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Escourolle & Poirier’s
Manual of Basic Neuropathology

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Escourolle & Poirier’s
MANUAL OF BASIC
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

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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

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UM B ER TO D E GI ROLAMI, MD

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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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Published in the United States of America by
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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

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Escourolle & Poirier’s manual of basic neuropathology / [edited by] Françoise Gray, Charles Duyckaerts, Umberto De Girolami ; foreword by
Martin A. Samuels. – 5th ed.

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p. ; cm.
Escourolle and Poirier’s manual of basic neuropathology
Manual of basic neuropathology

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Rev. ed. of: Escourolle & Poirier’s manual of basic neuropathology / Françoise Gray, Umberto De Girolami, Jacques Poirier. c2004.
Includes bibliographical references and index.

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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

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

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

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Contents

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Foreword vii

- 5. Infections of the Central Nervous

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Martin A. Samuels System 114

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Preface to the Fifth Edition ix Françoise Gray, Kum Thong Wong,

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Contributors xi Francesco Scaravilli, and Leroy R. Sharer

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1. Basic Pathology of the Central
Nervous System 1
6. Human Prion Diseases 149

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James W. Ironside, Matthew P. Frosch, and
Danielle Seilhean, Umberto De Girolami, and Bernardino Ghetti
Françoise Gray
7. Multiple Sclerosis and Related
2. Tumors of the Central Nervous System 20 Inflammatory Demyelinating
Diseases 161
Keith L. Ligon, Karima Mokhtari, and
Thomas W. Smith Hans Lassmann, Raymond A. Sobel, and
Danielle Seilhean
3. Central Nervous System Trauma 59
8. Pathology of Degenerative Diseases of
Colin Smith the Nervous System 173
Charles Duyckaerts, James Lowe, and
4. Neuropathology of Vascular Disease 76 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
Leila Chimelli and Françoise Gray Hart G. W. Lidov, Umberto De Girolami,
Anthony A. Amato, and Romain Gherardi

10. Hereditary Metabolic Diseases 227 13. Pathology of Peripheral Nerve 313
Frédéric Sedel, Hans H. Goebel, and Jean-Michel Vallat, Douglas C. Anthony, and
Douglas C. Anthony Umberto De Girolami

14. Diseases of the Pituitary Gland 343


11. Congenital Malformations and Vânia Nosé and E. Tessa Hedley-Whyte
Perinatal Diseases 257
Féréchté Encha-Razavi, Rebecca Folkerth,
Appendix: Brief Survey of Neuropathological

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Brian N. Harding, Harry V. Vinters, and
Techniques 365
Jeffrey A. Golden
Homa Adle-Biassette and Jacqueline Mikol

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Index 379

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vi • CONTENTS

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Foreword

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It has been a decade since the previous edition of brain could react to disease. My roadmap in this new

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the Manual of Basic Neuropathology was published terrain was the then-new little blue book, Escourolle

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in 2003. In 1971, Raymond Escourolle and his and Poirier’s Manual of Basic Neuropathology. My

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student, Jacques Poirier, published a book on the heavily worn copy remains on my bookshelf.

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basic aspects of neuropathology, the English ver- A  second edition appeared in 1977 and a third in
sion of which was translated by Lucien Rubinstein 1989, with Françoise Gray succeeding Raymond

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and published in 1973. I  was in the midst of my Escourolle, who had died in 1984. Then, after a lon-

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neurology residency at the time and on July 1, ger interval, Umberto De Girolami joined Françoise
1973, I was embarking with trepidation on a year of Gray and Jacques Poirier for the fourth edition, pub-
neuropathology, a requirement of my training pro- lished in 2003. In the foreword to the fourth edition
gram in that era. Knowing only the pathology that I noted how dependent I was on the original manual
I  had learned in medical school and having virtu- and bemoaned the loss of intense neuropathology
ally no concept of neuropathology, I  found myself training in the making of modern neurologists.
immersed in an alien world. Little did I know that In the past decade, neuroimaging and molecu-
this was to be one of the most influential years in my lar medicine have become even greater parts of
career. The ritual of removing the brains, obtaining the routine life of the clinician. At our daily morn-
the appropriate sections for microscopic analysis, ing report conferences, it is difficult to prevent
and wading through the slides converted me from our residents from showing the images first, skip-
an internist into a neurologist. Neuropathology was ping the history and the neurological examination
the basic science of clinical neurology. I learned how entirely. Some have even argued that listening
to correlate clinical symptoms and signs with find- to the patient, performing a careful neurological
ings in the brain and the various ways in which the examination, and trying to localize the lesion have

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become quaint fossils of times past. This has led For the fifth edition of the Manual, the distin-
to a new problem, the “incidentaloma,” a finding guished neuropathologist Charles Duyckaerts,
on imaging or other testing that is unrelated to the himself an expert in neurodegenerative diseases, par-
patient’s actual problem. The only way to put “inci- ticularly Alzheimer’s disease, joins Drs. Gray and De
dentalomas” in perspective and to prevent harm Girolami as the editors. Over 30 additional experts
to patients is to fully understand what is actually have written authoritative but characteristically brief
possible in the nervous system; in other words, and clear chapters on the full array of major topics in
neuropathology. the field. The organization of the book remains reas-
Other powerful societal forces aimed at saving suringly unchanged. The first chapter reviews the
time and money have put pressure on the effort basic pathology of the nervous system, followed by
it takes to think through complex patient prob- chapters on tumors, trauma, vascular diseases, and
lems carefully and to correlate them rigorously infections. A separate chapter deals with the increas-
with the real pathology found in the nervous sys- ingly important prion diseases, followed by chap-

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tem. Fortunately for us, Umberto De Girolami has ters on multiple sclerosis, degenerative disorders,
championed the continuing need to use modern- acquired metabolic diseases, hereditary metabolic

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ized neuropathology as a powerful tool for better diseases and congenital malformations, and peri-
patient care and for progress in understanding the natal diseases. Separate chapters follow on skeletal

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causes of diseases of the nervous system. His suc- muscle, peripheral nerve, and the pituitary gland.
cessor as Chief of Neuropathology at the Brigham, The book ends with a modernized survey of neuro-

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Rebecca Folkerth (a co-author of the chapter on pathology techniques.
congenital malformations and perinatal diseases, This newly updated version of a truly venerated

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in the Manual), has continued this tradition. Each book will be valued by students, trainees, and practi-
week at our neuropathology conference we are tioners in all of the fields related to the nervous sys-
impressed with how much is learned from the neu- tem, including neurology, neurosurgery, psychiatry,

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ropathological analysis of patients, whether that be neuroradiology, neuroendocrinology, neuropathol-
autopsy or biopsy material. With the prudent appli- ogy, and neuroscience. The new edition will have

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cation of modern techniques, including molecular an honored place on my bookshelf, right next to the
and genetic analysis, we repeatedly learn that we little blue book that got me started over 40 years ago.

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often did not have a full grasp of clinical problems,
even with the most skilled application of modern Martin A. Samuels, MD, DSc (hon),

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technology. FAAN, MACP, FACP
My own clinical practice and education is contin- Chairman, Department of Neurology,

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uously in flux based largely on the reflection on our Brigham and Women’s Hospital

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clinical analysis using the powerful tools of modern Professor of Neurology, Harvard Medical School

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neuropathology. Boston, Massachusetts, USA

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viii • FOREWORD

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Preface to the Fifth Edition

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The first two French editions of the Manuel

- This fifth edition of the Manual attempts to delib-

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Elémentaire de Neuropathologie, published in 1971 erately maintain the general intention of the first

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and 1977, were conceived, written, and edited by and subsequent editions of Professors Escourolle

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Raymond Escourolle and Jacques Poirier. After and Poirier’s monograph—that is, to provide a basic

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the death of R. Escourolle in 1984, Françoise Gray description of the lesions underlying the diseases of
joined Jacques Poirier for the third edition; in addi- the nervous system and to limit pathophysiological

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tion, Jean-Jacques Hauw and Romain Gherardi considerations to essential principles. Historical,

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contributed to selected chapters. The first three edi- clinical, neurological, and radiologic imaging data,
tions reached the English-speaking public thanks once again, are specifically excluded, as well as refer-
to the friendship and translating ability of the ence listings, while recognizing this to be essential
now-deceased Lucien Rubinstein. For the fourth information for the erudite and informed practice
edition, Umberto De Girolami joined as co-editor of neuropathology. Our premise, however, has been
and the scope of the monograph was expanded that it would be presumptuous for us to do justice to
with the collaborative efforts of multiple experts this vast body of information, well beyond the scope
throughout the world to write the English-language of a basic overview of neuropathology. We also have
text. Jacques Poirier is now retired, and we are made the assumption that the reader has some
delighted that Charles Duyckaerts has agreed to join familiarity with general concepts of neuroanatomy,
the editorial team for the fifth edition. There have neurohistology, and the principles of anatomical
also been some changes in the authorship of several pathology as well as clinical neurology.
chapters in response to the changing status of senior With these guidelines in mind, our aim has been
authors and the need to recruit active investigators to produce a text that mainly presents those aspects
to replace them. of neuropathology that are morphologic, and to

• ix
demonstrate these with accurate descriptions and degenerative and metabolic disorders, develop-
good illustrations, all within the scope of a concise mental disorders, and neuromuscular diseases.
and inexpensive “manual.” Morphologic neuropathological data, obtained
For several reasons, we think that the time is now at biopsy or at postmortem examination, there-
right for a new edition since the last one in 2003. fore need to be integrated with this new knowl-
Over the past decade, specialty training in neu- edge for the reinterpretation and reclassification
rology, neurosurgery, and pathology has changed of many diseases. For example, neuropathologi-
throughout much of the world, such that in these cal information obtained at biopsy, combined
disciplines less time is being devoted to neuro- with molecular biology and genetic data, is now
pathology. This has been due in large part to the required for the diagnosis, prognosis, and guid-
tremendous expansion of knowledge in allied sub- ance of the choice of treatment modalities for
specialty areas, requiring that more time be devoted cerebral tumors.
to them. As a result, the trainee is now very much in • Lastly, an urgent responsibility to present an

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need of a concise introductory text. updated synopsis of neuropathology is that this
In addition, several other important changes in knowledge is important to allied disciplines, as

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medicine and society have had an impact on the there is a constant need for surveillance of newly
field of neuropathology and need to be addressed in recognized diseases, including iatrogenic ones.

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this text.
We need to thank first of all Susan Pioli, who

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• For a variety of social and scientific reasons, although now retired from the publishing business
autopsy studies are currently being performed was instrumental in the prior edition and led us to

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much less frequently than in years past. This Craig Panner with Oxford University Press, who has
change has been brought about in part because given fundamental support. Secondly, we thank the
the progress in radiological imaging, both struc- contributing authors and their staff for the text and

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tural and functional, has decreased the need to illustrations provided in this new edition.
draw on clinical–anatomical correlations derived In the Introduction to the First Edition,

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from autopsy data to guide medical practice. Professors Escourolle and Poirier offered an apology
Oddly enough, conversely, autopsy-derived to the reader that is still valid 40 years later:

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knowledge of the anatomical distribution and the
neuropathological basis of lesions continues to The compilation of a basic work designed to famil-

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be a valuable body of information for the inter- iarize physicians-in-training with such a highly
pretation of imaging data. To this aim we have specialized discipline as Neuropathology entails

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made ample use of macroscopic illustrations and two opposing risks:  in attempting to compress

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whole-brain celloidin-/paraffin-embedded sec- the maximum amount of information within the

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tions from our archives. minimum space, the text is liable to become unin-

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• Progress in molecular biology and genetics has telligible to beginners; if on the contrary, one tries to
revolutionized the laboratory diagnosis of many maintain too elementary a level, the danger is that

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groups of neurological diseases. Neuropathology only the obvious will be stated. In presenting to the
stands at the vanguard of the development and non-initiated reader neuropathological informa-
implementation of these diagnostic studies. tion that some may find too simple, we have pre-
In the past decade, progress in immunohisto- ferred the hazard of the second pitfall.
chemistry methods for in situ identification of
abnormal proteins, and the enormous advances Françoise Gray
in molecular biology to uncover specific gene Charles Duyckaerts
mutations, have led to greater understanding of Umberto De Girolami
many hereditary neurological diseases, including

x • 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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Contributors

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Homa Adle-Biassette, M.D., Ph.D.

- Umberto De Girolami, MD

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Maitre de Conférence en Anatomie Pathologique, Professor of Pathology

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University of Paris VII Harvard Medical School

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Neuropathologiste, Practicien Hospitalier, APHP, Neuropathologist, Brigham and Women’s Hospital;

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Hopital Lariboisière, Paris, France Consultant Neuropathologist
Boston Childrens’ Hospital,

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Anthony A. Amato, MD
Boston, MA
Professor of Neurology

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Harvard Medical School Charles Duyckaerts, MD, PhD
Vice-chairman, Department of Neurology; Professor of Pathological Anatomy,
Chief, Neuromuscular Division University of Paris VII
Brigham and Women’s Hospital, Director, Neuropathology Laboratory, Pitié-
Boston, MA Salpêtrière Hospital,
Paris, France
Douglas C. Anthony, M.D., PhD.
Professor, Alpert Medical School of Brown University Féréchté Encha-Razavi, MD
Pathologist-in-Chief, Lifespan Academic Medical Fetal Pathology, Necker Hospital
Center, Paris, France
Providence, RI
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 Brian N. Harding, MD PhD
Associate Professor of Pathology Professor of Pathology & Laboratory Medicine,
Harvard Medical School University of Pennsylvania
Director, Neuropathology Service, Brigham and Neuropathologist, Department of Pathology and
Women’s Hospital; Laboratory Medicine
Consultant Neuropathologist, Boston Childrens’ Children’s Hospital of Philadelphia
Hospital, Philadelphia, PA
Boston, MA
Jean-Jacques Hauw, MD
Matthew P. Frosch, MD, PhD Emeritus Professeur d’Anatomie Pathologique,
Lawrence J. Henderson Associate Professor of University of Paris VI
Pathology and Health Sciences & Technology Paris, France
(HST); Associate Director, HST
E. Tessa Hedley-Whyte
Harvard Medical School

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Professor of Pathology
Director, Neuropathology Service
Harvard Medical School
C.S. Kubik Laboratory for Neuropathology

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Neuropathologist, C.S. Kubik Laboratory for
Massachusetts General Hospital,
Neuropathology
Boston, MA

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Massachusetts General Hospital,
Bernardino Ghetti, MD Boston, MA

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Distinguished Professor and Director of
James W. Ironside, FRCPath
Neuropathology

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Professor of Clinical Neuropathology
Department of Pathology and Laboratory Medicine
School of Clinical Sciences
Indiana University School of Medicine
University of Edinburgh, UK
Indianapolis, Indiana

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Honorary Consultant Neuropathologist
Romain K. Gherardi, MD Lothian University Hospitals Division and Tayside
Professor of Histology University Hospitals

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Reference Center, INSERM U955 Scotland, UK

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Henri Mondor University Hospital
Hans Lassmann, MD
Paris-Est University, F-94010 Créteil, France
Professor of Neuroimmunology

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Hans H. Goebel, MD Center for Brain Research
Professor of Neuropathology Medical University of Vienna

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Department of Neuropathology Vienna, Austria

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University Medical Center of the Johannes

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Hart G. W. Lidov, MD, PhD
Gutenberg University
Associate Professor of Pathology

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Mainz, Germany
Harvard medical School
Jeffrey A. Golden, MD Director of Neuropathology

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Harvard Medical School Department of Pathology ; 
Chair, Boston Children’s Hospital 
Brigham and Women’s Hospital Neuropathologist Brigham and Women’ Hospital 
Boston, MA Boston, MA
Françoise Gray, MD, PhD Keith L. Ligon, MD, PhD
Professeur d’Anatomie Pathologique, Assistant Professor of Pathology
University of Paris VII Harvard Medical School
Praticien Hospitalier, AP,HP, Hôpital Lariboisière, Investigator, Dana-Farber Cancer Institute Center
Paris, France for Molecular Oncologic Pathology
Neuropathologist, Brigham and Women’s Hospital,
Boston Children’s Hospital
Boston, MA

xii • CO N T R I BU TO R S

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James Lowe, DM, FRCPath Colin Smith, MD, FRCPath
Professor of Neuropathology Reader in Pathology
University of Nottingham Medical School University of Edinburgh
Hon Consultant in Neuropathology, Nottingham Honorary Consultant in Neuropathology
University Hospitals NHS Trust, Nottingham NHS Lothian
UK Edinburgh, UK
Karima Mokhtari, MD Thomas W. Smith, MD
Neuropathologist, Pitié-Salpêtrière Hospital, Professor of Pathology and Neurology
Paris, France University of Massachusetts Medical School
Director of Neuropathology and Diagnostic
Jacqueline Mikol, MD
Electron Microscopy,
Emeritus Professeur d’Anatomie Pathologique,
UMass Memorial Medical Center
University of Paris VII
Worcester, MA

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Praticien Hospitalier, AP, HP, Hôpital Lariboisière,
Paris, France Raymond A. Sobel, MD

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Professor of Pathology (Neuropathology)
Vânia Nosé, MD, PhD
Stanford University School of Medicine
Associate Professor of Pathology

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Neuropathologist, Veterans Affairs Health Care
Harvard Medical School
System
Director of Anatomic and Molecular Pathology

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Palo Alto, CA
Massachusetts General Hospital

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Boston, MA Jean-Michel Vallat, MD, PhD
Professor of Neurology
Francesco Scaravilli, MD, PhD, FRCPath, DSc
University of Limoges
Emeritus Professor of Neuropathology

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Department of Neurology
Institute of Neurology, UCL, London, UK
University Hospital Dupuytren
Frédéric Sedel, MD, PhD Limoges, France

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Professor of Neurology
Harry V. Vinters, MD, FRCPC, FCAP

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Fédération des Maladies du Système Nerveux
Distinguished Professor of Pathology & Laboratory
APHP, Pitié-Salpêtrière Hospital
Medicine, and Neurology,
University Paris of VI

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David Geffen School of Medicine at University of
Danielle Seilhean, MD, PhD California Los Angeles (UCLA),

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Professor of Pathological Anatomy, University of Chief, Section of Neuropathology, Ronald Reagan-

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Paris VI UCLA Medical Center

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Neuropathologist, Pitié-Salpêtrière Hospital, Member, Brain Research Institute, UCLA

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Paris, France Los Angeles, CA
Leroy R. Sharer, MD Kum Thong Wong, MBBS, MPath,

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Professor of Pathology FRCPath, MD
New Jersey Medical School Dept of Pathology, Faculty of Medicine,
Neuropathologist, University Hospital, University of Malaya,
Newark, NJ Kuala Lumpur, Malaysia

Contributors • xiii
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1
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 characterized morphologically by the co-expression of


based on the macroscopic and microscopic study multiple reactions to injury that may not be diagnos-
of the brain, brainstem, cerebellum, and spinal cord. tic in themselves. These reactions affect the cellular
Increasingly, the ability to reach greater diagnostic elements of the nervous system (neurons, astrocytes,
precision is buttressed by the new laboratory tech- oligodendrocytes, and microglia) and/or the support-
niques of molecular biology and genetics. Three ing structures (meninges, connective tissue, or blood
consecutive steps are involved in reaching a diagno- vessels). Basic cellular reactions are demonstrable only
sis and these are, in fact, closely interrelated: (1) a on microscopic examination, whereas tissue lesions
morphologic/laboratory analysis of the lesions; that can be associated with more extensive destructive
(2) a topographic analysis of the lesions; and (3) a or atrophic changes are recognized macroscopically or
critical integration of these findings and their subse- with the help of a magnifying lens.
quent correlation with the clinical data and the gen- Although, for didactic purposes, the reactions
eral autopsy findings, thus permitting an etiological to injury seen in the neurons, glia, connective tis-
diagnosis to be made in most instances. sue, and vascular structures will be described sepa-
rately in the text below, it is essential to emphasize
that there is a close functional interdependence of
1. MORPHOLOGIC ANALYSIS the various cellular elements of the nervous system.
OF CENTRAL NERVOUS This is particularly important in the case of nerve
cell alterations where, except for very acute injury,
SYSTEM LESIONS the possibility of artifactual change should be enter-
With the exception of tumors and malformations, most tained whenever the reaction is not accompanied by
disorders of the central nervous system (CNS) are a glial cell response.

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1.1. BASIC cellular reactions to sclerosis). It is also seen in anterograde and retro-
CNS injury grade transsynaptic degeneration, as may occur in
the lateral geniculate body following a lesion of the
1. 1. 1. NE UR ONAL LES I O NS optic nerve.
Neuronal injury may sufficiently severe to result in Programmed cell death (apoptosis) is an active,
irreversible damage (cell death) or may be transient genetically controlled, energy-consuming process
or minimal and cause reversible functional dam- frequent in neurodegeneration and involving pri-
age. Destruction of neurons may be focal, or extend marily the nucleus of the cell. Neurons undergoing
diffusely, involving many populations of neurons simple neuronal atrophy or apoptosis have similar
throughout the nervous system. In acute neuro- morphologic features and may show positive in situ
nal injury, when the tissue is examined with H&E end labeling of internucleosomal DNA fragmen-
preparations at a time shortly after a lethal insult to tation (Fig.1.1)or be demonstrable by activated
the cell, one observes eosinophilia of the cytoplasm, caspase-3 immunostaining.
shrinkage and hyperchromasia of the nucleus, and Nerve cell atrophy should not be mistaken for
disappearance of the nucleolus; subsequent to the what is referred to as “dark neurons.” This phenom-
disintegration of the cell, neuronophagia by scav- enon is now recognized to be an artifactual change
enger cells ensues. In chronic diseases, evidence of of the neuron cell body, seen particularly in brain
cell death is recognized morphologically as neuro- biopsies fixed in formalin by immersion, and charac-
nal “cell loss” or, alternately, as “atrophy” when the terized by shrunken cytoplasm and deeply-stained
irreversible injury has occurred relatively slowly and and irregularly-shaped nucleus without other cellular
has progressively involved ever greater numbers of alterations.
cells. In some degenerative diseases of the nervous
system in which there is progressive loss of neurons 1.1.1.2. Acute Neuronal Necrosis (Anoxic/
over variable time periods, the affected cells have Ischemic Neuronal Change) This type of cell death
distinctive morphologic hallmarks (e.g., neurofibril- occurs in a variety of acute injuries, including anoxia
lary degeneration, neuronal storage of metabolic and ischemia, but may also be seen in many other
products, disorders associated with intracellular acute pathological processes (e.g., hypoglycemia or
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 popula-
tion. 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 “atro-


phy” 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 FIGURE 1.1 Two neurons undergoing apopto-
cell. Neuronal “atrophy” is characterized morpho- sis are positively stained by in situ end labeling to
logically by retraction of the cell body with dif- demonstrate internucleosomal DNA fragmentation.
fuse basophilia of the cytoplasm and pyknosis and In one neuron, on the left, only the nucleus is stained,
hyperchromasia of the nucleus of the neuron, in whereas in the other, which is at a later stage of the
the absence of an inflammatory reaction. Neuronal programmed cell death process, the entire cell body is
“atrophy” is thought to occur in many degenera- stained. Compared to a normal neuron, on the right,
tive disorders that involve several interconnected both apoptotic neurons have similar morphologic
neuronal systems (i.e., multiple system atrophy, in features and show pyknotic nucleus and shrunken
Friedreich ataxia, and even in amyotrophic lateral cytoplasm.

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FIGURE 1.2 Acute ischemic nerve cell change FIGURE 1.3 Ferrugination (mineralization)
(H&E). Eosinophilic, shrunken cytoplasm and hyper- of the neurons at the edge of an old hemorrhagic
chromatic nucleus. infarct (H&E).

exposure to excessive amounts of excitotoxic neu- degeneration or axonal reaction). Subsequent recov-
rotransmitters). Unlike apoptosis, the predominant ery of normal cell morphology or, conversely, further
cellular changes in acute neuronal necrosis involve progression to nerve cell degeneration depends on the
the cytoplasmic organelles and the cell membrane, reversibility of the axonal lesion (Fig.  1.5). Central
which ruptures, leading to cell death. chromatolysis may also be seen in upper motor neu-
In experimental animal studies and in carefully rons, but the phenomenon is rare and difficult to
preserved human tissue at postmortem, by light interpret. Axonal lesions of neurons whose axons do
and electron microscopy, the following sequence of not leave the confines of the CNS apparently either
changes is noted over the course of 12 to 24hours after do not produce changes in perikaryal cell body mor-
the insult: (a) cytoplasmic microvacuolation due to phology or result in “simple” type of atrophy. Oddly
swelling of mitochondria and endoplasmic reticulum; enough, some metabolic disorders that do not a priori
(b) shrinkage of cell body with retraction of the cel- involve axons (e.g., Wernicke encephalopathy, pellagra
lular outlines, and disappearance of Nissl bodies with encephalopathy, porphyria) may be accompanied by
eosinophilic condensation of the cytoplasm (“red central chromatolysis in cortical neurons.
neuron”); (c) condensation of nuclear chromatin and A confident diagnosis of central chromatolysis
nuclear pyknosis (Fig. 1.2); (d) late disappearance of requires comparison with the normal morphology
the nuclear chromatin, resulting in increased acido-
philia 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 ferrugi-
nation of neurons (Fig.1.3).

1.1.1.3. Central chromatolysis Central chroma-


tolysis is characterized morphologically by swelling
of the cell body, disappearance of Nissl bodies begin-
ning centrally and extending outward, and flatten-
ing and eccentric displacement of the nucleus to the
periphery (Fig. 1.4). It is seen usually in lower motor FIGURE 1.4 Central chromatolysis (Nissl stain).
neurons (anterior horns of the spinal cord, cranial Note the cellular swelling, the eccentric displace-
nerve nuclei), where it represents a reparative reac- ment of the nucleus, and the margination of the Nissl
tion of the cell body to a lesion of the axon (retrograde 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
Stages of hypertrophy (Nissl stain).
hyperchromasia
FIGURE 1.5 Nerve cell changes in central
chromatolysis. 1.1.1.5. Binucleated neurons These lesions are
seen rather infrequently, sometimes under normal
of the affected gray matter structure because the circumstances, at the edge of old focal destructive
nerve cell-body in some nuclei (e.g., the mesen- lesions, as a dysplastic/malformation phenomenon
cephalic nucleus of the fifth cranial nerve, Clarke’s (e.g., tuberous sclerosis), or in certain neoplasms
column) normally contains rounded neurons with (e.g., ganglion-cell tumors).
marginated Nissl bodies.
1.1.1.6. Neuronal storage In some hereditary
1.1.1.4. Vacuolated neurons and neuropil metabolic diseases related to enzymatic defects
Vacuolated neurons and neuropil are observed involving synthetic or degradative pathways for lip-
in Creutzfeldt-Jakob disease (Fig.  1.6). In rare ids or carbohydrates, interruption of the pathway
instances, swelling with vacuolization of the nerve leads to cytoplasmic accumulation of intermediate
cell is thought to result from transsynaptic degen- substrates or their byproducts, resulting in swelling
eration—for example, in the neurons of the inferior and distention of the cell body of nerve cells, with
olive in olivary hypertrophy, secondary to a lesion of eccentric displacement of the nucleus (Fig. 1.8). In
the ipsilateral central tegmental tract, or of the con- several neuronal storage disorders, the stored mate-
tralateral dentate nucleus—so-called “fenestrated rial has distinctive histochemical and ultrastruc-
neurons”(Fig. 1.7). tural features that may help characterize clinically

FIGURE 1.8 Distended nerve cell bodies in a case


FIGURE 1.6 Vacuolated neuron in a case of of neuro-lipidosis (combined Luxol fast blue and
Creutzfeldt-Jakob disease (H&E). Bodian silver impregnation).

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suspected cases. Biochemical tests on blood, leu- cells (Fig.1.10B, C). Compact globose perikaryal
kocytes, and other body fluids are now particularly NFTs are mainly seen in small cortical neurons
useful to more precisely diagnose many of these (Fig.1.10D). Large globose NFTs reminiscent of
disorders. a ball of string are more common in neurons of
Lipofuscin accumulation within the perikaryon the nucleus basalis of Meynert and in the brain-
of neurons and other cells in the nervous system stem (Fig.1.10E). In the final stages of the disease,
is a characteristic aging change. Lipofuscin accu- the cell outline disappears and only the distorted
mulates in neurons diffusely throughout the brain fibrils remain as “ghost NFT” (Fig.1.10F).The pre-
in ceroid-lipofuscinosis, a neuronal storage disor- dominant biochemical component of NFTs is the
der. Lipofuscin is identified on H&E preparations microtubule-associated protein tau, which accumu-
as refractile yellow-brown pigment aggregates lates in an abnormally highly phosphorylated form.
(Fig.  1.9). It is autofluorescent and rich in acid Tangles are particularly well demonstrated by tau
phosphatase. The pigment is PAS-positive and can immunocytochemistry, which is now used routinely
be stained by Luxol fast blue. It has distinctive ultra- in diagnostic work. Some NFTs can also be immu-
structural features (see Chapter 10). noreactive for ubiquitin. On electron microscopic
examination most NFTs consist of paired helical fil-
1.1.1.7. Alzheimer neurofibrillary degenera- aments measuring around 20 nm across, with a regu-
tion and granulovacuolar degeneration Alzheimer lar constriction to 10nm occurring every 80nm. In
neurofibrillary degeneration is characteristically seen Alzheimer disease, they may also be associated with
in the brains of aged individuals and in patients with straight filaments. In progressive supranuclear palsy,
senile dementia of Alzheimer type but has also been NFTs have been found to consist mainly of straight
described in a variety of other cerebral disorders. filaments measuring 15 nm in diameter.
This degenerative change is manifest by the forma- Granulovacuolar degeneration is a neuronal altera-
tion of neurofibrillary tangles (NFTs), structures tion found in pyramidal cells of Ammon’s horn; this
that are well demonstrated by silver impregnation abnormality is seen in normal aging as well as in
and by immunohistochemical techniques and con- Alzheimer disease and Pick disease. It consists of an
sists of thickened and tortuous skeins within the accumulation of small clear vacuoles measuring 4 to
neuronal perinuclear cytoplasm. The configuration 5μm in diameter, containing an argyrophilic granule
of the tangle may vary according to the anatomical that is also well stained by hematoxylin (Fig. 1.11).
site, the type of neuron affected, and the stage of its Some of the granules are immunoreactive for phos-
development (Fig.1.10). A band-shaped perikaryal phorylated neurofilaments tubulin, tau, and ubiq-
NFT can be seen both in large and small pyrami- uitin, suggesting that the vacuoles are autophagic
dal cells and is perhaps an early stage of NFT for- lysosomal structures in which cytoskeletal compo-
mation (Fig.1.10A). A  triangular flame-shaped nents are being degraded.
perikaryal NFT is seen mainly in large pyramidal
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 intracytoplas-
mic neuronal inclusions (Fig. 1.12), characteristic of
Pick disease, where they may be seen in pyramidal
neurons and dentate granule cells of the hippocam-
pus, 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 interme-
diate filaments, 15-nm straight filaments, and some
FIGURE 1.9 Lipofuscin in neuronal cell paired helical filaments, as well as entrapped vesicu-
body (H&E). lar 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 inclu- (Fig.1.13A, B). They may also be oval or elongated
sions; their appearance varies depending whether structures, especially when they occur in axonal
they are found in the perikaryon or in the nerve cell processes or in sympathetic ganglia (Fig.1.13C, D).
processes, in the cortex, brainstem, or sympathetic Cortical Lewy bodies are less clearly circumscribed
ganglia (Fig.  1.13). Typical (brainstem) Lewy bod- and consist of a homogenous zone of hypereosino-
ies are roughly spherical with an eosinophilic core philia that usually lacks the characteristic surrounding
surrounded by a paler “halo.” One or more inclusions “halo”(Fig.1.13E, F). Lewy bodies are immunoreac-
may be present in the cytoplasm of a single neuron tive for ubiquitin, αB-crystallin, and α-synuclein.

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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 struc-
tures; 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 cyto-
plasm of motor neurons in amyotrophic lateral scle-
rosis. Ultrastructurally, they consist of bundles of
filaments of 15 to 25 nm in diameter, with a tubular
FIGURE 1.11 Granulovacuolar degeneration profile on cross section.
(Bodian silver impregnation). Marinesco bodies are small eosinophilic intranu-
clear inclusions located chiefly in melanin-containing
By electron microscopy, they consist of an amor- brainstem neurons (Fig.  1.16A). They are strongly
phous electron-dense core surrounded by a corona ubiquitin positive.
of radiating filaments. Their presence defines several When ubiquitinated intranuclear inclusions
conditions termed “Lewy body disorders”; the most occur in other regions of the brain they suggest
common disorder in this group is Parkinson disease. various other disorders. Small round eosinophilic
Hirano bodies are brightly eosinophilic inclusions (about the same size of the nucleo-
rod-shaped or elliptical cytoplasmic inclusions that lus) are found in neurons of CAG-repeat dis-
appear to overlap the cell border of a neuron cell eases (including SCA, Huntington, and DRPLA)
body. They are mostly found in the CA1 field of (Fig.  1.16B). Larger, eosinophilic, ubiquitinated
the hippocampus and are particularly numerous in inclusions are found in association with CGG
Alzheimer disease, Pick disease, and in patients with repeats (fragile X) and NIID (neuronal intranu-
the Guam parkinsonism-dementia complex. They clear inclusion disease). Similar large intranuclear
are immunoreactive for actin and actin-associated inclusions are found in INIBD (intranuclear inclu-
proteins. Ultrastructurally, they consist of parallel sion body disease).
filaments 60 to 100  nm in length, which alternate Lafora bodies are rounded structures composed
with a longer sheet-like material. of polyglucosan (polymers of sulfated polysac-
Bunina bodies are eosinophilic, nonviral intra- charides) and are similar to corpora amylacea (see
cytoplasmic inclusions found in motor neurons further on) in composition and staining character-
in cases of familial or sporadic amyotrophic lateral istics. They are found in large number in myoclonic
sclerosis (Fig.1.14A , B). They are immunoreactive 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
FIGURE 1.12 Neuronal argyrophilic inclusion in to as Negri bodies. In some instances (e.g.,  cyto-
Pick disease (Bodian silver impregnation). megalovirus 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 peri-
karyon of a cortical neuron, in a case of Lewy body disease.

intracytoplasmic inclusion bodies may be seen. 1.1.1.9. Axonal alterations Following focal
Viral inclusion bodies are immunoreactive with axonal lesions that disrupt the integrity and con-
appropriate antivirus antibodies, allowing for a tinuity of the nerve fiber, the distal part of the cell
specific diagnosis. Electron microscopy may also process undergoes Wallerian degeneration, which
be used to identify virions; however, it is now used will be described further on (see basic lesions of the
less often in diagnostic work. 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).

In conditions associated with nerve cell “atro-


phy” 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 even-
tually undergo disintegration. This phenomenon,
if widespread, as occurs in system degenerations,
results in rarefaction of the white matter demonstra-
ble 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 eosino-
philic enlargements of the axon. At these sites along
FIGURE 1.15 Skein-like inclusion in an anterior the axon there is a condensation of neurofilaments,
horn cell, in a case of motor neuron disease (immuno- organelles, and other materials that are normally
cytochemistry for ubiquitin). conveyed along the axon by an anterograde trans-
port system, but accumulate focally when the trans-
port system is interrupted. Spheroids are a feature

A 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


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 dis-
eases. Torpedoes are well demonstrated by silver
impregnation and by the immunohistochemical
methods. They are most notable in the initial por-
tion of the axis cylinder before the origin of the col-
lateral branches (Fig. 1.18C).
The axonal swellings that develop when axonal
transport is disrupted by neuronal metabolic dys-
function are usually termed dystrophic. This occurs
FIGURE 1.17 Lafora body in a case of myoclonic in some acquired (e.g., vitamin E deficiency) or
epilepsy (PAS). inherited metabolic diseases. Extensive formation
of axonal swellings is characteristic of neuroaxonal
of axonal damage by diverse extrinsic insults and dystrophy and of some leukodystrophies.
are seen especially in trauma and ischemia. They The term dystrophic neurite is used to describe
are well demonstrated by either silver impregnation neuronal cytoplasmic processes distended by tau
(Fig.  1.18A) or by immunostaining with ubiqui- protein or other abnormal ubiquinated material.
tin (Fig. 1.18B) and with the precursor of the beta These occur in several neurodegenerative diseases.

A B

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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1.1.2. ASTROCYTIC LESIONS nucleus, which is often hyperchromatic and eccentri-
cally placed in the perikaryon. As mentioned above,
1.1.2.1. Gliosis (astrogliosis) The presence of
the cytoplasm around the nucleus and cell processes
gliosis (alternate term astrogliosis) is the most cer-
becomes more extended than normal and contains
tain indication that a microscopic finding is of patho-
glycogen(Fig.  1.19A). Characteristically, at this
logical significance and not artifactual. This reactive
stage, in H&E preparations, the cytoplasm is homog-
process accompanies almost any type of subacute or
enized and eosinophilic: these reactive astrocytes are
chronic injury of the CNS. The process of gliosis is
referred to as gemistocytic astrocytes(Fig. 1.19B, C).
in essence the response of astrocytes to CNS tissue
Over time, in chronic disease states and
injury. The associated morphologic changes include
slowly-evolving degenerative processes, astrocyte
an increase in the number of astrocyte nuclei per
nuclei return to their resting size and shape, although
unit area, eosinophilia of the cytoplasm around the
their cytoplasmic network of cell processes is more
nucleus, and expansion and distortion of the astro-
extensive and can best be appreciated with immu-
cytic cytoplasmic arborization. For reasons that are
nostaining for glial fibrillary acidic protein (GFAP).
not understood, mitotic figures are only rarely iden-
An older term, isomorphorphic fibrillary gliosis,
tified in gliotic tissue, and techniques that bring out
refers to the alignment of reactive astrocyte pro-
dividing cells (Mib-1/Ki 67) also confirm the slow
cesses conforming to a degenerating fiber tract.
turnover.
The morphologic aspects of the process of gliosis
will vary depending on the location, stage of evolu- 1.1.2.2. Alzheimer type II glia Alzheimer type
tion, and nature of the pathological process. The II glia is seen particularly in hyperammonemic
early stages are characterized by hypertrophy of the states such as occur in Wilson disease and in liver

A B

FIGURE 1.19 Gliosis. Fibrillary gliosis, (A) hypertrophy of nucleus as of cytoplasm and processes that are
well seen on GFAP stain. Gemistocytic astrocytes with large homogenized and eosinophilic cytoplasm (H&E)
(B), (GFAP) (C).

Chapter 1 Basic Pathology of the Central Nervous System • 11


pilocytic astrocytomas, particularly of the cerebel-
lum) (cf. Chapter 2), and of Alexander disease (cf.
Chapter 10).
Eosinophilic granular bodies are rounded hyaline
droplets that occupy the cytoplasm of astrocytes and
are seen in pilocytic astrocytomas and ganglion-cell
tumors.

1.1.2.4. Inclusions and storage material


Accumulation of lipofuscin occurs in astrocytes as
part of aging as it does in neurons. Similarly, in lipid
storage diseases, glial lipid storage may accompany
neuronal storage.
FIGURE 1.20 Alzheimer type II glial cells (H&E). Tau protein, which is the main component of
NFTs, can also accumulate in astrocytes, particu-
failure from acquired or hereditary metabolic dis- larly in progressive supranuclear palsy (PSP) and cor-
ease, but it can also be found in other systemic ticobasal degeneration (cf. Chapter 8).
metabolic disorders (e.g., renal failure). This reac- Tufted astrocytes are considered to be highly char-
tion of astrocytes is characterized by enlargement acteristic of PSP (see Fig. 8.5A). The whole length
of the nucleus, reaching 15 to 20 μm in diameter, of their processes contains tau protein and they are
which appears irregular in shape and pale and often binucleated. They may be demonstrated by
empty-looking because of the disappearance of Gallyas stain or tau immunocytochemistry. Thorn
chromatin granules (Fig. 1.20). One or two dense astrocytes have an argyrophilic cytoplasm with a
rounded PAS-positive bodies resembling nucle- few short processes (see Fig. 8.5B) and often a small
oli are often seen next to the nuclear membrane, eccentric nucleus. They are commonly seen in PSP
which is always sharply outlined. The cell body is but are not specific to this disease and may be seen
not usually visible on conventional preparations in other neurodegenerative conditions.
and stains poorly with GFAP. Alzheimer II glia In corticobasal degeneration, the accumulation
(unrelated to Alzheimer disease) occur in the gray of tau protein in astroglial cells results in distinctive
matter, involving particularly deep gray nuclei, structures in gray matter which are termed astrocytic
especially the pallidum and the dentate nuclei and plaques. In these plaques, tau protein accumulates at
also the cerebral cortex. Alzheimer type II glia are the end of the astrocytic processes, while the center
metabolically active cells engaged in the detoxifi- of the plaque is devoid of tau immunoreactivity (see
cation of ammonia; on ultrastructural study, they Fig. 8.11).
are shown to contain numerous mitochondria. Viral inclusion bodies may also be found in
astrocytes, particularly in subacute sclerosing pan-
1.1.2.3. Rosenthal  fibers By light microscopy, encephalitis and cytomegalovirus (CMV) infection
Rosenthal fibers are rounded, oval, or elongated, (cf. Chapter 5).
beaded structures, measuring 10 to 40μm, which Corpora amylacea are spherical, basophilic,
appear homogenous, and brightly eosinophilic. On PAS-positive inclusions, 10 to 50  μm in diameter,
electron microscopy, they consist of swollen astro- that are predominantly found in astrocytic pro-
cytic processes that are filled with electron-dense cesses, although they occasionally occur within
amorphous granular material and glial filaments. axons. Ultrastructurally, they consist of densely
With immunohistochemical methods peripheral packed 6- to 7-nm filaments that may be admixed
labeling for GFAP, ubiquitin, and ΑBcrystallin can with amorphous granular material and are not
be demonstrated. Rosenthal fibers are seen in vari- membrane bound. Corpora amylacea increase in
ous pathological conditions that have in common number with aging, particularly in the subpial and
intense fibrillary gliosis of long standing, as seen subependymal regions, around small blood vessels
throughout the brain in multiple sclerosis plaques, and in the posterior columns of the spinal cord.
in the spinal cord in syringomyelia, and in the Adult polyglucosan body disease (cf. Chapter  10)
hypothalamus around craniopharyngiomas. They is characterized by diffuse accumulation of corpora
are also characteristic of certain neoplasms (e.g., amylacea, involving the cortex and white matter,

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and associated with diffuse and/or focal myelin In normal brain, microglia has been subdivided
damage. into (a)  resident microglia, with little turnover and
present throughout the CNS parenchyma and
(b)  perivascular microglia, found within the perivas-
1.1.3. LESIONS OF OLIGODENDROCYTES
cular basal lamina and showing characteristic turn-
Like neurons and astrocytes, oligodendrocytes over as with hematogenous monocytes. Microglial
may be infected by virus and show intranuclear or activation occurs in inflammatory conditions of the
intracytoplasmic inclusions (e.g., progressive mul- CNS and involves (a) increased entry of hematog-
tifocal leukoencephalopathy) (cf. Chapter 5) or be enous monocytes into the CNS; (b) proliferation of
affected with excess storage of lipid or glycogen in resident microglia; and (c) expression or secretion
genetically-determined enzymopathies (e.g., meta- of a wide range of proteins, most of which are con-
chromatic leukodystrophy). cerned with antigen presentation and inflammation.
Cytoplasmic inclusions involving mainly oligo- Microglial basic reactions to injury are typically
dendrocytes have been shown to be a characteristic seen in three situations:
feature of multiple system atrophy (cf. Chapter 8).
These inclusions are usually flame- or sickle-shaped • Macrophage proliferation and phagocytosis (the
and can be demonstrated by silver impregnation and cells are also known as compound granular cor-
are immunoreactive for ubiquitin, αB-crystallin, puscles, foam cells, lipid phagocytes, or gitter
and α-synuclein. cells). This is a frequent finding in many brain
The accumulation of tau protein in oligodendro- lesions, particularly those associated with demy-
cytes, known as “coiled body,” may be found in PSP, elinating processes or with traumatic or ischemic
corticobasal degeneration, and argyrophilic grain tissue destruction. After a destructive or demy-
disease (cf. Chapter8). These are fibrillary structures elinating insult, macrophages invade the dam-
“coiling” around the nucleus. aged region within 48 hours of injury. These are
rounded cells with distinct cytoplasmic borders
and measure 20 to 30 μm in diameter. They have
a small, darkly-staining and sometimes eccentric
1.1.4. MICROGLIAL LESIONS
nucleus, and a clear, granular cytoplasm that can
Microglial cells are of monocyte lineage and have contain lipids, hemosiderin pigment, or any other
important phagocytic functions. They can be dem- phagocytized material (Fig. 1.21A , B). The num-
onstrated by silver impregnation, lectin-binding ber of these scavenger cells increases over a period
techniques, and immunohistochemical techniques of days and weeks, and they may still be present in
using antibodies that react with monocyte/macro- injured tissue many months after the injury. Most
phages (e.g., CD68) (Fig. 1.21B). derive from blood monocytes.

A B

FIGURE 1.21 Perivascular lipid-laden macrophages (compound granular corpuscles, foam cells, or gitter
cells) in a demyelinating lesion (Luxol fast blue combined with Bodian silver impregnation) (A) and with CD68
immunostaining (B).

Chapter 1 Basic Pathology of the Central Nervous System • 13


specific pathological processes (i.e., vascular, infec-
tious, inflammatory, demyelinating, metabolic,
degenerative). As will be described in the forthcom-
ing chapters, these may accompany one or more of
the specific pathological processes visible under the
microscope that are described above or may result
in more extensive changes that can be visible to the
naked eye.

1 .2 . 1. CEREBRAL ATROPHY
Cerebral atrophy is the end-stage of a num-
ber of neurological diseases. The brain weight
FIGURE 1.22 Rod-shaped microglia in a case of is lighter than a normal age-matched control.
general paresis of the insane (Nissl stain). Macroscopically, there is narrowing of the gyri and
widening of sulci. On section, the cortical ribbon
• Rod cell proliferation(Fig. 1.22 and 5.25) is a form is thinned, and ventricular dilatation is often pres-
of microglial response to subacute parenchymal ent. The histological substratum consists of a vari-
injury in which necrosis is minimal or absent. Rod able loss of neurons often associated with gliosis,
cells are elongated, spindle-shaped cells that can depending on the underlying illness, and a variety
be recognized on H&E preparations by the pres- of neuronal alterations, which will be discussed in
ence of a cigar-shaped nucleus. The best descrip- turn in subsequent chapters.
tions of this glial change are found in reports of
cases of general paresis in the older literature (cf.
Chapter 5). Rod cells are also seen in cases of sub- 1 .2 . 2. CEREBRAL  EDEM A
acute encephalitis and evolving ischemic lesions. Cerebral edema is defined as an increase in brain
• Microglial nodules consist of discrete clusters of volume due to an increase in water and sodium con-
microglial cells that are typically found in subacute tent. Depending on its pathogenesis, brain edema
viral encephalitis, in and around sites of neuronal has been classified as vasogenic, cytotoxic, or inter-
destruction—neuronophagic nodules (cf. Chapter 5). stitial (hydrocephalic). Combination of these proto-
types of edema is frequent.
1. 1. 5. E PE NDYMAL  C EL L S
• Vasogenic edema, probably the most common type
Ependyma have a limited range of reactions to
of brain edema, complicates head injury, abscess,
injury. Along with neurons and other glial cells,
tumors, and hemorrhages. Both vasogenic edema
ependymal cells may be infected in viral diseases. In
and cytotoxic edema occur with ischemia. Vasogenic
the adult CNS, ependymal cells do not proliferate
edema results from blood–brain barrier injury lead-
in response to injury and cell loss. Their destruction
ing to increased permeability of the microcircula-
leaves bare stretches of the ventricular lining; this
tion to macromolecules, particularly to proteins.
is accompanied by proliferation of subependymal
By radiological imaging, sites of vasogenic edema
astrocytes that form small hillocks along the ventric-
are marked by contrast enhancement, because the
ular surface—ependymal granulations. Occasionally,
injected contrast medium leaks across the perme-
surviving ependymal cells may be overgrown by the
able vascular lining. Biochemically, the edema fluid
astrocytic reaction and appear as clusters of tubules
resembles a plasma filtrate. It is located chiefly in the
buried within the ependymal granulations.
extracellular spaces of the white matter.
• In cytotoxic edema, excessive amounts of water
enter one or more of the intracellular compart-
1.2. General Tissue Reactions ments of the CNS (neurons, glia, endothelial cells,
of the CNS to Injury and Herniations or myelin sheaths) because the cellular concen-
A set of general tissue reactions are known to occur tration of osmotically active solutes is increased.
in the CNS that stand apart from the reactions to This usually results from an injury impairing the

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capacity of the cell to maintain ionic homeosta-
sis. It is also seen in association with systemic
disturbances in fluid and electrolyte metabolism.
Cytotoxic edema complicates hypoxia and isch-
emia because of failure of the ATP-dependent
sodium pump in the affected cells. It also occurs
in osmotic-disequilibrium syndromes associated
with hemodialysis or diabetic ketoacidosis and in
acute plasma hypo-osmolality states such as water
intoxication and inappropriate secretion of antidi-
uretic hormone. In contrast to vasogenic edema,
because the blood-brain macromolecular barrier
remains intact, disease processes that give rise to
cytotoxic edema are not associated with radio- FIGURE 1.23 Cerebral edema of the left cerebral
hemisphere with swelling of the parenchyma that
logical enhancement after injection of contrast
appears paler, flattening of the gyri, narrowing of the
medium.
sulci and left lateral ventricle.
• Interstitial or hydrocephalic edema is the accu-
mulation of cerebrospinal fluid (CSF) in the
extracellular spaces of the periventricular white and reabsorption. Rarely, it results from increased
matter resulting from obstructive hydrocephalus. production of CSF (e.g., choroid plexus papilloma).
As fluid collects within the obstructed ventricles, More commonly, it is the consequence of altered
pressure increases and the CSF is forced across flow and absorption of the CSF as a result of obstruc-
the ependymal lining into the adjacent extracel- tion of CSF pathways within the ventricular system
lular spaces. (noncommunicating hydrocephalus) or in the sub-
arachnoid space (communicating hydrocephalus).
Obstruction at “bottleneck” areas such as the foram-
Macroscopically, the edematous areas of brain
ina of Monro, the aqueduct of Sylvius, and the exit
are swollen and soft (Fig.  1.23). The swelling
foramina of the fourth ventricle (lateral foramina
increases the volume of the intracranial contents,
of Luschka and midline foramen of Magendie) can
with consequent increased intracranial pressure (see
occur when there is extension of blood or tumor
below). When the brain is cut, the slice surfaces may
into the ventricular system. Subarachnoid pathways
be wet and shiny. If the edema is diffuse, the ventri-
most often become blocked over the cerebral con-
cles are compressed; in severe cases they are reduced
vexities and around the rostral brainstem (incisural
to slit-like cavities.
block) as a result of inflammation or hemorrhage.
Under light microscopy, myelin stains demon-
In the acute phases, the blood clot or inflammatory
strate pallor of the white matter. The cerebral tissue
exudate forms a barrier to flow. Subsequently, orga-
has a loose appearance and is split by vacuoles of
nization of the clot or exudate leads to fibrous oblit-
variable size. Glial cells are swollen, and perivascular
eration of the subarachnoid space.
spaces are dilated.
Hydrocephalus is often associated with increased
These macroscopic and microscopic features cor-
intracranial pressure. In children, in the absence of
respond to ultrastructural features that vary accord-
appropriate shunting procedures, the head can
ing to the etiological and pathogenetic mechanism.
become enlarged when hydrocephalus develops
They include dilatation of the perivascular and extra-
before the cranial sutures close. When the progres-
cellular spaces, swelling of astrocytic cell processes,
sive obstructive lesion causing the hydrocephalus
and splitting of the myelin lamellae (Fig. 1.24).
is not severe, the hydrocephalic process may stabi-
lize and the CSF pressure returns to normal limits
(“normal-pressure hydrocephalus”).
1.2.3. HYDROCEPHALUS
Several alterations in the brain are common to
Hydrocephalus is an abnormal increase in the intra- all forms of hydrocephalus. These include dilation
cranial volume of CSF associated with dilatation of of the ventricular system, interstitial edema, reduc-
all or some portion of the ventricular system. It is sec- tion of the volume of the white matter, accentuation
ondary to a dysequilibrium between CSF formation of the primary, secondary, and tertiary cerebral sulci

Chapter 1 Basic Pathology of the Central Nervous System • 15


A B
Ast.
A A A
L

Ast. G
Ast. E.C. G
B.M. A
E.C.S
Ast. A
G G
N.

A
V
M
V V

M V

A A

FIGURE 1.24 Cerebral edema: principal ultrastructural forms.

(producing a prominent gyral pattern), and perfora- flow and blood volume, or the development of
tion of the septum pellucidum. Disruption and loss of space-occupying lesions such as tumors, abscesses,
the ependymal lining, with localized subependymal hematomas, or large, recent infarcts accompanied
astrocytic proliferations protruding into the ventricu- by edema. The effects of space-occupying lesions
lar cavities—ependymal granulations—is frequent on intracranial pressure are the result not only of
(see above). Proliferation of the subependymal glia the mass of the lesion, but also of the accompany-
may bring about stenosis of the aqueduct, which is a ing edema and obstruction of venous or CSF path-
cause of obstructive hydrocephalus in childhood. ways. In children with still-open cranial sutures,
an increase in volume of intracranial contents
will lead to splaying of the sutures, resulting in
1.2.4. INCREASED INTRACRANIAL an increase in the size of the skull and in digital
convolutional markings. In older children and in
PRESSURE AND BRAIN HERNIATION
adults when the bony skull can no longer expand,
After closure of the sutures, the volume of the cranial intracranial hypertension leads to compression
cavity is fixed by rigid bony walls and compartmen- of the brain surfaces against the inner table of the
talized by partitions of bone and dura. The normal skull, with consequent flattening of cerebral gyri,
contents of the cranial cavity (blood, brain, and narrowing of intervening sulci, and accentuation
CSF) are relatively incompressible. Under these of foraminal and tentorial markings on the infe-
circumstances, an increase in the volume of the rior cerebellar and medial temporal surfaces. The
cranial contents will result in increased intracranial expanding cerebral mass will also insinuate itself
pressure. into the anatomical openings that can accom-
The intracranial contents may expand because modate it. These compensatory displacements
of diff use brain edema, increased cerebral blood of brain from one intracranial compartment to

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A Skull B C 5
Falx 1

Tentorium 2
cerebelli
Tentorial 4
3
notch
Foramen
magnum
D E F

6 6

3 4 4
3
7 7

FIGURE 1.25 Principal types of cerebral herniation.

another, caused by an increase in the volume of a hemiparesis contralateral to the lesion may
intracranial contents, are referred to as cerebral ensue; when the contralateral peduncle is dis-
herniations. The site of herniation differs depend- placed and compressed against the free edge of
ing on whether the space-occupying lesion is the tentorium (Kernohan’s notch), an ipsilateral
supratentorial or infratentorial (Fig. 1.25). hemiparesis may follow; if the adjacent posterior
cerebral artery is compressed, there can be sec-
1.2.4.1. Cerebral herniations in supratentorial ondary infarction anywhere along its territory of
lesions A unilateral lesion (Fig. 1.26)that increases distribution.
the hemispheric volume is likely to cause a hernia- • Compression due to temporal herniation and the
tion of the cerebral hemisphere through openings downward thrust of central diencephalic hernia-
limited by the inferior border of the falx and by the tion may result in stretching of the blood vessels,
free edge of cerebellar tentorium on the ipsilateral especially the veins, that supply the midbrain and
side of the lesion. Depending on the size and the site pons, which may be torn and cause potentially
of the expanding lesion within the hemisphere, one lethal brainstem hemorrhages; these are called
of several forms of herniation will occur, sometimes Duret hemorrhages.
in combination: • External cerebral herniation through surgi-
cal or traumatic defects in the calvarium may
also occur.
• Herniation of the cingulate gyrus under the falx
(subfalcine herniation) with lateral displacement
of the anterior cerebral arteries Bilateral cerebral lesions or circumstances
• Lateral displacement of the midline structures that  result in a global increase of the volume
(i.e., the third ventricle, pineal gland, vein of  both hemispheres will ordinarily result in
of Galen) central diencephalic herniation and/or bilateral
• Downward herniation of the diencephalon temporal lobe herniation. A  midline, expanding
through the tentorial notch with downward dis- lesion will likely result in central diencephalic
placement of the floor of the hypothalamus and herniation.
of the mammillary bodies (central, diencephalic
herniation) 1.2.4.2 Cerebellar herniations in infratentorial
• Herniation of the hippocampal gyrus in the lesions
tentorial notch between the brainstem and the Two types of herniations exist:
free edge of the tentorium cerebelli. The herni-
ated temporal lobe can compress and stretch the • Upward herniation of the mesencephalon and cere-
third and sixth cranial nerves. When the ipsilat- bellum through the tentorial notch. Direct mesence-
eral cerebral peduncle is compressed directly, phalic lesions may result from this complication,

Chapter 1 Basic Pathology of the Central Nervous System • 17


A B

FIGURE 1.26 Cerebral herniations. (A) Inferior aspect of the cerebral hemispheres; note the herniated rim
of the right hippocampal gyrus compressing the oculomotor nerve and displacing the brainstem. (B) Cerebral
metastases causing temporal herniation; note displacement of the midline structures and cingulate herniation.
(C) Midbrain; note hemorrhagic lesion in the crus of the peduncle contralateral to the temporal herniation
(Kernohan’s notch). (D,E) Midbrain and pontine hemorrhages involving mostly the tegmentum, secondary to
temporal herniation.

as well as secondary lesions due to vascular 2. TOPOGRAPHIC ANALYSIS


compression.
• Cerebellar tonsillar herniation through the foramen
OF CNS LESIONS
magnum is the most frequent and most danger- Topographic analysis of the lesions observed is just as
ous complication of an infratentorial expanding important as the study of their morphologic aspects.
process, regardless of the nature of the insult or, It constitutes a crucial step in the attempt to arrive at
in case of a neoplasm, the degree of malignancy. an etiological diagnosis and necessitates a rigorous and
The result of increased intracranial pressure in the systematic examination of all the neural structures.
posterior fossa is the herniation of the cerebellar Systematic sampling of multiple anatomical levels is
tonsils downward through the foramen magnum necessary and, wherever possible, techniques that allow
(Fig. 1.27), culminating in medullary compres- for whole-brain sections provide invaluable material
sion with compromise of vital cardiorespiratory that permits the synchronous study of various areas of
centers. the CNS under the dissecting and the light microscope.

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A B

FIGURE 1.27 Cerebellar tonsillar herniation. (A) Posterior view. (B) Anterior view.

2.1. Diffuse Distribution systems—for example, involvement of upper and


lower motor neurons in amyotrophic lateral sclero-
Lesions that are diffusely distributed thought the sis, spinocerebellar involvement in Friedreich ataxia.
brain may be seen in systemic diseases such as meta-
bolic or circulatory disorders or also can be the
result of blood-borne, infective processes. Some of 3. SYNTHETIC INTEGRATION
the degenerative diseases may likewise cause diffuse
lesions of the CNS. Nevertheless, it is important to The findings in the two components of the neuro-
emphasize that, despite the diffuse character of these pathological examination, artificially set apart as
changes, lesions often show regional predominance. morphologic and topographic analyses, need to be
integrated. Furthermore and most importantly,
correlation of these findings with the clinical data,
2.2. Focal Distribution laboratory and radiological data, general autopsy
findings, and all other available diagnostic data must
Lesions may be localized to an anatomically
occur to arrive at an accurate etiological diagnosis.
well-defined area (lobe of the cerebral hemisphere,
Thus, for example, a thorough neuropathologic
basal ganglia, brainstem), and certain preferential
understanding of cerebral infarcts is possible only
sites of involvement are linked to specific etiologi-
after careful and complete postmortem examination
cal entities (e.g., some cerebral tumors preferentially
of the vascular tree, heart, and lungs and after com-
occur in certain locations of the brain). Lesions may
paring the anatomical findings with information
also be localized to a vascular territory.
provided by the clinical picture, the chronology of
the functional disturbances, and data from cerebral
2.3. Disseminated Distribution and vascular imaging.
Likewise, the study of the lipidoses cannot be
This is seen essentially in multifocal processes, of based solely on neuropathological findings. It neces-
which multiple sclerosis is the most characteristic sitates detailed correlation with data from the gen-
example. eral postmortem examination and neurochemical/
genetic analysis.
As a further example, the interpretation of mor-
2.4. Systematized Distribution phologic findings in hereditary disorders of the CNS
A number of nervous system disorders, espe- or peripheral nervous system and of diseases of skel-
cially degenerative diseases, cause changes that etal muscles requires correlation with molecular and
involve certain functionally related morphologic genetic data.

Chapter 1 Basic Pathology of the Central Nervous System • 19


2
Tumors of the Central Nervous System
K E I T H L . LIGON, KAR I M A M O KH TA RI , A N D T H O M A S W . S MIT H

1. CLASSIFICATION when alterations occur in growth regulatory genes,


such as oncogenes and tumor suppressor genes. Thus
The basis of classification of nervous system tumors it is paramount that any classification scheme be flex-
remains the histological appearance of a particular ible enough to allow for the inclusion of new diagnostic
neoplasm by light microscopic examination (sup- categories as well as the modification and even removal
plemented by immunohistochemical and electron of prior categories on the basis of information derived
microscopic observations where appropriate). It is from newer methodologies. The classification scheme
becoming clear, however, that information derived used in this book is based on the current (2007) World
from cytogenetics and molecular genetics will play Health Organization (WHO) classification of nervous
an increasingly important role in tumor classification, system tumors.
particularly with respect to providing more precise CNS tumors can be grouped into two major
diagnostic and prognostic information about a par- categories:  primary tumors and secondary tumors.
ticular tumor. Underlying most histology-based clas- Primary tumors arise from cells that are intrinsic to
sification approaches has been an implicit assumption the CNS or its coverings, including the calvarium,
that the phenotypic appearance of a particular tumor and include tumors of neuroepithelial origin and
accurately reflects its cellular origins (e.g., low-grade non-neuroepithelial origin. Secondary tumors arise
astrocytomas are derived from mature astrocytes, from sites elsewhere in the body and involve brain or
etc.). Recent evidence, however, suggests that at least spinal cord mainly by hematogenous dissemination
some CNS tumors, such as glioblastoma and medul- (metastases) or less often by contiguous extension.
loblastoma, might be derived from neural progenitor CNS tumors can also be grouped according to
cells that persist throughout adult life. It is also clear location and their corresponding incidence by age.
that, as with other human cancers, CNS tumors arise In adults, approximately 70% of all brain tumors

20 •

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occur supratentorially (i.e., within the cerebral hemi- above features), this has proved to be such a rare and
spheres or coverings); these include, in order of possibly controversial entity that the WHO scheme
frequency, metastases followed by gliomas, menin- uses modifications of the Sainte Anne/Mayo crite-
giomas, and schwannomas. By contrast, in children, ria for only the three higher grades of diffuse astro-
approximately 70% of brain tumors are infratento- cytoma (Table 2.1). The WHO grade I category is
rial in location (e.g., cerebellum, brainstem) and are reserved for circumscribed astrocytomas, including
neuroepithelial in origin, the most common being the pilocytic astrocytoma and subependymal giant
pilocytic astrocytoma, medulloblastoma, and epen- cell astrocytoma (SEGA).
dymoma in decreasing order of frequency. Spinal
cord tumors constitute about 15% of all primary 2.1.1.1.1. Diffuse Astrocytoma (WHO Grade II).
CNS tumors and include schwannomas, meningio- These tumors constitute about 10 to 15% of all
mas, and gliomas (ependymoma, astrocytoma) in astrocytic neoplasms. They can affect all age groups
decreasing order of frequency. but are mainly tumors of adults, with 25% occurring
between the ages of 30 and 40. They most commonly
occur in the cerebral hemispheres (especially frontal
2. PRIMARY NEOPLASMS and temporal lobes), followed by brainstem and spi-
nal cord, and are rarely seen in the cerebellum. The
2.1. Tumors of Neuroepithelial Tissue clinical features reflect the location of the tumor,
with seizures being a frequent presenting symptom.
2.1.1. ASTROCYTIC TUMORS
Imaging studies usually show an ill-defined, homo-
2.1.1.1. Diffusely Infiltrating Astrocytomas. geneous, non–contrast-enhancing lesion; the pres-
As a group these astrocytomas share the following ence of focal contrast enhancement may suggest
features:  widespread occurrence throughout the progression toward anaplasia and a higher grade.
CNS, clinical presentation in adults, diffuse infiltra- Macroscopically, these tumors enlarge and dis-
tion of adjacent and often distant brain structures, tort involved brain structures, often with blurring of
and tendency for progression to anaplasia over time. normal anatomical landmarks (Fig. 2.1A). Cysts of
A number of histological grading schemes have varying sizes and focal calcifications may be present.
been used for diffusely infiltrating astrocytomas; Microscopically, diffuse astrocytomas are low to
however, the Sainte Anne/Mayo grading system and moderately cellular tumors composed of well-differ-
its adaptation to the current WHO classification has entiated astrocytes (Fig. 2.1B). Some degree of nuclear
proved to be the most reproducible and predictive atypia is almost always present, which should help dis-
of tumor behavior. The Sainte Anne/Mayo criteria tinguish the neoplastic cells from reactive astrocytes.
are based on the presence or absence of four easily Mitoses are extremely rare or absent. Microvascular
recognizable histological features:  nuclear pleomor- proliferation and necrosis are never present. The back-
phism, mitoses, microvascular proliferation, and necro- ground matrix may be loose, vacuolated, or even micro-
sis. While the Sainte Anne/Mayo system recognizes cystic. The Ki-67/MIB-1 labeling index (a measure of
a grade I  diffuse astrocytoma (lacking all of the cellular proliferation) is usually less than a few percent.

