Biopsy Diagnosis of Peripheral Neuropathy

Juan M. Bilbao • Robert E. Schmidt

Second Edition Juan M. Bilbao, MD, FRCP (C) Robert E. Schmidt, MD, PhD Professor Emeritus of Neuropathology Professor of Pathology and Immunology Director Sunnybrook and St Michael’s Hospitals Division of Neuropathology University of Toronto Department of Pathology Toronto , ON Washington University School of Medicine Canada St. Louis , MO USA

First published in 1995 by Butterworth-Heinemann, an imprint of Elsevier with the following title: Biopsy Diagnosis of Peripheral Neuropathy

ISBN 978-3-319-07310-1 ISBN 978-3-319-07311-8 (eBook) DOI 10.1007/978-3-319-07311-8 Springer Cham Heidelberg New York Dordrecht London

Library of Congress Control Number: 2014946574

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Springer is part of Springer Science+Business Media (www.springer.com) Foreword

Neurologists specializing on the peripheral nervous system like to boast that theirs is the only area of neurology with no “black box”: All connections are known and there is a good understanding of the correlation between the pathological processes, electrophysiological fi ndings, and clinical signs and symptoms. However, prior to the 1995 publication of Midroni and Bilbao “Biopsy Diagnosis of Peripheral Neuropathy” pathological diagnosis was a muddy fi eld obscured by the absence of guidance on how to handle and examine the biopsy, scarcity of high quality images, and over-emphasis on morphometry and nerve fi ber teasing. Their book allowed those of us entering the fi eld from different disciplines to decide when to order a nerve biopsy, and to fully understand the clinical implications of the fi ndings on the one hand, and provided us with the intellectual tools to reach a pathological diagnosis on the other. Almost 20 years have gone by, and molecular genetics is now a major player in the diagnosis of peripheral neuropathy. While the number of nerve biopsies has decreased, their importance has not. Furthermore the detailed understanding of the underlying pathological process is critical to the care of patients with peripheral neuropathy, even those who do not undergo a biopsy. In the new edition, Drs. Bilbao and Schmidt have updated the book, incorporating the molecular advances into the fully integrated contributions of the clinical data and histology to the diagnostic process. They also introduce a condensed review of current developments in the use of skin biopsy for the study of peripheral neuropathy. The book is consistently thorough in its review of the literature, clear in its exposition, and balanced in its assessment of the value of procedures. It is, however, the superb quality of the images that will remain in the minds of most readers as the main vehicle through which understanding of the pathological processes discussed in the book is achieved. The convenience of this monograph lies in that it is also a work of reference, since much of it consists of detailed descriptions of the various clinical and physiopathological manifestations of diseases. I highly recommend this book to any neurologist or pathologist seeking guidance in the study of the peripheral nervous system. It will be as useful to those using a microscope as to those who do not.

David G. Munoz, MD Division of Pathology, St. Michael’s Hospital Toronto, ON, Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto, ON, Canada

