2533 Pages
English

You can change the print size of this book

Neurology and General Medicine E-Book

-

Gain access to the library to view online
Learn more

Description

Better understand your patients' complete medical profile and provide the best possible care! This one-of-a-kind reference provides a practical look at neurological disease and how it affects, and is affected by, other disease. It helps neurologists manage patients with co-existing medical conditions, and helps internists understand and treat the neurological manifestations of patients' primary diseases. A new emphasis on diagnosis and management—including advances in pharmacology, genetic-based therapies, and new imaging techniques—makes this 4th Edition more clinically valuable than ever!
  • Focused content highlights the vital links between neurology and other medical specialties, promoting a better understanding of all disciplines, as well as enhancing patient care.
  • Comprehensive coverage of advances in pharmacology, such as new antibiotics for infectious diseases, helps you successfully manage a full range of diseases and disorders.
  • An interdisciplinary team of authors provides insight into the neurological aspects of the conditions you see in daily practice.
  • Easy-to-read chapters apply equally well to neurologists and non-neurologists, providing essential knowledge that covers the full spectrum of medical care.
  • Expanded chapters emphasize key diagnostic and therapeutic information, including appropriate testing and treatments for neurological disease.
  • An emphasis on advances in pharmacology and new imaging techniques helps you better manage your patients and understand how new drugs or therapies will affect your patients and practice.
  • New chapters on auditory and vestibular disease, ocular disease, and cutaneous disease provide a well-rounded look at the specialty.
  • Updated illustrations make complex concepts easier to understand and apply.

Subjects

Books
Savoirs
Medicine
Derecho de autor
Vértigo (desambiguación)
Delírium
Cardiac dysrhythmia
Choreia
Lepromatous leprosy
Parkinson's disease
Cirrhosis
Human T-lymphotropic virus
Spinal cord
Pertussis vaccine
Meningitis
Systemic lupus erythematosus
Atrial fibrillation
Myocardial infarction
Fungus
Psychiatry
Alzheimer's disease
Hematologic disease
Ageing
Bone disease
Paraneoplastic syndrome
Tonic?clonic seizure
Endocrine disease
Gastrointestinal physiology
Systemic disease
AIDS
Contrast medium
Phakomatosis
Partial seizure
Arthropathy
Atopic dermatitis
Connective tissue disease
Neurosarcoidosis
Pregnancy
Hepatic encephalopathy
Digestive disease
Traumatic brain injury
Hypopituitarism
Cryptococcosis
Subdural hematoma
Subarachnoid hemorrhage
Interventional cardiology
Sex steroid
Vasculitis
Anesthetic
Nephropathy
Stroke
Peripheral neuropathy
Tuberous sclerosis
Low molecular weight heparin
Infective endocarditis
Neurotoxicity
Diabetic neuropathy
Hypotension
Nutrition disorder
Weakness
Itch
Pulmonary edema
Sexual dysfunction
Human T-lymphotropic virus 1
Biopsy
Multiple myeloma
Sarcoidosis
Health care
Apnea
Immunosuppressive drug
Internal medicine
General practitioner
Hyponatremia
Ventricular fibrillation
Urinary incontinence
Rapid eye movement sleep
Organ transplantation
Poisoning
Delirium
Dehydration
Hypothermia
Bleeding
Orthostatic hypotension
Atherosclerosis
Hypertension
Electrocardiography
Headache
Hypothyroidism
Cardiac arrest
Neurofibromatosis
Multiple sclerosis
Philadelphia
Hearing impairment
Phenytoin
Electrolyte
Diabetes mellitus
Dementia
Pancreas
Infection
Transient ischemic attack
Tuberculosis
Thiamine
Epileptic seizure
Psychosis
Paralysis
Estrogen
Nervous system
Neurologist
Neurology
Malaria
Magnetic resonance imaging
Erectile dysfunction
Hyperthyroidism
Epilepsy
Major depressive disorder
Central nervous system
Alcoholism
Antibacterial
Anxiety
Fractures
Méthamphétamine
Hypertension artérielle
Divine Insanity
Concussion
Headache (EP)
Father
Neurotoxicité
Heroin
Alcohol
Delirium tremens
Sleep
Apnéa
On Thorns I Lay
Fatigue
Vaccine
Hypotension artérielle
Coma
Vertigo
Hypothermie
Électrolyte
Chorea
Constipation
Sphincter
Maladie infectieuse
Philadelphie
Death
Paludisme
Syncope
Copyright
Virus

Informations

Published by
Published 06 December 2007
Reads 0
EAN13 9780702036064
Language English
Document size 10 MB

Legal information: rental price per page 0.1019€. This information is given for information only in accordance with current legislation.

Neurology and General
Medicine
Fourth Edition
Michael J. Aminoff, MD, DSc, FRCP
Professor, Department of Neurology, School of Medicine,
University of California, San Francisco, California
Churchill LivingstoneCopyright
CHURCHILL LIVINGSTONE ELSEVIER
1600 John F. Kennedy Blvd.
Suite 1800
Philadelphia, PA 19103-2899
NEUROLOGY AND GENERAL MEDICINE
ISBN: 978-0-443-06707-5
Copyright © 2008, 2001, 1995, 1989 by Churchill Livingstone, an
imprint of Elsevier Inc.
All rights reserved. No part of this publication may be reproduced or
transmitted in any form or by any means, electronic or mechanical, including
photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Permissions may be sought directly from
Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865
843830 (UK); fax: (+44) 1865 853333; e-mail: healthpermissions@elsevier.com.
You may also complete your request on-line via the Elsevier website at <_http3a_
_www.elsevier.com2f_permissions="">.
Notice
Knowledge and best practice in this Eeld are constantly changing. As new
research and experience broaden our knowledge, changes in practice, treatment,
and drug therapy may become necessary or appropriate. Readers are advised to
check the most current information provided (i) on procedures featured or (ii) by
the manufacturer of each product to be administered, to verify the recommended
dose or formula, the method and duration of administration, and
contraindications. It is the responsibility of the practitioners, relying on their own
experience and knowledge of the patients, to make diagnoses, to determine
dosages and the best treatment for each individual patient, and to take all
appropriate safety precautions. To the fullest extent of the law, neither the
Publisher nor the Editor assumes any liability for any injury and/or damage to
persons or property arising out or related to any use of the material contained in
this book.
The Publisher
Library of Congress Cataloging-in-Publication DataNeurology and general medicine / edited by Michael J. Aminoff.—4th ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-443-06707-5
1. Neurologic manifestations of general diseases. 2. Nervous system—Diseases
—Complications.I. Aminoff, Michael J. (Michael Jeffrey) II. Title.
[DNLM: 1. Nervous System Diseases—complications. 2. Neurologic
Manifestations. WL 340 N4932 2008]
RC347.N479 2008
616.8—dc22
2007025633
Acquisitions Editor: Adrianne Brigido
Developmental Editor: Joan Ryan
Design Direction: Steven Stave
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1D e d i c a t i o n
This book is dedicated to the memory of Abraham S. Aminoff, my father and
friend.
It is also dedicated to my three children, Alexandra, Jonathan, and Anthony, as
they go their own ways and face the many opportunities and challenges ahead of
them.Contributors
Gary M. Abrams, MD , Associate Professor, Department
of Neurology, School of Medicine, University of
California, San Francisco, Rehabilitation Section Chief,
San Francisco Veterans Affairs Medical Center, San
Francisco, California, Other Endocrinopathies and the
Nervous System
Gregory W. Albers, MD , Professor, Department of
Neurology and Neurological Sciences, Stanford
University School of Medicine, Stanford, Director,
Stanford Stroke Center, Stanford University Medical
Center, Palo Alto, California, Stroke as a Complication of
General Medical Disorders
Bradley L. Allen, MD, PhD , Clinical Associate Professor,
Department of Medicine, Division of Infectious Diseases,
Indiana University School of Medicine, Chief, Medicine
Service and Section of Infectious Diseases, Richard L.
Roudebush Veterans Affairs Medical Center,
Indianapolis, Indiana, Neurological Manifestations of
Infective Endocarditis
Michael J. Aminoff, MD, DSc, FRCP , Professor,
Department of Neurology, School of Medicine,
University of California, San Francisco, California,
Postural Hypotension; Neurological Dysfunction and
Kidney Disease; Sexual Dysfunction in Patients With
Neurological Disorders; Pregnancy and Disorders of the
Nervous System; The Neurology of Aging; Seizures and
General Medical Disorders; Movement Disorders
Associated With General Medical Diseases; Neuromuscular
Complications of General Medical Disorders; Care at the
End of Life
Bruce O. Berg, MD , Professor Emeritus, Departments ofNeurology and Pediatrics, School of Medicine,
University of California, San Francisco, California,
Neurocutaneous Syndromes
Joseph R. Berger, MD , Professor and Chair, Department
of Neurology, University of Kentucky College of
Medicine, Lexington, Kentucky, AIDS and the Nervous
System
Timothy G. Berger, MD , Professor, Department of
Dermatology, School of Medicine, University of
California, San Francisco, California, Dermatological–
Neurological Interactions
Adil E. Bharucha, MD , Associate Professor, Department
of Medicine, Mayo Clinic College of Medicine,
Rochester, Minnesota, Disturbances of Gastrointestinal
Motility and the Nervous System
Charles F. Bolton, MD, FRCP(C) , Adjunct Professor,
Department of Neurology, School of Medicine, Queen’s
University, Kingston, Ontario, Canada, Neurological
Complications in Critically Ill Patients
David L. Brown, MD , Edward Rotan Distinguished
Professor and Chair, Department of Anesthesiology and
Pain Medicine, University of Texas, M. D. Anderson
Cancer Center, Houston, Texas, Neurological
Complications of Anesthesia
Christine E. Burness, MSc, MB, ChB, MRCP , Research
Fellow, Department of Neurology, University of
Sheffield Medical School, Sheffield, England, Thyroid
Disease and the Nervous System
Michael Camilleri, MD , Professor, Departments of
Medicine and Physiology, Mayo Clinic College of
Medicine, Rochester, Minnesota, Disturbances of
Gastrointestinal Motility and the Nervous System
Vinay Chaudhry, MD, FRCP , Professor, Department ofNeurology, Johns Hopkins University School of
Medicine, Baltimore, Maryland, Other Neurological
Disorders Associated With Gastrointestinal, Liver, or
Pancreatic Diseases
Chadwick W. Christine, MD , Assistant Professor,
Department of Neurology, School of Medicine,
University of California, San Francisco, California,
Movement Disorders Associated With General Medical
Diseases
Kimberly P. Cockerham, MD, FACS , Associate Clinical
Professor, Department of Ophthalmology, Stanford
University School of Medicine, Stanford, California,
Orbital and Ocular Manifestations of Neurological Disease
Gary M. Cox, MD , Associate Professor, Department of
Medicine, Duke University School of Medicine, Durham,
North Carolina, Fungal Infections of the Central Nervous
System
G.A.B. Davies-Jones, MD, FRCP , Lecturer in Medicine,
University of Sheffield Medical School, Consultant
Neurologist, Royal Hallamshire Hospital, Sheffield,
England, Neurological Manifestations of Hematological
Disorders
Larry E. Davis, MD , Professor, Department of Neurology,
University of New Mexico School of Medicine, Chief,
Neurology Service, New Mexico Veterans Affairs Health
Care System, Albuquerque, New Mexico, Nervous System
Complications of Systemic Viral Infections
Lisa M. Deangelis, MD , Professor, Department of
Neurology and Neuroscience, Weill Medical College of
Cornell University, Chair, Department of Neurology,
Memorial Sloan-Kettering Cancer Center, New York,
New York, Neurological Complications of Chemotherapy
and Radiation Therapy
Philip R. Delio, MD , Director of Stroke Services,Department of Neurology, Santa Barbara Cottage
Hospital, Santa Barbara, California, Stroke as a
Complication of General Medical Disorders
William P. Dillon, MD , Professor, Departments of
Radiology, Neurology, and Neurosurgery, School of
Medicine, University of California, San Francisco,
California, Neurological Complications of Imaging
Procedures
Christopher F. Dowd, MD , Associate Professor,
Departments of Radiology and Neurological Surgery,
School of Medicine, University of California, San
Francisco, California, Neurological Complications of
Imaging Procedures
AdrÉ J. Du Plessis, MBChB, MPH , Associate Professor,
Department of Neurology, Harvard Medical School,
Associate in Neurology and Director, Fetal-Neonatal
Neurology Program, Department of Neurology,
Children’s Hospital, Boston, Massachusetts, Neurological
Complications of Congenital Heart Disease and Cardiac
Surgery in Children
David T. Durack, MB, DPhil, FRCP , Consulting Professor,
Department of Medicine, Duke University School of
Medicine, Durham, North Carolina, Senior Vice
President, Corporate Medical Affairs, Becton, Dickinson
and Company, Franklin Lakes, New Jersey, Fungal
Infections of the Central Nervous System
Jacob S. Elkins, MD , Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, California, Neurological Complications of
Hypertension
John W. Engstrom, MD , Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, California, HTLV-I Infection and the
Nervous SystemRandolph W. Evans, MD , Clinical Professor, Department
of Neurology and Neuroscience, Weill Medical College
of Cornell University, New York, New York, Clinical
Associate Professor, Department of Neurology, Baylor
College of Medicine, Houston, Texas, The Postconcussion
Syndrome
Eva L. Feldman, MD, PhD , Russell N. DeJong Professor,
Department of Neurology, University of Michigan
Medical School, Ann Arbor, Michigan, Diabetes and the
Nervous System
Bruce J. Fisch, MD , Professor, Department of Neurology,
Louisiana State University School of Medicine, New
Orleans, Louisiana, Neurological Aspects of Sleep
Joseph M. Furman, MD, PhD , Professor, Departments of
Otolaryngology and Neurology, University of Pittsburgh
School of Medicine, Pittsburgh, Pennsylvania,
Otoneurological Manifestations of Otological and Systemic
Disease
Douglas J. Gelb, MD, PhD , Professor, Department of
Neurology, University of Michigan Medical School, Ann
Arbor, Michigan, Abnormalities of Thermal Regulation
and the Nervous System
David J. Gladstone, MD, FRCP(C), PhD , Assistant
Professor, Department of Neurology, University of
Toronto Faculty of Medicine, Toronto, Ontario, Canada,
Neurological Manifestations of Acquired Cardiac Disease,
Arrhythmias, and Interventional Cardiology
Douglas S. Goodin, MD , Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, California, Neurological Complications of
Aortic Disease and Surgery
Sean A. Grimm, MD , Fellow, Department of Neurology,
Memorial Sloan-Kettering Cancer Center, New York,
New York, Neurological Complications of Chemotherapyand Radiation Therapy
John J. Halperin, MD , Clinical Professor, Department of
Neurology, New York University School of Medicine,
New York, New York, Spirochetal Infections of the
Nervous System
J. Claude Hemphill, III , MD , Associate Professor,
Department of Neurology, School of Medicine,
University of California, San Francisco, California,
Disorders of Consciousness in Systemic Diseases
John R. Hotson, MD , Professor, Department of
Neurology and Neurological Sciences, Stanford
University School of Medicine, Stanford, California,
Neurological Complications of Cardiac Surgery
Cheryl A. Jay, MD , Clinical Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, California, Other Endocrinopathies and the
Nervous System
S. Claiborne Johnston, MD, PhD , Professor, Department
of Neurology, School of Medicine, University of
California, San Francisco, California, Neurological
Complications of Hypertension
Charles H. King, MD , Professor, Center for Global
Health and Diseases, Case Western Reserve University
School of Medicine, Cleveland, Ohio, Parasitic Infections
of the Central Nervous System
Nerissa U. Ko, MD , Assistant Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, California, Cardiac Manifestations of
Acute Neurological Lesions
Allan Krumholz, MD , Professor, Department of
Neurology, University of Maryland School of Medicine,
Baltimore, Maryland, Sarcoidosis of the Nervous SystemColin D. Lambert, BM, FRCP, FRCP(C) , Associate
Professor, Department of Medicine, University of
Toronto Faculty of Medicine, Toronto, Ontario, Canada,
Neurological Manifestations of Acquired Cardiac Disease,
Arrhythmias, and Interventional Cardiology
J. William Langston, MD , Scientific Director,
Parkinson’s Institute, Sunnyvale, California,
Neuropsychiatric Complications of Substance Abuse
John M. Leonard, MD , Professor, Department of
Medicine, Division of Infectious Diseases, Vanderbilt
University School of Medicine, Nashville, Tennessee,
Tuberculosis of the Central Nervous System
Catherine Limperopoulos, PhD , Assistant Professor and
Canada Research Chair in Brain and Development,
Departments of Neurology and Neurosurgery, McGill
University Faculty of Medicine, Montreal, Quebec,
Canada, Neurological Complications of Congenital Heart
Disease and Cardiac Surgery in Children
Alan H. Lockwood, MD , Professor, Departments of
Neurology and Nuclear Medicine, University at Buffalo
School of Medicine and Biomedical Sciences, Buffalo,
New York, Hepatic Encephalopathy
W.T. Longstreth, JR. , MD, MPH , Professor, Department
of Neurology, University of Washington School of
Medicine, Adjunct Professor, Department of
Epidemiology, University of Washington School of
Public Health and Community Medicine, Seattle,
Washington, Neurological Complications of Cardiac Arrest
Elliott L. Mancall, MD , Professor, Department of
Neurology, Thomas Jefferson University Hospital,
Philadelphia, Pennsylvania, Nutritional Disorders of the
Nervous System
Frank L. Mastaglia, MD , Professor, Centre for
Neuromuscular and Neurological Disorders, Universityof Western Australia School of Medicine, Nedlands,
Western Australia, Australia, Drug-Induced Disorders of
the Nervous System
Una D. Mccann, MD , Associate Professor, Department of
Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine, Baltimore, Maryland,
Neuropsychiatric Complications of Substance Abuse
Robert O. Messing, MD , Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, Associate Director, Ernest Gallo Clinic
and Research Center, Emeryville, California, Alcohol and
the Nervous System
Andrea Olmos, BA , Research Assistant, Department of
Ophthalmology, Stanford University School of Medicine,
Stanford, California, Orbital and Ocular Manifestations of
Neurological Disease
Richard K. Olney, MD , Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, California, The Neurology of Aging
Jack M. Parent, MD , Associate Professor, Department of
Neurology, University of Michigan Medical School, Ann
Arbor, Michigan, Seizures and General Medical Disorders
Gareth J. Parry, MD , Professor, Department of
Neurology, University of Minnesota Medical School,
Minneapolis, Minnesota, Neurological Complications of
Toxin Exposure in the Workplace
Roy A. Patchell, MD , Professor, Department of
Neurosurgery, University of Kentucky Medical School,
Chief of Neuro-oncology, University of Kentucky
Medical Center, Lexington, Kentucky, Neurological
Complications of Organ Transplantation and
Immunosuppressive Agents
John R. Perfect, MD , Professor, Department ofMedicine, Division of Infectious Diseases, Duke
University School of Medicine, Durham, North Carolina,
Fungal Infections of the Central Nervous System
Ann Noelle Poncelet, MD , Professor, Department of
Neurology, School of Medicine, University of California,
San Francisco, California, Neurological Disorders
Associated With Bone and Joint Disease
Rodica Pop-Busui, MD, PhD , Assistant Professor,
Department of Internal Medicine, University of
Michigan Medical School, Ann Arbor, Michigan,
Diabetes and the Nervous System
Jerome B. Posner, MD , Professor, Department of
Neurology and Neuroscience, Weill Medical College of
Cornell University, Attending Neurologist, Memorial
Sloan-Kettering Cancer Center, New York, New York,
Paraneoplastic Syndromes Involving the Nervous System
Jeffrey W. Ralph, MD , Assistant Professor, Department
of Neurology, School of Medicine, University of
California, San Francisco, California, Neuromuscular
Complications of General Medical Disorders
William J. Ravich, MD , Associate Professor, Department
of Medicine, Johns Hopkins University School of
Medicine, Baltimore, Maryland, Other Neurological
Disorders Associated With Gastrointestinal, Liver, or
Pancreatic Diseases
George A. Ricaurte, MD, PhD , Professor, Department of
Neurology, Johns Hopkins University School of
Medicine, Baltimore, Maryland, Neuropsychiatric
Complications of Substance Abuse
Jack E. Riggs, MD , Professor, Department of Neurology,
West Virginia University School of Medicine,
Morgantown, West Virginia, Neurological Manifestations
of Electrolyte DisturbancesKaren L. Roos, MD , Professor, Departments of
Neurology and Neurosurgery, Indiana University School
of Medicine, Indianapolis, Indiana, Acute Bacterial
Infections of the Central Nervous System
Andrew P. Rose-Innes, MBChB , Assistant Professor,
Department of Neurology, University of Washington
School of Medicine, Seattle, Washington, Neurological
Disorders Associated With Bone and Joint Disease
Richard B. Rosenbaum, MD , Clinical Professor,
Department of Neurology, School of Medicine, Oregon
Health & Science University, Attending Neurologist,
Oregon Clinic, Portland, Oregon, Connective Tissue
Diseases, Vasculitis, and the Nervous System
Thomas D. Sabin, MD , Professor, Department of
Neurology, Tufts University School of Medicine, Boston,
Massachusetts, Neurological Complications of Leprosy
Robert A. Salata, MD , Professor, Department of
Medicine, Case Western Reserve University School of
Medicine, Cleveland, Ohio, Parasitic Infections of the
Central Nervous System
Hyman M. Schipper, MD, PhD, FRCP(C) , Professor,
Departments of Neurology and Neurosurgery and
Department of Medicine (Geriatrics), McGill University
Faculty of Medicine, Neurologist and Director, Center
for Neurotranslational Research, Lady Davis Institute
for Medical Research, Sir Mortimer B. Davis Jewish
General Hospital, Montreal, Quebec, Canada, Sex
Hormones and the Nervous System
Pamela J. Shaw, MD, FRCP , Professor, Department of
Neurology, University of Sheffield Medical School,
Sheffield, England, Thyroid Disease and the Nervous
System
Roger P. Simon, MD , Director and Chair, Dow
Neurobiology Laboratories, Portland, Oregon, Breathingand the Nervous System
Michele B. St. Martin, MD , Visiting Instructor,
Department of Otolaryngology, University of Pittsburgh
School of Medicine, Pittsburgh, Pennsylvania,
Otoneurological Manifestations of Otological and Systemic
Disease
Barney J. Stern, MD , Professor, Department of
Neurology, University of Maryland School of Medicine,
Baltimore, Maryland, Sarcoidosis of the Nervous System
Kelli A. Sullivan, PhD , Assistant Research Professor,
Department of Neurology, University of Michigan
Medical School, Ann Arbor, Michigan, Diabetes and the
Nervous System
Jon D. Sussman, MB, ChB, PhD, FRCP , Honorary
Lecturer, Department of Neurology, University of
Manchester Medical School, Consultant Neurologist,
Greater Manchester Neuroscience Centre, Hope
Hospital, Salford, Greater Manchester, England,
Neurological Manifestations of Hematological Disorders
Michael Swash, MD, FRCP , Professor, Department of
Neurology, Royal London Hospital, London, England,
Sphincter Disorders and the Nervous System
Thomas R. Swift, MD, FAAN , Professor, Department of
Neurology, Medical College of Georgia, Augusta,
Georgia, Neurological Complications of Leprosy
Michael R. Trimble, MD, FRCP, FRCPsych , Emeritus
Professor of Behavioural Neurology, Institute of
Neurology, University College London, London,
England, Psychiatry and Neurology
Angela T. Truong, MD , Assistant Professor, Department
of Anesthesiology and Pain Medicine, University of
Texas, M. D. Anderson Cancer Center, Houston, Texas,
Neurological Complications of AnesthesiaAlex C. Tselis, MD, PhD , Associate Professor,
Department of Neurology, Wayne State University
School of Medicine, Detroit, Michigan, Neurological
Complications of Vaccination
David B. VoduŠek, MD, DSc , Professor and Chair,
Department of Neurology, School of Medicine,
University of Ljubljana, Ljubljana, Slovenia, Sexual
Dysfunction in Patients With Neurological Disorders
Kevin C. Wang, MD, PhD , Resident Physician,
Department of Dermatology, School of Medicine,
University of California, San Francisco, California,
Dermatological–Neurological Interactions
Linda S. Williams, MD , Professor, Department of
Neurology, Indiana University School of Medicine,
Indianapolis, Indiana, Neurological Manifestations of
Infective Endocarditis
Marc D. Winkelman, MD , Associate Professor,
Department of Neurology, Case Western Reserve
University School of Medicine, Cleveland, Ohio,
Neurological Complications of Thermal and Electrical
Burns
G. Bryan Young, MD, FRCP(C) , Professor, Department of
Neurology, University of Western Ontario Faculty of
Medicine, Consultant Neurologist, London Health
Sciences Centre, London, Ontario, Canada, Neurological
Complications in Critically Ill Patients
Jonathan G. Zaroff, MD , Assistant Professor,
Department of Medicine, School of Medicine, University
of California, San Francisco, California, Cardiac
Manifestations of Acute Neurological Lesions$
$
$
$
$
!
Preface to the Fourth Edition
Medical practice continues to evolve, but with changes that occasion both
excitement and dismay. Technological developments have led to a gradual erosion
of clinical skills; easy access to information technology has led to more informed
but not necessarily better educated patients; an increasing bureaucracy has
required physicians to spend time on paperwork rather than on patient care;
translational research has lagged behind the spectacular advances occurring in the
laboratory—the list seems endless. In addition, the mistaken belief is perpetuated
that the excellence of a health care delivery system is re ected by its cost. In many
countries of the developed world, costs have risen sharply but the quality of care
has seemed to decline. A lack of clinical common sense, a failure to grasp the
importance of the quality of life, and an inability to optimize the use of limited
resources help to round out the picture of a eld in some disarray. Even so,
advances have been spectacular. For example, new imaging modalities and new
therapeutic agents allow clinicians in the developed world to manage patients
with greater precision and optimism, and advances in basic and applied
immunology and an increased understanding of molecular biology at the level of
genes, proteins, and ion channels have helped practitioners to clarify and solve
previously impenetrable clinical problems.
The medical literature, which has grown at an alarming rate, is now all but
unmanageable in size. With new journals proliferating, quarterly journals
becoming monthlies, and monthly journals now appearing weekly, the reader is
faced with a daunting prospect in endeavoring to keep abreast of advances in the
eld. Furthermore, to clinicians, much of the material published in the leading
medical journals seems divorced from the realities of clinical medicine and of little
relevance to its practice. Specialties are fragmenting into ever smaller
subspecialties, many with their own certi cation process to give them legitimacy,
and—in part because of the jargon that has evolved within each area—
communication among specialists or even among subspecialists within the same
overall specialty is becoming increasingly limited.
It is in this context that the new edition of this book has been developed. As
with earlier editions, which received a generous acceptance, it is hoped that the
book will appeal to neurologists, specialists in other clinical elds, hospitalists, and
primary health-care providers by both de ning the neurological aspects of general$
!
medical disorders and discussing the non-neurological (general medical and other)
aspects of various neurological diseases. The book is intended not to provide a
comprehensive account of clinical neurology but to serve as an interface between
neurology and the other clinical specialties. Despite the trend toward
specialization, it is essential that all physicians—and especially neurologists—gain
or retain expertise in general medicine. Many patients with neurological disorders
are middle-aged or elderly and have a wide variety of general medical disorders,
and many general medical disorders have neurological complications or manifest
as neurological diseases. This is exempli ed by patients who present with strokes.
Cardiac disease and hematological disorders account for a sizable number of
strokes; infection (e.g., infective endocarditis and meningitis), in ammatory
diseases (e.g., vasculitis and connective tissue disease), and neoplastic diseases are
other well-recognized causes. Clearly, competent neurologists require knowledge
of general medicine to manage such patients successfully. Further, as neurologists
and other specialists work alongside and communicate with those in other medical
areas, they require basic knowledge of specialties outside their own at a time when
the advance of medicine is so rapid that it is hard to remain current. The lack of
consensus among primary care physicians and specialists concerning the
appropriate extent of specialist involvement in the care of patients with
neurological conditions requires not only that patient care be coordinated among
physicians but also that neurologists have some understanding of the general
medical issues relating to their patients and that primary care physicians, in turn,
have an appreciation of their neurological disorders.
This book is aimed at both general physicians and neurologists, regardless of
their level of training or experience. I hope that it will help to guide more junior
physicians in the diagnosis and management of patients and in the development of
a fundamental base of clinical knowledge. Experience is necessary to become an
outstanding physician, and it requires not only years of training to acquire the
requisite knowledge and skills to be a neurologist but also lifelong learning to
maintain these skills. As diagnostic strategies and treatment modalities advance,
more senior practitioners can be left behind. Thus, it is my hope that this book will
appeal to them also as a source of reference and guide to the care of patients with
diseases that may already be familiar to them.
This edition includes chapters updated from the third edition (or replaced by
new chapters on the same topic), as well as three new chapters on additional
topics. The references have also been updated. Although many of the older
references have been replaced (but can be found by interested readers in earlier
editions), a number have been retained because they are classic papers or provide
seminal descriptions of particular diseases, clinical phenomena, or treatment to6
$
$
$
$
5
$
$
$
which reference may still usefully be made. This edition also features the addition
of a companion website with full-text search capability and links to PubMed. It is
my hope that the online site will allow readers to access the text easily while out of
the office.
I am grateful to the authors who contributed to this volume and gracefully
tolerated my editorial suggestions and interventions. Their generosity in sharing
their knowledge and skill with others is particularly appreciated at a time when
there are so many competing and conflicting demands on their time.
During the production of the second edition of Neurology and General Medicine,
my father died unexpectedly, and I dedicated the book to his memory. In the 13
years that have passed since that time, I have thought of him often. I still
remember how he—an engineer by profession—read my rst book, a small
monograph on spinal angiomas published in the mid-1970s, from cover to cover
when rst it appeared, even though he must have found much of it di cult to
understand, and how he showed it proudly to all his friends. I like to think that he
would have had the same pride in the present volume, which is once again
dedicated to his memory as a measure of my a ection, esteem, and gratitude. This
edition is also again dedicated to my three children, who have given me so much
happiness over the years. My daughter, Alexandra, is now a nal-year medical
student; my son Jonathan is a nal-year law student; and my younger son,
Anthony, is in his nal year as an undergraduate at the University of California at
Berkeley, from which he also hopes to go on to law school. It is my hope that they
will nd their professional lives as ful lling, rewarding, challenging, and
enjoyable as I have my own.
I could not have undertaken the compilation of this book without the assistance
of my wife, Jan, who gave me the support, encouragement, and time to complete
this new revision, taking on many additional chores, without complaint, to ease
my burden. Finally, I am grateful to my editors at Elsevier, and especially to Susan
Pioli, Joan Ryan, and Adrianne Brigido for their unfailing assistance in the
development of this book, and to Joan Sinclair and Joan Vidal for seeing it
through the production process. They all were a joy to work with and went out of
their way to help with any special requests and to satisfy my every concern.
Michael J. Aminoff, MD, DSc, FRCP

'




