Ebook Escourolle poirier’s manual of basic neuropathology Part 1

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Escourolle & Poirier’s
Manual of Basic Neuropathology

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Escourolle & Poirier’s
MANUAL OF BASIC
G
NEUROPATHOLOGYR

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F I F T H EDITION

FRANÇ O IS E G RAY, MD, PHD

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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

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CH A R L ES D U YCKAERTS, MD, PHD

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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

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3
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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

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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
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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: 1. Central Nervous System Diseases—pathology. WL 301]
RC347
616.8′047—dc23
2013010266

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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
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Printed in the United States of America
on acid-free paper

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Contents

Foreword vii
Martin A. Samuels
Preface to the Fifth Edition
Contributors xi

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1. Basic Pathology of the Central
Nervous System 1

5. Infections of the Central Nervous
System 114
Françoise Gray, Kum Thong Wong,
Francesco Scaravilli, and Leroy R. Sharer

6. Human Prion Diseases 149

Danielle Seilhean, Umberto De Girolami, and
Françoise Gray

2. Tumors of the Central Nervous System 20
Keith L. Ligon, Karima Mokhtari, and
Thomas W. Smith

3. Central Nervous System Trauma

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James W. Ironside, Matthew P. Frosch, and
Bernardino Ghetti

7. Multiple Sclerosis and Related
Inflammatory Demyelinating
Diseases 161

Hans Lassmann, Raymond A. Sobel, and
Danielle Seilhean

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Colin Smith

4. Neuropathology of Vascular Disease 76

8. 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
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9. 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

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CONTENTS

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Foreword

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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

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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.

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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.

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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

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Preface to the Fifth Edition

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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.

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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 do 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


demonstrate these with accurate descriptions and
good illustrations, all within the scope of a concise
and inexpensive “manual.”
For several reasons, we think that the time is now
right for a new edition since the last one in 2003.
Over the past decade, specialty training in neurology, neurosurgery, and pathology has changed
throughout much of the world, such that in these
disciplines less time is being devoted to neuropathology. This has been due in large part to the
tremendous expansion of knowledge in allied subspecialty areas, requiring that more time be devoted
to them. As a result, the trainee is now very much in
need of a concise introductory text.
In addition, several other important changes in
medicine and society have had an impact on the

field of neuropathology and need to be addressed in
this text.
• For a variety of social and scientific reasons,
autopsy studies are currently being performed
much less frequently than in years past. This
change has been brought about in part because
the progress in radiological imaging, both structural and functional, has decreased the need to
draw on clinical–anatomical correlations derived
from autopsy data to guide medical practice.
Oddly enough, conversely, autopsy-derived
knowledge of the anatomical distribution and the
neuropathological basis of lesions continues to
be a valuable body of information for the interpretation of imaging data. To this aim we have
made ample use of macroscopic illustrations and
whole-brain celloidin-/paraffin-embedded sections from our archives.
• Progress in molecular biology and genetics has
revolutionized the laboratory diagnosis of many
groups of neurological diseases. Neuropathology
stands at the vanguard of the development and
implementation of these diagnostic studies.
In the past decade, progress in immunohistochemistry methods for in situ identification of
abnormal proteins, and the enormous advances
in molecular biology to uncover specific gene
mutations, have led to greater understanding of
many hereditary neurological diseases, including

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degenerative and metabolic disorders, developmental disorders, and neuromuscular diseases.
Morphologic neuropathological data, obtained
at biopsy or at postmortem examination, therefore need to be integrated with this new knowledge for the reinterpretation and reclassification
of many diseases. For example, neuropathological information obtained at biopsy, combined
with molecular biology and genetic data, is now
required for the diagnosis, prognosis, and guidance of the choice of treatment modalities for
cerebral tumors.
• Lastly, an urgent responsibility to present an
updated synopsis of neuropathology is that this
knowledge is important to allied disciplines, as
there is a constant need for surveillance of newly
recognized diseases, including iatrogenic ones.

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We need to thank first of all Susan Pioli, who
although now retired from the publishing business
was instrumental in the prior edition and led us to
Craig Panner with Oxford University Press, who has
given fundamental support. Secondly, we thank the
contributing authors and their staff for the text and
illustrations provided in this new edition.
In the Introduction to the First Edition,
Professors Escourolle and Poirier offered an apology
to the reader that is still valid 40 years later:

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The compilation of a basic work designed to familiarize physicians-in-training with such a highly
specialized discipline as Neuropathology entails
two opposing risks:  in attempting to compress
the maximum amount of information within the
minimum space, the text is liable to become unintelligible to beginners; if on the contrary, one tries to
maintain too elementary a level, the danger is that
only the obvious will be stated. In presenting to the
non-initiated reader neuropathological information that some may find too simple, we have preferred the hazard of the second pitfall.

