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9 ri h a n U https://kat.cr/user/Blink99/ d ti e R V Escourolle & Poirier’s Manual of Basic Neuropathology r i h ta 9 - n U V d ti e G R This page intentionally left blank r i h ta 9 - n U V d ti e https://kat.cr/user/Blink99/ G R Escourolle & Poirier’s MANUAL OF BASIC G NEUROPATHOLOGYR V d ti e F I F T H EDITION FRANÇ O IS E G RAY, MD, PHD - n U PROFE S S OR OF PATHOL O G Y UNIVE R S I TY PAR I S V I I N E U R O PAT H O L O G IS T A P H P L A RI B O I SI È RE H O SPI TA L PARIS, FR ANC E 9 CH A R L ES D U YCKAERTS, MD, PHD r i h ta PROFE S S OR OF PATHOL O G Y UNIVE R S I TY PAR I S V I N E U R O PAT H O L O G IS T A P H P, G H P I T I É - SA L PÊ T RI È RE PARIS, FR ANC E UM B ER TO D E GI ROLAMI, MD PROFE S S OR OF PATHOL O G Y HARVA R D M EDI C AL S C H O O L N E U R O PAT H O L O G IS T B R IG H A M A N D W O M E N ’S H O SPI TA L BOSTO N, M A Oxford University Press is a department of the University of Oxford It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam V d ti e Oxford is a registered trademark of Oxford University Press in the UK and certain other countries Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016 © Françoise Gray, Charles Duyckaerts, Umberto De Girolami 2014 G R n U All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer 9 - Library of Congress Cataloging-in-Publication Data Escourolle & Poirier’s manual of basic neuropathology / [edited by] Françoise Gray, Charles Duyckaerts, Umberto De Girolami ; foreword by Martin A Samuels – 5th ed p ; cm Escourolle and Poirier’s manual of basic neuropathology Manual of basic neuropathology Rev ed of: Escourolle & Poirier’s manual of basic neuropathology / Françoise Gray, Umberto De Girolami, Jacques Poirier c2004 Includes bibliographical references and index ISBN 978–0–19–992905–4 (alk paper)—ISBN 978–0–19–933048–5 (alk paper)—ISBN 978–0–19–933049–2 (alk paper) I Gray, Françoise II Duyckaerts, C III De Girolami, Umberto IV Escourolle, Raymond, 1924– V Gray, Françoise Escourolle & Poirier’s manual of basic neuropathology VI Title: Escourolle and Poirier’s manual of basic neuropathology VII Title: Manual of basic neuropathology [DNLM: Central Nervous System Diseases—pathology WL 301] RC347 616.8′047—dc23 2013010266 r i h ta The science of medicine is a rapidly changing field As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy occur The author and publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is accurate and complete, and in accordance with the standards accepted at the time of publication However, in light of the possibility of human error or changes in the practice of medicine, neither the author, nor the publisher, nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete Readers are encouraged to confirm the information contained herein with other reliable sources, and are strongly advised to check the product information sheet provided by the pharmaceutical company for each drug they plan to administer Printed in the United States of America on acid-free paper https://kat.cr/user/Blink99/ Contents Foreword vii Martin A Samuels Preface to the Fifth Edition Contributors xi 9 ix r i h ta - n U Basic Pathology of the Central Nervous System Infections of the Central Nervous System 114 Françoise Gray, Kum Thong Wong, Francesco Scaravilli, and Leroy R. Sharer Human Prion Diseases 149 Danielle Seilhean, Umberto De Girolami, and Françoise Gray Tumors of the Central Nervous System 20 Keith L. Ligon, Karima Mokhtari, and Thomas W. Smith Central Nervous System Trauma V d ti e G R James W. Ironside, Matthew P. Frosch, and Bernardino Ghetti Multiple Sclerosis and Related Inflammatory Demyelinating Diseases 161 Hans Lassmann, Raymond A. Sobel, and Danielle Seilhean 59 Colin Smith Neuropathology of Vascular Disease 76 Pathology of Degenerative Diseases of the Nervous System 173 Charles Duyckaerts, James Lowe, and Matthew Frosch Jean-Jacques Hauw, Umberto De Girolami, and Harry V. Vinters • v Acquired Metabolic Disorders 205 12 Pathology of Skeletal Muscle 278 Hart G W Lidov, Umberto De Girolami, Anthony A Amato, and Romain Gherardi Leila Chimelli and Françoise Gray 10 Hereditary Metabolic Diseases 227 13 Pathology of Peripheral Nerve 313 Jean-Michel Vallat, Douglas C Anthony, and Umberto De Girolami Frédéric Sedel, Hans H. Goebel, and Douglas C. Anthony 14 Diseases of the Pituitary Gland 343 11 Congenital Malformations and Perinatal Diseases 257 Vânia Nosé and E Tessa Hedley-Whyte Féréchté Encha-Razavi, Rebecca Folkerth, Brian N. Harding, Harry V. Vinters, and Jeffrey A. Golden Appendix: Brief Survey of Neuropathological Techniques 365 Homa Adle-Biassette and Jacqueline Mikol Index 9 r i h ta vi • - 379 n U V d ti e CONTENTS https://kat.cr/user/Blink99/ G R Foreword - n U It has been a decade since the previous edition of the Manual of Basic Neuropathology was published in 2003 In 1971, Raymond Escourolle and his student, Jacques Poirier, published a book on the basic aspects of neuropathology, the English version of which was translated by Lucien Rubinstein and published in 1973 I  was in the midst of my neurology residency at the time and on July 1, 1973, I was embarking with trepidation on a year of neuropathology, a requirement of my training program in that era Knowing only the pathology that I  had learned in medical school and having virtually no concept of neuropathology, I  found myself immersed in an alien world Little did I know that this was to be one of the most influential years in my career The ritual of removing the brains, obtaining the appropriate sections for microscopic analysis, and wading through the slides converted me from an internist into a neurologist Neuropathology was the basic science of clinical neurology I learned how to correlate clinical symptoms and signs with findings in the brain and the various ways in which the r i h ta 9 V d ti e G R brain could react to disease My roadmap in this new terrain was the then-new little blue book, Escourolle and Poirier’s Manual of Basic Neuropathology My heavily worn copy remains on my bookshelf A  second edition appeared in 1977 and a third in 1989, with Françoise Gray succeeding Raymond Escourolle, who had died in 1984 Then, after a longer interval, Umberto De Girolami joined Françoise Gray and Jacques Poirier for the fourth edition, published in 2003 In the foreword to the fourth edition I noted how dependent I was on the original manual and bemoaned the loss of intense neuropathology training in the making of modern neurologists In the past decade, neuroimaging and molecular medicine have become even greater parts of the routine life of the clinician At our daily morning report conferences, it is difficult to prevent our residents from showing the images first, skipping the history and the neurological examination entirely Some have even argued that listening to the patient, performing a careful neurological examination, and trying to localize the lesion have • vii become quaint fossils of times past This has led to a new problem, the “incidentaloma,” a finding on imaging or other testing that is unrelated to the patient’s actual problem The only way