Giant axon Ghost fiber (no axon or myelin) MDC in the longitudinal section

Paranodal widening Tomacula Onion-bulb formation

Semithin Section

Clusters of tiny thinly myelinated fiber Giant axon Myelin break-down Myelin-ovoids Ghost fiber (no axon or myelin)

Thinly myelinated fiber (remyelination) Tomacula Onion-bulb formation Denuded axon (demyelination)

Teased Nerve Fiber

Row of myelin-ovoids Giant axon

Paranodal demyelination Segmental demyelination Remyelination Tomacula

Frozen Section Modified trichrome

H & E stain

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Myelin-digestion chambers (MDC)

Paraffin Section Modified trichrome Kulschitzky’s stain

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Segmental Demyelination

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Axonal Degeneration

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TABLE 13.2 Pathological Features in Axonal Degeneration and Segmental Demyelination

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has to assume that a few demyelinated fibers are secondary to severe axonal degeneration. The finding of a fairly normal density of myelinated fibers with markedly thin myelinated sheaths can be diagnosed with confidence as demyelinating neuropathy. Giant axons, tomacula, and polyglucosan bodies can easily be recognized on the semithin sections. OBFs are best assessed in the transverse cut on the semithin section and, in fact, most OBFs are recognized by this technique. Macrophage-mediated demyelination can rarely be recognized with confidence on the semithin section, and usually requires ultrastructural EM studies. Active myelin breakdown, a hallmark of axonal degeneration, is obvious on the semithin section. However, the recognition of myelin ovoids can be tricky on the semithin section because crush artifact can mimic myelin ovoids. The semithin section is the only reliable way to recognize axonal sprouting, the presence of clusters of two to several tiny, thinly myelinated fibers, which is the diagnostic hallmark of chronic axonal degeneration. The teasing technique is the best method for recognizing mild demyelination and axonal degeneration. Most cases do not require the teasing technique. To analyze teased fibers, at least 100 fibers must be evaluated, a process requiring 4 to 5 hours. Values obtained should be compared with the normal values in order to avoid any bias in assessing the abnormality of teased fibers. On the other hand, fiber teasing can identify axonal degeneration or demyelinating neuropathy, but it cannot shed any light on a specific etiology. Thus, the teased nerve fiber technique is useful only in limited cases where the nature of the neuropathy cannot be decided by other studies. The best known scheme for the classification of teased nerve fibers is based on nine categories described by Dyck et al.3 A. Teased nerve fibers with normal appearance; myelin is regular except in paranodal regions. Myelin thickness at the internode with the thinnest myelin is 50% or more of that at the internode with the thickest myelin. B. Teased nerve fibers with excessive irregularity, wrinkling, and folding of myelin that are not due to preparatory artifact. C. Teased nerve fibers with one or more regions of paranodal or internodal segmental demyelination with relatively normal myelin thickness; paranodal demyelination (widening) is defined when the site of the node of Ranvier is recognized and the nodal gap is increased beyond that seen in normal fibers. Internodal demyelination is defined when a part or the entire former internode is demyelinated. D. Teased nerve fibers with one or more regions of paranodal or internodal segmental demyelination with decreased myelin thickness. E. Teased strands of nerve tissue with linear rows of myelin ovoids and balls at the same stage of degeneration. F. Teased fibers without regions of segmental demyelination but with excessive variability of myelin thickness between internodes. G. Teased fibers without regions of segmental demyelination but with excessive variability of myelin thickness within internodes and the formation of “globules” or “sausages.” H. Teased fibers of normal appearance as described in A. above, but in which there are myelin ovoids or balls contiguous to two or more internodes; this condition clearly implies regeneration of myelinated fibers. I. Teased fibers having several proximal internodes or parts of internodes with or without paranodal or internodal segmental demyelination and, distal to these, a linear row of myelin ovoids or balls; this type of fiber change is typically seen several days after and at the site of crush. After repair has occurred, this nerve will show internodal remyelination.

