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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.
1676 FM Final 07/13/2001 7:54 AM Page iv
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 per-
mission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reli-
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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, includ-
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Visit the CRC Press Web site at www.crcpress.com
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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
1676 FM Final 07/13/2001 7:54 AM Page v
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.
2000 CRC Press LLC

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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 neu-
ropathology. 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 pathol-
ogy 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 prac-
ticing pathologist, neuropathologist, and neuromuscular disease specialist will find it an invaluable
companion in his or her daily practice.
2000 CRC Press LLC

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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 pathol-
ogy 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 estab-
lished 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, LambertEaton 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 GuillainBarr 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 limita-
tion 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
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 1m) 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
ChurgStrauss Syndrome (Allergic Granulomatosis)
Wegeners Granulomatosis
Temporal (Giant Cell) Arteritis
Vasculitis Associated with Connective Tissue Diseases
Rheumatoid Arthritis
Systemic Lupus Erythematosus (SLE)
Sjgrens 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: GuillainBarr Syndrome?
Case 9: Progressive Multifocal Motor and Sensory Deficits over 3 Months
References
Chapter 7
Inflammatory Demyelinating Neuropathy
Pathogenesis of Inflammatory Demyelinating Neuropathies
GuillainBarr 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 Waldenstrms 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
Fabrys 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
RoussyLevy Syndrome)
RoussyLevy Syndrome
Sex-Linked CMT
HMSN Type II (Neuronal Type of CMT; CMT 2)
HMSN Type III (DejerineSottas 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 DennyBrown; 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)
Friedreichs 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
Workers 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
EosinophiliaMyalgia 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: GuillianBarr Syndrome Following Ingestion of an Unknown
Amount of Antifreeze
References
Chapter 13
Interpretation of Nerve Biopsy
References
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Chapter 1 Final Proof 07/13/2001 7:56 AM Page 1
1 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 periph-
eral 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 dis-
ease. 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 improve-
ment 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 meta-
bolic products are transported as axoplasm at different velocities in both directions.1 This system ren-
ders 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 lam-
ina. 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 remyeli-
nation before resuming normal impulse conduction.4
Depending on which component of the peripheral nerve is predominantly involved in the patho-
logical process, peripheral neuropathy can be classified into two main categories: axonal degenera-
tion and segmental demyelination (Table 1.1). There are also clear pathophysiological differences
between axonal degeneration and segmental demyelination, as noted in Table 1.1.
2002 CRC Press LLC

TABLE 1.1
Pathophysiology of Two Types of Peripheral Neuropathy
Type Axonal Neuropathy Demyelinating Neuropathy
Primary lesion Axon Myelin

Pathological process Axonal degeneration Demyelination
Pathology by teasing Myelin ovoids Segmental demyelination
preparation
Regeneration:
mechanism Axonal sprouting Remyelination
speed Slow Rapid
Nerve conduction:
velocity Mildly slow: Markedly slow:
above 30 m/sec below 30 m/sec
CMAP: Low amplitude Dispersion:
conduction block
Needle EMG:
Fibrillation and (++++) (-) or ()
positive sharp wave
Fasciculation Absent Present in chronic form
Examples: Arsenic, thallium, gold GuillainBarr syndrome
Alcoholic CIDP
Nutritional Hypertrophic
Vasculitic Metachromatic
Giant axonal Tomaculous
Porphyric neuropathy Leprosy
Vitamin B12 Multifocal motor neuropathy
Diabetic neuropathy Diphtheric
Uremic neuropathy CharcotMarieTooth 1 A
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 seg-
mental 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 mecha-
nisms: (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 meta-
bolic 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 degen-
eration are as follows:
It results from transection of an axon.

Paralysis and anesthesia in the distribution of the nerve are immediate, due to the conduc-
tion 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 inex-
citable.
Distal muscles undergo denervation atrophy.
Prominent fibrillation and positive sharp waves occur in distal muscles in 814 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, per-
ineurium, and epineurium) when the neural tube is intact, regeneration occurs sponta-
neously and is of excellent quality; (2) the proximodistal 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.
2002 CRC Press LLC

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 vasculi-
tides, the nerve fiber damage results from local ischemia severe enough to produce focal axonal dam-
age 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-diame-
ter 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 appropri-
ate 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).
2002 CRC Press LLC

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 mani-
festations 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 CharcotMarieTooth 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 gan-
glia diseases, normal motor nerve conduction and markedly abnormal sensory nerve con-
duction (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 proprio-
ception 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, recov-
ery 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 neu-
ropathies12,13 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 seg-
mental demyelination. In the GuillainBarr 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 Wallers classic description of axonal degeneration, Gombault16 described seg-
mental 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 galac-
tocerebroside neuropathy; and (4) peeling and engulfment of myelin by activated lympho-
cytes and macrophages, as noted in the GuillainBarr 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 com-
plete 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 Friedreichs
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 distribu-
tion of segmental demyelination, secondary demyelination is characterized by segmental demyelina-
tion 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 GuillainBarr syn-
drome (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 unde-
termined 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 differen-
tiation between axonal neuropathy and demyelinating neuropathy; (2) classification of inflammatory
neuropathies such as GBS as a known cause; (3) monoclonal neuropathy and paraneoplastic neu-
ropathy 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 mononeu-
ropathy. 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 Unknown Comments
Number Cause (%)
Mathews 46 70 GBS is listed as an unknown cause.
(1956)
Rose 80 56 GBS is listed as a known cause.

(1960)
Prineas 278 14 GBS is listed as a known cause.

(1970)
Dyck 205 24 Inflammatory neuropathy is listed

(1981) as a known cause.
Fagius 91 74 Chronic inflammatory or hereditary

(1983) neuropathies are listed as unknown causes.
McLeod 519 13 Inflammatory neuropathy is listed

(1984) as a known cause. All cases had sural nerve biopsy.
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 mel-
litus or uremia), and toxic neuropathy. Sensory polyneuropathy suggests a benign idiopathic sensory
neuropathy, neuropathy related to diabetes or pernicious anemia, chronic sensory demyelinating neu-
ropathy, and arsenic neuropathy. Sensory ataxic neuropathy is classically seen in paraneoplastic
polyneuropathy or Sjgrens neuropathy. Motor polyneuropathy suggests GuillainBarr 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 fre-
quently involve the facial nerves. Respiratory muscle weakness is rare but is one of the most dread-
ful 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 ophthal-
moplegic 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 motor-
sensory 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 neu-
ropathy 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 effer-
ent 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 neu-
ropathy 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 usu-
ally 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 com-
mon in leprosy, diabetes, and amyloidosis.
AUTONOMIC NERVE DYSFUNCTION

As subtle signs of autonomic nerve dysfunction, skin discoloration and hair loss are common find-
ings in peripheral neuropathy. When autonomic nerve dysfunction is severe, the most common com-
plaint 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-void-
ing 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 paral-
ysis of the gut muscles.
DIAGNOSTIC INVESTIGATIONS
The first diagnostic step is to rule out other lower motor neuron diseases which can mimic periph-
eral 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 Peripheral Neuromuscular Muscle
Horn Cell Nerves Junctions
Involved Widespread Distal Proximal/ Proximal

area oculobulbar
Motor or sensory Motor Mixed Motor Motor

impairment
Reflexes Weak/absent Weak/absent Normal Normal
Other helpful Fasciculation Myasthenic

signs symptoms
Disease Amyotrophic Peripheral Myasthenia Myopathy

lateral neuropathy gravis
sclerosis
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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 neu-
rologist.
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 neu-
ropathies have an acute (within a month) or subacute (13 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 sys-
temic 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 work-
up 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, spe-
cific 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 CharcotMarieTooth 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, rheuma-
toid diseases, hypothyroidism, or other autoimmune diseases) that could be the cause of the periph-
eral 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 thal-
lium poisoning.
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TABLE 1.4
Helpful Tips in Etiological Diagnosis of Peripheral Neuropathy
Family history, pes cavus, CharcotMarieTooth disease

stork-leg
Relapse Chronic inflammatory demyelinating neuropathy, HNPP
Acute GuillainBarr syndrome, acute intermittent porphyria
Alopecia, predominantly sensory neuropathy Thallium neuropathy
Painful ophthalmoplegia with Diabetes mellitus
sparing of pupil
Gum lead line, wrist drop Lead neuropathy
Anesthesic depigmented skin Leprosy
Angiokeratoma, sensory neuropathy Fabrys disease
Mees line, predominantly sensory neuropathy, Arsenic neuropathy
hyperkeratosis of skin
Femoral neuropathy Diabetes mellitus
Palpable thick nerves Leprosy, CharcotMarieTooth disease 1A
DejerinneSottas disease
Charcot joint Diabetes mellitus, leprosy
Trophic ulcer, insensitivity to Diabetes mellitus, amyloidosis, leprosy, hereditary sensory
pain neuropathy
Dysautonomia Diabetes mellitus, amyloidosis
Kaposi sarcoma AIDS neuropathy
lymphadenopathy
Erythema chronicum migrans, Lyme disease
facial palsy
Painful small-fiber neuropathy Diabetes, alcoholism, AIDS, amyloid
benign chronic sensory neuropathy
Proximal muscle weakness GuillainBarr 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 neuropa-
thy, 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 includ-
ing 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 periph-
eral 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 sensi-
tive 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 ante-
rior 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 GuillainBarr 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 con-
duction velocity (NCV). On the other hand, the hallmark of nerve conduction abnormalities in
demyelinating neuropathy are conduction block, abnormal temporal dispersion (dispersion phenom-
enon), 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 neu-
ropathy, 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 neu-
ropathies, 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 heredi-
tary motor and sensory neuropathy I (hypertrophic type of the CharcotMarieTooth (CMT) disease).
A B
ankle ankle
1000 v
5 msec 500 v
5 msec
knee knee
C D
2 v 2 v
3 msec 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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A 8.5
B 20
100 v
5 msec
FIGURE 1.5 CMAP in demyelinating neuropathy. CMAP in segmental demyelination. This is from the pos-
terior 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 A
-
1000v
+
5 msec
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 ampli-
tude 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.)
2002 CRC Press LLC

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 demyelina-
tion. 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) den-
ervation, 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 first-
line 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 defi-
ciency, 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 evalua-
tion is essential for the diagnosis of GBS, CIDP, and a few other neuropathies. An elevated total pro-
tein 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 reac-
tion 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 Diagnostic Possibilities
First-Line Tests
CBC, sedimentation rate Collagen disease, leukemia, vasculitis
Renal and liver functions Uremic and hepatic neuropathy
Rheumatoid profiles Collagen disease, vasculitis
Blood sugar, fasting 2 hour Diabetes
post-brandial; HbA1C
Serum B12 and folate level Neuropathy with macrocytosis
Thyroid functions Hypothyroid neuropathy
Immunoelectrophoresis of Dysproteinemia, monoclonal gammopathy
serum protein by immunofixation test lymphoma, amyloidosis
Second-Line Tests
Porphobilinogen in urine Acute porphyria
Heavy metals in urine Lead, arsenic, thallium, mercury
Arsenic in hair and nails Arsenic neuropathy
Hepatitis B antigen Polyarteritis nodosa
Schilling test Vitamin B12 deficiency
Antineutrophile cytoplasmic antibody Wegeners granulomatosis
Chest x-ray, cancer survey Carcinomatous neuropathy
High CSF protein GuillainBarr syndrome, chronic
inflammatory demyelinating polyneuropathy
Increase cell in CSF Lyme disease, AIDS, paraneoplastic neuropathy
Serum HIV antibody AIDS neuropathy
Serum Borrelia burgdorferi Lyme disease
antibody
Metastatic bone survey Sclerotic multiple myeloma
Anti-Hu antibody Paraneoplastic neuropathy
GM1 and MAG antibody Autoimmune neuropathy
CMT1A DNA duplication test CMT1A neuropathy
HNPP DNA deletion test HNPP
Source: Reproduced with permission from Oh, S.J., Clinical Electromyography: Case Studies, Williams & Wilkins,
Baltimore, MD, 1998.
2002 CRC Press LLC

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11. 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.
12. Asbury, A.K., Arnason, B.G., and Adams, R.D., The inflammatory lesion in idiopathic polyneuritis,
Medicine, 48, 173, 1969.
13. Dyck, P.J. et al., Chronic inflammatory polyradiculoneuropathy, Mayo Clin. Proc., 50, 621, 1975.
14. Bradley, W.G. and Jennekens, F.G.I., Axonal degeneration in diphtheric neuroapthy, J. Neurol. Sci., 13, 415,
1971.
15. Oh, S.J., Clinical Electromyography: Nerve Conduction Studies, 2nd ed., Williams & Wilkins, Baltimore,
MD, 1993.
16. Gombault, A., Contribution ltude anatomique de la nvrite paraenchymateuse subaigu et chronique
nvrite segmentaire pri-axile, Arch. Neurol., (French), 1, 11, 1880.
17. Dyck, P.J., Johnson, W.J., Lambert, E.H., and OBrien, P.C., Segmental demyelination secondary to axonal
degeneration in uremic neuropathy, Mayo Clin. Proc., 46, 400, 1971.
18. Dyck, P.J. and Lais, A.C., Evidence for segmental demyelination secondary to axonal degeneration in
Friedreichs ataxia, in Clinical Studies in Myology, Kakulas, B.K., Ed., Excerpta Medica, Amsterdam, 253,
1973.
19. Dyck, P.J., Oviatt, K.F., and Lambert, E.H., Intensive evaluation of referred unclassified neuropathies yields
improved diagnosis, Ann. Neurol., 10, 222, 1981.
20. 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.)
2 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 patients 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 asympto-
matic patients and because vasculitis was invariably found in the sural nerve when the nerve con-
duction 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
Oh Midroni Schrder
(N = 385) (N = 267) (N = 5266)
Specific diagnoses 92 (24%) 43 (16%) 1200 (23 %)
Vasculitic neuropathy 46 (12%) 20 (7.5%) 769 (15%)
Hypertrophic neuropathy 27 (7%) 124 (2.3%)
Inflammatory neuropathy 12 (3%) 4 (1.6%) 116 (2%) a
Ischemic neuropathy 3 (0.8%)
Amyloid neuropathy 2 (0.5%) 4 (1.6%) 47 (0.9%)
Metachromatic neuropathy 1 (0.3%) 22 (0.2%)
Sarcoid neuropapthy 1 (0.3%) 2 (0.8%)
Leprosy 1 (0.4%)
Lymphoma 2 (0.8%)
Fabrys disease 1 (0.4%) 4
Tomaculous neuropathy 3 (1.2%) 118 (2%)
Amidarone 3 (1.2%)
Chronic inflammatory 46 (12%) 51 (19%) 830 (16%) b
demyelinating polyneuropathy
Hereditary neuropathy 35 (9%) 12 (4.5%) 273 (5%)
Total 173 (45%) 106 (40%) 2303 (44%)
a
GBS. b Demyelinating neuropathy. This is not necessarily CIDP.
2002 CRC Press LLC

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 sig-
nificant 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 (19711986),
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 CharcotMarieTooth (CMT) 1A and hereditary neuropathy with liability to pres-
sure 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 dyses-
thesia.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
Oh Midroni Schrder
(N = 385) (N = 267) (N = 5266)
Specific diagnosis 92 (24%) 43 (16%) 1200 (23%)
Demyelinating neuropathy 132 (32%) 830 (44%)
Axonal neuropathies 89 (23%) 1572 (30%)
Nonspecific findings 62 (16%)
Normal 19 (5%) 27 (10%)
2002 CRC Press LLC

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 per-
oneal 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 conduc-
tion 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% lido-
caine 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 def-
inite 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 con-
trast 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 pre-
vent 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 proxi-
mal 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 uncom-
mon, 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 vas-
culitic neuropathy or chronic inflammatory demyelinating polyneuropathy immediately after the
biopsy, contributing to delayed wound healing. Midroni and Bilbaro reported 2 patients who had sig-
nificant 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 biop-
sies. 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 fol-
lowing 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, usu-
ally along the lateral edge of the fascia. In practice, the superficial peroneal nerve is not readily iden-
tifiable 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 oper-
ative 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 neu-
ropathy.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. Wees, S.J., Sunwoo, I.N. and Oh, S.J., Sural nerve biopsy in systemic necrotizing vasculitis, Am. J. Med.,
71, 525, 1981.
2. Frohnert, P.P. and Sheps, S.G., Long-term follow-up study of periarteritis nodosa, Am. J. Med., 43, 8, 1967.
3. Cohen, R.D., Conn, D.L., and Ilstrup, D.M., Clinical features, prognosis, and response to treatment in pol-
yarteritis, Mayo Clin. Proc., 55,1 46, 1980.
4. Claussen, G.C., Thomas, D., Coyne, C., Vsques, LG., and Oh, S.J., Diagnostic value of nerve and muscle
biopsy in suspected vasculitis cases, J. Clin. Neuromuscular, 1, 117, 2000.
5. Oh, S.J., Diagnostic usefulness and limitations of the seural nerve biopsy, Yonsei Med. J., 31(1), 1, 1990.
6. Schrder, M., Recommendations for the examination of peripheral nerve biopsies, Virchos Arch., 432, 199,
1998.
7. Argov, X., Steiner, I., and Soffer, D., The yield of sural nerve biopsy in the evaluation of peripheral neu-
ropathies, Acta Neurol. Scand., 79, 243, 1989.
8. Neundrfer, B., Grahmann, F., Engelhart, A., and Harte, U., Postoperative effects and values of sural nerve
biopsies: a retrospective study, Eur. Neurol., 30, 350, 1990.
9. Fauci, A.S., Katz, P., Haynes, B.F., and Wolff, S.M., Cyclophosphamide therapy of severe systemic necro-
tizing vasculitis, New Eng. J. Med., 301, 235, 1979.
10. Oh, S.J., Subacute demyelinating polyneuropathy responding to croticosteroid treatment, Arch. Neurol., 35,
509, 1978.
11. Said, G., Indications and value of nerve biopsy, Muscle and Nerve, 22(12), 1617, 1999.
12. Midroni, G. and Bilbaro, J.M., Biopsy Diagnosis of Peripheral Neuropathy, Butterworth-Heinemann,
Boston, MA, 1995.
13. Gabriel, C.M. et al., Prospective study of the usefulness of sural nerve biopsy, J. Neurol. Neurosurg.
Psychiatry, 69, 442, 2000.
14. Dyck, P.J. and Lofgren, E.P., Nerve biopsy. Choice of nerve, method, symptoms and usefulness, Med. Clin.
North Am., 52, 885, 1968.
15. Pollock, M., Nukada, H., Taylor, P., Donaldson, I., and Carrol, G., Comparison between fascicular and
whole sural nerve biopsy, Ann. Neurol., 13, 65, 1983.
17. Oh, S.J., Clinical Electromyography, Nerve Conduction Studies, 2nd Ed., Williams & Wilkins, Baltimore,
MD, 1993.
18. 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.
19. Asbury, A.K. and Connolly, E.S., Sural nerve biopsy: technical note, J. Neurosurg., 38, 391, 1973.
20. Johnson, P.C., Diagnostic peripheral nerve biopsy, Barrow Neurological Institute Q., 1, 2, 1985.
21. Perry, J.R. and Bril, V., Complications of sural nerve biopsy in diabetic versus non-diabetic patients, Can.
J. Neurol. Sci., 21, 34, 1994.
22. Solders, G., Discomfort after fascicular sural nerve biopsy, Acta Neurol. Scand., 77, 503, 1988.
23. 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.
24. 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.
25. Said, G., Lacroix-Ciaudo, C., Fujimura, H., Blas, C., and Faux, N., The peripheral neuropathy of necrotiz-
ing arteritis: a clinicopathological study, Ann. Neurol., 23, 461, 1988.
26. Kissel, J.T. and Mendell, J.R., Vasculitic neuropathy, Neurol. Clin., 10(3), 761, 1992.
2002 CRC Press LLC

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.)
3 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 impor-
tant 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 distrib-
ution 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 -180C in liquid nitrogen for 15 sec-
onds. 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 sec-
tions 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 1.5 4 cm
Neutral-buffered formalin 4% glutaraldehyde Isopentane in -180C liquid N