P R E FA C E TO T H E F I F T H E D I T I O N

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Françoise Gray
Charles Duyckaerts
Umberto De Girolami

Contributors

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Homa Adle-Biassette, M.D., Ph.D.
Maitre de Conférence en Anatomie Pathologique,
University of Paris VII
Neuropathologiste, Practicien Hospitalier, APHP,
Hopital Lariboisière, Paris, France

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Anthony A. Amato, MD

Professor of Neurology
Harvard Medical School
Vice-chairman, Department of Neurology;
Chief, Neuromuscular Division
Brigham and Women’s Hospital,
Boston, MA
Douglas C. Anthony, M.D., PhD.
Professor, Alpert Medical School of Brown University
Pathologist-in-Chief, Lifespan Academic Medical
Center,
Providence, RI

Umberto De Girolami, MD
Professor of Pathology
Harvard Medical School
Neuropathologist, Brigham and Women’s Hospital;
Consultant Neuropathologist
Boston Childrens’ Hospital,
Boston, MA

Charles Duyckaerts, MD, PhD
Professor of Pathological Anatomy,
University of Paris VII
Director, Neuropathology Laboratory, PitiéSalpêtrière Hospital,
Paris, France
Féréchté Encha-Razavi, MD
Fetal Pathology, Necker Hospital
Paris, France

Leila Chimelli, MD, PhD

Professor of Pathology
Federal University of Rio de Janeiro
Neuropathologist, National Cancer Institute,
Rio de Janeiro, Brazil
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Rebecca Folkerth, MD
Associate Professor of Pathology
Harvard Medical School
Director, Neuropathology Service, Brigham and
Women’s Hospital;
Consultant Neuropathologist, Boston Childrens’
Hospital,
Boston, MA

Brian N. Harding, MD PhD
Professor of Pathology & Laboratory Medicine,
University of Pennsylvania
Neuropathologist, Department of Pathology and
Laboratory Medicine
Children’s Hospital of Philadelphia
Philadelphia, PA
Jean-Jacques Hauw, MD
Emeritus Professeur d’Anatomie Pathologique,
University of Paris VI
Paris, France

Matthew P. Frosch, MD, PhD
Lawrence J. Henderson Associate Professor of

Pathology and Health Sciences & Technology
(HST); Associate Director, HST
Harvard Medical School
Director, Neuropathology Service
C.S. Kubik Laboratory for Neuropathology
Massachusetts General Hospital,
Boston, MA
Bernardino Ghetti, MD
Distinguished Professor and Director of
Neuropathology
Department of Pathology and Laboratory Medicine
Indiana University School of Medicine
Indianapolis, Indiana
Romain K. Gherardi, MD
Professor of Histology
Reference Center, INSERM U955
Henri Mondor University Hospital
Paris-Est University, F-94010 Créteil, France

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Hans H. Goebel, MD
Professor of Neuropathology
Department of Neuropathology
University Medical Center of the Johannes
Gutenberg University
Mainz, Germany

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Françoise Gray, MD, PhD
Professeur d’Anatomie Pathologique,
University of Paris VII
Praticien Hospitalier, AP,HP, Hôpital Lariboisière,
Paris, France

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James W. Ironside, FRCPath
Professor of Clinical Neuropathology
School of Clinical Sciences
University of Edinburgh, UK
Honorary Consultant Neuropathologist
Lothian University Hospitals Division and Tayside
University Hospitals
Scotland, UK

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Hans Lassmann, MD
Professor of Neuroimmunology
Center for Brain Research
Medical University of Vienna
Vienna, Austria
Hart G. W. Lidov, MD, PhD
Associate Professor of Pathology
Harvard medical School
Director of Neuropathology
Department of Pathology ; 
Boston Children’s Hospital 
Neuropathologist Brigham and Women’ Hospital 
Boston, MA

Jeffrey A. Golden, MD
Harvard Medical School
Chair,
Brigham and Women’s Hospital
Boston, MA

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E. Tessa Hedley-Whyte
Professor of Pathology
Harvard Medical School
Neuropathologist, C.S. Kubik Laboratory for
Neuropathology