Table 2.1. Grading of Diffuse Astrocytoma

WHO GR ADE D E S I G N AT I O N H I S T O L O G I C A L C R I T E R I A ( S T E . A N N E / M AY O )
I (Pilocytic astrocytoma; SEGA) (Not applicable)
II Diffuse astrocytoma One criterion—usually nuclear pleomorphism
III Anaplastic astrocytoma Two criteria—usually nuclear pleomorphism and
mitoses*
IV Glioblastoma Three OR four criteria—nuclear pleomorphism,
mitoses, microvascular proliferation, AND/OR
necrosis **

* The presence of a single mitosis in a diffuse astrocytoma that only exhibits nuclear pleomorphism is not usually sufficient to reclassify it as a
WHO grade III tumor (except in the case of very small samples).
** Necrosis is not required for the diagnosis of glioblastoma as long as microvascular (endothelial) proliferation is present.

Chapter 2 Tumors of the Central Nervous System • 21


A B

C D

FIGURE 2.1 Diffuse astrocytoma. (A) Thalamic astrocytoma (gross). Microscopic features: (B) Low-grade fibril-
lary astrocytoma (H&E). (C) Gemistocytic astrocytoma (H&E). (D) Anaplastic astrocytoma (H&E).

Three histological variants of diffuse astrocytoma have also be focally seen in other tumors (e.g., oligodendro-
been recognized, although in practice most have a mix- glioma, dysembryoplastic neuroepithelial tumor). For
ture of cell types. By far the most common variant is this reason the inclusion of protoplasmic astrocytoma as
the fibrillary astrocytoma, which is composed of neo- a distinct variant of astrocytoma has been challenged.
plastic cells with scant perikaryal cytoplasm within a Characteristic molecular changes in grade II
loose but consistently GFAP-positive fibrillary matrix. astrocytomas include polysomy of chromosome 7
Gemistocytic astrocytoma is defined as a tumor in which PMID:  21343879 (~76% of cases), mutations of
at least 20% of the neoplastic cells resemble gemisto- isocitrate dehydrogenase genes 1 or 2 (IDH1/2) in
cytic astrocytes (i.e., have abundant eosinophilic cyto- more than 70% of tumors, mutations in the TP53
plasm and peripherally-displaced nuclei)(Fig.  2.1C). tumor suppressor gene in about 50% of cases, over-
These tumor cells strongly express GFAP. Although expression of the platelet-derived growth factor and
gemistocytic astrocytomas are highly associated with its receptor, and loss of portions of chromosome
progression to anaplastic astrocytoma and glioblas- 22. Most adult diffuse low-grade astrocytomas will
toma, they should not automatically be assigned a progress to a higher-grade tumor such as anaplastic
higher grade unless the appropriate histological cri- astrocytoma WHO grade III. The average interval to
teria are fulfilled. The protoplasmic astrocytoma is the malignant change is about 4 to 5 years, but this may
least common (and most controversial) variant. It is vary considerably.
an astrocytic tumor composed mainly of small round
cells with scant, minimally GFAP-reactive processes 2.1.1.1.2. Anaplastic Astrocytoma (WHO Grade
in a prominent mucoid or microcystic background III) These tumors often arise in the setting of a
matrix. This pattern bears a striking resemblance to the preexisting low-grade diffuse astrocytoma but can
loose/spongy tissue of pilocytic astrocytomas and may also present de novo without clear evidence of a

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less malignant precursor. The average age of pre- CNS; however, the cerebral hemispheres, in par-
sentation is about 10  years higher than low-grade ticular the frontal and temporal lobes, basal ganglia,
diffuse astrocytoma; the location, clinical presenta- and commissural pathways are recognized sites of
tion, macroscopic appearance, and imaging features predilection. The radiological features of GBM typi-
are otherwise similar, except that some contrast cally include the presence of an irregular mass with
enhancement may be present within the tumor a central hypodense region of necrosis surrounded
(but not the typical “ring” enhancement seen in by a contrast-enhancing “ring,” which represents
glioblastoma). the more cellular and vascularized portions of the
Microscopically, this tumor has the appearance tumor. A classic radiological (and macroscopic) pre-
of a diffusely infiltrating astrocytoma but shows sentation is the “butterfly” pattern due to spread of
increased cellularity, nuclear atypia, and mitotic the tumor across the corpus callosum into the oppo-
activity in comparison to its low-grade counterpart, site hemisphere. The tumor may be surrounded by
but microvascular proliferation and necrosis are considerable vasogenic edema manifested as hyper-
absent (Fig. 2.1D). Many but not all tumor cells may intensity on a T2-weighted MRI scan.
express GFAP and OLIG2. Ki-67/MIB-1 labeling Macroscopically, GBMs often appear as rela-
indices are generally increased (usually 5% to10%) tively well-defined mass lesions, although there is
but can overlap with both low-grade diffuse astro- almost always significant microscopic infiltration
cytoma and glioblastoma. These tumors are aggres- of tumor into the surrounding parenchyma. They
sive, with typical survivals of only 2 to 3 years from typically have a “variegated” appearance with solid
diagnosis. gray-pink tissue at the periphery and yellow zones
At a molecular level, anaplastic astrocytomas of central necrosis (Fig. 2.2A). Some have old and
share the molecular features of diffuse astrocytoma recent hemorrhage. In common with other diffuse
grade II lesions including chromosome 7 polysomy, astrocytomas, GBMs may widely infiltrate adjacent
IDH1/2 mutation, and TP53 mutations. However, tissue and extend for long distances within fiber
in addition they also acquire events critical to malig- tracts. They may sometimes form additional masses
nant progression, such as inactivation of cell cycle at distant sites, creating the impression of a multifo-
control pathway genes CDKN2A/p16/ARF and RB, cal or “multicentric” glioma on neuroimaging stud-
amplification of CDK4/6, losses on chromosome ies (see below discussion of gliomatosis cerebri). True
10, as well as loss of parts of the long arm of chromo- multifocal gliomas probably do occur, although their
some 19. Given that these mutations are also seen exact frequency has been difficult to establish and
in glioblastoma, no alterations specific to anaplastic may actually be much lower than their previously
astrocytoma have yet been proposed. Conversely, estimated range (2.4% to 7.5% of all gliomas). These
it is generally felt that the glioblastoma-associated tumors would by definition be polyclonal and, at
molecular alterations of EGFR amplification and present, can only be proved by the use of molecular
EGFRvIII should be present only rarely in WHO markers. Some GBMs extend into the subarachnoid
grade III tumors. space or ventricles with the potential for cerebro-
spinal fluid (CSF) dissemination, although this
2.1.1.1.3. Glioblastoma (WHO grade IV) appears to be a relatively infrequent phenomenon.
Glioblastoma (also known as glioblastoma multi- Extracranial extension and hematogenous dissemi-
forme and still abbreviated as GBM) is a malignant, nation are very rare in patients who have not had
rapidly progressive, and fatal astrocytic neoplasm. It prior surgery. GBMs are among the most malig-
is the most common primary brain tumor, account- nant tumors, having a mean survival ranging from
ing for approximately 10% to 15% of all intracranial less than 1 year to 18 months, with less than 2% of
tumors and 40% to 50% of all glial tumors. They patients surviving longer than 3 years.
most commonly arise de novo in the absence of a All GBMs share in common the histological
preexisting astrocytic tumor (“primary GBM”, more features of high cellularity, marked nuclear atypia,
than 90% of tumors) but may also develop from a mitoses, microvascular proliferation, and necro-
less-malignant diffuse astrocytoma typically associ- sis. However, their microscopic appearance can be
ated with IDH1/2 mutation (“secondary GBM”). highly variable, with considerable regional heteroge-
GBMs occur in all age groups, but most arise in neity. In some GBMs the tumor cells may show con-
adults, with a peak incidence between the ages of siderable nuclear and cytoplasmic pleomorphism
45 and 70 years. They may arise in any region of the with multinucleated giant cells (Fig. 2.2B), whereas

Chapter 2 Tumors of the Central Nervous System • 23


A

D
C

FIGURE 2.2 Glioblastoma. (A) Glioblastoma (gross). Microscopic features: (B) Cellular anaplasia, mitoses
(H&E). (C) Necrosis with pseudopalisading (H&E). (D) Microvascular proliferation with glomeruloid struc-
tures (H&E).

others may consist mainly of small “undifferentiated” small undifferentiated cells. Necrosis is a character-
cells with scant cytoplasm and often poor GFAP istic feature of GBM and can consist of either large
expression (see small cell GBM below). While many confluent foci of coagulative necrosis and/or small
GBMs contain zones having better-differentiated band-like or serpiginous “geographic” necrotic foci
fibrillary and gemistocytic astrocytes, all astrocy- surrounded by a rim of densely packed tumor cells
tomas, including GBM, have significant oligoden- imparting the characteristic and highly diagnostic
droglial cell populations in almost all cases and are pseudopalisading pattern (Fig. 2.2C). Microvascular
positive for OLIG2 like other diffuse gliomas. Other proliferation is defined as the presence of abnormal
cell types that may be infrequently present in GBM vessels with walls composed of two or more lay-
include cells with glandular or epithelioid features, ers of mitotically active endothelial (and/or other
PAS-positive granular cells, and heavily lipidized vascular wall) cells, often forming glomeruloid
cells. Proliferative activity is prominent in GBM and structures (Fig.  2.2D). Microvascular proliferation
both typical and atypical mitoses are found. Ki-67/ has also been referred to as “capillary endothelial
MIB-1 labeling indices are likewise high, commonly proliferation,” although it is likely that other vas-
averaging 15% to 20%. Proliferative activity is usu- cular components besides the endothelial cells
ally greatest in tumors composed predominantly of undergo proliferation. Microvascular proliferation

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is frequently associated with thrombosis of the mutations. Pediatric GBMs (most of which arise de
affected vessels. Occasional GBMs may show con- novo) also differ genetically from adult GBMs in
siderable connective tissue reaction, which may be that they frequently harbor mutations in H3F3A
due to meningeal invasion by tumor or organiza- and ATRX, which are presumed to affect the epi-
tion of zones of necrosis, or as a response to marked genetic state of tumor cells. Pediatric GBMs also
microvascular proliferation. frequently exhibit mutations in the core pathways
The pathogenesis and molecular genetics of involved in adult GBMs such as TP53 gene muta-
GBM have been an area of intense investigation in tions, PDGFRA amplification, and loss of chromo-
recent years. The origin of GBM remains controver- some 17p, particularly in children older than 4 years
sial:  the “traditional” explanation is that they arise of age and in childhood brainstem GBMs.
from differentiated adult astrocytes or astrocyte pre- The prognostic evaluation of GBM patients is a
cursors. However, based on recent human and ani- frequent clinical problem, and genetic testing has
mal studies, it is now suggested that they arise from emerged as a reliable means for predicting patient
neuroepithelial progenitor cells, including oligoden- outcomes. Studies have consistently identified
droglial progenitor cells, that are present throughout that increased methylation of the promoter of the
adult life, MGMT gene is associated with increased progres-
GBM represents one of the best-characterized sion-free survival in adult GBM. Subsequent stud-
cancers at the molecular level in all of oncology and ies have expanded on this finding to determine that
was one of the first cancers to be studied in large- such tests likely identify patients with an increased
scale integrative genomic approaches. Collectively, methylation state, not just at the MGMT locus but
these molecular studies have consistently identified throughout the tumor genome, consistent with a
three core signaling pathways that are disrupted in “methylator phenotype” (G-CIMP), which is asso-
GBM:  increased activation of receptor tyrosine ciated with or may result from mutations in IDH1/2.
kinase/RAS/PI3K signaling, loss of function in Detection of IDH1/2 mutations by immunohisto-
TP53 signaling, and reduced signaling of the RB chemistry or sequencing has therefore emerged as
pathway, The activation of RTK/RAS/PI3K signal- the most effective means of identifying patients with
ing is evident in 88% of GBMs and most character- a more favorable prognosis.
istically occurs due to amplification of the EGFR
gene, along with rearrangements and overexpres- 2.1.1.1.4. Glioblastoma variants Giant cell glio-
sion of mutant EGFRvIII and extracellular domain blastoma (WHO grade IV) This is a rare tumor,
mutants. Additional activation of these pathways accounting for less than 5% of all GBMs. They usually
can occur through amplification of PDGRA, MET, arise de novo without evidence of a preexisting astrocy-
AKT, or PIK3CA and aberrations that lead to loss toma and are otherwise similar in clinical presentation
of function for the PTEN tumor suppressor gene. to typical GBMs. Radiologically and macroscopically
Studies of the TP53 gene have shown that rates they tend to be better circumscribed than ordinary
of mutation and inactivation of this pathway are GBMs. They are characterized histologically by the
higher than once previously thought in adult GBM, presence of giant and multinucleated cells that may
and TP53 is now known to be the most frequently show variable expression of GFAP. Many examples
mutated gene in GBM, occurring in at least 42% of have an abundant stromal reticulin network. They have
adult tumors. The RB pathway is targeted through other histological features typical of GBM, includ-
a number of different means, including genomic ing mitoses, necrosis, and microvascular proliferation,
losses and mutation of RB1, along with genomic which distinguishes them from the morphologically
losses targeting the CDKN2A family of genes or similar pleomorphic xanthoastrocytoma (see below).
amplification of the negative regulators of the RB Genetically this tumor has a high frequency of TP53
pathway, such as CDK4. mutations. Giant cell GBMs generally have a poor
Molecular studies have shown that primary and prognosis, although some reports have suggested a
secondary GBMs often have different sets of genetic somewhat better clinical outcome, possibly due to their
alterations:  primary GBMs are commonly charac- greater resectability and less infiltrative behavior.
terized by EGFR gene amplification/overexpression
while secondary GBMs arising from lower-grade Gliosarcoma (WHO grade IV) Gliosarcomas
precursors have a sequential series of genetic altera- are tumors having a biphasic pattern of both neo-
tions, including concurrent IDH1/2 and TP53 gene plastic glial and mesenchymal tissue. They represent

Chapter 2 Tumors of the Central Nervous System • 25


approximately 2% of all GBMs. They are usually nodules of “small blue cells” resembling medullo-
found in the cerebral hemispheres, with a predilec- blastoma (see below). These PNET-like foci immu-
tion for the temporal lobes. Their clinical presenta- nohistochemically express neuronal markers (e.g.,
tion is similar to ordinary GBM. The radiographic synaptophysin), diffuse p53 reactivity, and a very
appearance can be identical to typical GBM or, if the high Ki-67/MIB-1 labeling index (often greater than
sarcomatous component predominates, can present 80%). Homer Wright rosettes or large-cell/anaplas-
as a hyperdense, circumscribed, uniformly contrast- tic histology may be present in these areas. This vari-
enhancing mass mimicking a meningioma. The his- ant may be more likely to show CSF dissemination.
tological diagnosis rests on establishing the presence
of unequivocally malignant glial and mesenchymal 2.1.1.1.5. Gliomatosis cerebri (GC) GC is defined
elements. The sarcomatous regions usually consist of as a diffusely infiltrating glioma that involves more
malignant spindle cells arranged in a fascicular, her- than two lobes of the brain. It is frequently bilateral
ringbone, or sometimes “storiform” pattern and rarely and may extend into posterior fossa structures and
show other types of mesenchymal differentiation, rarely the spinal cord. Until recently the diagnosis of
including cartilage, bone, and skeletal and smooth GC was only made at postmortem examination, but
muscle. Rare examples have shown cytokeratin-pos- it may be suggested clinically on the basis of MRI
itive epithelial and adenoid structures. GFAP immu- findings and a biopsy showing an infiltrating glioma.
nohistochemistry is very helpful in distinguishing Molecular biological data suggest that GC most
between the glial and mesenchymal components; likely represents a clonal diffuse astrocytic tumor
likewise, a reticulin stain will show abundant reticu- with unusually infiltrative behavior. Some cases of
lin fibrils in the sarcomatous but not the glial compo- GC may originate from a small, often inapparent
nent. The origin of the sarcomatous component has focus of GBM; however, GC may also occur as a de
been traditionally ascribed to malignant transforma- novo phenomenon. Some patients with GC may sec-
tion of the proliferating blood vessels in GBM, but ondarily develop multiple small foci of GBM. This
there is now convincing cytogenetic and molecular feature may account for many instances of so-called
evidence for a monoclonal origin of both the glial “multicentric” GBM. The microscopic appearance
and mesenchymal components of the tumor (i.e., the of GC can be quite variable, with some neoplastic
mesenchymal component probably represents a form cells resembling astrocytes and others having more
of metaplasia analogous to carcinosarcoma of epithe- indeterminate features (often resembling microglia)
lial tumors). The overall prognosis of gliosarcoma is or rarely oligodendroglial histology. GFAP immu-
essentially the same as ordinary GBM. nostaining can likewise be variable. Tumor nuclei
usually show enough atypia to facilitate their iden-
Small Cell GBM (WHO grade IV) This tumor tification as neoplastic, although mitoses may be
is a variant of GBM composed predominantly, or minimal or even absent. Microvascular proliferation
exclusively, of small cells with scant, minimally and necrosis are usually absent. For these reasons,
GFAP-positive cytoplasm and oval to round nuclei it has often been difficult to assign a specific WHO
exhibiting mild to moderate atypia. Mitoses may grade to GC: although a small biopsy may show his-
be numerous, and the Ki-67/MIB-1 labeling index tological features compatible with a grade II or III
is typically very high. Since the histological appear- glioma, the overall biological and clinical behavior
ance of this tumor may closely resemble anaplastic of GC often reflects a more aggressive tumor.
oligodendroglioma or GBM with an oligodendrog-
lial component (see below), ancillary immunohis- 2.1.1.2. Circumscribed astrocytomas
tochemical and molecular studies may be helpful in 2.1.1.2.1. Pilocytic astrocytoma (WHO grade I)
distinguishing these entities. Small cell GBM almost This tumor is a well-circumscribed, slow-growing,
always presents as a de novo or “primary” GBM, and often cystic glioma that predominantly occurs in
molecular studies have shown that greater than 70% children and young adults (Fig.  2.3A). They are
will have amplification of EGFR. the most common glioma in children but are much
less frequent in adults and are rare after age 50. The
GBM (or malignant glioma) with PNET-like most common sites are the cerebellum followed
foci  (WHO grade IV) This tumor is a recently by hypothalamus/third ventricular region, optic
described variant of high-grade glioma (usually nerves, brainstem, cerebral hemispheres, and spinal
GBM or gliosarcoma) that focally contains discrete cord. The clinical presentation is largely dependent

26 • 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

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A B

FIGURE 2.3 Pilocytic astrocytoma. (A) Optic glioma (gross). Microscopic features: (B) Rosenthal fibers
(H&E). (C) Microcystic change (H&E).

on tumor location, with an evolution in keeping of pilocytic astrocytoma. Pilocytic astrocytomas


with the slow rate of growth. Imaging studies show may also contain histological features that could be
a circumscribed, cystic or (less often) solid mass mistaken for evidence of anaplasia; these include
with contrast enhancement. In the cystic examples, microvascular proliferation (including glomeruloid
contrast enhancement may be localized to a mural vessels), nuclear atypia, extension into the subarach-
nodule. noid space, and occasionally bland (infarct-like)
The histological features of pilocytic astrocy- areas of necrosis. Mitoses are rare and most exam-
toma are highly distinctive and classically consist of ples have a very low Ki-67/MIB-1 labeling index
a biphasic pattern of compact and loose (“spongy”) (usually less than 1%).
tissue (Fig. 2.3B, C). The compact zones consist of The vast majority of pilocytic astrocytomas are
dense aggregates of elongated bipolar astrocytes indolent and treated primarily by surgical excision
with variable numbers of strongly eosinophilic irreg- with excellent long-term survivals; however, hypo-
ular Rosenthal fibers, whereas the loose or spongy thalamic and brainstem tumors can be difficult to
areas consist of small round multipolar astrocytes in manage and often recur, with adverse consequences.
association with microcysts and eosinophilic granu- True malignant transformation of a pilocytic
lar bodies. The proportion of these two classic his- astrocytoma is very rare, and most examples have
tological patterns may vary within a given tumor, occurred following radiotherapy. Histologically they
and some tumors (especially in small biopsies) show significantly increased proliferative activity
may show a predominance of one pattern. Adding (e.g., mitoses, Ki-67 labeling), focally high cellular-
to the diagnostic difficulty is the presence of other ity, and/or pseudopalisading necrosis.
tissue patterns (e.g., foci of oligodendrocyte-like The most common molecular alteration identified
cells) that can form part of the histological spectrum in pilocytic astrocytoma is a tandem duplication/

Chapter 2 Tumors of the Central Nervous System • 27


fusion event involving the genes KIAA1549 and histological features include the presence of a con-
the serine/threonine kinase BRAF. This alteration spicuous reticulin network (possibly reflecting a
leads to creation of loss of a negative regulatory putative origin from subpial astrocytes), lympho-
domain in the BRAF fusion protein and constitu- cytic infiltrates, and eosinophilic granular bodies
tive activation of the MAPK/ERK signaling path- similar to those found in pilocytic astrocytomas
way. Such alterations can be identified in more than and ganglion cell tumors. The prognosis of this
90%  of  cerebellar pilocytic astrocytomas but are tumor is excellent with surgical excision alone,
found to a lesser degree in gliomas with piloid fea- with recurrence-free 10-year survivals of greater
tures in the supratentorial regions (~50%). Recent than 60%. Recurrences may show the same histol-
studies suggest that the presence of KIAA1549- ogy as the original tumor or evidence of anapla-
BRAF aberrations may also indicate a more favor- sia, including significantly increased proliferative
able prognosis. activity, necrosis, and microvascular proliferation.
PXAs are highly associated with BRAFV600E
2.1.1.2.2. Pilomyxoid astrocytoma (WHO grade point mutations at a similar rate to that seen in gan-
II). Pilomyxoid astrocytoma is a recently described gliogliomas (more than 50%); however, this muta-
variant of pilocytic astrocytoma that most often tion is also detected in several other CNS tumor
presents in the hypothalamic region as a solid, types.
well-circumscribed contrast-enhancing mass.
Histologically it consists of a monomorphous pop- 2.1.1.2.4. Subependymal giant cell astrocytoma
ulation of bipolar cells with fibrillary GFAP-positive (SEGA) (WHO grade I). SEGA is a benign, slow-
processes within a loose myxoid background that growing intraventricular tumor that is characteris-
often have an angiocentric arrangement. Mitoses tically associated with tuberous sclerosis. In some
may be present. Histological features character- cases SEGA may be the presenting feature of this
istic of typical pilocytic astrocytoma, such as a disease; however, it is unresolved whether SEGAs
biphasic pattern and Rosenthal fibers, are absent. occur in the absence of tuberous sclerosis. Most
Pilomyxoid astrocytomas have been reported to SEGAs arise during the first two decades of life
have a more aggressive clinical course and are con- and present with worsening of a seizure disorder
sidered WHO grade II tumors. or symptoms of increased intracranial pressure.
They typically occupy the wall of one of the lateral
2.1.1.2.3. Pleomorphic xanthoastrocytoma (WHO ventricles and can cause blockage of the foramen
grade II). Pleomorphic xanthoastrocytoma (PXA) of Monro. Rare examples have undergone massive
is a low-grade, slow-growing cortical astrocytoma hemorrhage. SEGAs have a characteristic histo-
that occurs primarily in children and young adults, logical appearance, being composed of relatively
often presenting with a chronic seizure disorder. large cells resembling gemistocytic astrocytes
PXAs characteristically involve the superficial cor- but often having “ganglioid” nuclei with promi-
tex with extensive involvement of the leptomenin- nent nucleoli (Fig. 2.4). Spindle-shaped cells with
ges and may be solid or cystic; the latter may have elongated fibrillar processes may also be encoun-
a mural nodule. Almost all are supratentorial in tered. Some tumor cells may show considerable
location and have a predilection for the temporal nuclear pleomorphism and occasional mitoses
lobes. Microscopically PXAs have a varied mix of may be present; however, these features do not
cell types, including more typical astrocytic cells indicate anaplastic change. Calcifications may be
with fibrillary processes as well as often strikingly present. Immunohistochemically the tumor cells
bizarre giant cells with single or multiple pleomor- may express either or both glial and neuronal-
phic nuclei and variable xanthomatous change in associated antigens, which may reflect their puta-
the cytoplasm. Mitoses are usually rare or absent, tive origin from dysplastic bipotential cells in the
as are necrosis and microvascular proliferation. subependymal region. Most genetic alterations in
The Ki-67/MIB-1 proliferative index is usually less SEGAs relate to the two genes implicated in tuber-
than 3%. Immunohistochemically the tumor cells ous sclerosis:  the TSC1 gene on chromosome 9q
show consistent but often variably intense GFAP that encodes the hamartin protein and the TSC2
immunoreactivity. Some examples also express gene on 16p that encodes the tuberin protein.
“neuronal” markers, including synaptophysin SEGAs are treated by surgical excision alone and
and neurofilament protein. Other characteristic rarely recur.

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from previously frozen material. These tumors also
characteristically contain a network of thin-walled
branching capillaries, often described as a “chicken-
wire” or “wishbone” vascular pattern (Fig.  2.5B).
The presence of occasional mitoses and nuclear
atypia (which may be marked in some cases) is still
compatible with a WHO grade II neoplasm; how-
ever, the presence of significant mitotic activity,
microvascular proliferation, or necrosis indicates
anaplastic transformation (WHO grade III). Most
WHO grade II oligodendrogliomas have a Ki-67/
MIB-1 labeling index less than 5% (an index of 5%
or greater has been associated with more aggres-
FIGURE 2.4 Microscopic appearance of subependy- sive clinical behavior). Some oligodendrogliomas
mal giant cell astrocytoma (H&E). may contain nodules of increased cellularity; careful
attention to these areas may reveal other anaplastic
features within these nodules. Small calcifications
2.1.2. OLIGODENDROGLIAL TUMORS
(calcospherites) are a characteristic histological fea-
2.1.2.1. Oligodendroglioma (WHO grade II). ture (Fig.  2.5A) but are only seen in 20% of cases
Oligodendrogliomas are diffusely infiltrating glio- and are not specific for oligodendroglioma. Another
mas composed of cells morphologically resembling characteristic and diagnostically useful feature is the
mature oligodendrocytes. They account for approxi- presence of perineuronal, perivascular, or subpial
mately 5% of all intracranial gliomas, and most occur tumor aggregates (so-called “secondary structures”)
in adults, with a peak incidence between  the ages when the tumor infiltrates the cortex. It is not
of 30 to 60. They are most often found in the cere- uncommon to find well-differentiated astrocytes
bral hemispheres but have been reported in the with visible cytoplasm admixed with the oligo-
cerebellum, brainstem, and spinal cord and even dendrocytes. In most cases, their morphology and
in the leptomeninges as a primary site. Because of uniform distribution suggest that they are reactive
the relatively benign, slow-growing nature of the rather than neoplastic.
tumor, patients may often present with a long his- Oligodendrogliomas can be immunohistochem-
tory of neurological symptoms, most often chronic ically identified using antibodies specific for the
seizures. Imaging studies usually show a well-demar- IDH1(R132H) mutant protein, which also serves
cated mass, often with calcification and occasionally as a tumor-specific antigen(Fig. 2.5C). In addition,
intratumoral hemorrhage, but peritumoral edema the oligodendroglial lineage-restricted transcription
and contrast enhancement are not common except factor OLIG2 is expressed in all oligodendrogliomas
in the more anaplastic examples. and in more than 90% of the tumor cells. While these
Macroscopically, oligodendrogliomas are usu- markers are not specific to oligodendrogliomas, oli-
ally well circumscribed and grayish-pink and godendrogliomas can often be distinguished from
often include areas of mucoid change, which may IDH mutant anaplastic astrocytomas, which more
result in a gelatinous consistency as well as zones frequently have TP53 staining and exhibit more het-
of cystic degeneration, focal hemorrhage, and erogeneous staining for OLIG2, with typically fewer
calcification. than 90% of tumor cells expressing the protein. In
Oligodendrogliomas have an easily recognizable, some cases, oligodendrogliomas may express GFAP,
highly uniform histological appearance. In paraf- and when present such cells often resemble small
fin sections, the tumor cells are closely packed and gemistocytic astrocytes and are referred to as micro-
appear swollen, consisting of a small round nucleus gemistocytes. These cells have no specific prog-
(usually slightly larger than a normal oligodendro- nostic significance but are often seen in anaplastic
cyte) surrounded by a clear halo (Fig.  2.5A). This oligodendrogliomas and oligoastrocytoma. They
imparts a very characteristic “honeycomb” or “fried are thought to be either a transitional form between
egg” appearance to the tumor; however, this pattern oligodendrocytes and astrocytes or a phenotypic
is not apparent in smear preparations or frozen sec- recapitulation of the premyelination stage of normal
tions and is often absent in paraffin sections made immature oligodendrocytes.

Chapter 2 Tumors of the Central Nervous System • 29


A B

C D

FIGURE 2.5 Microscopic appearance of oligodendroglioma. (A) Oligodendroglioma with microcalcifica-


tions (H&E). (B)“Chicken-wire” vascular pattern (H&E). (C) IDH1 R132 immunoreactivity in tumoral cells.
Anaplastic oligodendroglioma (D) Microvascular proliferation (H&E). (E) Nuclear atypia, mini-gemistocytes
(H&E).

Cytogenetic evaluation of the 1p and 19q chro- with the oligodendroglial phenotype; thus, the find-
mosome arms (usually tested by fluorescence in situ ing of co-deleted 1p/19q within in a glial tumor
hybridization [FISH]) is now commonly done as with equivocal oligodendroglial histology may
part of the workup of oligodendroglial tumors or provide additional support for the diagnosis of oli-
mixed gliomas. Concurrent whole-arm co-deletion godendroglioma (or oligodendroglial component
of 1p and 19q, resulting from a translocation involv- of a mixed glioma). Mutations in the transcription
ing these chromosomes, has been strongly associated factor, CIC, appear to be more specifically associated

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with oligodendrogliomas, and concurrent identifi- astrocytomas such as glioblastoma:  most com-
cation of IDH mutations could help to specifically monly CDKN2A/p16/ARF deletions. Such tumors
distinguish oligodendroglioma and oligoastrocy- often have a poorer prognosis, with less favorable
toma from other CNS tumors with similar histo- response to chemotherapy and median survivals of
logical features (e.g., clear cell ependymoma, central less than 2 years.
neurocytoma).
Oligodendrogliomas with 1p/19q co-deletion
2.1.3 . MIXED GL IOMAS
and IDH mutation generally have a highly favorable
outcome, with a median postoperative survival of 3 2.1.3.1. Oligoastrocytoma (WHO grade II).
to 5 years. Some patients have extensive postopera- These are tumors which are felt to prominently
tive recurrences with progression to frank anaplasia. contain a population of tumor cells with astrocytic
Metastases through the cerebrospinal pathways may morphology as well as distinct populations of tumor
also occur. cells with oligodendroglial morphology. Their exact
incidence has been difficult to determine due to
2.1.2.2. Anaplastic oligodendroglioma (WHO lack of uniformity of the histological criteria used
grade III). The exact incidence of anaplastic oligo- to define this tumor as distinct from other diffuse
dendroglioma has been difficult to determine for astrocytic class tumors (grades II to IV) that also
various reasons, including the lack of clear-cut his- biologically have been revealed to always contain a
topathological criteria in prior studies. Age of onset, mixture of oligodendroglial and astrocytic lineage
location, and clinical features are generally similar cells. Their reported incidence varies between 2%
to those of oligodendroglioma. Imaging studies and 10% of all gliomas. The age and sex distribu-
usually show some degree of contrast enhance- tion, location, clinical presentation, and imaging
ment. The macroscopic appearance is similar to oli- features are all similar to those of WHO grade II
godendroglioma except that areas of necrosis may oligodendroglioma.
be present. Two histological variants have been recog-
Microscopically these tumors have the general nized: a “compact” or biphasic variant and a “dif-
histological appearance of an oligodendroglioma fuse” or intermingled variant. Neither component
but in addition demonstrate focal or diffuse fea- should have anaplastic histology. The diagnosis
tures of overt malignancy, including increased cel- of oligoastrocytoma is usually much easier and
lularity, cytological atypia, frequent mitoses, and less controversial in the biphasic variant, which
usually microvascular proliferation and/or necrosis shows distinct areas of oligodendroglial and astro-
with or without pseudopalisading (Fig.  2.5D, E). cytic differentiation. The diagnosis of the inter-
GFAP-positive “microgemistocytes” are often pres- mingled variant is much more difficult because
ent but have no prognostic significance. Although of the occurrence of reactive astrocytes within
the presence of a clear-cut oligodendroglial pattern the tumor and GFAP-positive oligodendrocytes
is a prerequisite for the histological diagnosis of this (i.e., microgemistocyte or gliofibrillary oligoden-
tumor, it is acknowledged that some examples may drocytes) and the inability to reliably distinguish
be difficult to distinguish from GBM (see below such tumors from diff use astrocytomas. However,
discussion of “glioblastoma with oligodendroglial the presence of GFAP-positive oligodendrocytes
component”). should prompt a search for more definitive areas
Many (but not all) anaplastic oligodendroglio- of astrocytoma.
mas share in common with low-grade oligoden- Molecularly, mixed gliomas have mutations most
drogliomas the characteristic loss of chromosome in common with diffuse astrocytomas WHO grade
arms 1p and 19q, mutation of IDH genes, and CIC II, including frequent mutations in IDH (>70% of
mutations. Tumors with this genetic signature have tumors) and TP53. The presence of 1p/19q whole-
been reported to show a more favorable response, arm co-deletions is rare in most studies of mixed
at least initially, to chemotherapy (previously com- gliomas. No mutations or combination of markers
bined procarbazine, CCNU, and vincristine [PVC], has been found to be specific for oligoastrocytomas.
and more recently temozolomide) and may have Oligoastrocytomas are generally considered to be
longer median survivals of over 10 years. However, monoclonal tumors in which the oligodendroglial
other anaplastic oligodendrogliomas can share and astrocytic components share the same genetic
some of the genetic alterations found in high-grade alterations.

Chapter 2 Tumors of the Central Nervous System • 31


2.1.3.2. Anaplastic oligoastrocytoma (WHO tumors. Some ependymomas, especially those aris-
grade III). These tumors consist of both neoplastic ing infratentorially, may spread widely throughout
oligodendrocytes and astrocytes in which one or the CSF and rarely outside the CNS.
both components show clearly anaplastic histology. Ependymomas have a characteristic and easily
The most challenging aspect of the diagnosis is dis- recognizable microscopic appearance, although cel-
tinguishing this tumor from a GBM due to a great lular density and cytoarchitecture may vary among
degree of histological and biological overlap. As pre- cases and within the same case. The typical tumor is
viously mentioned, anaplastic oligodendrogliomas moderately cellular and composed of polygonal cells
may have features in common with glioblastoma, having uniform nuclei. Two diagnostically impor-
including the presence of GFAP-positive cells, often tant but often inconstant features include the pres-
in transition with microgemistocytes. Since the ence of perivascular pseudorosettes (Fig.  2.6B) and
presence of necrosis within an anaplastic oligoastro- true ependymal rosettes or tubules (canals)(Fig. 2.6C).
cytoma has now been shown to be prognostically Perivascular pseudorosettes are by far the more
significant and associated with shorter patient sur- common pattern and consist of tumor cells arranged
vival, the WHO consensus recommends classifying radially around a central vessel with a “clear” region
this tumor as a GBM with an oligodendroglial compo- composed of slender GFAP-positive cytoplasmic
nent. Regardless, the presence of mutations in IDH processes oriented perpendicular to the vessel wall.
genes in these tumors is associated with favorable The ependymal rosettes (tubules) are composed of
prognosis relative to GBMs with absence of IDH ependymal cells lining central lumens that recapitu-
mutations. late the appearance of a normal ventricle. In general
the tumor cells show minimal atypia and mitoses are
rare or absent; however, some WHO grade II epen-
2. 1. 4. E P E NDY MAL TU M O R S
dymomas may have foci of necrosis without pseu-
2.1.4.1. Ependymoma (WHO grade II). Epen- dopalisading. Occasional examples show myxoid
dymomas account for approximately 6% of intracra- degeneration, focal hemorrhage, and occasionally
nial gliomas. Although they are encountered at any bone and cartilage formation. GFAP immunoreac-
age, they are definitely more frequent in childhood tivity is almost always present in the cytoplasmic
and adolescence. They occur at any level of the ven- process surrounding the perivascular pseudoro-
tricular system, but supratentorial tumors (approxi- settes but is more variable elsewhere; the tumor cells
mately 40%) are less common than infratentorial in ependymal canals may express epithelial mem-
ones (approximately 60%). In the spinal cord, epen- brane antigen (EMA) in the luminal surface of
dymomas are the most common neuroepithelial ependymal rosettes or as dot-like signal (Fig. 2.6D).
tumor, accounting for approximately 60% of the Ependymomas generally lack significant expression
spinal gliomas; they are most often found in the of the diffuse glioma marker OLIG2, which can be
lumbosacral segments and region of the filum ter- a very useful negative feature. Ultrastructurally the
minale/cauda equina. The clinical symptoms vary tumor cells show features of ependymal differen-
with location of the tumor and include local effects tiation, including cilia, basal bodies blepharoplasts,
as well as hydrocephalus and symptoms of increased surface microvilli, and sometimes microrosettes.
intracranial pressure. Imaging studies show a rela- Several histological variants are recognized:
tively well-circumscribed mass with varying degrees
of contrast enhancement, with tumor infiltration Cellular ependymomas show high cellularity with-
and edema being infrequent. Hydrocephalus or out increased mitotic rate or other anaplastic
displacement of the ventricles or brainstem can be features; perivascular rosettes and ependymal
observed. Some spinal ependymomas are associated tubules are uncommon.
with syringomyelia. Papillary ependymomas have well-formed papillary
Macroscopically, ependymomas are gray-red, structures and are distinguished from choroid
lobulated, and usually well-demarcated tumors plexus papillomas by the presence of GFAP-
that often have a relationship to a ventricular cavity positive processes abutting central vessels.
(Fig. 2.6A). Some infratentorial tumors may extend Clear cell ependymomas have tumor cells with promi-
into the cerebellopontine angle or within the cisterna nent clear perinuclear halos; immunohistochem-
magna along the medulla. In the spinal cord they istry or electron microscopy may be needed to
usually present as circumscribed intramedullary distinguish this variant from oligodendroglioma

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A B

C D

E F

FIGURE 2.6 Ependymoma. (A) Ependymoma of fourth ventricle (gross). Microscopic features: (B) Perivascular
pseudorosettes (H&E). (C) Ependymal tubules (H&E). (D)Dot-like EMA positivities. (E)Anaplastic ependy-
moma with increased cellularity and brisk mitotic activity (H&E). (F)Myxopapillary ependymoma (H&E).

or central neurocytoma. The clear cell variant is Ependymomas are generally considered to be
frequently associated with anaplastic histology slow-growing “benign” tumors; however, it has been
(see below) and more aggressive biological behav- difficult to precisely correlate tumor histology with
ior, and would be considered a grade III tumor. prognosis, partly due to the prior inability to define
Tanycytic ependymomas have tumor cells arranged reliable indicators of anaplasia (see below). As a gen-
in fascicles with ill-defined perivascular pseudo- eral rule, ependymomas in the pediatric age group
rosettes and rare ependymal tubules; they most tend to fare worse than in adults, primarily due to
often occur in the spinal cord and may appear a higher incidence of anaplastic histology and their
similar to astrocytomas or schwannomas. location in the posterior fossa, making surgical

Chapter 2 Tumors of the Central Nervous System • 33


resection more challenging, and leading to a greater not present. This tumor is slow growing and has an
likelihood of CSF dissemination, which by itself is overall favorable survival, although some patients
associated with a poorer prognosis. experience local recurrence after surgical resection.
Neurofibromatosis type 2 (NF2) is associated An exception is the sacrococcygeal variant of myxo-
with the occurrence of spinal cord ependymo- papillary ependymoma, which is associated with a
mas, indicating a role for the NF2 tumor suppres- greater rate of regrowth and potential for metastatic
sor gene (located on chromosome 22q12) in this dissemination.
tumor. In sporadic tumors, spinal ependymomas
more frequently have alterations of the NF2 gene. 2.1.4.4. Subependymoma (WHO grade I).
Ependymomas have been the focus of several Subependymomas are well-demarcated, slow-grow-
genomic studies, which have revealed a complex ing benign tumors composed of cells resembling
landscape of mutations and copy number aberra- subependymal glia. They are typically attached
tions, the clinical significance of which is currently to the ventricular wall and project into the lumen.
being evaluated. They may occur at any site but are most often
encountered in the fourth ventricle. Most subepen-
2.1.4.2. Anaplastic ependymoma (WHO dymomas are clinically silent, but some are symp-
grade III). As noted above, histology and clinical tomatic due to ventricular obstruction, increased
outcome in ependymomas have not always shown intracranial pressure, or rarely spontaneous hemor-
a good correlation. However, recent studies have rhage. Microscopically they consist of small nests
identified more rigorous criteria for identifying of glial cell nuclei embedded in a hypocellular
anaplasia and more aggressive clinical behavior GFAP-positive fibrillary matrix. Mitoses are rare or
in these tumors. The diagnosis of WHO grade III absent. Additional histological features include the
(anaplastic) ependymoma can be made if the tumor presence of microcysts, calcifications, focal hemor-
has two or more of these histological features: ele- rhage, and abnormal vasculature. Mixed tumors with
vated mitotic index, hypercellularity with nuclear features of both subependymoma and ependymoma
hyperchromasia and/or pleomorphism, microvas- have been described; their overall behavior is more
cular proliferation, and pseudopalisading necrosis aligned with ependymomas and they are considered
(Fig. 2.6E). An elevated Ki-67/MIB-1 labeling index WHO grade II neoplasms.
also correlates well with anaplastic histology.
2 .1 . 5. CHOROID PLEXUS TUM ORS
2.1.4.3. Myxopapillary ependymoma (WHO
grade I). This is a distinct subtype of ependy- Choroid plexus tumors (papilloma and carcinoma)
moma that almost exclusively occurs in the conus account for 0.5% of all brain tumors and for 2% of
medullaris/cauda equina region of the spinal cord, the tumors of the glioma group. They are encoun-
where they are thought to arise from ependymal tered most frequently in the first decade, with 10%
cells in the filum terminale. They have rarely been to 20% presenting in the first year of life. The ratio of
described in other locations in the brain and spi- choroid plexus papilloma to carcinoma is approxi-
nal cord. Subcutaneous sacrococcygeal or presa- mately 5:1; however, 80% of the carcinomas arise in
cral myxopapillary ependymomas arising from children. These neoplasms occupy the sites of the
ectopic ependymal remnants are a recognized vari- ventricular system where choroid plexus is normally
ant. They occur primarily in young adults, usually found. They occur, in order of decreasing frequency,
presenting clinically with back pain. On imaging within the fourth ventricle, the lateral ventricles
studies, they appear as well-circumscribed lesions (more so on the left), and the third ventricle. Most
with strong contrast enhancement and sometimes lateral ventricle tumors occur in individuals less
cystic change and hemorrhage. Myxopapillary than 20 years old, whereas those in the fourth ven-
ependymomas have a characteristic histological tricle are more evenly age-distributed. Patients
appearance, consisting of GFAP-positive cuboidal present clinically with signs of hydrocephalus and
tumor cells arranged around vascularized stromal increased intracranial pressure. Only rarely do they
cores, which exhibit variable amounts of mucoid produce excessive amounts of CSF. Imaging studies
material or fibrous tissue (Fig.  2.6F). The tumor show them to be hyperintense, contrast-enhancing
may also contain microcystic areas. Mitoses are very intraventricular tumors. Choroid plexus tumors are
rare or absent and other features of anaplasia are treated primarily by surgical excision. The prognosis

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is excellent for choroid plexus papilloma (nearly is most confidently made in children, whereas in
100% 5-year survival) but much less favorable adults the major differential diagnosis is that of met-
(40%) for carcinoma. astatic carcinoma, which would be distinctly more
common in this age group. Immunohistochemistry
2.1.5.1. Choroid plexus papilloma (WHO may be helpful, especially if the tumor expresses
grade  I) and atypical choroid plexus papilloma markers that are considered more characteristic
(WHO grade II). Choroid plexus papilloma (CPP) of choroid plexus. However some of these mark-
is a histologically benign tumor whose structure ers (e.g., transthyretin) are not always expressed in
recapitulates that of normal choroid plexus except choroid plexus carcinoma, or conversely may also
for having slightly more crowded and elongated be expressed by some metastatic carcinomas. Some
papillae (Fig.2.7A , B). The papillae consist of vascu- CPCs may have prominent rhabdoid histology,
lar connective tissue cores (cf. gliovascular cores of which can lead to confusion with atypical teratoid/
papillary ependymoma) lined by a simple columnar rhabdoid tumors; however, unlike the latter, CPCs
or cuboidal epithelium. Prominent mitotic activity, will show normal nuclear immunoreactivity for
necrosis, and brain invasion are absent. The major- INI-1. As for their carcinoma counterparts outside
ity of CPPs are immunoreactive for transthyretin the brain, the molecular alterations of CPC can be
as well as for vimentin, pancytokeratin, and S-100 complex, although mutations in TP53 have been
protein but not epithelial membrane antigen. Focal found to be present in a subset of these tumors,
staining for GFAP may also be present (25% yo 55% including familial variants.
of cases). Atypical CPPs (WHO grade II) are distin-
guished from CPPs (WHO grade I) primarily by the
2.1.6 . GL IAL TUMORS OF UNCERTAIN
presence of elevated mitotic activity (defined as 2 or
ORI GIN
more mitoses per high-power field) and clinically
may show an increased risk of recurrence. Some 2.1.6.1. Angiocentric glioma (WHO grade I).
atypical CPPs also have more complex architecture This is a rare tumor that most often occurs in chil-
and other histological features that may overlap with dren and young adults and presents as a slow-grow-
choroid plexus carcinoma (CPC) but do not exhibit ing mass in the cerebral hemispheres; it is most often
the frankly anaplastic morphology characteristic of associated with a history of treatment-refractory sei-
the latter. zures. On imaging studies, the tumor is mainly local-
ized to the cortex with minimal mass effect and no
2.1.5.2. Choroid plexus carcinoma (WHO contrast enhancement. Histologically it consists of
grade III). CPCs show clear histological features elongated GFAP-positive bipolar glial cells arranged
of malignancy, including frequent mitoses, nuclear either radially or perpendicularly around blood
and cytoplasmic atypia, more solid growth pattern vessels. Tumor cells also infiltrate the surrounding
with at least some loss of papillary architecture, and brain parenchyma, although the angiocentric pat-
often diffuse brain invasion. The diagnosis of CPC tern is clearly the predominant morphologic feature.

A B

FIGURE 2.7 Choroid plexus papilloma. (A) Surgical specimen (gross). (B) Microscopic features (H&E).

Chapter 2 Tumors of the Central Nervous System • 35


Mitoses are absent or very rare, and other histologi- neurofilament protein, synaptophysin). Tumors
cal features of anaplasia are absent. Electron micro- with neuronal elements tend to occur more often
scopic studies suggest a possible ependymal origin in children and young adults and are often located
for the tumor cells. within or adjacent to foci of cortical dysplasia
(defined as cortex having disorganized, nonlami-
2.1.6.2. Astroblastoma. This is a rare glial neo- nar architecture and bizarre cytological features,
plasm of uncertain histogenesis. It is characterized such as binucleation).
histologically by perivascular pseudorosettes com-
posed of GFAP-positive tumor cells with processes 2.1.7.1. Gangliocytoma and ganglioglioma.
radiating to a central blood vessel, which often has Gangliocytomas and gangliogliomas occur most
a thickened hyalinized wall. The tumor cell pro- commonly in the temporal lobe where they are
cesses are usually shorter, thicker, and less vari- often associated with seizures; however, they
able in diameter and lack the fibrillar characteristic can arise in almost all regions of the neuraxis,
of ependymomas. Most astroblastomas occur in including the spinal cord. They most often appear
young adults, but some have also been reported in as circumscribed, homogeneous masses hav-
children and infants. Although both low- and high- ing an even, granular cut surface, although small
grade examples have been described, this tumor cysts or calcifications can be encountered. They
has not been assigned a WHO grade due its vari- may present as a cyst with a mural nodule (simi-
able biological behavior and the lack of adequate lar to pilocytic astrocytoma and pleomorphic
clinical correlative data. Pure astroblastoma should xanthoastrocytoma).
be distinguished from conventional astrocytomas
and glioblastomas that may have focal “astroblas- 2.1.7.1.1. Gangliocytoma (WHO grade I).
toma-like” histology. Gangliocytomas consist entirely of mature, readily
recognized ganglion cells, some of which may be
2.1.6.3. Chordoid glioma of the third ventri- binucleated or bizarre (Fig.  2.8A). A  fine reticu-
cle (WHO grade II). This rare glioma exclusively lin network may be identified around individual
occurs within the rostral third ventricle and hypo- cells, particularly in those occupying a very super-
thalamus. It consists of nests and cords of strongly ficial cortical location. Mitoses and necrosis are
GFAP-positive cells within a mucinous stroma, absent, and, while conspicuous in number, vessels
often containing lymphoplasmacytic infiltrates. do not have multilayered walls. A  variant is seen
The tumor has little or no mitotic activity and a rarely in a sellar or suprasellar location, with con-
very low Ki-67/MIB-1 labeling index. They are current pituitary adenomas in some instances. By
relatively circumscribed, slow-growing tumors but definition a neoplastic glial component should be
are difficult to treat surgically because of their loca- absent.
tion. A putative origin from specialized ependymal
cells has been proposed on the basis of ultrastruc- 2.1.7.1.2. Ganglioglioma (WHO grade I  or III)
tural studies. Gangliogliomas have a neoplastic glial compo-
nent, which is usually astrocytic, although oli-
godendroglial differentiation has been reported
2. 1. 7. NE URONAL A N D
(Fig.  2.8B). In some cases, the neuronal com-
G L I O N E UR ONALT UM O R S
ponent may be overshadowed by the glial com-
These tumors are less common than pure glial ponent and requires immunostaining for neural
tumors and are made up either entirely or partially markers for confirmation. Care must be taken that
by cells having neuronal features. These cells may “entrapped” neurons, for example in a segment of
be evident at the light-microscopic level and may cortex infiltrated by astrocytoma, are not mistak-
range from small “blue” cells reminiscent of neuro- enly identified as neoplastic. The presence of binu-
blasts to differentiated neurons or “ganglion cells” cleated or bizarre forms, as well as disorganized
with vesicular chromatin, prominent nucleoli, and cytoarchitecture, serves to distinguish neoplastic
even cytoplasmic Nissl substance. It is not unusual, from entrapped ganglion cells. Immunostains for
however, for neuronal features to be appreciated CD 34 can be helpful with a positivity in the neu-
only on ultrastructure or after immunostain- ronal component or in the peritumoral area. The
ing for neuronal epitopes (e.g., phosphorylated glial component often shares histological features

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A B

FIGURE 2.8 Neuronal-glial tumors (microscopic appearance). (A) Gangliocytoma (H&E). (B) Ganglioglioma


(H&E). (C) Desmoplastic infantile ganglioglioma (H&E).

in common with pilocytic astrocytoma, includ- 2.1.7.1.3. Dysplastic gangliocytoma of the cerebel-
ing fibrillary or piloid cytoarchitecture, granu- lum (Lhermitte-Duclos disease) This is a distinctive
lar eosinophilic bodies, and Rosenthal fibers. lesion that is characterized by grossly visible expan-
Gangliogliomas may also have prominent lym- sion of the cerebellar folia, usually in only one hemi-
phoid infiltrates and stromal fibrosis. sphere. The centers of the affected folia contain large,
The behavior of gangliogliomas is determined bizarre ganglion cells, with morphologic and focal
by the degree of anaplasia of the glial component, immunohistochemical resemblance to Purkinje cells,
so documentation of necrosis, mitotic activity, and and some small granular neurons, while the surface
vascular proliferation must be made. Most ganglio- is covered by aberrant white matter bundles, a con-
gliomas are WHO grade I and are indolent tumors figuration sometimes referred to as “inverted cerebel-
best treated by excision. Gangliogliomas that show lar cortex.” In the WHO classification, this lesion is
anaplasia of the glial component would be desig- considered a grade I tumor, but biologically it tends
nated as anaplastic ganglioglioma (WHO grade III). to behave more like a hamartoma than a true neo-
A  high percentage of gangliogliomas of all grades plasm. Local recurrences after surgical resection are
have BRAFV600E point mutations, which are not uncommon. About half of all cases of Lhermitte-
thought to be activating the RAS/MAPK signaling Duclos disease are associated with Cowden syndrome
pathway in these tumors and may represent a thera- which is a constellation of multiple verrucous skin
peutic target in these cancers, given the success of lesions, facial trichilemmomas, fibromas of the oral
targeted therapeutics in BRAF mutant melanoma mucosa, and hamartomatous polyps of the gastro-
and other cancers. intestinal tract, as well as thyroid and breast tumors

Chapter 2 Tumors of the Central Nervous System • 37


(both benign and malignant). Cowden syndrome histology, including microvascular proliferation,
arises from mutations in the PTEN gene on chromo- focal necrosis, and elevated mitotic activity. These
some 10q, and it is therefore likely that alterations tumors, referred to as atypical central neurocytomas,
of PTEN function are related to Lhermitte-Duclos have not been assigned a higher WHO grade; how-
pathogenesis. This association is supported by a ever, they may be associated with more aggressive
recent mouse model of disrupted PTEN activity, growth and a greater tendency toward recurrence,
which develops lesions that are histologically similar especially if accompanied by a Ki-67/MIB-1 prolif-
to those seen in Lhermitte-Duclos disease. eration index of greater than 2%.

2.1.7.1.4. Desmoplastic infantile ganglioglioma/ 2.1.7.2.2. Cerebellar liponeurocytoma (WHO grade


astrocytoma (WHO grade I) These are rare tumors II) This is a variant tumor composed of neurocy-
that occur up to the age of 2 years and most often toma-like cells admixed with lipidized neuroepi-
involve the superficial aspect of the frontal and thelial cells (not true adipocytes) that arises in the
parietal lobes, often with an accompanying cyst. cerebellum of adults. “Atypical” histological features
Histologically the tumor may have both astrocytic are usually absent. Although the clinical behavior of
and neuronal components (Fig.  2.8C) or, in some this tumor is generally favorable following surgical
cases, only an astrocytic component. Additional excision, recent reports have documented a rela-
characteristic histological features include the pres- tively high rate of recurrence.
ence of abundant connective tissue (desmoplasia)
and a tendency to adhere to overlying meninges. 2.1.7.3. Other glioneuronal tumors
Both are slow-growing and treatable by surgery. 2.1.7.3.1. Dysembryoplastic neuroepithelial tumor
(WHO grade I) The dysembryoplastic neuroepi-
2.1.7.2. Neurocytic tumors thelial tumor (DNT) is a low-grade tumor con-
2.1.7.2.1. Central Neurocytoma (WHO grade II) taining oligodendroglial-like and neurocytic areas
Central neurocytoma is a low-grade tumor that usu- but with a nodular (or multinodular) architecture
ally arises in the third or lateral cerebral ventricle in and intracortical location. The tumor occurs in
the region of the foramen of Monro, most commonly children, although adult examples have been rec-
in older children and young adults. It is composed ognized. It is often heralded by medically intrac-
of small, well-differentiated neurons with uniform table seizures. A  histological hallmark of DNT is
round nuclei, fine chromatin, and occasional nucle- the “specific glioneuronal element,” which is the
oli, in a loose neuropil-like background (Fig. 2.9A). micro-architectural association of round oligoden-
An artifact of fixation results in perinuclear clearing, droglial- or neurocytic-like cells with axon bundles
which results in a histological appearance similar bounding microcystic spaces in which larger gan-
to oligodendroglioma. These tumors were initially glion cells lie (“floating neurons”) (Fig.  2.9B, C).
thought to be unusual intraventricular oligoden- The cortex adjacent to the tumor nodules is often
drogliomas or ependymomas until their neuronal dysplastic, suggesting a developmental (or ham-
character was established by electron microscopy. artomatous) nature. Calcifications and cysts are
Immunostaining for NeuN (generally weak but frequent accompaniments. Mitoses are usually
diffuse) is the most specific means of their identi- absent or rare. Microvascular proliferation or focal
fication, while strong diffuse staining for synapto- necrosis very rarely occur and does not appear to
physin can also confirm the neuronal nature of the have a negative prognostic effect. Surgical excision
lesion. Tumors having a morphologic appearance is considered curative. The existence of anaplastic
similar to central neurocytoma may occasionally versions has been suggested but is not universally
occur in other regions of the CNS (extraventricu- accepted.
lar neurocytoma). In the latter situation, distinction
from similar-appearing tumors such as oligodendro- 2.1.7.3.2. Papillary glioneuronal tumor (WHO
glioma can be aided by immunohistochemistry for grade I) This is a recently described low-grade glio-
OLIG2, which is rarely expressed in neurocytomas, neuronal tumor that most often arises in the cere-
and IDH-1 or FISH for 1p/19q co-deletions, both bral hemispheres (usually temporal lobe) of young
of which are negative in neurocytoma. Most cen- adults. Grossly they present as contrast-enhancing
tral neurocytomas are low-grade tumors (WHO circumscribed solid or cystic masses. Histologically
grade II); however, some may show more aggressive these tumors are characterized by pseudo-papillary

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A B

FIGURE 2.9 Neuronal-glial tumors (microscopic appearance). (A)Central neurocytoma (H&E).


(B) Dysembryoplastic neuroepithelial tumor (DNT) (H&E). (C) DNT (immunostain for synaptophysin).

structures consisting of a central hyalinized blood 2.1.7.3.4. Paraganglioma Tumors of extra-


vessel surrounded by spindle-shaped to cuboidal adrenal chromaffin tissue, analogous to pheochro-
GFAP-positive glial cells with an intervening syn- mocytomas of the adrenal gland, can arise within
aptophysin-positive neuronal component. Based the cranial vault and spinal canal. Most often these
on their indolent behavior following surgical resec- are circumscribed nodules in the filum terminale,
tion, they are currently regarded as WHO grade although cranial and spinal nerve root masses
I tumors. extending into skull or vertebral foramina have been
noted. Those arising in the middle ear, often extend-
2.1.7.3.3. Rosette-forming glioneuronal tumor of ing into the posterior fossa at the cerebellopontine
the fourth ventricle (WHO grade I) This is a rare angle, are also known as “glomus jugulare” tumors.
low-grade glioneuronal tumor exclusively aris- Regardless of where they are seated within the neur-
ing in the midline posterior fossa region (usually axis, these neoplasms are identical histologically to
fourth ventricle) of adults. Grossly they are cir- paragangliomas elsewhere in the body, being made
cumscribed solid masses that show no or hetero- up of nests or “Zellballen” of plump neuroendo-
geneous contrast enhancement. Histologically crine cells separated by fine fibrovascular septa.
they demonstrate a biphasic neurocytic and glial Tumor cells are chromogranin- and synaptophysin-
architecture, the former characterized by the pres- positive, while interspersed sustentacular cells are
ence of neurocytic rosettes and perivascular pseu- S100positive. Focal ganglion cell differentiation
dorosettes. The glial component closely resembles may occur in some examples. They only rarely pro-
a pilocytic astrocytoma. The tumor is generally duce catecholamines, instead causing symptoms as
considered clinically benign and is treated by sur- a result of local compression. The biological behav-
gical excision. ior of these neoplasms is determined more by their

Chapter 2 Tumors of the Central Nervous System • 39


anatomical extent at the time of presentation than transcription factor, CRX, has been identified as a
by histological features. useful diagnostic immunohistochemical marker for
these tumors. Ultrastructurally, synaptic vesicles and
2.1.7.3.5. Olfactory neuroblastoma The olfac- microtubules confirm neural differentiation; cyto-
tory neuroblastoma (or esthesioneuroblastoma) plasmic annulate lamellae are further reminiscent
is a neuroblastic small “blue” cell tumor localized of retinal differentiation. The molecular genetics of
to the olfactory epithelium in the upper nasal cav- pineal tumors appears to be complex and is not yet
ity. It occurs in late childhood through adulthood, incorporated into clinicopathological management.
with presenting symptoms of sinus obstruction
or headache. Destruction of the cribriform plate 2.1.8.1. Pineocytoma (WHO grade I) The
may allow growth of tumor into the anterior cra- pineocytoma occurs in young to middle-aged adults
nial fossa, meninges, and frontal lobes of the brain. and represents about 45% of all pineal parenchy-
It has a characteristic broad, nodular growth pat- mal tumors. The component cells are uniform, with
tern. The neoplastic cells have a neural immuno- round to oval nuclei and occasional fine nucleoli,
phenotype and ultrastructure. Homer Wright-type and have fibrillary or club-shaped eosinophilic pro-
rosettes (with central neurofibrillary processes) or cesses, which may converge in the center of pineo-
occasionally Flexner-Wintersteiner rosettes (with cyte rosettes. The tumor has a lobular architecture
central lumina) may be seen. Olfactory neuroblas- recalling the normal structure of the pineal gland;
tomas may be either low-grade (Hyams grade I and however, the lobules are separated by delicate fibro-
II) or high-grade (Hyams grade III and IV). The lat- vascular septa (Fig. 2.10A , B). Variable amounts of
ter are characteristic by loss of differentiation, a high neuropil may be present in the background. The
mitotic rate, nuclear pleomorphism, and necrosis tumor is histologically low grade and lacks mitotic
and generally portend more aggressive biological activity or pleomorphism. It is well-circumscribed
behavior. Some high-grade olfactory neuroblasto- and slow-growing but not easily resectable because
mas may express epithelial markers and thus overlap of its central location. Nonetheless, 5-year survivals
with small-cell neuroendocrine carcinoma. of up to 90% may be expected.

2.1.8.2 Pineal parenchymal tumor of inter-


2. 1. 8. P I NE AL PARE N C H Y M A L TU M O R S
mediate differentiation (WHO grade II or III)
Pineal region tumors are rare and represent less than These tumors occur in both children and adults but
1% of all CNS tumors. They are grouped into three are relatively rare. Histologically they are either dif-
major categories:  germ cell tumors (most common), fuse (neurocytoma-like) or slightly lobulated and
pineal parenchymal tumors, and gliomas. Other non- have somewhat more atypical cytology compared
glial tumors (e.g., meningioma) may rarely occur in to pineocytoma, with moderately high cellularity,
this region. This section will only discuss the pineal mild to moderate nuclear pleomorphism, and low
parenchymal tumors, which are derived from pineo- to moderate mitotic activity. They do not have the
cytes (or their precursors). Pineocytes have pheno- overt small-cell malignant phenotype of the pineo-
typic characteristics of both neuroendocrine cells blastoma. Well-validated histological grading cri-
and retinal photoreceptors, with which they share teria for this variant have not yet been established
a common embryonic lineage. Pineal parenchy- although it has provisionally been assigned grade II
mal tumors may be well-differentiated and difficult or III in the WHO classification. Biological behavior
to distinguish on biopsy from normal pineal gland and clinical survival are intermediate between those
(pineocytoma) or they may be poorly differentiated, of the aggressive pineoblastoma and the more indo-
small “blue” cell tumors (pineoblastoma). Tumors lent pineocytoma.
with histological features that fall between these
two extremes are currently designated as pineal 2.1.8.3. Pineoblastoma (WHO grade IV)
parenchymal tumors of intermediate differentiation. The pineoblastoma arises in children and young
All demonstrate neural characteristics on immu- adults as a rapidly growing mass, with heterogene-
nohistochemistry (synaptophysin, neuron-specific ity on neuroimaging reflecting its tendency toward
enolase, neurofilament protein) and may addition- hemorrhage, necrosis, and cystic degeneration.
ally show retinal S-antigen and rhodopsin, as well as Histologically, it is a densely cellular “small blue
melatonin. More recently, the retinal/pineal specific cell” tumor made up of oval, hyperchromatic nuclei

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A B

FIGURE 2.10 Pineal parenchymal tumors. (A) Pineocytoma (H&E). (B) Pineocytoma (immunostain for
synaptophysin). (C) Pineoblastoma with Homer Wright rosettes (H&E).

with little visible cytoplasm, resulting in molding of of its gross similarity to pineocytoma. This tumor
nuclear contours. Some cells may have recognizable presents as a relatively large, well-circumscribed,
eosinophilic processes or form rosettes of Homer and occasionally cystic mass that on MR imaging
Wright or Flexner-Wintersteiner type (Fig. 2.10C). exhibits low T1 signal, increased T2, and contrast
Single-cell invasion of adjacent brain structures, enhancement. Histologically this tumor has epithe-
high mitotic activity, and necrosis are evidence of lial features and papillary architecture with occa-
malignancy. Like other small blue cell tumors of sional ependymal-like differentiation. The tumor
the CNS, pineoblastomas are “seeding” tumors that shows immunoreactivity for cytokeratins and
can invade parenchyma, gain access to the CSF, and focally GFAP; it is negative for neurofilament pro-
spread within the ventricles and subarachnoid space tein but may be weakly positive for synaptophysin
to other sites in the neuraxis. Such malignancies are and chromogranin. Proliferative activity (mitotic
often treated prophylactically with craniospinal irra- index, Ki-67/MIB-1 labeling) has been described
diation and systemic chemotherapy in anticipation as moderate. Necrosis may be present but micro-
of such a route of spread, which carries a very high vascular proliferation is usually absent. Because of
mortality. its immunohistochemical and ultrastructural fea-
tures suggestive of ependymal, secretory, and neu-
2.1.8.4 Papillary tumor of the pineal region roendocrine differentiation, a possible origin from
(WHO II or III) This is a rare neuroepithelial specialized ependymal cells of the subcommissural
tumor that primarily occurs in the pineal region of organ has been proposed. The biological behavior
both children and adults. Although it is not consid- of this tumor is variable and may correspond to
ered a true pineal parenchymal tumor derived from either WHO grades II or III; however, more precise
pineocytes, it is included in this section because histological grading criteria remain to be defined.