2
Paraffin section Semithin section Frozen section

Teasing Thin section for EM
H&E Toluidine blue or H&E

Modified trichrome Toluidine blue and basic Modified trichrome
Congo-red fuchsin PASH
Congo-red
Cresyl-fast-violet
FIGURE 3.1 Treatment of nerve biopsy specimens.
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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 stud-
ied with paraffin sections stained with Kulschistkys 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 axonmyelin relationship, for identifying
onion-bulb formations and clustering of regenerated fibers, and for calculating the density of myeli-
nated fibers (Table 3.1). The semithin EM section is also the only reasonably sure means of detect-
ing thinly myelinated fibers (remyelination).
Nerve fiber teasing is superior for documenting segmental demyelination and also allows recog-
nition 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 diam-
eter. Teasing is not practical because of the time-consuming nature of the technique. However, teas-
ing 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 unmyeli-
nated fibers has been identified by such studies in amyloid neuropathy, Fabrys 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 Krabbes disease, BatternKufs disease, adrenoleucodystrophy,
Farbers disease, Tangiers disease, or NiemannPick disease, the EM study shows the distinct ultra-
structural features of storage inclusion which are helpful in diagnosing such diseases.7,8 There are sev-
eral 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
2002 CRC Press LLC

TABLE 3.1
Advantages and Disadvantages of Tissue Sections
Section Type Advantage Disadvantage
Frozen section Rapid diagnosis Details of cells are not clear
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 Artifact is unavoidable
Semithin section Population of myelinated fiber Details of cells are not clear
Detection of thinly myelinated fibers
Detection of clustering of regenerated fibers
Detection of onion-bulb formation
Axonmyelin relationship
EM section The only test for the unmyelinated fibers Special training
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 Too much time
axonal neuropathy vs. demyelinating neuropathy
TABLE 3.2
Diagnosis by the Ultrastructural EM Study
Pathological Features Diagnosis
Loss of unmyelinated fibers Small-fiber neuropathya
Macrophage mediated demyelination Inflammatory demyelinating neuropathy
Widely spaced myelin (WSM) MAG/IgM neuropathy
Uncompacted myelin lamella (UML) POEMS neuropathy
Schwann cell inclusions and demyelination
Tuffstone inclusions Metachromatic leucodystrophy
Needle-like inclusion of GLDb Krabbes disease
Lipid inclusions Nieman pick
Banana body Farbers disease
Pi body-like cytosomes Adrenoleukodystrophy
Lysosomal inclusions (myelinoid bodies) Toxic neuropathies due to Amidarone, perhexiline,
chloroquine
Schwan cell inclusion and axonal degeneration
Lipid storage in perineurium Fabrys disease
a
Amyloidosis, Fabrys disease, small-fiber diabetic neuropathy.
b
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 -180C isopentane solution cooled
in liquid nitrogen for 15 seconds and then cut at 10 m 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 m, except for Congo-red stain, which should be cut at 8 to 10 m, 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 m 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 (0.51% HCl in 70% alcohol) by 2 dips. Rinse in tap water. Dip in ammo-
nia 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 Bouins fixative (LabChem Inc. LC, cat. #117902)
for 30 minutes at 56C at room temperature. Wash well in running water to remove all yellow color.
Stain nuclei with Gills hematoxylin (Surgipath Gills II formula, cat. #01520) for 5 minutes. Wash
in tap water for 2 minutes. Stain in Gomoris 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: Sorensens phosphate buffer, 2.5 ml; DW, 7.5 ml; 8% glutaraldehyde, 10 ml. For Sorensens phosphate buffer,
consult a later section of this book.
Gills 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.
Gomoris 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.
2002 CRC Press LLC

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 m. Deparaffinize and hydrate slides to water. Stain nuclei in Harris hema-
toxylin 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 solu-
tion* 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 Gills hematoxylin for 5 minutes. Wash in warm running water to remove excess stain. Stain
in Gomoris 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.
2002 CRC Press LLC

PASH (PERIODIC ACID SCHIFF AND HEMATOXYLIN) STAIN

Put the section in Carnoys 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 Schiffs solution (Sigma,
cat. #S-5133) for 10 minutes. Wash in warm, running tap water for 10 minutes. Counterstain in Gills
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
HIRSCHPEIFFER 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 m. Follow the Congo-red staining proce-
dure 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 Sorensens phosphate buffer for 10 minutes, three times, each time in a new buffer solu-
tion. Place sample in a 1:1 mixture of 1% osmium tetroxide and the phosphate buffer for 2 hours and
* Carnoys 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.
Schiffs 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 50C and filter. Add HCl and cool to 250C. 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.
Sorensens phosphate buffer: A solution: 17.6 gm sodium phosphate monobasic in 500 ml DW. B solution: 28.4 gm sodium phosphate diba-
sic in 500 ml DW. For 100 ml of Sorensens phosphate buffer: 13.0 ml A solution and 87 ml B solution.
2002 CRC Press LLC

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 65C oven for 24 hours.
SEMITHIN (0.51 m) SECTION STAININGS

After embedding, cut the nerve at 1 m 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 main-
tain 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 stain-
ing. 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.
2002 CRC Press LLC

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 pre-
fer fixation in glutaraldehyde.17, 11,** The teasing of one nerve fiber from beginning to end requires a min-
imum 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 Sorensens 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 num-
ber of pieces in the container on the lid. Any fat in the sample will begin to dissolve, sometimes caus-
ing 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 con-
tainer, 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 jewelers forceps), strip off the softened epineurium and per-
ineurium 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 dis-
odium phosphate, 6.5 gm.
** Asburys 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 4C. 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.
2002 CRC Press LLC

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 sur-
face 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 impos-
sible 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 with-
out 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.
2002 CRC Press LLC

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 sec-
tions, 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 analy-
sis 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 520 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. Asbury, A.K. and Connolly, E.S., Sural nerve biopsy: technical note, J. Neurosurg., 38, 391, 1973.
2. 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., Gomoris 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 ner-
vous 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.
2002 CRC Press LLC

4 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 super-
ficial peroneal and radial nerves are smaller than the sural nerve in diameter. There are three com-
partments 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 tis-
sue 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 m. Pacinian cor-
puscles 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 B-
cells.5 As a practical guideline, Midroni stated that a few (three to four on cross-section) LCA-posi-
tive 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 signif-
icant 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 asso-
ciated 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 m 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 m and show bimodal distribution with peaks at 5 m
and 13 m. The thickness of the myelin sheath is proportional to axon diameter in the semithin sec-
tions (Color Figure 4.4) and Kultschitzkys 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 m in diameter should
have a myelin sheath. If there is no myelin sheath in axons over 3 m in diameter, one can interpret
them as denuded axons (demyelinated axons). This G-ratio is not applicable in the frozen or paraffin
2002 CRC Press LLC

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 4.84.11). Frozen and paraffin sections tend to predominantly show the large-diame-
ter 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 sec-
tions 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 4.134.15) 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 m 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 demyeli-
nating 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 pro-
gressive 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 histo-
logic 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 myeli-
nated 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 regener-
ation 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 base-
ment membranes, but the membranes did not appear to be thickened. In older subjects there was obvi-
ous 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 abnormali-
ties, 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 m. (With permission from Jacobs, J.M. and Love, S., Qualitative
and quantitative morphology of human sural nerve at different ages. Brain, 1985, 108:900901.)
2002 CRC Press LLC

REFERENCES
1. 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.
Boston, MA, 1995.
3. Kerkoff, A. et al., Inflammatory cells in the peripheral nervous sytem in motor neuron disease, Acta
Neuropathol., 85, 560, 1993.
4. Hanovar, M. et al., A clinicopathological study of the GuillainBarr syndrome: nine cases and literature
review, Brain, 114, 1245, 1991.
5. De la Monte, S.M. et al., Peripheral neuropathy in the acquired immunodeficiency syndrome., Ann. Neurol.
23, 485, 1988.
6. Behse, F., Morphometrric studies on the human sural nerve, Acta Neurol. Scand., S132, 1, 1990.
7. Bergouignan, F.X. and Vital, C., Occurrence of Renault bodies in a peripheral nerve, Arch Pathol. Lab.
Med., 108, 330, 1984.
8. Weis, J., Alexianu, M.E., Heide, G., and Schroder, J.M., Renault bodies contain elastic fiber components,
J. Neuropathol. Exp. Neurol., 52, 444, 1993.
9. Ouvier, R.A., McLeod, J., and Conchin, T., Morphometric studies of sural nerve in childhood, Muscle and
Nerve, 10, 47, 1987.
10. Jacobs, J.M. and Love, S., Qualitative and quantitative morphology of the human sural nerve at different
ages, Brain, 108, 897, 1985.
11. Schroder, J.M., Bohl, J., and Brodda, K., Changes of the ratio between myelin thickness and axon diame-
ter in the human developing sural nerve, Acta Neuropathol., 84, 416, 1992.
12. Ferriere, G., Denef, J.F., Rodriguez, J., and Guzzeta, F., Morphometric studies of normal sural nerve in chil-
dren, Muscle and Nerve, 8, 697, 1983.
13. Schellens, R.L.L.A. et al., A statistical approach to fiber diameter distribution in human sural nerve, Muscle
and Nerve, 16, 1342, 1993.
14. Tohgi, H., Tsukagoshi, H., and Toyokura, Y., Quantitative changes with aging in normal sural nerves, Acta
Neuropathol., 38, 213, 1977.
15. OSullivan, 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 mag- CHAPTER 4 Figure 2 Three compartments in a
nification.) 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 3 Three compartments in a CHAPTER 4 Figure 4 Normal sural nerve. G-ratio
normal nerve: epineurial space (ep), perineurium (p), in one myelinated fiber (arrow) is 0.6. Semithin
endoneurial space (en); subperineurial space (sps); ar- section. Toluidine blue and basic fuchsin. (400
teriole (a). Each fascicle is filled with red myelinated magnification.)
fibers. This is normal. Paraffin section. Modified
trichrome stain. (100 magnification.)
CHAPTER 4 Figure 5 Normal sural nerve. G-ratio in CHAPTER 4 Figure 6 Normal sural nerve. Axon is
one myelinated fiber (arrow) is 0.5. Paraffin section. visible as a dot in the center of myelinated fibers. Axon
Kultschitzkys stain. (400 magnification.) is rarely visible in the paraffin section; lm means large-
diameter 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 CHAPTER 4 Figure 8 Entire nerve fascicle is filled
(a) is somewhat larger in the frozen section than the with red myelinated fibers in normal nerve. Frozen
paraffin section. Again, the axon is rarely visible in section. Modified trichrome stain. (100 magnifica-
the frozen section; sm means small myelinated fiber tion.)
and lm means large myelinated fiber. Frozen section.
Modified trichrome stain. (400 magnification.)
CHAPTER 4 Figure 10 Normal sural nerve. Entire
nerve fascicle is filled with red large-diameter myeli-
nated fibers in the longitudinal cut. Frozen section.
H & E stain (200 magnification.)
CHAPTER 4 Figure 9 Normal sural nerve. Myeli-

nated 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 myeli-
nated fibers in the longitudinal cut. Curved distortion CHAPTER 4 Figure 12 Normal sural nerve.
(arrow) of the specimen is unavoidable in the Varying diameter fibers are clearly identifiable in the
paraffin section. Modified trichrome stain. (200 semithin section. Semithin section. Toluidine blue and
magnification.) basic fuchsin. (200 magnification.)
CHAPTER 4 Figure 13 Renaults body (double CHAPTER 4 Figure 14 Renaults body (arrow) in
arrow) in the endoneurial space. Semithin section. the endoneurial space in the longitudinal cut. Frozen
Toluidine blue and basic fuchsin. (200 magnifica- section. Modified trichrome. (200 magnification.)
tion.)
CHAPTER 4 Figure 15 Four Renault bodies (arrows) in each nerve fascicle in

the transverse cut. Frozen section. H & E stain. (100 magnification.)
5 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 necro-
sis 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 ChurgStrauss 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 surpris-
ing 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 nec-
essary 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 inflam-
matory cells within the vessel wall (Color Figures 5.1 and 5.2).* Perivascular infiltration of inflam-
matory 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 pre-
dominant 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 neuropa-
thy 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 neu-
ropathies 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
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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 com-
bined nerve and muscle biopsy is recommended because, in rare cases, amyloid is positive in the mus-
cle biopsy whereas it is negative in the nerve biopsy.
The hallmark of amyloid neuropathy is amyloid in the nerve. Amyloid is histochemically Congo-
red 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 biop-
sied 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 bio-
chemical assay is not possible. Metachromatic granules are demonstrable in all cases. For demon-
stration 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-posi-
tive 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), Laforas 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 m 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 sur-
rounded 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 forma-
tion 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, onion-
bulb formation is indicative of repeated demyelination and remyelination.25 Thus, hypertrophic neu-
ropathy itself is indicative of demyelinating neuropathy.
The presence of onion-bulb formation is diagnostic of hypertrophic neuropathy. Thus, hyper-
trophic neuropathy represents a pathological diagnosis observed in many clinical entities. Among
these, the hypertrophic type of the CharcotMarieTooth disease (hereditary motor sensory neu-
ropathy [HMSN] type I) is best known. In RoussyLevy syndrome, DejerinneSottas disease
(HMSN type III), congenital hypomyelinative neuropathy, and Refsums disease (HMSN type IV),
onion-bulb formation is the most prominent finding in the biopsied nerve. In CIDP, onion-bulb for-
mation 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 inflamma-
tory cells in the endoneurial space are specific to this type of neuropathy, which is the type of neu-
ropathy 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-Barr

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 com-
monly 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 lym-
phocytes. 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 Prineass 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 abnormali-
ties, 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 dyspro-
teinemic neuropathies associated with osteosclerotic myeloma, benign monoclonal gammopathy, and
Waldenstrms macroglobulinemia.
INFLAMMATORY CELLS AND AXONAL DEGENERATION

The presence of inflammatory cells in the nerve fibers and axonal neuropathy is diagnostic of inflam-
matory axonal neuropathy. In inflammatory axonal neuropathy, inflammatory cells are characteristi-
cally 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 neu-
ropathy. 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 non-
systemic vasculitic neuropathy. In Dycks 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 sar-
coidosis once leprosy has been ruled out by the acid fast baccilus (AFB) stain. In sarcoidosis, micro-
scopic 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 pro-
cedure 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,
Langhans giant cells, and lymphocytes (Color Figure 5.15). No organisms are found in sarcoid gran-
uloma. 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 sus-
pected 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 promi-
nent features. Granuloma can be found in the epi- and perineurial spaces as well as in the endoneur-
ial 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 per-
ineurial 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 lep-
rosy, granuloma and endoneurial foamy cells are present. In all of these cases, the pathological diag-
nosis 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-sniffers neu-
ropathy, huffers 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. Huffers neuropathy is peripheral
neuropathy due to huffing of lacquer thinner. Thus, glue-sniffers neuropathy and huffers neu-
ropathy are, in essence, due to inhalation of n-hexane or methyl n-butyl ketone. In disulfiram neu-
ropathy, 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
m but typically range from 20 to 30 m. 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 neu-
ropathy, one with a pressure-sensitive neuropathy, and one with a chronic distal sensorimotor neu-
ropathy 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 m
in diameter and from 80 to 250 m in length in Madrid and Bradleys 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 heredi-
tary 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 neu-
ropathy 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 neu-
ropathy, and CIDP.64 Segmental demyelination is the unform finding in these cases. Onion-bulb for-
mation 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 respon-
sible 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 fasci-
cular 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 malig-
nancy including lymphoma, lymphomatous granulomatosis, leukemia, and myeloma. The infiltrating
cells have all the characteristics of malignant cells: mitotic figures, pleomorphism, and atopia. A dif-
fuse massive infiltration of all peripheral nerve compartments is most typical of lymphomatous neu-
ropathy. 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 lym-
phomatoid 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 neu-
ropathy, being positive in 40 to 80% of patients with this neuropathy, usually in the presence of anti-
MAG 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 sev-
eral cases of Waldenstrms 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 activ-
ity 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, segmen-
tal 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). De-
myelination 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 histo-
logical 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 degenera-
tion 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 smol-
dering 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, eti-
ology should be sought by conducting other tests.
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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.
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the peripheral nerve: clinical, electrophysiological and histological study of two cases, Eur. Neurol., 23,
459, 1984.
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polyneuropathy: analysis of a sural nerve biopsy, Neurology, 31, 1217, 1981.
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Tropical Neurology, Hohnbrook, R.W., Ed., F.A. Davis Co., Philadelphia, PA, 1975, 17.
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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.
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53. Oh, S.J. and Kim, J.M., Giant axonal swelling in Huffers 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 ONeill, 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.
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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 associ-
ated 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., OBrien, 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 clin-
ico-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
Waldenstrms macroglobulinemia: a specific ultrastructural pattern related to the presence of cryoglobu-
lin in one case, Clin. Neuropathol., 12, 49, 1993.
73. Dubas, F., Pouplard-Barthelaix, A., Delestre, F., and Emile, J., Polyneuropathies avec gammapathies mon-
oclonale IgM. 12 cas, Rev. Neurol., 143, 670, 1987.
74. Schroeder, J.M., Die Hyperneurotisation buengnerscher baender bei der experimenellen isoniazid-neu-
ropathie: 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 CHAPTER 5 Figure 2 Inactive vasculitis. Intra-
cells of intimal and muscular layers of arterioles in mural red blood cells and mononuclear inflammatory
the epineurial space. Almost total occlusion of vessels cells in a thickened arteriole in the epineurial space.
due to intimal thickening. Paraffin section. H & E Paraffin section. H & E stain. (400 magnification.)
CHAPTER 5 Figure 3 Amyloid. Congo-red mater- CHAPTER 5 Figure 4 Bright apple-green birefrin-
ial (arrow) in the wall of tiny vein in the epineurial gence of Congo-red material under the polarizing fil-
space. Paraffin section. Alkaline Congo-red stain. (200 ter. Paraffin section. Alkaline Congo-red stain. (200
magnification.) magnification.)
CHAPTER 5 Figure 5 Metachromatic granules are
stained as dirty yellow in the perivascular area in the
endoneurial vessel. Dirty yellow granules represent CHAPTER 5 Figure 6 Scattered metachromatic
metachromasia. The normal color for this stain is granules in the endoneurial space are stained brown
blue. Frozen section. Thionine stain. (400 magnifi- instead of normal purple color. Frozen section. Cresyl-
cation.) fast violet stain. (400 magnification.)
CHAPTER 5 Figure 7 Polyglucosan body (blue

arrow): pearly body with laminated rings and green-
ish core. Red arrow indicates myelin digestion
chambers in one myelinated fiber. Paraffin section.
CHAPTER 5 Figure 8 Diffuse loss of myelinated
fibers. One axon contains a large polyglucosan body
(approximately 30 m) 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 CHAPTER 5 Figure 10 Onion-bulb formation
proliferated Schwann cell processes. There is about a (OBF) is recognized by many fine lines around nerve
50% loss of myelinated fibers. Frozen section. fibers with varying myelin thickness. Red arrow indi-
Modified trichrome. (200 magnification.) cates denuded axon (demyelination) and blue arrow
indicates OBF without any recognizable axon. Some
fibers with OBF have more than one Schwann cell nu-
cleus. Semithin section. Toluidine blue. (400 mag-
nification.)
CHAPTER 5 Figure 12 Remyelinated fibers in