Massachusetts General Hospital,
Boston, MA

Keith L. Ligon, MD, PhD
Assistant Professor of Pathology
Harvard Medical School
Investigator, Dana-Farber Cancer Institute Center
for Molecular Oncologic Pathology
Neuropathologist, Brigham and Women’s Hospital,
Boston Children’s Hospital
Boston, MA

CO N T R I BU TO R S

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James Lowe, DM, FRCPath
Professor of Neuropathology
University of Nottingham Medical School
Hon Consultant in Neuropathology, Nottingham
University Hospitals NHS Trust, Nottingham
UK

Colin Smith, MD, FRCPath
Reader in Pathology
University of Edinburgh
Honorary Consultant in Neuropathology
NHS Lothian
Edinburgh, UK

Karima Mokhtari, MD
Neuropathologist, Pitié-Salpêtrière Hospital,
Paris, France

Thomas W. Smith, MD
Professor of Pathology and Neurology
University of Massachusetts Medical School
Director of Neuropathology and Diagnostic
Electron Microscopy,
UMass Memorial Medical Center
Worcester, MA

Jacqueline Mikol, MD
Emeritus Professeur d’Anatomie Pathologique,
University of Paris VII
Praticien Hospitalier, AP, HP, Hôpital Lariboisière,
Paris, France
Vânia Nosé, MD, PhD
Associate Professor of Pathology
Harvard Medical School
Director of Anatomic and Molecular Pathology
Massachusetts General Hospital
Boston, MA
Francesco Scaravilli, MD, PhD, FRCPath, DSc
Emeritus Professor of Neuropathology
Institute of Neurology, UCL, London, UK
Frédéric Sedel, MD, PhD
Professor of Neurology
Fédération des Maladies du Système Nerveux
APHP, Pitié-Salpêtrière Hospital

University Paris of VI

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Danielle Seilhean, MD, PhD
Professor of Pathological Anatomy, University of
Paris VI
Neuropathologist, Pitié-Salpêtrière Hospital,
Paris, France

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Leroy R. Sharer, MD
Professor of Pathology
New Jersey Medical School
Neuropathologist, University Hospital,
Newark, NJ

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Raymond A. Sobel, MD
Professor of Pathology (Neuropathology)
Stanford University School of Medicine

Neuropathologist, Veterans Affairs Health Care
System
Palo Alto, CA

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Jean-Michel Vallat, MD, PhD
Professor of Neurology
University of Limoges
Department of Neurology
University Hospital Dupuytren
Limoges, France

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Harry V. Vinters, MD, FRCPC, FCAP
Distinguished Professor of Pathology & Laboratory
Medicine, and Neurology,
David Geffen School of Medicine at University of
California Los Angeles (UCLA),
Chief, Section of Neuropathology, Ronald ReaganUCLA Medical Center
Member, Brain Research Institute, UCLA
Los Angeles, CA
Kum Thong Wong, MBBS, MPath,
FRCPath, MD
Dept of Pathology, Faculty of Medicine,
University of Malaya,

Kuala Lumpur, Malaysia

Contributors • xiii


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Basic Pathology of the Central
Nervous System
D A NI ELLE S E I LHE AN , U MB ER TO D E G I R O L A MI , A ND FRA NÇO ISE   G RAY

AUTOPSY DIAGNOSIS in neuropathology is
based on the macroscopic and microscopic study
of the brain, brainstem, cerebellum, and spinal cord.
Increasingly, the ability to reach greater diagnostic
precision is buttressed by the new laboratory techniques of molecular biology and genetics. Three
consecutive steps are involved in reaching a diagnosis and these are, in fact, closely interrelated: (1) a
morphologic/laboratory analysis of the lesions;
(2) a topographic analysis of the lesions; and (3) a
critical integration of these findings and their subsequent correlation with the clinical data and the general autopsy findings, thus permitting an etiological
diagnosis to be made in most instances.

1. MORPHOLOGIC ANALYSIS
OF CENTRAL NERVOUS
SYSTEM LESIONS
With the exception of tumors and malformations, most
disorders of the central nervous system (CNS) are

characterized morphologically by the co-expression of
multiple reactions to injury that may not be diagnostic in themselves. These reactions affect the cellular
elements of the nervous system (neurons, astrocytes,
oligodendrocytes, and microglia) and/or the supporting structures (meninges, connective tissue, or blood
vessels). Basic cellular reactions are demonstrable only
on microscopic examination, whereas tissue lesions
that can be associated with more extensive destructive
or atrophic changes are recognized macroscopically or
with the help of a magnifying lens.