Pref ace

This book represents a thorough revision of the text (with the addition of new cases) and illustrations of the monograph entitled Biopsy Diagnosis of Peripheral Neuropathy published in 1995 and authored by Gyl Midroni and Juan M. Bilbao (Butterworth and Heinemann, publisher). We designed this second edition to present current comprehensive knowledge of the pathology and pathogenetic mechanisms of peripheral nerve disease for pathologists involved in the interpretation of nerve biopsies as well as neurologists, neuropathologists and neurosci- entists in training. The fi rst eight chapters present the normal anatomy of peripheral nerve and its cellular constituents, assessment of the biopsy (how to blow away the cobwebs of artefacts), followed by discussions of basic pathologic processes, and of the role of whole nerve biopsy in diagnosis of peripheral neuropathy compared to other techniques of nerve analysis. Following this introduction, the traditional categories of nerve diseases are organized in 13 chapters and the spectrum of microscopic pathology is illustrated profusely. Over the past 20 years, the impact of molecular genetics on the diagnostic accuracy and understanding of the pathogenesis of peripheral neuropathy has been enormous. The fi rst and still major causal genetic defect for inherited peripheral neuropathies, the CMT1A duplication of the PMP-22 gene, was discovered in 1991. Since that time, our knowledge of the molecular genetic groundwork of this group of diseases has grown considerably. By applying next- generation genetic techniques, well over 70 causal genes are now identifi ed in patients affected with Charcot-Marie-Tooth disease and cognate disorders alone. Similarly, direct DNA sequenc- ing permits the diagnosis of most of the hereditary amyloidoses that are associated with peripheral neuropathy. Consequently, the indications for nerve biopsy in these suspected entities have sharply declined. Nonetheless, nerve biopsy represents the gold standard to which other test results and pathogenetic mechanisms have been and are compared. Valid requests for whole nerve biopsy include a search for an interstitial pathological process (vasculitis, and amyloid infi ltration in non-secretory myeloma), diagnosis of a hereditary polyneuropathy when genetic-molecular studies are not helpful and the phenotype is atypical, confi rmation of the diagnosis of Guillain- Barre syndrome or chronic demyelinating infl ammatory polyneuropathy with atypical fi ndings, and diagnosis of a protracted polyneuropathy with negative or incongruous lab studies results (i.e. sarcoidosis, diabetic neuropathy with prominent motor fi ndings). In Chaps. 1 and 17 , we discuss the role of skin biopsies in the evaluation of small fi ber neuropathy, a technique which may obviate the need for sural nerve biopsy. This method permits visualization and quantifi cation of intraepidermal (unmyelinated) nerve fi bers. Furthermore, glabrous skin biopsy has recently been established to be useful for the assessment of dermal myelinated fi bers and for the detection of infl ammation and Ig deposits. Quantifi cation of the myelinated endings and mechanoreceptors in glabrous skin can expand the role of skin biopsy to include all distal sensory axonopathies. Nonetheless, it remains unproven if the results of skin biopsy alone will provide the overall diagnostic insight possible with whole nerve biopsy. We are grateful to Ms. Sandra Cohen for providing many of the electron photomicrographs, and to Dr. Gyl Midroni for advice. Dr. Charles Kassardjian gave valuable suggestions in updat- ing Chaps. 1 and 8. We are especially indebted to Drs. Maria Nolano, William Kennedy, and Jun Li for providing many elegant and informative confocal photomicrographs of skin

vii viii Preface

preparations showing normal and abnormal innervation (see Chap. 1 ). Drs. Shinji Ohara, Mitsunori Yamada and Hitoshi Takahashi provided us their material for the AMAN case pre- sented. We would also like to thank Karen Green, Chris Dunham, Toral Patel, Connie Marshall and William Kraft, our EM colleagues at Washington University. Ms. Jordana Stewart provided secretarial assistance. Ms. Martina Himberger, who has been in charge of the work for Springer, has been inﬁ nitely helpful. Dr. Schmidt would like to thank his wife Pam for her patience and counsel during the preparation of this book and dedicate his work to his children Andrea and David.

Toronto, ON, Canada Juan M. Bilbao St. Louis, MO, USA Robert E. Schmidt

Preface to First Edition

This monograph is directed at neurologists and pathologists who require a work that combines a practical approach to nerve biopsy interpretation in peripheral neuropathy with an overview of the progress that has accumulated over the past two decades in the understanding of peripheral nerve pathobiology. Also covered are clinical features of polyneuropathy and the microscopic anatomy of nerves, both essential to the interpretation of pathological change. In this book attention is on the usefulness and limitations of nerve biopsy as a diagnostic tool, and for a broad perspective, the literature has been extensively reviewed. We hope that our efforts to provide a rich pictorial exposition of peripheral nerve histology and pathology will be helpful to the initiate. Our material consists of nearly 700 consecutive nerve biopsies collected over a 22-year period at St. Michael’s Hospital in Toronto. In the study of this tissue we employ techniques of classical histology, resin histology, immunohistochemistry, electron microscopy, and, to a much lesser degree, morphometry and ﬁ ber teasing. We acknowledge that biopsy of a subcutaneous nerve provides only a window into the rnor- phological alterations in peripheral neuropathies; thus throughout the text we refer to other works for a more complete view of the pathology of the human peripheral nervous system. This work was made possible through the support of the Sisters of St. Joseph, the St. Michael’s Hospital Department of Pathology, and Dr. Alan Hudson. Our editor Susan Pioli, who supervised this work from inception, was a constant source of encouragement. We are grateful to the following pathologists who sent us specimens from conditions not available in our collection: Dimitris Agamanolis (Ohio), George Davidson (Toronto), John Deck (Toronto), Venita Jay (Toronto), Edward Johnson (Edmonton), Jacques Lamarche (Sherbrooke, Quebec), John Maguire (Hamilton), Jean Michaud (Monheal), and David Munoz (London, Ontario). To the many physicians who shared their cases with us goes our appreciation: Peter Ashby, Sheldon Baryshnick, Neville Bayer, Catherine Bergeron, Henry Berry, Alexander Birnbaum, Donald Barrett, Joseph Bruni, T.C. Chen, Sam Cheung, Joseph Chu, Sharon Cohen, Michael Cusimano, AI-Noor Dhanani, Farouk Dindar, Eric Duncan, Sherali Esmail, Ignatio Fong, Victor Fornasier, Richard Gladstone, Warren Goldstein, Allan Gordon, Trevor Gray, Arthur Gryffe, Mark Guttman, Gaspar Israelian, Dennis Izukawa, Ralph Kern, Edward Keystone, Peter Kopplin, Colin Lambert, Arnold Lang, Richard Magder, James Mahoney, Zbieg Manowski, Ronald McDonald, Donald McGillivray, Stephn McKenzie, Arline McLean, Gary Moddel, David Morganthau, Ayoob Mossanen, Richard Moulton, Paul Muller, John Norris, Paul O’Connor, Richard Perrin, Ali Qizilbash, Paul Ranalli, Gordon Sawa, Carol Sawka, Jacob Schneiderman, Daniel Selchecn, Raold Serebrin, David Sutton, Bryan Temple, William Tucker, Jean Turley, Felix Tyndel, C. Peter Watson, John Wherrett, Ronald Wilson, and Catherine Zahn. Dr. Peter Ashby, Dr. Kalman Kovacs, and Dr. James Perry gave valuable suggestions for the monograph. We thank Dr. Rob Macaulay for his many contributions to this work. Daniel A. Hunter, RT, of Washington University School of Medicine, St. Louis, Missouri, generously performed morphometry. The librarial services at St. Michael’s Hospital were critical to the collection of reference material: The authors wish to thank Leica Canada and the Mount Sinai