chronic inflammatory demyelinating polyneuro-
pathy. About 50% of myelinated fibers are
remyelinated fibers (blue arrow) characterized by a
CHAPTER 5 Figure 11 Scattered mononuclear in- thin myelin sheath in proportion to axon diameter.
flammatory cells in the endoneurial space (double ar- Red arrow indicates normal myelinated fibers. Yellow
rows). Perivascular collections of inflammatory cells arrow indicates thinly myelinated fibers with two
in the endoneurial space (arrow). These are typically Schwann cell nuclei and tiny OBF. Semithin section.
seen in inflammatory demyelinating neuropathy. Toluidine blue. (400 magnification.)
Paraffin section. H & E stain. (200 magnification. )
CHAPTER 5 Figure 13 Perivascular lymphocytes CHAPTER 5 Figure 14 Myelin-digestion cham-
in the epineurial space in a case of vasculitic neuro- bers (arrows) in the longitudinal cut. Frozen section is
pathy. Paraffin section. H & E stain. (200 magnifica- indicative of axonal degeneration. Frozen section.
tion. ) Modified trichrome. (200 magnification.)
CHAPTER 5 Figure 15 Noncaseating granuloma CHAPTER 5 Figure 16 Foamy cells in the en-
(arrow) with many epithelioid cells and mononuclear doneurium, diagnostic of leprosy (arrows). The entire
inflammatory cells in the subperineurial space. field is replaced by fibrosis. No myelinated fiber is
Arrow head indicates another granuloma in the noted. Semithin section. Toluidine blue stain.
subperineurial space. No granuloma or inflammatory (Courtesy of Professor I. Sunwoo, Yonsei University
cell is present in the endoneurium itself in the middle. Medical School, Seoul, Korea.)
Paraffin section. H & E stain. (200 magnification.)
CHAPTER 5 Figure 18 Three giant axons are visi-
CHAPTER 5 Figure 17 Mycobacterium leprae. ble in one nerve fascicle. Normally, the axon is stained
Many acid-fast bacilli (bright red rods or globs) in the green as a dot in the middle of red myelinated fibers.
foamy cells. Paraffin section. Wade-Fite stain. The giant axon is easily identified here as a green cen-
(Courtesy of Dr. Y. Harati, Baylor Medical College, ter surrounded by thin red myelin. Giant axons are
Houston, TX.) three times larger in diameter than normal fibers. The
population of myelinated fibers is minimally de-
creased. 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)
CHAPTER 5 Figure 19 Giant axon. The dark line represents tomaculous formation near the node of
represents an axon in the nerve fiber (red arrow). The Ranvier. The diameter is twice that of normal myeli-
giant axon (blue arrow) is characterized by a hazel- nated fibers. There is also a moderate decrease in the
colored center marked as a dark line. The diameter of population of myelinated fibers. (With permission
the giant axon is 10 times that of the axon. Paraffin from Oh, S.J., Yonsei Med. J., 31, 22, 1990.)
section. Glees and Marslands silver stain. (400
magnification.)
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 CHAPTER 5 Figure 22 Occlusion of a tiny arteri-
stain. (400 magnification.) ole in the subperineurial space in a case of diabetic
neuropathy. Near occlusion of an endoneurial arteri-
ole due to arteriosclerotic endothelial thickening.
There are a few scattered red myelinated fibers, indi-
cating a decreased population of myelinated fibers.
Paraffin section. Gomori trichrome (200 magnifica-
tion.)
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 fig- CHAPTER 5 Figure 24 IgM deposits in the
ures, pleomorphism, and atopia. This patient had lym- myelin sheaths in a patient with MAG-positive neu-
phomatous neuropathy caused by natural killer cell ropathy. Immunofluorescent stain for IgM outlines all
lymphoma. Paraffin section. H & E stain. (200 mag- myelinated fibers. Frozen section. Immunofluores-
nification.) cent 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 re-
myelination. Blue arrow indicates one denuded axon
(demyelinated fiber), and red arrow indicates one
thinly myelinated fiber (remyelinated fiber). Inflam-
matory cells are scattered in the endoneurial space.
There is also a decrease in the population of myeli-
nated 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 CHAPTER 5 Figure 28 Axonal degeneration. All
fibers) are noted in the endoneurium, indicating myelinated fibers are undergoing myelin breakdown
axonal degeneration. Frozen sections. Modified tri- indicative of axonal degeneration. Semithin section.
chrome. (100 magnification.) Toluidine blue. (400 magnification.)
6 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 necro-
tizing 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 involve-
ment 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 sur-
prising 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 m.1,2
Peripheral nerves have a rich anastomotic blood supply through two functionally distinct vas-
cular systems: the extrinsic system composed of the epineurial vessels and regional arteries, arteri-
oles, 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 pro-
vide 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 sus-
ceptible 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 autoregu-
late 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 asso-
ciated 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, Raynauds phenome-
non, 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 neu-
ropathy, mononeuropathy multiplex, asymmetrical polyneuropathy, and symmetrical polyneuropa-
thy.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 Siekerts 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 justifi-
able. 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 (mononeu-
ropathy multiplex, asymmetrical polyneuropathy, and symmetrical polyneuropathy), though the rel-
ative 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 Rare 5260
ChurgStrauss syndrome Rare 6469
Wegeners granulomatosis Rare 1121
Giant cell artertis Common in elderly 514
Rheumatoid diseasesb
Rheumatoid arthritis Common 10
Systemic lupus erythematosus Common 221
Sjgrens syndrome Common 1015
Progressive systemic sclerois Uncommon 1.5
Other conditions with vasculitis

Crygolobulinaemia Rare 50
Malignancy Common Rare
HIV infection Variable 2
Lyme disease Variable <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 sev-
eral 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 pro-
gressed. 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 neu-
ropathy; and (2) abnormal sural nerve conduction is an excellent marker for the demonstration of vas-
culitis 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 abnor-
mality 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 com-
mon abnormality in SNV. It is invariably elevated in the PAN group of SNV, Wegeners granulo-
matosis, 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, abnor-
mal 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 cryoglobu-
linemia, 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 devel-
opment 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 diag-
nosing or monitoring disease activity in different vasculitic syndromes.24 In up to 97% of cases of
Wegeners granulomatosis (WG), cANCA (cytoplasmic) was positive. Importantly, pANCA (perinu-
clear) 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 stud-
ied 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 vas-
culitic neuropathy and also in 6 of 44 patients with inflammatory or immunologically mediated neu-
ropathies. 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 neu-
ropathy, 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 vas-
culitic 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 read-
ily 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 com-
mon 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 sensi-
tivity 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 Saids 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 vas-
culitis 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 find-
ings, 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 tib-
ialis 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 recom-
mended. 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, electrophysi-
ological 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 fasci-
cular 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 multi-
focal 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 m. 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 vas-
culitis must be present: active, inactive, or healed necrotizing changes and infiltration of inflamma-
tory 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
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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 neu-
ropathy 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 necro-
sis 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 pre-
dominate in the vessel wall and perivascular area. Eosinophils occur in vasculitis of various etiolo-
gies, but marked eosinophilic infiltration suggests ChurgStrauss syndrome.31,32 Together with these
cardinal findings, dissolution of the internal elastic membrane and edema or thickening of the adven-
titia are typically found (Color Figure 6.3). Active vasculitis represents Type I lesion in our classifi-
cation. 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 char-
acterized 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 clus-
ter in a periadvential location (Color Figure 6.7). There are no perivascular or intramural inflamma-
tory 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 occasion-
ally 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 dis-
ease, 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 myeli-
nated 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 neuropa-
thy and in acute lesions in patients with clinically acute neuropathy.
It is not possible to diagnose specific vasculitic syndromes from nerve biopsy specimens. In gen-
eral, the caliber of involved vessels may allow one to assign a given biopsy to one of two broad groups.37
Vasculitic involvement of larger (100250 m) epineurial arterioles is a typical feature of PAN,
ChurgStrauss syndrome, Wegeners granulomatosis, and rheumatoid vasculitis, whereas predominant
involvement of smaller (<100 m) epineurial arterioles is more suggestive of Sjgrens syndrome, SLE,
and nonsystemic vasculitis of the nerve.37 Involvement of epineurial veins occurs more commonly in
Wegeners granulomatosis and ChurgStrauss syndrome than in PAN.38 Vasculitis of endoneurial ves-
sels 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 vasculi-
tis in the nerve is introduced because the definite criteria of vasculitis are too stringent for clinical util-
ity 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 can-
not be made on this basis alone.16 This is most likely due to the lack of medium- and small-sized arter-
ies 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 endoneur-
ial inflammatory cells favor inflammatory demyelinating polyneuropathy. Because of this, we rec-
ommend that perivascular infiltration of inflammatory cells and axonal degeneration (Color Figures
6.86.11) and/or central fascicular degeneration or SNFD (Color Figures 6.126.14) 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 Dycks 13 cases of probable vasculitic neuropathy, vasculitis was confirmed by liver and kid-
ney biopsies and post-mortem findings.10 In Hawkes 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 sec-
ondary 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 bor-
der 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 Renaults 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 tem-
poral progression of the vasculitis-induced ischemic changes.42 Mononeuropathy multiplex, the clas-
sical 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 mononeu-
ropathy multiplex) results from an increasing confluence of mononeuropathy multiplex or the simul-
taneous patchy discrete infarction of smaller vessels in many individual peripheral nerves, together
with superimposed mononeuropathy due to damage of whole-nerve trunks. Symmetrical polyneu-
ropathy 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 vas-
culitic 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 char-
acteristically 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 neu-
ropathy 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 long-
term 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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CHURGSTRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS)

The Churg-Strauss syndrome (allergic granulomatosis) is clinically similar to PAN, with the excep-
tion of prominent pulmonary symptoms including asthma and eosinophilia. Pathologically there is
necrotizing vasculitis of small arterioles and veins with extravascular granulomas, as well as infiltra-
tion 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 vas-
culitic 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 gran-
ulomatous lesions were seen in only one case.50
WEGENERS GRANULOMATOSIS
Wegeners 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 activ-
ity in Wegeners granulomatosis.52 In up to 97% of cases of Wegeners granulomatosis, cANCA was
positive, but pANCA was only rarely found in patients with WG. The frequency of peripheral nerve
involvement in Wegeners granulomatosis is 11 to 21%.53,54 Cranial neuropathy and peripheral neu-
ropathies 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 tem-
poral 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 biopsy-
proven 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 vas-
culitis is the second most common cause of vasculitic neuropathy in most series.37,61 Vasculitic neu-
ropathy 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 vas-
culitis 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 mononeuropa-
thy 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
SJGRENS SYNDROME
The diagnosis of Sjgrens 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 Sjgrens 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 Sjgrens 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 small-
vessel involvement, usually in the skin, and associated with a recognizable precipitating event or expo-
sure. 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 vas-
culitis, postinfectious vasculitis, serum sickness, HenochSchonlein purpura, and some cases of essen-
tial 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, arteri-
oles, 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 biopsy-
proven 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 pathologi-
cal 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 persis-
tent 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, intra-
venous pyelogram (IVP), CT, and ultrasound scans of the abdomen, and chest x-ray. Abnormal phys-
ical findings were an ill-looking male with a temperature of 101F 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 physicians
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 arte-
rioles 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 treat-
ment were given with a gradual improvement in the patients 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 con-
duction 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 neuropa-
thy. We found this practice extremely helpful for the rapid tissue diagnosis of SNV, and it is proba-
bly 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 ChurgStrauss syndrome (CSS): asthma, hypereosinophilia,
and vasculitis. The patients 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 neu-
ropathy 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 vas-
culitis. 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 fea-
ture 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 carci-
noma 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 patients history of cancer, paraneoplastic neuropathy was suspected. High CSF pro-
tein 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 intra-
mural 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 patients 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 degen-
eration, 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 asymmetri-
cal 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 cryoglobuline-
mia. 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 myeli-
nated 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.
The patients 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 periph-
eral 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 neuropa-
thy in two. There were a few more cases of hepatitis Cinduced 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 polyneu-
ropathy 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 pre-
viously 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 pharmaceuti-
cal 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 Tinels 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 evi-
dence 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 neu-
ropathy.
Sural Nerve Biopsy
The population of myelinated fibers was relatively normal. There were a few scattered myelin diges-
tion 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.
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 neu-
rological 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 sed-
imentation 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.
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 cyclophosphamide-
induced 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 polyneuropa-
thy 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 periph-
eral 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 clin-
icians because of a low index of suspicion of vasculitic neuropathy as a diagnostic possibility. In fact,
in Hawkes 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 labora-
tory 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 cul-
minating 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 multi-
focal 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 indica-
tive 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.
A combined therapy of cyclophosphamide and steroids was recommended. No follow-up informa-

tion was available in regard to the outcome.
Comments
In this case, the nerve biopsy showed probable vasculitic features suggestive of vasculitic neuropa-
thy, 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: GUILLAINBARR 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 wide-
spread 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.
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-Barr type neu-
ropathy in SLE is generally more gradual in its evolution, mimicking CIDP. Vasculitis was clearly
documented in Goldbergs case, which meets the diagnostic criteria of the Guillain-Barr syndrome.80
However, in other cases, demyelination was clearly documented. Kissel suggested that the mecha-
nism of the GuillainBarr syndrome and CIDP in SLE may be due to a pathogenic antinerve anti-
body 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 sen-
sation 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 weak-
ness. The first neurologist suggested motor neuron disease, which was clearly ruled out by the pres-
ence 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 patients 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-digestion-
chambers in the semithin as well as frozen sections (Color Figure 6.35). There were perivascular col-
lections 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.
With prednisone and cytoxan therapy for 1 year, the patient was completely normal, including his res-
piratory 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 prob-
able 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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53. Drachman, D.A., Neurological complications of Wegeners 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 Wegeners 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 Wegeners
granulomatosis: a clinicopathological study of four cases, Brain, 88, 151, 1965.
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57. MacFayden, D.J., Wegeners 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., Wegeners granulomatosis: prospective and thera-
peutic 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 clinico-
pathologic 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 angiopa-
thy 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 auto-
nomic 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 Sjgrens syn-
drome, Arth. Rheum., 28, 1341, 1985.
68. Mellgren, S.L., Conn, D.L., Stevens, J.C., and Dyck, P.J., Peripheral neuropathy in primary Sjgrens syn-
drome, Neurology, 39, 390, 1989.
69. Griffin, J.W., Cornblath, D.R., and Alexander, E., Ataxic sensory neuropathy and dorsal root ganglionitis
associated with Sjgrens syndrome, Ann. Neurol., 27, 304, 1990.
70. Calabrese, L.H. et al., The American College of Rheumatology 1990 criteria for the classification of hyper-
sensitivity vasculitis, Arth. Rheum., 33, 1108, 1990.
71. Oh, S.J., Paraneoplastic vasculitis of the peripheral nervous system, Neurol. Clin., 15, 849, 1997.
73. Kissel, J.T., Vasculitis of the peripheral nervous system, Semin. Neurol., 14, 361,1994.
74. Bouche, P., Lger, 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
GuillainBarr 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 2 Active vasculitis (Type I
lesion) in a larger arteriole in the epineurial space.
CHAPTER 6 Figure 1 Perivascular cuffing of in- Arteriole is greatly enlarged in size due to active vas-
flammatory cells. Perivascular collection of mononu- culitic process. The normal structure of the arteriole
clear inflammatory cells (Type III lesion) in a small is completely destroyed by the prominent intramural
vessel in the epineurial space. There is no intramural infiltration of mononuclear cells and fibrinoid necro-
infiltration of inflammatory cells or fibrinoid necrosis of muscular and adventitial layers and near occlu-
sis. Paraffin section. H & E stain. (400 magnifica- sion due to an intimal thickening. One nerve fascicle
tion.) (arrow) is noted in the right upper corner. Paraffin
section. H & E stain. (200 magnification.)
CHAPTER 6 Figure 3 Active vasculitis with re-

canalization of occluded lumen, discontinuous elas-
tica (arrow head), edema in the adventitia, and
prominent intramural infiltration of mononuclear CHAPTER 6 Figure 4 Active vasculitis with hem-
cells producing fibrinoid necrosis. In the surrounding orrhage in the intimal layer associated with fibrinoid
nerve fascicles (arrow), there is obvious loss of myeli- necrosis and intramural lymphocytes in the muscular
nated fibers. Paraffin section. Modified trichrome. layer in the small arterioles in muscle biopsy. Paraffin
(100 magnification.) section. H & E stain. (200 magnification.)
CHAPTER 6 Figure 5 Inactive vasculitis (Type II le-
sion). Thickened intimal and muscular layers and a few
scattered intramural inflammatory cells in the
muscular and adventitial layers of a small arteriole in CHAPTER 6 Figure 6 Healed vasculitis. Marked
the epineurial space, representing an inactive vasculitis. narrowing of lumen of small arteriole in the epineur-
The involved arterioles are larger in size than the non- ial space due to thickened intima and muscular layers.
involved arterioles next to them due to an inactive No inflammatory cells are visible. Other areas of this
vasculitic process. Paraffin section. H & E stain. (100 section showed inactive vasculitic changes. Paraffin.
magnification.) H & E stain. (200 magnification.)
CHAPTER 6 Figure 7 Healed vasculitis. Thick- CHAPTER 6 Figure 8 Many myelin ovoids typical
ened wall of epineurial small arterioles with hemo- of active axonal degeneration are obvious. Arrow in-
siderin in the intimal layer, representing old dicates one of many myelin ovoids. Arrow head indi-
hemorrhage, and total occlusion of lumen of cates one of many myelin-digestion chamber.
arterioles due to thickened intimal layer. PASH. Semithin EM section. (200 magnification.)
(200 magnification.)
CHAPTER 6 Figure 10 Active axonal degenera-
tion in the longitudinal section. Prominent myelin-di-
CHAPTER 6 Figure 9 Active axonal degeneration gestion chambers (arrow indicates one of them)
in two teased fibers characterized by myelin ovoids of indicative of axonal degeneration in one nerve fasci-
various sizes (arrowheads). Successive segments of cle. Arrow head indicates one myelin ovoid. Frozen
teased nerve fibers from top to bottom. section. Modified trichrome. (200 magnification.)
CHAPTER 6 Figure 12 Sectional selective nerve

fiber degeneration (SNFD) indicative of ischemic
neuropathy in vasculitic neuropathy. Loss of myeli-
nated fibers in a wedge-shaped section of one nerve
fascicle (arrowhead) with central fascicular degenera-
tion is due to occlusion of the vasa nervorum supply-
CHAPTER 6 Figure 11 Active axonal degener- ing blood to this section of the fascicle. Myelinated
ation in the transverse section. Prominent myelin- fibers are stained red. The normal number of myeli-
digestion chambers (arrow indicates one of them) in- nated fibers is noted in the lower half of the fascicle.
dicative of active axonal degeneration in one nerve Frozen section. Modified trichrome. (100 magnifi-
fascicle. (200 magnification.) cation.)
CHAPTER 6 Figure 13 SNFD indicative of is-
chemic neuropathy in vasculitic neuropathy in the CHAPTER 6 Figure 14 SNFD in the transverse
longitudinal section. Total SNFD: total loss of myeli- section. Two small nerve fascicles are totally devoid
nated fibers in one nerve fascicle (arrows). In the of any myelinated fibers (total SNFD) (double
lower nerve fascicle, a few myelin-digestion cham- arrowheads), while one larger nerve fascicle has
bers indicating active axonal degeneration are also sectional SNFD (arrowhead) with a normal number of
observed. Frozen section. Modified trichrome. (100 relatively well preserved myelinated fibers in most
magnification.) areas of the nerve fascicle. (200 magnification.)
CHAPTER 6 Figure 15 Polyneuropathy vs. mono-

neuropathy multiplex and their pathogenetic
mechanisms in vasculitic neuropathy. (A) Mono-
neuropathy 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) Asym- CHAPTER 6 Figure 16 Most intramural mononu-
metrical polyneuropathy due to more patch damage clear cells are T-cells. Frozen section. CD4 marker
in the scattered nerves, but not corresponding to the stain. (200 magnification.)
named nerves. Red areas represent a milder degree of
involvement; (C) Symmetrical polyneuropathy,
which is more likely to affect longer nerves.
CHAPTER 6 Figure 17 Type I vasulitic lesion with CHAPTER 6 Figure 18 Temporal arteritis. Type I
total occlusion of arterioles in the epineurial space. vasculitic lesion in the temporal artery. Prominent in-
Many myelin-digestion chambers (arrow heads) are timal thickening with narrowing of the lumen of the
obvious in the nerve fascicle. Frozen section. H & E artery and fibrinoid necrosis of the muscular layer
stain. In the frozen sections, myelin-digestion cham- with many inflammatory cells and giant cells (arrow-
bers are often detectable on H & E stain. (100 mag- head). Paraffin section. H & E stain. (Courtesy of
nification.) Dr. Cheryl Palmer.)
CHAPTER 6 Figure 19 Type I vasculitic lesions CHAPTER 6 Figure 20 Type I vasculitic lesion
with total occlusion of arteriole in the perimysial space. with near-total occlusion of the arteriole between two
Many nearby muscle fibers (arrow) show nerve fascicles. Also, a prominent perivascular collec-
subtle changes of myopathy (purple-tinged smear in tion of mononuclear cells (arrow). Paraffin section.
muscle fibers) with internal nuclei. Frozen section. H & E stain. (200 magnification.)
H & E stain. (100 magnification.)
CHAPTER 6 Figure 21 Three different features in CHAPTER 6 Figure 22 Type I lesion with total oc-
three tiny arterioles in the same epineurial space: long clusion of vessel lumen due to the fibrinoid necrosis
arrow indicates normal, short arrow indicates a Type of intima and muscular layers. Details of pathological
I vasculitic lesion, and arrowhead, indicates a Type II features are obscured because of frozen section.
inactive vasculitic lesion. (200 magnification.) Frozen section. PASH. (100 magnification.)
CHAPTER 6 Figure 23 Type I vasculitic lesion CHAPTER 6 Figure 24 Type I lesion with near-
with scattered red blood cells in all layers. One nerve total occlusion of the arterioles lumen in the epineur-
fascicle shows minimal decrease in the population of ial space. One nerve fascicle is indicated with an
myelinated fibers. Paraffin section. Modified arrow. Arrowhead indicates a collection of many
trichrome. (200 magnification.) eosinophilic leucocytes (see Figure 6.25). Paraffin
section. H & E stain. (200 magnification.)
CHAPTER 6 Figure 25 Higher magnification of CHAPTER 6 Figure 26 Microvasculitis in a tiny
Figure 6.24 showing many eosinophilic leucocytes capillary in the epineurial space. Arrow indicates
(with reddish cytoplasm) among many infiltrating nerve fascicle. Paraffin section. H & E stain. (200
inflammatory cells in the walls of arteriole. Paraffin magnification.)
section. H & E stain. ( 400 magnification.)
CHAPTER 6 Figure 28 Type III vasculitic lesion:

prominent collections of small mononuclear cells
CHAPTER 6 Figure 27 Type I vasculitic lesions in in the perivascular area (double arrow heads). There
the upper smaller arterioles in the longitudinal cut. are no intramural inflammatory cells in the wall of
Lower larger arterioles are not affected by the the small arteriole in the epineurial space (arrow).
vasculitic process. Paraffin section. H & E stain. (200 Paraffin section. H & E stain. (100 magnification.)
magnification.)
CHAPTER 6 Figure 29 Type I vasculitic lesion: CHAPTER 6 Figure 30 Type I vasculitic lesion
prominent intramural infiltration of inflammatory (arrow) with near-total occlusion of the vessel in the
cells is in the muscular and adventitial layers in the tiny arteriole in the epineurial space and prominent
larger arterioles in the epineurial space. There is also perineurial collections of mononuclear cells (arrow-
microvasculitis in the tiny arterioles (arrow head). head). Paraffin section. H & E stain. (200 magnifi-
Frozen section. PASH. (100 magnification.) cation.)
CHAPTER 6 Figure 31 Invasion of mononuclear CHAPTER 6 Figure 32 Type I vasculitic lesion in

cells into the endoneurial space from the perineurial the arteriole in the perimysial space. In a nearby area,
space (see Figure 6.30) through the fragmented seg- there are histological features of inflammatory
ment of the wall of the nerve fascicle. Endoneurial myopathy: endomyisial inflammatory cells and some
inflammatory cells are extremely rare in vasculitic muscle fibers undergoing regeneration and phagocy-
neuropathy. Paraffin section. H & E stain. (200 tosis. Frozen section. H & E stain. (100 magnifica-
magnification.) tion.)
CHAPTER 6 Figure 33 Myositis in an area distant CHAPTER 6 Figure 34 Perivascular collections of
from vasculitic arterioles. Endomysial mononuclear inflammatory cells in a small vessel in the epineurial
inflammatory cells with a few muscle fibers undergo- space (Type III). Notice the relatively normal popula-
ing regeneration (arrow). Sometimes, myositic fea- tion of myelinated fibers in lower nerve fascicle, but
tures are seen without vasculitic features. Frozen the decreased population of myelinated fibers in one
section. H & E stain. (200 magnification.) 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
CHAPTER 6 Figure 35 Minimal decrease in the space (Type III). Double arrows indicate perivascular
population of myelinated fibers is obvious. The arrow collections of macrophages and inflammatory cells.
indicates one nerve fiber undergoing active Notice the lack of any inflammatory cells in a small
axonal degeneration (MDC). Arrowheads indicate arteriole. Paraffin sections. H & E stain. (200 mag-
two of many clusters of regenerating axon sprouting. nification.)
Semithin section. (200 magnification.)
7 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 GuillainBarr syndrome
(GBS), is a well-known entity. In Western countries, GBS is the most frequent cause of acute para-
lytic illness since poliomyelitis has become uncommon. The prime example of chronic inflamma-
tory 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 neu-
ropathy (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 com-
monly 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 macrophage-
induced 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 experi-
mental 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
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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 dis-
appointing.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 under-
lying 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 sup-
ports such a mechanism. However, why there is such a clear difference in steroid responsiveness in
GBS and CIDP is a mystery.
GUILLAINBARR SYNDROME
(ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY; AIDP)
The GuillainBarr 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 paral-
ysis 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 conduc-
tion abnormalities is observed, diffuse slowing of conduction accompanied by a dispersion phenom-
enon 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 demyeli-
nating 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 ther-
apy, we recommend the sural nerve biopsy before initiation of steroid treatment for histological con-
firmation 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
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the motor and sensory roots join to form the spinal root, and (3) the majority of findings in the cen-
tral 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 inflamma-
tory 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 inflamma-
tory infiltration of the peripheral nerve from the earliest stages of disease; (2) all levels of the periph-
eral 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 correspond-
ing to the areas of inflammatory cells; and (4) the 3 slowly evolving cases (CIDP) were pathologi-
cally 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 demyelina-
tion 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 consis-
tent finding was primary demyelination (Color Figures 7.37.6). 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 sec-
tion, 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 Hughes2 Oh Oh Brechenmacher3
GBS GBS Recurrent GBS
(N = 9) (N = 10) (N = 17) (N = 7) (N = 65)
Loss of myelinated fibers 6 3 12 6
Endoneurial or
subneurial edema 2
Mononuclear cells 3 4 (40%) 7 (41%) 4 (57%) 7 (N = 57)
Endoneurial (6) 3 1 4 5 (57) b
Perivascular 4 7 3 2
Primary demyelination 5 (6) a 7 15 5 (63)
Onion bulb formation (1) 1
Axonal degeneration 2 (4) 8 4 1 (10)

Mixed
Normal 2 0
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 con-
trast 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 distin-
guishes inflammatory demyelinating neuropathies from vasculitic neuropathies. Thus, it is a desir-
able 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 lym-
phocytes is seen only in the epineurial space (Color Figure 7.9). In those cases, the histological dif-
ferentiation 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 lym-
phocytes. Plasma cells are scattered among the lymphocytes. In the most intense cases, polymor-
phonuclear 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 inflamma-
tory 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 neuropa-
thy, 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 sec-
ondary to primary demyelination.
In summary, the sural nerve biopsy in GBS shows (1) segmental demyelination as the most con-
sistent 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 pro-
tein 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 unmyeli-
nated nerve fibers, explaining dysautonomia.18 In one case of acute autonomic and sensory neuropa-
thy, 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.
MillerFisher syndrome of acute ophthalmoplegia, ataxia, and areflexia, described by Fisher in
1956, is generally considered a variant of the GuillainBarr 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 MillerFisher syndrome, the classical pathological findings of the
GuillainBarr 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 MillerFisher 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 GuillainBarr syndrome has been well-known for years. Until Austin
reported a remarkable case of recurrent polyneuropathy with dramatic response to various corticos-
teroid 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 polyneuropa-
thy, 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 polyneu-
ropathy. According to Ohs 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 GuillainBarr Syndrome CIDP
Onset Acute; peak deficit in Subacute or chronic; peak deficit
less than 4 weeks in more than 4 weeks
Antecedent infection Present in 70% of cases Absent
Cranial nerve deficit Common Rare
Respiratory failure Not uncommon Rare
CSF High protein High protein
NCV Normal or slightly slow in 50% Markedly slow
of cases; markedly slow in 50%
Response to steroids Not proven Yes
Response to IVIG and PE Yes Yes
Relapse Rare Common
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indicative of demyelinating neuropathy. According to our experience, this disorder cannot be diag-
nosed 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 ini-
tiated 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 sec-
tions. Onion-bulb formation (Color Figures 7.12 and 7.13), a histological feature of chronic demyeli-
nation 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 inflamma-
tion 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 mononu-
clear cells in the sural nerve biopsy varies from 1128,29 to 65%.52 Midroni et al. used the immunohisto-
chemical 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 necro-
sis, intimal proliferation, arterial occlusion, hemorrhage, or hemosiderin-laden macrophages adjacent
to the small arterioles. This observation is important in the differentiation between inflammatory neu-
ropathies 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 histo-
logical finding in his patient with chronic relapsing polyneuropathy, was observed in some cases
Axonal degeneration was observed in 5 to 25% of cases in most series and was most likely sec-
ondary 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 find-
ing, 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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Chapter 7 Final Proof
TABLE 7.3
Histological Features of Sural Nerve Biopsy and Autopsies in CIDP
Histological Feature Dyck 4 Prineas 10 Oh Barohn28 Small 29 Krendal 79 Midroni 26 d Bouchard 80 Autopsiesa
07/13/2001
(N = 26) (N = 23) (N = 110) (N = 56) (N = 19) (N = 14) (N = 51) (N = 95) (N = 11)
Loss of myelinated fibers 7 89 (81%) 1
Endoneurial or 5 7 2 2
subneurial edema
Mononuclear cells 30 (27%) 6 (11%) 2 (11%) 33 (65%)*d
8:06 AM
Endoneurial 6 slight 6 (26%) 6 (5%) 4 (29%) 18 (19%) 8 (73%)
Perivascularb 14 (54%) 0 30 (27%) 6 (55%)
Onion-bulb formation 4 10 (44%) 12 (11%) ? 4 (21%) 5 (36%) 10 (20%) 17 (18%) 1
Primary demyelination 6 (N = 24) f 12 (52%) 86 (78%) g 27 (48%) 5 (26%) 7 (50%) 38 (75%) e 68 (72%)
Page 79
Axonal degeneration 6 (N = 24) 7*c 18 (16%) g 12 (21%) 3 (16%) 46 (88%) 5 3
Mixed 18 34 (67%) 20 (21%)
Normal 2 10 (18%) 16 (37%) 1
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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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 fascicula-
tions 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 spec-
trum 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 myeli-
nated 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 Corses 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 Corses 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. Ohs patient had progressive motor weakness with exaggerated
reflexes over a 5-year period, with motor conduction block but normal anti-GM1 ganglioside titer.
Ohs 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 sec-
tion. In both cases, there were extensive IgG and IgM deposits in the nerve, supporting an autoim-
mune 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 start-
ing 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 identi-
cal 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 supraclavic-
ular mass (prominent onion-bulb formations and inflammatory cells), multifocal conduction blocks,
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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 fea-
ture40-44 (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 Ohs 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 major-
ity 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, indi-
cating 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 for-
mation 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 weak-
ness 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 quadri-
plegia, bulbar palsy, and facial diplegia. A second NCS a week later showed pure motor polyneu-
ropathy. 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 wide-
spread fibrillations and PSW. Sensory nerve conduction was normal except for a low CNAP ampli-
tude 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 demyelinat-
ing neuropathy, but instead showed severe axonal motor neuronopathy with almost normal sensory
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nerve conduction. The main reason for performing a nerve biopsy was to rule out vasculitic neu-
ropathy 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.
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 hospi-
talization, 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 fibrilla-
tions 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 find-
ings 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 pres-
ence of frequent para-axonal and occasional intra-axonal macrophages in the large motor fibers, sug-
gesting 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 sen-
sory 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 exten-
sive, 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 iliop-
soas, mild weakness in other leg muscles, and areflexia. His CSF protein level was 486 mg/dl. A diag-
nosis 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 pin-
prick sensation in his toes. An NCS revealed marked demyelinating neuropathy with markedly pro-
longed terminal latencies (36 msec in the median and 58 msec in the peroneal nerves) and markedly
slow NCV (2030 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 recur-
rence of symptoms. In view of this unusual feature, a nerve biopsy was needed to confirm the clini-
cal 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.
Over the next 10 years, this patient was kept on a small maintenance dosage of prednisone daily with-
out any major relapse. He had three minor relapses involving numbness of the hands and feet, one fol-
lowing 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 pred-
nisone dose was being tapered downward, and continued prednisone therapy eventually controlled
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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 GrandMaison et al. differed from this view
in that recurrent GBS was found to be distinctively different from CIDP, with rapid onset of symp-
toms 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, GrandMaison 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 per-
formed 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 nonreac-
tive 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 patients 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 con-
firmed 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 neu-
ronopathy, 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
Final Diagnosis
The final diagnosis was acute autonomic and sensory neuropathy (AASN).

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 amy-
loid 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 dysau-
tonomic 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 hear-
ing 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 bilat-
erally, absent position sense in the toes, and absent ankle reflex. The only abnormal laboratory find-
ing 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 per-
ineurial 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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The patient was treated with IVIG and prednisone with definite improvement in neuropathy but min-
imal 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 major-
ity 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 neuro-
logical 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 phenome-
non. 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 segmen-
tal 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.
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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 m. Electronmicrograph.
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: Refsums disease and metachromatic leukodystrophy. Metachromatic leukodystrophy
was ruled out by the absence of metachromatic substance in the sural nerve, and Refsums 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 onion-
bulb 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 ner-
vous 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 weak-
ness 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 demyelina-
tion but did show severe axonal motor-sensory neuropathy with lumbar polyradiculopathy.
Case Analysis
The patients 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.
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 ques-
tion 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 patients CSF protein level was 28 mg/dl. An NCS showed
demyelinating neuropathy with uniform slowing of motor NCV (1612 m/sec in the forearm and
2318 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 slow-
ing 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.
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 patients 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-strip-
ping, (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 immunohisto-
logical 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 per-
oneal 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 fascicula-
tions, 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 myeli-
nated fibers, indicative of demyelination, were noted.
Final Diagnosis
Multifocal motor neuropathy was the final diagnosis.
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
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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 mag-
nification.) (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 sus-
pected 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 neu-
ron syndrome over a 6-year period with motor conduction block in many motor nerves and high anti-
GM1 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 chro-
matolysis 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 iden-
tical 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 pro-
gressed distally over the previous 3 years. In the 1 year prior to examination, the patient had diffi-
culty 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, pro-
longed 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, fibril-
lations, and PSW. Flail arms are supposed to be pathognomomic of ALS. Brisk knee reflexes and nee-
dle 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 demyeli-
nating 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).
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 sec-
ond 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 remis-
sion 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 ini-
tial 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 mod-
erate atrophy in the right and left forearm flexor surfaces; fasciculations in the intrinsic hand muscles;
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asymmetrical weakness in the right arm, left forearm, right lower leg, and left anterior tibialis mus-
cles; 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 sen-
sory 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).

With high daily prednisone treatment, the patient returned to normal within four months and main-
tained 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 dis-
cussed above, the features of MMSDN are almost identical to MMN, except for an additional sen-
sory 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 Lewiss paper,75 which has
often been quoted as the first paper on MMN, showed sensory symptoms and findings. Thus, this
condition is sometimes called LewisSumner syndrome.
CASE 11: PAINFUL SENSORY NEUROPATHY FOR 5 YEARS
Case Presentation
A 58-year-old female with a 12-year history of Crohns disease and a permanent ileostomy for 3
years developed burning pain in her feet 5 years prior to our evaluation, while taking metronidazole
for Crohns 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 find-
ings 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
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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 neu-
ropathy 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.
With IVIG treatment and low-dose prednisone, this patients 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 cen-
ters 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 dis-
ease.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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with specific clinical, electrodiagnostic and laboratory features. Dutch GuillainBarr study group, Brain,
118(Pt. 4), 841, 1995.
52. Griffin, J.W. et al., GuillainBarr 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 GuillainBarr 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
GuillainBarr 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 degen-
eration in acute GuillainBarr 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 GuillainBarr syndrome: the spectrum of distal conduc-
tion 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 GuillainBarr
syndrome: evidence for macropahge-associated demyelination, Muscle and Nerve, 16, 744, 1993.
58. Berciano, J. et al., Fulminant GuillainBarr syndrome with universal inexcitability of peripheral nerves: a
clinicopathological study, Muscle and Nerve, 20, 846, 1997.
59. GrandMaison, F., Feasby, T.E., Hahn, A.F., and Koopman, W.J., Recurrent GuillainBarr syndrome.
Clinical and laboratory features, Brain, 115, 1093, 1992.
60. Thomas, P., Lscelles, R., Hallpike, J., and Hower, R., Recurrent and chronic replasing GuillainBarr poly-
enuritis, 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 fol-
low-up, J. Neurol., 242, 623, 1995.
63. Frohyman, E.M., Rusa, R., Mark, A.S., and Cornblath, D.R., Vestibular dysfunction in chronic inflamma-
tory demyelinating polyneuropathy, Ann. Neurol. 39, 529, 1996.
64. Ro, Y.I., Alexander, B., and Oh, S.J., Multiple sclerosis and hypertrophic demyelinating peripheral neu-
ropathy, 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 aller-
gic 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 per-
sistent 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 demyeli-
nating 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: CHAPTER 7 Figure 2 Macrophage-induced de-
many mononuclear inflammatory cells are scattered myelination (arrowhead). Arrow indicates one thinly
throughout the endoneurial space. CIDP. Paraffin sec- myelinated fiber (remyelinated fiber). CIDP. Semi-
tion. H & E stain. (200 magnification.) thin section. Toluidine/basic fuchsin. (1000 magni-
fication.)
CHAPTER 7 Figure 4 Probable demyelination of

CHAPTER 7 Figure 3 Paranodal widening. Arrow large-diameter fibers. Between two normal myelinated
indicates normal paranodal gap. Two arrowheads in- fibers (arrowheads), there is an area where the large
dicate paranodal widening. CIDP. Frozen section. myelinated fibers are lacking. This is probably due to
Modified trichrome. (400 magnification.) 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 magnifica- CHAPTER 7 Figure 6 Denuded axon (de-
tion.) (C) The segment between two arrows indicates seg- myelination). Semithin section. Toluidine blue
mental demyelination. (100 magnification.) and basic fuschin.
CHAPTER 7 Figure 7 Perivascular cuffing of CHAPTER 7 Figure 8 T-cell marker stain identi-
mononuclear inflammatory cells in the endoneurial fies many cells in the endoneurial space. Paraffin sec-
space (arrowhead). A few inflammatory cells are scat- tion. T-cell marker stain. (200 magnification.)
tered nearby in the endoneurial space. Paraffin sec-
tion. H & E stain. (200 magnification.)
CHAPTER 7 Figure 10 Demyelinating and re-
myelinating 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
CHAPTER 7 Figure 9 Perivascular collections of myelinated fiber. Possible lymphocytes are scattered.
mononuclear inflammatory cells along the vessels Semithin section. Vesicular degeneration of myelin is
in the epineurial space in the longitudinal cut. Paraffin seen in one myelinated fiber in the right low corner.
section. H & E stain. (400 magnification.) Toluidine blue/baso fuchsin. (1000 magnification.)
CHAPTER 7 Figure 11 Demyelinated segment of

nerve fiber; segmental demyelination (between two CHAPTER 7 Figure 12 Onion-bulb formation.
arrows). The arrowhead indicates one normal node of Onion bulb formations are observed in almost all nerve
Ranvier. Straightness of nerve fibers in this section fibers: Onion-bulb formations in the normal myeli-
guarantees that this section is cut on an equal plane. nated (arrow) as well as thinly myelinated fibers
Frozen section. Modified trichrome. (200 magnifi- (arrowhead). Semithin section. Toluidine blue. (1000
cation.) magnification.)
CHAPTER 7 Figure 13 Many onion-bulb forma- CHAPTER 7 Figure 14 Endoneurial and epineur-
tions (OBF). One OBF is indicated by the arrowhead. ial perivascular inflammatory cells. The arrow indi-
Notice there are two Schwann cell nuclei surrounding cates some mononuclear inflammatory cells scattered
this nerve fiber. Also notice the marked reduction of in the endoneurial space, and the arrowhead indicates
population of myelinated fibers. Frozen section. a perivascular collection of mononuclear inflamma-
Modified trichrome. (200 magnification.) tory cells in the epineurial space. Paraffin section.
CHAPTER 7 Figure 15 Impressive collection of CHAPTER 7 Figure 16 Prominent endoneurial

small mononuclear cells around the vessels in the edema and many scattered mononuclear cells are
epineurial space. The arrowhead indicates the en- obvious. The bubbly appearance of myelin (arrow)
doneurial space where no obvious inflammatory cells may represent a vesicular degeneration of myelin in
are observed. Paraffin section. H & E stain. (200 the frozen section. Frozen section. H & E stain. (200
magnification.) magnification.)
CHAPTER 7 Figure 18 Remyelinating fibers.
CHAPTER 7 Figure 17 Demyelinating and re- Prominent reduction of population of myelinated
myelinating fibers. The arrow indicates a thinly fibers and a few thinly myelinated fibers. The arrow-
myelinated fiber (remyelinating), and the arrowhead head indicates one thinly myelinated fiber, and the
indicates an almost denuded (demyelinating) fiber. arrow indicates a cluster of tiny fibers (regenerating
Semithin section. Toluidine blue. (1000 magnifica- axonal sprouting). Semithin section. Toluidine blue/
tion.) basic fuchsin. (400 magnification.)
CHAPTER 7 Figure 20 Onion-bulb formation