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According to Dyck’s classification, teased fibers are considered normal when A and B above, are the predominant findings. Teased fibers are considered to show axonal degeneration when E and H are the predominant findings and to reveal demyelination when C, D, F, and G are the predominant findings. Dyck’s classification has two advantages4: (1) emphasis is placed on variation of myelin sheath characteristics within individual nerve fibers rather than on absolute criteria for internodal length or diameter, and (2) categories are identified by letters rather than more descriptive terms. Although this classification is good, particularly for the purpose of unbiased interpretation, the lettered categories are not easily understood in practice. Recently, Kalichman et al. proposed a simpler and more practical classification and evaluated the inter-reader variability of the interpretation of teased nerve fibers.4 Among 10 readers, including 6 who did not have any prior experience looking at teased fibers, there were high rates of true-positive (56–85%) classification and low rates of false-positive (3–18%) classification. As the minimal technical requirement for adequate interpretation of teased fibers, Kalichman et al. proposed that fibers must be sufficiently osmicated to distinguish the nodes of Ranvier, must span at least four nodes (three internodes), and must not be intertwined with other fibers. According to Kalichman et al.’s system, there is no category for demyelination with tomaculous change, regeneration, or proximal demyelination with distal axonal degeneration.6 In regard to regeneration fibers, they did not include this category because the probability of identifying regeneration in a given fiber depends on the fortuitous inclusion of both intact proximal internodes and regenerating distal internodes. In theory, regeneration can be identified in a teased fiber by the presence of at least one internode followed by an interrupted series of short and more thinly myelinated internodes. At UAB, we tease at leat 50 nerve fibers and use a much simpler 3-category system — normal, axonal degeneration, and demyelination (Table 13.3) — and compare the patient’s values with normal values in the literature: axonal degeneration, less than 8% of teased nerve fibers,7 and demyelination, less than 10% of teased nerve fibers for under 45-year-old individuals and 24% for over 45-years-old. More detailed information regarding normal values for the different age groups is available in Dyck’s book.3 Axonal degeneration includes active axonal degeneration and regeneration. Demyelination includes paranodal demyelination, segmental demyelination, and remyelination. As the minimal technical requirements, fibers must be sufficiently osmicated to distinguish the nodes of Ranvier and to recognize segmental demyelination or hypomyelination, and fibers must be long enough to clearly demonstrate segmental demyelination or remyelination. In our classification, there is no requirement as to the number of nodes, because, in practice, it is not always possible to have three internodes in a teased nerve. Our criteria for axonal degeneration, paranodal demyelination, segmental demyelination, and remyelination are essentially the same as the criteria given by Kalichman et al.4 (Figures 13.1–13.3). In our system, hypomyelination is classified as segmental demyelination because it is often impossible to distinguish complete demyelination from partial demyelination (hypomyelination). In our system, “remyelination” requires a further additional finding to be meaningful because it can be seen following demyelination or regeneration (axonal sprouting) from axonal degeneration. “Remyelination” with normal myelin thickness alone represents a well-healed process and may represent a full remyelination following demyelination. However, we interpret this as a borderline abnormality because we found this in many otherwise normal nerves. In “remyelination“ with decreased myelin thickness, the additional findings are required to make it meaningful. When it is observed together with clusters of two to several tiny, thinly myelinated fibers in semithin sections, the diagnostic hallmark of chronic axonal degeneration, this should be interpreted as axonal regeneration and, thus, axonal degeneration. Depending on the clinical features, special stains or sections are required to reach a definite diagnosis. These include immunohistochemistry, immunofluorescence, immunotyping, and special stains such as the common leucocyte antigen stain. These are discussed in appropriate chapters throughout this book. As a general rule, electron microscopy serves only to confirm abnormalities

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Segmental demyelination

Wider than normal paranodal gap (compared with same size fiber) or thinly myelinated paranodal gap (thickness < 50% of the rest of the internode); in either case, the region of decreased myelination should be at least twice the nodal axonal diameter. 1. Absence of myelin along part of or an entire internode, regardless of internodal length, with preservation of the axon (no myelin sheath visible with the high-dry objective: fragments of myelin may be seen along the internode).a 2. Thinly myelinated internode of normal length (myelin thickness < 50% of neighboring internodes and internodal length ≥ 60% of the longest internode)a 3. 1 or 2, but with the formation of “globules” or “sausages” or “remyelination” Segmental demyelination, but with the formation of “globules” or “sausages” At least one abnormally short internode (length < 60% of longest internode); myelin thickness is decreased. Additional segmental or paranodal demyelination has to be present with remyelination Additional “clusters of two-to-several tiny thnly myelinated fibers” in the semithin sections have to be present with remyelination

Modified from Kalichman’s classification. No. 1 criterion in segmental demyelination is classified as demyelination in Kalichman’s classification, and no. 2 criterion in segmental demyelination is classified as hypomyelination in Kalichman’s classification.

a

b

Normal values: for axonal degeneration, < 8% for all ages; for demyelination, <10% for age < 45 years and < 24% for age > 45 years.3

c

Remyelination with normal thickness alone is borderline finding.