ix x Preface to First Edition

Hospital for permission to use their equipment. Lianne Friesen and George Trogadis created the original artwork. Dr. Maja Steinlin and Dr. Steffen Albrecht provided German translations. Sandra M. Cohen wishes to thank Steven M. Doyle of the department of microbiology at the University of Toronto for his invaluable technical assistance and generosity in the loan of a diamond knife. One of us is a clinical neurologist with a special interest in peripheral neuropathy; the other is a neuropathologist with remote training in clinical neurology and a special interest in the pathology of nerves. Juan M. Bilbao is especially indebted to the late Dr. Morrison Finlayson.

Toronto, ON, Canada Juan M. Bilbao Contents

1 Peripheral Neuropathy and the Role of Nerve Biopsy ...... 1 1.1 Epidemiology of Peripheral Neuropathy ...... 1 1.1.1 Etiologies of Peripheral Neuropathy ...... 1 1.1.2 Cryptogenic Peripheral Neuropathy...... 2 1.2 Usefulness of Nerve Biopsy in Evaluation of Peripheral Neuropathy ...... 3 1.2.1 Review of Experience at St. Michael’s Hospital ...... 3 1.2.2 Literature Data on the Usefulness of Nerve Biopsy...... 5 1.3 Indications for Nerve Biopsy ...... 5 1.3.1 Clinical and Electrophysiological Criteria Cannot Exclude the Need for Biopsy ...... 6 1.3.2 Nerve Biopsy Has Limited Usefulness in Suspected CIDP...... 6 1.3.3 Suggested Guidelines for Use of Nerve Biopsy...... 7 1.4 Site of Biopsy ...... 7 1.4.1 Alternative Biopsy Sites...... 7 1.4.2 Nerve to Be Biopsied ...... 8 1.4.3 Combined Muscle and Nerve Biopsy...... 8 1.4.4 Fascicular vs. Whole Nerve Biopsy ...... 9 1.5 Sequelae of Nerve Biopsy...... 9 1.5.1 Delayed Healing, Wound Infections, and Neuroma Formation ...... 9 1.5.2 Temporary Discomfort ...... 9 1.5.3 Lasting Discomfort...... 9 1.6 Future Directions...... 9 1.6.1 Skin Biopsy ...... 9 1.6.2 Imaging of the Peripheral Nervous System ...... 14 1.6.3 Molecular Techniques ...... 15 References ...... 18 2 Normal Anatomy of the Peripheral (Sural) Nerve ...... 21 2.1 Normal Peripheral Nerve Structure and Function...... 21 2.1.1 Macroscopic Anatomy of the Sural Nerve...... 21 2.1.2 The Microscopic Architecture of Nerves ...... 22 2.1.3 Other Endoneurial Cell Content...... 29 2.2 Age-Related Changes ...... 36 2.2.1 Aged Individuals ...... 36 2.2.2 Early Life ...... 37 2.2.3 Age-Related “Degenerative” Changes ...... 38 References ...... 39