to put “incidentalomas” in perspective and to prevent harm to patients is to fully understand what is actually possible in the nervous system; in other words, neuropathology Other powerful societal forces aimed at saving time and money have put pressure on the effort it takes to think through complex patient problems carefully and to correlate them rigorously with the real pathology found in the nervous system Fortunately for us, Umberto De Girolami has championed the continuing need to use modernized neuropathology as a powerful tool for better patient care and for progress in understanding the causes of diseases of the nervous system His successor as Chief of Neuropathology at the Brigham, Rebecca Folkerth (a co-author of the chapter on congenital malformations and perinatal diseases, in the Manual), has continued this tradition Each week at our neuropathology conference we are impressed with how much is learned from the neuropathological analysis of patients, whether that be autopsy or biopsy material With the prudent application of modern techniques, including molecular and genetic analysis, we repeatedly learn that we often did not have a full grasp of clinical problems, even with the most skilled application of modern technology My own clinical practice and education is continuously in flux based largely on the reflection on our clinical analysis using the powerful tools of modern neuropathology 9 r i h ta viii • - For the fifth edition of the Manual, the distinguished neuropathologist Charles Duyckaerts, himself an expert in neurodegenerative diseases, particularly Alzheimer’s disease, joins Drs Gray and De Girolami as the editors Over 30 additional experts have written authoritative but characteristically brief and clear chapters on the full array of major topics in the field The organization of the book remains reassuringly unchanged The first chapter reviews the basic pathology of the nervous system, followed by chapters on tumors, trauma, vascular diseases, and infections A separate chapter deals with the increasingly important prion diseases, followed by chapters on multiple sclerosis, degenerative disorders, acquired metabolic diseases, hereditary metabolic diseases and congenital malformations, and perinatal diseases Separate chapters follow on skeletal muscle, peripheral nerve, and the pituitary gland The book ends with a modernized survey of neuropathology techniques This newly updated version of a truly venerated book will be valued by students, trainees, and practitioners in all of the fields related to the nervous system, including neurology, neurosurgery, psychiatry, neuroradiology, neuroendocrinology, neuropathology, and neuroscience The new edition will have an honored place on my bookshelf, right next to the little blue book that got me started over 40 years ago V d ti e n U G R Martin A. Samuels, MD, DSc (hon), FAAN, MACP, FACP Chairman, Department of Neurology, Brigham and Women’s Hospital Professor of Neurology, Harvard Medical School Boston, Massachusetts, USA FOREWORD https://kat.cr/user/Blink99/ Preface to the Fifth Edition - n U The first two French editions of the Manuel Elémentaire de Neuropathologie, published in 1971 and 1977, were conceived, written, and edited by Raymond Escourolle and Jacques Poirier After the death of R. Escourolle in 1984, Françoise Gray joined Jacques Poirier for the third edition; in addition, Jean-Jacques Hauw and Romain Gherardi contributed to selected chapters The first three editions reached the English-speaking public thanks to the friendship and translating ability of the now-deceased Lucien Rubinstein For the fourth edition, Umberto De Girolami joined as co-editor and the scope of the monograph was expanded with the collaborative efforts of multiple experts throughout the world to write the English-language text Jacques Poirier is now retired, and we are delighted that Charles Duyckaerts has agreed to join the editorial team for the fifth edition There have also been some changes in the authorship of several chapters in response to the changing status of senior authors and the need to recruit active investigators to replace them r i h ta 9 V d ti e G R This fifth edition of the Manual attempts to deliberately maintain the general intention of the first and subsequent editions of Professors Escourolle and Poirier’s monograph—that is, to provide a basic description of the lesions underlying the diseases of the nervous system and to limit pathophysiological considerations to essential principles Historical, clinical, neurological, and radiologic imaging data, once again, are specifically excluded, as well as reference listings, while recognizing this to be essential information for the erudite and informed practice of neuropathology Our premise, however, has been that it would be presumptuous for us to justice to this vast body of information, well beyond the scope of a basic overview of neuropathology We also have made the assumption that the reader has some familiarity with general concepts of neuroanatomy, neurohistology, and the principles of anatomical pathology as well as clinical neurology With these guidelines in mind, our aim has been to produce a text that mainly presents those aspects of neuropathology that are morphologic, and to • ix A B FIGURE 8.20 Glial pathology in progressive supranuclear palsy (A) Fairly specific finding of tufted astrocytes seen in gray matter (Gallyas silver stain) (B) Thorn-shaped astrocytes are commonly seen but not entirely specific feeling that the offending limb does not belong to them Difficulty in walking develops due to apraxia of leg movement together with pyramidal deficits caused by upper motor neuron involvement Cognitive abnormalities occur in some patients with aphasia and dementia of frontotemporal type In some patients, the cognitive abnormalities may even predominate over the movement disorder The biochemical and genetic associations of CBD are comparable to those of PSP 4.1.3.1 Gross appearance Cortical atrophy is the typical finding, most prominent around the Sylvian fissure or with a frontotemporal distribution, and often asymmetrical The substantia nigra shows loss of pigment There may be atrophy of the basal ganglia A 4.1.3.2 Microscopic lesions The characteristic features include the combination of neuronal loss, astrocytic gliosis, and 4R-tau-containing inclusions in neurons and glia In addition, in the cortex it is possible to find swollen (“achromatic”) neurons that have lost their Nissl substance (Fig 8.21A, B) In the substantia nigra, cell loss is associated with astrocytic gliosis Remaining nigral cells show large globose, pale-staining neurofibrillary tangles (Fig. 8.22) Immunostaining for tau protein shows tangles in neurons as well as immunoreactivity in many swollen neurons Accumulation of tau protein in astrocytes forms distinctive structures in gray matter areas termed astrocytic plaques: tau protein accumulates at the end of the astrocytic processes, while the center of the plaque is devoid of tau immunoreactivity (Fig. 8.23) They are conspicuous in the cortex and in the putamen B FIGURE 8.21 Corticobasal degeneration (A) Swollen achromatic neurons in the cerebral cortex (H&E) (B) Swollen neurons show immunoreactivity for alpha B-crystalline, which is a useful method for detection 190 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ FIGURE 8.22 Corticobasal degeneration Nigral neurons contain pale areas that displace the neuromelanin These are large globose tangles composed of tau protein (H&E) 4.1.4 MULTIPLE SYSTEM ATROPHY (MSA) As the term “multiple” implies, MSA is a degenerative process that crosses functional systems and hence does not fit well into only one of the clinically discussed categories We made the choice of presenting this disorder in this sequence because of the frequency of parkinsonism and because it is, like Parkinson disease, included in the synucleinopathies Three disorders (the parkinsonian striatonigral degeneration, the ataxic olivopontocerebellar atrophy [OPCA], and the autonomic failure of Shy-Drager syndrome), which were originally thought to be distinct, were united after it was recognized that affected individuals often began with one symptom complex but eventually gradually FIGURE 8.23 Corticobasal degeneration Astrocytic plaques can be detected in gray matter by tau immunostaining, as here, or by Gallyas staining acquired the others This clinical aggregation was further validated by the recognition that the neuropathological finding of distinctive inclusion bodies in glial cells was common to all these patients These inclusions were subsequently shown to contain α-synuclein, leading to the classification of MSA as a synucleinopathy, along with Parkinson disease and DLB; no mutations in the gene for α-synuclein have been found in MSA, which appears to exist only as a sporadic disorder The clinical features of MSA may show a predominance of the parkinsonian components (MSA-P) or of the cerebellar ataxia (MSA-C); it is relatively rare to have the autonomic dysfunction be the sole manifestation of the illness, although some features of autonomic disturbances are seen in nearly all cases In addition to the extrapyramidal motor symptoms, evidence of pyramidal involvement with hyperreflexia is commonly seen The tempo of progression is not strikingly different across the various clinical subtypes, and the disease is fatal in most patients within a decade of the onset of symptoms 4.1.4.1 Gross appearance As would be expected from the spectrum of clinical presentations, there can be a range of gross abnormalities observed in cases of MSA The best correlate of MSA-P is the combination of pallor of the substantia nigra with atrophy of the putamen, often associated with a gray-green discoloration of the latter structure (Fig. 8.24) When a prominent cerebellar component has been present (MSA-C), the cerebellum, basis pontis, and inferior olivary complex are generally atrophied (see 5.1.2 and Fig. 8.30) FIGURE 8.24 Multiple system atrophy Macroscopic examination of the fixed brain shows shrinkage of basal ganglia and discoloration of the putamen, which takes on a gray-green discoloration Chapter Pathology of Degenerative Diseases of the Nervous System • 191 4.1.4.2 Microscopic lesions Grossly and symptomatically involved brain regions show neuronal loss and astrocytic gliosis, and on routine stains (H&E, with or without Luxol fast blue) little else is evident Use of silver stains such as Gallyas (Fig 8.25A) or Bodian (Fig.  8.25B), or immunohistochemistry of α-synuclein or of ubiquitin (Fig 8.26A, B) will show characteristic glial cytoplasmic inclusions in oligodendroglia They are widely distributed through the brain, and appear as crescenticor sickle-shaped structures in glial cells, partially wrapping the nucleus and extending away from it NCIs and NIIs may also be seen but are generally much less obvious S E CONDARY PA R K I N S O NI A N S Y N DROME S changes similar to those described in progressive supranuclear palsy At microscopic examination, neurofibrillary tangles are found in widespread distribution but particularly affect the substantia nigra, the locus coeruleus, and the nuclei of the reticular formation, hypothalamus, and the nucleus basalis of Meynert Affected regions show cell loss with astrocytic gliosis 4.1.5.2 Pharmacologic/toxic Extrapyramidal disturbances can be seen in the course of treatment with neuroleptics; the anatomical substrate is poorly defined Toxic exposure to a byproduct of illicit drug synthesis, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), resulted in a parkinsonian syndrome with neuronal loss relatively selectively involving the substantia nigra Functional disruption of the basal ganglia circuitry and, in particular, of nigrostriatal projections may result in the development of a parkinsonian syndrome The diagnostic challenge is usually to separate these syndromes from the primary neurodegenerative diseases affecting the same brain regions 4.1.5.3 Carbon monoxide poisoning With nonfatal exposure, there can be bilateral necrosis of the superomedial part of the pallidum (see Chapter  9) Lesions in the substantia nigra are inconstant and usually moderate and involve the pars reticulata of the nucleus rather than the dopaminergic pars compacta 4.1.5.1 Postencephalitic parkinsonism Postencephalitic parkinsonism followed a pandemic of encephalitis lethargica (von Economo disease) between 1915 and 1927 (see Chapter  5) Half of the individuals who survived the acute encephalitic phase of the illness developed a parkinsonian syndrome after a typical latent period of about 9 years Cases coming to medical attention in recent times are very rare Macroscopic examination shows 4.1.5.4 Vascular disease The combination of hypertensive cerebrovascular disease involving the basal ganglia, with lacunes, as well as involvement of the brainstem and white matter projections essential for basal ganglia circuitry, can result in parkinsonism In these cases, there is usually marked asymmetry of symptoms reflecting the anatomical location of discrete lesions, as well as pseudobulbar palsy when there is more widespread brainstem involvement A B FIGURE 8.25 Multiple system atrophy Glial cytoplasmic inclusions of multiple system atrophy, which have been termed Papp-Lantos inclusions, can be detected by Gallyas staining (A) or Bodian silver impregnation (B) 192 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ A B FIGURE 8.26 Multiple system atrophy Alpha synuclein can be detected in glial cytoplasmic inclusions (A), neuronal nuclear inclusions, and neuronal cytoplasm The neuron shown in (B) has both nuclear and cytoplasmic inclusions 4.1.5.5 Trauma Individuals exposed to repeated traumatic injury, as seen particularly in professional boxers, can develop a parkinsonian syndrome, which often is associated with progressive dementia (dementia pugilistica) (see Chapter 3) 4.2 Hyperkinetic Movement Disorders The clinical signs and symptoms of hyperkinetic movement disorders are chorea, ballism, myoclonus, dystonia, and tics Chorea is characterized by “dance-like,” non-rhythmic rapid involuntary movements These disorders may be separated into two main groups, hereditary and sporadic, with a wide range of causes, the most common being