Preface to the First Edition
The increasing sophistication and complexity of modern medicine have led to
greater specialization among practitioners and to more restricted communication
between physicians in di erent disciplines. Perhaps, inevitably, this trend has
created certain major problems. These di culties are particularly well exempli ed
by the relationship between neurology and general medicine.
For non-neurologists, evaluation of patients with neurological symptoms and
signs has always been di cult because of the compexity of the anatomy and
physiology of the nervous system and frustrating because the therapeutic options
have seemed somewhat limited. Nevertheless, a number of neurological diseases
are exacerbated by, or occur as speci c complications of, general medical
disorders. Appropriate management of these neurological disturbances requires
their early recognition and an appreciation of their prognosis. It is equally
important to recognize the manner in which such neurological disorders may
in uence the management of the primary or coexisting medical condition, as well
as the manner in which systemic complications of neurological disorders may
require somewhat di erent management than when these complications occur in
other settings.
For neurologists, who are being asked increasingly to evaluate neurological
disturbances presenting in the context of other medical disorders, the di culty is
equally apparent. The general background of cases is frequently confusing, the
relationship of the neurological to the other medical problems is commonly not
appreciated, and the manner in which treatment needs to be “tailored” to the
speci c clinical context is often not clear. Furthermore, neurological disturbances
may themselves be the presenting feature of general medical disorders or lead to
general medical complications requiring speedy recognition and e ective
management.
I hope that the present volume will appeal to both neurologists and physicians
in other specialties by providing a guide to the neurological aspects of general
medical disorders and to some of the medical complications of certain
neurological diseases. It is not intended to be a textbook of neurology, but rather a
“bridge” between neurology and the other medical specialties.
It is a pleasure to acknowledge the help that I received from various people in
developing this book. I am grateful to the various contributors, who devoted agreat deal of time and energy to reviewing developments in their own elds of
interest and showed considerable tolerance of the many demands that I made
upon them. I am grateful also to Mr. Robert Hurley and Ms. Margot Otway at
Churchill Livingstone for their help and advice during the preparation of this
book. Finally, the support and encouragement of my wife, Jan, and of our
children, Alexandra, Jonathan, and Anthony, did much to ease the burden
involved in seeing this volume to its conclusion.
Michael J. Aminoff, MD, FRCPTable of Contents
Copyright
Dedication
Contributors
Preface to the Fourth Edition
Preface to the First Edition
Chapter 1: Breathing and the Nervous System
Chapter 2: Neurological Complications of Aortic Disease and Surgery
Chapter 3: Neurological Complications of Cardiac Surgery
Chapter 4: Neurological Complications of Congenital Heart Disease and
Cardiac Surgery in Children
Chapter 5: Neurological Manifestations of Acquired Cardiac Disease,
Arrhythmias, and Interventional Cardiology
Chapter 6: Neurological Manifestations of Infective Endocarditis
Chapter 7: Neurological Complications of Hypertension
Chapter 8: Postural Hypotension
Chapter 9: Neurological Complications of Cardiac Arrest
Chapter 10: Cardiac Manifestations of Acute Neurological Lesions
Chapter 11: Neurocutaneous Syndromes
Chapter 12: Dermatological–Neurological Interactions
Chapter 13: Neurological Manifestations of Hematological Disorders
Chapter 14: Hepatic Encephalopathy
Chapter 15: Other Neurological Disorders Associated With
Gastrointestinal, Liver, or Pancreatic Diseases
Chapter 16: Disturbances of Gastrointestinal Motility and the Nervous
System
Chapter 17: Nutritional Disorders of the Nervous SystemChapter 18: Neurological Dysfunction and Kidney Disease
Chapter 19: Neurological Manifestations of Electrolyte Disturbances
Chapter 20: Thyroid Disease and the Nervous System
Chapter 21: Diabetes and the Nervous System
Chapter 22: Sex Hormones and the Nervous System
Chapter 23: Other Endocrinopathies and the Nervous System
Chapter 24: Neurological Disorders Associated With Bone and Joint
Disease
Chapter 25: Otoneurological Manifestations of Otological and Systemic
Disease
Chapter 26: Orbital and Ocular Manifestations of Neurological Disease
Chapter 27: Paraneoplastic Syndromes Involving the Nervous System
Chapter 28: Neurological Complications of Chemotherapy and Radiation
Therapy
Chapter 29: Connective Tissue Diseases, Vasculitis, and the Nervous
System
Chapter 30: Psychiatry and Neurology
Chapter 31: The Postconcussion Syndrome
Chapter 32: Neurological Aspects of Sleep
Chapter 33: Sphincter Disorders and the Nervous System
Chapter 34: Sexual Dysfunction in Patients With Neurological Disorders
Chapter 35: Pregnancy and Disorders of the Nervous System
Chapter 36: Drug-Induced Disorders of the Nervous System
Chapter 37: Alcohol and the Nervous System
Chapter 38: Neuropsychiatric Complications of Substance Abuse
Chapter 39: Neurological Complications of Toxin Exposure in the
Workplace
Chapter 40: Acute Bacterial Infections of the Central Nervous System
Chapter 41: Spirochetal Infections of the Nervous System
Chapter 42: Tuberculosis of the Central Nervous System
Chapter 43: Neurological Complications of Leprosy
Chapter 44: Nervous System Complications of Systemic Viral InfectionsChapter 45: AIDS and the Nervous System
Chapter 46: Neurological Complications of Organ Transplantation and
Immunosuppressive Agents
Chapter 47: HTLV-I Infection and the Nervous System
Chapter 48: Fungal Infections of the Central Nervous System
Chapter 49: Parasitic Infections of the Central Nervous System
Chapter 50: Neurological Complications of Vaccination
Chapter 51: Sarcoidosis of the Nervous System
Chapter 52: Neurological Complications in Critically Ill Patients
Chapter 53: Neurological Complications of Imaging Procedures
Chapter 54: Neurological Complications of Anesthesia
Chapter 55: Neurological Complications of Thermal and Electrical Burns
Chapter 56: Abnormalities of Thermal Regulation and the Nervous System
Chapter 57: The Neurology of Aging
Chapter 58: Seizures and General Medical Disorders
Chapter 59: Movement Disorders Associated With General Medical
Diseases
Chapter 60: Neuromuscular Complications of General Medical Disorders
Chapter 61: Stroke as a Complication of General Medical Disorders
Chapter 62: Disorders of Consciousness in Systemic Diseases
Chapter 63: Care at the End of Life
IndexChapter 1
Breathing and the Nervous System
Roger P. Simon
RESPIRATORY EFFECTS OF NERVOUS SYSTEM DYSFUNCTION
Alteration of Gas Exchange
Pulmonary Hydrostatic Pressure
Capillary Permeability
Central Effects on Ventilation
Autonomic Dysfunction
Extrapyramidal Disorders
Forebrain Influences on Ventilation
Apraxia of Ventilatory Movements
Posthyperventilation Apnea
Hindbrain Control of Ventilation
Other Ventilatory Patterns
Cheyne–Stokes Breathing
Central Hyperventilation
Alveolar Hypoventilation
NERVOUS SYSTEM EFFECTS OF RESPIRATORY DYSFUNCTION
Hypoxia
Acute Hypoxia
Hypercapnia
Chronic Hypercapnia
Acute Hypercapnia
Hypocapnia
Acute Hypocapnia
Chronic Hypocapnia
HICCUP
SNEEZING
YAWNING
The relationship between breathing and the nervous system can be considered from
two perspectives, both of which are important to neurologists as well as to general
physicians. First, neurological dysfunction can have e. ects on respiration that may be the
most disturbing aspects of the underlying neurological disease. Second, primaryrespiratory dysfunction may a. ect the nervous system and lead to a request for
neurological consultation. Both interactions are considered in this chapter. In revising this
chapter for the current edition, many old but classic references were removed, but
interested readers will find these cited in earlier editions, to which they are referred.
RESPIRATORY EFFECTS OF NERVOUS SYSTEM DYSFUNCTION
Alteration of Gas Exchange
One of the most dramatic and life-threatening e. ects of nervous system dysfunction on
respiration is the impairment of alveolar gas exchange by a neurologically induced
increase in pulmonary interstitial and alveolar 2uid: the phenomenon of acute pulmonary
edema. The 2uid producing pulmonary edema originates in the pulmonary capillaries.
Fluid movement from the pulmonary capillary bed into the alveolar air space is governed
by the variables in the classic Starling equation. In its simplest form, the Starling
equation expresses transcapillary 2uid 2ux as a balance between intravascular pressures
(tending to push 2uid out of the vascular lumen) and plasma osmotic forces (which tend
1to retain 2uid within the vascular lumen) (Fig. 1-1). Although the mechanisms by which
2neurogenically induced pulmonary edema occurs remain uncertain, the major
recognized factors are discussed in the following sections.
FIGURE 1-1 Relationships between microvascular hydrostatic pressure (P );MV
perimicrovascular hydrostatic pressure, that is, within the interstitial space (P );PMV
plasma colloid osmotic pressure ( π ); and perimicrovascular pericolloid osmoticMV
pressure (π ). Under normal conditions, the sum of forces is slightly positive, producingMv
a small vascular 2uid 2ux into the pericapillary interstitium of the lung, which is drained
as lymph.
(From Fein A, Grossman RF, Jones JG, et al: The value of edema fluid protein measurement in=
=
=
patients with pulmonary edema. Am J Med 67:32, 1979, with permission.)
Pulmonary Hydrostatic Pressure
The main variable under the control of the nervous system a. ecting pulmonary capillary
2uid 2ux is pulmonary intravascular pressure. A marked increase in this pressure can
force 2uid from the vascular compartment, 2ood the interstitial space (Fig. 1-1), produce
pulmonary edema, and impair oxygenation.
An elevation in intracranial pressure can unbalance the Starling equation and result in
2neurogenic pulmonary edema. This early experimental observation in animals has been
3con rmed in patients with traumatic head injury. Experimental studies have
demonstrated that the e. ect of increased intracranial pressure on pulmonary vascular
pressure and transcapillary 2uid 2ux occurs as intracranial pressure approaches systemic
pressure. An increase in systemic pressure (the Cushing response) then occurs to protect
cerebral perfusion. In most studies, an increase in intracranial pressure alone, in the
absence of the Cushing response, has no e. ect on transcapillary 2uid 2ux in the lung.
During the Cushing response, pulmonary vascular pressure increases in concert with
4systemic pressure, with a resultant increase in pulmonary transcapillary 2uid 2ux. Only
one experimental study has shown an increase in pulmonary transcapillary 2uid 2ux in
5the absence of elevated pulmonary vascular pressure. Other classic models of induction
of neurogenic pulmonary edema also appear to be those of centrally induced pulmonary
vascular hypertension. These models include “sympathetic activation” induced by
intracisternal veratrine and intracisternally administered thrombin and brinogen with or
6-8without vagotomy in rabbits.
Focal central nervous system (CNS) lesions can cause both an elevation of systemic
vascular pressure and pulmonary edema. Although hemodynamic data in humans are
lacking, there are many reports that the brainstem, particularly the medulla, is the site of
2,9-11focal CNS injuries that result in pulmonary edema. In unanesthetized small
animals, brainstem lesions in the region of the nucleus tractus solitarius produce marked
systemic hypertension and fulminant pulmonary edema; pulmonary vascular pressure
cannot be measured in these small animals. Following bilateral lesion placement in the
ventral lateral nucleus tractus solitarius in sheep, however, pulmonary arterial pressures
and transcapillary 2uid 2ux in the lung can be measured and may increase signi cantly
12without a change in systemic or left atrial pressures. This pattern of response to a CNS
2injury is similar to that reported for neurogenic pulmonary edema in humans.
Furthermore, a patient has been reported in whom a unilateral injury occurred to the
tractus solitarius during a neurosurgical procedure and in whom the contralateral tractus
solitarius was absent because of a congenital brainstem syrinx. The patient died of
9pulmonary edema and hypoxemia 34 hours postoperatively. The localization by
magnetic resonance imaging (MRI) of a lesion at the obex (Fig. 1-2) in patients with
recently diagnosed multiple sclerosis (MS) and acute pulmonary edema supports this
13,14anatomical site as that inducing neurogenic pulmonary edema. Recent
corroborative data come from a subset of patients with EV71 encephalitis in whombrainstem encephalitis and a polio-like acute 2accid paresis picture occur associated with
neurogenic pulmonary edema. Brain MRI performed within hours of onset of pulmonary
edema showed restricted di. usion in the posterior medulla, anterior to the inferior aspect
15of the fourth ventricle (Fig. 1-3).
FIGURE 1-2 Rostral to caudal (A to C) schematic reconstruction of the medullary lesion
in a patient with multiple sclerosis and pulmonary edema, based on magnetic resonance
imaging, illustrating the major nuclear groups and tracts involved. AP, area postrema;
4th, fourth ventricle; LRN, lateral reticular nucleus; MLF, medial longitudinal fasciculus;
MRN, medial reticular nucleus; NA, nucleus ambiguus; NTS, nucleus of the solitary tract;
Ob, obex; ST, solitary tract; V, spinal trigeminal nucleus; X, dorsal motor nucleus of the
vagus; XII, hypoglossal nucleus.
(From Simon RP: Respiratory manifestations of neurologic diseases. p. 496. In Goetz CG,
Tanner CM, Aminoff MJ [eds]: Handbook of Clinical Neurology. Vol 63. Elsevier, Amsterdam,
1993, with permission.)=
FIGURE 1-3 A, Di. usion magnetic resonance image at the level of the fourth ventricle,
performed within hours of onset of neurogenic pulmonary edema, showing paired areas
of restricted di. usion paracentrally in the region of the dorsal motor nucleus of the vagus,
nucleus tractus solitarius, and medial reticular formation. Axial (B) and sagittal (C)
T1weighted images of same patient performed 4 weeks after onset of neurogenic pulmonary
edema. Note the well-de ned signal abnormality anterior to the inferior aspect of the
fourth ventricle consistent with encephalomyelomalacia.
( A kindly provided by Dr. P. Ian Andrews; B and C modified from Nolan MA, Craig ME, Lahra
MM, et al: Survival after pulmonary edema due to enterovirus 71 encephalitis. Neurology
60:1651, 2003.)
Generalized seizures produce an abrupt, marked increase in sympathetic out2ow from
16the brain, and both systemic and pulmonary vascular pressures increase. The degree of
systemic pressure elevation cor relates with the number of seizures and is maximal duringstatus epilepticus. The magnitude of the pressure elevation in the pulmonary vasculature
is independent of the number of seizures, however, although the duration of the elevation
is maximal with status epilepticus (Fig. 1-4). The increase in transcapillary 2uid 2ux
resulting from this transient pulmonary vascular hypertension persists for hours after the
17pressure transient and probably explains the phenomenon of pulmonary edema
following seizures in humans.
FIGURE 1-4 Vascular pressure changes that occur during seizures in sheep. Mean values
have been plotted at 10-second intervals. Spinal cord refers to animals with cervical
spinal cord transection prior to seizures. Single, 5, and 20 shocks refer to the number of
electroconvulsive seizures induced; bicuculline refers to bicuculline-induced status
epilepticus. LA, left atrial; PA, pulmonary arterial.
(From Bayne LL, Simon RP: Systemic and pulmonary vascular pressures during generalized
seizures in sheep. Ann Neurol 10:566, 1981, with permission.)
The development of postictal pulmonary edema requires an increase in pulmonary
vascular pressures. If these pressure transients are aborted by a diversion of blood from
the pulmonary artery and left atrium during experimental status epilepticus, pulmonary
edema does not occur. As these peripheral vascular manipulations do not alter central
sympathetic output during the seizure, the studies support a hydrodynamic mechanism
for postictal pulmonary edema rather than the pulmonary edema being a manifestation
18of increased activity of the sympathetic nervous system.=
Capillary Permeability
Fulminant neurogenic pulmonary edema occurs in the setting of an alteration in
5 19pulmonary capillary permeability, possibly independent of or in association with an
imbalance of the forces in the Starling equation. The classic explanation for the
pathogenesis of the altered permeability is that the rapid elevation of pulmonary vascular
pressures and blood 2ow mechanically disrupts the pulmonary capillary bed, resulting in
20a pulmonary capillary leak phenomenon and noncardiogenic pulmonary edema.
Although this explanation is likely, some studies indicate the possibility that altered
5capillary permeability occurs in the absence of altered intravascular pressure. Other
studies in animals have demonstrated an inverse correlation between maximal pulmonary
vascular pressures and altered capillary permeability, suggesting that a combination of
“cardiogenic” and “noncardiogenic” factors may be the most common cause of
19neurogenic pulmonary edema. A similar conclusion has been reached from the study of
patients in whom the ratio of the protein concentration of edema 2uid to plasma protein
21concentration has been used as an index of altered capillary permeability.
Central Effects on Ventilation
Autonomic Dysfunction
Neural pathways subserving volitional ventilation descend from cortex through the
brainstem and spinal cord in the region of the corticospinal tract. The neuronal pools
subserving rhythmic involuntary ventilation originate in the caudal medulla and give rise
to descending pathways in the ventrolateral brainstem and spinal cord. Accordingly,
appropriately placed focal lesions may interfere with voluntary or involuntary ventilation
independently.
Impairment of autonomic but not volitional ventilation produces the phenomenon of
sleep apnea, or “Ondine’s curse.” This term was taken from a 1956 play by Jean
Giraudoux, who recreated a German mythical legend. The sea nymph Ondine cursed the
unfaithful knight Hans with the necessity of voluntary control over all of his autonomic
functions: “He died, they will say, because it was a nuisance to breathe.” In the
brainstem, bilateral medullary infarctions (Fig. 1-5A) have resulted in sleep apnea, as has
22unilateral medullary infarction (Fig. 1-5B). In the latter case, the lesion depicted in
Figure 1-5B will have destroyed primary ventilatory nuclei in and about the nucleus
retroambigualis and the nucleus tractus solitarius as well as bers from these nuclear
groups, which descend contralaterally. Transient vertebrobasilar ischemia has also
23resulted in transient episodes of Ondine’s curse. Congenital disorders of central alveolar
hypoventilation may represent a primary defect in neural crest cell migration and
function, resulting in altered central chemoreceptors. Accordingly neuroblastoma
24formation and Hirschsprung’s disease sometimes occur in these patients. Patients with
myotonic dystrophy and alveolar hypoventilation have lost catecholaminergic neurons in
25the medullary reticular formation. Incomplete and asymmetric involvement in the
region of the dorsal and ventral ventilatory complex of the medulla at about the obex has26been described in two patients with multiple sclerosis who died of sleep apnea.
FIGURE 1-5 A, Location of bilateral brainstem infarcts in a patient with automatic
respiratory failure. B, Brainstem section showing a unilateral lesion that resulted in
failure of autonomic respiration.
( A from Devereaux MW, Keane JR, Davis RL: Automatic respiratory failure associated with
infarction of the medulla. Arch Neurol 29:46, 1973, with permission. B from Levin BE, Margolis
G: Acute failure of automatic respirations secondary to a unilateral brain stem infarct. Ann
Neurol 1:583, 1977, with permission.)
Primary involvement of autonomic ventilatory nuclei was a common consequence of
bulbar poliomyelitis (Fig. 1-6). As with lesions of the descending pathways from these
nuclear groups, these lesions led to temporary or permanent sleep apnea. There are rare
27,28reports of hypoventilation in patients with systems degeneration, and pathological
material from such cases suggests that the causal abnormalities are located in the region
of the solitary tracts in the caudal medulla. Vertebral artery dissection involving the
dorsal medulla and anterior spinal artery with resultant central ventilatory failure has
29been reported.FIGURE 1-6 Medullary lesions found in 17 patients with bulbar poliomyelitis who died
of respiratory failure.
(From Baker AB, Matzke HA, Brown JR: Poliomyelitis. III: Bulbar poliomyelitis: a study of
medullary function. Arch Neurol Psychiatry 63:257, 1950, with permission.)
Iatrogenic sleep apnea occurs in some patients following bilateral cervical tractotomy
30performed for intractable pain (6 of 112 patients reported by Tranmer and associates ).
Figure 1-7 shows the most common site of the cordotomy lesion and the descending
autonomic pathways in the reticulospinal tract. Descending pathways for voluntary
ventilation are located in the corticospinal tract and thus are distant from the lesion site
(Fig. 1-7).
FIGURE 1-7 Cervical spinal cord at the C1–C2 level showing the area commonly
damaged in cervical cordotomies and the site of the descending autonomic pathway
subserving ventilation.
(From Tranmer BI, Tucker WS, Bilbao JM: Sleep apnea following percutaneous cervical=
cordotomy. Can J Neurol Sci 14:262, 1987, with permission.)
Sleep apnea also occurs on an obstructive or mixed basis. Such patients are usually
obese, hypertensive men older than 40 years. Excessive daytime sleepiness and sleep
attacks are associated symptoms. Nocturnal breath cessation is associated with prominent
snoring, snorting, and gasping sounds. Obstructive sleep apnea has been associated with
neurodegenerative diseases, such as syringobulbia and olivopontocerebellar degeneration,
31and miscellaneous unilateral lesions of the rostrolateral medulla, which may produce
32oropharyngeal weakness. Nonobstructive ventilatory dysfunction may occur as well.
33Treatment with continuous positive airway pressure (CPAP) during sleep is e. ective.
Further discussion of this syndrome can be found in Chapter 32.
Impairment of voluntary ventilatory e. orts with preservation of autonomic ventilation
may also occur. Cases have been reported from a demyelinating lesion in the high
cervical cord and a bilateral pyramidal tract lesion in the medulla resulting from
syphilitic arteritis. In another case, an infarct of the basal pons produced quadriplegia;
autonomic ventilation was modulated normally by laughing, crying, and anxiety,
supporting a nonpyramidal location of descending pathways from limbic structures to
27medullary ventilatory nuclei. The most common cause, however, is a midpontine lesion
that produces the “locked-in” syndrome. Patients may have a regular ventilatory pattern
and a preserved response to CO2 stimulation, or a Cheyne–Stokes pattern that is
volitionally unalterable.
Extrapyramidal Disorders
Symptomatic or asymptomatic ventilatory dysfunction is an infrequently recognized but
relatively common manifestation of extrapyramidal syndromes of multiple causes.
34Respiratory dysrhythmias were common in postencephalitic parkinsonism. Tachypnea,
the most common abnormality, may be episodic or continuous during sleep or
wakefulness; rates as high as 100 per minute are reported. Ventilatory dysrhythmias are
less common and manifest as breath-holding spells, sighing, forced or noisy expiration,
inversion of the inspiration/expiration ratio, or the Cheyne–Stokes pattern. Respiratory
tics occur as well, manifesting as yawning, hiccupping, spasmodic coughing, and sniffing.
In a study by Kim, all nine patients with postencephalitic parkinsonism had an increase
35in respiratory rate, and the normal variation in respiratory amplitude did not occur.
The most striking abnormality in these patients was their inability to alter the respiratory
rhythm voluntarily so that, for instance, they were unable to hold their breath.
Direct beroptic visualization of the upper airway in patients with extrapyramidal
36disease (essential tremor, parkinsonian tremor, rigid parkinsonism, or dyskinesia) has
disclosed rhythmic or irregular glottic and supraglottic involuntary movements.
Symptomatic stridor and ventilatory failure that could be reversed by endotracheal
intubation were described in a number of these patients and suggested upper airway
obstruction. Abnormal 2ow-volume curves were commonly found. Such upper airway
dysfunction may be a factor in the retention of secretions and respiratory infections that=
=
occur in many patients. Alternatively, a reduction in both maximal static inspiratory and
expiratory pressures precluding the ability to rapidly increase peak expiratory 2ow for
37maximally effective coughing may be an important factor.
Respiratory distress and dyspnea are also described in patients with extrapyramidal
dysfunction in whom no cardiopulmonary cause is found, but in whom respiratory rates
are irregular owing to involuntary respiratory dyskinesias that are either levodopa
38induced or related to a tardive dyskinesia. Respiratory dyskinesias, then, may be an
accompaniment of choreiform movement disorders and may account for subjective
39complaints of dyspnea in Parkinson’s disease and dystonia.
Forebrain Influences on Ventilation
That the forebrain in2uences both ventilatory rate and rhythm is documented by the
volitional acts of overbreathing and breath-holding as well as by the coordinated
semivoluntary or involuntary rhythmic alterations in ventilatory pattern that occur as
part of speaking, singing, laughing, and crying. Furthermore, during sleep, normal
ventilatory patterns become more irregular, total ventilatory volume decreases, Paco is2
elevated, and the CO2 response curve shifts to the right. Cortical “readiness potentials”
originating from supplementary motor and primary motor cortex can be recorded from
40humans prior to volitional but not automatic inspiration or expiration. Using positron
emission tomography of changes in regional cerebral blood-2ow, areas of cortical
41activation during volitional inspiration and expiration have been identi ed. Inspiration
is associated with increased cerebral blood-2ow in primary motor cortex bilaterally, the
right supplementary motor cortex, and left ventrolateral thalamus. In expiration, the
structures implicated are similar and overlapping but extend beyond those in inspiration
and include the cerebellum. In the cortex, the identi ed regions activated during
ventilation conform to the homuncular regions of thoracic and abdominal muscles.
Diaphragmatic contraction induced from these cortical regions with magnetic stimulation
42does not, however, affect automatic breathing.
Hemispheric stroke results in attenuation of diaphragmatic excursion on the hemiplegic
side but only during volitional breathing; thus, the diaphragm lacks bilateral cortical
43 44representation. The intercostal muscles are similarly a. ected by hemispheric stroke.
Sleep-disordered breathing is common in acute supra- and infratentorial stroke but rarely
45has localizing value.
The cortical areas e. ective in inducing apnea in humans are similar to those in
primates (Fig. 1-8) and include the anterior portion of the hippocampal gyrus, the ventral
and medial surfaces of the temporal lobe, the anterior portion of the insula, and the
anterior portion of the limbic gyrus. An episode of partial seizures with ictal apnea
following encephalitis in humans has been studied with ictal-interictal subtraction
singlephoton emission computed tomography (SPECT), showing an abnormality in the left
posterior lateral temporal region consistent with the ictal electroencephalographic (EEG)
46findings. Respiratory changes have also been associated with paroxysmal abnormalities
on the electroencephalogram. Such episodes have been implicated in epileptic sudden=
47death.
FIGURE 1-8 Points on the anterior lateral (top) and ventromedial (bottom) cerebral
cortex of Macaca mulatta where electrical stimulation elicited inhibition of respiration. C,
cingulate gyrus; CC, corpus callosum; CF, central ssure; HG, hippocampal gyrus; IN,
insula; LO, lateral orbital gyrus; OLF, olfactory tract; OT, optic tract; PO, posterior orbital
gyrus; R, gyrus rectus; ST, superior temporal gyrus.
(From Kaada BR: Somato-motor, autonomic, and electrocorticographic responses to electrical
stimulation of “rhinencephalic” and other structures in primates, cat, and dog. Acta Physiol
Scand 24:1, 1951, with permission.)
Apraxia of Ventilatory Movements
The inability to take or hold a deep breath despite normal motor and sensory function is
termed respiratory apraxia. This phenomenon is noted most often in elderly patients with
evidence of mild or moderate cerebrovascular disease. For example, in a patient with
progressive supranuclear palsy, rhythmic breathing movements persisted during planned
48volitional inspiration or breath-holding. As cortical magnetic stimulation of primary
motor cortex produces diaphragmatic contraction but does not a. ect ongoing
nonvolitional ventilation, cortical or subcortical regions other than primary motor cortex
must be the site of respiratory apraxia in such patients.
Posthyperventilation Apnea
In 1867, Hering observed that brief periods of apnea followed hyperventilation inanesthetized animals, and in 1908, Haldane reported apnea after voluntary
49,50hyperventilation in humans. Modern reanalysis of posthyperventilation apnea in
awake normal human subjects shows that both hyperpnea and apnea of 10 to 30 seconds
may occur in an individual subject; apneic pauses occur about 1 minute after cessation of
hyperventilation; the apnea’s length and occurrence, although variable among subjects,
was reproducible in individual subjects; and the occurrence of apnea was unrelated to the
51Pco during hyperventilation. In patients with brain injury, apnea occurred for more2
than 10 seconds with equal frequency in patients with unilateral (67%) and bilateral
52(70%) damage. No correlation was found between the decrease in end-tidal CO and2
the occurrence of apnea. A depressed level of consciousness in normal subjects, as during
drowsiness, sleep, or anesthesia, also leads to posthyperventilation apnea.
Posthyperventilation apnea has also been described in normal patients engaged in an
53intellectual task.
Hindbrain Control of Ventilation
The concept that the hindbrain controls ventilatory function, rate, and rhythm has grown
from the experiments of Lumsden (Fig. 1-9). These studies in anesthetized cats localized
the brainstem ventilatory centers to regions below the inferior colliculus because
transection at this level did not alter the ventilatory pattern when the vagi were intact.
Transection at the medullary-cervical junction produced the cessation of all ventilatory
functions. Accordingly, the neuronal centers responsible for ventilation are located
between these levels. Transection at the pontomedullary junction resulted in rhythmic
breathing with a gasping quality unchanged by vagal transection, demonstrating that the
most primitive respiratory oscillator is located within the medulla. The higher brainstem
“centers” play a modulatory role. A modern example of such experiments in anesthetized
cats is found in Figure 1-10.FIGURE 1-9 A, The original illustration from Lumsden (1923) showing the level of
“crucial sections” producing ventilatory alteration in cats. Ventilatory e. ects produced
with lesions: 1, no alteration; 2, apneusis; between 3 and 4, uncoordinated inspiratory
spasms and gasping; 4, gasping; between 5 and 6, cessation of all respiratory movements.
B, Respiratory tracings from Lumsden (1923). a, normal animal; b, after vagotomy; c,
apneusis (transection 2); d, gasping (transection 4).
(From Lumsden T: Observation on the respiratory centres in the cat. J Physiol [Lond] 57:153,
1923, with permission.)FIGURE 1-10 E. ects of brainstem and vagal transection on the ventilatory pattern in
an unanesthetized cat. APC, apneustic center; CP, cerebellar peduncle; DRG, dorsal
ventilatory group; IC, inferior colliculus; PNC, pneumotaxic center; VRG, ventral
ventilatory groups. Transections at di. erent levels are indicated by roman numerals.
Tracings on right represent the tidal volume with inspiration upward.
(From Berger AJ, Mitchell RA, Severinghaus JW: Regulation of respiration. N Engl J Med
297:139, 1977, with permission.)
Cerebellum
Classic studies of the role of the cerebellum in ventilation focused on the inhibitory e. ects
of the anterior lobe induced by stimulation. Modern studies have extended these
observations to the posterior lobe, showing stimulation-induced ventilatory inhibition
from the fastigial nucleus and uvula. Stimulation of large regions of the cerebellum,
however, produced no ventilatory alteration. Stimulation of the fastigial nucleus
produced early termination of bursting in both the inspiratory and the expiratory
54medullary neurons in the cat. Functional magnetic resonance imaging and positron
emission tomography studies have also shown activation of the cerebellum along with
other brainstem and basal forebrain structures during volitional breathing in humans. In
41,55,56some studies, expiration particularly involved the cerebellum. A congenital
syndrome associated with hypoplastic posterior cerebellar vermis (Joubert’s syndrome) is
57characterized by prominent ventilatory abnormalities: episodic hyperpnea and apnea.
Pneumotaxic Center
Lumsden named the pneumotaxic center (pneumotaxy: normal rhythmic ventilation) and
58localized it to the rostral pons in the parabrachial complex. Transection at this level
results in regular breathing, and the rate of this breathing, but not the rhythm, is slowed
by vagotomy. Destruction of this region or transection below it produces the phenomenon
of apneusis (Fig. 1-9B), which is discussed in the next section. Modern
electrophysiological and cytoarchitectural studies have localized respiratory-related
59neuronal activity to multiple nuclei in the dorsal and ventral pons and its connections.
Electrical stimulation within this region produces premature switching of respiratory=
=
=
=
=
=
=
=
phases. This o. -switching is modi ed at least in part by the classic Hering–Breuer (and
60possibly other) a. erents carried within the vagus. Glycinergic and GABAergic input is
61critical for o. -switching. Neuroanatomical and neurophysiological studies in animals
support the belief that the pneumotaxic center functions as a relay station, nely tuning
the ventilatory pattern generator. Stimulation by glutamate injection of the parabrachial
complex Kolliker–Fuse nucleus to include the margins of the sensory and motor
trigeminal nuclei have identi ed functionally distinct cell populations producing speci c
but sometimes opposing ventilatory responses, which include both respiratory facilitation
62and inhibition.
Apneustic Center
The phenomenon of apneusis consists of prominent, prolonged end-inspiratory pauses
58,63that can be pro- duced by pontine transection in vagotomized animals (Fig. 1-9).
Although the phenomenon of apneusis is well recognized, anatomical de nition of a
neuronal aggregate that can reasonably be called the apneustic center is still lacking.
Apneusis is de ned operationally as a failure of activation of normal inspiratory o. -
switching. The phenomenon of apneusis may result from one of a number of lesions (Fig.
1-11) or pharmacological manipulations. Systemic, but not local, administration of
antagonists of the N-methyl-d-aspartate (NMDA) subset of the glutamate receptor, but
64not non-NMDA antagonism induces apneusis, thus de ning the neurotransmitter
65system involved and the lack of a speci c inducing site. However, altered membrane
potentials in neurons of the ventral respiratory group are produced by NMDA
66antagonists.
FIGURE 1-11 Areas of the brainstem infarction in two patients with apneustic
breathing.
(From Plum F, Alvord EC: Apneustic breathing in man. Arch Neurol 10:101, 1964, with
permission.)
Apneustic respiration is rare in humans. Children with brainstem damage from
hypoxic-ischemic injury or other brainstem lesions may have apneustic breathing, with=
=
cyanosis during inspiratory pauses. Tandospirone or buspirone, serotonin-1A agonists,
67,68normalize breathing. Five patients with cervicomedullary compression from
achondroplasia had apneustic breathing patterns that were “reduced in the majority”
following decompressive surgery. The absence of a compressive e. ect at the level of the
pneumotaxic center and the integrity of the vagus nerves are notable in this clinical
69description.
Medullary Center
Rhythmic ventilatory excursions persist with brainstem transection at the pontomedullary
level, and all ventilatory movements are abolished by transection at the
medullarycervical junction. Accordingly, attention has been focused on the medulla as the
generator of rhythmic ventilatory movements. Medullary centers responsible for
inspiration and expiration were identi ed and were held to explain both ventilatory
function and ventilatory rhythmicity. Two major neuronal pools are responsible for
ventilation. Primary inspiratory cells located in the ventrolateral nucleus tractus solitarius
constitute the dorsal respiratory group, which receives all primary pulmonary a. erents
70from the vagus nerves. GABA receptors are the major modulators. Inspiratory andB
expiratory neurons are found in a separate grouping within the nucleus ambiguus and the
nucleus retroambigualis, which together constitute the ventral respiratory group (Fig.
112). Excitatory amino acid neurotransmitter function is necessary to modulate ventral
respiratory group function. NMDA receptors are the major mediators of ventral
71respiratory group ventilatory drive, with modulation by non-NMDA glutamate systems.
Thus, ventilatory rhythmicity is mediated by the dorsal respiratory group, and projection
to spinal respiratory motor neurons and vagally mediated auxiliary muscles of respiration
occurs via the ventral respiratory group. Although rhythmic ventilatory responses occur
from the medulla following ponto-medullary transection, this respiratory pattern has a
rather gasping quality and is not normal rhythmic ventilation. A gasping center has been
72found just rostral and ventral to the dorsal respiratory group. The primary ventilatory
rhythm generator appears to reside in a limited region of the ventral medulla (the
preBötzinger complex) just rostral to the rostral ventilatory group (Fig. 1-12). Rhythm
generation is eliminated by removal of this region, and medullary slices containing this
73region generate respiratory-related oscillations. The pre-Bötzinger complex responds to
74hypoxia, and this response is modi ed by glutamate receptors. The network and
intrinsic membrane properties of this region are an intensive area of current
75,76investigation.FIGURE 1-12 A, Dorsal view of brainstem and cervical spinal cord indicating regions
involved in control of breathing and progression of labeling with a viral tracer injected
into the phrenic nerve. The percentage of labeled third-order neurons (propiobulbar
neurons) in the pre-Bötzinger complex and adjacent regions is plotted in the set at right.
Note that the pre-Bötzinger complex contains almost entirely third-order neurons, whereas
adjacent regions, rVRG and BötC, contain 0 to 20 percent. BötC, Bötzinger complex;
cVRG, caudal ventral respiratory group; KF, Kölliker-Fuse nucleus; NTS, nucleus tractus
solitarius; PB, parabrachial nuclei; PGi, paragigantocellular reticular nucleus; preBötC,
pre-Bötzinger complex; RTN, retrotrapezoid nucleus; rVRG, rostral ventral respiratory
group. B, Sagittal and transverse view of the location of the pre-Bötzinger complex. cNA,
caudal nucleus ambiguus; LRN, lateral reticular nucleus; rNA, rostral nucleus ambiguus;
VII, facial nucleus.
(From Rekling JC, Feldman JL: PreBötzinger complex and pacemaker neurons: hypothesized site
and kernel for respiratory rhythm generation. Annu Rev Physiol 60:385, 1998, with permission.)
Other Ventilatory Patterns
Cheyne–Stokes Breathing
Periodic, or Cheyne–Stokes, breathing suggests left ventricular failure or nervous system=
77dysfunction. Its original description by Cheyne was in a patient who died of heart
failure, but both CNS and cardiac dysfunction (or a combination of the two) can produce
78this ventilatory pattern.
The Cheyne–Stokes pattern is that of escalating hyperventilation followed by
decremental hypoventilation and nally apnea, which recurs in cycles. Cycle lengths of
7940 to 100 seconds have been reported in humans. Arterial blood gas assays during
Cheyne–Stokes breathing indicate a rising pH and a falling Paco , which become2
80maximal at the apnea point and never return to normal values (Fig. 1-13). Cheyne–
Stokes patterns are seen in 30 to 40 percent of patients in congestive heart failure, and
81-83Cheyne–Stokes breathing is associated with an increased mortality. This ventilatory
pattern also occurs in normal premature infants, during normal sleep, in subjects at high
altitude, and with equal frequency in association with supratentorial and infratentorial
80,84 85stroke. Associated changes in arousal, pupillary size, cardiac rhythm, heart rate,
86blood pressure, muscle tone, and consciousness may occur cyclically in patients with
Cheyne–Stokes breathing. The alterations in Paco also a. ect the cerebral vasculature,2
producing changes in the intracerebral volume of the vascular compartment with
associated alterations in cerebral blood-2ow and intracranial pressure. The periodicity of
80ventilation can be eliminated by intravenous theophylline or by oxygen inhalation.
FIGURE 1-13 Periodicity of arterial oxygen saturation (Sao ; upper trace), chest wall2
motion (middle trace), and CO concentration in the expired air (lower trace) in a stroke2
patient with Cheyne–Stokes respiration. The phase shift between the upper and middle