CHAPTER 7 Figure 19 Perivascular collection of (OBF). The arrow indicates OBF in one nearly de-
mononculear cells in the epineurial space. The arrow- nuded axon (demyelinating). OBF is also observed
head indicates a histiocyte. Paraffin section. H & E around a few normal myelinated fibers. Semithin sec-
stain. (200 magnification.) tion. Toluidine blue/basic fuchsin. (1000 magnifica-
tion.)
CHAPTER 7 Figure 21 Normal population of CHAPTER 7 Figure 22 Minimal decrease in the
myelinated fibers. Scattered myelin-digestion cham- population of myelinated fibers. The arrow indicates
bers (arrowheads). Frozen section. Modified tri- one myelin-digestion chamber and the arrowhead
chrome. (200 magnification.) indicates a myelin-ovoid. Semithin section. Toluidine
blue/basic fuchsin. (400 magnification.)
CHAPTER 7 Figure 23 Perivascular inflammatory

cells in the epineurial space. Paraffin section. CHAPTER 7 Figure 24 Thinly myelinated fibers
Leucocyte common antigen (LCA) stain. (200 mag- (arrow) in the longitudinal cut. Semithin section.
nification.) 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 degenera- CHAPTER 7 Figure 26 Scattered mononuclear
tion. Frozen section. Modified trichrome. (400 mag- cells in the endo- and epineurial spaces. Paraffin sec-
nification.) tion. 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 CHAPTER 7 Figure 29 MDCs representing active
myelinated fibers. Frozen section. Modified tri- axonal degeneration are obvious. Frozen section.
chrome. (400 magnification.) Modified trichrome. (200 magnification.)
CHAPTER 7 Figure 30 Minimal loss of myeli-

nated fibers and active axonal degeneration. The CHAPTER 7 Figure 31 Moderate loss of myeli-
arrow indicates one lipid-laden macrophage among nated fibers. Onion-bulb formation (OBF) is present
many scattered macrophages. The arrowheads indi- in almost all fibers. The arrowhead indicates OBF
cate clusters of regenerating fibers. The diamond indi- around normal fibers, the short arrow indicates OBF
cates myelin ovoids. Semithin section. Toluidine blue around thinly myelinated fibers, and the long arrow
and basic fuchsin stain. (400 magnification.) 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 mononu-
clear cells and macrophages around vessels in the en-
doneurial space in the ventral root. Paraffin section.
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 popula- CHAPTER 7 Figure 36 Minimal but definite peri-
tion of myelinated fibers. Thinly myelinated fibers vascular mononuclear cells in the epineurial space in
are scattered in the fascicles. The arrow indicates one the longitudinal cut. Nerve fascicle is in the upper
thinly myelinated fiber. Semithin section. Toluidene portion of the figure. Paraffin section. H & E stain.
blue and basic fuchsin stain. (400 magnification.) (200 magnification.)
CHAPTER 7 Figure 37 Moderate loss of myeli- CHAPTER 7 Figure 38 Moderate loss of myeli-
nated fibers. The arrow indicates a denuded axon. The nated fibers. The arrow indicates one denuded axon.
arrowhead indicates thinly myelinated fibers. Semi- The arrowhead indicates one of many thinly myeli-
thin section. Toluidine blue and basic fuchsin stain. nated fibers; the larger arrow indicates a lipid-laden
(400 magnification.) macrophage. Semithin section. Toluidine blue and
basic fuchsin stain. (1000 magnification.)
8 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 neu-
ropathies, which were well established in 1990, and dysproteinemic neuropathies (neuropathies asso-
ciated 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 GuillainBarr syn-
drome (GBS). IgM GM1 antibody was positive in 50 to 80% of cases of multifocal motor neuropa-
thy (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 patho-
logical process.7
ANTI-MAG ASSOCIATED NEUROPATHY

This neuropathy is a disease of the elderly, with a clear-cut male predominance and the following dis-
tinct features: predominantly sensory abnormality, IgM paraprotein, high CSF protein, and unsatis-
factory 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 neu-
ropathy, 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 para-
globside (SGPG), anti-SGPG was also often positive. The NCS showed a distinct pattern: demyeli-
nating neuropathy with markedly prolonged terminal latency.9,10
The pathological findings in the sural nerve biopsy were characterized by segmental demyeli-
nation 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 interme-
diate 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
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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 per-
mission 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 anti-
MAG 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 anti-
bodies 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 demyeli-
nation 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 Waldenstrms
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 gam-
mopathy 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 para-
protein (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 demyeli-
nating 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 par-
ticularly IgM, Waldenstrms 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. 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).
2. 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 predom-
inant feature is equally represented in IgG- or IgA-associated neuropathy.26,29 In monoclonal
gammopathy associated with amyloid neuropathy, axonal degeneration is typical.
3. IgM deposits in the myelin sheaths are specific for IgM-associated neuropathy, being pos-
itive 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 Waldenstrms macroglobulinemia and in a few cases of IgM MGUS neu-
ropathy.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.
4. 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 antibodyassociated neuropathy, and uncompacted myelin (UCM) is typical
of POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin
changes).
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07/13/2001
TABLE 8.1
Dysproteinemic Polyneuropathy
Clinical Features CSF Protein Pathology Nerve Conduction Pattern
Monoclonal gammopathy of undetermined significance CIDP a High Segmental demyelination Demyelinating neuropathy
8:07 AM
(MGUS; benign monoclonal gammopathy)
Amyloidosis, light chain Sensory-motor b Normal Axonal neuropathy; amyloid Axonal neuropathy
Multiple myeloma without amyloidosis c
Sensory-motor Normal Axonal neuropathy Axonal neuropathy
Osteosclerotic myeloma including POEMS d CIDP High Segmental demyelination Demyelinating neuropathy
Page 102
Angiofollicular lymph node hyperplasia CIDP High Segmental demyelination Demyelinating neuropathy
(Castlemans disease)
Waldenstrms macroglobulinernia CIDP High Segmental demyelination Demyelinating neuropathy
Cryoglobulinemic neuropathy Sensory-motor Normal Vasculitis 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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5. 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 demyeli-
nation 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.)
2002 CRC Press LLC

In 25 patients with IgG neuropathy, the nerve biopsy most commonly demonstrated demyelinat-
ing 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 one-
third of the nerve biopsies examined.39 Bleasel et al. reported demyelinating neuropathy with inflam-
matory 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 mon-
oclonal 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 conduc-
tion abnormalities.46,47 In testing OSM patients, the majority had detectable levels of monoclonal M-
protein (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 demyeli-
nation, 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 Ohnishis 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 Castlemans disease, observed in 63 to 82% of cases.50,52
Castlemans 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 dis-
abling.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 degen-
eration 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
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mixture of axonal degeneration and demyelination.53,56 One case revealed an epineurial infiltrate con-
sisting 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 involve-
ment. 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 resem-
blance 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 cel-
lular 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 sen-
sory neuropathy, carpal tunnel syndrome, and autonomic neuropathy are common findings.
NEUROPATHY ASSOCIATED WITH WALDENSTRMS MACROGLOBULINEMIA (WM)

Waldenstrms 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 manifes-
tation. Anti-MAG antibody was found in 50% of patients with neuropathy.63 Neuropathy in
Waldenstrms macroglobulinemia is almost identical to IgM neuropathy in clinical, electrophysio-
logical, and pathological aspects. In most cases, the neuropathy develops after the systemic mani-
festations. 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 anti-
body.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 cryoglobuline-
mia is much more common.
The incidence of clinical neuropathy in cryoglobulinemia is about 7 to 19%.67 Characteristically,
patients present symptoms of Raynauds 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 inflam-
matory axonal neuropathy was observed. In three cases, focal deposits of cryoglobulin, staining pos-
itive 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 exam-
ination, 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 occa-
sional 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 stud-
ies. Examination showed normal muscle strength, mild pes cavus with hammer toes, pin-prick sen-
sation 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 pro-
longed terminal latency (10 msec for median nerve), minimally slow NCV (34.7 m/sec) and no sen-
sory 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 autoan-
tibody-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
patients 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 gammopa-
thy 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. Modified-
trichrome-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 antibodypositive CSDN.
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With azathioprine and intermittent IVIG treatment, this patients 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-MAG-
associated neuropathy. Our patients 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 evalua-
tion. 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, pin-
prick 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 pat-
tern of sensory neuronopathy: normal motor NCS with marked sensory nerve conduction abnormal-
ity. These findings were indicative of a lesion in the sensory neurons in the dorsal root (sensory
neuronopathy), which is typically seen in anti-Hu antibodyassociated 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 antibodyassociated neuropathy.
All work-ups for small-cell lung cancer were negative. With an aggressive combined therapy of high-
dose 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 pro-
longed use of a chain saw and he later experienced some numbness of both feet, which gradually pro-
gressed 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 gas-
trocnemius and anterior tibialis muscles, areflexia, decreased vibration, proprioception, and pin-
prick 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.
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 mon-
oclonal 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 mel-
phalan. 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 gam-
mopathy 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 patients 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 patients 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 fea-
tures of this multisystem syndrome polyneuropathy, organo-megaly, endocrinopathy, M-protein,
2002 CRC Press LLC

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 effu-
sion, 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 are-
flexia and distal leg weakness. An NCS showed axonal neuropathy with some features of demyeli-
nation. 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. BenceJone 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 BenceJone protein was unusual for multiple myeloma and primary amyloidosis.
Sural Nerve Biopsy

The population of myelinated fibers was moderately decreased. Perivascular collections of mononu-
clear cells were noted in the epineurial space (Color Figure 8.16). There were no intramural inflam-
matory 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 neuropa-
thy (Color Figure 8.17). These findings were indicative of inflammatory axonal neuropathy.

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 Castlemans disease. Chest, abdominal, and pelvic CT scans showed patchy interstitial lung dis-
ease 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 Castlemans disease was the final diagnosis.
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Clin. Neurophysiol., 110, 1133, 1999.
55. Scherokman, B., Vukelja, S., and May, E., Angiofollicular lymph node hyperplasia and peripheral neu-
ropathy. 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., OBrien, 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 mul-
tiple myeloma and Waldenstrms 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 mul-
tiple myeloma and Waldenstrms 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 neu-
ropathy 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 mag-
nification.)
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 CHAPTER 8 Figure 4 Many mononuclear inflam-
myelin-digestion chambers (one of them indicated by matory cells in the endoneurial space. Arrow indi-
an arrow) are noted in almost all myelinated fibers. cates one of the ghost fibers as a result of
Inflammatory cells are scattered in the endoneurial myelin-digestion chambers. Paraffin section. H & E
space, especially in the upper section. Paraffin sec- stain. (400 magnification.)
tion. Gomori trichrome stain. (200 magnification.)
CHAPTER 8 Figure 6 Segmental demyelination.

Moderate loss of large-diameter fibers and a few
thinly myelinated fibers (remyelinating) are obvious.
CHAPTER 8 Figure 5 Perivascular inflammatory The arrow indicates a small onion-bulb formation.
cells in the epineurial space. Paraffin section. H & E The arrowhead indicates one denuded axon (de-
stain. (200 magnification.) myelination). Semithin section. Toluidine blue. (400
magnification.)
CHAPTER 8 Figure 7 Axonal degeneration: many CHAPTER 8 Figure 8 Active axonal degenera-
scattered myelin-digestion chambers. Marked loss of tion: many myelin ovoids (arrowhead) and active
population of large-diameter fibers is obvious. Frozen myelin breakdowns (arrow). There is also a minimal
section. Modified trichrome. (200 magnification.) loss of myelinated fibers. Semithin section. Toluidine
blue. (200 magnification.)
CHAPTER 8 Figure 9 Active vasculitis in an epi- CHAPTER 8 Figure 10 Minimal loss of myel-
neurial arteriole. Fibrinoid necrosis is prominent in nated fibers. One thinly myelinated (remyelinating)
the intimal layer of the arteriole (arrow). The arrow- fiber is indicated by an arrow. Semithin section.
head indicates one nerve fascicle. Paraffin section. Toluidine blue and basic fuchsin. (400 magnifica-
H & E stain. (200 magnification.) tion.)
CHAPTER 8 Figure 11 IgM deposit on myelin
sheaths. Myelin sheath of almost all large-diameter CHAPTER 8 Figure 12 Active axonal degenera-
myelinated fibers is clearly stained with IgM anti- tion: many myelin ovoids. Almost all myelinated
body immunofluorescence staining (arrow). Frozen fibers are undergoing active axonal degeneration.
section. IgM antibody immunofluorescence stain. Frozen section. Modified trichrome. (200 magnifi-
(200 magnification.) cation.)
CHAPTER 8 Figure 13 Perivascular collection of

mononuclear cells in the epineurial space (arrows).
CHAPTER 8 Figure 14 Segmental demyelination:
many thinly myelinated fibers of large and intermedi-
ate diameter fibers. Moderate loss of population of
myelinated fibers is present. Semithin section. Tolui-
dine blue. (400 magnification.)
CHAPTER 8 Figure 15 Mixed axonal degenera-
tion 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 pre- CHAPTER 8 Figure 16 Perivascular infiltration of
sent. Semithin section. Toluidine blue. (200 magni- a few mononuclear cells in the epineurial space
fication.) (arrow). H & E stain. (200 magnification.)
CHAPTER 8 Figure 17 Active axonal degenera-

tion. The arrow indicates the largest myelin ovoid.
Almost total loss of large-diameter fibers is obvious.
Semithin section. Toluidine blue and basic fuchsin.
9 Neuropathies with Abnormal

Deposits
There are many neuropathies with abnormal deposits. Most of them are rare and require ultrastruc-
tural electron microscopic study, which is beyond the scope of this book. Readers can find an excel-
lent treatise on this subject in several books.1-3 Amyloid neuropathy, metachromatic neuropathy,
polyglucosan body neuropathy, Fabrys 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 amy-
loidosis, 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 diag-
nosis. 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 pro-
teins 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 con-
duction 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
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TABLE 9.1
Molecular and Genetic Classification of Amyloidosis
Types Clinical Features Molecule of Protein Common Mutation
Nonfamilial amyloidosis
07/13/2001
Primary typea Except for the onset at an older age,
the clinical features and NCS are the
Secondary type associated with same as familial Type I amyloidosis
chronic disease
Familial amyloidosisb
8:10 AM
Type I (Andurade): Lower limb form Sensory neuropathy Transthyretin TTR Met 30
Onset:Third decade. of the leg (preferentially involving pain
and temperature) and autonomic neuropathy
NCS: The markedly abnormal CNAP
Page 116
(either absent potential or reduced amplitude)
in the presence of a normal or mildly slow
motor NCV
Type II (Rukavian): Upper limb form Carpal tunnel syndrome and vitreous Transthyretin TTR Tyr 77
Onset: Middle age. opacity. Relatively benign
NCS: Typical carpal tunnel findings
.
Type III (Van Allen): Generalized form Progressive painful distal Apolipoprotein Point mutation in apolipoprotein A1
Onset: Fourth decade. sensorimotor polyneuropathy gene
NCS: Not reported
Type IV (Meretoja): Cranial nerve form Multiple cranial nerve palsy Gelsolin Point mutation in gelsolin gene
Onset: Third decade. and lattice corneal dystrophy.
NCS: Not reported
a
This includes amyloidosis associated with multiple myeloma and Waldenstrms macroglobulinemia.
b
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.
Abbreviation: NCS, nerve conduction study
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the presence of a normal or mildly slow motor NCV. In Type II FAP, typical findings of carpal tun-
nel syndrome are observed.
Correct diagnosis of familial amyloidosis is important both for genetic counseling and early rec-
ommendation 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 amy-
loid 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 presymp-
tomatic 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 immunoelec-
trophoresis 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 insuffi-
ciency 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 two-
thirds 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 amyloi-
dosis is made on the basis of amyloid in the tissue and serious chronic disease. A few cases of amy-
loid 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, mus-
cle 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

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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 degen-
eration.
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 bire-
fringence 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 use-
ful 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 bire-
fringence has been reported. Almost all types of amyloids also give reddish metachromasia with crys-
tal- 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 neu-
ropathy, 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 syn-
drome may precede generalized amyloidosis by several years and that surgical release usu-
ally affords good relief of symptoms.
2. 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
3. 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 neuropa-
thy, 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 diag-
nostic of familial amyloid neuropathy. For technical adequacy, serial sections must be stained alter-
nately 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 criti-
cal to diagnosis of a small number of sporadic cases. Unfortunately, in 10 to 30% of cases, this tech-
nique 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 accu-
mulation 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 multi-
ple 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 aryl-
sulfatase-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 pro-
nounced, 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
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Diagnosis of MLD does not usually require nerve biopsy. Nerve biopsy is indicated in the fol-
lowing 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. There is an accumulation of metachromatic granules of 0.5 to 1 m in diameter in the per-

inuclear 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
2. In semithin sections, there is a reduction in the myelinated fiber population, metachro-
matically stained granules, many thinly myelinated fibers in relation to the axon diame-
ter, and occasional small onion-bulb formations (Color Figure 9.14).
3. In teased fibers, segmental demyelination and remyelination occur.48,50
4. With electron microscopy, many types of membrane-bound inclusion materials were
reported. Among these, tuffstone bodies seems to be most typical of MLD51: myelin fig-
ures in Schwann cells and lamellated inclusions corresponding to the metachromatic gran-
ules. Both Martin43 and Thomas51 failed to detect any differences in the types of inclusion
among the different forms.
5. 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 macro-
phages, 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%), neuro-
genic bladder (72%), and upper motor neuron signs (82%).53 Atypical cases present with amy-
otrophic 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 apoc-
rine 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 m in diameter. Polyglucosan
bodies were stained pale blue with the modified trichrome stain, basophilic with H & E, metachro-
matic with toluidine blue, and strongly positive with PAS (Color Figure 9.16) before and after amy-
lase 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 der-
mal nerve bundle. Since these bodies increase with aging58,59 as well as with the presence of neu-
ropathy,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 m) should lead to consider-
ation of APGBD, type IV glycogenosis, and Laforas 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 Laforas 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
FABRYS DISEASE (ALPHA-GALACTOSIDASE-A DEFICIENCY)