Chapter 2 Tumors of the Central Nervous System • 41


2. 1. 9. E MBRY ONAL TU M O R S 3. Anaplastic medulloblastoma, which shows
marked nuclear pleomorphism and molding,
This category comprises neoplasms of immature
cell–cell “wrapping,” and high mitotic activity,
cells resembling the primitive neuroepithelium,
often with atypical forms; these features must be
the origin of the precursor cells of the nervous sys-
the predominant pattern within the tumor.
tem. Tumors made up of these cells may retain the
4. Large cell medulloblastoma, which closely resem-
capability to differentiate along both neural and
bles typical medulloblastoma but has larger
glial lines, as detected by immunohistochemical or
vesicular nuclei containing prominent nucleoli
ultrastructural means. As a group they tend to pres-
and may show unusually intense immunohisto-
ent as large, bulky tumors that grow rapidly and have
chemical staining for synaptophysin. This tumor
a marked tendency to spread (“seed”) along CSF
often overlaps cytologically with the anaplastic
pathways. Metastatic dissemination to extraneural
variant and for this reason has sometimes been
sites such as bone, lymph nodes, and rarely other
termed large cell/anaplastic medulloblastoma.
organs has been described, often as a late complica-
5. Medulloblastoma with myogenic differentiation,
tion following treatment or recurrence.
which includes “strap” cells representing imma-
ture rhabdomyoblasts.
2.1.9.1. Medulloblastoma (WHO grade IV)
6. Medulloblastoma with melanotic differentiation,
Medulloblastoma is the most common and “proto-
which has scattered tubular clusters of pig-
typical” embryonal tumor of the CNS, representing
mented, melanosome-laden tumor cells. The
a significant proportion of primary brain tumors
latter two variants are extremely rare.
in children. A second peak age incidence occurs in
early adulthood. This tumor by definition arises in
the cerebellum, usually the vermis, and may cause All medulloblastomas are considered malignant
ataxia, headache, and vomiting due to acute obstruc- (WHO grade IV) biologically aggressive tumors;
tion of the fourth ventricle with hydrocephalus however, advances in current treatment, including
(Fig. 2.11A). aggressive surgical excision, craniospinal radiation,
Neuroimaging studies reveal an enhancing, lobu- and adjuvant chemotherapy, have resulted in 5-year
lated mass, and as many as one third of patients will survivals in the range of up to 60% to 70%.
have leptomeningeal enhancement representing A great deal of progress has been made in char-
CSF seeding at presentation. Histologically, classic acterization of medulloblastoma at the molecular
medulloblastoma is a densely cellular “small blue- level. Several clinically relevant subclasses of medul-
cell” tumor that may contain Homer Wright rosettes loblastoma have been defined using RNA expres-
with central neurofibrillary processes (only seen in sion and genetic copy number aberrations. The
about 40% of cases)(Fig.  2.11B). Necrosis occurs most common subclass is characterized as having a
both as single cells (apoptosis) as well as in conflu- “classic” histology and frequently exhibits isochro-
ent fields. Mitotic activity is conspicuous. mosome 17q. The association of medulloblastoma
The major histological variants of medulloblas- with Gorlin syndrome (basal cell nevus syndrome,
toma include: from mutation of the PTCH gene on chromosome
9q) and other recent studies has implicated the
1. Desmoplastic/nodular medulloblastoma, which is SHH-PTCH-SMO signaling pathway in desmo-
characterized by broad nodules of tumor cells plastic and non-desmoplastic tumors. A  rarer but
separated by collagenous septa. The periphery clinically more favorable subclass is characterized by
of the nodules is occupied by densely-arranged alterations in the WNT-ß-catenin pathway, includ-
tumor cells, while the centers are neuropil-rich ing tumors arising in association with Turcot syn-
“pale islands.” drome (colon and brain tumors, due to mutation
2. Medulloblastoma with extensive nodularity (“cer- of the APC gene on chromosome 5q or defects in
ebellar neuroblastoma”) (Fig. 2.11C), which mismatch repair genes) and those with chromo-
differs from the desmoplastic subtype by less some 6 monosomy. Tumors not associated with
conspicuous collagenous stroma and greater these classes generally are more heterogeneous and
evidence of neural differentiation in the form of include those with large cell/anaplastic histology
neurocytoma-like areas and rarely mature gan- and are considered to have a less favorable progno-
glion cells (following radio/chemotherapy). sis, with frequent amplification of MYC/NMYC.

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A B

FIGURE 2.11 Medulloblastoma. (A) Medulloblastoma of cerebellar vermis with ependymal and leptomen-
ingeal spread (H&E whole mount). Microscopic features: (B) Homer Wright rosettes (H&E). (C) Nodular
architecture (H&E).

2.1.9.2. CNS primitive neuroectodermal glial, neuronal, sometimes mesenchymal) by ultra-


tumors (PNETs) (WHO grade IV) These con- structural or immunohistochemical methods.
stitute a heterogeneous group of tumors that arise CNS PNETs exhibiting only neuroblastic differ-
mainly in children and adolescents and can occur entiation have been termed cerebral neuroblastoma,
almost anywhere along the neuraxis. They are bio- or cerebral ganglioneuroblastoma if more mature
logically aggressive tumors. Histologically they neurons (ganglion cells) and neuroblastic cells are
share in common a population of relatively undif- both present. Molecular studies have shown that
ferentiated neuroepithelial cells (“small blue cell” supratentorial PNETs are genetically distinct from
component) variably admixed with more differen- medulloblastomas.
tiated neuroepithelial cells of neuronal and/or glial
phenotype. The specific subtypes of CNS PNET are 2.1.9.2.2. Medulloepithelioma The medulloepi-
described below. thelioma is a very rare tumor that arises in infants
and young children and has a distinctive papillary,
2.1.9.2.1. CNS/supratentorial PNET This trabecular, or tubular growth pattern of primitive,
tumor histologically resembles medulloblastoma small “blue” cells recapitulating the appearance
and primarily occurs in the cerebral hemispheres of the embryonic neural tube. They may be found
(supratentorial PNET). Other sites of occur- throughout the CNS but most often occur in the
rence in the CNS, including the suprasellar region, cerebral hemispheres in a periventricular location.
brainstem, and spinal cord, have been described. On neuroimaging, the tumor has a heterogeneous
Histologically these tumors consist largely of small, appearance corresponding to areas of necrosis, hem-
poorly differentiated neuroepithelial cells but can orrhage, cysts, and calcification. In addition to the
demonstrate multiple lines of differentiation (e.g., primitive neural tube-like histology, multiple lines

Chapter 2 Tumors of the Central Nervous System • 43


of differentiation, which may include neuronal, glial, of one copy of chromosome 22 and mutation in
and sometimes mesenchymal elements, may be INI1/SNF5 (a putative tumor suppressor gene)
found in the tumor. It is mitotically active and clini- on the remaining copy of 22q. The diagnosis of
cally aggressive. AT/RT and its distinction from other histologi-
cally similar tumors has been facilitated by immu-
2.1.9.2.3. Ependymoblastoma This rare, highly nohistochemical staining for the INI1protein,
aggressive CNS embryonal tumor occurs primarily which is normally expressed within the nucleus of
in the cerebral hemispheres of infants and young chil- normal cells and other CNS tumors but is absent
dren and is histologically characterized by the pres- in AT/RTs. Molecular testing (e.g., FISH) may be
ence of distinctive ependymoblastic rosettes. These helpful in the evaluation of AT/RTs with equivo-
are multilayered rosettes with true lumina bounded cal INI1 immunohistochemistry or in establishing
by ciliated neuroepithelial cells, which are distinct the presence of a germline mutation.
from the single-layered ependymal tubules present
in ependymomas. Ultrastructurally the tumor cells
lining the rosettes may contain basal bodies (bleph- 2.2. Peripheral Nerve Sheath Tumors
aroplasts) and “abortive” cilia. Ependymoblastic These are defined as tumors that clearly arise from
rosettes may be widely scattered or form back-to- an identifiable peripheral nerve or whose compo-
back arrangements amid a population of small, nent cells show evidence (by immunohistochemis-
undifferentiated cells or more differentiated cells try and/or electromicroscopy) of nerve sheath cell
with glial and/or neuronal characteristics within an differentiation (i.e., Schwann or perineurial cells).
abundant neuropil. The existence of ependymoblas- Only the four major categories of nerve sheath
toma as a distinct pathological entity has recently tumor will be considered here:  schwannoma, neu-
been challenged, largely due to uncertainty regard- rofibroma, perineurioma, and malignant peripheral
ing the precise histological criteria required for diag- nerve sheath tumor.
nosis since ependymoblastic rosettes can also occur
in other well-characterized embryonal tumors such
2 .2 . 1. SCHWAN N OM A (W HO GRADE I)
medulloblastoma, supratentorial PNETs, and atypi-
cal teratoid/rhabdoid tumor. Although ependymo- Schwannomas are benign encapsulated tumors
blastoma may appear histologically similar to some that are composed entirely of Schwann cells. They
examples of anaplastic ependymoma (see above), it may occur at all ages, with a peak of incidence in
lacks the perivascular pseudorosettes that character- the fourth to sixth decades, and are rare in the
ize the latter. pediatric age group. As they originate wherever
Schwann cells are present, they may be found
2.1.9.3. Atypical teratoid/rhabdoid tumor on cranial nerves, spinal nerve roots, peripheral
(WHO grade IV) Atypical teratoid/rhabdoid nerve trunks, and even at nerve endings, leading
tumor (AT/RT) is a highly malignant embryonal to cutaneous, subcutaneous or, less often, visceral
tumor that primarily occurs in infants within the tumors. Intracranial schwannomas most often
supra- and infratentorial compartments. It is histo- involve the vestibular branch of the eighth cra-
logically characterized by the presence of distinc- nial nerve, where they are referred to as vestibular
tive rhabdoid cells, which have an eccentric nucleus schwannomas (Fig.  2.12A). Most are situated in
with a prominent nucleolus and “inclusion-like” the cerebellopontine angle and, when reaching a
pink cytoplasm. These cells often exhibit positive critical size, can cause clinical symptoms due to
immunostaining for vimentin, epithelial mem- changes on neighboring structures, which include
brane antigen, and sometimes desmin or cytoker- enlargement and erosion of the internal auditory
atin. The rhabdoid cell component is frequently meatus, stretching of neighboring cranial nerves,
admixed with undifferentiated small “blue” cells and cerebellar and brainstem compression.
resembling medulloblastoma or PNET; the lat- Schwannomas of the fifth, ninth, and tenth cra-
ter may be the predominant histological pattern, nial nerves are much less common. Motor cranial
which can lead to diagnostic confusion. Some AT/ nerves are involved only rarely. Spinal schwanno-
RTs may express widely divergent differentiation mas are situated most frequently on dorsal sensory
along neuronal, glial, and mesenchymal lines. AT/ nerve roots, but some have also been described
RTs are nearly always associated with allelic loss on the ventral motor nerve roots. The thoracic

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A

C D

FIGURE 2.12 Schwannoma. (A) Vestibular schwannoma (gross). Microscopic features: (B) Antoni A tissue
with nuclear palisading (Verocay bodies) (H&E). (C) Antoni B tissue (H&E). (D) Pleomorphic nuclei (H&E).

segments are most often implicated, but cervical erosion is sometimes evident on imaging studies.
and lumbar schwannomas are not rare. They may As a general rule schwannomas are solitary tumors;
also be situated in the cauda equina. The tumor is however, in neurofibromatosis (NF) type 2, mul-
usually restricted to the subdural space but may tiple schwannomas, especially bilateral vestibu-
sometimes extend through the intervertebral lar schwannomas (which are pathognomonic for
foramen, resulting in an hourglass appearance. NF2), may be found. Multiple schwannomas in the
Intraparenchymatous (intracerebral or intraspi- absence of other features of NF2 are seen in schwan-
nal) or intraosseous schwannomas have been nomatosis. The clinical evolution of schwannomas
exceptionally reported. is slow, and they remain histologically benign but
Macroscopically schwannomas are firm, well- may recur. More than half of schwannomas have a
circumscribed, encapsulated tumors of variable size. deletion of the long arm of chromosome 22 and a
Small tumors are spherical and white or slightly mutation or a deletion of NF2 gene on the remain-
translucent and have an elastic consistency. Larger ing allele. Total inactivation of NF2 gene, with sub-
examples are irregularly lobulated and may be cys- sequent loss of merlin (schwannomin) expression
tic. On section, some may show hemorrhages and demonstrated by immunocytochemistry or Western
yellowish foci. These tumors displace rather than blotting, seems to be a crucial step in the tumorigen-
invade the nerves from which they originate. Bone esis of schwannomas.

Chapter 2 Tumors of the Central Nervous System • 45


Microscopically, schwannomas consist of two cases. However, cellular schwannomas always have a
characteristic tissue types, which are often inter- benign course and show a high degree of schwann-
mingled within the same tumor:  (1)dense fibril- ian differentiation by electron microscopy and
lary (Antoni A) tissue, which consists of elongated immunohistochemistry.
bipolar cells having scant cytoplasm and cylindrical
nuclei arranged in elongated drifts, whorls, or char- 2.2.1.3. Melanotic Schwannomas These
acteristic palisades (Verocay bodies) (Fig.2.12B), relatively rare, grossly pigmented tumors consist
and (2)  loose reticulated (Antoni B) tissue, which is of Schwann cells with melanosomes and exhibit
less densely cellular and consists of small round immunoreactivity for melanocytic markers such as
nuclei randomly arranged in a matrix containing HMB-45 and MART-1. They are divided into non-
microcysts and vacuolated cells, imparting a finely psammomatous and psammomatous forms, the for-
honeycombed appearance (Fig.  2.12C). Reticulin mer having a predilection for posterior spinal nerves
fibers are present in both tissue types. Antoni B and ganglia and the latter frequently involving
tissue usually predominates in intracranial schwan- autonomic ganglia and viscera as part of the Carney
nomas. Although a moderate degree of nuclear pleo- complex (a multi-endocrine autosomal dominant
morphism may be seen (Fig. 2.12D), mitotic figures disorder). Melanotic schwannomas generally have
are absent. Many examples show hyaline thickening a benign course, although about 10% to 25% may
of vessel walls and sometimes thrombosis and evi- have more aggressive or frankly malignant behavior,
dence of prior hemorrhage. Unlike neurofibromas, including metastases.
nerve fibers are usually not present within a schwan-
noma but are displaced and incorporated within
2 .2 . 2. N EUROFIBROM A (W HO GRADE I)
the surrounding fibrous capsule. Ultrastructurally
schwannomas are composed solely of Schwann cells Neurofibromas constitute a spectrum of benign nerve
ensheathed by a continuous basal lamina in associa- sheath tumors that include (1)  localized or diffuse
tion with a variable proliferation of collagen fibers. cutaneous lesions; (2)  solitary or plexiform intra-
Virtually all schwannomas show strong immunore- neural lesions, and (3)  massive soft tissue tumors.
activity for S100 protein; some examples may also Multiple and plexiform neurofibromas (involving
show variable GFAP expression. multiple nerve fascicles) are a hallmark of NF1. All
ages and both sexes may be affected. Histologically
2.2.1.1. Plexiform Schwannomas These neurofibromas contain a variable mixture of Schwann
are most often dermal or subcutaneous in loca- cells, perineurial-like cells, fibroblasts, and cells with
tion and occur on the trunk or upper extremities. intermediate features. They often have a more cellular
Histologically they consist of multiple nodules of central zone that contains fibroblasts and Schwann
varying sizes embedded in fibrous connective tis- cells, as well as dense collagen bundles and myelin-
sue. Occasional examples may be locally aggressive ated/unmyelinated nerve fibers (Fig. 2.13) and usu-
and recur but are not considered overtly malignant. ally a less-dense peripheral zone devoid of nerve
Plexiform schwannomas may be associated with fibers. The Schwann cells and fibroblasts are embed-
NF2; they must be distinguished from plexiform ded in a clear, often myxoid-appearing matrix. Some
neurofibromas, which are almost always associated neurofibromas may contain numerous atypical nuclei
with NF1. (atypical neurofibromas) or show increased cellularity
(cellular neurofibromas), but mitoses are typically rare
2.2.1.2. Cellular Schwannomas These are or absent. Large diffuse neurofibromas may contain
composed exclusively or predominantly of an tactile-like structures (“pseudo-Meissnerian” cor-
Antoni A  pattern of spindle-shaped Schwann cells puscles) and occasionally melanotic cells. Malignant
without Verocay bodies. The tumor is characteristi- change in a neurofibroma may occur, with produc-
cally located near the vertebral column in the medi- tion of a malignant peripheral nerve sheath tumor (see
astinum or retroperitoneum. Occasionally, bone below). Such an evolution is frequently associated
destruction and neurological symptoms develop. with NF1 and affects particularly plexiform neurofi-
Their clinical appearance, together with the high bromas and neurofibromas of major nerves.
cellularity, fascicular pattern, moderate nuclear Although there has been some controversy
pleomorphism, and mitotic activity, has led to the about the clonal nature of neurofibromas, they are
erroneous diagnosis of a soft tissue sarcoma in some most likely derived from Schwann cells since allelic

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are not specifically related to NF1 or NF2, altera-
tions of the long arm of chromosome 22 have been
documented in these tumors and probably involve
the NF2 gene. Some authors believe that intraneural
perineuriomas may represent a relatively organized
hyperplastic process that selectively involves peri-
neurial cells, perhaps as a reaction to minor trauma
to the perineurial sheath. A closely related, but histo-
logically distinct, tumor also composed of perineu-
rial cells is the soft tissue perineurioma, which is very
rarely associated with a nerve.

FIGURE 2.13 Microscopic appearance of neurofi- 2.2.4 . MAL IGNANT PERIPHERAL NERVE


broma (H&E). SHE ATH TUMOR (MPNST) (WHO GRADES
II, III OR IV)
loss can be demonstrated at the NF1 locus in the MPNST is defined as a malignant tumor that either
Schwann cells of neurofibromas. The genetic basis arises from or within a peripheral nerve or occurs
of neurofibroma formation is unclear, but the NF1 in soft tissues unassociated with a nerve but shows
gene on the long arm of chromosome 17 is clearly histological evidence of nerve sheath differentiation.
involved in the early stages of tumorigenesis. Studies Several terms (e.g., malignant schwannoma, neuro-
in mouse models of the disease have interestingly genic sarcoma, and neurofibrosarcoma), which are
suggested that the genetic aberrations in stromal more or less synonymous with MPNST, are mislead-
cells may also modify or contribute to disease ing and should be avoided. Tumors derived from
progression. epineurial elements or blood vessels are excluded.
MPNSTs primarily occur in adults and represent
about 5% of soft tissue sarcomas. They can occur de
2.2.3. INTRANEURAL PERINEURIOMA
novo, although most arise from a preexisting tumor,
( WHO GRADE I)
usually a neurofibroma. MPNSTs are very closely
This rare neoplasm most often presents in adoles- associated with NF1: 25% to 65% occur during the
cence or early adulthood and shows no sex predi- course of NF1, and approximately 4% of patients
lection. It mainly affects peripheral nerves of the with NF1 will develop a MPNST. The most com-
extremities and presents as a localized segmental or mon locations are along the main nerve trunks of
tubular enlargement of the nerve. Multiple fascicles limbs (sciatic nerve, brachial plexus, sacral plexus),
may be involved, although the lesion does not have on the trunk, and in the head and neck. MPNSTs of
a “plexiform” growth pattern. Microscopically, the cranial nerves are rare. Most MPNSTs have a poor
tumor is characterized by proliferations of perineu- prognosis, with a 10-year survival rate of about 23%.
rial cells in the form of concentric layers (“pseudo- Histologically MPNSTs are highly cellular malig-
onion bulbs”) around nerve fibers within the nant spindle cell tumors that exhibit nuclear atypia,
endoneurium. Although the histology of intraneural numerous mitoses, and frequent geographical necro-
perineurioma may closely resemble the onion-bulb sis. Invasion through the perineurium and epineu-
formations seen in the various forms of hypertrophic rium into adjacent soft tissues may occur. MPNSTs
neuropathy (e.g., Charcot-Marie-Tooth disease), can be further subdivided into low-grade (WHO
the tumor lacks the multiplicity of nerve involve- grade II) and high-grade (WHO grade III or IV)
ment or genetic background of those conditions. tumors, which are distinguished from the former by
Electron microscopy and immunohistochemistry high mitotic activity and necrosis. The majority of
of the cells forming the pseudo-onion bulbs support MPNSTs have a high Ki-67/MIB-1 labeling index.
their perineurial nature:  they are immunopositive Various forms of divergent differentiation may be
for EMA and negative for S100 protein. They are observed in some MPNSTs, which may include
benign tumors with no tendency toward recurrence elements of osteosarcoma, chondrosarcoma, lipo-
or metastasis. Although intraneural perineuriomas sarcoma, angiosarcoma, or rhabdomyosarcoma

Chapter 2 Tumors of the Central Nervous System • 47


(malignant Triton tumor). Epithelial components (tentorium, foramen magnum) and intraventricu-
(epithelioid, epidermoid, or glandular), mela- lar meningiomas are considerably less common
nocytes (melanotic malignant schwannoma), or (approximately 10%); spinal meningiomas are most
perineurial cells may also be encountered in some frequently situated in the thoracic segments and are
MPNSTs. Immunohistochemistry can be an invalu- usually located in the lateral compartment of the
able aid in the diagnosis of MPNSTs and in particu- subdural space.
lar distinguishing them from other different spindle Macroscopically the typical meningioma is a
cell tumors with a similar histological appearance. spherical or lobulated, well-circumscribed tumor
However, in keeping with the overall poor differen- that is firmly attached to the inner surface of the dura
tiation of MPNSTs, only 50% to 70% will show S100 (Fig.  2.14A, B) and displaces the underlying brain
protein immunoreactivity for schwannian differen- parenchyma without invading it. Meningiomas en
tiation. For the same reasons, electron microscopy plaque spread along the deeper surface of the dura
has generally limited diagnostic utility. and tend to invade the overlying bone, which often
Sporadic and NF1-associated MPNSTs have results in hyperostosis. Meningiomas are usually
complex numerical and/or structural karyotypic single, but multiple tumors may occur either as spo-
abnormalities. More common ones include trip- radic cases or in patients with NF2.
loidy, loss of the NF1 locus (17q11), and loss of The light-microscopic appearance of meningio-
the band containing the tumor suppressor gene mas can be variable and sometimes quite challeng-
TP53 (17p13). The genetic evolution of MPNSTs ing. However, with the possible exception of some
appears to be a multistep process initiated by poorly differentiated anaplastic tumors, virtually
mutations in one or both copies of the NF1 gene, all meningiomas will demonstrate morphologic
leading to subsequent loss or mutation of the features consistent with their arachnoid origin,
TP53 tumor suppressor gene. MPNSTs also show either ultrastructurally (e.g., abundant intermedi-
alterations in other genes involved in cell cycle ate filaments, complex interdigitating cell processes,
regulation. desmosomes) or by immunohistochemistry (e.g.,
reactivity for epithelial membrane antigen). The
current WHO classification groups meningiomas
2.3. Tumors of the Meninges into three histological grades which are described
in further detail below. The WHO grade, which is
2. 3. 1. T UMORS OF M ENI N G O TH EL I A L
currently based primarily on histological appear-
C EL LS:   ME NI NGI OM A S
ance, correlates relatively well with the overall bio-
Meningiomas are tumors originating from arachnoi- logical and clinical behavior of a given tumor; this
dal cells and attached to the inner surface of the dura can often be enhanced by additional data provided
mater. They are very commonly encountered neo- by the Ki-67/MIB-1 proliferative index. Grade
plasms, accounting for 13% to 25% of primary intra- I meningiomas are considered clinically benign and
cranial tumors and approximately 25% of intraspinal have a low risk of recurrence or aggressive growth,
tumors. Most meningiomas occur in adults between whereas grade II and III tumors are associated with
the ages of 20 and 60, with a peak incidence around a greater probability of recurrence and/or aggressive
45. They are predominantly found in females (male behavior.
to female ratio between 2:3 and 1:2), except for
atypical and anaplastic meningiomas, whose inci- 2.3.1.1. WHO grade I  meningiomas WHO
dence is higher in males. Many small meningiomas grade I  meningiomas are benign tumors that
are incidental findings due to the wide clinical use of (1) have a mitotic index of less than 4 mitoses per
CT and MRI imaging. 10 high-power (40×) fields, (2)  have fewer than
Meningiomas arise wherever arachnoidal cells three (or none) of the “atypical” histological features
are present but have a predilection for the follow- associated with grade II or III tumors (see below),
ing sites: convexity meningiomas (parasagittal, falx, (3) do not belong to one of the defined grade II or
lateral convexity) are the most frequent (approxi- III subtypes, and (4) do not show evidence of true
mately 50%); basal meningiomas (olfactory groove, brain invasion. They have a low Ki-67/MIB-1 prolif-
intraorbital, lesser wing of the sphenoid, pterion, eration index (usually less than 4% to 5%). The fol-
parasellar or suprasellar) are next in frequency lowing well-recognized meningioma subtypes are
(approximately 40%); posterior fossa meningiomas almost always classified as WHO grade I.

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A B

FIGURE 2.14 Meningioma. (A) Convexity meningioma (gross). (B) Meningioma of skull base (gross).
Microscopic features: (C) Cellular whorls (H&E). (D) Whorls and psammoma body (H&E).

2.3.1.1.1. Meningothelial meningioma This is 2.3.1.1.2. Fibrous (fibroblastic) meningioma This


composed of polygonal epithelial-like cells, with is composed of elongated fusiform cells, arranged in
ill-defined cell borders, pale cytoplasm, and a rela- wavy interlacing fascicles. A well-developed network
tively voluminous spherical nucleus containing a of collagen and reticulin fibers is found between the
conspicuous nucleolus and occasionally showing individual cells. Whorls and occasionally psam-
a pseudo-inclusion in the shape of a clear, well- moma bodies may be present.
defined intranuclear vacuole. The distribution
of the cells is fairly uniform, being diffuse and 2.3.1.1.3. Transitional (mixed) meningioma This
arranged in elongated sheets or in islands sepa- is a frequent subtype with intermediate features
rated by scant vascular connective tissue trabecu- between those of meningothelial and fibroblastic
lae. In some cases the tumor cell borders may be meningioma. Whorls and sometimes psammoma
difficult to visualize, imparting a “syncytial” pat- bodies are often numerous.
tern to the tumor. A characteristic and diagnostic
pattern, which is almost always present to a greater 2.3.1.1.4. Psammomatous meningiomaThis vari-
or lesser extent, is the formation of cellular whorls ant has exceptionally numerous psammoma bodies,
(Fig.  2.14C) in which the tumor cells are closely which may become confluent. They are most com-
wrapped around one another. The whorls show a monly encountered in the spinal region.
hyalinized and calcified center and are then termed
psammoma bodies(Fig.  2.14D). However, the fre- 2.3.1.1.5. Angiomatous meningioma This shows
quency of psammoma bodies in a given tumor is a very rich degree of vascularization. The vessels,
variable, and some meningothelial meningiomas most often of small diameter, have frequently
may have very few. hyalinized walls. The histological features of this

Chapter 2 Tumors of the Central Nervous System • 49


variant often overlap with those of microcystic (4) uninterrupted patternless or sheet-like growth,
meningioma. and (5) foci of spontaneous or “geographic” necro-
sis. Necrosis (infarction) that clearly results from
2.3.1.1.6. Microcystic meningioma This vari- therapeutic embolization must be excluded. The
ant has tumor cells with elongated processes that presence of “cytologic atypia” (enlarged or bizarre-
circumscribe multiple small “cystic” spaces with a appearing hyperchromatic nuclei) is neither a
variable mucinous content. Pleomorphic cells and required nor a defining histological feature used to
nuclei may be prominent, as well as many vessels classify a tumor as an atypical meningioma. These
with thickened hyalinized walls. nuclei are usually considered a form of degenerative
change and may be seen in otherwise typical WHO
2.3.1.1.7. Secretory meningioma This variant is grade I  tumors. The Ki-67/MIB-1 labeling indices
characterized by the presence of small eosinophilic of WHO grade II meningiomas are moderately high
PAS-positive globular inclusions within cells that (usually less than 10%) but can be variable, with
are immunoreactive for carcinoembryonic antigen some cases overlapping with grade I  tumors and
and cytokeratin (in addition to EMA). These inclu- others approaching the range of anaplastic menin-
sions should not be confused with calcified psam- gioma. The additional presence of true brain inva-
moma bodies. sion may be prognostically significant but by itself is
not sufficient to reclassify an atypical meningioma
2.3.1.1.8. Lymphoplasmacyte-rich meningioma as anaplastic (grade III).
This demonstrates a conspicuous plasma cell-lym-
phocytic component and should be distinguished 2.3.1.2.2. Chordoid meningioma In this rare
from other intracranial masses that are rich in lym- variant, some regions of the tumor histologically
phocytes and/or plasma cells and resemble menin- resemble chordoma with trabeculae of vacuolated
giomas on imaging studies or at surgery. cells in a myxoid matrix. Inflammatory cell infil-
trates may be conspicuous. They frequently show a
2.3.1.1.9. Metaplastic meningiomas This variant high rate of recurrence following subtotal surgical
include tumors that show (1)  xanthomatous change resection.
with the presence of lipid-filled cells, (2)  myxoma-
tous change characterized by an abundant homo- 2.3.1.2.3. Clear cell meningioma This rare vari-
geneous stroma separating the individual cells, ant is characterized by a patternless proliferation of
(3) cartilage or bone within the tumor, and (4) mela- polygonal cells with clear PAS-positive glycogen-
nin pigment within the connective tissue trabeculae rich cytoplasm. They generally lack other histo-
(pigmented meningiomas). logical features typical of meningioma. They have
a predilection for the spinal cord and posterior
2.3.1.2. WHO grade II meningiomas A menin- fossa and tend to occur more often in children and
gioma is classified as WHO grade II if it belongs to young adults. They can be biologically aggressive,
one of these three categories: (1) atypical menin- with frequent recurrence and occasional seeding of
gioma based on the specific histological criteria the CSF.
outlined below, (2)  chordoid or clear cell subtype,
or (3)  a meningioma whose histological appear- 2.3.1.3. WHO grade III meningiomas A
ance resembles a benign (WHO grade I) tumor but meningioma is classified as WHO grade III if it
shows true brain invasion. The latter are classified as belongs to one of these two categories:  (1)  ana-
WHO grade II due to their more aggressive clinical plastic meningioma based on the histological cri-
behavior. teria outlined below or (2)  papillary or rhabdoid
subtype.
2.3.1.2.1. Atypical meningioma This is defined as
a tumor that has increased mitotic activity (4 or more 2.3.1.3.1. Anaplastic meningioma This is defined
mitoses per 10 high-power fields) and/or the presence as a meningioma having either histological features
of three or more of the following histological features: that are clearly malignant (i.e., resembles a carci-
(1) increased cellularity, (2) small cells with a high noma, sarcoma, or melanoma) and/or has 20 or
nuclear–cytoplasmic ratio, (3) prominent nucleoli, more mitoses per 10 high-power fields. The histological

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distinction between atypical and anaplastic menin- commonly in females and can express progesterone
gioma is usually fairly clear-cut, but there are bor- (common) and estrogen (infrequent) receptors, the
derline cases that remain difficult to classify. Tumors functional significance of these hormone receptors
that show diffusely anaplastic histology can be diag- is uncertain. There is a clear connection between the
nostically challenging and may require documenta- occurrence of meningiomas (especially multiple)
tion of evolution from a lower-grade meningioma at and NF2; however, other families with an increased
the same site or convincing immunohistochemical susceptibility to meningiomas but without NF2
and/or ultrastructural evidence of meningothelial have been described, indicating the likely presence
differentiation (which may itself be challenging due of other genetic predisposition loci.
to poor differentiation of the tumor). Anaplastic The cytogenetic alterations found in meningio-
meningiomas typically have Ki-67/MIB-1 labeling mas most commonly consist of loss of chromosome
indices greater than 15% to 20%. They are clinically 22q and mutations of the NF2 gene. As meningio-
and biologically aggressive tumors, with a median mas increase in histological grade, additional genetic
survival of about 2  years. Invasion of the brain events often occur, including loss of the short arm of
parenchyma, although frequent in anaplastic menin- chromosome 1 and the long arms of chromosomes
giomas, is not by itself sufficient for the diagnosis 10 and 14 and 9p21 deletions.
of anaplastic meningioma since brain invasion may
also be observed in atypical or even histologically
2.3.2 . NONMENINGOTHEL IAL TUMORS
benign meningiomas. Rare anaplastic meningiomas
may metastasize within the CNS along CSF path- 2.3.2.1 Meningeal Hemangiopericytoma
ways or systemically. (WHO grade II or III) Meningeal hemangio-
pericytomas (HPC) are much less frequent than
2.3.1.3.2. Papillary meningioma This rare sub- meningiomas. Despite its name, the histogenesis of
type is characterized by the presence of a perivas- hemangiopericytoma is uncertain:  convincing evi-
cular papillary or pseudo-papillary pattern. These dence of a pericytic origin has been lacking, and many
tumors are highly aggressive and are often invasive, surgical pathologists regard HPCs as a fibroblastic
recurrent, and even metastatic. tumor that is part of the spectrum of solitary fibrous
tumor (see below). Macroscopically HPCs are solid,
2.3.1.3.3. Rhabdoid meningioma This uncom- rather firm tumors, attached to the dura mater, and
mon and clinically aggressive tumor contains disco- well-delineated from the adjacent CNS parenchyma
hesive aggregates or sheets of cells resembling classic (i.e., resembling a meningioma). Microscopically
rhabdoid cells, which are characterized by plump they consist of a highly cellular, homogeneous pro-
eccentric nuclei with prominent nucleoli and pink liferation of elongated cells individually embedded
inclusion-like cytoplasm. Although these tumor in a dense network of reticulin fibers. They are highly
cells resemble those found in rhabdoid tumors in vascular and often display prominent slit-like, branch-
other sites, they show normal nuclear immunoreac- ing channels (“staghorn sinusoids”). The distinction
tivity for INI1 protein. Other histological features of between WHO grade II and III HPC is based mainly
anaplasia are also usually present. The diagnosis of on the degree of cellular anaplasia and mitotic activ-
rhabdoid meningioma should be restricted to cases ity. Grade III tumors should have 5 or more mitoses
where greater than 50% of the tumor has rhabdoid per 10 high-power fields and/or necrosis and at least
architecture. Tumors having both rhabdoid and two of these features: hemorrhage, moderate to high
papillary architecture may occur. nuclear atypia, and cellularity. The tumor cells are
The etiology of most meningiomas remains consistently immunoreactive for vimentin and more
unknown. However, there is a well-established variably for CD34 (in contrast to diffuse staining in
association between the occurrence of a menin- solitary fibrous tumor) and are negative for EMA and
gioma and prior radiation therapy, which usu- S100 protein. The Ki-67/MIB-1 labeling indices may
ally precedes tumor presentation by many years. range from 5% to 10%, the latter approaching the level
Radiation-induced meningiomas are more com- of anaplastic meningiomas. Meningeal HPCs are con-
monly multiple, often have atypical or anaplastic sidered to be tumors of variable malignant potential,
histology, and occur at younger ages. A possible role similar to their soft-tissue counterparts, and have the
of sex hormones in the causation of meningiomas same tendency to recur and metastasize. Brain inva-
is less certain. Although meningiomas occur more sion may also occur.

Chapter 2 Tumors of the Central Nervous System • 51


Solitary fibrous tumor is a rare benign tumor Angiolipomas are rare benign mesenchymal
that involves the cranial or spinal meninges or lat- tumors composed of mature adipose tissue and
eral ventricles of adults and mimics a meningioma. blood vessels that are either normal or may mimic a
Elongated fibroblasts, disposed in fascicles between capillary angioma, cavernous angioma, or arteriove-
conspicuous bands of collagen fibers, display strong nous malformation. It may be difficult to distinguish
and uniform immunoreactivity for both vimentin them from hemangiomas, which are often accompa-
and CD34 but not EMA. As noted above, solitary nied by adipose tissue. They are usually found in the
fibrous tumors may have a histological pattern that epidural space at the thoracic level. Invasion of sur-
is very difficult to distinguish from HPC, and many rounding tissues and especially vertebral bodies has
pathologists now consider solitary fibrous tumor been noticed in rare cases so that total removal is not
and HPC to be part of the same morphologic and always possible. The exceptional angiomyolipomas
histogenetic spectrum. contain a more or less conspicuous smooth muscle
component intermingled with blood vascular chan-
2.3.2.2. Other mesenchymal non-menin- nels and mature adipose tissue. Spinal angiolipomas
gothelial tumors Various benign and malignant and angiomyolipomas are to be distinguished from
tumors of mesenchymal origin may arise within spinal epidural lipomatosis associated with Cushing
the CNS; their histological appearance is essen- syndrome or induced by long-term corticosteroid
tially identical to their extra-CNS counterparts therapy.
arising from soft tissue and bone. They are rela-
tively rare, accounting (in aggregate) for less than 2.3.2.2.2. Fibrous tumors Solitary fibrous tumor
0.5% of all intracranial tumors, and may occur at is described above (see Meningeal Hemangio-
any age. Many of these tumors are localized to pericytoma).
the skull,  vertebral column, or meninges but can Fibromatosis is an infiltrative but benign lesion
also occur within the brain or spinal cord itself composed of elongated fibroblasts within a dense
(e.g., lipomas). Their etiology is largely unknown, collagenous stroma. Their occurrence within the
although some malignant examples (sarcomas) CNS is extremely rare. From a histological stand-
have been related to prior cranial radiation, and point, this process must be distinguished from sim-
more recently Epstein-Barr virus (EBV) has been ilar-appearing but likewise uncommon entities such
implicated in the pathogenesis of cranial and spinal as childhood cranial fasciitis, cranial infantile myo-
smooth muscle tumors in immunocompromised fibromatosis, myofibroblastoma, and hypertrophic
patients. intracranial pachymeningitis.
Intracranial fibrosarcomas are very rare neo-
2.3.2.2.1. Tumors of adipose tissue Lipomas are plasms that account for less than 1% of all intra-
rare benign growths. In the cranial cavity, they cranial tumors. They are derived from fibroblasts,
favor midline sites:  corpus callosum (often asso- which may be situated in the dura, leptomeninges,
ciated with partial or complete agenesis of that perivascular spaces, tela choroidea, or stroma of the
structure), quadrigeminal plate, and cerebellopon- choroid plexus. Fibrosarcomas are most frequently
tine angle. Most intraspinal lipomas are discov- attached to the meninges but may sometimes be
ered in childhood and are congenital lumbosacral entirely parenchymatous. Macroscopically they are
lipomas associated with spinal dysraphism (spina well circumscribed but nonencapsulated, they are
bifida occulta) or “tethered cord” (abnormally low- firm in consistency, and they have fairly homoge-
lying conus tethered by the lipomatous mass). In neous gray cut surfaces. In some cases, the tumor
adults intraspinal intradural lipomas are isolated is not a well-defined mass but consists of a diffuse
tumors, composed of normal-appearing adipose infiltration of the meninges (meningeal sarcoma-
tissue and most frequently located at the thoracic tosis). Their microscopic appearance is identical
level; they represent less than 1% of all spinal cord with that of fibrosarcomas arising elsewhere in the
tumors. Rare complex lipomas containing bundles body and presents the same range of cellular dif-
of nerve fibers associated with muscle fibers have ferentiation. The better-differentiated examples are
been described. They have been referred to as neu- characterized by interlacing bundles of elongated
romuscular hamartomas, suggesting a possible fibroblastic cells of which only the nuclei are clearly
relationship with peripheral nerve fibrolipomatous visualized, separated by a rich network of reticulin
hamartomas. fibers. Nuclear abnormalities are usually rare, but

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mitoses are common. Foci of necrosis are frequent. Osteosarcomas of the skull or spinal bones may be
They may invade the neural parenchyma. encountered in Paget disease.
Fibrohistiocytic tumors are rare tumors com-
posed of a mixture of spindle-shaped fibroblast-like 2.3.2.2.5. Blood vessel tumors Hemangiomas
and round histiocyte-like cells that may be benign of either the capillary or cavernous type (cav-
(benign fibrous histiocytoma) or malignant with ernomas) are not true tumors but vascular
numerous mitoses and foci of necrosis (malignant malformations.
fibrous histiocytoma). Some authors believe that Epithelioid hemangioendothelioma is an endothe-
exhaustive study of such tumors by immunohisto- lial cell tumor rarely encountered in the region of
chemistry or electron microscopy will usually allow the skull base and exceptionally in the brain paren-
more definitive classification as a neural or myo- chyma. Histological examination reveals typical
genic sarcoma. epithelioid cell cords or nests in a myxoid stroma.
Mitoses and necrosis may be present. Tumor cells
2.3.2.2.3. Muscle tumors Leiomyosarcoma is a express endothelial-specific antigens such as factor
very exceptional tumor, corresponding microscopi- VIII or CD31.
cally to its well-known soft-tissue counterpart. It Angiosarcoma may rarely occur as a primary CNS
is positive for desmin and smooth muscle actin by malignancy, often requiring immunohistochemical
immunohistochemistry. Rare examples have been and ultrastructural studies for a definitive diagnosis.
described in HIV-positive immunocompromised Cerebral involvement by Kaposi sarcoma is meta-
individuals; the tumor cells in these cases often static, probably from primary foci in the lungs.
express the EBV genome.
Rhabdomyosarcoma may arise within the menin- 2.3.2.3 Primary melanocytic lesions These
ges or CNS parenchyma, and virtually all are histo- are relatively rare tumors that originate from mela-
logically of the embryonal type, consisting primarily nocytes located within the leptomeninges. They
of small cells that show little or no myogenic dif- can present either as circumscribed or diffuse
ferentiation on H&E staining. Thus immunohis- tumors and may be benign or malignant. Three
tochemistry (tumor cells reactive for myoglobin, major categories are recognized:  (1)  diffuse mela-
desmin, and muscle-specific actin) and/or elec- nosis and melanomatosis, (2) melanocytoma, and (3)
tron microscopy (demonstration of myofilaments malignant melanoma. The first category is associated
arranged in sarcomeres) is usually required for diag- with a rare childhood phakomatosis known as neu-
nosis. Primary CNS rhabdomyosarcoma should be rocutaneous melanosis, which in addition to the CNS
distinguished from other tumors that may occasion- lesion is characterized by numerous large congeni-
ally show skeletal muscle differentiation, such as tal cutaneous nevi. The histological diagnosis of all
medulloblastoma with myogenic differentiation. of these lesions rests on confirmation of their mela-
nocytic nature, which is most easily achieved by
2.3.2.2.4. Osteocartilaginous tumors Chondroma, demonstrating immunohistochemical reactivity for
osteoma, and osteochondroma are benign osteocartilagi- S100 protein and one of the melanocytic markers,
nous tumors, commonly arising from the bones of the HMB45 and/or MART-1. The differential diagno-
skull base or spine. Their histology is similar to that of sis of a primary CNS melanocytic lesion must also
their more frequent systemic counterparts. include (1) metastatic melanoma from another pri-
Chondrosarcomas are preferentially located in mary site (which may be occult) and (2) occasional
the petrosal, occipital, or sphenoid bone. They are primary CNS tumors (e.g., schwannoma, menin-
histologically classified in four subtypes of increas- gioma, medulloblastoma) that may show melano-
ing malignancy:  grade I, grade II, mesenchymal, cytic differentiation.
and myxoid. Examples located at the skull base
must be distinguished from chordomas (especially 2.3.2.4 Hemangioblastoma (WHO grade I)
so-called chondroid chordomas); thus immuno- Hemangioblastomas account for approximately 1%
histochemistry is of paramount importance. S100 to 2.5% of all intracranial tumors. They are encoun-
protein is expressed in both tumors, but chordomas tered at any age but are seen most frequently in
are vimentin-negative and EMA and cytokeratin- young and middle-aged persons. They are most
positive, whereas chondrosarcomas are vimentin- often situated in the cerebellum; indeed, they rep-
positive and EMA and cytokeratin-negative. resent approximately 7% of the primary tumors

Chapter 2 Tumors of the Central Nervous System • 53


originating in the posterior fossa. In addition, they that have been emptied of their lipid contents as a
may be found within the parenchyma of the spinal result of the embedding procedure. Mitoses are rare.
cord, in the medulla oblongata, and, exceptionally, A fine network of reticulin fibers surrounds the cap-
in the supratentorial compartment. illary blood vessels and individual stromal cells. The
Although hemangioblastomas are often demon- endothelial cells express factor VIII, CD31, CD34,
strably or apparently solitary, in approximately 25% and VEGF receptor. The stromal cells do not express
of cases they are multiple and, in that setting, they endothelial cell markers, GFAP, EMA, or cytokera-
permit the diagnosis of von Hippel-Lindau (VHL) tin, but they do express vimentin and VEGF. In
disease. This inherited autosomal dominant con- some cases, these immunohistochemical charac-
dition is caused by mutations of the VHL tumor teristics may be helpful in distinguishing between
suppressor gene located on chromosome 3p. The hemangioblastoma and metastatic clear cell renal
diagnosis of VHL disease is based on the presence carcinoma. Approximately 10% of hemangioblasto-
of a CNS or retinal hemangioblastoma, associated mas will have foci of extramedullary hematopoiesis,
with a known family history, or with a pheochro- most likely due to erythropoietin production by the
mocytoma, clear cell renal carcinoma, pancreatic stromal cells.
tumor, or endolymphatic sac tumor of the inner ear. The histogenesis of hemangioblastoma remains
Macroscopically hemangioblastomas are well unresolved, primarily due to uncertainty about the
circumscribed and very often cystic; they some- nature of the neoplastic stromal cell component
times consist solely of a small mural nodule attached of the tumor. Although these cells had long been
to the wall of a considerably larger cyst. The fairly regarded as being derived from capillary endothe-
characteristic yellow color is due to its abundant lial cells, this has never been proved. More recently
lipid content. In addition, the tumor is usually vas- the stromal cells have been found to express pro-
cularized and drained by well-developed vascular teins characteristic of embryonic progenitor cells
pedicles, which in some cases may erroneously sug- associated with hemangioblastic differentiation.
gest an associated arteriovenous malformation. This From the molecular standpoint, inactivation of the
rich vascularization accounts for the frequency of VHL tumor suppressor gene and subsequent loss
bleeding within the tumor. of function of VHL and VHL elongin BC results in
The histological picture of hemangioblastoma is abnormal ubiquitination of hypoxia inducible fac-
highly characteristic, consisting of numerous capil- tor (HIF), which in turn leads to overexpression of
lary blood vessels of different sizes separated by tra- several hypoxia-inducible genes, including VEGF,
beculae or sheets of clear cells (stromal cells) with erythropoietin and PDGF, which have been related
round or elongated nuclei(Fig. 2.15). These stromal to the development of various angiogenic tumors.
cells, which are considered the neoplastic compo- Hemangioblastomas are histologically benign
nent of the tumor, often have a spongy appearance tumors (WHO grade I) and have a low Ki-67 pro-
due to an abundance of intracytoplasmic vacuoles liferation index (less than 2%), but postoperative
recurrences occur if incompletely resected. The
prognosis in patients with VHL is somewhat less
favorable due to the occurrence of multiple tumors.

3. LYMPHOMAS AND
HEMATOPOIETIC NEOPLASMS
3.1. Lymphomas
3 .1 . 1. PRIM ARY CN S LYM PHOM AS
Primary CNS lymphomas (PCNSLs) are by defini-
tion confined to the brain, spinal cord, eyes, or lep-
tomeninges without evidence of lymphoma outside
the CNS. They occur in two distinct clinical popu-
FIGURE 2.15 Hemangioblastoma. Microscopic lations:  immunocompetent and immunosuppressed
appearance (H&E). patients. In immunocompetent patients, PCNSL

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is uncommon, accounting for approximately 4% to immunophenotyping of the diffuse large B-cell vari-
5% of all primary CNS tumors and 1% to 2% of all ant of PCNSL has shown that the majority stain
non-Hodgkin lymphomas. In this group, they tend for bcl6, MUM1/IRF4 (a marker of late germinal
to occur in older adults, with a slight male prepon- center/post-germinal center stage of differentia-
derance. In immunodeficient patients, most cases tion), and SHP1 (a non-germinal center marker).
of PCNSL occur in the setting of HIV infection, but PCNSLs are negative for CD138 (a plasma cell
they can also occur in immunosuppressed transplant marker). Ki-67/MIB-1 proliferation indices may
recipients, patients with autoimmune disorders, vary from 20% to more than 90%. Almost all cases
and patients with congenital immunodeficiency of PCNSL in immunocompromised patients show
syndromes. Recently the occurrence of PCNSL expression of the EBV genome in tumor cells.
in HIV-infected individuals has been diminishing The origin of PCNSL remains uncertain.
due to the effects of highly effective antiretroviral Lymphoid cells are normally quite sparse in the
therapy. For unexplained reasons, the incidence of CNS, and it is unclear whether neoplastic trans-
PCNSL in older immunocompetent patients has formation of these cells occurs within the CNS or
been increasing. before they enter the CNS. It has been suggested
PCNSLs may occur as either single or mul- that the CNS, as a relatively immune-privileged
tiple masses (the latter more common in immuno- organ, could provide a “safe haven” for circulating
suppressed patients) and can rarely infiltrate the neoplastic lymphoid cells, or alternatively lymphoid
cerebral parenchyma in a diffuse manner (lympho- cells existing within the CNS as part of a chronic
matosis cerebri). PCNSLs can occur almost any- inflammatory reaction could become neoplasti-
where in the CNS, including the spinal cord (very cally transformed. Likewise, the specific type of B
rare) and leptomeninges, but their most frequent cell that gives rise to the diffuse large B-cell variant
site is supratentorially in the deep periventricular of PCNSL is undetermined:  immunophenotyping
region (Fig.  2.16A).PCNSLs contiguous with the suggests that the majority of these tumors corre-
subarachnoid space or ventricles can lead to CSF spond to a post-germinal center stage of differen-
dissemination. tiation and are activated B-cell-type lymphomas by
PCNSLs are classified on the basis of their his- gene expression profiling.
tological appearance and immuno- and molecular Patients who present with a CNS lymphoma
phenotype. The vast majority (nearly 95%) are dif- must be staged to exclude systemic lymphoma
fuse large B-cell lymphomas, with the remaining 5% with secondary CNS involvement, and this should
being T-cell lymphomas, low-grade B-cell lympho- include ophthalmologic examination due to the
mas, and Burkitt lymphomas (rare). The CNS is high frequency of concurrent ocular involvement
involved in about one third of cases of intravascular in PCNSL and spinal fluid examination for possible
lymphoma, most of which are large B-cell lympho- CSF dissemination of lymphoma. The management
mas. Histologically the diffuse large B-cell variant of PCNSL currently emphasizes limiting surgery to
of PCNSL consists of dense aggregates of relatively biopsy only rather than removal of the tumor, with
large atypical lymphoid cells (mainly centroblasts treatment primarily being radiation and chemother-
with variable numbers of immunoblasts), which apy (especially methotrexate); this approach has
are frequently centered around blood vessels and extended median survivals of PCNSL to the 2.5- to
associated with prominent perivascular reticulin 5-year range.
hoops (Fig. 2.16B, C). Disseminated small infarcts
are commonly present, and the parenchyma adja-
3.1.2 . SECONDARY CNS INVOLVEMENT
cent to the main tumor may show variable num-
BY SYSTEMIC LYMPHOMAS AND
bers of reactive T cells, macrophages, and gliosis.
LEUKEMIAS
Immunohistochemical and molecular phenotypic
analysis is now routinely used to further character- Secondary involvement of the CNS by systemic non-
ize the biological behavior, prognosis. and response Hodgkin lymphoma is more common than PCNSL,
to therapy of PCNSL. Most CNS diffuse large B-cell with an incidence ranging from 2% up to 27% (usu-
lymphomas typically express the leukocyte com- ally around 5%). Leukemias (especially acute lym-
mon antigen (CD45), pan-B cell antigens (e.g., phoblastic leukemia/lymphoma) also involve the
CD20), and monotypic immunoglobulin (almost CNS relatively frequently. The propensity for CNS
all PCNSLs are IgM positive). More detailed involvement by these hematopoietic neoplasms is

Chapter 2 Tumors of the Central Nervous System • 55


A B

FIGURE 2.16 Primary CNS lymphoma. (A) Tumor in periventricular white matter (gross). Microscopic fea-
tures: (B) Perivascular localization of tumor cells (H&E). (C) Immunoreactivity of neoplastic lymphoid cells for
B-cell marker (CD20).

most often a function of the specific tumor type and the CNS most often occur in children and are rare,
stage of the disease. Diffuse large B-cell lymphomas with a 0.5% incidence of involvement by LCH; the
are the most likely lymphoma subtype (greater than other types are distinctly rarer. The etiology of these
80%) to secondarily involve the CNS. They usually tumors is unknown and in most patients there may
manifest as dural or leptomeningeal disease with occa- be only mild or no known abnormality of immune
sional superficial cortical involvement, in contrast to function. Regardless, it is likely that abnormal T-cell/
PCNSLs, which more often present as deep periven- macrophage interaction or other immune-regulation
tricular lesions. Hodgkin lymphoma rarely involves abnormalities underlie these disorders. Viral infec-
the CNS and most often occurs in the setting of a tion, especially by EBV, is associated with some forms
relapse with widespread concurrent systemic disease. of hemophagocytic lymphohistiocytosis.

3.2. Histiocytic Tumors 3 .2 . 1. LAN GERHAN S CELL


H I STIOCYTOSIS
The common histological feature of this relatively het-
erogeneous group of tumors is the presence of histio- LCH involving the CNS occurs most often in chil-
cytes, which occurs primarily as dendritic Langerhans dren and may present in several ways: bone involve-
cells (Langerhans cell histiocytosis [LCH]) or as ment (skull base, craniofacial bones); intracranial
conventional macrophages in the non-LCH vari- extra-axial involvement of pituitary-hypothalamus,
ants. The histopathological features of these tumors meninges, or choroid plexus; and intracranial
in the CNS generally mimic those of their systemic intra-axial involvement of the brain. Histologically
counterparts. As a group histiocytic tumors involving the LCH lesions consist of variable numbers of

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eosinophils, macrophages, lymphocytes, plasma 3.2.2 . NON- L ANGERHANS CEL L
cells, Langerhans cell histiocytes, and sometimes HISTIOCYTOSES
Touton giant cells. Abundant collagen may be pres-
This somewhat diverse group of diseases arising
ent. The diagnosis of LCH requires identification of
from mononuclear phagocytes includes intracra-
the characteristic Langerhans cells by immunohis-
nial Rosai-Dorfman syndrome, Erdheim-Chester
tochemistry (reactivity for S100 protein and CD1a)
disease, hemophagocytic lymphohistiocytosis,
and/or electron microscopy (intracytoplasmic
juvenile xanthogranuloma, and xanthoma dissemi-
Birbeck granules). Recent molecular studies have
natum, and also the usually asymptomatic cases of
identified a mutation in the serine/threonine kinase,
choroid plexus xanthoma and xanthogranuloma.
BRAF (V600E), in LCH tumors at multiple sites,
CNS involvement by malignant histiocytic tumors
which may be causative for these tumors.

FIGURE 2.17 Metastatic tumors. (A) Multiple hemorrhagic metastases from melanoma (gross). (B) Lung
carcinoma metastatic to cerebrum (gross). (C) Meningeal carcinomatosis involving cauda equina (gross).
(D) Metastatic adenocarcinoma (lung) involving parenchyma and leptomeninges (H&E).

Chapter 2 Tumors of the Central Nervous System • 57


(e.g., histiocytic sarcoma, follicular dendritic cell well-circumscribed masses, either firm or soft, and
sarcoma) is extremely rare. may have hemorrhage, necrosis, or cystic degenera-
tion within the tumor. Hemorrhagic metastases are
4. SECONDARY (METASTATIC) especially frequent in choriocarcinoma, melanoma,
and renal cell carcinoma. Meningeal involvement
NEOPLASMS (carcinomatosis) may cause diffuse meningeal
This category includes any tumor that originates out- opacification or present as discrete nodules, which
side the CNS and spreads secondarily to the CNS can conspicuously involve the spinal nerve roots of
either via the hematogenous route (metastasis) or the cauda equina. Dural involvement can manifest as
by direct spread from adjacent tissues. Metastatic diffuse plaque-like lesions or discrete nodules.
tumors are the most common intracranial and intra- In most cases the histopathological appearance
spinal tumors, occurring in about 25% of patients and immunophenotype of the metastatic tumor
who die of cancer. Their incidence increases with resembles that of the primary source. However,
age. They may occur in virtually any region of the determination of a primary site of origin can be chal-
cranial cavity or spinal canal, including the central lenging in poorly-differentiated or undifferentiated
neuraxis (cerebral hemispheres, cerebellum, brain- tumors or in cases with scant tissue, hemorrhage,
stem, or, less often, spinal cord), spinal or cranial or extensive necrosis. Immunohistochemistry can
nerve roots, choroid plexus, or meningeal cover- prove especially useful in these situations, even in
ings (e.g., meningeal carcinomatosis, spinal epidural what may appear to be significantly “suboptimal”
metastases, dural metastases at skull base or convex- specimens. Published algorithms for the immuno-
ity)(Fig. 2.17A–D). In adults the most common pri- histochemical evaluation of CNS metastatic tumors
mary sources of brain metastases are lung (especially may also be helpful. Even when the primary site is
adenocarcinoma and small-cell carcinoma), breast well-established, immunohistochemical testing of a
cancer, melanoma, renal cancer, and colon cancer. cerebral metastatic tumor for important treatment/
In children, the most common sources are leukemia, prognosis-associated markers (e.g., estrogen and
lymphoma, osteogenic sarcoma, rhabdomyosar- progesterone receptors and HER2/neu in meta-
coma, and Ewing sarcoma. Prostate, breast, and lung static breast carcinoma) may be indicated. Electron
cancer are the most common sources of spinal epi- microscopy may occasionally be helpful in defining
dural metastases. Direct extension of a tumor to the the nature of a metastatic (or primary) CNS tumor
CNS is relatively uncommon by contrast, and most but has largely been supplanted by immunohisto-
are head and neck tumors such as squamous cell car- chemistry. While not yet routine, as whole-genome
cinoma and olfactory neuroblastoma. and multiplexed molecular testing methods have
Macroscopically, CNS metastases may be soli- emerged (e.g., array CGH, expression profiling),
tary but are most often multiple. Their size ranges such tests are showing promise for diagnostically
from less than a millimeter to over several centi- aiding determination of the site of origin for meta-
meters. In the brain parenchyma they are generally static tumors.

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3
Central Nervous System Trauma
COLIN SMITH

The various pathological processes that result response. In general, patients with mild head injury
from head injury are now collectively referred to as have a score 13 to 15, moderate head injury a score 9 to
traumatic brain injury (TBI). 12, and severe head injury a score of 8 or less.
Based on clinical and neuroradiological data,
1. CLASSIFICATION OF TBI can be categorized as either focal or diffuse
(multifocal). In individuals with focal damage
TRAUMATIC BRAIN INJURY lesions  are detectable by scans and these patients
No single classification of TBI encompasses all the are often responsive to treatment. In unconscious
clinical, pathological, and cellular/molecular fea- individuals with diffuse damage there is wide-
tures of the complex series of process that occur in spread pathology, but not always demonstrable
these cases. In practice, the various classification sys- neuroradiologically.
tems employed have been clinical, pathological, or The neuropathological classification of TBI is
mechanistic or have combined various components based on information derived from postmortem
of these. studies in patients who have had clinical evidence of
The clinical classification of TBI in adults includes neurological disability of varying severity after the
the widely used Glasgow Coma Scale (GCS). The injury. In fatal cases, the extent of clinical impair-
scale is less useful in the assessment of children and is ment ranges from persistent coma from the moment
also not effective in assessing the extent of mild head of injury until death, to normal initial examination
injury. The GCS summarizes the numerical evalua- immediately after injury but subsequent progressive
tion of three clinical parameters (eye response, verbal deterioration and death as a result of complications.
response, and motor response) and results in a score Pathological classifications can be anatomi-
between 3 and 15, 3 being the worst and 15 the best cal, describing injuries as focal or diffuse, or

• 59
Table 3.1. Mechanisms of TBI

MECHANISM M A I N PAT H O L O G Y
Impact Vascular (hemorrhages)
Traumatic axonal injury
Inertial loading Traumatic axonal injury
Penetrating Local tissue necrosis
Blast Brain swelling

pathophysiological, based on primary (occurring caused by the pressure cavities produced by the
at the moment of injury) and/or secondary (occur- projectile passing through brain tissue.
ring in an already mechanically injured brain) • Blast injuries are less well described and are seen
injuries. Secondary damage is often due to com- particularly in military or terrorist situations;
plications that are not unique to trauma but that here, the shock waves from an explosive device
are also seen in association with other intracranial can result in injuries to the brain parenchyma.
diseases.
Mechanistic classifications describe impact, iner- The description of the neuropathology of trau-
tial loading (acceleration–deceleration), penetrat- matic brain injury that is presented in this chapter
ing, and blast injuries (Table 3.1). will consider traditional subdivisions (i.e., focal
and diffuse injuries) (Table 3.2); it will also discuss
• Impact injuries are invariably associated with penetrating and blast injuries, as well as specific
situations where the head makes contact with an pediatric issues and long-term problems associated
object; here the forces of impact are transmitted with TBI.
to the brain,
• Acceleration–deceleration brain injury results from
unrestricted movement of the head, leading to 2. FOCAL INJURY
shear and compressive strains.
While the focal lesions associated with impact are 2.1. Scalp and Skull Lesions
likely to be sustained from a fall or an assault, and
2 .1 . 1. SCALP LESION S
diffuse lesions are more commonly seen in trauma
cases after vehicular accidents, in any given The scalp and skull may be injured by contact injury.
patient, the distribution of lesions is the product The presence of scalp bruising is indicative of con-
of many associated factors; therefore, the inter- tact injury and in some situations may provide clues
pretation of the physical circumstances leading to to the possible intracranial lesions; occipital bruising
the brain damage may be complex and difficult to is typically associated with a backward fall and indi-
interpret. rect “contrecoup” contusions (see below) involving
• Penetrating injuries produce brain damage when the frontal and temporal tips. Incised wounds are
an object passes through the skull and extends usually insignificant and easily managed in the emer-
directly into the underlying brain, causing paren- gency room, but some patients with these types of
chymal damage; in the case of fire arm injuries lesions may have had significant blood loss and
there is an additional element of tissue damage hypotension with consequent brain injury.

Table 3.2. Classification of TBI

FOCAL DIF F USE


Scalp lacerations Global ischemic injury
Skull fractures Traumatic axonal injury/diffuse vascular injury
Contusions/lacerations Brain swelling
Intracranial hemorrhage
Focal lesions secondary to raised intracranial pressure

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Table 3.3. Types of Skull Fracture

T YPE DESCRIP TION


Linear Break in bone extending through both the outer and the inner tables of the skull.
No bone displacement.
Depressed Fragments of the inner table of the skull are displaced inwards.
Compound A depressed skull fracture with associated scalp laceration. Complex, or
penetrating, fractures are associated with additional dural tearing.
Hinge (basilar) Fracture extends across the base of the skull.
Diastatic Seen in infants and young children, with a fracture line extending across skull bone
sutures causing  widening of the suture.
Growing In infancy, meninges extend through fracture, preventing fracture healing.

2.1.2. SKULL LESIO NS forces more arachnoid through the dural defect,
adhesions form, and what is essentially an enlarg-
The prevalence of skull fractures is directly related
ing, CSF-filled leptomeningeal cyst continues
to the severity of the head injury. In one autopsy
to erode bone, preventing healing. The result is
study, skull fracture was found in 80% of subjects
that the fracture widens as the child gets older
with fatal head injury. Clinical series indicate that
(Fig. 3.1A , B).
skull fractures occur in 3% of patients with mild
head injury at the time of presentation in the emer-
No direct correlation can be drawn between the
gency room and in 65% of patients requiring neuro-
presence or absence of a skull fracture and likelihood
surgical attention.
of an underlying parenchymal brain injury, unless
A description and classification of skull fractures,
the fracture is depressed and the broken bone makes
including linear, depressed, and basilar fractures, is
direct contact with the underlying brain tissue. This
given in Table 3.3.
is particularly true in pediatric practice, where the
pliable skull may not actually fracture, but the dis-
• Fractures of the cranial vault are usually linear and
torted bone may allow for considerable underlying
situated between the bony ridges of the skull.
traumatic brain damage. On the other hand, there
• Fractures of the skull base also include fractures
does seem to be a direct correlation between the
of the vault where the fracture lines radiate toward
presence of a skull fracture and the development of
the base involving the anterior fossa, the middle
intracranial hemorrhages (see further on).
fossa, or the posterior fossa. The impact neces-
sary to cause the fracture is much greater than
that required for other fractures. In these cases,
there may be severe brain damage in addition to 2.2. Contusions and Lacerations
the bone injury. Furthermore, the cranial nerves Contusion is a hallmark of brain damage in head
and blood vessels are also particularly vulnerable injury; it consists of a bruise on the surface of the
in cases of fracture involving the floor of the skull. brain. By definition the overlying pia mater is intact
Finally, patients who survive these injuries may in contusions but torn in lacerations.
develop complications such as ascending infec- Two prototypical types of contusions are recog-
tion or pneumocephalus. nized:  “coup contusions” and “contrecoup contu-
• Infants who incur skull fracture may develop sions”. In coup contusions the damaged brain tissue
a characteristic though less common lesion occurs beneath the point of impact; for example,
that has been termed “growing” fracture. The when scalp bruising is over the forehead, the brain
pathogenesis of this lesion is believed to evolve contusions involve frontal and temporal lobes. In
from an initial tear in the dura at the time of the contrecoup contusions, on the other hand, the iden-
injury, through which a small piece of arachnoid tical structural damage to the surface of the brain
becomes extruded and interposed between the occurs in a region diametrically opposite the point
fractured bone edges. Over ensuing months and of external impact—e.g., bruising in the occipital
years, pulsation of the cerebrospinal fluid (CSF) scalp after a forehead blow (Fig. 3.2).