traces is due to the sampling time of the pulse oximeter of approximately 40 seconds. The
drops in CO concentration during hypopnea are due to dead space ventilation.2
(From Nachtmann MD, Siebler M, Rose G, et al: Cheyne-Stokes respiration in ischemic stroke.
Neurology 45:820, 1995, with permission.)=
=
=
Based on studies in patients with heart failure, the ventilatory oscillations result from
87Pco 2uctuations about the apneic threshold. The reciprocal fall in Po results from2 2
attenuated ventilatory drive. Cheyne–Stokes breathing is abolished by inhalation of CO2
88(increasing the Pco2 over the apneic point) but not by inhalation of oxygen.
A host of factors that might explain Cheyne–Stokes ventilatory oscillations has been
addressed experimentally and clinically. The possibility that a prolonged circulation time
may itself produce ventilatory oscillations by creating a feedback loop delay to central
receptors was classically considered as the factor responsible for the Cheyne–Stokes
ventilatory pattern. However, Ho. man and associates, studying patients with cardiogenic
pulmonary edema, found no di. erences in left ventricular ejection fractions in patients
89with or without Cheyne–Stokes breathing. Hall and colleagues found that circulatory
90delay did correlate with Cheyne–Stokes cycle length, but not with apnea length.
Lorenzi-Filho and co-workers showed that CO inhalation blocked Cheyne–Stokes2
breathing in patients with heart failure and argued that reduction in Paco sensed by2
88peripheral chemoreceptors triggered central apneas. The issue of an abnormal
feedback to the CNS in the genesis of respiratory oscillations was studied in animals by
91Cherniack who used the normal phrenic nerve stimulus to trigger a mechanical
ventilator that had been modi ed so that the gain could be varied to amplify or retard
the induced tidal volume triggered by the phrenic stimulus. This model produced
periodic ventilations when the gain was increased. Supporting the concept of abnormal
feedback loops generating Cheyne–Stokes breathing, ventilatory periodicity was
eliminated by destruction of peripheral chemoreceptors but was unchanged by vagotomy.
Furthermore, all animals had a persistent respiratory alkalosis. Duplicating observed
clinical phenomena, the oscillations were enhanced by hypoxia and eliminated by
increasing the oxygen or CO2 content of inspired air. Hypoxemia (during sleep) also
92induces Cheyne–Stokes breathing in humans.
Originally described as a variant of Cheyne–Stokes breathing, Biot breathing is
characterized by clusters of breaths having equal and regular inspiratory and expiratory
phases, rather than the spindle characteristics of Cheyne–Stokes breathing. The similarity
to Cheyne–Stokes breathing is in the separation of the ventilatory periods by apnea,
which in Biot breathing occurs in end-expiration. Although rst described in patients
with meningitis, a ganglioglioma involving the cerebellum and pons was responsible in
93 94one patient, and bihemispheric infarction in another.
Central Hyperventilation
Hyperventilation was thought, at one point, to be the respiratory pattern characteristic of
95midbrain dysfunction during transtentorial herniation. The exhaustion resulting from
such hyperventilation may be fatal; morphine or methadone will suppress the abnormal
96ventilatory drive.
A speci c midbrain localization for lesions pro-ducing this ventilatory pattern cannot
be supported any longer. Cases of isolated brainstem tumors and sustained tachypnea=
o. ered the possibility of an unambiguous anatomical localization of the source of this
ventilatory pattern. In some instances the pons or medulla was involved. Extra-axial
97medullary compression has also caused central hyperventilation. Central
hyperventilation has been associated with CNS lymphoma, the in ltrating nature of
98,99which has been suggested as the common feature in such cases. Table 1-1 shows the
incidence of various abnormal ventilatory patterns associated with lesions at di. erent
CNS sites.
TABLE 1-1 Incidence of Various Abnormal Ventilatory Patterns Associated With Lesions
at Different Central Nervous System Sites
The possibility of central stimulation of medullary chemoreceptors due to local lactate
production from tumors or stroke has been suggested to explain the lack of correlation
between anatomical lesion site and ventilatory pattern. However, a markedly alkaline
cerebrospinal 2uid (CSF) pH was reported in a patient with central hyperventilation and
100a pontine tumor.
Pulmonary congestion of neurogenic cause (neurogenic pulmonary edema) might
induce this respiratory pattern via stimulation of pulmonary receptors in the pulmonary
interstitial space. At the San Francisco General Hospital, the author saw three patients
with sustained tachypnea following stroke. Their in vivo lung water content was
measured with a double indicator dilution technique (by Dr. Frank Lewis), and no
elevation was found.
Alveolar Hypoventilation
Hypoventilation, hypoxia, and apnea are major risks in diseases of the anterior horn cells,
peripheral nerves, myoneural junctions, and muscles. Motor neuron disease,
polyneuropathy, myasthenia gravis, and the muscular dystrophies are, respectively, the=
101most common examples of such diseases that cause ventilatory disturbances. In part
because of the decreased exercise demands induced by the disease processes, dyspnea is
often absent and arterial blood gases may show little alteration immediately prior to fatal
ventilatory compromise. Furthermore, the amount of muscle weakness in extremity and
girdle muscles is often a poor predictor of ventilatory muscle function. Vincken and
associates examined this point and documented that maximal inspiratory
(diaphragmatic, intercostal, and accessory neck muscles) and expiratory (abdominal and
intercostal muscles) pressure measurements were required to assess the risk of respiratory
102compromise in patients with chronic neuromuscular disease. Unsuspected ventilatory
dysfunction was found in one half of the 30 patients studied, and in one third of patients,
it was severe. In no case was the ventilatory dysfunction clinically suspected. Traumatic
myelopathies or myelopathies resulting from in ltrative tumors produce ventilatory
insuQ ciency with lesions above the cervical roots innervating the phrenic nerve (C3, C4,
C5). Such patients’ ventilatory dysfunction has been successfully managed without
mechanical ventilation by electrical pacing of the diaphragm. In patients with lesions
between C3 and C5, this treatment is feasible if the C5 root is preserved below the level of
the lesion. Each of eight patients with traumatic tetraplegia reported by Vanderlinden
and co-workers were successfully weaned from ventilator support using this
103technique. Cervical and cortical magnetic stimulation have been used to assess
104diaphragm strength in patients proposed for phrenic pacing.
Although ventilatory compromise is often the terminal event in advanced motor neuron
disease, isolated respiratory insuQ ciency may be the presenting feature of the disease. In
patients with primary bulbar disease, sleep apnea or nocturnal hypoventilation occurs,
manifesting itself by both obstructive and central apnea. Orthopnea may be the
presenting symptom of motor neuron disease. Such patients have predominantly
diaphragmatic weakness, and this may be unilateral or bilateral. Paradoxical chest wall
and abdominal movements are seen during inspiration, and vital capacity is reduced,
especially when the patient is tested in the supine position. In this group of patients with
diaphragmatic weakness in the absence of bulbar impairment), symptomatic relief is
obtained with ventilatory support (CPAP or nocturnal intermittent positive pressure
105ventilation) without unwarranted prolongation of life. Continuous bimodal positive
105,106airway pressure (BiPAP) is now an important alternative to tracheostomy.
Ventilatory failure requiring mechanical assistance has been reported in 10 to 80
percent of patients with Guillain–Barré syndrome. Intubation and ventilation were needed
104in 43 percent of the 111 patients from the French plasmapheresis study and in 47
107percent of the 123 patients in the American study. The mean duration of the assisted
ventilation was 31 days in the French study, and it was reduced to 18 days by
plasmapheresis. Intubation is usually required when vital capacity falls below 18 ml/kg.
Sunderrajan and Davenport analyzed the presenting and early stages of their patients’
illness and were unable to identify any characteristics or neurological features that would
108predict the need for assisted ventilation. While the mean hospital day on which
intubation was required was 4.4, the range was broad (0 to 21 days). The hospital day on=
=
=
which the patient was extubated had an equally wide range: hospital days 5 to 90. Two
unusual cases required ventilatory support for more than a year. This experience suggests
that extubation will be successful when vital capacities exceed 1 liter. A detailed study of
diaphragmatic performance in patients with Guillain–Barré syndrome suggested that
improvement in the maximal transdiaphragmatic pressure was the best predictor of
recovery, and this measure was correlated with maximal inspiratory force, but not forced
109vital capacity. The duration of mechanical ventilatory support required in patients
with the Guillain–Barré syndrome was nearly halved by treatment with plasma exchange;
110treatment with intravenous gamma globulin is equivalent.
An acute, primary axonal degeneration of motor and sensory bers occurs in the
111setting of prolonged sepsis (approximately 2 weeks) with multiple organ failure. This
syndrome has been termed critical illness neuropathy and is described in detail in Chapter
52. The neuropathy is characterized clinically by distal weakness with reduced or absent
tendon re2exes; when it is severe, there is paralysis with are2exia. The syndrome is
frequently recognized only because of unexpected diQ culty in weaning patients from
assisted ventilation. Phrenic nerve conduction velocities have been abnormal, and
autopsy studies have shown axonal degeneration of the phrenic nerve, with denervation
112atrophy in the intercostal muscles and diaphragm. Complete recovery over a period of
6 months is the rule in mild and moderate cases, but patients with severe polyneuropathy
may fail to improve and have a fatal outcome. A similar syndrome of critical care
113,114myopathy is recognized, with a similar prognosis. Neuromuscular blockade and
113corticosteroid treatment may be risk factors, especially in transplant patients.
Temporary ventilatory support may be required in myasthenia gravis. Indications
include the post-thymectomy period and failure of outpatient pharmacological therapy.
Of 22 such patients seen at the Mayo Clinic, the duration of ventilatory support required
115 116was 1 to 32 days, with 1 to 41 days reported by O’Donohue and colleagues. Both
plasma exchange and intravenous immunoglobulin treatments may be useful in
117myasthenic crisis.
In patients with myopathy, ventilatory dysfunction may occur and may be
disproportionate to the severity of the muscle weakness. Although the poor prognosis in
the muscular dystrophies usually commits patients to ventilatory support for the remainder
of their lives, two patients with Duchenne muscular dystrophy were weaned from
39continual positive pressure ventilation with intermittent negative pressure techniques.
Recurrent episodes of ventilatory failure independent of muscle weakness have been
118reported in patients with mitochondrial myopathies. Patients have depressed
respiratory responses to hypoxia and often to hypercapnia as well. Life-threatening
hypoventilation often occurs in the setting of surgery, sedation, or infection. Reported
cases include typical Kearns-Sayre syndrome, MERRF (myoclonic epilepsy and ragged-red
bers) syndrome, and familial mitochondrial myopathy. No speci c biochemical defect
118has been found, although a defect in cytochrome-c oxidase has been suggested. The
119cause of the hypoventilation may be central rather than muscular.=
=
=
=
=
NERVOUS SYSTEM EFFECTS OF RESPIRATORY DYSFUNCTION
Hypoxia
Acute Hypoxia
The terms hypoxic and anoxic encephalopathy are frequently used to describe neurological
syndromes that occur following cardiac arrest. The encephalopathy, however, is due
primarily to cerebral ischemia. Acute hypoxia results in transient alterations of cognitive
function similar to those due to intoxication with alcohol. Hallucinations and alterations
in judgment and behavior are well known in mountain climbers at high altitudes.
Climbers to the Mt. Everest summit, at 8,854 meters (29,000 feet) have been studied to
determine the potential acute and long-term neurological de cits from hypoxia at these
altitudes. The results of simple tests of short-term memory (number recall) and simple
motor tasks ( nger tapping) are shown in Figure 1-14. Signi cant reductions in
performance in both tests were found immediately after the expedition, and signi cant
120impairments persisted 12 months later.
FIGURE 1-14 Results of nger-tapping and short-term memory tests performed before,
immediately after, and 1 year following an expedition to Mt. Everest.
(From West JB: Do climbs to extreme altitude cause brain damage? Lancet 2:387, 1986, with
permission.)
Neuropathological studies of the CNS in primates subjected to hypoxia have revealed
lesions only in the watershed distribution between major arterial territories. Thus, the
121e. ects of acute hypoxia on the brain are those of cerebral hypoperfusion. Structural
abnormalities do not occur in the brain in the setting of hypoxia without
122,123ischemia, However, polymerase chain reaction (PCR) techniques to
simultaneously amplify long random segments of DNA have shown that pure hypoxia for
30 minutes in vivo produces both nuclear and mitochondrial DNA damage, which have
124dissimilar repair kinetics.=
=
=
=
Hypercapnia
Chronic Hypercapnia
A reversible syndrome of headache, papilledema, and impaired consciousness with
“tremor of the extremities” has been described in patients with chronic pulmonary
125insufficiency. Tremulousness is most prominent with the ngers outstretched and has
the characteristics of an action tremor or the features of asterixis; in some patients, it
resembles myoclonus. The headaches are attributed to the increased intracranial
125pressure. Arterial oxygen saturations in one study ranged from 81 to 94 percent (but
may be as low as 40%), and the Paco levels ranged from 39 to 68 mmHg (but can be2
higher). The electroencephalogram shows slowing in the theta or delta range. The
etiology of such CO2 narcosis is probably multifactorial, including hypercapnia, hypoxia,
and elevated intracranial pressure. The increased intracranial pressure may produce
126papilledema that can progress to blindness. Ventilatory support and discontinuation
of sedative drugs constitute effective treatment.
Acute Hypercapnia
Nervous system abnormalities from hypercapnia are related in signi cant measure to the
rate of increase of Paco . The rapid di. usibility of carbon dioxide across the blood–brain2
barrier produces a prompt fall in CSF pH in respiratory acidosis, a decrease that does not
+occur in metabolic acidosis. A potent inhibitory e. ect of H upon the postsynaptic
receptor for glutamate, the brain’s major excitatory neurotransmitter, has been described
127and may be responsible for the acute encephalopathy of hypercapnia.
Hypocapnia
Acute Hypocapnia
Acute hypocapnia occurs during hyperventilation. The symptom complex of dizziness,
lightheadedness, faintness, paresthesias, and impaired consciousness can be reproduced
in normal subjects during hyperventilation, supporting a cause-and-e. ect relationship
between acute hypocapnia and the symptoms of the hyperventilation syndrome (Table
12), although some have found hyperventilation as a consequence, rather than a cause, of
128 129the attacks. Asthma was signi cantly associated in one series. This syndrome has
its maximal incidence during the third decade. Distal paresthesias are notable and may
be asymmetric, prompting evaluation for a more sinister cause. Alteration or loss of
consciousness is common (31% in the series of Perkin and Joseph; Table 1-2), leading to
an inappropriate diagnosis of epilepsy. Symptoms can often be reproduced by voluntary
hyperventilation, and the electroencephalographic ndings while the patient is
symptomatic can help to exclude a diagnosis of seizure disorder. The e. ects of
hypocapnia include cerebral vasoconstriction, alteration in the ionic balance of calcium,
and a shift in the oxyhemoglobin dissociation curve with reduced delivery of oxygen to
peripheral tissues. A combination of these events is responsible for the clinical symptoms.=
Symptoms During Attacks in 78 Patients With Hyperventilation Syndrome*TABLE 1-2
Symptoms Number Percent
N e u r o l o g i c a l
Giddiness 46 59
Paresthesias 28 36
Loss of consciousness 24 31
Visual disturbance 22 28
Headache 17 22
Ataxia 14 18
Tremor 8 10
Tinnitus 2 3
C a r d i o r e s p i r a t o r y
Dyspnea 41 53
Palpitations 33 42
Chest discomfort 6 8
G a s t r o i n t e s t i n a l
Nausea 15 16
Abdominal pain 1 1
Vomiting 1 1
* Most patients had more than one symptom.
From Perkin GD, Joseph R: Neurological manifestations of the hyperventilation syndrome. J R Soc
Med 79:448, 1986, with permission.
Chronic Hypocapnia
Fixed respiratory alkalosis is a common or even diagnostic nding in a number of
metabolic disorders, the most prominent being hepatic encephalopathy; sepsis and
salicylate poisoning are additional examples. However, the role of the alkalosis itself in
causing CNS dysfunction is uncertain. Potential mechanisms by which alkalosis may
a. ect the brain include a shift in the oxyhemoglobin dissociation curve (which decreases
oxygen availability to tissues), a decrease in cerebral blood-2ow resulting from cerebral
vasoconstriction, and alkalosis-induced hypophosphatemia. Posner and Plum also found
that control of the alkalosis by mechanical ventilation did not alter the encephalopathic
130manifestations in patients with hepatic failure. Accordingly, alkalosis per se appears
to have a minimal effect on the CNS.=
HICCUP
131Persistent or intractable hiccup is an abnormality resulting from many systemic,
132 133pharmacological, and CNS causes, including brainstem neoplasm, multiple
134 135sclerosis, and thoracic herpes zoster. It may also occur with cortical
136,137pathology. Cases of intractable hiccup are much more common in men than
138women. Hiccup results from CNS-induced synchronous contraction of the diaphragm
and the external (inspiratory) intercostal muscles, followed rapidly by inhibition of
139expiratory intercostal muscles and glottal closure. The glottal closure minimizes air
exchange. However, with tracheostomy, the induced ventilatory movements of hiccup
139,140cause air exchange, and a respiratory alkalosis is produced.
The frequency, but not amplitude, of hiccuping is modulated by arterial Paco2. Hiccup
frequency is reduced with elevated Paco levels and increased with a fall in arterial2
139Paco . This observation is in keeping with the traditional cure for hiccups—breath-2
holding. Another common lay remedy for hiccup is swallowing or pharyngeal
stimulation, maneuvers that may increase vagal tone. Thus, hiccups are most common at
maximal inspiration because vagal a. erents are inhibited by maximal lung in2ation.
High-frequency diaphragmatic 2utter, responsive to carbamazepine, is responsible for
137hiccups in some patients. Chlorpromazine remains the most popular pharmacological
141-143treatment, although baclofen and gabapentin are now also popular ; a host of
144other approaches has been suggested.
SNEEZING
The coordinated act of sneezing arises from a caudal brainstem center near the nucleus
145ambiguus. A medullary mass lesion or lateral medullary syndrome can prevent
146-148sneezing despite the urge to do so.
Cortical input to sneezing has long been recognized. The central mediation of sneezing
149was noted by Pen eld and Jasper in a patient during temporal lobe stimulation when
both sneezing and chewing movements were induced. A common re2ex that induces
150sneezing is that which occurs on sudden exposure to bright light. This re2ex was
found in 80 percent of the families of medical students in whom the phenomenon of
light-induced sneezing was reported. It has been suggested that this re2ex is inherited in
151an autosomal dominant manner.
YAWNING
152Yawning is coordinated from brainstem sites near the paraventricular nucleus via
153extrapyramidal pathways using a number of neurotransmitters and neuropeptides.
This re2ex may occur in patients “locked in” from pontine transection who have
154nonvolitional mouth opening with spontaneous yawns. Yawning in the setting of a
pyramidal lesion (capsular infarction) may be associated with arm stretching in the155paretic limb, supporting the involvement of extrapyramidal circuitry. Cortical input
156also occurs, as reflected by the yawning related to boredom and somnolence. Yawning
149has been seen to initiate a temporal lobe seizure.
REFERENCES
1 Hux W. A new view of Starling’s hypothesis at the microstructural level. Microvasc Res.
1999;58:281.
2 Simon RP. Neurogenic pulmonary edema. Neurol Clin. 1993;11:309.
3 Rogers FB, Shackford SR, Trevisani GT, et al. Neurogenic pulmonary edema in fatal and
nonfatal head injuries. J Trauma. 1995;39:860.
4 Simon RP, Bayne LL. Pulmonary lymphatic flow alterations during intracranial
hypertension in sheep. Ann Neurol. 1984;15:188.
5 McClellan MD, Dauber IM, Weil JV. Elevated intracranial pressure increases pulmonary
vascular permeability to protein. J Appl Physiol. 1989;67:1185.
6 Maron MB, Holcomb PH, Dawson CA, et al. Edema development and recovery in
neurogenic pulmonary edema. J Appl Physiol. 1994;77:1155.
7 Bosso FJ, Lang SA, Maron MB. Role of hemodynamics and vagus nerves in development of
fibrin-induced pulmonary edema. J Appl Physiol. 1990;69:2227.
8 Lane SM, Maender KC, Awender NE, et al. Adrenal epinephrine increases alveolar liquid
clearance in a canine model of neurogenic pulmonary edema. Am J Respir Crit Care Med.
1998;158:760.
9 Brown RHJr, Beyerl BD, Iseke R, et al. Medulla oblongata edema associated with
neurogenic pulmonary edema. Case report. J Neurosurg. 1986;64:494.
10 Keegan MT, Lanier WL. Pulmonary edema after resection of a fourth ventricle tumor:
possible evidence for a medulla-mediated mechanism. Mayo Clin Proc. 1999;74:264.
11 Inobe JJ, Mori T, Ueyama H, et al. Neurogenic pulmonary edema induced by primary
medullary hemorrhage: a case report. J Neurol Sci. 2000;172:73.
12 Darragh TM, Simon RP. Nucleus tractus solitarius lesions elevate pulmonary arterial
pressure and lymph flow. Ann Neurol. 1985;17:565.
13 Simon RP, Gean-Marton AD, Sander JE. Medullary lesion inducing pulmonary edema: a
magnetic resonance imaging study. Ann Neurol. 1991;30:727.
14 Crawley F, Saddeh I, Barker S, et al. Acute pulmonary oedema: presenting symptom of
multiple sclerosis. Mult Scler. 2001;7:71.
15 Nolan MA, Craig ME, Lahra MM, et al. Survival after pulmonary edema due to
enterovirus 71 encephalitis. Neurology. 2003;60:1651.
16 Bayne LL, Simon RP. Systemic and pulmonary vascular pressures during generalized
seizures in sheep. Ann Neurol. 1981;10:566.
17 Simon RP, Bayne LL, Tranbaugh RF, et al. Elevated pulmonary lymph flow and protein
content during status epilepticus in sheep. J Appl Physiol. 1982;52:91.
18 Johnston SC, Darragh TM, Simon RP. Postictal pulmonary edema requires pulmonary
vascular pressure increases. Epilepsia. 1996;37:428.19 Maron MB. Analysis of airway fluid protein concentration in neurogenic pulmonary
edema. J Appl Physiol. 1987;62:470.
20 West JB, Mathieu-Costello O. Structure, strength, failure, and remodeling of the
pulmonary blood-gas barrier. Annu Rev Physiol. 1999;61:543.
21 Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human neurogenic
pulmonary edema. Chest. 1997;111:1326.
22 Bogousslavsky J, Khurana R, Deruaz JP, et al. Respiratory failure and unilateral caudal
brainstem infarction. Ann Neurol. 1990;28:668.
23 Kraus J, Heckmann JG, Druschky A, et al. Ondine’s curse in association with diabetes
insipidus following transient vertebrobasilar ischemia. Clin Neurol Neurosurg.
1999;101:196.
24 Strauser LM, Helikson MA, Tobias JD. Anesthetic care for the child with congenital
central alveolar hypoventilation syndrome (Ondine’s curse). J Clin Anesth. 1999;11:431.
25 Ono S, Takahashi K, Jinnai K, et al. Loss of catecholaminergic neurons in the medullary
reticular formation in myotonic dystrophy. Neurology. 1998;51:1121.
26 Auer RN, Rowlands CG, Perry SF, et al. Multiple sclerosis with medullary plaques and
fatal sleep apnea (Ondine’s curse). Clin Neuropathol. 1996;15:101.
27 Munschauer FE, Loh L, Bannister R, et al. Abnormal respiration and sudden death during
sleep in multiple system atrophy with autonomic failure. Neurology. 1990;40:677.
28 Glass GA, Josephs KA, Ahlskog JE. Respiratory insufficiency as the primary presenting
symptom of multiple-system atrophy. Arch Neurol. 2006;63:978.
29 Lanczik O, Szabo K, Lecei O, et al. Central respiratory dysfunction following vertebral
artery dissection. Neurology. 2006;66:944.
30 Tranmer BI, Tucker WS, Bilbao JM. Sleep apnea following percutaneous cervical
cordotomy. Can J Neurol Sci. 1987;14:262.
31 Morrell MJ, Heywood P, Moosavi SH, et al. Unilateral focal lesions in the rostrolateral
medulla influence chemosensitivity and breathing measured during wakefulness, sleep,
and exercise. J Neurol Neurosurg Psychiatry. 1999;67:637.
32 Nogues M, Gene R, Benarroch E, et al. Respiratory disturbances during sleep in
syringomyelia and syringobulbia. Neurology. 1999;52:1777.
33 Bradley TD, Shapiro CM. ABC of sleep disorders. Unexpected presentations of sleep
apnoea: use of CPAP in treatment. BMJ. 1993;306:1260.
34 Turner WA, Critchley M. Respiratory disorders in epidemic encephalitis. Brain.
1925;48:72.
35 Kim R. The chronic residual respiratory disorder in post-encephalitis parkinsonism. J
Neurol Neurosurg Psychiatry. 1968;31:393.
36 Vincken WG, Gauthier SG, Dollfuss RE, et al. Involvement of upper-airway muscles in
extrapyramidal disorders. A cause of airflow limitation. N Engl J Med. 1984;311:438.
37 Boggard JM, Hovestadt A, Meervaldt J, et al. Maximum expiratory and inspiratory
flowvolume curves in Parkinson’s disease. Am Rev Respir Dis. 1989;39:610.
38 Zupnick HM, Brown LK, Miller A, et al. Respiratory dysfunction due to L-dopa therapy forparkinsonism: diagnosis using serial pulmonary function tests and respiratory inductive
plethysmography. Am J Med. 1990;89:109.
39 Braun N, Abd A, Baer J, et al. Dyspnea in dystonia. A functional evaluation. Chest.
1995;107:1309.
40 Macefield G, Gandevia SC. The cortical drive to human respiratory muscles in the awake
state assessed by premotor cerebral potentials. J Physiol. 1991;439:545.
41 Ramsay SC, Adams L, Murphy K, et al. Regional cerebral blood flow during volitional
expiration in man: a comparison with volitional inspiration. J Physiol. 1993;461:85.
42 Corfield DR, Murphy K, Guz A. Does the motor cortical control of the diaphragm ‘bypass’
the brain stem respiratory centres in man? Respir Physiol. 1998;114:109.
43 Cohen E, Mier A, Heywood P, et al. Diaphragmatic movement in hemiplegic patients
measured by ultrasonography. Thorax. 1994;49:890.
44 Przedborski S, Brunko E, Hubert M, et al. The effect of acute hemiplegia on intercostal
muscle activity. Neurology. 1998;38:1882.
45 Bassetti C, Aldrich MS, Quint D. Sleep-disordered breathing in patients with acute
supraand infratentorial strokes. A prospective study of 39 patients. Stroke. 1997;28:1765.
46 Lee HW, Hoang SB, Tae WA, et al. Partial seizures manifesting as apnea only in an adult.
Epilepsia. 1991;40:1828.
47 Nashef L, Walker F, Allen P, et al. Apnoea and bradycardia during epileptic seizures:
relation to sudden death in epilepsy. J Neurol Neurosurg Psychiatry. 1996;60:297.
48 Haouzi P, Chenuel B, Barroche G. Interactions between volitional and automatic
breathing during respiratory apraxia. Respir Physiol Neurobiol. 2006;152:169.
49 Plum F, Brown HW, Snoep E. Neurologic significance of post-hyperventilation apnea.
JAMA. 1962;181:1050.
50 Haldane JS, Poulton EP. The effects of want of oxygen on respiration. J Physiol.
1908;37:390.
51 Meah MS, Gardner WN. Post-hyperventilation apnoea in conscious humans. J Physiol.
1994;477:527.
52 Jennett S, Ashbridge K, North JB. Post-hyperventilation apnoea in patients with brain
damage. J Neurol Neurosurg Psychiatry. 1974;37:288.
53 Chin K, Ohi M, Fukui M, et al. Inhibitory effect of an intellectual task on breathing after
voluntary hyperventilation. J Appl Physiol. 1996;81:1379.
54 Xu F, Frazier DT. Medullary respiratory neuronal activity modulated by stimulation of the
fastigial nucleus of the cerebellum. Brain Res. 1995;705:53.
55 Colebatch JG, Adams L, Murphy K, et al. Regional cerebral blood flow during volitional
breathing in man. J Physiol (Lond). 1991;443:91.
56 Gozal D, Omidvar O, Kirlew KA, et al. Functional magnetic resonance imaging reveals
brain regions mediating the response to resistive expiratory loads in humans. J Clin
Invest. 1996;97:47.
57 Maria BL, Hoang KB, Tusa RJ, et al. “Joubert syndrome” revisited: key ocular motor signs
with magnetic resonance imaging correlation. J Child Neurol. 1997;12:423.58 Lumsden T. Observation on the respiratory centres in the cat. J Physiol (Lond).
1923;57:153.
59 Song G, Yu Y, Poon CS. Cytoarchitecture of pneumotaxic integration of respiratory and
nonrespiratory information in the rat. J Neurosci. 2006;26:300.
60 St. John WM, Zhou D. Rostral pontile mechanisms regulate durations of expiratory
phases. J Appl Physiol. 1991;71:2133.
61 Schmid K, Foutz AS, Denavit-Saubie M. Inhibitions mediated by glycine and GABAA
receptors shape the discharge pattern of bulbar respiratory neurons. Brain Res.
1996;710:150.
62 Chamberlin NL, Saper CB. Topographic organization of respiratory responses to
glutamate microstimulation of the parabrachial nucleus in the rat. J Neurosci.
1994;14:6500.
63 Wang W, Fung ML, St. John WM. Pontile regulation of ventilatory activity in the adult
rat. J Appl Physiol. 1993;74:2801.
64 Fung ML, Wang W, St. John WM. Involvement of pontile NMDA receptors in inspiratory
termination in rat. Respir Physiol. 1994;96:177.
65 Haji A, Okazaki M, Yamazaki H, et al. NMDA receptor-mediated inspiratory off-switching
in pneumotaxic-disconnected cats. Neurosci Res. 1998;32:323.
66 Haji A, Pierrefiche O, Takeda R, et al. Membrane potentials of respiratory neurones
during dizocilpine-induced apneusis in adult cats. J Physiol (Lond). 1996;495:851.
67 Wilken B, Lalley P, Bischoff AM, et al. Treatment of apneustic respiratory disturbance
with a serotonin-receptor agonist. J Pediatr. 1997;130:89.
68 Saito Y, Hashimoto T, Iwata H, et al. Apneustic breathing in children with brainstem
damage due to hypoxic-ischemic encephalopathy. Dev Med Child Neurol. 1999;41:560.
69 Mador MJ, Tobin MJ. Apneustic breathing. A characteristic feature of brainstem
compression in achondroplasia? Chest. 1990;97:877.
70 Wagner PG, Dekin MS. GABAb receptors are coupled to a barium-insensitive outward
rectifying potassium conductance in premotor respiratory neurons. J Neurophysiol.
1993;69:286.
71 Abrahams TP, Hornby PJ, Walton DP, et al. An excitatory amino acid(s) in the
ventrolateral medulla is (are) required for breathing to occur in the anesthetized cat. J
Pharmacol Exp Ther. 1991;259:1388.
72 St. John WM. Neurogenesis, control, and functional significance of gasping. J Appl Physiol.
1990;68:1305.
73 Smith JC, Ellenberger HH, Ballanyi K, et al. Pre-Botzinger complex: a brainstem region
that may generate respiratory rhythm in mammals. Science. 1991;254:726.
74 Solomon IC. Glutamate neurotransmission is not required for, but may modulate, hypoxic
sensitivity of pre-Botzinger complex in vivo. J Neurophysiol. 2005;93:1278.
75 Ramirez JM, Richter DW. The neuronal mechanisms of respiratory rhythm generation.
Curr Opin Neurobiol. 1996;6:817.
76 Koshiya N, Smith JC. Neuronal pacemaker for breathing visualized in vitro. Nature.
1999;400:360.77 Naughton MT. Pathophysiology and treatment of Cheyne-Stokes respiration. Thorax.
1998;53:514.
78 Nopmaneejumruslers C, Kaneko Y, Hajek V, et al. Cheyne-Stokes respiration in stroke:
relationship to hypocapnia and occult cardiac dysfunction. Am J Respir Crit Care Med.
2005;171:1048.
79 Lange RI, Hecht HH. The mechanism of Cheyne-Stokes respiration. J Clin Invest.
1962;41:42.
80 Nachtmann A, Siebler M, Rose G, et al. Cheyne-Stokes respiration in ischemic stroke.
Neurology. 1995;45:820.
81 Ponikowski P, Anker SD, Chua TP, et al. Oscillatory breathing patterns during
wakefulness in patients with chronic heart failure: clinical implications and role of
augmented peripheral chemosensitivity. Circulation. 1999;100:2418.
82 Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes
respiration in patients with congestive heart failure. Am J Respir Crit Care Med.
1996;153:272.
83 Leung RS, Floras JS, Bradley TD. Respiratory modulation of the autonomic nervous
system during Cheyne-Stokes respiration. Can J Physiol Pharmacol. 2006;84:61.
84 Khoo MC, Anholm JD, Ko SW, et al. Dynamics of periodic breathing and arousal during
sleep at extreme altitude. Respir Physiol. 1996;103:33.
85 Gonyea EF. The abnormal pupil in Cheyne-Stokes respiration. Case report. J Neurosurg.
1990;72:810.
86 Leung RS, Bradley TD. Respiratory modulation of heart rate and blood pressure during
Cheyne-Stokes respiration. J Electrocardiol. 2003;36(suppl):213.
87 Hanly P, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respiration in patients with
congestive heart failure. Relationship to arterial PCO2. Chest. 1993;104:1079.
88 Lorenzi-Filho G, Rankin F, Bies I, et al. Effects of inhaled carbon dioxide and oxygen on
Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med.
1999;159:1490.
89 Hoffman R, Agatston A, Krieger B. Cheyne-Stokes respiration in patients recovering from
acute cardiogenic pulmonary edema. Chest. 1990;97:410.
90 Hall MJ, Xie A, Rutherford R, et al. Cycle length of periodic breathing in patients with
and without heart failure. Am J Respir Crit Care Med. 1996;154:376.
91 Cherniack NS, Longobardo G, Evangelista CJ. Causes of Cheyne-Stokes respiration.
Neurocrit Care. 2005;3:271.
92 Cherniack NS. Apnea and periodic breathing during sleep. N Engl J Med. 1999;341:985.
93 Kuna ST, Smickley JS, Murchison LC. Hypercarbic periodic breathing during sleep in a
child with a central nervous system tumor. Am Rev Respir Dis. 1990;142:880.
94 Freeman WD, Sen S, Roy TK, et al. Cluster breathing associated with bihemispheric
infarction and sparing of the brainstem. Arch Neurol. 2006;63:1487.
95 Plum F, Posner JB. The Diagnosis of Stupor and Coma, 3rd Ed. Philadelphia: FA Davis,
1980.96 Jaeckle KA, Digre KB, Jones CR, et al. Central neurogenic hyperventilation:
pharmacologic intervention with morphine sulfate and correlative analysis of
respiratory, sleep, and ocular motor dysfunction. Neurology. 1990;40:1715.
97 Dubaybo BA, Afridi I, Hussain M. Central neurogenic hyperventilation in invasive
laryngeal carcinoma. Chest. 1991;99:767.
98 Shibata Y, Meguro K, Narushima K, et al. Malignant lymphoma of the central nervous
system presenting with central neurogenic hyperventilation. Case report. J Neurosurg.
1992;76:696.
99 Tarulli AW, Lim C, Bui JD, et al. Central neurogenic hyperventilation: a case report and
discussion of pathophysiology. Arch Neurol. 2005;62:1632.
100 Siderowf AD, Balcer LJ, Kenyon LC, et al. Central neurogenic hyperventilation in an
awake patient with a pontine glioma. Neurology. 1996;46:1160.
101 Sivak ED, Shefner JM, Sexton J. Neuromuscular disease and hypoventilation. Curr Opin
Pulm Med. 1999;5:355.
102 Vincken W, Elleker MG, Cosio MG. Determinants of respiratory muscle weakness in
stable chronic neuromuscular disorders. Am J Med. 1987;82:53.
103 Vanderlinden RG, Epstein SW, Hyland RH, et al. Management of chronic ventilatory
insufficiency with electrical diaphragm pacing. Can J Neurol Sci. 1988;15:63.
104 Efficiency of plasma exchange in Guillain-Barré syndrome: role of replacement fluids.
French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Ann Neurol.
1987;22:753.
105 Lo Coco D, Marchese S, Pesco MC, et al. Noninvasive positive-pressure ventilation in
ALS: predictors of tolerance and survival. Neurology. 2006;67:761.
106 Aboussouan LS, Khan SU, Meeker DP, et al. Effect of noninvasive positive-pressure
ventilation on survival in amyotrophic lateral sclerosis. Ann Intern Med. 1997;127:450.
107 Plasmapheresis and acute Guillain-Barré syndrome. The Guillain-Barré Syndrome Study
Group. Neurology. 1985;35:1096.
108 Sunderrajan EV, Davenport J. The Guillain-Barré syndrome: pulmonary-neurologic
correlations. Medicine (Baltimore). 1985;64:333.
109 Borel CO, Tilford C, Nichols DG, et al. Diaphragmatic performance during recovery from
acute ventilatory failure in Guillain-Barré syndrome and myasthenia gravis. Chest.
1991;99:444.
110 Randomised trial of plasma exchange, intravenous immunoglobulin, and combined
treatments in Guillain-Barré syndrome. Plasma Exchange/Sandoglobulin Guillain-Barré
Syndrome Trial Group. Lancet. 1997;349:225.
111 Zochodne DW, Bolton CF, Wells GA, et al. Critical illness polyneuropathy. A
complication of sepsis and multiple organ failure. Brain. 1987;110:819.
112 Witt NJ, Zochodne DW, Bolton CF, et al. Peripheral nerve function in sepsis and
multiple organ failure. Chest. 1991;99:176.
113 Lacomis D, Giuliani MJ, Van Cott A, et al. Acute myopathy of intensive care: clinical,
electromyographic, and pathological aspects. Ann Neurol. 1996;40:645.
114 Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in the intensivecare unit: a study of ninety-two patients. Muscle Nerve. 1998;21:610.
115 Gracey DR, Divertie MB, Howard FMJr. Mechanical ventilation for respiratory failure in
myasthenia gravis. Two-year experience with 22 patients. Mayo Clin Proc. 1983;58:597.
116 O’Donohue WJJr, Baker JP, Bell GM, et al. Respiratory failure in neuromuscular disease.
Management in a respiratory intensive care unit. JAMA. 1976;235:733.
117 Qureshi AI, Choudhry MA, Akbar MS, et al. Plasma exchange versus intravenous
immunoglobulin treatment in myasthenic crisis. Neurology. 1999;52:629.
118 Barohn RJ, Clanton T, Sahenk Z, et al. Recurrent respiratory insufficiency and depressed
ventilatory drive complicating mitochondrial myopathies. Neurology. 1990;40:103.
119 Ono S, Takahashi K, Kanda F, et al. Decrease of neurons in the medullary arcuate
nucleus in myotonic dystrophy. Acta Neuropathol (Berl). 2001;102:89.
120 West JB. Do climbs to extreme altitude cause brain damage? Lancet. 1986;2:387.
121 Graham DI. Hypoxia and vascular disorders. In: Adams JH, Duchen LW, editors.
Greenfield’s Neuropathology. 5th Ed. New York: Oxford University Press; 1992:153.
122 Pearigen P, Gwinn R, Simon RP. The effects in vivo of hypoxia on brain injury. Brain
Res. 1996;725:184.
123 Miyamoto O, Auer RN. Hypoxia, hyperoxia, ischemia, and brain necrosis. Neurology.
2000;54:362.
124 Englander EW, Greeley GHJr, Wang G, et al. Hypoxia-induced mitochondrial and
nuclear DNA damage in the rat brain. J Neurosci Res. 1999;58:262.
125 Austen FK, Carmichael MW, Adams RD. Neurologic manifestations of chronic pulmonary
insufficiency. N Engl J Med. 1957;257:579.
126 O’Halloran HS, Berger JR, Baker RS, et al. Optic nerve edema as a consequence of
respiratory disease. Neurology. 1999;53:2204.
127 Tang CM, Dichter M, Morad M. Modulation of the N-methyl-D-aspartate channel by
+extracellular H . Proc Natl Acad Sci U S A. 1990;87:6445.
128 Hornsveld HK, Garssen B, Dop MJ, et al. Double-blind placebo-controlled study of the
hyperventilation provocation test and the validity of the hyperventilation syndrome.
Lancet. 1996;348:154.
129 Saisch SG, Wessely S, Gardner WN. Patients with acute hyperventilation presenting to
an inner-city emergency department. Chest. 1996;110:952.
130 Posner JB, Plum F. Toxic effects of carbon dioxide and acetazolamide in hepatic
encephalopathy. J Clin Invest. 1980;39:1246.
131 Launois S, Bizec JL, Whitelaw WA, et al. Hiccup in adults: an overview. Eur Respir J.
1993;6:563.
132 Lauterbach EC. Hiccup and apparent myoclonus after hydrocodone: review of the
opiate-related hiccup and myoclonus literature. Clin Neuropharmacol. 1999;22:87.
133 Nagayama T, Kaji M, Hirano H, et al. Intractable hiccups as a presenting symptom of
cerebellar hemangioblastoma. Case report. J Neurosurg. 2004;100:1107.
134 Funakawa I, Terao A. Intractable hiccups and syncope in multiple sclerosis. Acta Neurol
Scand. 1998;98:136.135 Berlin AL, Muhn CY, Billick RC. Hiccups, eructation, and other uncommon prodromal
manifestations of herpes zoster. J Am Acad Dermatol. 2003;49:1121.
136 Jansen PHP, Joosten EMG, Vingerhoets HM. Persistent periodic hiccups following brain
abscess: a case report. J Neurol Sci. 1991;103:144.
137 Vantrappen G, Decramer M, Harlet R. High-frequency diaphragmatic flutter: symptoms
and treatment by carbamazepine. Lancet. 1992;339:265.
138 Liaw CC, Wang CH, Chang HK, et al. Gender discrepancy observed between
chemotherapy-induced emesis and hiccups. Support Care Cancer. 2001;9:435.
139 Newsom-Davis J. An experimental study of hiccup. Brain. 1970;93:851.
140 Campbell LA, Schwartz SH. An unusual cause of respiratory alkalosis. Chest.
1991;100:1159.
141 Friedman NL. Hiccups: a treatment review. Pharmacotherapy. 1996;16:986.
142 Petroianu G, Hein G, Petroianu A, et al. Idio-pathic chronic hiccup: combination therapy
with cisapride, omeprazole, and baclofen. Clin Ther. 1997;19:1031.
143 Hernandez JL, Pajaron M, Garcia-Regata O, et al. Gabapentin for intractable hiccup. Am
J Med. 2004;117:79.
144 Kolodzik PW, Eilers MA. Hiccups (singultus): review and approach to management. Ann
Emerg Med. 1991;20:565.
145 Nonaka S, Unno T, Ohta Y, et al. Sneeze-evoking region within the brainstem. Brain Res.
1990;511:265.
146 Martin RA, Handel SF, Aldama AE. Inability to sneeze as a manifestation of medullary
neoplasm. Neurology. 1991;41:1675.
147 Hersch M. Loss of ability to sneeze in lateral medullary syndrome. Neurology.
2000;54:520.
148 Seijo-Martinez M, Varela-Freijanes A, Grandes J, et al. Sneeze related area in the
medulla: localisation of the human sneezing centre? J Neurol Neurosurg Psychiatry.
2006;77:559.
149 Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain.
Boston: Little, Brown, 1954.
150 Whitman BW, Packer RJ. The photic sneeze reflex: literature review and discussion.