Although, for didactic purposes, the reactions
to injury seen in the neurons, glia, connective tissue, and vascular structures will be described separately in the text below, it is essential to emphasize
that there is a close functional interdependence of
the various cellular elements of the nervous system.
This is particularly important in the case of nerve
cell alterations where, except for very acute injury,
the possibility of artifactual change should be entertained whenever the reaction is not accompanied by
a glial cell response.
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1.1. BASIC cellular reactions to
CNS injury
1. 1. 1. NE UR ONAL LES I O NS

Neuronal injury may sufficiently severe to result in
irreversible damage (cell death) or may be transient
or minimal and cause reversible functional damage. Destruction of neurons may be focal, or extend
diffusely, involving many populations of neurons
throughout the nervous system. In acute neuronal injury, when the tissue is examined with H&E
preparations at a time shortly after a lethal insult to
the cell, one observes eosinophilia of the cytoplasm,
shrinkage and hyperchromasia of the nucleus, and
disappearance of the nucleolus; subsequent to the
disintegration of the cell, neuronophagia by scavenger cells ensues. In chronic diseases, evidence of
cell death is recognized morphologically as neuronal “cell loss” or, alternately, as “atrophy” when the
irreversible injury has occurred relatively slowly and
has progressively involved ever greater numbers of

cells. In some degenerative diseases of the nervous
system in which there is progressive loss of neurons
over variable time periods, the affected cells have
distinctive morphologic hallmarks (e.g., neurofibrillary degeneration, neuronal storage of metabolic
products, disorders associated with intracellular
inclusion bodies).
The end stage of all irreversible lesions that
affect the nerve cells is neuronal loss, evidenced
by an appreciable reduction in the number of cell
bodies in a particular area, as compared to normal.
This assessment can be difficult to estimate in the
absence of rigorous morphometric analysis, when
it involves less than 30% of the normal cell population. This estimate depends on the thickness of the
section and on the normal cytoarchitectonics of the
region examined.
1.1.1.1. Nerve cell “atrophy” Neuronal “atrophy” is the descriptive term that is given to a wide
range of irreversible neuronal injuries that give
rise to a relatively slowly-evolving death of the
cell. Neuronal “atrophy” is characterized morphologically by retraction of the cell body with diffuse basophilia of the cytoplasm and pyknosis and
hyperchromasia of the nucleus of the neuron, in
the absence of an inflammatory reaction. Neuronal
“atrophy” is thought to occur in many degenerative disorders that involve several interconnected
neuronal systems (i.e., multiple system atrophy, in
Friedreich ataxia, and even in amyotrophic lateral
2 •

sclerosis). It is also seen in anterograde and retrograde transsynaptic degeneration, as may occur in
the lateral geniculate body following a lesion of the
optic nerve.
Programmed cell death (apoptosis) is an active,

genetically controlled, energy-consuming process
frequent in neurodegeneration and involving primarily the nucleus of the cell. Neurons undergoing
simple neuronal atrophy or apoptosis have similar
morphologic features and may show positive in situ
end labeling of internucleosomal DNA fragmentation (Fig.1.1)or be demonstrable by activated
caspase-3 immunostaining.
Nerve cell atrophy should not be mistaken for
what is referred to as “dark neurons.” This phenomenon is now recognized to be an artifactual change
of the neuron cell body, seen particularly in brain
biopsies fixed in formalin by immersion, and characterized by shrunken cytoplasm and deeply-stained
and irregularly-shaped nucleus without other cellular
alterations.
1.1.1.2. Acute Neuronal Necrosis (Anoxic/
Ischemic Neuronal Change) This type of cell death
occurs in a variety of acute injuries, including anoxia
and ischemia, but may also be seen in many other
acute pathological processes (e.g., hypoglycemia or

FIGURE 1.1 Two neurons undergoing apoptosis are positively stained by in situ end labeling to
demonstrate internucleosomal DNA fragmentation.
In one neuron, on the left, only the nucleus is stained,
whereas in the other, which is at a later stage of the
programmed cell death process, the entire cell body is
stained. Compared to a normal neuron, on the right,
both apoptotic neurons have similar morphologic
features and show pyknotic nucleus and shrunken
cytoplasm.

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FIGURE 1.2 Acute ischemic nerve cell change
(H&E). Eosinophilic, shrunken cytoplasm and hyperchromatic nucleus.

