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INFECTIONS OF THE

CENTRAL NERVOUS
SYSTEM
FOURTH EDITION

Editors
W. Michael Scheld, MD Christina M. Marra, MD
Bayer-Gerald L. Mandell Professor of Infectious Professor of Neurology
Diseases Adjunct Professor of Medicine (Infectious Diseases)
Professor, Myles H. Thaler Center for AIDS and University of Washington School of Medicine
Human Retrovirus Research Seattle, Washington
Professor of Medicine
Clinical Professor of Neurosurgery
Director, Pfizer Initiative in
International Health
University of Virginia Health System
Charlottesville, Virginia

Richard J. Whitley, MD
Distinguished University Professor
Loeb Scholar in Pediatrics
Professor of Pediatrics, Microbiology, Medicine,
and Neurosurgery
University of Alabama at Birmingham
Birmingham, Alabama

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Library of Congress Cataloging-in-Publication Data


Infections of the central nervous system (Scheld)
Infections of the central nervous system / editors, W. Michael Scheld, Richard J. Whitley,
Christina M. Marra. Fourth edition.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4511-7372-7 (hardback : alk. paper)
ISBN-10: 1-4511-7372-5 (hardback : alk. paper)
I. Scheld, W. Michael, editor of compilation. II. Whitley, Richard J., editor of compilation.
III. Marra, Christina M., editor of compilation. IV. Title.
[DNLM: 1. Central Nervous System Infections. WL 301]
RC359.5
616.8dc23
2014004822

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describe generally accepted practices. However, the authors, editors, and publisher are not
responsible for errors or omissions or for any consequences from application of the informa-
tion in this book and make no warranty, expressed or implied, with respect to the currency,
completeness, or accuracy of the contents of the publication. Application of the information
in a particular situation remains the professional responsibility of the practitioner.
The authors, editors, and publisher have exerted every effort to ensure that drug
selection and dosage set forth in this text are in accordance with current recommendations
and practice at the time of publication. However, in view of ongoing research, changes in
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Some drugs and medical devices presented in the publication have Food and Drug
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responsibility of the health care provider to ascertain the FDA status of each drug or device
planned for use in their clinical practice.
10 9 8 7 6 5 4 3 2 1

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WITH GRATITUDE TO ALL OF OUR MENTORS
AND
TO OUR TRAINEES WHO UNIFORMLY GAVE MORE
THAN THEY RECEIVED

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CONTRIBUTORS

Philipp Agyeman, MD Itzhak Brook, MD, MSc


Research Fellow Professor
Neuroinfection Laboratory, Institute for Infectious Diseases Department of Pediatrics
University of Bern Georgetown University School of Medicine
Attending Physician Attending Physician in Infectious Diseases, Pediatrics
Department of Pediatrics Georgetown University Hospital
University of Bern Washington DC, Washington
Inselspital
Bern, Switzerland Mary T. Caserta, MD
Professor
Kelly J. Baldwin, MD Department of Pediatrics
Clerkship Director University of Rochester Medical Center School of Medicine
Department of Neurology and Dentistry
Temple University, School of Medicine Attending Physician
Philadelphia, Pennsylvania Department of Pediatrics
Associate Golisano Childrens Hospital
Department of Neurology Rochester, New York
Geisinger Medical Center
Danville, Pennsylvania Kevin A. Cassady, MD
Associate Professor
Kyra J. Becker, MD Department of Pediatric Infectious Diseases
Professor University of Alabama at Birmingham
Department of Neurology and Neurological Surgery Birmingham, Alabama
University of Washington School of Medicine
Seattle, Washington Matthias Cavassini
Private-Decent and Senior Lecturer
J. David Beckham, MD Chief of Service, Department Chair
Assistant Professor of Medicine and Neurology Service of Infectious Diseases, Department of Medicine
Departments of Medicine (Infectious Diseases) and University Hospital of Lausanne
Neurology Lausanne, Switzerland
University of Colorado School of Medicine
Aurora, Colorado Maxine Caws, PhD, MSc, BSc
Research Lecturer
Jeana L. Benwill, MD Department of Clinical Sciences
Assistant Professor of Medicine Liverpool School of Tropical Medicine
The University of Texas Health Science Center at Tyler Liverpool, United Kingdom
Tyler, Texas Head of TB Research Programme
Oxford University Clinical Research Unit
Sven Bergstrm, PhD Hospital for Tropical Diseases
Professor Ho Chi Minh City, Vietnam
Department of Molecular Biology
Ume University Won K. Chung, MD
Ume, Sweden Post-doctoral Fellow
Department of Internal Medicine, Division of Infectious
Ari Bitnun, MD, MSc, FRCPC Disease
Associate Professor University of Texas Medical Branch
Department of Pediatrics Galveston, Texas
University of Toronto
Staff Physician David J. Coffey, MD
Department of Pediatrics Associate Professor
The Hospital for Sick Children Department of Neurology
Toronto, Ontario, Canada Geisel School of Medicine at Dartmouth
Lebanon, New Hampshire

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vi Contributors

Jeffrey I. Cohen, MD Carol Glaser, MD


Chief Chief
Laboratory of Infectious Diseases Encephalitis and Special Investigations Section
National Institute of Allergy and Infectious Diseases, Division of Communicable Disease Control
National Institutes of Health California Department of Public Health
Bethesda, Maryland Richmond, California
Associate Clinical Professor
Amanda C. Cohn, MD Department of Pediatrics, Division of Pediatric Infectious
Medical Epidemiologist Diseases
Division of Bacterial Diseases University of California, San Franciso
National Center for Immunizations and Respiratory Diseases, San Francisco, California
Centers for Disease Control and Prevention
Atlanta, Georgia John W. Gnann, Jr., MD
Professor
Moshe Ephros, MD Department of Medicine, Division of Infectious Diseases
Associate Clinical Professor Medical University of South Carolina
Department of Pediatrics Charleston, South Carolina
Faculty of Medicine
Technion-Israel Institute of Technology Denis Grandgirard, PhD
Director Senior Postdoc
Pediatric Infectious Disease Unit Neuroinfection Laboratory
Department of Pediatrics Institute for Infectious Diseases
Carmel Medical Center University of Bern
Haifa, Israel Bern, Switzerland

Jeremy Farrar, FRCP, FRCP(Ed), FMedSci, PhD, OBE Diane E. Griffin, MD, PhD
Director Professor and Alfred and Jill Sommer Chair
Oxford University Clinical Research Unit W. Harry Feinstone Department of Molecular Microbiology
Wellcome Trust Major Overseas Programme and Immunology
Ho Chi Minh City, Vietnam Johns Hopkins Bloomberg School of Public Health
Baltimore, Maryland
Kathleen R. Fink, MD
Assistant Professor Paul D. Griffiths, MD, DSc
Department of Radiology Professor of Virology
University of Washington Centre for Virology
Harborview Medical Center University College London Medical School
Seattle, Washington Royal Free London NHS Foundation Trust
London, United Kingdom
Sven Forner, BA
CJD Clinical Research Team John J. Halperin, MD
University of California, San Francisco Professor
UCSF Memory and Aging Center Departments of Neurology and Medicine
San Francisco, California Icahn School of Medicine at Mount Sinai
New York, New York
Michael D. Geschwind, MD, PhD Chair
Associate Professor Department of Neurosciences
Michael J. Homer Chair in Neurology Overlook Medical Center
University of California, San Francisco Summit, New Jersey
UCSF Memory and Aging Center
San Francisco, California Barry J. Hartman, MD
Clinical Professor of Medicine
Michael Giladi, MD, MSc Department of Medicine, Division of Infectious Diseases
Associate Professor of Medicine Weill Cornell Medical Center
Sackler Faculty of Medicine Attending Physician
Tel Aviv University Department of Medicine
The Infectious Disease Unit and the Bernard Pridan New York Presbyterian Hospital
Laboratory for Molecular Biology of Infectious Diseases New York, New York
Tel Aviv Medical Center
Tel Aviv, Israel Rodrigo Hasbun, MD, MPH
Associate Professor
Stefano Giulieri, MD Department of Medicine, Infectious Diseases
Chief Resident University of Texas Health Science Center
Service of Infectious Diseases, Department of Medicine Attending Physician
University Hospital of Lausanne Department of Medicine
Lausanne, Switzerland Memorial Hermann Hospital
Houston, Texas

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Contributors vii

Dorothee Heemskerk, MSc, MD Matthias Klein, MD


Clinical Research Fellow Attending Physician
Oxford University Clinical Research Unit VN Department of Neurology
University of Oxford University of Munich
Ho Chi Minh City, Vietnam Klinikum Grosshadern
Munich, Germany
David C. Helfgott, MD
Assistant Professor of Medicine Serggio C. Lanata, MD
Internal Medicine Clinical Fellow
Weill Cornell Medical College Department of Neurology
Assistant Attending Physician University of California, San Francisco
Department of Medicine, Division of Infectious Diseases UCSF Memory and Aging Center
New York Presbyterian Hospital San Francisco, California
New York, New York
Stephen L. Leib, MD
Jerzy Hildebrand, MD, PhD Associate Professor
Professor of Neurology Neuroinfection Laboratory, Institute for Infectious Diseases
Department of Medicine University of Bern
Institut Jules Bordet Bern, Switzerland
Universit Libre de Bruxelles Head
Brussels, Belgium Biology Division, Spiez Laboratory
Swiss Federal Office for Civil Protection
Marc Hildebrand, MD, PhD Austrasse
Department of Medicine, Division of Infectious Diseases Spiez, Switzerland
Hpitaux Iris Sud
Brussels, Belgium Matthias Maiwald, MD, PhD
Adjunct Associate Professor
Susan E. Hoover, MD, PhD Department of Microbiology
Associate Professor National University of Singapore
Internal Medicine Consultant in Microbiology
University of South Dakota Sanford School of Medicine Department of Pathology and Laboratory Medicine
Sanford Health KK Womens and Childrens Hospital
Sioux Falls, South Dakota Singapore, Singapore

Jennifer L. Horan, MD, PharmD Carrie P. Marder, MD, PhD


Medical Instructor Acting Instructor
Department of Medicine Department of Radiology
Duke University Medical Center University of Washington
Durham, North Carolina Department of Radiology
University of Washington Medical Center
Alan C. Jackson, MD, FRCPC Seattle, Washington
Professor
Departments of Internal Medicine (Neurology) and Medical James D. Marks, MD, PhD
Microbiology Professor and Vice Chairman
University of Manitoba Department of Anesthesia and Perioperative Care
Head University of California, San Francisco
Section of Neurology, Internal Medicine Chief of Anesthesia
Health Sciences Centre Department of Anesthesia and Perioperative Care
Winnipeg, Canada San Francisco General Hospital
San Francisco, California
David W. Kimberlin, MD
Professor of Pediatrics Christina M. Marra, MD
Department of Pediatrics Professor of Neurology
University of Alabama at Birmingham Adjunct Professor of Medicine (Infectious Diseases)
Birmingham, Alabama University of Washington School of Medicine
Seattle, Washington
Louis V. Kirchhoff, MD, MPH
Professor Matthew McCarthy, MD
Departments of Internal Medicine (Infectious Diseases) and Fellow
Epidemiology Department of Medicine
University of Iowa Health Care Weill Cornell Medical Center
Staff Physician New York, New York
Medical Service
Department of Veterans Affairs Medical Center
Iowa City, Iowa


Deceased

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viii Contributors

Tony M. McGrath, MD Adjanie Patabendige, PhD


Associate Professor NC3Rs David Sainsbury Fellow
Department of Pediatrics, Division of Child Neurology Department of Clinical Infection, Microbiology and
University of Alabama at Birmingham Immunology
Attending Physician Institute of Infection and Global Health
Division of Child Neurology University of Liverpool
Childrens of Alabama Liverpool, United Kingdom
Birmingham, Alabama
John R. Perfect, MD
Thomas O. McPharlin, RPh Professor
Clinical Associate Professor Department of Medicine
University of Washington School of Pharmacy Duke University Medical Center
Clinical Pharmacist Durham, North Carolina
Department of Neurology and Rehabilitation Medicine
Pharmacy William A. Petri, Jr., MD, PhD
Harborview Medical Center Professor and Chief
Seattle, Washington Division of Infectious Diseases
University of Virginia School of Medicine
Nancy E. Messonnier, MD Charlottesville, Virginia
Medical Epidemiologist
Division of Bacterial Diseases Hans-Walter Pfister, MD
National Center for Immunizations and Respiratory Diseases, Senior Consultant
Centers for Disease Control and Prevention Department of Neurology
Atlanta, Georgia University of Munich
Senior Consultant
Reto Antoine Meuli, MD, PhD Department of Neurology
Full Professor Klinikum Grosshadern
Department of Radiology Munich, Germany
University of Lausanne, Faculty of Biology and Medicine
Chief of Service, Department Chair Douglas G. Postels, MD
Department of Radiology Associate Professor
CHUV, University Hospital of Lausanne Department of Neurology
Lausanne, Switzerland Michigan State University
East Lansing, Michigan
Augusto Miravalle, MD
Assistant Professor of Neurology Didier Raoult, MD, PhD
Director, Neurology Residency Training Program Director
University of Colorado Denver School of Medicine URMITE UMR 7278, Facult de Mdecine
Aurora, Colorado Aix-Marseille Universit
Chief
John F. Modlin, MD Fdration de Microbiologie Clinique
Professor of Pediatrics and Medicine Hpital de la Timone
Department of Pediatrics and Medicine Marseille, France
Geisel School of Medicine at Dartmouth
Hanover, New Hampshire David A. Relman, MD
Deputy Director for Research, Polio Thomas C. and Joan M. Merigan Professor
Global Development Departments of Medicine and Microbiology and Immunology
Bill & Melinda Gates Foundation Stanford University School of Medicine
Seattle, Washington Stanford, California
Chief
Jose G. Montoya, MD, FACP, FIDSA Infectious Diseases Section
Professor Veterans Affairs Palo Alto Health Care System
Department of Medicine Palo Alto, California
Stanford University
Attending Physician Susan Richardson, MD, CM
Department of Medicine Professor
Stanford Hospital and Clinics Department of Laboratory Medicine and Pathobiology
Stanford, California University of Toronto
Head
Shannon Moonah, MD, ScM Department of Paediatric Laboratory Medicine, Division of
Clinical and Research Fellow Microbiology
Division of Infectious Diseases The Hospital for Sick Children
University of Virginia School of Medicine Toronto, Ontario, Canada
Charlottesville, Virginia

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Contributors ix

Jos R. Romero, MD Khoi Duc Than, MD


Professor Chief Resident
Department of Pediatrics Department of Neurosurgery
University of Arkansas for Medical Sciences University of Michigan
Director Ann Arbor, Michigan
Section of Infectious Diseases
Arkansas Childrens Hospital Allan R. Tunkel, MD, PhD
Little Rock, Arkansas Professor of Medicine
Associate Dean for Medical Education
Karen L. Roos, MD Warren Alpert Medical School of Brown University
John and Nancy Nelson Professor of Neurology Providence, Rhode Island
Professor of Neurological Surgery
Indiana University Health Neuroscience Center Kenneth L. Tyler, MD
Indianapolis, Indiana Reuler-Lewin Family Professor and Chair of Neurology
Professor of Medicine & Microbiology
Jeffrey P. Ross, MD Departments of Neurology, Medicine, and Microbiology
Assistant Clinical Professor University of Colorado Denver School of Medicine
Medicine Chair
University of New Mexico School of Medicine Department of Neurology
Albuquerque, New Mexico University of Colorado Hospital
Aurora, Colorado
Oren Sagher, MD
William F. Chandler Collegiate Professor Diederik van de Beek, MD, PhD
Department of Neurosurgery Professor
University of Michigan Department of Neurology
Neurosurgery Faculty Academic Medical Center
Department of Neurosurgery University of Amsterdam
University of Michigan Health System Amsterdam, The Netherlands
Ann Arbor, Michigan
Arun Venkatesan, MD, PhD
W. Michael Scheld, MD Assistant Professor
Bayer-Gerald L. Mandell Professor of Infectious Diseases Department of Neurology
Professor, Myles H. Thaler Center for AIDS and Human Johns Hopkins University School of Medicine
Retrovirus Research Director
Professor of Medicine Encephalitis Center
Clinical Professor of Neurosurgery Johns Hopkins Hospital
Director, Pfizer Initiative in International Health Baltimore, Maryland
University of Virginia Health System
Charlottesville, Virginia Richard J. Wallace, Jr.
Chairman
Jose A. Serpa, MD, MS Department of Microbiology
Assistant Professor Chief
Department of Medicine Infectious Disease Section
Baylor College of Medicine The University of Texas Health Science Center at Tyler
Attending Physician Tyler, Texas
Medicine
Ben Taub Hospital Thomas J. Walsh, MD, PhD (hon), FCCP, FAAM, FIDSA
Houston, Texas Director
Transplantation-Oncology Infectious Diseases Program
Tom Solomon, MD Chief
Director Infectious Diseases Translational Research Laboratory
Institute of Infection and Global Health Professor of Medicine, Pediatrics, and Microbiology &
University of Liverpool Immunology
Honorary Consultant Neurologist Henry Schueler Foundation Scholar
Department of Neurology Weill Cornell Medical Center and New York Presbyterian
Walton Centre NHS Foundation Trust Hospital
Liverpool, United Kingdom New York, New York

Terrie E. Taylor, DO Anthony C. Wang, MD


University Distinguished Professor Department of Neurosurgery
Osteopathic Medical Specialties University of Michigan
Michigan State University College of Osteopathic Medicine House Officer
East Lansing, Michigan Department of Neurosurgery
Scientific Director University of Michigan Health System
Blantyre Malaria Project Ann Arbor, Michigan
University of Malawi College of Medicine
Blantyre, Malawi

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x Contributors

David F. Welch, PhD, D(ABMM) Joseph R. Zunt, MD, MPH


Medical Microbiologist Professor
Department of Pathology Departments of Neurology, Global Health, Medicine
Medical City (Infectious Diseases), Epidemiology
Dallas, Texas University of Washington
Attending Neurologist
A. Clinton White, Jr., MD Department of Neurology
Paul R. Stalnaker Distinguished Professor and Director Harborview Medical Center
Infectious Disease Division, Department of Internal Medicine Seattle, Washington
University of Texas Medical Branch
Galveston, Texas John Zurasky, MD
Neurocritical Care Medical Director
Richard J. Whitley, MD Department of Neurology
Distinguished University Professor Chair of Neurology
Loeb Scholar in Pediatrics Providence Health and Services Oregon
Professor of Pediatrics, Microbiology, Medicine, and Portland, Oregon
Neurosurgery
University of Alabama at Birmingham
Birmingham, Alabama

Gary P. Wormser, MD
Professor of Medicine
Departments of Microbiology and Immunology and
Pharmacology
New York Medical College
Chief
Division of Infectious Diseases
Westchester Medical Center
Valhalla, New York

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PREFACE

The first edition of Infections of the Central Nervous System completely with essentially the same team of authors (e.g.,
was published in 1991, a comprehensive treatise addressing Chapter 23 on the Pathogenesis and Pathophysiology of
all aspects of central nervous system (CNS) infections for Bacterial Infections). We have added one new chapter, on
advanced readers. In its preface, we clearly stated our goal: to acute encephalitis, by Glaser and Venkatesan. A discussion of
develop the gold standard reference text using the best infor- the diagnostic approach to the acute encephalitis syndrome
mation from the best authors with the best format. Judging was lacking in the last edition as well as any mention of some
from the reviews that followed publication, and from feed- noninfectious entities (e.g., antiNMDA receptor encephalitis)
back that we received from colleagues, we believe that the first literally unknown at the time. Dr. Glaser headed the California
edition succeeded in meeting our objectives. Encephalitis Project for much of the last decade, an effort
The second edition of Infections of the Central Nervous which has contributed substantially to our current knowledge
System was published in 1997 with identical goals and objec- of encephalitis.
tives. The same format was followed, but the 37 chapters of As with prior editions, we chose contributors with clinical
the first edition were expanded to 51 chapters. Reviews and experience as well as basic and/or clinical investigative inter-
comments were again positive. The third edition, of 50 chap- ests in their topic. Although many of the primary authors of
ters, was published in 2004, with a similar positive reception the chapters of the third edition have been retained, fully 21
from readers. A great deal of new information has accumu- of the 51 chapters of this edition employ a new author team
lated in the past decade, and we wanted to further improve (11 chapters have completely new author teams). In choosing
the book in other ways: hence the fourth edition. With this these new authors, we attempted to maintain the excellence of
explosion of new knowledge, the text has changed dramati- the prior editions while emphasizing cutting edge science and
cally, but we have retained the same editorial team. In ad- a more international perspective. This is an outstanding group
dition, we have kept the same basic format: approximately overall drawn from the disciplines of medicine, pediatrics,
50 chapters divided into 10 sections. infectious diseases, neurology, neurosurgery, neurointensive
As for previous editions, the first three chapters of the book care, neuroradiology, virology, epidemiology, parasitology,
cover the approach to diagnosis of CNS infections, including vaccines and prevention, and the basic neurosciences. Tables,
detailed discussion of diagnostic tests. The chapters that fol- illustrations, and photographs have again been used liberally.
low provide an in-depth discussion of individual infectious In many chapters, more than 50% of the references have been
agents and the CNS diseases that they produce in humans, published since 2012.
including differential diagnosis, clinical symptoms and find- We plan to further develop and refine the book through
ings, abnormalities on laboratory and imaging studies, treat- future editions. We will continue to provide a comprehensive
ment, and prevention. readable resource for all physicians who deal with infections
Although the number of chapters is approximately the of the CNS. We welcome your comments.
same as the third edition (51 versus 50), several other changes
are noteworthy. Every chapter has been extensively revised
and updated appropriately, with cited references through W. Michael Scheld, MD
early 2014. Some, reflecting a huge amount of new infor- Richard J. Whitley, MD
mation accumulated in the past decade, have been rewritten Christina M. Marra, MD

xi

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ACKNOWLEDGMENTS

We thank everyone who has helped us in the preparation of We are particularly grateful to our assistants, Lisa Cook and
this large book. Most importantly, we thank all of the authors Dunia Ritchey. The editorial staff at Lippincott Williams &
for their outstanding contributions, especially those who have WilkinsJulie Goolsby, acquisitions editor, and Kristina
replaced prior author teams. As editors, we were privileged Oberle, development editordeserve our gratitude for ensur-
to see their work first; as students of CNS infections, we ing completion of the project. Finally, we thank our families
admire their special insights and expertise. Numerous other for their tolerance and support during interminable hours
colleagues provided helpful discussion, advice, and criticism. required to bring this undertaking to closure.

xiii

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PREFACE TO THE FIRST EDITION

From the brain, and from the brain only, arise our pleasures, joys, sequelae, elegantly described by Hippocrates above, may de-
laughter and jests, as well as sorrows, pains, griefs and tears.... It is prive survivors of hearing, intellect, or function, demeaning
the same thing which makes us mad or delirious, inspires us with the quality of human life and burdening health resources and
dread or fear, whether by night or by day, brings sleeplessness, social services.
inopportune mistakes, aimless anxieties, absent-mindedness, and
acts that are contrary to habit. These things that we suffer all come
The distinctive nature and natural history of CNS infections
from the brain, when it is not healthy, but becomes abnormally set them somewhat apart from the mainstream of infectious
hot, cold, moist or dry. diseases. The scope of todays knowledge of these infections
can no longer be presented adequately within the confines of
Hippocrates, The Sacred Disease, Section XVII a subsection in a general textbook. Indeed, the understanding
and management of CNS infections is evolving toward a sub-
Every physician, almost, hath his favourite disease, to which he specialty in its own right. For these reasons, a new major text
ascribes all the victories obtained over human nature. The gout, seems justifiedhence this book, devoted to a comprehensive
the rheumatism, the stone, the gravel, and the consumption have
coverage of human CNS infections.
all their several patrons in the faculty; and none more than the
nervous fever, or the fever on the spirits. The work is a comprehensive treatise for the advanced
reader on all aspects of CNS infections. The book occupies a
Henry Fielding, Tom Jones, Book II, Chapter 9 central niche between large general texts on pediatrics, medi-
cine, neurology, neurosurgery, and infectious diseases on the
I hasten to give you a sketch of the spotted fever in this place. It one hand, and specialized single-subject treatises on the other.
made its first appearance about the beginning of January last: but We have assembled an outstanding group of contributors,
the instances were few and distant from each other, until last week. drawn from the ranks of internal medicine, pediatrics, neurol-
Although it had proved fatal in most instances, seven only had died
ogy, neurosurgery, infectious diseases, epidemiology, virology,
belonging to this town, previous to the 25th of February. Since that
time the disorder has come upon us like a flood of mighty waters. neuroradiology, and the basic neurosciences.
We have buried eight persons within the last eight days. About After a brief introduction that emphasizes the syndrome-
twelve or fifteen new cases appeared on Thursday last; many of oriented clinical approach to the patient with a CNS syndrome
them very sudden and violent. This was the most melancholy and and fever, the book is divided into parts based on microorgan-
alarming day ever witnessed in this place. Seven or eight physicians isms. The major CNS pathogens (viruses, bacteria, fungi, and
were continually engaged in the neighborhood north of the meet- protozoa) receive the most attention, although rarer patho-
ing house, and I believe not one half hour passed in the forenoon gens such as mycoplasmas, slow viruses, and helminths are
without presenting a new case. Pale fear and extreme anxiety were also covered in depth. In keeping with our philosophy that
visible in every countenance....
advances in diagnosis, therapy, prognosis, and prevention
Reverend Festus Foster of Petersham, Massachusetts require better understanding of the pathogenesis and patho-
in a letter to the editor of The Worchester Spy, 6 March 1810 physiology of these disorders, an introductory chapter on
these subjects is included in each of the major sections of the
These vignettes concerning central nervous system (CNS) book. Within each section a syndromic approach has been
infections come down to us over a span of 25 centuries. maintained whenever possible, but in many instances we felt
The Reverend Fosters graphic description of an outbreak of that specific diseases required separate coveragefor example,
meningococcemia and meningococcal meningitis in the late tetanus, neurosyphilis, and Lyme disease. In some sections we
winter of 1810 makes it easy to understand why these infec- have separated processes that primarily present as meningitis
tions engendered fear among physicians and lay persons alike. or meningoencephalitis from those that usually present as
Today, even with the comforts of vastly better knowledge and focal CNS lesions. The book concludes with discussions on
treatments, CNS infections continue to pose serious problems two major diagnostic modalities: (i) evaluation of the cere-
in health care. Some CNS infections are common, occurring brospinal fluid and (ii) neurodiagnostic imaging by computed
either as sporadic cases or in epidemics. For example, major tomography and magnetic resonance imaging.
outbreaks of meningococcal disease have occurred in Africa In choosing the contributors, we have sought individuals
and Asia during the past few years. Furthermore, despite with clinical experience as well as with active basic and/or
the introduction of new antimicrobial agents and diagnostic clinical investigative interests in their topic. We asked them to
techniques, the mortality associated with some infections of take a comprehensive approach, ranging from recent advances
the central nervous system remains high, particularly in tu- in molecular pathogenesis to the clinical manifestations,
berculosis, pneumococcal, and gram-negative aerobic bacil- therapy, and prevention of CNS infections. We also estab-
lary meningitis; rabies; tetanus; cryptococcal meningitis in lished certain other ground rules. To gain a measure of unity
patients with acquired immunodeficiency syndrome (AIDS); among the chapters, each contributor was asked to write
and Jakob-Creutzfeldt disease. The morbidity associated under common subheadings: history of the syndrome, epide-
with CNS infections may be even more important than the miology, etiology, pathogenesis and pathology, clinical mani-
death rate, especially in developing countries. Neurologic festations, approach to diagnosis, therapy, and prevention.

xv

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xvi Preface to the First Edition

We asked authors to provide an extensive but not exhaus- format. Inevitably, the size and complexity of the field means
tive bibliography, emphasizing classical papers and recent that we will fall short in some areas. Recognizing this, we hope
(19851991) references while limiting each chapter total to to develop and improve the book through future editions. Our
350 citations or fewer. We strongly encouraged the liberal use ambition will remain the same: to present the best available
of tables, drawings, and photographs. Although a degree of comprehensive resource and reference text for all who deal
overlap between chapters is inevitable (and sometimes even with infections of the central nervous system.
desirable) in a multiauthored volume, we have attempted to
minimize redundancies as much as possible.
From its inception 3 years ago, we intended that this should W. Michael Scheld
be a gold standard reference text. We set out to bring Richard J. Whitley
together the best information from the best authors in the best David T. Durack

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CONTENTS

Contributors v
Preface xi
Acknowledgments xiii
Preface to the First Edition xv

PART I APPROACH TO THE PATIENT AND DIAGNOSTIC EVALUATION

Chapter 1 Introduction: Approach to the Patient with


Central Nervous System Infection 1
Christina M. Marra, Richard J. Whitley, and W. Michael Scheld

Chapter 2 Cerebrospinal Fluid in Central Nervous System Infections 4


Rodrigo Hasbun

Chapter 3 Imaging of Intracranial Infections 24


Carrie P. Marder and Kathleen R. Fink

PART II VIRAL INFECTIONS AND RELATED DISORDERS

Chapter 4 Pathogenesis and Pathophysiology of


Viral Infections of the Central Nervous System 49
Kevin A. Cassady and Richard J. Whitley

Chapter 5 Viral Meningitis and Aseptic Meningitis Syndrome 65


Jos R. Romero

Chapter 6 Encephalitis 84
Carol Glaser and Arun Venkatesan

Chapter 7 Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis Syndrome 112


John F. Modlin and David J. Coffey

Chapter 8 Measles and Rubella 125


Diane E. Griffin

Chapter 9 Herpes Simplex Virus 137


Richard J. Whitley

Chapter 10 Neurologic Manifestations of Varicella and Herpes Zoster 157


John W. Gnann, Jr. and Richard J. Whitley

Chapter 11 Cytomegalovirus 168


Paul D. Griffiths

xvii

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xviii Contents

Chapter 12 Epstein-Barr Virus 183


Susan E. Hoover, Jeffrey P. Ross, and Jeffrey I. Cohen

Chapter 13 Human Herpesvirus-6 191


Mary T. Caserta

Chapter 14 B Virus 204


Richard J. Whitley

Chapter 15 Arthropod-Borne Viral Encephalitides 210


Tom Solomon, Adjanie Patabendige, and Richard J. Whitley

Chapter 16 Meningitis and Encephalitis Caused by Mumps Virus 239


John W. Gnann, Jr.

Chapter 17 Rabies 251


Alan C. Jackson

Chapter 18 Human Prion Diseases 261


Serggio C. Lanata, Sven Forner, and Michael D. Geschwind

Chapter 19 Human Immunodeficiency Virus 286


Christina M. Marra

Chapter 20 Guillain-Barr Syndrome 299


Tony M. McGrath

Chapter 21 Acute Viral Myelitis 315


J. David Beckham and Kenneth L. Tyler

Chapter 22 Postinfectious Encephalomyelitis 331


Karen L. Roos and Augusto Miravalle

PART III BACTERIAL AND MYCOPLASMAL INFECTIONS

Chapter 23 Pathogenesis and Pathophysiology of Bacterial Infections 341


Philipp Agyeman, Denis Grandgirard, and Stephen L. Leib

Chapter 24 Acute Bacterial Meningitis 365


Karen L. Roos, Allan R. Tunkel, Diederik van de Beek, and W. Michael Scheld

Chapter 25 Mycoplasmal and Ureaplasmal Infections 420


Ari Bitnun and Susan Richardson

Chapter 26 Bartonella Infections, Including Cat-Scratch Disease 434


Michael Giladi, Moshe Ephros, and David F. Welch

Chapter 27 Rickettsioses, Anaplasmoses, and Q Fever 444


Didier Raoult

Chapter 28 Whipples Disease 461


Matthias Maiwald and David A. Relman

Chapter 29 Tuberculous Meningitis 474


Dorothee Heemskerk, Jeremy Farrar, and Maxine Caws

Chapter 30 Infections Due to Nontuberculous Mycobacteria 501


Jeana L. Benwill and Richard J. Wallace, Jr.

Chapter 31 Brain Abscess 522


Matthias Klein, Hans-Walter Pfister, Allan R. Tunkel, and W. Michael Scheld

Chapter 32 Epidural Abscess 550


Hans-Walter Pfister, Matthias Klein, Allan R. Tunkel, and W. Michael Scheld

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Contents xix

Chapter 33 Subdural Empyema and Suppurative Intracranial Phlebitis 566


Barry J. Hartman and David C. Helfgott

Chapter 34 Complications of Infective Endocarditis 579


Stefano Giulieri, Reto Antoine Meuli, and Matthias Cavassini

Chapter 35 Iatrogenic Infections of the Central Nervous System 608


Kelly J. Baldwin and Joseph R. Zunt

PART IV CENTRAL NERVOUS SYSTEM SYNDROMES MEDIATED BY BACTERIAL TOXINS

Chapter 36 Botulism 621


James D. Marks

Chapter 37 Tetanus 634


Itzhak Brook

PART V SPIROCHETAL INFECTIONS

Chapter 38 Neurosyphilis 659


Christina M. Marra

Chapter 39 Neuroborreliosis: Nervous System Involvement with Borrelia Species 674


John J. Halperin, Sven Bergstrm, and Gary P. Wormser

PART VI FUNGAL INFECTIONS

Chapter 40 Fungal Meningitis 687


Jennifer L. Horan and John R. Perfect

Chapter 41 Space-Occupying Fungal Lesions 711


Matthew McCarthy and Thomas J. Walsh

PART VII PROTOZOAL AND HELMINTHIC INFECTIONS

Chapter 42 Cerebral Malaria 729


Douglas G. Postels and Terrie E. Taylor

Chapter 43 Toxoplasma gondii and Toxoplasmosis 745


Jose G. Montoya

Chapter 44 Trypanosomiasis 756


Louis V. Kirchhoff

Chapter 45 Free-Living and Parasitic Amebic Infections 770


Shannon Moonah and William A. Petri, Jr.

Chapter 46 Helminthic Infections 776


Jose A. Serpa, Won K. Chung, and A. Clinton White, Jr.

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xx Contents

PART VIII CHRONIC MENINGITIS AND MENINGITIS OF NONINFECTIVE OR


UNCERTAIN ETIOLOGY

Chapter 47 Chronic Meningitis Syndrome and Meningitis of 805


Noninfective or Uncertain Etiology
Jerzy Hildebrand and Marc Hildebrand

PART IX NEUROSURGICAL MANAGEMENT

Chapter 48 Surgical Management of Central Nervous System Infections 819


Anthony C. Wang, Khoi Duc Than, and Oren Sagher

Chapter 49 Critical Care of Central Nervous System Infections 849


John Zurasky, Thomas O. McPharlin, and Kyra J. Becker

PART X PREVENTION

Chapter 50 Vaccines for Viral Diseases with Significant


Central Nervous System Manifestations 859
David W. Kimberlin

Chapter 51 Vaccines Against Bacterial Meningitis 876


Amanda C. Cohn and Nancy E. Messonnier

Index 891

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PART I APPROACH TO THE PATIENT AND
DIAGNOSTIC EVALUATION
CHAPTER 1 INTRODUCTION: APPROACH TO
THE PATIENT WITH CENTRAL NERVOUS SYSTEM
INFECTION
CHRISTINA M. MARRA, RICHARD J. WHITLEY, AND W. MICHAEL SCHELD

Infections of the central nervous system (CNS) are notable of brain or spinal cord herniation after lumbar puncture.
for their diversity. They range from common to rare, acute to Such findings mandate neuroimaging before lumbar puncture.
chronic, and benign to fatal. Although some are self-limited Identification of concomitant pneumonia, diarrhea, and skin
or are easily cured with modern treatment, others are relent- or bone lesions may offer clues to the etiology of infection.
lessly progressive despite treatment or have no known treat- Most importantly, findings on neurologic examination allow
ment. For the many CNS infections that are treatable, prompt for identification of the most likely site or sites of infection
diagnosis and aggressive management afford the best chance among cerebrospinal fluid (CSF) space, brain, or spinal cord
of recovery without sequelae. and allow for a syndrome recognition approach to diagno-
The clinical hallmarks of CNS infection are fever, head- sis, as described below.
ache, and alteration of mental status. Focal neurologic signs
may also be evident. Nonetheless, these four symptoms and
signs are nonspecific and can also be seen in noninfectious Acute Meningitis Syndrome
CNS syndromes. To narrow the differential diagnosis, other
characteristics must be evaluated. Among these, risk factors The dominant features of the acute meningitis syndrome are
for CNS infections are particularly helpful. Physical exami- acute onset over a few hours to a few days of fever, headache,
nation may also yield information that provides clues to the photophobia, stiff neck, and altered mental status. The latter
etiology of a given infection. An approach to the diagnosis of may range from simple irritability to confusion, obtundation,
CNS infections is shown in Figure 1.1. or coma. Vomiting may occur, especially in young children. In
many cases, there is no warning, but an acute upper respira-
tory tract infection may precede the onset of meningitis by
RISK FACTORS FOR CENTRAL a few days. The two leading causes of acute meningitis are
bacteria and viruses. The differential diagnosis includes nonin-
NERVOUS SYSTEM INFECTIONS fectious conditions, such as systemic lupus erythematosus and
Behet syndrome, or rare chemical meningitis caused by non-
Many infections of the CNS are geographically distributed or
steroidal antiinflammatory drugs.
occur seasonally. Therefore, a thorough travel history and con-
sideration of the date of onset of illness can provide clues to the
etiology. For example, Lyme disease is endemic in the northeast-
ern United States but uncommon in the southwestern states. Subacute or Chronic Meningitis Syndrome
Similarly, transmission of arborviral encephalitides requires
In contrast to acute meningitis, subacute and chronic men-
the presence of an insect vector, and thus these illnesses most
ingitis syndromes run their course over weeks, months, or
commonly occur in summer and fall. Certain environments
years. Because symptoms and signs may fluctuate, subacute or
facilitate acquisition and transmission of CNS infections, as ex-
chronic meningitides may be confused with the syndrome of
emplified by outbreaks of meningococcal infection in military
recurrent acute meningitis. Although in subacute and chronic
recruits and college students. Concomitant illnesses such as
meningitis the clinical findings of fever, headache, stiff neck,
HIV infection or diabetes, alcoholism, receipt of immunosup-
and altered mental status may resemble those of acute menin-
pressant medications, or cancer chemotherapy all predispose to
gitis, the time course is quite different. Onset is usually grad-
specific CNS infections. Similarly, receipt of prophylactic thera-
ual, often without any evident predisposing condition. Fever,
pies protects against individual CNS infections. For example,
though often present, tends to be lower and less hectic than in
primary prophylaxis against Pneumocystis jiroveci pneumonia
acute meningitis. The patient with chronic meningitis is likely
with trimethoprim-sulfamethoxazole in HIV-infected individu-
to be lethargic and generally debilitated, in addition to having
als decreases the risk of CNS toxoplasmosis.
symptoms referable to the CNS. Focal neurologic findings are
more common than in acute meningitis, although less common
than in the space-occupying syndromes.
CLUES ON PHYSICAL The differential diagnosis for subacute and chronic men-
EXAMINATION ingitis is extensive. The most likely infectious causes are
tuberculosis; fungal infections including cryptococcosis, coc-
Physical examination in the setting of suspected CNS infec- cidioidomycosis, and histoplasmosis; and spirochetal infections
tion has three purposes: (a) to identify contraindications to including syphilis and Lyme disease. Important noninfectious
lumbar puncture, (b) to identify concomitant sites of infec- conditions include sarcoidosis, systemic lupus erythematosus,
tion or pathology that provide clues to the infectious etiology, systemic or primary CNS vasculitides, and neoplastic menin-
and (c) to define the site of CNS infection. Depressed level gitis. Establishing a specific diagnosis is challenging. Of the
of consciousness, focal neurologic abnormalities, or seizures important treatable conditions, cryptococcosis and syphilis
may indicate a structural CNS abnormality that poses a risk usually can be diagnosed or excluded quickly on the basis of

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2 Part I: Approach to the Patient and Diagnostic Evaluation

Assess Risks for Infection


Exposures
Travel
Environment (daycare, military)
Season
Concomitant illnesses
CMI dysfunction (HIV, organ transplant)
Neutropenia (cancer chemotherapy)
Diabetes
Alcoholism
Prophylactic agents

Perform Physical Examination


Assess safety of lumbar puncture
Identity concomitant illness or pathology
Pneumonia
Diarrhea
Skin or bone lesions

Define Probable Site of Infection Neuroimaging


CSF
Acute meningitis
Subacute or chronic meningitis
Recurrent meningitis
Brain
Acute encephalitis
Chronic encephalitis
Space-occupying lesions
Toxin-mediated syndromes
Encephalopathy with systemic infections
Postinfectious syndromes
Spinal cord
Acute encephalomyelitis
Chronic encephalomyelitis
Space-occupying lesions
Toxin-mediated syndromes
Postinfectious syndromes

Laboratory Evaluation
Pathogen-specific CSF Evaluation
Pathogen nonspecific

FIGURE 1.1 Approach to the diagnosis of CNS infections. CMI, cell mediated immunity.

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Chapter 1: Introduction: Approach to the Patient with Central Nervous System Infection 3

serology or antigen detection. However, tuberculous meningi- as shooting sensations or electric shocks; third, motor
tis is more difficult to diagnose or exclude, and patients with weakness followed by sensory changes with bowel or bladder
suspected tuberculous meningitis should be treated empirically dysfunction; and fourth, paralysis, often accompanied by less-
while evaluation continues. The decision whether and when to ening in pain. The rate of progression from one stage to the
obtain a meningeal biopsy is complex and depends on many next is unpredictable. Because the incidence and severity of
factors, including the unfortunate fact that in practice even neurologic sequelae depend on the stage of the disease and
this invasive gold standard test often does not yield a defini- the degree of neural damage sustained before intervention,
tive diagnosis. this syndrome presents an emergency that requires immediate
diagnosis and treatment.

Acute Encephalitis Syndrome


Toxin-Mediated Syndromes
The acute encephalitis syndrome is characterized by inflam-
mation of the cerebral cortex and is most commonly caused Microbial toxins mediate several distinctive neurologic syn-
by viruses. It shares many features with the acute meningitis dromes. The leading examples are tetanus and botulism.
syndrome. Indeed, the two conditions often coexist as me- Toxin-mediated conditions are the least likely to show the
ningoencephalitis. Acute encephalitis may be either diffuse usual manifestations of CNS infection, including fever, head-
or focal. Focal encephalitis reflects tropism of some viruses ache, disturbance of consciousness, and focal neurologic signs.
for specific locations in the CNS, such as temporal lobe infec- For example, botulism is characterized by absence of fever and
tion by herpes simplex virus type 1 (HSV-1), or the anterior normal consciousness in most patients.
horn cells in flavivirus infections, such as West Nile. Nonviral
organisms that may produce the acute encephalitis syndrome
include Rickettsia, Mycoplasma, and Bartonella species Encephalopathy with Systemic Infection
that may cause encephalitis as one component of systemic
infection. Diverse conditions, including infective endocardi- Many systemic infections involve the CNS, for example, rick-
tis, Whipple disease, and recrudescent toxoplasmosis in the ettsial diseases, infective endocarditis, typhoid fever, malaria,
immunocompromised host may cause diffuse or focal acute and Whipple disease. Usually, the systemic manifestations of
encephalitis. the disease dominate the clinical picture, but sometimes the
CNS findings are prominent. In a few cases, CNS symptoms
are the only features. Because this is such a large and varied
Chronic Encephalitis Syndrome group of diseases, the syndromic approach to diagnosis is less
effective. In the setting of an undiagnosed CNS infectious syn-
The chronic encephalitis syndrome shares many features drome, an important principle is to consider systemic infection
with the acute encephalitis syndrome. However, the onset is as a possible underlying cause.
more gradual and the course is less hectic. The clinical find-
ings may be less dramatic or less severe. The patient with
chronic encephalitis is likely to be generally debilitated rather Postinfectious Syndromes
than acutely ill. Chronic encephalitis evolves over weeks to
months or years and relapses or recrudescences may occur. Several important CNS syndromes can develop following mi-
Complications such as pressure sores, contractures, or demen- crobial infections. The usual sequence begins with a common,
tia may ensue in the course of disease. often rather trivial, viral infection that may go unnoticed.
A postinfectious neurologic syndrome develops. Rarely, these
syndromes follow routine vaccinations. Examples include
Space-Occupying Lesion Syndrome postinfectious encephalitis, postinfectious encephalomyelitis,
and transverse myelitis. These reactions are presumably medi-
Patients with space-occupying brain lesions have focal neuro- ated by an immunologic response to the etiologic microbe or to
logic abnormalities referable to the location of the lesion or antigens revealed as a result of the initial infection. Although
lesions. These include cognitive abnormalities, weakness, sen- rare, these syndromes can be severe or fatal.
sory changes, and visual loss. Clinical manifestations, such as
headache, nausea, or vomiting, often begin intermittently, but
they progress steadily to a crisis at about the time the patient is CONCLUSION
admitted to the hospital. This crisis may consist of (a) a focal
or generalized seizure or (b) onset of obtundation progressing A systematic approach to the patient with a suspected CNS
to coma. infection can be undertaken. This includes assessment of risks
When a space-occupying lesion occurs in the extramedul- and a careful physical examination to assess safety of lumbar
lary space in the spinal canal, a distinctive set of manifestations puncture, identify non-CNS sites of infection, and define the
may develop in a typical sequence: first, localized back pain, site of CNS infection. A consideration of the different CNS
often severe; second, nerve root pain with associated altera- infection syndromes as outlined above can then be used to
tion in reflexes and sometimes paresthesias, often described promptly establish a diagnosis and implement therapy.

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CHAPTER 2 CEREBROSPINAL FLUID IN
CENTRAL NERVOUS SYSTEM INFECTIONS
RODRIGO HASBUN

Infections within the central nervous system (CNS) frequently, The fourth ventricle drains into the subarachnoid space
but not always, produce changes in cerebrospinal fluid (CSF). through three small openings, the foramina of Luschka and the
The changes produced may provide invaluable information foramen of Magendie. The foramina of Luschka are located in
about the nature of the infectious process and, in many cases, the lateral recesses of the fourth ventricle and are absent in up
may permit specific identification of the offending organism. to 20% of the population. The foramen of Magendie is located
Despite the great diagnostic value of CSF analysis, however, in the midline and, in most persons, represents the major com-
injudicious attempts to obtain CSF (as in the setting of in- munication between the fourth ventricle and the subarachnoid
creased intracranial pressure) can sometimes cause brain her- space. As is discussed later, these narrow openings are impor-
niation or death, and casual handling of the CSF obtained may tant in CNS infections because they represent the sites at which
render the analysis useless. obstruction of CSF flow may most easily occur.
This chapter is divided into three parts. The first part re-
views the anatomy of the CSF spaces, the physiology of CSF
production and reabsorption, and the effect of infection on
CSF physiology and composition. The second part discusses
The Meninges and Subarachnoid Space
methods of CSF analysis in CNS infections, and the third part The brain and spinal cord are surrounded by three layers of
summarizes the CSF analysis in specific CNS infections. meninges (2). The outermost layer of the meninges is a tough
fibrous membrane, the dura mater. Within the skull, the dura
forms the inner layer of the cranial periosteum and is tightly
ANATOMY AND PHYSIOLOGY adherent to bone. Below the foramen magnum, the dura and
OF THE CEREBROSPINAL FLUID periosteum diverge and are separated by a fat-filled epidural
space. The middle layer of meninges, the arachnoid, is joined
COMPARTMENTS to the dura by a specialized layer of fibroblasts, the dural bor-
der cell layer. The cells of this inner dural border are devoid of
The CSF is contained within two connecting compartments, the collagen and have few cellular junctions, providing a cleavage
cerebral ventricles and the subarachnoid space (1). Infectious plane in which infection may develop and rapidly spread. The
organisms may affect both compartments, and analysis of CSF arachnoid covers the brain and spinal cord loosely and extends
from both may reflect changes produced by infectious or para- outward along the course of cranial and spinal nerves.
infectious processes within meninges, brain, or spinal cord. The third layer of meninges, the pia mater, is continuous
with the surface of the brain and spinal cord. The pia mater
also follows vessels into brain and spinal cord parenchyma
The Ventricular System and projects into the ventricles to form the choroid plexuses.
The pia mater and the ventricular ependyma merge at the
The cerebral ventricular system represents, in greatly elabo- foramina of Luschka and Magendie. The CSF is contained
rated form, the remnants of the embryologic neural tube. A in the subarachnoid space, enclosed between the arachnoid
single layer of neuroglial-derived cells, the ventricular epen- and the pia. The subarachnoid space surrounds the brain and
dyma, lines the ventricles; a dense network of astrocytic foot extends within the spinal canal to the level of the second sacral
processes backs these. The ventricular system consists of two vertebra. Within the skull, the subarachnoid space widens into
lateral ventricles, the third ventricle, and the fourth ventricle cisterns where pia and arachnoid are more widely separated by
(Fig. 2.1). The lateral ventricles are located within the cere- irregularities in the contour of the brain. The largest of these,
brum and consist of frontal, temporal, and occipital horns; the cisterna magna, surrounds the brainstem and the cerebel-
these join at the ventricular trigone within the parietal lobe. lum at the base of the skull and is occasionally used as a source
The third ventricle is an elongated, slitlike cavity that lies of CSF for analysis and culture. The subarachnoid space is
within the midbrain and is bounded inferiorly by the hypo- crossed by trabecular extensions of the arachnoid itself, by
thalamus. The fourth ventricle overlies the brainstem from the cranial nerves, by a network of small arteries, the rete mirabile,
level of the midpons to the extreme rostral end of the spinal and by numerous bridging veins, which connect the meningeal
cord. The roof of the fourth ventricle is the cerebellum poste- veins with the deeper intracranial venous system (2).
riorly and the superior and inferior medullary veli anteriorly. The subarachnoid space is normally a closed system.
The fourth ventricle is roughly diamond shaped and is wid- Occasionally, however, congenital or posttraumatic communi-
est at the lateral recesses, which lie between the superior and cations may exist between the subarachnoid space and super-
middle cerebral peduncles. ficial tissues and may provide a route for single or recurrent
The cerebral ventricles are connected to each other and with episodes of meningitis. Congenital defects arise from incom-
the subarachnoid space through a series of small openings. plete closure of the neural tube. These defects may extend for
Each lateral ventricle drains into the third ventricle through variable distances into subcutaneous tissues or to the cutaneous
the foramen of Monro, located in the inferomedial wall of the surface and are most common in the upper cervical regions
frontal horn. The third and fourth ventricles are connected by and over the sacrum. Their presence may be suggested by a
the aqueduct of Sylvius, which extends through the midbrain. cutaneous dimple or a patch of hair. Traumatic communications

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Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 5

FIGURE 2.1 The cerebral ventricles. Inset:


Shown are the structure of the fourth ventricle
and the locations of the foramina of Luschka
and Magendie. (From Greenlee JE. Anatomical
considerations in central nervous system infec-
tions. In: Mandell GL, Bennett JE, Dolin R, eds.
Principles and Practice of Infectious Diseases.
4th ed. New York: Churchill Livingstone; 1994:
821831, with permission.)

into the subarachnoid space are most often associated with Formation of CSF involves both filtration and active
basilar skull fractures. The most common sites of involvement transport (1,3). Filtration of CSF varies inversely with
are (a) the thin layers of bone that separate the cranial cavity serum osmolality. In experimental animals, and possibly in
from the paranasal sinuses and (b) the petrous bone, which humans, CSF production changes 7% for each 1% change in
separates the auditory canals and mastoid from the cranial serum osmolality (4). Active secretion of CSF involves Na,
cavity. In rare instances, traumatic defects may occur over the K-adenosine triphosphatase (ATPase)mediated transport of
cranial convexities or along the spinal column. sodium across choroidal epithelium into the ventricular lumen,
with water, chloride, and bicarbonate ions following through
facilitated transport. In experimental animals, the carbonic
PHYSIOLOGY OF CEREBROSPINAL anhydrase inhibitor acetazolamide reduces CSF secretion by
approximately 50%, whereas furosemide and ethacrynic acid
FLUID PRODUCTION AND reduce CSF production by 25% to 35% (5). Simultaneous use
REABSORPTION of both agents reduces CSF formation by 75%.
Reabsorption of CSF occurs through arachnoid villi. Most
CSF is produced by the choroid plexuses of the lateral, of these are located along the superior sagittal sinus. Smaller
third, and fourth ventricles and, to a lesser extent, by extra- numbers of arachnoid villi are found along other intracranial
choroidal sites (1,3). In adults, the choroid plexus produces venous sinuses and around spinal nerve roots (1). During
approximately 500 mL of CSF per day, with 150 mL present health, the arachnoid villi along the superior sagittal sinus
in the ventricular system at any time. The choroid plexuses are provide the major site of CSF uptake. The arachnoid villi
specialized projections of vessels and pia mater into the ven- along other sinuses and surrounding spinal nerve roots may
tricular cavities. Each choroid plexus branches into frondlike provide alternative sites of CSF absorption following superior
villi, each of which contains a capillary surrounded by loose sagittal sinus thrombosis.
connective tissue and a layer of specialized ependymal cells Each arachnoid villus represents an extension of the arach-
termed choroid epithelium. Choroidal epithelial cells, in con- noid membrane through the dura mater into the lumen of the
trast to ependymal cells elsewhere in the ventricular system, venous sinus and functions as a one-way valve, permitting
are columnar in shape and are covered on their ventricular unidirectional flow from CSF into blood. Early work by
surfaces by a brush border of microvilli. The villous structure Welch (6) demonstrated that the arachnoid villi have a critical
of the choroid plexus and the presence of microvilli greatly in vitro opening pressure of 2 to 5 cm H2O; this study also
increase the surface area available for secretion of CSF (1). demonstrated that particles up to the size of erythrocytes

Scheld_Ch02.indd 5 2/21/14 5:27 PM


6 Part I: Approach to the Patient and Diagnostic Evaluation

that provide host defense elsewhere in the body. Normally,


T cells and B cells are present in very small numbers in CSF
and only rarely in brain; immunoglobulins and complement
are largely excluded from both CSF and brain; and opsonic
activity of CSF, even in the presence of meningitis, is far less
than that of serum (1114). Therefore, both the brain and the
CSF are poorly equipped to deal with infectious agents.
The barrier systems that isolate CSF, brain, and spinal
cord from blood are not static systems but, instead, are highly
dynamic in their ability to interact with and transport a
wide variety of substances (15). In addition, it is increasingly
recognized that the endothelial cells and astrocytes of the BBB
and the bloodCSF barrier are important sources of cytokines
(including tumor necrosis factor [TNF] and interleukins), and
that astrocytes, in addition to their abilities to regulate solute
entry into brain, have the ability to act as antigen-presenting
cells (16). The release of cytokines by endothelial cells and
astrocytes in response to bacterial endotoxins and other bacte-
rial products is fundamental in the production of inflammation
and injury during CNS infections and provides an extremely
important area for early therapy (9,1719).