the inherited condition Huntington disease 4.2.1 HUNTINGTON DISEASE Huntington disease (HD) is an autosomal dominant disorder, without a sporadic counterpart Its frequency varies in different populations, with levels of between and per 100,000 The disease usually starts in middle or late life, but it may become manifest earlier in life (see further on) It is characterized by chorea and mental deterioration leading to dementia In some juvenile or early-onset forms, chorea is replaced by hypertonia HD is associated with a mutation in the gene coding for the huntingtin protein, located on the distal portion of chromosome 4p Huntingtin is widely expressed in a variety of tissues and contains a polyglutamine tract that varies in size from to 37 copies of the amino acid, encoded by a trinucleotide (CAG) repeat in the gene In patients with HD, the length of this repeat is expanded, with the average repeat length around 46 and a range of 36 to 86 In general, the length of the repeat influences the age of onset of the illness, with longer repeats associated with earlier onset There is a propensity for expansion of the CAG repeat during paternal transmission, such that this disease can occur at younger and younger ages in subsequent generations, a phenomenon referred to as anticipation Unanswered questions remain in HD, including the determination of anatomical specificity given that the protein is widely expressed throughout the nervous system as well as the processes that drive neurodegeneration Proposed mechanisms contributing to pathology include loss of function of huntingtin because of the expanded repeat, gain of toxicity by mutant protein, transcriptional dysregulation caused by nuclear inclusions, excitotoxicity, oxidative stress, impaired proteolysis, and stimulated apoptosis 4.2.1.1 Gross appearance There is commonly mild to moderate cerebral atrophy On cut surface, the main neuropathological abnormality is atrophy of the caudate nucleus and putamen At the earliest stages of the disease, the caudate atrophy is primarily seen in the posterior portion of the structure (Grade 1), but with time there is evidence of volume loss from the caudate head as well (Grade 2) As the disease progresses further, the contour of the caudate shifts from the normal convex bulge into the lateral ventricle to flat (Grade 3)  or even concave (Grade 4) outline (Fig. 8.27) Atrophy of the putamen follows the same overall gradient and tempo, Chapter Pathology of Degenerative Diseases of the Nervous System • 193 with changes seen in the globus pallidus in the later stages primarily organelle membranes, particularly the endoplasmic reticulum) 4.2.1.2 Microscopic lesions In the involved regions of the striatum, there is neuronal loss with astrocytic gliosis The initial burden of degeneration is borne by the medium spiny neurons, although in late stages of the illness most striatal neurons are lost The cerebral cortex may show some degree of neuronal loss and gliosis, particularly in the setting of greater cognitive impairment Immunohistochemistry for huntingtin or for the expanded polyglutamine tract or for ubiquitin shows accumulation of abnormal protein as nuclear inclusion bodies Abnormal protein also accumulates in cortical neurites (Fig. 8.28) Intranuclear inclusions are relatively infrequent in striatal neurons but are more abundant in the cerebral cortex 4.2.2.2 Neurodegeneration with brain iron accumulation (NBAI) The combination of behavioral changes with a progressive extrapyramidal syndrome typically combining rigidity with hyperkinesia, dystonia, and tremor is characteristic of this set of disorders, which can be caused by a series of different mutations There are common histological features, including the presence of axonal spheroids predominantly in the internal globus pallidus and substantia nigra, as well as increased levels of brain iron, again primarily in these regions Interestingly, coincident lesions such as Lewy bodies and tangles are often found in the basal ganglia with the diseases The ability to detect the elevated iron levels through imaging methods has made it possible to invoke the diagnosis at the time of clinical evaluation; patients will show a characteristic “eye of the tiger” sign in the basal ganglia with T2-weighted imaging Mutations in an enzyme involved in the synthesis of coenzyme A (pantothenate kinase 2) are found in many of the cases of NBAI, particularly those with adult onset, now termed NBAI1 When the disease begins in early childhood, is it usually associated with more diffuse formation of axonal spheroids across the nervous system, hence the previous name of infantile neuroaxonal dystrophy This form of the disease (NBAI2) is associated with regression of milestones and emergence of combinations of 2 OT HE R HYPE R K I NETI C D I S O R D ER S 4.2.2.1 HD-like diseases Individuals and families have been identified with clinical and neuropathological features of HD but without expansion of the polyglutamine tract in the gene for huntingtin The best understood of these is known as Huntington disease-like (HDL2), in which the genetic locus is an expansion of a CTG/CAG tract in the gene for junctophilin-3 (a protein involved in the complexes linking the plasma membrane with FIGURE 8.27 Huntington disease Loyez stain showing atrophy of the caudate nucleus and putamen with dilation of frontal horn and cortical atrophy 194 • FIGURE 8.28 Huntington disease Neurites can be detected in the cerebral cortex with immunostaining with anti-huntingtin or anti-ubiquitin Neuronal nuclear inclusions are also identified by these stains E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ hypotonia and rigidity as well as optic atrophy; a distinct genetic locus has been identified 4.2.2.3 Choreoacanthocytosis This disorder is defined by the combination of chorea, dystonia, and tics with a hemolytic anemia including the presence of acanthocytes (“thorny” red blood cells detectable on a blood smear) Usually showing recessive inheritance, a range of mutations have been detected in a chromosome 9q encoding a protein involved in cellular trafficking of proteins, including in red blood cell precursors Acanthocytes can also be seen in association with movement abnormalities, with McLeod syndrome with mutations in the XK locus on the X chromosome that is also required for generation of the Kell blood antigen, Kx CEREBELLAR DEGENERATIONS (ATAXIC DISORDERS) Disorders that include neurodegeneration of the cerebellum can be variously classified either by the patterns of inheritance and underlying genetic basis or by the patterns of cellular degeneration While classifications based on the topographical distribution of injury were used in the past, the emergence of genetic information has allowed neurologists and neuropathologists to use alternate methods of classification to draw a greater understanding of the underlying basis of cerebellar degeneration (Table 8.3) In addition to the neurodegenerative disorders, cerebellar degeneration may be seen in a variety of other conditions, including toxic and metabolic disorders and infectious diseases (Table  8.4) Knowledge of