Neurology. 1993;43:868.
151 Peroutka SJ, Peroutka LA. Autosomal dominant transmission of the “photic sneeze
reflex”. N Engl J Med. 1984;310:599.
152 Sato-Suzuki I, Kita I, Oguri M, et al. Stereotyped yawning responses induced by
electrical and chemical stimulation of paraventricular nucleus of the rat. J Neurophysiol.
1998;80:2765.
153 Argiolas A, Melis MR. The neuropharmacology of yawning. Eur J Pharmacol. 1998;343:1.
154 Krasnianski M, Gaul C, Neudecker S, et al. Yawning despite trismus in a patient with
locked-in syndrome caused by a thrombosed megadolichobasilar artery. Clin Neurol
Neurosurg. 2003;106:44.
155 Wimalaratna HS, Capildeo R. Is yawning a brainstem phenomenon? Lancet. 1988;1:300.156 Perriol MP, Monaca C. “One person yawning sets off everyone else”. J Neurol Neurosurg
Psychiatry. 2006;77:3.+
Chapter 2
Neurological Complications of Aortic Disease and
Surgery
Douglas S. Goodin
CLINICAL NEUROLOGICAL SYNDROMES DUE TO AORTIC PATHOLOGY
Spinal Cord Ischemia
Anatomy
Ischemic Cord Syndromes
Cerebral Ischemia
Anatomy
Strokes and Transient Ischemic Attacks
Peripheral Neuropathy
Mononeuropathies
Radiculopathies
Polyneuropathies
Autonomic Neuropathies
AORTIC DISEASES AND SURGERY
Aortitis
Syphilitic Aortitis
Takayasu’s Arteritis
Giant Cell Arteritis
Aortic Aneurysms
Nondissecting Aneurysms
Dissecting Aortic Aneurysms
Traumatic Aortic Aneurysm
Coarctation of the Aorta
Surgery and Other Procedures
Aortic Surgery
Aortography and Other Procedures on the Aorta
Intraoperative Adjuncts to Avoid Spinal Cord Ischemia
The aorta is the main conduit through which the heart supplies blood to the body,
including the brain, brainstem, and spinal cord. In addition, this vessel is situated close to
important neural structures. In consequence, both disease of the aorta and operations on
it may have profound but variable e ects on nervous system function. Often the
neurological syndrome produced by aortic disease or surgery depends more on the part of+
the aorta involved than on the nature of the pathological process itself. For example,
either syphilis or atherosclerosis may produce symptoms of cerebral ischemia if the
disease a ects the aortic arch or of spinal cord ischemia if the pathological process is in
the descending thoracic aorta. Even when the nature of the pathological process is
important in determining the resultant neurological syndrome, several diseases may result
in the same pathological process. Thus, atherosclerosis, infection, in. ammation, and
trauma may each result in the formation of aortic aneurysms; similarly, coarctation of the
aorta may be congenital, a result of Takayasu’s arteritis, or a sequela of radiation
exposure during childhood.
The initial focus of this chapter is on the three major areas of neurological dysfunction
resulting from aortic disease and surgery: spinal cord ischemia, cerebral ischemia, and
peripheral neuropathy. Speci4c conditions that merit special consideration are then
discussed individually. The normal anatomical relationships are also considered in order
to provide insight into the pathogenesis of the resulting neurological syndromes.
CLINICAL NEUROLOGICAL SYNDROMES DUE TO AORTIC PATHOLOGY
Aortic disease may produce a variety of neurological syndromes. The speci4c syndrome
depends to a large extent on the site of involvement along the aorta.
Spinal Cord Ischemia
Anatomy
Embryological Development
During embryological development, primitive blood vessels arise along the spinal nerve
roots bilaterally and at each segmental level. Each of these segmental vessels then divides
into anterior and posterior branches, which ramify extensively on the surfaces of the
developing spinal cord. As development proceeds, most of these vessels regress and a few
enlarge, so that by birth, the blood supply to the spinal cord depends on a small but
1-11highly variable number of persisting segmental vessels (Fig. 2-1). In the thoracic
region, where the aorta is situated to the left of the midline, the persisting vessels entering
5,6,8the spinal canal are those from the left in 70 to 80 percent of cases.+
+
FIGURE 2-1 Extraspinal contributions to the anterior spinal arteries showing the three
arterial territories. In the cervical region, an average of three arteries (derived from the
vertebral arteries and the costocervical trunk) supply the anterior spinal artery. The
anterior spinal artery is narrowest in the midthoracic region, often being di? cult to
distinguish from other small arteries on the anterior surface of the cord; occasionally it is
discontinuous with the anterior spinal artery above and below. In addition, this region is
often supplied by only a single small radiculomedullary vessel. The lumbosacral territory
is supplied by a single large artery, the great anterior medullary artery of Adamkiewicz,
which turns abruptly caudal after joining the anterior spinal artery. If it gives o an
ascending branch, that branch is usually a much smaller vessel. This artery is usually the
most caudal of the anterior radiculomedullary arteries, but when it follows a relatively
high thoracic root, there is often a small lumbar radiculomedullary artery below. In this
and subsequent illustrations, a indicates artery; m, muscle; n, nerve.
Anterior Spinal Artery
The anterior spinal artery is formed rostrally from paired branches of the intracranial
vertebral arteries that descend from the level of the medulla (Fig. 2-1). These two arteries
fuse to form a single anterior spinal artery that overlies the anterior longitudinal 4ssure of
1the spinal cord. This artery is joined at di erent levels by anterior radiculomedullary
arteries, which are branches of certain segmental vessels (Fig. 2-2). The number of these
vessels is variable among individuals, ranging from 2 to 17, although 85 percent of
5,6individuals have between 4 and 7.+
FIGURE 2-2 Anatomy of the spinal cord circulation, showing the relationship of the
segmental arteries and their branches to the spinal canal and cord. The left rib and the
left pedicle of the vertebra have been cut away to show the underlying vascular and
neural structures.
The anterior spinal artery in the region that includes the cervical enlargement (C1 to
T3) is particularly well supplied, receiving contributions from an average of three
6segmental vessels. One constant artery arises from the costocervical trunk and supplies
the lower segments; the others arise from the extracranial vertebral arteries and supply
6the middle cervical segments. In addition, branches of the vertebral arteries have rich
anastomotic connections with other neck vessels, including the occipital artery, deep
6cervical artery, and ascending cervical artery.
The anterior spinal artery in the midthoracic portion of the cord (T4 to T8) often
receives only a single contribution from a small artery located at about T7, most often on
6,8the left. The anterior spinal artery has its smallest diameter in this region, and it is
5,6sometimes discontinuous with the vessel in more rostral or caudal regions.
The anterior spinal artery in the region of the lumbar enlargement (T9 to the conus
medullaris) is, as at the cervical enlargement, richly supplied, deriving its blood supply
predominantly from a single large (1.0 to 1.3 mm in diameter) artery, the great anterior
medullary artery of Adamkiewicz. This artery almost always accompanies a nerve root
between T9 and L2, usually on the left, although rarely it may accompany a root above
5,6or below these levels. Identi4cation of the actual location of this great vessel has
become an important part of the planning and execution of operations on the aorta such
as repair of thoracoabdominal aortic aneurysms. Although digital subtraction
angiography has been used for this purpose, the use of contrast-enhanced magnetic
11resonance angiography has recently been proposed to o er a noninvasive alternative.+
+
Caudally, at the conus medullaris, the anterior spinal artery anastomoses with both
6posterior spinal arteries.
Posterior Spinal Arteries
The paired posterior spinal arteries are formed rostrally from the intracranial portion of
the vertebral arteries. They are distinct paired vessels only at their origin, however, and
5,6thereafter become intermixed with an anastomotic posterior pial arterial plexus (Fig.
2-3). This plexus is joined at di erent levels by a variable number (10 to 23) of posterior
5radiculomedullary vessels that accompany the posterior nerve roots.
FIGURE 2-3 Vascular anatomy of the spinal cord. The anterior spinal artery gives o
both peripheral and sulcal branches. The sulcal branches pass posteriorly, penetrating the
anterior longitudinal 4ssure. On reaching the anterior white commissure, they turn
alternately to the right and to the left to supply the gray matter and deep white matter on
each side.5 Occasionally two adjacent vessels pass to the same side, and on other
occasions, a common stem vessel bifurcates to supply both sides. Terminal branches of
these vessels overlap those from vessels above and below on the same side of the cord.
The peripheral branches of the anterior spinal artery pass radially and form an
anastomotic network of vessels, the anterior pial arterial plexus, which supplies the
anterior and lateral white matter tracts by penetrating branches. The posterior pial
arterial plexus is formed as a rich anastomotic network from the paired posterior spinal
arteries. Penetrating branches from this plexus supply the posterior horns and posterior
funiculi.
Intrinsic Blood Supply of the Spinal Cord+
+
In contrast to the extreme interindividual variability in the extraspinal arteries that
supply the spinal cord, the intrinsic blood supply of the cord itself is more consistent. The
anterior spinal artery gives o central (sulcal) arteries that pass posteriorly, penetrating
the anterior longitudinal 4ssure and supplying most of the central gray matter and the
deep portion of the anterior white matter (Fig. 2-4). The number of these sulcal vessels is
variable, with 5 to 8 vessels per centimeter in the cervical region, 2 to 6 vessels per
centimeter in the thoracic region, and 5 to 12 vessels per centimeter in the lumbosacral
5,6region.
FIGURE 2-4 Intrinsic blood supply of the spinal cord. The vascular territories are
depicted on the right half of the cord. The hatched lines indicate the territory supplied by
the posterior spinal arterial system. The remainder is supplied by the anterior circulation,
with the dark stippling indicating the area supplied exclusively by the sulcal branches of
the anterior spinal artery.
The anterior spinal artery also gives o peripheral arteries that pass radially on the
anterior surface of the spinal cord to supply the white matter tracts anteriorly and
laterally. These arteries form the anterior pial arterial plexus, which is often poorly
5anastomotic with its posterior counterpart. The posterior horns and posterior funiculi are
supplied by penetrating vessels from the posterior pial arterial plexus.
Ischemic Cord Syndromes
Ischemia of the spinal cord may be produced either by the interruption of blood . ow
through critical feeding vessels or by aortic hypotension. The resulting neurological
syndrome depends on the location of ischemic lesions along and within the spinal cord,
which depends, in turn, on the vascular anatomy discussed previously. A wide variety of
pathological disturbances of the aorta result in spinal cord ischemia. They include both+
12-15iatrogenic causes, such as surgery and aortography, and intrinsic aortic diseases,
16,17 6,18,19such as dissecting and nondissecting aneurysms, in. ammatory aortitis,
20 21,22occlusive atherosclerotic disease, infective and noninfective emboli, and
6,23 24congenital coarctation. Spinal cord ischemia is a rare complication of pregnancy,
25possibly due to aortic compression, which can occur toward the end of gestation.
Some authors have suggested that the midthoracic region (T4 to T8) is particularly
vulnerable to ischemia because of the sparseness of vessels feeding the anterior spinal
6artery in this region and its poor anastomotic connections. Others have stressed the
vulnerability of the watershed areas between the three anterior spinal arterial territories.
Although the concept is theoretically appealing, documentation of the selective
vulnerability of these regions is not completely convincing. For example, a review of 61
16,26-29case reports with respect to the distribution of ischemic myelopathies resulting
from surgery on the aorta does not especially suggest that either of these areas is more
vulnerable than other cord segments (Table 2-1). Even when the operation was
performed on the thoracic aorta (and thus the proximal clamp was placed above the
midthoracic cord feeder), the lumbosacral cord segments were the site of the ischemic
damage more often than the supposedly more vulnerable midthoracic segments (Table
21). Similarly, the watershed area between these two arterial territories (T8 to T9) does not
seem particularly vulnerable. In fact, the most frequently a ected cord segment within
each vascular territory in these 61 cases was centrally placed—T6 in the midthoracic
territory and T12 in the lumbosacral territory—rather than at the borders, as would be
anticipated with watershed vulnerability (Fig. 2-5).
TABLE 2-1 In. uence of Location of Aortic Surgery on the Vascular Territory of Resulting
Spinal Cord Ischemia
Location of Surgery
Vascular Territory of Ischemia Abdominal Aorta Thoracic Aorta
Cervical region (C1–T3) 0 0
Midthoracic region (T4–T8) 1 14
Lumbosacral region (T9–conus) 25 21
Based on 61 reported cases.16,26-29+
+
FIGURE 2-5 Upper segmental level of spinal cord involvement in 61 cases of spinal
cord ischemia after surgery on the aorta (based on previously published reports16,26-29).
Moreover, of the 25 cases of spinal cord infarction in an unselected autopsy series of
6300 cases, two thirds were in cervical cord segments ; the most commonly a ected
segment was C6. Such a distribution would be unexpected if either the midthoracic or the
watershed area was particularly vulnerable. Perhaps relating to such observations, it was
recently found that, contrary to earlier reports, the anterior spinal artery is continuous
9along its length without interruption in all 51 cadavers studied. If this observation can
be generalized, it may be the case that the poorly vascularized thoracic cord, which has
much less gray matter than the cervical and lumbar enlargements, actually matches its
3,6,30sparse blood supply with its reduced metabolic requirements.
The site of aortic disease also plays an important role in the location of the lesion along
the spinal cord. For example, distal aortic occlusion often presents with lumbosacral
6,20involvement, whereas dissecting aneurysm of the thoracic aorta commonly presents
6,17,31,32with infarction in the midthoracic region. Similarly, cord ischemia following
surgery on the abdominal aorta is essentially con4ned to the lumbosacral territory,
whereas surgery on the thoracic aorta not infrequently involves the midthoracic segments
(Table 2-1). Regardless of the pathological process a ecting the aorta, however, it
6,33generally involves the suprarenal portion if there is cord ischemia because the
important radiculomedullary arteries usually originate above the origin of the renal
arteries.
Anterior Spinal Artery Syndrome
Ischemic injury of the spinal cord at a particular segmental level may present with a+
+
6complete transverse myelopathy. Within the spinal cord, however, there are certain
vascular territories that can be a ected selectively. In particular, the territory of the
3,6anterior spinal artery, especially its sulcal branch, is prone to ischemic injury. This
increased vulnerability probably relates to two factors. First, the anterior circulation
1,3,4,6receives a much smaller number of feeding vessels than the posterior circulation.
1,3,6Second, the posterior circulation is a network of anastomotic channels and therefore
probably provides better collateral . ow than the single anterior artery, which in some
patients is discontinuous along its length. The relative constancy of the resulting
6,34,35syndrome presumably re. ects the relative constancy of the intrinsic vascular
anatomy of the cord.
As mentioned earlier, the anterior spinal artery supplies blood to much of the spinal
gray matter and to the tracts in the anterior and lateral white matter. Ischemia in this
arterial territory therefore gives rise to a syndrome of diminished pain and temperature
sensibility with preservation of vibratory and joint position sense. Weakness (either
paraparesis or quadriparesis, depending on the segments involved) occurs below the level
of the lesion and may be associated with other evidence of upper motor neuron
involvement, such as Babinski signs, spasticity, and hyperre. exia. Bowel and bladder
functions are a ected, owing to interruption of suprasegmental pathways. Segmental
gray matter involvement may also lead to lower motor neuron de4cits and depressed
tendon re. exes at the level of the lesion. Thus, a lesion in the cervical cord may produce
. accid are. exic paralysis with amyotrophy in the upper extremities, spastic paralysis in
the lower extremities, and dissociated sensory loss in all limbs. In contrast, a lesion in the
thoracic cord typically presents with only spastic paraplegia and dissociated sensory loss
in the legs. The syndrome usually comes on abruptly, although occasionally it is more
36insidious and progressive.
Motor Neuron Disease
On occasion, diseases of the aorta (e.g., dissecting aneurysms or atherosclerosis) that
interfere with the blood supply to the anterior spinal artery result in more restricted cord
ischemia, perhaps because of better anastomotic connections between the anterior and
the posterior pial arterial plexuses in some individuals or because of greater vulnerability
6,14,36of the anterior horn cells with their greater metabolic activity. The ischemic injury
in these circumstances is limited to the gray matter supplied by the sulcal branches (Fig.
2-6). Clinical impairment is then con4ned to the motor system and is associated with
6amyotrophy. When the onset is abrupt, the ischemic nature of the lesion usually is
6,36apparent, but when the onset is more gradual, and especially when pyramidal signs
are also present, it may mimic other diseases, such as amyotrophic lateral sclerosis or
spinal cord tumors.FIGURE 2-6 Area of infarction within the spinal cord over four adjacent spinal
segments in a patient reported by Herrick and Mills (Herrick MK, Mills PE: Infarction of
spinal cord. Two cases of selective gray matter involvement secondary to asymptomatic
aortic disease. Arch Neurol 24:228, 1971). The infarction was extensive but limited to the
gray matter, particularly the anterior horns.
Posterior Spinal Artery Syndrome
In contrast to the anterior spinal artery syndrome, selective ischemia of the posterior
circulation, characterized by prominent loss of posterior column function with relative
2,14sparing of other functions, is rarely recognized clinically and only occasionally
10,20,37reported pathologically. For example, in a review of 27 cases of nonsurgical
10spinal cord ischemia, only 2 (7%) had posterior spinal artery patterns. The relative
infrequency of this syndrome presumably relates to the more abundant feeding vessels
and better anastomotic connections in this arterial system compared to the anterior spinal
artery.
Unilateral Cord Syndromes
In some cases, the area of ischemic damage can be con4ned to only a small portion of the
10spinal cord. For example, in the review cited previously, eight (29%) of the patients
with nonsurgical spinal cord ischemia had unilateral syndromes involving either the
anterior or posterior aspects of the spinal cord.
Intermittent Claudication
Intermittent claudication (limping) refers to a condition in which a patient experiences
di? culty in walking that is brought about by use of the lower extremities. Charcot
initially described this syndrome in 1858 and related it to occlusive peripheral vascular
38disease in the lower extremities. In 1906, Dejerine distinguished claudication caused by
39ischemia of the leg muscles from that caused by ischemia of the spinal cord. In the
latter condition, the arterial pulses in the legs tend to be preserved, pain tends to be
dysesthetic or paresthetic in quality and may not occur, and neurological signs are
frequently present, especially after exercise. In 1961, Blau and Logue identi4ed another
form of neurogenic claudication caused by ischemia or compression of the cauda equina
and resulting from a narrowed lumbosacral canal (either congenital or due to
40degenerative disease). This condition is similar to that produced by ischemia of thespinal cord; however, the sensory complaints tend to have a more radicular distribution,
and signs of cord involvement (e.g., Babinski signs) are not present.
The clinical distinction between various types of claudication, particularly between the
two neurogenic varieties, is sometimes di? cult. The cauda equina variety, however, is far
6,41more common than the spinal cord form. Intermittent spinal cord ischemia, when it
occurs, is often associated with intrinsic diseases of the aorta, such as coarctation or
6atherosclerotic occlusive disease.
Bony erosion through vertebral bodies from an abdominal aortic aneurysm with direct
compression of the spinal nerve roots has also been reported to produce intermittent
42neurological symptoms. The clinical details of the single reported case, however, are
not su? cient to determine whether the symptoms resemble those of intermittent
claudication.
Cerebral Ischemia
Anatomy
The aortic arch gives rise to all the major vessels that provide blood to the brain,
brainstem, and cervical spinal cord (Fig. 2-7). The 4rst major branch is the innominate
(brachiocephalic) artery, which subsequently divides into the right common carotid and
right subclavian arteries. The latter artery subsequently gives rise to the right vertebral
artery, which ascends through the foramina of the transverse processes of the upper six
cervical vertebrae to join with its counterpart on the left and form the basilar artery. The
basilar artery provides blood to the posterior fossa and posterior regions of the cerebral
hemispheres. The second major branch of the aortic arch is the left common carotid
artery, and the third is the left subclavian artery, which, in turn, gives rise to the left
vertebral artery.FIGURE 2-7 Vascular anatomy of the aortic arch and its branches.
Strokes and Transient Ischemic Attacks
Diseases of the aortic arch, such as atherosclerosis, aneurysms, and aortitis as well as
surgery on this segment of the aorta, may give rise to symptoms of cerebrovascular
6,13,18,32,43-47insu? ciency, such as strokes or transient ischemic attacks (TIAs). A
young woman has even been reported with a stroke secondary to an occlusion of the
aorta that was associated with the use of birth control pills and recurrent venous
48thromboses. Cerebral ischemia is produced either by occlusion of a major vessel or by
embolization of atheromatous or other material to more distal arteries. The resulting
neurological syndromes are not speci4c for any disease process but depend on the
location and duration of the vascular occlusion.
Atherosclerosis
Atherosclerosis of the aortic arch and its branches, compared with atherosclerosis at the
origin of the internal carotid artery, is an infrequent cause of stroke or TIAs, probably for
two reasons. First, atherosclerosis is much less common in this location than at the carotid
49bifurcation (Table 2-2). Second, the anastomotic connections between the major
6,50vessels in the neck are extensive, and an occlusion at their origin from the aortic arch
is therefore less likely to be associated with symptoms of ischemia than a more peripheral
obstruction.+
TABLE 2-2 Distribution of Atherosclerosis in the Aorta and Its Branches
Location Number of Lesions
External carotid artery 9
Internal carotid artery 256
Common carotid artery 16
Innominate artery 16
Subclavian artery 29
Vertebral artery 55
Aortoiliac region 952
Femoropopliteal region 772
Based on data from Crawford ES, DeBakey ME, Cooley DA, et al: Surgical considerations of
aneurysms and atherosclerotic occlusive lesions of the aorta and major arteries. Postgrad Med
29:151, 1961.
Transient Emboligenic Aortoarteritis
Transient emboligenic aortoarteritis has been reported by Wickremasinghe and
51colleagues to be a cause of stroke in young patients. They described 10 patients (aged
16 to 36 years), all of whom had presented with pathologically veri4ed thromboembolic
strokes, and 3 of whom had a history of TIAs preceding the event by as much as 4 years.
All these patients had both active and healed in. ammatory lesions of the central elastic
arteries, such as the aorta, innominate, common carotid, and proximal subclavian
arteries. Active lesions were small (200 to 300 μm in diameter) and associated with a
mural thrombus on the intimal surface. Healed lesions usually were associated with
4brous plaques but not with a mural thrombus. More peripheral arteries supplying the
brain were normal. This condition seems to be distinct from segmental aortitis of the
Takayasu type. Clinically it is an acute, intermittent disorder with an approximately
equal sex incidence, whereas Takayasu’s disease is more chronic and has a strong female
predominance. The systemic symptoms of Takayasu’s disease are absent, and occlusion of
the central arteries does not occur in this condition.
Subclavian (Cerebral) Steal
Disease of the aortic arch may result in occlusion of either the innominate artery or the
left subclavian artery proximal to the origin of the vertebral artery. This, in turn, may
result in the reversal of the usual cephalad direction of blood . ow in the ipsilateral
vertebral artery (Fig. 2-8), depending on individual variations in the collateral circulation
52-56and may result in ischemia in the posterior cerebral circulation. In some patients,
this is particularly evident when the metabolic demand (and therefore the blood . ow) of
52the a ected arm is increased during exercise. If the innominate artery is blocked+
+
+
proximally, it may also cause a reversal of blood . ow in the right common carotid artery,
resulting in anterior circulation ischemia (Fig. 2-8).
FIGURE 2-8 Mechanisms producing subclavian steal syndrome in diseases of the aortic
arch and its branches. A, Obstruction of the left subclavian artery at its origin, resulting in
reversal of blood . ow in the left vertebral artery. B, Obstruction of the right subclavian
artery distal to the takeo of the right common carotid artery, resulting in reversal of
blood . ow in the right vertebral artery. C, Obstruction of the innominate artery at its
origin, producing reversal of blood flow in the right common carotid artery.
Killen and colleagues reviewed the clinical features of a series of patients with
demonstrated reversals of arterial blood-. ow in a vertebral artery (i.e., with . ow from
52the vertebral artery into the ipsilateral subclavian artery). The left subclavian artery
was a ected more than twice as often as the right subclavian and innominate arteries
combined, probably as a result of the more frequent involvement of this artery by
atherosclerosis (Table 2-2). Men were a ected three times as often as women, probably
re. ecting the greater prevalence of atherosclerosis in men. Of the 87 patients in this series
with symptoms that were adequately described, 75 (86%) had symptoms referable to the
central nervous system (CNS). These symptoms were usually transient, lasting seconds to
a few minutes, although the de4cits were sometimes permanent. The neurological
manifestations of steal were varied but most frequently included motor di? culties,
vertigo, visual de4cits, or syncope. Ischemic symptoms in the arms occurred in only a few
patients, and precipitation of CNS symptoms by exercise of the arm ipsilateral to the
occlusion was uncommon. Although reconstructive surgery relieved symptoms in most
52patients in this series, it was the frequent failure of surgery to correct such nonspeci4c
56symptoms that led to a more recent reassessment of the importance of cerebral steal.
Thus, when noninvasive techniques such as Doppler ultrasonography have been used
to de4ne the direction of blood . ow in the great vessels in a large spectrum of patients+
with vascular disease, the majority (50% to 75%) of patients with documented
53-55subclavian steal are found to be asymptomatic, even when the steal is bilateral.
When symptoms do occur, they are suggestive of transient vertebrobasilar insu? ciency in
only 7 to 37 percent of patients with steal; the occurrence of infarcts in this vascular
54,55territory is distinctly rare. For this reason, a recent review of this topic concluded
that subclavian steal is a actually a marker of generalized atherosclerotic disease and that
56it is rarely a cause for symptoms of cerebral ischemia.
Peripheral Neuropathy
The peripheral nervous system is sometimes a ected by aortic disease or surgery. The
syndromes produced may be the presenting manifestations of aortic disease and may
mimic less life-threatening conditions.
Mononeuropathies
Left Recurrent Laryngeal Nerve
The left recurrent laryngeal nerve descends in the neck as part of the vagus nerve and
wraps around the aortic arch just distal to the ligamentum arteriosum (Fig. 2-7) before
reascending in the neck to innervate all the laryngeal muscles on the left side except the
cricothyroideus. It may be compressed by disease of the aortic arch, such as dissecting
and nondissecting aneurysms or aneurysmal dilatation proximal to a coarctation of the
56aorta. The resulting hoarse, low-pitched voice may be one of the earliest presenting
symptoms of these conditions, although it is often overshadowed by other symptoms or
57signs, such as chest pain, shortness of breath, congestive heart failure, or hypertension.
Femoral Nerve
The femoral nerve arises from the nerve roots of L2, L3, and L4. It forms within the belly
of the psoas muscle and then exits on its lateral aspect to innervate the quadriceps
femoris, iliacus, pectineus, and sartorius muscles and the skin of the anterior thigh and
medial aspect of the leg. The nerve is located considerably lateral to the aorta (Fig. 2-9)
and hence is rarely involved by direct compression. It may, however, be compressed by a
hematoma from a ruptured aortic aneurysm into the psoas muscle and thereby signal a
6,58-60life-threatening condition that requires an urgent operation.FIGURE 2-9 Anatomy of the abdominal aorta showing its relationship to the femoral
and obturator nerves, which form within the psoas muscle from branches of the L2, L3,
and L4 segmental nerves.
The femoral nerve may also be injured as a consequence of aortic surgery. Boontje and
Haaxma reported this complication in 3.4 percent of 1,006 abdominal aortic operations
for atherosclerotic or aneurysmal disease, the left femoral nerve being involved
unilaterally in two thirds of the cases and jointly with the right femoral nerve in another
616 percent. The mechanism of injury in these cases was presumed to be ischemic and
related to poor collateral blood supply to the intrapelvic portions of the femoral nerves,
especially on the left.
Obturator Nerve
The obturator nerve also forms within the belly of the psoas muscle by the union of 4bers
from the L2, L3, and L4 segments, but, in contrast to the femoral nerve, exits medially
from this muscle (Fig. 2-9). It innervates the adductors of the leg and the skin on the
medial aspect of the thigh. It too is lateral to the aorta and not usually involved by direct
compression. Like the femoral nerve (and often together with it), the obturator nerve may
6be compressed by a hematoma in the psoas muscle.
Radiculopathies
Nerve roots, particularly L4, L5, S1, and S2, which lie almost directly underneath the
terminal aorta and iliac arteries (Fig. 2-10), may be directly compressed by an aortic
aneurysm in this region. The syndromes produced are typical of radicular disease, with+
6unilateral radiating pain and a radicular pattern to the sensory and motor findings.
FIGURE 2-10 Anatomy of the terminal branches of the aorta in relationship to the
nerve roots that subsequently join to form the sciatic nerve. Aneurysmal dilatation of the
abdominal aorta often includes dilatation of these branch vessels, which can compress the
nerve roots, particularly the L4, L5, S1, and S2 nerve roots, which lie directly underneath.
Radiculopathies may also be produced by erosion of one or more vertebral bodies by
an aortic aneurysm, with consequent compression of the nerve roots in the cauda equina
or at the root exit zones. The syndrome produced is not necessarily associated with back
62-64pain; it may result in multisegmental involvement on one side or even in paraplegia.
Polyneuropathies
Ischemic Monomelic Neuropathy
Ischemic monomelic neuropathy was described in detail by Wilbourn and co-workers,
who reported 3 patients (and alluded to another 11) who had a distal “polyneuropathy”
65in one limb after sudden occlusion of a major vessel. One of their patients had a saddle
embolus to the distal aorta that occluded the right common iliac artery, another had a
super4cial femoral artery occlusion after placement of an intra-aortic balloon pump, and
the third had upper-extremity involvement. The syndrome consists of a predominantly
sensory neuropathy with a distal gradient. It a ects all sensory modalities and is
associated with a constant, deep, causalgia-like pain. The symptoms persist for months,
even after revascularization or without evidence of ongoing ischemia. The results of nerve
conduction studies and needle electromyography suggest an axonal neuropathy. There is+
no evidence of ischemic muscle injury, such as induration, muscle tenderness, or elevated
serum creatine kinase levels. This condition is rare, although a similar syndrome has been
66reported in the setting of an acute aortic dissection, and it may be that it is more
prevalent than currently appreciated.
Autonomic Neuropathies
Anatomy
The autonomic nerves, particularly the lower thoracic and lumbar sympathetic 4bers that
lie close to the aorta and its branches, may be injured by disease of or surgery on the
aorta. The preganglionic e erent sympathetic 4nerve 4bers originate in the
intermediolateral cell column in the spinal cord (Fig. 2-4) and exit segmentally between
67T1 and L2 with the ventral roots. The sympathetic 4bers part company with the
segmental nerves through the white rami communicantes (Fig. 2-2), which enter the
paravertebral sympathetic ganglia and trunks to form bilateral sympathetic chains; these
chains are situated lateral to and parallel with the vertebral column (Fig. 2-11). Some of
these 4bers synapse on postganglionic neurons in the ganglia of their segmental origin,
whereas others ascend or descend in the trunk to different segmental levels before making
such synapses. In the lumbosacral and cervical segments, where there are no white rami
(i.e., below L2 or above T1), the segmental ganglia receive preganglionic contributions
only from cord segments either above them (lumbosacral ganglia) or below them
67(cervical ganglia). The postganglionic 4bers rejoin the segmental nerves through the
gray rami communicantes (Fig. 2-2) to provide vasomotor, sudomotor, and pilomotor
innervation throughout the body.FIGURE 2-11 Anatomy of the terminal aorta and pelvis in the male in relationship to
the sympathetic and parasympathetic nerves in the region.
Some of the preganglionic 4bers, in contrast, do not synapse in the paravertebral
ganglia but pass through them to form splanchnic nerves, which then unite in a series of
prevertebral ganglia and plexuses (many of which overlie the thoracic and abdominal
aorta). These structures, in turn, provide sympathetic innervation to the viscera. The
plexus that overlies the aorta in the region of its bifurcation, the superior hypogastric
plexus (Fig. 2-11), is responsible (via the inferior hypogastric and other pelvic plexuses)
for sympathetic innervation of the pelvic organs, including the prostate, prostatic urethra,
bladder, epididymis, vas deferens, seminal vesicles, and penis in men (Fig. 2-12) and the
uterus, bladder, fallopian tubes, vagina, and clitoris in women. This plexus is formed by
the union of the third and fourth lumbar splanchnic nerves with 4bers from the more
rostral inferior mesenteric plexus. Its segmental contribution usually derives from T11 to
L2.+
+
+
FIGURE 2-12 Distribution of sympathetic (left) and parasympathetic (right) nerves to
the pelvic viscera and sexual organs in the male.
The visceral a erent 4bers accompany the e erent autonomic 4bers and pass
uninterrupted back through the trunk, ganglia, and white rami to reach their nerve cells
of origin in the dorsal root.
Postsympathectomy Neuralgia
Operations on the distal aorta to treat symptomatic aortic disease from atherosclerosis or
other causes frequently include intentional sympathectomy as part of the e ort to
improve blood . ow to the legs. This is usually done by dividing the sympathetic chain
below the last white ramus at L2, thereby depriving the lower lumbar and sacral ganglia
of their preganglionic innervation. Such an operation is often followed by a distinctive
68,69 68pain syndrome, which Raskin and associates termed postsympathectomy neuralgia.
In their experience with 96 such operations, this syndrome occurred in 35 percent of the
patients. In each case, the sympathetic chain was interrupted at L3 by removal of the
segmental ganglion. The pain was characterized as deep, boring, nonrhythmic, and
nonradiating; it had an abrupt but delayed onset. The mean delay from sympathectomy
to onset of pain was 12 days. The pain was located predominantly in the thigh, either
medially or laterally, and was associated with tenderness in the area of pain. The course
was always self-limited, with an average duration of 3 weeks.+
+
Disorders of Sexual Function
Normal male sexual function has two distinct components. The 4rst, erection, is a
response mediated predominantly through the parasympathetic nervous system by the
pelvic splanchnic nerves (nervi erigentes) arising from segments S2, S3, and S4 (Fig.
212). Activation of these nerves causes vasodilatation and engorgement of the penile
6,70musculature and sinuses. The blood supply to the penis is provided by the internal
pudendal artery via the internal iliac artery (Fig. 2-10). The sympathetic nervous system,
however, must have at least a modifying in. uence on erection because sympathectomy
6,70may disturb it. The second component, ejaculation, can be divided into two phases.
The 4rst phase, expulsion of seminal . uid into the prostatic urethra, is a response
mediated predominantly by the sympathetic nervous system through the superior
6,70hypogastric plexus. The second phase, emission, is produced by the clonic
contraction of penile musculature (bulbocavernosus and ischiocavernosus) innervated by
somatic (pudendal) nerves (Fig. 2-12).
6,71-76Male sexual function may be disturbed by aortic disease or surgery. Female
sexual function has not been as well studied in these circumstances, although it seems to
77be a ected to a similar degree as in men. Because the superior hypogastric plexus lies
close to the aortic bifurcation (Fig. 2-11), most preoperative and postoperative sexual
disturbances occur with disease of this portion of the aorta, and most involve ejaculation
(Table 2-3). The pelvic splanchnic nerves are not situated near the aorta (Fig. 2-11) and
usually are not a ected by aortic disease or surgery. Disturbances in erection, however,
do occur, possibly because of sympathetic dysfunction, a reduction in blood . ow to the
71-76internal pudendal artery and penis, or cavernovenous leakage. To determine
whether blood . ow or sympathetic function was more important in this regard, Ohshiro
and Kosaki examined the outcome of (1) terminal aortic operations either done
traditionally or designed to spare the superior hypogastric plexus and (2) operations that
74did or did not preserve internal iliac blood-. ow. Their results indicated that
preservation of the hypogastric plexus appeared to be more important for maintenance of
normal erection and ejaculation than was preservation of internal iliac artery blood-. ow
(Table 2-4). Other authors have also found that modi4cation of operative technique to
spare the superior hypogastric plexus considerably improves postoperative sexual
6,71,73function.
TABLE 2-3 Male Sexual Dysfunction in Patients With Disease of or Surgery on the AortaTABLE 2-4 In. uence of Blood Flow and Sympathetic Function on Male Sexual Function
After Abdominal Aortic Operations
Despite the importance of operative technique in preserving sexual function,
preservation of blood . ow is probably also important. Thus, Nevelsteen and colleagues
reported a clear relationship between the occurrence of preoperative impotence and the+
75adequacy of blood . ow through the internal iliac arteries. In this study, however, no
special attempt was made to improve blood . ow in the internal iliac artery during
surgery, so that it is unclear whether a di erent operative approach might have been
beneficial in restoring postoperative sexual function.
AORTIC DISEASES AND SURGERY
Certain conditions affecting the aorta merit special consideration because of the variety of
nervous system syndromes that each can produce.
Aortitis
Injury to the aorta by a variety of infectious, toxic, allergic, or idiopathic causes may
18produce similar in. ammatory pathological changes in the elastic media (Table 2-5).
Such aortic damage may lead to neurological syndromes either primarily through direct
involvement of important branch arteries by the pathological process or secondarily
through the development of aneurysms, aortic stenosis, or atherosclerosis. The
neurological syndromes produced either primarily or secondarily by aortitis depend on
both the nature and the location of the resulting aortic lesion.
TABLE 2-5 Causes of Aortitis
Stenosing Aortitis
Takayasu’s arteritis
Postradiation during infancy
Nonstenosing Aortitis
Syphilis
Mycotic aneurysms
Rheumatic fever
Rheumatoid arthritis
Giant cell arteritis
*Collagen vascular and other diseases
Ankylosing spondylitis
Reiter’s syndrome
Relapsing polychondritis+
+
+
+
+
* Systemic lupus erythematosus, scleroderma, psoriasis, Crohn’s disease, and ulcerative
colitis.
Syphilitic Aortitis
18,78During the prepenicillin era, syphilis was a common cause of aortitis, although by