FIGURE 1.3 Ferrugination (mineralization)
of the neurons at the edge of an old hemorrhagic
infarct (H&E).

exposure to excessive amounts of excitotoxic neurotransmitters). Unlike apoptosis, the predominant
cellular changes in acute neuronal necrosis involve
the cytoplasmic organelles and the cell membrane,
which ruptures, leading to cell death.
In experimental animal studies and in carefully
preserved human tissue at postmortem, by light
and electron microscopy, the following sequence of
changes is noted over the course of 12 to 24hours after
the insult: (a) cytoplasmic microvacuolation due to
swelling of mitochondria and endoplasmic reticulum;
(b) shrinkage of cell body with retraction of the cellular outlines, and disappearance of Nissl bodies with
eosinophilic condensation of the cytoplasm (“red
neuron”); (c) condensation of nuclear chromatin and
nuclear pyknosis (Fig. 1.2); (d) late disappearance of
the nuclear chromatin, resulting in increased acidophilia of the nucleus, which appears to merge into the
surrounding cytoplasm (karyorrhexis).
Occasionally, dead neurons, especially those
adjacent to old, mostly hemorrhagic, infarcts, or to
traumatic scars, become encrusted with basophilic
mineral deposits, chiefly iron and calcium salts. This
condition is referred to as mineralization or ferrugination of neurons (Fig.1.3).

degeneration or axonal reaction). Subsequent recovery of normal cell morphology or, conversely, further
progression to nerve cell degeneration depends on the
reversibility of the axonal lesion (Fig.  1.5). Central
chromatolysis may also be seen in upper motor neurons, but the phenomenon is rare and difficult to
interpret. Axonal lesions of neurons whose axons do
not leave the confines of the CNS apparently either
do not produce changes in perikaryal cell body morphology or result in “simple” type of atrophy. Oddly
enough, some metabolic disorders that do not a priori
involve axons (e.g., Wernicke encephalopathy, pellagra
encephalopathy, porphyria) may be accompanied by
central chromatolysis in cortical neurons.
A confident diagnosis of central chromatolysis
requires comparison with the normal morphology

1.1.1.3. Central chromatolysis Central chromatolysis is characterized morphologically by swelling
of the cell body, disappearance of Nissl bodies beginning centrally and extending outward, and flattening and eccentric displacement of the nucleus to the
periphery (Fig. 1.4). It is seen usually in lower motor
neurons (anterior horns of the spinal cord, cranial
nerve nuclei), where it represents a reparative reaction of the cell body to a lesion of the axon (retrograde

FIGURE 1.4 Central chromatolysis (Nissl stain).
Note the cellular swelling, the eccentric displacement of the nucleus, and the margination of the Nissl
bodies.

Chapter 1 Basic Pathology of the Central Nervous System • 3


Complete
central

chromatolysis

Normal
neuron

Recovery

Cell death

FIGURE 1.7 Fenestrated neuron in a case of olivary
hypertrophy (Nissl stain).

Stages of
hyperchromasia

FIGURE 1.5 Nerve cell changes in central
chromatolysis.

of the affected gray matter structure because the
nerve cell-body in some nuclei (e.g., the mesencephalic nucleus of the fifth cranial nerve, Clarke’s
column) normally contains rounded neurons with
marginated Nissl bodies.

1.1.1.5. Binucleated neurons These lesions are
seen rather infrequently, sometimes under normal
circumstances, at the edge of old focal destructive
lesions, as a dysplastic/malformation phenomenon
(e.g., tuberous sclerosis), or in certain neoplasms
(e.g., ganglion-cell tumors).

1.1.1.4. Vacuolated neurons and neuropil
Vacuolated neurons and neuropil are observed
in Creutzfeldt-Jakob disease (Fig.  1.6). In rare
instances, swelling with vacuolization of the nerve
cell is thought to result from transsynaptic degeneration—for example, in the neurons of the inferior
olive in olivary hypertrophy, secondary to a lesion of
the ipsilateral central tegmental tract, or of the contralateral dentate nucleus—so-called “fenestrated
neurons”(Fig. 1.7).

1.1.1.6. Neuronal storage In some hereditary
metabolic diseases related to enzymatic defects
involving synthetic or degradative pathways for lipids or carbohydrates, interruption of the pathway
leads to cytoplasmic accumulation of intermediate
substrates or their byproducts, resulting in swelling
and distention of the cell body of nerve cells, with
eccentric displacement of the nucleus (Fig. 1.8). In
several neuronal storage disorders, the stored material has distinctive histochemical and ultrastructural features that may help characterize clinically

FIGURE 1.6 Vacuolated neuron in a case of
Creutzfeldt-Jakob disease (H&E).