MAINTENANCE OF
CEREBROSPINAL FLUID
HOMEOSTASIS
FIGURE 2.2 Uptake of CSF by an arachnoid villus. (From Fishman
RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. The BBB and the bloodCSF barrier maintain the cellular and
Philadelphia: WB Saunders; 1992, with permission.) chemical elements of the CSF within narrow ranges (1,3,20).
Lipid-soluble substances within blood readily diffuse across
choroidal epithelium or vascular endothelium into CSF or brain
(3). Passage of fluid and ionically polar substances, however,
readily pass from CSF into blood, whereas particles larger requires mechanisms for transport and facilitated diffusion.
than 7.5 m are excluded. Although these early data suggested Sodium enters CSF both by Na, K-ATPasemediated trans-
that the arachnoid villi might provide a direct communication port during secretion of CSF and by passive diffusion (20).
between CSF and blood, studies using electron microscopy Potassium is secreted into CSF by active transport mechanisms
have demonstrated that arachnoid villi and venous sinuses and is actively removed from CSF into brain by transport
are separated by a layer of endothelial cells connected by mechanisms that are believed to be located in astrocyte foot
tight junctions, and that movement of CSF and particulate processes. Movement of calcium, magnesium, and phospho-
matter across the arachnoid villi occurs by transport within rus into CSF and brain also occurs predominantly by active
giant vesicles (7,8) (Fig. 2.2). These giant vesicles, although transport, and the concentrations of these substances are rela-
they provide efficient transfer of CSF into blood under normal tively independent of their concentrations in serum. Chloride
circumstances, can become obstructed by bacteria and inflam- and bicarbonate, like potassium, are actively secreted into and
matory cells during meningitis or by red blood cells (RBCs) actively removed from CSF. Glucose, amino acids, amines,
during subarachnoid hemorrhage (9,10). and thyroid hormone enter the brain by carrier-mediated
transport mechanisms (1,15). Insulin and transferrin require
receptor-mediated transport (15). Although lipids complexed
BRAIN AND CEREBROSPINAL to proteins were once thought to be excluded from the CNS,
FLUID BARRIER SYSTEMS it is now known that complexed lipids undergo dissociation
from their carrier proteins at the bloodbrain interface and
The brain and CSF are contained within a series of barrier sys- may enter the CNS without significant exodus of protein from
tems (1). These prevent entry of fluids, electrolytes, and other brain capillaries (15).
substances from blood into CSF or brain by simple diffusion Chloride represents the major anion in CSF. Normal CSF
and isolate the CNS from systemic immune responses. The chloride concentration is 15 to 20 mEq/L higher than that in
bloodbrain barrier (BBB) is formed by tight junctions between serum. Early workers observed that CSF chloride concentrations
endothelial cells of CNS capillaries and is further reinforced were lowered in tuberculous meningitis; for many years, levels
by a surrounding layer of astrocytes, whose processes termi- of CSF chloride were used to diagnose and follow the course
nate in overlapping fashion on the capillary walls. In contrast, of this infection (1). It is now recognized, however, that the
the bloodCSF barrier is formed by the endothelial cells of the lowered CSF chloride concentration observed in tuberculous
choroid plexus and the tight junctions that link them. The cells meningitis is nothing more than a reflection of lowered serum
of the pia mater, like those of choroid plexus and arachnoid chloride values and has no diagnostic or prognostic value.
capillaries, are separated by gap junctions; entry of substances The acidbase balance of the CSF, like its electrolyte con-
from CSF into brain is modulated by a basement membrane centration, tends to remain fairly constant despite fluctuations
subjacent to the pia and by a continuous layer of astrocytes in systemic acidbase balance. In CSF, as opposed to plasma,
beneath the basement membrane, forming a CSFbrain barrier. however, movement of CO2 occurs readily by diffusion, whereas
The barrier systems that surround spinal cord and brain movement of bicarbonate occurs more slowly by carrier-
exclude from the CNS most of the immunologic mechanisms mediated transport. The discrepancy in the rate of movement

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Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 7

of these two substances may produce delayed (and, at times, Occlusion of the aqueduct of Sylvius by granulomatous epen-
paradoxical) responses in CSF pH as compared to systemic pH dymitis may occur as a complication of tuberculosis, fungal
during rapid changes in bicarbonate concentration (1). The CSF infections, or sarcoidosis. Mumps virus, which replicates in ven-
acidbase balance is also maintained by the choroid plexuses, tricular ependymal cells, has been shown to produce congenital
which possess transport mechanisms capable of removing weak aqueductal stenosis in experimental animals (23). Rare cases of
organic acidsincluding antibiotics such as the penicillins, hydrocephalus have also been reported following mumps and
cephalosporins, and aminoglycosidesfrom CSF (21,22). with Toscana meningoencephalitis in humans (24,25). Extrinsic
Choroid plexus transport of antibiotics and other weak organic compression of the aqueduct of Sylvius may be produced by
acids can be blocked by probenecid. abscesses or other localized infections within the pons or mid-
brain. Involvement of the foramen of Monro is almost always
unilateral and is the consequence of severe brain shifts caused
ALTERATIONS OF by abscess, focal encephalitis, or hemorrhage. Hydrocephalus
CEREBROSPINAL FLUID caused by the occlusion of one foramen of Monro is particularly
dangerous because the CSF trapped within the involved lateral
DYNAMICS AND PRESSURE IN ventricle acts as a unilateral space-occupying lesion, greatly in-
CENTRAL NERVOUS SYSTEM creasing the risk of transtentorial brain herniation.
Computerized tomography (CT) and magnetic resonance
INFECTIONS: HYDROCEPHALUS, imaging (MRI) are invaluable in demonstrating the presence of
INTRACRANIAL HYPERTENSION, hydrocephalus and in determining its cause. Ventricular dilation
AND BRAIN HERNIATION is common in the elderly and is characterized by symmetric ven-
tricular dilation accompanied by evidence of cerebral cortical
Acute or chronic CNS infections may produce profound alter- atrophy. In contrast, hydrocephalus is defined as a frontal horn
ations in intracranial pressure (ICP) by obstructing CSF flow ratio (Evans index) of 0.3 or greater in the absence of cerebral
or reabsorption, by behaving as space-occupying lesions, or by atrophy (26). Hydrocephalus that occurs from impaired CSF
producing hemorrhage or cerebral edema. These pathologic circulation is accompanied by loss of cortical markings visible
consequences of infection, acting individually or together, may on CT or MRI as the brain is forced outward against the skull
cause brain herniation and death. and by periventricular areas of increased lucency, represent-
ing transependymal leakage of CSF. Communicating hydro-
cephalus and hydrocephalus from obstruction of the foramina
Alteration of Cerebrospinal Fluid Circulation of Luschka and Magendie are characterized by symmetric
enlargement of all four ventricles. Hydrocephalus from occlu-
in Central Nervous System Infections sion of the fourth ventricle or aqueduct of Sylvius results in
loss of that structure on CT or MRI, with dilation of the third
Impairment of normal CSF circulation may result in ventricu-
and lateral ventricles. Hydrocephalus following compression
lar enlargement and hydrocephalus. Interruption of CSF reab-
of the foramen of Monro is almost invariably associated with
sorption produces communicating hydrocephalus with normal
an identifiable space-occupying lesion and a prominent midline
circulation of CSF through the ventricular system and into the
shift. Thrombosis of the superior sagittal sinus may be difficult
subarachnoid space. Communicating hydrocephalus is a com-
to detect as a cause of communicating hydrocephalus and can
mon complication of bacterial meningitis and, in most cases,
be missed with the use of routine CT scanning. MRI and CT
results from obstruction of the arachnoid villi by bacteria and
venogram are more sensitive and are used to diagnose superior
white blood cells (WBCs) (9). Communicating hydrocephalus
sagittal sinus (SSS) thrombosis (27).
may also result from functional occlusion of arachnoid villi
during severe meningitis or by RBCs in the course of subarach-
noid hemorrhage during bland or septic subarachnoid hemor-
rhage (10). Thrombosis of the superior sagittal sinus may also Intracranial Hypertension and
block CSF reabsorption and thereby produce communicating Brain Herniation
hydrocephalus. Occlusion of a large portion of the superior
sagittal sinus usually produces catastrophic, often hemor- The normal mechanisms of CSF secretion and drainage main-
rhagic, cerebral infarction. Involvement of the anterior third tain CSF pressure at a level less than 150 mm of CSF in most
of the sinus, however, may be clinically silent except for the patients. Infection, however, greatly alters these homeostatic
development of hydrocephalus. mechanisms; moreover, death during the acute stages of intra-
Obstructive hydrocephalus results from interruption of CSF cranial CNS infections often results from extreme elevation in
flow within the ventricular system or at its point of exit into ICP followed by brain herniation and respiratory arrest.
the subarachnoid space (2). This may be the consequence of For a period of time, the intracranial contents are able to
infection of the ventricular ependyma or basilar meninges or compensate in response to space-occupying lesions before a rise
may result from extrinsic compression of the ventricular sys- in ICP occurs. This compensatory ability is termed compliance
tem by infection within brain parenchyma. Lesions producing (dV/dP) and represents the ratio of changes in volume (dV) to
obstructive hydrocephalus most commonly involve the ventric- changes in pressure (dP). Compliance in response to space-
ular system at its narrowest points: the foramina of Luschka and occupying intracranial lesions consists of several factors.
Magendie, the fourth ventricle, the aqueduct of Sylvius, and the These include increased rate of reabsorption of CSF (this may
foramina of Monro. Obstruction of the foramina of Luschka be prevented in meningitis by obstruction of the arachnoid
and Magendie is characteristic of exudative basilar menin- villi by cells and exudate); displacement of CSF; reduction
gitides such as those caused by Mycobacterium tuberculosis, in the total volume of intracranial blood, predominantly by
Coccidioides immitis, and Cryptococcus neoformans but may compression of veins and venous sinuses; and plasticity of the
also be seen in bacterial meningitis. Hydrocephalus as a result brain itself. Compliance is extremely limited when infection is
of obliteration of the fourth ventricle is almost always extrinsic accompanied by a rapid increase in ICP, such as during acute
and is the result of ventricular compression by large cerebel- bacterial meningitis or subdural empyema. In contrast, the
lar mass lesions such as cerebellar abscess or hemorrhage. ability of CNS compliance to compensate for increased ICP

Scheld_Ch02.indd 7 2/21/14 5:27 PM


8 Part I: Approach to the Patient and Diagnostic Evaluation

may be extensive where space-occupying lesions develop over patients with a negative head CT scan. The procedure is of
time (28). Once compliance is exceeded, however, the increase little specific diagnostic value in the diagnosis of brain abscess
in pressure in chronic lesions may occur rapidly. or parameningeal infections. Lumbar punctures (LPs) should
The elevation in CSF pressure seen in infections and other not be done in patients with impending herniation or with
pathologic conditions is not constant but fluctuates consider- intracranial mass lesions with severe mass effect. Furthermore,
ably. This fluctuation is usually not observed during the brief inappropriate LP can cause patient death or serious neurologic
period of measurement provided by LP but becomes an impor- injury, and the procedure should never be initiated without
tant parameter to observe during monitoring of ICP. Minor consideration of its potential danger to the patient.
variation in pressure occurs during Cheyne-Stokes respiration Clinicians have relied on the meningeal signs (nuchal rigid-
and during variations in blood pressure produced by Hering- ity, Kernig sign, Brudzinski sign) for over 100 years to evaluate
Breuer reflexes, the inflation and deflation reflexes that help patients with suspected meningitis to help them decide who
regulate the rhythmic ventilation of the lungs. More major should undergo a LP. A prospective study of 297 adults with
variations in ICP occur during plateau waves. These are suspected meningitis documented a very low sensitivity of the
abrupt elevations in ICP (usually lasting 5 to 20 minutes) in Kernig sign (sensitivity, 5%), Brudzinski sign (sensitivity, 5%),
which ICP may reach 600 to 1,300 mm of CSF (50 to 100 and nuchal rigidity (sensitivity, 30%) (35). The absence of the
mm Hg) (29,30). Plateau waves are believed to represent a meningeal signs should not defer the performance of the LP.
consequence of disturbed cerebrovascular autoregulation be- The decision to perform a LP on those suspected of having
cause of either abnormal sympathetic tone or cyclic changes meningitis is largely based on a combination of clinical signs
in perfusion in which mild hypotension is followed by cerebral and symptoms at presentations. The classic triad of fever, stiff
vasodilation and increased cerebral blood flow (30). Although neck, and altered mental status was present in only 44% of
plateau waves may be without any detectable clinical effect, patients in a prospective study involving 696 patients with
they may also be associated with signs of brainstem compres- confirmed bacterial meningitis (36). However, at least two
sion and impending herniation. of the four symptoms of headache, fever, neck stiffness, and
Increased pressure that exceeds intracranial compliance altered mental status were found in 95% of patients.
causes downward and backward shifting of the cerebrum
and brainstem (31). Minimal degrees of shift are well toler-
ated, but a more extensive shift may cause herniation of the Major Complications of Lumbar Puncture
cingulate gyrus beneath the falx cerebri, herniation of the
uncus of the temporal lobe over the tentorium cerebelli, and Role of Head Computerized Tomography Scan Before
ultimately, herniation of the lower brainstem and cerebellar
Lumbar Puncture and Risk of Brain Herniation
tonsils into the foramen magnum. Herniation of the cingu-
late gyrus is usually asymptomatic. Uncal herniation, however, It has become a routine practice to obtain a CT scan of the
initially produces compression of the third cranial nerve as it head prior to performing a LP in patients with suspected
passes beneath the tentorium; it subsequently causes compres- meningitis. This is done to rule out the possibility of an
sion of the midbrain, with resultant coma. The aqueduct of intracranial mass, hydrocephalus, edema, or any other signs of
Sylvius is often occluded during uncal herniation, and the re- increased ICP that could theoretically place the patient at risk
sultant hydrocephalus increases the mass effect already pres- for cerebral herniation after CSF removal during the LP (37).
ent. Herniation of the cerebellar tonsils through the foramen Herniation of the brain as the consequence of severe cerebral
magnum, with compression of medullary respiratory centers edema or acute hydrocephalus can sometimes occur in acute
and respiratory arrest, is often the terminal event in CNS in- bacterial meningitis and other CNS infections. Clinically, this
fections. Occasionally, space-occupying lesions within the cer- is manifested by altered state of consciousness, abnormalities
ebellum cause upward herniation of posterior fossa contents in pupil reflexes, and decerebrate or decorticate posturing. The
through the tentorial notch (32). Extreme elevation of CSF incidence of herniation after LP even in patients with papill-
pressure may elevate ICP above systemic arterial perfusion edema is approximately 1% (37).
pressure, producing global cerebral and brainstem infarction. In order to clarify the role of a screening CT scan, a pro-
Elevation in CSF pressure, as monitored by ICP monitor- spective study involving 301 adults with suspected meningitis
ing devices, may provide an indication of prognosis in bacterial was done (38). Baseline characteristics that were associated
meningitis and possibly in other CNS infections. Rebaud et al. with an abnormal finding on head CT were age 60 years and
(33) found that CSF pressures were significantly higher and older, immunocompromised host (i.e., HIV/AIDS, immuno-
cerebral perfusion pressure were significantly lower (mean sys- suppressive therapy, or transplantation), a history of CNS
temic arterial pressure minus ICP) in patients who died due to disease, a history of seizure within 1 week before presenta-
meningitis or encephalitis than in those who survived. Goitein tion, and any abnormality on neurologic examination. These
and Tamir (34) found that all pediatric patients with meningitis factors have now been included in the Infectious Diseases
or encephalitis who had a cerebral perfusion pressure more than Society of America guidelines to decide who should undergo
30 mm Hg survived, whereas those with lower pressures died. CT prior to the LP (39). The decision to obtain a brain CT
scan before LP should not result in delay in instituting anti-
biotic therapy because delay can increase mortality (40). It
CEREBROSPINAL FLUID ANALYSIS should be also noted that herniation can occur in patients
with bacterial meningitis who have a normal brain CT scan.
IN CENTRAL NERVOUS SYSTEM The most reliable clinical signs of impending herniation
INFECTIONS include deteriorating level of consciousness, brainstem signs,
and a very recent seizure (41).
Indications for Lumbar Puncture Spinal Hematoma with Cord Compression
LP is essential in the diagnosis of bacterial, viral, or fungal Case reports of LP in patients with severe disorders of blood
meningitis and may provide valuable information in encepha- coagulation, thrombocytopenia, or in patients anticoagulated
litis. LP is also used to diagnose subarachnoid hemorrhage in with heparin or Coumadin have described complications

Scheld_Ch02.indd 8 2/21/14 5:27 PM


Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 9

with either continued bleeding at the site of puncture or with decreased CSF volume, which would cause cerebral vasodila-
epidural or subdural hematomas that may compress the cauda tation and stretching of pain-sensitive cerebral structures (46).
equina, thereby producing permanent neurologic injury (42). The incidence of the postLP headache is not associated
These complications appear to be rare. In a study of 5,223 LPs with the volume of CSF removed, hydration, the position of
performed, no complications were seen in 941 children with the patient (lying on their side or sitting up), or the opening
leukemia who had severe thrombocytopenia (platelet count pressure (47). Factors that can be associated with a decrease
50) (43). in the incidence of headache are the type and size of needle,
the direction of the bevel during needle placement, the replace-
Introduction of Infection into the Subarachnoid Space ment of the stylet, and possibly the number of LP attempts
(47). Atraumatic needles with a blunt end are recommended by
Inadvertent LP through an area of infection overlying the spi-
the American Academy of Neurology to reduce the incidence
nal canal may result in seeding of the subarachnoid space and
of postLP headaches (48). The blunt end produces a more
meningitis. This is a particular risk in spinal epidural abscess
traumatic opening with tearing and disruption of the collagen
or subdural empyema but may occasionally occur in the set-
fibers that is closed faster by an immunologic reaction and
ting of superficial or deep paraspinal infections. The problem
thus associated with a decrease incidence of headache (49).
can be avoided by entering the subarachnoid space at a level
Additionally, smaller needles have been shown to decrease
well removed from the site of presumed infection. Thus, in
the incidence of the postLP headache (46). The direction
patients with known or suspected focal lumbar infection, spi-
of the bevel should be parallel to the long axis of the spine
nal fluid should be obtained under fluoroscopic guidance by
to decrease the incidence of headache. If the patient is lying
high cervical (C2) or cisternal puncture, whereas the lumbar
on his or her side, the bevel should face up. This way, the
route should be used in patients with suspected cervical or
needle will separate the dural collagen fibers, which also run
upper thoracic infections. Introduction of infection into the
along the long axis of the spine, rather than cutting them (47).
subarachnoid space during LP in uninfected individuals has
Several techniques to treat the postLP headache exist
been reported in 1 out of 50,000 LPs (44). The most com-
including the instillation of a blood patch, dextran, or saline
monly implicated organism is Streptococcus salivarius, and
into the epidural space. A blood patch refers to the injection
this could be potentially prevented by using a mask during the
of 20 to 30 mL of the patients fresh blood into the epidural
procedure (45).
space. It is thought to work by closing the CSF leak by forming
a clot, and it works in about 70% to 98% of patients (47). If a
PostLumbar Puncture Headache blood patch does not work, 20 mL of dextran or saline can be
The most frequent complication of LP is the postLP head- injected into the epidural space to raise the epidural pressure
ache, which can occur in 10% to 60% of patients, more com- and reduce the CSF leak. Oral or intravenous caffeine can be
monly in young women with a lower body mass index (BMI) used because they act as a cerebral vasoconstrictor and blocks
and in pregnancy (46). The diagnosis is a clinical one, and it is adenosine receptors. Surgical closure of the dural gap is the
usually defined as a bilateral headache that worsens while sit- last resort (46).
ting up and improves lying down, develops within 7 days after
a LP, and disappears within 14 days (Fig. 2.3). It is thought Less Common Complications of Lumbar Puncture
that the headache is caused by a CSF leak that decreases ICP.
Cortical Blindness. Downward displacement of the brainstem
This causes headache either by gravitational traction on sensi-
in states of increased ICP may compress the posterior cerebral
tive meningeal vascular coverings as a result of CSF volume
arteries against the edge of the tentorium cerebelli, causing isch-
depletion or by activation of adenosine receptors as a result of
emic infarction of the occipital lobes and cortical blindness (31).
Although this complication of intracranial hypertension is often
accompanied by signs of uncal or tonsillar herniation, compres-
sion of the posterior cerebral arteries may also occur before other
signs of herniation appear. Prognosis for return of vision is poor.

Cervical Spinal Cord Infarction. Rarely, LP in the setting of


bacterial meningitis may be followed within a few hours by
respiratory arrest accompanied by flaccid tetraplegia (50).
A variety of mechanisms, including hypotension and vasculi-
tis, have been postulated as the cause of cervical cord ischemia
in these patients. In some patients, however, it is likely that
displacement of the cerebellar tonsils through the foramen
magnum as the result of greatly elevated ICP compresses the
anterior spinal artery or its penetrating branches, with resul-
tant ischemic infarction of the upper cord (50).

Technique of Lumbar Puncture


The LP was first performed by Quincke in 1891 on children
suffering from headaches in hopes to relieve their symptoms.
Soon after, using CSF as a diagnostic tool became the standard
way for evaluating patients with meningitis (47). The LP is
generally performed with the patient in the lateral recumbent
FIGURE 2.3 Gadolinium-enhanced MRI scan of a patient with intra- position in a fetal position with the knees flexed toward the
cranial hypotension. There is diffuse, symmetric meningeal enhance- chest, and the neck slightly flexed. Only this position allows
ment (arrows). the opening pressure to be measured. The other positions

Scheld_Ch02.indd 9 2/21/14 5:27 PM


10 Part I: Approach to the Patient and Diagnostic Evaluation

include sitting the patient upright on the edge of the bed and TA B L E 2 . 1
bending forward over a bed stand or sitting with the feet sup-
ported and chest resting on the knees. MINIMAL VOLUMES OF CEREBROSPINAL FLUID
The spinal cord typically ends as the conus medullaris at REQUIRED FOR COMMON DIAGNOSTIC TESTSa
the L1 to L2 level in adults, and in children at the L3 to L4
level. The landmarks used are the anterior superior iliac crests, Test Volume of CSF Required
which correlate with the L4 to L5 interspace. The needle may
be inserted between the L3 and L4, L4 and L5, or L5 and Cell count and differential 0.55.0 mLb
S1 interspace (51). Insertion above the L3 level may puncture Glucose and protein 0.5 mLc
the conus medullaris and should not be attempted. Also, the Bacterial culture 35 mLd
needle should not be inserted over a skin infection or abscess Mycobacterial culture; fungal 20 mLe
because this has the potential of inserting bacteria into the culture (includes acid-fast smear
CSF. The performer of the LP should follow a sterile technique and India ink preparation)
including hand washing, gloves, gown, and mask. After the
anterior superior iliac spine is identified, the spinous process Viral culture and/or PCR 12 mL
superior to the interspace is palpated. Prior to inserting the Cryptococcal antigen 0.5 mL
spinal needle, local anesthetic should be utilized, usually 2 to 3 VDRL 0.5 mL
mL of lidocaine without epinephrine deposited subcutaneously Oligoclonal bands 2 mL serumf
and then deeper, allowing 1 to 2 minutes for it to take effect.
The needle should be inserted 1 cm below this and directed in
VDRL, Venereal Disease Research Laboratory.
a horizontal position toward the umbilicus to an approximate a
Volumes required represent minimal quantities of CSF required
depth of 2 cm (51). During the LP, if bone is encountered, the by most hospital laboratories. The clinician should determine the
needle should be withdrawn to the subcutaneous layer and amounts of CSF required by his or her hospital laboratory by each
reinserted at a slightly different angle. The needle is inserted intended test before performing the LP.
b
until a pop is felt indicating penetration of the ligamentum Approximately 0.5 mL will be needed for cell count. Amount of
flavum and presence of the needle in the subarachnoid space. CSF required for differential will vary, depending on whether cyto-
centrifugation is used or material from centrifuged CSF sediment is
The stylet is then removed and CSF obtained. A manometer studied.
to measure the CSF pressure should be attached in all cases c
Blood drawn before initiating the LP should also be submitted with
if possible. If CSF is not obtained, rotate the needle as part of spinal fluid for determination of simultaneous blood glucose level.
d
the dura may be blocking the hole of the needle. If this does As little as 0.5 mL may be submitted for culture if there is great
not work, reinsert the stylet and advance the needle, stopping difficulty obtaining fluid. However, the use of centrifuged sediment
from larger volumes of CSF will improve yield on culture in acute
frequently to withdraw the stylet (51). bacterial meningitis. The use of large volumes of CSF is essential in
more chronic infections.
e
Yield on culture for acid-fast bacilli and fungi is, in general,
Alternative Routes of Obtaining extremely poor unless large volumes of CSF (20 mL or more in
adults) are cultured.
Cerebrospinal Fluid f
Serum (25 mL) drawn before or after the LP should be submitted
for electrophoresis along with CSF.
Cisternal, high cervical (C2), and ventricular approaches may
be used to obtain CSF if a lumbar approach is contraindicated
by infection or is technically impossible (1). Cisternal puncture
was initially described in 1923, but it can cause vascular injuries
(52,53). Spinal puncture at the level of the second cervical ver- Cerebrospinal Fluid Pressure
tebra under fluoroscopic guidance has been suggested as a less
hazardous approach than cisternal puncture, but its actual CSF pressure must be measured in the lateral decubitus
value remains unproven. Ventricular CSF may be of great position with the head of the bed being flat. Opening CSF
diagnostic value if there is a predominantly intraventricular pressure in healthy adults lies between 50 and 195 mm CSF
infection with obstructive hydrocephalus or in the presence of (1). Values higher than 200 mm are abnormal. Normal lumbar
a ventriculoperitoneal shunt (54). CSF pressures in neonates and premature infants are signifi-
cantly lower, with mean values of 100 mm H2O and 95 mm
H2O, respectively (55). CSF pressure is not affected during
pregnancy (56). A CSF baseline pressure of greater than
Routine Studies of Cerebrospinal Fluid 250 mm H2O was associated with higher incidence of neuro-
logic complaints including papilledema, hearing loss, and with
Studies routinely obtained at the time of LP include measure-
mortality in AIDS patients with cryptococcal meningitis (57).
ment of CSF pressure, gross examination of the fluid for tur-
Extreme elevation of CSF pressure may also herald impending
bidity or changes in color, measurement of CSF protein and
brain herniation. Occasionally, CSF pressure may be normal
glucose concentrations, RBC and WBC counts, Gram and/or
or even low in the setting of ongoing tonsillar herniation. The
acid-fast stains of CSF sediment, and Gram stain and bacte-
falsely low readings obtained in this setting are believed to
rial culture of the fluid. Differentiation of bacterial meningitis
reflect occlusion of the CSF space at the foramen magnum by
from viral, mycobacterial, or fungal meningitis on the basis of
the herniated tonsils wedged against the lower brainstem. The
CSF abnormalities is presumptive unless an organism is cul-
possibility of complete spinal block should be kept in mind if
tured or detected by antigen tests or PCR. Amounts of CSF
CSF pressure falls to zero during the procedure.
required by most laboratories for commonly obtained deter-
minations are listed in Table 2.1. Because clinical laborato-
ries differ in the amounts of CSF required for individual tests,
Gross Appearance of the Spinal Fluid
however, the clinician must determine the amounts of CSF re- Once CSF is obtained, it is centrifuged down to give a super-
quired by the hospital laboratory for each intended test before natant. Normal CSF is colorless and clear. Under pathologic
performing the LP. conditions, CSF may become turbid, discolored, or both.

Scheld_Ch02.indd 10 2/21/14 5:27 PM


Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 11

The CSF may become turbid as a result of entry of cells, bacte- valuable in following the course of illness and response to
ria, or fat; it can be made turbid by as few as 200 WBCs/mm3 treatment (Table 2.2). Improperly handled or counted CSF,
or 400 RBCs/mm3 (1,58). CSF containing RBCs will be grossly however, can be a dangerous source of error. The cell count in
bloody if 6,000 or more RBCs are present per cubic millimeter, CSF tends to decrease over time and may be falsely low if mea-
and it will be cloudy and xanthochromic or pinkish if 400 to sured after 30 to 60 minutes. This decrease in cell count occurs
6,000 cells are present (1). partly because leukocytes and RBCs settle out over time if the
The yellow discoloration of the supernatant is termed xan- tube of CSF is allowed to stand. In addition, however, lysis of
thochromia and is often used to distinguish between a so-called RBCs, polymorphonuclear (PMN) leukocytes, and to a lesser
bloody tap and subarachnoid hemorrhage. Xanthochromia can extent, lymphocytes begins in vitro within 1 to 2 hours of the
be assessed visually or by spectrophotometric methodology by LP and may occasionally occur even more rapidly. WBCs also
scanning the CSF over a range of wavelengths. The discolor- adsorb to the glass or plastic walls of the tube and are not
ation is from degradation products of hemoglobin from lysis of easily dislodged by agitation. Because of these factors, the re-
RBCs. This usually forms 2 to 4 hours after RBCs have entered duction in cell count that occurs over time is only partially
the subarachnoid space (1), which is why some experts suggest reversible if the tube is vigorously agitated before counting.
waiting at least 6 hours after the onset of headache when a Any CSF destined for cell counts should, thus, be handled
subarachnoid bleed is suspected because you may get a false- carefully and expeditiously. Similarly, where serial tubes must
negative result (58). A traumatic tap should clear as the CSF be counted to exclude a traumatic tap, the samples must be
is collected in serial vials but not in all cases of subarachnoid handled in the same manner and counted at the same time by
hemorrhage. Xanthochromia resulting from lysis of RBCs is the same person.
initially a result of oxyhemoglobin. After 12 hours, the pig-
ment represents predominantly bilirubin (1). Visual assessment White Blood Cell Count
of xanthochromia can be deceitful because it may also be seen
Quantification of numbers of cells in CSF can be carried
in the presence of increased amounts of protein, in metastatic
out manually, using a Neubauer counting chamber, but this
melanoma, or as a consequence of systemic hyperbilirubinemia
methodology is labor-intensive, time-consuming, technique-
with a bilirubin level higher than 10 to 15 mg/dL. The most
dependent, and prone to variability. Although electronic cell
appropriate and sensitive way to assess xanthochromia is by
counters are available, they can have poor reproducibility
spectrophotometry of the CSF to detect the hemoglobin break-
especially if the CSF samples have low WBC counts. Novel
down products, oxyhemoglobin and bilirubin.
instruments using flow cell digital imaging have excellent cor-
relation with manual hemacytometer method and should be
Cell Count and Differential the method of choice (59). The accuracy of the cell count is
Enumeration and characterization of cells within spinal fluid open to question unless the specimen is examined immediately
is of crucial value in the diagnosis of CNS infections and is after the LP has been completed. Normally, CSF contains fewer

TA B L E 2 . 2
NORMAL CEREBROSPINAL FLUID VALUES OF IMPORTANCE IN INFECTIOUS
DISEASES OF THE NERVOUS SYSTEM: VALUES IN ADULTS, TERM INFANTS,
AND PREMATURE INFANTS

Parameter Adults Term Infants Premature Infants

Cell count (per cubic millimeter) 5 9a 9a


Percent polymorphonuclear leukocytes 0b 61b 57b
Protein (mg/dl) (lumbar)
Mean 30 90 115
Range 958 20170 65150
Glucose (mg/dl)
Meanc 62 52 50
Rangec 4580 34119 2463
CSF:blood glucose ratio
Mean 0.60 0.81 0.74
Range 0.50.8c 0.442.48 0.551.55

a
Cell counts in term and premature infants represent mean values. The range of cell counts found in nor-
mal neonates is 032 cells/mm3 and in premature infants is 029, with 2 standard deviations encompassing
a range of 022.4 cells/mm3 in term and 024.4 cells/mm3 in premature infants. By 1 month of age, normal
CSF contains 20 cells/mm3 (2).
b
Rare polymorphonuclear leukocytes may be seen in cytocentrifuged samples of CSF from normal adults.
This is not necessarily abnormal if the CSF leukocyte count is 4 cells/mm3 or less and if protein and glucose
levels are normal.
c
Assumes a blood glucose level of 70120 mg/dl. At high blood glucose levels (700 mg/dl), normal lower
limit of CSF: blood glucose ratios may approach 0.4 (see text).
Adapted from Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia:
WB Saunders; 1992, with permission.

Scheld_Ch02.indd 11 2/21/14 5:27 PM


12 Part I: Approach to the Patient and Diagnostic Evaluation

than five cells per cubic millimeter (Table 2.2). Most of these TA B L E 2 . 3
cells are small lymphocytes (nuclear diameter about 6 to 7 m)
with scant cytoplasm. Larger numbers of PMN leukocytes are CONDITIONS ASSOCIATED WITH CEREBROSPINAL
abnormal in uncentrifuged CSF. C. neoformans is similar in FLUID EOSINOPHILIA
size to a small CSF lymphocyte, and nonbudding forms may
be mistaken for these cells in the counting chamber, though not Parasitic infestations
in stained cytocentrifuged or otherwise concentrated samples. Taenia solium (cysticercosis)
Neonatal CSF usually contains 8 to 9 WBCs/mm3, and up to Angiostrongylus cantonensis
32 WBCs/mm3 has been reported in the absence of disease (60)
Gnathostoma spinigerum
(Table 2.2).
The WBC count is usually between 1,000 and 5,000/mm3 Trichinella spiralis
in untreated bacterial meningitis (60), and more than 90% Ascaris lumbricoides
of patients with bacterial meningitis will have a WBC count Toxoplasma gondii
greater than 100 cells/mm3 (61). The most common three types
of viral meningitis in the United States (enterovirus, West Nile Toxocara cati
virus, and herpes simplex virus) have a median WBC count Toxocara canis
between approximately 100 and 250 cells/mm3 (25). Other infectious agents or conditions
Mycobacterium tuberculosis
Differential White Blood Cell Count Treponema pallidum
A differential count of CSF leukocytes may be obtained fol- Mycoplasma pneumoniae
lowing concentration of CSF through a Millipore filter, cen- Rocky Mountain spotted fever
trifugation of a volume (usually 5 mL) of CSF, concentration Subacute sclerosing panencephalitis
by sedimentation, or cytocentrifugation. The number of neu- Lymphocytic choriomeningitis virus
trophils is increased in various conditions. In adults with bac-
terial meningitis, neutrophils make up an average of 86.4% Fungal meningitides
of cells counted, with neutrophils making up an average of Central nervous system disorders of noninfectious or
34.2% of cells counted in aseptic meningitis (1,62). In the unknown origin
early stages of meningitis, this distinction between bacterial Idiopathic eosinophilic meningitis
and viral etiologies may not be clear because a neutrophilic Granulomatous meningitis
pleocytosis (50% neutrophils) may accompany early viral
meningitis or encephalitis (63). Up to two thirds of enterovi- Malignant lymphoma
ral meningitis cases initially have a neutrophilic predominance Hodgkin disease
(64). Within 12 to 24 hours, there is usually a shift from a Leukemia
neutrophilic predominance to a lymphocytic predominance,
Multiple sclerosis
which is why some may suggest a repeat LP if the first LP
was nonspecific (47). A lymphocytic pleocytosis is typically Subarachnoid hemorrhage
observed in patients with viral meningitis, M. tuberculosis, Obstructive hydrocephalus with shunt
Borrelia burgdorferi, Treponema pallidum, or C. neoformans, Reaction to intrathecal antibiotics
as well as in neoplastic and drug-induced meningitis (63). In
AIDS-associated cryptococcal meningitis, CSF pleocytosis Data from references 1, 6165, with permission.
may be absent, a finding that is associated with a worse
prognosis. Only up to 30% of patients with AIDS-associated
cryptococcal meningitis have a CSF WBC greater than 20 with
a lymphocytic predominance (57). In tuberculous meningitis,
the range of CSF pleocytosis is more commonly between 50 of RBCs are present. In such cases, one should compare num-
and 300 cells/mm3 with a lymphocytic predominance. Plasma bers of RBCs present in CSF obtained at the beginning of
cells and eosinophils should not be present in normal CSF (60). the LP with numbers present in CSF obtained at the end of
Increased numbers of B cells can be seen in neurosyphilis and the procedure (e.g., one should count cells from tubes 1 or
could represent another diagnostic option (65). Eosinophilic 2 and then from tube 4). The presence of xanthochromia in
meningitis can be caused by several parasitic infections, the samples centrifuged immediately after obtaining CSF argues
most common being angiostrongyliasis, gnathostomiasis, against a traumatic tap, although it must be kept in mind that
toxocariasis, cysticercosis, schistosomiasis, baylisascariasis, lysis of RBCs in vitro in CSF obtained during a traumatic tap
and paragonimiasis (66) (Table 2.3). In addition, however, will produce xanthochromia if the specimen is allowed to sit.
CSF eosinophilia has been reported in a wide variety of other Crenation of RBCs may occur in vitro and has no diagnos-
infectious and noninfectious conditions (Table 2.3), so detec- tic significance (67). Blood entering CSF during spontaneous
tion of eosinophils within the CSF is not pathognomonic of subarachnoid hemorrhage or as the result of a traumatic tap
parasitic infestation (66). contains WBCs and RBCs, and thus, the CSF leukocyte count
will increase. Numbers of WBCs relative to those of RBCs in
CSF after a traumatic tap should be consistent with the leuko-
Red Blood Cells
cyte count of the peripheral blood, and the differential count
The presence of RBCs in CSF may result from a traumatic LP of CSF will be the same. In contrast, actual subarachnoid
or may indicate subarachnoid or parenchymal hemorrhage. hemorrhage often produces pleocytosis and alteration in the
Grossly bloody fluid that clears visibly as CSF is collected sug- differential count. A traumatic tap in the setting of CNS infec-
gests a traumatic tap. Differentiation between a traumatic LP tion will increase the numbers of WBCs already present by an
and subarachnoid blood as the result of intracranial or intra- amount that can be calculated by comparing the ratio of RBCs
spinal pathology becomes more difficult if only small numbers to WBCs in CSF with that seen in peripheral blood.

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Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 13

Cerebrospinal Fluid Glucose greater than 0.3 was felt to exclude most (but not all) cases
of bacterial meningitis. Additionally, Spanos, Harrell, and
Most glucose present in CSF (Table 2.2) moves across the Durack (81) performed a retrospective study of 422 patients
choroid plexus and across ventricular and subarachnoid with acute bacterial or viral meningitis and found that CSF
capillaries by facilitated transport. A smaller amount of glu- glucose levels less than 18 mg/dL (1.9 mmol/L) and a CSF/
cose enters the CSF by simple diffusion. Glucose is removed blood glucose ratio less than 0.23 were predictors of bacterial
from CSF through utilization by cells lining the ventricles and meningitis. Furthermore, hypoglycorrhachia is associated with
subarachnoid space and by transport across capillaries and an adverse clinical outcome in patients with meningitis and a
arachnoid villi. Entry of glucose occurs over time, and more negative Gram stain (82).
than 2 to 4 hours is required before serum and CSF glucose
levels reach equilibrium (1). In the absence of infection or Cerebrospinal Fluid Protein
other pathologic conditions, CSF glucose levels are a predict-
able reflection of blood glucose, and the ratio of CSF to blood Protein is largely excluded from CSF by the bloodCSF bar-
glucose concentrations is approximately 0.6. The CSF glucose rier and, under normal conditions, reaches CSF by pinocytotic
level, equilibrated with a normal blood glucose level of 70 to transport across capillary endothelia (83). Total CSF protein
120 mg/dL, thus ranges between 45 and 80 mg/dL (Table 2.2). concentration in lumbar CSF of a healthy adult (Table 2.2) is
Levels of glucose in ventricular fluid are 6 to 18 mg/dL higher less than 45 mg, and the CSF/serum ratio of albumin is 1:200
than those in lumbar fluid (1,68). (1,13). Mean values of lumbar CSF protein in healthy children
CNS infections may alter glucose transport across the and adults have ranged from 23 to 38 mg/dL, and the extreme
bloodCSF barrier, resulting in a low CSF glucose level, upper and lower concentrations have been 58 and 9 mg,
termed hypoglycorrhachia (1). Further reduction in CSF glu- respectively (1). The CSF protein level in premature and full-
cose levels may result from glucose consumption by WBCs term neonates may range between 20 and 170 mg/dL, with
and organisms (1). Reduction of CSF glucose relative to blood a mean of 90 mg/dL (58) (Table 2.2). Protein concentrations
glucose is characteristic of meningitis caused by bacteria, in cisternal and lumbar CSF are lower, ranging from 13 to
mycobacteria, or fungi (69,70). The CSF glucose level is usu- 30 mg/dL (1). Elevation of protein concentration in the set-
ally normal during viral infections, but low CSF glucose levels ting of CNS infections results from disruption of tight junc-
are occasionally observed in meningoencephalitis caused by tions between endothelial cells of venules and, to a lesser
mumps, enteroviruses, lymphocytic choriomeningitis, herpes extent, other small meningeal or parenchymal vessels (83).
simplex, and herpes zoster viruses (25,71). Low CSF glucose Elevation of CSF protein level to more than 150 mg/dL may
values have also been described in CNS complications of cause the CSF to be xanthochromic. Extreme elevation of pro-
Mycoplasma pneumoniae infection, carcinomatous meningi- tein (to 1.5 g/dL) may cause formation of a weblike surface
tis, CNS sarcoidosis, and subarachnoid hemorrhage (7275). pellicle or an actual clot, as may high levels of fibrinogen (1).
During recovery from meningitis, CSF glucose levels tend Levels of CSF protein may be falsely elevated by deteriorating
to return toward normal more rapidly than cell counts and RBCs following subarachnoid hemorrhage or traumatic LP.
protein levels, making CSF glucose levels an important param- The amount of increase is roughly 1 mg/dL per 1,000 RBCs.
eter to follow in assessing response to therapy (76,77). Accurate assessment of the contribution to total CSF protein
Both reduction in CSF glucose values and altered ratios made by RBCs requires that the cell count and protein deter-
of CSF to blood glucose levels are used as indicators of mination be carried out on the same tube of CSF.
infection. However, the literature contains a variety of recom- Changes in the concentration of protein in CSF are the most
mendations about the point at which CSF glucose should be common and least specific of CSF alterations in disease and
considered abnormally low (78); this is partly because of the are seen in a wide variety of infectious and noninfectious neu-
prolonged interval over which CSF glucose equilibrates with rologic conditions. Thus, an elevated CSF protein level, taken
serum glucose. In general, a CSF/blood glucose ratio less than alone, has little specific value in the diagnosis of CNS infections.
0.5 should be considered abnormal. In premature and full- Elevation of CSF protein to levels more than 100 mg/dL, par-
term infants, however, the normal CSF/blood glucose ratio is ticularly if obtained on serial LPs, argues against viral infec-
0.74 to 0.96, and a ratio of 0.6 is usually considered abnor- tion, however, and Spanos, Harrell, and Durack (81) have
mal (79). In severe hyperglycemia, transport of glucose into demonstrated that elevation of protein to a level of 220 mg/dL
CSF may lag, and at a blood sugar level of 700 mg/dL, the (2.2 g/L) suggests bacterial meningitis. The CSF protein levels
CSF/blood glucose ratio may approach 0.4. For this reason, return to normal more slowly than glucose levels and cell count
a ratio of 0.3 has been suggested as abnormal in diabetics during recovery from meningitis and may remain abnormal for
(80). Silver and Todd (78) addressed the problem of diag- months after parenchymal infections. Although elevation of
nostically significant hypoglycorrhachia in a study of 181 CSF protein is common in CNS infections, normal protein val-
pediatric patients with CSF glucose levels less than 50 mg/dL ues are occasionally seen in all types of CNS infections, includ-
or a CSF/blood glucose ratio less than 50%. Patients ranged ing bacterial meningitis. In children with bacterial meningitis,
in age from younger than 1 week to 14 years, with an average antibiotic administration more than 12 hours before the LP
age of 1 years. Their series included patients with bacterial is associated with lower CSF protein and higher CSF glucose
meningitis, aseptic meningitis, subarachnoid hemorrhage, and concentrations (84).
CNS carcinomatosis but did not include patients with tuber-
culous or fungal meningitis. Blood for glucose analysis was
Cerebrospinal Fluid Immunoglobulins
obtained 1 to 114 minutes before the LP (average interval, Immunoglobulins are almost totally excluded from normal
30 minutes). Of 35 patients with bacterial meningitis in this CSF. The blood/CSF ratio of immunoglobulin G (IgG) in
series, 27 (77%) had CSF glucose levels of 20 mg/dL or less, normal CSF is usually in the range of 500:1. Immunoglobulin
whereas CSF glucose levels of 20 mg/dL or less were found in M (IgM) is essentially absent from CSF. Studies with radio-
only 10 (7%) of 146 patients with other conditions. A CSF iodinated IgG have demonstrated that CSF IgG in healthy
glucose level less than 20 mg/dL or a CSF/blood glucose ratio individuals is derived entirely from serum, requiring 3 to
less than 0.30 was highly correlated with bacterial meningi- 6 days to reach equilibrium (1). Immunoglobulins enter CSF
tis, whereas an absolute CSF glucose value between 20 and less readily than albumin; and in health, immunoglobulin/
50 mg/dL was nonspecific; also, a CSF/serum glucose ratio albumin ratios in CSF are reduced relative to those in serum.