78the 1950s, its occurrence had markedly declined. A report in 1958 on the relative
occurrence of atherosclerotic and syphilitic thoracic aortic aneurysms showed cases of
79syphilis outnumbering atherosclerosis by a ratio of 1.3:1.0. A similar report published
79in 1982 gave this ratio as 0.13:1.0. The pathological process in syphilitic aortitis is
19,78almost always in the thoracic aorta, in contrast to the distribution of atherosclerosis,
which is more prevalent in the abdominal aorta (Table 2-2). The aortitis is accompanied
78by aneurysmal dilatation of the aorta in approximately 40 percent of cases. Rarely, it
6presents with multiple arterial occlusions and mimics Takayasu’s arteritis, although
patients are generally older than those with Takayasu’s arteritis and are usually men.
Takayasu’s Arteritis
Takayasu’s arteritis is an idiopathic in. ammatory condition a ecting the large arteries,
6,45,80,81particularly the aorta and its branches. The pathogenesis seems to involve
cellmediated autoimmunity, although the responsible antigen is unknown. The onset of
disease is typically between the ages of 15 and 30 years, and the condition seems most
6prevalent in Asian and Hispanic populations. More than 85 percent of a ected
individuals are women. In the early (prepulseless) phase, the disease may be
characterized by systemic symptoms such as fever, night sweats, weight loss, myalgia,
arthralgia, arthritis, and chest pain. In some patients, however, the systemic symptoms
are either inconspicuous or absent. The later (pulseless) phase of the disease is
characterized by occlusion of the major vessels of the aortic arch, producing symptoms
such as Takayasu’s retinopathy, hypertension (secondary to renal artery stenosis,
coarctation, or both), aortic regurgitation, and aortic aneurysms. Symptoms of cerebral
6,45,81ischemia can occur; however, they are typically reported in only a few patients.
Nevertheless, a report from South Africa on 272 patients who were diagnosed with
Takayasu’s arteritis, based on the criteria of the American College of Rheumatology,
found that 20 percent of the cohort had symptoms of cerebrovascular disease, including
81TIAs and stroke. In addition, 32 percent of this cohort experienced intermittent
81claudication of either upper or lower limbs. Seizures and headaches have also been
6reported but are uncommon. Involvement along the aorta is typically di use, although
some patients (perhaps as many as 20%) present with symptoms related to more
18,81restricted aortic involvement. The disorder is discussed further in Chapter 29.
Giant Cell Arteritis
Giant cell arteritis (GCA) seems to be a particularly important cause of aortitis in the
6,18,19,82elderly ; although it typically a ects medium-sized vessels, as many as one
83fourth or more of a ected individuals have large-artery involvement. For example, inone series of eight consecutive patients with aortitis, GCA seemed to be its basis in
18many. Thus, four had de4nite GCA diagnosed based on their age at onset, the new
onset of headaches, and an elevation in erythrocyte sedimentation rate. However, all
these patients were older than 57 years, each of the eight had an elevation of some serum
inflammatory marker (e.g., increase in Creactive protein levels, erythrocyte sedimentation
6rate, or 4brinogen levels), and three had symptoms of polymyalgia rheumatica. In
another series of 45 patients undergoing aortic resection and who had microscopic
evidence of active noninfectious aortitis, the majority had either unclassi4able aortitis
82(47%) or GCA (31%), two entities that were histopathologically indistinguishable. The
presenting symptoms in patients with GCA or unclassi4ed aortitis are generally
nonspeci4c and include exhaustion, night sweats, weight loss, chest and back pain,
19,82headache, fevers of unknown origin, TIAs, and arm claudication. Typically, all
segments of the aorta (ascending aorta, arch, and descending aorta) are involved in the
6,18,19in. ammatory process, although involvement can be more restricted. Between 10
and 20 percent of patients with unclassi4ed aortitis or GCA will subsequently develop
82,83either dissecting or, more commonly, nondissecting aortic aneurysms.
Aortic Aneurysms
Nondissecting Aneurysms
Nondissecting aortic aneurysms can be caused by any pathological process that weakens
6,15,18,53,60,84,85the arterial wall, such as in. ammation, infection, or atherosclerosis.
86In the past, syphilis was an important cause, but at present, almost all these aneurysms
are caused by atherosclerosis. As a result, the distribution of aortic aneurysms essentially
parallels the distribution of atherosclerosis within the aorta, with most occurring in the
abdominal aorta (Tables 2-2 and 2-6). In a study from Sweden, it was found that the
incidence of ruptured abdominal aortic aneurysms in men (but not women) had
87increased by more than 100 percent between 1971 to 1986 and 2000 to 2004. The
reason for this increased incidence is unclear, and it is unknown whether a similar
increase has occurred in other parts of the world. The prognosis of untreated aneurysms is
grave, with 80 percent of patients dying of rupture within 12 months of the onset of
84symptoms. Disturbances of neurological function in aortic aneurysms are uncommon,
but when they occur, they are variable and depend in part on the location and extent of
the lesion. Abdominal aneurysms may result in sexual dysfunction, compressive
6,58-62,71-77neuropathies, or, rarely, spinal cord ischemic syndromes, including
88intermittent claudication, asymmetric paraparesis, and paraplegia ; descending thoracic
16aneurysms may produce spinal cord ischemia, and aortic arch aneurysms may result in
6,57cerebral ischemia or recurrent laryngeal nerve dysfunction. Most commonly,
neurological symptoms are produced by either rupture or direct compression. Even when
aneurysms result in paraplegia, the neurological de4cit is often caused by bony erosion
through the vertebral bodies and direct compression of the spinal cord or cauda equina
64,89rather than by ischemia.+
+
TABLE 2-6 Distribution and Nature of Aortic Aneurysms
Site Number of Cases
Nondissecting Aneurysms
Aortic arch 56
Descending thoracic aorta 116
Thoracoabdominal aorta 25
Abdominal aorta 829
Dissecting Aneurysms
Thoracic aorta 62
Based on data from Crawford ES, DeBakey ME, Cooley DA, et al: Surgical considerations of
aneurysms and atherosclerotic occlusive lesions of the aorta and major arteries. Postgrad Med
29:151, 1961.
Dissecting Aortic Aneurysms
Dissecting aortic aneurysms, in contrast to nondissecting aortic aneurysms,
predominantly involve the thoracic aorta, either at the beginning of the ascending
segment (type A) or immediately distal to the left subclavian artery (type
6,17,32,57,66,89,90B). Their etiology has not been established. Atherosclerosis is probably
not a major factor because atherosclerosis is seldom found in the region of the intimal
tear because the distribution of these aneurysms along the aorta is unlike that of
90-92atherosclerosis and because atherosclerosis is only infrequently present.
Nevertheless, hypertension probably is a factor as it is present in the large majority of
91,92patients with either type A or type B dissections. Moreover, dissecting aortic
aneurysms have been associated with cystic medial necrosis, a degenerative condition
focally a ecting the arterial media, which may itself be related to hypertension. This
condition is increased in patients with Marfan’s syndrome, as are dissecting aneurysms.
Most aneurysms, however, do not occur in patients with Marfan’s syndrome or other
89,91,92identi4able collagen disorders, and the pathophysiology remains unknown.
Neurological involvement from dissecting aneurysms (due to the cuto of important
arteries by the dissection or by embolization) is well described but uncommon. It occurs
91,92more frequently with type A than type B dissections, and it usually involves either
spinal or cerebral ischemia. Neurological involvement may also occur during surgery to
57repair the aneurysm. Thus, in one large series of 527 patients, preoperative stroke
occurred in 4 percent, and paraparesis occurred in another 2 percent. Patients with aortic
dissection usually present with acute chest or back pain, which generally leads to the
57,91,92proper diagnosis. On occasion, however, pain is absent, and the neurological
6,66syndrome is the presenting feature. Moreover, the neurological de4cit produced by
the dissecting aneurysm is sometimes only transient, lasting for several hours, and6thereby mimicking other transient disturbances of neurological function.
Traumatic Aortic Aneurysm
Brutal deceleration injuries to the chest, especially from motor vehicle accidents, may
result in traumatic rupture of the thoracic aorta, often just distal to the left subclavian
artery. Many of these patients die immediately, but some present with an acute
93-96paraplegia. Still others have a chronic aortic aneurysm that may present years later
93 94with acute spinal cord ischemia or other neurological symptoms.
Coarctation of the Aorta
97Coarctation of the aorta, a relatively common congenital condition, typically results in
constriction of the thoracic aorta just distal to the origin of the left subclavian artery. Less
commonly, it occurs as part of Takayasu’s arteritis, and this condition should be
6,81suspected if the location of the coarctation is atypical. It may also follow radiation
6,98exposure during infancy ; in these cases, the pathological process is focal and limited
to the segment of aorta that was in the 4eld of irradiation. Coarctation can result in a
6,23,97,98variety of neurological symptoms (Table 2-7). Cerebral infarcts probably result
from embolization of thrombotic material in the dilated aorta proximal to the
6obstruction.
Neurological Sequelae of Coarctation of the Aorta*TABLE 2-7
Sequela Incidence (%)
Ruptured intracerebral aneurysms 2.5
Ischemic stroke during childhood 1.0
Neurogenic intermittent claudication† 7.5
Headache 25.0
Episodic loss of consciousness 3.0
Intracerebral hemorrhage‡
Spinal cord compression‡
Based on a review of 200 patients with coarctation of the aorta.97*
† Patients with exercise-induced motor or sensory disturbances in the lower extremities.
These complications were not found in the series reported by Tyler and Clark97 but have‡
been reported by others, as described elsewhere.6
Subarachnoid hemorrhage from ruptured saccular aneurysms can occur with
coarctation. In the general population, aneurysmal hemorrhage has an annual incidence6,99 6,99of approximately 8 per 100,000 and rarely occurs before the age of 20 years.
Accordingly, the reported occurrence of ruptured aneurysms in 2.5 percent of patients
97with coarctation of the aorta suggests an association of these two disorders, although
6the coincidental occurrence of the two conditions cannot be completely excluded.
Headache is a common accompaniment of coarctation, perhaps as a result of
secondary hypertension, but, again, the incidental occurrence of two unrelated conditions
cannot be excluded.
Episodic loss of consciousness may also occur in patients with coarctation of the aorta.
It may result either from syncope due to associated cardiac abnormalities or from
6,97seizures. It is unclear, however, whether seizures unrelated to cerebrovascular disease
97are more prevalent in these patients than in the general population.
Neurogenic intermittent claudication can result from aortic coarctation. In patients
with coarctation of the aorta, blood . ow to the legs is often provided by collateral
connections between the spinal arteries and the distal aorta. In these situations, the blood
. ow through the radiculomedullary and intercostal arteries distal to the obstruction is
6,52reversed, and the exercise-related spinal ischemia may be related to “steal” by the
6increased metabolic demands (and thus increased blood . ow) of the legs rather than
aortic hypotension distal to the coarctation (Fig. 2-13). These collaterals are sometimes so
extensive that they cause spinal cord compression and mimic (clinically and
6,14,98radiologically) vascular malformations of the spinal cord.FIGURE 2-13 Mechanism of steal in coarctation of the aorta. Obstruction of the aorta at
the isthmus causes dilatation of the anterior spinal artery and reversal of blood . ow in
anterior radiculomedullary arteries distal to the obstruction. In this circumstance, the
blood . ow to the lower extremities is provided by these (and other) collaterals, and use of
the lower extremities may cause shunting of blood from the spinal circulation to the legs,
which, in turn, sometimes results in spinal cord ischemia.
Surgery and Other Procedures
Aortic Surgery
As with diseases of the aorta, the risks of aortic surgery depend in part on the site of
operation. Thus, operations on the aortic arch may produce cerebral ischemia either by
intraoperative occlusion of major vessels or by embolization of material such as calci4ed
6,13,46,47plaque loosened during surgery. Operations on the suprarenal aorta may result
13in spinal ischemia, whereas operations on the distal aorta may result in sexual
6,58-62,71-77dysfunction or ischemia of the femoral nerve.
The major complication of all aortic operations, however, is intraoperative spinal cord
ischemia with resultant paraplegia or paraparesis. The occurrence of this complication
varies with the location of the surgery and the nature of the pathological process affecting
the aorta (Table 2-8). Thus, operations on dissecting or nondissecting aortic aneurysms
that are entirely abdominal are associated with a lower incidence of this complication+
6,26,100-104than operations on aneurysms con4ned to the thoracic aorta. Surgery on
aneurysms involving the entire abdominal and thoracic aorta carries the highest risk of
100producing cord ischemia. Operations on the distal aorta for occlusive disease only
26,33rarely result in spinal ischemia, especially when con4ned to the infrarenal portion.
This variability presumably occurs because important feeding arteries to the spinal
circulation are more likely to be ligated during surgery, included within the segment of
the aorta that is cross-clamped, or subjected to distal hypotension when the aortic lesion
is above the level of origin of the renal arteries.
TABLE 2-8 Spinal Cord Ischemia During Surgery and Procedures on the Aorta
Number of Percentage With Spinal Cord
Diagnosis
Patients Damage
Nondissecting aortic
aneurysm
Abdominal* 1,724 0.46
Thoracic† 585 6.3
Thoracoabdominal‡ 102 21.6
Dissecting aortic aneurysm§ 102 30.4
Abdominal aortic occlusion¶ 1,089 0
Coarctation of aorta¶ 12,532 0.41
Aortography* 17,949 0.01
Based on a report by Szilagyi and associates.26*
Based on reports by DeBakey and associates,79 Kahn and Sloan,104 Livesay and†
colleagues,101 Crawford and associates (group I),100 Bloodwell and coworkers,103 and
Neville and associates.102
Based on the findings of Crawford and co-workers (group II).100‡
Based on a report by Crawford and associates.100 The relative risk of operation in these§
patients depended on the location along the aorta and essentially paralleled the experience
in nondissecting aneurysms, although the numbers in each subcategory were too small to
be included separately.
¶ Based on the findings of Brewer and associates (J Thorac Cardiovasc Surg 64:368, 1972).
Operations on the thoracic aorta for coarctation are much less frequently complicated
23by spinal ischemia than thoracic operations done for other reasons. There are probably
at least two reasons for this di erence. First, the former patients are younger, and the+
extent of overall arterial disease is therefore less. Second, as mentioned earlier, the flow in
6,105the radiculomedullary vessels below the coarctation is frequently reversed, so
obstruction of blood . ow in them (either by ligation or cross-clamping the aorta above
and below their origin) may actually result in an increased blood supply to the spinal
cord.
Aortography and Other Procedures on the Aorta
16 6,106Aortography may be associated with either spinal or cerebral ischemia,
depending on the portion of the aorta visualized. This complication, however, is distinctly
rare (Table 2-8). Paraplegia may also occur during intra-aortic balloon assistance after
6,107myocardial revascularization.
Intraoperative Adjuncts to Avoid Spinal Cord Ischemia
Several adjuncts are commonly used during surgery in an attempt to avoid spinal cord
injury. They include the use of deep hypothermia and circulatory arrest in addition to
thiopental anesthesia and intraoperative corticosteroids, all of which are thought to
reduce the metabolic requirements of the cord or otherwise enhance tolerance to
57ischemia. In addition, many authors have reported that minimization of cross-clamp
time results in a lower incidence of spinal ischemia.
Other adjunctive methods such as the reattachment of intercostal arteries, the use of
shunts to maintain distal perfusion pressure, and the use of cerebrospinal . uid drainage
7,46,49,108-114have not proved consistently e ective at preventing cord ischemia,
although the more recent experience with such adjunctive techniques has been quite
7,49,113,114favorable. Part of the di? culty with these procedures may relate to the
extreme variability of the blood supply to the spinal cord. For example, if a crucial spinal
artery leaves the aorta within the cross-clamped section, the preservation of distal
blood. ow is irrelevant. Furthermore, because the important intercostal arteries are few and
unpredictably situated, the random reattachment of a few intercostal arteries may be
fruitless.
There has been considerable interest in the use of somatosensory evoked potentials
(SEPs) and motor evoked potentials (MEPs) for assessing spinal cord function during
94,115-125operations on the aorta. The combined use of SEPs and MEPs may ultimately
124prove better than either technique alone, and, indeed, the most recent reports with
7,46,123-125both techniques have been encouraging. An approach that seems
particularly valuable is the use of intraoperative MEPs or SEPs to identify those vessels
that perfuse the spinal cord and therefore need reattachment, should not be sacri4ced, or
7,121,124should not be included within the aortic cross-clamp. Another approach that
has been reported to be useful is the use of intraoperative MEPs to monitor patients and
to quickly increase both the distal aortic pressure and the mean arterial pressure in
123response to a drop in MEP amplitude. Nevertheless, although these reports are quite
encouraging, the best method of monitoring intraoperative spinal cord function and how
best to use the information to alter the operative technique so that postoperative spinalcord function is maintained are still being determined.
REFERENCES
1 Adamkiewicz A. I. Die Gefasse der Ruckenmarkersubstanz. Sitzungsb Akad Wissensch Wien
Math-Naturw. 1881;84:469.
2 Adamkiewicz A. Die Blutgefasse des menschlichen Ruckenmarkes: II. Die Gefasse der
Ruckenmarksoberflache. Sitzungsb Akad Wissensch Wien Math-Naturw. 1882;85:101.
3 Kadyi H. Über die Blutgefasse des menschlichen Ruckenmarker. Anat Anz. 1886;1:304.
4 Kadyi H. Über die Blutgefasse des menschlichen Ruckenmarkes: Nach einer im XV Bande
der Denkschriften d Math-Naturw C1 d Akad d Wissensch in Krakau erschienenen
Monographie aus dem Polnischen Ulsersatzt vom Verfasser. Lemberg: Grubrynowicz &
Schmidt, 1889.
5 Turnbull IM. Blood supply of the spinal cord. Vinken PJ, Bruyn GW, editors. Handbook of
Clinical Neurology. Amsterdam: North Holland; 1972;Vol 12:478.
6 Goodin DS. Neurologic sequelae of aortic disease and surgery. In: Aminoff MJ, editor.
Neurology and General Medicine. 3rd Ed. New York: Churchill Livingstone; 2001:23.
7 Griepp RB, Ergin MA, Galla JD, et al. Looking for the artery of Adamkiewicz: a quest to
minimize paraplegia after operations for aneurysms of the descending thoracic and
thoracoabdominal aorta. J Thorac Cardiovasc Surg. 1996;112:1202.
8 Milen MT, Bloom DA, Culligan J, et al. Albert Adamkiewicz (1850–1921): his artery and its
significance for the retroperitoneal surgeon. World J Urol. 1999;17:168.
9 Biglioli P, Roberto M, Cannata A, et al. Upper and lower spinal cord blood supply: the
continuity of the anterior spinal artery and the relevance of the lumbar arteries. J
Thorac Cardiovasc Surg. 2004;127:1188.
10 Novy A, Carruzzo A, Maeder P, et al. Spinal cord ischemia: clinical and imaging patterns,
pathogenesis, and outcomes in 27 patients. Arch Neurol. 2006;63:1113.
11 Nijenhuis RJ, Jacobs MJ, van Engelshoven JMA, et al. MR angiograph of the
Adamkiewicz artery and anterior radiculomedullary vein: postmortem validation. AJNR
Am J Neuroradiol. 2006;17:573.
12 Skillman JJ. Neurological complications of cardiovascular surgery: I. Procedures
involving the carotid arteries and abdominal aorta. Int Anesthesiol Clin. 1986;24:135.
13 Shaw PJ. Neurological complications of cardiovascular surgery: II. Procedures involving
the heart and thoracic aorta. Int Anesthesiol Clin. 1986;24:159.
14 Aminoff MJ. Vascular disorders of the spinal cord. In: Davidoff RA, editor. Handbook of
the Spinal Cord. New York: Marcel Dekker; 1987:259.
15 Ross RT. Spinal cord infarction in disease and surgery of the aorta. Can J Neurol Sci.
1985;12:289.
16 Kewalramani LS, Orth MS, Katta RSR. Atraumatic ischaemic myelopathy. Paraplegia.
1981;19:352.
17 Leramo OB, Char G, Coard K, et al. Spinal stroke as a presentation of dissecting
aneurysm of the aorta. West Indian Med J. 1986;35:203.18 Scheel AK, Meller J, Vosshenrich R, et al. Diagnosis and follow up of aortitis in the
elderly. Am Rheum Dis. 2004;63:1507.
19 Tavora F, Burke A. Review of isolated ascending aortitis: differential diagnosis, including
syphilitic, Takayasu’s and giant cell aortitis. Pathology. 2006;38:302.
20 Nedeltchev K, Loher TJ, Stepper F, et al. Long-term outcome of acute spinal cord ischemia
syndrome. Stroke. 2004;35:560.
21 Dickson AP, Lum SK, Whyte AS. Paraplegia following saddle embolism. Br J Surg.
1984;71:321.
22 Syrjanen J, Iivanainen M, Kallio M, et al. Three different pathogenic mechanisms for
paraparesis in association with bacterial infections. Ann Clin Res. 1986;18:191.
23 Rao PS. Coarctation of the aorta. Curr Cardiol Rep. 2005;7:425.
24 Barré JA, D’Andrade C. Paraplegie par ramollissement aigu unisegmentaire de la moelle
survenne au cours de la grossesse: étude anatomo-clinique. Rev Neurol (Paris).
1938;69:133.
25 Chen GY, Kuo CD, Yang MJ, et al. Return of autonomic nervous activity after delivery:
role of aortocaval compression. Br J Anaesth. 1999;82:932.
26 Szilagyi DE, Hageman JH, Smith RF, et al. Spinal cord damage in surgery of the
abdominal aorta. Surgery. 1978;83:38.
27 Lynch C, Weingarden SI. Paraplegia following aortic surgery. Paraplegia. 1982;20:196.
28 Costello TG, Fisher A. Neurological complications following aortic surgery. Anaesthesia.
1983;38:230.
29 Picone AL, Green RM, Ricotta JR, et al. Spinal cord ischemia following operations on the
abdominal aorta. J Vasc Surg. 1986;3:94.
30 Duggal N, Lach B. Selective vulnerability of the lumbosacral spinal cord after cardiac
arrest and hypotension. Stroke. 2002;33:116.
31 Jacobs MJ, Elenbaas TW, Schurink GW, et al. Assessment of spinal cord integrity during
thoracoabdominal aortic aneurysm repair. Ann Thorac Surg. 2002;74:S1864.
32 Ohmi M, Shibuya T, Kawamoto S, et al. Spinal cord ischemia complicated with acute
aortic dissection and intramural hematoma; report of two cases. Kyobu Geka.
2003;56:473.
33 Webb TH, Williams GM. Thoracoabdominal aneurysm repair. Cardiovasc Surg. 1999;7:573.
34 Hakimi KN, Massagli TL. Anterior spinal artery syndrome in two children with genetic
thrombotic disorders. J Spinal Cord Med. 2005;28:69.
35 Ogun SA, Adefuye B, Kolapo KB, et al. Anterior spinal artery syndrome complicating
aortic dissecting aneurysm: case report. East Afr Med J. 2004;81:549.
36 Skinhoj E. Arteriosclerosis of the spinal cord. Acta Psychiatr Neurol Scand. 1954;29:139.
37 Blanc R, Hosseini H, Le Guerinel C, et al. Posterior cervical spinal cord infarction
complicating the treatment of an intracranial dural arteriovenous fistula embolization.
Case report. J Neurosurg Spine. 2006;5:79.
38 Charcot JM. Sur la claudication intermittente observée dans un cas d’oblitération
complète de l’une des artéres iliaques primitives. C R Mem Soc Biol. 1858;5:225.39 Dejerine J. Sur la claudication intermittente de la moelle épinière. Rev Neurol (Paris).
1906;14:341.
40 Blau JN, Logue V. Intermittent claudication of the cauda equina. Lancet. 1961;1:1081.
41 Truumees E. Spinal stenosis: pathophysiology, clinical and radiologic classification. Instr
Course Lect. 2005;54:287.
42 Crawford ES, Snyder DM, Cho GC, et al. Progress in treatment of thoracoabdominal and
abdominal aortic aneurysms involving celiac, superior mesenteric, and renal arteries.
Ann Surg. 1978;188:404.
43 Jex RK, Schaff HV, Piehler JM, et al. Early and late results following repair of dissections
of the descending thoracic aorta. J Vasc Surg. 1986;3:226.
44 Frist WH, Baldwin JC, Starnes VA, et al. A reconsideration of cerebral perfusion in aortic
arch replacement. Ann Thorac Surg. 1986;42:273.
45 Mwipatayi BP, Jeffery PC, Beningfield SJ, et al. Takayasu arteritis: clinical features and
management: report of 272 cases. Aust N Z J Surg. 2005;75:110.
46 Erlich M, Grabenwoger M, Luckner D, et al. Operative management of aortic arch
aneurysm using profound hypothermia and circulatory arrest. J Cardiovasc Surg.
1996;37:63.
47 Okita T, Ando M, Minatoya K, et al. Predictive factors for mortality and cerebral
complications in arteriosclerotic aneurysm of the aortic arch. Ann Thorac Surg.
1999;33:72.
48 Bogousslavsky J, Regli F. Ischemic stroke in adults younger than 30 years of age. Arch
Neurol. 1987;44:479.
49 Crawford ES, DeBakey ME, Cooley DA, et al. Surgical considerations of aneurysms and
atherosclerotic occlusive lesions of the aorta and major arteries. Postgrad Med.
1961;29:151.
50 Wylie EJ, Effeney DJ. Surgery of the aortic arch branches and vertebral arteries. Surg Clin
North Am. 1979;59:669.
51 Wickremasinghe HR, Peiris JB, Thenabadu PN, et al. Transient emboligenic aortoarteritis.
Arch Neurol. 1978;35:416.
52 Killen DA, Foster JH, Walter GGJr, et al. The subclavian steal syndrome. J Thorac
Cardiovasc Surg. 1966;51:539.
53 Aseem WM, Makaroun MS. Bilateral subclavian steal syndrome through different paths
and different sites. Angiology. 1999;50:149.
54 Ackermann H, Diener HC, Dichgans J. Stenosis and occlusion of the subclavian artery:
ultrasonographic and clinical findings. J Neurol. 1987;234:396.
55 Hennerici M, Klemm C, Rautenberg W. The subclavian steal phenomenon: a common
vascular disorder with rare neurologic deficits. Neurology. 1988;38:669.
56 Taylor SL, Selman WR, Ratcheson RA. Steal affecting the central nervous system.
Neurosurgery. 2002;50:670.
57 DeBakey ME, McCollum CH, Crawford ES, et al. Dissection and dissecting aneurysms of
the aorta: twenty-year follow-up of five hundred twenty-seven patients treated
surgically. Surgery. 1982;92:1118.58 Merchant RFJr, Cafferata HT, DePalma RG. Ruptured aortic aneurysm seen initially as
acute femoral neuropathy. Arch Surg. 1982;17:811.
59 Owens ML. Psoas weakness and femoral neuropathy: neglected signs of retroperitoneal
hemorrhage from ruptured aneurysm. Surgery. 1982;91:363.
60 Sterpetti AV, Blair EA, Schultz RD, et al. Sealed rupture of abdominal aortic aneurysms. J
Vasc Surg. 1990;11:430.
61 Boontje AH, Haaxma R. Femoral neuropathy as a complication of aortic surgery. J
Cardiovasc Surg. 1987;28:286.
62 Wilberger JE. Lumbosacral radiculopathy secondary to abdominal aortic aneurysms. J
Neurosurg. 1983;58:965.
63 Rothschild BM, Cohn L, Aviza A, et al. Aortic aneurysm producing back pain, bone
destruction, and paraplegia. Clin Orthop. 1982;164:123.
64 Higgins R, Peitzman AB, Reidy M, et al. Chronic contained rupture of an abdominal
aortic aneurysm presenting as a lower extremity neuropathy. Ann Emerg Med.
1988;17:284.
65 Wilbourn AJ, Furlan AJ, Hulley W, et al. Ischemic monomelic neuropathy. Neurology.
1983;33:447.
66 Beach C, Manthey D. Painless acute aortic dissection presenting as left lower extremity
numbness. Am J Emerg Med. 1998;16:49.
67 Afifi AK, Bergman RA. Functional Neuroanatomy, 2nd Ed. New York: McGraw-Hill, 1998.
68 Raskin NH, Levinson SA, Hoffman PM, et al. Post-sympathectomy neuralgia: amelioration
with diphenylhydantoin and carbamazepine. Am J Surg. 1974;128:75.
69 Smead WL, Vaccaro PS. Infrarenal aortic aneurysmectomy. Surg Clin North Am.
1983;63:1269.
70 Quayle JB. Sexual function after bilateral lumbar sympathectomy and aortoiliac by-pass
surgery. J Cardiovasc Surg. 1980;21:215.
71 DePalma RG. Impotence in vascular disease: relationship to vascular surgery. Br J Surg.
1982;69(suppl):S14.
72 Ohshiro T, Takahashi A, Kosaki G. Sexual function in patients with aortoiliac vascular
disorders. Int Surg. 1982;67:49.
73 Flanigan DP, Schuler JJ, Keifer T, et al. Elimination of iatrogenic impotence and
improvement of sexual function after aortoiliac revascularization. Arch Surg.
1982;117:544.
74 Ohshiro T, Kosaki G. Sexual function after aortoiliac vascular reconstruction. J Cardiovasc
Surg. 1984;25:47.
75 Nevelsteen A, Beyens G, Duchateau J, et al. Aortofemoral reconstruction and sexual
function: a prospective study. Eur J Vasc Surg. 1990;4:247.
76 Cormio L, Edgre J, Lepäntalo M, et al. Aortofemoral surgery and sexual function. Eur J
Vasc Endovasc Surg. 1996;11:453.
77 Hultgren R, Sjögren B, Söderberg M, et al. Sexual function in women suffering from
aortoiliac occlusive disease. Eur J Vasc Endovasc Surg. 1999;17:306.78 Heggtveit HA. Syphilitic aortitis: a clinicopathologic autopsy study of 100 cases, 1950 to
1960. Circulation. 1964;29:346.
79 DeBakey ME, Cooley DA, Crawford ES, et al. Aneurysms of the thoracic aorta: analysis of
179 patients treated by resection. J Thorac Surg. 1958;36:393.
80 Bickerstaff LK, Pairolero PC, Hollier LH, et al. Thoracic aortic aneurysms: a
populationbased study. Surgery. 1982;92:1103.
81 Rizzi R, Bruno S, Stellacci C, et al. Takayasu’s arteritis: a cell-mediated large-vessel
vasculitis. Int J Clin Lab Res. 1999;29:8.
82 Miller DV, Isotalo PA, Weyand CM, et al. Surgical pathology of non-infectious ascending
aortitis: a study of 45 cases with an emphasis on an isolated variant. Am J Surg Pathol.
2006;30:1150.
83 Bongartz T, Matteson EL. Large vessel involvement in giant cell arteritis. Curr Opin
Rheumatol. 2006;18:10.
84 Haimovici H. Abdominal aortic aneurysm. In: Haimovici H, editor. Vascular Surgery. East
Norwalk, CT: Appleton-Century-Crofts; 1984:685.
85 Johansen K, Devin J. Mycotic aortic aneurysms: a reappraisal. Arch Surg. 1983;118:583.
86 Brindley P, Schwab EH. Aneurysms of the aorta, with a summary of pathological findings
in 100 cases at autopsy. Tex State J Med. 1930;25:757.
87 Acosta S, Ögren M, Bengtsson H, et al. Increasing incidence of ruptured abdominal aortic
aneurysms: a population-based study. J Vasc Surg. 2006;44:237.
88 Roquer J, Martí N, Cano A, et al. Spinal cord ischemia indicating aneurysm of the
abdominal aorta: report of three cases. Neurologia. 1995;10:201.
89 Rosen SA. Painless aortic dissection presenting as spinal cord ischemia. Ann Emerg Med.
1988;17:840.
90 Dalen JE, Pape LA, Cohn LH, et al. Dissection of the aorta: pathogenesis, diagnosis, and
treatment. Prog Cardiovasc Dis. 1980;23:237.
91 Xu SD, Huang FJ, Yang JF, et al. Endovascular repair of acute type B aortic dissection:
Early and mid-term results. J Vasc Surg. 2006;43:1090.
92 Tsai TT, Evangelista A, Nienaber CA, et al. Long-term survival in patients presenting with
type A acute aortic dissection: insights from the international registry of acute aortic
dissection (IRAD). Circulation. 2006;114(suppl 1):350.
93 Conti VR, Calverley J, Safley WL, et al. Anterior spinal artery syndrome with chronic
traumatic thoracic aortic aneurysm. Ann Thorac Surg. 1982;33:81.
94 Mitchell RL, Enright LP. The surgical management of acute and chronic injuries of the
thoracic aorta. Surg Gynecol Obstet. 1983;157:1.
95 Schmidt CA, Jacobson JG. Thoracic aortic injury: a ten-year experience. Arch Surg.
1984;119:1244.
96 Naude GP, Back M, Perry MO, et al. Blunt disruption of the abdominal aorta: report of a
case and review of the literature. J Vasc Surg. 1997;25:931.
97 Tyler HR, Clark DB. Neurologic complications in patients with coarctation of aorta.
Neurology. 1958;8:712.98 Lerberg DB, Hardesty RL, Siewers RD, et al. Coarctation of the aorta in infants and
children: 25 years of experience. Ann Thorac Surg. 1982;33:159.
99 Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med. 2006;355:928.
100 Crawford ES, Crawford JL, Safi HJ, et al. Thoracoabdominal aortic aneurysms:
preoperative and intraoperative factors determining immediate and long-term results of
operations in 605 patients. J Vasc Surg. 1986;3:389.
101 Livesay JJ, Cooley DA, Ventemiglia RA, et al. Surgical experience in descending thoracic
aneurysmectomy with and without adjuncts to avoid ischemia. Ann Thorac Surg.
1985;39:37.
102 Neville WE, Cox WD, Leininger B, et al. Resection of the descending thoracic aorta with
femoral vein to femoral artery oxygenation perfusion. J Thorac Cardiovasc Surg.
1968;56:39.
103 Bloodwell RD, Hallman GL, Cooley DA. Partial cardiopulmonary bypass for
pericardiectomy and resection of descending thoracic aortic aneurysms. Ann Thorac Surg.
1968;6:46.
104 Kahn DR, Sloan H. Resection of descending thoracic aneurysms without left heart
bypass. Arch Surg. 1968;97:336.
105 Krieger KH, Spencer FC. Is paraplegia after repair of coarctation of the aorta due
principally to distal hypotension during aortic cross-clamping? Surgery. 1985;97:2.
106 Galbreath C, Salgado ED, Furlan AJ, et al. Central nervous system complications of
percutaneous transluminal coronary angioplasty. Stroke. 1986;17:616.
107 Ussia GP, Marasini M, Pongiglione G. Paraplegia following percutaneous balloon
angioplasty of aortic coarctation: a case report. Catheter Cardiovasc Interv. 2001;54:510.
108 Laschinger JC, Cunningham JN, Cooper MM, et al. Prevention of ischemic spinal cord
injury following aortic cross-clamping: use of corticosteroids. Ann Thorac Surg.
1984;38:500.
109 Robertson CS, Foltz R, Grossman RG, et al. Protection against experimental ischemic
spinal cord injury. J Neurosurg. 1986;64:633.
110 Kumagai H, Isaka M, Sugawara Y, et al. Intra-aortic injection of propofol prevents
spinal cord injury during aortic surgery. Eur J Cardiothorac Surg. 2006;29:714.
111 Oldfield EH, Plunkett RJ, Nylander WAJr, et al. Barbiturate protection in acute
experimental spinal cord ischemia. J Neurosurg. 1982;56:511.
112 Patel HJ, Shillingford MS, Mihalik S, et al. Resection of the descending thoracic aorta.
Ann Thorac Surg. 2006;82:90.
113 Safi HJ, Mille CCIII. Spinal cord protection in descending thoracic and
thoracoabdominal aortic repair. Ann Thorac Surg. 1999;67:1937.
114 Coselli JS, LeMaire SA. Left heart bypass reduces paraplegia rates after
thoracoabdominal aortic aneurysm repair. Ann Thorac Surg. 1999;67:1931.
115 Laschinger JC, Cunningham JNJr, Nathan IM, et al. Experimental and clinical
assessment of the adequacy of partial bypass in maintenance of spinal cord blood flow
during operations on the thoracic aorta. Ann Thorac Surg. 1983;36:417.
116 Ogino H, Sasaki H, Minatoya K, et al. Combined use of Adamkiewicz arterydemonstration and motor evoked potentials in descending thoracoabdominal repair.
Ann Thorac Surg. 2006;82:592.
117 Kaplan BJ, Friedman WA, Alexander JA, et al. Somatosensory evoked potential
monitoring of spinal cord ischemia during aortic operations. Neurosurgery. 1986;19:82.
118 Mizrahi EM, Crawford ES. Somatosensory evoked potentials during reversible spinal
cord ischemia in man. Electroencephalogr Clin Neurophysiol. 1984;58:120.
119 MacDonald DB. Intraoperative motor evoked potential monitoring: overview and
update. J Clin Monit Comput. 2006;20:347.
120 Coles JG, Wilson GJ, Sima AF, et al. Intraoperative detection of spinal cord ischemia
using somatosensory cortical evoked potentials during thoracic aortic occlusion. Ann
Thorac Surg. 1982;34:299.
121 Svensson LG, Patel V, Robinson MF, et al. Influence of preservation or perfusion of
intraoperatively identified spinal cord blood supply on spinal motor evoked potentials
and paraplegia after aortic surgery. J Vasc Surg. 1991;13:355.
122 Reuter DG, Tacker WA, Badylak SF, et al. Correlation of motor-evoked potential
response to ischemic spinal cord damage. J Thorac Cardiovasc Surg. 1992;104:262.
123 Jacobs MJHM, Meylaerts SA, de Haan P, et al. Strategies to prevent neurologic deficit
based on motor-evoked potentials in type I and II thoracoabdominal aortic aneurysm
repair. J Vasc Surg. 1999;29:48.
124 Guerit JM, Witdoeckt C, Verhelst R, et al. Sensitivity, specificity, and surgical impact of
somatosensory evoked potentials in descending aorta surgery. Ann Thorac Surg.
1999;67:1943.
125 Galla JD, Ergin MA, Lansman SL, et al. Use of somatosensory evoked potentials for
thoracic and thoracoabdominal aortic resections. Ann Thorac Surg. 1999;67:1947.Chapter 3
Neurological Complications of Cardiac Surgery
John R. Hotson
EXTRACORPOREAL CIRCULATION
Technique
Consequences During “Normal” Convalescence
NEUROLOGICAL SEQUELAE OF CARDIAC SURGERY
Brain Disorders
Peripheral Nerve Disorders
Neuro-ophthalmological Disorders
NEUROCOGNITIVE DECLINE
RISK FACTORS FOR STROKE
PREVENTION OF NEUROLOGICAL COMPLICATIONS
CARDIAC TRANSPLANTATION
Neurological complications are a potential consequence of cardiac surgery that
1-8can nullify or limit any bene0ts of such surgery. The probability of these
complications increases as coronary artery bypass graft surgery is used for treating
ischemic heart disease in older patients, in patients with multiple comorbid
9conditions, and as heart transplantation programs expand. In spite of the
increased use of catheter-based coronary revascularization, more than 400,000
10people per year have coronary artery bypass graft surgery in the United States. A
substantial number of patients have a postoperative adverse cerebral outcome such
6,11as stroke or hypoxic-ischemic encephalopathy. Many more patients may
8,12develop loss of cognitive performance after heart surgery. Prevention of
perioperative neurological complications remains an important medical problem.
EXTRACORPOREAL CIRCULATION
Cardiopulmonary bypass was 0rst used successfully in cardiac surgery in 1953 and
13was the pivotal development that led to modern cardiac surgery. Its early use inhumans resulted in frequent complications, which restricted its employment to
seriously ill patients with progressive heart failure. Although the safety of
extracorporeal circulation has increased, it remains a potential cause of
neurological complications independent of other heart surgery procedures.
Technique
Open heart surgery with cardiopulmonary bypass begins with exposure of the
heart, usually by a median sternotomy, followed by cannulation of the ascending
13aorta and vena cava or right atrium. Insertion of the aortic cannula can dislodge
atheromatous material in a severely diseased aorta, thereby leading to cerebral
14embolization. In addition, this procedure can produce rotational torsion or
15,16compression of the brachial plexus, with subsequent injury.
Extracorporeal circulation is used in association with systemic heparinization,
13hypothermia, and hemodilution. Anticoagulation is used to prevent clot
formation when blood is exposed to the nonendothelial surfaces of the bypass
pump oxygenator and microaggregation 0ltration system. Core hypothermia is
often used in combination with selective cooling of the heart, or cold cardioplegia,
in order to protect the heart, brain, and other vital organs from ischemic damage.
Infusion of ice slush solutions into the pericardium is one technique for inducing
17-19cold cardioplegia, but it occasionally produces focal phrenic nerve injuries.
Normothermic cardiopulmonary bypass may also be used in patients with few risk
factors for stroke because it provides better hemodynamic function and decreases
20,21cardiopulmonary bypass time.
Normovolemic hemodilution is used in part to conserve blood loss. It also
compensates for the progressive hemoconcentration, decrease in plasma vol ume,
13and reduced blood flow that is associated with hypothermia.
During cardiac surgery with extracorporeal circulation, the ascending aorta is
routinely cross-clamped; during valve-replacement surgery, congenital heart
disease repair, or left ventricular aneurysm resection, the cardiac chambers are
entered. These procedures may disrupt diseased tissue and produce emboli. Arterial
systolic, diastolic, and mean pressure, pump pressure and Cow rate, and central
venous pressure are monitored during cardiopulmonary bypass. Mean arterial
pressure is usually maintained above 40 to 50 mmHg by vasodilators, pressors, or
13volume expanders.
Consequences During “Normal” Convalescence
Extracorporeal circulation has predictable eEects that result in a postperfusion
syndrome and systemic inCammatory response during “normal”
13,22convalescence. This syndrome includes the following conditions.Reduced Clotting Factors.
Exposure of blood to an abnormal environment during cardiopulmonary bypass
leads to consumption of platelets and coagulation factors. Platelets adhere to the
unphysiological surface of the oxygenators and 0ltration system of the bypass
pump. This clumping of platelets not only predisposes to platelet emboli but also
can reduce the number of circulating platelets. The exposure to foreign surfaces
also causes release and depletion of granule-stored aggregating proteins in
surviving platelets. Therefore, the remaining platelets have decreased
13,22adhesiveness.
Coagulation factors are also consumed during cardiopulmonary bypass. A variety
of carrier proteins and lipoproteins are denatured when blood passes through the
bypass pump oxygenator. Even with adequate heparin levels, these damaged
proteins can initiate a cascade in several coagulation and inCammatory
22,23systems. The clinical signi0cance of these hematological changes is usually
minor. They may contribute, however, to the intracranial hemorrhages that are
24occasionally observed after open heart surgery.
Cardiovascular Response.
During the early postoperative period, the degree of peripheral vasoconstriction
13provides a clinical estimate of cardiac output. Transient atrial 0brillation, which
25,26carries a risk of cardiac emboli, is common during the convalescent period. A
metabolic acidosis is also common during the 2 hours immediately after operation