the cerebellar circuitry is useful to understand the various classic descriptions of cerebellar neurodegeneration; however, clinical and neuropathological overlaps are frequent 5.1 Types of Atrophy According to the Topography of the Lesions in the Cerebellar Circuitry Three main patterns of cerebellar degeneration are recognized: • Cerebellar cortical atrophy • Olivopontocerebellaratrophy • Cerebellofugal atrophy These are summarized in Figure 8.29 Table 8.3 Classification of Some Inherited Spinocerebellar and Cerebellar Ataxias Autosomal recessive cerebellar ataxia Friedreich ataxia Ataxia with vitamin E deficiency Ataxia-telangiectasia Autosomal dominant cerebellar ataxia Spinocerebellar ataxia (SCA1-31) Dentato-rubro-pallido-luysial atrophy (DRPLA) X-linked cerebellar ataxia Fragile X tremor/ataxia syndrome 5.1.1 CEREBEL L AR CORTICAL ATROPHIES Within this group of disorders, some diseases manifest relatively consistent patterns of tissue injury, although some variability in the distribution and severity of the neuropathological changes can be seen from case to case The common denominator in all is degeneration of the cerebellar cortex, with early and eventually severe loss of Purkinje cells (Fig.  8.29B) Loss of Purkinje cells is associated with Bergmann gliosis—reactive proliferation of Table 8.4 Classification of Ataxias Primary cerebellar and spinocerebellar degenerations Inherited Autosomal recessive Autosomal dominant Sex-linked Sporadic Multiple system atrophy (OPCA) Idiopathic cerebellar degeneration Secondary cerebellar and spinocerebellar degenerations Neurometabolic Prion disease Toxic Infectious Vascular Paraneoplastic cerebellar degeneration Chapter Pathology of Degenerative Diseases of the Nervous System • 195 A B Axons of granular neurons Dendrites of Purkinje cells Granular neurons Purkinje cells Axons of Purkinje cells Mossy fibers Climbing fibers Middle cerebellar peduncle Inferior cerebellar peduncle Dentate nucleus of cerebellum Superior cerebellar peduncle MCP ICP SCP Inferior olive C D Dentate nucleus MCP ICP Dentate nucleus of cerebellum MCP SCP ICP SCP Inferior olive FIGURE 8.29 The principal lesions seen in various cerebellar atrophies: (A) normal cerebellum; (B) cerebello-olivary atrophy; (C) olivopontocerebellar atrophy; (D) dentatorubral atrophy The main afferent pathways are in black and the main efferent pathways in red; lost pathways are stippled astrocytes at the interface of the Purkinje cell layer and the molecular layer Early and subtle evidence of Purkinje cell loss may be demonstrated with the use of silver staining to reveal the processes of basket cells that normally wrap around the cell bodies of Purkinje cells; when Purkinje cells are lost, these processes remain as “empty baskets.” Granule cell degeneration typically follows the loss of Purkinje cells, with marked loss of folial volume As Purkinje cells die, their projections to the deep nuclei are lost and this phenomenon is demonstrable as pallor in the fibers that wrap around the dentate nucleus (amiculum) Degenerative changes are also common in the deep nuclei of the cerebellum, although 196 • this finding is inconstant in the various forms of cerebellar degeneration Structures that are functionally connected to the cerebellum are also commonly involved The frequent involvement of spinal cord tracts, particularly the spinocerebellar pathways, in the autosomal dominant forms of diseases has led to the emergence of the term spinocerebellar ataxia (SCA)—a range of disorders with several dozen distinct entities Other spinal cord tracts may also be involved, including the dorsal columns (which not have direct connections with the cerebellar cortex) Within the brainstem, there is commonly involvement of the inferior olivary nuclei and their fiber connections E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ 5.1.2 OLIVOPONTOCEREBELLAR ATROPHIES OPCA, classically regarded as the prototype of cerebellopetal atrophy, is characterized by selective involvement of the afferent fibers of pontine and olivary origin (Fig 8.29C) The condition is characterized by pontine and cerebellar lesions, with variable degeneration of the inferior olives • Atrophy of the basis pontis is evident on macroscopic examination There is neuronal loss from the pontine nuclei and degeneration of the pontocerebellar fibers, which constitute the middle cerebellar peduncles In myelin stains, there is pallor of the pontocerebellar fibers, which contrasts with preserved staining of the uninvolved superior cerebellar peduncles, tegmentum, and pyramidal tracts (Fig. 8.30) A • The cerebellar atrophy is characterized by severe degeneration of the cerebellar white matter with astrocytic gliosis (to a large extent due to loss of pontocerebellar fibers) The relative sparing of the amiculum of the dentate nucleus indicates the preservation of Purkinje cell axons • Inferior olivary involvement is characterized by neuronal cell loss and degeneration of the olivocerebellar fibers The neuropathological picture of OPCA is seen in several types of inherited spinocerebellar atrophy (such as SCA2) as well as multiple system atrophy, which is sporadic (4.1.4) 5.1.3 CEREBEL L OF UGAL ATROPHIES Dentato-rubral atrophy is characterized by atrophy of the dentate nucleus and its efferent fibers in the B C FIGURE 8.30 Olivopontocerebellar atrophy in a case of MSA (Loyez stain for myelin) (A) Upper pons: massive myelin loss of pontocerebellar fibers sparing the superior cerebellar peduncles, tegmentum, and pyramidal tracts (B) Medulla: loss of olivocerebellar fibers; note the pale appearance of the median raphe due to loss of crossing fibers (C) Medulla and cerebellum: myelin loss of the cerebellar white matter with relative sparing of the amiculum of the dentate nucleus Chapter Pathology of Degenerative Diseases of the Nervous System • 197 superior cerebellar peduncles and of the red nucleus (Fig 8.29D) Spared Purkinje cell axons may form large growth cones in the dentate nucleus, visible on H&E stain and responsible for the aspect of “grumose degeneration.” It may be associated with pallidal atrophy in the inherited condition dentato-rubro-pallido-luysial atrophy S E CONDARY C ER EB EL L A R AT R O PHI E S Although strictly speaking the following patterns of pathology are not degenerative disease, they are classically considered in this context 5.1.4.1 Crossed cerebellar atrophy This unilateral general atrophy of all the neocerebellar structures is secondary to massive destruction of the efferent corticopontine pathways It is a rare consequence of extensive contralateral cerebral hemispheric lesions and only seen when the survival after the initial lesions has been long Crossed cerebellar atrophy, which has been occasionally described in adults, is particularly obvious when the responsible lesion has developed in utero or in the neonatal period 5.1.4.2 Pseudohypertrophy of the inferior  olive Palatal myoclonus (rhythmical movements of the soft palate occurring 60 to 180 times a minute) is associated with hypertrophy of the inferior olive in which enlarged neurons may appear “fenestrated” (i.e contain lacunae in