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14 Part I: Approach to the Patient and Diagnostic Evaluation

Elevation in CSF immunoglobulins may follow disruption glucose and protein levels if administered within 12 hours of
of the BBB, allowing passage of immunoglobulins across the LP (84). The sensitivity of the Gram stain in children and
capillary endothelium, or may result from local antibody adults with pneumococcal meningitis ranges between 69% and
synthesis within the brain. Increased levels of CSF IgG per se 95% and in meningococcal meningitis between 30% and 89%.
have little diagnostic value in CNS infections. Detection of Blood cultures will be positive in 50% to 80% of patients, and
oligoclonal IgG bands unique to CSF and not seen in serum the CSF cultures will be positive between 80% and 90% of
on gel electrophoresis provides strong evidence for an ongoing cases (86). In general, the sensitivity of the Gram stain ranges
immune response within the brain and is part of the diagnostic from 50% to 90%; however, the specificity approaches 100%
criteria for multiple sclerosis (85). (61,86). In one study, only 22 (4%) out of 567 patients with
community-acquired meningitis and a negative Gram stain had
culture-proven bacterial meningitis (82).
Microscopic Methods for Detecting
Infectious Organisms
Partially Treated Bacterial Meningitis
Gram Stain The diagnosis of patients that present with possible bacterial
Gram stain is of crucial value in providing rapid identification meningitis who have received antibiotics remain a challenge
of the offending organism in bacterial meningitis, and it is fast, to clinicians. The acridine orange stain is a fluorochrome
inexpensive, and fairly reliable (Fig. 2.4). It is usually the single stain that has been shown to improve detection of bacteria
most important piece of information the clinician uses to guide in CSF specimens, especially in patients who have partially
initial antibiotic therapy and should be an invariable part of treated bacterial meningitis (87). A more recent approach is
the CSF evaluation. Diagnostic accuracy of a properly prepared detection of Streptococcus pneumoniae C-polysaccharide,
Gram stain is a function of the number of organisms present, which is found in the cell wall and is common to all serotypes,
the type of meningeal pathogen, and by the receipt of prior in CSF by using rapid immunochromatographic membrane
antibiotic therapy (61). In one large study of bacterial men- assays (88,89). Two large, multicenter studies have shown
ingitis in children, prior antibiotic exposure did not alter the a sensitivity and specificity of 99% detecting S. pneumoniae
sensitivity of the Gram stain but decreased the sensitivity of even in patients who have been pretreated with antibiotics that
the blood and CSF cultures by 18% and also altered the CSF have negative CSF cultures (90,91).

FIGURE 2.4 Gram stains of CSF from patients with bacterial men-
ingitis. A: Streptococcus pneumoniae. B: Neisseria meningitides.
C: Gram-negative meningitis.

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Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 15

Cerebrospinal Fluid Bacterial Culture


Choice of culture media, methods of handling, and lengths of
time over which cultures are to be maintained are thoroughly
discussed in standard reviews and texts (92,93). The CSF
should be submitted to the laboratory immediately after the LP
and should be placed in culture promptly to avoid loss of fas-
tidious organisms such as Haemophilus influenzae, Neisseria
meningitidis, or anaerobes. CSF cultured for bacteria should,
at a minimum, be plated on a 5% sheep blood agar, chocolate
agar, and inoculated into an enrichment broth (93). A mini-
mum of 2 mL (ideally 5 mL or more) should be submitted for
Gram stain and bacterial culture.

Cerebrospinal Fluid Acid-Fast Bacilli Stains


and Cultures
A positive acid-fast stain for detection of M. tuberculosis is FIGURE 2.5 India ink preparation of CSF from a patient with
highly suggestive of tuberculous meningitis, but positive results cryptococcal meningitis. The capsule of a cryptococcal organism is
occur in only 10% (94). The sensitivity of the acid-fast stain clearly outlined by ink particles.
depends greatly on the skill and persistence of the examiner and
the amount of fluid concentrated. In general, collecting four
serial samples and spinning of large volumes (20 mL) of CSF for
30 minutes enhances the rate of detection by smear microscopy,
but it is impractical (95). Isolating mycobacteria in culture is diffi- Viral Culture
cult with detection rates for M. tuberculosis between 10.2% and
55.8% for conventional Lowenstein-Jensen medium and from Isolation of viral agents by tissue culture methods has been the
4.3% to 48.9% for the automated commercial system BACTEC traditional means of diagnosis in cases of suspected viral men-
Mycobacteria Growth Indicator Tube (MGIT) 960 (96). ingitis or encephalitis. Newer methods of virus isolation have
improved diagnostic yield; these include the incorporation of
multiple tissue culture cell lines and a combination of culture
Microscopic Detection of Anaplasma, Fungi, and staining procedures (shell vial assay for early antigen
and Protozoa in Cerebrospinal Fluid detection, enzyme immunoassays, and immunofluorescence
staining). Enteroviruses can be isolated in 43% to 77% of
In a few cases, intracellular morulae have been detected in CSF of patients, depending on the predominant viral serotype in a
patients with meningitis due to Anaplasma infection (97). Fungi, particular community. In approximately half of these cases,
including C. neoformans, Blastomyces dermatitidis, C. immitis, virus will be isolated by day 3 and in more than 80% by day 7
and Candida albicans, may occasionally be detected on Gram or (104). Mumps virus and lymphocytic choriomeningitis virus,
silver stains of concentrated CSF (98). In many cases of fungal the agents of western and eastern equine encephalitides, may
meningitis, however, organisms are too few to be readily detect- also be recovered from CSF. Herpes simplex virus (HSV) types
able, and negative Gram or silver stains of CSF sediment in no 1 and 2 can be isolated from cases of meningitis but are rarely
way excludes the possibility of fungal infection. India ink prepa- recovered from CSF in cases of encephalitis. Varicella-zoster
rations, in which CSF sediment from 3 to 5 mL of CSF is mixed virus; cytomegalovirus; and California, St. Louis, and Japanese
with a drop of India ink, provide a useful means of outlining the encephalitis viruses are rarely recovered (105).
capsule of C. neoformans (Fig. 2.5). Sensitivity of the India ink
preparation is about 60% in patients who are not infected with
acquired immunodeficiency syndrome (AIDS) and more than
75% in patients with AIDS (98). Cryptococcal antigen detection
ADJUNCTIVE AND
has replaced India ink preparations in most laboratories because MOLECULAR STUDIES OF
of its high sensitivity and specificity (99).
Wet mount preparations may be used to identify motile
CEREBROSPINAL FLUID IN
trophozoites in the CSF of patients with primary amebic THE DIAGNOSIS OF CENTRAL
meningoencephalitis (100). Search for motile organisms in NERVOUS SYSTEM INFECTION
wet mounts may be made more reliable by the use of phase-
contrast microscopy. The need for rapidly available accurate diagnostic informa-
C. neoformans is cultured from the CSF in approximately tion in CNS infections, the poor sensitivity of microscopic
72% of patients on the first LP and in more than 90% on examination of CSF sediment, and the delays inherent in
multiple attempts (101). Frequency of recovery of C. albicans obtaining results of CSF culture have led to the development
from CSF is also high (102). Isolation of other organisms such of a wide variety of rapid diagnostic tests for CNS infections.
as Histoplasma capsulatum or Brucella species often proves At present, PCR methods have largely replaced tissue culture
difficult (103). methods for enteroviruses, Herpetoviridae (herpes simplex,
In most bacterial and fungal infections, extraneural sites herpes zoster, cytomegalovirus, Epstein-Barr virus), JC virus,
of possible infection should also be cultured. Depending on and West Nile virus. West Nile virus meningoencephalitis is
the organism being sought, these sites may include blood, diagnosed largely by serology because the virus is only rarely
urine, paranasal sinuses, ears, skin, oropharynx, sputum, bone isolated by tissue culture methods at the time patients present
marrow, prostate, or abscess material. with neurologic symptoms (106).

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16 Part I: Approach to the Patient and Diagnostic Evaluation

S. pneumoniae, E. coli K1, and Streptococcus agalactiae. In


Bacterial Infections general, these tests find little application; antigen-detection tests
are less sensitive than bacterial culture, offer no advantages over
Lactic Acid the Gram stain, and their diagnostic reliability and usefulness
Elevation of lactic acid levels in CSF occurs more frequently may vary from institution to institution (114,115). Situations
in bacterial than in viral meningitis. A CSF lactate cutoff value in which antigen-detection tests are not likely to be helpful
of more than 3.5 to 4.2 mmol/L provides supportive evidence include cases in which the Gram stain is positive, in which the
for a bacterial infection in untreated patients. Two large CSF WBC count and chemistries are within normal limits, and
metaanalyses have concluded that the determination of CSF in which the CNS infection is hospital acquired (115).
lactate level is better than the CSF WBC, glucose, or protein
in differentiating bacterial meningitis from aseptic meningitis Polymerase Chain Reaction
(sensitivity of 93% and 97% and specificity of 96% and 94%, Molecular techniques such as polymerase chain reaction (PCR)
respectively) (107,108). are well suited for the diagnosis of CNS infections because the
presence of microorganisms is highly suggestive of infection.
C-Reactive Protein PCR has emerged as a novel technique for identifying viral,
C-reactive protein (CRP) is an acute phase reactant released bacterial, and mycobacterial causes of meningitis (116119).
from the liver in response to an inflammatory reaction, such as Although CSF makes an ideal source to examine by PCR because
meningitis. CRP is released within 6 hours of insult and peaks it is sterile and without contaminants, the presence of inhibitors,
after 36 hours. One of the functions of CRP is to bind to phos- assay contamination, and experimental conditions may some-
pholipid components of damaged cells or bacteria resulting in times alter its diagnostic value (118). There are a variety of PCR
activation of the classical complement pathway (109). Both methods used today including multiplex and nested PCR.
serum and CSF CRP have been studied as potentially useful Multiplex PCR has the advantage of potentially detecting more
tools for discriminating bacterial meningitis from aseptic than one organism in the same PCR reaction. This is done by
or viral meningitis. A large retrospective study in children using two or more primer pairs, each specific for a single agent.
showed a sensitivity of 93% and a specificity of 100% with In nested PCR, products from the first amplification are reampli-
a CRP greater than 40 mg/L to detect bacterial meningitis fied from a second set of primers that is nested between the first
(110). Furthermore, a metaanalysis showed that a CRP level set. This essentially overcomes nonspecific amplification (i.e.,
greater than 20mg/L was conveyed significantly higher odds of assay contaminations) and increases the sensitivity of detection.
bacterial meningitis (odds ratio [OR] 9.9 [4.8 to 20.8]) (111).
Current literature supports the assertion that CRP may be Bacterial Polymerase Chain Reaction. The use of PCR in
useful, but it should be used with caution as the sole criterion bacterial meningitis may serve a role in patients previously
in the differentiation of bacterial versus viral meningitis (61). treated with antibiotics or in the detection of difficult to
culture organisms such as Mycoplasma or Brucella. However,
Procalcitonin molecular tests are not routinely available, and Gram stain
Procalcitonin (PCT) is a calcitonin propeptide synthesized and culture of the CSF is still the gold standard for diagnosis.
by C cells of the thyroid gland and released from leukocytes Broad-range PCR amplifies the 16S ribosomal RNA (rRNA)
of the peripheral blood (112). It has been used as a marker gene that is present in all bacterial species. Broad-range PCR
of severe inflammation such as those caused by bacterial and organism-specific PCR have been used in detecting menin-
infections, pancreatitis, burns, or trauma (113). In a prospec- geal pathogens with sensitivities between 89% and 100% and
tive multicenter trial of 151 patients with a negative Gram specificities of 95% to 100% (61). In a study of 409 patients
stain, 18 had confirmed bacterial meningitis; a serum PCT with bacterial meningitis in Burkina Faso, PCR was able to
greater than 0.5 ng/mL (sensitivity 87%, specificity 100%, make the diagnosis in a third of patients who had negative
positive predictive value 1.0, negative predictive value 0.99) bacterial cultures (120). The availability, expense, and time to
had better diagnostic accuracy than serum CRP, CSF leukocyte run these test may prove difficult, and positive results ideally
count, CSF/blood glucose ratio, CSF protein, and the physi- should be confirmed by species-specific PCR. Furthermore,
cians assessment (109). A metaanalysis showed that a procal- contamination of PCR specimens may cause false-positive
citonin level greater than 0.5 g/L was predictive of bacterial results, which can be encountered by improper handling or
meningitis with an OR 434 (95% confidence interval [CI] contaminated work equipment from previous PCR reactions.
57 to 1,000) (111). Procalcitonin in the CSF may also be
elevated in patients with probable Alzheimer disease, vascular Viral Polymerase Chain Reaction. The use of PCR is the
dementia, dementia with Lewy bodies, frontotemporal demen- preferred method of diagnosing patients with suspected
tia, and encephalitis (113). viral encephalitis such as those caused by HSV, enterovirus,
varicella-zoster virus, cytomegalovirus, or Epstein-Barr virus
Additional Biomarkers (117). This is very important in cases of suspected HSV
encephalitis that can cause significant morbidity and mortality
Bacterial meningitis results in systemic and intrathecal inflamma- if untreated. There are over 100 known viruses that may infect
tory reactions that may lead to significant morbidity and mortal- the CNS although only a limited number of tests are available
ity. Several inflammatory markers (interleukin-1 [IL-1], IL-6 for confirmation (117). The decision to perform molecular
and -12, TNF-, soluble triggering receptor expressed on myeloid tests is physician-driven and is often based on the clinical
cells-1 (sTREM1), cortisol, heparin-binding protein, and comple- presentation. In a study of 760 adult patients presenting with
ment factor 3 and complement B) have all been evaluated in small meningitis and a negative Gram stain, only 44% had PCR in
studies with adequate diagnostic accuracy (61). the CSF performed for a viral pathogen (116).
Detection of Bacterial Antigens Herpes simplex virus. Herpes simplex encephalitis (HSE)
Antigen-detection tests using latex agglutination assays are is the most common cause of sporadic encephalitis in the
available to rapidly detect meningitis caused by H. influenzae United States, and it is the most common cause of severe viral
type b, N. meningitidis serogroups A, B, C, Y, and W135, encephalitis (121). In immunocompetent adults, 90% of HSE

Scheld_Ch02.indd 16 2/21/14 5:27 PM


Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 17

is caused by HSV-1, with the remaining 10% caused by HSV- the Centers for Disease Control and Prevention (CDC) recom-
2. In AIDS patients, the rate of HSV-2 may be higher (122). mends using a two-step process for testing serum from patients
Empirical antiviral therapy and prompt identification are of suspected of having Lyme disease (130). Step one involves
crucial importance because of the high morbidity and mor- screening with a sensitive assay such as enzyme-linked immu-
tality associated with HSE. Early initiation of intravenous nosorbent assay (ELISA) or immunofluorescence assay. Those
acyclovir has been shown to reduce mortality in patients with samples that are negative by such an assay are not tested further.
HSE (123). The availability of PCR has now become the diag- All equivocal or positive results are subsequently confirmed by
nostic modality of choice for diagnosing HSE (117,121,123). immunoblotting (Western blot) (131). Standardized criteria
Numerous studies have shown sensitivities greater than 90%, for interpretation of both IgM and IgG are outlined elsewhere
with specificities near 100% (117). Viral cultures are not rou- (131). Antibody to B. burgdorferi may be absent early in the
tinely recommended because they are positive in less than 5% course of infection, and seronegative Lyme disease, diagnosed
of adults. Prior to PCR, the gold standard for diagnosing HSE by T-cell proliferation to Lyme disease, has been reported
was brain biopsy (121). A negative PCR for HSV does not rule (132). False-positive test results for Lyme disease may be seen
out HSV encephalitis but rather makes it less likely (117). in patients with infectious mononucleosis, positive serology for
syphilis, and autoimmune conditions.
Enterovirus. Enteroviruses are one of the most common causes In the acute form of neuroborreliosis, there is usually
of aseptic meningitis in children and in adults (71). Enterovirus pronounced synthesis of IgM antibody production (133). IgG
PCR in the CSF has improved the detection rates compared to and IgA synthesis is seen in the chronic forms of disease (133).
viral cultures, and results can be available within 2 hours. The Detection of intrathecal antibody production is considered
Gene Xpert Enterovirus PCR had a sensitivity of 97.1% (95% the most specific test for neuroborreliosis (134). However,
CI, 84.7% to 99.9%) and a specificity of 100% (95% CI, 94.6% not all patients develop CSF antibodies. The CSF antibody
to 100%) for the diagnosis of enteroviral meningitis (124). production in subtle CNS disease is inconsistent and may be
A rapid diagnosis of enteroviral meningitis could impact care by lacking in patients with only peripheral nerve involvement
avoiding hospitalization or empirical antibiotic therapy (71). (135). Detection of CSF antibody is not essential for diagnosis
(134,135). Accuracy and reliability of tests vary considerably
between laboratories; therefore, positive values reported by
Mycobacterial Polymerase Chain Reaction laboratories unfamiliar to the physician must be approached
with caution and, if necessary, confirmed.
The diagnosis of tuberculous meningitis (TM) can be difficult There is currently not a validated PCR method commercially
because culture sensitivities are low, and the organism may available (136). There are several parameters that can have sig-
take up to 6 weeks to grow (96). PCR has received interest in nificant effects on the performance of the PCR such as sample
hopes it may serve as a rapid, sensitive, and specific test for type and volume, extraction method (nested PCR, PCR followed
TM. One of the more frequently used M. tuberculosis PCR by hybridization, real-time PCR), target, primers, template DNA,
targets is IS61100 (125). Investigators prospectively studied and PCR chemistry (136). A metaanalysis derived from published
677 CSF samples in patients with clinically suspected TM PCR results irrespective of methods or targets from patients with
(125). All culture-positive samples (n 136) were positive all stages of Lyme neuroborreliosis demonstrated an overall sensi-
(100%) by the PCR assay. In those patients with clinically sus- tivity of 19% and a specificity of 100% (137). Other reports have
pected (culture negative) TM, the assay was positive in 70% indicated that PCR is no more sensitive as a diagnostic tool than
(n 541). Not all studies have shown as good of results, with the measurement of intrathecal antibody production and overall
some sensitivities being reported as low as 33% (126) and as is less useful (138139). PCR should not be considered a stand
high as 87% (127). Specificities also have a wide range from alone test, and a negative result does not rule out neuroborrelio-
88% to 100% (94). This discrepancy could be due to the sis. At present, molecular assays may, at most, have a limited role
different types of measuring methods with the use of different as adjunctive tests in patients who are seronegative and who have
targets used in the laboratories (127). a high likelihood of infection (e.g., as in the case of the immuno-
deficient patient). Elevated levels of CSF CXCL13 (C-X-C motif
Measurement of Adenosine Deaminase Levels chemokine 13) have been described in Lyme neuroborreliosis and
in Cerebrospinal Fluid could serve as a diagnostic marker. Furthermore, CSF CXCL13
decreased with intravenous ceftriaxone and oral doxycycline
Adenosine deaminase is an enzyme that is widely distributed
(140). As research tools, molecular assays may provide insight
in human tissues and is present in high concentrations in
into pathogenesis and clinical course when used prospectively
lymphocytes. Elevation of CSF adenosine deaminase levels
during the course of illness.
may occur in a variety of neurologic disorders, including
bacterial meningitis, brain abscess, neurobrucellosis, cryp-
tococcal meningitis, and CNS lymphoma. Elevated levels of Fungal and Other Infections
lymphocyte adenosine deaminase are frequently present in the
CSF of patients with TM, and measurement of this enzyme has
Fungal Infections
been used to provide presumptive evidence of M. tuberculosis
infection and to evaluate response to treatment (128,129). The Detection of cryptococcal antigen in spinal fluid is the most
test, though both sensitive and useful, is not specific because practical diagnostic test for cryptococcal meningitis. The
it detects a component of host response and does not detect a test has a high degree of specificity and is positive in 83% to
structural component of the organism itself. 98% of patients (141). Detection of cryptococcal antigen has
replaced India ink stains. Despite its sensitivity and specificity,
however, assays for cryptococcal antigen may occasionally
Lyme Disease give false-negative results in both immunocompetent and
immunocompromised patients (142). Screening for cryptococ-
The overall sensitivity and specificity of tests for diagnosis of cal meningitis as a point of care test by using the cryptococcal
Lyme disease are still being determined, as is the accuracy of antigen in urine or plasma could help identify patients at high
tests used to diagnose CNS involvement. In the United States, risk sooner and possibly decrease mortality (143,144).

Scheld_Ch02.indd 17 2/21/14 5:27 PM


18 Part I: Approach to the Patient and Diagnostic Evaluation

Complement-fixing antibodies have been reported in CSF is less sensitive (117). Comparison of serum and CSF titers of
in up to 95% of cases of meningitis caused by C. immitis IgG and IgM antiviral antibodies has been proposed as a diag-
(145), although yield of detection has not been that high in nostic test in encephalitis caused by HSV and other agents, but
all series (146). Diagnosis of Histoplasma meningitis can be the test, which is dependent on intrathecal antibody synthesis,
extremely difficult, especially the chronic form of the disease, is of limited value at the time of presentation, and intrathecal
which may occur in the absence of other manifestations of antibody may become detectable only as virus is cleared from
disseminated infection (147,148). Detection of CSF antibodies the CSF compartment (161). Most patients presenting with
may be useful, but false-positive results have been reported West Nile virus infection already have CSF IgM antibodies to
in patients with fungal meningitis caused by other organisms the virus, making this the diagnostic method of choice (162).
and by diffusion of serum antibodies to H. capsulatum into Compared to viral culture (overall sensitivity, 14% to 24%),
the CSF during other inflammatory conditions of the meninges the sensitivity of PCR ranges from 75% to 100% depending
(149). Histoplasma polysaccharide antigen detection can be on the virus (163175). Molecular detection of viral nucleic
detected in CSF, serum, or in urine. Small studies of less than acid sequences in CSF has not only improved diagnosis but
20 patients have documented sensitivities between 38% and also has largely replaced invasive methods such as brain
71% (149,150). biopsy, has shortened time to specific diagnosis, and particu-
Development of molecular techniques for diagnosis of fun- larly in enteroviral CNS infections, has proven cost-effective
gal infections has lagged behind those assays for detection of through decreased use of empirical antibacterial therapy and
other pathogens. There are many reasons for this, but the most reduction in hospital stay (163165). Finally, molecular assays
compelling is the ubiquitous nature of fungi in the environment have added greatly to our understanding of the epidemiology
and the difficulties with contamination control. Initial assays and pathogenesis of these infections (125,166,167).
used species-specific, single-copy genes (150). More recently,
investigators have evaluated the use of highly conserved,
multicopy genes that are universal to all or most fungal species Other Adjunctive Tests in the Diagnosis
(150). Such targets have included 18S rRNA subunit genes, of Central Nervous System Infections
28S rRNA genes, mitochondrial genes, and the intergenic
transcribed spacer (ITS) region of the rRNA gene (149,150). Detection of Cytokines in Cerebrospinal Fluid
Toxoplasmosis TNF, IL-1, and other cytokines have received increasing
Encephalitis is the most common presentation of toxoplasmo- attention as mediators of the inflammatory response during
sis in the immunocompromised patient and most commonly bacterial meningitis and can help distinguish between bacterial
results from reactivation of latent infection (151). CSF antibody and viral meningitis (176180). Lopez-Cortez et al. (178) have
titers have been used to diagnose and follow CNS infections recently demonstrated that a TNF- level of more than 150 pg/
caused by Toxoplasma gondii in both patients with AIDS and mL and IL-1 level more than 90 pg/mL showed sensitivities of
patients without AIDS (152,153). PCR may be useful in the 74% and 90%, respectively, in discriminating viral from aseptic
absence of typical serologic or radiologic studies and could po- meningitis. Pinto Junior et al. (179) found that an elevated CSF
tentially decrease the need for a brain biopsy (154,155). IL-8 level was higher in patients with acute bacterial meningitis
compared to aseptic meningitis and controls (100% of sen-
Whipple Disease sitivity and 94% of specificity). Tang et al. (180) determined
the concentrations of IL-1 and TNF- in the CSF of 171
Whipple disease is a systemic illness caused by Tropheryma specimens of 144 patients whose cases were classified as fol-
whippelii. Illness is characterized by a predominance of intesti- lows: bacterial meningitis (n 23), aseptic meningitis (n 26),
nal manifestations, but extraintestinal manifestations including and nonmeningitis (n 95). Significantly higher serum IL-1
endocarditis, myocarditis, pericarditis, and CNS disease occur and TNF- concentrations were detected in those with bacterial
with relative frequency (156). Although cultivation of the meningitis than those with aseptic meningitis or among those
organism has been reported (157), diagnosis is generally made patients without meningitis (p 0.001). These findings, though
by a combination of cytologic analysis of tissue and fluids using requiring both confirmation and amplification, suggest that
periodic acidSchiff (PAS) staining to demonstrate the presence analysis of TNF and other cytokines, in particular IL-1, may
of macrophages laden with intracellular organisms and electron prove valuable in differentiating acute bacterial meningitis from
microscopy (158). PCR has also been used to determine the viral meningitis and possibly in detecting patients at particular
stage of disease and monitor response to therapy (158,159). risk of adverse outcome. Their role in guiding adjunctive
False-positive PCR results have been reported in asymptomatic therapy, such as corticosteroids and nonsteroidal treatment of
individuals, and for this reason, PCR cannot be recommended BBB injury, is also under investigation.
in place of standard diagnostic techniques (159).

CHARACTERISTIC
Viral Infections CEREBROSPINAL FLUID FINDINGS
PCR methods have had their greatest impact in the diagnosis IN MAJOR CENTRAL NERVOUS
of viral meningitis and encephalitis and have replaced tissue
culture methods (117, 123). Additionally, before the advent
SYSTEM INFECTIONS
of PCR, CSF antibody titers and determination of CSF/serum
antibody ratios were routinely used as methods of acute viral Bacterial Meningitis
diagnosis. Determination of CSF antibody titers per se has
been found valuable in the diagnosis of chronic CNS infec- Bacterial meningitis characteristically produces a neutrophilic
tions such as tropical spastic paraparesis or subacute sclerosing pleocytosis, hypoglycorrhachia (CSF glucose 45 mg/dL), and
panencephalitis (160), but CSF antibody titers alone are of an elevated protein level. Numbers of PMN leukocytes may
limited value in most cases of acute viral encephalitis with the vary from a few to many thousand and usually range between
exception of arboviruses such as West Nile virus where the PCR 1,000 and 10,000 cells. A predominantly (50% of cells)

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Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 19

lymphocytic pleocytosis has been reported in up to 14% of H. capsulatum, Brucella, or other organisms as indicated by
patients (181), and atypical CSF profiles can especially be seen history and occupational exposure. Serum and CSF should be
in Listeria monocytogenes infection (182). A predominance frozen and held for future serologic studies. CSF findings in
of lymphocytes may also be seen in neonatal gram-negative fungal infections are similar to those described for tuberculous
meningitis (183). Leukocytes may be absent from CSF very meningitis, except that PMN leukocytes may be found less
early in the course of infection, in neonatal meningitis, or in often. The number of cells present may vary widely, and as
severely immunocompromised patients (184). in tuberculous meningitis, CSF may be acellular in severely
immunocompromised patients, including those with AIDS
(190). An exception to this rule is seen in infections with
Brain Abscess and Parameningeal Infection Mucorales, in which the extremely destructive nature of the
infection may result in large numbers of neutrophils (191).
Subdural empyema complicates community-acquired bacterial As in tuberculous meningitis, CSF glucose level may return
meningitis in 2.7% of cases and is usually caused by S. pneu- toward normal before changes are seen in cell count and
moniae in association with sinusitis or otitis (185). CSF protein.
cultures are positive in 93% of these patients. In contrast, LP
in brain abscess is not helpful and has been complicated with
brain herniation in 4 out of 296 (1.3%) of patients (186). The Neurosyphilis
CSF findings are nonspecific and may include (a) a mixed, pre-
dominantly lymphocytic pleocytosis, (b) normal glucose level, Suspicion of neurosyphilis is predicated on the presence of
and (c) elevated protein level. Organisms are not present un- reactive serum nontreponemal tests such as the rapid plasma
less there is accompanying meningitis, in which case CSF find- reagin (RPR) or the Venereal Disease Research Laboratory
ings will be those of bacterial meningitis (187188). (VDRL) and reactive serum treponemal tests such as the
fluorescent treponemal antibody-absorption (FTA-ABS),
Treponema pallidum particle agglutination (TPPA), or various
Tuberculous Meningitis enzyme immunoassays. A serum RPR titer 1:32 or greater is
associated with a higher probability of neurosyphilis in both
Typical findings in tuberculous meningitis are (a) a pleocytosis HIV and nonHIV-infected individuals; a CD4 less than 350
with lymphocytic predominance, (b) lowered glucose level, cells/L is another predictor in HIV-infected patients (192).
and (c) elevated protein level (94,95). In approximately 70% A reactive CSF VDRL test confirms the diagnosis but it may
of patients, the cell count is between 100 and 400 cells (95). be insensitive, and a nonreactive test does not rule out neu-
However, as many as 1,000 to 1,200 cells may be present, rosyphilis (193,194). The CSF may contain variable numbers
and in few patients, the CSF is acellular despite the presence of lymphocytes and an elevated protein level in asymptomatic
of organisms, elevation in protein, and hypoglycorrhachia. or symptomatic neurosyphilis (1). The findings are extremely
Although most cells in the CSF are lymphocytes, relative variable, however, and normal CSF cell count, protein, and
numbers of lymphocytes and PMN leukocytes may vary from glucose values do not exclude active disease (193,194). Rarely,
LP to LP. Protein levels are 100 to 500 mg/dL in 65% of syphilis may present as an acute meningitis, with CSF findings
patients and may reach levels of 1,000 mg or more if treat- similar to those of bacterial meningitis (1). The T. pallidum
ment is delayed (94,95). In 25% of patients, protein levels PCR detection has been of value in primary syphilis, but the
are normal (94). Glucose levels are 30 to 45 mg/dL in 50% utility in neurosyphilis is still under investigation (195).
of patients and may occasionally be less than 10 mg/dL. In
17% of patients, CSF glucose levels are normal (94). More
recently, clinical models that include a duration of symptoms Lyme Borreliosis
for more than 5 days, abnormal neurologic status, a CSF to
serum glucose ratio less than 0.5, a low CSF neutrophilic per- The CSF changes in Lyme neuroborreliosis are typically a
centage (50%), and a CSF protein greater than 100 mg/dL mild lymphocytic pleocytosis, modest elevation of protein
among others can aid clinicians distinguish between TM from level, normal glucose level, and may mimic viral meningitis.
bacterial meningitis but need to be validated in other patient A clinical model named the rule of 7s can help distinguish
populations (189). patients with Lyme meningitis from aseptic meningitis with a
M. tuberculosis may be extremely difficult to detect on sensitivity of 96%. If all the variables (7 days of headache,
smear or to recover by culture. When tuberculous meningi- 70% CSF mononuclear cells, and absence of seventh or
tis is strongly suspected, obtaining more than 6 mL of CSF other cranial nerve palsy) are absent, the patient has a low risk
and repeating LPs can be associated with a higher degree of of having Lyme meningitis (196).
positive acid-fast bacilli smears and cultures (189). PCR may
provide a rapid means of diagnosis superior to acid-fast stain
(125127). Infections Caused by Mycoplasma, Rickettsia,
Ehrlichia, Anaplasma
Fungal and Other Chronic Meningitides CSF in meningoencephalitis associated with M. pneumoniae
infections may be normal but has also been characterized by
Initial requirements for CSF analysis in suspected fungal infec- a usually lymphocytic pleocytosis, elevated protein level, and
tions are similar to those described for tuberculous meningi- mildly depressed glucose level (72). CSF in Rocky Mountain
tis, and the same material may be sent for both mycobacterial spotted fever is usually acellular but may contain increased
and fungal culture. CSF should be submitted for cryptococ- protein concentration (197); typhus may be accompanied by
cal antigen and, if the patient has a history of residence in lymphocytic pleocytosis and elevation of protein concentra-
an endemic area such as the southwestern United States, tion (198). Meningoencephalitis has been reported in human
for complement-fixing antibodies to C. immitis. Additional granulocytic anaplasmosis (Anaplasma phagocytophilum)
samples of CSF should be submitted for serologic studies for in approximately 1% of cases and in human monocytic

Scheld_Ch02.indd 19 2/21/14 5:27 PM


20 Part I: Approach to the Patient and Diagnostic Evaluation

ehrlichiosis (Ehrlichia chaffensis and E. ewingii) in about 20% other conditions. As in viral meningitis, CSF should be sent for
of cases, and it usually has a mild lymphocytic pleocytosis PCR and/or viral culture as appropriate, and both serum and
(199). One study has detected Ehrlichia morulae in CSF (97). CSF should be held for future serologic studies. Serum or CSF
should be sent for IgM and IgG antibody determination in cases
of suspected West Nile or other flavivirus encephalitis (123).
Viral and Other Acute Meningoencephalitis
Viral meningitis produces a lymphocytic pleocytosis, usually AIDS
in the range of 10 to 1,000 cells/mm3 with mildly elevated
protein and normal CSF glucose (25). PMN leukocytes may Abnormalities of CSF in HIV infection are protean and may
at times constitute more than 50% of the cells during the first reflect either (a) a response to CNS invasion by the agent
24 to 36 hours of the infection, and this can change in a re- itself, as in HIV-related meningitis, meningoencephalitis, and
peat LP (200,201) and in one series were shown to be present encephalopathy; (b) meningitis or parenchymal infection by
for several days (202). In some patients with coxsackievirus other agents; or (c) meningeal reaction to neoplastic or ischemic
infections of the CNS, PMN leukocytes may constitute 90% events within brain or spinal cord. The response to any of these
of cells at the onset of infection, and the predominance of conditions is often modified by the immunosuppressive effect
PMN leukocytes may persist for longer than 24 hours. There of the virus (206). In HIV-infected individuals, normal find-
are also reports of CSF samples with few or no cells yield- ings on routine CSF studies do not exclude infectious disease
ing enteroviruses on culture or by PCR (203). Protein is el- of the nervous system. The neurologic complications of HIV
evated in the range of 50 to 100 mg/dL but may sometimes infection and the approach to the patient with suspected neu-
be higher. Glucose is usually normal, but depression of glu- rologic involvement are discussed in detail elsewhere.
cose to levels approaching those of bacterial meningitis has
been reported in infections with HSV-2, herpes zoster virus,
mumps, and lymphocytic choriomeningitis virus (204,205). Prion Diseases
CSF should be routinely sent for PCR analysis for entero-
viruses, including parechoviruses and for HSV. In patients Prion diseases do not elicit a cellular reaction in CSF, so the
who have vesicular rashes, a varicella-zoster virus PCR presence of a CSF pleocytosis essentially excludes this group
should also be sent. Both CSF and serum should be frozen for of diseases. Mild elevation of protein may occasionally be
future serologic testing. seen (207). In recent years, 14-3-3 protein, S100 protein, tau
Requirements for CSF analysis in cases of suspected viral protein, and neuron-specific enolase in CSF have been studied
encephalitis are similar to those for viral meningitis, and CSF as markers for Creutzfeldt-Jakob disease; of these, CSF tau
findings are often similar. PMN leukocytes may be present and 14-3-3 protein has proven most valuable when used in
in large numbers in severe encephalitides accompanied by appropriate clinical context. CSF may contain 14-3-3 protein
extensive destruction of brain tissue. HSV classically produces in other neurologic conditions, however, and its detection
a hemorrhagic encephalitis. However, HSV is not unique is thus not specific for prion diseases (208). CSF from cases
in its ability to produce hemorrhagic necrosis of brain, and of known or suspected Creutzfeldt-Jakob disease should be
RBCs are often not detected; thus, the presence or absence of regarded as infectious and handled according to current guide-
RBCs cannot be used to differentiate HSV encephalitis from lines (208).

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CHAPTER 3 IMAGING OF INTRACRANIAL
INFECTIONS
CARRIE P. MARDER AND KATHLEEN R. FINK

Intracranial infections are usually diagnosed by clinical assess- According to the American College of Radiology Appro-
ment and laboratory investigations, particularly cerebrospi- priateness Criteria for headache (3), both NCCT and contrast-
nal fluid (CSF) analysis, combined with radiologic findings. enhanced MRI of the head are usually appropriate for patients
Imaging plays an important role by providing or narrowing presenting with new headache and suspected meningitis or
the differential diagnosis and occasionally identifying a par- encephalitis, with the choice of test depending on local prefer-
ticular entity that has a characteristic appearance, such as ence and availability. When MRI is unavailable or contrain-
herpes simplex virus encephalitis, pyogenic abscess, or empy- dicated, contrast-enhanced CT may be a suitable alternative.
ema. Imaging is also crucial for identifying complications of Cerebrovascular complications of infection are relatively fre-
disease and assessing response to treatment. Finally, imaging quent, and therefore magnetic resonance angiography (MRA)
contributes to the evaluation of opportunistic infections in and magnetic resonance venography (MRV), either with or with-
immunocompromised patients and other patients at high risk out contrast, may also be appropriate tests. Computed tomogra-
for infection. phy angiography (CTA) may be performed when there is strong
Here, we emphasize the overall strategy for imaging intra- suspicion for vascular disease or to further evaluate abnormalities
cranial infections and highlight specific entities in which imag- detected by MRA. Other advanced imaging techniques such as
ing findings contribute to diagnosis or management. We stress computed tomography perfusion (CTP) or magnetic resonance
the major complications of intracranial infections and address perfusion (MRP), magnetic resonance spectroscopy (MRS), and
special considerations for immunocompromised patients. nuclear medicine studies such as single-photon emission com-
puted tomography (SPECT) and 18F-fluorodeoxyglucose posi-
tron emission tomography (FDG-PET) or PET/CT are usually
IMAGING STRATEGY only performed for problem solving after the standard imaging
evaluation has been performed.
Patients suspected of harboring intracranial infection who For evaluation of a new headache in an HIV-positive or
present with altered mental status, seizures, or focal neurologic immunocompromised individual, MRI with or without con-
deficits should emergently undergo noncontrast computed trast is usually appropriate as the initial imaging test (ACR
tomography (NCCT) to exclude life-threatening conditions. Appropriateness Criteria Headache [3]). For an indeterminate
In the acute setting, NCCT is the test of choice to assess for cerebral mass in an immunocompromised patient, additional
hydrocephalus, cerebral edema, mass lesions, or hemorrhage problem-solving techniques such as FDG-PET/CT, SPECT, MRS,
and is often performed prior to lumbar puncture (LP) to ex- and MRP may be helpful to narrow the differential diagnosis.
clude impending brain herniation. NCCT is widely available, In neonates in whom the anterior fontanelle is patent, cra-
and the images are rapidly acquired, making the examination nial ultrasound may be used to evaluate for hydrocephalus,
well tolerated even by critically ill patients. subdural and epidural collections, and parenchymal masses (4).
Clinically stable patients in whom immediately life- Uncomplicated rhinosinusitis is usually managed clinically
threatening conditions have been excluded by NCCT often without the need for imaging, but for suspected intracranial
require further evaluation with contrast-enhanced magnetic or orbital complications of sinonasal disease, both NCCT and
resonance imaging (MRI), which has a greater sensitiv- contrast-enhanced MRI of the head, orbits, and paranasal
ity for leptomeningitis, ventriculitis, cerebral abscess, and sinuses are usually appropriate, with CT and MRI serving as
empyema as well as downstream complications of infec- complementary examinations (ACR Appropriateness Criteria
tion such as infarctions. MRI lacks ionizing radiation, so it Sinonasal Disease [5]). Brain imaging is critical if there is a
is relatively safe to perform, but specific contraindications concern for intracranial extension and is best accomplished
include pacemakers and other implanted metallic devices or with contrast-enhanced MRI. If the patient is unable to tol-
metallic foreign bodies. The risks and benefits of MRI should erate gadolinium contrast, noncontrast MRI augmented with
be weighed carefully in pregnant patients. Studies have not contrast-enhanced CT of the head and sinuses is recommended.
proven any negative effects of MRI to the fetus, but the Immunocompromised patients with acute or subacute rhino-
American College of Radiology recommends deferring MRI sinusitis are at high risk for developing intracranial or orbital
until after pregnancy if possible (1). Because MRI acquisi- complications, and therefore the threshold for obtaining imag-
tion time is much longer than CT, MRI may not be feasible ing should be lower than for immunocompetent patients.
in critically ill patients who require intensive monitoring.
Additionally, if a patient is unable to lie still, motion artifact
may significantly degrade the images obtained.
Gadolinium contrast agents improve the sensitivity of
PYOGENIC INFECTIONS
MRI but are generally avoided in patients with severe renal
dysfunction and a glomerular filtration rate of less than Meningitis
30 mL/min/1.73 m2 due to the risk for nephrogenic systemic
fibrosis (2). Administration of gadolinium-based contrast Meningitis refers to inflammation of the pia and arachnoid
should be avoided in pregnancy due to the unknown effects of membranes. LP with CSF analysis is the test of choice for diag-
exposure to free gadolinium ions on the developing fetus (1). nosis (6), and imaging plays an ancillary role.

24

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Chapter 3: Imaging of Intracranial Infections 25

FIGURE 3.1 Pyogenic (Streptococcus pneumoniae) meningitis. Contrast-enhanced CT (A) shows lepto-
meningeal enhancement (white arrows). MRI FLAIR sequence (B) shows subarachnoid hyperintensity
(black arrows).

Meningitis may be classified based on the pattern of involve- Imaging is also helpful to assess for complications of men-
ment. Pyogenic and viral meningitis typically involve the ce- ingitis, including extensive cerebral edema resulting in brain
rebral cortices. Granulomatous or chronic meningitis typically herniation, infarcts, hydrocephalus, extraaxial pus collections,
involves the basal surfaces of the brain (basilar meningitis) and ventriculitis, cerebritis, and cerebral abscess.
may be due to infectious or noninfectious causes. Pyogenic in- Sterile subdural effusions occur with meningitis but, unlike
fections may also produce a basilar pattern of meningitis. infected extraaxial collections, generally resolve spontaneously.
The primary goals of imaging are to evaluate for contrain- Sterile subdural effusions may develop internal membranes or
dications to LP and to exclude unexpected clinical mimics or septations and occasionally become infected, resulting in sub-
complications. NCCT can satisfy these goals, but not all patients dural empyema (SDE) (13). Subdural effusions occur more
with suspected meningitis require CT. Reported risk factors for often in children with bacterial meningitis and typically de-
an abnormal CT in patients with suspected bacterial meningitis velop over the frontal and temporal lobes (13). Sterile effusions
include age 60 years or older, immunocompromise, recent sei- appear similar to CSF in density or signal intensity or may be
zure, focal neurologic deficits, and impaired consciousness (7). In mildly proteinaceous, resulting in slight signal hyperintensity
the absence of these clinical indicators, CT may not be necessary. on FLAIR compared to CSF. They may be mistaken for promi-
Five percent of patients with acute bacterial meningitis suffer nent subarachnoid spaces, a normal finding in infants. One
brain herniation, and herniation accounts for 32% of deaths (8). distinguishing feature is the finding of bridging vessels crossing
A causal relationship between LP and brain herniation has not the collections, which are present in prominent subarachnoid
been proven, but generally accepted imaging contraindications spaces but not subdural effusions (14).
to LP include midline shift, effacement of the basilar cisterns, and Hydrocephalus is a potentially life-threatening complica-
posterior fossa mass effect (8, 9). Clinical signs of increased intra- tion of meningitis resulting from impaired resorption of CSF
cranial pressure are also a contraindication to LP. by the arachnoid granulations or by diminished CSF outflow
Imaging is usually normal in cases of bacterial meningi- due to viscous material in the ventricles or basilar cisterns.
tis (10). Imaging findings supporting the diagnosis include Hydrocephalus may be the only imaging finding in patients
cerebral edema, inflammatory material in the subarachnoid with meningitis, particularly those with basilar meningitis
spaces, and leptomeningeal enhancement. Cerebral edema (Fig. 3.2). In some cases, proteinaceous or enhancing material
manifests as narrowed or compressed sulci, ventricles, and may also be evident in the basilar cisterns on CT (Fig. 3.2A)
basilar cisterns. Inflammatory material in the subarachnoid or MRI (Fig. 3.2B).
spaces manifests as hyperdense or enhancing material on CT
(Fig. 3.1A) and abnormal fluid-attenuated inversion recovery
(FLAIR) signal hyperintensity (Fig. 3.1B), enhancement, or Cerebritis
restricted diffusion (11) on MRI. Leptomeningeal enhance-
ment manifests as thin, linear enhancement extending along Cerebritis refers to focal brain inflammation due to any cause,
the sulci and basilar cisterns in a gyriform pattern (12). including pyogenic infection (15). Unlike meningitis, which is
Leptomeningeal enhancement should not be confused with localized to the pia and arachnoid, cerebritis involves the brain
pachymeningeal enhancement, which refers to enhancement parenchyma and may occur adjacent to infected subdural or
of the dura mater. epidural collections.

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26 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.2 Pyogenic basilar meningitis. NCCT (A) demonstrates hydrocephalus, with enlarged temporal
horns of the lateral ventricles (white arrow). Additionally, there is subtle effacement of basilar cisterns,
including the interpeduncular fossa (arrowhead). Contrast-enhanced MRI (B) shows corresponding en-
hancement in the interpeduncular fossa (arrowhead).

Cerebritis has a nonspecific imaging appearance. CT find- Regardless of etiology, abscesses share common imaging
ings include focal low attenuation (16) (Fig. 3.3A) without features. On NCCT, abscesses appear as hypodense masses
enhancement or with nodular or peripheral enhancement, with surrounding vasogenic edema, sometimes with a hyper-
which may resemble infarct or mass lesion. MRI findings in- dense rim corresponding to the abscess capsule (16) (Fig. 3.4A).
clude hyperintensity on T2 and FLAIR (Fig. 3.3B) with vari- MRI also shows a localized mass with a T2-hyperintense ne-
able enhancement (Fig. 3.3C). There may be hemorrhage or crotic core and a markedly T2-hypointense rim surrounding
restricted diffusion. MRI appearance may be similar to that the collection that corresponds to the capsule (22) (Fig. 3.4B).
seen in status epilepticus, ischemia, or neoplasm. The central core demonstrates markedly restricted diffusion
If inadequately treated, cerebritis may develop into a cere- (hyperintense on diffusion-weighted image [DWI] sequence
bral abscess, following a well-described progression through [Fig. 3.4C] and dark on apparent diffusion coefficient [ADC]
the stages of early cerebritis, late cerebritis, early abscess for- maps). Quantitative ADC values of the necrotic core are signifi-
mation, and late abscess formation (16,17) (Fig. 3.3C and D). cantly lower for abscesses than necrotic neoplasms (23).
Features suggesting the formation of an abscess within an area On both CT and MRI, cerebral abscesses demonstrate thick
of cerebritis include development of a ring-enhancing mass smooth rim enhancement, sometimes with thinning of the me-
with restricted diffusion of the central cystic or necrotic core. dial wall. Focal wall rupture results in formation of a daugh-
This is in contrast to the restricted diffusion that may be seen ter abscess (22) (Fig. 3.4D). In immunocompromised patients,
with cerebritis, which affects the brain parenchyma itself. ring enhancement may be absent and vasogenic edema may be
mild (15), requiring a high index of suspicion for diagnosis.
Complications of cerebral abscess include mass effect and
Abscess brain herniation. It is important to evaluate for intraventricu-
lar rupture of the abscess with resulting ventriculitis because
Cerebral abscess refers to a focal pus collection within brain this is a marker of poor prognosis that requires aggressive
parenchyma with a surrounding capsule (15). Abscesses may treatment (21). Imaging findings indicating ventricular rupture
result from direct extension of local infection or from hema- include layering debris in the lateral ventricles and enhance-
togenous spread. Local infections associated with cerebral ment of the ependymal lining.
abscesses include otomastoiditis, sinusitis, and odontogenic The differential diagnosis of a ring-enhancing mass includes
infections (18). Bloodborne infections may be associated high-grade glial neoplasm, metastasis, and less commonly,
with intravenous drug use, bacterial endocarditis, pulmonary tumefactive demyelination or subacute infarction. Usually, the
infections, pulmonary arteriovenous malformations, congeni- clinical scenario helps distinguish these entities, but in difficult
tal heart disease, and other causes (1821). Cerebral abscesses cases, MRP and MRS may be helpful.
may also occur after trauma or neurosurgical intervention. MRP allows comparison of the cerebral blood volume of
Abscesses from bloodborne infections tend to be multiple the lesion with that of contralateral normal white matter, re-
and located at the graywhite junction, most commonly in sulting in a measure of relative cerebral blood volume (rCBV).
the frontal lobes (1821). Abscesses arising from local spread The enhancing component of high-grade tumors demonstrates
are often spatially related to the primary infection. For ex- elevated rCBV (increased perfusion) compared to normal
ample, a frontal abscess may develop adjacent to frontal si- white matter, whereas pyogenic abscesses demonstrate signifi-
nusitis. In these cases, the primary infection is usually visible cantly reduced rCBV, which is less than that of contralateral
on imaging. normal white matter (23,24). It is important to evaluate the

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Chapter 3: Imaging of Intracranial Infections 27

FIGURE 3.3 Cerebritis progressing to abscess. NCCT (A) and MRI (B, C) on presentation shows focal
parenchymal abnormality with decreased density on CT and increased FLAIR signal involving gray and
white matter (white arrows), with ill-defined central enhancement (C) (white arrowhead). Despite treat-
ment, contrast-enhanced MRI 2 weeks later demonstrated rim-enhancing abscess (D) (black arrowhead).
Notice also development of leptomeningeal enhancement (black arrow).

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28 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.4 Pyogenic (Streptococcus milleri) abscess. NCCT (A) shows right frontal mass with slightly
hyperdense rim (white arrow) and surrounding vasogenic edema. MRI T2 sequence (B) shows hypointense
rim corresponding to abscess capsule (black arrow) and extensive surrounding edema. C: Central necrotic
core demonstrates restricted diffusion (DWI). Postcontrast T1 sequence (D) shows thick rim enhancement
with daughter abscess (white arrowhead).