and reCects a washout of lactic acid from regions of poor perfusion during
extracorporeal circulation. Persistence of a metabolic acidosis may indicate
13inadequate tissue perfusion secondary to low cardiac output.
Red Blood Cell Fragmentation.
Exposure of blood to nonendothelial surfaces during bypass surgery causes a
breakdown of red blood cells, with subsequent anemia, hemoglobinemia, and
13hemoglobinuria.
Mild Mental Confusion.
Transient mild disturbances of orientation, memory, and level of alertness that
resolve within the 0rst few days after open heart surgery with cardiopulmonary
13bypass are frequent. Whether the changes in mentation are totally reversible
events that accompany most major operations or whether they indicate long-term
8,11sequelae is an area of sustained interest.
Brain Swelling.
Brain swelling is present when magnetic resonance imaging (MRI) is obtainedimmediately following coronary artery bypass surgery. When brain imaging studies
are repeated 2 to 3 weeks after the surgery, the brain swelling has remitted. There
are no clinical 0ndings associated with the brain swelling, and its cause is
27unknown.
These expected consequences of cardiopulmonary bypass are functionally
reversible and compensated for during convalescence. Firm evidence that
extracorporeal circulation itself permanently harms the brain is lacking.
Cardiopulmonary bypass, however, does create numerous potential hazards that, if
augmented by procedural mishap, may lead to permanent injury of the central
nervous system (CNS). Cardiac operations using extracorporeal circulation carry
the risks of embolus formation (from platelets, 0brin, tissue or surgical debris, air,
13,22or fat), cerebral hypoperfusion, and even hemorrhage. For these reasons,
there is interest in performing coronary artery surgery without the use of
28cardiopulmonary bypass. This oE-pump technique can produce excellent cardiac
outcomes. It is associated with fewer cerebral microemboli and less short-term
29,30neurocognitive decline when compared to on-pump coronary artery surgery.
The short-term diEerence in cognitive performance, however, is limited, has not
been consistently found across studies, and is not statistically signi0cant at 1
28,30,31year. The oE-pump technique does not lower the overall stroke rate, but
may decrease stroke in a high-risk subgroup of patients with a severely
32atheromatous aorta. Comparisons of performing coronary artery bypass grafting
oE-pump and with cardiopulmonary bypass have not proven the overall superiority
28of either method.
NEUROLOGICAL SEQUELAE OF CARDIAC SURGERY
DiEuse or multifocal anoxic-ischemic damage, focal cerebral infarction, and
brachial plexus injuries remain the main causes of permanent, disabling
1,6,15,33neurological complications after cardiac surgery. Therefore, the common,
obvious postoperative symptoms include diEuse impairment of cognition and level
of consciousness, focal de0cits from stroke, and isolated peripheral weakness and
sensory loss in one arm and hand.
Brain Disorders
Stroke, encephalopathy, coma, and seizures are the major brain disorders
6,34complicating cardiac surgery. Stroke is reported in prospective studies to occur
in 1 percent to more than 5 percent of patients following coronary artery bypass
surgery, and the incidence increases in association with preoperative stroke risk
6,21,35-37factors. Stroke after cardiac surgery increases hospital mortality
approximately 0ve- to sixfold, prolongs intensive care, and typically requires38,39inpatient rehabilitation or nursing home placement. The majority of stroke
39patients who survive to hospital discharge are substantially disabled. Most
strokes occur in the 0rst 2 to 3 days after coronary artery bypass surgery, but they
may continue with increased frequency during the 0rst 2 postoperative
8,39,40weeks. Stroke occurs more frequently when valvular heart surgery is
41,42combined with coronary artery bypass graft operations. This increase is due
to the additional risk of cerebral macroemboli with operations that require opening
a heart chamber and removal or repair of diseased mitral or aortic valves. Imaging
and clinical studies, including cerebral arteriograms, suggest that the main cause of
cerebral infarction with either coronary artery bypass surgery or valvular heart
40,43surgery is embolization and not hypoperfusion. DiEusion-weighted brain MRI
is more sensitive that computed tomography (CT) for detecting acute stroke after
heart surgery and, when combined with measurements of the apparent diEusion
44coeI cient, distinguishes acute from chronic ischemic lesions. Intra-arterial
thrombolysis for stroke occurring 1 to 14 days after heart surgery has been reported
45-47as a potential treatment option that merits further study.
Intracranial hemorrhage is an infrequent cause of stroke, but its rapid
identi0cation is important so that surgical evacuation can be undertaken if
40,48,49necessary. Hematomas may be located in the brain parenchyma or in
subdural or epidural spaces. Intracranial hemorrhage may be related to reduced
platelet adhesion and coagulation factors during cardiopulmonary bypass.
The global encephalopathy that can follow heart surgery varies from coma to
confusion or delirium with impaired cognition. Stupor or coma after uncomplicated
34surgery is infrequent, occurring in less than 1 percent of patients. It may be due
to global anoxia-ischemia, massive stroke, or multiple brain infarctions.
Postoperative hyponatremic encephalopathy is important to recognize and reverse
50because it can lead to brain damage and death, particularly in younger women.
Additional, rarely reported causes of encephalopathy or coma include
51 52hypoglycemia, a hypernatremic hyperosmolar state, and acute obstructive
53hydrocephalus.
When anoxia-ischemia is the cause of coma, myoclonus, at times accompanied
by seizures, may be prominent. Recurrent postanoxic myoclonus and seizures are
often poorly responsive to anticonvulsant therapy. The outcome in these comatose
patients is usually extremely poor, with only a rare patient making a meaningful
54recovery.
Clinical assessment identi0es confusion or delirium after cardiac surgery in
55,56greater than 8 percent of patients. Its prevalence is even greater in patients
older than 65 to 70 years and in patients with known preexisting cerebrovascular57disease. Confusion and delirium after cardiac surgery increase postoperative
morbidity and prolong postoperative hospitalization.
These encephalopathic patients may be slow to emerge from anesthesia, are
often agitated, and have Cuctuating moderate to severe impairment of cognitive
function. Hallucinations may be present, and occasionally there are bilateral
Babinski signs. Improvement often occurs during the 0rst postoperative week. In
comparison, patients who are matched for age and clinical condition but who have
major surgery for peripheral vascular disease without cardiopulmonary bypass
3rarely develop such transient impairment of intellectual function. Some confused
patients have multiple, acute, small ischemic brain lesions detected with
diEusion44weighted MRI, suggesting multiple emboli. However, in many patients, the cause
of confusion or delirium cannot be clinically de0ned. Coronary artery bypass
grafting without the use of cardiopulmonary bypass results in less frequent
postoperative delirium, whereas prolonged operating time increases its
55frequency. Therefore, exposure to cardiopulmonary bypass appears to be a
contributing factor to a transient encephalopathic state in otherwise uncomplicated
cardiac surgery.
Acute psychosis after open heart surgery has been attributed to a situational
58psychiatric reaction if the level of alertness and memory remain intact. When the
latter processes are also impaired, the psychotic behavior has been called an
organic delirium. In patients undergoing cardiac surgery, this diEerentiation may
be incorrect. When the psychotic response has cleared and neuropsychological
testing is performed, both groups have similar, multiple cognitive impairments
59compared to patients without neurobehavioral complications. The diagnosis of
an intensive care unit psychosis is usually restricted to reactions that begin 2 to 5
days after surgery, are associated with preserved memory and alertness, and
rapidly resolve after treatment with neuroleptic agents or discharge from the
intensive care unit. Psychotic reactions that occur during the 0rst 48 postoperative
hours in a previously stable patient probably represent a behavioral response to an
anoxic-ischemic insult associated with cardiac surgery and cardiopulmonary
58,60bypass.
Seizures may accompany coma, encephalopathy, or delirium, or they may occur
6,34independently after cardiac surgery. They occur in fewer than 1 percent of
patients, usually early in the postoperative period and often within the 0rst 24
hours. Tonic-clonic or partial motor seizures are clinically apparent, but partial
complex seizures in an encephalopathic patient may be diI cult to recognize
clinically. Choreoathetosis after heart surgery, a complication that occurs mainly in
61children, sometimes raises the question of a seizure disorder. Nonconvulsive
status epilepticus may occur with stroke complicating cardiac surgery and will thencontribute to a prolonged confusional state that is treatable with anticonvulsant
62drugs. Therefore, the electroencephalographic evaluation of patients with a
persistent encephalopathy may be valuable.
Peripheral Nerve Disorders
The brachial plexus and phrenic nerves are the most frequent peripheral nerves
injured during cardiac surgery. A polyneuropathy may also occur under certain
circumstances.
A persistent brachial plexopathy after median sternotomy has been reported to
1,15,16occur in more than 5 percent of patients. Transient and minor brachial
63plexus injuries may be even more common. Most frequently, the lower trunk of
the brachial plexus is injured. Therefore, the intrinsic hand muscles are often most
severely impaired, and the triceps reCex may be decreased in the aEected arm.
Sensory loss is sometimes present in the aEected hand. Pain is prominent in some
patients, and a minority have Horner’s syndrome. Injuries of the upper brachial
plexus can also occur but are less frequent. Although not life-threatening and
usually reversible in 1 to 3 months, a brachial plexus injury may produce
permanent disability, particularly if it aEects the dominant hand or produces
intractable causalgia.
The plexus injuries may be due to torsional traction or compression during the
16,63open heart surgery. Intraoperative electrophysiological monitoring of upper
extremity sensory nerve conduction reveals signi0cant disturbances during sternal
retraction in the majority of patients. This intraoperative monitoring technique can
detect functional disorders of the brachial plexus during surgery, predict
postoperative nerve injury, and identify intraoperative factors that predispose to
64,65brachial plexus injury. Brachial plexus injuries may be reduced by
minimizing the opening of the sternal retractor, placing the retractor in the most
16caudal location, and avoiding asymmetric traction.
Unilateral phrenic nerve injuries with hemidiaphragmatic paralysis occur in at
18,66,67least 10 percent of patients during open heart surgery. The location of the
phrenic nerve adjacent to the pericardium makes it particularly vulnerable to
injury from hypothermia associated with topical cold cardioplegia, as well as injury
from manipulation and ischemia. Unilateral phrenic nerve injury causes atelectasis
and inspiratory muscle weakness, predisposing to postoperative respiratory
complications. Phrenic nerve injury in patients with preoperative chronic
obstructive pulmonary disease adds particularly to postoperative morbidity. In
most patients, however, morbidity is low. Some recovery is usually evident by
about 6 months after injury, but there may be a more protracted course consistent
with axonal injury and regeneration. Severe, bilateral phrenic nerve injury is a rare68complication of heart surgery and leads to prolonged mechanical respiration.
Mononeuropathies resulting from compression or trauma during surgery may
involve the accessory, facial, lateral femoral cutaneous, peroneal, radial, recurrent
15,69-72laryngeal, saphenous, long thoracic, and ulnar nerves. A recurrent
laryngeal nerve injury with vocal cord paralysis and a persistent peroneal
15neuropathy can be disabling. Ischemia to the cochlea-auditory nerve can result
73in severe hearing loss. Most compressive mononeuropathies, however, are
transient. This reversibility, usually within 4 to 8 weeks, may reCect the focal
selective injury to myelin, with relative sparing of nerve axons, which occurs with
74compression neuropathies. Awareness of possible intraoperative compression
sites helps to prevent these complications.
DiEuse paralysis as a result of the Guillain–Barré syndrome may follow otherwise
75uncomplicated cardiac surgery as well as other surgical procedures. Persistent
paralysis also occurs after cardiac surgery in critically ill patients who have renal
76failure and require days of vecuronium to facilitate mechanical respiration. If
heart surgery is complicated by sepsis and multiorgan failure lasting for more than
a week, a “critical illness” polyneuropathy and myopathy may develop, with
diI culty in weaning from a respirator, distal weakness, and reduced tendon
77reflexes.
Neuro-ophthalmological Disorders
Visual disorders from cardiac surgery are frequent but usually asymptomatic and
reversible. Retinal disorders include multifocal areas of retinal nonperfusion in
almost all patients, cotton wool spots consistent with retinal infarctions in 10 to 25
percent of patients, and visualization of retinal emboli in fewer individuals. These
5,78retinal disorders are infrequently associated with reduced visual acuity.
An anterior ischemic optic neuropathy is an uncommon, disabling complication
of heart surgery. It produces infarction of the optic nerve head, optic disc swelling
with a painless and usually permanent decrease in visual acuity. An anterior
ischemic optic neuropathy may produce a monocular altitudinal, arcuate, or
78central scotoma. A retrobulbar or posterior ischemic optic neuropathy due to
79infarct of the intraorbital nerve is even less common. It produces acute blindness
80without optic disc swelling accompanied by impaired pupillary reactions. Both
the anterior and posterior ischemic optic neuropathies may produce unilateral or
79bilateral blindness.
Homonymous visual 0eld defects occur with focal ischemic injury of the visual
cortex or retrochiasmal visual pathways. An occasional patient is found to be
cortically blind after heart surgery, usually from bilateral ischemia of the occipitalcortex. Retinal and pupillary examination are both normal in patients with cortical
blindness. Some of these patients deny any visual impairment. At least partial
5,78recovery from cortical blindness is possible.
Horner’s syndrome occurs in association with injuries to the lower brachial
plexus and may result from concomitant injury to the preganglionic sympathetic
50bers that travel through the eighth cervical and 0rst thoracic ventral roots. It
also develops in the postoperative period in hypertensive and diabetic patients,
81presumably due to ischemic injury to sympathetic fibers.
Gaze deviations, gaze paralysis, and dysconjugate gaze may occur in
postoperative patients who have a brainstem or large hemispheric stroke involving
eye movement systems. Intermittent gaze deviation with nystagmoid movements
82raises concerns about postoperative focal seizures.
Pituitary apoplexy resulting from acute hemorrhage or infarction of a pituitary
83adenoma is a rare complication of cardiopulmonary bypass. The pituitary tumor
is usually not recognized prior to surgery and is particularly susceptible to the
ischemic and hemorrhagic risks associated with cardiopulmonary bypass. After
heart surgery, patients awake with headache, ptosis, ophthalmoplegia, and visual
impairment from compression of the adjacent cranial nerves and the anterior visual
pathways. Transsphenoidal surgical decompression has been used safely in some
patients. Infarction of a normal pituitary during coronary artery bypass surgery
84also occurs, may initially be silent, and leads to panhypopituitarism.
Visual hallucinations solely on eye closure have been reported following
85,86cardiovascular surgery. Patients are otherwise fully alert and lucid and can
stop the hallucinations simply by opening their eyes. Atropine or lidocaine toxicity
and complex partial seizures have been associated with such hallucinations.
NEUROCOGNITIVE DECLINE
Neuropsychological studies of cognitive function before and after cardiac surgery
have identi0ed both a transient early and a subsequent late decline in cognitive
7,87-91function occurring after heart surgery. The early postoperative changes in
cognition have been shown by comparing repetitive neuropsychological test results
in patients undergoing coronary artery surgery with extracorporeal circulation to
nonsurgical control subjects. Performance declines on tests of attention,
visuospatial ability, and memory 3 days after coronary artery bypass surgery
compared to preoperative testing. A similar decline does not occur in age- and
gender-matched nonsurgical control subjects. The impaired neurocognitive
performance, however, typically returns to the preoperative level within
87,89-92weeks. Although numerous factors may contribute to this transientpostoperative cognitive impairment, direct evidence of a speci0c etiology in
7individual patients is often lacking.
A late decline in cognitive function occurs in the interval from 1 to 5 years after
88,90,93coronary artery bypass surgery. The cause of this late decline is unproven,
92in part because few of the longitudinal studies included control groups. One
postulated etiology is that diEuse brain microemboli associated with extracorporeal
circulation injure a neuronal reserve that is needed to compensate for brain aging
94,95and to prevent dementia. Transcranial Doppler ultrasonography of the middle
cerebral artery and carotid artery can detect microemboli during heart surgery.
During cardiopulmonary bypass, there is a continuous dissemination of brain
microemboli producing microvascular occlusions followed by
78,94,96-98reperfusion. The washout of brain emboli and reperfusion may be
99impaired if there is concurrent systemic or localized hypoperfusion.
Patients with a high total microemboli count during heart surgery have a
signi0cantly higher frequency of neuropsychological test de0cits than patients with
low microemboli counts. Patients with long cardiopulmonary bypass durations also
have a higher total microemboli count and higher frequency of neuropsychological
100-102decline. If extracorporeal circulation does lead to a late decline in cognitive
performance, then patients with oE-pump coronary surgery on the beating heart
103should have less of a late decline. This comparative study is pending.
Evidence exists against the belief that disseminated brain microemboli from the
extracorporeal circulation account for the late cognitive decline. Cognitive function
5 years after patients are randomly assigned to undergo either coronary surgery or
104angioplasty is similar. Cognitive performance at 3 years is also similar in
patients receiving on-pump coronary artery bypass surgery and a nonsurgical
103control group with coronary artery disease. One study with a small number of
patients in which individuals with preexisting neurological or psychiatric diseases
or impaired cognition were excluded showed no late decline in cognitive
performance after 3 to 5 years. These patients also had very good vascular risk
105factor control over the interval of neuropsychological testing. A case-control
study found a similar incidence of coronary artery bypass surgery in control
subjects and patients with dementia, including a subgroup with a diagnosis of
Alzheimer’s disease. Coronary artery bypass surgery does not appear to be a major
106risk factor for dementia.
A slow accumulation of microvascular brain ischemia due to vascular risk factors
is an alternative explanation for the late decline in neurocognitive performance
after cardiac surgery. Elderly subjects with asymptomatic ischemic lesions on brain
imaging who have not had heart surgery have a greater decline in cognitivefunction over a period of 3 to 4 years than individuals without ischemic
107-109lesions. Similarly, subjects with symptomatic cerebrovascular disease have
110,111increased progressive cognitive decline compared to control subjects.
Patients undergoing coronary artery bypass grafts typically have vascular risk
factors for asymptomatic and symptomatic brain lesions that are associated with
112cognitive decline. It would be valuable to know whether very good control of
vascular risk factors eliminates the late decline in cognitive performance that
7,105follows heart surgery.
RISK FACTORS FOR STROKE
Several preoperative factors have been identi0ed as placing a patient at a higher
risk of a neurological complication (Table 3-1). Increasing older age is associated
with increasing frequency of neurological and cognitive disorders following
6,113,114coronary artery bypass surgery. A multicenter, prospective study of 5,000
patients found that the occurrence of stroke was 1 percent in patients younger than
50 years of age, almost 2 percent in patients aged 50 to 59 years, approaching 4
percent in patients aged 60 to 69 years, and greater than 5 percent in patients
115older than 70 years. With a growing elderly population, the number of patients
older than 80 years who are evaluated for coronary artery bypass grafts may
116increase.
TABLE 3-1 Risk Factors for Cerebral Ischemia During Cardiac Surgery
P r e o p e r a t i v e
Older age
Atheromatous aorta
Hypertension
Diabetes mellitus
Previous stroke
Carotid artery disease
I n t r a o p e r a t i v e
Prolonged cardiopulmonary bypass
High count of cerebral microemboliCombined coronary artery bypass and valvular heart surgeries
Large hemodynamic fluctuations
P o s t o p e r a t i v e
Atrial fibrillation
Dislodgment of prothrombotic atheroma during instrumentation of the aorta is a
14,32,117-120risk factor for stroke. Atheromatous aortic disease can be identi0ed
with intraoperative ultrasonographic scanning and transesophageal
echocardiography. Approximately 25 to 50 percent of patients receiving a coronary
artery bypass graft have atherosclerotic plaques in their ascending aorta identi0ed
by these techniques. The frequency of such aortic disease increases with age and is
particularly prominent in patients older than 70 years. Identi0cation of a
118,121moderately to severely atheromatous aorta may alter surgical management.
A preoperative history of hypertension, diabetes mellitus, stroke, severe stenosis
of the carotid artery (>70%), and other markers of vascular disease are also risk
6,8,38,114,115,122factors for stroke following coronary artery bypass surgery.
Cardiac surgery within 3 months of a stroke may carry a risk of worsening
123preoperative neurological de0cits. The greater the number of preoperative risk
factors, the higher is the probability of a perioperative stroke. For example, a 65- to
75-year-old patient with a history of a stroke and hypertension has a risk of
postoperative stroke that is three times greater than that of a patient of the same
age without a history of stroke or hypertension. A patient older than 75 years with
a history of stroke and hypertension has a probability for postoperative stroke that
is 13 times greater than a patient younger than 65 years with no previous stroke or
history of hypertension. Stroke risk indexes may identify patients prior to coronary
124,125artery bypass surgery who are at high risk of a perioperative stroke.
Intraoperative factors also inCuence the frequency of stroke (Table 3-1). As
noted previously, individuals who require coronary artery bypass surgery combined
38,126with a left-sided intracardiac procedure have a relatively high rate of stroke.
Patients who require cardiopulmonary bypass lasting more than 2 hours have a
higher number of intraoperative cerebral microemboli detected by transcranial
38,115,127,128Doppler ultrasound monitoring and a higher frequency of stroke. A
large fluctuation in hemodynamic parameters during surgery, such as mean arterial
129pressure, has been associated with postoperative stroke and encephalopathy.
The risk from sustained intraoperative hypotension with a mean arterial pressure
below 40 to 50 mmHg during cardiopulmonary bypass remains unclear.
Atrial 0brillation occurs in approximately one third of continuously monitoredpatients following cardiac surgery and is a risk factor for stroke. Its initial
occurrence is most common during the 0rst 3 postoperative days, and 20 percent of
patients have more than one episode. Advancing age is a risk factor for atrial
0brillation, and patients older than 70 years are at high risk of arrhythmia.
Withdrawal from β-adrenergic receptor–blocking agents or angiotensin-converting
enzyme inhibitors is also associated with recurrent atrial 0brillation. Use of β -
blocking drugs or angiotensin-converting enzyme inhibitors preoperatively and
postoperatively and β-blockers postoperatively is associated with a reduced risk of
25,115,122,130,131atrial fibrillation.
PREVENTION OF NEUROLOGICAL COMPLICATIONS
Attempts to prevent neurological sequelae after cardiac surgery have focused on
improved surgical and cardiopulmonary bypass techniques and neuroprotective
8,132,133drugs.
Identi0cation of surgical and technical factors that carry particular risks of
neurological complications after cardiac surgery has led to the adoption of
8,13,132preventive measures. An arterial line micro0lter system has been
incorporated into the extracorporeal circulation with the aim of reducing cerebral
embolization. Improved surgical techniques reduce the bypass time and the total
number of cerebral microemboli. Maintenance of the mean arterial blood pressure
above 50 mmHg provides a safety margin against periods of relative
hypoperfusion. The use of a membrane oxygenator decreases the magnitude of air
emboli. Preoperative or early postoperative administration of β-blocking agents
decreases the incidence of postoperative atrial 0brillation. Early postoperative use
of aspirin decreases ischemic complications of multiple organs including the
134brain. Perioperative monitoring and control of hyperglycemia may inCuence
132,135outcome. Delaying heart surgery for 4 or more weeks after a recent stroke
132has been recommended if the cardiac condition allows such a delay.
The bene0t of combined carotid revascularization and coronary artery bypass
surgery in patients with asymptomatic carotid stenosis awaits con0rmation in a
114,136-139prospective clinical trial. Carotid endarterectomy for patients with
severe (70% to 99%) internal carotid stenosis that has been neurologically
symptomatic in the past 6 months is of established bene0t independent of cardiac
140surgery. Performing a carotid endarterectomy before or simultaneous with
132,141,142coronary artery bypass surgery in such patients is an accepted practice.
Carotid stenting has evolved as an alternative procedure for such
8,138,139,143,144patients.
An increased concern that an atheromatous aorta is a primary source of embolic
stroke has led to intraoperative identi0cation with transesophageal14echocardiography and epiaortic scanning. The presence of prominent aortic
atheroma alters surgical techniques including the site of aortic cannulation, the
aorta clamping technique, the use of intra-aortic 0ltration, and using oE-pump
coronary artery surgery to avoid manipulation of a severely diseased
28,32,118,132,145,146aorta.
The magnitude of cerebral microemboli and the frequent neuropsychological and
anoxic-ischemic 0ndings associated with cardiac surgery suggest a need and
opportunity to study brain protective agents. Proposed mechanisms of
pharmacological neuroprotection include decreasing cerebral oxygen consumption;
decreasing cerebral blood-Cow and, with it, the total number of microemboli;
interrupting the cascade of cerebral ischemic events that are mediated via
excitotoxins such as glutamate; and decreasing the inCammatory response and
133,147-151coagulation cascade associated with cardiopulmonary bypass. Clinical
trials, however, have yet to identify an eEective pharmacological neuroprotective
agent that has wide clinical application during coronary artery bypass surgery.
CARDIAC TRANSPLANTATION
Cardiac transplantation is an established treatment for selected patients with
progressive, preterminal heart failure. Cardiac transplantation centers now report
survival rates at 1 year of greater than 80 to 85 percent, at 5 years of 60 to 80
percent, at 10 years of approximately 50 percent, and at 15 years of 30 to 40
152,153percent. The annual number of heart transplantations worldwide is
153estimated to be greater than 4,000. Neurological sequelae occurring either in
the perioperative period or as a late complication may negate an otherwise
successful heart transplantation. The early identi0cation of treatable complications
offers the best opportunity to prevent severe disability.
The perioperative neurological sequelae from cardiac transplantation are similar
to the complications associated with valvular or bypass graft surgery, dis cussed
previously, except that neurological complications occur more frequently in
41transplant recipients. Postoperative encephalopathy, stroke, headaches,
psychosis, seizures, and peripheral nerve disorders are the most common
154-160problems.
Vascular headaches accompanied by nausea and vomiting may occur in the 0rst
156week after transplantation. The headaches are associated with a rapid shift
from low preoperative to high postoperative mean arterial pressures. Similar
headaches may rarely precede an intraparenchymal hemorrhage. These vascular
headaches respond to β-adrenergic receptor–blocking agents.
Seizures have been reported in as many as 15 percent of patients with cardiac157transplants. They commonly occur during the perioperative period. They also
occur as a side eEect of cyclosporine or as a late complication of a brain infection
or tumor. Seizures in the perioperative period are usually due to stroke and may
not require long-term anticonvulsant therapy. When anticonvulsant drugs are
indicated, phenytoin, phenobarbital, and carbamazepine are often avoided because
they induce the hepatic metabolism of cyclosporine, tacrolimus, and sirolimus.
When these antiepileptic agents are used, immunosuppression may be reduced.
Levatiracetam and gabapentin have negligible hepatic enzyme–inducing eEects
161and few drug interactions and may be preferred anticonvulsants. Pregabalin, a
newer antiepileptic drug, has similar characteristics.
Psychotic behavior with hallucinations, delusional thought processes, and
disorganized behavior can occur during the 0rst 2 weeks after transplantation or as
a late complication. When it occurs during the postoperative period, multiple
causal factors may be present, but with time, the psychotic behavior usually
resolves. When psychotic behavior occurs as a late complication, it is often a
manifestation of an intracranial infection, most commonly viral. A thorough
neurological evaluation is therefore indicated when a cardiac transplant recipient
154,155develops an acute late psychosis.
Immunosuppression remains a cause of late neurological complications after
cardiac transplantation. Opportunistic infections can occur as early as 2 weeks after
surgery and immunosuppression, but usually there is an interval of at least 1
month. Focal meningoencephalitis or brain abscess, meningitis, and diEuse
encephalitis are three common presentations of infections in cardiac transplant
154,155,162recipients. Aspergillus fumigatus, Toxoplasma gondii, Cryptococcus
neoformans, Listeria monocytogenes, and herpesvirus infections are the more
162,163common causes of CNS infections in heart transplant recipients.
Aspergillosis is the most frequent fungal infection that produces a necrotizing
162meningoencephalitis and single or multiple brain abscesses. Cerebral
aspergillosis is almost always disseminated from a preceding pulmonary infection.
The abscesses may have ring, irregular, or no contrast enhancement on MRI and
164CT scans. DiEusion-weighted MRI may demonstrate restricted diEusion of
165water in the center of the abscess. Aspergillosis also causes an invasive necrosis
of intracranial vessels that may lead to hemorrhagic infarction. Therefore, focal
hemorrhage on brain imaging is suggestive of Aspergillus infection. The diagnosis is
con0rmed by direct needle aspiration or biopsy; cerebrospinal Cuid studies and
cultures usually are not helpful. If the diagnosis is made late, the disease is fatal;
early diagnosis and treatment in an immunosuppressed patient, however, improve
166,167survival.
T. gondii is the second most common cause of focal or multifocalmeningoencephalitis and abscess formation following cardiac
162,168transplantation. It can produce multiple ring-enhancing lesions, seen with
contrast CT scans. MRI may demonstrate additional lesions not apparent on CT and
may also show a rapid response to antibiotic therapy. Serological evidence of T.
gondii is supportive evidence, particularly if there is seroconversion after
transplantation or an increase in titer compared to the preoperative baseline
168serology. While tissue diagnosis with material aspirated from a brain abscess is
diagnostic, a presumptive diagnosis based on imaging and serological testing may
lead to a therapeutic trial. Consideration of the diagnosis is mandatory because of
169the excellent therapeutic response to antitoxoplasmic antibiotics. Toxoplasmosis
may also cause an inCammatory myopathy in association with intracranial and
170,171multisystem infection.
Other less frequent opportunistic infections that produce focal
meningoencephalitis or brain abscess include the rhinocerebral phycomycotic
organisms, Candida albicans in the setting of disseminated candidiasis, Nocardia
155,162,172-175infections, Klebsiella (abscess), and Rhodococcus equi.
Meningitis after cardiac transplantation is most commonly due to C. neoformans
when the symptoms are subacute or chronic and the white blood count in the
cerebrospinal Cuid is mildly to moderately elevated with predominantly
mononuclear cells. L. monocytogenes is the most common organism when the
symptoms are acute and there is a prominent cerebrospinal Cuid pleocytosis
consisting of polymorphonuclear and mononuclear cells. Coccidioides immitis and
Pseudoallescheria boydii, as well as previously mentioned fungi, are less frequent
154,157,176,177causes of meningitis.
Cytomegalovirus, herpes simplex, and herpes zoster encephalitis also occur, in
association with a disseminated viremia, in patients who have undergone cardiac
157,163,178transplantation. Immunosuppression, however, transforms the acute
necrotizing focal herpes simplex encephalitis into a more diEuse and slowly
progressive process. Progressive multifocal leukoencephalopathy after heart
transplantation is thought to be due to reactivation of a JC virus infection that is
179initially acquired during childhood. Pathogens can also be transferred from
donor to transplant recipients, typically causing neurological deterioration during
the 0rst post-transplantation month. West Nile virus has been transferred from a
donor heart to a heart recipient causing an encephalitis shortly after
180transplantation. Rabies virus, lymphocytic chorimeningitis virus, and
181-183Trypanosoma cruzi are also reported donor-derived infections.
Immunosuppression for cardiac transplantation combined with Epstein–Barr
virus infection can cause a post-transplantation lymphoproliferative disorder that
leads to systemic malignant lymphoproliferation including involvement of the184brain. Post-transplantation lymphoproliferative disorders may regress with
185,186reduction of immunosuppressive therapy or they may require radiotherapy.
The CNS can be the only site of malignant lymphoproliferation in association with
Epstein–Barr virus in brain tissue. The response of this post-transplantation primary
184,187CNS lymphoma to multimodal therapies is often poor. Glioma is another
isolated brain tumor that can occur after heart transplantation, although the
188relationship to immunosuppression is unclear.
Immunosuppressive agents can also cause neurological side eEects more directly.
Prior to the use of cyclosporine, high-dose prednisone in combination with
azathioprine was commonly used. The main side eEect of the prednisone was
weakness of the proximal lower extremities, osteoporosis with lower thoracic and
176lumbosacral compression fractures, or psychiatric complications. With the use
of calcineurin inhibitors, cyclosporine, and tacrolimus, the dose of prednisone has
189,190been lowered, thereby reducing its side effects. Cyclosporine and tacrolimus
themselves, however, may have neurotoxic side eEects, including prominent
tremor, headache, a lowered seizure threshold, paresthesias, mental confusion,
acute mania, weakness, ataxia, dysarthria, visual hallucinations, and cortical
blindness. Brain imaging may reveal a posterior leukoencephalopathy.
DiEusionweighted MRI studies suggest that the onset of neurotoxicity is due to vasogenic
brain edema. Vasogenic edema is reversible, which is consistent with the typical
remission of adverse eEects and MRI 0ndings following reduction of the
cyclosporine or tacrolimus dose. Prolonged drug exposure at neurotoxic levels,
191-193however, may cause residual neurological impairment. The newer
immunosuppressive agent sirolimus has few reported neurotoxic eEects and may be
194used as an alternative to cyclosporine or tacrolimus when neurotoxicity occurs.
190Cyclosporine also induces gout and produces chronic nephrotoxicity. When
gout is treated with colchicines, the impaired renal function may lead to colchicine
toxicity and a peripheral neuromuscular disorder that improves when the
195colchicine is stopped.
The monoclonal anti-CD3 antibody (OKT3) is used to prevent and treat graft
rejection following cardiac transplantation. Aseptic meningitis with fever,
headache, seizures, and a variable encephalopathy is reported to occur in 5 percent
of patients as a reaction to it. This aseptic meningitis may occur during the course
of OKT3 therapy or in the weeks immediately subsequent to it. The aseptic
176,196,197meningitis and encephalopathy resolve within days of onset.
As noted previously, most of the neurological complications of cardiac
transplantation with immunosuppression may present with a confusional state in
which headache and focal neurological 0ndings may be present or absent. It is not
uncommon, however, for more than one complication of immunosuppression to155cause symptoms in an individual cardiac transplant recipient.
REFERENCES
1 Shaw PJ, Bates D, Cartlidge NEF, et al. Neurological complications of coronary
artery bypass graft surgery. BMJ. 1986;293:165.
2 Shaw PJ, Bates D, Cartlidge NEF, et al. Early intellectual dysfunction following
coronary bypass surgery. QJM. 1986;58:59.
3 Shaw PJ, Bates D, Cartlidge NEF, et al. Neurologic and neuropsychological morbidity
following major surgery: comparison of coronary artery bypass and peripheral
vascular surgery. Stroke. 1987;18:700.
4 Shaw PJ, Bates D, Cartlidge NEF, et al. Long-term intellectual dysfunction following
coronary artery bypass graft surgery. QJM. 1987;62:259.
5 Shaw PJ, Bates D, Cartlidge NEF, et al. Neuro-ophthalmological complications of
coronary artery bypass graft surgery. Acta Neurol Scand. 1987;76:1.
6 Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after
coronary artery bypass surgery. N Engl J Med. 1996;335:1857.
7 Selnes OA, McKhann GM, Borowicz LMJr, et al. Cognitive and neurobehavioral
dysfunction after cardiac bypass procedures. Neurol Clin. 2006;24:133.
8 McKhann GM, Grega MA, Borowicz LMJr, et al. Stroke and encephalopathy after
cardiac surgery: an update. Stroke. 2006;37:562.
9 McKhann GM, Goldsborough MA, Borowicz LM, et al. Predictors of stroke risk in
coronary artery bypass patients. Ann Thorac Surg. 1997;63:516.
10 Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics—update:
a report from the American Heart Association Statistics Committee and Stroke
Statistics Subcommittee. Circulation. 2006;113:e85.
11 Seines O, Goldsborough M, Borowicz L, et al. Neurobehavioral sequelae of
cardiopulmonary bypass. Lancet. 1999;353:1601.
12 Murkin JM, Baird DL, Martzke JS, et al. Long-term neurological and
neuropsychological outcome 3 years after coronary artery bypass surgery. Anesth
Analg. 1996;82:328S.
13 Kirklin J, Barratt-Boyes B. Cardiac Surgery: Morphology, Diagnostic Criteria,
Natural History, Techniques, Results and Indications, 2nd Ed. New York: Churchill
Livingstone, 1993.
14 Djaiani G, Fedorko L, Borger M, et al. Mild to moderate atheromatous disease of
the thoracic aorta and new ischemic brain lesions after conventional coronary
artery bypass graft surgery. Stroke. 2004;35:e356.
15 Lederman RJ, Breuer RC, Hanson MR, et al. Peripheral nervous system
complications of coronary artery bypass graft surgery. Ann Neurol. 1982;12:297.
16 Vahl CF, Carl I, Muller-Vahl H, et al. Brachial plexus injury after cardiac surgery. JThorac Cardiovasc Surg. 1991;102:724.
17 Katz MG, Katz R, Schachner A, et al. Phrenic nerve injury after coronary artery
bypass grafting: will it go away? Ann Thorac Surg. 1998;65:32.
18 Dimopoulou I, Daganou M, Dafni U, et al. Phrenic nerve dysfunction after cardiac
operations. Chest. 1998;113:8.
19 Cohen AJ, Katz MG, Katz R, et al. Phrenic nerve injury after coronary artery
grafting: is it always benign? Ann Thorac Surg. 1997;64:148.
20 Mclean RF, Wong BI. Normothermic versus hypothermic cardiopulmonary bypass. J
Cardiothorac Vasc Anesth. 1996;10:45.
21 Engleman R, Pleet A, Rousou J, et al. Influence of cardiopulmonary bypass
perfusion temperature on neurologic and hematologic function after coronary
artery bypass grafting. Ann Thorac Surg. 1999;67:1547.
22 Murphy GJ, Angelini GD. Side effects of cardiopulmonary bypass: what is the
reality? J Card Surg. 2004;19:481.
23 Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary
bypass. Ann Thorac Surg. 1993;55:552.
24 Nakajima M, Tsuchiya K, Kanemaru K, et al. Subdural hemorrhagic injury after
open heart surgery. Ann Thorac Surg. 2003;76:614.
25 Almassi GH, Schowalter T, Nicolosi AC, et al. Atrial fibrillation after cardiac