xi xii Contents

3 Quantitative Techniques ...... 43 3.1 Fiber Teasing...... 43 3.2 The Morphometric Study of Nerve Biopsies ...... 44 3.2.1 Fiber Counts and Histograms...... 45 3.2.2 Usefulness of Fiber Counts and Histograms in Assessment of Nerve Biopsy ...... 46 3.2.3 The G-Ratio ...... 46 3.2.4 Endoneurial Area and Cell Counts...... 47 3.2.5 Regenerating Clusters...... 48 3.2.6 Assessment of Unmyelinated Fiber Loss...... 48 3.2.7 Internode Length ...... 48 3.3 Summary: The Utility of Morphometric Analysis ...... 49 References ...... 49 4 The Axon: Normal Structure and Pathological Alterations ...... 51 4.1 The Normal Axon...... 51 4.1.1 Contents of the Normal Axon ...... 51 4.1.2 Organization of Axonal Structure ...... 53 4.1.3 Axonal Transport ...... 54 4.1.4 Regulation of Axonal Diameter ...... 56 4.2 Axonal Degeneration ...... 56 4.2.1 Distal Axonopathy ...... 56 4.2.2 Pathological Alterations in Axonopathy ...... 57 4.3 Wallerian Degeneration...... 63 4.3.1 Changes Distal to Transection ...... 64 4.3.2 Mechanisms of Wallerian Degeneration ...... 72 4.4 Axonal Pathology in Nerve Biopsy Specimens ...... 73 4.4.1 Axonal Inclusions...... 74 4.5 Axonal Regeneration...... 75 4.5.1 Mechanisms of Regeneration ...... 75 4.5.2 Histological Hallmarks of Regeneration ...... 79 References ...... 80 5 Schwann Cells and Myelin in the Peripheral Nervous System ...... 85 5.1 Normal Structure and Function of Schwann Cells and Myelin ...... 85 5.1.1 Myelinating Schwann Cells ...... 85 5.1.2 Myelin ...... 89 5.1.3 Nonmyelinating Schwann cells ...... 90 5.1.4 Schwann Cell Inclusions ...... 91 5.2 Demyelination...... 94 5.2.1 Nonspeciﬁ c Features of Demyelination ...... 95 5.2.2 Speciﬁ c Myelin Changes in Primary Demyelinating Neuropathies. . . 96 5.2.3 Schwannopathy ...... 101 5.2.4 Secondary Demyelination ...... 101 5.2.5 Mechanisms of Demyelination...... 102 5.3 Remyelination...... 103 5.3.1 Normal Remyelination...... 103 5.3.2 Onion-Bulb Formation ...... 104 References ...... 105 6 The Peripheral Nerve Vasculature ...... 111 6.1 Normal Structure and Function...... 111 6.1.1 Vascular Anatomy ...... 111 6.1.2 Resistance of Peripheral Nerve to Ischemia...... 113 6.1.3 The Blood–Nerve Barrier...... 114 Contents xiii

6.2 Pathological Alterations ...... 115 6.2.1 Alteration in the Blood–Nerve Barrier in Neuropathy...... 115 6.2.2 Endoneurial “Edema”...... 116 6.2.3 Signifi cance of Alterations in the Blood–Nerve Barrier ...... 117 6.3 Focal Ischemic Injury of Peripheral Nerves ...... 117 6.3.1 Fascicular Geography of Nerve Damage ...... 118 6.3.2 Involvement of Endoneurial Contents ...... 118 6.4 Chronic Vascular Insuffi ciency ...... 119 6.5 Chronic Hypoxemia ...... 120 References ...... 120 7 Examination of the Peripheral Nerve Biopsy ...... 123 7.1 Methods...... 123 7.1.1 Paraffi n-Embedded Sections ...... 123 7.1.2 Plastic-Embedded Sections ...... 123 7.1.3 Frozen Sections ...... 124 7.1.4 Fiber Teasing ...... 124 7.2 Approach to Specimen Examination...... 124 7.2.1 Biopsy Examination...... 124 7.2.2 Essential Points to Be Addressed by the Examination...... 124 7.3 Assessment of Specimen Quality ...... 124 7.4 Light Microscopy ...... 127 7.4.1 Examination of the Epineurium ...... 127 7.4.2 Examination of the Perineurium...... 133 7.4.3 Examination of the Endoneurium...... 135 7.5 Electron Microscopy ...... 140 7.5.1 Assessment of Unmyelinated Fibers ...... 140 7.5.2 Electron Microscopy: Assessment of Myelin and Demyelination ...... 142 7.5.3 Axonal Ultrastructural Changes ...... 144 7.5.4 Ultrastructural Examination of Inclusions in Endoneurial Cells . . . . . 146 7.5.5 The Interstitial Compartment ...... 147 7.6 Immunohistochemical Techniques ...... 147 7.7 Fiber Teasing...... 148 References ...... 148 8 Clinical Aspects of Peripheral Neuropathy ...... 151 8.1 Clinical Approach to Peripheral Neuropathy ...... 151 8.1.1 Clinical Questions ...... 151 8.2 Classifi cation of Peripheral Neuropathies...... 154 8.3 Laboratory Testing in Peripheral Neuropathy...... 155 8.3.1 Electrophysiological Testing ...... 155 References ...... 158 9 The Infl ammatory Demyelinating Neuropathies ...... 161 9.1 Guillain–Barré Syndrome ...... 161 9.1.1 Clinical Manifestations ...... 161 9.1.2 Pathology ...... 162 9.1.3 Pathogenesis ...... 169 9.1.4 Differential Diagnosis ...... 174 9.2 Chronic Infl ammatory Demyelinating Polyradiculoneuropathy...... 174 9.2.1 Clinical Manifestations ...... 174 9.2.2 Pathology ...... 175 9.2.3 Pathogenesis ...... 186 9.2.4 Differential Diagnosis ...... 187 xiv Contents