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Chapter 3: Imaging of Intracranial Infections 29

enhancing rim of these lesions rather than the central necrotic Cranial epidural abscesses appear on NCCT as hypo- or
regions, which do not statistically differ. isodense extraaxial collections in the epidural space (33) that
MRS evaluates the presence and relative ratios of metab- may contain gas (Fig. 3.6A). On MRI, epidural abscesses are
olites present in a region of interest. Metabolites commonly T2 hyperintense and T1 iso- or hypointense relative to brain,
evaluated include choline, a marker of cell membrane turn- depending on the viscosity of the infectious material. There is
over; N-acetylaspartate (NAA), a marker of neuronal integ- usually intense enhancement of the dura (Fig. 3.6B).
rity; lactate, a marker of anaerobic metabolism; and lipid, a Coexistence of subdural and epidural collections is com-
byproduct of necrosis. Creatine, a marker for energy metabo- mon, and differentiating them is sometimes difficult, particu-
lism, is often used as an internal control against which other larly by CT (31,34). MRI may help by allowing delineation
metabolite peaks are compared. In the central necrotic core of of the thickened or enhancing dura with respect to the col-
both tumors and abscesses, the metabolite peaks of NAA, cho- lection (34). Additionally, like epidural hematomas, epidural
line, and creatine are all depressed or absent (25). In brain ab- abscesses tend to be lentiform and can freely cross dural reflec-
scesses, additional metabolite peaks may be present, including tions such as the falx but are bounded by the cranial sutures.
amino acids, alanine, acetate, succinate, and lactate/lipid (26).
Although lactate and lipid may be present in necrotic tumors,
the other metabolites are more specific to abscesses (23,25,27). SPECIFIC ENTITIES
Treatment alters the metabolite profile of the central abscess
cavity and must be considered in the evaluation.
Tuberculosis
Tuberculous meningitis typically involves the basilar cisterns,
Ventriculitis which become filled with a thick inflammatory exudate (35).
NCCT findings may be subtle and hydrocephalus may be the
Ventriculitis may result from intraventricular rupture of an only finding, although isodense material in the basilar cisterns
abscess, severe pyogenic meningitis (13), or as a complica- may be evident. Contrast-enhanced CT may demonstrate
tion after ventricular drainage procedures. Imaging findings enhancing material in the basilar subarachnoid spaces (36),
include layering debris within the ventricles, which appears which may involve the pachymeninges. However, the absence
hyperdense on CT, hyperintense on FLAIR, and hypointense of basilar meningeal enhancement should not preclude the
on T2 compared to CSF (28). Infected ventricular debris may diagnosis (37). Additional findings that support the diagno-
also show markedly restricted diffusion, similar to the central sis include infarcts and tuberculomas (36,37). HIV patients
core of an abscess. Hydrocephalus is usually present, and there with tuberculous meningitis are more likely to have tuber-
may be enhancement of the ependymal lining. Ventricular sep- culomas and infarcts rather than basilar enhancement or
tations may develop as a late sequela of ventriculitis (28). hydrocephalus (35).
MRI is useful in the assessment for tuberculous meningitis
and allows better visualization of basilar meningeal enhance-
Subdural Empyema ment (Fig. 3.7A), infarcts, pachymeningeal involvement, and
tuberculomas than CT (38). MRI may also show enhancement
SDE refers to an infected subdural collection, occurring of cranial nerves.
between the dura and arachnoid membranes. SDE is often as- Tuberculomas are punctate or large granulomatous lesions
sociated with direct spread of infection from sinusitis or otitis that have a variable appearance depending on the extent of cen-
media but also occurs as a complication of meningitis, trauma, tral caseation (39). On CT, tuberculomas may appear target-
or neurosurgical procedures. Seeding of subdural effusions in like with central calcification surrounded by an enhancing rim.
infants with meningitis, or seeding of subdural hematomas, On MRI, tuberculomas may be uniformly T2 hypointense or
also leads to SDE (29,30). Early recognition of SDE is vital be- may appear target-like, with a T2-hyperintense core surrounded
cause urgent surgical decompression is usually required (31). by a low T2 rim (39). Enhancement may be solid, nodular, or
On CT, SDE appears as a hypo- or isodense crescentic ringlike.
subdural collection (Fig. 3.5A) with rim enhancement (31), Tuberculous abscesses are encapsulated masses contain-
which may be subtle. On MRI, SDE appears as a protein- ing pus and viable mycobacteria that occur more commonly
aceous subdural collection, hyperintense on T1 and FLAIR in immunocompromised patients (40). Unlike tuberculo-
relative to CSF (Fig. 3.5B). This is in contrast to a subdural mas, tuberculous abscesses are not primarily granulomatous
effusion, which follows CSF signal intensity on all sequences. (35). By imaging, differentiating a tuberculoma with central
SDEs are usually hyperintense on DWI (11) (Fig. 3.5C) and caseation from a tuberculous abscess is difficult. Tuberculous
demonstrate rim enhancement (Fig. 3.5D), similar to other pus abscesses also resemble pyogenic abscesses on conventional
collections. Sterile subdural effusions may demonstrate mild imaging, with rim enhancement and a central necrotic core
rim enhancement but do not typically demonstrate restricted demonstrating restricted diffusion. MRS may help differenti-
diffusion (32). Complications of SDE include dural venous ate a tuberculous abscess from pyogenic abscess or necrotic
sinus thrombosis (Fig. 3.5D), cerebral edema, cerebritis, and tumor. Metabolites specifically associated with tuberculous
cerebral abscess (Fig. 3.5B and C). abscesses include high lipid and lactate peaks (Fig. 3.7B).
Unlike pyogenic abscesses, amino acid, succinate, acetate, and
alanine peaks are absent (25,26).
Epidural Abscess
Epidural abscesses are usually the result of direct extension of Lyme Disease
adjacent infections, particularly sinusitis or otomastoiditis (33),
but may also occur after trauma (30) or neurosurgical proce- Lyme neuroborreliosis refers to central nervous system (CNS)
dures. Infected material collects between the dura and calvarium. involvement of Lyme disease. Although no specific imaging
Epidural abscesses may extend to involve the subdural space findings exist, neuroborreliosis is often included in the dif-
and may be associated with cerebritis or cerebral abscesses. ferential diagnosis for nonspecific white matter lesions and

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30 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.5 Subdural empyema. NCCT (A) shows isodense left hemispheric subdural collection (white
arrows). MRI FLAIR sequence (B) shows collection is hyperintense to CSF (white arrows) and is associated
with cerebritis (white arrowhead), and these areas demonstrate restricted diffusion (C). Contrast-enhanced
MRI (D) confirms rim-enhancing collection (arrows) with collection deep to the enhancing dura (black
arrowhead), confirming subdural location. Note also the left sigmoid sinus thrombosis (black arrowhead)
complicating the subdural empyema.

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Chapter 3: Imaging of Intracranial Infections 31

FIGURE 3.6 Epidural abscess complicating maxillary sinusitis. Contrast-enhanced CT (A) shows left
maxillary sinus mucosal thickening and opacification (asterisk) with orbital subperiosteal rim-enhancing
collection (arrow) and intracranial extraaxial gas-containing collection (arrowhead). Contrast-enhanced
MRI (B) redemonstrates sinus disease (asterisk), subperiosteal abscess (black arrow), and enhancing
extraaxial collection (arrowhead), which can be localized to the epidural space by presence of the
overlying enhancing dura.

may share overlapping features with multiple sclerosis. Most Syphilis


patients with neuroborreliosis appear normal on MRI. When
imaging abnormalities exist, leptomeningeal enhancement and Neurosyphilis presents clinically in several discrete phases,
cranial nerve root enhancement may be equally as common as with variable imaging findings in each stage. A high index
white matter lesions (41). The seventh cranial nerve is most of clinical suspicion is needed for diagnosis. Imaging may
commonly involved, followed by the third and fifth cranial be normal or may show cerebral atrophy, nonspecific white
nerves (42). matter lesions, parenchymal masses, or vascular complications

FIGURE 3.7 Tuberculosis: Postcontrast T1-weighted MRI (A) shows thick basilar enhancement (white
arrowhead) and enlarged temporal horns of the lateral ventricles, indicating hydrocephalus. MRS (B) of
the central necrotic core of a tuberculous abscess (white arrow) (yellow box) shows a marked lipid peak
(black arrowhead) and relative paucity of other metabolites.

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32 Part I: Approach to the Patient and Diagnostic Evaluation

TA B L E 3 . 1
PARENCHYMAL NEUROCYSTICERCOSIS:
IMAGING FINDINGS BY STAGE

Stage Description Imaging

Vesicular Cyst or cluster of Thin-walled cyst


cysts with scolex containing simple
fluid; no edema;
scolex may be
visible.
Colloidal Cyst degenerates; Cyst may become
vesicular incites dense on CT, T1
inflammatory hyperintense on
response MRI, with ring
enhancement;
vasogenic edema
Granular Cyst retracts; edema Cyst becomes
nodular begins to ebb. more solid and
smaller; decreasing
enhancement and
edema
Calcified Chronic Calcified nodules
nodular without edema
or enhancement;
FIGURE 3.8 Neurosyphilis. Postcontrast coronal T1-weighted MRI nodules dark on T2
shows left posterior parietal edema (dark area) (arrowhead), which is or gradient-echo
associated with parenchymal, leptomeningeal, and dural enhancement sequences.
(white arrow). (Case provided courtesy of James Fink, MD.)

including infarcts (43,44). T2/FLAIR-hyperintense lesions colloidal vesicular stage, the cyst degenerates, becomes pro-
measuring less than 1 cm occur in the deep periventricular and teinaceous, and the scolex may disappear (Fig. 3.9AC). The
subcortical white matter (43,44). granular nodular stage occurs as the cyst retracts. Vasogenic
Syphilitic gummas are granulomatous lesions of the menin- edema lessens, although nodular or ring enhancement per-
ges that subsequently involve brain parenchyma or dura or sists. Differentiating the colloidal vesicular stage from the
both and that may contain Treponema pallidum. Gummas are granular nodular stage may be difficult (47). Finally, dur-
hypodense on CT and T1 hypointense and T2 hyperintense ing the nodular calcified stage, edema and enhancement
on MRI, with mass-effect, enhancement, and surrounding va- subside, leaving a small calcified nodule (Fig. 3.9D). MRI
sogenic edema (44,45) (Fig. 3.8). Dural thickening indicates is best for identifying lesions in the vesicular, colloidal ve-
dural involvement. Gummas typically occur in the cerebral sicular, and granular nodular stages. CT is excellent at de-
hemispheres but may also appear in unexpected locations, tecting lesions in the nodular calcified stage (47), as is MR
such as the pituitary gland (45). gradient-echo sequence.
Meningeal syphilis may manifest as meningeal enhancement Intraventricular neurocysticercosis may occur alone or in
on CT or MRI. Cranial nerve enhancement may also occur, conjunction with parenchymal neurocysticercosis. Imaging
often involving cranial nerves VII and VIII (46). Syphilitic vas- findings include cystic lesions within the ventricles, commonly
culitis (meningovascular syphilis) may affect medium and large in the fourth ventricle (47). There may be associated noncom-
vessels (Heubner arteritis) or small vessels (Nissl-Alzheimer municating hydrocephalus. Cysts usually are thin walled and
type) (46). Infarctions can complicate either type. Angiographic contain CSF-like fluid, making them difficult to see on stan-
findings of infectious vasculitis are discussed further later in dard MRI sequences. High-resolution heavily T2-weighted
this chapter. MRI sequences (MR cisternography) may help to delineate the
cyst walls.
Neurocysticercosis may also involve the subarachnoid spaces,
Neurocysticercosis particularly the basilar cisterns, and appears as multilobular cys-
tic lesions (racemose neurocysticercosis) (Fig. 3.9E). The scolex
Neurocysticercosis results from CNS invasion by the parasitic is often not visible.
organism Taenia solium and may involve brain parenchyma,
ventricles, or subarachnoid spaces. The imaging appearance
varies with location and stage of infection. Creutzfeldt-Jakob Disease
Parenchymal neurocysticercosis can be classified into
four stages from acute to chronic (47), as summarized in Creutzfeldt-Jakob disease (CJD) is a prion disease that may
Table 3.1. In the vesicular stage, a thin-walled cyst forms be sporadic, hereditary, or acquired from exposure to infected
containing the invaginated scolex, which may be visible on CNS tissue. Variant CJD (vCJD) most commonly occurs
FLAIR and contrast-enhanced sequences (48). During the after consumption of meat from cows infected with bovine

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Chapter 3: Imaging of Intracranial Infections 33

FIGURE 3.9 Neurocysticercosis. Colloidal vesicular phase on CT (A), FLAIR (B), and postcontrast T1
MRI (C) demonstrating central scolex (black arrows), thick rim enhancement (black arrowhead), and
surrounding vasogenic edema. D: Calcified nodular phase by CT (arrowheads). Subarachnoid neurocys-
ticercosis on T1 MRI (E), with multiple cysts (arrowheads) causing distortion of adjacent parenchyma.
(Cases provided courtesy of James Fink, MD.)

spongiform encephalopathy. Kuru occurs with cannibalism. (Fig. 3.10B). The precentral gyrus is usually spared (51).
Iatrogenic CJD occurs with surgical exposures such as corneal Globus pallidus, thalamus, and periaqueductal gray matter
transplantation. Most cases of CJD are sporadic (sCJD) (49). may be involved (49). Cortical atrophy occurs with disease
The imaging appearances of sCJD and vCJD have been best progression.
described. vCJD is associated with the pulvinar signsymmetric
MRI is the preferred imaging modality (49) to sup- FLAIR signal hyperintensity in the pulvinar nuclei of the
port the diagnosis and exclude other etiologies. Criteria thalamus (52). The dorsal medial nucleus of the thalamus may
to support the diagnosis of sCJD include DWI or FLAIR also be hyperintense (hockey stick sign) (49,52), as may be
signal hyperintensity in the caudate nucleus and putamen the tectal plate, periaqueductal gray matter, or cerebral cortex.
(Fig. 3.10A), with involvement of at least one cortical Cortical atrophy may occur but is usually less severe than with
gyrus or involvement of more than three cortical gyri (50) the sCJD.

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34 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.10 Sporadic Creutzfeldt-Jakob disease in two patients. DWI MRI (A) demonstrates restricted
diffusion in the caudate and anterior putamen (arrowhead). Cortex was also involved (not shown).
Predominantly cortical pattern of involvement in a second patient (B) showing restricted diffusion affect-
ing more than three gyri. (Case provided courtesy of James Fink, MD.)

VIRAL INFECTIONS and treatment are critical to limit morbidity and mortality.
Although all patients suspected of having HSV encephalitis
Viral infections of the CNS manifest variably as meningitis, en- should receive prompt treatment regardless of imaging find-
cephalitis, myelitis, radiculitis, postinfectious encephalomyeli- ings, it is important to recognize the characteristic imaging
tis, or various combinations thereof. Unlike most bacterial and features because these may precede clinical suspicion of the
fungal infections, the intracranial imaging findings in viral en- disease.
cephalitis may predict a specific causative organism (Table 3.2). Infection usually begins in the anterior and medial aspects
of the temporal lobe(s) but may extend to the lateral temporal
lobes, inferior frontal lobes, insular cortex, and frontal and
Viral Meningitis parietal cingulate gyri. Findings may be unilateral or bilateral.
Extension to the pons may occur through retrograde viral
Uncomplicated viral meningitis is usually diagnosed by clini- spread along the trigeminal nerve (55). CT may be normal
cal presentation combined with CSF evaluation. Enteroviruses initially or may show low attenuation in the affected regions,
are the most frequent cause (53). Imaging may be normal or sometimes with associated mass effect, gyral enhancement,
may show cortical leptomeningeal enhancement on contrast- or petechial hemorrhage (56,57) (Fig. 3.11A). MRI is more
enhanced CT or MRI (12). Viral meningitis is less likely than sensitive for early disease and better demonstrates the edema-
bacterial, fungal, or tuberculous meningitis to produce FLAIR tous changes as T2/FLAIR-hyperintense areas (Fig. 3.11B)
signal hyperintensity in the subarachnoid space (54), but this with concomitant decreased T1 signal intensity (55,58). DWI
finding is not reliable for distinguishing the entities. may show restricted diffusion (Fig. 3.11C), which may pre-
cede findings on other sequences (5961). Hemorrhages occur
with disease progression and are demonstrated with high
Herpes Simplex Virus sensitivity on MRI as petechial areas of intrinsic T1 signal
hyperintensity or as susceptibility artifact on gradient-echo se-
Herpes simplex virus (HSV) type 1 is the most common quences. Variable enhancement may also develop at this stage.
cause of sporadic acute viral encephalitis, and early diagnosis Progressive encephalomalacia occurs over several weeks, often

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Chapter 3: Imaging of Intracranial Infections 35

TA B L E 3 . 2
CHARACTERISTICS OF VIRAL ENCEPHALITIS BY ENTITY

Viral Infection Pearls

Enteroviruses Normal or thin linear leptomeningeal enhancement

HSV Bilateral medial temporal and inferior frontal lobes, sparing basal ganglia
/ Abnormal DWI, enhancement, hemorrhages
Mass effect initially, followed by atrophy over several weeks

VZV Lesions at graywhite interface, white matter, gray matter


Vascular imaging may show vasculitis

Arboviruses Bilateral basal ganglia and thalami lesions


Can involve any brain area, including medial temporal lobes

ADEM Large, asymmetric lesions in supratentorial white matter


/ Deep gray nuclei, brainstem, spinal cord, optic nerves
Open ring sign of enhancement
Monophasic, with resolution on follow-up imaging

HIV Generalized cerebral atrophy


Symmetric periventricular white matter FLAIR hyperintensity with T1
isointensity

PML Asymmetric white matter signal abnormality (hyperintense T2,


hypointense T1) involving subcortical U-fibers
Cerebellar crescent-shaped lesions
Minimal mass effect and enhancement, except with IRIS
May see leading edge of abnormal DWI and enhancement
Progresses on follow-up; may lead to atrophy long-term

CMV Periventricular enhancement or calcification

Noteworthy features highlighted in bold text.

leading to marked temporal lobe atrophy (Fig. 3.11D) with aneurysm formation, and arterial dissection (66). Parenchymal
associated seizure disorder. lesions in VZV infection characteristically occur at the graywhite
The differential diagnosis includes infarct, glioma, limbic interface but may also occur in the cortical gray matter and deep
encephalitis (paraneoplastic syndrome), Rasmussen encephali- white matter. Multiple lesions at the graywhite interface should
tis (chronic viral encephalitis), and other viral infections, such specifically suggest VZV vasculopathy in the right clinical setting,
as arboviral encephalitis. Bilateral abnormalities, sparing of along with the differential diagnosis of emboli and metastases.
the basal ganglia, and involvement of both medial and lateral VZV vasculopathy may coexist with meningitis, radiculitis, and
portions of the temporal lobes (posterior cerebral artery [PCA] myelitis and may occur with or without rash (66).
and middle cerebral artery [MCA] vascular territories) are all
features that increase the specificity for HSV.
Advanced techniques are not typically required for diagnosis Arboviruses
but may be helpful for problem solving. Both CTP (62) and SPECT
(63) show hyperperfusion of the involved areas acutely. MRS may Arthropod-borne viruses, also known as arboviruses, consti-
show decreased NAA and increased choline levels acutely, which tute an important cause of viral meningoencephalitis world-
can mimic neoplasm (64). Follow-up conventional MRI usually wide. Examples from this diverse group include the viruses
distinguishes these entities however, because HSV leads to atro- causing Eastern equine, Western equine, Venezuelan equine,
phy, whereas infiltrating glioma persists or progresses (64,65). West Nile, Japanese, St. Louis, California, Murray Valley, and
tick-borne encephalitides. Affected patients may have normal
MRI findings or may have signal abnormalities on T2, FLAIR,
Varicella-Zoster Virus or DWI. Classically, lesions are located in the basal ganglia and
thalami bilaterally (Fig. 3.12), and this imaging pattern should
Neurologic manifestations of varicella-zoster virus (VZV) may strongly suggest arboviral encephalitis in a potentially exposed
occur in the setting of primary infection (chickenpox) or reacti- patient. The differential diagnosis includes anoxic or hypoxic
vation (shingles). Reactivation is usually associated with immu- encephalopathy, toxic exposures such as carbon monoxide
nosuppression or normal age-related declining immunity. VZV poisoning, metabolic disorders such as Wilson disease and
infection is distinct among viral infections in that it causes a vas- mitochondrial abnormalities, and other entities such as CJD.
culopathy, which may involve either small or large vessels. Small The basal ganglia and thalami are classically involved
artery involvement may lead to monocular visual loss. Large artery in arboviral infections, but additional nonspecific areas of
involvement classically leads to ischemic infarctions. Other mani- involvement include the meninges, the brainstem and spinal
festations of vasculopathy include subarachnoid hemorrhage, cord, the cortical gray matter, and the cerebral and cerebellar

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36 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.11 HSV encephalitis. A: NCCT shows left temporal low density and volume expansion with
petechial areas of hemorrhage (arrowhead). B: Coronal FLAIR MRI in a different patient shows bilateral
involvement of the anterior and medial temporal lobes and insula. C: DWI shows restricted diffusion in
the corresponding areas, confirmed on ADC map (not shown). D: Axial NCCT in a third patient with
prior HSV encephalitis shows left temporal lobe atrophy.

white matter (65,67,68). Leptomeningeal or parenchymal abruptly 2 to 3 weeks following a viral illness or vaccination.
enhancement is variable. Isolated substantia nigra lesions have In contrast to multiple sclerosis, ADEM follows a monophasic
been reported with St. Louis encephalitis (69). Arboviral en- course lasting several weeks.
cephalitis commonly involves the mesial temporal lobes, but CT may be normal or may show nonspecific areas of low
involvement of the basal ganglia and thalami with relative attenuation (Fig. 3.13A). Lesions may show peripheral en-
sparing of the anterior portions of the temporal lobes help to hancement (7072). MRI is more sensitive, but lesions may not
distinguish arboviral infections from HSV (65). be visible until several days after the onset of symptoms (73).
Like other demyelinating lesions, ADEM lesions have high T2
and FLAIR and low T1 signal intensity. They are located most
Acute Disseminated Encephalomyelitis commonly in the supratentorial white matter (Fig. 3.13B)
and are often multiple, bilateral, and asymmetric, although
Acute disseminated encephalomyelitis (ADEM), also known as involvement of the deep gray structures may be symmetric (74).
postinfectious or postvaccination encephalitis, is an inflamma- Lesions may be small and round or large and irregular, some-
tory autoimmune demyelinating condition that typically begins times with a central T2-hyperintense portion creating a fried

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Chapter 3: Imaging of Intracranial Infections 37

egg appearance (75). Mass effect and surrounding edema


are typically absent. Tumefactive demyelinating lesions and
rare hemorrhagic forms of ADEM may show surrounding
edema (74,75). A peripheral incomplete ring of enhancement,
the open ring sign, may occur in lesions that partially abut
white matter and cortex (Fig. 3.13C). In this situation, only the
white matter edge enhances, a sign that is highly specific for
demyelinating lesions and only rarely occurs with neoplasms
or abscesses (76,77). Other patterns of enhancement observed
in ADEM include closed ring, solid, nodular, or gyral enhance-
ment (74,75). Patterns of signal abnormality on DWI are vari-
able (78,79), and single lesions may have heterogeneous signal
intensity on DWI and ADC map (80).
MRS shows selective reduction of NAA initially, with nor-
mal levels of the other metabolites. NAA returns to normal
levels on follow-up imaging (81). Elevated choline and/or lac-
tate may also be observed (79,82) (Fig. 3.13D), resembling
other demyelinating conditions and brain tumors. MRP usu-
ally reveals hypoperfusion (Fig. 3.13E) (80), which may help
to distinguish ADEM from neoplastic lesions.
ADEM lesions usually either resolve or improve on follow-
up imaging, although sometimes there is residual gliosis.
Clinical resolution may precede radiographic resolution (73).
FIGURE 3.12 Eastern equine encephalitis. Symmetric hyperintense FLAIR
A subset of patients may have a relapsing form of the disease
signal in the bilateral basal ganglia, including caudate, putamen, and glo-
bus pallidus. Bilateral thalamic involvement is also typical but not present resembling multiple sclerosis. The terms multiphasic or recur-
in this case. (Case provided courtesy of Mahmud Mossa-Basha, MD.) rent ADEM, however, should be reserved for cases in which

FIGURE 3.13 ADEM. NCCT (A) shows multiple large ill-defined areas of low attenuation bilaterally, which
are hyperintense on FLAIR (B). C: Postcontrast coronal T1-weighted image shows open ring signs (arrow-
heads) with incomplete peripheral enhancement abutting the white matter edge. Single voxel short echo time
MRS (D) of a left parietal lesion shows elevated choline:NAA ratio and a lactate peak (black arrows) mimick-
ing neoplasm. MRP (E) showing decreased perfusion in the lesions. Another patient with ADEM isolated to
the posterior fossa (F) demonstrating FLAIR hyperintense lesions in the pons and middle cerebellar peduncle.

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38 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.14 HIV. NCCT at presentation (A) and 5 years later (B) (obtained after trauma) demonstrate
progressive atrophy and patchy periventricular white matter hypoattenuation. B: Incidental right frontal
contusion and small intraventricular hemorrhage evident related to trauma. FLAIR (C) better shows
confluent periventricular white matter disease.

new MRI lesions develop or recur at least 3 months after the such as HIV, cancers such as leukemia, and medications such
initial demyelinating event and longer than 4 weeks after com- as chemotherapy and immunosuppressive agents, which are
pleting steroid therapy (74). These criteria help to distinguish used following bone marrow or solid organ transplantation to
relapse from monophasic disease with a protracted course or prevent rejection. Immunocompromised patients are prone to
an incomplete response to treatment (83). frequent, severe, and long-lasting CNS infections that may be
Supratentorial white matter lesions are most common in caused by opportunistic pathogens. Neutropenic patients are
ADEM, but lesions may also occur in the deep gray nuclei, in- particularly susceptible to bacterial and fungal infections. The
fratentorial white matter, spinal cord, and optic nerves (71,83). most common CNS opportunistic infections to affect immuno-
Lesions may sometimes be isolated to the infratentorial white compromised patients are discussed below.
matter (Fig. 3.13F).

Progressive Multifocal Leukoencephalopathy


HIV
PML is a progressive and frequently fatal demyelinating oppor-
Patients infected with HIV may have imaging findings related tunistic infection caused by the JC virus, a ubiquitous patho-
directly to HIV infection in the CNS or related to opportunis- gen that causes disease primarily in patients with impaired
tic infections. Associated opportunistic infections include viral T-cell immunity. The JC virus causes demyelination by directly
diseases such as progressive multifocal leukoencephalopathy infecting the myelin-producing oligodendrocytes. Most cases
(PML) and cytomegalovirus (CMV) infections and fungal occur in the setting of HIV infection, hematologic disorders,
infections such as Cryptococcus infection and coccidioidomy- organ transplantation, and treatment with the monoclonal
cosis. Tuberculosis and syphilis are also increasingly prevalent antibody natalizumab for multiple sclerosis or Crohn disease.
in HIV-infected patients. The diagnosis is established by demonstrating JC viral DNA
Direct effects of HIV infection include generalized cerebral in the CSF by polymerase chain reaction or by immunohisto-
volume loss and symmetric patchy or confluent periventricular chemical analysis of brain tissue, but characteristic findings on
white matter low attenuation on CT and signal hyperintensity MRI (Fig. 3.15) may first suggest the diagnosis.
on T2 and FLAIR (Fig 3.14), with corresponding isointensity PML appears as confluent areas of hypoattenuation on CT
on T1-weighted images. There is no contrast enhancement or and signal abnormality on MRI within the subcortical white
mass effect (40). HIV infection may be difficult to distinguish matter involving arcuate or U-fibers, sparing the cortex. MRI
from chronic microvascular ischemia and age-related volume shows confluent areas of T2 and FLAIR hyperintensity with
loss if comparison studies are not available. Symmetry, peri- progressive hypointensity on T1-weighted images and little to
ventricular location, and T1 isointensity help to distinguish no mass effect or contrast enhancement. Scant peripheral en-
imaging abnormalities due to HIV from those due to PML. hancement as well as restricted diffusion is sometimes observed
at the leading edge of demyelination (84,85). More marked
enhancement and mass effect may be observed when PML is
OPPORTUNISTIC INFECTIONS associated with the immune reconstitution inflammatory syn-
drome (IRIS), further discussed below (8688).
Immune system compromise may affect humoral immunity Parietooccipital lobes and corpus callosum are typically
(B cells) or cell-mediated immunity (T cells) and may be due to affected. Unlike multiple sclerosis, periventricular white
a primary immune deficiency or may be secondary to infections matter is relatively spared. Lesions are frequently multiple

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Chapter 3: Imaging of Intracranial Infections 39

FIGURE 3.15 PML in a patient after autologous stem cell transplant. NCCT (A) shows a right frontal
hypodense lesion. MRI redemonstrates lesion (black arrowheads) as an area of subcortical T2 hyperin-
tensity (B) sparing the cortical ribbon. Restricted diffusion (C) and slight contrast enhancement (D) at
the posterior white matter margin corresponds to the leading edge of demyelination. There is hypo-
metabolism evident on FDG-PET (E). JC virus was confirmed by lumbar puncture. Posterior fossa PML
in a separate patient with advanced AIDS (F) shows a crescentic T1-hypointense lesion with minimal
enhancement (white arrow).

and asymmetric bilaterally and become increasingly conflu- The imaging features of PML can resemble ADEM, but
ent with progression to new areas on follow-up imaging. the two entities can usually be distinguished clinically. PML
Infratentorial lesions may occur, sometimes in isolation. occurs in immunocompromised patients and has a subacute
Cerebellar lesions often have a characteristic crescent-shaped onset and progressive course of worsening neurologic im-
morphology (Fig. 3.15) (85,89,90). pairment and lesion enlargement on MRI. ADEM occurs in
Although PML lesions have a fairly characteristic ap- immune competent individuals, usually children, following
pearance on conventional MRI, advanced techniques are a viral infection or vaccination and has an abrupt onset of
sometimes performed. MRS may show elevated choline and neurologic impairment followed by gradual improvement
depressed NAA peaks as well as lipid and lactate peaks (91). clinically and radiologically during the course of steroid
This spectrum of metabolites reflects the underlying demyelin- treatment.
ating process and resembles other demyelinating conditions
such as ADEM but also resembles high-grade neoplasms.
MRP typically shows hypoperfusion in the affected areas, and Cytomegalovirus Infection
SPECT and FDG-PET or PET/CT studies show reduced meta-
bolic activity (Fig. 3.15), helping to differentiate PML from CMV produces two distinct types of disease, one in newborns
lymphoma or a high-grade glioma. related to in utero transmission of maternal infection and one in

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40 Part I: Approach to the Patient and Diagnostic Evaluation

immunocompromised patients. Intracranial imaging findings pyogenic abscesses, there is no central restricted diffusion
of congenital infection include periventricular calcifications, (97). Ring enhancement is common. The eccentric target
migrational abnormalities, atrophy, and leukoencephalopathy sign (Fig. 3.16) refers to an enhancing nodule along the
(55,65,92). In acquired CMV infections that occur in the set- ring-enhancing wall of the lesion, which is highly specific,
ting of immune deficiency, the intracranial imaging findings are but insensitive, for toxoplasmosis (98). Typical abscess
nonspecific but may include findings of meningoencephalitis, locations include the basal ganglia, thalamus, and cerebral
ventriculitis, and/or leukoencephalopathy (40,55,65,92,93). hemispheres at the graywhite junction (40). MRS typically
Rarely, acquired CMV infection manifests as a space-occupying shows a large lipid and lactate peak, and perfusion studies
or peripherally enhancing mass (40,90). Extracranial imaging demonstrate decreased rCBV (98).
findings of acquired CMV infection include chorioretinitis and Differentiating toxoplasmosis from lymphoma in a patient
polyradiculitis. with AIDS remains a clinical conundrum (46). FDG-PET and
The major differential diagnosis of CMV ventriculitis in thallium-201 SPECT have both been used for differentiating
an immunocompromised patient is CNS lymphoma. Tuber- the two entities, but the utility of thallium-201 SPECT is vari-
culosis, toxoplasmosis, and bacterial ventriculitis are addi- able (99101). DWI MRI sequence may sometimes be helpful,
tional considerations. The pattern of contrast enhancement but there is significant overlap of ADC values between toxo-
may help distinguish these entities because smooth linear plasmosis and lymphoma (102). Serial imaging confirming
enhancement favors viral or bacterial ventriculitis, whereas expected response to antibiotic treatment, namely, resolution
nodular or mass-like enhancement favors lymphoma (94). of ring-enhancing lesions, may be the most helpful in diagnos-
Involvement of the corpus callosum also suggests lymphoma ing toxoplasmosis (40).
but can rarely occur with toxoplasmosis (95). Definitive diag-
nosis of CMV ventriculitis requires polymerase chain reaction
analysis for detection of viral DNA in the CSF. Lymphoma is Cryptococcus Infection
usually confirmed by detection of abnormal cells in the CSF
or by biopsy. Cryptococcus CNS infection may affect immunocompe-
tent patients but is more common in immunocompromised
patients. Neuroimaging studies may be normal or may
Toxoplasmosis demonstrate findings of meningitis, meningoencephalitis,
or vasculitis, better depicted with MRI than CT (103).
Cerebral toxoplasmosis usually presents clinically due to Meningitis findings include leptomeningeal enhancement
reactivation of latent infection in immunocompromised pa- and subarachnoid space DWI hyperintensity (11). CNS
tients (46). Toxoplasmosis appears as one or more ring- or cryptococcal infection may also manifest as parenchymal
nodular-enhancing masses, corresponding to abscesses. T2 mass lesion(s) or hydrocephalus.
signal is heterogeneous and may vary according to the stage Cryptococcus infection often results in accumulation of
of abscess formation and treatment effects (96). Unlike gelatinous exudate, which causes dilation of the perivascular
spaces and formation of pseudocysts (Fig. 3.17). These gelatinous

FIGURE 3.16 CNS toxoplasmosis. Contrast-enhanced MR shows FIGURE 3.17 Cryptococcus. T2-weighted image demonstrates nodu-
ring-enhancing lesions, one of which demonstrates eccentric target-like lar lesions in the basal ganglia (black arrowhead) that are hyperintense
enhancement (arrowhead), a relatively specific sign for toxoplasmosis. to brain but hypointense compared to CSF, consistent with gelatinous
Note the second ring-enhancing lesion in the left thalamus (arrow). pseudocysts.

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Chapter 3: Imaging of Intracranial Infections 41

FIGURE 3.18 PML-IRIS. Initial FLAIR MRI (A) shows subtle right frontal hyperintense lesion
(white arrow). Follow-up scan 2 1/2 months later (B) shows interval enlargement of the FLAIR hyper-
intense lesion (white arrow) with mild mass effect. Postcontrast T1 images (C) shows new enhancement
with an open-ring configuration (black arrow), consistent with demyelination.

pseudocysts favor the basal ganglia and may have enhanc- worsening opportunistic infection. The diagnosis is usually
ing walls, particularly in immunocompetent patients (104). suspected when there is paradoxical clinical deterioration
Pseudocysts are hyperintense to CSF on FLAIR due to the pro- with imaging findings that are atypical for a given oppor-
teinaceous contents. Prominent perivascular spaces without tunistic infection. For example, in IRIS-PML (Fig. 3.18),
gelatinous exudate also occur, in concert with cerebral volume there may be greater than expected enhancement or mass
loss, but should demonstrate the same signal characteristics as effect (40,8688,108).
CSF on all sequences.
Cryptococcomas may form, which are either granuloma-
tous lesions with few organisms or inflammatory lesions with CEREBROVASCULAR
many organisms (40). Cryptococcomas appear as a cluster
of nodules that are non- or minimally enhancing in immuno-
COMPLICATIONS OF INFECTION
compromised patients and enhancing in immunocompetent Intracranial vascular complications of infections may be arte-
patients (104). There is no central restricted diffusion, unlike rial or venous and may occur in the setting of meningitis, head
pyogenic abscesses. Most occur in the basal ganglia, thalamus, and neck infections, or systemic infections. Examples include
and cerebellum (40). infectious vasculitis, venous septic thrombophlebitis, septic
emboli, septic (mycotic) aneurysms, and disseminated intra-
vascular coagulation.
Coccidioidomycosis
Coccidioidal meningitis may occur in both immunocompetent
and immunocompromised patients and presents as chronic
Infectious Vasculitis
(basilar) meningitis. Associated hydrocephalus is common Cerebral vasculitis may be primary and idiopathic, known
(105,106). Vasculitis and infarctions may complicate the in- as primary angiitis of the central nervous system (PACNS),
fection (107). Focal-enhancing parenchymal brain lesions may or may be secondary to a variety of systemic vasculitides,
occur in severe disease as a result of direct extension of basilar drugs, or infections. Infectious causes of cerebral vasculitis
meningeal disease (105). The presence of either hydrocepha- are potentially treatable; therefore, patients with known or
lus alone or hydrocephalus with infarction is associated with suspected infections and new neurologic deficits warrant
higher mortality (106). evaluation with brain and cerebrovascular imaging. Vascular
complications of pyogenic bacterial meningitis are common
and outcomes are poor, with a high risk for stroke and asso-
Immune Reconstitution Inflammatory ciated morbidity and mortality (109,110). Diagnosis of infec-
Syndrome tious vasculitis is usually established by characteristic clinical
and radiologic signs combined with CSF analysis using cul-
IRIS is a complication of highly active antiretroviral therapy ture, PCR, and serologic tests directed toward the most com-
(HAART) that occurs in the setting of severe AIDS-related mon pathogens.
immunodeficiency shortly after the initiation of therapy. Pathogens known to cause infectious cerebral vasculitis in-
The syndrome is characterized by an exaggerated inflam- clude bacteria such as Streptococcus pneumoniae (Fig. 3.19A
matory response to dead, latent, or viable organisms or and B), Mycobacterium tuberculosis, and T. pallidum; vi-
self-antigens and may coexist with a variety of opportunis- ruses such as VZV (Fig. 3.19C and D); and a variety of fungi
tic infections, most commonly JC virus and Cryptococcus (Fig. 3.19E and F) and parasites (66,107,111116). Any
(108). The imaging findings might be confused with new or cause of infectious basilar meningitis can potentially lead to

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42 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.19 Infectious vasculitis. A, B: Pyogenic (Streptococcus pneumoniae). T2-weighted MRI at


presentation (A) and 2 weeks later (B) demonstrate interval decrease in caliber of the basilar artery flow
void (open arrowhead) and new pontine infarcts (white arrow). C, D: Varicella-zoster vasculitis. Cerebral
angiography of the left internal carotid artery in the lateral (C) and PA (D) projection demonstrate
irregular narrowing of the posterior cerebral artery (C) (arrow) and middle cerebral artery (D, arrow).
E, F: Fungal (coccidioidal). Postcontrast T1 image demonstrates extensive basilar and subarachnoid en-
hancement (E, arrowhead) with evidence of subacute infarct in the posterior limb of the left internal
capsule (F, arrow) due to vasculitis affecting the lenticulostriate arteries.

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Chapter 3: Imaging of Intracranial Infections 43

vasculopathy involving the cerebral vessels at the base of the complicate meningitis (13). Septic thrombophlebitis can in-
brain either by inducing vasospasm or by inciting an inflam- volve dural venous sinuses, cavernous sinuses, or cortical
matory reaction within the vessel walls. In VZV vasculitis, veins. High-risk patients include those with diabetes or
there is productive viral infection within the media of cerebral immunosuppression and those presenting with coalescent
vessel walls (66,117). It is controversial whether other viruses mastoiditis or acute bacterial or fungal sinusitis involving
such as HIV also cause cerebral vasculitis, because opportunis- the frontal or sphenoid sinuses (119). Specific patterns of
tic infections frequently coexist (66,115). septic thrombophlebitis include sigmoid dural venous sinus
The vascular imaging findings of infectious vasculitis thrombosis secondary to coalescent mastoiditis, superior
are similar to other vasculitides and include segmental va- sagittal sinus thrombosis secondary to frontal sinusitis, and
soconstriction creating a beads-on-a-string appearance, cavernous sinus thrombophlebitis secondary to sphenoid
irregularities of the vessel wall, smooth vessel narrowing, dis- sinusitis or osteomyelitis (Fig. 3.20), orbital cellulitis, or
sections, occlusions, or aneurysm formation. VZV vasculitis other facial infections.
may show contrast enhancement of the vessel walls, possi- Imaging signs of cavernous sinus thrombosis include fill-
bly reflecting the underlying productive viral infection (114). ing defects, diminished enhancement, or an expanded con-
Leptomeningeal contrast enhancement on CT or MRI is vari- tour of the cavernous sinus (120,121). Indirect findings may
able in basilar meningitis but, if present, may suggest infection include proptosis; enlargement of the extraocular muscles;
as the cause of vasculitis. Complications of vasculitis visible and enlargement, nonenhancement, or filling defects within
on CT or MRI include infarcts and hemorrhages, including the superior ophthalmic vein(s). Occasionally, gas bubbles are
subarachnoid hemorrhage. present in the cavernous sinus due to dehiscence of the sphe-
noid sinus walls related to osteomyelitis. Secondary arterial
complications involving the cavernous internal carotid artery
Septic Thrombophlebitis may occur, including arteritis, thrombosis (Fig. 3.20A), and
aneurysm formation (Fig. 3.20B and C).
Cerebral venous septic thrombophlebitis represents an im- Imaging signs of dural venous sinus thrombosis include a
portant pathway for intracranial spread of extracranial hyperdense venous sinus on NCCT, abnormal flow voids on
infections from the paranasal sinuses, mastoid air cells, noncontrast MRI, absence of the normal flowrelated signal
orbits, and other facial structures (118,119) and may also on noncontrast MRV, and filling defects on contrast-enhanced

FIGURE 3.20 Septic thrombophlebitis and complications in two patients with sphenoid sinusitis.
A: Contrast-enhanced CT demonstrates mild expansion and nonopacification of the right cavernous
sinus (arrowhead) with thrombosis of the right cavernous carotid artery (white arrow). B: Contrast-
enhanced T1 MRI demonstrates patchy nonopacification of the cavernous sinuses bilaterally, with
abnormal left carotid artery flow void (black arrowhead). Cerebral angiogram (C) confirms mycotic
left cavernous carotid aneurysm (black arrowhead).

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44 Part I: Approach to the Patient and Diagnostic Evaluation

computed tomography venography (CTV) or MRV. Findings emboli, septic (mycotic) aneurysms, or complex clotting
on noncontrast MRI or MRV may be subtle in cases of in- disorders such as disseminated intravascular coagulation
complete thrombosis or following partial recanalization. (DIC). Septic emboli may lead to multiple cerebral infarctions,
Obstructive dural venous sinus thrombosis may lead to microhemorrhages, and microabscesses. The imaging find-
secondary complications of venous hypertension and venous ings on NCCT include loss of graywhite differentiation or
infarction, visible on CT or MRI as vasogenic edema, paren- hypoattenuation corresponding to acute infarcts (Fig. 3.21A).
chymal hemorrhages, ischemic or hemorrhagic infarcts, or MRI may show multifocal areas of FLAIR signal hyperinten-
sometimes as isolated convexal subarachnoid hemorrhage. sity or restricted diffusion at the graywhite interface, often
Multiple infarcts or hemorrhages in a nonarterial distribu- associated with small areas of abnormal susceptibility on
tion may suggest the diagnosis. Unlike arterial infarcts, which gradient-echo images (Fig. 3.21B). Contrast-enhanced im-
show restricted diffusion, findings on DWI are variable in ages characteristically reveal multiple peripherally enhanc-
venous infarctions. ing lesions at the graywhite interface, but this finding is
Cortical vein thrombosis may be difficult to detect by imag- sometimes absent, especially early in disease. Multifocal sub-
ing. The characteristic finding on NCCT is the cord signa arachnoid hemorrhage isolated to the cerebral convexities is
hyperdense, serpiginous cortical structure corresponding to the another presentation of septic emboli, possibly secondary to
thrombosed vein, which does not opacify on CTV. MRI may focal arteritis or rupture of small vessels at the sites of em-
show abnormal susceptibility on gradient echo sequences, but bolic occlusion. Convexal subarachnoid hemorrhage may be
this finding is often obscured by susceptibility artifact from visible on NCCT as peripheral areas of hyperdensity within
the adjacent calvarium. Secondary complications related to the cerebral sulci or as subarachnoid space FLAIR signal hy-
venous hypertension are similar to those of dural venous sinus perintensity on MRI.
thrombosis. Septic aneurysms may form in association with septic em-
boli or as a consequence of systemic sepsis or spread from
local head and neck infections. Rupture of a septic aneurysm
Septic Emboli, Septic Aneurysms, and may result in diffuse subarachnoid hemorrhage indistin-
Disseminated Intravascular Coagulation guishable from saccular aneurysm rupture or a more local-
ized presentation of subarachnoid hemorrhage confined to
Infectious endocarditis, as well as systemic sepsis from any a sylvian fissure or a cerebral convexity. On angiography,
cause, can lead to intracranial complications from septic septic aneurysms often appear irregular in shape and arise in

FIGURE 3.21 Septic emboli. NCCT (A) demonstrates loss of graywhite differentiation consistent with
acute cortical infarct (arrowhead). Gradient-echo MRI sequence (B) demonstrates multiple small micro-
hemorrhages (arrow).

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Chapter 3: Imaging of Intracranial Infections 45

atypical locations, usually more distally in the vascular tree


compared to saccular aneurysms.
DIC usually occurs in the setting of systemic sepsis and
may also result in multiple cerebral infarcts and hemorrhages.
Multifocal convexal subarachnoid hemorrhage is another pre-
sentation of DIC (Fig. 3.22). Infarcts and hemorrhages result
from clot formation, consumption of platelets and clotting
factors, and bleeding complications in multiple organ systems.
The imaging findings are nonspecific and may share overlap-
ping features with septic emboli.

CONCLUSION
The spectrum of imaging findings in CNS infections includes
leptomeningeal enhancement, extraaxial collections, cerebri-
tis, encephalitis, white matter abnormalities, and enhancing
lesions. The pattern of these findings, however, may aid in
diagnosis of the underlying infectious agent and sometimes
predicts a specific organism. Additionally, imaging is key in
evaluating complications of CNS infections, including hydro-
cephalus, brain herniation, cerebral edema, infarcts, and other
vascular abnormalities.

ACKNOWLEDGMENTS
We gratefully acknowledge the contribution of some illustra-
FIGURE 3.22 DIC. NCCT demonstrates multiple scattered areas of tive cases from Dr. Mahmoud Mossa-Basha and Dr. James
convexal subarachnoid hemorrhage (SAH) (arrows). Fink from the University of Washington.

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PART II VIRAL INFECTIONS AND
RELATED DISORDERS
CHAPTER 4 PATHOGENESIS AND
PATHOPHYSIOLOGY OF VIRAL INFECTIONS
OF THE CENTRAL NERVOUS SYSTEM
KEVIN A. CASSADY AND RICHARD J. WHITLEY

Viral infections of the central nervous system (CNS) occur direct viral entry into the CNS that produces clinically evident
infrequently and most often result in relatively benign, self- cortical or brainstem dysfunction. Subsequent damage occurs
limited disease. Nevertheless, CNS infections have tremendous as a consequence of the host immune response, but invasion
importance because of the potential for death and neurologic by the pathogen initiates CNS damage (6). The parenchyma
damage. The highly specialized brain tissue is exquisitely sen- exhibits neuronophagia, and viral antigen or nucleic acids can
sitive to metabolic derangements. Injured brain tissue recovers be detected (6). Postinfectious or parainfectious encephalitis is
slowly and often incompletely. Even in patients who recover an acute demyelinating process temporally associated with a
fully from viral encephalitis, months may be required for re- systemic viral infection but without evidence of direct viral in-
turn to normal function (1). The brain and spinal cord pro- vasion in the CNS and is included as one of the causes of acute
vide diagnostic and therapeutic obstacles. On an anatomic disseminated encephalomyelitis (ADEM) (6,7). Pathologic
level, the brain is housed in a closed skull with the spinal cord specimens demonstrate demyelination and perivascular aggre-
suspended within a bony columnar cage. A unique immuno- gation of immune cells but no evidence of virus or viral antigen,
logic surveillance system and the bloodbrain barrier further suggesting an immune-mediated etiology (1). The presence of
distinguish infections of the CNS from those involving other immune cells distinguishes primary and postinfectious enceph-
organ systems. Pathologic processes in the CNS have limited alitis from an encephalopathy.
clinical expressions and frequently share pathogenic mecha- Inflammation occurs at multiple sites within the CNS and
nisms. Tumors, infections, and autoimmune processes in the accounts for the myriad of clinical descriptors of viral neuro-
CNS often produce similar signs and symptoms (2). Clinical logic disease. Inflammation of the spinal cord, leptomeninges,
presentation and patient history, though frequently suggestive dorsal nerve roots, or nerves results in myelitis, meningitis,
of a diagnosis, remain unreliable methods for determining the radiculitis, and neuritis, respectively. Aseptic meningitis is
specific etiology of CNS disease (2,3). Understanding the path- frequently used to refer to a benign, self-limited, viral infec-
ogenic mechanism of a disease provides a rational basis for tion causing inflammation of the leptomeninges (1). The term
the development of antiviral medications and strategies for the aseptic meningitis is used instead of viral meningitis because
prevention of viral CNS infections. a pathogen fails to grow in conventional culture media and
The pathogenesis of viral infections is multifactorial: age, reflects the historic ability to diagnose and treat only bacterial
immune status, cultural practices, and genetic makeup can and fungal CNS infections (6,8). This misnomer hinders epide-
influence the clinical manifestations of viral infection as read- miologic studies, because the definition fails to differentiate be-
ily as viral load, gene polymorphisms, receptor preference, and tween infectious (fungal, tuberculous, viral, or other infectious
cell tropism. Although asymptomatic enteroviral infection pre- etiologies) and noninfectious causes of meningitis. Meningitis
dominates, some patients progress to viral meningitis or, rarely, and encephalitis can represent separate clinical entities; how-
fulminant encephalitis (1,4). A detailed description of the ever, a continuum exists between these distinct forms of CNS
pathogenesis of the individual viral encephalitides is beyond the disease (1). A change in a patients clinical condition can reflect
scope of this chapter. Instead, general concepts of viral infec- disease progression, with involvement of different regions of
tion and the pathogenic mechanisms of viral CNS infection are the CNS making it difficult to predict the extent of CNS infec-
reviewed and specific examples developed where applicable. tion early in the clinical course. A patient may present with
meningismus and be diagnosed as having viral meningitis and
then progress to meningoencephalitis with altered conscious-
DEFINITIONS ness and focal CNS changes (6). Epidemiologic data in many
cases provide clues to the viral etiology.
Viruses display tissue tropism and cause illness with a charac-
teristic temporal course. The definition of viral CNS disease
is often based on both viral tropism and disease duration. EPIDEMIOLOGY
Encephalitis refers to inflammation of parenchymal brain
tissue. Acute encephalitis occurs over a relatively short pe- Epidemiology studies of meningitis and encephalitis potentially
riod of time (days), whereas chronic encephalitis presents over underestimate the true incidence of viral CNS infections. Even
weeks to months. The temporal course of slow infections and when aseptic meningitis was a reportable disease, not all pa-
spongiform encephalopathies of the CNS (kuru, visna, variant tients having a cerebrospinal fluid (CSF) pleocytosis or symp-
Creutzfeldt-Jakob disease) overlaps with that of the chronic en- toms consistent with a viral meningitis had viral cultures or
cephalitides. These progressive CNS diseases are distinguished other diagnostic studies performed. An overview is difficult,
by a long incubation period, eventually resulting in death or because each pathogen fills a different ecologic niche with
extreme neurologic disability over months to years (1,5). unique seasonal, host, and/or vector properties (1) (Tables 4.1
Viral disease in the CNS can also be classified by pathogen- and 4.2). Instead, it is useful to analyze the individual agents
esis. Neurologic disease is frequently categorized as either pri- responsible for viral brain infections in an effort to find popu-
mary or postinfectious (1). A primary encephalitis results from lation patterns and trends.