Chapter 3 Central Nervous System Trauma • 61


A hemorrhage (DTICH) usually becomes apparent
within 48 hours after the head injury. The precise
mechanism of this form of injury is uncertain but is
thought to reflect increased blood flow or pressure
through a vascular capillary network that is focally
damaged, possibly compounded by posttraumatic
coagulopathy.
Topography:  Contusions typically involve the
frontal poles, the inferior frontal lobe including
the gyrus rectus and medial and lateral orbital gyri,
the temporal poles and lateral and inferior aspects
of the temporal lobes, and the cortex above and
below the Sylvian fissure. Fracture contusions may
be seen at atypical sites in direct relationship to a
B skull fracture. Contusions typically involve the
crests of gyri and are often superficial, involving the
gray matter only. However, the lesion may be found
to extend into underlying white matter and develop
into a hematoma. In severe cases, extensive lacera-
tion injury with underlying parenchymal hemor-
rhage may be associated with subdural hemorrhage,
forming a so-called burst lobe. This type of injury
involves most often the temporal lobes.
On neuropathological examination, the smallest
contusions are merely collections of minute peri-
vascular hemorrhages in the cortex, often only a
few millimeters in diameter, without any edema
(Fig.  3.3A , B). Larger contusions contain areas of
tissue destruction as well as hemorrhage and are
often associated with focal swelling. In the weeks
after an injury, on macroscopic examination the
affected brain appears abnormally pigmented and
is shrunken (Fig.  3.4). Over time, the hemorrhage
FIGURE 3.1 An arrested growing fracture found in and the dead tissue are removed by macrophages
a woman of 38. When asked about childhood injuries, and there are foci of gliosis, often with associated
she remembered having been told she fell out of her hemosiderin deposition. Old contusions are not
carriage as a very young child. (A) Plain skull x-ray. infrequent incidental autopsy findings, particularly
(B) The excised portion of bone. in at-risk groups, such as patients with chronic alco-
holism. The lesion can usually be distinguished from
an old infarct because the topographic distribution
Coup lesions may follow a fall forwards, contre- is typically on the ventral surface of the frontal and
coup lesions a backwards fall, or underlying frac- temporal lobes and can overlap multiple vascular
tures. Contusions involving the occipital lobes and territories. In addition, the lesion is characteristi-
cerebellum are rare, perhaps in part because the cally wedge-shaped, with the base on the crest of the
adjoining smooth inner surface of the posterior cortical gyri and apex in white matter, and there is
fossa of the skull offers less attrition as compared often evidence of previous hemorrhage.
with the irregular bony ridges of the anterior and
middle fossae. These lesions are usually associated
with an adjacent skull fracture.
The size of a contusion may increase over
2.3. Intracranial Hemorrhage
time, some hours after the initial head injury. This Intracranial hemorrhages are classified according to
phenomenon of delayed traumatic intracerebral the anatomical compartment in which they develop.

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A B

C D

FIGURE 3.2 Typical patterns of distribution of contusion injury, showing contusions related to the site of
impact (“coup”) and contusions away from the impact (“contrecoup”). (From Courville CB. Pathology of the
Central Nervous System. 1937.)

2.3.1. EXTRADURAL (EPIDURAL) to the underlying middle meningeal artery or vein.


HEMORRHAGE Subsequent to the fracture, the dura (periosteum) is
stripped from the inner table of the skull to form a
An extradural hemorrhage (EDH) is an extravasa- circumscribed ovoid mass, producing an extradural
tion of blood between the inner table of the skull space that is then filled by blood (Fig.  3.5). Other
and the dura. It is composed of a dense blood clot sites of involvement include the anterior cranial
that tends to adhere early and firmly to the dura. fossa (damage to the anterior meningeal artery),
EDHs are limited in size; the bleeding remains parasagittal region (superior sagittal sinus), and
localized to this space. EDH most commonly occipital lobe and posterior fossa (damage to the
(approximately 50%) results from fracture of the occipital meningeal artery or transverse or sigmoid
squamous temporal bone causing contact damage sinuses). EDH has also been described in relation to

A B

FIGURE 3.3 Small intracortical contusions in typical sites at the base of frontal (A) and temporal lobes (B).

Chapter 3 Central Nervous System Trauma • 63


FIGURE 3.5 Gross appearance of a classical
extradural hematoma situated in the parietotemporal
region.

and outer layer of the arachnoidal layer (arachnoid


FIGURE 3.4 Old contusions on the base of the cap cell layer). This is a potential space, not an ana-
frontal lobes. (Reproduced with the permission tomical space; during life the two layers are apposed.
of Springer-Verlag, from Geddes JF, Whitwell HL. Bleeding that occurs underneath the dura results in
Head injury in routine and forensic pathological the physical separation of the inner surface of the
practice. In Love S (ed). Current Topics in Pathology: dura from the outer surface of the arachnoid. .
Neuropathology. Vol. 95. Berlin: Springer-Verlag, After blunt force head injury, acute SDH may
2001:101–24.) be due to rupture of a bridging vein (cortical vein
passing from the cortical surface to a dural sinus)
the internal carotid artery before it enters the intra- or, probably more commonly, secondary to contu-
cranial dura. Spontaneous EDH has been described sions with damage to cortical veins or arteries and
in association with vascular malformation, infec- the overlying leptomeninges. In this latter situa-
tions, and rarely as a complication of malignancy tion there may be an associated intracerebral hem-
and anticoagulation therapy. orrhage and the term “burst lobe” is applied (cf.
In up to 30% of cases, EDH may be associated supra). Occasionally, the subdural bleeding results
with a “lucid interval”. In patients with this clini- from the rupture of a cortical artery rather than a
cal phenomenon, there may be a period of vari- vein. Previous head injury with subdural adhesions,
able duration after the head injury with normal which tend to limit displacement of the brain within
neurologic function, prior to the development of the cranial cavity, may predispose to this type of
an often-rapid clinical decline. This syndrome has injury.
been presumed to be the consequence of the rapid Experimental studies in nonhuman primates
volumetric expansion of the EDH. Indeed, in the have demonstrated that, biomechanically, acute
absence of surgical evacuation of the hematoma, SDHs secondary to torn bridging veins occur in a
extension of the EDH results in a “space-occupying” setting of rapid acceleration–deceleration injuries.
lesion with concave deformation of the underly- This is consistent with the recognized association
ing brain, midline shift and axial displacement; between SDH and falls or assaults in human beings,
increased intracranial pressure and brain herniation both situations in which there is a rapid acceleration
can be the terminal event. or deceleration of the head on impact. Patients with
SDH may also develop the clinical phenomenon of
a lucid interval as defined above. Rarely, a SDH may
occur in the setting of a ruptured cerebral saccular
2. 3. 2. S UBDUR AL H EM O R R H A G E
aneurysm with extension into the subdural space.
Subdural hemorrhages (SDH) develop within the SDH may follow an episode of relatively trivial
subdural space, which is located between the dural head injury, and in 25% to 50% of cases there is no

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history of trauma. This is particularly the case in Secondly, multiple episodes of rebleeding within a
patients with brain atrophy, in whom the bridging subdural hematoma are known to occur not infre-
veins are presumably stretched out and therefore quently, making problematic definitive judgment of
potentially more vulnerable to tearing. Medical the age of the lesion. The process of resolution of a
conditions associated with SDH include anticoagu- SDH starts with proliferation of arachnoidal cells
lation therapy, intracranial shunting procedures, epi- over the surface of the hematoma, which eventually
lepsy, alcohol abuse, and, rarely, intracranial tumors. becomes encapsulated in a fibrous membrane. In the
Pathologically, SDH can be separated into acute early stages, numerous thin-walled capillaries grow
(Fig.  3.6A , B), subacute (Fig.  3.6C), and chronic into the edges of the clot. Rebleeding from these
(Fig. 3.7) forms. Notwithstanding this empiric sub- blood vessels may cause a resolving hematoma to
division, it is often most difficult to be absolutely enlarge and produce symptoms. The usual end stage
certain of the exact age of a hematoma using radio- of the involution of SDH is a collapsed, pigmented,
logical, intraoperative, and/or histological criteria. membranous sac adherent to the undersurface of
The reasons for this predicament are multiple and the dura.
complex. In the first place, although it may be pos- At postmortem, the subdural blood extends
sible to give the time of onset of an episode of acute within the subdural space; the dura is tense and
SDH, radiological imaging studies have demon- blood can be seen underneath the dura. This fresh
strated that in many patients, acute SDHs involute blood spills out when the dura is incised at surgery or
spontaneously and do not become chronic lesions. autopsy (Fig. 3.6A , B). In subacute lesions the blood

A B

FIGURE 3.6 Acute and subacute subdural hematomas. Acute subdural hematoma: gross appearance before
(A) and after (B) incision of the dura. (C) Subacute subdural hematoma: gross appearance.

Chapter 3 Central Nervous System Trauma • 65


clot shows at least focal attachment to the dura, and such a patient, who may be predisposed to develop
there may be early golden-brown color change due subdural bleeding because of cerebral atrophy, there
to hemosiderin (Fig. 3.6C). Chronic subdural hemor- may be no history of preceding trauma, and the clin-
rhage refers to a clot that is encapsulated in fibrous ical signs develop slowly because there is a relatively
membranes. Magnetic resonance imaging (MRI) large subdural space to accommodate the blood.
is the most sensitive method of demonstrating the With time, the fibrous tissue encapsulating the
heterogeneous nature of such lesions (Fig.  3.7A), hematoma becomes very thick (Fig. 3.7B, C). By the
and MRI scans suggest that chronic subdurals may time the patient comes to medical attention, there
be either old hemorrhages undergoing resolution may be considerable distortion and compression of
or chronic lesions into which acute rebleeding has the underlying cerebral hemisphere (Fig. 3.7D).
occurred.
A unilateral—or sometimes bilateral—SDH is
2 .3 . 3. SUBDURAL HYGROM A
not uncommonly found in the radiological evalu-
ation of an elderly person being investigated for A subdural hygroma is a collection of CSF within the
fluctuating confusion or subtle cognitive decline. In subdural space. The lesion may be associated with

A B

C D

FIGURE 3.7 Chronic subdural hematomas. (A) MRI showing a unilateral chronic subdural hematoma, not
causing midline shift, but flattening the left hemisphere) Old organized subdural hematoma, gross appearance
after removal of the dura. (C) The brain of a 6-year-old child with cerebral palsy: bilateral chronic subdurals,
encapsulated by a thick collagenous membrane resembling dura. (D) After removal of the hematomas, both
hemispheres are seen to be markedly flattened.

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trauma, chronic SDH in adults, or infection in infants contusion may develop some time after the initial
or may be seen after ventricular shunting. In the major- traumatic insult, and this phenomenon may be wit-
ity of these cases, the lesion is not clinically signifi- nessed clinically when a patient is observed to dete-
cant; however, some patients with subdural hygroma riorate several hours after the initial head injury.
develop acute neurological deficits after a traumatic Deep-seated ICH in the region of the basal gan-
injury that may mimic acute SDH. The two types of glia may be seen in a high-velocity blunt force head
lesions can be distinguished by MRI. At surgery or injury, such as is seen in road traffic accidents. If
autopsy, subdural hygroma fluid is clear or xantho- extensive, it can be difficult to distinguish them from
chromic and not associated with a fibrous membrane. a primary hypertensive hemorrhage. However, in
motor vehicle accidents, the more typical lesions are
the small parenchymal hemorrhages in the region
2.3.4. SUBARACHNOID HEMORRHAGE of the diencephalic structures. These are considered
Within the setting of blunt force head injury, sub- to be part of the spectrum of lesions associated with
arachnoid bleeding is commonly observed and rotational damage (Fig. 3.8A), including diffuse trau-
typically associated with damage to cortical veins matic axonal injury and diffuse vascular injury. In
located in the subarachnoid space, or related to sites themselves, these hemorrhagic lesions do not pro-
of contusions. The autopsy finding of basal sub- duce a significant mass effect but rather are an indica-
arachnoid hemorrhage (SAH) is most often second- tion that severe parenchymal damage has occurred.
ary to intraventricular bleeding (see further on). Parasagittal white matter lesions, also known
In general, the development of subarachnoid as gliding contusions, are hemorrhagic lesions seen
bleeding, in itself, is not necessarily of adverse clini- predominantly in frontal parasagittal white mat-
cal/prognostic significance in traumatic injury. ter (Fig.  3.8B). As deep-seated hemorrhages,
Occasionally, traumatic damage to an artery at they are secondary to rotational forces and severe
the base of the brain or at the craniocervical junc- head injury. These lesions are often symmetrical,
tion may produce abundant arterial subarachnoid and when the interval of time between the initial
bleeding. Such extensive basal hemorrhage can injury and postmortem examination is prolonged,
mimic a ruptured berry aneurysm and should be they evolve into a gliotic scar with surrounding
excluded by angiography or at postmortem by care- hemosiderin-containing macrophages (Fig. 3.8C).
ful examination. It is typically seen in the setting
of vertebral artery trauma. The bleeding originates
2.3.6 . INTRAVENTRICUL AR
from the extracranial vertebral arteries. This is well
HEM ORRHAGE
described following a blow to the under-aspect of
the jaw resulting in tearing of the vertebral artery. Intraventricular hemorrhage is relatively uncom-
The clinical picture is one of sudden collapse and mon in blunt force head injury, but when present,
coma, usually with a short survival period. At post- it carries the risk of acute hydrocephalus. Blood
mortem examination, the site of origin of the mas- within the ventricular system may be a consequence
sive bleeding may be difficult to identify. However, of direct extension of a parenchymal hemorrhage
when the vertebral arteries are carefully dissected into the ventricular system or of retrograde flow of
from the point at which they enter the foramina subarachnoid hemorrhage. In rare cases, there is
transversaria at the low cervical vertebrae and fol- isolated intraventricular hemorrhage with no obvi-
lowed up to the point where they leave the vertebrae ous source of primary bleeding. In these cases the
and enter the base of the skull, the site of traumatic hemorrhage is considered to be from subependymal
rupture, or the identification of a pseudo-or dissect- veins, choroid plexus, or damage to the septum pel-
ing aneurysm, will be found in most cases. lucidum and forniceal vessels.

2.3.5. INTRACEREBRAL HEMORRHAGE


2.4. Other Focal Lesions
Intracerebral hemorrhage (ICH) may be found at
2.4.1 . VASCUL AR
autopsy in association with contusions and may
attain sufficient size to cause mass effect with asso- Large blood vessels may be damaged as a conse-
ciated shift of midline structures. As discussed quence of blunt force head injury. Posttraumatic
above, in some cases, hemorrhagic expansion of a pseudo-aneurysms may involve both the external

Chapter 3 Central Nervous System Trauma • 67


A B

FIGURE 3.8 Severe head injury. (A) and (B) show gliding contusions in the parasagittal white matter, on
the left, and small hemorrhages in the corpus callosum. There are also small parenchymal hemorrhages in the
diencephalic structures (A). In a patient unconscious after head injury, such lesions are the hallmark of severe
DAI. Chronic lesions may form scars with surrounding hemosiderin-containing macrophages (C); note that the
lesions are often symmetrical.

and internal carotid arteries and are thought to be hemorrhages) or are part of diffuse traumatic axonal
a consequence of stretching of the blood vessel after injury with a dorsolateral localization.
neck injury. Vessel wall dissection is described after
trauma involving most large arteries, and symptoms
develop over several hours as a consequence of 3. DIFFUSE BRAIN INJURY
thrombus formation (Fig. 3.9).
Diffuse lesions in TBI include diffuse ischemia,
diffuse traumatic axonal injury (TAI), and diffuse
2. 4. 2. BRAI NS T E M L ES I O NS brain swelling. In the absence of a demonstrable
mass lesion, persistent coma after head injury can be
A number of brainstem lesions are described in the
assumed to be a consequence or either TAI or dif-
setting of blunt force head injury. At the most severe
fuse ischemia, or a combination of both.
end, there is pontomedullary rent, a lesion incompat-
ible with life. A tear is seen at the junction between
the lower pons and medulla, and histologically tis-
sue damage can be identified. Such lesions are rare
3.1. Ischemia
and are associated with high-velocity lesions causing Ischemic brain injury may be focal or diffuse. Either
extreme hyperflexion- or hyperextension-type inju- form of injury is a common finding in fatal traumatic
ries, such as falls from a height or motorcycle acci- brain injury and was found to be present in 91%
dents with primary head impact. of brains studied in one autopsy study. Ischemia
Hemorrhages within the brainstem are second- remains an important factor in determining clini-
ary to axial displacement causing large midline cal outcome after head injury. Early stabilization of
hemorrhages in the midbrain and pons (Duret patients reduces the incidence of focal hypotensive

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vegetative state in survivors of head injury. In cases
of diffuse TAI there is always a period of uncon-
sciousness; this period may be short, or one of
prolonged coma.
Experimental studies have shown that TAI is pri-
marily a non-impact phenomenon, resulting from
angular or rotational acceleration. This is in keep-
ing with the circumstances in which TAI primar-
ily occurs in human injuries—namely, road traffic
accidents and falls from a height. In such situations,
TAI is primarily the result of inertial phenomena,
and there is a lower incidence of impact lesions and
skull fractures. TAI is also found occasionally in fatal
cases following accelerated falls from standing, nota-
FIGURE 3.9 A man of 31 developed a large right
bly assaults, but in these cases, impact phenomena
middle cerebral artery territory infarct after an assault play an important role, and a skull fracture is much
and died 2 days later of raised intracranial pressure. more usual.
The cause of the infarct was traumatic dissection of the
right middle cerebral artery with occlusive thrombus
(arrow). 3.2.1 . MACROSCOPIC ASPECTS OF  TAI
In the most severe cases of TAI, hemorrhagic
lesions are seen in the lateral aspects of the corpus
brain injury but not of diffuse ischemic injury. There callosum and dorsolateral quadrant of the brain-
are a number of causes of ischemia after head injury stem. Three grades of TAI have been described. In
(Table 3.4), and many types of lesions may be seen, Grade 1 lesions, there are only microscopic changes
including neuronal injury within selectively vulnera- in the white matter of the cerebral cortex, corpus
ble areas documented on microscopic examination, callosum, brainstem, and cerebellum. In Grade 2
and infarcts, involving watershed areas or within lesions, macroscopically visible focal lesions are
major arterial territories. present in the corpus callosum only (Fig. 3.10A). In
Grade 3 lesions, additional focal lesions are seen in
the dorsolateral quadrants of the rostral brainstem
3.2. Diffuse Traumatic Axonal Injury (Fig. 3.10B).
The term diffuse axonal injury (DAI) was introduced
to apply to the structural lesions of axons found at
autopsy examination that follow severe traumatic 3.2.2 . MICROSCOPIC ASPECTS OF  TAI
injury. By definition, the phenomenon occurs in the A recommended protocol for microscopic assess-
absence of focal lesions. It may be seen in fatal cases ment of TAI is presented in Table 3.5.
of progressively severe coma or in patients surviv-
ing head injury who manifest severe disability,
eventually evolving into vegetative state. Nowadays, Table 3.4. Patterns and Causes of
the term DAI is used primarily in clinical practice Ischemic Brain Damage After TBI
to apply to the clinical syndrome and supporting
neuroradiological data. The term currently used to PAT T E R N CAUSE
apply to the neuropathological substrate of DAI is
traumatic axonal injury (TAI). TAI contributes to Diffuse Cardiorespiratory arrest
at least 35% of the mortality and morbidity of TBI Focal Raised intracranial pressure
cases that do not have associated space-occupying Vasospasm
lesions and also contributes to the mortality and Hypotension
morbidity in focal brain injuries. In addition, along Embolism
with diffuse ischemic injury, TAI is considered
Penetrating injuries
to be an important cause of severe disability and

Chapter 3 Central Nervous System Trauma • 69


A Originally, trauma-induced axonal injury was
thought to be the result of axonal disconnection at
the time of the impact (primary axotomy), lead-
ing to axonal retraction and axoplasmic pooling.
However, current opinion, based on experimental
studies, offers an alternative view. The applied forces
affect axons focally, resulting in mechanoporation
(i.e., mechanically-induced membrane pores) with
calcium influx. Calcium influx results ultimately in
the activation of calcium-dependent proteases and
B caspases. There is modification of neurofilament
subunits, particularly in relation to the phosphoryla-
tion of side arms, resulting in microtubule compac-
tion causing local axonal transport impairment and
axonal swelling. Over time this is followed by rup-
ture of the axon.
On routine histological preparations (e.g.,
stained with H&E), the damaged axons can be
seen as eosinophilic swellings (Fig. 3.11A). Several
special histological techniques have been used
to demonstrate them to better advantage. The
abnormal axons can be detected by silver stains
and, in affected long white matter tracts, using the
appropriate stain techniques for demonstration of
myelin breakdown products. The relative disadvan-
tage of these techniques is that the abnormal axons
can only be demonstrated after a survival period
of at least 12 to 18 hours. Immunostaining for
beta-amyloid precursor protein (ß-APP), which is
able to detect axonal flow disruption, is the most
sensitive and widely used method (Fig.  3.11B).
ß-APP, a membrane-spanning glycoprotein and a
normal component of neuronal cells, is transported
along axons by fast transport mechanisms. When
there is axonal transport interruption, ß-APP has
been shown to accumulate, indicative of dysfunc-
tion or possibly rupture of the axon. ß-APP accu-
mulation has been demonstrated in subjects who
have survived for a period as short as 35 minutes
from the time of injury.
ß-APP accumulation is well known to occur in
many other conditions that cause axonal damage
(e.g., ischemia). In the context of TBI, the topo-
graphic pattern of axonal injury is rather distinctive.
Because of the anatomical orientation of certain
FIGURE 3.10 Macroscopic aspects of traumatic white matter bundles (namely the corpus callosum,
axonal injury. Hemorrhagic lesions in the lateral internal capsule, cerebellar peduncles, and descend-
aspects of the corpus callosum (A) and in the upper ing long tracts in the brainstem), these tracts are
brainstem (B). Note that the lesions in the dorsolat- particularly vulnerable in TBI (Fig.  3.11A , B). In
eral quadrant of the brainstem are very different from ischemia, axonal injury and ß-APP accumulation
the brainstem hemorrhages seen as a result of raised does not follow this pattern of white matter damage;
intracranial pressure and brain shift. rather, it involves all fiber tracts within the ischemic

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Table 3.5. Histology in Cases Where Diffuse Brain Injury Is Suspected

R E C O M M E N D E D M I N I M U M S A M P L E F O R A D I A G N O S I S O F TA I +
Corpus callosum with adjacent parasagittal cortex and white matter
Deep gray matter including posterior limb of internal capsule
Temporal lobe including hippocampus
Genu (anterior sections) of corpus callosum
Cerebellar hemisphere including the dentate nucleus
Midbrain at the level of the decussation of the superior cerebellar peduncles
Pons at the level of the middle cerebellar peduncles
Medulla

R E C O M M E N D E D S TA I N S * *
Survival < 12 hours H&E, β-APP
Survival > 12 hours H&E, β-APP, silver preparation, CD68¶
Survival > 1 week H&E, β-APP, silver preparation, CD68
Survival > 6 weeks H&E, CD68

O T H E R U S E F U L S TA I N I N G M E T H O D S
Method Demonstrates
Perls hemosiderin
Reticulin stain, hematoxylin van Gieson organization of a subdural hematoma

Cresyl-fast violet microglial “clusters” or “stars”


Modified PTAH‡, Marchi method secondary long tract degeneration

+
Blocks to beas large as possible; if only small blocks are taken, bilateral samples are recommended
** Survival times given as an approximate guide

CD68 in short-survival cases may show (i) evidence of a previous TAI; (ii) selective cortical or hippocampal damage from an
episode of global hypoxia

A modification of the routine PTAH stain that eliminates myelin staining (Manlow A, Munoz DG. A non-toxic method for the
demonstration of gliosis. J Neuropathol Exp Neurol 1992;51:298–302)

regions. Often a zigzag pattern can be seen in isch- 3.2.3 . AXONAL INJURY IN MIL D
emic injury. In some cases the degree of ischemic HEA D INJURY
axonal injury may be so severe that it is not possible
After mild head injury, axonal pathology has been
to comment on the presence or absence of TAI.
detected in patients who have died from unrelated
There is a sequence of cellular responses that
causes relatively soon after the insult. In these cases, the
evolves over time following TAI injury. In general, at
axonal injury was seen in the corpus callosum and for-
5 to 10 days’ survival after injury, microglial activa-
nices; it has been suggested that the forniceal pathology
tion is first noted and followed by the formation of
may be particularly relevant to posttraumatic amnesia.
microglial “clusters” or “stars” around degenerating
axons. There is nevertheless some variability from
case to case as axonal degeneration is a continu-
3.2.4 . F OCAL AXONAL  INJURY
ing process. Eventually, the swellings are no longer
detectable by any technique; the microglial nod- Focal axonal injury (AI) is characterized by scattered
ules remain as the only sign of damage. In some foci of damaged axons scattered in various parts of
long-term survivors after widespread TAI, long tract the neuraxis; in the context of TBI, its significance
degeneration can be detected by the traditional is currently uncertain. Focal AI within the brainstem
method of Marchi (Fig.  3.12A) or immunohisto- occurs in the hyperflexion–hyperextension type of
chemically using a macrophage marker (e.g., CD68) injuries. In adults, this abnormality may be seen in
(Fig. 3.12B). With time, glial scarring occurs in the fatal falls or in motorcycle accidents, and in children,
central white matter and long tracts. it is described in abusive head trauma (AHT). Focal

Chapter 3 Central Nervous System Trauma • 71


A B

FIGURE 3.11 Microscopic aspects of traumatic axonal injury. (A) Two days’ survival after injury: damaged
axons are easily seen on routine stains. (B) Short survival after head injury: immunohistochemistry for β-APP
delineates damaged axons and reveals early axonal swelling.

AI has been described within the corpus callosum diffuse within one cerebral hemisphere, or diffuse
in the absence of any diffuse process, and its sig- involving both cerebral hemispheres.
nificance is currently uncertain. It is associated with The swelling may be congestive, secondary to
concussive syndromes. an increase in the cerebral blood volume, or due to
edema. The majority of edema in trauma is cytotoxic,
3.3. Diffuse Vascular Injury with only a small component of swelling due to vaso-
genic edema, mostly in focal swelling adjacent to
Diffuse vascular injury is a severe form of rotational contusions. Adjacent to contusions, there is physical
injury seen in fatal head injury with only a short disruption of the tissues, including the blood–brain
survival. Hemorrhagic lesions are seen throughout barrier, and loss of the normal autoregulation within
the brain with a distribution similar to TAI; lesions the local vasculature. Focal brain swelling may be
occur in the frontal parasagittal white matter, basal seen in mild TBI, but diffuse brain swelling is ordi-
ganglia, and brainstem (Fig. 3.13). narily only associated with severe head injury.

3.4. Brain Swelling 4. PENETRATING INJURIES


Brain swelling is a common finding in fatal TBI. The Penetrating injuries are injuries in which an object
swelling may be localized, in relation to contusions, enters the cranial cavity; in strict terms a penetrating

A B

FIGURE 3.12 In sections from a patient with DAI who survived 6 months after injury, secondary long tract
degeneration may be demonstrated by two methods. (A) The Marchi method reveals myelin breakdown prod-
ucts (black) in the long tracts and in the cerebellar peduncles. (B) Immunohistochemistry for CD68 demon-
strates the numbers of foamy macrophages in the corticospinal tracts in a more rostral section of the pons.

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A

FIGURE 3.14 Perforating injury by a bullet produc-


ing a hemorrhagic tract through the two cerebral
hemispheres into which the missile extended.
B
extends (Fig. 3.14). High-velocity missiles, such as
bullets, cause considerably more damage, the extent
of the damage being related to the velocity of the
missile. High-velocity military weapons will pro-
duce greater tissue damage than small firearms. As
the missile travels through the parenchyma it will
produce pressure cavities, which can lead to tissue
damage.

5. BLAST INJURIES
Traditionally the study of blast injuries has focused
on the damage caused by blast waves to air-filled
viscera, such as the lungs in the thoracic cavity.
However, increasingly attention has now focused
on the possibility of injury to solid viscera as well,
particularly the brain. The abrupt pressure changes
associated with a blast can lead to a mild head injury,
FIGURE 3.13 Diffuse vascular injury. Widespread in particular to concussion. Long-term clinical
small hemorrhages in the hemispheres (A) and brain- behavioral sequelae (e.g., impaired concentration,
stem (B) of a road traffic accident victim who died of memory difficulties) have been found with a greater
a head injury almost immediately after the accident. frequency in these individuals in particular when
Such widespread damage is believed to be incompat- compared with others exposed to non-blast TBI.
ible with survival. The cellular events that occur in this type of
injury are poorly defined; microscopic examination
injury is one in which the missile enters the cra- of brain tissue has shown microglial and astrocytic
nial cavity but does not exit, whereas a perforating activation.
injury is one where the missile also exits. While
infection is an important complication of almost all 6. CHRONIC TRAUMATIC
penetrating injuries, the actual damage to the brain
is extremely variable and depends on the nature of
ENCEPHALOPATHY
the missile. Sharp objects, such as knives, long nails, For many years, an association has been known
or metal poles, may pierce the skull and extend into between repetitive head injury and the develop-
the underlying brain parenchyma, causing local ment of late neurological sequelae, including severe
damage. They produce a hemorrhagic tract through impairment of cognitive function. Although rare,
the regions of parenchyma into which the missile dementia pugilistica, the neurological syndrome

Chapter 3 Central Nervous System Trauma • 73


7. SPINAL CORD INJURIES
Acute spinal cord injury is most commonly seen
in road traffic accidents and in contact sports, or in
the specific setting of rheumatoid arthritis with cer-
vical spine instability, with the risk of atlanto-axial
subluxation. The most usual mechanism of acute
spinal cord injury is vertebral fracture–dislocation,
or a ruptured intervertebral disc. Vertebral body dis-
location may impinge directly on the cord, causing
contusion injury (Fig.  3.16) or, in the most severe
injuries, cord transection.

FIGURE 3.15 Chronic brain damage in a


23-year-old boxer dying from the effects of an acute
subdural hematoma. Immunohistochemistry for tau
protein reveals neurofibrillary tangles and neuropil
threads around a small vessel in the neocortex.

recognized in elderly boxers, is one of the earli-


est described manifestations of chronic traumatic
encephalopathy. Neurodegenerative disorders that
occur more commonly following repetitive head
injury include cerebellar and parkinsonian syn-
dromes. In these patients, neuropathological stud-
ies have demonstrated septum pellucidum damage
(and cavum septum), substantia nigra pallor, and
cerebellar cortical degeneration. Neocortical early
neurofibrillary tangles (often in a perivascular dis-
tribution deep within sulci) (Fig.  3.15), neuro-
pil threads, and diffuse amyloid plaques have all
been described, but not the neuritic plaques seen
in Alzheimer disease. The term chronic traumatic
encephalopathy (CTE) has been used in recent
literature to describe this condition, which has
now been linked to contact sports, such as soc-
cer, American football, and ice hockey, in selected
cases, in some studies.
The association between a single head injury and
subsequent cognitive decline is less well established.
However, epidemiological studies suggest the asso-
ciation is more common in males and is related to
the severity of the head injury. There is likely to be FIGURE 3.16 Trauma at the craniocervical
a genetic influence, and some neuropathological junction—the patient died following transoral exci-
studies of long- term survivors have described an sion of fragments of a fractured odontoid. The lower
increased incidence of Alzheimer-type pathology. medulla and upper cervical segments are compressed.

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is central cavitation with the development of a post-
traumatic syrinx.
It is now recognized that some patients with
traumatic spinal cord injury may have no demon-
strable evidence of a radiological or structural
lesion (spinal cord injury without radiographic
abnormality[SCIWORA]); the hypothesis in these
instances is that the patient’s symptoms reflect a
type of spinal cord “concussion”.

8. PEDIATRIC HEAD INJURY
FIGURE 3.17 Subdural bleeding in an infant
with a head injury, believed to have been inflicted. Fatal head injury is not common in young chil-
As in this case, severe brain swelling is the usual dren. Pediatric head injury after the age of 9 to
immediate cause of death. (Reproduced with the 12  months very much reflects adult patterns of
permission of Springer-Verlag, from Geddes JF, head injury; that is, focal and diffuse injuries deter-
Whitwell HL. Head injury in routine and foren- mined by the force and direction of the impact.
sic pathological practice. In Love S (ed). Current Most injuries in this age group are due to falls or
Topics in Pathology:Neuropathology. Vol. 95. road traffic accidents.
Berlin: Springer-Verlag, 2001:101–24.) In the infant population, inflicted (“nonacciden-
tal”) injury, also called abusive head trauma (AHT),
is an important cause of TBI. AHT may occur after
Traumatic damage to the spinal column may the age of 9 to 12  months but it is more common
cause acute or chronic cord compression with local- in younger infants, and in this group, head injury is
ized axonal damage at the level of the injury and rather different, presumably because of the anatomi-
secondary changes in ascending and descending cal and physiological immaturity of the infant’s ner-
fiber tracts. Hyperflexion–hyperextension injuries vous system. Infants younger than 9 months believed
to the neck in the absence of craniocervical fracture to have been shaken show a much higher incidence
or subluxation may cause damage to the long tracts of global brain ischemia and focal pontomedul-
in the lower brainstem or upper cervical segments. lary axonal injury. A thin film of subdural bleeding
Spinal nerve roots may be damaged in cases of non- or a small subdural hematoma, often midline, and
accidental head injury in infants, possibly caused by retinal hemorrhages accompany the brain swell-
a similar mechanism of excessive movement at the ing (Fig. 3.17), and this “triad” is often considered
craniocervical junction, resulting in stretch to the “diagnostic” of abusive injury. However, the triad is
spinal cord and nerve roots. not in itself pathognomonic of AHT. It has been sug-
The neuropathology of acute spinal cord trauma gested that this unique type of SDH may sometimes
is similar to that of head injury, and comparable have a “congestive” and/or hypoxic rather than a
findings indicating the progression of damage traumatic etiology, and that retinal hemorrhages
after injury are seen on microscopic examination. may result from the rapid rises in intracranial pres-
However, because of the peculiar anatomical posi- sure aggravated by hypoxia. There is also evidence
tion of the cord within the confines of the bony that low-level accidental falls in children may on
spinal canal and the distinctive blood supply of occasion prove fatal. DAI frequently found in chil-
the cord, the patterns of injury and the likelihood dren, are not specific of trauma and may, at least in
of clinical recovery following even relatively minor part, result from ischemia (see supra). It is therefore
trauma (e.g., after small parenchymal contusions or important to develop as high a degree of certainty
hemorrhages) are quite different than in the brain. as possible from objective criteria before ascribing a
One possible late outcome of a traumatic cord lesion brain injury in a child to nonaccidental causes.

Chapter 3 Central Nervous System Trauma • 75


4
Neuropathology of Vascular Disease
J E AN-JACQUES   HAU W, U M B E RT O D E G I RO LA M I , A N D H A R R Y V. V IN T E R S

FOR CONVENIENCE of presentation we will 1. INTRACEREBRAL


divide the discussion of the neuropathology of cere-
brovascular disease in this chapter into three broad
AND SUBARACHNOID
categories: hemorrhage, infarction, and other dis- HEMORRHAGE: PRINCIPAL
orders. Within these subdivisions it is also possible PATHOPHYSIOLOGICAL
to consider these entities under the general concept MECHANISMS
of disorders that involve large vessels and those that
primarily involve arterioles or various components An extravasation of blood within the brain and/or
of the microcirculation. The term “cerebral micro- the leptomeninges, whatever its cause, constitutes
circulation” has been used in various settings; in an intracerebral and/or meningeal hemorrhage.
its broadest sense, the microcirculation includes Intracranial hemorrhage due to trauma (includ-
brain parenchymal and leptomeningeal arterioles, ing subdural or epidural hematoma) is described
venules, and capillaries—capillary endothelium is in Chapter  3. Also excluded from present con-
the site of the blood–brain barrier, the important siderations are the topics of hemorrhagic infarct
regulator of brain metabolism. Many pathologists (cf.  2.1.2), hemorrhage within neoplasms, and
include arteries and veins with external diameters brainstem hemorrhage secondary to herniation
of 350 to 400 um or less as components of the (cf. Chapter 1).
microcirculation. Within the limits delineated above, the two main
types of intracranial and/or cerebral hemorrhage to

76 •

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be discussed here are subarachnoid hemorrhage and compartments provides a practical anatomical
intraparenchymal hemorrhage. approach to assess different pathophysiological
mechanisms (Figs. 4.1 and 4.2), these subdivi-
• In subarachnoid hemorrhage (SAH), bleeding pri- sions are somewhat arbitrary. Causative agents and
marily takes place in the leptomeningeal spaces, risk factors that lead to SAH, for example, are also
potentially extending diffusely throughout the important in intracerebral hemorrhage.
subarachnoid space (SAS), or rarely it is localized
in the form of a subarachnoid hematoma. Under
certain circumstances, the causative factors that Subarachnoid Hemorrhage
give rise to an SAH may be such that the bleed- Hemorrhage into the subarachnoid space is an
ing bursts into the brain parenchyma and even important cause of morbidity and mortality in
extends into the ventricles, either directly from people of all age groups. A major cause of primary
brain parenchyma or by extension from the SAS. SAH is the rupture of an arterial aneurysm, usually
• In intracerebral hemorrhage, or intraparenchy- within the circle of Willis or one of its main branches
mal hemorrhage (IPH), bleeding occurs first and most often at a major bifurcation point. Less
within the brain parenchyma. The hemorrhage often, SAH may complicate a vascular malformation
may remain entirely within the brain substance, within brain parenchyma and, if in close proximity
or may extend into the ventricular cavities and to the surface of the brain, associated with extension
thence the SAS. Extensive outpouring of blood of bleeding to the subarachnoid space. SAH may
into the ventricles eventually makes its way to the also be seen in a number of other settings, including
subarachnoid space via the foramina of Luschka systemic hemorrhagic diatheses (e.g., severe throm-
and Magendie. Less often, in cases of intracerebral bocytopenia) or vasculitides (see below).
hemorrhages that involve the superficial portions
of the hemispheres, there may be direct extension
of the bleed into the subarachnoid space (cerebro-
meningeal hemorrhage). 1.1.1 . BERRY/SACCUL AR ANEURYSMS
An aneurysm is a localized pathological dilatation
Notwithstanding the considerations delineated of the cardiac ventricular wall or of a blood vessel;
above, although hemorrhage into various intracranial this phenomenon is the result of an abnormality of

TRAUMATIC

Cerebral and/or meningeal hemorrhage in the usual sense

From Hypertensive
ARTERIOLAR CHANGE Amyloid angiopathy

Intracranial arterial aneurysms


From rupture of
Arteriovenous malformations
Cerebral and/or VASCULAR MALFORMATION
Capillary telangiectases and
meningeal hemorrhage
cavernous angiomas (cavernomas)

Leukemias
Thrombocytopenic purpura
Hemophilia
From Hypothrombinemia
BLOOD DYSCRASIAS (especially anticoagulant therapy)
NONTRAUMATIC Sickle cell anemia
(“spontaneous”)
Polycythemia
Afibrinogenemia
Waldenström’s macroglobulinemia

Brainstem hemorrhage secondary


to herniation
Secondary to Hemorrhage within a tumor
VARIOUS CAUSES Hemorrhagic infarcts
Other causes
FIGURE 4.1 The principal causes of cerebral and/or meningeal hemorrhages.

Chapter 4 Neuropathology of Vascular Disease • 77


4 5

3 6

2
8

1 9

Cerebral parenchyma
Cerebral ventricles Subarachnoid space
Subdural space
Dura
Extradural space
Skull
1. Pure cerebral hemorrhage (or cerebral hematoma)
2. Cerebral hemorrhage with ventricular rupture Cerebral hemorrhages
3. Cerebromeningeal hemorrhage
4. Cerebromeningeal hemorrhage with ventricular ruputre
5. Meningocerebral hemorrhage with ventricular rupture
6. Meningocerebral hemorrhage
Meningeal hemorrhages
7. Pure meningeal (subarachnoid) hemorrhage
8. Subdural hematoma
9. Extradural (epidural) hematoma
FIGURE 4.2 Distribution of the blood in the various forms of intracranial hemorrhages.

the components of the wall of the involved structure 1.5 to 2 times more common in women than men;
such that it eventually gives way under pressure. Berry 10% to 30% of patients have multiple aneurysms,
aneurysms are localized sac-like dilatations of intra- and familial cases are rare. Though referred to as
cranial arteries. The aneurysmal outpouching is usu- “congenital”, clinically significant berry/saccular
ally connected to the artery by a narrow segment, or aneurysms are almost never encountered in infants
“neck”; its wall is formed by thin fibrous tissue with or children. As in all aneurysms, berry aneurysms
patchy interruption and attenuation of the elastic develop as the result of degenerative changes within
laminae and is associated with thinning of the media
(Fig. 4.3). Berry aneurysms usually occur at major
bifurcation points on the circle of Willis (Figs. 4.4
and 4.5). Most are found in the carotid anterior cir-
culation and involve the following sites: junction of
internal carotid (ICA) and posterior communicat-
ing artery, the origin of the anterior choroidal artery,
middle cerebral artery (MCA) bi/trifurcation in the
Sylvian fissure, and anterior cerebral artery (ACA)
and anterior communicating artery junction. Ten
percent of all aneurysms are found in the vertebro-
basilar territory, mainly at the tip of the basilar artery
in the interpeduncular cistern.
Most patients with symptomatic berry aneu-
rysms come to medical attention between the ages of FIGURE 4.3 Berry aneurysm, microscopic
40 and 70 years. Berry aneurysms are approximately appearance.

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A B 30%

INTERNAL
CAROTID
(terminal bifurcation and angle with
AC posterior communicating artery)
A

MCA I C I C

APPROXIMATELY 90% OF ANEURYSMS ANTERIOR MIDDLE CEREBRAL


COMMUNICATING (especially at origin
30% (and anterior 30%
BA of first main branches)
cerebrals)

10% Vertebrobasilar system

FIGURE 4.4 Distribution and frequency of arterial aneurysms. ACA, anterior communicating artery; IC,
internal carotid artery; MCA, middle cerebral artery; BA, basilar artery.

cerebral blood vessel walls, possibly secondary to (subarachnoid hematoma). In a number of cases,
abnormal smooth muscle and connective tissues. the bleeding penetrates into the adjacent cere-
There is an increased incidence of intracerebral bral parenchyma (meningocerebral hemorrhage)
aneurysms in polycystic kidney disease, Marfan and (Figs. 4.8 and 4.9). Bleeding of a ruptured aneurysm
Ehlers-Danlos syndromes, pseudoxanthoma elasti- may also occur directly into brain parenchyma and
cum, fibromuscular dysplasia, sickle cell disease, and not extend into the SAH immediately, especially if
coarctation of the aorta. the site of rupture on the dome of the aneurysm is
The clinical course of patients with berry aneu- embedded within brain substance. In these patients,
rysms depends on whether the lesion goes on to intraventricular rupture and life-threatening intra-
rupture (Fig.  4.6). Rupture of a berry aneurysm cranial hypertension may ensue.
usually produces life-threatening SAH (Fig.  4.7).
Bleeding within the subarachnoid spaces spreads • Cerebral infarcts associated with aneurysmal rup-
rapidly through the cerebrospinal fluid (CSF), caus- ture are frequent. Although their pathogenesis is
ing multiple neurological manifestations, including uncertain, possible causes include one or more of
sudden onset of headache, neck stiffness, and evi- the following: vascular compression from a sub-
dence of irritation of cranial nerves. Some patients arachnoid hematoma, thrombosis of the affected
experience smaller “leaks” from an aneurysm vessel, embolization arising from thrombus within
(before a large life-threatening hemorrhage), some- the aneurysmal sac, and arterial spasm.
times described as “sentinel leaks or bleeds”. Blood • Compression of structures adjacent to the aneu-
products elicit vasospasm in subarachnoid arteries, rysmal sac, particularly cranial nerves, may occur,
which may cause multifocal infarcts or extensive especially in relation to large aneurysms.
anoxic-ischemic change. Very extensive SAH may • Survivors of a SAH may have significant late
also result in rapidly increasing intracranial pres- postbleed morbidity, often associated with the
sure, leading to death; alternately, the hemorrhage development of hydrocephalus (secondary to
may stop spontaneously or in response to thera- fibrosis of the meninges resulting from accumula-
peutic intervention. The blood in the CSF under- tion of blood products within the leptomeninges).
goes resorption within a period of approximately 3 A rare sequela of repeated episodes of smoldering
weeks. Rebleeding may occur within 1 or 2 weeks SAH is subpial cerebral siderosis. This phenom-
after the initial event. In some patients, the spread enon is the result of seepage of breakdown prod-
of hemorrhage in the SAH may be contained by the ucts of red blood cells, including iron pigment,
development of a localized pool of clotted blood from the SAS into the adjacent molecular layer,

Chapter 4 Neuropathology of Vascular Disease • 79


A B

C D

FIGURE 4.5 Different types of berry aneurysms. (A) Vestigial aneurysm at the termination of the internal
carotid artery, obliterated by a clip. (B) Massive aneurysm at the termination of the internal carotid artery.
(C) Bilateral berry aneurysms at the termination of the internal carotid arteries. (D) Middle cerebral artery
aneurysm. (E) Aneurysm of the anterior communicating artery. (F) Aneurysm of the bifurcation of the basilar
artery.

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Inf ct
Extr
H

S,A.H

Compression Rupture
Intrasaccular thrombosis

FIGURE 4.7 Diffuse subarachnoid hemorrhage,


FIGURE 4.6 Representation of the main complica-
gross appearance.
tions resulting from arterial intracranial aneurysms.
Infct, infarction; Extr., ventricular extravasation;
H, intracerebral hematoma; S.A.H., subarachnoid infective/mycotic aneurysms usually occur in distal
hematoma. branches of the arterial tree. Rupture may result in
subarachnoid or intraparenchymal bleeding. In the
course of pathological examination of an intracere-
with secondary toxic injury of the crests of the
bral blood clot, the presence of an infective/mycotic
cerebellar folia.
aneurysm, friable and weakened because of polymor-
• In the general population, unruptured aneurysms
phonuclear leukocytes in the vessel wall, should be
are a relatively common “incidental” finding at
an important diagnostic consideration and diligently
autopsy, or detected on imaging studies under-
sought within the specimen. Stainable microorgan-
taken in the workup of patients with neurological
isms may be demonstrable among inflammatory
manifestations for other reasons.
cells on sections of infective aneurysms.
Infective/mycotic aneurysms due to endocardi-
Though neurosurgical “clipping” of a ruptured
tis result from a septic embolus that lodges within a
aneurysm is still standard therapy; “noninvasive”
branch of a cerebral artery, with subsequent exten-
endovascular treatments (e.g., “coiling” to induce
sion of microorganisms from the embolus into the
thrombosis of the aneurysm, or wrapping) are
adjacent vessel wall. Septic emboli in individuals
increasingly being used in various parts of the world.
with infective endocarditis may also lead to an isch-
emic (bland) infarct that may undergo hemorrhagic
1.1.2. INFLAMMATORY/INFECTIVE transformation, or result in a pyogenic arteritis,
ANEURYSMS (“MYCOTIC” ANEURYSMS) causing an intracerebral hematoma.
These lesions, which account for 3% to 6% of all intra-
cranial aneurysms, are usually associated with sub-
1.1.3 . DISSECTING ANEURYSMS
acute or acute infective endocarditis. They are seen
(ARTERIAL DISSECTIONS)
less often with spread of infection from a contiguous
site (e.g., osteomyelitis, meningitis) into the vessel These are almost always encountered in young and
wall. The microorganisms causing the endocarditis middle-aged patients (25 to 45  years) and may be
are multiple and frequently of low virulence; both associated with infarcts and SAH. Dissection may
bacteria and fungi can be responsible (particularly occur in extracranial and/or intracranial branches
in immunocompromised subjects and persons who of the carotid or vertebrobasilar system. When intra-
use intravenous drugs). Unlike berry aneurysms, cranial dissection occurs in the anterior circulation,

Chapter 4 Neuropathology of Vascular Disease • 81


A B

C D

FIGURE 4.8 The sites of hematomas secondary to rupture of an arterial aneurysm. (A) Aneurysm of the ante-
rior communicating artery (and of the anterior cerebral artery). (B) Aneurysm of the posterior communicating
artery. (C) Aneurysm of the middle cerebral artery. (D) Aneurysm of the bifurcation of the internal carotid artery.

the site of dissection is usually between the internal to the neck (often perceived as rather minimal), cer-
elastic lamina and the media, often with resultant vical manipulation, exercise, administration of hepa-
intravascular thrombosis. When dissection occurs rin, or in the context of fibromuscular dysplasia, but
in the posterior circulation, transmural dissection in most cases, the pathological substrate remains
can result in SAH. undefined.
Specific vasculopathies associated with dissec-
tion include fibromuscular dysplasia and connective
1 .1 . 4. FUSIFORM AN EURYSM S
tissue disorders, including Marfan syndrome and
Ehlers-Danlos syndrome (type IV). Arterial dissec- These lesions result from enlargement and widen-
tion of cervical arteries may occur following trauma ing of an arterial segment along its length (arterial

A B

FIGURE 4.9 Hematomas resulting from the rupture of an arterial aneurysm. (A) Bifrontal hematoma
with ventricular rupture, following rupture of an aneurysm of the anterior communicating cerebral artery.
(B) Hematoma of the Sylvian fissure, following rupture of an aneurysm of the middle cerebral artery.

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A B

FIGURE 4.10 Giant atherosclerotic aneurysm (A) of the anterior cerebral artery and (B) of the basilar artery.

dolichoectasia). They are unusual lesions, more cavernous hemangiomas) and aneurysms, and “rec-
frequently recognized in the geriatric population. reational” drug use.
Although not believed to be directly caused by ath-
erosclerosis, they are often associated with it. On
1.2.1 . HYPERTENSION AND
microscopic examination of the involved portion of
HYP ERTENSIVE CEREBROVASCUL AR
the arterial wall, there is interruption of the smooth
DISEASE
muscle layers and fraying of the internal elastic lam-
ina. A  pathogenic theory recently advanced is that Arterial hypertension has long been consid-
fusiform aneurysms may be related to internal elastic ered the major cause of IPH; however, given the
lamina injury and dysfunction of matrix metallopro- increasingly effective pharmacological treatment
teinases. Fusiform aneurysms are defined as widen- of hypertension, the incidence of “hypertensive
ing of the artery to a diameter larger than 2.5 cm, but hemorrhage” has markedly declined in many parts
they may reach giant proportions (Fig. 4.10A). They of the world.
most often involve the basilar artery (Fig.  4.10B),
causing brainstem displacement and compression, 1.2.1.1. Mechanisms IPH resulting from hyper-
resulting in cranial nerve deficits, among other focal tension is largely attributed to hypertensive cerebral
neurological manifestations. vascular disease, i.e., due to arteriosclerosis, arteriolo-
When examined in cross-section, the aneu- sclerosis (AS) and to lipohyalinosis (a term now less
rysm often contains laminated thrombi within the commonly used). The molecular pathogenesis of AS
expanded lumen, the result of severe, complicated is poorly understood. Its evolution has been firmly
atherosclerosis. As a result, platelet-fibrin or athero- associated with a documented history of hyperten-
matous emboli may travel distally in the circulation sion; however, despite effective prophylactic treat-
to produce transient ischemic attacks or infarcts ment of severe and moderate hypertension in many
in branches of the vertebrobasilar circulation. The countries, arteriosclerotic microvascular disease is
aneurysm rarely ruptures or produces SAH. still seen commonly in autopsy brain specimens,
especially in the elderly. In such individuals, other
accompaniments of chronic hypertension (e.g., car-
1.2. Intraparenchymal Hemorrhage diomegaly, left ventricular hypertrophy, and nephro-
The site and mechanisms of IPH vary according sclerosis) may be absent.
to etiology. The most common causes of IPH are Histopathological features of AS include hya-
hypertension inducing small artery diseases, coag- line thickening (sometimes with degeneration of
ulopathies (including hemorrhagic diatheses and the internal elastic lamina), intimal fibromuscular
iatrogenic causes in the setting of anticoagulation), hyperplasia, variable degrees of luminal narrowing,
cerebral amyloid (congophilic) angiopathy (CAA), thinning of the media, concentric “onion-skin”-type
vasculitis, primary or secondary brain neoplasms, smooth muscle cell proliferation or hyperplasia, and
arteriovenous malformations (AVMs) (less often the presence of foamy macrophages in the arterial

Chapter 4 Neuropathology of Vascular Disease • 83


commonly encountered in association with other
microangiopathies, especially CAA (see below).

1.2.1.2. Evolution The appearance of the hema-


toma varies depending on the duration between
the clinical ictus and the time of neuropathological
examination.
Initially, the intraparenchymatous bleeding gives
rise to an accumulation of blood that is under pres-
sure, contains little parenchymatous debris, and dis-
places the adjoining cerebral structures (Fig. 4.13A,
C, D). The outer boundaries of the lesion are irregu-
lar and small petechial hemorrhages are present
FIGURE 4.11 Arteriolosclerosis: narrowing of
along its borders.
the lumen, concentric smooth muscle cell prolifera-
The bleeding may remain localized, or it may
tion, and the presence of foamy macrophages in the
expand rapidly, resulting in increased intracranial
arterial wall.
pressure and brain herniation. Rupture into the
ventricles with subsequent passage of blood into
wall (lipohyalinosis) (Fig. 4.11). Fibrinoid necrosis the subarachnoid space and basal cisterns can also
occurs in malignant hypertension. occur. Less often, the hemorrhage bursts directly
These microvascular lesions may lead to occlu- through the cerebral cortex into the SAS, though
sion of arterioles and to lacunar infarcts (cf. 3.2.3) this is much more common with CAA-related IPHs.
or to weakening of the vessel leading to rupture This is not surprising because they are caused by a
and IPH. meningocortical form of microvascular disease.
As already mentioned, hypertensive IPH is due In time, over the course of 2 to 14 days after the
to the rupture of small intracerebral arterioles 50 to initial bleed, the hemorrhage begins to lyse and there
200  μm in diameter, the walls of which have been is an acute inflammatory response that then evolves
weakened by replacement of the normal media to phagocytosis of the breakdown products largely
(muscular and elastic components) by collagenous by blood-derived scavenger cells. Macroscopic
fibrous tissue. In classic studies, Charcot-Bouchard autopsy studies of patients who survive the intra-
(C-B) microaneurysms have been described in the cranial hemorrhage beyond a month show the site
affected arterioles (Fig.  4.12), although often they of the hemorrhage to be a cavity with remnants of
are difficult to find even when brain parenchyma resorbed blood imparting an orange/yellow margin
around a hypertensive hemorrhage is extensively and adjacent discolored and firm gliotic brain tissue
and carefully sampled. As well, C-B aneurysms are (Fig. 4.13B). This lesion may (especially after many

A B

FIGURE 4.12 Miliary aneurysm (Charcot-Bouchard). (A) Charcot-Bouchard microaneurysms as drawn by


J-M Charcot. “Location: Hemispheric gray matter. The vessel is 26/100 (1/4) mm wide; in spite of its size, the
wall is devoid of a muscle layer and is thickened.” (B) Microscopic appearance.

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A B

C D

FIGURE 4.13 Basal ganglia hemorrhages. (A) Lateral basal ganglia hemorrhage. (B) Cystic scar of an old
capsulo-lenticular hemorrhage. (C) Massive hemorrhage. (D) Medial thalamic hemorrhage.

years) be difficult to distinguish from an old (hem- subthalamic nucleus and midbrain. Extension into
orrhagic) infarct. Microscopic sections around the the third ventricle is seen in over 50% of cases;
edges of the hematoma show hemosiderin-laden and (d) the massive hemorrhages destroying most
macrophages and reactive astrocytes. of the above-mentioned structures are relatively
infrequent. Increased intracranial pressure with
1.2.1.3 Topography Approximately 80% of herniation is commonly seen with massive hem-
hypertensive IPHs are situated in the cerebrum, orrhages and is infrequent in medial/thalamic
mostly in the basal ganglia (Fig. 4.13). hemorrhages.
• Hypertensive hemorrhages may also be seen
• Within the basal ganglia, the most common in the subcortical white matter. They may be
sites of involvement can be divided in four massive or localized small extravasations at the
groups: (a) the putamen and external capsule junction of the cortex and white matter (“slit
(lateral basal ganglia): these may extend superi- hemorrhages”).
orly and medially into the internal capsule and
lateral ventricle; (b) medial basal ganglia: these Intracerebellar hemorrhages (Fig.  4.14) rep-
always extend into the internal capsule and usu- resent about 10% of all hypertensive IPHs. The
ally the globus pallidus and frequently the third clinical evolution of these hemorrhages is that of a
ventricle; they may also involve the white mat- space-occupying mass in the posterior fossa, and
ter of the superior temporal gyrus; (c) medial/ rupture into the fourth ventricle may occur.
thalamic: these are less common (10% to 20% Brainstem hemorrhages (Fig.  4.15) represent
of hypertensive IPHs) and can involve the about 10% of hypertensive IPHs. These are most
internal capsule and caudate nucleus, rarely the often situated in the pontine tegmentum/basis

Chapter 4 Neuropathology of Vascular Disease • 85


FIGURE 4.14 Intracerebellar hemorrhage. FIGURE 4.15 Brainstem hemorrhage.

pontis and can be clinically associated with the with moderate to severe CAA shows a considerably
“locked-in” state. higher prevalence of hemorrhagic (and sometimes
ischemic) lesions than is seen in cases without CAA.
Relatively rare familial forms of CAA are also
1. 2. 2. C E RE BRAL AM Y L O I D A N G I O PATH Y
found in various countries around the world.
This microvascular lesion is more commonly associ-
ated with cerebral hemorrhage than with ischemia. • In a circumscribed coastal region of the
The microscopic characteristics of the lesion consist Netherlands, an autosomal dominant form of severe
of deposition of amyloid within the media and/or CAA (hereditary cerebral hemorrhage with amyloido-
adventitia of small parenchymal and leptomenin- sis, Dutch type/HCHWA-D) is attributed to a unique
geal vessels. Amyloid has the unique physicochemi- APP gene mutation (at codon 693). Massive Aβ—
cal structure of beta-pleated fibrils, giving it specific deposition occurs within the media of cerebral arte-
staining and optical properties. Upon staining with rioles, and fatal or debilitating cerebral parenchymal
thioflavin T the deposits emit bright-green fluores- hemorrhages frequently ensue. Less prominent
cence under ultraviolet light. Amyloid stains red with senile plaque-like parenchymal Aβ—deposits may
Congo red and gives apple-green birefringence under also be present within cerebral cortex.
polarized light (Fig.  4.16A). Immunohistochemical • APP codon 692 and 694 mutations appear to
methods are now also often used to demonstrate the cause, respectively, a rare Flemish form of CAA
various types of amyloid deposits. The deposits have (also with frequent IPH) and AD with prominent
a characteristic ultrastructural fibrillary appearance CAA in a family reported from the state of Iowa.
and correspond to misfolded protein. The nature of • An Icelandic form of CAA leading to hemorrhagic
the amyloid deposit varies depending on the bio- stroke, hereditary cerebral hemorrhage with amyloido-
chemical nature of the protein (see below). sis, Icelandic type/HCHWA-I, results from mutation
in the gene encoding cystatin C/gamma-trace;
1.2.2.1. Etiology The most common form of hence this condition is also sometimes described
CAA is associated with deposition of Aβ—pro- as hereditary cystatin C amyloid angiopathy
tein, a small, 42 amino acids peptide cleaved from (HCCAA). It causes cerebral bleeds in young
the amyloid precursor protein (APP) and encoded and middle-aged adults. Brains from HCHWA-I
by a gene on chromosome 21. CAA has a strong patients show extensive deposition of gamma-trace
association with aging, Alzheimer disease (AD), protein within arteriolar walls, associated with
and other conditions such as Lewy body dementia. degeneration of the affected vessel walls.
In these conditions, to variable extents in different • Also, familial British and Danish forms of CAA
patient populations, there is excessive deposition of have been described and attributed to unique
Aβ in both the brain gray matter (as senile plaques mutations on the BR12 gene, situated on chro-
and diffuse deposits) and vessel walls (as CAA) (cf. mosome 13. These two and other genetically
Chapter  8) (Fig.  4.16B, C). The brain of patients determined forms of CAA (e.g., meningovascular

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A B

FIGURE 4.16 CAA.Apple-green birefringence of the vessel wall under polarized light with Congo red stain
(A); immunocytochemistry for Aβ shows diffuse infiltration of the arteriolar wall by amyloid (B,C). There is
also involvement of the capillaries (dyshoric angiopathy), with amyloid appearing to be “leaking” from the capil-
lary wall into brain parenchyma (C).

amyloidosis associated with transthyretin deposition, angiopathy, also called type 1 of Thal, amyloid is
familial amyloidosis of the Finnish type caused by thought to be “leaking” from the capillary wall into
gelsolin deposition) are less consistently associ- brain parenchyma (Fig.  4.16C). Type 1 is always
ated with IPH than are the Dutch, Flemish, and found when type 2 is present, although sometimes
Icelandic familial variants of CAA. the presence of amyloid renders difficult the accu-
rate identification of the vessel type affected.
1.2.2.2. Pathology All regions of neocortex and Histologically there is infiltration of the media and
overlying meninges may be affected by CAA, with adventitia of small vessels by an acellular amorphous
minor variations in the distribution of affected arter- eosinophilic substance, which gives the vessel wall a
ies among lobes. While cerebellum and its meninges homogeneous pale appearance, often allowing the
are occasionally involved by CAA, the microvascular diagnosis to be made on routine stains. In addition,
abnormality is almost never found within deep cen- some affected vessels, particularly pia mater arteri-
tral gray matter, subcortical white matter, the brain- oles, have a “double- barrel” appearance (Fig. 4.17A).
stem, or spinal cord. CAA may be patchy within the Amyloid deposition in the arterial wall causes dam-
cerebral cortex and adjacent leptomeninges; it can age of the medial smooth muscle cells. These changes
be segmental in given small vessels. disrupt the vascular architecture and weaken the
The term CAA encompasses amyloid deposition affected arterial walls. A variety of secondary changes
within the walls of small and medium-sized venules, may be found in the affected vessels, including fibro-
arteries, and arterioles (congophilic angiopathy, also sis, microaneurysm formation, chronic (including
called type 2 of Thal) (Fig.  4.16B, C). In dyshoric granulomatous [Fig. 4.17B]) inflammation, fibrinoid

Chapter 4 Neuropathology of Vascular Disease • 87


necrosis, thrombosis, and, very rarely, vessel wall cal- 1 .2 . 3. VASCULAR M ALFORM ATION S
cification. These CAA-associated microangiopathies
These may be found in the CNS parenchyma, over-
(CAA-AM), especially microaneurysm formation
lying meninges and dura, or (rarely) both.
and fibrinoid necrosis, appear to increase the likeli-
hood of vessel rupture leading to IPH.
1.2.3.1. Arteriovenous malformations AVMs
1.2.2.3. Complications  of  CAA The extent of are the most clinically important of these lesions;
amyloid deposition within vessel walls correlates they rarely become manifest clinically beyond the
with increasing risk of IPH. CAA is the cause of age of 60 years.
hemorrhages with highly distinctive clinicopatho- AVMs may cause intraparenchymal or/and sub-
logical features (Fig.  4.18). When the hemorrhage arachnoid hemorrhage. AVMs usually occur in the
occurs within the cortex, it may dissect into the MCA territory, often involving a wedge-shaped area
subarachnoid space; when at the junction with the of brain parenchyma and overlying leptomeninges,
subcortical white matter (“lobar” hemorrhages), the but may be seen anywhere in the central nervous
lesion may rupture into the lateral ventricles. This system (CNS), including posterior fossa structures,
“lobar” predilection reflects the topography of and even on the circle of Willis. An AVM represents
CAA, a cortical and meningeal vasculopathy. CAA an abnormal tangle of vessels with direct communica-
may be readily detected on neuropathological tion between one or more arteries of the brain or spi-
examination in neurosurgical specimens of frag- nal cord parenchyma and one or more draining veins,
ments of brain parenchyma evacuated together with without an intervening capillary bed. The shunt most
a hematoma. Evidence of cerebral bleeds of different often involves a core of abnormal channels, called the
ages (months or years) can be seen at postmortem nidus. Arteriovenous fistulas are single-hole arterio-
examination involving different lobes of both cere- venous shunts. The arterial feeders are supplied either
bral hemispheres. As many as one third of patients by brain arteries or by dural arteries. The venous
afflicted with CAA-related lobar hemorrhage may drainage may take place in the superficial or the deep
also have clinical evidence of hypertensive microan- draining systems of the brain. Also, the microscopic
giopathies, and features of associated arterioloscle- morphologic features of AVMs are quite distinctive
rosis may also be seen. (Fig. 4.19A). The lesion consists of a mass of vascu-
Less frequent manifestations of CAA include lar channels of variable mural thickness and diameter,
SAH without IPH, leukoencephalopathy (cf. 3.2.5), embedded within abnormal, gliotic, and occasionally
granulomatous angiitis (Fig.  4.17B), recurrent malformed brain parenchyma. The CNS parenchyma
transient neurological symptoms (possibly due to may show morphologic evidence of old hemorrhage,
microinfarcts and/or miliary hemorrhages in the but an absence of blood breakdown products does
cerebral cortex), and brain infarct. not rule out the possibility that the AVM has bled

A B

FIGURE 4.17 CAA. Infiltration of the vessel wall by the acellular amorphous eosinophilic amyloid sub-
stance; note “double barrel” appearance of a leptomeningeal arteriole (A) and inflammatory granulomatous
reaction (B).