surgery: a major morbid event? Ann Surg. 1997;226:501.
26 Mathew J, Parks R, Savino J, et al. Atrial fibrillation following coronary artery
bypass graft surgery. JAMA. 1996;276:300.
27 Harris DNF, Baily SM, Smith PLC, et al. Brain swelling in the first hour after
coronary artery bypass surgery. Lancet. 1993;342:586.
28 Sellke FW, DiMaio JM, Caplan LR, et al. Comparing on-pump and off-pump
coronary artery bypass grafting: numerous studies but few conclusions: a scientific
statement from the American Heart Association council on cardiovascular surgery
and anesthesia in collaboration with the interdisciplinary working group on
quality of care and outcomes research. Circulation. 2005;111:2858.
29 Lund C, Hol PK, Lundblad R, et al. Comparison of cerebral embolization during
offpump and on-pump coronary artery bypass surgery. Ann Thorac Surg.
2003;76:765.
30 van Dijk D, Moons KG, Keizer AM, et al. Association between early and three
month cognitive outcome after off-pump and on-pump coronary bypass surgery.
Heart. 2004;90:431.
31 Lund C, Sundet K, Tennoe B, et al. Cerebral ischemic injury and cognitive
impairment after off-pump and on-pump coronary artery bypass grafting surgery.
Ann Thorac Surg. 2005;80:2126.
32 Sharony R, Grossi EA, Saunders PC, et al. Propensity case-matched analysis of off-pump coronary artery bypass grafting in patients with atheromatous aortic
disease. J Thorac Cardiovasc Surg. 2004;127:406.
33 Shaw PJ, Bates D, Carlidge NEF, et al. An analysis of factors predisposing to
neurological injury in patients undergoing coronary bypass operations. QJM.
1989;72:633.
34 Coffey CE, Massey EW, Roberts KB, et al. Natural history of cerebral complications
of coronary artery bypass graft surgery. Neurology. 1983;33:1416.
35 McKhann GM, Goldsborough MA, Borowicz LM, et al. Cognitive outcome after
coronary artery bypass: a one-year prospective study. Ann Thorac Surg.
1997;63:510.
36 Redmond JM, Greene PS, Goldsborough MA, et al. Neurologic injury in cardiac
surgery patients with a history of stroke. Ann Thorac Surg. 1996;61:42.
37 Tuman KJ, McCarthy RJ, Najfi H, et al. Differential effects of advanced age on
neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc
Surg. 1992;104:1510.
38 Bucerius J, Gummert JF, Borger MA, et al. Stroke after cardiac surgery: a risk factor
analysis of 16,184 consecutive adult patients. Ann Thorac Surg. 2003;75:472.
39 Salazar JD, Wityk RJ, Grega MA, et al. Stroke after cardiac surgery: short- and
long-term outcomes. Ann Thorac Surg. 2001;72:1195.
40 Likosky DS, Marrin CA, Caplan LR, et al. Determina-tion of etiologic mechanisms
of strokes secondary to coronary artery bypass graft surgery. Stroke.
2003;34:2830.
41 Inque K, Luth JU, Pottkamper KM, et al. Incidence and risk factors of perioperative
cerebral operations: heart transplantation compared to coronary artery bypass
grafting and valve surgery. J Cardiovasular Surg. 1998;39:201.
42 Goldsborough MA, Borowicz LM, Mckhann GM, et al. Variation in stroke
occurrence by cardiac procedures. Perfusion. 1997;12:47.
43 Hise JH, Nipper ML, Schnitker JC. Stroke associated with coronary artery bypass
surgery. AJNR Am J Neuroradiol. 1991;12:811.
44 Wityk RJ, Goldsborough MA, Hillis A, et al. Diffusion- and perfusion-weighted
brain magnetic resonance imaging in patients with neurologic complications after
cardiac surgery. Arch Neurol. 2001;58:571.
45 Katzan IL, Masaryk TJ, Furlan AJ, et al. Intra-arterial thrombolysis for
perioperative stroke after open heart surgery. Neurology. 1999;52:1081.
46 Moazami N, Smedira NG, McCarthy PM, et al. Safety and efficacy of intraarterial
thrombolysis for perioperative stroke after cardiac operation. Ann Thorac Surg.
2001;72:1933.
47 Fukuda I, Imazuru T, Osaka M, et al. Thrombolytic therapy for delayed, in-hospital
stroke after cardiac surgery. Ann Thorac Surg. 2003;76:1293.48 Yokote H, Itakura T, Funahashi K, et al. Chronic subdural hematoma after open
heart surgery. Surg Neurol. 1985;24:520.
49 Humphreys RP, Hoffman HJ, Mustard WT, et al. Cerebral hemorrhage following
heart surgery. J Neurosurg. 1975;43:671.
50 Ayus JC, Arieff AI. Brain damage and postoperative hyponatremia. Neurology.
1996;46:323.
51 Criado A, Dominguez E, Carmona J, et al. Hypoglycemic coma after cardiac
surgery. Crit Care Med. 1984;12:409.
52 Hiramatsu Y, Sakakibara Y, Mitsui T, et al. Clinical features of hypernatremic
hyperosmolar delirium following open heart surgery. Nippon Kyobu Geka Gakkai
Zasshi. 1991;39:1945.
53 Gonzalez-Santos JM, Gonzalez-Santos ML, Vallejo JL. Acute obstructive
hydrocephalus: an unusual complication after cardiopulmonary bypass. Thorac
Cardiovasc Surg. 1986;77:586.
54 Krumholz A, Stern B, Weiss H. Outcome from coma after cardiopulmonary
resuscitation: relation to seizures and myoclonus. Neurology. 1988;38:401.
55 Bucerius J, Gummert JF, Borger MA, et al. Predictors of delirium after cardiac
surgery delirium: effect of beating-heart (off-pump) surgery. J Thorac Cardiovasc
Surg. 2004;127:57.
56 Eriksson M, Samuelsson E, Gustafson Y, et al. Delirium after coronary bypass
surgery evaluated by the organic brain syndrome protocol. Scand Cardiovasc J.
2002;36:250.
57 Rolfson DB, McElhaney JE, Rockwood K, et al. Incidence and risk factors for
delirium and other adverse outcomes in older adults after coronary artery bypass
graft surgery. Can J Cardiol. 1999;15:771.
58 Dubin WR, Field HL, Gastfriend DR. Postcardiotomy delirium: a critical review. J
Thorac Cardiovasc Surg. 1979;34:201.
59 Juolasmaa A, Outakoski J, Hirvenoja R, et al. Effect of open heart surgery on
intellectual performance. J Clin Neuropsychol. 1981;3:181.
60 Smith LW, Dimsdale JE. Postcardiotomy delirium: conclusions after 25 years. Am J
Psychiatry. 1989;146:452.
61 DeLeon S, Ilbawi M, Arcilla R, et al. Choreoathetosis after deep hypothermia
without circulatory arrest. Ann Thorac Surg. 1990;50:714.
62 Fagan KJ, Lee SI. Prolonged confusion following convulsions due to generalized
nonconvulsive status epilepticus. Neurology. 1990;40:1689.
63 Canbaz S, Turgut N, Halici U, et al. Brachial plexus injury during open heart
surgery—controlled prospective study. Thorac Cardiovasc Surg. 2005;53:295.
64 Hickey C, Gugino LD, Aglio LS, et al. Intraoperative somatosensory evoked
potential monitoring predicts peripheral nerve injury during cardiac surgery.Anesthesiology. 1993;78:29.
65 Jellish WS, Blakeman B, Warf P, et al. Hands-up positioning during asymmetric
sternal retraction for internal mammary artery harvest: a possible method to
reduce brachial plexus injury. Anesth Analg. 1997;84:260.
66 Katz ES, Tunik PA, Rusinek H, et al. Protruding aortic atheromas predict stroke in
elderly patients undergoing cardiopulmonary bypass: experience with
intraoperative transesophageal echocardiography. J Am Coll Cardiol. 1992;20:70.
67 Canbaz S, Turgut N, Halici U, et al. Electrophysiological evaluation of phrenic
nerve injury during cardiac surgery—a prospective, controlled, clinical study.
BMC Surg. 2004;4:2.
68 Werner RA, Geiringer SR. Bilateral phrenic nerve palsy associated with open-heart
surgery. Arch Phys Med Rehabil. 1990;71:1000.
69 Marini SG, Rook JL, Green RF, et al. Spinal accessory nerve palsy: an unusual
complication of coronary artery bypass. Arch Phys Med Rehabil. 1991;72:247.
70 Parsonnet V, Karasakalides A, Gielchinsky I, et al. Meralgia paresthetica after
coronary bypass surgery. J Thorac Cardiovasc Surg. 1991;101:219.
71 Lavee J, Schneiderman J, Yorav S, et al. Complications of saphenous vein
harvesting following coronary artery bypass surgery. J Cardiovasc Surg.
1989;30:989.
72 Tewari P, Aggarwal SK. Combined left-sided recurrent laryngeal and phrenic nerve
palsy after coronary artery operation. Ann Thorac Surg. 1996;61:1721.
73 Plasse HM, Mittleman M, Frost JO. Unilateral sudden hearing loss after open heart
surgery: a detailed study of seven cases. Laryngoscope. 1981;91:101.
74 Burns T. Neuropathy caused by compression, entrapment or physical injury. In:
Dyck PJ, Thomas PK, editors. Peripheral Neuropathy. 4th Ed. Philadelphia: Elsevier
Saunders; 2005:1391.
75 Hogan JC, Briggs TP, Oldershaw PJ. Guillain-Barré syndrome following
cardiopulmonary bypass. Int J Cardiol. 1992;35:427.
76 Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill
patients after long-term administration of vecuronium. N Engl J Med.
1992;327:524.
77 Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve.
2005;32:140.
78 Shahian DM, Speert PK. Symptomatic visual deficits after open heart operations.
Ann Thorac Surg. 1989;48:275.
79 Nuttall GA, Garrity JA, Dearani JA, et al. Risk factors for ischemic optic neuropathy
after cardiopulmonary bypass: a matched case/control study. Anesth Analg.
2001;93:1410.
80 Buono LM, Foroozan R. Perioperative posterior ischemic optic neuropathy: reviewof the literature. Surv Ophthalmol. 2005;50:15.
81 Barbut D, Gold JP, Heinemann MD, et al. Horner’s syndrome after coronary artery
bypass surgery. Neurology. 1996;46:181.
82 Tusa RJ, Kaplan PW, Hain TC, et al. Ipsiversive eye deviation and epileptic
nystagmus. Neurology. 1990;40:662.
83 Cooper DM, Bazaral MG, Furlan AJ, et al. Pituitary apoplexy: a complication of
cardiac surgery. Ann Thorac Surg. 1986;41:547.
84 Davies JS, Scanlon MF. Hypopituitarism after coronary artery bypass grafting.
BMJ. 1998;316:682.
85 Laloux P, Osseman M. Visual hallucinations on eye closure after cardiovascular
surgery. J Clin Neuroophthalmol. 1992;12:242.
86 Eissa A, Baker RA, Knight JL. Closed-eye visual hallucinations after coronary artery
bypass grafting. J Cardiothorac Vasc Anesth. 2005;19:217.
87 Mullges W, Berg D, Schmidtke A, et al. Early natural course of transient
encephalopathy after coronary artery bypass grafting. Crit Care Med.
2000;28:1808.
88 Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of
neurocognitive function after coronary-artery bypass surgery. N Engl J Med.
2001;344:395.
89 Selnes OA, Grega MA, Borowicz LMJr, et al. Cognitive changes with coronary
artery disease: a prospective study of coronary artery bypass graft patients and
nonsurgical controls. Ann Thorac Surg. 2003;75:1377.
90 Stygall J, Newman SP, Fitzgerald G, et al. Cognitive change 5 years after coronary
artery bypass surgery. Health Psychol. 2003;22:579.
91 Keith JR, Puente AE, Malcolmson KL, et al. Assessing postoperative cognitive
change after cardiopulmonary bypass surgery. Neuropsychology. 2002;16:411.
92 McKhann GM, Grega MA, Borowicz LMJr, et al. Is there cognitive decline 1 year
after CABG? Comparison with surgical and nonsurgical controls. Neurology.
2005;65:991.
93 Selnes OA, Royall RM, Grega MA, et al. Cognitive changes 5 years after coronary
artery bypass grafting: is there evidence of late decline? Arch Neurol. 2001;58:598.
94 Moody DM, Bell MA, Challa VR, et al. Brain microemboli during cardiac surgery or
aortography. Ann Neurol. 1990;28:477.
95 Brown W, Moody D, Tytell M, et al. Microembolic brain injuries from cardiac
surgery: are the seeds of future Alzheimer’s disease? Ann N Y Acad Sci.
1997;826:386.
96 Blauth CI, Arnold JV, Schulenberg WE, et al. Cerebral microembolism during
cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1988;95:668.
97 Challa V, Lovell M, Moody D, et al. Laser microprobe mass spectrometric study ofaluminum and silicon in brain emboli related to cardiac surgery. J Neuropathol Exp
Neurol. 1998;57:140.
98 van der Linden J, Casimir-Ahn H. When do cerebral emboli appear during open
heart operations? Ann Thorac Surg. 1991;51:231.
99 Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important
link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol.
1998;55:1475.
100 Pugsley W, Klinger L, Paschalis C, et al. The impact of microemboli during
cardiopulmonary bypass on neuropsychological functioning. Stroke. 1994;25:1393.
101 Stump DA, Tegeler CH, Rogers AT, et al. Neuropsychological deficits are
associated with the number of emboli detected during cardiac surgery. Stroke.
1993;24:509.
102 Sylivris S, Christopher L, Matalanis G, et al. Pattern and significance of cerebral
microemboli during coronary artery bypass grafting. Ann Thorac Surg.
1998;66:1674.
103 Selnes OA, Grega MA, Borowicz LMJr, et al. Cognitive outcomes three years after
coronary artery bypass surgery: a comparison of on-pump coronary artery bypass
graft surgery and nonsurgical controls. Ann Thorac Surg. 2005;79:1201.
104 Hlatky MA, Bacon C, Boothroyd D, et al. Cognitive function 5 years after
randomization to coronary angioplasty or coronary artery bypass graft surgery.
Circulation. 1997;96(9 Suppl):11.
105 Mullges W, Babin-Ebell J, Reents W, et al. Cognitive performance after coronary
artery bypass grafting: a follow-up study. Neurology. 2002;59:741.
106 Knopman DS, Petersen RC, Cha RH, et al. Coronary artery bypass grafting is not
a risk factor for dementia or Alzheimer disease. Neurology. 2005;65:986.
107 Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of
dementia and cognitive decline. N Engl J Med. 2003;348:1215.
108 Prins ND, van Dijk EJ, den Heijer T, et al. Cerebral white matter lesions and the
risk of dementia. Arch Neurol. 2004;61:1531.
109 Prins ND, van Dijk EJ, den Heijer T, et al. Cerebral small-vessel disease and
decline in information processing speed, executive function and memory. Brain.
2005;128:2034.
110 Sachdev PS, Brodaty H, Valenzuela MJ, et al. Progression of cognitive impairment
in stroke patients. Neurology. 2004;63:1618.
111 Altieri M, Di Piero V, Pasquini M, et al. Delayed poststroke dementia: a 4-year
follow-up study. Neurology. 2004;62:2193.
112 Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive
decline in middle-aged adults. Neurology. 2001;56:42.
113 Newman MF, Wolman R, Kanchuger M, et al. Multicenter preoperative stroke riskindex for patients undergoing coronary artery bypass graft surgery. Circulation.
1996;94(suppl II):74.
114 Naylor AR, Mehta Z, Rothwell PM, et al. Carotid artery disease and stroke during
coronary artery bypass: a critical review of the literature. Eur J Vasc Endovasc
Surg. 2002;23:283.
115 Almassi G, Sommers T, Moritz T, et al. Stroke in cardiac surgical patients:
determinants and outcome. Ann Thorac Surg. 1999;63:391.
116 Smith KM, Lamy A, Arthur HM, et al. Outcomes and costs of coronary artery
bypass grafting: comparison between octogenarians and septuagenarians at a
tertiary care centre. CMAJ. 2001;165:759.
117 Mackensen GB, Ti LK, Phillips-Bute BG, et al. Cerebral embolization during
cardiac surgery: impact of aortic atheroma burden. Br J Anaesth. 2003;91:656.
118 Hangler HB, Nagele G, Danzmayr M, et al. Modification of surgical technique for
ascending aortic atherosclerosis: impact on stroke reduction in coronary artery
bypass grafting. J Thorac Cardiovasc Surg. 2003;126:391.
119 van der Linden J, Hadjinikolaou L, Bergman P, et al. Postoperative stroke in
cardiac surgery is related to the location and extent of atherosclerotic disease in
the ascending aorta. J Am Coll Cardiol. 2001;38:131.
120 Mathew JP, Rinder HM, Smith BR, et al. Transcerebral platelet activation after
aortic cross-clamp release is linked to neurocognitive decline. Ann Thorac Surg.
2006;81:1644.
121 Gaudino M, Glieca F, Alessandrini F, et al. Individualized surgical strategy for the
reduction of stroke risk in patients undergoing coronary artery bypass grafting.
Ann Thorac Surg. 1999;67:1246.
122 Eagle K, Guyton R, Davidoff R, et al. ACC/AHA guidelines for coronary artery
bypass graft surgery: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol.
1999;34:1262.
123 Rorick MB, Furlan AJ. Risk of cardiac surgery in patients with prior stroke.
Neurology. 1990;40:835.
124 McKhann GM, Grega MA, Borowicz LMJr, et al. Encephalopathy and stroke after
coronary artery bypass grafting: incidence, consequences, and prediction. Arch
Neurol. 2002;59:1422.
125 Charlesworth DC, Likosky DS, Marrin CA, et al. Development and validation of a
prediction model for strokes after coronary artery bypass grafting. Ann Thorac
Surg. 2003;76:436.
126 Boeken U, Litmathe J, Feindt P, et al. Neurological complications after cardiac
surgery: risk factors and correlation to the surgical procedure. Thorac Cardiovasc
Surg. 2005;53:33.127 Barbut D, Lo Y, Gold JP, et al. Impact of embolization during coronary artery
bypass grafting on outcome and length of stay. Ann Thorac Surg. 1997;63:998.
128 Libman RB, Wirkowski E, Neystat M, et al. Stroke associated with cardiac surgery.
Arch Neurol. 1997;54:83.
129 Ganushchak YM, Fransen EJ, Visser C, et al. Neurological complications after
coronary artery bypass grafting related to the performance of cardiopulmonary
bypass. Chest. 2004;125:2196.
130 Amar D. Postoperative atrial fibrillation. Heart Dis. 2002;4:117.
131 Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial
fibrillation after cardiac surgery. JAMA. 2004;291:1720.
132 Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for
coronary artery bypass graft surgery: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines
(Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft
Surgery). Circulation. 2004;110:e340.
133 Arrowsmith JE, Harrison MJG, Newman SP, et al. Neuroprotection of the brain
during cardiopulmonary bypass. Stroke. 1998;29:2357.
134 Mangano DT. Aspirin and mortality from coronary bypass surgery. N Engl J Med.
2002;347:1309.
135 Guyton RA, Mellitt RJ, Weintraub WS. A critical assessment of neurological risk
during warm heart surgery. J Card Surg. 1995;10:488.
136 Naylor R, Cuffe RL, Rothwell PM, et al. A systematic review of outcome following
synchronous carotid endarterectomy and coronary artery bypass: influence of
surgical and patient variables. Eur J Vasc Endovasc Surg. 2003;26:230.
137 Hill MD, Shrive FM, Kennedy J, et al. Simultaneous carotid endarterectomy and
coronary artery bypass surgery in Canada. Neurology. 2005;64:1435.
138 Pullicino P, Halperin J. Combining carotid endarterectomy with coronary bypass
surgery: is it worth the risk? Neurology. 2005;64:1332.
139 Randall MS, McKevitt FM, Cleveland TJ, et al. Is there any benefit from staged
carotid and coronary revascularization using carotid stents? A single-center
experience highlights the need for a randomized controlled trial. Stroke.
2006;37:435.
140 Chaturvedi S, Bruno A, Feasby T, et al. Carotid endarterectomy—an
evidencebased review: report of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology. Neurology. 2005;65:794.
141 Moore W, Barnett H, Beebe H, et al. Guidelines for carotid endarterectomy: A
multidisciplinary consensus statement from the Ad Hoc Committee, American
Heart Association. Stroke. 1995;26:188.
142 Durand DJ, Perler BA, Roseborough GS, et al. Mandatory versus selectivepreoperative carotid screening: a retrospective analysis. Ann Thorac Surg.
2004;78:159.
143 Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus
endarterectomy in high-risk patients. N Engl J Med. 2004;351:1493.
144 Ziada KM, Yadav JS, Mukherjee D, et al. Comparison of results of carotid stenting
followed by open heart surgery versus combined carotid endarterectomy and open
heart surgery (coronary bypass with or without another procedure). Am J Cardiol.
2005;96:519.
145 Tsang JC, Morin JF, Tchervenkov CI, et al. Single aortic clamp versus partial
occluding clamp technique for cerebral protection during coronary artery bypass:
a randomized prospective trial. J Card Surg. 2003;18:158.
146 Hammon JW, Stump DA, Butterworth JF, et al. Single crossclamp improves
6month cognitive outcome in high-risk coronary bypass patients: the effect of
reduced aortic manipulation. J Thorac Cardiovasc Surg. 2006;131:114.
147 Nagels W, Demeyere R, Van Hemelrijck J, et al. Evaluation of the neuroprotective
effects of S(+)-ketamine during open-heart surgery. Anesth Analg. 2004;98:1595.
148 Kanbak M, Saricaoglu F, Avci A, et al. Propofol offers no advantage over
isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a
preliminary study of S-100beta protein levels. Can J Anaesth. 2004;51:712.
149 Taggart DP, Browne SM, Wade DT, et al. Neuroprotection during cardiac surgery:
a randomised trial of a platelet activating factor antagonist. Heart. 2003;89:897.
150 Luciani GB, Menon T, Vecchi B, et al. Modified ultrafiltration reduces morbidity
after adult cardiac operations: a prospective, randomized clinical trial. Circulation.
2001;104(suppl I):I253.
151 Whitaker DC, Newman SP, Stygall J, et al. The effect of leucocyte-depleting
arterial line filters on cerebral microemboli and neuropsychological outcome
following coronary artery bypass surgery. Eur J Cardiothorac Surg. 2004;25:267.
152 Ozduran V, Yamani MH, Chuang HH, et al. Survival beyond 10 years following
heart transplantation: the Cleveland Clinic Foundation experience. Transplant
Proc. 2005;37:4509.
153 Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society
for Heart and Lung Transplantation: twenty-second official adult heart transplant
report—2005. J Heart Lung Transplant. 2005;24:945.
154 Hotson J, Enzmann D. Neurologic complications of cardiac transplantation.
Neurol Clin. 1988;6:349.
155 Hotson J, Pedley T. The neurological complications of cardiac transplantation.
Brain. 1976;99:673.
156 Furlan A, Sila C, SC C. Neurologic complications related to cardiac surgery. Neurol
Clin. 1992;10:145.157 Sila C. Spectrum of neurologic events following cardiac transplantation.
Neurology. 1989;20:1586.
158 Jarquin-Valdivia AA, Wijdicks EF, McGregor C. Neurologic complications
following heart transplantation in the modern era: decreased incidence, but
postoperative stroke remains prevalent. Transplant Proc. 1999;31:2161.
159 Perez-Miralles F, Sanchez-Manso JC, Almenar-Bonet L, et al. Incidence of and risk
factors for neurologic complications after heart transplantation. Transplant Proc.
2005;37:4067.
160 Mayer TO, Biller J, O’Donnell J, et al. Contrasting the neurologic complications of
cardiac transplantation in adults and children. J Child Neurol. 2002;17:195.
161 Glass GA, Stankiewicz J, Mithoefer A, et al. Levetiracetam for seizures after liver
transplantation. Neurology. 2005;64:1084.
162 Britt R, Enzmann D, Remington J. Intracranial infections in cardiac transplant
recipients. Ann Neurol. 1981;9:107.
163 Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med.
1998;338:1741.
164 DeLone DR, Goldstein RA, Petermann G, et al. Disseminated aspergillosis
involving the brain: distribution and imaging characteristics. AJNR Am J
Neuroradiol. 1999;20:1597.
165 Gaviani P, Schwartz RB, Hedley-Whyte ET, et al. Diffusion-weighted imaging of
fungal cerebral infection. AJNR Am J Neuroradiol. 2005;26:1115.
166 Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive
aspergillosis. Clin Infect Dis. 2004;39:797.
167 Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous
system aspergillosis, using voriconazole treatment. Blood. 2005;106:2641.
168 Luft B, Naot Y, Araujo F, et al. Primary and reactivated toxoplasma infection in
patients with cardiac transplants. Ann Intern Med. 1983;99:27.
169 Renold C, Sugar A, Chave J-P, et al. Toxoplasma encephalitis in patients with the
acquired immunodeficiency syndrome. Medicine (Baltimore). 1992;71:224.
170 Cuturic M, Hayat GR, Vogler CA, et al. Toxoplasmic polymyositis revisited: case
report and review of literature. Neuromuscul Disord. 1997;7:390.
171 Plonquet A, Bassez G, Authier FJ, et al. Toxoplasmic myositis as a presenting
manifestation of idiopathic CD4 lymphocytopenia. Muscle Nerve. 2003;27:761.
172 Montero C, Martinez A. Neuropathology of heart transplantation: 23 cases.
Neurology. 1986;36:1149.
173 Lopez FA, Johnson F, Novosad DM, et al. Successful management of disseminated
Nocardia transvalensis infection in a heart transplant recipient after development
of sulfonamide resistance: case report and review. J Heart Lung Transplant.
2003;22:492.174 Hall WA, Martinez AJ, Dummer JS, et al. Nocardial brain abscess: diagnostic and
therapeutic use of stereotactic aspiration. Surg Neurol. 1987;28:114.
175 Kohl O, Tillmanns HH. Cerebral infection with Rhodococcus equi in a heart
transplant recipient. J Heart Lung Transplant. 2002;21:1147.
176 Patchell RA. Neurological complications of organ transplantation. Ann Neurol.
1994;36:688.
177 Alsep SG, Cobbs CG. Pseudoallescheria boydii infection of the central nervous
system in a cardiac transplant recipient. South Med J. 1986;79:383.
178 Pollard R, Arvin A, Gamberg P, et al. Specific cell-mediated immunity and
infections with herpes viruses in cardiac transplant recipients. Am J Med.
1982;73:679.
179 Flomenbaum MA, Jarcho JA, Schoen FJ. Progressive multifocal
leukoencephalopathy fifty-seven months after heart transplantation. J Heart Lung
Transplant. 1991;10:888.
180 Iwamoto M, Jernigan DB, Guasch A, et al. Transmission of West Nile virus from
an organ donor to four transplant recipients. N Engl J Med. 2003;348:2196.
181 Srinivasan A, Burton EC, Kuehnert MJ, et al. Transmission of rabies virus from an
organ donor to four transplant recipients. N Engl J Med. 2005;352:1103.
182 Fischer SA, Graham MB, Kuehnert MJ, et al. Transmission of lymphocytic
choriomeningitis virus by organ transplantation. N Engl J Med. 2006;354:2235.
183 Centers for Disease Control and Prevention (CDC). Chagas disease after organ
transplantation—United States, 2001. MMWR Morb Mortal Rep Wkly. 2002;51:210.
184 Aull MJ, Buell JF, Trofe J, et al. Experience with 274 cardiac transplant recipients
with posttransplant lymphoproliferative disorder: a report from the Israel Penn
International Transplant Tumor Registry. Transplantation. 2004;78:1676.
185 Swinnen L. Treatment of organ transplant-related lymphoma. Hematol Oncol Clin
North Am. 1997;11:963.
186 Kang SK, Kirkpatrick JP, Halperin EC. Low-dose radiation for posttransplant
lymphoproliferative disorder. Am J Clin Oncol. 2003;26:210.
187 Phan T, O’Neill B, Habermann T. Posttransplant primary central nervous system
lymphoma. Ann Neurol. 1999;46:463.
188 Schiff D, O’Neill B, Wijdicks E, et al. Gliomas arising in organ transplant
recipients: an unrecognized complication of transplantation? Neurology.
2001;57:1486.
189 Mueller XM. Drug immunosuppression therapy for adult heart transplantation.
Part 2: clinical applications and results. Ann Thorac Surg. 2004;77:363.
190 Mueller XM. Drug immunosuppression therapy for adult heart transplantation.
Part 1: immune response to allograft and mechanism of action of
immunosuppressants. Ann Thorac Surg. 2004;77:354.191 Wijdicks EF. Neurotoxicity of immunosuppressive drugs. Liver Transpl. 2001;7:937.
192 Small SL. Pharmacotherapy of aphasia: a critical review. Stroke. 1994;25:1282.
193 Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical
management. Transplant Int. 2000;13:313.
194 Maramattom BV, Wijdicks EF. Sirolimus may not cause neurotoxicity in kidney
and liver transplant recipients. Neurology. 2004;63:1958.
195 Rana SS, Giuliani MJ, Oddis CV, et al. Acute onset of colchicine myoneuropathy in
cardiac transplant recipients: case studies of three patients. Clin Neurol Neurosurg.
1997;99:266.
196 Adair J, Woodley S, O’Connell J, et al. Aseptic meningitis following cardiac
transplantation: clinical characteristics and relationship to immunosuppressive
regimen. Neurology. 1991;41:249.
197 Pittock SJ, Rabinstein AA, Edwards BS, et al. OKT3 neurotoxicity presenting as
akinetic mutism. Transplantation. 2003;75:1058.Chapter 4
Neurological Complications of Congenital Heart
Disease and Cardiac Surgery in Children
Catherine Limperopoulos, Adré J. Du Plessis
NEUROLOGICAL DYSFUNCTION BEFORE CARDIAC SURGERY
Chromosomal Disorders
Cerebral Dysgenesis
Acquired Preoperative Cerebrovascular Injury
MECHANISMS OF NEUROLOGICAL INJURY DURING CARDIAC SURGERY
Intraoperative Brain Injury
Focal or Multifocal Hypoxic-Ischemic Injury
Global Hypoxic-Ischemic Injury
Mechanisms of Postoperative Injury
MANIFESTATIONS OF NEUROLOGICAL DYSFUNCTION IN THE
POSTOPERATIVE PERIOD
Delayed Recovery of Consciousness
Postoperative Seizures
Periventricular White Matter Injury
Stroke
Movement Disorders
Spinal Cord Injury
Brachial Plexus and Peripheral Nerve Injury
NEUROLOGICAL COMPLICATIONS OF CARDIAC TRANSPLANTATION
Pediatric neurologists have become increasingly challenged by diagnostic and
management decisions in children with congenital or acquired heart disease
experiencing neurological dysfunction. Of the 30,000 infants born with heart
defects in the United States each year, approximately half require some form of
1,2surgical intervention within the first year of life. Since the late 1960s, there have
been major changes in the clinical pro: le of neurological injury in children with
congenital heart disease. In earlier years, the neurological complications of
congenital heart disease were mediated for the most part by chronic hypoxia and<
polycythemia in cyanotic children, uncorrected right-to-left shunts, and the e ects
3,4of repeated palliative heart operations. Advances in surgical technique and
intensive care management have allowed the anatomical correction of many heart
lesions in early infancy. These early-life corrective procedures have resulted in
major decreases in the mortality rate of congenital heart disease. Consequently,
neurological sequelae are now increasingly seen in adult survivors of congenital
heart disease. Heart defects considered inoperable in the mid-1980s are now
successfully repaired with a very low mortality rate. More infants with critical
congenital heart disease and profound hemodynamic disturbances in the newborn
period are now rescued, only to manifest later the neurological consequences of this
early-life morbidity. Furthermore, the same surgical support techniques responsible
for advancing survival have, paradoxically, been associated with an incidence of
5neurological complications that approaches 25 percent in some centers.
Consequently, mechanisms of brain injury during cardiac surgery have been the
focus of intense investigation over the past two decades. Understanding of these
intraoperative mechanisms has been advanced through animal experimental
6,7 7-12models and several large clinical trials, as well as by intraoperative cerebral
monitoring and perioperative magnetic resonance imaging (MRI).
More recently, there has been increased recognition that both acquired and
developmental brain disturbances in infants with congenital heart disease may
have their origin prior to surgical intervention, in many cases during the fetal
13-22period. It is expected that these mechanisms will receive particular attention
over the next few years as the role of fetal imaging expands and the potential for
23,24fetal interventions is explored.
NEUROLOGICAL DYSFUNCTION BEFORE CARDIAC SURGERY
Recent studies have demonstrated a high prevalence of neurological abnormalities
prior to infant cardiac surgery, in some studies exceeding 50 percent. These
abnormalities include microcephaly, hypotonia, behavioral dysregulation, and
8,13,15,25 14,16feeding difficulties as well as abnormal electrophysiological studies.
These preoperative neurological and electrophysiological abnormalities are
increasingly recognized as signi: cant predictors of longer term
14,16,25-28neurodevelopmental sequelae. The presence of these preoperative
abnormalities in the early neonatal period strongly suggests a fetal onset of
neurological impairment.
Chromosomal Disorders
A number of chromosomal disorders have a phenotype that includes both cardiac
and neurological malformations, including trisomies 11, 18, and 21. The mostcommon neurological manifestation in children with trisomy 21, or Down
syndrome, is cognitive dysfunction. Epilepsy develops in approximately 5 percent
of children with trisomy 21. Congenital heart defects, most commonly endocardial
cushion defects, are present in 40 percent of children with Down syndrome. Gross
structural brain alterations in Down syndrome include a narrow superior temporal
29gyrus and a disproportionately small cerebellum and brainstem. Trisomy 13 is
associated with ventricular septal defects and patent ductus arteriosus; the
associated cerebral dysgenesis in this syndrome is often severe, with
holoprosencephaly and agenesis of the corpus callosum being the most common
lesions. The most common cardiac lesions in infants with trisomy 18 are ventricular
septal defects and patent ductus arteriosus, with neuronal migration defects the
30usual form of brain dysgenesis.
The phenotypic spectrum of specific chromosome 22 deletions, particularly in the
22q11 region, includes a variety of cardiac malformations and neurological
31features. Recent population-based data suggest that at least 700 infants with
32chromosome 22 deletion syndromes are born annually in the United States. The
acronym CATCH 22 (cardiac defect, abnormal facies, thymic hypoplasia, cleft
palate, hypocalcemia, chromosome 22q11 deletions) has been used to designate
this group of apparently related syndromes. The two most common syndromes,
DiGeorge and velocardiofacial (or Shprintzen) syndromes, have neurological and
33cognitive manifestations in association with structural cardiac defects. The
fundamental problem in DiGeorge syndrome is a developmental defect of the third
and fourth pharyngeal pouches, manifesting with thymic and parathyroid
hypoplasia and conotruncal cardiac malformations, which include interrupted
aortic arch (type B), truncus arteriosus, and tetralogy of Fallot.
A common neurological presentation in both DiGeorge and the velocardiofacial
syndrome is hypocalcemic seizures due to hypoparathyroidism. In addition to the
usual cardiac lesions (i.e., ventricular septal defect or tetralogy of Fallot), the
velocardiofacial syndrome is associated with cleft palate or velopharyngeal
insuD ciency and a typical facial appearance, including a broad, prominent nose
and retrognathia, and microcephaly in up to 40 percent. Neuroimaging and
autopsy studies may show a small posterior fossa and vermis, small cystic lesions
adjacent to the frontal horns of the lateral ventricles, dysgenesis of the corpus
34-42callosum, and abnormal cortical gyri: cation patterns. Delayed opercular
development and disproportionately enlarged sylvian : ssures as well as white
matter abnormalities might underlie some of the developmental problems in these
43 44children, including nearly universal learning diD culties. The mean
33,44intelligence quotient (IQ) in this syndrome is around 70, with mild to
moderate mental retardation in up to 50 percent of patients.<
In recent years, a high rate of autism spectrum disorders and attention
45,46de: cit/hyperactivity disorder has been described in this group. Psychiatric
disorders occur in up to 22 percent of patients with 22q11 deletion
34,36syndromes. A peculiar and inappropriately blunt a ect may be evident
47during childhood, often evolving to frank psychosis during adolescence and
48adulthood. Altered prefrontal cortex-amygdala circuitry, reduced cerebellar and
thalamic volumes, and increased basal ganglia and corpus callosal volumes, as
shown by quantitative neuroimaging studies, may underlie the disrupted emotional
processing and form the neurobiological substrate for the psychiatric disturbances
38,39,44,49-51in these children.
Cerebral Dysgenesis
The prevalence of brain dysgenesis in children with congenital heart disease
29,52,53approaches 30 percent in some autopsy studies. The risk of cerebral
dysgenesis appears related to the underlying cardiac lesion. For example, infants
with hypoplastic left heart syndrome may be at particular risk of associated
developmental brain lesions, which range in severity from microdysgenesis to gross
52malformations, including agenesis of the corpus callosum, holoprosencephaly,
and immature cortical mantle. With advances in neuroimaging, the relationship
between cardiac and brain dysgenesis is becoming more clearly de: ned. Clinically,
these dysgenetic lesions may present in the newborn period with seizures,
alterations in level of consciousness, and abnormalities in motor tone. Conversely,
these lesions may remain clinically occult until later infancy and childhood, when
they present with developmental delay, epilepsy, and cerebral palsy. For these
reasons, it is important to consider cerebral dysgenesis in any child with congenital
heart disease and neurological manifestations.
Acquired Preoperative Cerebrovascular Injury
Infants with congenital heart disease are at increased risk of acquired antenatal or
perinatal brain injury. During fetal life, congenital heart lesions may be associated
with changes in cerebrovascular blood-Gow distribution and resistance. Fetuses
with hypoplastic left heart syndrome, whose cerebral perfusion is supplied
19,20retrograde through the ductus arteriosus, may be at particular risk.
Preoperative MRI studies have demonstrated that brain injury is common in infants
with critical congenital heart disease and during invasive diagnostic procedures
54,55(e.g., balloon-atrial septostomy). Preoperative : ndings detected by MRI
include intracranial hemorrhage, cerebral venous thromboses, thromboembolic
infarctions, dilation of the ventricles and subarachnoid spaces (suggestive of
cerebral atrophy), periventricular leukomalacia, and gray matter
17,18,20,56,57injury. Elevated preoperative brain lactate levels have been found by<
17,24,56magnetic resonance spectroscopy in over half of newborns.
Complex corrective operations are performed in ever smaller and less mature
58newborn infants. Consequently, the vascular lesions associated with less mature
infants are now seen. Intraventricular/periventricular hemorrhage (IVH-PVH) is a
59common neurological complication in the newborn. The risk of IVH-PVH is
related to the severity of the vascular insult and inversely to the infant’s gestational
age. Prematurity predisposes to IVH-PVH because of the structural and
physiological vulnerability of the immature periventricular germinal matrix. The
hemodynamic instability commonly seen in more severe forms of congenital heart
disease predisposes to the systemic hypotension or Guctuations in blood pressure
59that trigger IVH-PVH. Compared with the incidence of 3.5 percent for IVH-PVH
in term infants overall, the incidence in term infants with congenital heart disease
22is as high as 16 percent in some studies. At autopsy, 25 percent of infants with
60hypoplastic left heart syndrome have intracranial hemorrhage. Infants with
coarctation of the aorta are also at increased risk of intracranial hemorrhage
because of the intracranial vascular malformations and hypertension associated
59,61with this condition.
The detection of intraventricular hemorrhage in infants with congenital heart
disease in the preoperative period creates a major management dilemma because
the risk of extending such hemorrhage is increased by cardiopulmonary bypass and
cardiac surgery. Speci: cally, cardiopulmonary bypass requires anti-coagulation to
prevent clot formation in the bypass circuit; in addition, it has been associated with
62enhanced systemic : brinolytic activity. The more complex operations require
periods of decreased perfusion to approach the cardiac defect. The requirement for
anticoagulation and the potentially severe intraoperative perfusion changes
increase the risk of extending any preoperative intracranial hemorrhage. The
dilemma is further complicated by the fact that intracranial hemorrhage occurs
most commonly in infants with the most critical cardiac lesions, that is, those in
greatest need of early surgical repair.
There are no prospectively tested protocols for managing the dilemma of
preoperative intracranial hemorrhage in infants requiring cardiac surgery. At our
center, we use the following guidelines. We perform preoperative cranial
ultrasonography to exclude IVH-PVH in all premature infants with a birth weight
less than 1,500 g and newborn infants with preoperative neurological dysfunction,
coagulation disturbances, or hemodynamic instability causing signi: cant metabolic
acidosis. In those infants with IVH-PVH, surgical planning is based on the severity
of the cardiac illness (which may directly a ect the risk of hemorrhage extension),
the likely complexity of surgery, and the severity of preoperative IVH-PVH. Minor
63,64subependymal hemorrhage carries a low risk of extension and should notdelay cardiac surgery. In infants with hemorrhage into the ventricles or the
parenchyma, we delay cardiopulmonary bypass for at least 7 days if the cardiac
condition permits.
MECHANISMS OF NEUROLOGICAL INJURY DURING CARDIAC
SURGERY
Neurological dysfunction presenting during the early postoperative period is likely
due in most cases to intraoperative hypoxic-ischemic/reperfusion injury. However,
the risk of cerebrovascular injury extends into the postoperative period, when
cardiorespiratory instability, together with cerebral autoregulatory dysfunction,
predisposes to cerebral hypoxic-ischemic injury. Despite the remarkable advances
facilitated by deep hypothermia and pharmacological agents, the persistent
neurological morbidity in the postoperative period attests to the incomplete
65,66neuroprotection offered by these strategies.
The precise onset and evolution of hypoxic-ischemic/reperfusion injury may be
diD cult to establish. First, the mechanisms of both parenchymal and vascular
hypoxic-ischemic/reperfusion injury are known to evolve over time. Second, during
the early posthypoxic-ischemic period, cells that have sustained an insult may be at
particular risk of irreversible injury from subsequent disturbances in oxygen
supply. Consequently, it is diD cult to ascribe with any certainty
hypoxicischemic/re-perfusion injury to one of the preoperative, intraoperative, or
postoperative periods. Rather, it is likely that in many cases the injury is
multifactorial and cumulative.
Intraoperative Brain Injury
There are multiple interrelated mechanisms by which brain injury may occur
during cardiac surgery. However, hypoxic-ischemic/reperfusion injury is likely the
principal mechanism, a notion supported by the topography of injury seen at
60,67autopsy, that is, laminar cortical necrosis and periventricular white matter
68,69injury. Animal models of deep hypothermic circulatory arrest have also
demonstrated selective neuronal necrosis in a distribution that corresponds closely
70to that seen after normothermic hypoxic-ischemic/reperfusion injury.
Neuropathological studies of infants after deep hypothermic cardiac surgery
suggest that cerebral white matter lesions tend to be the most prevalent and severe,
67followed by a spectrum of gray matter lesions.
The changes in cerebral perfusion and metabolism during cardiac surgery are
complex, interrelated, and often extreme. When these changes exceed the brain’s
ability to maintain a balance between cerebral oxygen/substrate supply and
utilization, a hypoxic-ischemic/reperfusion insult is triggered. The multiple factors<