their cell body) Olive hypertrophy is secondary to a longstanding, usually vascular, contralateral lesion involving the dentate nucleus or the superior cerebellar peduncle, or to an ipsilateral lesion of the central tegmental tract 5.2 Autosomal Recessive Cerebellar Ataxias Cerebellar ataxias with autosomal recessive inheritance are an important group of relatively rare disorders, with patients commonly showing early age of onset and often with associated lesions outside of the cerebellar system The two most frequent of these diseases (Friedreich ataxia [FA] and ataxia-telangiectasia [AT]) will be considered here with another rare disorder that may be prevented by adequate treatment (vitamin E) 198 • FRIEDREICH  ATAXIA A childhood-onset illness, FA typically manifests with some combination of clumsiness, gait ataxia, and signs of sensory peripheral neuropathy Weakness and spasticity often emerge and can be a source of significant morbidity Skeletal changes including scoliosis and pes cavum are common, as is a hypertrophic cardiomyopathy (seen in up to 75% of cases), as well as diabetes (seen in a third of cases) The disease is caused by mutations in the gene on chromosome coding for the protein frataxin Normal frataxin is an 18 kDa mitochondrial protein with 210 amino acids involved in the regulation of iron homeostasis in mitochondria The most common mutation is expansion of an intronic GAA repeat in the gene, which may reach 1,000 copies, with the normal length ranging from 6 to 34 5.2.1.1 Gross appearance The spinal cord and dorsal roots are consistently atrophic The volume of the cerebellum is often unremarkable, but the degeneration of the dentate nucleus results in widening of the superior end of the fourth ventricle as the superior cerebellar peduncles atrophy Systemic manifestations often include cardiomegaly and a characteristic diffuse cardiac fibrosis, which is distinguishable from the scarring seen after myocardial infarction 5.2.1.2 Microscopic findings Spinal cord sensory input is severely affected with loss of large myelinated axons, dorsal root ganglion cells, and the dorsal columns Involvement of the spinocerebellar tracts is also characteristic (Fig.  8.31) Clarke’s columns, from which the dorsal spinocerebellar tract arises, show neuronal loss and the dorsal spinocerebellar tract appears degenerated, atrophied, and pale in myelin stains The ventral spinocerebellar tract is generally less severely involved There is severe neuronal loss in the dentate nuclei, and the cerebellar white matter is generally gliotic although the cerebellar cortex is usually normal, as are the inferior olives The pyramidal tract often shows myelin pallor Cardiomyopathy with fibrosis is frequently present and may lead to cardiac failure ATAXIA- TELAN GIECTASIA This is the most common cause of progressive ataxia in infancy and is caused by mutations in a gene (ataxia-telangiectasia mutated [ATM]) on E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ 5.2.3 CEREBEL L AR ATAXIA WITH ISO L ATED VITAMIN E DEF ICIENCY A This neurological condition has been described in patients with mutations of the alpha-tocopherol transfer protein gene, leading to low availability of vitamin E. Symptoms are similar to that seen in FA The disease has a relatively high prevalence in NorthAfrica Neuropathology shows axonal spheroids with degeneration at the rostral ends of the posterior columns and lipofuscin accumulation in neurons, especially those of dorsal root ganglia There may be Purkinje cell loss Early treatment with vitamin E prevents the occurrence of lesions B 5.3 Autosomal Dominant Cerebellar Ataxias C FIGURE 8.31 Friedreich ataxia (Loyez stain for myelin) Sections of the spinal cord at cervical (A), thoracic (B), and lumbar (C) levels Involvement of the spinocerebellar tracts, mostly dorsal, and of the dorsal columns Note the early involvement of the pyramidal tracts in this case chromosome 11q The common symptoms (in relative order of appearance) are the combination of oculomotor apraxia, cerebellar ataxia, and conjunctival telangiectasias Patients have increased sensitivity to injury from ionizing radiation, which can be attributed to the role of the ATM protein in the regulation of DNA repair mechanisms This dysfunction is also associated with some degree of immunodeficiency as well as an increased risk of leukemia and lymphoma With progression of the disease, there is cerebellar degeneration, typically involving the Purkinje cells as well as the dentate nucleus; dorsal column involvement can be seen as well as lower motor neuron degenerations In addition, histological examination shows bizarre large, irregular, and hyperchromatic nuclei associated with vascular endothelial cells This form of vascular abnormality appears to be independent of the telangiectasias that contribute to the name of the entity About three dozen distinct forms of this complex set of diseases are now recognized; they are collectively termed spinocerebellar ataxias (SCA) Within this heterogenous group of diseases, a set of disorders are polyglutamine diseases, similar to HD:  SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and dentato-rubro-pallido-luysian atrophy Among the other loci, a range of types of genetic mutation, including frameshift mutations, point mutations, deletions, expansion of noncoding repeats, and missense mutations, have been described; for some, a mapped locus but not an identified genetic alteration has been identified A  summary of the present classification of autosomal dominant cerebellar ataxias is presented in Table 8.5 While the detailed discussion of the patterns of clinical symptomatology and gross and microscopic pathological changes in each one of these diseases is clearly well beyond the scope of this chapter, a few generalizations can be made By and large, those forms of SCA linked to expanded polyglutamine tracts show some clinical similarities with HD: the age of onset is inversely correlated with the length of the repeat; “anticipation” (see above) is due to expansion of the repeat during genetic transmission Intranuclear inclusions in neurons contain ubiquitinated proteins, including the expanded polyglutamine portion of the mutated protein Of note, patients with two of the CAG-repeat forms of SCA (SCA17 and DRPLA) can also have a clinical presentation that mimics HD, with prominent choreoathetosis In all of the SCAs, there is commonly involvement of a range of brain structures outside of the cerebellum—and this is the basis for the Chapter Pathology of Degenerative Diseases of the Nervous System • 199 Table 8.5 Autosomal Dominant Forms of Cerebellar Ataxia with Known Mutations DISORDER CHROMOSOME PRODUCT T YPICA L DISE ASE R E P E AT S T YPICAL NORMAL R E P E AT S SCA1 SCA2 SCA3/MJD SCA4 SCA5 SCA6 SCA7 SCA8 6p23 12q24 14q 16q22.1 11p12-q12 19p 3p21 13q21 42 to 81 (CAG) 35 to 64 (CAG) 68 to 79 (CAG) 16 to 36 15 to 24 13 to 36 Anticipation seen 21 to 30 (CAG) 38 to 130 (CAG) 16 to 37 (CTG) to 17 to17 107 to 127 SCA10 22q13 800 to 4,500 (ATTCT) 10 to 22 SCA11 SCA12 SCA13 SCA14 SCA15 SCA16 SCA17 SCA27 15q14-21.3 5q31 19q13.3 19q13.4 Unlinked 8q23-24 6q27 