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A B

FIGURE 4.18 Lobar intracerebral hemorrhages in patients with CAA involving the right temporal lobe
(A) and the left parietal-occipital region (B).

prior to resection. Thrombosed and recanalized vas- A


cular channels are usually present within an AVM.
Other characteristic abnormalities include hyalinized,
sometimes calcified (rarely, ossified) arterial walls, or
abnormalities in the blood vessels characteristic of
intimal fibromuscular hyperplasia. However, “compli-
cated” atheromatous change (with cholesterol clefts,
necrosis, and hemosiderin-laden macrophages) is
almost never seen on the intimal aspect of AVM
channels. Patients with AVMs become symptomatic
following rupture of the abnormal vessels and bleed-
ing into brain tissue and/or the SAS, direct pressure
on adjacent brain substance, or because of a “steal” of
blood from adjacent structures in the setting of arte-
riovenous shunting. In 10% of patients with AVM
there may be one or more coexistent berry aneu-
rysms somewhere along the circle of Willis, usually in
an artery “feeding” the AVM, presumably because of
increased flow/pressure within its lumen. AVMs are
also rarely seen along the spinal cord, where they fre-
quently occur as dural arteriovenous fistulas. AVMs
are usually treated by excision or iatrogenic emboli- B
zation therapy (the latter performed with the hope
of occluding the AVM nidus). As well, iatrogenic
embolization materials of many sorts, often with a
brisk granulomatous inflammatory response, may be
seen within the vascular lumina of autopsy or surgical
AVM specimens.

1.2.3.2. Venous angiomas Venous angiomas


(VAs) consist of one or more dilated, often grossly
apparent veins and their smaller tributaries, lack-
ing an obvious arterial component. If the lesion is FIGURE 4.19 Vascular malformations. (A) Medial
a single tortuous vein (e.g., in the spinal subarach- frontal cerebral arteriovenous aneurysm. (B) Vein of
noid space), it is described as a “varix”(Fig. 4.19B). Galen aneurysm.

Chapter 4 Neuropathology of Vascular Disease • 89


Component vessels of a VA are more dilated and
have thicker walls than normal veins, and brain
parenchyma between the vessels shows negligible
reactive changes or evidence of prior bleeding. The
lesion is most often discovered as an incidental find-
ing at postmortem examination.

1.2.3.3. Capillary telangiectases These are


also common incidental lesions found at autopsy.
They consist of multiple dilated capillaries without
alterations of the surrounding brain substance. On
macroscopic examination, both VAs and capillary
telangiectases appear as small, fairly well-defined FIGURE 4.20 Multiple lobar hemorrhages in a
hemorrhagic lesions that initially suggest a localized patient with leukemia.
region of bleeding (e.g., petechial hemorrhage).

1.2.3.4. Cavernous hemangiomas (caverno- surgically resected blood clot (in current practice
mas) Less common than AVMs, these appear as removed either by craniotomy or endoscopic meth-
closely packed blood vessels (of varying wall thick- ods) should always be studied carefully for a lesion
ness) without intervening CNS parenchyma. The that may have caused the IPH. Sometimes examina-
lesion is most often found in the pons or subcorti- tion of the specimen under a dissecting microscope
cal white matter. On occasion, a patient with a cav- may be helpful, so that brain fragments can more
ernoma may present with signs and symptoms of a easily be separated from blood clot. Evidence of
space-occupying lesion and/or a seizure disorder, microangiopathies (AS, CAA), fragments of a vas-
in which case the clinical differential diagnosis and cular malformation, (clinically unsuspected or undi-
distinction from a primary brain tumor may be dif- agnosed) primary or metastatic neoplasm, portion
ficult. Though cavernoma is ordinarily not the cause of an inflammatory/mycotic aneurysm, etc., may be
of a massive hemorrhage, on microscopic study the found in this way.
lesion is almost always surrounded by deposits of
hemosiderin, indicating slow or recurrent leakage of
blood from component abnormal vessels. Familial
syndromes of cavernous angiomas (especially
2. INFARCTION: PRINCIPAL
among Hispanic subjects) have been linked to genes PHYSIOPATHOLOGICAL
on chromosomes 3q, 7q, and 7p. MECHANISMS
The terms “cerebral infarct,” “cerebral softening,”
and “encephalomalacia” are used to denote an area
1. 2. 4. S Y S T E MI C DIS EA S E
of tissue necrosis localized to a particular territory
IPH may occur in the setting of systemic disease of vascular supply. In most cases, an infarct is due to
associated with bleeding disorders, including occlusion of a branch of the feeding arterial tree. It
thrombocytopenia, coagulopathy (either iatrogenic may also follow a severe decrease in blood flow in
or secondary to hepatic failure), hemophilia, dis- the absence of arterial occlusion. In venous infarc-
seminated intravascular coagulation (DIC), and tion, the tissue ischemia is due to the occlusion of a
leukemia (Fig.  4.20). Although, often, the intra- large vein and consequent stasis.
cranial hemorrhages that are seen in many of these
diseases manifest as multifocal extravasations of
blood throughout the brain, with associated sub-
arachnoid bleeding, in some cases, the lesions are
2.1. General Features
single and fairly circumscribed and may therefore Arterial occlusion or severe reduction of blood flow
mimic hematomas associated with hypertension of sufficient duration produces ischemic necrosis.
or CAA, in terms of both their extent and topogra- The gross and microscopic appearances associated
phy. As suggested above (in the context of CAA), with infarction are manifest by a series of sequential

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though the tissue is irreparably damaged. From 8 to
48 hours (Fig.  4.21), the damaged brain becomes
discolored, and the demarcation between the white
and gray matter is indistinct. Edematous swelling is
apparent and is sometimes accompanied by vascular
congestion, which is more marked in the cortex. At
this stage, the softer consistency of the involved area
is the only feature that permits the infarct to be rec-
ognized macroscopically after 2 to 3 weeks of brain
formalin fixation. From 2 to 10 days in the course of
the evolution of an infarct, the swelling persists, pro-
gressively decreasing over time, while the softened
tissue becomes more friable and the boundaries of
the infarcted territory become better defined.
Microscopically, after 6 to 12 hours, the neurons
within the infarcted territory demonstrate the fea-
FIGURE 4.21 Recent anemic or pale infarct involv- tures of acute ischemic cell injury (i.e., the cytoplasm
ing the territory of the right anterior cerebral artery. is eosinophilic, the Nissl substance is dispersed, the
nucleus is shrunken, and the nucleolus is no longer
visible) (Fig.  1.2). In the cortex and white matter,
changes that are distinctive regardless of the site of the capillary blood vessels show endothelial swell-
the affected territory within the CNS. ing accompanied by vasogenic and cytotoxic edema
The main types of infarction generally recognized fluid and by some extravasation of red blood cells
are anemic, or pale, infarcts, in which the cellular reac- (even in anemic infarction). Glia also shows isch-
tions to ischemic necrosis predominate (Fig. 4.21), emic cell damage, and somewhat later myelinated
and hemorrhagic infarcts, wherein the lesions are fibers lose their usual tinctorial affinity. Between 24
associated with hemorrhagic phenomena; the latter and 48 hours there is evidence of an emigration of
especially involve the cortical ribbon and the basal neutrophils, which can be severe and may simulate
ganglia (Fig. 4.22). an acute infectious process (Fig. 4.23).
After 48 hours, the leukocytes are replaced by
macrophages. These cells, which are laden with
2.1.1. ANEMIC/PALE INFARCTION
breakdown products of myelin disintegration, clus-
On macroscopic examination, the lesions are poorly ter around the swollen capillary blood vessels walls.
circumscribed early in the course of the evolution The macrophage proliferation becomes considerably
of the infarct. In the first 6 hours or so, no visible more marked after 5 days. Cerebral edema is usually
alteration can be demonstrated with the naked eye, maximal 3 to 5 days after a large infarct and may (at

A B

FIGURE 4.22 Hemorrhagic infarcts (A and B).

Chapter 4 Neuropathology of Vascular Disease • 91


run across the cavity. In the case of cortical infarcts,
very often, layer I of the (infarcted) cerebral cortex
persists with a dense accumulation of (gemisto-
cytic) astrocytes.

2 .1 . 2. HEM ORRHAGIC IN FARCTION


This type of infarction is classically regarded as dis-
tinct from anemic bland infarction, although as men-
tioned above, microscopic evidence of red blood cells
extravasation is often found in the latter, especially
at the outer border of the lesion. In hemorrhagic
infarction, patches or confluent areas of hemorrhage
FIGURE 4.23 Microscopic features of cerebral
are evident, particularly in the cortex. These hemor-
infarcts. Diffusely scattered and perivascular groups of
rhages may involve the entire extent of the ischemic
polymorphonuclear leukocytes after 35 hours.
region (Fig. 4.22A), and in the cerebral cortex they
predominate along boundary zones supplied by men-
this time) lead to fatal herniation, sometimes with ingeal arterial anastomoses; in middle cerebral artery
Duret brainstem hemorrhages. After 10 days, mac- occlusion, the basal ganglia are involved (Fig. 4.22B).
roscopically, liquefaction begins, and from the third It is generally accepted that an important pathoge-
week onward the process of cavitation becomes netic mechanism of hemorrhagic infarction holds
more evident. From then on, the area of necrosis is that tissue reperfusion occurs following thromboly-
replaced by yellowish sunken gray tissue. The mac- sis or mobilization of an occluding thromboembo-
rophage proliferation persists, although to a decreas- lism. Extravasation of blood to varying extent then
ing degree, during the subsequent months, and the occurs in a capillary bed irreversibly damaged by the
number of reactive (gemistocytic) astrocytes pro- ischemic insult (see Fig. 4.26F). Indeed, this type of
gressively increases. After a few months, the necrotic infarction most often follows cerebral embolization,
zone becomes a cystic cavity with ragged outlines, where breakdown of the occluding thrombus and
intersected by vascular connective tissue strands distal migration commonly occurs.
and covered by leptomeninges on its cortical surface
(Fig. 4.24). During the phase of scar formation, the
residual cystic cavity is surrounded by a glial prolif-
2.2. Pathophysiology and Etiology
eration, while a few macrophages remain along the Cerebral infarction caused by prolonged isch-
persisting vascular connective tissue strands that emia localized to a particular vascular territory is

A B

FIGURE 4.24 Old cystic infarct in the territory of the middle cerebral artery. (A) Left cerebral hemi-
sphere. (B) Coronal section: note the involvement of a large part of the middle cerebral artery, sparing the
temporal lobe.

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commonly secondary to arterial occlusion. It may the vascular territory that is normally served by the
be due to either thrombosis, most often in the occluded artery (Fig. 4.26D, E). However, the extent
setting of atherosclerosis, or to embolization (of of this reinforcement varies from case to case, and
cardiac origin or via artery-to-artery embolism). anatomical variations from the norm are frequent
Atheroemboli (e.g., from a severely atheroscle- (Fig.  4.26B). Moreover, these anastomotic path-
rotic cervical artery) may be encountered within ways may themselves be occluded by atherosclerotic
infracted brain, though in a small minority of lesions or become incompetent as a result of throm-
cases. On neuropathological examination of cere- bus propagation (Fig. 4.26C).
bral infarcts where no arterial occlusion is seen,
the presumption is that (1)  the occluding emboli 2.2.1.2 Site of occlusion
have undergone secondary lysis; (2)  severe and Proximal occlusion of a blood vessel, such as the
prolonged hypotension involving arteries with internal carotid artery, may, because of collateral
extensive or multifocal atheromatous stenosis has flow from the contralateral arterial network and via
resulted in hypoperfusion of tissue; or (3) stenosis the ophthalmic artery, produce only a limited lesion.
has been the result of arterial spasm. Reirrigation is generally adequate in the proximal
The appearance and extent of the cerebral infarct territory, and the lesions will then predominate in
depends on a number of modifying hemodynamic the distal regions (“last fields of irrigation”) or at the
and etiological factors (Fig. 4.25 and 4.26). junction of two vascular territories (“watershed or
boundary-zone infarct”) (Fig.  4.26D). Should the
proximal arterial anastomotic network (i.e., circle
2.2.1. HEMODYNAMIC FACTORS
of Willis) be anatomically incompetent (Fig. 4.26B)
2.2.1.1. Presence and efficacy of anastomotic or pathologically occluded (Fig. 4.26C), the infarct
pathways of vascular supply In the course of arte- will then be massive and will involve the entire arte-
rial occlusion, the ischemic cerebral territory is par- rial territory.
tially reirrigated by arteries at the base of the brain In the case of distal occlusion involving an
(circle of Willis, ophthalmic artery) and by super- end-artery, such as the middle cerebral artery, collat-
ficial corticomeningeal anastomoses (Fig.  4.26A). eral flow is dependent on a superficial anastomotic
This potential arterial anastomotic reirrigation sup- network, which is often precarious, and as a result,
ply explains why, in most cases, the resulting area of the infarct proximal to the circle of Willis will usu-
cerebral softening remains limited to only the part of ally be extensive (Fig. 4.26E).

ATHEROSCLEROTIC
CARDIOPATHIES STENOSIS Atherosclerotic
stenosis of
Anatomical byways of Functional
EMBOLI Mural thrombus
abnormalities supply factors*

Complete
THROMBOSIS

Failure of substitution
OCCLUSION OF MAIN
+ byways of
ARTERIAL TRUNK
supply

Extension of
thrombus

Inadequacy of
OCCLUSION OF A
+ arterial cortico-
PERICEREBRAL ARTERY
meningeal anastomes

CEREBRAL
INFARCT

FIGURE 4.25 Etiological and pathophysiological factors determining cerebral infarcts. *Functional fac-
tors: decrease in caliber of ischemic arteries; drop in blood pressure; loss of autoregulation of arterial caliber.

Chapter 4 Neuropathology of Vascular Disease • 93


SC
A B C

SA
DC

AC

D E F

a b
1 2
1 2

FIGURE 4.26 Anastomotic patters of collateral supply and corresponding extent of cerebral lesions (AC,
anastomotic vascular network; SC, superficial arterial circulation; DC, deep vascular territory; SA, superficial
meningeal anastomoses). (A) Arterial occlusion but with effective and adequate anastomotic substitution net-
work of supply: no infarction. (B) Arterial occlusion without anatomically effective anastomotic collateral supply
(AC): massive infarction of the corresponding cerebral territory. (C) Arterial occlusion extending beyond the
origin of the anastomotic collateral supply. Absence of collateral supply: massive infarction. (D) Occlusion
proximal to the anastomotic collateral supply. Insufficient collateral supply. Anemic infarct of variable extent
in the territory (2) distal to the junction of two vascular territories (last field of irrigation or watershed infarct)
and in border zone between superficial and deep vascular territories (1). (E) proximal occlusion of one divid-
ing branch; collateral supply provided by superficial meningeal anastomoses: limited proximal infarction.
(F) Embolic occlusion. Mobilization of thrombus from 1 to 2. Sudden occlusion in 1, resulting in total ischemia
of both deep and superficial vascular territories and in hemorrhages in the superficial territory when border
zones are undergoing reirrigation (b); secondary mobilization of the thrombus in 2, with hemorrhages due to
secondary extravasation of blood into the originally ischemic deep vascular territory.

2.2.1.3. Type of occlusion In general, throm- 2 .2 . 2. ETIOLOGICAL FACTORS


bosis that leads to gradual occlusion of a vessel
2.2.2.1. Atherosclerosis General features.
allows for compensatory mechanisms of collateral
Atherosclerosis is the principal etiological factor in
flow. The resulting infarct is then usually pale and of
the production of cerebral infarction. The structural
relatively limited extent.
features and development of atherosclerosis in the
In contrast, emboli often produce sudden
brain are comparable to those in other organs. With
occlusion, with cessation of flow and inadequate
regard to the brain, atherosclerosis affects chiefly
irrigation. Hence, the resulting infarct is usually
large intracranial blood vessels and the carotid
extensive. In addition, migration and second-
arteries in the neck, even though the latter are infre-
ary fragmentation of the embolus is frequent.
quently examined at necropsy. It predominates at
This accounts for the hemorrhagic component of
sites of bifurcation (particularly at the level of the
the infarct frequently observed in the proximal
carotid sinus), at sites of curvature of the arteries, and
part of the ischemic territory, which follows sud-
at sites where the arteries are anatomically fixed. The
den reentry of arterial blood into damaged tissue
distribution of atherosclerosis in the thoracocervical
(Fig. 4.26F).
arterial tree and in the circle of Willis is illustrated in

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however, microatheroma may be encountered (e.g.,
in parenchymal arteries within the basal ganglia, espe-
cially in subjects with severe basal atherosclerosis).
Increase in the size of the atherosclerotic
plaque and focal lesions, such as intramural hem-
orrhage, calcification, and mural thrombosis,
leads to increasing arterial stenosis (Fig.  4.28). It
is generally believed that the latter must involve
more than 75% of the original lumen of the artery
to cause a clinically significant decrease of blood
flow. The evolution of arterial stenosis is variable
(Fig.  4.29). The main complication lies in the
development of arterial thrombosis secondary to
local changes. Thrombosis may occlude the arte-
rial lumen completely and, as a result, a new event
may take place, namely anterograde extension of
a so-called stagnation thrombus, usually into the
first sizable collateral branch. The thrombus is ulti-
mately replaced by loose-textured connective tis-
sue in which new vessels of variable permeability
Lesions in increasing frequency. may develop. In many cases, the mural thrombus
can fragment and, in doing so, gives rise to arterial
emboli (artery-to-artery emboli). These emboli are
believed to account for cerebrovascular accidents
FIGURE 4.27 Frequency and severity of ath- from which some degree of recovery is possible,
erosclerotic lesions in the arterial cervico-cerebral particularly when the ischemic period is of short
arterial tree. duration (“transient ischemic attacks” [TIA]), or
which may be permanent when disintegration of
the classical diagram by Baker and Fisher (Fig. 4.27). the thrombus has not been sufficiently rapid.
The internal carotid arteries and the basilar artery are
the most heavily involved both at their origins and Atherosclerotic thrombosis (Figs. 4.27 to 4.29)
at their terminations. Atherosclerosis less severely
affects the most distal branches of the arterial tree • Internal carotid thrombosis develops in a setting of
compared to the vessels of the base of the brain; stenosing atheromatous lesions. These lesions are

A B

FIGURE 4.28 Stenosing atherosclerotic lesion. (A) Gross appearance of atherosclerosis of the basilar artery.
(B) Microscopic appearance, narrowing of the arterial lumen by arteriosclerotic lesions.

Chapter 4 Neuropathology of Vascular Disease • 95


Stagnation
Atheromatous thrombus
plaque Mural
Emboli
(stenosis) thrombus

Occlusive
thrombus

FIGURE 4.29 Evolution of lesions caused by atheromatous carotid stenosis.

most often observed at the carotid bifurcation or at may also result from ascending extension of ver-
the level of the carotid sinus. A stagnation throm- tebral artery thrombosis and causes infarcts in the
bus is formed and usually extends rostrally to the midbrain or pons.
ostium of the first collateral branch, namely the • Thrombosis of a posterior cerebral artery is sel-
ophthalmic artery; collateral contribution through dom an isolated event. It usually occurs as the
the external carotid artery may ensure more or less result of anterograde extension of basilar artery
adequate perfusion of the proximal hemispheric thrombosis. When the posterior cerebral artery is
territory. The zone of infarction is then limited to a tributary of the internal carotid artery, its occlu-
the distal portion of the middle cerebral artery ter- sion may be secondary to extension from a throm-
ritory and, to a lesser extent, the anterior cerebral bosed carotid. As a result, these lesions frequently
territory. Anterograde extension of the thrombus result in massive hemispheric infarction.
beyond the ophthalmic artery, as well as beyond • Subclavian artery thrombosis may give rise to
the origin of the posterior communicating and the ischemic lesions in the vertebrobasilar territory
anterior cerebral arteries, will then result in mas- via diversion of the arterial flow (so-called subcla-
sive infarction. Less often, thrombosis takes place vian steal syndrome).
at the level of the carotid syphon (i.e., at the termi- • These artery-to-artery emboli play an important
nation of the internal carotid artery). Occlusion, role in the development of cerebral infarcts. They
due to atheromatous lesions in this terminal por- can arise from ulcerated plaques anywhere along
tion of the artery, is usually accompanied by retro- the arterial tree or from the aortic arch and spread
grade extension of the thrombus into the carotid distally. The most common sites of origin are the
sinus. When the lesion is old and organized, it may carotid sinus and the vertebral/basilar arteries.
be difficult to determine whether thrombosis of
the carotid artery originally took place at its distal Emboli of atherosclerotic origin (Fig. 4.29)
or proximal end.
• Isolated thrombosis of the middle or anterior • Platelet emboli frequently detach as small frag-
cerebral artery is much less common than internal ments from a thrombus and may cause transient
carotid thrombosis. It often follows extension of cerebral accidents or occlude terminal arterial
a carotid thrombus beyond the bifurcation of the branches.
internal carotid artery. • Fibrin emboli originate from a mural thrombus or
• Vertebral artery thrombosis may be clinically from fragmentation of a stagnation thrombus. They
and/or pathologically silent or may cause discrete often produce occlusion in the branches of larger
lesions, provided the thrombus does not reach the arteries (middle, anterior, or posterior cerebral) in a
ostium of the posterior inferior cerebellar artery setting of carotid or vertebrobasilar thrombosis.
and provided it is unilateral. • Purely atherosclerotic emboli most often are the
• Basilar artery thrombosis occurs in the setting result of spontaneous detachment of thrombotic
of atherosclerotic lesions, common at this site. It material from ulcerated plaques.

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2.2.2.2. Cardiac  emboli Cardiac (cardiogenic)
emboli are a frequent cause of arterial occlusion
(Fig. 4.30). They can originate from an atrial throm-
bus in mitral stenosis, from atrial vegetations and
atrial fibrillation from a mural thrombus in the
course of myocardial infarct, from various forms of
endocardial vegetations (e.g., bacterial endocarditis,
nonbacterial thrombotic endocarditis), or from a
cardiac prosthesis.
Emboli of other than those of cardiac origin are
less frequent.

2.2.2.3. Other Causes
• Arteritis is a rare cause of cerebral infarction.
Syphilitic arteritis, which affects especially FIGURE 4.30 Arterial embolus (superficial tempo-
the basal arteries, is seen infrequently today. ral artery). Note the normal appearance of the arterial
Meningovascular syphilis is characterized by a wall (H&E).
transmural plasma cell-rich infiltrate, associated
with intimal thickening. Tuberculous and other
bacterial meningitides, as well as meningitis caused Within the guidelines already outlined, the site and
by parasitic organisms, can produce occlusive arte- extent of the vascular occlusion will determine if the
ritic lesions (usually manifest as an endarteritis) infarct is to affect a greater or lesser portion of the
which may account for cerebral and spinal infarcts relevant vascular territory affected.
(cf. Chapter 5). In long-term survivors of HIV
infection, cerebral infarcts are rather frequent, for
reasons that are still unclear. “Collagen-vascular” 2.3.1 . CEREBRAL INFARCTS
diseases, especially polyarteritis nodosa, may The neuropathological analysis of cerebral infarcts
sometimes affect small superficial arterioles and, requires complete anatomical study of both the
more infrequently, the deep intracerebral or spinal carotid and the vertebrobasilar system from the
intramedullary vessels. The resulting parenchyma- aortic arch up to the cerebral branches (Fig. 4.31).
tous lesions consist of circumscribed and widely The study must also include a meticulous exami-
disseminated foci of softening. In children, otitis nation of the heart cavities, heart valves, and
media and rhinopharyngitis can occasionally be myocardium.
a cause of internal carotid occlusion, which may
result in cerebral infarction. 2.3.1.1. Infarcts of the carotid territory Brain
• Amyloid angiopathy of the cortical blood vessels infarction due to carotid occlusion may involve
may cause multiple disseminated cortical infarcts either the whole or only part of any of the territo-
(especially microinfarcts involving both cortex ries of distribution irrigated by the branches of the
and white matter), in addition to cerebral hemor- internal carotid artery (Fig.  4.32). Carotid artery
rhages, as discussed above (cf. 1.2.2). occlusion may result in a single infarct, but often
• Injuries to the neck or in the mouth may give rise enough, multiple infarcts that vary in size and age
to internal carotid occlusion. are the rule.
• Vascular malformations, especially arteriovenous
aneurysms, are sometimes associated with cere- • Infarct of the anterior cerebral artery territory (Fig.
bral infarcts (cf. 1.2.3). 4.33D). This area of vascular supply includes
the superior frontal gyrus, inferior and medial
surfaces of the frontal lobe extending back to
2.3. Topography the level of the precuneus, corpus callosum, and
Regardless of the specific cerebral or spinal territory anterior portions of the basal ganglia, which
involved by an infarct, the extent of the infarct will are variably supplied by the recurrent artery of
be determined by the general rules outlined above. Heubner. Because of collateral flow provided

Chapter 4 Neuropathology of Vascular Disease • 97


to the superficial branches of the MCA results
from occlusion distal to the origin of the perforat-
Corticomeningeal ing branches (superior and inferior divisions)
anastomoses (Fig. 4.33A), whereas proximal vascular occlusion
Anastomoses of the by atherosclerosis is responsible for isolated deep
circle of Willis middle cerebral infarcts (Fig. 4.33B). Most often,
infarction involves only part of the vascular ter-
ritory (e.g., territory of the ascending branches).
Anastomosis via the This may result from occlusion of the terminal
ophthalmic artery
branches but more often results from proximal
occlusion of the internal carotid artery coupled
with adequate reirrigation of the proximal terri-
tory through vascular anastomoses at the base of
the brain.
• Infarct of the anterior choroidal artery territory
(Fig. 4.33E). The posterior part of the internal
capsule, pallidum, and optic tract are located
within this vascular territory. Infarction of this
deep area of supply, especially when recent, is
often difficult to detect because of the limited
extent of the involved territory. Isolated infarc-
tion of this area is quite rare; compromise of
FIGURE 4.31 The carotid-vertebral vascular tree this vascular territory more often is associated
and its chief anastomotic pathways. with total infarction of the middle cerebral terri-
tory, the affected region being part of a massive
infarct.
by the contralateral anterior cerebral artery via • Massive hemispheric infarct. The term describes an
the anterior communicating artery, infarcts of infarct that affects the entire territory supplied by
the anterior cerebral territory are less common the internal carotid artery (Fig. 4.33F, Fig. 4.34).
than those in the middle cerebral territory. The The infarct results from sudden occlusion of the
well-known anatomical variability of the circle terminal portion of the internal carotid artery,
of Willis at this site accounts for the differing either by an embolus or by a propagation of an
size and distribution of the infarct (e.g., a single internal carotid thrombus beyond the terminal
anterior cerebral artery associated with bilateral bifurcation of the artery, in the setting of a total
infarction) observed in clinical practice. In the absence of all potential sources of collateral sup-
case of internal carotid thrombosis with com- ply. The mere size of the large portion of the brain
promise of the territory supplied by the anterior that is rendered ischemic accounts for the wide-
cerebral artery, infarction is almost invariably spread edematous reaction and, consequently, the
associated with involvement of the middle cere- high frequency of temporal herniation (Fig. 4.33F,
bral territory (Fig. 4.33F). Fig. 4.34).
• Infarct of the middle cerebral artery territory. This • “Watershed” or boundary-zone infarcts (Fig. 4.35).
area of supply includes the lateral surface of the These involve mostly the boundaries between the
frontal and parietal lobes, insula, superior and anterior and middle cerebral territories, especially
middle temporal gyri, and deep striatal terri- posterior to the interparietal sulcus. This type of
tory. In most cases, occlusion of the proximal lesion is also seen sometimes in the distal fields
part of the middle cerebral artery results in total of irrigation between the middle, anterior, and
infarction of the middle cerebral artery territory posterior cerebral territories. Watershed infarcts
(Fig. 4.33C), since the superficial collateral arte- may also involve the zones of arterial supply
rial circulation is only able to provide minimal at the junction of the deep and superficial ter-
collateral flow. The occlusion is more often the ritories of the middle cerebral artery, thereby
result of embolization than of primary intravas- affecting the deep white matter and in particular
cular thrombosis. Cerebral infarction restricted the midportions of the centrum semiovale. This

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A D

F
Posterior cerebral
artery
Anterior cerebral
artery
Middle cerebral
artery
Anterior choroidal
artery

H J

g, anterior
communicating
artery; h,
thalamic
perforating
arteries

FIGURE 4.32 Cerebral vascular territories. (A) Outer surface. (B) Inner surface. (C) Basal surface. (D–K)
Coronal slices from front to back.

type of infarction results from internal carotid granular appearance of the cerebral cortex is
thrombosis, particularly when the thrombosis is apparently the result of multiple, small chronic
bilateral, or follows prolonged episodes of arterial ischemic lesions manifest as punched-out foci
hypotension/shock. of cavitated cicatricial softening, and of focal
• Granular atrophy of the cerebral cortex of arte- glial scars affecting the cortex predominantly.
riopathic origin (Fig.4.36). This rare disorder is The lesions are often bilateral and involve the
characterized on macroscopic examination by watershed territories along the crest of the gyri at
an abnormality of the cerebral cortex whereby the junction of the middle and anterior cerebral
the gyral pattern over the convexities is thinned arteries, and may also affect the superficial water-
out and distorted, giving it a granular appear- shed territory between the middle and posterior
ance. The histopathological basis of the abnormal cerebral artery.

Chapter 4 Neuropathology of Vascular Disease • 99


A B C

D E F

FIGURE 4.33 Principal topographical areas of distribution of infarcts in the internal carotid territory (Loyez
stain for myelin). (A) Recent right-sided superficial middle cerebral infarct. Note the presence of a small
associated infarct involving the corpus callosum and the cingulated gyrus (territory of the anterior cerebral
artery). (B) Recent, deep, right-sided middle cerebral infarct. Note its hemorrhagic character in association
with older, more superficial lesions (insula and claustrum). (C) Old, total, right-sided middle cerebral infarct.
(D) Right-sided anterior cerebral infarct. (E) Right-sided anterior choroidal infarct. (F) Recent, right-sided mas-
sive hemispheric infarct involving the whole territories of the anterior, middle, and anterior choroidal cerebral
arteries. Note right temporal herniation.

The distribution of the lesions is indicative of


global chronic watershed ischemia related to bilat-
eral internal carotid stenosis coupled with cardiac
insufficiency.

2.3.1.2. Infarcts of the vertebrobasilar terri-


tory (“posterior circulation”)
The same pathophysiological principles and neuro-
pathological features described above for the “ante-
rior” or carotid circulation also apply to infarcts in
the “posterior circulation.” In addition, the distinc-
tive anatomical aspects of the posterior arterial cir-
culation and its systems of collateral flow need to be
FIGURE 4.34 Recent massive hemispheric infarct. taken into account to further understand the clinico-
Gross appearance. pathological manifestations of these infarcts.

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FIGURE 4.36 Granular atrophy; old ischemic
lesion involving the watershed territories at the junc-
tion of the middle and anterior cerebral territories at
the crest of the gyrus along the frontal superior sulcus
(Loyez stain).
FIGURE 4.35 Old infarct at the junction of the left
anterior and middle cerebral territories
inferomedial surface of the occipital lobe, of the
cuneus, and especially of the calcarine cortex, as
The posterior circulation system consists of well as part of Ammon’s horn (the hippocampus).
a median axis, the basilar artery, formed by the The infarct is the result of occlusion of the posterior
junction of two vertebral arteries originating from cerebral artery beyond its junction with the poste-
the subclavian arteries, which undergo a tortuous rior communicating artery. The arterial occlusion
course through the foramina transversaria, and is generally embolic in origin, and most often sec-
of two terminal branches, the posterior cerebral ondary to preexisting vertebrobasilar thrombosis.
arteries. There are considerable anatomical varia- Infarcts of the deep territory of the posterior cere-
tions of this vascular arrangement. The caliber of bral artery most often affect either the thalamoge-
the vertebral artery, the integrity of the posterior niculate territory (i.e., the ventrolateral thalamus
communicating artery, which may be narrowed or and the pulvinar) or the paramedian thalamic terri-
hypoplastic, and the caliber of the proximal poste- tory (i.e., the intralaminar nuclei). In the latter situa-
rior cerebral artery ultimately determine the flow tion, a bilateral butterfly-shaped lesion may develop
patterns through the circle of Willis. with unilateral origin of the paramedianartery and is
Variable anastomotic communications exist associated with variable involvement of the mesen-
with the internal carotid arteries, through the pos- cephalon (i.e., a thalamomesencephalic infarct).
terior communicating arteries, with branches of • Infarcts of the brainstem (Fig. 4.38). In the major-
the external carotid and subclavian arteries, and ity of cases, brainstem infarction is secondary to
between the vertebral arteries themselves through atherosclerotic thrombosis of the vertebral or
the spinal perimedullary arterial network. basilar artery. These infarcts may also be secondary
Finally, there are lateral anastomotic rings formed to embolization of cardiac origin. The general pat-
between the cerebellar arteries. tern of arterial supply of the brainstem is such that
These special anatomical features account for there is a relatively stereotyped arterial intraparen-
the commonly observed patterns of infarction that chymal vascular network, whereas the arborization
result from occlusive arterial disease in the vertebro- in the SAS of the extraparenchymal feeding vessels
basilar axis that are manifest as bilateral, multifocal, is highly variable and complex. Accordingly, the
and asymmetrical lesions. patterns of infarction often defy classification, but
for purposes of simplification they could roughly
• Infarcts of the posterior cerebral artery territory be subdivided into the following types:
(Fig. 4.37). Infarcts within this hemispheric terri- – Focal lesions corresponding to infarction of a
tory are often bilateral, producing necrosis of the specific vascular territory: these are the result

Chapter 4 Neuropathology of Vascular Disease • 101


A B

FIGURE 4.37 Infarcts of the posterior cerebral territory (Loyez stain for myelin). (A) Occipital infarct
involving the calcarine cortex. (B) Recent infarct of the thalamogeniculate territory. Note involvement of
Ammon’s horn.

of occlusion of either paramedian branches – (B) the territory of the posterior inferior cer-
or circumferential branches of the basilar ebellar artery (PICA), distributed over the
artery: (A) paramedian infarcts—(1) midline ventral surface of the hemisphere; and
infarct of the midbrain tegmentum with or with- – (C) the inferior anterior cerebellar artery
out associated thalamic lesions (paramedian (AICA), which usually supplies the flocculus,
thalamic infarct); (2) paramedian infarct of the the middle cerebellar peduncle, and the infe-
pontine tegmentum; (3) paramedian infarct of rior lateral territory of the pons (Fig. 4.39C).
the medulla; (B)infarcts in the distribution of • Between 10% and 25% of cerebellar infarcts are
short circumferential branches: (1) infarct of the due to embolic vascular occlusion. The infarct
middle cerebellar peduncle; (2) infarct of the lat- can be confluent and involve most or all of the
eral medullary region (causing Wallenberg syn- territory supplied by one of the three major ves-
drome; usually due to occlusion of the PICA). sels that supply the cerebellum, or the ischemic
– Multifocal and diffuse lesions. These may insult may result in multiple foci of necrosis in
involve many vascular territories and sometimes the cerebellum with concomitant infarcts in the
consist of lesions of different ages. Single “geo- brainstem. Any of these lesions can behave as
graphic” lesions may also bridge the usual topo- space-occupying masses resulting in cerebellar
graphical limits of irrigation of a particular vessel herniation with brainstem compression. A surgi-
in this territory. cal pathologist may be surprised to find, at the
• Cerebellar infarcts (Fig.4.39) time of frozen section from a cerebellar “mass
– Cerebellar infarcts are three to five times lesion,” only infarcted cerebellar fragments.
more frequent than cerebellar hemorrhages. Border-zone infarcts, situated at the boundaries
The lesions frequently appear as territorial between the territories of distribution of the dif-
infarcts, the result of occlusion of the long ferent cerebellar arteries, are not uncommon.
circumferential branches of the vertebral
and basilar arteries (Fig. 4.39A). These may 2.3.1.3. Complications of therapy In the mod-
involve: ern era, aggressive therapy for acute stroke (espe-
– (A) the territory of the superior cerebellar cially ischemic stroke) is often carried out, and
artery (SCA), which comprises the superior a pathologist encountering tissue from the brain
portion of the cerebellum down to the dentate or blood vessels of an affected patient should be
nucleus and the posterolateral portion of the aware of this. Intravenous tissue plasminogen acti-
pontine tegmentum (Fig. 4.39C); vator (TPA) administered to a patient with acute

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A B

C D

E F

FIGURE 4.38 Infarcts of the brain stem (Loyez stain for myelin). (A) Midbrain infarct. (B) Massive infarct
of the midbrain tegmentum. (C) Massive upper pontine infarct with right-sided paramedian predominance.
(D) Massive infarct of the basis pontis. (E) Central medullary infarct. (F) Lateral medullary infarct (causing
Wallenberg syndrome).

thrombosis may precipitate IPH; this is especially and such extractions may themselves be compli-
common in elderly individuals who have (clini- cated by subintimal dissection or arterial occlu-
cally unsuspected) CAA. Increasingly sophisticated sion. Various endovascular treatments may lead
devices are used to surgically extract intraluminal to intra-arterial embolization of “catheter sheath”
thromboemboli (e.g., from the MCA bifurcation), materials that can cause microvascular thrombosis,

Chapter 4 Neuropathology of Vascular Disease • 103


A

A B C

A A A
B B B
1
C C C
2
D D D
3

B C

FIGURE 4.39 Cerebellar infarcts. (A) Diagram showing the full extension of lesions in cerebellar infarcts.
From top to bottom: Posterior view; lateral view; serial sections perpendicular to the brainstem axis through the
upper cerebellum and pons, middle cerebellum and lower pons, middle cerebellum and middle medulla oblon-
gata, lower cerebellum and medulla oblongata. A, posterior and inferior cerebellar artery (PICA) territory. B,
anterior and inferior cerebellar artery (AICA) territory. C, superior cerebellar artery (SCA) territory. (Modified
fromAmarenco P, Hauw JJ. Anatomie des artères cérébelleuses. Rev Neurol (Paris), 1989: 145:267–276 with per-
mission. See also Amarenco P, Hauw JJ, Caplan LR. Cerebellar Infarction. In: Lechtenberg R (ed.), Handbook of
Cerebellar Diseases. New York, Marcel Decker, 1993:251–290). (B) Right-sided recent pale infarct of the superior
cerebellar artery. (C) Left-sided hemorrhagic infarct of the posterior inferior cerebellar artery.

often with a foreign body giant cell reaction, and 2.3.2.1. Arterial organization of the spinal
brain infarcts. cord Distinctive features in the arterial supply of the
spinal cord determine the principal topographical
patterns of infarction following vascular occlusion
(Figs. 4.40 and 4.41). As in the brainstem, the extra-
2. 3. 2. S P I NAL I NT R A M ED U L L A RY
medullary arterial network is variable, whereas the
I N FA RC T S
intramedullary network is fairly constant.
Spinal intramedullary infarcts are much less com- The intramedullary arteries are principally
mon than cerebral infarcts. In cases of infarction of branches of the anterior spinal artery, which extends
the spinal cord, because it is technically difficult to downward along the ventral aspect of the spinal
carry out a thorough postmortem study of the blood cord and is responsible for the blood supply of the
supply of the spinal cord, clinicopathological corre- anterior two thirds of the cord, including most of
lation studies are often incomplete. the gray matter, except for the posterior portions

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Posterior spinal Vertebral
territory artery
C1
Anterior spinal territory Radicular arteries supplying the
(stippled) central enargement (collaterals
Rostral from the subclavian and
territory vertebral arteries)
Aorta

ANTERIOR SPINAL ARTERY


T4
Middle Dorsal radicular artery
Peripheral territory territory
T6
FIGURE 4.40 The three transverse arterial territo-
Radicular artery supplying
ries of the spinal cord. the lumbar enlargement
Caudal (artery of Adamkiewicz)
territory
of the posterior horns in most cases. Two posterior
spinal arteries irrigate the dorsal third of the cord,
including the dorsal three fourths of the posterior
columns. A  perimedullary anastomotic network
gives off a few branches to the subpial portions of S5
the cord. The extramedullary network, which is FIGURE 4.41 The three principal longitudinal arte-
complex and variable, is formed from multiple and rial territories of the spinal cord.
anastomosing branches of the radicular arteries.
Furthermore, on the longitudinal axis, following
territories are recognized: part of the posterior columns (i.e., at the bound-
ary between the anterior and posterior spinal ter-
• A superior, or cervicothoracic, territory corre- ritories) (Fig. 4.42B, C).
sponding to the cervical and upper two or three • Anterior spinal artery infarction involves a greater
thoracic segments and supplied by arterial twigs or lesser portion of the anterior spinal territory
originating from the vertebral arteries or from and especially the ventral horns (Fig. 4.43). It
branches of the subclavian arteries is the most frequent type of infarct in the spinal
• An intermediary or middle thoracic terri- cord. Cord infarcts in the anterior spinal artery
tory extending from T4 to T8 with a poor distribution have been described at almost any
blood supply segmental level but are most often seen in the
• An inferior, or thoracolumbar, territory whose lumbar region; this is probably because of the spe-
abundant vascularization is supplied by a single cial vulnerability of this territory, which ordinarily
lumbar artery (i.e., the artery of the lumbar depends on a single artery with limited collateral
enlargement, or artery of Adamkiewicz). This supply from the delicate middle thoracic arterial
artery ordinarily takes a leftward course, running network.
along the lower thoracic or upper lumbar nerve • Infarcts of the posterior spinal territory
roots, and can be reinforced by an upper or a (Fig. 4.44) are considerably rarer.
lower branch.
2.3.2.3. Microscopic features
2.3.2.2. Topographical features Histopathologically the cellular evolution of the
• Massive infarction (Fig. 4.42A) usually occurs ischemic lesion is comparable to what has been
in the middle thoracic zone, which is normally described above for cerebral infarcts. In other words,
poorly vascularized. It is presumably the result of hours after the insult there is an initial edematous
sudden total ischemia, when reirrigation of the stage involving the intracellular and extracellular
middle thoracic segments by the abundant cervi- compartments. This is followed by death and dis-
cal and lumbar networks is inadequate. The infarct integration of all constituents with secondary liq-
extends over several segments and often extends uefaction necrosis. Then an inflammatory cellular
proximally and distally in the form of a fusiform response occurs with tissue resorption through the
or pencil-like zone of tissue necrosis involving the mobilization of macrophages and, in the end, cavita-
centromedian portions just adjacent to the ventral tion and surrounding gliosis.

Chapter 4 Neuropathology of Vascular Disease • 105


A B
C6
Upper fusiform
extension

T4 Total transverse
infarct

Lower fusiform
extension
T9

FIGURE 4.42 Transverse infarcts of the spinal cord. (A) Maximal extent of the lesions (Loyez stain for
myelin). (B) Diagram of fusiform extensions of the lesion. (C) Upper fusiform extension of the lesion (Loyez
stain for myelin).

FIGURE 4.43 Focal infarct of the spinal cord FIGURE 4.44 Focal infarct of the spinal cord (Loyez
(Loyez stain for myelin). Anterior spinal artery infarct. stain for myelin). Posterior spinal artery infarct.

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2.3.2.4. Etiology Atherosclerosis and arterial variable depth, some reaching the deep white mat-
thrombosis involving either the feeding vessels or the ter as medullary branches. Other perforators enter
aorta play an important role. Vascular supply to the spi- the brain at the base (supplying the basal ganglia and
nal cord may be compromised because of obstruction thalamus), and yet others irrigate the brainstem aris-
of the orifices of the intercostal and lumbar arteries or ing from long and short circumferential branches.
via an aortic aneurysm. For the most part, these are end-arteries with lim-
Ordinarily, it is difficult to demonstrate an arte- ited collateral anastomoses until the capillary net-
rial embolic occlusion as the etiological factor of a work is reached.
spinal cord infarct, the exception being the case of
cholesterol emboli originating from ulcerated aortic
atheromatous plaques. Also, there are several case 3.1. Vascular Diseases Affecting the
reports on record where cartilaginous emboli fol- Small Blood Vessels
lowing relatively minor trauma to the spine have
Important disorders in this category include hyperten-
been implicated in spinal cord infarction.
sive cerebrovascular disease (discussed above: cf.1.2.1)
Rarely, primary angiitis of the CNS may prefer-
and cerebral amyloid angiopathy (cf. 1.2.2).
entially or predominantly involve the spinal cord.
Less common entities include cerebral autoso-
Other established predisposing factors in the
mal dominant arteriopathy with subcortical infarcts
pathogenesis of spinal cord infarction include tho-
and leukoencephalopathy (CADASIL) and other
racoabdominal surgery, aortography, and dissecting
rare disorders of small vessels.
aneurysm of the aorta.

3. SMALL VESSEL DISEASE 3.1.1 . CADASIL


The two broad categories of cerebrovascular diseases CADASIL is a hereditary disease of the brain vessels
described above, large hemorrhages and infarctions, due to a mutation of the Notch 3 gene on chromosome
account for the majority of cerebrovascular cases 19. It is characterized by deposition of pathognomonic
that come to medical attention. As indicated, these granular osmiophilic material (GOM) in the media of
conditions result in focal or multifocal injury affect- vessels throughout the body (Fig. 4.45D, E), including
ing relatively large areas of the brain and are related dermal arteries (where the deposit can easily be iden-
to arterial rupture or arterial occlusion. Apart from tified on skin biopsy by electron microscopy). Though
these, there remain a number of diseases in which the GOMs are suspected by routine light microscopy,
vascular lesions affect relatively small blood vessels, their presence must be confirmed by electron micros-
often at many sites throughout the neuraxis and are copy. The extracellular domain cleaved from Notch 3
associated with ischemic and/or hemorrhagic mani- in response to ligand binding accumulates outside the
festations. In some, the principal clinical manifesta- degenerating vascular smooth muscle cells and can
tions are those of focal neurological deficits, whereas be identified immunohistochemically. At the cellular
in others syndromes of dementia (with or without level, the topographical distribution of these deposits
associated degenerative diseases; cf. Chapter  8) or differs from that of the granular deposits (Fig. 4.45C),
encephalopathies predominate. The armamentarium and they are associated with degeneration of vascu-
of new radiological imaging methods has enhanced lar smooth muscle cells with progressive wall thick-
awareness of these important causes of neurologi- ening/fibrosis and luminal narrowing of small and
cal morbidity. Some of these affect predominantly medium-sized penetrating arteries. This vascular dis-
or exclusively the CNS, whereas others are systemic ease gives rise to multiple small infarcts involving the
vascular disorders that involve the brain and spinal white matter or deep gray matter, ordinarily not asso-
cord along with other organ systems. ciated with a hemorrhagic component. The cerebral
For purposes of classification, and conceptually, cortex is less often affected.
these are disorders of the “microcirculation” and Other rare hereditary cerebral and/or retinal vas-
small blood vessels in general. The so-called “small cular diseases have been described, and for some, a
arteries ”or arterioles include perforators with diam- gene mutation has been identified. These include cere-
eters from 40 to 400  μm. Some emerge from the bral autosomal recessive arteriopathy with subcorti-
leptomeningeal arteries, enter the brain parenchyma cal infarcts and leukoencephalopathy (CARASIL)
from the surface of the brain, and extend within to a and hereditary vascular retinopathy, cerebroretinal

Chapter 4 Neuropathology of Vascular Disease • 107


A B

D E

FIGURE 4.45 CADASIL. (A) Gross appearance of the subcortical infarcts and leukoencephalopathy


(Woelcke stain). (B) Gross appearance of status cribrosus at the cortico-subcortical junction in the pole of the
temporal lobe and fronto-orbital cortex. (C) White matter arteriole, immunostaining of the extracellular domain
of Notch 3. Note positive deposit around the lumen and the vascular smooth muscle cells clearly different from
the unstained granular deposit deeper in the arteriolar wall. (D) Granular osmiophilic material in arterial walls
on semi-thin section and (E) at ultrastructural examination.

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vasculopathy, hereditary endotheliopathy with unifying histopathological features in these condi-
retinopathy, nephropathy, and stroke (HERNS). tions are the presence of intramural inflammation
CARASIL, thus far found only in Japanese patients, and destruction of the vascular wall, manifesting in
results from mutations in the HTRA1 gene 9 on chro- some conditions as fibrinoid necrosis in the early
mosome 10q, which encodes a serine protease that stages of the disease. Recognized among these
appears to regulate the expression of vascular growth disorders are infectious vasculitides secondary to
factors. The result of mutations in this gene is pro- direct invasion of blood vessel walls by microorgan-
found intimal hyperplasia affecting parenchymal and isms and noninfectious CNS vasculitides, wherein
leptomeningeal arteries, leading to a severe ischemic the primary mechanism of injury is presumed to be
leukoencephalopathy. HERNS results from a muta- immunopathological.
tion in the trex 1 gene on 3p21, but the precise mecha-
nism of the resultant microangiopathy and multifocal 3.1.3.1. Infectious vasculitides Infectious vas-
(predominantly white matter) microinfarcts and lacu- culitides due to direct infection of blood vessels by
nar infarcts is poorly understood. Neuropathological microorganisms have been described in viral infec-
studies are mostly lacking or limited to single cases. tions (HIV, VZV, EBV, HSV, CMV—the latter espe-
Recently, growing interest has developed in a micro- cially in AIDS), bacterial infections (tuberculosis,
angiopathy associated with cerebral hemorrhages syphilis, mycoplasma, rickettsia), fungi (cryptococ-
and lacunar infarcts, resulting from mutations in the cosis), or parasitoses (cysticercosis) (cf. Chapter 5).
COL4A1 gene.

3.1.3.2. Non-infectious CNS vasculitides


3.1.2. SMALL VESSEL DISEASE IN OTHER
These may arbitrarily be divided into primary or
RARE SYSTEMIC DISORDERS
secondary forms.
Small vessel disease is also a part of some systemic Primary angiitis of the CNS is defined as vascu-
disorders, including mitochondrial encephalopathy, litis occurring predominantly in the CNS in the
lactic acidosis, and stroke-like episodes (MELAS) (cf. absence of systemic inflammatory diseases, infec-
Chapter 10) or merosin-negative congenital muscu- tions, neoplasms or exposure to drugs. The disease
lar dystrophies (cf. Chapter 12), in which a leukoen- affects, in a segmental distribution, multiple small
cephalopathy is a frequent and characteristic feature. and medium-sized arterioles and venules through-
out the brain and, to a lesser extent, the spinal
cord. Histologically, the typical acute/subacute
3.1.3. ACUTE INFLAMMATION OF SMALL
lesion consists of perivascular aggregates of multi-
VESSELS: CNS VASCULITIS WITH OR
nucleated giant cells and macrophages, which can
WI THOUT SYSTEMIC MANIFESTATIONS
extend into the vessel wall (Fig. 4.46). Sometimes,
In a wide variety of inflammatory diseases of the the vascular lesions are characterized by a predom-
CNS, small blood vessels may be affected. The inance of lymphohistiocytic infiltrates, without

A B

FIGURE 4.46 Primary angiitis of the CNS. Infiltration of the vessel walls by histiocytes, giant cells, and mono-
nuclear cells involving a leptomeningeal and a perforating artery (A); an intraparenchymal artery (B).

Chapter 4 Neuropathology of Vascular Disease • 109


giant cells or mononuclear cells. Rarely, foci of 3.2. Parenchymal Changes Associated
necrosis are seen adjacent to the affected vessels. with Diseases of Small Arteries
Chronic lesions consist of thickening and fibrosis
of the vessel wall without significant inflamma- Of interest in these conditions is the correlation
tory infiltrates. Acute lesions often coexist with between the findings of neuroimaging data and neu-
more chronic healing or healed lesions. When ropathology in small hemorrhages, microbleeds,
CNS vasculitis/angiitis is identified in an older lacunes, status cribrosus (état criblé), and arterio-
subject (60+ years), angiitis secondary to CAA pathic leukoencephalopathies.
must be suspected and further evaluated with
appropriate immunohistochemical examination
of the specimen (using anti- Aβ primary antibod- 3 .2 . 1. SM ALL IN TRAPAREN CHYM AL
ies). CAA-associated angiitis (Aβ-related angiitis H EM ORRHAGES
[ABRA]) is usually characterized by a prominent As discussed above, large IPHs (cf. 1.2) are most
granulomatous transmural inflammatory infiltrate. often associated with hypertensive cerebrovascu-
Secondary inflammation of CNS blood ves- lar disease (cf. 1.2.1) and/or with cerebral amyloid
sels includes manifestations of systemic diseases, angiopathy (cf. 1.2.2). Smaller intracerebral hemor-
malignancy-related vasculitis, and drug-induced rhages, 10 to 20 mm in diameter, also occur. These
vasculitis. In secondary angiitis of the CNS the neu- are cavitated and destructive, usually with a regu-
rological syndrome is associated with a systemic lar outline (Fig.  4.47C). Their walls are the site of
disease, including systemic lupus erythematosus, ochre-yellow pigmentation that corresponds to the
polyarteritis nodosa, Wegener granulomatosis, and abundant presence of hemosiderin-laden macro-
Churg-Strauss syndrome; neurological manifesta- phages (Fig. 4.47D), which are also found inside the
tions have been described in the context of Sjögren cavity. They may be solitary and located in the basal
syndrome and Behçet disease. Diagnosis relies ganglia or, more seldom, in the hemispheric white
mostly on clinical assessment, imaging studies, and matter. However, multiple subcortical small “slit
laboratory analysis by immunological serological hemorrhages” may be seen in hypertensive patients.
tests. Brain biopsy is rarely utilized as a diagnos- Historically, they have been considered to be due
tic test. Neuropathological autopsy studies have to the rupture of microaneurysms, but lipohyali-
shown that the characteristic histopathological fea- nosis and amyloid degeneration of the vessel wall
tures of the vasculitis in these disorders are rather have also been implicated. Imaging and pathologi-
nonspecific and consist of variable perivascular cal studies now allow them to be distinguished from
and intravascular chronic inflammatory infiltrates cerebral “microbleeds” (cf. 3.2.2).
with mural fibrosis, thickening, and variable lumi-
nal compromise.
Vasculitides of the nervous system may 3 .2 . 2. CEREBRAL “M ICROBLEEDS”
occur in patients with neoplasia. They predomi- Cerebral microbleeds (CMBs) are small (less
nantly involve the peripheral nervous system (cf. than 5 to 10  mm in diameter), well-demarcated,
Chapter 13). CNS vasculitis is particularly associ- hypointense, rounded small lesions seen on MRI
ated with Hodgkin disease. In most cases it pres- sequences sensitive to magnetic susceptibility
ents as granulomatous angiitis. The neurological effects. Radiological studies suggest that CMBs are
symptoms may precede the diagnosis of the under- an imaging marker for small vessel pathology within
lying neoplasm, and brain biopsy is necessary for brain, especially CAA. They are observed more
definite diagnosis. frequently with increasing age. They occur mainly
Drug-induced vasculitis has been studied by in primary intracerebral hemorrhage patients and
radiological imaging methods but there are very are less frequent in patients with ischemic cerebro-
few confirmatory neuropathological studies. The vascular disease. They appear to be a predictor of
reported cases of biopsy/autopsy-proven cerebral recurrent vascular events. The neuropathological
vasculitis in cocaine abusers have shown a necrotiz- correlate of these imaging studies is in the process of
ing angiitis affecting cerebral arteries and arterioles being analyzed. Iron deposits have been seen in the
(in some, documentation of multiple drugs, includ- capillary wall, at the abluminal endothelial surface,
ing amphetamines, was documented). in association with pericytes, and in perivascular

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A B

C D

E F

FIGURE 4.47 Cerebral lacunes. (A, C, E) Macroscopic features. (A) Lacune. (C) Small cavitated IPH (also
called type 2 lacune). (E) État criblé. (B, D, F) Microscopic features. (B) Lacune. (D) Small cavitated IPH.
(F) État criblé.

macrophages on the arterial side of the microcir- commonly  found. Neuropathologic examination
culation. They are also found at some distance of may, in addition, reveal other lesions, such as small
evolved vessels, apparently in the extracellular space. vascular malformations (capillary hemangiomas
They are seen in association with amyloid angiopa- and capillary telangiectases.
thy as well as arterial hypertension, in the subcorti-
cal white matter as well as in the basal ganglia. At
3.2.3 . L ACUNAR INFARCTS
the latter sites, the identification of the nature of
the mineral deposits by MRI study can be prob- These are small, deep infarcts due to occlusion
lematic because other vessel mineral deposits are of small penetrating arteries originating from

Chapter 4 Neuropathology of Vascular Disease • 111


the circle of Willis, its main branches at the base 3 .2 . 5. ARTERIOPATHIC
of the brain, and basilar artery. They have been L EU KOEN CEPHALOPATHIES
sometimes classified as type 1 lacunes. Old lesions
Diffuse white matter lesions can be seen in certain
appear as irregular, ragged cavities that on micro-
forms of vascular diseases. The neuropathological
scopic examination have all the characteristics of
appearance of these disorders is diffuse myelin pal-
ischemic necrosis. A lacunar cavity contains small
lor of the cerebral white matter, best demonstrated
amounts of parenchymatous debris and lipid- or
on whole brain sections stained for myelin. Often
hemosiderin-laden macrophages (Fig. 4.47B). The
enough, the subcortical U fibers, the interhemi-
cavities are traversed by blood vessels of small cali-
spheric commissures (corpus callosum and anterior
ber and are surrounded by variably severe astrocytic
commissure), and the internal capsule are spared
gliosis, often including gemistocytic astrocytes.
(Fig.  4.48A, B). On microscopic examination, the
Lacunes may be solitary or multiple; they involve
principal abnormalities are an ill-defined, incom-
preferentially the basal ganglia (Fig.  4.47A), the
plete myelin loss, intramyelinic edema, and abnor-
internal capsule, and basis pontis. Their diameter
malities of oligodendrocytes (Fig. 4.48C). These are
is variable, ranging from a small cavity to one that
associated with dilatation of the perivascular spaces
reaches 15 mm in diameter. In the majority of cases,
and diffuse reactive gliosis.
lacunar infarcts are the result of vascular occlusion
Binswanger arteriopathic subcortical encepha-
secondary to segmental arteriolosclerosis in the
lopathy is an arteriopathic leukoencephalopathy
setting of systemic hypertension, though in prac-
occurring in hypertensive patients. In addition
tice the “guilty” occluded arteriole is rarely iden-
to the previously described white matter lesions,
tified. They may also be related to atherosclerosis
numerous small chronic ischemic cavities are seen
involving arterial trunks when a plaque occludes
in the white matter and deep gray matter (lacunes)
the ostium of the artery. Artery-to-artery emboli
(Fig.  4.48A), and the arterioles of these regions
or emboli of cardiac origin may infrequently cause
are the seat of severe arteriosclerotic lesions
lacunar infarcts. Some lacunar infarcts may be the
(Fig. 4.48D).
result of resorbed small hemorrhages.
In CAA, similar lesions can be seen, although
there are no lacunes or infarcts in the white matter.
Amyloid angiopathy is present in the cerebral cortex
3. 2. 4. É TAT C R I BL É ( S TATU S and leptomeninges, and microinfarcts and miliary
C R I B ROSUS ) hemorrhages may be found in the cortex.
This condition is defined as a dilatation of the peri- Arteriopathic leukoencephalopathy is a feature
vascular spaces containing CSF. The resulting cavi- of CADASIL. In this condition, subcortical infarcts
ties have a rounded and smooth outline. They always or lacunes are frequent in the white matter and basal
contain in cross-section vessels with an open lumen ganglia (Fig. 4.45A).
(Fig. 4.47F). The cavity is lined by the pial cells that
form the outer walls of the Virchow-Robin space, 4. VASCULAR PATHOLOGY OF
which is greatly expanded and surrounds the blood
vessels. The adjoining brain parenchyma is devoid of
VENOUS ORIGIN
gliosis. Abnormalities within the cerebral venous sys-
No single mechanism has been put forth to tem that lead to cerebrovascular disease are most
explain état criblé, although it is mostly a second- often related to pathological processes in connec-
ary lesion. État criblé may be seen in association tion with infectious diseases in the brain; indeed,
with disease processes that result in loss of brain cerebral phlebitis is most often secondary to
tissue (degenerative or vascular), where it is mani- infectious lesions. In addition, important causes
fest adjacent to advanced or chronic lesions. Status of venous-related cerebrovascular disease occur
cribrosus often involves the basal ganglia and in a number of systemic diseases associated with
thalamus (Fig.  4.47E). Rarely, it may involve the coagulopathies. The result of venous occlusion is
cortico-subcortical junction, particularly in the tem- circulatory stasis, followed by diapedesis of red
poral lobe, in CADASIL (Fig. 4.45B). blood cells and IPH proximal to the site of vascular

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A B

C D

FIGURE 4.48 Binswanger arteriopathic subcortical encephalopathy. (A, B) Macroscopic appearance with


Loyez stain for myelin. Note the presence of myelin pallor of the deep white matter and lacunes in the basal
ganglia (A) and in the posterior white matter (B). (C, D) Microscopic features (H&E). Edema and glial swelling
(C), dilatation of perivascular space and arteriolar hyalinosis (D).

occlusion. A  venous infarct is the final outcome


of this process. In contrast to arterial hemor-
rhagic infarcts, which predominate in the cortex,
hemorrhage in venous infarction involves simul-
taneously the leptomeninges, the cortex, and the
white matter. In superior sagittal sinus thrombosis
(Fig.  4.49), hemorrhagic lesions involve symmet-
rically the hemispheric white matter and mostly
affect the centrum semiovale. Vein of Galen throm-
bosis is associated with venous infarction involving
the periventricular regions and the portions of the
thalamus. In superficial phlebitis, lesions are often
FIGURE 4.49 Bilateral venous infarction resulting seen in the hemispheric gray matter and the under-
from thrombosis of the superior sagittal sinus. lying white matter.

Chapter 4 Neuropathology of Vascular Disease • 113


5
Infections of the Central Nervous System
F R ANÇOISE GRAY, KU M T H O N G  WO N G , FRA N CE SC O S C A R AV IL L I, A N D L E R O Y R .   S H A R E R

A WIDE variety of pathogenic infectious organisms— in diagnosis and treatment that have been made in
bacteria, fungi, parasites, viruses, prions— recent years.
may affect the central nervous system (CNS).
Organisms can be classified as pathogenic or
opportunistic; infections by the former group cause 1. BACTERIAL INFECTIONS
diseases in every individual and those by the lat- Depending on their virulence/pathogenicity deter-
ter affect patients with lower resistance. Infectious minants, bacteria can induce (a)  purulent lesions
agents can enter the CNS in many ways:  through involving the recruitment and lysis of polymorphs,
the blood, by retrograde spread via peripheral (b)  cellular inflammatory reactions with influx of
nerves, or by direct invasion. The hematogenous mononucleated leukocytes, or (c)  inflammatory
route is the most common, either by direct spread edema due to toxins and other inflammatory sub-
or via host cells. stances released by bacterial secretion or lysis, in the
The brain and spinal cord are relatively well absence of bacterial replication.
protected from infective agents by the skull and
vertebral column, by the meninges, and by the
blood–brain barrier. However, once the pathogen
1.1. Pyogenic Infections
enters the CNS, host defense mechanisms are sub- The bone, dura mater, arachnoid, and pia mater
optimal to control its replication and pathogenicity. delimit four compartments and tend to pre-
In addition, immunodeficiency conditions in the vent the spread of infection from one to another.
host are increasingly frequent. This may account for Accordingly, infections can occur in each of the four
the continuing high mortality and morbidity rates compartments—epidural, subdural, subarachnoid,
from infections of the CNS despite the advances and intraparenchymal.

114 •

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1.1.1. EPIDURAL ABSCESSES A  variety of bacterial species, gram-positive or
gram-negative, aerobic or anaerobic, can be incrimi-
Infection of the epidural space is rare. It usually
nated in acute bacterial meningitis. Some species
causes circumscribed abscesses and is localized
are most often found in children older than 1 year
more commonly to the epidural space of the verte-
and in adults, and infection results from either oti-
bral canal than to the intracranial epidural space. It
tis or a primary respiratory infection (sinusitis, rhi-
spreads frequently from an osteomyelitis secondary
nopharyngitis, or pneumonia); three major agents,
to frontal or mastoid sinusitis, trauma, or surgery
pneumococcus (Streptococcus pneumoniae), menin-
and may complicate epidural analgesia. Spinal epi-
gococcus, and Haemophilus influenzae each account
dural abscesses usually extend over several vertebral
for one third of the recorded cases. Other species,
levels. Intracranial epidural abscesses are biconvex,
such as Streptococcus agalactiae, Escherichia coli,
sharply outlined by the skull and the displaced dura.
Citrobacter koseri, and Listeria monocytogenes, are
most frequently isolated in young children or new-
1.1.2. SUBDURAL ABSCESSES OR borns, and they can be transmitted from mother to
EMPYEMA infant.
The purulent exudate may be seen macroscopi-
Infection of the subdural space most often extends cally in the leptomeninges (Fig. 5.1). Microscopically,
from an adjacent sinusitis, otitis, or osteomyelitis. large numbers of polymorphs invade the leptomen-
Infection from a purulent leptomeningitis is the ingeal and Virchow-Robin spaces (Fig. 5.2). Bacteria
main cause of subdural empyema in infants. The may be seen either free or within polymorphs. Later,
infections tend to spread over the convexities but in the absence of early resolution, the polymorphs
are prevented by the falx from crossing the midline. degenerate and disappear, to be replaced by a fibrin-
In most cases an empyema is situated over the ten- ous exudate containing lymphocytes, plasma cells,
torium, occasionally adjacent to the falx cerebri. histiocytes, and macrophages. After a few weeks, the
Empyema occurs less commonly in the posterior exudate organizes into fibrous connective tissue.
fossa, and rarely in the spinal canal. All the CNS structures in contact with the cere-
brospinal fluid (CSF) participate in the infectious
process. Thus, (a)  there is a polymorphic inflam-
1.1.3. ACUTE BACTERIAL MENINGITIS
matory cellular infiltrate in the walls of the lepto-
Purulent infection of the leptomeningeal spaces is meningeal blood vessels, mainly the veins, that may
the most frequent pyogenic infection of the CNS. undergo thrombosis and cause cerebral infarcts;
The overwhelming majority of cases of pyogenic (b) there is cellular infiltration of the cranial nerves
meningitis are secondary to hematogenous dissemi- and spinal roots, sometimes with degeneration
nation of bacteria. Meningitis may also complicate of the myelinated fibers; and (c)  there is invasion
trauma, surgery, or developmental malformations. of the ventricular walls with consequent purulent

FIGURE 5.1 Gross appearance of purulent FIGURE 5.2 Microscopic appearance of purulent


leptomeningitis. leptomeningitis (H&E).