49

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50 Part II: Viral Infections and Related Disorders

TA B L E 4 . 1
TYPE OF DISEASE, EPIDEMIOLOGIC DATA, AND PATHOGENESIS OF VIRAL INFECTIONS
OF THE CNS: DNA VIRUS

Temporal Pathway Laboratory


Viral Agent CNS Disease Course Transmission to CNS Frequency Confirmation

Herpesviridae
Herpes simplex Encephalitis, meningitis, Acute Human Neuronal  Gold standardcell
virus type 1 meningoencephalitis Latent Blood culture brain biopsy
and type 2 reactivation sample; PCR has
replaced routine
brain biopsy.
Cytomegalovirus Encephalitis Acute Blood  Gold standardcell
(immunosuppressed culture, brain biopsy
and neonate) or CSF sample; PCR
may supplant this.
Epstein-Barr Encephalitis, meningitis, Acute  Serologic evidence.
virus myelitis, Guillain-Barr
Varicella-zoster Cerebellitis, Postinfectious Blood  Clinical findings,
virus encephalitis, Acute and latent Neuronal cell culture from a
meningitis, myelitis, reactivation lesion, brain biopsy
zoster ophthalmicus (zoster) or necroscopy.
Human herpes Encephalitis, febrile Acute ? ? ?PCR; high rate of
virus-6 seizures, latent form? Latent infection latent virus in
certain sites makes
interpretation
difficult
B virus Encephalitis Acute Animal bite Neuronal  Culture.
and human
Adenoviridae
Adenovirus Meningitis, encephalitis Acute Human Blood  Cell culture of CSF or
brain.
Poxviridae
Vaccinia Encephalomyelitis Postinfectious Vaccine Blood Extinct Recent

, frequent;  , infrequent; , rare; ?, unknown.

Historically, laboratory techniques for identifying neuro- sensitivity; however, the techniques sensitivity can lead to
logic infections were insensitive, invasive, and required brain erroneous diagnosis, because PCR may detect latent or in-
biopsy. Over the last two decades, molecular detection tech- tegrated viral DNA potentially unrelated to the pathogenic
niques have improved the detection of pathogens nucleic process (1). The introduction and testing of new antiviral
acids in the CSF (8,9). Despite the improved sensitivity of drugs will likely provide an impetus for accurate and timely
these techniques, the pathogen remains unidentified in the diagnosis.
majority of cases of encephalitis. Depending on the study Acute viral meningitis and meningoencephalitis represent
and diagnostic methods used, investigators fail to identify an most viral brain infections and frequently occur in epidemics
agent in the majority of presumed CNS infections (10,11). (1). Enteroviruses cause an estimated 60% to 90% of cases,
CSF viral culture rates differ based on etiology. They can whereas arboviruses constitute the majority of the remain-
often be diagnosed only presumptively by acute and conva- ing reported cases (1,8). The Centers for Disease Control
lescent serologic testing or isolation of virus from another lo- and Prevention (CDC) received notification of approximately
cation in the body (6,12). In a retrospective review of patients 7,200 to 14,500 cases of aseptic meningitis annually (1).
who had positive bacterial CSF cultures, 1 of 20 had a con- Most of these cases occurred from the late spring to autumn
comitant virus isolated from the CSF (13,14). Historically, months, reflecting the increased incidence of enteroviral and
the definitive method for virus detection in encephalitis was arboviral infections during these seasons (17,18). The inci-
brain biopsy and viral culture (1,2). Polymerase chain reac- dence and etiology of encephalitis varies based on geography,
tion (PCR) techniques and other molecular biologic methods environmental factors, and frequency of exposure to vectors
from CSF samples have replaced culture and brain biopsy responsible for viral transmission (19,20).
as the standard for diagnosing encephalitis for some viruses The CDC received 740 to 1,340 annual reports of per-
(herpes simplex virus [HSV], enterovirus, varicella-zoster sons with encephalitis from 1990 to 1993 (1). Herpes sim-
virus [VZV], and JC virus) (8,15,16). PCR has exquisite plex virus infection of the brain occurs year round without

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Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 51

TA B L E 4 . 2
TYPE OF DISEASE, EPIDEMIOLOGIC DATA, AND PATHOGENESIS OF VIRAL INFECTIONS OF THE CNS: RNA VIRUSES

Fatality Geographic Disease Pathway Laboratory


Viral Taxonomy CNS Disease Rate Vector Distribution Pattern to CNS Frequency Confirmation

TogaviridaeAlphavirus (arborvirus)
Western Meningitis, 310% Mosquito, U.S.west of Epidemic Blood  Serologic titers
equine encephalitis bird Mississippi (HI, CF,
encephalitis River NA, IFA),
virus viral antigen
detection in
brain. Rarely
culture.
Eastern 30% U.S.Atlantic Sporadic  Viral culture
equine and Gulf or antigen
encephalitis Coast states detection in
virus brain, serologic
titers (HI, CF,
NA, IFA), CSF
IgM ELISA.
Venezuelan 1% Mosquito, Central and Sporadic,  Serologic titers
equine horse South epidemic (HI, CF, NA,
encephalitis America, IFA), CSF IgM
virus southwestern ELISA.
U.S., and
Florida
FlaviviridaeFlavivirus (arbovirus)
Japanese Meningitis, 25% Mosquito, Japan, China, Epidemic, Blood  Peripheral blood
encephalitis encephalitis swine, Korea, endemic ELISA, serologic
virus bird Taiwan, titers (HI, CF,
Southeast NA, IFA), CSF
Asia, India, antigen tests.
Nepal
St. Louis 7% U.S.  CSF IgM ELISA,
encephalitis serologic titers
virus (HI, CF, NA,
IFA). Rarely
culture.
West Nile Rarely Uganda, Egypt,  Culture (rare),
fever virus Israel serology (HI,
IFA).
Murray Valley virus Encephalitis 2060% Australia  Viral culture,
serologic titer
(HI, CF, NA).
Tickborne 20% Tick, Eastern Epidemic,  Serologic titer
encephalitis unpasteur- Russia and sporadic (HI, CF, NA),
virus (TBE ized milk Central IgM ELISA.
complex) Europe
Bunyaviridae (arbovirus)
California Meningitis, 1% Mosquito, Northern Endemic Blood  Viral culture, CSF
(La Crosse) encephalitis rodent Midwest (LCV)  IgM ELISA,
encephalitis and (CEV) serologic titers
virus northeastern (HI, CF, NA,
U.S. IFA), CIE.
ReoviridaeOrbivirus (orvivirus)
Colorado Meningitis, 1% Tick, rodent Rocky Endemic Blood  Antigen detection
tick fever encephalitis Mountains, on RBC
Pacific membrane, viral
Coast states culture, serologic
titers (HI, CF,
NA, IFA).

(continued)

51

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52 Part II: Viral Infections and Related Disorders

TA B L E 4 . 2
TYPE OF DISEASE, EPIDEMIOLOGIC DATA, AND PATHOGENESIS OF VIRAL INFECTIONS OF THE CNS:
RNA VIRUSES (CONTINUED)

Fatality Geographic Disease Pathway Laboratory


Viral Taxonomy CNS Disease Rate Vector Distribution Pattern to CNS Frequency Confirmation

Picornaviridae (enterovirus)
Poliovirus Meningitis 4.550%a Fecal-oral Worldwide Endemic Blood and  Viral culture
myelitis neuronal CSF or brain,
viral culture
from other
side. Serologic
testing for some
serotypes. PCR
becoming gold
standard.
Coxsackievirus Meningitis, Rarelyb Blood 
Echovirus Meningo- 
encephalitis,
myelitis

Paramyxoviridae (xanthematous virus)


Measles virus Encephalitis, 15% Postinfectious, Worldwide Sporadic Blood  Serology, ELISA,
SSPE blood clinically.
Mumps virus Meningitis, 1% Blood  CSF, viral culture.
encephalitis,
myelitis
Orthomyxoviridae (upper respiratory virus)
Influenza viruses Encephalitis 1% Postinfectious Worldwide Sporadic Blood  Viral culture from
another site.
Rhabdoviridae
Rabies virus Encephalitis, 100% Mammal Worldwide Sporadic Neuronal  Antigen detection
encephalo- in brain,
myelitis serologic tests
(IFA, CF, HI,
CIE), viral
culture.
Retroviridae
Human Encephalopathy, Ultimately Human Worldwide ? Blood  PCR autopsy
immunodeficiency encephalitis, 100% samples, MRI
virus type 1 leukoence- findings.
(HIV-1) phalopathy
Arenaviridae
Lymphocytic Meningitis, 2.5% Rodent Worldwide Sporadic Blood  CSF, blood culture,
choriomeningitis encephalitis urine culture,
virus serology.

CF, complement fixation; CIE, counterimmunoelectrophoresis; ELISA, enzyme-linked immunosorbent assay; HI, hemagglutination inhibition; IFA, immu-
nofluorescence antibody; NA, neutralizing antibody titer; SSPE, subacute sclerosing panencephalitis.
Frequency:   , frequent;  , infrequent; , rare; ?, unknown.
a
Case fatality from poliomyelitis is increased in sporadic cases. With vaccination, the epidemic forms of polio have decreased, as has morbidity. In turn, the
calculated case-fatality rate in the U.S. has increased in sporadic and vaccine-associated disease relative to the number of cases of disease.
b
Rarely fatal except in neonate and agammaglobulinemic patient in whom fatality rates can approach 50% even with treatment.

seasonal variation, affects all ages, and constitutes most infections vastly outnumber those that are symptomatic.
fatal cases of endemic encephalitis in the United States (21). Patients with symptomatic infections may develop a mild,
Arboviruses, a group of more than 500 arthropod-transmit- systemic febrile illness or a viral meningitis. Encephalitis oc-
ted RNA viruses, are the leading cause of encephalitis world- curs in a minority of persons with arboviral infections, but
wide and in the United States (1). Arboviral infections occur the case-fatality rate varies extremely from 5% to 70%, de-
in epidemics and show a seasonal predilection, reflecting the pending on viral etiology, age of the patient, and unique host
prevalence of the transmitting vector (22). Asymptomatic differences (1,23).

52

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Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 53

WNV 2011
Japanese B encephalitis and rabies constitute most cases of
encephalitis outside of North America. Japanese B encephalitis
virus, a member of the genus Flavivirus, occurs throughout
Asia and causes epidemics in China despite routine immuni-
zation for the virus (24,25). In warmer locations, the virus
occurs endemically (26). The disease typically affects children,
although adults with no history of exposure to the virus are also
susceptible (27). As with the other arboviral infections, asymp-
tomatic infections occur more frequently than symptomatic in-
fections. However, the disease has a high case-fatality rate and
leaves half of the survivors with a high degree of neurologic
morbidity (27). Of note, West Nile virus (WNV) encephalitis,
a member of the Flavivirus family, has increased in incidence
strikingly in the United States (28). In 2002 alone, the CDC
reported more than 3,989 cases and nearly 250 deaths. WNV
infection declined in the United States such that between 2008
and 2011, only 712 to 1,356 cases were reported. There was
an increase in cases (5,387) in the United States in 2012. Many
of the cases occurred in the Mississippi Valley and Southern WNV 2012
and Central United States, suggesting an evolving epidemi-
ology for this introduced pathogen (Fig. 4.1) (http://www
.cdc.gov/ncidod/dvbid/westnile/surv&controlCaseCount12_
detailed.htm). Rabies virus, a bullet-shaped RNA virus of the
family Rhabdoviridae, remains endemic around the world
(29). Human infections in the United States decreased over
the last decades to one to three cases per year because of the
immunization of domesticated animals. Bat exposure is in-
creasingly recognized as the source of infection. Fifteen per-
cent (685 of 4,470) of bats tested carried the rabies virus in
one study analyzing risk of bat exposure and rabies (30). In
most cases, (22 of 24) there was no evidence of bite; how-
ever, in half of the cases, direct contact (handling of the bats)
was documented (31). There is experimental evidence that
bat-associated rabies virus variants transmit across the dermis FIGURE 4.1 Cases of West Nile virus (WNV) in the United States
and potentially through hair follicles (29). Alternatively, bat 2011 (top panel) and 2012 as of December 11, 2012 (bottom panel).
bites may not have been recognized (1). In areas outside the Shaded area demonstrates counties where human WNV infection was
United States, annual cases of rabies encephalitis number in reported. (Courtesy of CDC Arboviral Branch.)
the thousands.
Postinfectious encephalitis, an acute demyelinating pro-
cess, accounts for approximately 100 additional cases of en-
cephalitis reported to the CDC annually in historical studies BSE cases, suggesting animal to human transmission (5). The
(32,33). The disease historically produced approximately report of atypical CJD (unique clinical and histopathologic
one third of the encephalitis cases in the United States and findings) affecting young adults (an age at which CJD rarely
was associated with measles, mumps, and other exanthema- has been diagnosed) led to the designation of a new disease,
tous viral infections (1). Postinfectious encephalitis is now variant Creutzfeldt-Jakob disease (vCJD). From 1996 to
associated with antecedent upper respiratory viral infection 2011, there have been 224 cases of vCJD reported, with 175
(noticeably with influenza virus) and varicella in the United of these occurring in Ireland and Great Britain (World Health
States (32). Measles continues to be a leading cause of postin- Organization [WHO] Web site: www.who.int). The numbers
fectious encephalitis worldwide. In addition to the postin- have declined since the ban in the use of bovine offal in fer-
fectious process, patients with paraneoplastic syndrome and tilizers, pet food, or other animal feed. Active monitoring is
autoantibodies to the N-methyl-d-aspartate (NMDA) auto- still important, and detection of BSE continues to be reported
antibodies have also been recently described (34). Recent in North America (Fig. 4.2) (CDC BSE Web site: http://www.
studies suggest that antigenic variation in the N-terminal do- cdc.gov/ncidod/dvrd/bse/).
main of the NMDA receptor may predispose these patients Environmental factors influence infections of the CNS.
to the autoimmune encephalitis (35). The slow infections Changes in behavior, cultural beliefs, and modification of
of the CNS and transmissible spongiform encephalopathies the environment result in changes in disease patterns and
(TSEs) occur sporadically worldwide (5). The prototypical exposure to new infectious agents. Arboviral infections will
TSE is Creutzfeldt-Jakob disease (CJD); it occurs at high likely increase as populations encroach on wilderness habi-
rates within families and has an estimated incidence of 0.5 tats and flood plains (1). Vaccination has further changed the
to 1.5 cases per million populations. In 1986, cases of a TSE character of viral CNS disease. In 1952, poliomyelitis affected
in cattle, bovine spongiform encephalopathy (BSE), were re- 57,879 Americans (1). Widespread vaccination has eradicated
ported in the United Kingdom. In addition to affecting other the disease currently from the Western Hemisphere. As so-
livestock throughout Europe that were fed supplements con- cial and environmental changes occur globally, the character
taining meat and bone meal, cross-species transmission of and prevalence of CNS viral infections will also change. CNS
BSE has been documented, leading to a ban in the use of infections must be examined in a geographic, cultural, and
bovine offal in fertilizers, pet food, or other animal feed (5). environmental context as well as at the cellular, molecular,
Increases in atypical CJD cases coincided with the peak of and genetic levels.

Scheld_Ch04.indd 53 2/21/14 5:30 PM


54 Part II: Viral Infections and Related Disorders

7
N = 23
6

5

4

3

2

1
* #
0
1993 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
as of 04/24/2012
FIGURE 4.2 Monitoring and overview
U.S. Canada Canadaborn after 1997 feed ban Canadaunknown birth date
of BSE in North America. Columns rep-
resent number of cases of BSE in North
* Imported UK to Canada # Imported Canada to US

Born after March 1, 1999 America by country of origin and year.
(Courtesy of CDC and WHO.)

PATHOGENESIS be permissive, providing an adequate environment for viral


replication. The initial steps involved in hematogenous spread
of virus to the CNS consist of replication at the local site of
Viral Spread entry and primary viremia (1). Infection of a secondary tissue
frequently ensues, permitting secondary replication and an ex-
Viruses use two basic pathways with fundamentally different tensive viremia that seeds the CNS. Not all viruses follow this
steps to gain access to the CNS: hematogenous and neuronal. sequence, and genetic factors of both virus and host influence
Viruses must survive and multiply at the cellular level effi- the route of viral spread.
ciently and in sufficient quantity to infect the CNS. The mech- The cornified layers of dead skin cells provide a structural
anism of spread to the CNS is in large part determined by viral defense for the greatest potential infective surface area of the
factors, site of entry, and successful replication in intermediate human body. Layers of keratin protect the underlying epi-
cells (1). The local immune response at the site of entry, the thelium from viral contact, thereby decreasing the incidence
systemic immune responses, and the limited vascular access of viral entry (1). Breaks in this defensive layer can result in
afforded by the bloodbrain barrier further reduce the oppor-
tunity for viral neurologic infections (1). Differences in host
physiology and mechanism of spread to the CNS further influ-
ence the clinical manifestations of neurologic disease (1). For
example, adults with herpes simplex encephalitis (HSE) have
different presenting signs and symptoms than newborn babies Mouth Conjunctiva
with HSV infection of the CNS. The route of viral spread and Respiratory
areas of neurologic involvement differ based on the age of the tract
patient and mechanism of exposure (36). The subsequent neu- Scratch,
rologic damage and poor outcome, however, are similar (1). injury
Subtle differences at the epidemiologic, host, tissue, cellular,
and genetic levels can alter this balance between viral exposure Alimentary
and symptomatic infection. tract

Hematogenous Spread
Enteroviruses and arboviruses are prototypes for viremic
spread to the CNS. Although the location of viral entry dif-
fers for each family, both cause primary and secondary viremia
prior to infecting the CNS. Reviewing the necessary steps and Arthropod
Urogenital
the numerous barriers to hematogenous neurologic infection tract Capillary
explains the low incidence of symptomatic viral infection and
the even lower frequency of viral neurologic infections. A virus Anus
must first bypass or attach to and enter host epithelial cells to Skin
produce infection (37) (Fig. 4.3). In addition, the cell must FIGURE 4.3 Body surfaces as sites of virus infection and shedding.

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Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 55

higher frequency of infection as well as more severe disease. opportunity for host eradication of viremia (1). Viruses infect
Some vector-borne viruses bypass the cornified epithelial layer tissues other than the liver and spleen, such as muscle, endo-
by inoculation into the subepithelial layer or directly into the thelium, and blood cells. These sites provide an environment
blood (1). The nonkeratinized epithelial layer that constitutes for viral replication in highly vascular locations that facilitate
the conjunctival, respiratory, oral, and nasopharyngeal sur- extensive viremia. Secondary viremia produces high titers
faces provides an ideal entry point for aerosolized viruses or of virus in the bloodstream for prolonged periods of time,
pathogens transmitted by large droplets. Parainfluenza and facilitating the seeding of target organs. Viral genetics and host
adenovirus, although uncommon, can cause primary encepha- physiology determine the location and extent of infection at
litis (1). More frequently, however, the respiratory viruses are these secondary sites (1).
associated with postinfectious encephalitis (32). A mucous Virus must localize in the vessels of the CNS before cross-
layer composed of mucopolysaccharides, secretory immu- ing the bloodbrain or bloodCSF barrier, a network of tight
noglobulins, and inflammatory cells provides a mechanical, endothelial junctions sheathed by glial cells that regulate mo-
chemical, and cellular defense against pathogens (1). In the lecular access to the CNS (43). The pathophysiology of viral
gastrointestinal and urogenital systems, constant transit pro- transport from blood to brain and of viral endothelial cell tro-
tects the mucosa. As in the respiratory mucosa, leukocytes pism is poorly understood. Virus infects endothelial cells, leaks
and secretory factors augment this mechanical defense. The across damaged endothelium, passively channels through en-
enteroviruses tolerate stomach acid, bile salts, proteolytic en- dothelium (pinocytosis or colloidal transport), or bridges the
zymes, and alkaline infusions to infect the host. Certain viruses endothelium within migrating leukocytes (1). Cell-associated
(coxsackievirus A9) actually require exposure to proteolytic and cell-free viruses can cross the endothelium and enter the
enzymes in the gut before they can infect select cell types (1). parenchyma or CSF. This bridging of the endothelium occurs
Once virus breaches the epithelial barrier and finds a per- in choroid plexus vessels, meningeal blood vessels, or cerebral
missive cell, primary replication occurs. Virus then can spread blood vessels (1) (Fig. 4.4). Once in the CSF, virus may remain
and replicate in the lymph node, or it can bypass the node limited to the meninges or may enter the brain parenchyma
and enter the circulatory system, where it seeds other tissues across either ependymal cells or the pial linings.
(arbovirus, enterovirus, measles virus, or varicella virus) (1).
Local immune responses are crucial in limiting systemic viral
infection. The generation of a swift inflammatory response
Neuronal Spread
can limit viremia and symptoms of infection. Some viruses Rabies and HSV infection are prototypes of viral CNS infections
resist phagolysosomal degradation, allowing them to circulate that access brain by peripheral neuronal spread. Historically,
and replicate within the protective sheath of a macrophage the peripheral neural pathway was considered the only path-
(38,39). Antigenic changes and the sequestration of viral re- way of viral neurologic infection. Experiments with HSV and
ceptors provide additional mechanisms that enable viruses rabies virus performed in the nineteenth and early twentieth
to evade lymphocytes. For example, human rhinovirus 14, centuries, combined with the discovery of the bloodbrain bar-
influenza virus, and poliovirus have receptors embedded in a rier at the turn of the century, led most investigators to con-
recess or canyon in the viral membrane (1). The virus is clude that all viral neurologic infections occurred by neuronal
able to evade the immune response by altering the molecules spread (1). Contemporary data, however, show that the blood-
on the surface surrounding the highly conserved, immunologi- stream provides the principal pathway for CNS infections in
cally inaccessible receptor molecules lining the canyon. Other humans. Some viruses (poliovirus and reovirus), previously
viruses have hypervariable sequences surrounding a small, thought to infect the CNS by the hematogenous route, have
molecularly conserved binding sequence. The viral binding been detected in peripheral neurons in experimental models
site may be smaller than the antigenic sequence recognized by (44). Viremia and neuronal spread to the CNS can occur con-
the immunoglobulin. Changes in the hypervariable molecules currently and are not mutually exclusive (1).
surrounding the binding site allow the virus to evade immune Neuronal spread occurs along peripheral or cranial
responses without disrupting the fidelity of the receptor bind- nerves. The nerve shields the virus from immune regulation
ing site (40,41). and allows access to the CNS. Rabies virus classically infects
Primary viremia allows virus to seed distant locations of by the myoneural route; however, infection has been docu-
the body and frequently marks the onset of clinical illness. mented from corneal transplantations, and aerosolized entry
Virus circulates in the vascular system attached to or within has occurred following spelunking in caves contaminated
host cells such or as free virus within the plasma (1). Viruses with infectious bat guano (29,45). These sources of infection
have limited access to the CNS via cerebral vessels and re- are infrequent and employ the same axonal mechanism of
quire sufficient numbers of progeny to overcome the improb- spread within the nerve, albeit from a different location than
ability of contact and entry into a permissive cell. In rare the myoneural route.
circumstances, such as disseminated neonatal herpes infec- Rabies virus replicates locally in the soft tissue following a
tion, virus infects the CNS after primary viremia. However, rabid animal bite, although entry into sensory nerves prior to
most infect an intermediate tissue prior to reaching the CNS. soft tissue replication has also been documented (1). Protection
Viral genes may be as important as host physiology in de- by antibody-mediated immune mechanisms in the soft tissue
termining the route and degree of viral dissemination. For provides the only known method of preventing neurologic dis-
example, the reovirus S1 gene determines the mechanism ease and death (29). After primary replication, the virus en-
of viral spread in the host. The S1 gene codes for a capsid ters the peripheral nerve. Experimental evidence demonstrates
hemagglutinin, 1, that binds to neuron receptors. Serotypes acetylcholine receptor binding as the mechanism of myocyte
with an intact 1 gene spread to the CNS by neuronal path- entry (1). However, viruses have also been documented in cells
ways, whereas 1-deficient mutants gain access to the CNS lacking these receptors. Once in the muscle, the virus buds
via the hematogenous route (42). from the plasma membrane and may cross myoneural spin-
The liver and spleen provide ideal locations for secondary dles or enter the nerve by the motor endplate. The virus then
viral replication because of their highly vascular structure. travels by anterograde and retrograde intraaxonal transport
The high degree of parenchymal contact and large number of to infect neurons in the brainstem and limbic system. Viruses
fixed mononuclear macrophage cells also provide an excellent appear to cross the transsynaptic space between neurons by

Scheld_Ch04.indd 55 2/21/14 5:30 PM


56 Part II: Viral Infections and Related Disorders

Brain substance
CSF
Cerebral blood vessel
Blood vessel in
choroid plexus

Ventricle

Nerve
Pia

CSF

Ependyma

From peripheral
nerve ending or
nasal mucosa Meningeal blood FIGURE 4.4 Routes of viral invasion of
or dorsal CSF vessel the central nervous system. CSF, cerebro-
root ganglion spinal fluid.

passive transport rather than receptor-mediated transport. viral neuroinvasion and neurovirulence. For example, reovirus
Recent evidence suggests rabies virus enters projections in the types 1 and 3 produce different CNS diseases in mice based on
postsynaptic neuron that extend into invaginations on the pre- serotype differences in receptor affinities (1,42). Escape mutant
synaptic side. These projections pinch off and fuse with the B4 of tick-borne encephalitis (TBE) virus also demonstrates
presynaptic membrane, allowing the virus to spread along viral differences in mouse neuroinvasiveness. A single amino
motor or sensory neural pathways (1,45). acid substitution (Tyr to His) in domain 2 of viral surface
Paresthesias near the location of the animal bite and protein E eliminates viral neuroinvasiveness without affecting
change in behavior follow over the next weeks. These signs neurovirulence (1). Receptor difference is only one determi-
and symptoms correlate temporally with the axoplasmic nant of viral neurotropism. Other viral factors may influence
transport of virus and infection of the brainstem and hippo- neurotropism. For example, enteroviruses in the same recep-
campal region (1). The infection spares cortical regions during tor family produce very different diseases. Coxsackieviruses
this phase, allowing animals to vacillate between periods of B1 through B5 readily produce CNS infections, whereas type
calm, normal activity and short episodes of rage and disorien- B6 rarely produces neurologic infection. Viral genes influence
tation (45). Eventually, the virus spreads from the diencephalic neurovirulence of HSV-1. Mutant HSV-1 viruses with either
and hippocampal structure to the remainder of the brain, 134.5 gene deletions or stop codons inserted into the gene
killing the animal. Experimental rabies infections in animals have a decreased ability to cause encephalitis and death fol-
demonstrate that the mode of acquisition influences the neu- lowing intracerebral inoculation in mice as compared with
roanatomic location of initial infection (1). wild type virus (46,47). Upon entering mouse neuronal cells,
Viruses also infect the CNS through cranial nerves. The these 134.5 () mutants trigger the shutdown of protein syn-
olfactory system is unique among cranial nerves in that the thesis and elicit interferon signaling responses that limit ef-
neurons regenerate and have approximately a 1-month life ficient viral replication (48).
span. The olfactory neurons are not protected by the blood Host physiology is also important in determining the
brain barrier, theoretically providing direct neuronal access extent and location of viral CNS disease. Age, sex, and ge-
to the brain (1). Animal studies have shown that HSV can netic differences between hosts influence viral infections and
infect the brain through the olfactory system as well as the clinical course. With respect to HSV infection, host muta-
trigeminal nerve. Moreover, the inferomedial temporal lobe, tions in pattern recognition receptors important for type I
the initial location of early HSV encephalitis, contains direct interferon production predispose patients to HSE (49). Host
connections with the olfactory bulb. The association of viral age influences the clinical manifestations and sequelae of
latency in the trigeminal ganglia, the relative infrequency of a viral infection (50). Differences in outcome are twofold:
HSE, and the confusing data regarding encephalitis from HSV mature neurons resist virally induced apoptosis, and younger
reactivation suggest that the pathogenesis is more complex patients can have more immature immune response to infec-
than described earlier (1). tion (51,52). Differences in macrophage function can alter
infections and disease. Moreover, macrophage processing
capacity can change with age in humans (1,38). Enteroviral
Host and Viral Factors Influencing infections exemplify the difference that host physiology plays
Neurotropism in determining the extent of viral disease. Enterovirus infec-
tions in children younger than 2 weeks of age can produce
As illustrated in Tables 4.3 and 4.4, viruses exhibit differences a severe systemic infection, including meningitis or menin-
in neurotropism (1). Strain and serotype differences influence goencephalitis (53). Ten percent of neonates with systemic

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Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 57

TA B L E 4 . 3
PROPOSED NEUROVIRULENCE FACTORS

Virus Viral Factor Effect

HSV-1 Viral 134.5 gene Decreased viral replication in neuronal tissue and
protein synthesis shutdown
Viral gE and gI glycoproteins Mutant viruses lacking these receptors do not
cause encephalitis
VZV Host cell-mediated immunosuppression Increased frequency of herpes zoster, visceral, and
disseminated cutaneous disease
CMV Viral Fc receptor protein Immune evasion: bind neutralizing antibodies
Virus binds 2-microglobulin Immune evasion
EBV Viral glycoproteins gp220 and gp350 Infect lymphocytes
Lassa fever virus Viral polymerase Changes the function of endothelium and platelets
Sindbis virus E2 envelope protein Neurovirulence receptor protein
Reovirus Viral proteins 1, 3, 1 Receptor proteins that influence CNS infection
Rabies virus Viral protein gG Major antigenic determinant, essential for
pathogenicity
Enterovirus Nucleotide 472 in the noncoding region Neurovirulence gene
Capsid proteins VP1 and VP3 Single amino acid changes in the capsid proteins
reduce neurovirulence
Measles virus M protein Deficiency of this protein inhibits release of virus
and is associated with SSPE
Tickborne encephalitis (TBE) virus Glycoprotein E (domain B) Neuroinvasiveness receptor domain
Murray Valley encephalitis virus Glycoprotein E (domain B) Neuroinvasiveness receptor domain
Louping ill virus Glycoprotein E (domain B) Neuroinvasiveness receptor domain

CMV, cytomegalovirus; SSPE, subacute sclerosing panencephalitis; VZV, varicella-zoster virus.

enteroviral infections die, and as many as 76% are left with poliomyelitis and may result in an increased incidence of
permanent sequelae (1). In older children, however, entero- enteroviral myocarditis and aseptic meningitis (1,54). The
viral infections produce less severe disease. In addition to frequency of infections in groups frequently reflects epidemi-
age, physical activity may be another important host fac- ologic differences in exposure. Increasingly, host differences
tor that determines the severity of infection. Exercise and are recognized as equally important determinants of disease
trauma have been associated with increased risk for paralytic at the cellular and molecular levels.

TA B L E 4 . 4
VIRAL NEUROTROPISM

Virus CNS Location

Herpes simplex virus (postnatal) Neurons in the inferomedial temporal lobe,


orbitofrontal areas
Varicella-zoster virus (postinfectious) White matter of the cerebellum
Cytomegalovirus Neurons, glial, ependymal, and subependymal cells
Epstein-Barr virus Cerebral blood vesselsvasculitis
Lassa fever virus Choroid plexus
Japanese encephalitis virus Brainstem and basal ganglia in humans, retinula cells
in mosquitoes
Rabies virus Neurons in the hippocampal, cerebellar,
mesencephalic areas
Mumps virus Ependymal and choroid plexus cells
Polyomavirus (immunosuppressed) Oligodendrocyte damage in subcortical white matter
Poliovirus Motor neurons in the anterior horn of the spinal cord
and brainstem

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58 Part II: Viral Infections and Related Disorders

Central Nervous System Physiology Arachnoid

The bloodbrain barrier limits chemical and environmental Subarachnoid


exposure to the CNS by a series of tight endothelial junctions space
bound and maintained by glial cell foot processes. This barrier
Pia
provides a physiologic boundary between the metabolically
sensitive neuronal cells and the chemical changes outside the Subpial
CNS (43). In addition, the endothelial cells and tight junctions space
Blood vessel
provide a physical barrier to most pathogens, limiting viral
access to the CNS. As with most biologic systems, the blood Glia
limitans Perivascular
brain barrier is more complex and heterogeneous than previ- macrophage
ously imagined. The bloodbrain barrier was first described
during the late nineteenth and early twentieth century, when Virchow-Robin
scientists noted that various dyes administered intravenously space
failed to penetrate the CNS (1). In the 1960s, experiments
certified that the tight junctions between endothelial cells
lining the cerebral vessels blocked the passage of small protein FIGURE 4.5 The relationship of the Virchow-Robin space to the sub-
molecules. pial and subarachnoid space.
The tight junctions between endothelial cells provide
a relatively impermeable layer to most polar substances.
Unique transport systems and enzymes further distinguish
the CNS capillaries from blood vessels in other organs. The
asymmetric distribution of transport proteins in the endothe- The brain is an immunologically privileged site into
lial cell membrane creates a highly resistant, polarized cell which immune cells do not readily enter. Increasingly, scien-
layer that limits paracellular diffusion (55). Hydrophilic sub- tists are discovering that immune cells reside in and circulate
stances cross the endothelial layer through receptor-mediated through the Virchow-Robin space, a lymphatic channel lining
endocytosis or through highly specific, saturable transport the perivascular space in the brain (1) (Fig. 4.5). Moreover,
systems. Respiratory gases and lipophilic chemicals passively many of the fixed glial support cells and pericytes surrounding
penetrate the layer of tight junctions readily. The cerebral the vessels in the CNS can transform to monocyte/macrophage
vessel endothelial cells also possess second-messenger mole- antigen-presenting cells. The circulating lymphocytes act as
cules that may regulate transmembrane permeability through surveillance cells, detecting small amounts of antigen presented
receptor binding (55). Substances produced during infection by the macrophages in the perivascular space and initiating the
or chemicals secreted by cells, such as histamine and inter- immune response either within the Virchow-Robin space or
leukins, change the permeability of the bloodbrain barrier, peripherally at the lymph node. During periods of infection,
thus modulating entry of viruses and immune cells into the immune cells readily enter the CNS and fill the Virchow-Robin
CNS. Astrocytes are metabolically important support cells space (1) (Fig. 4.6). The perivascular space provides a staging
of mononuclear macrophage origin that surround cerebral area where lymphocytes interact chemically and differentiate
capillaries, induce tight junctions, and may regulate immune prior to entering the neuropil. Cells in the perivascular space
cell entry (1). as well as cerebral capillary endothelial cells are capable of

Virchow-Robin space Enlarged Virchow-Robin


around CNS blood vessel- space around
resting state CNS blood vessel-
state during reaction
to intra-CNS immune
Some macrophages stimulation
containing antigen
migrate to lymph node
T cells stimulated
to respond
T and B
lymphocytes
activated

Virchow-Robin space Macrophage

T cells Plasma cells


Perivascular
macrophage

Rare Microglia
lymphocyte
Plasma cells

FIGURE 4.6 Illustration of the Virchow-Robin space as an immunologic space that can become expanded
with immunocompetent cells interacting together under conditions of immunostimulation in the brain.

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Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 59

regulating T-helper cell subsets in vitro and may influence the


expression of the immune response, dictating which cells enter Attachment and Entry
the CNS. Different viruses may activate characteristic lympho-
Attachment is an essential first step in viral infection. Multiple
cyte subsets for entry into the parenchyma. In some cases, the
copies of proteins line the surface of a virus. These capsid or
immune response is instrumental in the pathogenesis of CNS
envelope proteins create high-affinity bonds with host recep-
damage (1,51,56,57).
tors and initiate viral infection or a host cell response (58,59).
Classically, this response involves viral entry but may include
a change in cellular metabolism or generation of immune
VIRAL REPLICATION IN THE responses by the cell. Temperature, pH, receptor affinity, and
CENTRAL NERVOUS SYSTEM the concentration of viral and host receptors influence the
hostviral receptor interaction similar to a receptor-ligand
The fundamental principles of viral replication and cell-to-cell reaction. The cell receptor consists of proteins, lipids, and/
spread provide a framework for examining the pathogenesis or oligosaccharides. Receptor binding provides close contact
and clinical repercussions of neurologic infections. The clini- between virus and cell, facilitating but not ensuring viral entry
cal manifestations and the severity of illness reflect the loca- into the cell. Some viruses require specific chemical or proteo-
tion and extent of viral replication in the CNS. Once virus lytic conditions before entering the cell (6062). For example,
accesses the CNS, it must introduce its genome and transport Semliki Forest virus requires the presence of cholesterol in the
proteins into the cytoplasm or the nucleus of the mammalian cell membrane as well as a pH change in the endosome for
cell. Once the viral genome has been uncoated, transcription entry (63). The presence of one type of receptor for cell entry
and translation proceed in a predictable and organized cas- does not preclude other mechanisms of entry into a host cell.
cade of gene expression, culminating in the replication of the Viral entry into the cell is essential. Although receptors have
viral genome. Translation of late viral genes produces struc- been identified, alternative entry mechanisms are being identi-
tural proteins essential for the construction of the next gen- fied for viruses (64). Studies determining the structure of viral
eration of viruses. Viral genomic material is packaged with glycoproteins and host receptor interactions as well as experi-
structural proteins and exits the cell (1) (Fig. 4.7). Viruses ments using viral recombinants and cell lines expressing cellular
exploit essential cell activities such as protein synthesis, in- receptors provide two methods used to characterize viral entry.
tracellular transport, and cellular communication to enter the Viruses can bind nonspecifically to the cell surface; however,
cell and replicate their genome. As in other biologic systems, these nonspecific interactions do not produce a biologic re-
both divergent and convergent evolution has resulted in an sponse. Viruses frequently target essential and/or tightly con-
array of mechanisms for successful viral reproduction. As a served host receptor domains. Some viruses appear to interact
result, numerous strategies exist for viral entry, gene expres- with neurotransmitter receptors in the CNS. Experimental data
sion, replication, assembly, and egress (1). The relative speed indicate that rabies virus binds to acetylcholine receptors on
and efficiency with which the virus replicates determine the mouse myocytes (1). Reovirus 3 binds to the -adrenergic recep-
progression of infection. tor. Viruses also bind to immunologic proteins on the surface of
cells. Poliovirus, HSV, and measles virus bind to receptors in the
immunoglobulin superfamily (65,66). Hormone and cytokine
receptors provide additional targets for viral cell entry. Viruses
can have more than one mechanism for entering a cell or differ-
ent receptors for different cell types (1). The number and distri-
1 Attachment bution of receptors help determine viral tissue tropism and the
extent of viral CNS disease. Receptor prevalence is not the only
determinant of viral tissue tropism (1). Transgenic mice, for
2 Penetration (endocytosis) example, develop poliovirus infection only in limited tissue sites
despite the widespread expression of the receptor. Some viruses
3 Uncoating require the presence of certain genes and transactivating factors
to infect a cell. While a cell may contain a certain receptor, a
4 Transcription of mRNA permissive environment for viral replication may not exist. The
tissue, in such a case, is resistant to infection (67).
5 Translation of early proteins Enveloped viruses have different mechanisms than nonen-
veloped viruses for cell entry. Once the virus binds to the host
6 Replication of viral DNA cell receptor domain, the virus can enter the cell by direct fu-
sion or receptor-mediated endocytosis. The receptor-bound
7 Transcription of mRNA virus frequently becomes encased in a clathrin-coated pit during
endocytosis. Other modes of endocytosis exist, and virus has
8 Translation of late proteins been found in uncoated vesicles (1,68). Fusion proteins contain
hydrophobic regions and initiate the union of viral and cell mem-
9 Assembly of virions branes in some enveloped viral infections. Nonenveloped viral
entry is more enigmatic. Conformational changes or proteolytic
cleavage may expose hydrophobic regions of capsid proteins,
enabling the protein capsid to fuse with or embed in the cell
membrane. The capsid then opens and releases the viral genome
10 Release by budding into the cytoplasm. Endocytosis may provide the pH change or
enzymes necessary for viruscell fusion and ensures that the cell
FIGURE 4.7 The viral multiplication cyclea stylized and greatly is metabolically viable. Furthermore, it has been suggested that
simplified diagram summarizing the key steps in the multiplication of endocytosis delivers the viral genome to the proper intracellular
a typical DNA virus. (From Fenner F, White DO. Medical Virology. location from which replication occurs. Viral fusion, in most
2nd ed. Orlando, FL: Academic Press; 1986, with permission.) cases, occurs before the endosome fuses with the lysosome.

Scheld_Ch04.indd 59 2/21/14 5:30 PM


60 Part II: Viral Infections and Related Disorders

glycosylation (72). Viruses contain regulatory proteins and


Replication and Egress promoter sequences that control the differential expression of
transcripts. Proteolytic modifications are made to the struc-
Viral replication begins after uncoating and delivery of the tural protein following attachment of fatty acids and oligo-
genome to a satisfactory intracellular location (68). Viruses saccharides in the Golgi apparatus (1). In some cases, these
replicating in the nucleus often contain nuclear targeting sig- proteolytic changes are necessary for producing infectious
nals and can use existing cellular mechanisms to enter the progeny. TBE virus, for example, requires cleavage of a mem-
nucleus (1). Alternatively, viruses that replicate in the cyto- brane-bound precursor protein (prM). The proteolytic change
plasm uncoat and deliver the genome to the perinuclear area produces a small, membrane-bound protein (M protein) that
(68). The production of positive stranded viral messenger RNA protects another membrane-bound protein from conforma-
(mRNA) and the subsequent translation of gene products pro- tional changes in the acidic secretory pathway. Viruses that
vide a unifying pathway for viral infections (Fig. 4.8). Viruses contain the uncleaved prM moiety lack fusion capability and
use either host enzymes or specialized viral polymerases car- are noninfectious (1).
ried with or encoded by the viral genome. Replication of the viral genome involves the synthesis of
Host protein synthesis decreases at the start of viral protein full-length, complementary genomic transcripts that act as
synthesis in most viral infections. Viruses have unique mecha- templates for replication of the viral genome. The efficiency
nisms for inhibiting protein synthesis and can interfere with and fidelity of genomic replication influence the likelihood of
the translation, transport, ribosomal binding, or stability of disease. Defects in the viral genome cause abortive replication
host transcripts (1). With some viruses, premade proteins and or result in conditionally defective viruses that multiply only in
synthesized viral gene products decrease the transcription of the presence of cells or viruses carrying complementary genes.
host mRNA (6971). Cellular transport of mRNA out of the The newly synthesized progeny genomes are transported
nucleus is inhibited late in adenovirus infections. Viral mRNA to capsid structures, where they enter viral capsid shells.
copies can outnumber host mRNA or can be more efficiently Enveloped viruses bud from the cell membrane, whereas non-
transcribed, thus restricting access to ribosomes (1). For ex- enveloped viruses exit the cell by lysis (1).
ample, poliovirus inactivates the host cap-binding protein.
This alters the cells ability to modify transcripts and results
in less efficient translation of host proteins (1). Degradation
of host mRNA is another mechanism used by some HSV to Viral Spread in the Central Nervous System
inhibit host protein synthesis (71). Some viral gene factors act
as repressors and inhibit host mRNA export (70). Viral disease of the CNS requires cell-to-cell spread of the
Viral protein translation occurs in a stereotyped progres- virus. The densely packed neuropil provides a unique envi-
sion. Early gene expression regulates the transcription and ronment with limited extracellular space for viral dispersion.
translation of the remaining viral genome, inhibits host pro- Viruses can spread through the CNS in four prototypical ways:
tein and nucleic acid synthesis, and codes for enzymes neces- (a) sequential cellular infection, (b) movement in the extracel-
sary for viral nucleic acid replication (1). After viral nucleic lular space, (c) neuronal axoplasmic transport, or (d) transit
acid replication, late viral genes are selectively expressed and via migrating lymphocytes or glial cells. Viruses may spread
transcribe templates for capsid and structural proteins nec- within the neural tissue using more than one mechanism.
essary for virion assembly. Proteins synthesized from viral Few viruses infect the CNS by contiguous cell-to-cell spread.
transcripts can undergo posttranslational modification and Sindbis virus provides one example of a virus that spreads
from ependymal cells directly to glial and neuronal cells in
experimentally infected mice (1). Viruses exhibit cell tropism,
frequently infecting one cell type more readily than another.
 DNA For example, HSV-1 infects neurons early during encephali-
Parvovirus tis but is not present in glial cells until late in the infection.
Herpesvirus spreads in the nervous system via axoplasmic
transport in neurons (73,74). Electron microscopy has dem-
 RNA  DNA DNA onstrated togaviruses within extracellular space in the CNS.
Retrovirus Some viruses enter the CNS through a Trojan horse mecha-
Papovavirus nism via leukocytes (1,75).
Adenovirus
Herpesvirus
Poxvirus
Hepadnavirus Host Defense and Immunopathogenesis
Intrinsic and systemic antiviral defenses limit viral replica-
Picornavirus
RNA
tion and infection (44,51,76). Viral replication can activate
Togavirus  mRNA
Coronavirus Reovirus enzymatic pathways that degrade viral nucleic acid tran-
scripts. Other cells undergo apoptosis, creating a nonviable
Orthomyxovirus environment for the virus (1). Interferon-mediated intrinsic
Paramyxovirus antiviral pathways within cells can retard viral penetration,
Arenavirus uncoating, transcription, translation, and assembly, represent-
Bunyavirus ing an important factor of host resistance to viral infection
Rhabdovirus (1,7779). Interferonstype I (interferon-
and interferon-),
type II (interferon-), and type III (interferon- )are secreted
by distinct cells, bind to different receptors, and represent
 RNA evolutionarily distinct molecules that limit viral replication
FIGURE 4.8 Six basic strategies for transcribing messenger RNA from (44,8084). Interferons activate a cascade of enzymes and ki-
different types of viral genome. (From Baltimore D. Expression of ani- nases that inhibit protein synthesis at different steps in the syn-
mal virus genomes. Bacteriol Rev. 1971;35:235, with permission.) thetic pathway. Interferons also modify the binding properties,

Scheld_Ch04.indd 60 2/21/14 5:30 PM


Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 61

electrostatic charge, and receptor expression (major histocom- of vCJD and most patients die less than a year after onset of
patibility complex [MHC] antigen, 2-microglobulin, and Fc their neurologic manifestations.
receptor) of cellular membranes, further restricting viral access These encephalopathies differ in mode of transmission.
and replication (1). These cytokines can enhance or suppress Although most of the TSEs are experimentally transmissible
expression of immune cell subsets (82,85). Although interferon by direct inoculation in the CNS, this mode rarely occurs
can protect host cells from viral infection, some pathogens except for iatrogenic transmissions (1). The scrapie agent
have developed resistance. Furthermore, the inflammatory re- spreads by contact and lateral transmission. There is no evi-
sponse in some cases causes damage to tissue and constitutes a dence for lateral transmission in the case of BSE or vCJD,
pathogenic mechanism for viral disease (57). and all cases appear to have occurred following parenteral
The presence of viral envelope proteins in the host cell or ingestion of affected materials. The transmissible agents
membrane elicits an immunologic response. The host immune remain infectious after treatments that would normally in-
response targets and destroys the infected CNS cells, thus lim- activate viruses or nucleic acids (detergent formalin, ionizing
iting spread of the virus but potentially compounding disease. radiation, nucleases). Most of the experimental work on TSEs
For example, rabies virus causes metabolic derangement in the has involved analysis of the scrapie agent. The current work-
neuron, usurps the cellular metabolic machinery, and inhibits ing model is that posttranslational alteration of the normally
the synthesis of cellular proteins (1). The actual pathogenic
-helical form of the PrP protein results in a protease resis-
cause of neuronal cell death is not known but may involve tant -pleated sheet structure that accumulates in neurons,
the synthesis of toxic metabolites by rabies virus. The immune leading to progressive dysfunction, cell death, and subsequent
response changes the character of disease and the pathologic astrocytosis. In studies on the scrapie agent, gastrointestinal
findings. In paralytic or dumb rabies, patients have disease lim- tract involvement with infection of abdominal lymph nodes
ited to the brainstem and demonstrate reduced B-cell, interleu- occurs first, followed by brain involvement a year or more
kin, and cellular activity in response to rabies antigens (86,87). later. Experimental subcutaneous inoculation in mice and
Patients with furious or classic rabies generate brisk, late intra- goats also lead to local lymph node involvement followed
cranial immune responses to rabies antigens. An experimental by splenic spread and then CNS involvement. The mode of
model, involving immunosuppression, demonstrates that this transmission to the CNS (direct vs. hematogenous) or the in-
late immune response compounds CNS damage in infected fectivity of body fluids at different stages of infection is not
animals (1). known at this time.
In postinfectious encephalitis, the immune response is misdi- The TSEs are currently only diagnosed by histologic ex-
rected against the brain itself. There is no evidence of direct viral amination, characteristic electroencephalography (EEG),
damage or viral antigens in the CNS (1). Viral antigens can share magnetic resonance imaging (MRI) changes, and the clini-
homology with host proteins, and the ensuing immune reaction cal context. Most laboratory tests are of little value in the
can damage normal host tissue resembling virally infected cells diagnosis. CSF examination shows normal values or slightly
(7,88). Immune deregulation may cause immune-mediated elevated protein levels. The EEG in classic CJD reveals gen-
demyelination. For example, most patients with (post-Semple) eralized slowing early in the disease, punctuated by biphasic
rabies vaccine encephalitis have antibodies against myelin basic or triphasic peaks late in the disease with the onset of myoc-
protein. Forty-seven percent of people with postinfectious lonus. MRI changes late in the illness reveal global atrophy
measles encephalitis have lymphocytes directed against myelin with hyperintense signal from the basal ganglia (5). Fluid-
basic protein, as compared with a 15% rate in nonencephalitic attenuated inversion recovery (FLAIR) MRI provides greater
patients with measles (1). The pathogenic mechanism of postin- sensitivity and demonstrates signal intensity changes in the
fectious encephalitis is not fully understood. cortex that are undetectable by T2-weighted spin-echo MRI.
HIV infection is associated with a variety of CNS diseases. Histopathologic examination of the brain using a specific an-
Patients can develop a leukoencephalopathy with diffuse glio- tibody to the PrP-res protein confirms the disease. In addition,
sis and loss of the cerebral white matter in addition to the evidence of gliosis, neuronal loss, and spongiform changes
opportunistic infections and neoplasms associated with the support the diagnosis. In cases of vCJD, characteristic amy-
disease (51,56,89,90). Pathologic specimens show a multifocal loid plaques (so-called florid plaques) microscopically define
accumulation of giant cells with focal cerebral necrosis. PCR the disease. The florid plaques are not seen in other TSEs and
in tissue samples demonstrates large amounts of HIV nucleic consist of flower-like amyloid deposits surrounded by vacu-
acids in multinucleated giant cells. The viral structural and/ olar halos. The detection of PrP-res in the tonsillar tissue by
or regulatory proteins may be toxic to the CNS tissue (91). immunohistochemical staining is also strongly supportive of
Alternatively, macrophages and T lymphocytes may dam- vCJD diagnosis (5).
age the brain by aberrant secretion of interleukin and tumor
necrosis factor (1).
Clinical Correlates to Disease
Transmissible Spongiform Encephalopathies Patients with encephalitis have clinical and laboratory evidence
of parenchymal disease. Some viruses (rabies, B virus) produce
The TSEs produce clinical changes related to CNS dysfunc- encephalitis without significant meningeal involvement; how-
tion similar to the encephalitides (1). Unlike encephalitis, the ever, most patients with encephalitis have concomitant men-
TSEs are slowly progressing noninflammatory CNS diseases ingitis (1). Most patients also have a prodromal illness with
with long incubation periods involving the accumulation of myalgias, fever, and anorexia reflecting the systemic viremia.
an abnormal form of a normal glycoprotein, the prion protein Neurologic symptoms can range from fever, headache, and
(PrP) (92). Sporadic CJD occurs between the ages of 50 and subtle neurologic deficits or change in level of consciousness
70 years and is characterized by dementia, tremors, and more to severe disease with seizures, behavioral changes, focal neu-
rarely abnormal movements and ataxia. Unlike sporadic CJD, rologic deficits, and coma (93,94). Clinical manifestations
vCJD disease affects young adults and adolescents and pro- reflect the location and degree of parenchymal involvement
duces cerebellar ataxia and sensory involvement (dysesthesias) and differ based on viral etiology. For example, HSE infects
with florid amyloid plaques detected in the brain on autopsy the inferomedial frontal area of the cortex, resulting in focal
(5). Neurologic deterioration progresses relentlessly in the case seizures, personality changes, and aphasia. These symptoms