9.3 Multifocal Neuropathy with Persistent Conduction Block ...... 190 9.3.1 Clinical Syndrome ...... 190 9.3.2 Findings in Multifocal Motor Neuropathy with Persistent Conduction Block ...... 190 9.3.3 Pathogenesis ...... 192 References ...... 192 10 Idiopathic Inﬂ ammatory Neuropathies ...... 197 10.1 Sarcoidosis...... 197 10.1.1 Clinical Manifestations ...... 197 10.1.2 Pathology ...... 197 10.1.3 Pathogenesis ...... 199 10.1.4 Differential Diagnosis ...... 199 10.2 Idiopathic Perineuritis...... 201 10.2.1 Clinical Manifestations ...... 201 10.2.2 Pathology ...... 201 10.2.3 Pathogenesis ...... 205 10.2.4 Differential Diagnosis ...... 205 References ...... 206 11 Infectious Diseases Causing Neuropathy ...... 209 11.1 HIV Infection...... 209 11.1.1 Distal Symmetrical Polyneuropathy (DSPN)...... 210 11.1.2 Inﬂ ammatory Demyelinating Polyneuropathy in HIV Infection ...... 212 11.1.3 Mononeuropathy Multiplex and Vasculitic Neuropathy in HIV Infection ...... 212 11.1.4 Cytomegalovirus-Associated Neuropathy ...... 215 11.1.5 Role of Nerve Biopsy in HIV Patients with Neuropathy ...... 216 11.1.6 Differential Diagnosis ...... 216 11.2 Neuropathy Associated with HTLV-I Infection...... 217 11.2.1 Clinical Features...... 217 11.2.2 Pathology ...... 217 11.2.3 Pathogenesis ...... 217 11.3 Neuropathy of Lyme Disease (Lyme Neuroborreliosis) ...... 217 11.3.1 Clinical Manifestations ...... 217 11.3.2 Pathology ...... 218 11.3.3 Pathogenesis ...... 218 11.3.4 Differential Diagnosis ...... 219 11.4 Non-Lyme Peripheral Neuropathy with Arthropod Stings ...... 219 11.5 Other Infection-Associated Neuropathies...... 219 11.5.1 Diphtheritic Polyneuropathy ...... 219 11.5.2 Herpes Zoster (“Shingles”) ...... 220 11.5.3 Syphilitic Neuropathy...... 220 11.5.4 Neuropathy in Creutzfeldt–Jakob Disease ...... 220 References ...... 222 12 Leprous Neuropathy ...... 225 12.1 Clinical Manifestations ...... 226 12.1.1 Lepromatous Leprosy...... 226 12.1.2 Tuberculoid Leprosy ...... 227 12.1.3 Borderline Leprosy...... 227 12.1.4 Pure Neuritic Leprosy ...... 227 12.1.5 Acute Neuritis...... 228 12.1.6 Treatment of Leprosy ...... 228 Contents xv