FIGURE 1.8 Distended nerve cell bodies in a case
of neuro-lipidosis (combined Luxol fast blue and
Bodian silver impregnation).

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suspected cases. Biochemical tests on blood, leukocytes, and other body fluids are now particularly
useful to more precisely diagnose many of these
disorders.
Lipofuscin accumulation within the perikaryon
of neurons and other cells in the nervous system
is a characteristic aging change. Lipofuscin accumulates in neurons diffusely throughout the brain
in ceroid-lipofuscinosis, a neuronal storage disorder. Lipofuscin is identified on H&E preparations
as refractile yellow-brown pigment aggregates
(Fig.  1.9). It is autofluorescent and rich in acid
phosphatase. The pigment is PAS-positive and can
be stained by Luxol fast blue. It has distinctive ultrastructural features (see Chapter 10).
1.1.1.7. Alzheimer neurofibrillary degeneration and granulovacuolar degeneration Alzheimer
neurofibrillary degeneration is characteristically seen
in the brains of aged individuals and in patients with
senile dementia of Alzheimer type but has also been
described in a variety of other cerebral disorders.
This degenerative change is manifest by the formation of neurofibrillary tangles (NFTs), structures
that are well demonstrated by silver impregnation
and by immunohistochemical techniques and consists of thickened and tortuous skeins within the
neuronal perinuclear cytoplasm. The configuration
of the tangle may vary according to the anatomical
site, the type of neuron affected, and the stage of its
development (Fig.1.10). A band-shaped perikaryal
NFT can be seen both in large and small pyramidal cells and is perhaps an early stage of NFT formation (Fig.1.10A). A  triangular flame-shaped
perikaryal NFT is seen mainly in large pyramidal

FIGURE 1.9 Lipofuscin in neuronal cell
body (H&E).

cells (Fig.1.10B, C). Compact globose perikaryal
NFTs are mainly seen in small cortical neurons
(Fig.1.10D). Large globose NFTs reminiscent of
a ball of string are more common in neurons of
the nucleus basalis of Meynert and in the brainstem (Fig.1.10E). In the final stages of the disease,
the cell outline disappears and only the distorted
fibrils remain as “ghost NFT” (Fig.1.10F).The predominant biochemical component of NFTs is the
microtubule-associated protein tau, which accumulates in an abnormally highly phosphorylated form.
Tangles are particularly well demonstrated by tau
immunocytochemistry, which is now used routinely
in diagnostic work. Some NFTs can also be immunoreactive for ubiquitin. On electron microscopic
examination most NFTs consist of paired helical filaments measuring around 20 nm across, with a regular constriction to 10nm occurring every 80nm. In
Alzheimer disease, they may also be associated with
straight filaments. In progressive supranuclear palsy,
NFTs have been found to consist mainly of straight
filaments measuring 15 nm in diameter.
Granulovacuolar degeneration is a neuronal alteration found in pyramidal cells of Ammon’s horn; this
abnormality is seen in normal aging as well as in
Alzheimer disease and Pick disease. It consists of an
accumulation of small clear vacuoles measuring 4 to
5μm in diameter, containing an argyrophilic granule
that is also well stained by hematoxylin (Fig. 1.11).
Some of the granules are immunoreactive for phosphorylated neurofilaments tubulin, tau, and ubiquitin, suggesting that the vacuoles are autophagic
lysosomal structures in which cytoskeletal components are being degraded.
1.1.1.8. Intraneuronal inclusion bodies
Intracytoplasmic or intranuclear inclusion bodies
are important indicators of neuronal injury. They
occur in degenerative, metabolic, and viral diseases
and often have diagnostic immunocytochemical
and ultrastructural features.

Pick bodies are round homogenous intracytoplasmic neuronal inclusions (Fig. 1.12), characteristic of
Pick disease, where they may be seen in pyramidal
neurons and dentate granule cells of the hippocampus, as in affected regions of the neocortex. They are
intensely argyrophilic and are immunoreactive for
ubiquitin, tau, and tubulin. Ultrastructurally, they
consist of poorly circumscribed masses of intermediate filaments, 15-nm straight filaments, and some
paired helical filaments, as well as entrapped vesicular structures.