Fabrys disease is a sex-linked recessive disorder with angiokeratoma, painful neuropathy, dimin-
ished 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 defi-
ciency of the lysosomal enzyme ceramide trihexosidase (alpha galatocidase A). Clinically, there are
no obvious objective findings of peripheral neuropathy except constant dysesthetic pain and occa-
sional 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 auto-
nomic neurons and correlate well with the loss of unmyelinated fibers in the peripheral nerves.
Nerve biopsy is not necessary for the diagnosis of Fabrys 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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1. 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 iden-
tified as osmophilic lipid in the semithin sections.1 In paraffin sections, these lipid inclusions
can be identified only by Kultschitzkys stain.2 These granular inclusions are observed in all
cases and under the electron microscope represent osmophilic lamellar inclusion bodies.
2. 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
3. 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 intern-
odal 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 typ-
ical granular lipid inclusions in the perineurial cells and in the endoneurial blood vessels is diagnos-
tic of Fabrys disease.
FIGURE 9.1 Maltese cross birefringence in perineurium (arrows) in Fabrys disease under polarized light. (With
permission from Bilbao, J.M., Ackermans 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 diag-
nosis of ALD or AMN is made on the assay of very long-chain (26 more carbon) fatty acids in the red-
cell or whole-plasma lipid. Motor nerve conduction is moderately slow in this disorder.12
Nerve biopsy showed the following:
1. Loss of myelinated fibers.73-76 Some authors have reported loss of large and small myeli-
nated fibers,73,74 while others have reported only large myelinated fiber loss.76,77
2. Thin myelin compared with the axon diameter and onion-bulb formation.75,76
3. Teased fibers showed evidence of chronic demyelination and remyelination.
4. 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 nor-
mal. 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 addi-
tion 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 pin-
prick, 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 pre-
sented with sensory neuropathy and autonomic neuropathy: diabetes mellitus and amyloidosis. Since
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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 dysau-
tonomia is rarer in this condition. This was ruled out by the chest CT scan and negative anti-Hu anti-
body. 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).
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 spec-
imen since amyloid may be present in a few sections. Thus, in cases of suspected amyloid neuropa-
thy, 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 great-
aunt 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 (810 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 (Krabbes 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 work-
up 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.
After the diagnosis of metachromatic leukodystrophy was made by the sural nerve biopsy, the refer-
ring 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 bradykine-
sia. 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
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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 neuropa-
thy. 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, neu-
rogenic 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 magni-
fication.) (Courtesy of Dr. Neil Robertson, University Hospital of Wales, Cardiff, Wales.)
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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 exces-
sive 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 dopamin-
ergic therapy.
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CHAPTER 9 Figure 1 Congo-red materials in the
epineurial space in the sural nerve. The red arrow in-
dicates Congo-red material at the edge of the epineur-
ial space, and the red arrowhead indicates one of
several Congo-red stained materials in the vessel
walls of the epineurial space. The green arrow indi-
cates 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 CHAPTER 9 Figure 3 Axonal degeneration.
are well recognizable in the endoneurial space. Marked loss of myelinated fibers is obvious. Arrows
Frozen section. Alkaline Congo-red stain. (200 indicate myelin-digestion chambers, indicating active
magnification.) axonal degeneration. Frozen section. Modified tri-
chrome. (200 magnification.)
CHAPTER 9 Figure 4 Moderate loss of myeli- CHAPTER 9 Figure 5 Congo-red materials in the
nated fibers. Note that many of the remaining myeli- vessel wall in the epineurial space. Paraffin section.
nated fibers are large-diameter fibers. The arrow Alkaline Congo-red stain. (200 magnification.)
indicates two clusters of tiny myelinated fibers indi-
cating regenerating axon sprouting. Semithin section.
Toluidine blue and basic fuchsin. (200 magnifica-
tion.)
CHAPTER 9 Figure 6 Apple-green colored Congo-
red materials (arrow) in a vessel wall in the epineurial
space confirming amyloid. In contrast, collagen fibers CHAPTER 9 Figure 7 Brown materials (arrow)
are colored white. Paraffin section. Alkaline Congo- between muscle fibers represent metachromasia from
red stain under the polarized light. (200 magnifica- the violet-stained muscle fibers. Frozen section.
tion.) Cresyl-violet stain. (100 magnification.)
CHAPTER 9 Figure 8 Amyloid: bright yellow CHAPTER 9 Figure 9 Apple-green amyloid in the
fluorescence (arrow) with thioflavin-T stain in the endoneurial space (red arrow) and in the wall of the
wall of arterioles in the perimysial space in the mus- tiny vessel (blue arrow). Alkaline Congo-red stain
cle. (100 magnification.) under the polarized light. (200 magnification.)
CHAPTER 9 Figure 10 Amyloid: bright red fluo- CHAPTER 9 Figure 11 Brown granules (arrows)
rescence positive to antibodies to kappa light chain. scattered in the endoneurial space represent meta-
See Figure 9.7. Frozen section. Monoclonal antibody chromatic granules. Nerve fibers are stained light
to kappa light-chain. (100 magnification.) pink. Frozen section. HirshPfeiffer cresyl-fast violet.
CHAPTER 9 Figure 12 Dark-gray granules in the CHAPTER 9 Figure 13 PAS-positive metachro-

macrophages (arrow) along the tiny vessels in the en- matic granules in macrophages around the endoneurial
doneurium. Frozen section. Thionine stain. (200 vessel. Frozen section. PASH. (200 magnification.)
magnification.)
CHAPTER 9 Figure 14 Many thinly myelinated CHAPTER 9 Figure 15 Two polyglucosan bodies
fibers (arrowhead). Metachromatic granules in a large (arrows). The red arrow indicates a polyglucosan
macrophage (red arrow). Metachromatic granules in a body with a central core. Semithin section. Toluidine
Schwann cell (blue arrow). Semithin section. blue and basic fuchsin. (400 magnification.)
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 mag-
nification.) (D) Green with modified trichrome.
Frozen section. (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 Fabrys 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 CHAPTER 9 Figure 20 Amyloid in the fatty tissue
the epimysial space in the muscle. (A) Congo-red main the epineurial space in the nerve. (A) Congo-red
terial; (B) Apple-green colored Congo-red material material; (B) Apple-green colored Congo-red mater-
under the polarized light. Paraffin section. Alkaline ial under polarized light. Arrows indicate a small
Congo-red stain. (100 magnification.) nerve fascicle. Paraffin section. Alkaline Congo-red
CHAPTER 9 Figure 22 Polyglucosan body. Dif-
fuse loss of myelinated fibers. One axon contains a
large polyglucosan body (approximately 30 m) with
a round profile in transverse section. It has a lami-
nated appearance with a slightly denser core. The sur-
CHAPTER 9 Figure 21 Scattered metachromatic rounding myelin sheath is thinned. Semithin section.
granules stained purple with crystal-violet stain. Thione and acridine orange. (600 magnification.)
Frozen section. Crystal-violet stain. (200 magnifi- (Courtesy of Dr. N.P. Robertson, University Hospitals
cation.) of Wales, Cardiff, Wales).
10 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 clas-
sification 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 under-
lying genetic disorders. Thus, the term CharcotMarieTooth (CMT) disease has become more pop-
ular 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: pro-
gressive muscular atrophy, CMT disease, RoussyLevy syndrome, DejerineSottas disease, and
Refsums disease.
HMSN TYPE I (HYPERTROPHIC FORM OF THE CMT DISEASE INCLUDING

ROUSSYLEVY 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 bottleleg 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 conduc-
tion 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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TABLE 10.1
Classification, Genetic Defect, and Cardinal Pathological Features of Inherited Neuropathiesa
07/13/2001
Neuropathies Gene Defect Cardinal Pathological Features
Hereditary Motor and Sensory Neuropathy

(HMSN; CharcotMarieTooth Disease [CMT])
HMSN I (CMT 1)
8:27 AM
HMSN IA (CMT 1A) Duplication PMP-22 Hypertrophic neuropathy;
Point mutation PMP-22 demyelination; onion-bulb formation
HMSN II (CMT 1B) Point mutations P0 of Schwann cell processes;
HMSN (CMT 1C) Location not known palpable nerve in 25% of cases
Page 132
HMSN (CMT 1D) Point mutation EGR2
X-linked (CMT-X1) Point mutation connexin-32
X-linked (CMT-X2) Locus on Xq24-q26
Autosomal recessive (see under CMT 4)
HMSN II (CMT 2)
HMSN IIA (CMT 2A) Locus on Lp35p36 Axonal degeneration;
HMSN IIB (CMT 2B) Locus on 3q13q22 loss of large diameter fiber;
HMSN IIC (CMT 2C) Location unknown no OBF
HMSN lID (CMT 2D) Locus on 7pI4
HMSN IIE (CMT 2E) Point mutation P0
Autosomal dominant Location unknown
Autosomal recessive (see under CMT 4)
HMSN III (DejerineSottas Disease ([DSD];

Congenital Hypomyelination Neuropathy)
DSD A Point mutation PMP-22 Hypomyelination/hypertrophic neuropathy,
DSD B Point mutation P0 Prominent OBF of Schwan with cell processes and
Autosomal dominant DSD Point mutations PG basal cell lamina; absence of myelin sheath;
Autosomal recessive Locus on 8q23q24 palpable nerve in most cases;
CSF protein: elevated
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Table 10.1 (continued)
CMT 4 (Autosomal Recessive CMT)

CMT 4A Locus on 8q1321.l Hypomyelination, basal lamina onion bulbs;
CMT 4B Locus on 11q23.l demyelinating, focally folded myelin sheaths;
07/13/2001
CMT 4C Locus on 5q23q33 hypomyelinaton, basal lamina OBF;
HMSNL (deafness, Balkan Gypsies) Locus on 8q24 demyelination with poorly developed OBF
Complex forms of HMSN Location unknown
Hereditary Sensory and Autonomic
8:27 AM
Neuropathies (HSAN)
HSAN I (dominant sensory neuropathy) Locus on 9q22.1q22.3 Axonal degeneration in the small and intermediate
fibers; sparing of large fibers;
Page 133
HSAN II (recessive sensory neuropathy) Location unknown virtual absence of myelinated fibers
HSAN III (RileyDay syndrome, Locus on 9q31-33
familial dysautonomia)
HSAN IV (congenital sensory neuropathy with anhydrosis) Virtual absence of unmyelinated fibers;
HSAN V (sensory neuropathy with loss of small myelinated fibers) marked loss of small myelinated fibers
Hereditary Neuropathy with Liability to

Pressure Palsies (HNPP)
HNPP Deletion PMP-22; Tomaculous neuropathy
point mutation PMP-22;
location unknown
Giant Axonal Neuropathy Locus unknown Giant axonal neuropathy
Familial Amyloid Polyneuropathies (FAP)

TTR-related FAP Mutations transthyretin Amyloid; axonal degeneration
Apolipoprotein A1-related FAP Mutations apolipo-protein A1
Gelsolin-related FAP Mutations gelsolin
a
This is based on two review articles.6,98
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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 (2545 m/sec) in the
intermediate group.2,11,12
Although the clinical and electrophysiological features are relatively uniform in autosomal dom-
inant 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 forma-
tion (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 dor-
sal 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. Numerous OBFs are the pathological hallmark of HMSN Type 1 (Color Figures
10.110.6).* These OBFs are made up of circumferentially directed Schwann cell
processes with abundant cytoplasm and a normal content of organelles.
2. Loss of large-diameter fibers5,8
3. Teased fibers showing extensive segmental demyelination and remyelination
4. 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. 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.
2. 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.
3. Motor NCV is inversely proportional to the number of onion-bulb lamellae and to the pop-
ulation 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 remyeli-
nation and OBF in sural nerve biopsies from five affected members of the same kinship. In this dis-
order, the peripheral nerves are thickened and palpable on clinical examination in only one-quarter of
patients.4
ROUSSYLEVY SYNDROME
RoussyLevy syndrome has the clinical features of both CMT disease (hypertrophic type) and essen-
tial tremor. Because of this combination of clinical features, Dyck and Lambert20 classified this syn-
drome 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 Levys 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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2. Conspicuous OBFs formed by overlapping Schwann cell processes together with

segmental demyelination
3. Teased fiber preparation showing segmental and paranodal demyelination and remyelina-
tion25
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 malemale 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 clas-
sic 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 involve-
ment of the hands, and normal nerve conduction in comparison with Type I HMSN. It is still inher-
ited 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. Loss of large-diameter fibers

2. Normal unmyelinated fibers
3. Teased fibers showing axonal degeneration, the most prominent change
4. A majority of studies noted no OBF,8,11,17 but occasional mild OBF was described by Dyck5
5. 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 dis-
orders. 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 (DEJERINESOTTAS DISEASE; DSA AND DSB)

The DejerineSottas 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 find-
ing in this disease.10
The sural nerve biopsy has the following characteristic findings:
1. 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
2. Severe loss of large- and intermediate-sized myelinated fibers.33
3. Teased fibers showing prominent segmental demyelination and remyelination.
Compared with HMSN Type I, this disorder shows a more severe form of hypertrophic neu-
ropathy.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 vari-
ant of HMSN Type III, has clinical features identical to those of DejerineSottas 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 find-
ings in the nerve: a virtual absence of myelin sheaths and myelin breakdown. Motor nerve conduc-
tion is markedly abnormal: terminal latencies are markedly prolonged, and motor NCVs are
markedly slow.10
FIGURE 10.1 Congenital dysmyelinating neuropathy. DejerineSottas: 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. A virtual absence of myelin sheaths in all of 12 reported cases (Color Figure 10.8).38,41-47
2. Prominent OBF in 8 of 12 reported cases.38,39,41,43,48 OBFs are essentially composed of multi-
ple layers of basement membrane (Figure 10.1). Schwann cell nuclei are also increased.38,39
3. No evidence of myelin breakdown in 11 of 12 reported cases, with a few exceptions in one case.43
4. Teased nerve fibers showing no myelin in two studied cases.39,43
Guzzeta et al. compared histological features between congenital hypomyelination neuropathy and
DejeriineSottas 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 juve-
nile forms (DejerineSottas 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 character-
ized 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
Morvans syndrome, lumbosacral syringomyelia, and sensory radicular neuropathy. In 1975, Dyck
and Ohta classified these disorders into four types: hereditary sensory neuropathy (HSN) Types
IIV.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 com-
mon 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 IIV are congenital or infantile-
onset, 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 DENNYBROWN; DOMINANT HSN; HSAN TYPE I)
This is a rare, dominantly inherited, sensory neuropathy primarily affecting the distal lower extrem-
ities. 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 pain-
less 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 DennyBrowns 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, DennyBrown
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 OBrien 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 OBrien 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 Danons three cases, large and small fibers were equally affected. Thus, the
sural nerve biopsy findings confirmed the autopsy findings in DennyBrowns 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. A virtual absence of myelinated fibers (Color Figure 10.10).

2. A relative preservation of unmyelinated fibers.
3. A teased fiber study showed no myelinated fibers in the several hundred strands of nerve
fiber examined.58 In Jedzejowska and Milczreks 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 fam-
ily 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) susceptibil-
ity to pressure palsies following relatively minor episodes of compression or ischemia; (2) improve-
ment 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 11.212, 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 dis-
ease has diminished considerably.
Sural nerve biopsies in HNPP show a characteristic pathology: tomaculous neuropathy.71,72
Features of this neuropathy are as follows:
1. 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 sec-
tions (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 m).71
2. 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 pro-
portion 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
3. In teased fibers, tomacula ranged from 40 to 250 m in length (Color Figure 10.15).
Segmental demyelination and remyelination were consistent findings.65,71,72
4. 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 clini-
cally 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 neu-
ropathy 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 syn-
onymous with HNPP, but HNPP should be the diagnostic choice until proven otherwise in the pres-
ence 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 abnor-
mal 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 micro-
filaments within the cytoplasm of many cells including endoneurial fibroblasts, endothelial cells, per-
ineurial 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. These giant axons are not morphologically different from giant axons found in toxic neu-
ropathies (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 sec-
tions, 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 m 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.
2. Teased nerve fibers characteristically show single or multiple spindle-shaped or fusiform
swellings along axons measuring from 40 to 350 m in length and 10 to 30 m in diame-
ter (Color Figure 10.20). Some segmental demyelination may be shown together with
giant axons.79,83
3. 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.
FRIEDREICHS ATAXIA
Friedreichs 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. A decrease in the number of myelinated fibers, predominantly large-diameter fibers.87,88

2. Teased fibers demonstrating segmental demyelination and remyelination.88 Statistical
evaluation of this segmental demyelination has shown that its occurrence is highly clus-
tered, 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 obser-
vations 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 his-
tory was normal. After giving birth to a child at age 18, the patients tremors became worse and she
began to have cramps in her toes and calf muscles. One year prior to examination, she began to expe-
rience 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 neu-
rological 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 sen-
sory polyneuropathy typical of HMSN Type 1 (CMT 1A).
Case Analysis
It is interesting that the initial presentation of this patients 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 autoso-
mal 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,
RoussyLevy 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 RoussyLevy syndrome were the final diagnosis.
Two other members of the patients 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 patients lower leg strength, and her tremor was
well controlled with Inderal and valium.
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Comments
RoussyLevy 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 syn-
drome as Type I HMSN because they concluded that RoussyLevy 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, mod-
erate weakness in the gastrocnemius muscles, pes cavus, diffuse atrophy in the lower leg, thick per-
oneal nerve at the fibular head, and sensory impairment below the mid-shin level. An NCS showed
uniform slowing (1520 m/sec) between the segments and nerves with conduction block in the wrist-
elbow 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.
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 pathog-
nomonic 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, DejerineSottas neu-
ropathy, 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.
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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 hered-
itary 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 moder-
ate numbers of nerve fibers with focally folded myelin (Color Figure 10.23).
PMP-22 duplication was found in the genetic blood test for CMT. Even with this information, fam-
ily 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 child-
hood. 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 demyelina-
tion. 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 reces-
sive 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 walk-
ing, but her mother had noted some clumsiness with frequent falling episodes. At age 2, she was eval-
uated for flat feet. She continued to have a clumsy gait, and at age 10 she underwent surgery for foot
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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 patients 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, diffi-
culty 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 pos-
itive. 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, DejerineSottas neuropathy (HMSN Type
III) was a definite possibility. NCS findings were compatible with DejerineSottas 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.
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 clini-
cal 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 electrophysiolog-
ical hallmarks of acquired demyelinating neuropathy, were supportive of acquired inflammatory neu-
ropathy.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
WORKERS 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 neuro-
logical findings were as follows: absent knee and ankle reflexes; decreased biceps, triceps, and bra-
chioradialis 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 workers 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 neu-
rological 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).
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 asym-
metrical polyneuropathy with pes cavus and high CSF protein (170 mg/dl) and had been treated with
prednisone with some improvement. His fathers NCS showed nonuniform demyelinating neuropa-
thy with conduction block and dispersion. A review of his biopsy also showed tomaculous neuropa-
thy. Over the next 6-month period, the patients 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 patients 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.
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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 pro-
gressed. 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 per-
oneal 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 pro-
gression of sensory neuropathy and nonuniform demyelinating neuropathy in the NCS.94 CSF pro-
tein 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.
The patient exhibited unresponsiveness to IVIG and a side-reaction to imuran. Within 2 months, weak-
ness developed in the patients 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 avail-
ability 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 polyneu-
ropathy, 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 dia-
betes 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 docu-
mented 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, preco-
cious puberty, and insulin-dependent diabetes.
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38. Kennedy, W.R., Sung, J.H., and Berry, J.F., A case of congenital hypomyelination neuropathy; clinical,
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ings 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.
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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. Gabrels-Festen, A. and Gabrels, 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 neu-
ropathy 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 fam-
ilies with an autosomal recessive demyelinating form of CharcotMarieTooth disease, Neurology, 48,
867, 1997.
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52. Kataydjieva, L. et al., Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromo-
some 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,
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. OBrien, 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 sen-
sory 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 CharcotMarieTooth disease type I and heredi-
tary 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 associ-
ated 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 Friedreichs ataxia: an
examination by light and electron microscopy of the posterior nerve roots, posterior root ganglia, and
peripheral sensory nerves in cases of Friedreichs ataxia, Brain, 91, 803, 1968.
88. Dyck, P.J. and Lais, A.C., Evidence for demyelination secondary to axonal degeneration in Friedreichs
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 heredi-
tary 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
CharcotMarieTooth disease, Neurology, 52, 859, 1999.
93. Gabrel-Festen, A.A.W.M. et al., Chronic inflammatory demyelinating polyneuropathy in two siblings, J.
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 ab-
sence 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 onion-
bulb formations, is the only feature which is clearly CHAPTER 10 Figure 3 Onion-bulb formation. Fine
seen. Fine layers of onion-bulb formations are not layers of onion-bulb formation around the myelinated
clearly seen in most nerve fibers. Paraffin section. fibers (arrow) are clearly visible here. Frozen section.
H & E stain. (400 magnification.) Modified trichrome stain. (1000 magnification.)
CHAPTER 10 Figure 4 One myelinated fiber sur- CHAPTER 10 Figure 5 Onion-bulb formations
rounded by seven Schwann cell nuclei (arrow) is the around a normal myelinated fiber (yellow arrow), de-
only feature suggestive of onion-bulb formations. nuded axon (demyelinated fiber; red arrow), and
Frozen section. H & E stain. (400 magnification.) thinly myelinated (remyelinated; pink arrow) fibers.
Semithin section. Toluidine blue. (400 magnifica-
tion.)
CHAPTER 10 Figure 6 Onion-bulb formations CHAPTER 10 Figure 7 Spotty loss of myelinated
around normal myelinated fibers (arrows). Separation fibers in neuronal CMT, otherwise normal findings.
between myelinated fibers is also obvious here. Semithin section. Toluidine blue. (400 magnifica-
Semithin section. Toluidine blue and basic fuchsin tion.)
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 (ar- CHAPTER 10 Figure 10 Severe loss of myeli-
rows). At least two fibers with focally folded myelin nated fibers in HSN II. Only six myelinated fibers are
are distinctly identifiable here. OBFs are clearly seen. identifiable in this nerve fascicle. In six other fasci-
Semithin section. Toluidine blue and basic fuchsin cles, there was total loss of myelinated fibers.
stain. (400 magnification.) Paraffin section. Kultschitzkys hematoxylin stain.
CHAPTER 10 Figure 11 Two sausage tomacu- CHAPTER 10 Figure 12 Four huge tomaculae
lous myelin (arrows) on the longitudinal cut. Frozen myelinated fibers (arrows) stand out from other
section. Modified trichrome. (200 magnification.) myelinated fibers in the transverse cut. Frozen sec-
tion. Modified trichrome. (200 magnification.)
CHAPTER 10 Figure 14 Thickened myelin is ob-
vious. Axon is tiny in comparison with hugely thick-
ened myelin. Some fibers have thinly myelinated
CHAPTER 10 Figure 13 Tomaculous myelin is fibers. Semithin section. Toluidine blue stain. (300
obvious in this field. Semithin section. Toluidine blue. magnification.)
A B
CHAPTER 10 Figure 15 (A) Segmental demyeli- CHAPTER 10 Figure 16 Two giant axons surrounded
nation in one internodal segment between two thin ar- by myelin sheaths (arrows). Frozen section. Modified
rows. Thick arrows indicate sausage like tomaculae. trichrome. (200 magnification.)
(B) Various forms of tomaculous change.
CHAPTER 10 Figure 18 Giant axon in giant ax-
onal neuropathy. Giant axons (arrows) are character-
CHAPTER 10 Figure 17 Two giant axons (arrows) ized by green globules which are not surrounded by
in one fascicle. Population of myelinated fibers is rel- any red myelin sheath. This is a strong contrast to the
atively normal in this nerve fascicle. Frozen section. giant axons in Figure 10.17. Frozen section. Modified
Modified trichrome. (200 magnification.) trichrome. (200 magnification.)
CHAPTER 10 Figure 19 Giant axons (red arrows) CHAPTER 10 Figure 20 Arrows indicate two spin-
with thinly myelinated fibers. The giant axon is com- dle-shaped giant axons in the teased nerve.
pared with the size of normal axon (yellow arrow).
Semithin section. Toluidine blue. (400 magnifica-
tion.)
CHAPTER 10 Figure 21 Onion-bulb formation in CHAPTER 10 Figure 22 Onion-bulb formation in
RoussyLevy syndrome. Moderate decrease in myeli- CMT 1A. Marked loss of myelinated fibers. Onion-
nated fibers. The red arrow indicates one of many bulb formations are present in every nerve fiber re-
onion-bulb formations around normal myelinated gardless of whether myelin is present or not. Semithin
fibers. The blue arrow indicates three Schwann cell section. Toluidine blue and basic fuchsin. (400 mag-
nuclei around myelinated fibers. Frozen section. nification.)
Modified trichrome. (200 magnification.)
CHAPTER 10 Figure 23 Three focally myelinated CHAPTER 10 Figure 24 Onion-bulb formation in