12.2 Pathology...... 228 12.2.1 General Considerations ...... 228 12.2.2 Lepromatous Leprosy...... 228 12.2.3 Tuberculoid Leprosy ...... 235 12.2.4 Borderline Leprosy...... 236 12.2.5 Indeterminate Leprosy ...... 237 12.2.6 Primary Neuritic Leprosy...... 238 12.2.7 Acute Neuritis...... 238 12.3 Pathogenesis ...... 240 12.3.1 Mechanism of Organism Spread ...... 240 12.3.2 Mechanism of Nerve Injury ...... 240 12.4 Differential Diagnosis ...... 241 References ...... 242 13 Vasculitic Neuropathy ...... 245 13.1 Clinical Manifestations ...... 246 13.1.1 Mononeuritis Multiplex ...... 246 13.1.2 Nonsystemic (Isolated) Peripheral Nervous System Vasculitis (NSVN) ...... 246 13.1.3 Primary Systemic Vasculitis...... 246 13.1.4 Other Vasculitides...... 248 13.2 Pathology...... 249 13.2.1 General Considerations: Sensitivity of Biopsy ...... 249 13.2.2 Some Pathological Considerations...... 249 13.2.3 Electron Microscopy ...... 252 13.2.4 Immunohistochemistry...... 252 13.3 Pathogenesis ...... 253 13.3.1 Signifi cance of Size of Involved Vessels ...... 254 13.3.2 Signifi cance of Infl ammatory Cell Types...... 255 13.3.3 Other Elements of Differential Diagnosis ...... 264 13.4 Lymphomatoid Granulomatosis ...... 264 References ...... 268 14 Dysproteinemic Neuropathies...... 273 14.1 Neuropathy Associated with Paraproteinemia ...... 273 14.1.1 Clinical Manifestations ...... 273 14.1.2 Pathology ...... 275 14.1.3 Pathogenesis ...... 283 14.1.4 Differential Diagnosis ...... 285 14.2 Cryoglobulinemic Neuropathy ...... 288 14.2.1 Clinical Manifestations ...... 288 14.2.2 Pathology ...... 288 14.2.3 Pathogenesis ...... 289 References ...... 289 15 Amyloid Neuropathy ...... 295 15.1 Clinical Manifestations ...... 295 15.1.1 Primary Amyloidosis ...... 295 15.1.2 Hereditary Amyloid Neuropathies...... 296 15.1.3 Transthyretin...... 296 15.1.4 Apolipoprotein A1 ...... 296 15.1.5 Gelsolin ...... 296 15.1.6 “Sporadic” Amyloid Neuropathy...... 297 15.1.7 Clinical Features...... 297 15.1.8 Treatment ...... 297 15.1.9 Secondary Amyloidosis ...... 298 xvi Contents

15.2 Pathology...... 298 15.2.1 Utility of Nerve Biopsy ...... 298 15.2.2 General Considerations ...... 298 15.2.3 Light Microscopy ...... 299 15.2.4 Electron Microscopy ...... 300 15.2.5 Immunohistochemistry...... 300 15.3 Pathogenesis ...... 305 15.4 Differential Diagnosis ...... 306 References ...... 307 16 Neuropathy Associated with Neoplasia ...... 311 16.1 Paraneoplastic Neuropathy ...... 311 16.1.1 Paraneoplastic Subacute Sensory Neuropathy (SSN) ...... 311 16.1.2 Paraneoplastic Sensorimotor Neuropathy ...... 314 16.1.3 Other Associations Between Neuropathy and Malignancy ...... 316 16.1.4 Differential Diagnosis ...... 316 16.2 Neuropathy Due to Neoplastic Infi ltration ...... 317 16.2.1 Lymphomatous Neuropathy ...... 317 16.2.2 Leukemic Infi ltration of the Nerve...... 318 16.2.3 Multiple Myeloma ...... 323 16.2.4 Differential Diagnosis of Infi ltrative Neuropathy ...... 325 16.3 Castleman Disease...... 325 16.3.1 Clinical Manifestations ...... 325 16.3.2 Pathology ...... 325 16.3.3 Pathogenesis ...... 326 16.4 Angioimmunoblastic T-Cell Lymphoma ...... 326 References ...... 327 17 Neuropathy Associated with Endocrine and Metabolic Disease ...... 331 17.1 Diabetic Neuropathy ...... 331 17.1.1 Clinical Manifestations ...... 331 17.1.2 Pathology ...... 332 17.1.3 Pathogenesis ...... 341 17.2 Neuropathy in Thyroid Disease...... 344 17.2.1 Clinical Manifestations ...... 344 17.2.2 Pathology ...... 344 17.2.3 Pathophysiology ...... 344 17.2.4 Neuropathy Associated with Hyperthyroidism ...... 344 17.3 Neuropathy in Acromegaly ...... 344 17.3.1 Clinical Manifestations ...... 344 17.3.2 Pathology ...... 345 17.3.3 Pathogenesis ...... 345 17.4 Uremic Neuropathy ...... 345 17.4.1 Clinical Manifestations ...... 345 17.4.2 Pathology ...... 345 17.4.3 Pathogenesis ...... 346 17.5 Neuropathy Associated with Liver Disease...... 346 17.6 Neuropathy Due to Vitamin Defi ciency ...... 346