Chapter 1 Basic Pathology of the Central Nervous System • 5


A

B

C

D

E

F

FIGURE 1.10 Different types of NFTs (Bodian silver impregnation combined with Luxol fast blue).
(A) Band-shaped perikaryal NFT. (B, C) Triangular, flame-shaped perikaryal NFT. (D) Small, compact, globose
perikaryal NFT. (E) Large globose NFT. (F) “Ghost NFT.”

Lewy bodies are neuronal cytoplasmic inclusions; their appearance varies depending whether
they are found in the perikaryon or in the nerve cell
processes, in the cortex, brainstem, or sympathetic

ganglia (Fig.  1.13). Typical (brainstem) Lewy bodies are roughly spherical with an eosinophilic core
surrounded by a paler “halo.” One or more inclusions
may be present in the cytoplasm of a single neuron
6 •

(Fig.1.13A, B). They may also be oval or elongated
structures, especially when they occur in axonal
processes or in sympathetic ganglia (Fig.1.13C, D).
Cortical Lewy bodies are less clearly circumscribed
and consist of a homogenous zone of hypereosinophilia that usually lacks the characteristic surrounding
“halo”(Fig.1.13E, F). Lewy bodies are immunoreactive for ubiquitin, αB-crystallin, and α-synuclein.

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FIGURE 1.11 Granulovacuolar degeneration
(Bodian silver impregnation).

By electron microscopy, they consist of an amorphous electron-dense core surrounded by a corona
of radiating filaments. Their presence defines several
conditions termed “Lewy body disorders”; the most
common disorder in this group is Parkinson disease.
Hirano bodies are brightly eosinophilic
rod-shaped or elliptical cytoplasmic inclusions that
appear to overlap the cell border of a neuron cell
body. They are mostly found in the CA1 field of
the hippocampus and are particularly numerous in
Alzheimer disease, Pick disease, and in patients with
the Guam parkinsonism-dementia complex. They

are immunoreactive for actin and actin-associated
proteins. Ultrastructurally, they consist of parallel
filaments 60 to 100  nm in length, which alternate
with a longer sheet-like material.
Bunina bodies are eosinophilic, nonviral intracytoplasmic inclusions found in motor neurons
in cases of familial or sporadic amyotrophic lateral
sclerosis (Fig.1.14A , B). They are immunoreactive

FIGURE 1.12 Neuronal argyrophilic inclusion in
Pick disease (Bodian silver impregnation).

for cystatin-C. Ultrastructurally they appear as
electron-dense membrane-bound bodies.
Skein-like inclusions are abnormal ubiquitinated
structures occurring in anterior horn cells in motor
neuron diseases. They are linear, thread-like structures; some are present singly and others form
networks of threads. Occasionally, the threads are
aggregated to form larger and dense inclusions
(Fig.1.15). They contain TDP-43, ordinarily a
nuclear protein, and accumulate within the cytoplasm of motor neurons in amyotrophic lateral sclerosis. Ultrastructurally, they consist of bundles of
filaments of 15 to 25 nm in diameter, with a tubular
profile on cross section.
Marinesco bodies are small eosinophilic intranuclear inclusions located chiefly in melanin-containing
brainstem neurons (Fig.  1.16A). They are strongly
ubiquitin positive.
When ubiquitinated intranuclear inclusions
occur in other regions of the brain they suggest
various other disorders. Small round eosinophilic
inclusions (about the same size of the nucleolus) are found in neurons of CAG-repeat diseases (including SCA, Huntington, and DRPLA)
(Fig.  1.16B). Larger, eosinophilic, ubiquitinated

inclusions are found in association with CGG
repeats (fragile X) and NIID (neuronal intranuclear inclusion disease). Similar large intranuclear
inclusions are found in INIBD (intranuclear inclusion body disease).
Lafora bodies are rounded structures composed
of polyglucosan (polymers of sulfated polysaccharides) and are similar to corpora amylacea (see
further on) in composition and staining characteristics. They are found in large number in myoclonic
epilepsy both in the CNS (chiefly in the dentate
nucleus) and in tissues outside the nervous system,
such as sweat glands, liver, and skeletal muscle. They
usually have a dense, intense periodic-acid-Schiff
(PAS)-positive core surrounded by filamentous,
fainter PAS-positive structures (Fig.1.17).
Viral inclusions. Eosinophilic intranuclear
inclusions that occupy a variable volume of the
nucleus and be surrounded by a clear halo are
associated with some viral infections of the CNS
(cf. Chapter  5). They are seen in herpes virus
infections, particularly in necrotizing encephalitis
caused by herpes simplex virus, and in subacute
sclerosing panencephalitis. In rabies, the viral
inclusions are intracytoplasmic and are referred
to as Negri bodies. In some instances (e.g.,  cytomegalovirus infection) both intranuclear and