Chapter 5 Infections of the Central Nervous System • 115


FIGURE 5.4 Parietal lobe abscess arising at the
cortico-subcortical junction with central necrosis,
surrounding granulation tissue, and peripheral
FIGURE 5.3 Purulent ventriculitis. capsule.

ventriculitis (Fig. 5.3). The process may also spread of hematogenous origin tend to occur at junctions
to the subpial and subependymal neural paren- between the gray and white matter (Fig. 5.4) and are
chyma. Cerebral abscesses secondary to purulent often multiple. They are secondary to septic emboli
meningitis are not unusual in infants and newborns. from bacterial endocarditis or chronic suppurative
The production of a fibrinocellular exudate and its intrathoracic infection. Paradoxical cerebral septic
subsequent fibrous organization may obstruct the emboli may also occur in congenital cyanotic heart
path of outflow of the CSF and result in the develop- disease. Abscesses resulting from direct spread from
ment of hydrocephalus, and even pyocephalus. an adjacent suppurative focus are usually situated in
Listeria monocytogenes infections deserve sepa- the temporal lobe (Fig. 5.5A) or in the cerebellum
rate mention because of the frequency with which following otitis media or mastoiditis, or in the fron-
microabscesses (“Listeria nodules”), localized par- tal lobe following sinusitis.
ticularly in the brainstem, are associated with this The initial stage of focal cerebritis (day 1 to 3
type of purulent meningitis. after inoculation) appears macroscopically as an
ill-defined region of hyperemia surrounded by
edema. Microscopically it is characterized by early
1. 1. 4. BRAI N ABS C ES S ES
parenchymal necrosis with vascular congestion,
Brain abscess is the second most common infection petechial hemorrhages, microthromboses, perivas-
of the CNS after bacterial meningitis and is the most cular fibrinous exudate, and infiltration by poly-
frequent space-occupying infection. Neuroimaging morphs. Surrounding edema is invariably associated
has greatly helped the diagnosis of brain abscess, and adds to the mass effect of the abscess itself.
resulting in a significant decrease of the mortality Late cerebritis (day 4 to 9)  is characterized by a
rate. It has also become possible to treat many cases necrotic purulent center resulting from the con-
with antibiotics alone. fluence of adjacent foci of necrosis. The pus is
As in leptomeningitis, the source of infec- surrounded by a narrow, irregular layer of inflamma-
tion producing brain abscesses may be local or tory granulation tissue infiltrated by polymorphs,
blood-borne, resulting in particular localizations. lymphocytes and some macrophages. The perivas-
Posttraumatic abscesses occur at the site of cra- cular spaces in the vicinity become cuffed with poly-
niocerebral wounds or neurosurgery. Abscesses morphs and lymphocytes.

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The early abscess capsule appears at day 10 to 13 wall. Despite the name, mycotic aneurysms are usu-
and is made up of granulation tissue, which includes ally due to pyogenic bacteria rather than to fungi.
lymphocytes, plasma cells, monocytes and mac- A  mycotic aneurysm may rupture, causing hemor-
rophages, numerous newly formed blood vessels, rhages into the brain or subarachnoid space, and
and scattered fibroblasts. The developing capsule is meningitis.
at first poorly defined; it is thickest on its cortical
surface and often very thin or even deficient on its
ventricular surface. For this reason, abscesses tend 1.1.6 . SUPPURATIVE INTRACRANIAL
to expand inward and rupture into the ventricular PHLEBITIS
system, resulting in ventriculitis. Septic intracranial thrombophlebitis most fre-
As time passes (day 14 and later), the capsule quently follows infection of paranasal sinuses, mid-
becomes firmer and can be stripped easily from the sur- dle ear, mastoid, face, or oropharynx. The infection
rounding edematous white matter. Microscopically, spreads centrally along the emissary veins. Septic
more fibroblasts appear, so that a well-encapsulated thrombophlebitis may also occur in association with
abscess consists of five layers:  a necrotic center epidural abscess, subdural empyema, or meningitis.
invaded by macrophages; granulation tissue with pro- Septic intracranial phlebitis may cause hemorrhagic
liferating fibroblasts and capillaries, and long, radially infarction. In addition, local suppuration may pro-
orientated blood vessels; a zone of lymphocytes and duce venous hemorrhage, venous necrosis, epidural
plasma cells in granulation tissue; dense fibrous tissue abscess, subdural empyema, meningitis, and brain
with embedded astrocytes; and a surrounding edem- abscess.
atous area of gliosis (Fig. 5.5B).
The two major and most serious complications
of brain abscesses are raised intracranial pressure 1.2. Tuberculosis
with the risk of cerebral herniation, and rupture of 1.2.1 . TUBERCUL OUS EPIDURAL OR
the abscess into a ventricle, resulting in ventricular SUB DURAL ABSCESSES
empyema.
Epidural tuberculous abscess is a recognized com-
plication of tuberculosis of the spine (Pott disease),
1.1.5. SEPTIC EMBOLISM involving either the vertebral bodies or the interver-
tebral discs. Subdural tuberculous abscess is also a
Apart from cerebral abscesses, septic emboli, when- frequent occurrence.
ever of sufficient size, may cause cerebral infarction
that is liable to become infected by extension from
1.2.2 . TUBERCUL OUS MENINGITIS
the septic embolus. Implantation of a septic embolus
in a cerebral artery may result in a mycotic aneurysm Tuberculous meningitis is the most common
due to local infection and weakening of the arterial form of tuberculosis of the CNS. In most cases, it

A B

FIGURE 5.5 Temporal lobe abscess with purulent necrosis in the center and surrounding granulation tissue.
(A) Gross appearance. (B) Microscopic appearance (HES).

Chapter 5 Infections of the Central Nervous System • 117


complicates the initial hematogenous dissemina- of involvement of the perforating blood vessels
tion that follows primary infection; it may also fol- (Fig. 5.8B).
low late reactivation of latent infection elsewhere in In treated patients dying several weeks after onset
the body. Tuberculous meningitis may be associated of the illness, the exudate is more fibrous. It is espe-
with miliary tuberculosis. cially thick over the base (Fig. 5.9A) of the brain and
Unlike purulent meningitis, which spreads over in the cisterna ambiens, where it may obstruct the
the cerebral convexities, in tuberculous meningitis, flow of CSF and lead to hydrocephalus (Fig. 5.9B).
the meninges over the base are most often involved.
There may be some gray-green opacity of the menin- 1 .2 . 3. TUBERCULOM AS OF BRAIN AN D
ges over the cerebral convexities, but a much thicker S P IN AL  CORD
exudate fills the basal cisterns, covering the basis
pontis and extending into the Sylvian fissures and Tuberculomas were formerly a very common type of
cisterna magna (Fig. 5.6). The spinal cord may also intracranial mass lesion and remain a serious prob-
be enveloped by exudate. Tubercles are not easily lem in areas of the world where tuberculosis is rife.
found in the exudate, but they can sometimes be Tuberculomas may be single but are more often
seen under the banks of the Sylvian fissures and near multiple (Fig. 5.10A). Their sites of predilection are
the pre- and post-central veins over the convexities. the cerebellum, the pontine tegmentum, and the para-
Microscopically, the inflammatory infiltrate central lobule. They have occasionally been described
involves the leptomeninges and the subpial regions, as in the spinal cord. They are spherical or multilobular
well as the ependyma and subependymal parenchyma. lesions with a caseous center, necrotic but firm and of
It is mostly composed of lymphocytes, mononuclear a creamy color, surrounded by a granulomatous reac-
cells, and epithelioid nodules with few giant cells and tion that includes giant cells, lymphocytes, and fibro-
tubercles. The latter consist of a central area of case- sis of variable extent (Fig. 5.10B). There is much less
ous necrosis surrounded by an epithelioid macro- swelling than around cerebral abscesses.
phage reaction with a peripheral ring of lymphocytes Tuberculomas, particularly of supratentorial
(Fig. 5.7). Acid-fast bacilli may be abundant or scanty. location, may spontaneously become cystic, fibrous,
Arterial lesions of reactive endarteritis obliterans or calcified; bacilli may be difficult to detect, and
(Fig.  5.8A) are constant and are frequently respon- inflammatory exudates can be scant. Tuberculomas
sible for the production of ischemic parenchymal may rupture into the meninges.
lesions, particularly within the basal ganglia because
1 .2 . 4. TUBERCULOUS ABSCESS
True abscesses of the brain, as opposed to tubercu-
lomas, are composed of a necrotic center containing

FIGURE 5.7 Tuberculous meningitis. Tubercles


FIGURE 5.6 Tuberculous meningitis. Thick exu- consisting of a central area of caseous necrosis sur-
date involving the basal meninges. (Courtesy of Pr. rounded by an epithelioid macrophage reaction with a
Leila Chimelli) peripheral ring of lymphocytes.

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A pus in which Mycobacterium tuberculosis are abun-
dant. They are surrounded by a capsule similar to
that in pyogenic abscesses, without the characteris-
tic granulomatous reaction. Tuberculous abscesses
of the CNS are usually multiple. In true abscesses,
the absence of a granulomatous epithelioid reac-
tion suggests the failure of immune mechanisms.
Tuberculous abscesses are now seen most often in
patients with AIDS.

1.3. Atypical Mycobacteriosis


B Nontuberculous mycobacteria (“atypical myco-
bacteria”) were considered in the past to be sap-
rophytic organisms. The Mycobacterium avium
complex, including M.  avium and M.  intracellulare,
is now recognized as one of the more common
causes of opportunistic infection in AIDS patients,
in whom it produces disseminated systemic infec-
tion. However, in most cases with generalized
M.  avium-intracellulare infection, involvement of
the CNS is asymptomatic. Neuropathological
examination only reveals diffuse perivascular mac-
rophages containing clusters of mycobacteria posi-
tive for acid-fast and periodic acid-Schiff (PAS)
stain. Symptomatic infection of the CNS due to
M.  avium-intracellulare or M.  fortuitum and brain
abscesses due to M. kansasii have been recorded in
rare case reports in patients with AIDS.

FIGURE 5.8 Tuberculous meningitis. (A) Marked


vascular changes forming endarteritis obliterans 1.4. Whipple Disease
(H&E). (B) Arterial lesions causing extensive cerebral Whipple disease is a multisystem disorder often
infarction (Loyez stain). involving the intestine, caused by a gram-positive
actinomycete, Tropheryma whipplei. Involvement

A B

FIGURE 5.9 Chronic tuberculous meningitis. (A) Massive fibrous infiltration of the basal meninges. (B) Basal
obstruction with ventricular dilatation.

Chapter 5 Infections of the Central Nervous System • 119


A B

FIGURE 5.10 Tuberculomas. (A) Gross appearance of multiple tuberculomas in the thalamus.


(B) Microscopic appearance. The caseous center is surrounded by a granulomatous reaction (H&E).

of the CNS is uncommon and is usually associated usually secondary to a focus elsewhere in the body,
with systemic disease. In rare instances, Whipple spreading to the nervous system either by direct
disease may be confined to the brain. extension or via the bloodstream. Multilocular
At neuropathological examination, small lesions abscesses are formed, with a central necrotic inflam-
are disseminated throughout the entire CNS but matory exudate containing polymorphs, necrotic
are especially abundant in the cortex, with a pre- debris, and colonies of branching organisms form-
dilection for the subpial regions, the basal ganglia, ing “sulfur granules,” surrounded by granulation
the hypothalamic nuclei, the periaqueductal gray tissue.
matter, the nuclei of the brainstem, and the dentate
nuclei of the cerebellum. They may become conflu-
ent to form more extensive foci. 1.6. Nocardiosis
Microscopically, there are meningeal and paren- Nocardia asteroides is a ubiquitous aerobic organ-
chymal lymphocytes and multinucleated cells ism that in the majority of cases produces infection
(Fig.  5.11A). The macrophages with lipid-filled in immunosuppressed patients. The nervous sys-
cytoplasm contain tiny sickle-shaped inclusions that tem is usually invaded through the hematogenous
are positive for PAS (Fig. 5.11B), Gram, and methe- route from a primary pulmonary lesion. In the
namine silver stain. The bacteria are also present brain, Nocardia produces abscesses or meningitis.
extracellularly in the tissue. By electron microscopy, Microscopically, the abscesses have fibrous walls and
lamellar, partially degraded bacterial cell walls and consist of polymorphs. The organism appears as thin
better-preserved bacilli are present in macrophages, branching filaments, about 1 μm in diameter. They
astrocytes, and pericytes. cannot be recognized in routinely stained prepara-
tions but can be identified using a modified Grocott
methenamine-silver stain or also on Gram stain,
1.5. Actinomycosis where they are gram positive. Nocardia is one of the
Actinomyces are small anaerobic gram-positive most common causes of bacterial brain abscess in
organisms whose appearance as thin, branching fila- people with AIDS, in whom brain abscesses are not
ments has long led to their inclusion (with Nocardia) especially common.
among fungi. Actinomyces have a worldwide distri-
bution but occur predominantly in rural areas. Most
infections in man are produced by Actinomyces israeli
1.7. Neurosyphilis
and A. bovis and are acquired from organisms situ- Involvement of the CNS is a sequela of primary
ated in the oral cavity or in the large intestine; they luetic disease that either has been undetected or
invade the tissues through a break in the mucosa. has been inadequately treated. Although invasion
Bone (mainly the mandible) is the most commonly of the leptomeninges during secondary syphilis
affected site. Lesions of the CNS are rare and are is relatively common, symptomatic neurosyphilis

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A B

FIGURE 5.11 Whipple disease. (A) Perivascular accumulation of lipid-laden macrophages surrounded by


reactive astrocytosis (H&E). (B) The foamy macrophages contain PAS-positive inclusions in the cytoplasm.

occurs predominantly at the tertiary stage of the attached to both the dura mater and the brain
disease. Classically, neurosyphilis may be separated and consist of round, red-tan-gray lesions that
into meningovascular (inflammatory) syndromes, are focally firm and rubbery, with a central area
occurring within a few years of infection, and paren- of necrosis (Fig. 5.12). Microscopically, they
chymatous (degenerative) syndromes, which have a consist of central gummatous necrosis with
latency of decades. However, considerable overlap ghost-like outlines of dead cells. This is sur-
of these syndromes is observed commonly. rounded by a granulomatous reaction including
epithelioid cells and fibroblasts with scat-
tered multinucleated foreign body giant cells.
1.7.1. MENINGOVASCULAR Spirochetes are rarely demonstrable since the
NEUROSYPHILIS gumma represents a hyperimmune form of tis-
This is due to a combination of chronic meningi- sue necrosis.
tis, multifocal arteritis, and gummatous necrotic
lesions.

• Chronic meningitis composed of lymphocytes


and plasma cells often leads to fibrous organiza-
tion and ultimate occlusion of the CSF pathways
with consequent hydrocephalus. Extension of
the inflammatory process into cranial and spinal
nerves and periarteritis may also cause optic atro-
phy or cranial nerve palsies.
• The vascular component of meningovascular
syphilis, “Heubner arteritis,” consists of an
infiltration of the arterial wall by lymphocytes
and plasma cells associated with intimal prolif-
eration (endarteritis obliterans). This arteritis
involves large and medium-sized blood vessels;
it may cause ischemic lesions in the brain or
spinal cord.
• Cerebral gummas are seen rarely in Europe
and North America; they seldom occur in the
meninges. They can involve the cerebral convex-
ity but may be found in the cerebral midbrain, FIGURE 5.12 Cerebral gumma in an AIDS patient.
hypothalamus, and spinal cord. They are usually (Courtesy of Dr. Marius Valsamis)

Chapter 5 Infections of the Central Nervous System • 121


1. 7. 2. PARE NC HYMATO U S characterized by Wallerian degeneration of the dor-
N E U R O S Y P HI L I S sal columns. Unlike in GPI, no inflammatory reac-
tion is demonstrable in the cord parenchyma, and
This takes two forms:  paretic dementia (general
T. pallidum is absent.
paralysis of the insane [GPI]) and tabes dorsalis.
Both forms may coexist as “tabo-paresis.”
In former days, in patients dying after several 1 .7 . 3. SYPHILIS AN D HIV IN FECTION
years of GPI dementia, the brain showed character-
istic macroscopic changes; it was shrunken and firm Neurosyphilis is not uncommon in patients with
and covered by a thick and opaque pia-arachnoid. AIDS. Co-infection with HIV may modify the clini-
These lesions were most marked frontally, decreas- cal spectrum of syphilis. Patients with HIV infec-
ing posteriorly. The ventricles were enlarged, and the tion are likely to progress rapidly to symptomatic
ependyma showed diffuse granular ependymitis. At neurosyphilis and to show an accelerated disease
the present time, GPI is rarely seen. In the healed course; treatment failure is also more frequent. The
stages of the disease, the brain is usually grossly nor- most common manifestations of symptomatic neu-
mal except perhaps for ependymal granulations. rosyphilis in HIV-infected patients are syphilitic
On microscopic examination, there is meningeal meningitis and meningovascular syphilis. General
thickening and striking involvement of the cerebral paresis, syphilitic meningomyelitis, syphilitic poly-
cortex, which is atrophic with loss of the normal lam- radiculopathy, and cerebral gummas have been
inar pattern. There is neuronal loss with proliferation reported in occasional cases.
of reactive astrocytes and rod-shaped microglia. The
lesions are distributed in scattered foci of different
age, giving a “bush-fire” or windswept appearance. 1.8. Borreliosis
Perivascular cuffing by lymphocytes and plasma cells This condition is due to an infection by a spirochete
is found in the cortex and leptomeninges. Specific sil- of the Borrelia group, which is transmitted to a human
ver impregnation may occasionally demonstrate the by insect bites. Examples include relapsing fever and
spirochetal organism of Treponema pallidum. Lyme disease. The latter is a multisystem disorder
Tabes dorsalis consists of degeneration of the due to the spirochete B.  burgdorferi. It involves the
posterior columns (Fig. 5.13) and spinal nerve roots skin, cardiovascular system, joints, and central and
with involvement of the dorsal roots and ganglia. It is peripheral nervous system. Neurological signs usu-
apparently the result of inflammatory meningovas- ally develop several weeks after a tick bite, which may
cular lesions localized to the subarachnoid portion cause erythema chronicum migrans, and culminate
of the dorsal nerve roots. Spinal cord involvement in lymphocytic meningitis, which is rich in plasma
is secondary to radiculo-ganglionic lesions. It is cells. Involvement of the spinal and/or cranial nerve
roots is frequent. Encephalomyelitic complications
are much rarer. Tertiary neurological complications
occurring years after inoculation include axonal
neuropathies and low-grade encephalopathy. The
pathogenesis of CNS lesions is unclear; it may be
an immunopathological process rather than a direct
effect caused by bacterial invasion.

1.9. Brucellosis
Brucellosis, or Malta fever, is a zoonosis transmitted
to humans by raw dairy products or by direct con-
tact with animal products (such as the placenta).
The disease is endemic in cattle-breeding countries.
Leptomeningeal involvement is common in the sep-
FIGURE 5.13 Tabes dorsalis. Horizontal section ticemic phase of the disease. Either spontaneously
of the lumbar cord showing the degeneration of the or after inadequate treatment, the disease may give
posterior columns (Loyez stain). rise to subacute neurological manifestations, either

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infectious or hyperergic. The different forms of neu- proliferation. Coalescence of granulomas may form
robrucellosis correspond to a variety of clinicopath- larger meningeal or parenchymatous masses, simu-
ological features, including meningoencephalitis, lating neoplasms.
meningomyelitis, and meningomyelitis-radiculitis,
with frequent involvement of the cranial nerves, par-
ticularly the acoustic nerves.
1.11. Chronic Pachymeningitis
In rare instances, there can be a chronic inflammatory
condition of the cerebral dura, which causes thickening
1.10. Sarcoidosis of the dura, with a mixed inflammatory cell infiltrate
Sarcoidosis is a granulomatous multisystem disor- consisting of plasma cells, lymphocytes, and occa-
der of unknown etiology. The lung is predominantly sional eosinophils. The inflammation often has a stori-
affected; skeletal muscle or peripheral nerve involve- form or whorled appearance, and germinal centers can
ment is not uncommon; CNS involvement occurs in also be seen. Cultures of this inflammatory lesion are
about 5% of cases. negative, and microorganisms cannot be demonstrated
The lesions may affect any part of the CNS but within them with special staining techniques. These
involve preferentially the base of the brain, especially lesions of the dura resemble similar inflammation of
the suprasellar and the hypothalamic regions, the the orbit, in some instances referred to as inflammatory
optic nerves and the optic chiasm, the basal ganglia, pseudotumor. Some patients with this disorder may
and the posterior fossa. Hydrocephalus may result have elevated levels of IgG4 in serum, and a diagnostic
from thickening of the basal meninges or aqueductal feature is considered to be the presence of 30 or more
obstruction by a periventricular parenchymal lesion. IgG4-positive plasma cells per high-power field on
The sarcoid granulomas consist of a central immunohistochemistry. This disorder is thought to be
mass of epithelioid cells and multinucleated giant part of the spectrum of IgG4-related disease.
cells surrounded by lymphocytes, monocytes,
and fibroblasts (Fig.  5.14A). The granulomatous
changes involve predominantly the leptomeninges;
1.12. Toxin-Induced Neurological
they are often perivascular and may extend to the
Disease
underlying parenchyma along the Virchow-Robin In addition to direct invasion of the CNS, bacteria
spaces. Cerebral vasculitis may give rise to vascular can cause neurological damage indirectly by produc-
occlusion and brain infarction. Within the brain, ing neurotoxic substances. A number of neurotoxins
granulomas may be confined to the perivascu- have been identified in specific bacterial infections
lar spaces (Fig.  5.14B). Parenchymal lesions may (diphtheria, tetanus, botulism); in other instances
also involve the periventricular areas, particularly (shigellosis, Bordetella pertussis infection, melioido-
around the third ventricle, and the choroid plexus; sis, legionellosis, etc.), because of the clinical fea-
they are often surrounded by marked astrocytic tures and persistent negative cultures of the CSF,

A B

FIGURE 5.14 Sarcoidosis. (A) Intraparenchymatous epithelioid granulomas (H&E). (B) Perivascular granu-


loma including lymphocytes, monocytes, and multinucleated cells. Note marked reactive astrocytosis (H&E).

Chapter 5 Infections of the Central Nervous System • 123


A B

FIGURE 5.15 Aspergillosis. (A) Gross appearance, coronal section of the frontal lobes showing multiple hem-
orrhagic abscesses. (B) Presence of branching and septate hyphae (methenamine silver).

the possibility of a toxin-induced involvement of the 2. MYCOSES AND PARASITIC


CNS has been postulated. In either case, although
the encephalopathy may be lethal, there are few neu-
INFECTIONS
ropathological descriptions, and CNS changes are A number of different fungi, protozoa, and metazoa
usually discrete or nonspecific. may affect the central and peripheral nervous system.

A C

B D

FIGURE 5.16 Cryptococcosis. (A) Cryptococcus meningitis, gross appearance: chronic meningitis involv-


ing the basal leptomeningitis. (B) Cryptococcus meningitis in an immunocompetent patient, with marked
lymphocytic and giant cell inflammation (H&E). (C) Parenchymal cysts in an AIDS patient (Loyez stain).
(D) Microscopic appearance: dilatation of the perivascular space forming a cystic cavity filled with cryptococci.
Note the absence of inflammation or astrocytic reaction in the surrounding parenchyma (H&E).

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These infections used to be relatively uncommon associated with hepatic and/or pulmonary
in everyday neuropathological practice in indus- involvement.
trialized countries and were restricted to certain • Free-living organisms may produce primary
geographical areas or involved small groups of indi- meningoencephalitis (by Naegleria fowleri) and
viduals. However, increased intercontinental travel, granulomatous encephalitis (Acanthamoeba and
loosening of health controls, and the AIDS epidemic Leptomyxid).
have made it possible for some infections to spread – Primary meningoencephalitis due to
into previously nonaffected areas. On the other Naegleria fowleri is usually contracted during
hand, the incidence of some opportunistic infec- the summer by healthy young people swim-
tions (in particular mycoses and toxoplasmosis) has ming in infected water. Parasites reach the
increased in the last decades owing to a considerable CNS through the nasal mucosa and the olfac-
increase in the number of immunocompromised tory epithelium. The pathology consists of
individuals. encephalitis with hemorrhagic necrosis, iden-
tifiable parasites, and basal leptomeningitis.
Virtually all cases are fatal.
2.1. Mycotic Infections – Granulomatous encephalitis presents with brain
Although fungal infections of the CNS are usually swelling, with moderate meningitis and conflu-
secondary to a primary focus elsewhere (respiratory ent areas of hemorrhagic necrosis. Histologically
system; gastrointestinal tract) or to a direct exten- it is a chronic vasculitis with the presence of
sion from the sinuses or bone, in some instances parasites and occasionally a granulomatous reac-
they may represent the only localization. In his- tion (Fig. 5.17).
tological specimens, organisms may be present as
yeasts (up to 20 μm in diameter), branching hyphae,
2.2.2 . CEREBRAL MAL ARIA
sometimes considerably long, or pseudohyphae of
intermediate size. These morphologic differences Responsible for 800,000 deaths a year in Africa
determine the type and size of the lesions: menin- alone, it is prevalent in 100 countries. There is
gitis in infections by the smallest; extensive infarcts marked heterogeneity between cases, probably
following occlusion of the vessels by the largest reflecting host susceptibility.
fungi; and multiple small infarcts in case of infection Macroscopically the brain is swollen with
by organisms of intermediate size, with infection of dusky leptomeninges and on section it appears
the ischemic lesions in turn causing abscesses and pale or slate-gray. Microscopically the most com-
granulomas. mon feature is sequestration of parasitized blood
The classical distinction of fungi into pathogens cells within cerebral microvessels, which also con-
and opportunists is not absolute, as some of them tain dark malarial pigment (Fig. 5.18A). Petechial
can manifest in both ways. hemorrhages of various types are also frequent.
The main fungal infections that may affect the Focal necrosis within the white matter is fol-
CNS are summarized in Table 5.1 lowed by a gliotic reaction (Dürck granuloma)
(Fig. 5.18B).

2.2. Protozoal Infections


2.2.3 . TOXOPL ASMOSIS
The main protozoa responsible for human infections
can be classified as summarized in Table 5.2. Feline species, particularly the domestic cat, are the
definitive host of the protozoan Toxoplasma gondii.
Toxoplasmosis in humans can present as congenital
2.2.1. AMEBIASIS toxoplasmosis (cf. Chapter 11) and as acquired/pri-
mary toxoplasmosis in adults.
In man, cerebral lesions are produced by Entamoeba Congenital toxoplasmosis is secondary to trans-
histolytica and by free-living amoebae. placental infection. There are diffuse necrotic and
inflammatory lesions of the cortex and white matter
• Entamoeba histolytica is rarely responsible for that are accompanied by calcifications, especially in
hematogenous brain abscesses that are usually the periventricular regions.

Chapter 5 Infections of the Central Nervous System • 125


Table 5.1. Main Fungal Infections Affecting the CNS

MYCOSIS ORGANISM T YPE OF AC TION GEOGR APHICAL PRIMARY FOCUS N E U R O PAT H O L O G Y


DIS T RIBU TION

Aspergillosis Aspergillus: flavus, Predominantly Ubiquitous Usually secondary Abscesses and granulomas; vascular
fumigatus -niger, opportunist to foci in lungs and involvement, with extensive
oryzae gastrointestinal tract. hemorrhage (Fig. 5.15A). Branching
and septate hyphae (Fig. 5.15B).
Blastomycosis Blastomyces Predominantly North America, Africa Primary focus in Meningeal lesions, epiduritis,
dermatitidis pathogen, mainly in lungs. pachymeningitis, purulent or
agricultural workers granulomatous meningitis (mimicking
tuberculosis).
Central, basophilic body with wall;
single bud.
Candidiasis Candida albicans Opportunist, mainly Ubiquitous Saprophyte in Abscesses or granulomas; vascular
Other species in premature infants, digestive and genital involvement. Sometimes meningitis.
immunosuppressed mucosae. Chains of elongated cylindrical
and diabetic patients pseudohyphae.
Chromomycosis Alternaria, Both in Ubiquitous Primary focus usually Meningitis, abscesses, or diffuse
Heterogenous group Cladophialophora, immunocompetent and in the skin. encephalitis.
of organisms that Curvularia, immunocompromised Mainly hyphae, more seldom spores.
appear pigmented Exophilia, Fonsecaea, patients
microscopically or in Madurella,
cultures Phialophora,
Rhinocladiella
Cladosporiosis Cladosporium Predominantly Ubiquitous Isolated from Abscesses or meningitis.
trichoides pathogen skin, conjunctiva, Hyphae.
(bantianum) lymph nodes,
gastrointestinal and
urinary tract.

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Coccidioidomycosis Coccidioides immitis Predominantly South America, Mexico, Primary foci in lungs. Basal meningitis with nodules;
pathogen southwestern United vasculitis.
States Hyphae.
Cryptococcosis Cryptococcus Predominantly Ubiquitous, but Usually secondary to Meningitis with occasional tubercles.
(Fig. 5.16) neoformans opportunist predominates in a focus in the lungs. Amount of inflammation depends on
southern United States degree of immunosuppression.
and Australia Spores with capsule.
Histoplasmosis Histoplasma Pathogen, but for CNS Ubiquitous, but Secondary to Meningitis with vasculitis. Granulomas
capsulatum infections it acts as common in the United pulmonary infection. are rare. Small ovoid budding bodies,
opportunist States intracellular.
Paracoccodioidomycosis Paracoccidioides Predominantly Brazil Primary focus in the Space-occupying lesions; meningitis.
brasiliensis pathogen lungs. Multiple budding.
Pseudoallescheriosis Pseudoallescheria Opportunist Ubiquitous Associated with Meningitis and abscesses; vasculitis.
boydii (immunodeficiency, disorders of the Sometimes granulomas.
diabetes) respiratory system. Septate hyphae and clamidospores.
Zygomycosis Rhizopus, Mucor, Opportunist, mainly Ubiquitous Secondary to focus in Necrosis and polymorphs with giant
Absidia diabetic patients, but skin, nasal mucosa or cells. Vasculitis with hemorrhage.
also drug users, patients lungs. Broad branching, nonseptate hyphae.
on antibiotics and
corticosteroids.
Table 5.2. Main Protozoa Responsible hemispheres, particularly the basal ganglia and
for Human Infections the cortico-subcortical junction (Fig.  5.19A).
These lesions contain central, eosinophilic, and
1. Amebiasis acellular pseudo-ischemic necrosis surrounded
a. Entamoeba histolytica: cerebral amebic by a cellular inflammatory reaction, usually with
abscesses polymorphs. Parasites are seen either within
b. Primary amebic encephalitis pseudocysts (bradyzoites) (Fig.  5.19D) or as
i. Primary amebic meningoencephalitis free forms (tachyzoites) (Fig. 5.19C). Associated
(Naegleria fowleri) hemorrhages are frequent. These abscesses can
undergo transformation during the illness and in
ii. Granulomatous amebic encephalitis
the course of treatment and appear at postmortem
(Acanthamoeba spp. and Leptomyxid)
as (1)  necrotizing (Fig.  5.19A) or (2)  organiz-
iii. Acanthamoeba keratitis ing (Fig. 5.19B) abscesses or 3) chronic “treated”
2. Cerebral malaria (Plasmodium falciparum lesions with a central cystic space. Rarely, in AIDS
infection) patients, diff use “septicemic” encephalitic forms
3. Toxoplasmosis (Toxoplasma gondii infection) may occur with dissemination of microglial nod-
4. Trypanosomiasis ules in some cases containing encysted bradyzo-
a. African trypanosomiasis (Trypanosoma brucei ites or tachyzoites.
spp.)
b. South American trypanosomiasis
2 .2 . 4. TRYPAN OSOM IASIS
(Trypanosoma cruzi)
African trypanosomiasis is caused by T. brucei sub-
species transmitted to human by the tsetse fly. It is
In immunocompetent individuals, CNS characterized neuropathologically by meningoen-
involvement is uncommon; it is usually benign cephalitis. There is perivascular inflammation with
and most often asymptomatic. In contrast, toxo- microglial nodules. Mott cells, characteristic of this
plasmosis is often fatal in immunocompromised form, are plasma cells with prominent eosinophilic
patients (HIV, posttransplantation, congenital cytoplasmic Russell bodies. No parasites are usually
immunodeficiencies). Cerebral toxoplasmo- seen in the brain tissue.
sis is one of the most frequent CNS complica- South American trypanosomiasis (Chagas dis-
tions of AIDS and represents the main cause of ease) remains a health problem in many areas of
focal and space-occupying cerebral lesions in Central and South America, where it affects up to
these patients. Typically, it presents as multiple 18  million individuals. The agent, Trypanosoma
abscesses involving predominantly the cerebral cruzi, is responsible for both an acute and a chronic
disease. The former can be asymptomatic or can
present as a mild meningoencephalitis with microg-
lial nodules in the brain, sometimes containing
parasites. The chronic form includes a “chagasic”
encephalopathy with neuronal loss and focal inflam-
matory changes and, more commonly, a peripheral
autonomic and occasionally somatosensory neu-
ropathy with ganglion cell loss. In AIDS patients,
T.  cruzi infection may cause multifocal necrotizing
encephalitis in which abundant amastigote parasites
are present, particularly within glial cells and neu-
rons (Fig. 5.20).

FIGURE 5.17 Amebiasis, granulomatous


2.3. Metazoal Infections
encephalitis. Chronic vasculitis with presence of The major helmintic infections of the CNS can be
parasites (H&E). classified as summarized in Table 5.3.

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A B

FIGURE 5.18 Cerebral malaria. (A) Sequestration of parasitized blood cells within cerebral microvessels,
which also contain dark malarial pigment. (B) Dürck granuloma (H&E).

2.3.1. CYSTICERCOSIS of the pig tapeworm; the disease occurs between


2  months and 30  years after initial infection. The
Cysticercosis is the most common parasitic infection
number of cysts in the CNS varies from one to sev-
of the CNS and is endemic in all countries, particu-
eral hundred (Fig. 5.21A). All of the cysts have similar
larly in Latin America. It is caused by the larval stage

A B

C D

FIGURE 5.19 Toxoplasmosis. (A) Multiple necrotizing abscesses, some of which are hemorrhagic involving the
basal ganglia and the cortico-subcortical junction. (B) Organizing abscesses with central necrosis and hyperemic
border in the genu of corpus callosum and in the white matter of the right frontal lobe. (C) Free tachyzoites at the
periphery of a necrotic lesion (H&E). (D) Numerous pseudocysts (bradyzoites) around a necrotic lesion (H&E).

Chapter 5 Infections of the Central Nervous System • 129


appearance; and (3)  inner reticular or fibrillary
(Fig. 5.21C). A granulomatous reaction with fibrosis
and calcification occurs only if the organism dies.

2 .3 . 2. HYDATIDOSIS
Hydatid cyst is endemic in the Mediterranean regions
and the Middle East, as well as in Latin America. Dogs
and other canids are the definitive hosts. Cysts in the
brain are usually solitary and unilocular and their wall
consists of two layers (1) the outer, laminated, cuticu-
lar layer and (2) the inner germinal layer.
FIGURE 5.20 Trypanosomiasis. Abundant amasti-
gote parasites are present within glial cells in a case of
2 .3 . 3. SCHISTOSOM IASIS
multifocal necrotizing encephalitis (H&E). (Courtesy
of Pr. Leila Chimelli) Schistosomiasis is caused by flukes of the genus
Schistosoma, which have man and other mam-
structure; they contain a single scolex with four suck- mals as definitive hosts. The infection is endemic
ers and a double row of hooklets (Fig.  5.21B). The in South America, the Middle and Far East, and
cyst wall consists of three layers: (1) outer or cutic- Africa. CNS lesions involve predominantly the spi-
ular; (2)  middle cellular with a pseudoepithelial nal cord. Macroscopic changes are uncommon.
Histological examination reveals three main appear-
ances: (1) necrotic-exudative with variable number
Table 5.3. Major Helminthic Infections of eggs; the area is surrounded by eosinophils, lym-
of the CNS phocytes, plasma cells, and macrophages; (2) a pro-
1. Cestodes ductive stage where eggs have lost the embryo; and
(3)  a late stage with a granulomatous reaction and
a. Neurocysticercosis (Taenia solium)
giant cells (Fig. 5.22).
b. Hydatid cyst (Echinococcus granulosus)
c. Coenuriasis (Taenia multiceps)
d. Sparganosis (Spirometra) 2 .3 . 4. EOSIN OPHILIC M EN IN GITIS
2. Trematodes These are due to infection by Angiostrongylus can-
a. Paragonimiasis (Paragonimus westermani) tonensis or Gnathostoma spinigerum. Larvae may be
b. Schistosomiasis (Schistosoma mansoni, demonstrated in the brain or meninges, which show
japonicum, haematobium, mekongi) a predominantly eosinophilic infiltrate.
c. Other trematode infections
3. Nematodes 2 .3 . 5. TOXOCARIASIS
a. Eosinophilic meningoencephalitis
Toxocara canis is a common agent and important
i. Angiostrongylus cantonensis
canine zoonosis that occurs worldwide. It may occa-
ii. Gnathostoma spinigerum sionally affect humans, particularly children. The
b. Toxocariasis (visceral larva migrans) death of the parasite in the brain is followed by a
i. Other forms of larva migrans nonencapsulated granulomatous reaction consist-
ii. Trichinella spiralis ing of lymphocytes, eosinophils, plasma cells, fibro-
c. Human filariasis. Loa-loa blasts, and epithelioid and giant cells.
ii. Dracunculus medinensis
iii. Onchocerca vulvulus 2 .3 . 6. TRICHIN OSIS
d. Nematodes and immunosuppression This infection exists in North and South America,
i. Strongyloides stercoralis but outbreaks have been reported also in Europe

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A B

FIGURE 5.21 Cysticercosis. (A) Gross appearance: two cystic cavities containing a parasite are present in the
thalamus and insular cortex (courtesy of Pr. Leila Chimelli). (B) Microscopic appearance of the scolex with suck-
ers and a double row of hooklets. (C) Higher magnification showing the three layers of the cyst walls (HES).

and in some Mediterranean countries. Involvement small hemorrhages. Histological findings include
of the striated muscle is the main complication (cf. granulomatous nodules, predominating in the white
Chapter  12). Involvement of the CNS is uncom- matter and consisting of lymphocytes, microglia,
mon. Macroscopic features may be limited to non- and histiocytes. Larvae are only rarely identified in
purulent meningitis, mild edema, and occasional nodules, suggesting an immune-mediated patho-
genesis of the lesions.

2.3.7 . STRONGYL OIDES STERCORAL IS


INFECTION
Strongyloides stercoralis infection should be consid-
ered in the presence of severe immunosuppression
during which larval infection can affect every organ.
In these circumstances larvae can be seen in the
subarachnoid spaces, and microinfarcts may be pro-
duced by obstruction of capillaries by the parasite.

3. VIRAL INFECTIONS
FIGURE 5.22 Schistosomiasis. Eggs within a granu- The lesions of the CNS induced by viral infections
lomatous reaction with giant cells (H&E). may result from various mechanisms. Some of them

Chapter 5 Infections of the Central Nervous System • 131


are nonspecific and are due to immuno-allergic 3 .1 . 2. ACUTE DISSEM IN ATED
reactions that are secondary to the viral infec- ENCEPHALOM YELITIS (ADEM ) OR ACUTE
tion; they involve the leptomeninges and espe- D I SSEM IN ATED LEUKOEN CEPHALITIS,
cially the white matter (leukoencephalitides). O R ACUTE POSTIN FECTIOUS/
Other, more specific lesions are directly caused P O STVACCIN IAL PERIVEN OUS
by the infection of the CNS by the virus. They ENCEPHALITIS
involve mainly, but not exclusively, the gray matter
Postinfectious encephalitis may complicate a variety
(polioencephalitides).
of systemic viral diseases, including measles, mumps,
Most viral encephalitides run an acute course.
chickenpox, rubella, influenza, and infectious mono-
However, special immunological phenomena may
nucleosis caused by Epstein-Barr virus (EBV). It was
modify the course of the disease and result in the
also well documented following smallpox or rabies
development of a latent infection, notably as in her-
vaccination. It closely resembles experimental aller-
pes, or a persistent infection, as in subacute scleros-
gic encephalomyelitis produced by injecting experi-
ing panencephalitis, which is presumably caused
mental animals with myelin proteins and adjuvant
by a defective measles virus. In AIDS, infection
and is believed to be due to a T-cell–mediated hyper-
by the retrovirus human immunodeficiency virus
sensitivity reaction. Clinically, it presents as an acute
(HIV) causes both a subacute encephalitis and
disseminated encephalomyelitis that is separated by
immunodeficiency.
a latent period of a few days to 3 weeks duration after
the causative viral infection or vaccination.
3.1. Nonspecific CNS The histological features are highly stereotypi-
Involvement in Viral Infections cal and consist of infiltrates of lymphocytes, plasma
cells, and macrophages around the venules of the
3. 1. 1. ACUT E V I R AL LY M P H O C Y TI C neural parenchyma. These involve mainly the white
M E N I NGI T I S OR ASEP TI C M EN I NG I TI S matter, where they are associated with perivenous
This response is common with several types of foci of demyelination (Fig.  5.23A, B) with rela-
viral infections, mainly enteroviruses (echovirus, tive sparing of the axons (cf. Chapter 7, section 4).
coxsackieviruses, enterovirus 71), but also mumps There may also be small perivascular hemorrhages.
virus, herpes simplex virus (HSV-2), arboviruses, Arteries are relatively free of inflammation, but there
lymphocytic choriomeningitis (LCM) virus, mea- are often inflammatory cells in the leptomeninges.
sles, parainfluenza, adenoviruses, and others.
It is characterized by vascular congestion and a
scanty infiltrate of lymphocytes in the leptomen- 3 .1 . 3. ACUTE HEM ORRHAGIC
inges, in the perivascular spaces surrounding some L EU KOEN CEPHALOPATHY OF  HURST
of the superficial cortical blood vessels, and in the This is a fulminant, usually fatal, disorder, regarded
choroid plexus. by some as a hyperacute form of ADEM. It is

A B

FIGURE 5.23 Acute perivenous encephalitis. (A) Perivenous foci of demyelination in the white matter (Loyez
stain). (B) Higher magnification showing perivenous inflammatory infiltrates (Klüver-Barrera stain).

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in one or more of the cell types in the CNS—
neurons, glial cells, or macrophages/microglial
cells, depending upon cell tropism. Some viruses
have a rather restricted or narrow cell tropism in
the CNS—for example, JC virus infecting oligo-
dendroglial cells in progressive multifocal leu-
koencephalitis (PML) and poliomyelitis viruses
infecting lower motor neurons. Other viruses have
wide cell tropism, infecting most of the cells in
the CNS, including endothelial cells, which is the
case for many of the herpes viruses. Cell tropism
is largely determined by cell receptors that allow
entry of virus into the cell.
FIGURE 5.24 Gross appearance of acute hemor- Whatever the causative virus, the basic neuro-
rhagic leukoencephalopathy. pathological picture of viral encephalitis includes
the following:
characterized by the presence of numerous scattered
hemorrhagic foci, which are more prominent in the • Involvement of the neuronal cell bodies, resulting
cerebral (Fig. 5.24) and cerebellar white matter and in their destruction and engulfment by macro-
in the pons. Microscopically, many small blood ves- phages (neuronophagia) (Fig. 5.25A)
sels undergo fibrinoid necrosis and are surrounded • Perivascular cuffing of inflammatory cells, mainly
by a narrow zone of necrotic tissue and a larger zone lymphocytes, macrophages, and plasma cells
of hemorrhage (ring- or ball-shaped perivascular (Fig. 5.25B)
hemorrhages). Still-recognizable vessels are veins • Microglial proliferation with the formation of
or venules, and they may be surrounded by fibrin microglial nodules and the appearance of rod cells
and an inflammatory infiltrate including neutrophils (Fig. 5.25C)
and mononuclear cells. Some neurites within the • In some cases, intranuclear or intracytoplasmic
infiltrate are demyelinated but many show axonal inclusion bodies are indicative of the presence of
fragmentation. virus in neurons and/or glia.

According to the type of the responsible virus


3.2. Infective viral encephalitis one may separate encephalitis due to RNA viruses
and encephalomyelitis (enterovirus, arbovirus, rabies, paramyxovirus,
Viral encephalitis—in the strict meaning of the term— rubivirus, and retrovirus), encephalitis due to
is due to infection of the brain by a virus. However, DNA viruses (herpes viruses, papovaviruses), and
quite often, viral infection also involves the meninges encephalitis suspected of being due to as yet uniden-
(meningoencephalitis) and/or the spinal cord (enceph- tified viruses (encephalitis lethargica, Behçet uveo-
alomyelitis, meningoencephalomyelitis) as well as the meningoencephalitis, chronic localized encephalitis
nerve roots (meningoencephalomyeloradiculitis). of Rasmussen).
Nervous system involvement is always second-
ary to infection elsewhere in the body. In fact, most
3.2.1 . ENCEPHAL ITIDES DUE TO RNA
viral infections of the CNS are rare complications
VIR USES
of common systemic viral diseases. The portal of
entry that has been directly exposed to infection 3.2.1.1. Poliomyelitis This is due to infection of
may be the skin (through direct contact or by an the CNS by a poliovirus, a small RNA virus of the
animal or insect bite), the airways (after inhala- genus Enterovirus.
tion), or the alimentary tract (after ingestion). The The most frequent form of the disease, “acute
virus may spread to the CNS directly along the anterior poliomyelitis,” is characterized by lytic
olfactory or peripheral nerves, or by the hematog- infection of the motor neurons. The lesions selec-
enous route in the course of viremia. This is fol- tively involve the motor neurons of the anterior
lowed by obligatory intracellular viral replication horns and the cranial nerve nuclei but may extend

Chapter 5 Infections of the Central Nervous System • 133


A B

FIGURE 5.25 Chief microscopic features of encephalitis. (A) Neuronophagia (Nissl stain). (B) Lymphocytic


perivascular cuffing (Nissl stain). (C) Proliferation of rod-shaped microglia (H&E).

to the frontal gyri, the hypothalamus, the reticular populations, poliomyelitis is usually caused either
formation, and the posterior horns. As a result of by the rare reversion to neurovirulence of attenu-
viral infection and lysis of the neurons, there is neu- ated vaccine-related strains of poliovirus, or by other
ronophagia and microglial nodules with microg- groups of enteroviruses, especially group A  cox-
lial/macrophage cell proliferation. Inflammation sackieviruses and enterovirus 71. The latter, a cause
in the leptomeninges and affected gray matter is of hand, foot, and mouth disease, has also been
intense (Fig.  5.26A, B). There is edema and vas- responsible for fulminant fatal brainstem encepha-
cular congestion, which may be associated with litis in children.
perivascular hemorrhages and, occasionally, focal
necrosis. 3.2.1.2 Arbovirus (arthropod-borne virus)
Following resolution, the residual lesions consist encephalitides These encephalitides are transmit-
of atrophy of the anterior horns with neuronal loss ted by insects and have a distinct geographical dis-
and astrocytic gliosis. There is atrophy and fibrosis tribution often indicated by the name of the virus.
of the anterior nerve roots, which appear thin and The best-known forms of the mosquito-borne
grayish at gross examination. The corresponding encephalitides include St. Louis encephalitis and the
skeletal muscles show wasting with severe denerva- Eastern, Western, and Venezuelan equine encepha-
tion atrophy. litides in America, Japanese B encephalitis in the
The introduction of vaccines for poliomyeli- Far East, Murray Valley encephalitis in Australia,
tis viruses has resulted in a sharp decline in the and West Nile fever primarily in Africa but also in
incidence of poliomyelitis. However, outbreaks Europe, Asia, and America. In these various forms
of paralytic infection by wild-type poliovirus the typical lesions of encephalitis are widely distrib-
still occur in developing countries. In vaccinated uted throughout the neuraxis.

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A B

FIGURE 5.26 Poliomyelitis. (A) Horizontal section of the cervical level of the spinal cord showing inflam-
mation in the anterior horns. (B) Higher magnification showing neuronophagia, microglial proliferation, and
perivascular cuffing of lymphocytes (H&E).

In Japanese encephalitis, which is the most disparity between the abundance of virus and the
important of the arboviral encephalitides in terms limited degree of inflammation.
of global incidence, morbidity, and mortality,
the inflammation tends to be particularly severe 3.2.1.4. Measles encephalitides Measles
in the thalamus, substantia nigra, pons, medulla, virus, a paramyxovirus, like influenza and mumps,
and spinal cord and is occasionally necrotizing is known to cause two rare forms of encepha-
(Fig. 5.27A, B). litis:  subacute sclerosing panencephalitis and
Tick-borne encephalitides, which include immunosuppressive measles encephalitis. In addi-
Russian spring–summer encephalitis and Central tion, it may provoke postinfectious encephalitis
European encephalitis, are characterized by menin- (cf. 3.1.2).
goencephalitic lesions and by involvement of the Subacute sclerosing panencephalitis occurs in chil-
lower cranial nerves and anterior horns, especially at dren, several years after an episode of measles. About
cervical levels. half of the patients are known to have had measles
In these encephalitides, inclusions are not before the age of 2  years. The lesions involve both
detectable by light microscopy, but some have the gray and the white matter. In the gray matter,
been observed ultrastructurally, and in many the the cortex is predominantly affected, but involve-
virus can be demonstrated immunohistochemically ment of the basal ganglia, mainly the thalamus, is
(Fig.5.27C). frequent and there may occasionally be extension
to the brainstem. Microscopic examination shows
3.2.1.3. Rabies Rabies is caused by a rhabdo- the features of subacute encephalitis. There is neu-
virus that is transmitted to humans by the bite of a ronal loss, occasional neuronophagia, and astrocytic
rabid animal. The animal reservoir includes foxes, and microglial reaction. Inclusion bodies may be
skunks, coyotes, jackals, and bats. However, the dog found in neuronal and glial nuclei (Fig. 5.29A). The
remains the main source of human infection. The white matter lesions are variable, including marked
disease may present as “furious” rabies or “dumb” astrocytic proliferation with inclusions in the glial
(paralytic) rabies. Once declared, the disease is nuclei and patchy myelin loss. Leptomeningeal,
almost always fatal. perivascular, and parenchymal inflammatory infil-
On neuropathological examination, rabies is trates are present both in the gray and white matter.
characterized by the presence in neurons of diag- In late cases, there may be considerable neuronal
nostic cytoplasmic inclusions called Negri bodies loss with atrophy of the cortex and basal ganglia;
(Fig. 5.28A, B). These are mainly found in the pyra- neurofibrillary degeneration of the Alzheimer type
midal neurons of the hippocampus and in Purkinje has been reported. The white matter shows thinning
cells. Accompanying lesions include leptomeningeal and demyelination with severe gliosis (Fig. 5.29B).
and perivascular inflammation, microglial nod- Inflammatory cells may be very scanty, as may be
ules (Babès nodules), and microglial hyperplasia. inclusion bodies, which may be better detected
These lesions are variable, but there may be striking immunohistochemically.

Chapter 5 Infections of the Central Nervous System • 135


A B

FIGURE 5.27 Japanese encephalitis. (A) Gross appearance of necrotic lesions in the thalamus (courtesy of Pr.
S.K. Shankar and Dr. A. Mahadevan). (B) Necrolytic lesions in the neuronal areas. (C) Viral antigens in neurons
around edematous/necrolytic areas.

Although measles virus has been demonstrated A  viral mutation resulting in defective M-protein
to be the causative agent by electron microscopy expression enabling the virus to elude the host
(Fig.  5.30), in tissue culture, and by immunologi- immune response has been postulated.
cal and virological assays, the pathogenesis of this Measles inclusion body encephalitis develops
type of prolonged viral infection remains uncertain. within months of the initial systemic infection in

A B

FIGURE 5.28 Rabies. (A) Negri bodies in a pyramidal neuron of the hippocampus (H&E). (B) Negri bodies
in a Purkinje cell stained in red using a specific antibody.

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A

B
FIGURE 5.30 Electron microscopy showing
intranuclear tubular formations characteristic of
measles myxovirus in a case of subacute sclerosing
panencephalitis.

to a lesser extent astrocytes and oligodendrocytes.


Occasionally, multinucleated giant cells containing
virus may be found. There may be accompanying
inflammatory infiltrates and reactive astrocytes and
microglia, but these may be very scanty, even absent,
and the presence of inclusions may thus be missed.

3.2.1.5. Henipaviruses Henipavirus is a


new genus of RNA viruses belonging to the
Paramyxoviridae family that emerged to cause severe
human encephalitis in the 1990s. The genus com-
prised the two closely related, fruit bat-originated
viruses, Hendra virus and Nipah virus. Important
intermediate hosts for transmission to humans were
FIGURE 5.29 Subacute sclerosing panencephalitis. horses and pigs, respectively. Both viruses appear
(A) Intranuclear inclusion bodies in neurons (H&E). to cause similar acute and relapsing henipavirus
(B) Massive demyelination of the white matter and encephalitides.
severe cortical atrophy (Loyez stain).

patients with impaired cell-mediated immunity.


In AIDS patients, similar changes have also been
reported to occur after measles vaccination.
The brain may be normal or may show extensive
zones of necrosis of gray and white matter. The diag-
nosis can be made only on microscopic examination.
The lesions may be focal or widespread throughout
the brain; involvement of the spinal cord has been
found in children with AIDS. The diagnostic feature
is the presence of eosinophilic inclusion bodies that
are readily seen on routine stain (Fig. 5.31) but can
also be demonstrated by immunohistochemistry FIGURE 5.31 Measles inclusion body encephalitis.
and electron microscopy. These are mostly intra- Presence of numerous eosinophilic intranuclear inclu-
nuclear and involve predominantly neurons, and sion bodies (H&E).

Chapter 5 Infections of the Central Nervous System • 137


Acute henipavirus encephalitis is character- and often viral inclusions, antigens (Fig. 5.32D), and
ized by disseminated small vessel vasculopathy and RNA can be demonstrated in adjacent neurons and
parenchymal pathology mainly in the CNS, but these more rarely in glial cells. Hence, necrotic plaques are
features are also found in extra-CNS organs such probably caused by a dual pathogenic mechanism
as lung, kidney, heart, etc. Vasculopathy consists of microinfarction and neuronal infection. In some
of true vasculitis with intramural necrosis, inflam- cases, focal neuronophagia, microglial nodule for-
mation, and endothelial ulceration (Fig. 5.32A). mation, clusters of foamy macrophages, perivascular
Vascular occlusion by vasculitis-induced thrombosis cuffing, and meningitis can be found.
or thromboembolism is readily observed and there In contrast to acute henipavirus encephalitis,
may be perivascular hemorrhage. Occasionally, mul- where there is systemic involvement, the pathology
tinucleated giant cells or syncytia arising from the of relapsing henipavirus encephalitis is confined to
endothelial surface can be found (Fig. 5.32B). Viral the CNS, and vasculopathy is absent throughout. In
inclusions, antigens, RNA, and nucleocapsids can affected neuronal areas and adjacent white matter,
be detected in vascular endothelium, multinucle- extensive confluent parenchymal necrosis, edema,
ated giant cells, and smooth muscle. and inflammation are observed. Reactive gliosis and
Parenchymal pathology of acute encephalitis prominent vascular proliferation in areas of severe
comprises discrete necrotic or more subtle vacuolar, neuronal loss were also seen. Severe meningitis may
plaque-like lesions often found adjacent to blood ves- be found in many areas. Like in acute henipavirus
sels with vasculopathy (Fig. 5.32C). These lesions are encephalitis, viral inclusions, antigens, and RNA can
characterized by necrosis, edema, and inflammation, be demonstrated in neurons and glial cells.

A B

C D

FIGURE 5.32 Acute Nipah encephalitis: (A) Vasculopathy consisting of true vasculitis and
thrombo-occlusion of vessel (Wong KT. Acta Neuropathol 2010; 120: 317–325; reproduced with kind
permission from Springer). (B) Multinucleated syncytia arising from the endothelial surface. (C) Necrotic
plaque with adajcent thrombotic vessel. (D) Viral antigens in neurons (Figures B–D, Wong KT et al. Am J Pathol
2002; 161: 2153–2167 reproduced with permission from Elsevier).

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3.2.1.6. Progressive rubella panencephalitis can also freely cross the blood–brain barrier, gain-
This is a very rare delayed complication of congenital ing entry into the CNS parenchyma.
or childhood rubella infection. At neuropathological CNS neurological complications of HIV infec-
examination, there is widespread neuronal loss with tion are frequent and result from various mecha-
gliosis and leptomeningeal and perivascular inflam- nisms. Apart from lesions directly related to infection
mation containing lymphocytes and macrophages, of the CNS by the virus, opportunistic infections
and vasculitis with fibrinoid necrosis and mineral and lymphomas may occur as a result of the immu-
deposition. There is also extensive myelin destruc- nodeficiency syndrome; HIV-associated systemic
tion with relative sparing of axons. Inclusion bodies disorders may also cause neuropathological changes.
are not found, and rubella virus is not detected by They include cerebrovascular disease (marantic
either electron microscopy or molecular techniques. endocarditis, thrombocytopenia, coagulopathy, and
The lesions may result from vasculitis produced by cerebral atherosclerosis), metabolic and nutritional
immune complex deposition. abnormalities (hypoxia, vitamin deficiencies caus-
ing Wernicke encephalopathy and, possibly, vacu-
3.2.1.7. Infection by the human immunodefi olar myelopathy, as well as electrolyte disturbances
ciency virus (HIV-1) HIV-1 is a retrovirus of the responsible for central pontine myelinolysis), liver
lentivirus subfamily, properly classified as an immu- failure causing hepatic encephalopathy, or increased
nodeficiency virus, a subgroup of lentiviruses that levels of circulating pro-inflammatory cytokines
also includes HIV-2 as well as the closely related likely to be responsible for multifocal necrotizing
simian immunodeficiency virus (SIV). HIV-1 leukoencephalopathy. Finally, neurological compli-
infects cells that carry on their surface the CD4 cations of treatment, particularly those involving the
antigen, which is present both on CD4+ helper peripheral nervous system, are increasingly frequent.
T-lymphocytes and monocytes/macrophages, HIV-induced CNS lesions are defined as original
with the chemokine receptor CCR5 serving as an and specific changes that had never been observed
important co-receptor for HIV-1 on monocyte/ before the AIDS epidemic, and are found only
macrophage cells. On the one hand, infection of in HIV-infected individuals, without evidence of
CD4+ lymphocytes leads to their destruction and another cause. They include HIV encephalitis result-
cell-mediated immunodeficiency (the acquired ing from direct infection of the CNS by the virus,
immune deficiency syndrome [AIDS]). On the HIV leukoencephalopathy, and diffuse poliodystro-
other hand, HIV-1 can invade the CNS via infected phy, which may be variably associated.
macrophages, which represent a major cell type
capable of supporting viral replication and thus • HIV encephalitis (HIVE) due to productive infec-
potentially serving both as a reservoir for the virus tion of the CNS by the virus is the most character-
and as an agent for its dissemination. Viral particles istic. It includes marked astrocytic and microglial

A B

FIGURE 5.33 HIV encephalitis. (A) Presence of abundant multinucleated giant cells (H&E).


(B) Immunocytochemistry using an anti-HIV p24 antibody demonstrates the presence of HIV antigen in the
cytoplasm of a multinucleated giant cell.

Chapter 5 Infections of the Central Nervous System • 139


activation with frequent multinucleated giant None of these HIV-induced CNS lesions can be
cells (MGC) (Fig. 5.33A) and abundant viral load precisely correlated with the specific progressive
demonstrated by either immunocytochemistry cognitive/motor syndrome termed HIV-associated
(Fig. 5.33B) or in situ hybridization. MGCs have neurocognitive disorder [HAND], suggesting that
been proposed as the hallmark of HIV encephali- HAND more likely reflects a specific neuronal dys-
tis. These cells are of macrophage lineage, contain function resulting from the combined effects of sev-
HIV in their cytoplasm, and result from the fusing eral neurotoxic factors, including those produced by
capacity of the virus. Thus, their presence pro- HIV itself as well as substances produced by acti-
vides evidence of productive HIV infection and of vated glial and microglial cells, some of which may
a cytopathic effect of the virus. The lesions consist be reversible.
of multiple disseminated foci that may affect any
part of the CNS but are more frequently found in 3.2.1.8. Human T-cell leukemia/lymphotro-
the deep white matter and basal ganglia. phic virus-1 (HTLV-1)-associated myelopathy
• Involvement of the white matter, HIV leukoencepha- HTLV-1, an oncogenic retrovirus (oncovirus) that
lopathy, is also a prominent feature of HIV-specific can cause T-cell leukemia, was the first human retro-
neuropathology (Fig. 5.34). It is often but not virus to be identified. It is endemic in the Caribbean,
invariably associated with HIV encephalitis. It is the southern United States, South America, parts
characterized both by diffuse myelin pallor with- of Africa, and Japan. In rare cases, it may cause
out true demyelination involving predominantly a myelopathy, HTLV-I-associated myelopathy
the deep white matter and usually sparing of the [HAM], characterized by progressive spastic para-
U fibers, and by widespread axonal damage. The paresis with sphincter and sensory disturbances.
white matter pallor is thought to be secondary to In longstanding cases of HAM, there may be
alterations in the blood–brain barrier. macroscopic meningeal thickening, spinal cord
• Involvement of the gray matter, diffuse poliodys- atrophy, and degeneration of the lateral columns.
trophy, is characterized by diffuse reactive astro- Microscopic examination shows myelin loss and
cytosis, and microglial activation in the cerebral some axonal degeneration in the long tracts of the
gray matter. It is associated with neuronal loss spinal cord, particularly in the lateral columns. There
resulting, at least partly, from an apoptotic process is fibrosis and lymphocytic infiltration of the lepto-
and, when severe, may cause macroscopic cortical meninges and astrocytosis and mononuclear inflam-
atrophy. mation in the spinal cord, more marked in the lower
thoracic region.

3 .2 . 2. EN CEPHALITIDES DUE TO DN A
V I RUSES
These include encephalitis due to herpes viruses and
Papova viruses. The main herpes viruses causing
CNS infection in humans include herpes simplex
virus (HSV) type 1 and type 2 (human herpes virus
types 1 and 2 [HHV1 and HHV2]), varicella-zoster
virus (VZV or HHV3), and cytomegalovirus
(HHV5). The main human infection caused by
Papova viruses is progressive multifocal leukoen-
cephalitis (PML) due to JC virus.

3.2.2.1. HSV encephalitis HSV is the most


common cause of sporadic acute encephalitis. Most
cases are due to infection by HSV type 1, but in
immunosuppressed individuals and neonates, HSV
FIGURE 5.34 HIV leukoencephalopathy (Loyez type 2 may also cause encephalitis. Following a pri-
stain). mary infection (oropharyngeal for HIV-1, genital

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for HIV-2), HSV establishes a latent infection in of meningeal, perivascular, and scanty parenchymal
the sensory ganglia, with periodic reactivation of inflammation with scattered cells (neurons and glial
the virus leading to recurrent lesions at mucocu- cells) containing intranuclear inclusion bodies. The
taneous junctions, at or near the site of primary presence of HSV may be identified by immunohis-
infection. The mechanism of entry of HSV-1 into tochemistry or electron microscopy (Fig. 5.35D). At
the CNS to cause encephalitis is debated (spread a more advanced stage the lesions are more charac-
along olfactory nerve fibers either during primary teristic and include foci of hemorrhage and necrosis
nasopharyngeal infection or after reactivation of a with parenchymal infiltration by lymphocytes and
latent virus in the olfactory bulbs, reactivation of macrophages (Fig. 5.35B). Changes more character-
a latent virus in the trigeminal ganglia and axonal istic of meningoencephalitis (mononuclear inflam-
spread into the brain, or reactivation of a previously mation of the leptomeninges, perivascular cuffing,
established latent infection in the CNS, mainly in neuronophagia, and diffuse microglial hyperplasia)
the temporal lobes). are also present. Nuclear inclusions (Fig. 5.35C) are
In patients who die at the acute stage of the disease, usually sparse, and the virus is more easily identified
gross examination has shown generalized swelling by immunohistochemistry. Early diagnosis is essen-
and bilateral asymmetric necrotic and hemorrhagic tial so that treatment with antiviral therapy, usu-
lesions involving predominantly the temporal lobes ally acyclovir, can be initiated promptly, in order to
and the limbic regions (Fig. 5.35A) (insulae, cingu- achieve a therapeutic response. The untreated case
late gyri, and posterior orbital frontal cortex). On fatality rate is very high, approaching 80%, with a
microscopic examination, the earliest lesions consist significant reduction of mortality in people who are

A B

C D

FIGURE 5.35 Herpes virus encephalitis. (A) Necrosis of the left temporal lobe (the right temporal lobe
was surgically excised). (B) Microscopic appearance: necrosis with parenchymal infiltration by macrophages.
Note the presence of hemorrhage and perivascular cuffing by lymphocytes (H&E). (C) Characteristic Cowdry
intranuclear inclusion bodies (H&E). (D) Electron micrograph showing typical “target-like” intranuclear viral
particles.