17.6.1 Thiamine (B1) Deﬁ ciency...... 346

17.6.2 Pyridoxine (B6) Deﬁ ciency and Excess ...... 347

17.6.3 Cobalamin (B12) Defi ciency ...... 347 17.6.4 Tocopherol (Vitamin E) Defi ciency ...... 348 17.6.5 Folate Defi ciency ...... 348 Contents xvii

17.7 Alcoholic Neuropathy ...... 348 17.7.1 Clinical Manifestations ...... 348 17.7.2 Pathology ...... 348 17.7.3 Pathogenesis ...... 349 References ...... 350 18 Toxic Neuropathies...... 355 18.1 General Aspects of Toxic Neuropathy ...... 355 18.2 Amiodarone ...... 357 18.2.1 Clinical Manifestations ...... 357 18.2.2 Pathology ...... 359 18.2.3 Pathogenesis...... 360 18.2.4 Differential Diagnosis ...... 360 18.3 Disulﬁ ram Neuropathy ...... 362 18.3.1 Clinical Manifestations ...... 362 18.3.2 Pathology ...... 363 18.3.3 Pathogenesis...... 363 18.4 Chemotherapy-Induced Peripheral Neuropathies (CIPN) ...... 364 18.5 Misonidazole Neuropathy...... 364 18.6 Vincristine...... 367 18.6.1 Clinical Manifestations ...... 367 18.6.2 Pathology ...... 367 18.6.3 Pathogenesis...... 367 18.7 Hexacarbons ...... 368 18.7.1 Clinical Manifestations ...... 368 18.7.2 Pathology ...... 368 18.7.3 Pathogenesis...... 368 18.8 Lead ...... 368 18.8.1 Clinical Manifestations ...... 368 18.8.2 Pathology ...... 369 18.8.3 Pathophysiology...... 369 18.9 Epidemic Toxic Inﬂ ammatory Neuropathy ...... 369 18.9.1 Eosinophilia Myalgia Syndrome ...... 369 18.9.2 Toxic Oil Syndrome...... 370 18.9.3 Pathogenesis...... 370 18.10 Differential Diagnosis of Toxic Neuropathies ...... 370 18.11 Drug Interactions ...... 370 References ...... 371 19 Genetically Determined Neuropathies ...... 375 19.1 Charcot–Marie–Tooth and Cognate Disorders ...... 375 19.2 CMT-1...... 376 19.2.1 Clinical Manifestations ...... 376 19.2.2 Pathology ...... 377 19.2.3 Pathogenesis...... 383 19.2.4 X-Linked CMT ...... 384 19.2.5 Differential Diagnosis ...... 384 19.3 Hereditary Neuropathy with Pressure Palsies...... 385 19.3.1 Clinical Manifestations ...... 385 19.3.2 Pathology ...... 386 19.3.3 Pathogenesis...... 391 19.3.4 Differential Diagnosis ...... 391 19.3.5 Inherited Recurrent Brachial Plexus Neuropathy (Hereditary Neuralgic Amyotrophy) ...... 392 xviii Contents

19.4 CMT-2...... 393 19.4.1 Clinical Manifestations ...... 393 19.4.2 Pathology...... 393 19.4.3 Pathogenesis ...... 394 19.4.4 Differential Diagnosis ...... 394 19.5 Autosomal Dominant Intermediate CMT...... 394 19.6 CMT-Associated Demyelinating Neuropathies of Early Onset ...... 398 19.6.1 Light Microscopy ...... 398 19.6.2 Electron Microscopy ...... 398 19.6.3 Pathogenesis ...... 399 19.6.4 CMT Type III with Basal Lamina Onion Bulbs (CMT-3 BLOB)...... 399 19.6.5 CMT-1 with Basal Lamina Onion Bulbs...... 400 19.6.6 CMT-3 with Amyelination ...... 402 19.6.7 Reconsideration of the Classiﬁ cation ...... 403 19.7 CMT-4 (Charcot–Marie–Tooth Type 4) ...... 403 19.8 Hereditary Sensory Neuropathies...... 405 19.9 Peripheral Neuropathy Associated with Hereditary Ataxias ...... 406 19.9.1 Friedreich’s Ataxia ...... 406 19.9.2 Non-Friedreich’s Inherited Spinocerebellar/Cerebellar Degenerations ...... 407 19.9.3 Abetalipoproteinemia (Bassen- Kornzweig Disease) ...... 408 19.9.4 Chediak–Higashi Syndrome ...... 408 19.10 Giant Axonal Neuropathy...... 408 19.10.1 Clinical Manifestations ...... 408 19.10.2 Pathology...... 409 19.10.3 Pathogenesis ...... 412 19.10.4 Differential Diagnosis ...... 413 19.11 Refsum Disease (CMT-4)...... 413 19.11.1 Clinical Manifestations ...... 413 19.11.2 Pathology...... 413 19.11.3 Pathogenesis ...... 414 19.12 Peripheral Neuropathy in Diseases with Defective DNA Repair Mechanisms ...... 414 19.12.1 Cockayne Syndrome ...... 414 19.12.2 Xeroderma Pigmentosum (XP)...... 415 19.12.3 Ataxia Telangiectasia ...... 415 19.13 Neuropathy with Defective Porphyrin Metabolism ...... 415 19.13.1 Clinical Manifestations ...... 415 19.13.2 Pathology...... 416 19.13.3 Pathogenesis ...... 417 19.14 Other Genetically Determined Neuropathies ...... 417 19.14.1 Infantile Neuroaxonal Dystrophy ...... 417 19.14.2 The Neuropathy of Oxalosis ...... 418 19.14.3 Peripheral Nerve Changes in Myotonic Dystrophy ...... 419 References ...... 420 20 Storage Diseases ...... 429 20.1 The Sphingolipidoses ...... 429 20.1.1 The Metachromatic Leukodystrophies ...... 429 20.1.2 Globoid Cell Leukodystrophy (Krabbe Disease) ...... 436 20.1.3 Fabry Disease ...... 437 20.1.4 Niemann–Pick Disease ...... 444 20.1.5 Farber Disease (FD, Lipogranulomatosis) ...... 448 20.1.6 Other Sphingolipidoses...... 449 Contents xix