Chapter 1 Basic Pathology of the Central Nervous System • 7


A

B

C

D

E

F

FIGURE 1.13 Lewy bodies (H&E). Single (A) and multiple (B) Lewy bodies in the perikaryon of pigmented
neurons of the substantia nigra in a case of Parkinson disease. Lewy bodies in axonal processes (C, D), in the
dorsal nucleus of the Xth cranial nerve, in a case of Parkinson s disease. Cortical Lewy bodies (E, F) in the perikaryon of a cortical neuron, in a case of Lewy body disease.

intracytoplasmic inclusion bodies may be seen.
Viral inclusion bodies are immunoreactive with
appropriate antivirus antibodies, allowing for a
specific diagnosis. Electron microscopy may also
be used to identify virions; however, it is now used
less often in diagnostic work.

8 •

1.1.1.9. Axonal alterations Following focal
axonal lesions that disrupt the integrity and continuity of the nerve fiber, the distal part of the cell
process undergoes Wallerian degeneration, which
will be described further on (see basic lesions of the
peripheral nervous system; Chapter 13).

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A

B

FIGURE 1.14 Bunina bodies in anterior horn cells of the spinal cord, in a case of motor neuron disease
(H&E) (A). Immunocytochemistry for ubiquitin (B).

FIGURE 1.15 Skein-like inclusion in an anterior
horn cell, in a case of motor neuron disease (immunocytochemistry for ubiquitin).

A

In conditions associated with nerve cell “atrophy” as described above, the destruction of the cell
body of the neuron results in degeneration of all of
its processes, including the dendrites and the axon,
which become swollen, then fragmented, and eventually undergo disintegration. This phenomenon,
if widespread, as occurs in system degenerations,
results in rarefaction of the white matter demonstrable with myelin and axon stains. In these diseases,
the phenomenon probably begins at the most distal
portions of the longest axons.
Axonal swellings or spheroids are localized eosinophilic enlargements of the axon. At these sites along
the axon there is a condensation of neurofilaments,
organelles, and other materials that are normally
conveyed along the axon by an anterograde transport system, but accumulate focally when the transport system is interrupted. Spheroids are a feature

B

FIGURE 1.16 Intranuclear inclusions. (A) Marinesco bodies: small intranuclear inclusion in a pigmented
neuron of the substantia nigra (H&E). (B)Ubiquitin-positive intranuclear inclusion in a case of spinocerebellar

degeneration with CAG repeat expansion (courtesy of Professor Francesco Scaravilli).
Chapter 1 Basic Pathology of the Central Nervous System • 9


FIGURE 1.17 Lafora body in a case of myoclonic
epilepsy (PAS).

of axonal damage by diverse extrinsic insults and
are seen especially in trauma and ischemia. They
are well demonstrated by either silver impregnation
(Fig.  1.18A) or by immunostaining with ubiquitin (Fig. 1.18B) and with the precursor of the beta

A

amyloid protein (beta APP) (Fig. 1.18C). The latter
is transported by axonal flow and accumulates when
this process is disrupted. The term torpedo is applied
to Purkinje cell axonal swellings and is a feature of
a many metabolic and degenerative cerebellar diseases. Torpedoes are well demonstrated by silver
impregnation and by the immunohistochemical
methods. They are most notable in the initial portion of the axis cylinder before the origin of the collateral branches (Fig. 1.18C).
The axonal swellings that develop when axonal
transport is disrupted by neuronal metabolic dysfunction are usually termed dystrophic. This occurs
in some acquired (e.g., vitamin E deficiency) or
inherited metabolic diseases. Extensive formation
of axonal swellings is characteristic of neuroaxonal
dystrophy and of some leukodystrophies.
The term dystrophic neurite is used to describe
neuronal cytoplasmic processes distended by tau
protein or other abnormal ubiquinated material.

These occur in several neurodegenerative diseases.

B

C

FIGURE 1.18 Axonal swellings in the white matter identified on silver impregnation (A) (Bodian stain)
and on ubiquitin immunostain (B). Torpedo (axonal swelling) on a Purkinje cell axon identified by β-APP
immunostaining (C).
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