Scheld_Ch04.indd 61 2/21/14 5:30 PM


62 Part II: Viral Infections and Related Disorders

reflect the neuroanatomic location of infection with inflamma- The age, immune status, and viral etiology also influ-
tion near the internal capsule, limbic, and Broca regions (1). ence the clinical manifestations of viral meningitis (51,100).
Paresthesias near the location of the animal bite and change in Patients with enterovirus meningitis often present with non-
behavior correlate temporally with the axoplasmic transport specific symptoms such as fever (38 to 40C) of 3 to 5 days
of rabies and the viral infection of the brainstem and hippo- duration, malaise, and headache (8,101). Approximately
campal region (94). Rabies has a predilection for the limbic 50% of patients have nausea or vomiting. Although nuchal
system, producing personality changes. The damage spares rigidity and photophobia are the hallmark sign and symptom
cortical regions during this phase, allowing humans to vacillate for meningitis, 33% of patients with viral meningitis have
between periods of calm, normal activity and short episodes of no evidence of meningismus. Fewer than 10% of children
rage and disorientation (1). Alternatively, Japanese encephali- younger than 2 years develop signs of meningeal irritation.
tis virus initially produces a systemic illness with fever, malaise, Most of these children with meningitis present with fever and
and anorexia, followed by photophobia, vomiting, headache, irritability. Children may also present with seizures secondary
and changes in brainstem function. Brainstem encephalitis to fever, electrolyte disturbances, or the infection itself (1). The
leads to difficulty with autonomic functions with increased clinician must have a high index of suspicion for meningitis
risk for cardiac and respiratory instability, reflecting infection especially in younger patients. In the immunocompromised
of brainstem nuclei (1,9597). Other patients have evidence of host, enterovirus infection is both a diagnostic quandary and
multifocal CNS disease involving the basal ganglia, thalamus, a potentially life-threatening disease. Immunocompromised
and lower cortex and develop tremors, dystonia, and parkin- patients frequently do not mount a brisk immune cell response,
sonian symptoms. and therefore CSF analysis may underrepresent the extent of
Seizures are frequent during encephalitis. For example, CNS involvement.
approximately 40% of patients with HSE develop seizures Symptoms of meningitis (nuchal rigidity, headache, and
(1). EEG patterns include focal slowing, spiking, and par- photophobia) occur in approximately 11% of men and 36%
oxysmal lateralizing epileptiform discharges. The cellular of women with primary HSV-2 genital infection (1,102104).
mechanisms for seizures are incompletely understood. This Examples exist of recurrent HSV-2 meningitis (with or with-
may result from dysfunction of the smaller, inhibitory, - out genital lesions), although cases associated with primary
aminobutyric acid (GABA)secreting neurons. Although the infection are more common (105,106). HSV meningitis may
seizures encountered in patients with HSE could be directly spread to the CSF by neuronal spread along the sacral nerves.
attributed to cellular destruction, an alternative hypothesis Alternatively, the virus may reach the CSF by hematogenous
for epileptogenesis in HSE centers on the uptake of virus in spread, as the virus has been cultured from the blood buffy coat
the long projections of neurons. This uptake causes pertur- layer. VZV, cytomegalovirus, Epstein-Barr virus (EBV), and
bations in the cellular machinery necessary for the retention parainfluenza virus have all been cultured or detected by PCR
of acetylcholine within the nerve terminal. As a result, the from the CSF of patients with meningitis (1). The three herpes-
excitatory neurotransmitter could leak from the cell and ul- virus infections occur more frequently in immunocompromised
timately trigger a seizure focus. In addition to this mecha- patients and rarely produce isolated meningitis. Instead, these
nism, suboptimal uptake of acetylcholine by malfunctioning infections usually progress and involve the parenchyma.
presynaptic and postsynaptic terminals can result in a rela-
tive excess of the neurotransmitter and abnormal electric dis-
charges. An excess of acetylcholine could also result from the
decreased synthesis of degradatory enzymes (such as acetyl- CONCLUSION
cholinesterase) as viral replication proceeds. Finally, chronic
seizure foci are known to be hypermetabolic during interictal Clinical symptoms produced by a disease have a pathophysio-
periods. The first stage of viral cellular infection is the in- logic basis. An understanding of the pathogenesis of viral CNS
hibition of the cells homeostatic mechanisms. The crippled disease provides the physician with a framework for studying
cell, unable to maintain homeostasis, may be predisposed to related neurologic diseases. Moreover, the pathogenic mecha-
disordered electric discharges (1). nism of a viral disease provides clues toward the development
Encephalitis, unlike meningitis, has higher mortality and of antiviral medications and strategies for the prevention of
complication rates. Case-fatality rates differ based on the viral viral CNS infections. Improved diagnostic techniques are
etiology and host factors. For example, within the arthropod- essential for advancing both research and therapy of viral
borne viral encephalitides, St. Louis encephalitis virus has an neurologic infections. Application of viral PCR and other
overall case mortality rate of 10%. The mortality rate is only molecular diagnostic techniques have already changed some
2% in children but increases to 20% in the elderly (1). Similarly, of the fundamental concepts of viral infection. Basic research
WNV meningoencephalitis produces greater mortality rates in in neurosciences and infectious diseases will result in a better
the elderly than in younger adults (98,99). Other viruses like understanding of the hostvirus interaction in the CNS. These
western equine and eastern equine encephalitis produce higher advances have the potential for improving the care of patients
mortality and morbidity in children than in adults (1). with neurologic diseases.

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CHAPTER 5 VIRAL MENINGITIS AND
ASEPTIC MENINGITIS SYNDROME
JOS R. ROMERO

Viral meningitis can be characterized as a central nervous sys- revealed a mononuclear pleocytosis and the absence of bacte-
tem (CNS) viral infection with signs of meningeal irritation ria on direct examination and by culture. In addition, no para-
(neck stiffness, Kernig and/or Brudzinski signs) and cerebro- meningeal process, acute/chronic systemic infectious disease,
spinal fluid (CSF) pleocytosis but without neurologic dysfunc- or community infectious disease could be identified that could
tion due to brain parenchymal involvement (1). It differs from produce the syndrome. With advances in diagnostic method-
viral encephalitis where evidence of brain parenchymal dys- ologies, it became evident that multiple infectious agents (e.g.,
function is manifested by an altered state of consciousness, Lyme disease), inflammatory conditions, drugs, environmental
change in personality, or other objective signs of neurologic agents, and so forth could cause the syndrome.
dysfunction (e.g., seizures, cranial nerve palsies, abnormal It is estimated that in the United States, the annual num-
reflexes, paralysis, etc.). Although it is common to discuss the ber of aseptic meningitis cases is at least 75,000. Viruses
two as wholly separate entities, it is important to note that account for the overwhelming majority of cases (Table 5.1).
overlap between them (i.e., meningoencephalitis) does occur Early reports indicated that mumps virus, lymphocytic cho-
following infection with many viral agents. riomeningitis virus (LCMV), and poliovirus (PV) were the
Almost 100 years ago, Wallgren (2) introduced the term major identifiable causes of aseptic meningitis (3). As diag-
acute aseptic meningitis to describe a short-lived, self-limited, nostic techniques improved as a result of the development of
benign CNS syndrome characterized by the acute onset of the cell culture, the enteroviruses were shown to have a major
signs of meningeal irritation in which examination of the CSF role in causation of syndrome (Table 5.2) (4,5). Nucleic acid

TA B L E 5 . 1
CAUSES OF THE ASEPTIC MENINGITIS SYNDROME AND CURRENT RELATIVE INCIDENCES

Common Rare
Viruses Viruses
Enteroviruses Herpes simplex virus type 1
Parechoviruses Varicella-zoster virus
Tick-borne encephalitis virusa Cytomegalovirus
Arbovirusesa Epstein-Barr virus
Herpes simplex virus type 2 Influenza A and B viruses
Bacteria Parainfluenza viruses
Borrelia burgdorferi (Lyme disease)a Human herpesvirus type 6
Partially treated bacterial meningitis (common pathogens) Measles virus
Parameningeal bacterial infection Rotavirus
Other Coronavirus
Kawasaki disease Encephalomyocarditis virus
Uncommon Parvovirus B19
Viruses Other
Mumps Brucella species
Lymphocytic choriomeningitis virus Mycoplasma hominis
Human immunodeficiency virus Mycoplasma pneumoniae
Bacteria Toxoplasma gondii
Mycobacterium tuberculosis Fungi (many)
Leptospira speciesa Autoimmune disorders
Other Behet syndrome
Fungi,a including Cryptococcus neoformans, Coccidioides Drugs (including immunomodulators, antibiotics)
immitis, Histoplasma capsulatum, Candida species, Malignancy
Blastomyces dermatitidis

a
Incidence varies greatly with geographic region.

65

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66 Part II: Viral Infections and Related Disorders

TA B L E 5 . 2
VIRAL CAUSES OF ASEPTIC MENINGITIS IN SELECTED LARGE SERIES

Viruses Identified, %

Investigators No. Consistent


(Reference No.) Years Cases PV NPEV Arboviruses Mumps Herpes LCMV Other None Methodologya

Adair, Gauld, 194752 480 13.3 5.3 9.7 no 74.8 yes


and Smadel (3)
Meyer et al. (11) 195358 430 8.8 29.8 0.7 15.8 1.4 8.8 no 29.0 yes
Lennette, 1958 368 2.0 57.0 9.0 1.0 yesb 31.0 yes
Magoffin, and
Knouf (5)
Buescher, 195863 374 4.8 38.5 0.8 7.5 0.5 1.9 yesc 43.5 yes
Artenstein, and
Olson (12)
Berlin et al. (96) 198690 274 0.007 61.3 yesd 38.4 yes

LCMV, lymphocytic choriomeningitis viruses; NPEV, nonpolio enteroviruses; PV, polioviruses.


a
Virologic and/or serologic studies performed by a single laboratory with most or all specimens subjected to all tests.
b
1% adenovirus.
c
1% each measles, Epstein-Barr, influenza A.
d
1% adenovirus (1 case).

amplification tests (NAATs) have bolstered this finding and led viridae, viruses) family of viruses known to cause disease in
to the identification of novel causes (6). humans. The original classification of the EVs, based on evidence
The incidence of aseptic meningitis is influenced by many of human origin, pathology in animal models, patterns of replica-
factors, including effective vaccine programs, sanitation, pov- tion in cell culture, and physicochemical characteristics, identified
erty, and regional endemic viruses (710). Previous significant 72 serotypes (18). This schema, although initially useful, resulted
causes of viral meningitis such as PVs, mump virus, and LCMV to the misclassification of several EV and inclusion of several non-
are now rare or infrequent as a result of effective vaccines, san- EV into the genus (19). The development of experimental and
itation, or improved housing (3,5,8,1113). Although many of computational methodologies for the study of the molecular biol-
the infectious causes of aseptic meningitis are reportable (14), ogy and genomic analysis of the EV allowed for refinement in the
the true incidence of the syndrome is unknown due to incom- classification of and identification of the EVs.
plete reporting, failure to test for specific agents, and because Currently, identification and classification of the EVs
aseptic meningitis is not a reportable condition. In Finland, is based on the nucleotide sequence of VP1, the largest and
a 14-year birth cohort study found the annual incidence of most surface exposed of the viral capsid proteins containing
viral meningitis in children younger than 14 years of age to important neutralizing epitopes (2023). Using this approach,
be 27.8 per 100,000 (15). A more recent study from Greece the EVs have been speciated into four groups (enterovirus A
documented the annual incidence of aseptic meningitis to be to D) containing more than 100 serotypes (Table 5.3) (24).
17 per 100,000 in children younger than 14 years of age (16). In addition, this approach has revealed that several of the
Two studies from the United States give widely discrepant es- traditional EV serotypes are actually strains of the same se-
timates of the incidence of aseptic meningitis. A 32-year (1950 rotype or are not genetically related to the EVs (echoviruses 22
to 1981) study from Olmsted County, Minnesota found that and 23) (20,21,2527).
the adjusted incidence rate of aseptic meningitis was 10.9 per The EVs are nonenveloped viruses 30 nm in diameter with
100,000 person-years (range 7.9 to 17.8 per 100,000) (8,13). a buoyant density of 1.30 to 1.34 g/cm3 in caesium chloride
The Centers for Disease Control and Prevention reported that (CsCl) (19). The lack of an envelope confers to them relative
the national incidence for aseptic meningitis ranged from 1.5 environmental stability where they can survive for days at
to 4.0 per 100,000 for the period spanning 1971 to 1981 (17). room temperature. Infectivity can be preserved for weeks at
The lower incidence in the latter report is most likely the re- 20C or with little or no loss of infectivity for years when
sult of passive surveillance and, therefore, underreporting. The stored at 70C. Similarly, the lack of a lipid envelope renders
incidence of aseptic meningitis is greater in males and in chil- them insusceptible to ether, chloroform, and alcohol. The EVs
dren, particularly those younger than 1 year of age (8,15,16). are inactivated by heating to greater than or equal to 50C,
chlorine, and formaldehyde.
The capsid of all EVs is composed of 60 units each of four
structural or capsid proteins: VP1 to VP4, alternatively known
ENTEROVIRUSES as 1A to 1D, arranged so as to give the virion icosahedral sym-
metry (2833). Each of proteins VP1 to VP3 is wedge-shaped
Virology and Pathogenesis and composed of an eight-stranded antiparallel -barrel core.
Each of the stands is connected to the next by intervening loops
The enteroviruses (EVs) are one of six genera (Enterovirus, Car- that determine antigenicity, receptor specificity, and confer cap-
diovirus, Cosavirus, Hepatovirus, Parechovirus, and Kobuvirus) sid stability (34). The basic structural element of the viral capsid,
in the Picornaviridae (pico, small; rna, ribonucleic acid; the protomer, is initially composed of the proteins VP0, VP1,

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Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 67

TA B L E 5 . 3
HUMAN ENTEROVIRUS AND PARECHOVIRUS SEROTYPES

Genus: Enterovirus

Species Serotype

Enterovirus A CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8,


(18 serotypes) CV-A10, CV-A12, CV-A14, CV-A16,
EV-A71, EV-A76, EV-A89, EV-A90, EV-A91, EV-A92, EV-A114
Enterovirus B CV-A9,
(59 serotypes) CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6,
E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20,
E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E-32, E-33,
EV-B69, EV-B73, EV-B74, EV-B75, EV-B77, EV-B78, EV-B79, EV-B80, EV-B81, EV-B82, EV-B83,
EV-B84, EV-B85, EVB-86, EV-B87, EV-B88, EV-B93, EV-B97, EV-B98, EV-B100, EV-B101,
EV-B106, EV-B107, EV-B110
Enterovirus C PV-1, PV-2, PV-3,
(21 serotypes) CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22, CV-A24,
EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105,
EV-C109, EV-C113, EV-C116
Enterovirus D EV-D68, EV-D70, EV-D94, EV-D111
(4 serotypes)

Genus: Parechovirus

Human parechovirus HPeV- 1, HPeV-2, HPeV-3, HPeV-4, HPeV-5, HPeV-6, HPeV-7, HPeV-8, HPeV-9, HPeV-10, HPeV-11,
(16 serotypes) HPeV-12 HPeV-13, HPeV-14, HPeV-15, HPeV-16

CV, coxsackievirus; E, echovirus; EV, enterovirus; PV, poliovirus; HPeV, human parechovirus (24).

and VP3 (35). Five protomers self-assemble to form a pentamer. The 5 UTR contains multiple regions of predicted higher
Twelve pentamers, in turn, assemble around a single strand of order structure and highly conserved nucleotide identity
viral RNA to produce the immature virion. The cleavage of VP0 among the EV. This region of the genome contains elements
to yield VP2 and VP4 completes the formation of the mature vi- essential for viral RNA replication, translation of ORF, and, in
rion. VP1 to VP3, and in particular VP1, have surface-exposed the PVs, determinants of neurovirulence. Because of the highly
amino acids which determine the antigenic diversity and the re- conserved nucleotide sequences within the 5 UTR found
ceptor specificity of the EV (20,33,36,37). VP4 is not surface ex- among all the EV, it serves as the target for NAATs for the
posed but shares close association with the viral RNA and plays detection of the EV now in common use (42,43).
a vital role in release of the genome after viral attachment (38). Translation of the ORF by host cell ribosomes is accom-
The surface topographies of the various EVs share a num- plished in a nonconical, cap-independent manner giving rise to
ber of similarities. These include a plateau or mesa located at a single polyprotein that is posttranslationally cleaved by viral
the fivefold axis of symmetry formed by the union of five pro- and host proteinases to yield 11 viral proteins (four structural
tomers. Surrounding this plateau is a deep cleft or canyon into and seven nonstructural) as well as several functional protein
which a viral receptor inserts when the EV encounters a sus- intermediates. The ORF can be subdivided into three regions:
ceptible host cell (36). Additionally, the host immune response P1 to P3. The P1 region encodes for the four structural pro-
to EV infection generates serotype-specific antibodies directed teins (VP1 to VP4 or 1A to 1D) that comprise the viral capsid.
to antigenic sites around the fivefold axis and canyon walls, These are organized 5 to 3 as VP4 (1A), VP2 (1B), VP3 (1C),
thus blocking viral-host receptor interaction and infection. and VP4 (1D). The P2 and P3 regions code for seven non-
Lastly, beneath the canyon floor exists a hydrophobic pocket structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) that are
containing a lipophilic factor. This pocket has been the target essential for the viral life cycle. The intermediate proteins play
for the development of anti-EV drugs that result in altered re- roles in viral replication.
ceptor binding and viral uncoating (39,40). Immediately downstream of the ORF is a short 3 UTR fol-
The EV genome consists of single-stranded, positive lowed by a terminal poly(A) tract. Similar to the 5 UTR, the
(messenger)-sense RNA of approximately 7,400 nucleotides 3 UTR is predicted to have higher order structures and play a
(nts) in length. The genome layout may be summarized as role in genome replication (44).
follows: VPg5UTR[1A-1B-1C-1D/2A-2B-2C/3A-3B-3C-3D] Following binding of the EV to a host cell receptor, confor-
3UTR-poly(A) (24,41). The 5 end of the genome is covalently mational changes in the virion result in release of the viral ge-
linked to a small protein, VPg, essential for viral RNA repli- nome into the cytoplasm of the host cell. The RNA genome is
cation. The genome is organized into a long 5 untranslated replicated through a double-stranded RNA intermediate that
region (5 UTR) of approximately 740 nts that immediately is formed by the EV RNA-dependent RNA polymerase (3D).
precedes a single open reading frame (ORF). The ORF mea- Despite more than 100 years of study of the pathogenesis of
sures approximately 6,630 nts and is followed by a short (ap- EV infections, much still needs to be learned. Most of what is
proximately 70 nts) 3 UTR and a terminal polyadenylated tail. known stems for the study of PV types 1 to 3 using information

Scheld_Ch05.indd 67 2/21/14 5:30 PM


68 Part II: Viral Infections and Related Disorders

derived from human disease and nonhuman primate, murine, the bloodbrain barrier (BBB) or via retrograde axonal trans-
and, most recently, transgenic (Tg) mouse models expressing port. For the development of paralytic disease in chimpanzees,
the PV receptor, PVR or CD155 (4550). It is likely that the viremia has been shown to be essential (76). This finding pro-
non-PV EVs share similar mechanisms of pathogenesis. vided initial support that the BBB may be a route to the CNS.
The majority of the EVs are transmitted via a fecal-oral Endothelial cells may express EV receptors that may influence
route. In addition to direct person-to-person or fecal-oral tissue susceptibility to the EV (77) and facilitate virus entry
transmission, experimental or clinical evidence exists for the into the CNS and other organs. Further buttressing of this hy-
transmission of the EV via houseflies, housefly-contaminated pothesis came from the finding that cultured human brain mi-
food, water, and sewage (5154). Bivalves have been found crovascular cells can support PV replication (78,79). However,
to accumulate EV (55,56). However, their role in transmis- in other studies, pharmacokinetic analysis of PV injected into
sion has not been established. Notable exceptions to fecal- Tg and non-Tg mice indicated that PV was delivered to the
oral transmission include coxsackievirus (CV)-A21, EV-D68, brain in significantly greater amounts than would be expected
and EV-D70, which may spread via contaminated fomites or from the vascular concentration (80). This suggests that PV
ocular and respiratory secretions. Evidence for transplacental may enter the CNS via the BBB but without need of PVR.
transmission exists, leading to congenital infection (5761). Evidence in humans supports EV access to the CNS via
Following ingestion of the EVs, infection of the cells of a neural route. Individuals inadvertently inoculated with an
the nasopharynx and, more significantly, the lower gastroin- incompletely inactivated PV vaccine developed initial paraly-
testinal (GI) tract occurs. The inherent acid-resistance of the sis in the limb receiving the vaccine (81). Trauma to a limb
EV favors the latter. Replication in the lymphatic tissues of preceding PV infection has been associated with the develop-
these sites (i.e., tonsils and Peyer patches) leads to shedding ment of paralysis of that limb. Provocation poliomyelitis
of the EV from the nasopharynx for 1 to 2 weeks and from following intramuscular injections into an extremity of a per-
the GI tract in feces for several weeks to months (7). Seeding son incubating wild type PV or those receiving live attenuated
of EV to the deep cervical and mesenteric lymph nodes ensues PV vaccines has been well documented (82,83).
and results in their spread to the systemic circulation via the Substantial evidence from nonhuman primate and murine
lymphatics. This primary or minor viremia leads to seeding models exists in support of EV access to the CNS via a neural
of various organs, including the CNS, liver, lungs, skin, and route. In monkeys, inoculation of the sciatic nerve with PV re-
heart. Further replication in the tissues of those organs results sults in viral spread along the inoculated nerve and the spinal
in a major (secondary) viremia. If the CNS was not seeded cord (84). The initial limb to develop paralysis following in-
during the initial viremic episode, spread there may occur with tramuscular inoculation of PV in monkeys and Tg mice is the
the major viremia. Viremia or presence of virus in the CNS one injected (8587). If the sciatic nerve of the intramuscularly
continues until the host develops type-specific neutralizing an- inoculated lower extremity is frozen or transected, paralysis of
tibodies directed to the capsid proteins, usually by day 7 to the limb is prevented (84,87). In Tg mice, it has been shown
10 postinfection. Immunoglobulin A (IgA) antibodies appear that in provocation PV, there appears to be induction of retro-
in the respiratory and GI tracts 2 to 4 weeks after infection. grade axonal transport (88). PV may gain access to neurons at
Unlike other viruses, which are largely contained by cellular the level of the neuromuscular junction.
immune mechanisms, the EVs are cleared from the host pri- The search for viral genomic determinants of neurotropism
marily by antibody-mediated mechanisms. and neurovirulence has focused on the PVs (89). After immu-
Great strides have been made in understanding the patho- nization with live, neuroattenuated vaccine (Sabin) PV strains,
genesis of EV infections at a molecular level. The presence of shedding of PV that has recovered the ability to cause pa-
an EV receptor is the primary, but not the sole, determinant ralysis (i.e., neurovirulent revertant strains) occurs routinely.
for cellular infection (62). As stated previously, PVR has been Comparison of wild type, vaccine, and revertant PV strains
shown to be the receptor for the PVs (62) and maps to chro- has identified a 10-nucleotide region within the 5 UTR (nts
mosome 19. PVR is a member of the immunoglobin superfam- 472 to 484 relative to PV type 3 Sabin strain) where neuroat-
ily and functions as an adhesion molecule. It helps to form tenuating mutations are found to cluster. Additional minor de-
adherens junctions and is a recognition molecule for natural terminants of virulence are localized to amino acids encoded
killer cells. In addition to PVR, at least 11 other cell proteins in the P1 and P3 regions. The search for determinants of neu-
have been identified as receptors or coreceptors for other rovirulence in other EV has been unsuccessful.
EV serotypes (Table 5.2) (6366).
The exact identity of the cells in the upper and lower in-
testinal tract infected by the PVs is unknown. However, they Histopathology
have been identified within the ileal wall and mesenteric nodes
in human infection (45,49,50). It is believed that the PV infect The benign nature of EV meningitis has made human patho-
either lower GI cells expressing the PVR or use transcytosis logic data for this disease sparse. A report of a child who died
through microfold (M) cells in the lower GI tract to gain access of CV-B5 myocarditis with concomitant meningitis describes
to lymphoid tissue. Supporting this is the finding of PVR on the inflammation of the choroid plexus of the lateral and fourth
surface of intestinal epithelium, M cells, and in the germinal ventricles, fibrosis of the vascular walls with focal destruction
centers of Peyer patches (67). Support for the latter comes from of the ependymal lining, and fibrotic basal leptomeninges (90).
the finding that M cells can bind and endocytose PVs (68,69). Parenchymal findings were limited to moderate symmetric dila-
Why the majority of EV infections do not result in clinically tion of the ventricles and an increase in the number and size of
apparent infection (7073) comes for a number of studies that subependymal astrocytes. The inflammatory reaction at the cho-
suggest that replication of PV in extraneural tissues is inhibited by roid plexus supports the concept of viremic spread to the CNS.
the host interferon (IFN) response. PVR Tg mice that are IFN / An adolescent presenting with a similar constellation of findings
receptor deficient are highly susceptible to PV infection, and PV died of systemic CV-B3 infection (91). The dura was grossly
replication in the small intestine is enhanced (74,75). Thus, IFN distended with swelling also of the pia, arachnoid, and brain
responses may be crucial in limiting the spread of EV infection. parenchyma. Microscopically, round cell infiltrates were noted
Lastly, the mechanism of EV entry into the CNS remains un- in the meninges overlying the cerebellum; the brain parenchyma
clear. Evidence for two pathways exist for PV: transit through was congested with increased numbers of oligodendrocytes.

Scheld_Ch05.indd 68 2/21/14 5:30 PM


Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 69

Lymphocytic infiltration was most prominent around blood CV-B3, E-7, CV-B4, E-18, CV-B1, E-3, and -5 (93). Some se-
vessels in the cerebral white matter and in the basal ganglia, rotypes cycle with varying periodicity within a community
again suggesting viremic CNS access; focal areas of necrosis and (58,93,109,110), a reflection of the availability of new sus-
hemorrhage were also seen (91). ceptible host populations (especially children). Other sero-
types appear de novo as novel epidemic-associated viruses
(111). Around the world, the serotypes most commonly iso-
Epidemiology lated from the CSF and, therefore, from cases of meningitis
or meningoencephalitis, belong to the Enterovirus B species
The EVs have a ubiquitous worldwide distribution; humans (93,108,112,93,113,114). In the United States, the serotypes
are their only natural reservoir (58,92). It is estimated that most frequently isolated from CSF specimens over a 36-year
they result in more than 1 billion annual infections worldwide period, in descending order of frequency, are E-9, -11, -30,
(22). In the United States alone, the non-PV EVs are estimated CV-B5, E-6, CV-B2, CV-A9, E-4, CV-B4, E-7, -18, and -5 (93).
to cause 30 to 50 million infections each year. Due to under- Outbreaks of EV meningitis are common. Large nation-
reporting of EV infections (93), a well-grounded estimate of and community-wide outbreaks involving thousands of in-
the number of cases of EV meningitis that occurs each year is dividuals have been well documented (115,116). Outbreaks
not possible. However, conservative estimates place the annual involving more localized venues such as neonatal units, nurs-
number to be between 30,0000 and 75,000 cases (22,94). The eries, daycare centers, orphanages, schools, pools, camps, and
EVs are responsible for 80% to 90% of identifiable causes of sports teams occur (53,117122). Sequential episodes of EV
viral meningitis (9497). Wild type PV were eradicated for the meningitis involving different serotypes have been reported to
West Hemisphere in 1991 (98) and are currently endemic only occur within a month of each other (123125). Mixed infec-
in Afghanistan, Nigeria, and Pakistan (99). As such, they do tions involving EVs, other viruses, or bacteria have been well
not contribute to the burden to EV in most of the world. described (102130).
In regions with temperate climates, the non-PV EV exhibit Children represent the overwhelming majority of cases of
marked seasonality with the majority of infections occurring in EV meningitis. An incidence peak among young infants and
the summer and fall (Fig. 5.1) (92,100,101). This being said, EV school-aged children ages 5 to 10 years has been reported in
infections do occur during the winter, warranting their inclusion multiple studies (58,131133). Occasional outbreaks of EV
in the diagnostic evaluation of aseptic meningitis during that time CNS infections occur predominantly among adults (134136).
of year (102106). In tropical and subtropical areas, EVs occur A possible explanation for these findings may lie in the his-
year-round, but with higher incidence during the rainy season. tory of the particular serotypes in the geographic area studied.
Despite the existence of more than 100 serotypes of EV, Serotypes with endemic patterns, those occurring with sig-
only a limited number are responsible for the majority of dis- nificant incidence annually, are most likely to affect only the
ease observed annually in each geographic region (58,93,107 youngest children because of their absence of previous expo-
110). The rank of each serotype within the most frequently sure and immunity. Older children and adults are more likely
isolated EVs varies annually and geographically. In the United to predominate in an outbreak of a serotype that has not been
States, 15 serotypes accounted for approximately 80% of present in a community for several years, thereby creating a
all EVs reported from 1970 to 2005 (in descending order): reservoir of susceptible individuals among children born since
echoviruses (E)-9, -11, -30, CV-B5, E-6, CV-B2, CV-A9, E-4, the last appearance of that serotype.

1.2

1.1

1.0
Reported Cases per 100,000 Population

0.9

0.8

0.7

0.6

0.5

0.4
FIGURE 5.1 The seasonal occurrence
of aseptic meningitis in the United
0.3
States from 1986 to 1994, as reported
to the Centers for Disease Control and
0.2 Prevention. The striking predominance
of cases during the summer months
0.1 reflects the predominance of entero-
viruses as etiologic agents in aseptic
0.0 meningitis. (From Centers for Disease
1986 1987 1988 1989 1990 1991 1992 1993 1994 Control and Prevention. MMWR Morb
Mortal Wkly Rep. 1993;42:69, with
Year (Month) permission.)

Scheld_Ch05.indd 69 2/21/14 5:30 PM


70 Part II: Viral Infections and Related Disorders

Host factors that predispose to EV meningitis, other than and upper respiratory tract findings (60,139,140,142). On
young age and immunodeficiency, have been difficult to iden- physical examination, the fontanelle may be full or bulg-
tify. A slight male-to-female predominance in the incidence ing. Signs of meningeal irritation such as nuchal rigidity,
ratio for EV infections has been noted in large series. However, Brudzinski, and Kernig signs are generally absent. An exan-
in a recent report, male predominance was present only among them may be present. If encephalitis in addition to meningitis
persons younger than 20 years of age (male/female ratio (meningoencephalitis) is present, the neonate may present
1.4:0.9) (101). This most likely represents the larger number with profound lethargy, seizures, and focal neurologic abnor-
of females exposed to young children who are principal source malities that suggest herpes simplex virus (HSV) infection.
of household exposure. Infection rates are higher among per- In some newborns, encephalohepatomyocarditis syndrome
sons of lower socioeconomic status, in areas of crowding, and may develop in which signs and symptoms of severe hepa-
larger families (7). titis and myocarditis are superimposed on those of menin-
goencephalitis (143). Disseminated intravascular coagulation
and other findings of sepsis result in an illness that may
Clinical Manifestations be indistinguishable from that caused by overwhelming
bacterial infection.
The clinical manifestations of aseptic meningitis do not sig- In infants and children, following an incubation period
nificantly differ among the non-PV EVs causing the syndrome of 5 to 10 days, the onset of EV meningitis is usually abrupt
(9,137). However, clinical manifestations do vary with the age with fever (38 to 40C), the most common presenting sign
and immune status of the patient. Meningitis or meningoen- (137,143147). The natural history of EV meningitis is
cephalitis, singularly or in combination with other syndromes, depicted in Figure 5.2. The fever pattern may be biphasic, ini-
are common manifestations of symptomatic EV infection in tially appearing in association with nonspecific constitutional
neonates and young infants. Two large retrospective reviews signs and symptoms followed by resolution and subsequently
have documented that 62% of infants younger than 3 months reappearing with the onset of meningeal signs (137,148).
of age with group B coxsackievirus infections and 27% of neo- Headache is nearly always present in those individuals old
nates younger than 2 weeks of age with infections due to the enough to report it. Interestingly, it may be ameliorated fol-
echoviruses had associated meningitis or meningoencephalitis lowing the performance of a lumbar puncture, indicating
(60,138). In two prospective studies, clinical or laboratory that it may be the result of increased intracranial pressure
evidence of meningitis was found in 42% to 75% of neonates (149,150). Photophobia is commonly reported. Infants and
with EV infection (139,140). young children may be irritable or, less commonly, lethargic
Early presentation of EV infection following birth suggests (142). Nonspecific findings, singly or in combinations, include
transplacental, intrapartum, or immediate postpartum acqui- anorexia, exanthems, malaise, sore throat, abdominal pain,
sition of virus (60,138,139). Maternal illness (fever, symp- nausea, emesis, and myalgias (144,147). In infants, the fonta-
toms of upper respiratory tract infection, abdominal pain) nelle may be full or bulging. Less than 5% of infants younger
has been reported to occur in 14% to 68% of infected neo- than 3 months of age have signs of meningeal irritation (142).
nates (60,138141). In neonates, fever (38.0C) is almost However, these become more common in older patients
universal and accompanied by any or all of the following (144,147,151,152). Seizures are noted in less than 5% of
nonspecific signs: irritability, lethargy, poor feeding, emesis, children (142,146). Other uncommon complications include

DAYS 2 4 6 8 10 12 14 16 18 20 22 24 26 28
TEMPERATIURE

104

102

100

98

HEADACHE
NAUSEA & VOMITING
SYMPTOMS STIFF NECK
AND SIGNS (MYALGIA)
(RASH)
(MUSCLE WEAKNESS)

CSF
CELLS 50 1000
PROTEIN

VIRUS ISOLATION
BLOOD
THROAT FIGURE 5.2 The clinical course of
FECES enterovirus aseptic meningitis. CSF,
CSF cerebrospinal fluid. (From Horstmann
ANTIBODIES DM, Yamada N. Enterovirus infec-
NEUTRALIZING tions of the CNS. Res Public Assoc
Nerv Ment Dis. 1968;44:236253,
COMP. FIX.
with permission.)

Scheld_Ch05.indd 70 2/21/14 5:30 PM


Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 71

coma, increased intracranial pressure, and inappropriate has resulted in stabilization of some of these patients; how-
secretion of antidiuretic hormone (142,153). The duration of ever, viral persistence has been documented during therapy
EV meningitis in infants and children is generally less than (159,162,163). With the availability of intravenous prepara-
1 week. tions of immune globulin and the early recognition of this
Fewer clinical reports exist documenting the presentation of illness, fewer patients appear to be progressing to the classic
EV meningitis in adolescents and adults (134,136,154157). description of this disease, and atypical neurologic presen-
Headache is the most frequently reported symptom and is tations have appeared. The mortality rate in patients with
nearly uniformly present. The severity of the headache may humoral immunodeficiencies may be as high as 50%.
be such as warrant the use of narcotic analgesics in order to The infected neonate is at greatest risk of severe morbidity
control the pain (157). Photophobia, fever, signs of meningeal and mortality when signs and symptoms develop in the first
irritation, nausea, emesis, and neck stiffness occur in more days of life (60,138,139,164). Neonates infected with CV-B4
than 60% of cases. Other less frequently encountered signs were found to be higher risk of death than those infected with
and symptoms include myalgia, exanthems, and abdominal other EV. The short-term prognosis of young children with EV
pain. Full recovery takes longer in adolescents and adults and meningitis early in life appears to be good; however, there has
may require up to 2.5 weeks (157). been some controversy over possible later sequelae. Neurologic,
In individuals with humoral immunodeficiencies (X-linked cognitive, developmental, and language abnormalities have
agammaglobulinemia, X-linked hyper IgM syndrome, com- been reported in controlled studies of long-term outcome in
mon variable immunodeficiency), EV infection may result in children with EV meningitis during infancy (165168). In the
chronic meningitis or meningoencephalitis that may last for largest and most meticulously controlled study, however, no
years and often have a fatal outcome (158161). In addition differences between patients and controls could be demon-
to the common signs and symptoms of EV meningitis men- strated in any of the neurodevelopmental parameters studied
tioned previously, neurologic manifestations include paraly- (142). Less well studied are the ultimate outcomes of aseptic
sis/paresis, seizures, cognitive impairment, developmental meningitis cases in older children and adolescents; preliminary
regression, sensorineural hearing loss, coma, dysarthria, data suggest possible school and learning difficulties, but con-
hydrocephalus, and aphasia. Extra CNS manifestations occur trol patients were not studied (169).
singly or in combination in a significant number of cases and
include dermatomyositis, chronic hepatitis, arthritis, myocar-
ditis, and subacute lumbosacral polyradiculopathy. In patients Laboratory Findings and Diagnosis
who have undergone repetitive, sequential lumbar punctures,
the cell culture detection of EV in CSF has been intermittent. Salient among the laboratory analyses performed for the evalu-
However, using NAATs, evidence of their persistence in CSF ation of EV meningitis is the evaluation of the CSF. CSF analysis
has been documented (162). Treatment with antibody prepa- can provide initial clues as to the etiology of the clinical syn-
rations intravenously and intrathecally or intraventricularly drome (Table 5.4). Cytochemical analysis of the CSF typically

TA B L E 5 . 4
TYPICAL CEREBROSPINAL FLUID PATTERNS DURING MENINGITIS

Pattern

Pathogen Number of WBCs Predominant Cell Glucose Protein

Bacteria (common) 100s1,000s Neutrophils


Viruses
Leptospira
Lyme disease
Mycoplasma
Mollarets 10s100s Mononuclears nl/sl nl/sl
Kawasaki disease
Parameningeal focusa
Partially treated meningitisa
Mycobacteria
Brucella 10s100s Mononuclears
Fungal
Toxoplasmab
Connective tissue disease
Parameningeala 10s100s Neutrophils nl/sl nl/sl
Partially treateda

nl, normal; sl, slightly; WBCs, white blood cells; , decrease; , increase.
a
Either pattern may be seen.
b
Glucose usually normal.

Scheld_Ch05.indd 71 2/21/14 5:30 PM


72 Part II: Viral Infections and Related Disorders

shows a mild to moderate lymphocytic pleocytosis ranging etiology for aseptic meningitis syndrome should rely on detec-
from 10 to 1,000 cells/mm3 (136,139,141,142,145,149,160). tion of the virus from the CSF. As previously discussed, follow-
White blood cell (WBC) counts exceeding 1,000 cells/mm3 are ing EV infection viral shedding may occur from the throat and
seen occasionally (60,103,147,170). Although pleocytosis is GI tract for up to several weeks (7,92). Therefore, detection
almost always present, EVs have been isolated by cell culture of the EV from the stool or throat of an individual with asep-
or detected by NAAT from the CSF of patients with clinical tic meningitis may represent an infection that occurred weeks
evidence of meningitis without pleocytosis (171). This is par- previously and is unrelated to the present syndrome. Shedding
ticularly true in the young infant. If the CSF is examined early from a past infection cannot be ruled out unless the virus is
in the course of the illness, a predominantly polymorphonu- detected in nonpermissive sites (i.e., CSF, blood, tissue) (189).
clear pleocytosis may be observed (136,139, 142,146,149). Lastly, rare reports of co-infections of the CSF by bacteria
Reexamination of the CSF several hours later will document and EVs exist (102,126,129,130). In these patients, the clini-
a typical lymphocytic pleocytosis (172174). The progres- cal and laboratory picture of bacterial meningitis dominated
sion of an initially polymorphonuclear pleocytosis to one of a and the virus was isolated incidentally. The patients were sick
more viral meningitis mononuclear pleocytosis has also been enough that identification of a virus before identification of
observed with St. Louis encephalitis virus (175). The CSF pro- the bacterium would have been unlikely to dissuade the cli-
tein concentration is mildly to moderately increased, whereas nician from continued use of antibiotics. Thus, the detection
the glucose concentration is generally normal. However, hypo- of an EV either by culture or NAAT must always be placed
glycorrhachia may occur, serving to confound the assessment in the context of the patients clinical picture and laboratory
by suggesting a bacterial etiology (146,147,170). findings. In the clinical presentation typical of viral meningitis,
Traditionally, the diagnosis of EV meningitis has relied on co-infection with a clinically silent bacterium would be ex-
isolation of the virus from CSF using cell culture or inocula- traordinarily unlikely.
tion of suckling mice (176). Although initially very useful, these
techniques have significant limitations. The sensitivity of tissue
culture for EVs is only 65% to 75% (177). The titer of EVs in Treatment and Prevention
the CSF of patients with aseptic meningitis may be as low as
101 to 103 TCID50 (median tissue culture infectious dose) per No specific treatment exists for EV meningitis. Supportive
milliliter of CSF. This results in slower growth than is observed measures include bed rest, antipyretics, and analgesics, as
with specimens of throat or rectal origin. The time to isolation indicated. Administration of parenteral fluids for individuals
of EV from CSF ranges from 4 to 8 days (178) using traditional unable to take adequate fluids orally, especially infants, is
cell culturetoo long to be clinically useful in patient man- indicated. Seizures should be controlled with appropriate
agement. Using shell vial culture, the time can be shortened anticonvulsant drugs.
to 2 to 3 days, but sensitivity may be lost (179,180). Lastly, Immune globulin preparations have been used for the treat-
optimum recovery of EVs from clinical specimens requires the ment of newborn infants with severe disease and immuno-
use of multiple cell lines, either individually or as mixtures, in compromised individuals, but their efficacy is not established
order to increase culture yield (181). Even using multiple cell (61,159,190). Intravenous, as well as intrathecal, administra-
lines, some EVs, in particular the group A CVs and some of the tion may be necessary to ameliorate or prevent CNS infection
newer EVs, fail to grow in cell culture (182). The added cost in immunocompromised patients.
and technical expertise required for suckling mouse inoculation The promising results from clinical trials of pleconaril
makes it impractical for use in the modern diagnostic labora- (39), an antiviral that inhibits EV binding and viral uncoat-
tory. Serologic confirmation of EV infection is also generally ing, were overshadowed by its adverse effects (40). In clini-
impractical and not useful in acute management of the patient. cal trials, pleconaril was found to induce cytochrome P450
As mentioned previously, the 5 UTR contains regions of 3A, resulting in menstrual irregularities in women taking
conserved nucleotide identity among the EVs. These regions hormonal contraceptives. This finding raised concerns that
have been exploited for the creation of primers and probes it might increase the metabolism of some hormonal contra-
that can be used in NAATs capable of detecting all EVs (43). ceptives and anti-HIV drugs, thereby reducing their efficacy,
Compared to cell culture, NAAT detection of EVs in the prompting the U.S. Food and Drug Administration not to
CSF has been shown to exhibit sensitivities that range from grant a license for its use.
86% to 100% and specificities ranging from 92% to 100%. The EVs are spread primarily through a lack of good
Furthermore, NAATs are capable of detecting EV genome in hygiene. Hand washing prevents the spread of the EVs and
CSF samples from individuals with syndromes clinically com- should be encouraged in families and institutions (191).
patible with aseptic meningitis previously deemed negative by In patients hospitalized with EV, meningitis infection con-
cell culture or without pleocytosis (163,162,183). These assays trol measures using standard precautions are sufficient.
are also able to detect EV that cannot be grown in cell culture. Community measures for the prevention of EV infections rely
Lastly, NAAT can be performed rapidly, generally in a mat- on the development and maintenance of sewage and potable
ter of hours. The results can be made available with sufficient water systems. No vaccines exist for the non-PV EV. However,
speed as to have an impact on patient management, resulting recent early studies suggest that it may be possible to develop
in a reduction in hospital stay, antibiotic use, and ordering an inactivated EV-A71 vaccine that can induce neutralizing
of ancillary tests (184188). A confirmatory polymerase chain antibodies and is well tolerated in humans (192).
reaction (PCR) test result obtained on a patient with clinical
aseptic meningitis can reassure the clinician that no further
diagnostic investigation is required. For these reasons, NAAT PARECHOVIRUSES
detection has become the method of choice for the diagnosis
of CNS EV infection. Because of the lack of sensitivity of viral The first two members of the genus human parechoviruses
culture for detection of the EV in CSF, it should be reserved for (HPeVs) were found in 1956 (193). However, it was not until
instances when NAAT is not available. the turn of the century that they were accorded their own genus.
Two caveats should be borne in mind when establishing Originally classified as EVs and designated as echoviruses 22
the diagnosis of EV meningitis. Confirmation of EV as the and 23 (18) (currently designated HPeV 1 and 2, respectively),

Scheld_Ch05.indd 72 2/21/14 5:30 PM


Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 73

it became evident early on that they exhibited characteristics


that differed from the other members of the genus (193,194). ARBOVIRUSES
The development of methodologies to probe the molecular
aspects of viral replication and viral genetics confirmed that The arboviruses are a group of more than 500 viruses from
they differed substantively from the EV (2527,195,196) and various viral families that are transmitted by the bite of an
led to their reclassification in a separate genus (24). insect or tick (i.e., an arthropod vector) (213); hence, the
Morphologically, HPeVs exhibit similar characteristics as derivation of their name ararthropod, boborne, viruses.
the EV: small size, lack of an envelope, a positive sense, and Transmission to humans (epizootic transmission) occurs by
single-stranded RNA genome of the length and organization chance and is secondary to the natural enzootic cycle involv-
consistent with that of the EVs (6). Important differences ing an arthropod vector and an avian or mammalian host.
are the lack of maturational cleavage of VP0 to yield capsid Mosquitoes serve as the vectors for the majority of clinically
proteins VP2 and VP4. As a result, the HPeV capsid is significant arbovirus endemic to North America. However,
composed of three, rather than four, proteins. Differences Colorado tick fever virus, Powassan (POW) virus in North
also exist in the function of two nonstructural proteins. America, and tick-borne encephalitis (TBE) virus in Eurasia
A detailed discussion of these and other differences is beyond are transmitted by ticks (214,215).
the scope of this chapter, and the reader is directed to a recent
review (6).
The genus is currently composed of 16 serotypes (Table 5.3) Flaviviridae
(24). HPeVs have been reported worldwide. The epidemiology
of the HPeV continues to evolve as new serotypes are identified
and detection is improved using NAATs. Current data indicates
West Nile Virus
that the HPeVs account for approximately 2% of the EV iso- West Nile virus (WNV) was first isolated in Uganda in 1937
lated using traditional cell culture in clinical laboratories (6). (216). Its incursion into the United States in 1999 (217) pre-
HPeV1 followed by HPeV3 are the types most frequently iso- ceded a rapid spread throughout the contiguous continental
lated. Infection with HPeV appears to occur early in life. In the United States as well as North and South America (218,219).
United States, 73% of HPeV1 and 67.6% of HPeV2 isolated In the United States, WNV has displaced all autochthonous
come from infants younger than 1 year of age. A longitudinal arboviruses as the single major cause of CNS disease (220).
study of Norwegian infants documented that the cumulative WNV is a member of the Flaviviridae family of RNA viruses,
incidence of HPeV infection by 24 and 36 months of age was within the genus Flavivirus (221). All members of the family
86% and 94%, respectively (197). possess a host cellderived lipid envelope that is modified by
HPeV infections exhibit a strong seasonal epidemiology. the insertion of viral proteins and a positive (message)-sense,
Worldwide, the peak incidence of infections occurs during the single-stranded RNA genome.
summer and fall months (197204). A unique biennial pat- WNV is maintained in an enzootic cycle that involves pri-
tern of circulation has been reported for HPeV3 (205208). marily avian hosts and mosquitoes (222). Culex mosquitoes are
As with the EVs, multiple HPeV serotypes circulate within a important vectors in the United States (223). Mosquitoes are im-
community at the same time. The majority of cases of HPeV portant in transgenerational and transseasonal maintenance of
meningitis occur in male infants younger than 3 months of the WNV enzootic cycle (224,225). WNV infections occur dur-
age. HPeV3 is the overwhelmingly dominant cause of HPeV ing the summer months, generally from July through October in
meningitis. Considerable variation in the annual prevalence of the United States, coinciding with periods of increased activity
HPeV meningitis is observed. of its vectors. However, as WNV has spread southward in the
Transmission of the HPeV occurs via the fecal-oral and United States, reported transmissions to humans have occurred
respiratory routes. They may be shed from these sites for as early as April and as late as December (223).
weeks to months (197,201,209). The finding of HPeV in the Transmission to humans (i.e., epizootic transmission) is
stool of healthy, asymptomatic infants indicates that many, if incidental and, with rare exception, results in a dead-end
not the majority, of infections are subclinical. infection without subsequent human transmission. The lat-
Irritability is present in nearly all cases of HPeV meningitis ter has occurred through transfusion of blood products and
(202,207,210). An exanthem is frequently present. Emesis, organ transplantation (226229). In addition, confirmed or
diarrhea, and distention are reported in approximately one- suspected maternalfetal and maternalinfant vertical trans-
quarter to half of cases. Rhinorrhea, cough, tachypnea, mission of WNV has been reported (230,231).
apnea, and wheezing may be present. Notably, findings of The majority of WNV infections in adults and children
increased intracranial pressure (bulging fontanelle) or men- result in subclinical disease. Infection of children results in
ingeal irritation (nuchal stiffness, Kernig or Brudzinski signs) asymptomatic infection or milder disease more frequently
are absent. The CSF cytochemical evaluation reveals no or than in adults (232236). During one outbreak, children
minimal abnormalities in WBC count or protein and glu- were 4.5 times more likely to become infected with WNV
cose concentrations in the overwhelming majority of patients but 110 times less likely to develop West Nile neuroinvasive
(202,207,210). disease (WNND) (237). In adults, age is the single most sig-
Currently, NAAT is the methodology of choice for HPeV nificant risk factor for development of WNND (235,236,238).
detection because of its sensitivity and ability to detect all The incidence of severe neurologic disease is 10 times higher
known HPeV types in a clinically meaningful time frame (6). in persons aged 50 to 59 years and 43 times higher in those
Optimum diagnostic assays target the HPeV 5 UTR and aged 80 years or older compared with individuals 20 years
are not type-specific. They are designed for increased sen- of age or younger. Other risk factors include hypertension,
sitivity and to broadly detect all HPeV types from clinical diabetes mellitus, cardiovascular disease, alcohol abuse, and
specimens. immunosuppression. Approximately 80% of those infected
The HPeV can produce cytopathic effect on appropriate with WNV remain asymptomatic. The majority of the remain-
cell lines (211). However, cell culture detection is limited by der develops an acute, self-limited febrile illness known as West
those factors discussed for the EV (see previous discussion) Nile fever. It is characterized by a sudden onset of fever (38 to
(211,212). 40C), accompanied by fatigue, malaise, anorexia, headache,