fibers (arrows) in addition to OBF in CMT 1A. Many congenital hypomyelination neuropathy. Severe loss
more fibers show onion-bulb formations. Semithin of myelinated fibers. Many ill-defined onion-bulb
section. Toluidine blue and basic fuchsin. (400 mag- formations surrounded by small or no myelinated
nification.) fibers (arrows). Frozen section. Modified trichrome.
CHAPTER 10 Figure 26 Tomaculous myelin changes
in hereditary neuropathy with liability to pressure
CHAPTER 10 Figure 25 Ill-defined onion-bulb palsy. Larger tomaculum (red arrow) and smaller one
formations are prominently recognized by PASH (blue arrow). Semithin section. Toluidine blue. (1000
stain, indicating basal lamina onion-bulb formation. magnification.)
PASH is good for staining basal lamina. Frozen sec-
tion. PASH stain. (400 magnification.)
CHAPTER 10 Figure 27 Tomaculous myelin changes CHAPTER 10 Figure 28 Four giant axons in giant
(arrows) are only visible here. All other myelinated axonal neuropathy. Semithin section. Toluidine blue.
fibers are lost. Frozen section. Modified trichrome. (400 magnification.)
11 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 neu-
ropathy, 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 sar-
coidosis 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,
Langhans 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 peri-
angiitis 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 sar-
coidosis 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 Tinels sign.13 To date, nine similar cases have been
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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 fasci-
cles. 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, 30C
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 inde-
terminate type which has not established itself into one of the three types. This classification depends
on the hosts 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 lepro-
matous 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 pres-
ence 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 manifes-
tation without typical skin lesions or a positive skin smear. In those cases, skin biopsied from anes-
thesic 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 super-
ficial 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, vas-
culitic, 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 biop-
sies. 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 find-
ings: 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 neurolog-
ical deficit occurs.
Pathological features in the nerve are different according to the type of leprosy.18,23 In indetermi-
nate 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 per-
ineurium 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 cardi-
nal 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). Granu-
lomatous inflammatory response is minimal. The overall architecture of the nerve is better pre-
served, 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 bac-
teria. 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 ery-
thema 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
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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 sub-
acute progressive sensorimotor polyneuropathy, cranial neuropathy, mononeuropathy multiplex, or
an isolated median or sciatic nerve palsy. The most common EMG abnormality was axonal neu-
ropathy. 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 diag-
noses have been made by nerve biopsy due to the emergence of this procedure as a definitive diag-
nostic 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 clini-
cally 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 11.911.11). Perivascular cuffing of lymphoma-
tous 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,3141 and 6 were positive for T-cell markers.37,4144
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DIABETIC NEUROPATHY
DIABETIC OPHTHALMOPLEGIA
Third, fourth, and sixth cranial neuropathies are commonly associated with diabetes. Ophthalmo-
plegia 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 intra-
cavenous 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 nar-
rowing of arterioles in Asbury et al.s case.46 From these, ischemia is considered a likely cause of dia-
betic ophthalmoplegia.
DIABETIC AMYOTROPHY (DIABETIC PROXIMAL NEUROPATHY)

Diabetic amyotrophy is characterized by painful amyotrophy involving pelvic girdle muscles, espe-
cially the thighs, occurring in older diabetic patients; high CSF protein; and lumbosacral radiculo-
plexoneuropathy 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 infiltra-
tion 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 m 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 dia-
betic 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 vascu-
lar and perivascular inflammation, vessel wall necrosis, and evidence of previous bleeding). Kelkar
et al.54 also reported polymorphonuclear vasculitis affecting epineurial vessels consisting of trans-
mural 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 neu-
ropathy (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 effec-
tive 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 associ-
ated 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 degen-
eration and segmental demyelination.63 According to Dyck et al., segmental demyelination in dia-
betic 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 biop-
sies 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 respon-
sible 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 dyspro-
teinemic 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, orig-
inally 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 demyelina-
tion may have been in excess of the amount of axonal loss, but frank demyelination was not demon-
strated. 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 seg-
mental 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 thin-
ner 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 degenera-
tion.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 sec-
ondary to axonal degeneration.
ALCOHOLIC NEUROPATHY
Alcoholic neuropathy is one of the most common neuropathies in the U.S. It usually produces a sym-
metrical polyneuropathy. There is considerable evidence that thiamine deficiency plays an important
role in the pathogenesis of alcoholic neuropathy. Three studies clearly established that alcoholic neu-
ropathy 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 Buchthals 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 degenera-
tion,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 infil-
tration 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
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PYRIDOXINE-INDUCED SENSORY NEUROPATHY

A few cases of sensory ataxic neuropathy have been reported after high daily pyridoxin consump-
tion. 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 popula-
tions.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: lympho-
cytic meningitis, cranial neuritis, and radiculoneuritis.96 In Europe, this disease is called
GarinBujadoux 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 neuropa-
thy.97 Lymphocytes and plasma cells were seen around many epineurial, perineurial, and endoneur-
ial small vessels. There was no vasculitic change. In addition, axonal degeneration was the
predominant finding, in contrast to demyelination in the GuillainBarr 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 immuno-
deficiency 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-posi-
tive 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 deci-
sion 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 devel-
oped. The predominant manifestation of HIV-vasculitic neuropathy was distal and symmetric
polyneuropathy (8 of 18 cases) and asymmetrical polyneuropathy (6 cases) with weight loss, myal-
gia, weakness, and leg tenderness. Mononeuritis multiplex was least common. In most patients, vas-
culitic neuropathy was not associated with other organ involvement and was usually monophasic
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TABLE 11.1
Peripheral Neuropathy in AIDS
Type of neuropathy Main etiology Rare etiology Main pathology of nerve
Distal polyneuropathy HIV-related Neurotoxic drugs Axonal neuropathy
Vitamin B12 deficiency
Diffuse infiltrative lymphocytosis
Inflammatory demyelinating Autoimmune Cytomegavirus Inflammatory demyelinating
polyneuropathy: GBS/CIDP neuropathy
Progressive polyradiculopathy Cytomegarovirus Lymphoma Cytomegarovirus
Diffuse infiltrative lymphocytosis
Mononeuropathy multiplex Vasculitis 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 electrophys-
iological 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, predomi-
nantly 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 hyper-
lymphomatosis and multivisceral CD8 T-cell infiltration, which may affect peripheral nerves.
Clinically, it resembles Sjgrens 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 CMV-
proven 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 m 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
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the nerve was assumed on the basis of large blasts with basophilic cytoplasm, vacuoles, and multi-
ple nucleolei consistent with Burkitts 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, ham-
strings, 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 11.111.3). Acid-fast baccilli, silver, and van Gieson
stains did not show any organisms.
Final Diagnosis
Sarcoid polyneuropathy was the final diagnosis.
With steroid therapy, the patients 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 tib-
ialis 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.
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 reso-
nance 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 myelo-
radiculopathy. 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 con-
tinued progression of symptoms, including ataxic gait, weakness, fatigue, anorexia with weight loss,
insomnia, dysesthesia, and dysarthria. Upon readmission, the patient was nonambulatory and ill-
appearing. Abnormal findings were poor attention, perseveration, bilateral ptosis, dysarthria, hyper-
active 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 pro-
gressive multifocal leukoencephalopathy (PML). Cerebral angiography was normal. Computed
tomography of the chest and abdomen revealed patchy atelectasis of the lungs with multiple nonen-
hancing 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 periph-
eral 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 find-
ings 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, Krabbes leukodystrophy, and neurolym-
phomatosis. 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, promi-
nent 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.
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 diag-
nosis 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, includ-
ing 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 compli-
cated by diabetic nephrotic syndrome, diabetic retinopathy, and hypertension with hypertensive car-
diovascular 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 Kulschitskys stain and marked small-
vessel 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 fragmen-
tation 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 patients weakness progressed to the point that she required a walker. In the mean-
time, 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 weak-
ness 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 patients neurological problem was
correctly identified as neuropathy. NCS/EMG findings were said to be typical of diabetic neuropa-
thy 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-diges-
tion 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 intra-
mural inflammatory cells were noted. Inflammatory axonal neuropathy was the biopsy diagnosis.
Final Diagnosis
Inflammatory diabetic neuropathy was the final diagnosis.
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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 inflam-
matory 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 pro-
teinuria. One year before examination, because of chronic renal failure, he was placed on hemodial-
ysis. 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 fail-
ure 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 symmetri-
cal sensory-motor polyneuropathy which could well be uremic neuropathy. In view of his high sedi-
mentation 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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Cytoxan and prednisone therapy improved this patients renal function and peripheral neuropathy.
Comments
This case represents the indication for nerve biopsy in the setting of possible neuropathy due to sys-
temic 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 vas-
culitic neuropathy. This changed the patients treatment. Another lesson from this case is that a sym-
metrical 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 dis-
tally; 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 patients 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.
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 sen-
sory and motor neuropathy, predominantly involving the distal segments and the legs. Sensory neu-
ropathy 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
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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 sensa-
tion 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 neu-
ropathy 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 patients neuropathy.
Sural Nerve Biopsy
The biopsy showed a minimal reduction of the myelinated fibers and many myelin-digestion cham-
bers 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 wide-
spread 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 degenera-
tion in two cases,122,123 while one other case revealed minimal axonal degeneration and onion-bulb for-
mation.123 These findings suggest that the predominant pathological process in porphyric neuropathy
is axonal degeneration.
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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 immunodefi-
ciency 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 demyelinat-
ing 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 immunod-
eficiency 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 lymphocyto-
sis 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 path-
logical study, Ann. Neurol., 29, 139, 1991.
114. Gold, J.E., Jimenez, E., and Zalusky, R., Human immunodeficiency virus-related lymphoreticular malig-
nancies and peripheral neurologic disease. A report of four cases, Cancer, 61, 2318, 1988.
115. Mazza, G., ber 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., Polyradiculonvrite au cours dune leucmie lymphode chronique. Etude ultrastructurale
dune biopsie de nerf priphrique. 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 inter-
mittent 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 copropor-
phyria. Light and ultrastructural studies in two sural nerve biopsies, Acta Neuropathol., 63, 96, 1984.
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CHAPTER 11 Figure 2 Granulomatous panangi-
itis in sarcoid neuropathy. Prominent granuloma infil-
CHAPTER 11 Figure 1 Noncaseating granuloma tration of the entire vessel wall and total occlusion of
(arrow) in the perineurium. A giant cell, epithelioid vessel in one arteriole in the epineurial space. Double
cells, and lymphocytes are present in a granuloma. arrows indicate giant cells. Lymphocytes are scat-
This granuloma compressed the endoneurium (arrow- tered in the epineurial and perineurial spaces. The ar-
head). Thickened perineurium with lymphocyte infil- rowhead indicates the nerve fascicle. Paraffin section.
tration is noted opposite the granuloma. Paraffin H & E stain. (400 magnification.)
section. H & E stain. ( 400 magnification.)
CHAPTER 11 Figure 4 Sural nerve of a patient

with tuberculous leprosy. A granuloma with epithe-
CHAPTER 11 Figure 3 Axonal degeneration in lioid and giant cells is observed. Paraffin section.
sarcoid neuropathy. Scattered myelin-digestion H & E stain. (400 magnification.) (Courtesy of
chambers (yellow arrows) are indicative of axonal Professors O.J.M. Nascimento and M.R.G. Freitas,
degeneration. The red arrow indicates granuloma in Universidad Federal Fluminense, Rio de Janeiro,
the perineurial space. Frozen section. Modified Brazil.)
trichrome. (200 magnification.)
CHAPTER 11 Figure 5 Intense fibrosis in the en- CHAPTER 11 Figure 6 Ulnar nerve (biopsy of
doneurium, perineurium, and epineurium, replacing the dorsal sensory branch of the hand) of a patient
the normal structures. Not a single myelinated fiber is with tuberculoid leprosy. Semithin section showing
present in the endoneurium. Mononuclear inflamma- complete loss of endoneurial structures with fibrosis;
tory cell infiltrates are seen in the endoneurial space. a small granuloma is seen. Toluidine blue, (200
Frozen section. Modified trichrome stain. (Courtesy magnification.) (Courtesy of Professors O.J.M.
of Professor Y. Harati, Baylor Medical School, Nascimento and M.R.G. Freitas, Universidad Federal
Houston, TX.) Fluminense, Rio de Janeiro, Brazil.)
CHAPTER 11 Figure 7 Sural nerve of a leproma-

tous leprosy patient. Semithin section showing reduc-
tion 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 CHAPTER 11 Figure 8 Sural nerve of a leproma-
endoneurial space. Semithin section. Toluidine blue tous leprosy patient. Intense mononuclear inflamma-
stain. (400 magnification.) (Courtesy of Professors tory reactions in the sural nerve obliterating normal
O.J.M. Nascimento and M.R.G. Freitas, Universidad anatomical structures. Paraffin section. H & E stain.
Federal Fluminense, Rio de Janeiro, Brazil.) (250 magnification.)
CHAPTER 11 Figure 10 Angiocentric involve-
ment of lymphoid cells in neurolymphomatosis.
Intramural immature lymphoid cell infiltration in one
small perineurial arteriole in the perineurial space.
CHAPTER 11 Figure 9 Immature lymphoid cell Notice many immature large lymphoid cells with
infiltration in the epineurial, perineurial (arrow), and bizarre shapes and some large lymphoid cells with
endoneurial spaces. Paraffin section. H & E stain. the nuclei showing fine chromatin. Paraffin section.
(200 magnification.) H & E stain. (400 magnification.)
CHAPTER 11 Figure 12 Perivascular collection

of inflammatory cells in diabetic neuropathy. Arrows
indicate a perivascular collection of inflammatory
CHAPTER 11 Figure 11 Axonal degeneration in cells in two small arterioles in the epineurial space of
neurolymphomatosis. Many myelin-digestion cham- the sural nerve. Arrowheads indicates two nerve fas-
bers (arrow). Many lymphoid cells (arrowhead) are cicles with total loss of myelinated fibers. Paraffin
scattered in the endoneurial space. Moderate loss of section. Modified trichrome. (200 magnification.)
myelinated fibers is obvious. 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 cal-
CHAPTER 11 Figure 13 Axonal degeneration in cium deposits. Minimal loss of myelinated fibers in
diabetic neuropathy. Scattered myelin-digestion the nearby nerve fascicles. Frozen section. Modified
chambers (yellow arrows) are indicative of axonal trichrome. (100 magnification.)
degeneration. The red arrow points to a normal
myelinated fiber. Moderate loss of myelinated fibers
is obvious. Frozen section. H & E stain. (200 mag-
nification.)
CHAPTER 11 Figure 15 Axonal degeneration in CHAPTER 11 Figure 16 Large-diameter fiber loss

alcoholic neuropathy. Almost all myelinated fibers in Vitamin B12 deficiency. No obvious myelin break-
show myelin-digestion chambers. The arrowhead in- down is observed. However, there are a few clusters
dicates edema in the subperineurial space. Frozen (arrow) of tiny, thinly myelinated fibers indicative of
section. Modified trichrome. (200 magnification.) 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 (Massons trichrome, 250 magnification); (b) marked angiocentric CD8 T-cell infiltra-
tion 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 infec- CHAPTER 11 Figure 19 Sural nerve biopsy
tion in the dorsal root in an AIDS patient. Inflamma- showing obvious endoneurial infiltration of immature
tory necrosis and intranuclear CMV inclusions lymphoid cells. Paraffin section. H & E stain. (200
(arrow). Paraffin section. H & E stain. (Courtesy of magnification.)
Dr. D.M. Simpson, The Mount Sinai Medical Center,
New York.)
CHAPTER 11 Figure 20 Muscle biopsy showing CHAPTER 11 Figure 21 Occlusion of a tiny
prominent endomysial infiltration of immature lym- arteriole in the subperineurial space in diabetic neu-
phoid cells. Frozen section. H & E stain. (400 mag- ropathy (red arrow). Recanalization and thickening of
nification.) 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 CHAPTER 11 Figure 23 Perivascular inflamma-

diabetic inflammatory neuropathy. Prominent myelin- tory cells in a tiny vessel in the subperineurial space.
digestion chambers and moderate loss of myelinated A few scattered inflammatory cells are noted in the
fibers are seen. Frozen section. Modified trichrome. nearby endoneurial space. Paraffin section. Congo-
(200 magnification.) red stain. (400 magnification.)
CHAPTER 11 Figure 24 Axonal degeneration in CHAPTER 11 Figure 25 Vasculitic change in a
vasculitic neuropathy. There are many myelin-diges- small arteriole in the epineurial space. Prominent
tion chambers (red arrow) and many fibers showing intramural infiltration of inflammatory cells and
myelin breakdown (yellow arrow). There are no nor- some narrowing of the central canal. Paraffin section.
mal myelinated fibers. Semithin section. Toluidine H & E stain. (400 magnification.)
blue and basic fuchsin. (400 magnification.)
CHAPTER 11 Figure 26 Axonal degeneration in CHAPTER 11 Figure 27 Axonal degeneration in

alcoholic neuropathy. Prominent myelin-digestion porphyric neuropathy. Varying degree of axonal de-
chambers involving all myelinated fibers. Frozen sec- generation is seen here from a ghost fiber (arrowhead)
tion. Modified trichrome stain. (200 magnification.) to a myelin-digestion chamber (arrow). Frozen sec-
tion. Modified trichrome. (200 magnification.)
12 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 neu-
ropathy is considered to be due to a nutritional deficiency, it is discussed under the heading of sys-
temic neuropathies in Chapter 11.
The following general principles are applied to toxic neuropathies:
1. 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, inflamma-
tory, or vasculitic changes. Exceptions to this rule are demyelinating neuropathies due to
diphtheric toxin, swine-flu vaccine, or amphiphilic drugs such as amodarone and perhex-
ilene. 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 elec-
trophysiological 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.
2. 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 neu-
ropathies are exceptions to this rule, as are individual differences in drug metabolism.
3. 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 continu-
ously 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 diagnos-
tic 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
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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-sniffers neuropathy
Huffers 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
Eosionphiliamyalgia syndrome
a
These are confirmed histologically.
b
Axonal degeneration and segmental demyelination are observed. Predominantly electrophysiologically axonal degeneration.
c
Axonal degeneration and segmental demyelination are observed. Predominantly electrophysiologically segmental
demyelination.
in industry.2-4 Arsenic neuropathy is predominantly sensory in character. In severe cases, motor weak-
ness 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
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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 neu-
ropathy 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 frag-
mentation of myelin and disintegration of axons.5,6 All nine of our cases showed active axonal degen-
eration in the biopsied sural nerve (Color Figures 12.112.4).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 recov-
ery.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, hyperk-
eratosis, 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.