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Tomaculous change Remyelinationc Demyelination Regeneration

Fragmentation of myelinated fiber into myelin ovoids and balls; cluster of at least three balls or ovoids along the axis of the degenerated axon is required. See below

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Regeneration Demyelinationb Paranodal demyelination

Normal myelinated fiber without any abnormality described below or any artifact

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Normal Axonal degenerationb Active axonal degeneration

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TABLE 13.3 Definitions of Teased Nerve Fiber Categories at the University of Alabama at Birminghama

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FIGURE 13.1 Light micrographs of teased fibers classified as normal and undergoing axonal degeneration. Sequential, overlapping photographs of each fiber are displayed left to right and top to bottom. (A) Intact myelin sheath and similar internodal lengths in the normal fibers. Nodes are identified by arrowheads. (B) Early axonal degeneration in which the myelin sheath has collapsed, forming balls and ovoids. (C) Axonal degeneration is illustrated at a later stage in which only a few ovoids and balls can be seen (arrowheads). Bar = 100 µm. (With permission of Kalichman, M.W., Chalk, C.H., and Mizisin, A.P., J. Peripheral Nerv. Syst., 4, 237, 1999.)

FIGURE 13.2 Light micrographs of teased fibers illustrating demyelination and hypomyelination. (A) Low and high power images of fiber undergoing segmental demyelination. The region outlined at low power is shown at higher magnification and illustrates a portion of an internode with macrophages (arrowheads) containing myelin debris adjacent to a region lacking an intact myelin sheath. (B) In an example of hypomyelination, note that nodes (arrowheads) demarcate internodes of similar length, but that at least two sequential internodes have considerably less myelin than those above and below. Bar = 100 µm (= 30 µm for high power image illustrating demyelination). (With permission of Kalichman, M.W., Chalk, C.H., and Mizisin, A.P. J. Peripheral Nerv. Syst., 4, 238, 1999.)

FIGURE 13.3 Examples of remyelination and paranodal demyelination. (A) Following two long internodes, a sequence of at least five short, thinly myelinated internodes is consistent with remyelination. Nodes are identified with arrowheads. (B) and (C) Low- and highpower micrographs illustrate two examples of paranodal demyelination, in which paranodal myelin has thinned and/or retracted, leaving abnormally widened nodes. The outlined regions of the abnormal nodes are shown at high magnification. Thin myelination of the axon in 3C may be the result of remylination following paranodal demyelination, possibly resulting in an intercalated internode. Bars = 100 µm (= 30 µm for high power images illustrating abnormal paranodal myelination). (With permission of Kalichman, M.W., Chalk, C.H., and Mizisin, A.P., J. Peripheral Nerv. Syst., 4,239, 1999.)

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observed in semithin sections.5 An exception is those diseases involving unmyelinated fibers, because unmyelinated fibers can be accurately identified only by ultrastructural EM testing. The ultrastructural EM study is needed in some neuropathies, as described in Table 3.2. Once all the sections and slides are reviewed, the pathologist has to make every effort to arrive at a definite diagnosis on the basis of his interpretation. Specific features can lead the pathologist to a specific diagnosis; this was achieved in only 24% of the cases in our series.6 If a specific diagnosis is not possible, the pathologist can, at least, differentiate between the diagnoses of demyelinating and axonal neuropathy, as was achieved in 55% of cases in our series. At any rate, the pathologist must incorporate clinical and laboratory information in his/her effort to reach a final pathological diagnosis.

REFERENCES 1. 2. 3. 4. 5. 6.

Asbury, A.K. and Johnson, P.C., Pathology of Peripheral Nerve, W.B. Saunders, Philadelphia, PA, 1978. Ochoa, J. and Mair, W.G.P., The normal sural nerve in man. 1. Ultrastructure and numbers of fibers and cells, Acta Neuropathl. 13, 197, 1969. Dyck, P.J., Pathologic alterations of the peripheral nervous system of humans, in Peripheral Neuropathy, Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R., Eds., W.B. Saunders, Philadelphia, PA, 1985, 818. Kalichman, M.W., Chalk, C.H., and Mizisin, A.P., Classification of teased nerve fibers for multicenter clinical trials, J. Peripheral Nerv. Syst., 4, 233, 1999. Said, G., Indications and value of nerve biopsy, Muscle and Nerve, 22, 1617, 1999. Oh, S.J., Diagnostic usefulness and limitations of the sural nerve biopsy, Yonsei Med. J., 31, 1, 1990.

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