13 66 to 93 < 29 63 (CAG) Point mutation 25 to 42 SCA28 18p11 Ataxin-1 Ataxin-2 Ataxin-3 Unknown Unknown CACNA1A Ataxin-7 Transcribed but untranslated Transcribed but untranslated Unknown PPP2R2B Unknown Unknown Unknown Unknown TBP Fibroblast growth factor 14 (FGF14) ATPase family gene 3-like (AFG3L2) presence of additional symptoms of neurological dysfunction For example, patients with SCA7 have associated retinal degeneration that can progress to blindness Combinations of pyramidal and extrapyramidal motor disturbances as well as peripheral neuropathy and other signs referable to focal degenerative changes can be seen in the SCAs 5.4 Fragile X Tremor/Ataxia Syndrome The fragile X syndrome is one of the causes of mental retardation, with the pathological expansion of a noncoding trinucleotide repeat (CGG) in the fragile X mental retardation (FMR1) gene being the underlying mutation When the repeat length is in the “premutation” range (typically described as 55 to 200 copies), a cerebellar degenerative disease 200 • Missense mutation can emerge in males and, less frequently, in obligate carrier females Characteristically, patients develop progressive ataxia with onset in adult life, often associated with tremor and parkinsonism Sensory nerves are commonly involved as well While there may be gross atrophy of the cerebellum, microscopic findings include loss of Purkinje cells, widespread changes in white matter with volume loss and vacuolization, and the presence of ubiquitin-positive intranuclear inclusions in neurons and glia 5.5 Sporadic Degenerative Ataxia Even with the increasing number of genetically determined forms of cerebellar system degeneration, some cases still fall outside of the currently established categories While some patients with E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ progressive ataxia have multiple system atrophy (vide supra) in which other portions of the nervous system are involved, there remain others—typically with idiopathic late-onset cerebellar ataxia, associated with cerebellar cortical atrophy and some involvement of afferent and efferent paths and nuclei MOTOR NEURON DISEASES Within the brain and spinal cord, a variety of neurons are referred to as being motor neurons—there are the cholinergic neurons in brainstem nuclei and the anterior horn of the spinal cord that project directly to muscle endplates (also known as lower motor neurons) as well as the large glutamatergic pyramidal neuronal of the precentral gyrus that descend from the cortex to innervate the lower motor neurons (and these are known as upper motor neurons) While a range of other neurons contribute to motor output, it is the involvement of these two sets of neurons that defines this category of illnesses In addition to the neurodegenerative disorders, motor system degeneration may be seen in a variety of other conditions, including toxic and metabolic disorders and infectious diseases 6.1 Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of both upper motor neurons and lower motor neurons While the balance between the severity and pace of involvement of these two sets of neurons may vary from case to case, the combination is characteristic of ALS In many cases, the disease begins with involvement of spinal lower motor neurons manifesting as weakness in the arms or legs In others, ALS begins with bulbar symptoms and may be termed progressive bulbar palsy Infrequently, the upper motor neurons may be predominantly involved in the face of preserved lower motor neurons; this disorder is typically referred to as primary lateral sclerosis, drawing its name from the changes in the descending corticospinal tracts of the lateral portion of the spinal cord The other pattern, with loss of lower but preservation of upper motor neurons and their associated corticospinal fibers, is referred to as progressive muscular atrophy While much of ALS appears to be sporadic, familial forms account for about 5% to 10% of cases, with an ever-increasing spectrum of mutations and genetic loci being identified While autosomal dominant inheritance is most common, both recessive and X-linked patterns of inheritance also occur Mutations involving superoxide dismutase (SOD1) were among the first recognized to cause familial ALS (fALS), with different point mutations associated with a range of disease spectrums, including both age of onset and rate of progression While the specific mechanism of cellular injury from the mutant SOD1 remains unclear, it is generally believed to represent a novel gain-of-function rather than being the consequence of loss of normal enzymatic activity A range of other genetic loci have been identified that can cause ALS, but of particular interest are those that overlap with familial forms of FTLD As was considered above, associations of ALS and forms of FTLD are relatively common, and this relationship has been strengthened by the recognition that disease-associated mutations in TDP43, FUS, and C9orf72 are linked to both processes 6.1.1 GROSS APPEARANCE Usually, the brain appears macroscopically normal Atrophy of the precentral gyrus can occur with long survival, particularly when nutritional and ventilator support has been provided In patients who have developed clinical dementia, atrophy of frontal and temporal lobes may be present Gross evidence of changes in the descending corticospinal tracts is often evident in the medullary pyramids, while the atrophy of roots of the hypoglossal nerve reflects bulbar lower motor neuron involvement Motor cranial nerves associated with extraocular muscles (III, IV, and VI) are not affected The spinal cord is usually thinner than normal, with discoloration of the lateral funiculus Anterior nerve roots are generally shrunken and gray in comparison with the posterior sensory roots (Fig. 8.32) 6.1.2 MICROSCOPIC L ESIONS The most prominent neuronal loss, with associated astrocytosis, is found in anterior horns of the spinal cord (Fig. 8.33), some brainstem motor nuclei, and the motor cortex Within these structures, the injury is relatively restricted to a specific population of neurons:  motor neurons in the spinal cord and Chapter Pathology of Degenerative Diseases of the Nervous System • 201 FIGURE 8.32 Motor neuron disease On the left, the spinal cord viewed from the dorsal surface shows normal-sized posterior (sensory) nerve roots In contrast, the spinal cord viewed from the ventral surface(right) shows marked atrophy of anterior (motor) nerve roots in a case of amyotrophic lateral sclerosis the involved brainstem nuclei (hypoglossal nucleus, nucleus ambiguus, motor nucleus of trigeminal nerve and of facial nerve), while in the motor cortex, the large projecting pyramidal neurons of layer V (Betz cells) are targeted Even when it is difficult to determine whether there is loss of Betz cells, gliosis at the gray–white junction of the precentral gyrus is commonly observed Associated with the loss of upper motor neurons, the white matter of the spinal cord shows pallor in both the lateral and anterior corticospinal tracts, related to their degeneration Pallor of myelin staining may also be seen in the corticospinal