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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 fasci-
culus 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 analy-
sis 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 sec-
tions 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 pre-
sent. The gum lead line, if present, is a helpful clue in diagnosis. Lead encephalopathy is more com-
mon 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 radia-
tors, as well as in alcoholics who drink lead-contaminated moonshine.
Since Gombaults 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 Fullertons 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 moon-
shine whiskey.20 Unfortunately, concurrent alcoholism was a confounding factor in Ohs 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 neu-
ropathy 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 pro-
duces 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 seg-
mental 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
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 signifi-
cant 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 neuropa-
thy. 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 thalido-
mide-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 neu-
ropathies, 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 neu-
ropathies. Exceptions have been few; perhexiline, amiodarone, and suramin neuropathies. Said
reported segmental demyelination in the sural nerve biopsy in five patients with perhexiline neu-
ropathy,34 Jacobs and Costa-Juss reported demyelination with only mild axonal loss in two cases of
amiodarone neuropathy (Color Figure 12.5).35 An accumulation of lysosomal inclusions character-
izes 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 inclu-
sions are well visualized in semithin toluidine-blue stained sections but are not well retained in paraf-
fin-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-Juss, 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 con-
tinuity. This was demonstrated in a teased nerve fiber preparation in Myers original paper.41 Two pre-
vious 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 GuillainBarr syndrome (GBS) follow-
ing 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 neuropa-
thy (Color Figures 12.612.9),45 which is identical to classical GBS, in the other. Brachial plexus
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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 neuropa-
thy, 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 cri-
teria establish the relationship of a suspected toxin to peripheral neuropathy: (1) a characteristic clin-
ical 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 docu-
mentation of neuropathy in experimental animals as yet.
The pathogenesis of these toxic neuropathies is unknown with regard to most agents. In acry-
lamide, 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 sniffers neuropathy,
n-hexane used as a solvent in some contact cements is responsible for neuropathy.49 In huffers neu-
ropathy, 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 con-
tains a high level of thiocyanate, is responsible for neuropathy.54,55
The most important diagnostic procedure in toxic neuropathy caused by industrial and environ-
mental 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 pro-
duce 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 envi-
ronmental 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 disor-
ders. 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 12.1012.13). 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.
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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 neu-
ropathies, 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-sniffers and huffers 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 sim-
ple 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 impair-
ments 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 (perineu-
ritis) and perineurial fibrosis.62 Axonal degeneration was the predominant process.
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EOSINOPHILIAMYALGIA SYNDROME
In 1989 and 1990, there was an epidemic of eosinophiliamyalgia 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 mul-
tisystem syndrome or in isolation.63,64 Electrophysiological studies showed predominantly axonal
neuropathy, and nerve biopsies revealed inflammatory axonal neuropathy. Active axonal degenera-
tion was the predominant feature in 12 of 14 cases.64-67 Inflammatory cells, predominantly lympho-
cytes 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 neuropa-
thy with histological evidence of active demyelination in the nerve biopsy.67 Frank fibrinoid necro-
sis 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 myopa-
thy.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 ner-
vosa with several psychotrophic medications. One week after admission there, she began to have trou-
ble 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 mod-
erate 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 patients fingers, arsenic neuropathy was suspected. An EMG study showed
acute axonal neuropathy with predominant sensory nerve conduction involvement.
Case Analysis
GuillainBarr 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 neu-
ropathy. 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 break-
down of various stages (Color Figures 12.16 and 12.17).
Final Diagnosis
Arsenic neuropathy was the final diagnosis.
The diagnosis of arsenic neuropathy was confirmed by the 24-hour urine, fingernail, and hair test-
ing. The patient gradually improved over a 2-year period. In the meantime, an investigation by law
enforcement authorities implicated the girls stepmother as the culprit who had poisoned her as well
as the stepmothers 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 gas-
trointestinal 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 toe-
nails, 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 promi-
nent electrophysiological findings are marked abnormalities in the sensory and mixed nerve con-
duction in the presence of moderate abnormalities in motor conduction. These electrophysiological
findings are well supported by the histological observation of axonal degeneration as the predomi-
nant 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 pro-
longed 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 neu-
ropathy 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.
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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 GleesMasland 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 12.1012.14).
Final Diagnosis
The final diagnosis was toxic neuropathy due to lacquer thinner (huffers neuropathy).
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 pre-
dominant 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 neu-
ropathy is the histological basis of huffers 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 extrem-
ities 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 demyelinat-
ing neuropathy.
Case Analysis
Subacute progression of predominantly motor weakness, high CSF protein, and demyelinating neu-
ropathy 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 12.612.9).
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Final Diagnosis
CIDP associated with swine-flu vaccination was the final diagnosis.
This patient was treated with 100 mg of prednisone and intensive physical therapy in the rehabilita-
tion 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 vaccinationinduced peripheral neuropa-
thy, many clinical features were similar to those of GuillainBarr syndrome except for two promi-
nent 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 patholog-
ical findings in these cases were identical to those of classical GBS, but there were several atypi-
cal clinical features.
CASE 4: GUILLAINBARR 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, vom-
iting, lethargy, and anuria after ingesting an unknown amount of antifreeze. Initial evaluation dis-
closed 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 pro-
gressive 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 expo-
sure for possible plasmapheresis under the diagnosis of GuillainBarr syndrome. Abnormal neuro-
logical 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 (GuillainBarr syndrome). However, a temporal rela-
tionship to the ingestion of ethylene glycol (EG), renal failure due to EG poisoning, and cranial neu-
ropathy as the initial manifestation of neuropathy strongly suggest that this patients 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 myeli-
nated fibers and a few fibers with thin myelin in proportion to axon diameters. Most likely, these lat-
ter fibers represent partially demyelinated fibers. Teasing of 83 nerve fibers showed paranodal
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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 demyeli-
nating 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 glycolinduced peripheral neuropathy.
Over the next 2 days, despite dialysis, the patient became confused and developed respiratory fail-
ure 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 neu-
rological complications of EG poisoning.69 Among the various neurological complications including
fixed pupils, decreased visual acuity, ophthalmoplegia, facial diplegia, and bulbar palsy, cranial neu-
ropathy 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 neu-
ropathy is not different from the descending form of GBS.
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CHAPTER 12 Figure 1 Many myelin-digestion CHAPTER 12 Figure 2 Many myelin-digestion
chambers indicative of active axonal degeneration. chambers in the longitudinal cut. The arrow indicates
Double arrows indicate two myelin-digestion cham- one myelin-digestion chamber. There are two normal
bers. Moderate decrease (60%) in population of myelinated fibers. Frozen section. Modified tri-
myelinated fibers is obvious. Frozen section. chrome stain. (200 magnification.)
CHAPTER 12 Figure 3 Almost all myelinated CHAPTER 12 Figure 4 Prominent myelin-diges-

fibers are undergoing myelin breakdown indicative of tion chambers in all myelinated fibers except two
active axonal degeneration. The arrow indicates one normal fibers (yellow arrows). The red arrow indi-
fiber undergoing myelin breakdown. Moderate loss cates edema in the subperineurial space. Frozen sec-
(60%) of population of myelinated fibers. Semithin tion. Modified trichrome stain. (200 magnification.)
section. Toluidine blue stain. (400 magnification.)
CHAPTER 12 Figure 5 Demyelination in amio- CHAPTER 12 Figure 6 Perivascular collection of
darone-induced neuropathy. Arrows point to thinly lymphocytes in an epineurial vessel. The arrow
myelinated fibers indicative of remyelination. Also, indicates one nerve fascicle. Paraffin section. H & E
there is a decrease in large-diameter fibers. Semithin stain. (400 magnification.)
section. Toluidine blue and basic fuchsin stain. (400
magnification.)
CHAPTER 12 Figure 7 Segmental demyelination: CHAPTER 12 Figure 8 Minimal loss of myelinated

demyelination in one internode between arrows. fibers in this nerve fascicle. No myelin-digestion
Contiguous to the demyelinated segment, a normal chamber is observed. Frozen section. Modified tri-
myelinated segment is clearly visible. Marked loss of chrome stain. (200 magnification.)
myelinated fibers is obvious in this nerve fascicle.
Frozen section. Modified trichrome stain. (100
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 (ar- CHAPTER 12 Figure 11 Two giant axons (arrows)
rows) are easily identified here as a green center sur- in one nerve fiber. Notice that the axon is not stained.
rounded by thin red myelin. The giant axon Arrowheads indicates myelin ovoids. Frozen section.
(1 arrow) is three times larger in diameter than in a H & E stain. (200 magnification.)
normal large-diameter fiber. The population of myeli-
nated fibers is minimally decreased. Frozen section.
CHAPTER 12 Figure 13 Giant axons in the trans-
CHAPTER 12 Figure 12 Four giant axons (arrow- verse section. Two giant axons are surrounded by a
head) in one nerve fiber. Paraffin section. Holmes sil- thin myelin sheath (arrowhead) while one giant axon
ver and Luxol fast blue stain. (100 magnification.) (arrow) has no myelin sheath. Semithin section.
Toluidine blue and basic function. (400 magnifica-
tion.) (With permission of Oh, S.J., Yonsei Med. J.,
31, 20, 1990.)
CHAPTER 12 Figure 15 Perivascular inflamma-

tory infiltrate in eosinophiliamyalgia. Two centrally
located epineurial vessels are surrounded by eosin-
CHAPTER 12 Figure 14 Giant axon (arrow) and ophilic leucocytes (reddish-brown cytoplasm) and
paranodal demyelination (arrowheads) in teased nerve mononuclear cells. At the bottom of the field is a
fiber. small collection of plasma cells. Paraffin section.
Congo-red stain. (312 magnification.) (With per-
mission 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.
13 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 recogniz-
ing 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 fas-
cicles is easily identified on paraffin sections. Inflammatory cells, Schwann cells, granulomata, and
vascular changes are assessed with the H & E stain. In general, H & Estained 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 inflam-
matory axonal and demyelinating neuropathies, as well as in vasculitic neuropathies. On the other
hand, endoneurial inflammatory cells are strongly indicative of inflammatory demyelinating neu-
ropathy. Perineurial inflammatory cells are commonly observed in lymphomatous neuropathy,
leprosy, and sensory perineuritis. H & E stain can suggest onion-bulb formation (OBF) by identi-
fying 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 subper-
ineurial 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 fea-
ture, 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 identi-
fiable 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 Kultschitzkys stain in the paraffin section. Kultschitzkys 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 semi-
thin sections are far superior to and more reliable than sections stained with Kultschitzkys 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
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TABLE 13.1
Pathological Features and Interpretation
07/13/2001
Histopathological Features Interpretation Diagnostic Possibilities
Paraffin Sections
H & E Stains
Inflammatory Cells
Endoneurial Inflammation Inflammatory demyelinating neuropathy
8:29 AM
Perineurial Inflammation Perineural sensory neuritis; leprosy
Epineurial (usually perivascular) Inflammation Inflammatory demyelinating neuropathy
Inflammatory axonal neuropathy; vasculitic neuropathy
Malignant cells Malignancy Lymphomatous neuropathy
Granuloma
Page 192
Noncaseating Sarcoidosis
Caseating (necrotizing) Leprosy
Vascular change
Intramural cell infiltration Vasculitis Vasculitic neuropathy
Fibrinoid necrosis of wall Vasculitis Vasculitic neuropathy
Occlusion Ischemia Ischemic neuropathy
Thickening Ischemia Diabetic neuropathy
Loss of myelinated fibers Nonspecific neuropathy
Myelin-digestion chamber Axonal degeneration Axonal neuropathy
Onion-bulb formation (OBF) (rarely) Demyelination and remyelination Hypertrophic neuropathy
Selective nerve fascicular degeneration Ischemia Ischemic neuropathy
Central fascicular degeneration Ischemia Ischemic neuropathy
Congo-red Stain
Congo-red materials Amyloid Amyloid neuropathy
Frozen Sections
Loss of myelinated fibers Nonspecific neuropathy
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TABLE 13.1 continued
Myelin-digestion chamber Axonal degeneration Axonal neuropathy

Sausage-like thickening of myelin Tomacula Tomaculous neuropathy
Swollen axon Giant axon Giant axonal neuropathy
07/13/2001
Onion-bulb formation Demyelination and remyelination Hypertrophic neuropathy
H & E Stain See above paraffin sections
PAS Stain
PAS positive body Polyglucosan body Polyglucosan body disease
Cresyl-fast Violet Stain
8:29 AM
Purple-colored material Metachromatic granules Metachromatic neuropathy
Congo-red Stain
Congo-red material Amyloid Amyloid neuropathy
Semithin Sections
Page 193
Loss of myelinated fibers Neuropathy Nonspecific neuropathy
Loss of large-diameter fibers Large-fiber neuropathy Most toxic or metabolic neuropathy
Loss of small fibers Small-fiber neuropathy Diabetic; amyloid; Fabrys disease
Thinly myelinated fiber Remyelination Demyelinating neuropathy
Cluster of tiny thinly myelinated fiber Regeneration (axonal sprouting) Chronic axonal neuropathy
Myelin breakdown Axonal degeneration Axonal neuropathy
Swollen axon Giant axon Giant axonal neuropathy
Onion-bulb formation Demyelination and remyelination Hypertrophic neuropathy
Thick myelin diameter Tomacula Tomaculous neuropathy
Teased Nerve Fibers
Row of myelin-ovoids Axonal degeneration Axonal neuropathy
Paranodal widening Early demyelination Demyelinating neuropathy
Segmental demyelination Active demyelination Demyelinating neuropathy
Remyelinated segment Remyelination* Demyelinating neuropathya
Sausage-like thickening of myelin Tomacula Tomaculous neuropathy
a Exception is axonal regeneration.
2002 CRC Press LLC

the qualitative assessment of the population of myelinated fibers, but it should not be used to evalu-
ate 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 rec-
ognizable by their red-tinged myelin surrounded by Schwann cell nuclei and fine Schwann cell pro-
liferation. 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 identifica-
tion 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 use-
less 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 paraf-
fin sections. PAS staining can easily show polyglucosan bodies. The Congo-red stain has an advan-
tage 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 stain-
ing 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 rec-
ognizing 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 recog-
nized, 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 remyeli-
nation (thus, previous demyelination), and denuded axons, a hallmark of demyelination. Recognition
of denuded axons (demyelination) is more difficult, even on the semithin section. Normally, non-
myelinated nerve fibers do not exceed 3 in diameter, and most fibers are between 0.5 and 2.0 .2 If
an axon is larger than 3 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
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TABLE 13.2
Pathological Features in Axonal Degeneration and Segmental Demyelination
07/13/2001
Axonal Degeneration Segmental Demyelination
Paraffin Section
Modified trichrome Myelin-digestion chambers (MDC) Onion-bulb formation
Kulschitzkys stain Onion-bulb formation
Thinly myelinated fibers
8:29 AM
Frozen Section
Modified trichrome Myelin-digestion chambers Paranodal widening
Giant axon Tomacula
Page 195
Ghost fiber (no axon or myelin) Onion-bulb formation
H & E stain MDC in the longitudinal section
Semithin Section Clusters of tiny thinly myelinated fiber Thinly myelinated fiber (remyelination)
Giant axon Tomacula
Myelin break-down Onion-bulb formation
Myelin-ovoids Denuded axon (demyelination)
Ghost fiber (no axon or myelin)
Teased Nerve Fiber Row of myelin-ovoids Paranodal demyelination

Giant axon Segmental demyelination
Remyelination
Tomacula
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has to assume that a few demyelinated fibers are secondary to severe axonal degeneration. The find-
ing 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 sec-
tions. 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 pres-
ence 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 degen-
eration. 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 nor-
mal 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 (widen-
ing) 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 regen-
eration 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 Dycks 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 predomi-
nant findings. Dycks classification has two advantages4: (1) emphasis is placed on variation of
myelin sheath characteristics within individual nerve fibers rather than on absolute criteria for intern-
odal 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 let-
tered 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-posi-
tive (5685%) classification and low rates of false-positive (318%) 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 proxi-
mal 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 the-
ory, 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 patients values with nor-
mal values in the literature: axonal degeneration, less than 8% of teased nerve fibers,7 and demyeli-
nation, 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 Dycks book.3 Axonal degeneration includes active axonal degeneration and regenera-
tion. Demyelination includes paranodal demyelination, segmental demyelination, and remyelina-
tion. 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 demyelina-
tion, segmental demyelination, and remyelination are essentially the same as the criteria given by
Kalichman et al.4 (Figures 13.113.3). 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 find-
ing to be meaningful because it can be seen following demyelination or regeneration (axonal sprout-
ing) 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 inter-
preted 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
2002 CRC Press LLC

TABLE 13.3
Definitions of Teased Nerve Fiber Categories at the University of Alabama at Birminghama
07/13/2001
Normal Normal myelinated fiber without any abnormality described below or any artifact
Axonal degenerationb
Active axonal degeneration 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.
Regeneration See below
8:29 AM
Demyelinationb
Paranodal 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.
Segmental demyelination 1. Absence of myelin along part of or an entire internode, regardless of internodal length, with preservation of the axon (no myelin
Page 198
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
Tomaculous change Segmental demyelination, but with the formation of globules or sausages
Remyelinationc At least one abnormally short internode (length < 60% of longest internode); myelin thickness is decreased.
Demyelination Additional segmental or paranodal demyelination has to be present with remyelination
Regeneration Additional clusters of two-to-several tiny thnly myelinated fibers in the semithin sections have to be present with remyelination
a
Modified from Kalichmans classification. No. 1 criterion in segmental demyelination is classified as demyelination in Kalichmans classification, and no. 2 criterion in
segmental demyelination is classified as hypomyelination in Kalichmans classification.
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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FIGURE 13.1 Light micrographs of teased fibers clas-

sified 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 nor-
mal 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 m. (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 illus-

trating 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) con-
taining myelin debris adjacent to a region lacking an
intact myelin sheath. (B) In an example of hypomyeli-
nation, note that nodes (arrowheads) demarcate intern-
odes of similar length, but that at least two sequential
internodes have considerably less myelin than those
above and below. Bar = 100 m (= 30 m for high
power image illustrating demyelination). (With per-
mission 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 paran-

odal demyelination. (A) Following two long intern-
odes, a sequence of at least five short, thinly myelinated
internodes is consistent with remyelination. Nodes are
identified with arrowheads. (B) and (C) Low- and high-
power micrographs illustrate two examples of paran-
odal 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 inter-
calated internode. Bars = 100 m (= 30 m for high
power images illustrating abnormal paranodal myeli-
nation). (With permission of Kalichman, M.W., Chalk,
C.H., and Mizisin, A.P., J. Peripheral Nerv. Syst.,
4,239, 1999.)
2002 CRC Press LLC

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 ultrastruc-
tural 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 diagno-
sis is not possible, the pathologist can, at least, differentiate between the diagnoses of demyelinat-
ing 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
2. 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.
3. 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.
4. Kalichman, M.W., Chalk, C.H., and Mizisin, A.P., Classification of teased nerve fibers for multicenter clin-
ical trials, J. Peripheral Nerv. Syst., 4, 233, 1999.
5. Said, G., Indications and value of nerve biopsy, Muscle and Nerve, 22, 1617, 1999.
6. Oh, S.J., Diagnostic usefulness and limitations of the sural nerve biopsy, Yonsei Med. J., 31, 1, 1990.
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Processing of the Nerve

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Case 5: Diffuse Areflexia in an MS Patient

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Vitamin B12 Deficiency Neuropathy

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1 General Concepts of Peripheral

CLASSIFICATION OF PERIPHERAL NEUROPATHY

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Primary lesion Axon Myelin

Abbreviations: CMAP, Compound muscle action potential

BASIC PATHOLOGICAL MECHANISM

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It results from transection of an axon.

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Wallerian degeneration occurs following direct trauma to a nerve. In peripheral neuropathy,

DYING-BACK AXONAL DEGENERATION

Metabolic abnormalities throughout the axon.

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Recovery by axonal sprouting that reinnervates denervated muscles.

Axonal Degeneration in Neuronopathy

Morphologic or metabolic abnormalities in the motor or sensory neurons.

SECONDARY AXONAL DEGENERATION

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Primary damage of the myelin sheath, leaving the axon intact.

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No denervation atrophy in muscles. Disuse atrophy occurs if paralysis is prolonged.

SECONDARY SEGMENTAL DEMYELINATION

ETIOLOGIES OF PERIPHERAL NEUROPATHY

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Rose 80 56 GBS is listed as a known cause.

Prineas 278 14 GBS is listed as a known cause.

Dyck 205 24 Inflammatory neuropathy is listed

Fagius 91 74 Chronic inflammatory or hereditary

McLeod 519 13 Inflammatory neuropathy is listed

A polyneuropathy is a symmetrical, distal, usually ascending neuropathy due to involvement of the

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SIZE OF NERVE FIBERS

SYMPTOMS AND SIGNS

MOTOR NERVE DYSFUNCTION

SENSORY NERVE DYSFUNCTION

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AUTONOMIC NERVE DYSFUNCTION

Involved Widespread Distal Proximal/ Proximal

Motor or sensory Motor Mixed Motor Motor

Reflexes Weak/absent Weak/absent Normal Normal

Other helpful Fasciculation Myasthenic

Disease Amyotrophic Peripheral Myasthenia Myopathy

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2002 CRC Press LLC

Family history, pes cavus, CharcotMarieTooth disease