Chapter 5 Infections of the Central Nervous System • 141


treated. Reactivation of encephalitis after therapy
has been reported.
In long-term survivors of untreated or unsuc-
cessfully treated herpes encephalitis, the affected
parts of the brain are shrunken and cavitated, with
yellow-brown discoloration. The entire parenchyma
is replaced by cavitated glial scar tissue. Occasional
clusters of lymphocytes are still seen in the lepto-
meninges and brain parenchyma. The virus is no
longer demonstrable by culture, immunohistochem-
istry, or electron microscopy, but viral DNA may be
identified by polymerase chain reaction (PCR).
Neonatal HSV encephalitis differs from the
adult disease in that it is usually due to HSV-2 and FIGURE 5.36 Cytomegalic cell in a case of CMV
causes more generalized encephalitis without any encephalitis in an AIDS patient (Nissl stain).
predilection for any part of the brain. It also pres-
ents as necrotizing encephalitis. Nuclear inclusions, 3.2.2.3. CMV infection In children, early fetal
viral antigen, and DNA are usually demonstrable in infection may result in necrotizing encephalitis or
abundance. ventriculoencephalitis. Residual lesions in those
surviving the acute neonatal illness include micro-
cephaly, microgyria, porencephalic cysts, hydro-
3.2.2.2. VZV infection Primary infection by
cephalus, and periventricular calcifications.
VZV causes chickenpox. Latent infection is subse-
In adults, CMV may cause an opportunistic
quently established in the dorsal root or trigeminal
infection. Diffuse, nonnecrotic encephalitic lesions
ganglia. Reactivation of latent virus usually mani-
consisting of a dissemination of microglial nodules,
fests as shingles.
some of which contain characteristic cytomegalic
The pathological changes in zoster infection are
cells (Fig. 5.36), have been described, especially in
usually limited to the dorsal root ganglia or to the
transplant recipients. In AIDS patients, in addition
ganglia of a sensory cranial nerve and the nerve root,
to microglial nodule encephalitis, other lesions have
but changes may extend to the corresponding meta-
been observed, including necrotizing ventriculoen-
meric segment of the spinal cord, where there can
cephalitis, necrotizing encephalitis with large cystic
be intense lymphocytic inflammation that may be
foci of encephalomalacia, and acute meningomy-
associated with vasculitis and necrosis. Arteritis of
eloradiculitis, the last usually with numerous poly-
large arteries may cause extensive infarction of neu-
morphs. Cytomegalic cells containing intranuclear
ral tissue.
and intracytoplasmic inclusion bodies are numer-
In immunocompromised patients, particularly
ous and involve all types of cells (neurons, glial
AIDS patients, several patterns of VZV encephalitis
cells, endothelial cells, or macrophages). The virus
and myeloradiculitis have been described, includ-
may be identified by immunohistochemistry, in situ
ing multifocal lesions predominantly involving the
hybridization, or electron microscopy, but these are
white matter, likely to be due to hematogenous
usually not necessary for the diagnosis, since the
spread of the virus; ventriculitis secondary to ven-
appearance of the infected cells on routine stains is
tricular spread; encephalitis involving the visual sys-
so characteristic.
tem or the brainstem; and myeloradiculitis resulting
from spread from ophthalmic, trigeminal, or dorsal
root zoster. In all cases, inflammatory necrotizing 3.2.2.4. Progressive multifocal leukoen-
lesions are associated with vasculitis. Intranuclear cephalitis The disease is due to infection by the JC
inclusion bodies are present, and the virus may virus. This is an opportunistic infection occurring
be identified by immunohistochemistry or in situ most often in patients with immunodeficiency,
hybridization. In addition, granulomatous, necrotiz- particularly AIDS. The virus infects specifically
ing, or noninflammatory (endarteritis obliterans) oligodendrocytes, causing a demyelinating dis-
lesions involving small or large intracranial vessels ease. The lesions are usually bilateral but may
may cause infarcts or hemorrhages. be asymmetrical. They involve predominantly

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the subcortical hemispheric white matter, espe- inclusions are particularly abundant and may be
cially in the parieto-occipital regions, but the cer- found in cells other than oligodendrocytes.
ebellum, brainstem, and even spinal cord may be
affected. They form limited spotty foci that very
3.2.3 . ENCEPHAL ITIS OF
often coalesce to form larger confluent demyelin-
UNCERTAIN ORIGIN
ating areas (Fig.  5.37A). They contain lipid-laden
macrophages and only scanty perivascular lym- 3.2.3.1. Encephalitis lethargica (epidemic
phocytes. The presence of giant astrocytes with encephalitis of von Economo) This supposed viral
bizarre hyperchromatic nuclei (Fig.  5.37B) and disease was rampant from 1916 to 1930 but attempts,
oligodendrocytes with enlarged nuclei containing with the limited techniques then available, to impli-
viral inclusions (Fig. 5.37C) is a striking and very cate a virus, as well as efforts to relate the encephalitis
characteristic feature. The virus may be identified with the contemporaneous pandemic of influenza,
in oligodendrocytes by immunocytochemistry, in were unsuccessful. The disorder was characterized by
situ hybridization, or electron microscopy. preferential involvement of the midbrain and basal
Since the AIDS epidemic, there has been a con- ganglia. In a large number of cases, a postencephalitic
siderable increase in the incidence of PML. The parkinsonism has been the sequela.
disorder is relatively frequent in AIDS patients, in
whom the lesions may be particularly severe, with 3.2.3.2. Behçet uveomeningoencephalitis Uveo-
sometimes necrotic, very extensive changes involv- meningoencephalitides present as inflammatory
ing particularly the cerebellum (Fig.  5.37D). Viral encephalitis, meningitis, and uveal lesions

A B

C D

FIGURE 5.37 Progressive multifocal leukoencephalitis. (A) Gross appearance, confluent demyelination in


the subcortical white matter of the parietal lobe (Loyez stain). (B) Presence of giant “bizarre” astrocytes in a
demyelinated area (H&E). (C) Presence of abnormal oligodendrocytes with enlarged nuclei containing viral
inclusions (H&E). (D) Extensive demyelination of the cerebellum and pons in an AIDS patient (Loyez stain).

Chapter 5 Infections of the Central Nervous System • 143


involving the choroid, ciliary body, and iris. The with this hypothesis. Other supporting data include
etiology is uncertain. Behçet disease is a rare dis- the demonstration by in situ hybridization of
ease that most commonly presents as recurrent Epstein-Barr virus and CMV reported in some stud-
ulceration of the mouth and genitalia accompa- ies, though not confirmed by others.
nied by uveitis or iridocyclitis. An encephalitic Autoimmune mechanisms of injury, including
syndrome may occur occasionally consisting of immune complex deposits and vasculitis, have also
multifocal necrotizing lesions that involve pre- been postulated. Antibodies to GluR3 have been
dominantly the thalamus, hypothalamus, and identified in RS, but these may be nonspecific. More
midbrain. The inflammatory changes are often recently, direct T-cell–mediated cytotoxicity against
necrotic and sometimes hemorrhagic. Vasculitis the neurons has been demonstrated.
is considered to be the underlying lesion, but The observation of cortical dysplasia, tuberous
cerebral blood vessel changes are nonspecific. sclerosis, cavernous angioma, and tumors in patients
Attempts to demonstrate a virus as the cause of with RS has raised the possibility that these lesions
Behçet disease have failed. may be instrumental in inducing seizures, altering
the blood–brain barrier, which could, in turn, trig-
ger a viral or autoimmune disorder.
3.2.3.3. Chronic localized encephalitis of
Rasmussen This rare, devastating disorder is char-
acterized by progressive, unilateral neurological
4. RICKETTSIOSIS
deficit with sudden onset of seizures, usually in Some forms of rickettsial infection (murine/
childhood, that are refractory to treatment. They are endemic typhus due to R. prowazeki, exanthematic/
of partial complex type and become generalized and epidemic typhus due to R.  typhi, Rocky Mountain
associated with hemiplegia, hemianopia, and intel- spotted fever due to R. rickettsii) may cause enceph-
lectual deterioration. alitides characterized histologically by perivascular
Macroscopic changes vary from case to case and mononuclear cuffing and microglial nodules that
are predominantly unilateral. They consist of cere- preferentially involve the gray matter of the cere-
bral atrophy, which may be patchy, and dusky dis- bral hemispheres and the brainstem. The agents,
coloration of the cortex (Fig.  5.38A). Histological which are obligatory intracellular microorganisms
examination confirms the largely unilateral distribu- that have the staining property of gram-negative
tion of the lesions, although bilateral involvement bacilli, may be demonstrated in the cytoplasm of
also occurs. Lesions are more diffuse and severe than endothelial cells.
can be assumed from macroscopic observation and
have a concentric distribution. They are necrotic and
destructive in their center, whereas at the periphery 5. OPPORTUNISTIC INFECTIONS
they have all the features of active encephalitis. They By definition, an opportunistic infection (OI) is an
include thickening of the leptomeninges with mild infection that takes the opportunity of a deficiency
lymphocytic infiltration and accompanying intrapa- in the immune response of the host to develop. It
renchymal cuffing of the vessels by lymphocytes and may be either a primary infection or a reactivation
macrophages (Fig.  5.38B). Microglial nodules and of a latent infection. Classically, OIs are due to
neuronophagia are ubiquitous (Fig. 5.38C–E), and saprophytic organisms that do not cause diseases
the former are seen also in the white matter. In older in immunocompetent individuals and that differ
lesions, there may be thinning of the cortex with loss from primary pathogens by several characteristics
of neurons and spongiosis, severe glial reaction, and (Table 5.4). However, one tends to include in this
less intense inflammatory clusters. group infections by common pathogens such as
The pathogenesis of Rasmussen Syndrome (RS) tuberculosis, syphilis, measles, or VZV, which may
is unknown. The possibility of an infectious etiol- behave as OIs in patients with impaired lympho-
ogy is raised by some studies, which have shown cyte function. One may also extend the concept
similarities between RS and the epilepsy seen of OIs to some neoplasms related to a specific
in Kozhevnikov encephalitis, a tick-borne viral viral infection that develop only in immunocom-
encephalitis with intractable seizures seen almost promised individuals, such as Kaposi sarcoma of
exclusively in Russia. The presence of an infectious AIDS patients, related to infection by HHV type
ipsilateral uveitis and chorioiditis is also consistent 8 (also known as Kaposi-sarcoma-associated virus

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A B

C D

FIGURE 5.38 Rasmussen encephalitis. (A) Gross appearance. (B) Intraparenchymal perivascular cuffing


by lymphocytes and macrophages (H&E). (C) Nodule of neuronophagia. (D) Microglial nodule (H&E).
(E) Proliferation of rod cell microglia (immunocytochemistry for CD68).

[KSHV]), and primary brain lymphoma related age of the population as well as from a growing num-
to infection by EBV or HHV type 4, occurring in ber and longer survival of patients with debilitating
AIDS patients and organ transplant recipients. diseases such as diabetes, alcoholism, and lymphoid
In addition to the exceptional congenital and idio- neoplasms. In addition, many patients have received
pathic immunodeficiency disorders, there has been immunosuppressive drugs for rheumatic and neo-
a dramatically increasing number of patients with plastic diseases, and for organ transplantation. Finally,
acquired immunodeficiencies in the past 20  years. the occurrence of the AIDS epidemic has represented
This situation has resulted from the steadily increasing a major cause of acquired immunodeficiency.

Chapter 5 Infections of the Central Nervous System • 145


Table 5.4. Differential Characteristics of Primary and Opportunistic Pathogens

P R I M A R Y PAT H O G E N S O P P O R T U N I S T I C PAT H O G E N S

• Induce specific diseases in • Induce atypical infections in immunocompromised


immunocompetent hosts with identified patients—present in wide environmental reservoirs or
reservoirs and routes of infection in commensal (endogenous) flora
• Interact with specific cellular or humoral • Lack defined cellular or humoral hostreceptors
target molecules
• Share specific virulence/pathogenicity • May express potentially virulent and pathogenic
determinants molecules (constitutive or inducible), once they have
colonized the host
• Can be transmitted from host to host and • Are acquired from the environment, from food sources,
induce the same disease (potential for or from the endogenous flora, and, for nosocomial
epidemics) infections, are communicable to susceptible contacts
• Clonal origin with limited genetic variability. • Genetic diversity and plasticity, which hamper
Induce specific immune responses, allowing indirect diagnosis and specific immunotherapies
for specific immunological diagnoses and and vaccines. High frequency of genetic variations
vaccines. and rearrangements, allowing acquired resistance to
antimicrobial agents.

Different types of immunodeficiency may be with lymphoid neoplasms (Hodgkin diseases or


associated with particular OIs, as described in the lymphoid leukemia) or other malignancies treated
following sections. with chemotherapy, or in patients on prolonged,
high-dose corticosteroid therapy.
In addition to mycoses (aspergillosis, cryptococ-
5.1. Opportunistic Infections cosis) and bacterial infections (listeriosis, nocar-
of the CNS in Patients with diosis), other cerebral OIs may occur, including
Granulocytic Disorders toxoplasmosis, PML, and CMV infection. Primary
Severe depletion of granulocytes is usually the conse- malignant non-Hodgkin lymphomas of the brain,
quence of decreased or absent production in the bone related to EBV infection, may also be seen. It is of
marrow. This may occur in myeloid leukemia or more historical interest that these tumors were first recog-
often in the course of treatment with cytotoxic drugs. nized as an opportunistic event in patients who had
More rarely severe granulocytopenia may result from undergone renal transplantation.
peripheral sequestration as in hypersplenism, or as an
idiosyncratic reaction to medication. In people who
develop severe granulocytopenia, the most common
5.3. Opportunistic Infections
OIs are mycoses, particularly those due to Aspergillus
of the CNS in Patients with
sp. and Candida sp., and to certain bacterial infections,
Lymphocytic Disorders,
particularly Pseudomonas aeruginosa, Listeria monocy-
Particularly in AIDS
togenes, and Nocardia asteroides. Prior to the introduction of highly active
anti-retroviral therapy (HAART) or combination
therapy including an HIV protease inhibitor, OIs
5.2. Opportunistic Infections secondary to the depletion in CD4+ T-cells caus-
of the CNS in Patients with ing the cell-mediated immunodeficiency syndrome
Combined Granulocytic and characteristic of AIDS were the more frequent com-
Lymphocytic Disorders plication of the disease. They usually occurred dur-
Immunodeficiency resulting from both granulo- ing the late stages, in full-blown AIDS, in people with
cytic and lymphocytic impairment is the rule in depletion of CD4 cells and with high viral loads,
transplant recipients. It may also occur in patients and they included multiple parasitic (Toxoplasma),

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fungal (cryptococcal), bacterial (mycobacterial), of anti-Toxoplasma therapy. Cryptococcal menin-
and viral (cytomegalovirus, PML) infections, as gitis and PML are also rare in children with AIDS.
well as primary brain lymphomas. Unlike the situ- The most common opportunistic pathogen in this
ation with granulocytopenia, these patients, by age group, even in young children, continues to be
and large, did not have frequent infections due to CMV. In addition, children with AIDS are also at
Aspergillus sp. While bacterial infections were rare, risk for developing bacterial meningitis, including
it should be noted that a brain abscess in a patient that caused by S. pneumoniae.
with AIDS who did not have bacterial endocarditis The introduction of HAART has dramatically
was more likely to be due to Nocardia sp. than to any modified the course and prognosis of HIV disease.
other agent. In the developed world, where HAART is readily
The occurrence of many OIs in immunosup- available and where there have been progressive
pressed patients, particularly in those with AIDS, improvements in the management of OIs in general,
has modified the presentation of these complica- the incidence of CNS OIs has declined dramatically
tions and has consequently made their diagnosis from the 1980s, and epidemiological studies have
difficult for the following reasons: (1) There is an shown that AIDS-defining events are no longer the
increased range of organisms involved. (2)  A  par- major causes of death in HIV-infected patients. The
ticular patient may have successive or simultane- benefit is mainly due to a decrease of HIV viral load
ous infections by different agents. (3)  There can and a restored functional immune system.
be involvement of several organs at the same time However, besides those related to drug toxicity,
with an increased incidence of neurological dis- new types of complications have occurred. On the
ease. (4) There is generally a reduced inflammatory one hand, “burnt-out” forms of treatable infections
reaction. in which no inflammation and no infectious agent
The occurrence of OIs of the CNS in AIDS could be detected have become more frequent. “Scar
patients varies with the geographical location where lesions” have been found with increasing frequency
the patient has lived, with the age of the patient, and in clinically and biologically cured patients who died
with therapy both for OIs and for HIV infection itself. from other causes. In other instances, despite effi-
With regard to geographical location, several cient treatment, the disease continued to progress
points can be made. Cerebral toxoplasmosis is clinically and often radiologically. This pattern was
more frequent in France and in Germany than it is particularly prevalent in patients with severe, mul-
in either the United States or the United Kingdom. tifocal toxoplasmosis, PML, or HIVE when treat-
In addition, this CNS complication has been ment had been administered too late in the course
reported in patients from sub-Saharan Africa, South of the disease, after irreversible cerebral destruction
America, and India. CNS histoplasmosis, blasto- had occurred with secondary progressive Wallerian
mycosis, and coccidioidomycosis are much more degeneration. On the other hand, new inflammatory
frequent in America than in Europe. Acute or reac- lesions related to the restoration of the immune system
tivated cerebral trypanosomiasis causing devastat- appeared. An “immune reconstitution inflammatory
ing necrotic lesions occurs only in South America. syndrome” (IRIS) was identified with four diagnos-
Mycobacterium tuberculosis infection of the CNS is tic criteria:  (1)  patients with AIDS; (2)  efficiently
especially common in patients with AIDS living in treated by HAART; (3)  presenting symptoms
developing countries that have a high incidence of consistent with an infectious/inflammatory condi-
tuberculosis, particularly in Africa. tion that appeared while on antiretroviral therapy;
Children up to 13  years of age in general have (4)  symptoms that could not be explained by a
a lower incidence of CNS OIs than do adults; this newly acquired infection, the expected course of a
phenomenon is particularly manifest in AIDS, prob- previously recognized infection, or side effects of
ably because children have had less time than adults therapy. In the CNS, IRIS caused paradoxical exac-
to be exposed to common opportunist pathogens. erbation of tuberculosis and cryptococcal infection,
This is especially true for toxoplasmosis, which is a as well as of CMV retinitis. In some patients with
much less common cause of CNS mass lesion than PML or HIVE, onset or worsening of neurological
is primary brain lymphoma in children with AIDS signs following HAART institution was associated
in the United States. For this reason, it is recom- with contrast enhancement on MRI, suggestive of
mended that children with mass lesions in the CNS an unusually intense inflammation with impair-
be biopsied at presentation rather than after a trial ment of the blood–brain barrier. Neuropathological

Chapter 5 Infections of the Central Nervous System • 147


studies confirmed intense inflammation with an Also, people with undiagnosed or unsuspected
influx of CD8+ lymphocytes variably associated HIV infection are still at risk of presenting with a
with an acute worsening of the underlying infection CNS OI, as are HIV-infected individuals who are
(HIV or JC Virus) and a nonspecific immunopatho- not compliant with their antiretroviral and pro-
logical reaction of the ADEM or Multiple Sclerosis phylactic therapy. In addition, this complication of
type. In most cases, this correlated with prolonged AIDS can be seen in people who develop resistance
survival and was interpreted as a marker of both mutations of HIV to antiretroviral agents. Finally,
improved immune status and outcome; however, in and of great importance, CNS OIs also continue to
rare instances, it coincided with clinical and radio- be a major problem in developing countries, where
logical aggravation and death. these types of therapy are often not available.

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6
Human Prion Diseases
J A M E S W.   I R ONS I DE , MATTH EW P. F R O S C H , A N D B ERNA RD INO   G H ETTI

PRION DISEASES, also known as transmissible 1. BIOLOGY OF PRIONS


spongiform encephalopathies, are rare fatal neu-
rodegenerative disorders with a unique biological 1.1. The Infectious Agent
mechanism.
The human prion diseases are distinct from The transmissible agent in prion diseases is differ-
other neurodegenerative disorders in that they may ent from any known infectious pathogen both in its
be sporadic (idiopathic), inherited, or acquired structure and its remarkable resistance to conven-
(Table 6.1). These diseases are characterized patho- tional forms of decontamination. While attempting
logically by varying combinations of spongiform to identify the agent responsible for scrapie (a prion
change (vacuolation of the gray matter due to dis- disease affecting animals, particularly sheep and
tention and swelling of neuronal cell processes), goats), it was determined that the agent was smaller
neuronal loss, reactive gliosis (involving microglia than conventional viruses, did not have RNA or
and astrocytes), and prion protein (PrP) deposi- DNA, and accumulated in the central nervous sys-
tion. These features are markedly variable from tem (CNS). The prion hypothesis, proposed by
case to case and within different brain regions in a Prusiner in 1982, stated that the transmissible agent
single case. The diagnosis of prion diseases requires (prion) was a protein with a molecular weight of 27
a neuropathological examination combined with to 30 kD and was partially resistant to proteolytic
biochemical and genetic analysis. Prion diseases are cleavage and consistently associated with infectiv-
also seen in other mammals with implications for ity in purified extracts of scrapie-infected brain. It
spread to humans; the unusual biological properties was subsequently demonstrated that this protein
of the infectious agents are also associated with pro- was an abnormal isoform of a protein that normally
teins in organisms extending even to yeast. occurs in the mammalian brain. The normal protein

• 149
Table 6.1. Classification of Human Prion Diseases
Idiopathic Sporadic Creutzfeldt-Jakob disease
Sporadic fatal insomnia
Variably protease-sensitive prionopathy

Familial Familial Creutzfeldt-Jakob disease


Gerstmann-Sträussler-Scheinker disease and variants
Prion disease with cerebral amyloid angiopathy
Prion diseases associated with octapeptide repeat region insertional
mutations (variable phenotype)
Fatal familial insomnia

Acquired From human: Kuru


Iatrogenic Creutzfeldt-Jakob disease
From bovine: Variant Creutzfeldt-Jakob disease

is encoded by the PRNP gene located on the short been identified, of which the most significant are
arm of chromosome 20. M129V and E219K, since these affect susceptibil-
ity to prion diseases (Table 6.2).

1.2. The Normal Prion


Protein (PrPc) 1.3. The Abnormal Prion Protein (PrPsc)
The normal prion protein (PrPc) is a 253-residue In prion diseases, an abnormal isoform of the
peptide, which is translated from a single exon prion protein, designated PrPSc, accumulates in the
within the prion protein gene (PRNP). The peptide CNS (alternative terms include PrPCJD, referring to
undergoes a series of posttranslational modifica- Creutzfeldt-Jakob disease, and PrPres, referring to the
tions, including cleavage of a signal peptide, addi- property of proteinase K resistance). PrPSc has an
tion of up to two N-linked oligosaccharide chains identical amino acid sequence and the same molec-
(at residues 181 and197), and attachment of a ular weight as PrPc but has a much longer half-life
GPI anchor. The protein contains five octapeptide and is partially resistant to proteolytic digestion
repeats from codons 51 to 91. Four putative alpha (Fig.  6.1A). Structural studies have indicated that
helices in PrPc are located between codons 109 and PrPSc has a predominant beta-pleated sheet struc-
122, 129 and 140,178 and 191, and 202 and 218. ture, with loss of the alpha helix regions that is pres-
Most PrPc is membrane-associated and has a short ent in PrPc. These structural differences are thought
half-life. As with other proteins, it is sensitive to to confer resistance to proteolytic degradation, and
proteolytic digestion in standard in vitro conditions also allow PrPSc to aggregate and accumulate as amy-
(commonly assessed using the bacterial enzyme, loid within the CNS. In the prion hypothesis, PrPc
proteinase K). PrPc is expressed in a wide vari- is converted to PrPSc, which then accumulates in the
ety of tissues, but the highest levels of expression CNS and is neurotoxic, ultimately resulting in the
are found within neurons in the CNS. The precise targeted death of groups of neurons within the brain,
function of the normal protein is uncertain, but eventually leading to the death of the organism.
studies on engineered PrPc-null mice, which do not The mechanisms and sites of conversion are not
express PrPc, have indicated that it has a likely role fully understood. Conversion of PrPc to PrPSc can
in synaptic function and long-term potentiation, be achieved in cell-free systems, including in vitro
and may be involved in the control of circadian amplification systems such as the protein misfolding
rhythms. PrPc can act as a copper binding protein, cyclical amplification (PMCA) reaction. This reac-
and a protective role in oxidative cell stress has also tion not only amplifies a PrPSc “seed” by converting
been proposed. Several PRNP polymorphisms have a PrPc “substrate,” but it can also amplify infectivity.

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Table 6.2. Prion Protein Gene This work, and other recent studies using recombi-
Polymorphisms in the Normal Population nant technology to create infectious PrPSc de novo,
and in Prion Diseases further supports the prion hypothesis.
Similarly, the mechanisms of neurotoxicity of
PRION PROTEIN PrPSc are not fully understood, although a range of
G E N E C O D O N 12 9 possibilities exist, from a direct toxic effect on neu-
P O LY M O R P H I S M S ( % ) rons to indirect toxicity mediated by microglia and
possibly astrocytes. No pathological changes occur
MM MV VV outside the CNS in prion diseases, although in some
diseases, PrPSc can be identified in the peripheral
Normal population 39 50 11 nervous system and in lymphoid tissues (see below).
Sporadic CJD 62 19 19
Variant CJD 100 – –
1.4. Diagnostic Methods for
M, methionine; V, valine; CJD, Creutzfeldt-Jakob disease Detecting PrPsc
A The resistance of PrPSc to protease digestion forms the
basis for its biochemical detection, which lies at the
Proteinase K − + heart of confirming the diagnosis of prion diseases.
When tissue homogenates are examined by Western
diglycosylated blot analysis with antibodies to PrP, samples con-
monoglycosylated taining PrPSc will show immunoreactivity even after
nonoglycosylated treatment with proteinase K, while PrPc is completely
digested. Although resistant to complete digestion,
PrPSc is partially cleaved in the experimental system;
B there are two common sites of cleavage, resulting in
CJD S S V fragments of different lengths. The size of the immu-
Codon 129 MM VV MM noreactive protein fragment that remains after prote-
ase digestion, along with the pattern of glycosylation, is
used to define PrPSc isotypes (Fig.6.1). Experimental

animals inoculated with a particular isotype of PrPSc
21kDa — will typically present with a disease that is character-
— 19kDa
ized by the same isotype; this relationship has given
Type 1 2A 2B
rise to the use of the term “strain” to characterize indi-
FIGURE 6.1 Western blot analysis. (A) Western vidual PrPSc forms. There is no current uniformity in
blot analysis of prion protein (PrP) in variant CJD the nomenclature or classification of PrPSc isotypes;
brain tissue with (+) or without (-) prior digestion the relationship between isotype and disease pattern
with proteinase K. Proteinase K results in complete is only moderately predictable, and the identification
degradation of PrPC and in N-terminal truncation of of multiple PrPSc isotypes in some cases of sporadic
PrPSc. The remaining protease-resistant PrP (PrPres) CJD makes it difficult to establish these correlations
occurs in di-, mono-, and non-glycosylated forms. with great certainty at present
(B) Western blot analysis of protease-resistant prion
protein (PrPres) in sporadic (S) and variant (V) CJD
brain. Nonglycosylated PrPres occurs as either a 21kDa 2. THE HUMAN PRION
band (termed type 1) or a more extensively truncated DISEASES
19kDa band (termed type 2). Variant CJD exhibits
a characteristic predominance of the diglycosylated
2.1. Sporadic Creutzfeldt-Jakob
band (*), and this protein isotype is termed type 2B
to distinguish it from the type 2A isotype seen in
Disease (sCJD)
sporadic CJD, where the diglycosylated form does not sCJD is the most commonly diagnosed human
predominate. The cases shown were homozygous for prion disease, occurring with a relatively uniform
methionine (MM) or valine (VV) at codon 129 of the incidence of around 1 to 2 individuals per million
PRNP gene. per annum in the countries in which it has been

Chapter 6 Human Prion Diseases • 151


studied. Although a wide range of ages at onset but recent reports have indicated that a past his-
has been reported, most cases of sCJD occur in tory of surgery (not specifically neurosurgery)
the seventh decade of life, with males and females appears to be significantly higher in patients with
being affected equally. The disease usually presents sCJD than in controls. Analysis of the PRNP has
as a rapidly progressive dementia accompanied by shown that most patients with sCJD are methio-
other neurological abnormalities, among which nine homozygotes at codon 129, in contrast to the
ataxia, myoclonus, visual abnormalities, and pyra- normal population (Table  6.2). This finding has
midal and extrapyramidal signs are common. The been reproduced consistently in many countries,
duration of the clinical illness of sCJD is typically but the significance of this genetic predisposing
about half a year, but both shorter and in some factor remains uncertain.
cases markedly longer clinical courses have been Clinical and pathological heterogeneity has long
observed. been associated with sCJD, and a wide range of acro-
Use of a combination of diagnostic tests can assist nyms have been applied to some of these clinical sub-
in identifying cases of sCJD. These include the elec- groups (e.g. Heidenhain variant with a short clinical
troencephalogram (EEG), which shows a character- history and cortical blindness as a prominent feature;
istic abnormality with periodic triphasic complexes Brownell-Oppenheimer variant with prominent cer-
in approximately 65% of patients, although not at all ebellar ataxia). Recent studies on large cohorts of
phases of the illness. Elevated levels of the chaper- patients with sCJD have identified an association
one protein 14-3-3 in the cerebrospinal fluid (CSF) between the clinicopathological phenotype, the
can also be seen, although this is also seen in other PRNP codon 129 genotype, and the PrPSc isotype on
settings. Imaging studies can also assist in making Western blot analysis.
the diagnosis of sCJD, with restricted diffusion and Cases of sCJD exhibit the typical neuropatho-
hyperintensity on FLAIR sequences evident in ana- logical features of prion diseases (Fig. 6.2A , B). As
tomically involved regions such as cerebral cortex discussed above, the typical histological features in
and striatum. These imaging changes typically prog- the six major subgroups of sCJD are summarized
ress along with clinical signs and symptoms during in Table 6.3. It is interesting to note that within one
the course of the disease. subgroup (MM2) there appear to be two distinct
The etiology of sCJD is unknown. It has been clinical presentations:  one with features character-
suggested that this disease might occur as a con- istic of sCJD, the other with features indicative of
sequence of a random stochastic event, which progressive thalamic and hypothalamic dysfunction.
results in the generation or spontaneous con- In this latter subgroup, the term “thalamic variant of
version of PrPSc within the brain. Case-control sCJD” is sometimes applied, although more recently
studies have failed to identify any consistent pre- a proposal has been made to name cases within the
disposing factors in terms of occupation or diet, subgroup as fatal sporadic insomnia.

A B

FIGURE 6.2 Sporadic CJD: microscopic features. (A) Spongiform change in the cerebral cortex in sporadic
CJD MM1 consists of multiple small vacuoles in the gray matter that occasionally join to form larger cyst-like
spaces (H&E). (B) Immunocytochemistry for PrP in the same case as Figure 6.1A shows accumulation of PrP in
amorphous deposits around areas of spongiform change.

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Table 6.3. Summary of Genotypes and Phenotypes of Sporadic Human Prion Diseases

CLINICAL PRNP PR N P C O D O N P R P RES PROPOSED PRP-


DISE ASE M U TAT I O N 12 9 ISOT YPE IMMUNOHIS TOCHEMIS T RY
C O R R E L AT E

Sporadic None MM, MV Type 1A Synaptic and coarse granular


CJD(Myoclonic, staining in cortex
Heidenhain
variants)
Sporadic CJD None VV Type 2A Plaque-like, focal and
(Brownell- perineuronal staining
Oppenheimer
variant)
Sporadic None MV Type 2A Amyloid plaques in the
CJD(Kuru-plaque cerebellum
variant)
Sporadic None MM Type 2A Staining faint and variable
CJD(Sporadic fatal
insomnia)
Sporadic None MM Type 2A (basic Cortical perivacuolar staining
CJD(Cortical glycans)
variant)
Sporadic CJD None VV Type 1A Faint synaptic staining
Variant CJD None MM Type 2B Florid and cluster plaques

M, methionine; V, valine

2.2. Variably protease-sensitive and spongiform change and microplaques are pres-
prionopathy ent in the cerebellar cortex (Fig.6.3A–C). The most
striking feature of VPSPr is the biochemistry of the
In 2008, 11 cases of a novel form of prion disease disease-associated prion protein in the brain on
now known as variably protease-sensitive prion- Western blot examination (Fig.6.3D). This shows
opathy (VPSPr) was reported in the United States. a ladder-like electrophoretic profile with five major
They had different clinical features from sCJD, with bands, in which the 7-8 kDa band may predomi-
features including behavioral and mood changes, nate. This appearance is in marked contrast to other
language deficits (including aphasia), cognitive human prion diseases.
impairment, and motor signs including parkinson- The identification and characterization of this
ism. The disease duration is longer than in sCJD (up novel disorder is still underway; the results of exper-
to 45  months), and in some cases a family history imental transmission studies are awaited, which
of a neurological disease was obtained. However, should allow a clearer understanding of the bio-
analysis of the PRNP gene in these patients found logical properties of the abnormal prion protein in
no pathogenic mutations. Subsequently around 30 this disorder, and its relationship to other forms of
cases have been identified in a wider range of coun- human prion disease.
tries, in which all three PRNP codon 129 genotypes
were affected. Interestingly, the clinical features and
to some extent the brain pathology vary according
to the PRNP codon 129 genotype.
2.3. Familial prion diseases
Spongiform change is present, particularly in the Familial prion diseases occur as autosomal domi-
neocortical and subcortical regions of the cerebrum, nant disorders with high penetrance and include

Chapter 6 Human Prion Diseases • 153


A B

C D

]
JD 10
v C r [X
sC r
SP

SP
JD

JD
VP

VP
vC
40
30
20

FIGURE 6.3 Variably protease-sensitive prionopathy (VPSPr). VPSPr shows spongiform change in the
frontal cortex (A), focal fine vacuolation in the cerebellar cortex (B), and microplaques in the cerebellar cortex
on immunohistochemistry for prion protein (C). Western blot analysis of protease-resistant prion protein in
VPSPr compared to that of variant Creutzfeldt-Jakob disease (vCJD) and sporadic Creutzfeldt-Jakob disease
(sCJD) shows a faint ladder of higher-molecular-weight bands in addition to the prominent ~8kDa band (*) that
characterizes VPSPr (D).

a wide range of clinicopathological phenotypes, and disease duration. For this reason, it has been
which are categorized as familial Creutzfeldt-Jakob proposed that mutations that cause familial forms
disease (fCJD), Gerstmann-Sträussler-Scheinker are to be identified with both the details of the muta-
disease (GSS), variable phenotypes, and fatal famil- tion and the codon 129 context.
ial insomnia (FFI). The first genetic abnormality
to be identified in a familial prion disease was the
2 .3 . 1. FAM ILIAL  CJD
PRNP P102L mutation in GSS in 1989. Since then,
over 40 different PRNP mutations, including mis- In fCJD, the range of clinical and pathological
sense, deletion, nonsense, and insertion, have been phenotypes resembles those observed for sCJD.
identified. The insertional mutations are in the octa- Some cases, initially suspected to be sCJD because
peptide repeat region. In addition to mutations, the of the apparent absence of a positive family his-
polymorphic codon 129 on both the mutant and tory, have subsequently been found to be associ-
nonmutated alleles of PRNP can strongly influence ated with a PRNP mutation. The most common
disease phenotype: the amino acid at codon 129 on PRNP haplotypes to be associated with fCJD are
the same allele as the disease-causing mutation can the E200K-129M and D178N-129V (Table  6.4).
influence the clinical and pathological features of the Phenotypic variability does occur within affected
disease, while the amino acid at codon 129 on the families in terms of both the clinical and pathologi-
other allele predominantly influences age of onset cal features of the disease.

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Table 6.4. Most Common Haplotypes and Phenotypes of Familial Human Prion
Diseases

CL INICA L DISE ASE PRNP H A PL OT Y PE P R P RESI S O T Y P E HIS TOLOGICA L


C O R R E L AT E S

Gerstmann- P102L-129M Type 1Band 8kD Spongiform change, synaptic


Sträussler- PrP, amyloid plaques
Scheinker disease 8 kD only PrP-amyloid plaques, no
spongiform changes
P105L-129VA117V- 8 kD Multicentric amyloid plaques,
129VH187R-129V no spongiform changes
F198S-129VQ217R-129V 8 kD Multicentric amyloid plaques,
no spongiform changes and
neurofibrillary tangles
Fatal familial insomnia D178N-129M Type 2B Thalamic atrophy, inferior
olivary gliosis
Familial D178N-129V Type 1B Cortical spongiform
Creutzfeldt-Jakob degeneration
disease E200K-129M Type 1B Diffuse PrP staining
E200K-129V Type 2B Diffuse PrP staining in
cortex, focal deposits in the
cerebellum, or plaque-like
deposits in the cerebellum

M, methionine; V, valine

2.3.2. GERSTMANN-STRÄUSSLER- vascular wall accumulation of this material can be


SCHEINKER DISEASE seen in the rare setting of stop mutations in PRNP
(Y145stop, Y226stop). In these cases, the clinical
GSS is a progressive cerebellar syndrome, accompa-
course is usually a relatively prolonged progressive
nied by pyramidal signs and progressive cognitive
cognitive decline leading to dementia, while the
decline, which may result in dementia. The shared
common histological feature is the vascular and
histological feature in GSS is the presence of mul-
perivascular amyloid deposits, minimal spongiform
ticentric PrP-amyloid plaques in the cerebral and
change, and tangle accumulation in neurons near the
cerebellar cortex, while spongiform change may
affected vessels. Interestingly, this pattern of disease
or may not be present (Fig.6.4A, B). A  number of
does not always result from truncation mutations in
point mutations resulting in a similar clinicopatho-
PrP, as another missense mutation (Q227stop) gives
logical phenotype has been described (Table  6.4).
rise to a pattern more in keeping with GSS, again
The F198S and Q217R mutations are associated
with abundant tangles.
with neocortical neurofibrillary tangles (similar to
those found in Alzheimer disease) in addition to
widespread multicentric and unicentric PrP amy- 2.3.4 . PRION DISEASES ASSOCIATED
loid plaques. WIT H OCTAPEPTIDE REPEAT REGION
INSERTIONAL MUTATIONS (VARIABL E
PHE NOTYPES)
2.3.3. PRION DISEASE WITH CEREBRAL
In patients with insertional mutations in the octa-
AMYLOID ANGIOPATHY (PRP-CAA)
peptide repeat region of the PRNP, the clinical mani-
While PrP-amyloid deposits in are found the paren- festations are highly variable both in terms of disease
chyma in some forms of prion disease, selective duration and in the disease phenotype. In general,

Chapter 6 Human Prion Diseases • 155


A B

FIGURE 6.4 Gerstmann-Sträussler-Scheinker disease. Immunocytochemistry for PrP shows multicentric PrP


plaques in the cerebellar molecular layer (A,B), with smaller plaques in the granular layer (A).

patients with up to four additional copies of the shared across FFI kindreds, is D178N—which had
octapeptide repeats have a clinical phenotype simi- already been demonstrated to cause fCJD. It was
lar to sCJD, with rapidly progressive dementia and recognized that D178N-129M results in FFI, while
characteristic EEG abnormalities. In patients with D178N-129V results in fCJD. Phenotypic variabil-
a larger number of extra repeats, the clinical pheno- ity has been described within FFI, usually under the
type is more variable, often with progressive ataxia influence of the codon 129 genotype on the nonmu-
and other movement disorders. Histologically, these tated allele.
cases often show unusual linear PrP deposits in the
molecular layer of the cerebellum (Fig. 6.5); how-
ever, the other histological features are somewhat 2.4. Acquired Prion Diseases
more variable. 2 .4 . 1. KURU
Kuru was described as an endemic disease among
2. 3. 5. FATAL FAMI LI A L I NS O M NI A the Fore tribe of Papua New Guinea in the 1950s.
The disease was characterized by progressive ataxia
FFI is a disorder characterized by sleep disturbance,
and tremor with marked emotional instability, but
dysautonomia, and motor signs, with cognitive
abnormalities, which are often relatively mild but
tend to increase with the duration of the disease. The
neuropathology of FFI is characterized by severe
neuronal loss and gliosis in the anterior thalamic
nuclei (Fig. 6.6A–C) and in the hypothalamus, in
the absence of spongiform change and PrPSc depo-
sition. Neuronal loss and gliosis are also evident in
the inferior olivary nuclei (Fig. 6.6D) and to a lesser
but variable extent, in the cerebral and cerebel-
lar cortex. Spongiform changes can be remarkably
difficult to detect in this disorder but are usually
apparent on careful study of the cerebellar cortex.
In some cases, tissue blots obtained from sections
of paraffin-embedded tissue may help to identify
PrPSc deposition, particularly in the entorhinal cor-
tex (Fig. 6.6E). FIGURE 6.5 Prion disease with octapeptide repeat
The discovery that FFI is caused by a mutation in region insertional mutations. Immunocytochemistry
PRNP highlights the impact of codon 129 on disease for PrP shows linear PrP deposits in the molecular
phenotype (Table  6.4). The identified mutation, layer of the cerebellum.

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rapidly progressive dementia was not a common presence of the amyloid deposits in the cerebellum
feature. The disease was associated with ritualistic (Fig.6.7B) but also has demonstrated diffuse depos-
cannibalism, and since this practice has been dis- its, which are not identifiable on routine stains.
couraged, the incidence of disease has declined sig-
nificantly. The disease is now extinct, and some of
2.4.2 . IATROGENIC CJD
the last symptomatic patients sustained incubation
periods of around 40 years. In 1974, the occurrence of iatrogenic CJD (iCJD)
The pathology of Kuru is similar to that of the was reported in a recipient of a corneal transplant.
sporadic CJD VV2 and MV2 subsets, with amy- Since then, well over 400 cases of human transmis-
loid plaques, so-called “Kuru plaques,” present in sion of CJD have been identified; the majority of
the cerebellum, particularly in the granular cell these have been recipients of autopsy-derived human
layer (Fig. 6.7A), and spongiform change noted pituitary hormones (mostly growth hormone) or
in the cerebellum, basal ganglia, and thalamus, human dura mater grafts. A summary of the routes
with a variable distribution in the cerebral cortex. of transmission of iCJD is given in Table 6.5. There
Immunocytochemistry for PrP has highlighted the is a relationship between the route of infection and

A B C

D E

FIGURE 6.6 Fatal familial insomnia. (A, B) Coronal section of the right thalamus through the mammil-
lary bodies showing atrophy of the anterior and medial nuclei in a FFI case (A) compared to a normal control
(B) (courtesy Pr. Danielle Seilhean). (C) Microscopic appearance of the medial thalamus: neuronal loss and
gliosis. Note the absence of spongiosis (H&E). (D) Immunocytochemistry for GFAP showing neuronal loss and
gliosis in the medullary olive. (E) PET immunoblotting shows PrP deposition in the entorhinal cortex (courtesy
of Pr. F. Scaravilli).

Chapter 6 Human Prion Diseases • 157


A B

FIGURE 6.7 Kuru. (A) Kuru plaque in the molecular layer of the cerebellum (H&E). (B) Small rounded
PrP amyloid plaques, well identified on PrP immunostain, are a characteristic feature in the granular layer of the
cerebellum.

incubation times:  a central route of infection has Histologically, iCJD is similar to sCJD, although the
the shortest incubation times, while the peripheral cerebellar pathology in the pituitary hormone recipi-
route of infection (particularly in growth hormone ents tends to be more severe than in sCJD (Fig. 6.8).
recipients) has a longer incubation period. In general, iCJD has developed more frequently in
The clinical features of iCJD are variable; some the setting of homozygosity at codon 129. There is
patients (particularly those with a “central” route an intriguing observation that cases from the United
of transmission) resemble sCJD, whereas others Kingdom are more commonly 129VV, while those
(including the human pituitary hormone recipients) from France are more commonly 129MM; this may
often present with a progressive cerebellar ataxia reflect differences in the original contaminating agent.
and other focal neurological symptoms as well as
dementia occurring only later in the illness.
2.5. Variant CJD
In 1996, a novel form of prion disease with unusual
clinical, biological, and pathological features was
Table 6.5 Routes of Iatrogenic identified by the National CJD Surveillance Unit in
Transmission of Creutzfeldt-Jakob the United Kingdom. A causative relationship with
Disease

SOURCE OF N U M B E R O F I N C U B AT I O N
INF EC TION REPORTED PERIOD (M)
CASES

Neurosurgical 4 12–28
instruments
Intracerebral 2 16–20
electrodes
Dura mater graft 215 18–216
Corneal graft 2 16–320
Human growth 227 550–456
hormone
Human 4 144–192 FIGURE 6.8 Iatrogenic CJD. In iatrogenic CJD in
gonadotrophin a growth hormone recipient, the cerebellum contains
small “kuru-type” plaques as well as more diffuse PrP
Courtesy of Dr. L. Schonberger, 2011 deposits, well identified on PrP immunostain.

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the epidemic of bovine spongiform encephalopathy
(BSE) in cattle seemed likely. Since then, just over
200 patients with this disease, subsequently known
as variant CJD (vCJD), have been identified.
Clinically, there is a relatively young age at onset
(mean 27 years, range 12 to 74). The lengthy dura-
tion of illness (13 months) and clinical presentation
are also characteristic. The latter includes psychiatric
and/or sensory manifestations at onset, followed by
severe progressive ataxia, extrapyramidal and pyra-
midal signs, and a progressive dementia, which in
some cases was severe. In vCJD, the EEG is abnormal
but does not exhibit the characteristic abnormalities
seen in sCJD. Cranial MRI scans show a symmetrical
area of hyperintensity on FLAIR sequences in the
posterior thalamus (the “pulvinar sign”) (Fig. 6.9),
which is highly characteristic and has been incorpo- FIGURE 6.9 Axial MRI FLAIR image at the level
rated into the clinical diagnostic criteria for vCJD. of the basal ganglia, showing bilateral hyperintensity
Analysis of CSF 14-3-3 levels has not proved useful of the pulvinar and dorsomedial thalamic nuclei in
in making the diagnosis of vCJD, but detection of variant CJD.
elevated CSF phosphorylated tau has been shown to
contribute to establishing such a diagnosis.
Pathologically, vCJD differs from other forms that most human cases of vCJD result from expo-
of human prion disease by the presence of large sure to BSE through the food chain (i.e., by the con-
numbers of “florid” plaques with a widespread dis- sumption of contaminated meat products). There is
tribution in the cerebral cortex (Fig. 6.10A , B) and also evidence to suggest from a case-control study
in the cerebellum. These lesions comprise a central that consumption of certain meat products is higher
eosinophilic amyloid core with radiating bundles of in patients with vCJD than in controls.
amyloid fibrils, surrounded by spongiform change. Since the most likely route of exposure to BSE
Apart from the florid plaques, other characteris- in humans is the oral route, studies have been per-
tic neuropathological features of vCJD include formed on tissues outside the CNS to investigate
extensive PrPSc accumulation both as small cluster the peripheral pathogenesis of this disease. PrPSc is
plaques and diffuse deposits (Fig. 6.10C, D), with detectable in follicular dendritic cells within germi-
spongiform changes most marked in the caudate nal centers in lymphoid tissues including the tonsil
nucleus and putamen. In the thalamus, there is (Fig. 6.10E), lymph nodes, spleen, thymus, and the
extensive neuronal loss and gliosis in the posterior gut-associated lymphoid tissues in the appendix and
nuclei, corresponding to the abnormalities on MRI. small intestine. On the basis of this finding, it has
Western blot analysis of the brain in vCJD shows been proposed that a tonsil biopsy is an important
a characteristic PrPSc isotype, with a predominant diagnostic test for patients suspected of having vCJD,
diglycosylated band and an unglycosylated band particularly when the characteristic MRI changes are
that migrates around 21 kD (see Fig. 6.1B). This gly- absent. Recent investigations have confirmed the
cosylation pattern is similar to that seen on Western presence of infectivity in the spleen and tonsil of
blots for PrPSc in cattle with BSE and in other species individuals with vCJD; however, the level of infectiv-
(e.g., cats) that have been infected with BSE. ity is two to three times lower than that in the brain.
At the time of the original description, it was sug- The potential number of future cases of vCJD is
gested that the most likely hypothesis for the emer- highly uncertain; estimates range from a few hun-
gence of vCJD is exposure of the human population dred to many thousands. At the time of writing, 225
to the BSE agent. A number of independent investi- cases of vCJD have been reported worldwide, 176
gations have demonstrated that the structural char- of them in the United Kingdom. Since all patients
acteristics of the transmissible agent in vCJD are with definite vCJD are homozygous for methionine
quite similar to those for BSE but share no similari- at codon 129 (129MM), estimates are restricted
ties with those of sCJD. On this basis, it is assumed to that genotype. However, vCJD infection has

Chapter 6 Human Prion Diseases • 159


A B

C D

FIGURE 6.10 Variant CJD, microscopic features. (A, B) The florid plaque in the cerebral cortex in vari-
ant CJD comprises a dense core with a paler outer layer of amyloid fibrils, surrounded by spongiform change
(H&E). (C, D) Immunocytochemistry for PrP shows strong staining of the florid plaques, as well as multiple
smaller plaques and diffuse PrP deposits. (E) PrP accumulation in the tonsil in variant CJD within follicular
dendritic cells and macrophages in a germinal center is demonstrated by PrP immunocytochemistry.

been transmitted on four occasions in the United but with no evidence of a neurological disorder; at
Kingdom by blood transfusion from asymptomatic autopsy, PrPSc was detected in the spleen and lymph
donors who subsequently died from vCJD. Three of nodes, although not in the brain and spinal cord. It
the four recipients were 129MM and later died from remains possible that cases of vCJD may yet emerge
vCJD, but the fourth recipient was a heterozygote after a longer incubation period in individuals with
(129MV). This recipient died from other causes genotypes other that 129MM.

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7
Multiple Sclerosis and Related Inflammatory
Demyelinating Diseases
H A NS LAS S M ANN, R AYMO N D A . S O B EL , A N D D A N IELLE SEILH EA N

INFL AMMATORY DEMYELINATING dis- by remyelination due to recruitment and differentia-


eases are defined by the selective destruction of tion of oligodendrocyte progenitor cells. In contrast,
myelin sheaths and oligodendrocytes, which arises spontaneous regeneration of axons and neurons
in a background of acute or chronic inflammation. does not occur in the affected central nervous system
There is a spectrum of inflammatory demyelinating (CNS). There is evidence that inflammation drives
diseases that includes multiple sclerosis (MS), acute the formation of lesions in inflammatory demyelin-
disseminated encephalomyelitis (ADEM), concen- ating diseases, but the cause of chronic inflamma-
tric sclerosis (Baló disease), and neuromyelitis optica tion (i.e. either of primary autoimmune nature or as
(NMO). These diseases have distinct pathology and a reaction to a chronic infectious or other injurious
pathogenesis but share some common pathologi- process) is still unresolved.
cal features and molecular pathways of tissue injury.
Within typical demyelinating lesions, myelin sheaths
are completely lost, while axons are in part preserved; 1. MULTIPLE SCLEROSIS
they appear naked and are embedded within glial The clinical spectrum of MS is highly variable. It
scar tissue. However, as demonstrated even in the is determined by the location of lesions within the
earliest descriptions of the pathology of MS, axons CNS and the disease stage. The disease most com-
are affected and variably lost in all lesions. In contrast monly starts with episodes of neurological deficit
to demyelination, neuroaxonal degeneration is the that generally resolve but are followed by phases
major correlate of irreversible functional deficits in of relapses (relapsing/remitting MS [RRMS]).
affected patients. Slow impulse conduction is pos- After about 10  years of disease duration, this pat-
sible in demyelinated axons and demyelination and tern switches to a phase of less episodic and unin-
oligodendrocyte loss can, at least in part, be repaired terrupted progression (secondary progressive MS

• 161
[SPMS]). In a minority of patients, the relapsing matter. Inflammatory infiltrates mainly consist of
stage of the disease is absent and the patients show T-lymphocytes, of which CD8+ cells outnumber
uninterrupted progression from the onset (primary CD4+ ones. CD8+ T-cells show dominant clonal
progressive MS [PPMS]). Acute MS (Marburg expansion, suggesting the expansion of this particu-
type) is a fulminant, usually monophasic disease lar cell type through local recognition of their cog-
that leads to death of the patient within 1  year nate antigen(s). B-lymphocytes are also components
after onset. of the infiltrates and contribute to about 1% to 10%
There are several features of the clinical picture of the total lymphocyte population. These cells and
that are particularly important for interpretation of plasma cells are mainly present in the leptomeninges
the pathology and understanding the pathogenesis and perivascular Virchow Robin spaces, while their
of the disease. In RRMS, clinical disease is largely infiltration into the parenchyma is less common.
characterized by new lesions in the white matter Inflammation in the MS brain is accompanied by
that show contrast enhancement on magnetic reso- additional recruitment of monocytes and macro-
nance imaging (MRI) (i.e. reflecting inflammation phages and even more abundantly by activation of
and blood–brain barrier damage). In this stage, the local microglia population. Active demyelination
anti-inflammatory and immunosuppressive treat- and tissue injury is invariably associated with the
ments are most effective. The progressive stage of presence of activated microglia and macrophages.
the disease mainly occurs later in life; the onset of At the sites of inflammation, and in particular
disease in PPMS generally occurs at the same age as within active lesions, molecules that are involved
when disease in other patients switches from RRMS in induction, propagation, and control of the
to SPMS. In the progressive stage, clinical deteriora- inflammatory process are expressed. They include
tion does not correlate as well with new white mat- class I and class II major histocompatibility complex
ter lesions, and enhancing lesions in MRI are rare molecules (necessary for antigen presentation for
or absent. The speed of progression of the disease is T-cells), adhesion molecules, chemokines and their
surprisingly uniform and poorly related to the num- receptors (which are important for recruitment and
ber and clinical severity of previous relapses. Most migration of inflammatory cells), cytokines (which
importantly, anti-inflammatory or immunosuppres- are involved in propagation or termination of the
sive treatments are ineffective at this stage of the dis- inflammatory process), Fc-receptors and comple-
ease. Thus, from a clinical point of view, MS seems ment (involved in antibody-mediated cell injury),
to start as an inflammatory disease that gives rise to and molecules involved in macrophage toxicity
new white matter lesions, whereas it may transform (e.g., cytotoxic cytokines, proteases, and enzymes
into a neurodegenerative disease in the progressive responsible for the production of reactive oxygen
phase. As will be discussed below, this view seems and nitric oxide species).
to be too simplistic in light of the knowledge on the Inflammation is most extensive in active lesions
pathology of the disease. at early stages of MS (acute and RRMS) but is invari-
ably also present in patients at the progressive stage
of the disease, when there is ongoing active demy-
1.1. Pathology of MS elination and neurodegeneration. At very late stages
The pathology of MS is defined by the triad of inflam- of the disease, inflammation may decline to levels
mation, demyelination, and glial scar formation. observed in age-matched controls. In these patients
no active demyelination is seen and active neurode-
generation is minimal. These observations suggest
1. 1. 1. I NF L AMMAT IO N that there may be no ongoing neurodegeneration in
MS patients in the absence of inflammation.
Inflammation can be present in all stages of MS.
Inflammatory infiltrates are present around small
1 .1 . 2. DEM YELIN ATED LESION S IN THE
veins and venules in the centers of active white
W H ITE  M ATTER
matter lesions. Parenchymal infiltration by inflam-
matory cells is generally associated with active Focal demyelinated plaques in the white matter
demyelination or neurodegeneration in discrete are the hallmark of MS pathology. They occur at
lesions known as plaques and, to a variable extent, any sites of the brain and spinal cord but are more
in the more normal-appearing white and gray frequently located in certain sites that include the

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periventricular and subcortical cerebral white mat- fan-shaped appearance with the tip of the triangle
ter, the optic nerves, chiasm, and tracts, the periven- pointing toward the central gray matter. There is no
tricular regions of the brainstem, the cerebellum, predilection of plaques for specific neuroanatomical
and the spinal cord (Figs. 7.1 and 7.2). In the spi- tracts, functional systems, neurons using a particular
nal cord, the lesions generally show a triangular, neurotransmitter, or vascular territories. However,

A B

D E

FIGURE 7.1 Principal topographical features of MS lesions (Loyez stain for myelin). (A) Right cerebral
hemisphere: disseminated plaques. (B) Cerebral hemispheres through the parieto-occipital region; note the
confluent periventricular distribution of the lesions. (C) Demyelination in the optic chiasm. (D) Left cerebellar
hemisphere and pons: plaques in the anterior aspect of the fourth ventricle and in the cerebellar white matter.
(E) Plaques involving the spinal cord. Note the absence of Wallerian degeneration. Although a plaque is present
in the right cerebrospinal tract at the thoracic level, there is no consequent demyelination at the lumbar level.

Chapter 7 Multiple Sclerosis and Related Inflammatory Demyelinating Diseases • 163


A B

FIGURE 7.2 Distribution of demyelinated lesions in the MS brain (secondary progressive MS). Focal white
matter lesions are the hallmark of MS pathology. They are easily depicted in fresh brain slices and on sections
stained for myelin. (A): Hemispheric brain sections stained with Luxol fast blue. The lesions tend to accumulate
in the periventricular white matter, while smaller lesions are seen in the depth of the white matter and subcor-
tical. (B): Detailed lesion map, which includes besides the white matter lesions (green) and also gray matter
lesions. Cortical lesions are present as cortico-subcortical lesions, as small intracortical lesions, and most abun-
dantly as band-like subpial lesions (red lesions). In addition, lesions are present in deep gray matter nuclei (blue
lesions). Subpial cortical lesions are predominantly found in invaginations of the brain surface (sulci, insular
cortex, cingulate cortex, and hippocampus).

areas with a high density of venules and veins are Reactive glial cells (astrocytes and microglia) are
more likely to be affected, and a topographical rela- intimately involved in the pathology of MS lesions.
tionship between plaques and draining veins was Perivascular cells and parenchymal microglia show
demonstrated in the earliest descriptions of the evidence of immune activation, and astrocytes show
disease. marked hypertrophy and proliferation. Astrogliosis
On gross examination of the CNS, the plaques is maximal at the edge of the plaque. Toward the
become more visible after a brief exposure to center of the plaque, gliosis tends to become more
room air; they are localized predominantly in the fibrillary and, in older lesions, forms a dense glial
white matter but may also extend into gray mat- scar consisting of expanded and thickened arboriza-
ter. They appear as rounded, geographical, sharply tion of astrocytic processes (Fig. 7.6).
demarcated zones (Fig. 7.3). Recent lesions tend
to be pink or yellowish, whereas older lesions tend
to have sharp borders and are grayish or trans-
lucent and firm. On microscopic examination,
plaques are characterized by loss of myelin in dis-
crete, well-circumscribed areas; this results in a
punched-out appearance when sections are stained
for myelin (e.g. Heidenhain-Woelcke, Loyez, or
Luxol fast blue stains) (Figs. 7.1 , 7.2 and 7.4). Silver
impregnation preparations demonstrate a network
of variably reduced but relatively preserved axons
in the plaque with some axonal swellings or “spher-
oids” that indicate acute axon injury. Overall axonal
density can be reduced by 60% on average within
chronic lesions compared to the surrounding white FIGURE 7.3 Gross appearance of MS. Coronal sec-
matter. Also, in a given case, the extent of axonal loss tion of the parieto-occipital region; note the periven-
is variable from one lesion to another (Fig. 7.5). tricular distribution of the plaques.

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B

A D
FIGURE 7.4 Structural features of white matter lesions. (A) Periventricular lesion in continuity with a large
white matter plaque. The plaque contains a demyelinated center (DM), a small region of remyelination (shadow
plaque areas, RM), and a broad zone of lesional activity (active). (B): Profound perivascular inflammation is
seen in the center of the plaque. (C): The active zone of the lesion contains numerous macrophages with early
(Luxol fast blue-positive) myelin degradation products. (D): The zone of remyelination (RM) contains myelin
sheaths, which are thinner than those in the normal-appearing white matter (NAWM).

B C D

E F G
FIGURE 7.5 Axonal pathology in MS lesions. (A): Low-magnification picture of the periventricular white matter
that contains numerous demyelinated plaques. The different staining intensity in the Bielschowsky silver impregnation
reflects the different degree of axonal loss in the lesions. (B, C, D): In sections stained for phosphorylated neurofila-
ment, the different axonal content between normal-appearing white matter (B), active plaques (C), and inactive
plaque center (D) is clearly visible. (E, F, G): Immunocytochemistry for amyloid precursor protein (APP) depicts
injured axons with disturbed fast axonal transport. This is rare or absent in the normal-appearing white matter (E); it is
pronounced in active lesions (F), where it is also reflected by numerous axon spheroids or end bulbs, seen in sections
stained for neurofilament (F). In the inactive plaque center, a single dystrophic axon is seen (G).

Chapter 7 Multiple Sclerosis and Related Inflammatory Demyelinating Diseases • 165


A B C

FIGURE 7.6 Astrocytic gliosis in MS lesions. (A):Several chronic focal white matter lesions are present in
the internal and external capsule. (B): Fibrillary gliosis is best visualized by Holzer stain, showing intense blue
staining in the plaque areas. (C)Right: Massive protoplasmatic gliosis with enlarged astrocytic cell bodies show-
ing a high immunoreactivity for glial fibrillary acidic protein (GFAP). This occurs on the background of massive
inflammation and active demyelination.

Actively demyelinating MS lesions (Fig.  7.7) immunohistochemistry to demonstrate amyloid


are seen as both classical active plaques and slowly precursor protein (APP) in axonal swellings and end
expanding lesions. Classical active plaques are mainly bulbs. Perivascular inflammatory infiltrates and dis-
seen in acute and RRMS. They are characterized by persed T cells are also present in slowly expanding
marked inflammation and blood–brain barrier dam- lesions but are not associated with any increase of
age. They are heavily infiltrated with macrophages, vascular permeability for serum proteins. In inactive
which contain early myelin degradation products lesions (Fig.  7.8), demyelinated areas are sharply
that have staining properties similar to those of nor- demarcated from the surrounding normal-appearing
mal myelin (e.g. appearing as blue granules in sec- white matter. They may contain some foci of inflam-
tions stained with Luxol fast blue). Macrophages are matory infiltrates and acutely injured axons, but
either dispersed throughout the whole lesion (as is they lack the rim of activated microglia and ongoing
seen in acute plaques) (Fig. 7.7B) or concentrated at demyelination at the outer limit of the lesion.
the margin in chronic active plaques (Fig. 7.4). The Remyelination in MS lesions is variable; when it
outer rim of chronic active plaques varies in thickness does occur, the thickness of the individual myelin
and contains large numbers of oligodendrocyte pro- sheaths never regains its original, normal diameter.
genitor cells or newly differentiated re-myelinating Remyelination may be restricted to the outer mar-
oligodendrocytes; myelin sheaths in these areas are gins of the lesion (Fig. 7.4, A, D) or may be pres-
in the initial stage of dissolution and are associated ent throughout. When remyelination is present
with activated microglia. These peripheral regions throughout the plaque, the lesion is referred to as a
are the advancing edge of demyelination and tissue “shadow plaque;” these are sharply demarcated areas
injury. Macrophages remaining in the center of the of myelin pallor due to widespread reduction in the
plaques express low levels of pro-inflammatory acti- thickness of the individual myelin sheaths. Although
vation markers (e.g. inducible nitric oxide synthase the extent of remyelination in most MS patients is
or NADPH oxidases), and they contain breakdown limited, rarely it can be quite considerable.
products of the late stages of myelin degradation (i.e.
oil red O-positive neutral lipids, Fig. 7.7D).
1 .1 . 3. M S LESION S IN CEREBRAL
In contrast, slowly expanding lesions are mainly
C O RTEX AN D DEEP GRAY  M ATTER
seen in patients with progressive disease (PPMS,
SPMS). These lesions are centered around an inac- Since the initial recognition of MS as a distinct path-
tive demyelinated lesion core with profound fibril- ological entity, it has been regarded as a primarily a
lary gliosis (Fig. 7.8) and are surrounded by a small disease of the white matter. However, with the intro-
rim of activated microglia, few macrophages with duction of more sensitive tools for the immunohis-
early myelin debris, and a variable extent of acute tochemical analysis of myelin proteins, it has now
axonal injury. Axonal injury is best detected using become clear that extensive demyelination also can

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A B

C D

FIGURE 7.7 Microscopic features of MS in active lesions. (A) Perivascular lymphocytic infiltrate associated


with macrophage infiltration and reactive astrocytosis. (B) Bodian silver impregnation combined with Luxol fast
blue shows diffuse infiltration by macrophages containing Luxol-positive myelin debris and relative preservation
of axons. (C) Immunostaining of neurofilaments in the same plaque as in (B) showing axonal swellings. (D) Oil
red O stain in a frozen section of an active MS plaque showing the sudanophilic (orthochromatic) catabolism
of the myelin. Macrophages containing late myelin degradation products, neutral lipids, strongly stained by
Oil red O.

occur in the gray matter, particularly in the cerebral cor- spaces and the cortical parenchyma, and blood–brain
tex (Figs. 7.1 and 7.9). Cortical demyelination is scant barrier leakage is minimal or absent. Active subpial
in the early stages but increases with disease progres- cortical lesions are associated with inflammation in
sion. Three different types of cortical lesions have been the adjacent leptomeninges, either as diffuse men-
described: cortico-subcortical, intracortical perivascu- ingeal infiltrates or as lymphocyte aggregates, which
lar, and band-like subpial lesions. Subpial lesions are the may show features of secondary B-cell follicles. Active
most abundant in patients with progressive MS. They demyelination in the cortex occurs at sites of microglial
affect the outer cortical layers and can span over several activation, which in chronic lesions demarcate them
cortical gyri and sulci. They are preferentially located from the surrounding normal-appearing gray matter.
within invaginations of the brain surface, such as corti-
cal sulci, insular, cingulate, or temporal cortex includ-
1.1.4 . PATHOL OGY OF THE
ing the hippocampus, and cerebellar cortex. Like white
NORMAL - APPEARING WHITE AND
matter plaques, cortical plaques show primary demy-
GRAY MATTER
elination with relative sparing of axons and neurons.
When they arise in early stages of MS, inflammation Although focal demyelinated plaques are the hall-
is prominent in active lesions. However, in progressive mark of MS pathology, there are profound dif-
MS, inflammatory cells are sparse in the perivascular fuse alterations in the normal-appearing white

Chapter 7 Multiple Sclerosis and Related Inflammatory Demyelinating Diseases • 167


A B

FIGURE 7.8 Microscopic features of MS in inactive lesions. (A) Gliosis with Rosenthal fibers and absence of
inflammation. Note rare perivascular remaining macrophages. (B) Bodian silver impregnation combined with
Luxol fast blue at the periphery of an old plaque shows myelin–axonal dissociation with relative preservation of
axons. Note the normal staining of myelin on the left. (C) Metallic impregnation preparation shows fibrillary
gliosis in the center of an old plaque but no axons.

and gray matter. They consist of perivascular 1.2. Etiology and


and less conspicuous parenchymal inflammatory pathogenesis of MS
infiltrates, microglial nodules, diffuse rarefaction
of myelin and axons, and diffuse astrogliosis. In There is little doubt that inflammation drives the
late stages of MS, this gives rise to severe white disease process in MS, but it is entirely unclear
and gray matter atrophy with expansion of cere- what induces and propagates the inflammatory
brospinal fluid spaces. These diffuse brain and process. Most researchers in the field favor the
spinal cord changes can be in part explained by autoimmune hypothesis. This view is supported
Wallerian degeneration following axonal transec- by the fact that a disease model with similarities in
tion within demyelinated plaques. However, dif- clinical presentation, pathology, and immunology
fuse white matter atrophy does not correlate with (i.e. experimental autoimmune encephalomyelitis)
the number, distribution, and extent of damage can be induced in experimental animals sensitized
of focal white matter plaques and correlates only with brain or myelin antigens. Furthermore, analo-
in part with the extent of cortical demyelination. gous autoimmune T-cells and autoantibodies can
It therefore appears that diffuse white and gray be detected in MS patients. An alternative view is
matter changes occur independently from focal that chronic inflammation is driven by infection(s),
demyelination in the white and gray matter. which either trigger T-cell autoimmunity in the
peripheral immune system or even persist in the

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able to propagate further oxidative injury. In addi-
tion, genetic deletions of mitochondrial DNA,
which can also be induced by radicals, tend to clon-
ally expand in injured cells, such as neurons. Thus,
increasing mitochondrial dysfunction renders these
cells more susceptible to further damage. Given the
characteristic features of progressive MS, it is not
surprising that current anti-inflammatory or immu-
nomodulatory treatments are not effective at this
stage, despite the key role played by inflammation
along the course of the disease.