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74 Part II: Viral Infections and Related Disorders

myalgias, and weakness. Ocular pain on eye movement has each with a specific geographic distribution, are the principal
been reported. A diffuse nonpruritic, macular, papular, macu- vectors (257). Younger patients tend to have milder forms of
lopapular, or morbilliform exanthem and diffuse lymphade- SLEV-associated CNS disease (1,258). Approximately 15% of
nopathy may be seen (222,235,239241). all symptomatic cases of SLEV infection present as meningitis.
Less than 1% (1:140 to 320) of adults develop WNND: asep- The frequency of SLEV meningitis in children is much higher:
tic meningitis (WNV meningitis), encephalitis, or poliomyelitis- approximately 40%. In contrast, patients older than 60 years
like syndrome (241245). WNND may be even rarer in of age rarely (5% or less) present with aseptic meningitis.
children: approximately 1:4,200 infected children according to No specific therapy is available.
one study (237,246). The median age of patients with WNV
meningitis is less than those with encephalitis (247). The per- Tick-Borne Encephalitis Virus
centage of individuals with WNV meningitis that comprise cases
of WNND varies by report. In an outbreak in Israel, 15.9% Tick-borne encephalitis virus (TBEV) is an important cause of
of hospitalized patients with WNND had meningitis (233). In meningitis in Europe. Cases in returning travelers from Europe
the United States, WNV surveillance data from 1999 to 2008 and China have been seen in the United States (259). The disease
found that 33% of WNND cases reported to the Centers for was first described in Austria in 1931 (260). TBEV is endemic
Disease Control and Prevention (CDC) were meningitis (247). from Europe through far-eastern Russia, northern China, and
Individuals 19 years of age or younger accounted for 8% of all Japan. Three subtypes of the virus exist: European, Siberian, and
cases of meningitis. However, when cases of WNND in children Far Eastern (10,215). It is maintained in enzootic cycles involving
were analyzed for nearly the same time frame, 47% of all pe- Ixodid ticks and wild rodents (215). Humans may be infected
diatric cases were of meningitis as compared to encephalitis or through the bite of an infected tick or, less commonly, the con-
meningoencephalitis, which accounted for 37% of cases (236). sumption of virus-infected milk. The majority of cases occur from
In adults and children, West Nile meningitis is clinically March to November (10). The annual incidence of disease var-
indistinguishable from other causes of viral meningitis. The ill- ies widely by country: Latvia, Estonia, Lithuania, and southern
ness begins abruptly with fever, headache, nuchal rigidity, and Germany30, 16.5, 11.2, and 2 cases per 100,000 inhabitants,
meningeal signs (222,235,244). Photo- and phonophobia may respectively (10). Aseptic meningitis is seen with infection due
be present. The headache may be so severe as to need the use to the European and Siberian viral subtypes. Meningitis is more
of narcotic analgesics to control. Weakness and dyskinesias in frequently seen in younger age-groups (10). Sixty-six percent of
the form of tremors, myoclonus, or parkinsonism may occur. cases in infants and children 15 years of age or younger are of
The outcome of West Nile meningitis is favorable, although it meningitis. This decreases progressively with advancing age such
may take 2 to 3 weeks to fully recover. that for individuals 60 years of age or older, 32% or less develop
Analysis of the CSF shows a lymphocytic pleocytosis of meningitis. Diagnosis of TBEV infection is established by the
generally less than 500 cells/mm3 (235). If the CSF is exam- detection of virus-specific IgM and IgG in serum. Vaccines for the
ined early in the course of the illness, a polymorphonuclear prevention of TBEV-related disease are available in Europe and
pleocytosis may be seen (248). The presence of plasma cells Canada and are recommended for certain regions of the world
may be indicative of WNV as the etiology (249). (10,215,261). No specific therapy is available.
The diagnosis of WNV infection relies on the detection Other flaviviruses such as POW virus (214,262) and
of WNV-specific antibodies in CSF or paired serum samples Japanese encephalitis virus (263,264) are far less commonly
(235,250). The most sensitive and commonly used diagnostic identified as causes of meningitis.
assay is the IgM antibody-capture enzyme-linked immunosor-
bent assay (MAC-ELISA). It is capable of detecting CSF IgM Colorado Tick Fever Virus
antibodies 3 to 5 days into the clinical illness and 3 or more
Colorado tick fever (CTF) virus is an Orbivirus, a member of
days earlier than detectable serum antibody (251). However,
the family Reoviridae. Orbiviruses are double-stranded, seg-
a positive test should always be interpreted in the context of
mented RNA viruses. The virion is nonenveloped, with an
clinical syndrome because the presence of WNV-specific IgM
outer diameter of 80 nm and an inner core of 50 nm diameter.
has been detected in the CSF for up to 199 days after onset
CTF virus is found mostly in western and mountainous regions
of illness (252). The finding of WNV-specific IgM in the CSF
of the United States. Its tick vector is Dermacentor andersoni,
of an individual with a clinically compatible CNS syndrome
also known as the Rocky Mountain wood tick (265). After a
generally is considered diagnostic of WNND. If only serum is
bite by an infected tick, a 3- to 6-day incubation period follows.
used for establishing a diagnosis, a second convalescent serum
Hematopoietic cells, principally erythrocytes, are the major tar-
sample, obtained 2 or more weeks later, should be collected to
gets, wherein viral replication and dissemination occurs (265).
document a fourfold increase in specific antibody titers using
A biphasic illness is characteristic but is actually observed in
a functional assay such as neutralization or hemagglutination
only half of patients (265). It consists of initial sudden onset of
inhibition (235). Because serologic cross reactions among
high fever and headache with flulike constitutional symptoms.
St. Louis encephalitis virus, WNV, and POW virus can occur,
Hepatosplenomegaly may occur, as well as GI symptoms. Stiff
serologic testing ideally should include a battery of region-
neck and other meningeal signs occur in as many as 18% of
specific arboviral antigens (253).
confirmed CTF cases (266). Meningoencephalitis and encepha-
litis can occur but less commonly than meningitis. The period
St. Louis Encephalitis Virus of illness is usually brief (2 to 3 days). A peripheral leukope-
St. Louis encephalitis virus (SLEV) was first identified in 1933 nia with relative lymphocytosis is common. A lymphocyte-
following an epidemic of encephalitis in St. Louis, Missouri predominant CSF pleocytosis and elevated protein level are
(254). Like others of the genus, it is an enveloped, positive typically found in patients with neurologic manifestations.
(message)-sense, single-stranded RNA virus (221). It is recog- Certain patients transiently improve (1 to 2 days), and then
nized as the cause of sporadic and epidemic encephalitis and a second phase of illness of equal or greater severity follows
meningitis throughout the Americas. In the United States, most (lasting an additional 2 to 3 days). Severe sequelae and death,
cases are seen from July through September (255). In Florida, though rare, have been reported. Typically, recovery is rapid
epidemics have continued into December (256). Birds are and complete within 2 weeks. Laboratory diagnosis can be
the reservoir, and four different species of Culex mosquitoes, made using PCR (within the first 5 days of illness) or IgM-based

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Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 75

serology (214). Virus may also be detected in peripheral blood mononuclear cells (277). Half of patients have 500 or fewer
smears by indirect immunofluorescence. Paired acute and con- cells/mm3, 75% of cases have 1,000 or fewer cells/mm3, and
valescent serology is useful for retrospective diagnosis. the remainder have fewer than 5,000 cells/mm3. Exceptional
cases with more than 5,000 cells/mm3 have been reported.
Pleocytosis may persist for weeks. CSF protein level has been
Bunyaviridae reported as normal in more than half of patients with mumps
meningitis (280,282).
The California encephalitis group of viruses include five viruses Several approaches exist for the diagnosis of mumps
in the family Bunyaviridae. ThreeLa Crosse, Jamestown virus meningitis: viral isolation, documentation of increased
Canyon, and snowshoe hareviruses have been associated antibody titers between serum acute and convalescent serum
with aseptic meningitis (128,267). Numerically, La Crosse is samples obtained 2 to 3 weeks apart, documentation of
the most clinically relevant. From 1999 to 2007, La Crosse the presence of mumps-specific IgM antibodies, or NAAT
virus was reported from 25 states. However, 87% of cases detection of mumps virus genome (283). Mumps virus can
came from 7 states: West Virginia, Ohio, North Carolina, be detected in saliva, blood, urine, and CSF. It is present in
Tennessee, Wisconsin, Minnesota, and Illinois (255). saliva 9 days prior to and 8 days after the onset of parotitis.
In urine, it is detectable for up to 2 weeks after the onset of
symptoms. Mumps-specific IgM is present in the blood within
PARAMYXOVIRUSES 3 to 4 days of the start of symptoms and may persist for up
to 3 months. A sole serum sample demonstrating the presence
of mumps-specific IgM obtained within 10 days of the onset
Mumps Virus of illness is sufficient to establish the diagnosis. IgG antibod-
ies are detectable 7 to 10 days after the start of symptoms
Mumps virus is a member of the genus Rubulavirus within the
and persist for life. Antibodies to other paramyxoviruses may
subfamily Paramyxoviridae (268). It is an enveloped, pleomor-
cross-react with in mumps virus in serologic assays, leading to
phic virus possessing a single-stranded, negative-sense RNA
false-positive results.
genome. Only a single serotype exists, although 13 genotypes
have been identified (269,270). In the United States, prior to
1967 and the introduction of an effective vaccine, mumps
infections are observed during the winter and spring, with epi- Other Paramyxoviruses
demics occurring approximately every 3 to 5 years (271,272).
It was responsible for 2.5% to 15% of all cases of aseptic Measles infection may be associated with pleocytosis in as
meningitis and between 17.5% and 22% of known causes of many as 30% of uncomplicated cases in normal patients,
meningitis (5,8,9,11). As a result of mumps vaccine and effec- usually without signs or symptoms of meningitis (284). The
tive vaccination programs, mumps cases have been reduced by parainfluenza viruses have been associated with CNS infection
99% (273). However, mumps outbreaks continue to occur in (285). The dominant serotype reported has been parainfluenza
the United States (274,275). virus type 3.
Mumps is transmitted via respiratory droplets. Once infec-
tion occurs, viremia is the likely means of spread to distant
target organs, including the CNS (276). Meningitis is the most
common neurologic manifestation of mumps infection (277).
ARENAVIRUSES
Mumps once was the leading identifiable cause of aseptic men-
ingitis. The widespread use of the attenuated live-virus vac- Lymphocytic Choriomeningitis Virus
cine in the United States has resulted in a dramatic drop in
incidence of mumps as well as its major role as a cause of LCMV, a member of the family Arenaviridae, is an enveloped
meningitis (278). Neurologic involvement is three times more virus with a genome consisting of two single-stranded, ambi-
common in males. More than 50% of patients with mumps sense RNA molecules (286). LCMV was one of the earliest
parotitis have CSF pleocytosis (277); however, most are not and significant viruses to be associated with aseptic meningitis
symptomatic of meningitis. in humans (3) (Table 5.2). It is now rarely identified as a cause
Clinically symptomatic meningitis occurs in up to 10% of CNS infection in humans. The virus is endemic in wild
of patients with parotitis (279). Symptoms of meningitis are mice, which serve as its reservoir (287). In the United States,
reported in cases of mumps parotitis by 4 to 10 days of illness the prevalence in wild mice is estimated to be 3.9% to 13.4%
but may precede parotitis by as much as 7 days; half or more (287). Seroprevalence studies in the United States suggest that
cases of mumps meningitis may not be associated with par- the 0.4% to 5% of patients sampled in three large cities had
otitis at all (280,281). The clinical manifestations of mumps evidence of LCMV infection (287289). The virus is trans-
meningitis are nonspecific and differ little from those of EV mitted by rodents (hamsters, guinea pigs, rats, mice) via their
cases. Fever is universal, usually lasting 3 days but occasion- saliva, urine, feces, and nasal secretions (290). Individuals who
ally persisting for a week (280). Bradycardia, drowsiness, leth- work with or own rodents as well as those living under impov-
argy, and anemia are all reported. More significant neurologic erished and nonhygienic circumstances have traditionally been
involvement can occur. Encephalitis is described concomi- at greatest risk (291294). Human-to-human transmission can
tantly with meningitis in as many as 35% of cases (280) or as occur through transplantation (295,296). Approximately one
few as 4% (166). third of LCMV infections are asymptomatic. Clinically mani-
Mumps virus meningitis and meningoencephalitis are usu- fest infections are usually mild and of brief duration. The infec-
ally benign and self-limited diseases (277,280). The prognosis tion frequently results in a biphasic illness characterized by an
for rapid and full recovery from mumps meningitis is excellent initial flulike illness with fever, headache, malaise, myalgia,
(277,280). The occasional fatalities demonstrate pathologic anorexia, nausea, and emesis. A temporary, brief period of
findings of demyelination near blood vessels (277). improvement follows and precedes the onset of symptoms of
Most but not all cases of symptomatic mumps menin- meningitis or encephalitis (291,292,297). Occasional severe
gitis have a primarily monocytic CSF pleocytosis, primarily neurologic disease (meningoencephalitis, encephalitis) has

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76 Part II: Viral Infections and Related Disorders

been reported (298). The course of meningitis and recovery are lethargy (321). In that study, all cases of meningitis occurred in
often prolonged (299), but permanent neurologic impairment children. When meningitis complicates zoster, typical vesicu-
is rare. CSF findings are indistinguishable from those of other lar lesions restricted to dermatomal distribution are seen. The
viral causes of aseptic meningitis: lymphocytic pleocytosis (up use of NAAT has identified individuals with meningitis due to
to several thousand), mildly elevated protein, and usually nor- reactivation of VZV but without skin lesions (301,321). The
mal or low glucose level. Other abnormalities include leukope- benign course is typical of other aseptic meningitides.
nia, thrombocytopenia, elevations of transaminase levels, and Reports of meningitis with EBV and CMV infection are
pulmonary infiltrates (297). Cell culture of CSF usually detects far less common that those of the agents discussed previously.
the presence of LCMV. In severe disseminated infection, virus Although HHV-6 and HHV-7 have been reported as causes
may be found in the blood, urine, and nasopharyngeal secre- of CNS infection, including meningitis (305,307,308), these
tions. NAAT can be used to detect viral genome in CSF. Acute reports must be interpreted with caution. HHV-6 has been
and convalescent serum specimens can be tested for raising shown to establish persistence in the CNS and has been found
antibody titers by enzyme immunoassays. in the CSF of asymptomatic individuals (322).

HUMAN HERPESVIRUSES OTHER VIRAL PATHOGENS


The majority of the human herpesvirusesHSV types 1 and HIV
2, varicella-zoster virus (VZV) (300,301), Epstein-Barr virus
(EBV) (302,303), cytomegalovirus (CMV) (304), human her- Aseptic meningitis is known to occur as part of the clinical
pesvirus (HHV)-6 (305308), and HHV-7 (308)have been constellation of syndromes associated with primary HIV infec-
associated with reports of aseptic meningitis. Numerically, tion (323325). The symptoms and signs are typical of aseptic
HSV-1 and HSV-2, in particular the latter, are the major causes meningitis and resolve rapidly. If the CSF is examined, a lym-
of aseptic meningitis among this family for viruses. phocytic pleocytosis is present along with mildly elevated pro-
HSVs appear to account for approximately 1% to 3% tein and normal glucose concentrations. HIV can be detected
of all cases of aseptic meningitis (Table 5.2). HSV-2 and, in the CSF. Pleocytosis may also be seen in asymptomatic HIV-
much less commonly, HSV-1 have been associated with asep- infected individuals.
tic meningitis in patients with primary genital herpes infec- Occasional cases of aseptic meningitis or meningoencephali-
tion (309311). HSV-2 meningitis following primary genital tis have been associated with adenoviruses in normal and immu-
infection is more frequently seen in women. Genital lesions nocompromised patients (326330), influenza A and B viruses
may not be present at the time of symptoms of aseptic men- (331333), parvovirus (334), and rotavirus (335337).
ingitis (310). Examination of the CSF demonstrates a lym-
phocytic pleocytosis, elevated protein, and normal glucose
concentrations. NONVIRAL PATHOGENS
Recurrent benign lymphocytic meningitis (RBLM), also
referred to as Mollaret meningitis, has been shown to be Multiple pro- and eukaryotic pathogens (bacteria, spirochete,
associated primarily with HSV-2 and, much less so, HSV-1 mycobacteria, fungi) can present with the classic features of
(312315). The prevalence of RBLM is difficult to assess aseptic meningitis. The majority of these agents would not be
because of its intermittent presentation, and it is not a report- readily detectable by Gram stain of the CSF and may require
able condition. However, two reports place it between 1 and special culture techniques to identify. As originally noted by
2.2 cases per 100,000 population (316,317). The syndrome Wallgren (2), parameningeal foci (sinusitis, otitis, mastoiditis,
is more frequently seen in young women and consists of trauma) can present similarly to viral meningitis and need to
recurrent episodes of aseptic meningitis, lasting 2 to 5 days, be always considered in the differential diagnosis of aseptic
which resolve spontaneously and without sequelae (318). The meningitis.
clinical presentation of RBLM is typical of viral meningitis.
However, approximately 50% of patients have transient neu-
rologic manifestations (seizures, hallucinations, diplopia, cra- Spirochetes
nial nerve palsies, altered consciousness). Lesions of genital
herpes are absent. Cytochemical analysis of the CSF reveals
a lymphocytic pleocytosis, mildly elevated protein, and nor-
Lyme Disease
mal glucose concentrations (318). Detection of HSV genome In areas of the United States where Lyme disease is endemic
is made by NAAT. The role of antiviral therapy in the manage- (338), CNS infection due to Borrelia burgdorferi may be
ment of RBLM is debated. Administration of acyclovir has encountered in 10% to 15% of individuals infected by this
been reported to result in rapid resolution of symptoms, and spirochete (339,340). B. burgdorferi is transmitted by Ixodes
suppressive therapy using valacyclovir or famciclovir may pre- species (scapularisEastern United States, or pacificus
vent recurrences. In individuals with HSV-2 detected from the Western United States) of ticks. Because the vector is so dimin-
CSF, counseling regarding prevention of transmission of geni- utive, a significant number of infected individuals do not recall
tal HSV should be undertaken (318). a tick bite. The illness is commonly seen in the spring and
VZV-related meningitis is a recognized complication of summer months and overlaps with EV and arboviral causes
primary infection (chickenpox) and reactivation (zoster) of meningitis. Meningitis usually occurs in the early dissemi-
(300,301,319,320). Meningitis has been associated with nated stage of infection. The clinical manifestations are similar
infection due to multiple different genotypes of the wild type to viral meningitis and may occur in association with cranial
strain as well the vaccine strain (Oka strain) of VZV (321) neuritis and radiculoneuritis (339343). The majority of chil-
and may be seen in immunocompetent and immunocompro- dren have associated findings such as facial or sixth nerve
mised individuals. The clinical and CSF presentation is typical palsies, papilledema, and increased intracranial pressure of
of aseptic meningitis. However, in recent report, only half of erythema migrans. Analysis of the CSF reveals a lymphocytic/
patients had fever, and nearly 25% had altered mental status or monocytic pleocytosis (500 cells/mm3) and elevated protein

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Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 77

concentration. The CSF glucose concentration is usually nor- hypoglycorrhachia. In addition to fungal culture of the CSF,
mal but may be slightly decreased. evidence of infection should sought through detection of fungal
The diagnosis of Lyme meningitis requires documenting antigen, fungal wall constituents, or specific antibodies in CSF
B. burgdorferi infection using a two-step diagnostic approach and blood. When attempting to detect fungi through culture, it
consisting of an initial enzyme-linked immunosorbent assay is important to use 10 to 15 mL of CSF. Evidence of fungal infec-
(ELISA) followed by a specific Western blot assay. In addi- tion in sites outside of the CNS should also be sought.
tion, the CSF should be examined for the presence of intra- A variety of neurologic manifestations have been reported to
thecal production of antibody to B. burgdorferi (339341). be associated with Mycoplasma pneumoniae infections (356).
Treatment with ceftriaxone, cefotaxime, or penicillin G for Of these, aseptic meningitis and encephalitis are the most com-
2 to 4 weeks is recommended (340,342,343). mon. Clinically, mycoplasmal meningitis is impossible to dis-
tinguish from viral meningitis, and as in typical viral infection,
sequelae are not observed. Diagnosis is by serology or PCR
Other Spirochetes (356,357). Mycoplasma hominis has been associated with cases
of neonatal meningitis, usually in preterm infants (358).
Leptospirosis is an acute systemic vasculitic disease caused by
a number of spirochetes in the Leptospira genus. Acquisition
is via contact with infected animal body fluids. Although more
Systemic Diseases
typically noted in the anicteric variety, meningitis is com- Kawasaki disease (KD) is an acute, self-limited vasculitis of
mon in icteric leptospirosis (Weil disease) as well (344). The unknown etiology affecting children. In the United States, the
CSF profile is indistinguishable from that caused by common estimated overall annual incidence among children younger than
viruses, except that overall, more patients develop elevated 5 years of age is 20 cases per 100,000 population (359). The
CSF protein than patients with common viral meningitis. incidence is higher among Asians and Pacific Islanders. Several
Aseptic meningitis is a relatively uncommon manifestation of reports indicate that between 40% and 60% of children with
secondary and tertiary syphilis (345). Meningitis due to tick- KD have a mild (usually 100 cells/mm3) mononuclear pleocy-
borne relapsing fever may be seen as frequently as with Lyme tosis on CSF examination (360,361). The incidence appears to be
disease (346). highest in reports from Japan. The CSF protein and glucose con-
centration are normal in the overwhelming majority of children.
Many other systemic vasculitides (e.g., polyarteritis nodosa,
Bacterial and Fungal Causes temporal arteritis, Takayasu arteritis, Wegener granulomatosis)
are associated with CSF pleocytosis (362). Meningitis has been
The majority of tuberculous CNS infections are caused by described as the initial manifestation of systemic lupus erythe-
Mycobacterium tuberculosis. A small percentage is due to matosus in several patients (363). Two percent to 4% of patients
bovine tuberculosis, Mycobacterium bovis. Children are par- with lupus may develop aseptic meningitis during the course of
ticularly prone to develop tuberculous meningitis (347). The their disease (363).
presentation is often subacute, occurring over 1 to 3 weeks
(348). The clinical course consists of three stages. Personality
change, irritability, anorexia, listlessness, and occasional fever Medication-Induced Aseptic Meningitis
characterize the first stage. Second stage signs and symptoms
reflect increased intracranial pressure and cerebral ischemia: The clinical features of medication-induced aseptic meningitis
drowsiness, nuchal rigidity, cranial nerve palsies, anisocoria, are not such that they set it apart from that caused by infectious
emesis, and seizures. In older children, adolescents, and adults, etiologies nor do they permit differentiation of the multiple
headache and emesis may be the dominant features. The third medication causes of the syndrome. A wide variety of medica-
stage is characterized by coma, autonomic instability, fever, and tions, vaccines, or dyes, administered systemically or within the
progressive cerebral dysfunction. Chest radiograph; tuberculin CNS, have been associated with aseptic meningitis (364372).
skin testing; and, in older children, adolescents, and adults, The most common class of medications associated with asep-
IFN gamma release assays should be performed, seeking evi- tic meningitis is nonsteroidal antiinflammatory drugs (NSAIDs)
dence of tuberculosis. The lumbar puncture reveals elevated (364). Of the nonselective and selective inhibitors of cyclooxygen-
opening pressure. The CSF reveals a markedly elevated protein ase 1 and 2, ibuprofen is the most frequently associated NSAID
and decreased glucose concentrations. A lymphocytic pleocy- with aseptic meningitis. Ibuprofen-associated aseptic meningitis
tosis of usually less than 500 cells/mm3 is seen. is frequently seen in association with systemic lupus erythemato-
CNS infections with Brucella species occur in less than 5% sus. The majority of cases are reported in women. The associated
of systemic brucella infections (349). Meningoencephalitis is pleocytosis is frequently polymorphonuclear in nature.
the usual presentation. Both acute and chronic forms have Antimicrobial agents have also been shown to cause
been reported. Antibiotic therapy is usually curative; however, aseptic meningitis (364). Leading this group of medications
some residual neurologic defects are the rule. are trimethoprim and penicillin (penicillin, amoxicillin, or
Fungal meningitis is more commonly seen in immunocom- amoxicillin-clavulanic acid). Intravenous immunoglobulin
promised individuals; however, occasional cases have been is a well-recognized cause of aseptic meningitis (364). In
reported in immunologically normal individuals (350355). pediatric clinical trials using intravenous immunoglobulin,
Cryptococcus is the most commonly recognized cause of fungal the incidence of aseptic meningitis ranged from 6% to 32%.
meningitis (352). Other causes include Candida, Histoplasma, Immunomodulators such as monoclonal antibodies against
Coccidioides, Blastomyces, and Aspergillus (350,351,353355). CD3 or tumor necrosis factor- are important causes of
The clinical presentation is that of a subacute or chronic meningi- aseptic meningitis (364,368). Vaccine strains of mumps have
tis with fever, headache, and altered consciousness. Meningismus been the most frequently associated (364,373). Greater than
and focal neurologic findings are common findings. Evaluation 10 mumps vaccine strains are used around the world (373).
of the CSF reveals a lymphocytic pleocytosis in most cases Although the Jeryl Lynn and related vaccine strains rarely, if
(a polymorphonuclear pleocytosis may be seen in some cases) ever, cause aseptic meningitis, other vaccine strains have been
in association with an increased protein concentration and associated with varying incidences of this side effect (373).

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CHAPTER 6 ENCEPHALITIS
CAROL GLASER AND ARUN VENKATESAN

Encephalitis is one of the most challenging syndromes for cli- and surveillance activities. In tropical regions of the world,
nicians to manage. Patients are often critically ill, and there the minimum estimated incidence of encephalitis is 6.3 per
are many potential etiologies. Despite exhaustive testing, an 100,000 (8). In the Western world, the incidence ranges
etiology is only identified in 40% to 70% of cases. Even when between 0.7 and 13.8 per 100,000 (810). Most reports find
a cause is identified, there may be no effective treatment (13). the incidence of encephalitis higher in the pediatric age-group
Mortality rates vary substantially across studies and range than in adults. For example, a study in England of hospitalized
from 3% to 15% (4,5). The frequency of sequelae, including patients with encephalitis over a 10-year period demonstrated
cognitive and motor impairment as well as seizures, is also an overall incidence of 1.5 per 100,000 population, a rate of
variable; some case series report severe disability in 20% to 2.8 per 100,000 in children, and a rate of 8.7 per 100,000 in
40% of patients (4,6,7). Not surprisingly, given the severity of infants (11). Somewhat higher rates in children were reported
the disease as well as the complexity of diagnosis and clinical from Finland (8.8 per 100,000 from 1973 to 1987) (12) and in
management, substantial health care costs are associated with Slovenia (6.7 per 100,000 from 1979 to 1991) (13).
encephalitis. The epidemiology of encephalitis is a dynamic process. In
The term encephalitis generally refers to inflammation of countries where vaccines are widely used for measles, mumps,
the brain parenchyma. However, without the identification rubella, and varicella infections, the incidence of encephali-
of a neurotropic agent or confirmation of inflammation in tis due to these viruses has decreased (14,15). However, there
brain tissue, the diagnosis of encephalitis is presumptive and is a growing list of emerging and reemerging pathogens
based on clinical features. Clinically, patients with encephalitis such as Nipah virus, enterovirus 71, Balamuthia mandril-
often present with fever, headache, and altered mental status. laris, European tick-borne encephalitis virus, Hendra virus,
Seizures or focal neurologic deficits may also be present. In Baylisascaris procyonis, and Chandipura virus that can cause
principle, alteration in mental status distinguishes encepha- encephalitis. Moreover, some agents are now identified in pre-
litis from uncomplicated meningitis as meningitis symptoms viously nonendemic regions of the world. Notable is West Nile
typically include fever, headache, and nuchal rigidity but lack virus, which has expanded its geographic region from Africa to
global or focal neurologic dysfunction. In practice, however, North and South America, Europe, the Middle East, Western
the distinction between these two entities is not always readily Asia, and Australia (16). Chikungunya virus is yet another
apparent, and in descriptions of central nervous system (CNS) striking example of a virus that has spread from its origin in
infections with mental status changes due to agents such as en- Africa to nearly 40 countries including a number of countries
teroviruses, rabies, West Nile virus or herpesviruses, the terms adjacent to the Indian Ocean: La Reunion Island, Madagascar,
encephalitis or meningoencephalitis are often broadly applied. the Maldives, the Seychelles, and India. (17).
In contrast to encephalitis, encephalopathy refers to The increasing recognition of specific autoimmune causes,
any diffuse disease of the brain that results in changes in as discussed later in this chapter, has also had a tremendous im-
function; the clinical hallmark of encephalopathy is an al- pact on our understanding of the epidemiology of encephalitis.
tered mental state. Many entities including metabolic or
mitochondrial dysfunction, toxins, trauma, poor nutrition,
or lack of oxygen or blood flow to the brain can lead to
encephalopathy.
INFECTIOUS CAUSES: SPECIFIC
This chapter focuses predominantly on the immunocom- EPIDEMIOLOGIC AND CLINICAL
petent host and pathogens in North America that either cause FEATURES
encephalitis or an encephalitis-like syndrome. Moreover, many
patients with encephalitis also have meningeal inflammation,
thus demonstrating the overlap of encephalitis and menin- Viruses
goencephalitis. For the purposes of this chapter, the terms
encephalitis and meningoencephalitis are used interchangeably. Many cases of viral encephalitis are either an uncommon
Other regions of the CNS may be variably affected, including complication of a common infection, such as a herpesvirus or
the spinal cord (myelitis), nerve roots (radiculitis), and nerves enterovirus infection, or a predictable presentation of a rare
(neuritis). pathogen such as rabies or lymphocytic choriomeningitis virus.
The clinical manifestations of encephalitis are variable and
reflect the degree of brain involvement, host factors, and the
inherent pathogenicity of the offending agent. Most patients
GENERAL: ETIOLOGIC AGENTS with encephalitis have headache and fever, followed by altered
AND EPIDEMIOLOGY mental status. Seizures, behavioral changes, impaired cogni-
tion, aphasia, hemiparesis, and other focal neurologic signs
Although the term encephalitis is often used in conjunc- may be seen. Arboviruses are often associated with global CNS
tion with a viral etiology, many other infections and nonin- dysfunction, whereas agents such as herpes simplex encepha-
fectious entities can cause encephalitis or encephalitis-like litis typically result in focal manifestations. Although there is
symptomatology. The incidence of encephalitis varies through- significant overlap in the clinical presentation of various agents
out the world and is contingent upon the population under and diagnosis can rarely be made on clinical grounds alone,
study, the geographic region, the availability of vaccines for the most typical and/or characteristic features of some of the
some causes of encephalitis, and differences in case definitions causes are highlighted in the following sections.

84

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Chapter 6: Encephalitis 85

Herpes Simplex Virus Epstein-Barr Virus


Herpesviruses are enveloped DNA viruses that are among the Epstein-Barr virus (EBV), another herpesvirus, is most often
most common causes of infections in humans. At least eight associated with mononucleosis but can also cause several
herpesvirus types are known to infect humans. Herpes simplex distinct neurologic syndromes including aseptic meningi-
virus type 1 (HSV-1) is one the most common causes of spo- tis, Guillain-Barr syndrome, Bell palsy, transverse myelitis,
radic encephalitis in the world (see Chapters 9 and 10). The cerebellitis, and encephalitis (37,38) (see Chapter 12). Most
epidemiology and clinical features of neonatal herpes CNS neurologic complications due to EBV occur during primary
infections differ from children and adults and are not covered infection, typically in childhood. Importantly, many patients
in this chapter. The incidence of herpes simplex encephalitis with EBV-associated encephalitis do not have classic mononu-
(HSE) caused by HSV-1 is estimated to be 4 per 1,000,000 cleosis symptoms (39,40). In a case series of 216 pediatric en-
(11,18). HSE is responsible for 10% to 20% of adult en- cephalitis patients in Canada, 21 (9.7%) were identified with
cephalitis cases (3,19). HSE is less common in children than EBV-associated encephalitis (40). Of these, only one patient
in adults; in a large cohort of over 300 pediatric encephalitis had classic mononucleosis symptoms; most others had a non-
patients over a 12-year period, only 5% were due to HSE. In specific prodrome of fever (81%) and headache (66%) (40).
the pediatric age-group, HSE is often a result of a primary in- Seizures occurred in almost half (48%) (40). Some individuals
fection, whereas most HSE infections in adults are the result of with EBV-associated encephalitis experience micropsia, mac-
HSV reactivation. Importantly, the presence of herpes labialis ropsia, and/or size distortion. This pattern of unusual images
has no diagnostic specificity for encephalitis causality but does of body and objects is referred to as the Alice in Wonderland
serve as a marker of HSV infection. syndrome (41). There are sporadic reports in the literature
The characteristic clinical presentation for HSE includes that reactivation of chronic EBV infection in adults may cause
altered mental status (97%), fever (90%), and headache neurologic manifestations, including encephalitis (42).
(81%) (20). Other common neurologic findings include per-
sonality change (85%), aphasia (40%), ataxia (40%), hemi- Human Herpesviruses 6 and 7
paresis (38%), cranial nerve deficits (32%), and seizures
Human herpesvirus-6 (HHV-6), the primary cause of ro-
(31%) (4,21). Children are more likely to have extratempo-
seola infantum in young children, has been identified as the
ral involvement as manifested by clinical symptoms as well as
causal agent of 10% to 20% of febrile seizures and is also
neuroimaging (22).
occasionally associated with encephalitis (43,44) (see Chapter
Unlike HSV-1, HSV-2 is more likely to cause disseminated
13). Several studies of encephalitis in children have identified
encephalitis and does not generally localize to the temporal
HHV-6 as a causative agent, with the incidence of HHV-6
and inferior frontal regions of the brain (23). Most neuro-
encephalitis ranging from 1% to 11% of cases (4549). In
logic CNS HSV-2 infections present with lymphocytic men-
one study of nine children with HHV-6 CNS infections,
ingitis. Relapsing meningitis, encephalitis, and myelitis can
characteristic clinical features included fever, gastroenteritis,
also occur.
rash, seizures, and ataxia (50). Another case series reported
HSV-1 and HSV-2 can also cause brainstem encephalitis.
three pediatric patients with HHV-6associated rhomben-
A recent comprehensive literature review of HSV brainstem
cephalitis; clinical manifestations included encephalopathy,
encephalitis identified 24 cases: 79% due to HSV-1 and 29%
seizures, ataxia, and myoclonus (51). HHV-7, a recently de-
due to HSV-2 (24). The most prominent features were neuro-
scribed herpesvirus, is occasionally associated with roseola
ophthalmologic manifestations; these were seen in over 80%
and is typically acquired in the first few years of life. Recent
of patients and included nystagmus, impaired ocular move-
studies from the United Kingdom suggest HHV-7 may be an
ments, anisocoria, ptosis, oscillopsia, or spasmodic move-
important cause of febrile seizures and encephalitis in young
ments (24). Other cranial deficits, altered mentation, ataxia,
children (52).
and corticospinal tract findings (e.g., hyperreflexia) were also
described. Although not common, quadriplegia was also pres- Enteroviruses and Parechoviruses
ent in some (19%) of the patients (24).
Enteroviruses (EVs) are small, nonenveloped, single-stranded
RNA picornaviruses. Similar to herpesvirus infections, EV
Varicella-Zoster Virus
infections are very common, and neurologic complications,
Both primary infections with varicella-zoster virus (VZV) and including encephalitis, represent a rare complication of EV
endogenous reactivation (herpes zoster) can lead to encepha- infection. Because EV infections occur frequently in children,
litis (25) (see Chapter 10). The most characteristic manifesta- they are a leading cause of encephalitis in children and are
tion of VZV encephalitis in children is acute cerebellar ataxia responsible for 10% to 15% of encephalitis cases for which an
(e.g., nystagmus, dysarthria, and ataxia), which usually occurs etiology is identified (53). In general, EVs cause a milder clini-
1 week after rash onset (26). VZV encephalitis, once a leading cal illness than many other etiologies of encephalitis. In the
cause of encephalitis in children, is much less common due to California Encephalitis Project, EV encephalitis patients had
the widespread use of VZV vaccine (27). less severe manifestations, including lower frequencies of coma
However, VZV encephalitis is relatively common in adults, and shorter hospitalization stays than those due to other agents
and its incidence rivals that of HSE (2831). The clinical pre- (54). CNS infections with EV-71 are an important exception
sentation in adults is different than in children and includes to the decreased severity of EVs (55,56). In addition to caus-
diffuse brain dysfunction, seizures, cranial nerve palsies, and ing acute flaccid paralysis (aka polio-like syndrome), EV-71
other focal neurologic signs (4,32). The presence of a diffuse has also been associated with a distinctive form of encephalitis
varicella rash or a vesicular rash in a dermatome distribution initially described in Taiwan and Malaysia (55,57). Most cases
can be an important clue to diagnosing VZV encephalitis. were in young children (younger than 5 years of age), with a
Notably, however, as many as 44% of patients lack cutaneous characteristic hand, foot, and mouth rash along with ataxia,
findings, a condition termed herpes sine zoster or preeruptive nystagmus, myoclonus, and oculomotor palsies (55). The
varicella (3236). Although the pathophysiology of VZV- predominant neurologic presentations included myoclonus
associated encephalitis remains unclear, some cases appear to (68%), vomiting (53%), and ataxia (35%) (57). Many of the
be due to a medium and large vessel vasculopathy (25). fatalities associated with EV-71 are due to pulmonary edema

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86 Part II: Viral Infections and Related Disorders

and hemorrhage, which are thought to be a consequence of Similar to many other arboviruses, most JEV infections are
pronounced autonomic instability due to lesions in the me- asymptomatic, with less than 1% of infections leading to clini-
dulla and spinal cord (58,59). Sporadic outbreaks involving cal disease. When symptoms occur, encephalitis is the most
substantial numbers of EV-71 encephalitis cases have been ob- common presentation. After a characteristic febrile prodrome
served among young children in Europe and Asia over the past including headache and vomiting, mental status changes,
several decades (6062). seizures, focal neurologic deficits, and movement disorders
The reclassification of former EVs, echovirus 21 and echo- develop. Similar to patients with WNV, those affected by JEV
virus 22, resulted in the human parechovirus (HPeV) genus. can also develop acute flaccid paralysis (77).
Echoviruses 21 and 22 are currently classified as HPeV-1 and In Europe, tick-borne encephalitis virus (TBEV), another
HPeV-2, respectively. At least 12 HPeV serotypes have been flavivirus, is the most common cause of arboviral encephali-
described to date; nearly all have been associated with enceph- tis (78). It is also found in China and Japan. Analogous to
alitis, typically in children younger than 2 years of age (63,64). WNV, neuroinvasive disease is more common in older popu-
Clusters of HPeV-3 CNS infections have been reported (65). lations (79). Growing numbers of cases have been recognized
Young children and infants with HPeV encephalitis develop in recent years as a result of improvements in diagnostics and
fever, seizures, irritability, feeding problems, and rash (66). case reporting as well as increased recreational activities in
The relative frequency of HPeV encephalitis is unknown, tick-infested areas (80). In Europe and Russia, there was an
particularly because HPeV testing has only recently become average of 8,755 reported cases per year from 1990 to 2007
available. compared to an average of 2,755 cases per year from 1976 to
1989 (81). TBEV is characterized by three different subtypes:
Arboviruses European (TBEV-Eu), Siberian (TBEV-Sib), and Far Eastern
(TBEV-Fe). The TBEV-Eu subtype circulates predominantly
Arboviruses, viruses transmitted by an arthropod vector, are
in Western, Central, Northern, and Eastern Europe; the
well-recognized causes of encephalitis. The vast majority of
TBEV-Sib circulates predominantly in Asian parts of Russia;
neurologic illnesses seen in humans are caused by three arbo-
and TBEV-Fe circulates predominantly in China, Japan, and
virus families: Togaviridae, Flaviviridae, and Bunyaviridae (see
Eastern Russia. The clinical spectrum of disease ranges from
Chapter 15).
mild meningitis to severe meningoencephalitis with or with-
West Nile virus (WNV), a flavivirus, was first detected in
out paralysis (82). In individuals affected with the European
the Western Hemisphere in 1999 in New York City and rapidly
virus subtype, the illness is often biphasic, with the first stage
spread across North America from the Atlantic to the Pacific
characterized by fever, fatigue, general malaise, headache,
coasts and into Mexico and Canada. It is the now the most
and body pain. During the second phase of the illness, clini-
common cause of arboviral encephalitis in the United States
cal manifestations range from mild meningitis to severe en-
(67). Most individuals infected with WNV will experience
cephalitis, with or without myelitis and paralysis. Seizures
subclinical infection (70% to 80%) or febrile illness (20% to
are uncommon. The disease associated with TBEV-Fe sub-
30%). Less than 1% of infected individuals develop West Nile
type is the most severe, with a case fatality of 20% to 40%
neuroinvasive disease (WNND), which includes meningitis,
and higher rates of neurologic sequelae compared with other
encephalitis, and/or acute flaccid paralysis.
subtypes (82).
WNND is more common in older individuals, with an inci-
Although JEV is recognized to cause more cases of enceph-
dence of 1.35 per 100,000 in persons 70 years of age or older
alitis than any other mosquito-borne virus worldwide, dengue
compared with 0.05 per 100,000 in persons younger than
viruses are the most prevalent arboviruses that infect humans
10 years of age (67). Other risk factors for WNND include
and result in an estimated 390 million infections every year
male gender, hypertension, diabetes, renal disease, and immu-
(83). Infections with dengue typically result in dengue fever,
nosuppression (68,69). Characteristic presentations of WNND
dengue hemorrhagic fever, and dengue shock syndrome.
include altered mental status or lethargy with or without move-
Unlike many of the aforementioned arboviruses, neurologic
ment disorders (tremors, Parkinsonism, or myoclonus). Acute
manifestations of dengue have traditionally been considered
flaccid paralysis is also a feature of WNV infection and can be
to be the result of an encephalopathy rather than encephalitis.
seen along with encephalitis or may occur in isolation (70,71).
However, detection of dengue viral RNA in brain tissue, virus
Although the number of WNND cases has far surpassed the
isolation in CSF, and the presence of dengue-specific CSF an-
number of cases due to other arboviruses in recent years, other
tibody suggesting intrathecal synthesis have been described in
arboviruses in the United States cause seasonal outbreaks and
recent studies and strongly suggest the neuroinvasive potential
sporadic cases of neurologic disease. These include La Crosse
of dengue (8486).
virus (LACV), eastern equine encephalitis virus (EEEV),
Powassan virus (POWV), and St. Louis encephalitis virus
(SLEV). In 2012, over 2,500 WNND cases were recognized
Rabies
in the United States compared with 78 LAC cases (71 neuro- Rabies virus is one of the oldest known infectious diseases and
invasive), 15 EEE cases (all neuroinvasive), 7 POW cases (all is considered to be the most deadly of all infectious diseases
neuroinvasive), and 2 SLE cases (1 neuroinvasive) (72). (see Chapter 17). The number of rabies encephalitis cases in
LACV, primarily found in the upper Midwestern, mid-Atlantic, the United States has declined dramatically from an average
and Southeastern regions of the United States, is the second most of 100 or more cases per year before 1940 to only 2 to 3 cases
common cause of arbovirus-associated CNS infections in the per year (87). Although rabies is rare in the United States, an
United States. Unlike WNV, most neuroinvasive LACV cases estimated 50,000 rabies cases occur annually worldwide; most
occur in the pediatric population rather than in adults; in 2012, are acquired via rabid dog contact (88). In Asia, Africa, and
86% of cases were younger than 20 years of age (73). Latin America, animal rabies control programs and postexpo-
Outside the United States, other arboviruses predominate. sure prophylaxis are limited. A recent report of 49 rabies cases
Japanese encephalitis virus (JEV) is the most common cause of in the United States, from 1995 to 2011, identified 10 im-
mosquito-borne encephalitis worldwide. An estimated 50,000 ported and 39 cases acquired in the United States; of the cases
cases of JEV clinical disease occur annually, primarily in chil- acquired in the United States, one was associated with a rac-
dren younger than 10 years of age in Asia, South Asia (east of coon strain of rabies, and the rest were due to bat exposures.
Pakistan), and Southeast Asia (7476). The incubation period is generally between 20 and 60 days but

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Chapter 6: Encephalitis 87

can range from a few days to several years (89). Paresthesia and often fatal form of encephalitis that typically occurs 7
at the site of the bite is unique to rabies and can be an im- to 12 years after the initial infection and usually affects chil-
portant clue to the diagnosis. Approximately 80% of human dren between 10 and 14 years of age (98,99). A history of
rabies cases develop the encephalitic (furious) form charac- prior measles vaccination does not preclude the diagnosis of
terized by unusual behavior, extreme agitation, hydrophobia, SSPE because an unrecognized measles infection may occur
delirium, and seizures. The remainder of cases develops the at an early age prior to immunization. This is supported
paralytic (dumb) form which is characterized by ascending by molecular studies that have identified wild type measles
paralysis followed by confusion and coma. Patients generally virus (rather than vaccine-type virus) from brain specimens
have a predominance of one form, but many affected individu- of SSPE cases (100). Early clinical features of SSPE include
als have components of both forms. personality and behavior changes, lethargy, decline in school
performance, and hyperactivity. More pronounced neuro-
Lymphocytic Choriomeningitis Virus logic manifestations such as aphasia, difficulty walking, and
involuntary movements (e.g., tremors, myoclonic jerks, and
Lymphocytic choriomeningitis (LCM) virus is an Old World choreoathetosis) later ensue. In the final stages, neurologic
arenavirus that can be acquired from infected house mice, deterioration resulting in a vegetative state occurs in most
hamsters, and guinea pigs. Humans become infected with affected patients (99).
LCM virus when aerosolized saliva, respiratory secretions, or
urine from rodents or virus-contaminated dust are inhaled or
possibly ingested. Infections occur more frequently in the win-
ter months when rodents migrate indoors (90). The incidence Bacteria
of LCM is unknown but appears to have decreased substan-
tially in the last several decades due to improvements in hous- While many infectious encephalitis cases have a viral etiol-
ing, which have resulted in less contact between house mice ogy, bacterial causes are important to consider in the diag-
and humans. However, it is likely that cases continue to occur nosis either as a mimicker of encephalitis or as an actual
but are not recognized (91). LCM often results in a bipha- cause of encephalitis. For example, Neisseria meningitidis and
sic illness with an initial phase of fever, anorexia, headache, Streptococcus pneumoniae do not cause encephalitis per se
muscle aches, nausea, and vomiting. Several days later, CNS but can cause clinical manifestations that are indistinguishable
symptoms can occur with either meningitis or encephalitis. from encephalitis. Mental confusion, drowsiness, convulsions,
Extra-CNS manifestations may also be present, including or- and coma are not uncommon manifestations of N. meningiti-
chitis, parotitis, arthritis, or alopecia (92,93). dis and S. pneumoniae bacterial meningitides (see Chapter 24).