tracts as they descend in the brainstem (Fig 8.34B) Similar FIGURE 8.33 Motor neuron disease This low-magnification view shows severe loss of motor neurons in the anterior horns of the spinal cord 202 • changes can be observed in these tracts at more rostral levels, including the medullary pyramids (Fig.  8.34A), the basis pontis, and the cerebral peduncles It is uncommon to be able to detect the loss of these descending fibers at higher levels than the upper brainstem, such as within the posterior limb of the internal capsule Although the overall gross and microscopic appearance of ALS is the same for sporadic and familial forms (including across the spectrum of different mutations), it is possible to demonstrate differences using immunohistochemistry directed against various proteins It has been observed that aggregates of SOD1 in an abnormal conformation can be detected in anterior horn cells both in sporadic ALS and in the setting of SOD1-linked fALS, although this is little used in diagnostic practice In contrast, immunohistochemistry for ubiquitinated TDP-43-containing inclusions will reveal aggregates of thread-like structures termed skeins in surviving motor neurons in the setting of sporadic ALS or fALS associated with TDP-43 mutations or expansion of the hexanucleotide repeat in C90rf72 but not in the setting of SOD1 mutations (see Fig.  1.15) In contrast, ubiquitinated, TDP43-negative, FUS-positive inclusions are observed in the setting of FUS-linked fALS 6.2 Spinal Muscular Atrophy In this condition, spinal motor neurons progressively degenerate, with resulting severe weakness Primarily a pediatric disorder, the disease is similar to other degenerative diseases where the more severe forms occur with earlier onset The spectrum ranges from a neonatal and rapidly fatal form (SMA 0) to an infrequently observed adult-onset form (SMA 4) The two best-recognized patterns are SMA (Werdnig-Hoffmann disease), with onset during the first 6 months of life, in which children never achieve the developmental milestone of sitting, and SMA (Kugelberg-Welander disease), with onset around the second birthday, in which children start to walk before the onset of motor weakness As would be expected, there is atrophy of skeletal muscles and of anterior nerve roots along with loss of motor neurons from the anterior horns of the spinal cord All of these different phenotypes of the disease are linked to mutations in the pair of genes SMN1 and SMN2, which sit as an inverted repeat on the long arm of chromosome (5q13) In addition to the few single amino acid differences between the protein products of the two genes, there is also a E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ A B FIGURE 8.34 Amyotrophic lateral sclerosis (A) Pallor of myelin staining of the medullary pyramid (B) Sections of the spinal cord at cervical, thoracic, and lumbar levels show pallor of myelin staining in uncrossed and crossed pyramidal tracts (Loyez stain) difference that decreases the efficiency of splicing into the mRNA of exon from SMN2 As a result, the SMN2 gene is far less efficient at generating function SMN protein than the SMN1 gene The severity of the phenotype is associated with the number of copies of SMN2 present in the setting of homozygous loss of SMN1 Currently novel therapeutic approaches to this disorder are focused on alteration of the splicing of SMN2 mRNA or mutagenic conversion of the SMN2 gene into an SMN1 gene 6.3 X-linked Spinal and Bulbar Muscular Atrophy (Kennedy Disease) This disorder involves lower motor neurons of the spinal cord and brainstem, with typical onset of symptoms in early to middle adult life Men are predominantly affected, as the causative mutation is an expansion of a polyglutamine tract in the androgen receptor, which is encoded by a gene on the X chromosome Neurological involvement typically includes weakness, muscle atrophy with fasciculations, and decreased tone without spasticity Systemic findings such as gynecomastia and testicular atrophy emerge as well, as a consequence of relative androgen insensitivity Grossly, there can be evidence of motor root atrophy both in the brainstem and spinal cord Microscopic examination reveals the corresponding loss of motor neurons from these nuclei, with the appearance of ubiquitinated polyglutamate-containing intranuclear inclusions in remaining neurons 6.4 Hereditary Spastic Paraparesis Hereditary spastic paraparesis is a genetically and clinically heterogeneous set of disorders in which patients develop slowly progressive paraparesis beginning with the legs and having more spasticity than weakness These symptoms reflect a length-dependent axonal injury process involving the descending corticospinal tracts There can be variability in age of onset (even within kindreds), in severity, and in associated other symptoms (sensory changes, cerebellar ataxia, epilepsy, and intellectual deficit) Despite the heterogeneity, autosomal dominantly inherited forms predominate, with mutations in the gene encoding spastin (SPG4/SPAST) being the most common overall, although aspects of the complex clinical phenotype can direct suspicion toward other known loci There is degeneration of corticospinal tracts, most marked in the lumbar and lower thoracic cord, with preservation of anterior horn cells In those cases with clinical evidence of sensory changes, degeneration of dorsal columns may also be observed In keeping with the length-dependent pattern of the disease, this is most marked in the upper thoracic and cervical cord INVOLVEMENT OF THE CENTRAL AUTONOMIC SYSTEMS IN DEGENERATIVE DISORDERS There are many causes of autonomic failure, which may be divided into primary and secondary types Chapter Pathology of Degenerative Diseases of the Nervous System • 203 Some are due to lesions of the central nervous system and some to lesions in the peripheral nervous system Patients who have autonomic failure with parkinsonism almost always have either MSA with glial cytoplasmic inclusions or Lewy body pathology In MSA cases, it is not uncommon for other clinical features of MSA (such as cerebellar ataxia) 204 • to develop over time In both cases, autonomic dysfunction is related to loss of cells from the intermediolateral column of the spinal cord At autopsy of patients who have primary progressive autonomic failure without any other neurological symptoms, the sympathetic ganglia may contain Lewy bodies or may show the characteristic inclusions of MSA E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y https://kat.cr/user/Blink99/ ... Martin A Samuels – 5th ed p ; cm Escourolle and Poirier’s manual of basic neuropathology Manual of basic neuropathology Rev ed of: Escourolle & Poirier’s manual of basic neuropathology / Françoise... 19 24– V Gray, Françoise Escourolle & Poirier’s manual of basic neuropathology VI Title: Escourolle and Poirier’s manual of basic neuropathology VII Title: Manual of basic neuropathology [DNLM:... previous edition of the Manual of Basic Neuropathology was published in 2003 In 19 71, Raymond Escourolle and his student, Jacques Poirier, published a book on the basic aspects of neuropathology,