2. ACUTE MULTIPLE SCLEROSIS


The designation “Marburg type” has been given to
MS that follows a rapidly progressive, monopha-
sic course and is usually fatal in a few months and
always within 1  year of onset. It is most common
FIGURE 7.9 Cortical lesions in the MS brain. in children and young adults but has also been
Cortical lesions are not easily seen in sections stained described in older patients.
with conventional myelin stains but are clearly visible Neuropathological examination shows multiple
on immunocytochemistry for major myelin proteins. plaques, the edges of which may be poorly defined,
Besides widespread subpial demyelination there are making them difficult to see macroscopically. All
also smaller perivascular intracortical lesions. the plaques are active, hypercellular with promi-
nent perivascular lymphocytic cuffing, numerous
brain tissue. Epidemiological and immunological foamy macrophages, and scattered reactive astro-
evidence suggests that Epstein-Barr virus could be cytes. Edema may be present in the surrounding
involved in MS pathogenesis, although its direct role white matter with mass effect in occasional cases.
in the pathogenesis of the disease, inside or outside Necrotic changes may be found, and in cases with a
the nervous system, has not been proven to date. more prolonged course, they may result in cavitary
Chronic inflammation induces a complex cascade lesions (Fig.  7.10). Some of these cases have now
of immune mechanisms, which may evoke differ- been reclassified as ADEM (see below).
ent mechanisms of tissue injury involving cytotoxic In the so-called “Schilder type” of MS, which is
T-cells, autoantibodies, and products of activated mostly encountered in children and runs a relatively
macrophages and microglia. In addition, the genetic progressive course, the lesions are characterized by
makeup of the tissue in which an immune response extensive, acute plaques with clear-cut borders, often
occurs may additionally determine its susceptibility asymmetrical and sparing the subcortical white mat-
to immune-mediated damage. ter (Fig. 7.11). Axonal lesions may be prominent, and
Various patterns of demyelination are found Wallerian degeneration is frequent. Some of the cases
in active lesions at the early stages of MS. One of originally described by Schilder included various
the most important involves mitochondrial injury forms of MS but also included what is now known as
induced by reactive oxygen and nitric oxide spe- adrenoleukodystrophy and perhaps other diseases as
cies. Nevertheless, during disease progression, well. “Transitional sclerosis” has also been described
tissue injury tends to become more and more inde- wherein extensive hemispheric lesions may be associ-
pendent from inflammation, which seems partly ated with typical disseminated plaques.
trapped behind a closed or repaired blood–brain
barrier. The human brain accumulates iron (mainly 3. BALÓ CONCENTRIC
in oligodendrocytes) with aging. In active lesions,
the release of iron from intracellular stores into an SCLEROSIS
environment of oxidative damage gives rise to the Baló disease is a rare variant of inflammatory demy-
formation of highly toxic hydroxyl radicals that are elinating diseases. The clinical course is generally

Chapter 7 Multiple Sclerosis and Related Inflammatory Demyelinating Diseases • 169


A A

FIGURE 7.11 Acute “Schilder-type” MS. Wide


hemispheric periventricular plaques. Note the presence
of smaller plaques at a distance from large lesions.
FIGURE 7.10 Cavitating MS. Wide, clear-cut
periventricular plaques with sharp borders around the
early chronic MS. The mechanisms of tissue injury
right frontal horn (A) and inferior aspect of corpus
in these lesions are not fully understood, but it seems
callosum (B).
likely that demyelination, as in other MS lesions,
occurs through mitochondrial injury (cf. supra), and
subacute, very severe and often fatal, resulting in the preserved concentric rings of myelinated tissue
profound neurological deterioration within months may be protected by hypoxic tissue preconditioning.
after disease onset. It is characterized by the alter-
nation of demyelinated foci with zones in which
4. ACUTE DISSEMINATED
the myelin is preserved, thereby resulting in a con-
centric or irregular pattern of demyelination (Fig. ENCEPHALOMYELITIS
7.12). The demyelinating lesions have all the histo- This disease has several different names, including
logical features of acute plaques and axonal injury is acute disseminated encephalomyelitis (ADEM),
often prominent. Rare cavitating forms have been acute disseminated leukoencephalitis, and acute
reported. Baló disease is generally regarded as a vari- postinfectious/postvaccinial perivenous encephali-
ant of MS, since single layers of concentric demy- tis. A particularly severe variant is acute hemorrhagic
elination are seen within acute plaques of acute and leukoencephalopathy of Hurst (see Chapter  5). In

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A

FIGURE 7.13 Acute disseminated (postinfectious)


encephalomyelitis (ADEM). Lesions in the cerebellar
white matter of a patient with postinfectious measles
encephalomyelitis. On immunostain for myelin pro-
teins, there is marked perivascular inflammation with
some perivascular demyelination. Unlike in MS, large
confluent plaques of demyelination are absent.

infiltrates and centering sleeves of demyelination,


without confluent MS-like plaques (Fig. 7.13). The
disorder is thought to be an autoimmune-mediated
complication of a non-CNS infection and its patho-
genesis seems mainly to be driven by T-lymphocytes.
In some patients, circulating demyelinating antibod-
ies (e.g. against myelin oligodendrocyte glycopro-
tein) are present.

5. NEUROMYELITIS OPTICA
FIGURE 7.12 Concentric sclerosis of Baló type. NMO has for long been regarded as a subtype of MS
The lesions of Baló disease are characterized by alter- but recently has been considered to be a separate
nating rings of myelinated and demyelinated white disease. In the majority of NMO patients, there are
matter. (A) A 5-cm-in-diameter lesion located in the autoantibodies against the astrocytic water channel
frontal white matter is identified by immunostain for aquaporin 4 that can be detected in the serum. The
myelin proteins. Smaller lesions with some concentric presence of these antibodies has an extremely high
layering of myelinated and demyelinated tissue are specificity (100%) and a very high sensitivity (70%
sometimes also seen in conventional MS patients with to 90%); they have been shown to be pathogenic
severe active disease. (B) Two lesions in the occipital after transfer into experimental animals.
white matter, one periventricular and one with a char- The pathology of NMO is in some respects differ-
acteristic concentric pattern (Loyez stain for myelin). ent from that seen in MS. Lesions mainly target the
spinal cord and the optic system and also can be dem-
contrast to typical MS, this is a monophasic illness onstrated as thin sleeves of tissue injury around the
that may occur spontaneously or may follow an third and fourth ventricles. In the spinal cord, the cen-
infection (e.g. measles) or a vaccination. It affects tral gray matter is more severely affected than the white
children more frequently than adults. In patients matter and the lesions are extensive along the length
who survive, there is usually rapid recovery, often of the cord, spanning several segments (Fig. 7.14).
without neurological sequelae. The CNS lesions Microscopic examination shows dense infiltrates of
are characterized by small perivenous inflammatory T-cells, less often B-cells, and macrophages, but in

Chapter 7 Multiple Sclerosis and Related Inflammatory Demyelinating Diseases • 171


A B C

FIGURE 7.14 Neuromyelitis optica (NMO). (A): NMO lesions in the spinal cord are mainly located in the
center, massively involving the gray matter but leaving the subpial white matter largely unaffected. These lesions
typically are longitudinally extensive, spanning several segments of the spinal cord. (B): A very typical feature
of NMO lesions is the extensive destruction and loss of astrocytes, reflecting areas devoid of GFAP reactiv-
ity. (C):The inflammatory infiltrates in active NMO lesions contain very high numbers of polymorphonuclear
leukocytes. In addition, deposition of immunoglobulins and activated complement (C9neo; red) is seen in a
perivascular rosette pattern, reflecting the astrocytic glia limitans and the distal astrocyte processes.

contrast to MS lesions, polymorphonuclear leukocytes compatible with an inflammatory demyelinat-


are abundant in active lesions. At sites of active tissue ing disease. Patients who come to biopsy under
injury, massive deposition of immunoglobulins and these circumstances are individuals with single
activated complement are seen on astrocytes and their tumor-like lesions in the brain or spinal cord in
processes in a rosette-like staining pattern that mainly whom a potential neoplasm has to be excluded.
targets the perivascular and subpial astrocyte foot The differential diagnosis in such biopsies is broad
processes. Astrocytes are in part destroyed through and difficult. In addition to inflammatory demy-
complement-mediated cellular injury mechanisms; elinating diseases it includes virus-induced lesions
they may survive in the periphery of the lesions but are of the white matter and a variety of metabolic
devoid of aquaporin 4 expression. Demyelination and diseases.
axonal loss, which is prominent in chronic, established As a first step, inflammation, demyelination,
NMO lesions, follow the destruction of astrocytes. and axonal destruction have to be assessed in
Overall, NMO lesions are much more destructive routine sections stained with H&E, Luxol fast
than classical MS lesions, frequently resulting in cystic blue, and silver impregnation. This also allows
damage of the spinal cord tissue, as well as brain tissue, distinguishing between primary demyelinating
when affected. and destructive lesions. Then, the extent of demy-
elination (perivenous versus confluent) has to be
established. Vasculitic changes, B-cell neoplasms,
6. DIAGNOSIS OF and viral inclusions in astrocytes and oligoden-
INFLAMMATORY drocytes have to be excluded and intracellular
DEMYELINATING DISEASES accumulation of proteins or lipids, suggesting
metabolic (storage) diseases, assessed. Only when
IN BRAIN BIOPSIES all these conditions have been excluded can the
Neuropathologists are sometimes called upon diagnosis of an MS-like inflammatory demyelinat-
to examine biopsy specimens containing lesions ing disease be made.

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8
Pathology of Degenerative Diseases of the
Nervous System
C H A R LE S DUY C K AE RTS , JA MES  L O W E, A N D MATTH EW  FRO SCH

1. INTRODUCTION AND tangles or Lewy bodies, or may be extracellular,


forming “plaques” such as the neuritic plaques of
BACKGROUND Alzheimer disease (AD).
Degenerative diseases of the nervous system are
characterized by several common factors that serve Degenerative diseases were once enigmatic
to separate them from other disorders: conditions with little understanding of pathogen-
esis. The combination of cell biology to under-
• These diseases affect specific neuronal groups, stand shared processes and insights from genetics
often spatially separated but functionally linked, has resulted in a reorganization of the classification
with clinical features determined by the involved schemes for some disorders. A common thread that
structures. runs across degenerative diseases is the accumula-
• The histopathological changes are generally char- tion of protein aggregates, often associated with tox-
acterized by neuronal loss in the affected regions icity and failure of clearance by cellular degradation
with a variable astrocytic and microglial reaction. pathways. These aggregates are also evident on his-
Neurons are thought to die through nonnecrotic, tological examination, and for this reason the disor-
often apoptotic processes. ders are sometimes referred to as “proteinopathies.”
• Specific proteins accumulate in many of the For some diseases, there are now well-characterized
degenerative diseases. These accumulations may genetic abnormalities; in some diseases all cases
be intracellular in neurons or glia, giving rise are associated with mutations, while in others both
to distinctive inclusions such as neurofibrillary inherited and sporadic forms occur.

• 173
2. CLASSIFICATION • Tauopathy: Disorders characterized by
accumulation of the alternatively spliced
There are several approaches to classification, each hav- microtubule-associated protein tau (encoded
ing advantages. The one adopted here classifies disor- by the MAPT gene). In some of these disorders,
ders according to the dominant pattern of initial clinical there are mutations in the tau gene, including
features, into five broad categories:  degenerations of missense mutations as well as mutations that alter
the cerebral cortex (dementia), movement disorders, splicing. Tau isoforms can contain either three
cerebellar ataxia, motor neuron disease and condi- (3R) or four (4R) of the microtubule-binding
tions associated with autonomic failure (Table  8.1). domains. Among the tauopathies are diseases
It is essential to realize that, with disease progression, characterized by inclusions with 3R tau (Pick
there is great overlap in the symptoms manifested by disease), 4R tau (progressive supranuclear palsy
patients with neurodegenerative disease. As an exam- [PSP], corticobasal degeneration [CBD], argyro-
ple, a patient with a hyperkinetic syndrome movement philic grain disease), both 3R and 4R tau (AD, in
disorder (e.g.,Huntington disease) may develop cere- combination with deposits of Aβ); the character-
bral cortical pathology leading to dementia. istic inclusions in the various forms of frontotem-
Cutting across this symptom-based scheme poral lobar degeneration (FTLD) may have 3R,
occurs commonly in neurodegenerative diseases 4R, or the combination of the two.
characterized by protein accumulation. When group- • α-synucleinopathy: Disorders in which there is
ing diseases on this basis, categories would include: accumulation of the synaptic vesicle-associated
protein α-synuclein. There can be aggregates
visible on routine sections, or the accumula-
Table 8.1. Classification of tions require immunohistochemistry to reveal
Neurodegenerative Diseases them. This group includes Parkinson disease,
other Lewy body diseases, and multiple system
Cortical Degenerations
atrophy.
Alzheimer disease • Diseases with accumulation of TAR
Frontotemporal lobar degeneration DNA-binding protein 43 (TDP-43): TDP-43
Dementia with Lewy bodies is a RNA/DNA-binding protein implicated in
alternative splicing, transcriptional regulation,
Movement Disorders
mRNA stabilization, and microRNA process-
Akinetic/rigid syndromes ing. The full-length protein is normally pres-
Parkinson disease ent in the nucleus. In pathological conditions,
Progressive supranuclear palsy the protein, fragmented, phosphorylated, and
Corticobasal degeneration ubiquitinated, accumulates in the cytoplasm of
Multiple system atrophy (striatonigral the cell body, principally of neurons, but also
degeneration) of glia. It may also be found in neurites. Such
accumulations define a subset of frontotemporal
Hyperkinetic syndromes
lobar degenerations, collectively referred to as
Huntingtonchorea FTLD-TDP.
Choreoacancythosis • Polyglutamine diseases: Various cellular pro-
Cerebellar ataxias teins contain a polyglutamine tract encoded
by repeats of CAG in the coding region of the
Inherited
corresponding gene. When one of these repeats
Sporadic expands, the protein contains a lengthened
Diseases of motor systems polyglutamine tract, generally accumulating as
Motor neuron diseases neuronal intranuclear inclusions (NIIs). This
group includes Huntington disease as well as
Hereditary spastic paraparesis
some of the dominantly inherited spinocer-
Autonomic Disorders ebellar ataxias; typically, a greater degree of
Parkinson disease repeat expansion is associated with younger
age of onset and increased severity. Uniquely
Multiple system atrophy (Shy-Drager syndrome)
among the degenerative diseases, these diseases

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exist only as genetically determined forms. 3.1.1 . GROSS APPEARANCE
The proteins associated with these diseases are
The shrinkage of cortical gyri and widening of sulci
not structurally or functionally related to one
is often striking. Cortical atrophy involves predomi-
another, apart from the presence of the polyglu-
nantly the hippocampus (Fig.  8.1), the parahip-
tamine tracts.
pocampal gyrus and the temporal amygdala, with
parietal and frontal lobes being next most severely
affected. The occipital lobe is generally spared. In
3. PATHOLOGY OF some cases, especially late-onset types, the cerebral
DEGENERATIVE DISEASES atrophy is inconstant and often mild, marked by a
OF THE CEREBRAL CORTEX symmetrical slight reduction in the volume of the
temporal gyri. On cut surface, the ventricular dila-
AND DEMENTIAS tation, generally of moderate degree, parallels the
Dementing diseases, with their clinical diagnostic severity of the cortical atrophy. Depigmentation of
features of decline in cognitive function across mul- the locus coeruleus in the face of relative preserva-
tiple modalities, are associated with processes affect- tion of the substantia nigra is also typical.
ing the cerebral cortex. The degenerative changes
may be accompanied by cerebrovascular disease,
3.1.2 . MICROSCOPIC L ESIONS
which contributes to cognitive impairment. The
main causes of dementia and an indication of their Senile plaques and neurofibrillary tangles are the
frequency are presented in Table 8.2. lesions required to make the diagnosis of AD.
Synaptic loss is early and constant. It correlates with
clinical dysfunction but is difficult to assess, as is the
neuronal loss. While both senile plaques and neu-
3.1. Alzheimer disease
rofibrillary tangles form, as a result of the biological
AD is the most common of the degenerative diseases changes that characterize AD, they are not in them-
and increases in incidence with age. Most patients selves specific for the disease. It is the combination
present with memory failure and develop deficits of Aβ deposits, senile plaques, and neurofibrillary
in other cognitive domains, commonly including tangles, all with appropriate density and distribu-
apraxia, aphasia, and agnosia. tion that allows a neuropathological diagnosis to

Table 8.2. Main Causes of Dementia and Their Frequency

DISORDER FREQUENCY

Alzheimer disease
Sporadic Very common
Familial Uncommon
Vascular and mixed dementia Very common
Dementia with Lewy bodies
Pure without AD changes Rare
Common (with AD changes) Common
Frontotemporal lobar degeneration
Pick disease Uncommon
FTLD with MAPT mutations Uncommon
FTLD-TDP Not rare
FTLD with motor neuron disease Not rare
FTLD-FUS Uncommon
Argyrophilic grains Common lesion; uncommonly diagnosed clinically

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 175


FIGURE 8.1 Alzheimer disease. On the right is the hippocampus from a patient with AD. On the left is that
from an age-matched individual with no cognitive abnormality. Note atrophy of cortex, shrinkage of white mat-
ter, and widening of the temporal horn of the left lateral ventricle.

be made. The clinical diagnostic criteria for the stages) typically follows a predictable sequence:  1,
diagnosis of AD have changed and now rely less on isocortex; 2, hippocampus; 3, basal ganglia; 4, mes-
the demonstration of severe dementia, considering encephalon; 5, pons and cerebellum.
rather earlier stages of the illness when cognitive
impairment is milder. Correspondingly, there has 3.1.2.2. Plaques Senile (or neuritic) plaques
been a need to shift neuropathological criteria to (Fig. 8.2A–C) consist of a core and a corona. The core
identify the burden and distribution of lesions that is an extracellular deposit of Aβ, while the corona is
are associated with the underlying disease process made of degenerating neurites, mainly axons, immu-
but are not typically associated with end-stage neu- noreactive for tau protein and highlighted on silver
rological impairment. staining methods such as Bielschowsky or Gallyas
(Fig. 8.2C), and enlarged ubiquitin-positive “dystro-
3.1.2.1. Aβ deposits The Aβ peptide is a 40-42 phic” neurites.
amino acid fragment from a normal neuronal pro- The Aβ peptide in the core of the senile plaque is
tein termed APP (amyloid precursor protein). The misfolded, enriched in β-pleated sheets, and has all
peptide is generated by sequential cleavage of APP of the features of amyloid (Fig. 8.2B); for example,
in the extracellular domain (by a protease known as it shows an apple-green birefringence after Congo
BACE) followed by an intramembranous cleavage red stain, is fluorescent after thioflavin S staining,
(by an enzymatic complex known as γ-secretase, and appears fibrillar at electron microscopy exami-
which includes presenilin). Generation of Aβ from nation. The neuritic plaque also elicits an astrocytic
APP is considered critical for the initiation of AD and microglial reaction. Neuritic plaques and diffuse
pathogenesis since mutations in APP that accelerate deposits are typically found in neocortex, entorhinal
generation of Aβ cause familial forms of AD, as do cortex, and hippocampus, while striatum and cere-
mutations in presenilin, which increase the rate of bellum show only diffuse deposits. Neuritic plaque
generation of Aβ or shift toward longer forms of Aβ. burden in neocortical areas is typically reported in
The recent discovery that an APP mutation that hin- the semiquantitative CERAD method, separated
ders the generation of Aβ is protective against AD into sparse, moderate, and abundant.
has further strengthened this argument.
The Aβ is highly prone to aggregate; small aggre- 3.1.2.3. Neurofibrillary tangles, neuronal and
gates (termed oligomers) are the currently suspected synaptic  loss Neurofibrillary tangles are intracel-
critical mediator for eliciting cellular and synaptic lular inclusion bodies, primarily containing tau as
dysfunction. Within the brain, aggregates of Aβ well as other proteins (Fig.  8.3). Tau is a microtu-
are extracellular deposits that commonly elicit sig- bule binding protein, but, in tangles, it has separated
nificant local reaction (neuritic plaques, see below). from the microtubules and is hyperphosphorylated
Diffuse deposits of Aβ are also present in AD; at a variety of serine and threonine residues. Tangles
these are wispy, larger, but less dense than plaques, may be detected by immunostaining for tau pro-
and have convoluted shapes. They are not seen on tein, as well as silver impregnation techniques such
hematoxylin and eosin or Congo red stains but are as Bielschowsky or Gallyas stains (see Fig.  1.10).
immunolabeled by Aβ antibodies. The progression When nerve cells die, tangles may be left behind in
of amyloid pathology within the brain (termed Thal the neuropil as so-called “ghost tangles.” Nerve cell

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A B

FIGURE 8.2 Alzheimer disease plaques. (A) With H&E staining, focal plaques can be sometimes seen as
compact, rounded alterations in the neuropil. (B) Immunostaining for the Aβ peptide positively stains the core
of the plaque. (C) Tau immunostaining reveals neurites containing tau protein surrounding the central amyloid
core material.

processes (mainly dendrites) in the cortical neuropil


may accumulate tau protein, in which case they are
called neuropil threads. Nerve cell processes run-
ning through neuritic plaques also accumulate tau
protein and are then termed degenerating neurites.
Both tangles and degenerating neurites contain a
mixture of 3R and 4R forms of tau.
A scheme known as Braak & Braak staging is used
to characterize the distribution of neurofibrillary
pathology with good correlation to clinical status.
In general, tangles and neuropil threads first occur
in the entorhinal cortex (Stage I), progress through
the subiculum (Stage II) into the hippocampus,
first through CA1 (Stage III) and on through the FIGURE 8.3 Alzheimer disease tangles. Tau
remainder of the pyramidal cell layer (Stage IV), immunostaining shows neurofibrillary tangles within
before reaching association neocortex (Stage V) and neuronal cell bodies. In addition, the neurites around
finally extending to the primary motor and sensory plaques detected by tau immunostaining as fine
neocortex (Stage VI). In addition, neurofibrillary threads in the cortex are termed neuropil threads.

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 177


changes are also found in some other brain regions, 3 .1 . 3. DIAGN OSTIC CRITERIA AN D
including the amygdala, limbic nuclei of the thala- S TAGIN G  OF  AD
mus (anterior complex, laterodorsal nucleus,
As the pathological processes of AD begin in the
and some intralaminar nuclei), nucleus basalis of
brain many years before the emergence of dementia,
Meynert, reticular formation of the mesencephalon,
it is not surprising that these lesions (Aβ deposits,
locus coeruleus, raphe nucleus, and selected subnu-
neuritic plaques, and tangles) may be seen in sub-
clei of the substantia nigra.
jects without subjective or objective evidence of
In the same areas where tangles develop, neuro-
cognitive decline—although typically with a lower
nal cell loss, varying according to the severity of the
burden of lesions and a more restricted distribution.
disease, may also be seen. Synaptophysin immuno-
As presented above, there are three scales by which
reactivity is decreased at an early stage of AD, and
the lesions of AD are assessed:  tangles are consid-
this finding is related to loss of synapses.
ered by the Braak staging scheme for AD, Aβ depos-
its by the Thal stages, and neuritic plaques according
3.1.2.4. Amyloid angiopathy Accumulation of
to the CERAD system. With the most recent con-
Aβ peptide in the vessel walls causes amyloid angiop-
sensus proposal, by definition, Alzheimer disease
athy (Fig. 8.4). It is especially seen in the neocortex
neuropathological changes necessarily include Aβ
(occipital, temporal, parietal, frontal, in decreasing
deposits with any combination of neuritic plaques
frequency) and later in Ammon’s horn and cerebel-
and tangles. Progression and increasing burden
lum. The amyloid deposit results in irregular thick-
along these histological scoring scales are associ-
ening of the terminal vascular bed. It may affect
ated with a greater probability of cognitive impair-
capillaries and then extends into the adjacent paren-
ment in affected individuals. At one extreme are
chyma (dyshoric angiopathy). Involvement of the
subjects with Thal phase 1 Aβ deposits, with low
capillary walls is seen particularly in a subgroup of
Braak stages and sparse neuritic plaques (CERAD),
patients who are of the ApoE ε4 genotype. Amyloid
who are expected to be cognitively intact. At the
vascular deposits may also affect small arteries and
other are cases with widespread Aβ deposits (Thal
veins in the meninges and superficial layers of the
phase 5) and abundant neuritic plaques and tangles
cortex (congophilic angiopathy). Cerebral amyloid
throughout the neocortex and mesial temporal lobe
angiopathy may also be seen in non-demented,
(Braak V or VI).
aged individuals, causing cerebral hemorrhages or
microscopic infarcts (see Chapter  4). It is a nearly
constant finding in patients with AD, although the
3 .1 . 4. M OLECULAR PATHOLOGY
vessel damage is only seldom associated with hem-
orrhage in this disorder. As mentioned above, recognition of the central
pathogenetic role of Aβ in AD has been driven by
observations from genetics. Several factors are rec-
ognized to promote or cause amyloid deposition.
Rare early-onset familial cases of AD are caused by
mutations in—or duplication of—the APP gene
on chromosome 21. It is believed that the associa-
tion between Down syndrome and AD relates to
the presence of three copies of the APP gene, due
to the trisomy 21. Mutations in genes coding for the
presenilins (PS1, PS2), which are components of
γ-secretase, are also recognized to cause early-onset
familial AD. These proteins are involved in the path-
ways of cleavage of APP, with mutations giving rise
to excess production of AE peptide. Genotype at the
apolipoprotein E (apoE) locus influences the risk
of AD:  individuals with copies of the apoE4 allele
FIGURE 8.4 Alzheimer disease amyloid angiopa- have a roughly four- to five-fold increased risk of
thy. Immunostaining for Aβ peptide shows affected developing AD for each copy of the allele they carry
vessels. compared to those carrying apoE2 or apoE3 alleles.

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Genetic studies continue to identify potential other pathological findings; for instance, one study of
contributing risk factor alleles, although each of well-characterized subjects with PPA found that, at
these makes only a small contribution to the risk autopsy, approximately half had AD and half had a
of developing AD. It is important to recognize that, form of FTLD, with a roughly even split between
even though tangles form an essential part of the his- FTLD-tau and FTLD-TPD43.
topathological findings of AD, mutations in the gene
encoding tau (the primary protein of tangles) do not
result in AD. 3.2.1 . F TL D- TAU
These diseases are defined by the combination of
3.2. Frontotemporal Lobar lobar degeneration and of inclusions containing 3R
Degenerations tau, 4R tau, or both forms. This group includes Pick
disease, tauopathies with mutation of the tau gene
Several diseases are characterized by neurodegen- (MAPT), and other tauopathies without MAPT
eration concentrated on the frontal and temporal mutation. Additionally, two disorders that are pri-
lobes with relative sparing of the parietal and occipi- marily classified as movement disorders (PSP and
tal lobes. The clinical features relate to behavioral CBD) may also include cognitive changes with lobar
disturbances or language dysfunction, with memory atrophy and tau-containing inclusions. They are dis-
dysfunction occurring later in the course of the cussed below with the akinetic movement disorders
disease. It is this distinct pattern of progression of (4.12 and 4.1.3).
clinical symptoms, albeit with other clinical mani-
festation, that helps distinguish these patients from
those with AD. The clinical condition is typically 3.2.1.1. Pick disease Pick disease is a sporadic
referred to as frontotemporal dementia (FTD); the dementia, characteristically beginning in the fifth
pathological substrate is FTLD. and sixth decades of life. The behavioral changes
Histopathological findings, as well as genetic are severe. This clinical pattern of symptoms corre-
underpinnings, have refined the classification of sponds to the distribution of lesions, involving pre-
FTLDs over the past decade. These diseases are now dominantly the frontal lobes early in the course of
characterized based on the type of protein inclu- the disease.
sions observed in neurons as well as mutational sta-
tus, if known. Current classification is based on the 3.2.1.1.1. Gross appearance Grossly the cerebral
presence of inclusions containing predominantly or atrophy, which is often so severe as to be described
exclusively one of three markers, shown by immu- as “knife-edge” atrophy, is circumscribed and most
nohistochemistry:  tau, in various combinations evident in the frontal lobes; even when it involves
of 3R and 4R tau (FTLD-tau); TDP-43, a DNA/ the temporal lobe, it typically spares the poste-
RNA binding protein (FLTD-TDP43); and FUS rior third of the superior temporal gyrus. Severe
(FTLD-FUS). Within each of these groups, genetic involvement of the hippocampus may be present
markers and the distribution pattern of inclu- and may be responsible for memory loss. The pari-
sions are heterogeneous. A  relationship between etal cortex is seldom involved, and the occipital
FTLD-TDP43 and FTLD-FUS and amyotrophic cortex is always spared. In keeping with this pattern
lateral sclerosis (ALS), in terms of histopathological of lobar involvement, there is greater dilatation of
findings, genetic causes, and clinical presentation, the anterior portion of the frontal and temporal
has been recognized in recent studies. horns of the lateral ventricles. This may be accen-
Characteristic clinical symptoms can be used tuated when, in some cases, there is also striatal
to group forms of FTLD; these reflect the ana- atrophy.
tomical distribution of neuronal loss rather than
the inclusion type. Among the major patterns of 3.2.1.1.2. Microscopic lesions Involved regions of
presentation, the three best characterized are the cerebral cortex show massive neuronal loss, associ-
behavioral variant (bvFTLD), primary progressive ated with dense astrocytic gliosis, usually accom-
non-fluent aphasia (PPA), and semantic dementia. panied by cortical microvacuolation. White matter
Importantly, however, there is still a lack of consis- in the involved gyri shows the expected secondary
tent correlation between clinical presentation and attenuation. Pick disease is characterized by the

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 179


mutations can be grouped into those that alter the
splicing of the mRNA for tau and those that are
point mutations changing the structure of the pro-
tein in other ways. The altered splicing results in
a shift of the balance between 3R and 4R tau, and
this disequilibrium is believed to contribute to the
initiation of the cellular dysfunction. The underly-
ing mechanisms relating the point mutations to the
disease are less clear.
The disease is characterized by a diffuse atrophy
of the frontal and temporal lobes, correlated with
corresponding cognitive changes. Parkinsonism
may accompany the dementia (hence the term fron-
FIGURE 8.5 Pick disease. Pick bodies are faintly totemporal dementia with parkinsonism linked to
visible with H&E staining. They appear as rounded, chromosome 17: FTDP-17, MAPT being localized
slightly basophilic inclusions in the neuronal cell body. on chromosome 17, used before the isolation of the
various tau mutations).
presence of Pick bodies—rounded, homogeneous
neuronal cytoplasmic inclusions, faintly visible on 3.2.1.2.1. Gross appearance The frontotemporal
H&E staining (Fig.  8.5). Immunohistochemical atrophy and the ventricular dilation are of variable
staining shows that these inclusions contain 3R tau severity. The caudate nucleus may be atrophic. The
(Fig. 8.6A , B). Pick bodies are also strongly argyro- substantia nigra is sometimes pale.
philic and well detected using appropriate silver
stains (Fig.  1.12). Ballooned neurons (sometimes 3.2.1.2.2. Microscopic lesions In involved corti-
referred to as Pick cells) are also frequent (Fig. 8.7). cal regions, there is extensive neuronal loss with
When deep gray matter structures are involved, there reactive gliosis. Glial tau inclusions are quite com-
is comparable neuronal loss and gliosis but not the mon (Fig. 8.8A). Tangles are present in remaining
accumulation of Pick bodies. Such changes are most neurons and in less affected regions. Neurons also
common in the head of the caudate, although they accumulate tau diffusely, in abnormal conforma-
may also be found in putamen, pallidum, and por- tions, referred to as “pre-tangles” (Fig.  8.8B). In
tions of the thalamus. addition, there is commonly vacuolation of the
upper layers of the cortex. Western blots and immu-
3.2.1.2. FTLD with MAPT mutations nohistochemistry can characterize the forms of tau
Mutations in the MAPT gene that encodes tau present in the inclusions—which can be 3R, 4R, or
are found in familial forms of FTLD-tau. These the combination. Additionally, glial tau inclusions

A B

FIGURE 8.6 Pick bodies are spherical tau-positive inclusions, seen in the neocortex (A) and in the dentate
gyrus of the hippocampus (B).

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3.2.2 . F TL D ASSOCIATED WITH
TDP - 4 3 - POSITIVE L ESIONS (F TL D- TDP)
FTLD with tau-negative, TDP-43-positive inclu-
sions (FTLD-TDP) may account for half the
autopsy-confirmed FTLD cases. Several genetic
loci harbor causative mutations for FTLD-TDP
and include the genes for TDP43 (an RNA binding
protein), progranulin, and C9orf72. Additionally,
sporadic forms of this disease also occur, with compa-
rable clinical features. Overall, the types of inclusions
that define a subtype of FTLD are not strongly cor-
related with the clinical presentation. FTLD-TDP is
FIGURE 8.7 Pick disease. Swollen cortical neu- often associated with ALS (vide infra). This is partic-
rons are a characteristic but nonspecific feature of ularly true for those cases associated with mutations
disease (H&E). in TDP-43 and the more frequent cases linked to
expansion of the hexanucleotide repeat in C9orf72.
Progranulin-linked FTLD-TDP is never associated
are quite common. These can occur diffusely in with ALS. Another genetic locus, valosin-containing
white matter, but also in patterns that involve astro- protein (VCP), has been identified in the setting
cytes within gray matter. There is moderate histo- of familial FTLD with the added clinical features
logical overlap in some cases between the lesions of inclusion body myositis and Paget disease of the
of FTLD-tau and those seen in forms of parkinso- bone (but without an associated link to ALS).
nian syndromes with tau-containing inclusions, as
mentioned above. Thus the tau-containing lesions
3.2.2.1 Gross appearance As with other forms
observed may resemble the tangles of AD, the
of FTLD, the frontotemporal atrophy is generally
tufted astrocyte of PSP, or the astrocytic plaque
most severe in anatomical regions that correspond
of CBD.
to the clinically observed functional deficits. There
is commonly ventricular dilation and there may be
3.2.1.3. FTLD-tau without tau mutation atrophy of the caudate nucleus (Fig. 8.9).
Some cases of FTLD-tau are neither associated
with MAPT mutations nor with Pick pathology, 3.2.2.2 Microscopic findings Superficial cor-
although neither gross nor microscopic appear- tical vacuolation is commonly observed, particu-
ance can differentiate them from cases with MAPT larly in layer II of the frontal cortex (Fig. 8.10). In
mutations. some cases, the neuronal loss is severe, involving

A B

FIGURE 8.8 Frontotemporal degeneration with parkinsonism linked to mutations of the tau gene. P301L
MAPT mutation, polyclonal anti-tau antibody. (A) Tau accumulation in an astrocyte. (B) Same case, pretangle
in the cerebral cortex.

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 181


neuronal inclusions are located in the cell body
(so-called neuronal cytoplasmic inclusions [NCIs])
(Figs. 8.12A and 8.13A), in the nucleus (NIIs)
(Fig.  8.12B), or in the neurites (Fig. 8.11A); glial
inclusions are also observed in affected regions. In
the inclusions, TDP-43 is phosphorylated and ubiq-
uitinated. The inclusions are most abundant in the
frontal and temporal cortex, in the striatum, and in
the dentate gyrus of the hippocampus (Figs. 8.11B
and 8.12A).
Different classification schemes have been pro-
posed for FTLD-TDP taking into account the
appearance, abundance, and distribution of inclu-
sions, and also attempting some correlation with
FIGURE 8.9 Frontotemporal lobar degeneration. underlying genetic alterations, but less so with the
There is severe cerebral atrophy with marked temporal clinical phenotype:
lobe involvement, especially marked in its medial
aspect (including hippocampus). • Type A shows the presence of many
TDP-43-positive NCIs (Fig. 8.12A) and short
neurites, both mostly in upper cortical layers.
all the cortical layers with microvacuolation and These are accompanied by needle-like NIIs
astrocytic gliosis. TDP-43 is normally a nuclear (Fig. 8.12B). This pattern is associated with muta-
protein. The staining of neuronal nuclei is uniform tion in the progranulin gene.
by immunohistochemistry; in the face of inclusion • Type B shows predominantly NCI (not lim-
formation, there is relative nuclear clearing and ited to upper cortical layers) (Fig. 8.13A) with
accumulation of TDP in abnormal cellular topogra- some neurites, but missing NIIs. This pattern
phy. In FTLD-TDP, immunohistochemistry shows is more commonly associated with the behav-
ubiquitin- and TDP-43-positive intraneuronal ioral variant of FTLD, with ALS (Fig. 8.13C),
inclusions of various types and with variable distri- and with expansion of the hexanucleotide
bution (Figs. 8.11, 8.12, and 8.13). TDP-43-positive repeat in C9orf72. In this case, it is selectively
associated with ubiquitin- and p62-positive,
TDP43-negative NCIs in the granule cells of the
cerebellum (Fig. 8.13B).
• Type C shows many long dystrophic neurites, less
abundant NCI, and very few NIIs. This type is
often associated with semantic dementia.
• Type D shows predominantly the lentiform NII,
with abundant short neurites but scant NCI.
This pattern is associated with the rare mutations
in VCP.

3 .2 . 3. FTLD- FUS
In rare cases, the neuronal inclusions are tau and
TDP-43 negative but are labeled by antibodies
directed against the RNA-binding protein FUS
(fused in sarcoma). This observation grew out
FIGURE 8.10 Frontotemporal lobar degeneration. of the demonstration that mutations in this gene
Neuronal loss and microvacuolation in the superficial were associated with some familial forms of ALS,
cortical layers is often seen. In more advanced cases and awareness of the relationship between ALS
(as here) there is severe neuronal loss and transcorti- and FTLD. Within the set of FLTD-FUS cases,
cal vacuolation (H&E). some have no other distinguishing characteristics

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A B

FIGURE 8.11 Frontotemporal lobar degeneration. (A) Ubiquitin-immunoreactive inclusions in layer II neu-


rons as well as accumulation in small neuritis. (B) Ubiquitin-immunoreactive inclusions in hippocampal dentate
granule cells.

and were previously known as atypical FTLD-U 3.2.4 . F TL D- UPS


(because the inclusions contained ubiquitin but not
In a few families with FTLD, the inclusions are detect-
the other recognized markers). Two other sporadic
able only by immunohistochemistry directed against
disorders fit into the category of FTLD-FUS: neu-
proteins belonging to the ubiquitin-proteasomal
ronal intermediate filament inclusion disease and
degradation system. The inclusions in these brains
basophilic inclusion body disease. The first of
are characterized by the presence of ubiquitin and
these can mimic Pick disease with spherical neu-
p62 (a protein that binds to polyubiquitinated pro-
ronal cytoplasmic inclusions, approximately the
teins and assists in transporting them toward the pro-
size of the nucleus, found in the cerebral cortex,
teasome and for autophagy). This neuropathological
basal nuclei, and brainstem. As the name implies,
pattern is associated with mutations in the gene for
the inclusions contain neurofilament proteins as
CHMP2B (charged multivesicular body protein 2B).
well as FUS and are tau negative. The latter has a
heterogeneous clinical phenotype that can include
behavioral-variant FTLD, with manifestations of
3.2.5. FTD LACKING INCLUSIONS (FTLD-NI)
lower motor neuron degeneration and extrapyra-
midal signs; again, there are neuronal cytoplasmic In a few cases of FTD, there is no cytoplasmic or
inclusions that are inconstantly ubiquitin positive nuclear inclusion detected. These cases are classified
but intensely FUS positive. as FTLD-ni (for no inclusion).

A B

FIGURE 8.12 Mutation of the progranulin gene (PGRN). (A) Ubiquitin- and TDP-43-positive neuronal
cytoplasmic inclusion in the dentate gyrus. (B)Ubiquitin- and TDP-43-positive neuronal intranuclear inclusion
with typical cat’s-eye appearance.

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 183


A B

FIGURE 8.13 C9ORF72 mutation. (A) TDP 43 antibody. The nucleus in the upper part of the field is nor-
mally immunostained. The nucleus in the lower part of the field is negative and is associated with a cytoplasmic
inclusion. (B) In the cerebellum, a typical ubiquitin- and P62-positive inclusion is negative for TDP-43. (C) In
the same case, an ubiquitin-positive skein-like inclusion is present in a motor neuron.

3.3. Dementia with Lewy Bodies remains unclear, it is likely that each can contribute
to cognitive impairment.
Dementia commonly emerges as an additional com-
ponent of the illness in individuals with Parkinson
disease (vide infra). There is somewhat arbitrary 3 .3 . 1. GROSS APPEARAN CE
separation between dementia with Lewy bodies
Cerebral atrophy is generally not as severe as that
(DLB, which becomes manifest within a year of
seen in a case of AD of equivalent cognitive impair-
the onset of parkinsonism or in advance of it) and
ment, with brain weight in the normal range.
Parkinson disease dementia (where the dementia
There is usually pallor of the substantia nigra and
follows the establishment of a Parkinson disease
of the locus coeruleus, as would be seen in typical
diagnosis by more than a year). In either setting, the
Parkinson disease. Atrophy of the limbic system may
dementia is a progressive disorder with early hallu-
be prominent.
cinations and prominent fluctuations in cognition.
Neuropathological changes include the presence
of Lewy bodies and Lewy neurites in the cerebral
3 .3 . 2. M ICROSCOPIC FIN DIN GS
cortex as well as in the brainstem. These are often
accompanied by some degree of AD neuropatho- Neuronal loss and gliosis are usually restricted
logical changes, often with a moderate plaque bur- to brainstem regions, particularly the substantia
den but relatively lower tangle burden. Although nigra and locus coeruleus. The severity of injury is
the etiological relationship between the processes typically comparable to that observed in Parkinson

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disease, along with Lewy bodies—eosinophilic, be localized atrophy of the ambient gyrus, and the
laminated cytoplasmic neuronal inclusions. In con- accumulation of grains appears to begin there, with
trast to these changes, the cerebral neocortex, hip- progressive involvement through medial temporal
pocampus, and amygdala are usually unremarkable lobe structures and thence to other limbic regions
with routine staining methods. With immunohis- such as cingulate and insular cortices.
tochemistry directed against α-synuclein, another
picture emerges. The brainstem Lewy bodies are
highlighted and their wider distribution in the retic- 3.5. Hippocampal sclerosis
ular formation becomes evident, along with the pres- Some aged subjects have memory loss as their pre-
ence of immunoreactive dystrophic neurites (Lewy dominant symptom, often leading to a presumptive
neurites). In the deeper layers of the cerebral cortex clinical diagnosis of AD. While the typical findings
(particularly temporal, insular, and cingulate corti- of AD are present in some, others have plaques but
ces) there are ill-defined cytoplasmic inclusions that limited tangle distribution in a manner less likely
are indistinct compared to the counterpart lesions in to explain the cognitive impairment. In these cases,
the brainstem, but stain comparably for α-synuclein there can be neuronal loss and gliosis limited to the
(Fig. 8.14A , B). These are also accompanied by CA1 sector of the hippocampus but lacking the
Lewy neurites in the cortical neuropil and a super- marked destructive changes that would suggest a
ficial spongiosis involving the outer several cortical prior ischemic event (or epileptic seizures). In this
layers. In the amygdala, Lewy bodies are detected in clinicopathological setting, TDP-43-containing
neurons, while in the hippocampus Lewy neurites in inclusions are commonly identified, suggesting a
CA2-3 can be the only finding (Fig. 8.15). As men- link to FTLD-TDP.
tioned above, most brains with DLB also show some
plaques and tangles, although in most instances the
lesions are not nearly as severe as in AD. 3.6. Vascular dementia/Vascular
cognitive impairment
3.3.3. DIAGNOSTIC CLASSIFICATION It is being increasingly recognized that injury to
the brain parenchyma associated with a wide range
Lewy body diseases (DLB and Parkinson disease) of vascular lesions may be a substrate for cognitive
can be neuropathologically stratified into three impairment and even dementia. The types of vas-
groups: brainstem, when Lewy bodies are restricted cular lesions that can contribute to loss of normal
to brainstem structures; transitional, when there cognition include large-territory infarcts leading to
is involvement of limbic structures; and neocorti- massive tissue destruction (multi-infarct demen-
cal, when there is additional involvement of the tia); small infarct(s) localized in strategic areas (e.g.,
neocortex. In the current diagnostic criteria, it is thalamus); diffuse white matter injury, as can been
recommended to systematically assess Alzheimer seen in the setting of poorly managed hypertension
pathology in order to evaluate the probability (high, (a pattern sometimes referred to as Binswanger leu-
intermediate, or low) that Lewy pathology is respon- koencephalopathy), with amyloid angiopathy, or
sible for the cognitive deficit. with diffuse small vessel diseases such as CADASIL
(see Chapter  4). While pure vascular-based cogni-
tive impairment is relatively infrequent, vascular
3.4. Argyrophilic grain disease co-morbidity commonly contributes to the demen-
Lacking a distinctive clinical picture that reliably tia in individuals who also have neurodegenerative
allows for diagnosis, argyrophilic grain disease is diseases, particularly with AD.
largely defined on neuropathological grounds—that
is, by the presence of small, silver-positive inclusions
containing 4R-tau in neurites along with inclusions 3.7. Other causes of dementia
in oligodendrocytes with similar staining character- Dementia can be seen as a component of neurode-
istics (“coiled bodies”). These pathological findings generative diseases that are discussed elsewhere in
in argyrophilic grain disease are not consistently this chapter because the primary burden of the dis-
associated with clinical evidence of cognitive impair- ease process is borne by other functional systems.
ment. Recent studies have suggested that there can Examples that will be encountered in subsequent

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 185


A B

FIGURE 8.14 Dementia with Lewy bodies. (A) Cortical Lewy bodies are immunoreactive for alpha synu-
clein. (B) Cortical Lewy bodies may also be detected by anti-ubiquitin.

sections include some of the movement disorders, “movement disorders” is commonly reserved for
such as the trinucleotide-disorder Huntington dis- those diseases in which dysfunction of the basal gan-
ease, as well as the tauopathy progressive supranu- glia circuitry results in either decreased or increased
clear palsy. Dementia is also a prominent component motor output.
of prion diseases (Chapter  6), bacterial infections The functional organization of the basal ganglia
including syphilis and Whipple disease (Chapter 5), (commonly defined to include the circuitry of the
and viral diseases, such as the HIV-associated neu- striatum, globus pallidus, the subthalamic nucleus,
rocognitive disorder (Chapter  5). Patients with the substantia nigra, and interconnecting white
certain types of storage disorders can develop matter tracts) serves to modulate the planning and
cognitive impairment leading to dementia, such execution of movement through two stereotypi-
as Kufs disease and adult-onset Tay-Sachs disease cal competing pathways. Because of this dynamic
(Chapter 10). balance, loss of neurons that shift the balance can
either allow the residual circuitry to decrease motor
capacity (akinetic movement disorders) or increase
4. MOVEMENT DISORDERS it (hyperkinetic movement disorders).
While numerous brain regions contribute to plan-
ning and execution of motor output, the term
4.1. Akinetic rigid syndromes
These disorders are characterized by the presence of
rigidity, bradykinesia, and tremor—a clinical triad
known as parkinsonism, although not all affected
individuals will manifest all features. The most
common disorder in this group is Parkinson dis-
ease. Other diseases may manifest a similar clinical
picture but show additional features and are desig-
nated, for example, as “Parkinson plus” syndromes,
or as atypical parkinsonism. A critical component of
these movement disorders is related to loss of stria-
tal dopamine, and associated abnormalities of the
nigrostriatal system.

FIGURE 8.15 Dementia with Lewy bodies. Lewy 4 .1 . 1. PARKIN SON DISEASE


neurites may be detected in both demented as well as
non-demented patients with Lewy body disease by The most common of the akinetic movement dis-
ubiquitin immunostaining. orders, Parkinson disease, is a degenerative disease

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mainly seen in older adults. The diagnosis is based characteristic of the disease may extend supraten-
on the presence of the parkinsonian triad (rest- torially to cortical regions, and the disease can be
ing tremor, rigidity, and bradykinesia), character- expressed clinically as a dementia (DLB, see above),
istic progression of the disease, and symptomatic often with the characteristic fluctuations and visual
response to treatment with agents that increase stria- hallucinations.
tal dopamine. In addition to the movement disorder,
other common components of the illness include
4.1.1.1. Gross appearance The brain weight is
autonomic dysfunction, depression or behavioral
ordinarily within normal limits for age in Parkinson
changes, and sleep disturbances. REM sleep behav-
disease; the most striking findings are pallor of the
ioral disorder is a relatively frequent antecedent to
substantia nigra in the midbrain (Fig. 8.16) as well
the onset of symptomatic parkinsonism.
as pallor of the locus coeruleus in the upper pons.
The annual incidence of Parkinson disease ranges
from about 7.0 to 19 per 100,000 and the prevalence
from about 30 to 190 per 100,000; the majority of 4.1.1.2. Microscopic lesions The brain-
cases are sporadic, although there are rare familial stem structures with pallor visualized on mac-
forms. Patients with familial forms may have domi- roscopic examination show neuronal loss and
nant or recessive inheritance patterns. From the astrocytic gliosis, recognized best in the pars com-
study of these familial forms have come important pacta of the substantia nigra (Fig.  8.17) and the
insights into the pathways critical for development coeruleus-subcoeruleus area. Neuromelanin pig-
of Parkinson disease and the nature of the diagnostic ment may be seen in macrophages or free in the neu-
pathologic hallmark of Parkinson disease, the Lewy ropil. Remaining neurons in these nuclei contain
body (the intraneuronal cytoplasmic inclusion Lewy bodies in varying abundance.
body primarily composed of α-synuclein already Other regions may be affected by Lewy body
seen in DLB) (Fig. 8.14A). With the recognition of pathology and may relate to other clinical features
α-synuclein as a marker of neuronal abnormalities in of disease. Changes in the dorsal vagal nucleus are
Parkinson disease, it has become clear that the dis- commonly observed, and patients may manifest
ease involves much of the brainstem and can prog- dysphagia. The nucleus basalis of Meynert and the
ress to involve cortical regions. In fact, it appears amygdaloid body are frequently affected. Lewy bod-
that the changes that mark Parkinson disease begin ies may be seen in the cerebral cortex, and extensive
in the medulla and only gradually progress rostrally pathology has been related to DLB, as discussed
to the brainstem, with the clinical onset of akinetic above. Lewy bodies may also be encountered in the
movement disorders when the substantia nigra neurons of the intermediolateral columns of the
begins to be moderately involved. Lewy body Braak spinal cord, sympathetic and parasympathetic gan-
stages (from 1 to 6) have been devised to describe glia, the enteric nervous system, the cardiac plexus,
this progression. The neuropathological changes the pelvic plexus, and the adrenal medulla—the

A B

FIGURE 8.16 Parkinson disease. Macroscopic appearance: Midbrain showing pallor of the substantia nigra
(A), compared with substantia nigra from an unaffected individual (B). The pallor is the result of loss of neurons
containing neuromelanin.

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 187


for the detection of Lewy bodies and Lewy neuritis,
which can otherwise be inconspicuous.

4.1.1.3 Molecular and cell biology of


Parkinson disease Several familial forms of
Parkinson disease have been documented, and the
genes for some have been characterized. Mutations
in the gene encoding α-synuclein and in the gene
of the leucine-rich repeat kinase 2 (LRRK2) have
been linked to autosomal dominant familial forms
of Parkinson disease. There are also kindreds with
Parkinson disease caused by duplication or trip-
FIGURE 8.17 Photomicrograph of the sub- lication of the α-synuclein locus. Mutations of
stantia nigra showing loss of pigmented neurons the gene of parkin (E3 ubiquitin ligase) and the
and astrocytic gliosis. Pigment can be seen in mitochondrial-associated proteins DJ-1, PINK1,
macrophages (H&E). and ATP13A2 cause autosomal recessive parkinson-
ism; these forms usually present before age 40 and
are sensitive to L-dopa therapy. In these recessive
involvement of these structures can be presumed to forms, Lewy bodies are absent, although neuronal
be the basis of the autonomic dysfunction seen in loss is severe in the substantia nigra.
some patients. The best-characterized genetic risk factor for the
In some affected brain regions, one may observe, development of Parkinson disease is the presence of
in addition to the typical Lewy bodies situated in a mutated allele of the GBA gene, which encodes the
the neuronal perikarya (Fig.  1.13A, B) hyaline aci- enzyme β-glucocerebrosidase and is the recessive locus
dophilic inclusions. The outline and the halo may be for Gaucher disease, a lysosomal storage disorder.
less distinctly defined; they are elongated and are sit- While the underlying mechanism of this relationship
uated in the cell processes (intraneuritic Lewy bodies is not known, these mutations are found in approxi-
or Lewy neurites) (Fig. 1.13C, D). Finally, the corti- mately 10% of cases of sporadic Parkinson disease.
cal (cerebral) Lewy bodies are situated in the peri-
karyon of cortical neurons, may not be spherical, and
are less eosinophilic; they have neither central core 4 .1 . 2. PROGRESSIVE
nor peripheral halo (Fig. 1.13E, F). The presence of S U PRAN UCLEAR  PALSY
α-synuclein within these inclusions (Fig.  8.18) has
PSP, or Steele-Richardson-Olszewski syndrome, is
led to the recommendation that immunohistochem-
clinically characterized by parkinsonism associated
istry against this normal synaptic protein be used
with supranuclear ophthalmoplegia. Additionally,
the parkinsonism is usually without tremor but
with hypertonia, retrocollis (rather than flexion
as in Parkinson disease), and axial rigidity (rather
than greater involvement of the extremities as in
Parkinson disease). Pseudobulbar palsy and cogni-
tive abnormality leading to dementia are common.
The average age of onset is about 64  years, with a
prevalence of about 7 per 100,000. In general, these
individuals obtain only minimal symptomatic ben-
efit from therapeutic approaches to elevate striatal
dopamine, in contrast to patients with Parkinson
disease.

4.1.2.1 Gross appearance The most strik-


FIGURE 8.18 Immunohistochemistry for alpha ing abnormality that can be observed is atrophy
synuclein showing Lewy bodies in a nigral neuron. of the midbrain and pontine tegmentum. There is

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commonly pallor of the substantia nigra and locus seen but are not specific and may be seen in other
coeruleus as in Parkinson disease, but with variable neurodegenerative conditions. Accumulation
atrophy of the globus pallidus. The cerebral cortex of tau protein in oligodendrocytes, which also
is usually spared, although in cases with prominent occurs in PSP but is less specific of it, is known as
cognitive impairment there may also be frontotem- “coiled body.”
poral atrophy.
4.1.2.3. Genetics and cell biology Nearly
all cases of PSP are sporadic, although there are
4.1.2.2. Microscopic lesions The diagnostic
rare cases in which MAPT mutations are pres-
features of PSP are the combination of regional
ent. The aggregates of tau in neurons and glia in
neuronal loss and astrocytic gliosis, with neuronal
PSP are primarily composed of the 4R isoform
and glial accumulation of tau protein, as highlighted
(4Rtau). While MAPT mutations are rare causes
best by immunohistochemistry. There is a high
of PSP, there is a strong risk association for the
lesion burden in basal ganglia (substantia nigra, the
H1 haplotype of the MAPT locus as defined by a
globus pallidus, and the subthalamic nucleus) as
series of genetic markers that are in strong linkage
well as the brainstem (superior colliculus, pretec-
disequilibrium.
tal areas, periaqueductal grey matter, and the mes-
encephalic and pontine reticular formations). In
addition, there can be moderate involvement of the
4.1.3 . CORTICOBASAL DEGENERATION
cerebellar dentate nucleus, locus coeruleus, oculo-
motor nuclei, pontine nuclei, the reticular forma- CBD is a clinicopathological entity in which there is
tion in the medulla, inferior olivary complex, and degeneration of cortical areas and of the basal gan-
the thalamus. glia (including the substantia nigra). It is related to
In these affected regions, the neuronal loss and PSP, with accumulation of 4R tau in neurons and
gliosis is accompanied by tau-containing inclu- glia, although the distinction between the two can
sions in both neurons and glia. Within neurons, tau be made both at the clinical level through distinct
protein forms neurofibrillary tangles, which have a patterns of symptoms and at the neuropathological
characteristic globose appearance (Fig. 8.19A , B). level by the distinct distribution of lesion burden
Tufted astrocytes, considered to be highly char- and lesion character.
acteristic of the disease, develop in affected areas, The disease presents with rigidity, clumsiness,
are usually abundant in the putamen, and are com- stiffness, or jerking of the arm or, less commonly,
monly found in the cerebral cortex, mostly motor a leg. There is early asymmetry in these movement
and premotor areas of the frontal lobe (Fig. 8.20A). abnormalities, and it is common for patients to
The length of their processes contains tau protein develop progressive apraxia and the so-called “alien
and they are often binucleated. Thorn-shaped astro- limb” phenomenon in which a limb moves with-
cytes (Fig. 8.20B) (see Chapter1) are commonly out their voluntary control in association with the

A B

FIGURE 8.19 (A) Neuron containing a globose neurofibrillary tangle (H&E). (B) Neuron containing a glo-
bose neurofibrillary tangle detected by immunostaining for tau protein.

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 189


A B

FIGURE 8.20 Glial pathology in progressive supranuclear palsy. (A) Fairly specific finding of tufted astro-
cytes 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 4.1.3.2. Microscopic lesions The characteristic
them. Difficulty in walking develops due to apraxia features include the combination of neuronal loss,
of leg movement together with pyramidal defi- astrocytic gliosis, and 4R-tau-containing inclusions
cits caused by upper motor neuron involvement. in neurons and glia. In addition, in the cortex it is
Cognitive abnormalities occur in some patients possible to find swollen (“achromatic”) neurons
with aphasia and dementia of frontotemporal type. that have lost their Nissl substance (Fig. 8.21A,
In some patients, the cognitive abnormalities may B). In the substantia nigra, cell loss is associated
even predominate over the movement disorder. The with astrocytic gliosis. Remaining nigral cells show
biochemical and genetic associations of CBD are large globose, pale-staining neurofibrillary tangles
comparable to those of PSP. (Fig. 8.22). Immunostaining for tau protein shows
tangles in neurons as well as immunoreactivity in
4.1.3.1. Gross appearance Cortical atrophy many swollen neurons. Accumulation of tau pro-
is the typical finding, most prominent around the tein in astrocytes forms distinctive structures in gray
Sylvian fissure or with a frontotemporal distribu- matter areas termed astrocytic plaques: tau protein
tion, and often asymmetrical. The substantia nigra accumulates at the end of the astrocytic processes,
shows loss of pigment. There may be atrophy of the while the center of the plaque is devoid of tau immu-
basal ganglia. noreactivity (Fig. 8.23). They are conspicuous in the
cortex and in the putamen.

A 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.

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acquired the others. This clinical aggregation was
further validated by the recognition that the neuro-
pathological 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 predom-
inance of the parkinsonian components (MSA-P) or
of the cerebellar ataxia (MSA-C); it is relatively rare
FIGURE 8.22 Corticobasal degeneration. Nigral to have the autonomic dysfunction be the sole man-
neurons contain pale areas that displace the neu- ifestation of the illness, although some features of
romelanin. These are large globose tangles composed autonomic disturbances are seen in nearly all cases.
of tau protein (H&E).
In addition to the extrapyramidal motor symptoms,
evidence of pyramidal involvement with hyperre-
4.1.4. MULTIPLE SYSTEM flexia is commonly seen. The tempo of progression
ATROPHY (MSA) is not strikingly different across the various clinical
As the term “multiple” implies, MSA is a degen- subtypes, and the disease is fatal in most patients
erative process that crosses functional systems and within a decade of the onset of symptoms.
hence does not fit well into only one of the clini-
cally discussed categories. We made the choice of 4.1.4.1. Gross appearance As would be
presenting this disorder in this sequence because expected from the spectrum of clinical presenta-
of the frequency of parkinsonism and because it tions, there can be a range of gross abnormalities
is, like Parkinson disease, included in the synucle- observed in cases of MSA. The best correlate of
inopathies. Three disorders (the parkinsonian MSA-P is the combination of pallor of the substan-
striatonigral degeneration, the ataxic olivopontocer- tia nigra with atrophy of the putamen, often asso-
ebellar atrophy [OPCA], and the autonomic failure ciated with a gray-green discoloration of the latter
of Shy-Drager syndrome), which were originally structure (Fig. 8.24). When a prominent cerebellar
thought to be distinct, were united after it was rec- component has been present (MSA-C), the cerebel-
ognized that affected individuals often began with lum, basis pontis, and inferior olivary complex are
one symptom complex but eventually gradually generally atrophied (see 5.1.2 and Fig. 8.30).

FIGURE 8.24 Multiple system atrophy.


FIGURE 8.23 Corticobasal degeneration. Macroscopic examination of the fixed brain shows
Astrocytic plaques can be detected in gray matter by shrinkage of basal ganglia and discoloration of the
tau immunostaining, as here, or by Gallyas staining. putamen, which takes on a gray-green discoloration.

Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 191


4.1.4.2. Microscopic lesions Grossly and changes similar to those described in progressive
symptomatically involved brain regions show neu- supranuclear palsy. At microscopic examination,
ronal loss and astrocytic gliosis, and on routine neurofibrillary tangles are found in widespread dis-
stains (H&E, with or without Luxol fast blue) little tribution but particularly affect the substantia nigra,
else is evident. Use of silver stains such as Gallyas the locus coeruleus, and the nuclei of the reticular
(Fig. 8.25A) or Bodian (Fig.  8.25B), or immuno- formation, hypothalamus, and the nucleus basalis of
histochemistry of α-synuclein or of ubiquitin (Fig. Meynert. Affected regions show cell loss with astro-
8.26A, B) will show characteristic glial cytoplasmic cytic gliosis.
inclusions in oligodendroglia. They are widely dis-
tributed through the brain, and appear as crescentic- 4.1.5.2. Pharmacologic/toxic Extrapyramidal
or sickle-shaped structures in glial cells, partially disturbances can be seen in the course of treatment
wrapping the nucleus and extending away from it. with neuroleptics; the anatomical substrate is poorly
NCIs and NIIs may also be seen but are generally defined. Toxic exposure to a byproduct of illicit drug
much less obvious. synthesis, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyr-
idine (MPTP), resulted in a parkinsonian syndrome
with neuronal loss relatively selectively involving the
4. 1. 5. S E CONDARY PA R K I N S O NI A N substantia nigra.
S Y N DROME S
Functional disruption of the basal ganglia circuitry 4.1.5.3. Carbon monoxide poisoning With
and, in particular, of nigrostriatal projections may nonfatal exposure, there can be bilateral necro-
result in the development of a parkinsonian syn- sis of the superomedial part of the pallidum (see
drome. The diagnostic challenge is usually to Chapter  9). Lesions in the substantia nigra are
separate these syndromes from the primary neu- inconstant and usually moderate and involve the
rodegenerative diseases affecting the same brain pars reticulata of the nucleus rather than the dopa-
regions. minergic pars compacta.

4.1.5.1. Postencephalitic parkinsonism Posten- 4.1.5.4. Vascular disease The combination of


cephalitic parkinsonism followed a pandemic of hypertensive cerebrovascular disease involving the
encephalitis lethargica (von Economo disease) basal ganglia, with lacunes, as well as involvement of
between 1915 and 1927 (see Chapter  5). Half of the brainstem and white matter projections essential
the individuals who survived the acute encephalitic for basal ganglia circuitry, can result in parkinsonism.
phase of the illness developed a parkinsonian syn- In these cases, there is usually marked asymmetry
drome after a typical latent period of about 9 years. of symptoms reflecting the anatomical location of
Cases coming to medical attention in recent times discrete lesions, as well as pseudobulbar palsy when
are very rare. Macroscopic examination shows 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).

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A B

FIGURE 8.26 Multiple system atr