Hendra Virus Mycobacterium tuberculosis


Hendra virus is a paramyxovirus first recognized in Hendra, Although meningitis is the most common form of neurotu-
Australia where it was associated with an outbreak of respira- berculosis, Mycobacterium tuberculosis was the third leading
tory and neurologic disease in horses and humans in 1994. cause of encephalitis in a French study where it was identi-
The natural reservoir of the virus is thought to be flying foxes fied in 15% of cases (101). In England, from 2005 to 2006,
(bats of the genus Pteropus). The virus is transmitted from M. tuberculosis was the causative agent in 12% of encephalitis
bats to horses and then transmitted to humans as a result of cases with an identified cause (29). Analogously, in a multi-
direct contact with infected horses. More than 60 equine and center study of encephalitis in Taiwan, M. tuberculosis was
4 human fatalities have been reported (94). The high fatality the third most common cause of encephalitis in both pediat-
rate of this infection in horses and people, as well as the large ric and adult patients (31). Of 20 patients with M. tubercu-
reservoir species, underscores the potential of this virus, and losis encephalitis referred to California Encephalitis Project
other similar viruses, to emerge and cause outbreaks of severe (CEP) between 1998 and 2005, many had features in common
illness. Human illness due to Hendra virus is characterized by with patients with viral encephalitis, including fever (75%),
influenza-like symptoms often followed by acute encephalitis. altered consciousness (65%), personality change (45%), and
A relapsing neurologic syndrome has also been described in a hallucinations (16%) (102). Because the base of the brain is
few individuals (94). often affected by M. tuberculosis, signs referable to cranial
nerves are often seen along with fever, headache, irritability,
and drowsiness. Diffuse meningeal irritation may also result
Nipah Virus in impairment of CSF resorption with accompanying hydro-
Nipah virus, another emerging paramyxovirus, was first rec- cephalus (see Chapter 29).
ognized in 1999 and associated with an encephalitis outbreak
among pig farmers in Malaysia. This virus has also caused Listeria monocytogenes
outbreaks in Singapore, Australia, Bangladesh, and India
(9597). Human infections can range from asymptomatic in- Unlike S. pneumoniae and N. meningitidis that rarely cause
fection to fatal encephalitis. When neurologic illness occurs, parenchymal brain infections, Listeria monocytogenes has tro-
individuals often experience influenza-like illness followed by pism for the brain parenchyma itself as well as the meninges
dizziness, excess drowsiness, and altered consciousness. (103). The most common CNS manifestation of listeriosis is
of an isolated meningitis, but approximately 10% of patients
present with brainstem encephalitis, encephalitis, diffuse cere-
Measles Virus britis, or abscess in cerebral cortex or spinal cord (104). In the
Measles virus infection causes acute encephalitis in approxi- French study cited earlier, L. monocytogenes was the fourth
mately 1 in 1,000 cases, often resulting in permanent brain most common etiology identified (101). Reported risk factors
injury (see Chapter 8). Although indigenous transmission of for CNS Listeria include male gender, immunosuppression,
measles was eliminated in the United States in 2000, it is chronic illness, and advanced age (35,105108). Conversely,
still a common infection in much of the world. In addition an in-depth review of Listeria rhombencephalitis found that
to acute encephalitis, measles is associated with subacute it was reported primarily in healthy, nonimmunosuppressed
sclerosing panencephalitis (SSPE), an indolent, progressive, middle-aged adults and affected both genders equally (109).

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88 Part II: Viral Infections and Related Disorders

Clinically, a biphasic disease course may be seen; a nonspecific B. procyonis occurs in raccoons in North America, Europe,
prodrome lasting several days is typical of the first phase. The and parts of Asia (119). More than 90% of juvenile raccoons
prodrome itself is similar to many viral illnesses with fever, are infected in some areas of the United States (118). Humans
headache, nausea, and vomiting, but the duration of prodrome become infected by ingesting raccoon roundworm eggs in rac-
is longer in CNS Listeria illnesses compared with viruses. The coon feces, by soil or water contaminated with raccoon feces,
second phase is characterized by progressive asymmetric cra- or via contaminated hands. Small children are particularly vul-
nial nerve palsies, cerebellar signs (e.g., ataxia or dysmetria), nerable to infection because of their propensity to place dirt
hemiparesis, and altered level of consciousness (109). and other objects in their mouths.
Other important neurotropic helminthes associated with
Treponema pallidum eosinophilic encephalitis or meningitis includes G. spinigerum
and Angiostrongylus species. Gnathostomiasis, most com-
Treponema pallidum, the cause of syphilis, is yet another bac-
monly caused by the nematode G. spinigerum, is a cause of
terial infection that can potentially be confused with CNS viral
eosinophilic myeloencephalitis. G. spinigerum is endemic in
etiologies. Syphilis, also known as the great mimicker, can be
Southeast Asia and is increasingly being recognized in Central
difficult to recognize; this is particularly true for neurologic pre-
and South America (120,121). Most cases are associated with
sentations. Neurologic manifestations can occur during any stage
the ingestion of raw or undercooked fish, frogs, snakes, chick-
of the infection and include meningeal syphilis, meningovascular
ens, or ducks. The median time from ingestion of infected food
syphilis, paretic neurosyphilis, and tabes dorsalis (see Chapter 38).
to onset of symptoms may be several weeks to several months
(122). Common early symptoms may include sporadic epi-
Borrelia Species sodes of cutaneous larva migrans (creeping eruption) with
Borrelia burgdorferi, the causative agent of Lyme disease, is localized pain and pruritus. When CNS involvement occurs,
primarily endemic to the eastern United States, although reser- it may result in the sudden onset of radicular pain or head-
voirs are also present in the Pacific Northwest and Midwestern ache. Paralysis of the extremities and loss of bladder control
states. Notably, the geographic range is expanding. Lyme dis- may also occur (123). Cranial nerve abnormalities are also de-
ease can affect both the peripheral and central nervous system; scribed. Intermittent symptoms can occur for 10 to 15 years
CNS involvement is typically characterized by meningitis, al- after exposure because the larvae are long lived (124).
though encephalitis can rarely occur (see Chapter 39). A. cantonensis, the rat lungworm, is the principal cause
of human eosinophilic meningitis worldwide, and although
many cases are self-limiting, severe forms of the disease
Rickettsia occur (125,126). Angiostrongylus spp. have been reported
in Louisiana and Hawaii as well as the South Pacific, Asia,
Rickettsial infections can also cause encephalitis. Of the rick- Australia, and the Caribbean (127,128). Humans become in-
ettsial diseases, Rocky Mountain spotted fever (RMSF) and fected by ingestion of the third stage larvae in the molluscan
epidemic typhus are most commonly associated with neuro- intermediate host (e.g., snails, crabs, freshwater prawns) or
logic manifestations (110). In patients with RMSF, an intense contaminated vegetables. Following ingestion, the larvae pen-
headache along with restlessness, irritability, confusion, and etrate the intestinal wall and reach the CNS via the blood-
delirium often occur. General or focal neurologic impairment stream. Clinical illness often consists of severe headache,
including vertigo, seizures, hemiparesis, and ataxia may also photophobia, meningeal signs, hyperesthesia, and paresthesia.
be present (111). In a study of 92 children hospitalized with Coma, paralysis of extremities, and seizures are seen in the se-
RMSF in the southeastern and south central United States from vere forms of the disease (125,126). Conjunctivitis, periorbital
1990 through 2002, 33% had altered mental status, 18% pho- swelling, retinal hemorrhage, retinal detachment, or blindness
tophobia, 17% seizures, and 10% coma (112). Ophthalmic may occur if the eye is infected (129,130) (see Chapter 46).
features including photophobia, conjunctivitis, petechiae of Free-living ameba are ubiquitous in nature, and a few have
the bulbar conjunctiva, exudates and retinal venous engorge- been associated with human disease. Those causing encephali-
ment, papilledema, and ocular palsies are frequently described tis are generally divided into two clinical entities: (a) primary
(113,114). Acute temporary hearing impairment may also amebic meningoencephalitis due to Naegleria fowleri (also
occur (115). Similar neurologic complications have also been known as the brain-eating ameba), and (b) granulomatous
described for other rickettsial infections, although generally amebic encephalitis.
are not as severe (116) (see Chapter 27). Primary amebic meningoencephalitis (PAM) is a fulminant
disease occurring in children and young adults. The disease has
been reported in Australia, Europe, Asia, Africa, and North
Parasites and Free-Living Ameba America. In the United States, most of the cases have developed
in the southern tier of the country, where warm water condi-
A number of parasites can cause encephalitis via direct in- tions are more likely to be encountered. Typically, humans be-
vasion of the brain. Helminthes including various ascaris, come infected with N. fowleri while swimming or washing in
hookworms, Gnathostoma spinigerum, Angiostrongylus canto- warm, fresh water containing the ameba. Recent cases associ-
nensis, Spirometra spp., Alaria spp., and others can cause larva ated with the use of neti pots where N. fowlericontaminated
migrans, which refers to the prolonged migration and persis- tap water were implicated as the source of infection have also
tence of helminth larvae in the tissues of humans (117,118). been described (131). The onset of PAM is usually within 2 to
Larva migrans can result in visceral (VLM), ocular (OLM), 3 days after exposure, and symptoms include severe headache,
neural (NLM), and cutaneous larva migrans (CLM) based on fever, stiff neck, nausea, vomiting, diplopia, seizures, behav-
the organ systems involved (118). VLM and NLM are usually ioral changes, and coma (132135). Distortion of taste or smell
diseases of childhood, affecting children ages 1 to 8 years old. may also be a clinical feature (136,137). The case fatality rate
B. procyonis, a common ascarid roundworm in raccoons, is very high; of 111 reported cases in the United States between
causes an eosinophilic encephalitis in humans and other 1962 and 2008, only one individual survived (131).
animals. It is most commonly identified in children and, Two different closely related ameba cause granuloma-
although it is rare, often results in a severe and fatal illness. tous encephalitis: Acanthamoeba spp. and B. mandrillaris.

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Chapter 6: Encephalitis 89

Acanthamoeba granulomatous encephalitis is an opportunistic, poorly understood. Influenza-associated encephalitis (IAE)


chronic disease that may have a prodromal period of weeks to and encephalopathy is typically characterized by a rapidly
months. Predisposing factors to acanthamebiasis include ste- progressive neurologic illness. Cases have been described
roid treatments, autoimmune conditions, organ transplants, sporadically and follow the seasonal influenza pattern, with
chemotherapy, radiation therapy, alcoholism, and pregnancy illnesses typically occurring during winter months in temper-
(134,138). A small number of Acanthamoeba granulomatous ate climates. IAE is more common in the pediatric population
encephalitis cases have been described in immunocompetent than in adults. Evidence of neuroinvasion by influenza is rarely
children. Clinical features of CNS Acanthamoeba infections seen; these cases are better characterized as an encephalopathy
are variable but typically have a subacute to chronic presenta- rather than encephalitis. Many cases of IAE, especially acute
tion with fever, headache, seizures, personality change, leth- necrotizing encephalopathy (ANE), have been reported from
argy, or confusion. Cranial nerve palsies, meningeal signs, or Japan, but cases of encephalitis and encephalopathy have been
hemiparesis may be seen on physical exam (138). Children reported throughout the world, including the United States
infected with Acanthamoeba have exhibited headache, stiff (156,157). Several case reports and case series describe neu-
neck, vomiting, abnormal behavior, fever, ataxia, and tonic- rologic illness associated with the pandemic H1N1 influenza
clonic seizures (139141). virus, including encephalitis/encephalopathy (158160).
When first described, B. mandrillaris was considered Similarly, the neurologic illness associated with Bartonella is
to be very rare, but recent reports suggest it may be more often an encephalopathy rather than encephalitis. Cat-scratch
common than previously recognized (142145). Symptoms disease (CSD), typically caused by Bartonella henselae, is usu-
of Balamuthia granulomatous encephalitis include fever, ally a self-limited infection associated with fever, regional
headache, vomiting, ataxia, hemiparesis, tonic-clonic sei- lymphadenopathy, and malaise. As the name implies, many
zures, cranial nerve palsies (third and sixth cranial nerves), affected individuals have contact with a cat, often a kitten.
and diplopia (146). Otitis media has preceded the onset of Atypical presentations can occur especially in children and
Balamuthia granulomatous encephalitis in several pediat- young adults and immunocompromised individuals. In a case
ric cases (146,147). Hydrocephalus develops in many cases series of 130 CSD cases in Japan, 19 (15%) had encepha-
(147,148). Interestingly, two independent case reports involv- lopathy (161). Although lymphadenopathy is a hallmark of
ing Balamuthia encephalitis patients describe associated CNS CSD, it is not always present in encephalopathy cases (161).
aneurysms (149,150) (see Chapter 45). Neuroretinitis can be an associated feature as well (162).

Fungi ACUTE DISSEMINATED


Although fungal CNS infections do not cause encephalitis per ENCEPHALOMYELITIS
se and often manifest as meningitis and abscesses, some pa-
tients present with encephalitis-like symptoms. These illnesses The incidence of acute disseminated encephalomyelitis
are more common in immunocompromised individuals, but (ADEM) is estimated to be 0.4 to 0.8 per 100,000 and it ac-
fungal neurologic infections can be seen in immunocompetent counts for 10% to 15% of encephalitis cases in the United
individuals. Important fungal causes of CNS infections in the States (163165). It is more common in children than adults,
United States include Cryptococcus neoformans, Coccidioides and many cases of ADEM have an identifiable trigger such
immitis, Histoplasma capsulatum, and Blastomyces dermatiti- as a recent illness or vaccination. Neurologic symptoms typi-
dis. Cryptococcus gattii is an emerging fungal infection in the cally develop 2 to 4 weeks after the trigger with rapid pro-
United States, particularly in the Pacific Northwest, and has gression of symptoms (165). Prior to the widespread use of
a greater tendency to affect normal hosts than Cryptococcus vaccine-preventable diseases in the United States, measles and
neoformans (151) (see Chapter 40). mumps were common triggers of ADEM. In regions of the
world where vaccines are widely used to prevent measles and
mumps, such as the United States and Canada, upper respira-
Other Agents tory infections are now the most commonly identified triggers
of ADEM.
Hundreds of other infectious agents have been associated with ADEM affects multiple regions of the brain and spinal cord
encephalitis, but the frequency and significance of many of and is characterized by the rapid onset of encephalopathy
them are unknown. This is especially true when a nonneu- along with multifocal neurologic deficits. Up to three quar-
rotropic agent is found in a patient with encephalitis, par- ters of patients with ADEM will have altered mental status,
ticularly when the agent is identified outside the CNS. For whereas seizures occur in 10% to 35% of patients (165).
example, Mycoplasma pneumoniae is one of the most com- Motor deficits (e.g., acute hemiparesis), ataxia, decreased ver-
monly diagnosed infections among children with encephalitis bal output or mutism, cranial neuropathies, and urinary disor-
(see Chapter 25). However, the significance of this association ders are common (166). Recovery can be complete, although
is unclear, particularly as most of the diagnoses are based on residual deficits can occur in up to 30% of patients.
a positive immunoglobulin M (IgM) antibody to M. pneu-
moniae. M. pneumoniae is a ubiquitous pathogen, and there is
a high background incidence of acute infection. Furthermore, NONINFECTIOUS ETIOLOGIES
there are many limitations of Mycoplasma serologic test-
ing (152). Other similar examples of nonneurotropic agents There is growing recognition that immune-mediated condi-
implicated as causative agents include parvovirus B19, rotavi- tions result in a substantial proportion of cases of encephalitis.
rus, and human metapneumovirus (153155). AntiN-methyl-d-aspartate receptor (NMDAR) encephalitis,
Although the association of influenza viruses and en- a relatively newly recognized neuronal antibody-associated
cephalitis is better documented and more accepted than encephalitis, deserves special mention because of the seemingly
parvovirus B19, rotavirus, or human metapneumovirus, the high frequency of the syndrome. In the California Encephalitis
mechanism by which influenza leads to neurologic illness is Project, the frequency of anti-NMDAR encephalitis surpasses

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90 Part II: Viral Infections and Related Disorders

that of any single viral entity in the pediatric population and patients with bacterial meningitis and rickettsial infections where
also contributes to cases in adulthood (167). associated vasculitis and elaboration of toxins can lead to CNS
Clinically, anti-NMDAR encephalitis is characterized by ab- dysfunction. Intense inflammatory responses to fungi, free-living
normal behavior, seizures, and movement disorders followed by ameba, and parasites can also lead to CNS dysfunction.
decreased level of consciousness and autonomic instability and Organisms enter the CNS by different routes. Most enter via
may be associated with ovarian teratoma (168). Importantly, the the bloodstream, as is the case for EVs, HPeVs, and arboviruses as
development of prodromal symptoms of headache, low-grade well as several bacteria, rickettsia, and fungal agents (171). Once
fever, or a nonspecific viral-like illness prior to the onset of neuro- the agent reaches the CNS, the bloodbrain barrier is penetrated
logic symptoms in many patients may initially suggest the diagno- via the choroid plexus or through vascular endothelium (172).
sis of an infectious, rather than autoimmune, encephalitis (168). The proposed mechanism for entry into brain of the ame-
Another important cause of immune-mediated encephalitis bae varies by organism. For example, Balamuthia is thought to
is antivoltage-gated potassium channel (VGKC) encephalitis. enter the CNS via a hematogenous route, with ameba entering
Patients are typically older than 50 years of age, present with the bloodstream either from the lungs or from cutaneous lesions.
symptoms of limbic encephalitis (memory dysfunction, be- Naegleria ameba, on the other hand, enter the nasal passages
havioral changes, and seizures) and hyponatremia, and rarely and directly extend into the CNS by penetrating the olfactory
have an underlying neoplasm. Although antibodies were ini- mucosa, entering the submucosal nervous plexus, migrating
tially thought to recognize the VGKC receptor, subsequent along the olfactory nerves, and traversing the cribriform plate. A
studies have demonstrated that the target of autoimmunity distinct mechanism of entry via axon transport resulting in intra-
is usually a different antigen (i.e., LGI1 or CASPR2) that is neuronal route is used by some viruses such as rabies and HSV-1.
tightly associated with the VGKC complex (168,169). Several Within the CNS, the pathogen often targets specific cells
other antibodies are also associated with limbic encephalitis, and, depending on the brain region affected, variable clinical
including those that recognize glutamic acid decarboxylase manifestations ensue (173). Agents with specific predilection to
(GAD), AMPA receptor, and the -aminobutyric acid (GABAb) areas such as the brainstem (e.g., EV-71 and Listeria) can cause
receptor. Intracellular onconeural antibodies associated with rapid decompensation with coma or respiratory failure. Herpes
paraneoplastic conditions (e.g., anti-Hu, Yo, Ma2, CV2, simplex encephalitis characteristically affect the temporal lobes
amphiphysin, CRMP5, etc.) also need to be considered (170). and cause hemorrhage and necrotizing lesions (174) (Fig. 6.2).
WNND has a predilection for the gray matter of the brain-
stem and spinal cord, but cerebellum, temporal lobe, basal gan-
PATHOLOGY glia, and thalamus may also be affected (175). Indeed, many of
the neuroinvasive flaviviruses such as JEV, TBEV, and WNV
Given the many different etiologies of encephalitis, the pathol- have a predilection for specific regions of the brain, including
ogy is highly variable and dependent not only on the under- those regions important for motor control (thalamus, basal
lying etiology but also the relative severity of the infection. ganglia, brainstem, and anterior horn cells of spinal cord) (176).
The characteristic histology of patients with viral encephalitis In other instances, the infectious agents do not necessarily in-
includes perivascular mononuclear cell inflammation, phago- fect neurons. Nonneuronal cells, such as oligodendroglia, may
cytosis of neurons, and microglial nodules. Distinctive char- be infected, with resultant demyelination (177). Alternatively, an
acteristic histopathologic features are seen with some viral infection may cause immune changes that result in damage. EBV-
infections; intranuclear inclusion bodies are sometimes seen in associated encephalitis, for example, may be a result of an im-
herpes simplex and varicella zoster, whereas Negri bodies (eo- munologic phenomena rather than acute neuroinvasion. There is
sinophilic cytoplasmic inclusions) are found within Purkinje typically a 1- to 3-week delay in the onset of neurologic symptoms
cells and are pathognomonic for rabies (Fig. 6.1). after acute EBV infection (40). Further, the virus itself is often not
EVs, parechoviruses, herpesviruses, arboviruses, and rabies found in the CSF (40). In one cohort of five EBV encephalitis pa-
have well-established neurotropic potential where the virus di- tients with CNS demyelination, four had prodromal symptoms
rectly invades the CNS and primarily affects the gray matter of the for 2 weeks or more and did not have EBV detected by polymerase
brain. Other viruses, such as measles and rubella viruses, primarily chain reaction (PCR) in CSF (40). Conversely, the development of
affect the white matter of the brain by triggering an autoimmune neurologic symptoms either in the absence of, or within a few days
reaction and result in a postinfectious encephalitis (e.g., ADEM). of prodrome onset in the presence of, EBV in the CSF is suggestive
Symptoms indistinguishable from viral encephalitis can be seen in of direct invasion. In the pediatric series cited previously, one such

FIGURE 6.1 Rabies encephalitis. Purkinje cell in cerebellum


with eosinophilic, intra-cytoplasmic inclusion (Negri body).
(Courtesy of Dr. Andrew Bollen, University of California, San
Francisco.)

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Chapter 6: Encephalitis 91

FIGURE 6.2 Herpes simplex encephalitis. Herpes simplex type


1 encephalitis with hemorrhage and necrosis of the right tempo-
ral lobe. (Courtesy of Dr. Andrew Bollen, University of California,
San Francisco.)

patient had EBV detected by PCR in brain tissue, suggesting that necrotic lesions. Multinucleated giant cells, focal necrosis,
direct invasion of the brain may occur in some cases. and hemorrhage are seen in brain histopathology. In some
Viruses such as influenza are well known to be associated instances, large sheets of ameba can be found in the perivascu-
with CNS manifestations, but the mechanisms by which they lar areas of brain tissue (Fig. 6.3).
cause neurologic signs and symptoms are not well under- B. procyonis and other nematodes that invade the CNS
stood. The lack of viral detection in most IAE cases in the cause damage by CNS larval migration, with histology demon-
CNS strongly points to a different pathogenesis; a number of strating inflammation and necrosis with track-like spaces.
potential mechanisms have been invoked, including excessive Pathologic findings of fatal cases demonstrate necrosis and
production of proinflammatory cytokines, vascular endothe- inflammation with eosinophils, macrophages, lymphocytes,
lial dysfunction, and mitochondrial dysregulation (178). and plasma cells concentrated in periventricular white matter
As discussed earlier, Listeria may be associated either with and leptomeninges in brain tissue. A characteristic of NLM/
a pure meningitis or encephalitis. Pathologically, a suppurative Baylisascaris infection is a large number of eosinophils and eo-
reaction is seen in the meningitic form, whereas a granuloma- sinophil granules surrounding the nematode migration track
tous response is seen in the meningoencephalitis form (104). and blood vessels (183).
Rickettsial agents invade and multiply in vascular endothe-
lial cells, leading to vasculitis both within and outside the CNS
(179,180). Vasculitis in the small vessels in the brain leads to DIAGNOSTIC APPROACH OF
meningeal irritation with perivascular mononuclear infiltrates. PATIENTS WITH ENCEPHALITIS
Characteristic pathologic lesions within the CNS include mul-
tifocal glial nodules and arteriolar microinfarctions (181). Identification of a specific etiology, even if there is no available
In partially treated bacterial meningitis and in tuberculous treatment, is important for counseling of patients and fami-
and fungal meningitis, a chronic basilar meningeal inflamma- lies, potential postexposure prophylaxis of contacts, and other
tion can cause a subarachnoid exudate, leading to obstruction public health interventions. Additionally, the identification of
of CSF reabsorption with resultant communicating hydro- a specific agent may lead to withdrawal of unnecessary an-
cephalus and cranial nerve palsies. CNS vasculitis can also timicrobial agents and reduce further testing. Knowledge of
lead to infarcts and focal neurologic deficits. limitations of testing, appropriate test selection, and timing of
N. fowleri, a free-living ameba, causes destruction of gray sample collection is crucial to optimal diagnosis.
matter and devastation of the olfactory bulbs with purulent A thorough assessment of exposures highlighting ill contacts,
meningitis and pronounced brain edema (182). In Balamuthia occupational exposures, vector and animal exposures, outdoor
and Acanthamoeba CNS infections, a granulomatous reaction activities, and ingestions should be ascertained. Both recent (e.g.,
occurs with affected areas including the cerebrum, cerebel- for arbovirus) and remote (e.g., rabies, fungal) travel history are
lum, and brainstem, where the amebae produce hemorrhagic important. Any recent or current respiratory, gastrointestinal,

FIGURE 6.3 Histopathology of B. mandril-


laris infections: (A) Brain tissue stained with
hematoxylin and eosin (100) showing B. man-
drillaris. Note that these B. mandrillaris organisms
may be mistaken for lymphocytes or macrophages.
(B) Higher magnification (1000) demonstrat-
ing trophozoites of B. mandrillaris in brain tis-
sue, some with single nucleolus (dotted arrow) or
double nucleoli (solid arrow). (Courtesy of Dr.
A B Govinda Visvesavara, Centers for Disease Control
and Prevention.)

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92 Part II: Viral Infections and Related Disorders

TA B L E 6 . 1
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN ADULTS

Routine Studies

CSF

Collect at least 20 mL fluid, if possible; freeze at least 510 mL fluid, if possible


Opening pressure, WBC count with differential, RBC count, protein, glucose
Gram stain and bacterial culture
HSV-1/HSV-2 PCR (if test available, consider HSV CSF IgG and IgM in addition)
VZV PCR (sensitivity may be low; if test available, consider VZV CSF IgG and IgM in addition)
Enterovirus PCR
Cryptococcal antigen and/or India ink staining
Oligoclonal bands and IgG index
VDRL

Serum

Routine blood cultures


HIV serology (consider RNA)
Treponema testing (RPR, specific treponemal test)
Hold acute serum and collect convalescent serum 1014 days later for paired antibody testing

Imaging

Neuroimaging (MRI preferred to CT, if available)


Chest imaging (chest x-ray and/or CT)

Neurophysiology

EEG

Other Tissues/Fluids

When clinical features of extra-CNS involvement are present, we recommend additional testing (e.g., biopsy of skin lesions,
bronchoalveolar lavage and/or endobronchial biopsy in those with pneumonia/pulmonary lesions, throat swab PCR/culture in
those with upper respiratory illness, stool culture in those with diarrhea); also see below.

Conditional Studies

Host Factors

ImmunocompromisedCMV PCR, HHV-6/HHV-7 PCR, HIV PCR (CSF); Toxoplasma gondii serology and/or PCR;
Mycobacterium tuberculosis testing; fungal testing; WNV testing

Geographic Factors

Africamalaria (blood smear), trypanosomiasis (blood/CSF smear, serology from serum and CSF), dengue testing
AsiaJapanese encephalitis virus testing, dengue testing, malaria (blood smear), Nipah virus testing (serology from serum and CSF;
PCR, immunohistochemistry, and virus isolation in a BSL4 lab can also be used to substantiate diagnosis)
AustraliaMurray Valley encephalitis virus testing, Kunjin virus testing, Australian bat Lyssavirus (ABLV) testing
Europetick-borne encephalitis virus (TBEV) (serology); if southern Europe, consider WNV testing, Toscana virus testing
Central and South Americadengue testing, malaria (blood smear), WNV testing, Venezuelan equine encephalitis testing
North Americageographically appropriate arboviral testing (e.g., WNV, Powassan, La Crosse, eastern equine encephalitis viruses,
Lyme [serum ELISA and Western blot])

(continued)

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Chapter 6: Encephalitis 93

TA B L E 6 . 1
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN ADULTS (CONTINUED)

Conditional Studies

Season and Exposure

Summer/fallarbovirus and tick-borne disease testinga


Cat (particularly if with seizures, paucicellular CSF)Bartonella antibody (serum), ophthalmologic evaluation
Tick exposuretick-borne disease test a
Animal bite/bat exposurerabies testing
Swimming or diving in warm freshwater or nasal/sinus irrigationNaegleria fowleri (CSF wet mount and PCR)

Specific Signs and Symptoms

Psychotic features or movement disorderanti-NMDAR antibody (serum, CSF); rabies testing; screen for malignancy, Creutzfeldt-
Jakob disease
Prominent limbic symptomsautoimmune limbic encephalitis testing; HHV-6/HHV-7 PCR (CSF); screen for malignancy
Rapid decompensation (particularly with animal bite history or prior travel to rabies-endemic areas)rabies testing
Respiratory symptoms Mycoplasma pneumoniae serology and throat PCR (if either positive, then do CSF PCR); respiratory virus testing
Acute flaccid paralysisarbovirus testing, rabies testing
Parkinsonismarbovirus testing, Toxoplasma serology
Nonhealing skin lesionsBalamuthia mandrillaris, Acanthamoeba testing

Laboratory Features

Elevated transaminasesrickettsia serology, tick-borne diseases testinga


CSF protein 100mg/dL, or CSF glucose 2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset
M. tuberculosis testing, fungal testing
CSF protein 100 mg/dL or CSF glucose 2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and
recent antibiotic useCSF PCR for Streptococcus pneumoniae and Neisseria meningitidis
CSF eosinophiliaM. tuberculosis testing, fungal testing, Baylisascaris procyonis antibody (serum), Angiostrongylus cantonensis and
Gnathostoma sp. testing
RBCs in CSFNaegleria fowleri testing
Hyponatremiaanti-VGKC antibody (serum); M. tuberculosis testing

RBC, red blood cell; VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; EEG, electroencephalogram; CMV, cytomegalovirus.
a
Tick-borne disease testing should be tailored to specific geographic region and typically consists of serology (i.e., Borrelia, Ehrlichia, Rickettsia sp.,
Anaplasma phagocytophilum, TBEV) and blood PCR (Ehrlichia, Anaplasma).
Data from Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the
International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):11141128.

or rash illness should be investigated. Based on this information, neutrophils degrade within a few hours (186). Additionally, if
specific assays can be performed (Tables 6.1 and 6.2) (184). the CSF cell counts are performed by an automated cell counter,
A complete blood count, renal function tests, hepatic enzyme eosinophils can be mistaken for neutrophils. Accurate identifica-
levels, and coagulation studies should be included in the evalua- tion of eosinophils is best done by Giemsa or Wright stain of CSF
tion of a patient with suspected encephalitis. An initial chest radio- (128). The identification of CSF oligoclonal bands, representing
graph should also be performed as focal infiltrates are suggestive intrathecal antibody synthesis, is a nonspecific finding but can be
of certain pathogens (e.g., fungal or mycobacterial infections) and helpful in corroborating an infectious or inflammatory etiology.
might lead to other diagnostic studies (e.g., bronchoscopy). A The CSF profile offers important diagnostic clues on
thorough eye exam by an ophthalmologist may identify a migra- whether a patient has an infectious or noninfectious etiology
tory nematode which would considerably narrow the differential. and, within the infectious sphere, whether the cause is likely
Unless there is a specific contraindication, a lumbar puncture viral, bacterial, fungal, or parasitic. The CSF profile in most
(LP) with cerebrospinal fluid (CSF) analysis (cell count with dif- viral encephalitis patients demonstrates CSF mononuclear
ferential analysis, glucose and protein concentrations) and a mea- cell pleocytosis, with cell counts ranging from 10 to 200 mg/
surement of the opening pressure should be performed (185). A dL. However, several studies have shown that pleocytosis can
simultaneous peripheral glucose should also be measured and is be absent or there may be an elevation in neutrophils early
particularly important in a diabetic patient because what appears in the course. Although many textbooks mention that poly-
to normal CSF glucose might actually be low if the ratio of morphonuclear leukocytes (PMNs) can predominate the first
CSF to serum glucose is not taken into consideration (102). The 24 hours of viral CNS infections and suggest that a shift to
CSF sample should be analyzed promptly, particularly because mononuclear cells occurs after that time period, there have

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94 Part II: Viral Infections and Related Disorders

TA B L E 6 . 2
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN CHILDREN

Routine Studies

CSF

Collect at least 5 mL fluid, if possible; freeze unused fluid for additional testing
Opening pressure, WBC count with differential, RBC count, protein, glucose
Gram stain and bacterial culture
HSV-1/HSV-2 PCR (if test available, consider HSV CSF IgG and IgM in addition)
Enterovirus PCR

Serum

Routine blood cultures


EBV serology (VCA IgG and IgM and EBNA IgG)
Mycoplasma pneumoniae IgM and IgG
Hold acute serum and collect convalescent serum 1014 days later for paired antibody testing

Imaging

Neuroimaging (MRI preferred to CT, if available)


Neurophysiology
EEG
Other Tissues/Fluids
M. pneumoniae PCR from throat sample
Enterovirus PCR and/or culture of throat and stool
When clinical features of extra-CNS involvement are present, we recommend additional testing (e.g., biopsy of skin lesions,
bronchoalveolar lavage and/or endobronchial biopsy in those with pneumonia/pulmonary lesions, throat swab PCR/culture in
those with upper respiratory illness, stool culture in those with diarrhea); also see below.

Conditional Studies

Host Factors

Age younger than 3 yearsparechovirus PCR (CSF)


ImmunocompromisedCMV PCR, HHV-6/HHV-7 PCR, HIV PCR (CSF); cryptococcal antigen; Toxoplasma gondii serology and/or
PCR; Mycobacterium tuberculosis testing; fungal testing; WNV testing

Geographic Factors

Africamalaria (blood smear), trypanosomiasis (blood/CSF smear, serology from serum and CSF), dengue testing
AsiaJapanese encephalitis virus testing, dengue testing, malaria (blood smear), Nipah virus testing (serology from serum and CSF;
PCR, immunohistochemistry, and virus isolation in a BSL4 lab can also be used to substantiate diagnosis)
AustraliaMurray Valley encephalitis virus testing, Kunjin virus testing, Australian bat Lyssavirus (ABLV) testing
Europetick-borne encephalitis virus (TBEV) (serology); if Southern Europe, consider WNV testing, Toscana virus testing
Central and South Americadengue testing, malaria (blood smear)
North Americageographically appropriate arboviral testing (e.g., WNV, Powassan, La Crosse, eastern equine encephalitis viruses,
Lyme [serum ELISA and Western blot])

Season and Exposure

Summer/fallarbovirus and tick-borne disease testinga


Cat (particularly if with seizures, paucicellular CSF)Bartonella antibody (serum), ophthalmologic evaluation
Tick exposuretick-borne disease testa
Animal bite/bat exposurerabies testing
Swimming or diving in warm freshwater or nasal/sinus irrigationNaegleria fowleri (CSF wet mount and PCR)

(continued)

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Chapter 6: Encephalitis 95

TA B L E 6 . 2
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN CHILDREN (CONTINUED)

Conditional Studies

Specific Signs and Symptoms

Abnormal behavior (e.g., new-onset temper tantrums, agitation, aggression), psychotic features, seizures, or movement disorder
anti-NMDAR antibody (serum, CSF), oligoclonal bands, IgG index, rabies testing
Behavior changes followed by myoclonic spasms/jerksmeasles IgG (CSF and serum)
Vesicular rashVZV PCR from CSF (sensitivity may be low; if test available, consider CSF IgG and IgM), VZV IgG and IgM from serum
Rapid decompensation (particularly with animal bite history or prior travel to rabies-endemic areas)rabies testing
Respiratory symptomschest imaging (chest x-ray and/or CT scan), respiratory virus testing, Mycoplasma pneumoniae PCR (CSF)
Acute flaccid paralysisarbovirus testing, rabies testing
Parkinsonismarbovirus testing, Toxoplasma serology
Nonhealing skin lesionsBalamuthia mandrillaris, Acanthamoeba testing
Prominent limbic symptomsautoimmune limbic encephalitis testing, HHV-6/HHV-7 PCR (CSF)

Laboratory Features

If EBV serology is suggestive of acute infection, perform EBV PCR (CSF)


Elevated transaminasesrickettsia serology, tick-borne diseases testinga
CSF protein 100 mg/dL, or CSF glucose 2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset
M. tuberculosis testing, fungal testing, Balamuthia mandrillaris testing
CSF protein 100 mg/dL or CSF glucose 2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and
recent antibiotic useCSF PCR for Streptococcus pneumoniae and Neisseria meningitidis
CSF eosinophiliaM. tuberculosis testing, fungal testing, Baylisascaris procyonis antibody (serum), Angiostrongylus cantonensis and
Gnathostoma sp. testing
HyponatremiaM. tuberculosis testing
M. pneumoniae serology or throat PCR positiveM. pneumoniae PCR (CSF)

RBC, red blood cell; VCA, viral capsid antigen; EBNA, Epstein-Barr nuclear antigen; EEG, electroencephalogram; CMV, cytomegalovirus.
a
Tick-borne disease testing should be tailored to specific geographic region and typically consists of serology (i.e., Borrelia, Ehrlichia, Rickettsia sp.,
Anaplasma phagocytophilum, TBEV) and blood PCR (Ehrlichia, Anaplasma).
Adapted from Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of
the International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):11141128.

been studies showing that PMNs may still predominate well increased protein content (75 to 970 mg/dL). The amebae
beyond this 24-time period (187). Therefore, a repeat LP a few can sometimes be seen in wet-mount preparations of spinal
days following the first LP may be useful (188,189). In viral fluid (139,140,190). In patients with CNS Balamuthia infec-
encephalitis, the CSF protein generally is elevated but is typi- tions, elevated CSF WBC is often seen along with mild to
cally less than 100 mg/dL, whereas the glucose level is almost markedly elevated protein (1,000 mg/dL) and normal or
always normal with a few important exceptions (e.g., LCM slightly decreased glucose.
and mumps; Table 6.3). Although brain biopsy in the setting of suspected enceph-
As outlined earlier, viral infections can sometimes be associ- alitis has become less common, examination of brain tissue
ated with a neutrophilic predominance; however, when a neu- still has utility because of limitations in both molecular and
trophilic pleocytosis is observed, particularly in cases where serologic methods. The use of targeted biopsy was recently
CSF white blood cell (WBC) count is more than 1,000 cells/ demonstrated by a report of 16 patients with undiagnosed
mm3, protein more than 100 mg/dL, or CSF glucose level less CNS illness where brain biopsy detected bacterial abscess (6),
than 2/3 of serum levels, a nonviral entity should be strongly toxoplasmosis (3), HSV (1), Aspergillus infection (2), and M.
considered. For most bacterial pathogens, the CSF shows a tuberculosis infection (2). Biopsies can also be particularly
WBC of 1,000 to 5,000 cells/mL with predominance of neu- helpful for the diagnosis of noninfectious entities such as small
trophils (80% to 95%), glucose less than 40 mg/dL in over half vessel vasculitis and intravascular lymphoma (191). An au-
the cases, and a CSF glucose level less than 2/3 serum levels. topsy should be encouraged to determine the cause of death in
In fungal infections, moderate lymphocytic pleocytosis usually patients who die with unexplained encephalitis.
is found along with elevated protein and low CSF glucose. In addition to studies done acutely, an extra red top serum
Eosinophils in the CSF are suggestive of a helminth infec- tube should be drawn during the acute phase of illness and
tion (e.g., B. procyonis, Angiostrongylus spp., and G. spi- held for later serologic studies. A convalescent serum should
nigerum). Eosinophils can also be seen in patients with be collected 10 to 21 days later. Similarly, extra spinal fluid
neurococcidiomycosis or neuro-Mycobacterium tuberculosis. should also be frozen for future testing. Specific caveats of test-
In patients with PAM, the CSF typically contains a very high ing are outlined in Table 6.3 and selected agents are outlined in
CSF cell count with a predominance of neutrophils, a slight the following sections.
to pronounced decrease in glucose concentration, and an Text continues on page 100

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96 Part II: Viral Infections and Related Disorders

TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES

Agent Recommended Diagnostic Studies Laboratory Findings; Limitations and Caveats

Viral Many CNS viral infections result in a mild CSF pleocytosis


(typically with a monocytic cell predominance but PMNs may
predominate, especially early in course); CSF protein normal to
mildly elevated (100 mg/dL) and normal glucose

Adenovirus CSF, respiratory, brain tissue PCR Pathogen of unknown neurologic potential
or culture CSF PCR testing rarely positive
Arboviruses Serology is the best assay for most PCR often negative due to acute viremia stage often completed
arboviruses: CSF IgM, serum IgM by the time of clinical presentation
and IgG (paired sera if possible) PCR may be helpful in immunocompromised host or very early
for specific viruses as suggested in clinical course.
by geography: CSF IgG for specific arbovirus usually not helpful because
West Nile virus (WNV) bloodbrain barrier integrity may be compromised; CSF blood
California serogroup viruses (e.g., contamination can cause false-positive results for both IgM
La Crosse virus [LACV]) and IgG.
Eastern equine encephalitis virus IgM can persist for several months and sometimes 1 year;
(EEEV) more likely to persist in serum, but persistence has also been
Powassan virus (POWV) described in CSF.
St. Louis encephalitis virus Serologic cross-reactivity among arbovirus of same family
(SLEV) (WNV, SLEV, and POWV antibodies cross-react; e.g.,
Western equine encephalitis virus individual with prior dengue infection will test positive for
(WEEV) WNV IgG)
Antibody typically positive early in presentation but if
negative, repeat on later specimen
WNV: PMNs can persist in CSF.
WNV: Reactive lymphocytes in CSF (e.g., Mollaret-like cells)
have also been described.
EEEV: CSF WBC counts may be similar to bacterial meningitis
(e.g., counts up to 4,000/mm3 described).
POWV testing only available at CDC and a few state
laboratories
Cytomegalovirus (CMV)a CSF PCR Serology can be problematic; false-positive IgM not uncommon
PCR: false positive (consider if viral load is low); CMV in CSF
also seen presumably because of latent infection
Atypical lymphocytes in CSF
Enteroviruses (EV) CSF PCR Testing of EV PCR on CSF alone may miss infection because
Respiratory PCR EV present only transiently in CSF; test non-CNS site
Stool PCR or culture (respiratory sample PCR, viral stool culture) to increase yield.
Epstein-Barr virus (EBV) CSF PCR Both serology (serum) and PCR (CSF) for EBV is recommended.
Serum: anti-VCA IgM/IgG, anti- Heterophil low sensitivity in children younger than 5 years of age
EBNA PCR false positives can occur if EBV-infected (latent)
Heterophil mononuclear cells present
EBV CSF PCR can be negative in true cases because of
either timing of LP (late) or mechanism other than direct
neuroinvasion.
Atypical lymphocytes in CSF or peripheral blood is consistent
with EBV but not always present.
Hepatitis C virus CSF PCR Pathogen of unknown neurotropic potential
Herpes simplex virus 1 CSF PCR HSV-1 causes the majority of HSE (outside neonatal period).
(HSV-1) Intrathecal antibody if 1 week ~5%10% of HSE patients have a normal CSF formula in the
of symptoms first LP, particularly in children.
False-negative PCRs occur; if clinical suspicion for HSE,
consider repeat lumbar puncture early in the course of illness
to repeat CSF HSV PCR and intrathecal HSV antibody testing
Presence of either IgG or IgM may be indicative of CNS
infection; however, bloodbrain barrier integrity and CSF-
blood contamination needs to be considered when interpreting
results

(continued)

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Chapter 6: Encephalitis 97

TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES (CONTINUED)

Agent Recommended Diagnostic Studies Laboratory Findings; Limitations and Caveats

Herpes simplex virus 2 CSF PCR Presence of either IgG or IgM may be indicative of CNS
(HSV-2) Intrathecal antibody if 1 week infection; however, bloodbrain barrier integrity and CSF-
of symptoms blood contamination needs to be considered when interpreting
results
Human herpes virus 6 CSF PCR Pathogen of unknown neurologic potential
(HHV-6) (Quantitative blood PCR if Not all positive HHV-6 CSF PCR results correlate with disease;
CSF positive to determine when positive, important to consider chromosomal integration
chromosomal integration) or latent infection
Human herpes virus 7 CSF PCR Unknown frequency of CNS illness
(HHV-7) Pathogen of unknown neurologic potential; detection of virus
may represent acute disease but could also represent latent
virus.
HIV ELISA and Western blot (single
serum)
Plasma and CSF PCR
Human Respiratory tract (NP or throat) Pathogen of unknown neurologic potential
metapneumovirus PCR CSF PCR rarely positive
Influenza A/B virus Respiratory viral culture PCR of CSF rarely positive
Respiratory viral antigen test PCR on respiratory specimens more sensitive and specific than
Respiratory PCR (if above antigen assays
negative) Most cases are encephalopathy (vs. encephalitis).
JC virusa CSF PCR A positive result corroborates diagnosis; negative result does
not rule it out.
Lymphocytic CSF IgM/IgG CSF profile may resemble bacterial etiology (e.g., CSF WBC
choriomeningitis Serum IgM/IgG sometimes 3,000, PMNs predominance, low glucose and/or
(LCM) virus very elevated proteins).
One of the few viruses that can decrease glucose in CSF
Measles virusacute CSF antibodies CNS illness occurs ~1 week after fever/rash.
CSF PCR Measles PCR and antibody testing (serum and CSF)
Serum IgG/IgM (paired serumb
samples if possible)
Brain tissue PCR
Measles virusSSPEc CSF IgG antibodies Incubation period several years
Serum IgG antibodies Because SSPE is a result of long-standing infection, IgM will be
Brain tissue PCR negative; IgG levels in both CSF and serum very high
Measles CSF PCR rarely positive, PCR brain tissue positive
CSF formula generally unremarkable
Oligoclonal bands present in CSF
Mumps virus CSF culture or PCR One of few viruses that can cause low glucose in CSF
CSF IgM/IgM
Serum IgM/IgG (paired serumb
samples if possible)
Throat swab PCR
Parvovirus B19 Serum IgM Pathogen of unknown neurologic potential
CSF PCR
Rabies virus Antemortem: Coordinate testing with local and state health department and
Serum antibodies CDC.
Saliva PCR Antemortem testing is possible; multiple samples and different
Nuchal biopsy PCR and DFA assays are important to run. Negative tests antemortem do not
Brain tissue DFA rule out rabies.
Postmortem:
Brain tissue; viral isolation or
antigen detection
Respiratory syncytial RSV antigen Pathogen of unknown neurologic potential
virus (RSV) CSF PCR rarely positive
CSF profile often unremarkable

(continued)

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98 Part II: Viral Infections and Related Disorders

TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES (CONTINUED)

Agent Recommended Diagnostic Studies Laboratory Findings; Limitations and Caveats

Rotavirus Stool antigen Pathogen of unknown neurologic potential


CSF PCR (testing available Typically young child with history of diarrhea; mechanism
specialized laboratories, unclear
e.g., CDC) CSF profile often unremarkable
Rubella virus Serology One of viral causes of low CSF glucose
CSF antibodies
Varicella-zoster virus CSF PCR Because some CNS VZV infections are reactivation, IgM not
(VZV) Intrathecal antibody if 1 week always positive
of symptoms Positive VZV skin lesions do not prove CNS etiology but may
Serum IgM/IgG be suggestive of etiology.
Skin lesions: DFA or PCR
West Nile virus See arboviruses (above)

Fungal Fungal CNS infections are often associated with CSF pleocytosis
with lymphocytic predominance, low glucose, and protein
100 mg/dL. EDTA-heat treated antigen test reported to
increase sensitivity for CSF and serum samples. Isolated CNS
disease can be difficult to diagnose because of insensitive
assays.
Note geographic locations of different fungal infections; order
antigen for each specific fungi.

Coccidioides spp.c CSF culture (large volume) Alert laboratory that coccidiomycosis is being considered if
fungal culture sent
Cryptococcus spp.c CSF-specific antigen Eosinophils sometimes present in CSF in coccidiomycosis
patients
Histoplasma capsulatumc CSF-specific antibody
and Blastomyces sp.c CSF India ink (for Cryptococcus
only)
Serum-specific antigen
Serum-specific antibody
Urine antigen (Histoplasma and
Blastomyces)

Free-living amebas and


parasites

Naegleria fowleri Wet mount of warm CSF Coordinate testing with local and state health department and
Brain histopathology the CDC.
Demonstration of motile ameba on wet mount of CSF
LP often demonstrates very high WBC (often PMN
predominance), high protein (100 mg/dL), and low glucose
(50 mg/dL).
Balamuthia mandrillarisc Serology Coordinate testing with local and state health department and
CSF and/or brain PCR the CDC.
Brain histopathology (special Serology and PCR available at specialized laboratories (CDC)
stains) Brain tissue may show necrotic and hemorrhagic
meningoencephalitis.
LP often shows high WBC (L or PMN) and protein 100 mg/
dL, resembling tuberculous meningitis.
Acanthamoeba spp.a,c Serology (research laboratories) Coordinate testing with local and state health department and
CSF and/or brain PCR the CDC.
Brain histopathology (special Serology and PCR available at specialized laboratories
stains)
Baylisascaris procyonis CSF and serum antibodies Serology available in specialized laboratories (CDC)
Eosinophils almost always present in CSF and CBC
Toxoplasma gondiia Older child: IgG, IgM, and PCR Often reactivation of disease, so IgM may not be positive; IgG
titers persistently high

(continued)

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Chapter 6: Encephalitis 99

TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES (CONTINUED)

Agent Recommended Diagnostic Studies Laboratory Findings; Limitations and Caveats

Bacteria

Bartonella henselae Serology (IFA) CSF PCR (if available) may also be useful to perform
PCR of lymph node CSF often negative
Borrelia burgdorferi Serology (serial EIA and Western Test both serum and CSF for Borrelia antibody; may be
blot) delayed in CNS intrathecal synthesis
CSF antibody index CSF PCR rarely positive (in contrast to synovial fluid) but may
be useful in some cases
Brucella spp. CSF IgG and IgM Serologyperform on both CSF and serum; culture increases
CSF culture sensitivity.
Serum IgG and IgM PCR available in some research settings; unknown sensitivity
False-positive IgM not uncommon
Leptospira spp. Serum IgM and IgG If serology negative on acute serum, important to repeat on
Urine culture convalescent serum
Listeria monocytogenes Routine bacterial culture on both CSF culture for Listeria relatively insensitive
CSF and blood CSF profile does not necessarily look bacterial, that is, can be
Multiple CSF cultures may be normal or have only a few hundred WBCs with predominance
helpful of lymphocytes; glucose and protein may be normal.
It may also be helpful to test CSF Listeria antibody because
detection of CSF antibody may be indicative of CNS infection.
Mycobacterium CSF AFB smear, culture, PCR, CSF PCR is insensitive tool for detection of CNS M. tuberculosis;
tuberculosisc direct examination important to test multiple samples.
Respiratory culture highly CNS M. tuberculosis should be considered in patients with
suggestive lymphocytic pleocytosis (but neutrophilic predominance can still
occur), CSF protein 100 mg/dL, and CSF glucose 50 mg/dL.
Mycoplasma pneumoniae PCR of NP or other respiratory Pathogen of unknown neurologic potential
specimen Perform PCR on respiratory samples, serology on acute/
Serum IgM convalescent serum
Serum IgG paired CSF PCR rarely positive
Single IgG titer is not helpful.
Treponema pallidum CSF VDRL CSF VDRL specific but CSF FTA-ABS more sensitive
Serum PCR with confirmatory
FTA-ABS

Rickettsia In patients with rickettsial infections, low peripheral WBC, low


platelets, and increased liver function tests (LFTS) often present

Anaplasma