20.2 Adrenoleukodystrophy ...... 451 20.2.1 Clinical Manifestations...... 451 20.2.2 Pathology...... 451 20.2.3 Pathogenesis ...... 452 20.3 Neuronal Ceroid Lipofuscinoses (Batten–Kufs Disease) ...... 454 20.3.1 Clinical Manifestations...... 454 20.3.2 Pathology...... 454 20.4 Tangier Disease (Analphalipoproteinemia) ...... 457 20.4.1 Clinical Manifestations...... 457 20.4.2 Pathology...... 458 20.4.3 Pathogenesis ...... 459 20.5 Cerebrotendinous Xanthomatosis (Cholestanosis)...... 459 20.5.1 Clinical Manifestations...... 459 20.5.2 Pathology...... 459 20.5.3 Pathogenesis ...... 460 20.6 Other Storage Diseases...... 460 20.6.1 The Mucopolysaccharidoses...... 460 20.6.2 Glycogen Storage Diseases...... 460 20.6.3 Sialidosis...... 461 20.6.4 Wolman Disease ...... 461 20.7 Aspects of Differential Diagnosis in the Storage Diseases...... 461 References ...... 462 21 Unclassiﬁ ed Neuropathies and Mimics ...... 469 21.1 Neuropathy in Mitochondrial Diseases ...... 469 21.1.1 Clinical Manifestations...... 469 21.1.2 Pathology...... 470 21.2 Adult Polyglucosan Body Disease ...... 472 21.2.1 Clinical Manifestations...... 472 21.2.2 Pathology...... 472 21.2.3 Pathogenesis ...... 472 21.2.4 Differential Diagnosis ...... 474 21.3 Sensory Neuropathy Syndrome ...... 474 21.3.1 Clinical Manifestations...... 474 21.3.2 Pathology...... 475 21.3.3 Pathogenesis ...... 475 21.4 Neuropathy in the Hypereosinophilic Syndrome...... 475 21.4.1 Clinical Manifestations...... 475 21.4.2 Pathology...... 475 21.4.3 Pathogenesis ...... 476 21.5 Motor Neuron Diseases ...... 476 21.5.1 Amyotrophic Lateral Sclerosis ...... 476 21.5.2 Other Motor Neuron Diseases...... 476 21.6 Critical Illness Polyneuropathy...... 476 21.7 Multiple Symmetrical Lipomatosis (Madelung Disease)...... 477 21.8 Traumatic Injuries...... 477 21.9 Perineurioma...... 481 References ...... 484

Conventions

AMAN Acute motor axonal neuropathy CIDP Chronic infl ammatory demyelinating polyradiculoneuropathy EM Electron microscopy GBS Guillain-Barré Syndrome H&E Hematoxylin and eosin HMSN Hereditary motor and sensory neuropathy LCA Leukocyte common antigen LM Light microscopy MF Myelinated fi ber NMSC Non-myelinating Schwann cell OB Onion bulb PAS Periodic acid-Schiff PNS Peripheral nervous system SC Schwann cell ScSu Schwann cell subunit UF Unmyelinated fi ber

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