determining intraoperative cerebral oxygen availability may be categorized as
extrinsic, that is, related to the extracorporeal circulation (e.g., loss of pulsatility,
low or no pump Gow, hypothermia, emboli) or intrinsic (e.g., disturbances in
cerebral blood-Gow autoregulation). During deep hypothermic cardiac surgery,
cerebral oxygen delivery may be impaired by focal or multifocal vaso-occlusive
phenomena generated by the bypass circuit or global hypoperfusion due to
65,66excessive attenuation of bypass flow rate.
Focal or Multifocal Hypoxic-Ischemic Injury
The relatively small intravascular volume of the young infant compared with the
large blood volume required to “prime” the cardiopulmonary bypass circuit results
65,66in increased exposure to insults related to the bypass. These may be either
71embolic or inGammatory due to the extensive interface between blood and
72arti: cial surfaces. The replacement of bubble oxygenators with membrane
devices has decreased but not eradicated the embolic “load” of bypass circuits.
Both gaseous and particulate emboli may enter the circulation directly from the
surgical : eld. Because the bypass circuit delivers oxygenated blood directly to the
aorta, circulating emboli circumvent the normal pulmonary filtration bed and enter
the systemic (and cerebral) arterial circulation directly. Earlier autopsy studies
described cerebral embolic brain injury after cardiac surgery, and subsequent
studies following cardiopulmonary bypass have described a signi: cant prevalence
71of cerebral capillary-bed aneurysmal dilatations.
Cardiopulmonary bypass activates a host of in ammatory cascades that cause
di use vascular injury, resulting in a postperfusion syndrome that in severe cases is
73associated with multiple organ failure. Pathways triggered include the
eicosanoid, complement, and kallikrein pathways. These pathways activate free
74 75radical generation, cause antioxidant depletion, and upregulate adhesion
molecules on neutrophils and endothelial cells. These activated neutrophils appear
to be potent mediators of reperfusion injury in the brain. Hypothermia delays and
76modifies the effect of these processes but does not completely prevent them.
Global Hypoxic-Ischemic Injury
Several techniques used during neonatal cardiac surgery jeopardize cerebral
oxygen delivery by altering cerebral perfusion, arterial oxygen content, and tissue
oxygen delivery. Under deep hypothermic conditions, cerebral oxygen availability
77,78may be limited by cold-induced increases in cerebral vascular resistance,
79,80impairment of cerebral pressure-Gow autoregulation, and increased
oxygen81hemoglobin aD nity. Normally, during periods of decreased perfusion pressure,
cerebral oxygen delivery is maintained by an initial vasodilatory response followed<
<
<
<
<
<
82by an increase in oxygen extraction. However, both these compensatory
83responses are compromised at deep hypothermia.
To approach the often tiny cardiac defects, the bypass Gow rate is decreased and
often arrested for periods depending on the complexity of the lesion. Although
there are general guidelines for “safe periods” of deep hypothermic circulatory
arrest at di erent temperatures, these remain controversial and unpredictable in
the individual infant. In addition, the safety of low-Gow bypass compared with
hypothermic circulatory arrest has been debated. Low-Gow bypass prolongs
exposure to bypass-related phenomena, as well as increasing the risk of incomplete
ischemia. Conversely, deep hypothermic circulatory arrest (DHCA) allows more
rapid completion of the intracardiac phases of the repair and reduces the exposure
to bypass perfusion; however, it exposes the infant to periods of complete
65,66ischemia. Over the past 15 years, a number of studies have focused on the
relationship between DHCA and neurological outcome; most studies have reported
84-87a deleterious e ect on outcome. In the : rst major clinical trial randomizing
infants to a strategy of predominant hypothermic circulatory arrest or low-Gow
bypass, infants exposed to the former were at signi: cantly greater risk of
8 9perioperative and 1-year neurological sequelae. At age 4 years, the DHCA group
10had signi: cantly worse behavior, speech, and language function, but no
di erence in mean intelligence score. Furthermore, at 8-year follow-up, those
assigned to DHCA scored worse on motor and speech domains, whereas those
11assigned to low-Gow bypass had worse scores for impulsivity and behavior.
Therefore, the long-term follow-up of this large cohort has provided important
insights into the evolution of neurodevelopmental outcome in this complex
88population over time. Although it is now generally accepted that prolonged
periods of uninterrupted DHCA may have adverse neurological e ects, certain
studies have shown that shorter durations of DHCA are not consistently associated
89-91with adverse outcomes. In fact, available data suggest that the relationship
between DHCA duration and neurodevelopmental sequelae is not linear and that
the risk of brain injury increases signi: cantly after about 40 minutes of
84,92DHCA. These studies have again emphasized that the neurological
dysfunction in this population is undoubtedly mediated by numerous interrelated
preoperative and postoperative risk factors in addition to DHCA.
In addition to the bypass Gow rate, a number of other factors associated with
cardiopulmonary bypass may a ect cerebral perfusion and predispose to
hypoxicischemic/reperfusion injury. Most centers in the United States use nonpulsatile
bypass devices as well as hemodilution to reduce the magnitude of blood cell
trauma. Deep hypothermia is widely used to suppress oxygen consumption during
infant cardiac surgery. In addition to their intended bene: cial e ects, these<
<
techniques all have potential adverse e ects on cerebral oxygen delivery. The
nonpulsatile perfusion of cardiopulmonary bypass, particularly at low-Gow rates,
93may fail to maintain perfusion in distal capillary beds. Furthermore, nonpulsatile
77,80,94blood-Gow may disrupt pressure-Gow and metabolism-Gow autoregulation.
Hemodilution is used during bypass to reduce rheologic injury to circulating red
cells during deep hypothermia. However, because the concentration of oxygenated
hemoglobin is the major determinant of oxygen-carrying capacity, hemodilution
may limit cerebral oxygen delivery. In animal studies, extreme hemodilution (to
hematocrit levels less than 10%) was associated with neurological injury, whereas
6hematocrit levels above 30 percent improved cerebral recovery after DHCA. These
experimental results were con: rmed by a randomized clinical trial in which infants
randomized to a hematocrit of 20 percent during cardiac surgery had signi: cantly
worse developmental scores at 1 year than those randomized to a hematocrit of
7around 30 percent.
Another important intraoperative factor is the management of acid-base status
during cardiopulmonary bypass. In a randomized, single-center trial, infants
undergoing cardiac operations were assigned to the alpha-stat versus pH-stat
12strategy during deep hypothermic cardiopulmonary bypass. The use of pH-stat
12management was associated with lower overall early postoperative morbidity.
Treatment assignment had no e ect on neurodevelopmental outcome at 1, 2, and 4
95years of age. Despite these equivocal : ndings, many centers are currently using
pH-stat management during core cooling.
After repair of the cardiac defect, bypass Gow rates are increased using
rewarmed and highly oxygenated blood. Rewarming aims to reactivate cellular
enzyme function and oxygen utilization. During this period of reperfusion, a
65,66number of factors may predispose to free radical injury. Several studies have
96suggested a delay in recovery of mitochondrial function, possibly by nitric oxide,
97which is generated in abundance during the bypass. The combination of a highly
oxygenated reperfusion and persistent mitochondrial dysfunction may be a major
98source of injurious oxygen free radicals. Excessively rapid rewarming after deep
99hypothermia may be deleterious. Hyperthermia is a trigger for glutamate
100release, predisposing to excitotoxicity as well as further stressing the recovering
cerebral metabolism.
Mechanisms of Postoperative Injury
During the postoperative period of intensive care, a number of factors may
predispose to brain injury. Cerebral perfusion pressure may be compromised by a
combination of decreased cardiac output and elevated central venous pressure
resulting from postoperative cardiac dysfunction. In addition to these systemiccirculatory factors, there may be intrinsic cerebrovascular disturbances in the
postoperative period. Speci: cally, elevated cerebral vascular resistance, decreased
3,66,79,101,102cerebral blood-Gow, and impaired vasoregulation have been
described after deep hypothermic circulatory arrest. Together, these factors may
render the brain vulnerable to injury in the postoperative period.
MANIFESTATIONS OF NEUROLOGICAL DYSFUNCTION IN THE
POSTOPERATIVE PERIOD
Recent studies suggest a decrease in acute neurological morbidity following
103surgery. However, intraoperative and postoperative insults may injure the
neuraxis at any level. Because a detailed discussion of the entire spectrum of
neurological manifestations is not possible in the current context, this review
focuses on the more common clinical issues confronting the child neurologist.
Delayed Recovery of Consciousness
Prolonged impairment of mental status after cardiac surgery, anesthesia, and
postoperative sedation is a common reason for neurological consultation. The
evaluation should follow the well-established clinical guidelines for assessing
104impaired consciousness. Certain speci: c etiologies should be excluded,
including postoperative hepatic or renal impairment, which may impair the
metabolism or excretion of sedating drugs. Prolonged use of neuromuscular
blocking agents in the preoperative or postoperative period may delay the recovery
105of motor function (discussed later) and, if severe, may suggest impaired
consciousness. This condition should be excluded at the bedside with a peripheral
nerve stimulator or formal nerve conduction studies. Postoperative seizures are a
common complication of cardiac surgery (as discussed in the next section), and not
8infrequently these seizures are clinically silent. Such “occult” seizures or a
prolonged postictal state should be considered in the evaluation of a depressed
postoperative mental state. In spite of this approach, the precise cause of an
impaired postoperative mental status is not established in most cases. Many of
these children ultimately demonstrate features suggestive of
hypoxicischemic/reperfusion injury.
Postoperative Seizures
Seizures early in the postoperative period are among the most common
neurological complications after open heart surgery. Postoperative clinical seizures
have been reported to occur in up to 19 percent of survivors of neonatal cardiac
106surgery, and in certain subgroups this risk may reach 50 percent. Clinical
seizures are reported less frequently than those detected by continuous<
<
8,107electroencephalographic monitoring since postoperative seizures may occur
8without typical motor correlates.
Postoperative seizures may be divided into two broad groups. First are those
seizures with a readily identi: able cause, such as hypoglycemia, hypocalcemia,
and cerebral dysgenesis. Postoperative seizures may also result from
hypoxicischemic/reperfusion injury due to either generalized cerebral hypoperfusion (e.g.,
cardiac arrest) or focal vaso-occlusive insults. The second and more common
category of postoperative seizures is that in which the etiology remains unknown.
Although these cryptogenic seizures, commonly referred to as postpump seizures,
are often assumed to relate to hypoxic-ischemic/reperfusion injury, their etiology is
likely multifactorial with risk factors that include the use and duration of deep
8,108hypothermic circulatory arrest, younger age at surgery, the type of heart
106defect (e.g., aortic arch obstruction), and genetic conditions. Furthermore,
postpump seizures di er in several respects from other forms of posthypoxic
seizures. First, these seizures typically develop later than, for instance, those
occurring after perinatal asphyxia. Second, although less benign than previously
9believed, the prognosis of postpump seizures is signi: cantly better than that of
asphyxial seizures, in which up to 50 percent of survivors are neurologically
109disabled. Both the delayed onset and more favorable outcome of postpump
seizures may be due to the partial protective e ect of hypothermia at the time of
110intraoperative hypoxic-ischemic/reperfusion insult.
The clinical course of postpump seizures is fairly typical. These seizures appear
con: ned to a relatively narrow time-window, with onset between 24 and 48 hours
after surgery. This is followed by several days during which serial seizures occur,
often evolving to status epilepticus; thereafter, the tendency toward further seizures
wanes rapidly. The clinical manifestations of these electrographic seizures are often
subtle even in the absence of sedating and paralyzing drugs and may be con: ned
to paroxysmal autonomic changes. When evident, convulsive activity is usually
focal or multifocal.
The therapeutic approach to postpump seizures should be based on their typical
clinical course. After excluding reversible etiologies such as hypoglycemia,
111,112hypomagnesemia, and hypocalcemia, the tendency toward repeated
seizures and status epilepticus should be countered by rapid achievement of
therapeutic anticonvulsant levels by an intravenous route. Most postpump seizures
are controlled by lorazepam, followed by phenobarbital or phenytoin. Potential
cardiotoxicity due to these agents in children recovering from cardiac surgery
should be monitored carefully, particularly during the initiation of treatment. The
apparently circumscribed window of susceptibility to postpump seizures often
allows early withdrawal of anticonvulsants.Prospective studies have demonstrated a signi: cant correlation between
8 9postoperative seizures and risk of perioperative and 1-year neurological sequelae,
9,106,113as well as abnormal MRI studies. The longer term impact of postpump
11,88,107seizures may be less than previously thought. The development of
subsequent epilepsy is rare; however, West syndrome (infantile spasms, mental
114retardation, and epilepsy) has been described after more intractable postpump
seizures.
When postoperative seizures have an identi: ed cause, the long-term outcome is
related to etiology. For instance, cerebral dysgenesis, which is increased in
congenital heart disease, may present with seizures in the early postoperative
period, and here the long-term outcome is usually poor, with epilepsy a common
106sequela. Infants with seizures due to postoperative stroke have a 20 to 30
115percent risk of subsequent epilepsy.
Periventricular White Matter Injury
Brain MRI of neonates following cardiac surgery has shown a prevalence of
116periventricular leukomalacia in excess of 50 percent in some studies ; this is a
rare : nding in older infants. The precise onset of these lesions remains unclear, but
56the MRI features appear to be transient in many cases. Reported risk factors for
these MRI lesions include prolonged exposure to cardiopulmonary bypass (with or
without DHCA), possibly related to inGammatory mechanisms activated by
cardiopulmonary bypass. In addition, early postoperative hypotension (especially
diastolic) and hypoxemia appear to increase the risk of periventricular
116,117leukomalacia in these MRI studies. Magnetic resonance spectroscopy
studies are beginning to provide insights into disturbed brain metabolism in the
17,118,119postoperative period. Although signi: cant decreases in brain
N-acetyl118,119aspartate, a neuronal-axonal marker, have been described, more recent
data have shown an apparently improved cerebral oxidative metabolism
17postoperatively as evidenced by improved lactate/choline ratios. The long-term
signi: cance of these acute structural and metabolic disturbances in children who
survive cardiac surgery remains to be determined.
Stroke
The incidence of cerebrovascular accidents (strokes) in children ranges from 2.5 to
1208 per 100,000. Congenital heart disease is the leading known association of
120-122childhood stroke and is present in 25 to 30 percent of cases. In earlier
autopsy studies, almost 20 percent of children with congenital heart disease
demonstrated features of cerebrovascular injury.<
Stroke associated with heart disease (cardiogenic stroke) may be classi: ed on the
basis of the likely embolic or thrombotic source as (1) cardioembolic (i.e., a
probable intracardiac embolic source); (2) paradoxical (i.e., a cardiac anatomy
that permits an embolus of systemic venous origin access to the cerebral
circulation); or (3) venous (i.e., cerebral vein thrombosis due to central venous
hypertension and venous stasis).
Risk factors for cardiogenic stroke include the elements of Virchow’s triad—
altered vascular surface, stasis, and hypercoagulability—as well as the presence of
“paradoxical” embolic pathways. Risk factors for cardiogenic stroke have changed
over the years. In earlier studies, the risk of stroke was related to the e ects of
longstanding heart defects, such as chronic hypoxia and polycythemia, and uncorrected
paradoxical pathways (e.g., right-to-left shunts). The trend in recent decades
1toward earlier corrective surgery has reduced exposure to such stroke risk factors,
shifting the focus to intraoperative and postoperative mechanisms for stroke.
A number of intraoperative mechanisms related to cardiopulmonary bypass may
71predispose to cerebral vascular occlusion. Embolic material (particulate/gaseous)
generated during bypass avoids : ltration by the pulmonary bed, gaining direct
entry to the systemic arterial circulation. Earlier autopsy data demonstrated a
substantial incidence of cerebral embolic infarction after surgery for congenital
heart disease. Advances in bypass technique, including re: nements in membrane
oxygenators, in-line arterial : lters, and anticoagulation, have reduced the
123incidence of macroembolization and large-vessel occlusion. The impact of these
advances on the incidence of microembolization and small-vessel disease is diD cult
to evaluate.
The extensive interface between circulating blood and the arti: cial surface of the
bypass circuit may trigger an inGammatory response, which in turn activates
72complex physiological cascades, including endothelium–leukocyte interactions.
This process further enhances the risk of ischemic injury during the intra-operative
and postoperative periods.
In the postoperative period, factors predisposing to stroke include stasis
(intracardiac and extracardiac), altered vascular surfaces (native or prosthetic),
and, in some situations, a potential procoagulant shift in the humoral clotting
124 125systems. Intracardiac stasis may result from localized areas of low Gow or
global ventricular dysfunction. Transient or sustained elevations of right heart and,
hence, central venous pressure in the early postoperative period predispose to local
126thrombosis in the right atrium and central veins. Prosthetic material in such
areas of disturbed Gow increases the likelihood of thrombus formation, and the
presence of a right-to-left shunt (native or iatrogenic) compounds the risk of
paradoxical embolization. Elevated right atrial pressure transmitted to the cerebral<
<
venous circulation predisposes to venous thrombosis, particularly in the dural
venous sinuses. Elevated systemic venous pressure may cause a protein-losing
127enteropathy, liver impairment, and pleural e usions, factors that may disturb
124the humoral coagulant systems. A number of the aforementioned stroke risk
factors may be present after the Fontan operation, as highlighted in several
125,128reports. In one study, a 2.6 percent incidence of stroke was found in a
retrospective review of 645 patients after the Fontan operation; the risk extended
125over 3 years after the procedure. Rosenthal and co-workers found a 20 percent
128incidence of thromboembolic complications after the Fontan procedure.
Strokes originating during or immediately after cardiac surgery may escape
clinical recognition for several days because of the e ects of postoperative sedating
and paralyzing agents. In the young infant, stroke often presents with focal
129seizures or changes in mental status; focal motor de: cits may be subtle. In older
infancy and childhood, stroke usually presents with acute focal motor de: cits,
language disturbance, or visual dysfunction.
The therapeutic approach to stroke in the child with heart disease includes (1)
preventive and (2) “rescue” strategies. Experience with rescue therapies remains
con: ned to adult and experimental stroke. These rescue therapies aim to salvage
potentially viable brain using techniques designed to revascularize ischemic brain
130regions (thrombolytic therapy) or to curtail injurious biochemical cascades.
This discussion focuses on the principles of stroke prophylaxis using antithrombotic
131agents. Preventive stroke therapy may be categorized as primary or secondary.
Primary stroke prevention aims to identify and treat high-risk patients before a
stroke, whereas secondary prevention aims at minimizing the risk of stroke
recurrence. Consistent and universally accepted guidelines for both primary and
secondary stroke prophylaxis in children are lacking. Current guidelines are largely
empirical, anecdotal, and derived from experience in adults. Established
indications for primary stroke prophylaxis in children include prosthetic heart
valves, dilated cardiomyopathy, or intracardiac thrombus on echocardiogram.
The decision regarding whether and when to initiate secondary stroke prophylaxis
with antithrombotic agents should aim to balance the risk of (1) recurrent cerebral
embolization and (2) potentiating secondary hemorrhage into an area of cerebral
infarction. Embolus recurrence risks after cardioembolic stroke are unknown in
children. In adults (after myocardial infarction), this risk is highest in the early
poststroke period, at approximately 1 percent per day (10% to 20% over the : rst 2
132weeks). Cardioembolic strokes are particularly prone to hemorrhagic
133transformation, especially in the early poststroke period. Hemorrhagic
transformation occurs (often silently) in 20 to 40 percent of adult cardioembolic
133strokes. The risk of signi: cant clinical deterioration after hemorrhagictransformation is greater in the anticoagulated patient.
Although it is diD cult to predict which infarcts will undergo hemorrhagic
transformation, certain guidelines have been formulated. Among infarcts destined
to undergo hemorrhagic transformation, 75 percent do so within 48 hours after
83stroke onset. Large infarcts, particularly those larger than 30 percent, or one
lobe, of a cerebral hemisphere, are at greater risk of hemorrhagic
134transformation. Uncontrolled systemic hypertension and stroke due to septic
emboli and cerebral venous thrombosis are additional risk factors for hemorrhagic
infarction. The details of antithrombotic management are discussed elsewhere.
The cerebrovascular disease associated with infective endocarditis warrants brief
mention. The protean neurological manifestations of infective endocarditis include
meningitis, brain abscess, and seizures. However, cerebrovascular injury,
speci: cally septic embolism and hemorrhage, is the most common complication.
Even with advanced antibiotic agents, neurological complications occur in one
third of infective endocarditis cases in children; in one half of such cases, the
135complications are embolic in origin. Cerebrovascular complications carry the
highest mortality rate (up to 80% to 90%), primarily due to intracranial
hemorrhage. The risk of and mortality rate of cerebral hemorrhage in this
population contraindicates anticoagulant therapy. In all cases of cardiogenic
stroke, the possibility of septic embolism should be considered before initiating
anticoagulant therapy.
Movement Disorders
136Reports of serious postoperative movement disorders go back to the early 1960s
137,138and the early days of deep hypothermic cardiac surgery. Choreoathetosis is
the most frequent form of dyskinesia complicating cardiac surgery; other rarer
postoperative movement disorders include oculogyric crises and parkinsonism. The
88reported incidence of postoperative choreoathetosis reached 19 percent in earlier
139years ; fortunately, this complication has become rare in recent years. Despite
their relative rarity, these movement disorders are often dramatic, frequently
intractable, and, in severe cases, associated with a substantial mortality rate.
Postoperative movement disorders have a fairly typical clinical course. The
involuntary movements are preceded in most cases by a 2- to 7-day latent period
during which postoperative neurological recovery appears to be uncomplicated.
Thereafter, a subacute delirium (marked irritability, insomnia, confusion, and
disorientation) develops, followed closely by the emergence of involuntary
movements. Typically, these movements start in the distal extremities and orofacial
muscles, progressing proximally to involve the girdle muscles and trunk. In severe
cases, violent ballismic thrashing may develop. The abnormal movements are<
<
<
present during wakefulness, peak with distress, and resolve during brief periods of
sleep. Oculomotor and oromotor apraxia are common, with loss of voluntary gaze
as well as feeding and expressive language skills. The involuntary movements often
intensify over a 1-week period, followed by a 1- to 2-week period during which
movements remain relatively constant. The period of recovery is highly variable in
duration. The long-term outcome of postoperative movement disorders depends
largely on their initial severity. Mild cases tend to resolve within weeks to months,
whereas severe cases have a mortality rate approaching 40 percent and a high
incidence of associated, signi: cant, long-term neurodevelopmental de: cits,
including di use hypotonia, persistent dyskinesia (47%), and pervasive de: cits in
137,139memory, attention, language, and motor abilities.
The diagnosis of postoperative hyperkinetic syndromes is essentially clinical.
Currently available neurodiagnostic studies are useful only for excluding other
disorders. Cerebral changes by computed tomography (CT), MRI, and
singlephoton emission CT are nonspeci: c, seldom focal, and most commonly consist of
137di use cerebral atrophy and a high incidence of both cortical and subcortical
perfusion defects. The electroencephalogram is usually normal or di usely slow,
with no ictal changes associated with the involuntary movements. Descriptions of
140the neuropathological : ndings at autopsy are limited and inconsistent. Findings
have ranged from normal to extensive neuronal loss and gliosis, particularly in the
140external globus pallidus. Typical features of infarction are characteristically
absent.
Certain risk factors have been suggested, including (1) cyanotic congenital heart
disease, particularly with systemic-to-pulmonary collaterals from the head and
neck; (2) age at surgery older than 9 months; (3) excessively short cooling periods
before attenuation of intraoperative blood-Gow; (4) alpha-stat pH management
strategy; (5) deep hypothermia and extracorporeal circulation; and (6) preexisting
141-143developmental delay. Postoperative dyskinesias, usually mild and transient,
144,145have been reported after prolonged use of fentanyl and midazolam.
Once manifest, the involuntary movements are very refractory to treatment and
generally respond poorly to a wide variety of conventional antidyskinetic
medications, including dopamine receptor blockers (phenothiazines and
butyrophenones), dopamine-depleting agents (reserpine, tetrabenazine), dopamine
agonists (levodopa), GABAergic agents (benzodiazepines, barbiturates, baclofen),
and other agents such as valproic acid, carbamazepine, phenytoin,
diphenhydramine, and chloral hydrate. In general, successful movement control
has been achieved only at the expense of excessive sedation.
Given these limitations, the management of postoperative movement disorders
should focus on the often severe agitation and insomnia. General measures, such as<
a decrease in the level of external (e.g., noise, light) and internal (e.g., pain)
stimuli, are useful in decreasing the intensity of involuntary movements. Judicious
use of sedation should aim to restore the fragmented sleep-wakefulness cycle.
Oromotor dyskinesia is often severe enough to impair feeding and predispose to
aspiration. Nasogastric or even gastrostomy tube feedings may be necessary to meet
the high caloric demands of the constant involuntary movements.
Spinal Cord Injury
Spinal cord injury is a relatively rare complication of pediatric cardiac
146,147surgery and usually occurs after aortic coarctation repair, in which 0.4 to
1.5 percent of cases may be a ected. Intraoperative spinal cord injury is mediated
by hypoxic-ischemic/reperfusion injury to watershed territories in the cord, most
commonly in the lower thoracic cord, where transverse infarction results in
postoperative paraplegia. An additional watershed zone runs between the supply
territories of the anterior and posterior spinal arteries; ischemia in this region
results in predominant or selective anterior horn cell loss.
Brachial Plexus and Peripheral Nerve Injury
Prolonged immobility during and after cardiac catheterization and surgery
predisposes peripheral nerves to pressure and traction injury. Pressure palsies may
occur at any dependent site, but most commonly involve the peroneal and ulnar
nerves. Brachial plexus injury is not uncommon after cardiac
148,149catheterization. Injury to the lower plexus results from prolonged traction
during the extreme and sustained arm abduction required in some procedures. This
neuropraxic lesion resolves gradually but usually completely. During cardiac
catheterization, the insertion of indwelling central venous catheters through the
internal jugular vein may injure the upper brachial plexus by direct physical
trauma or extravasation of blood into the plexus.
Phrenic nerve injury results from hypothermic injury by ice packed around the
150heart or from direct intraoperative transection. Postoperative phrenic nerve
151,152injury has also been described after malposition of chest tubes.
Intraoperative phrenic nerve injury presents with diaphragmatic palsy and
prolonged postoperative ventilator dependence. The lesion may be confirmed at the
153bedside by nerve conduction studies and electromyography. Most phrenic nerve
injuries resolve spontaneously, but occasionally diaphragmatic plication or, in rare
154instances, diaphragmatic pacing is required. Younger infants are more likely
151,152than older children to require diaphragm plication.
Postoperative ventilation is commonly facilitated by the use of neuromuscular
blocking agents. Prolonged use of nondepolarizing agents, especially vecuronium<
and pancuronium, has been associated with neuromuscular
105,155-157 157dysfunction. The concomitant use of steroids may increase the risk.
The neuropathological spectrum in these conditions is highly variable, ranging
from necrotizing myopathy to axonal motor neuropathy with variable sensory
156involvement. These conditions may be diD cult to distinguish from “critical
illness polyneuropathy.”
NEUROLOGICAL COMPLICATIONS OF CARDIAC TRANSPLANTATION
Cardiac transplantation has become a rescue treatment for children with either
primary (myocarditis/cardiomyopathy) or secondary (to associated congenital
158heart disease) end-stage myocardial failure. Reported 10-year survival rates
159from various pediatric institutions range from 42 to 73 percent.
More e ective immunosuppression has advanced the survival of transplant
recipients; however, long-term immunosuppression remains a major challenge and
has well-recognized neurological complications. The passage to heart
transplantation is itself fraught with risk of neurological injury, particularly
hypoxic-ischemic, as is the transplantation procedure, which may be complex and
involve long periods of bypass support. Adult autopsy studies have described brain
injury in more than 80 percent of transplant recipients, consisting of vascular (up
to 60%), infectious (20%), and lymphoproliferative disorders (13%). In a recent
pediatric autopsy study, brain injury was described in 87 percent of transplant
160recipients.
In the : rst 2 weeks after transplantation, the most common complications are
stroke, drug neurotoxicity, hypoxic-ischemic encephalopathy, and acute psychosis.
In a recent report, seizures occurred in 21 percent of children
post161transplantation. Later, the complications of chronic immunosuppression, such
as opportunistic infections, lymphoma, drug neurotoxicity, and metabolic
162encephalopathy, are more common. Further discussion of these complications is
provided in Chapters 3 and 46.
REFERENCES
1 Benson D. Changing profile of congenital heart disease. Pediatrics. 1989;83:790.
2 Rudolph AM. Congenital Diseases of the Heart: Clinical-Physiologic Considerations
in Diagnosis and Management. Chicago: Year Book Medical Publishers, 2001.
3 du Plessis AJ. Neurologic complications of cardiac disease in the newborn. Clin
Perinatol. 1997;24:807.
4 du Plessis AJ. Mechanisms of brain injury during infant cardiac surgery. Semin
Pediatr Neurol. 1999;6:32.5 Ferry PC. Neurologic sequelae of open-heart surgery in children. An ‘irritating
question.’. Am J Dis Child. 1990;144:369.
6 Shin’oka T, Shum-Tim D, Jonas RA, et al. Higher hematocrit improves cerebral
outcome after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg.
1996;112:1610.
7 Jonas RA, Wypij D, Roth SJ, et al. The influence of hemodilution on outcome after
hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J
Thorac Cardiovasc Surg. 2003;126:1765.
8 Newburger JW, Jonas RA, Wernovsky G, et al. A comparison of the perioperative
neurologic effects of hypothermic circulatory arrest versus low-flow
cardiopulmonary bypass in infant heart surgery. N Engl J Med. 1993;329:1057.
9 Bellinger DC, Jonas RA, Rappaport LA, et al. Developmental and neurologic status
of children after heart surgery with hypothermic circulatory arrest or low-flow
cardiopulmonary bypass. N Engl J Med. 1995;332:549.
10 Bellinger DC, Wypij D, Kuban KC, et al. Developmental and neurological status of
children at 4 years of age after heart surgery with hypothermic circulatory arrest
or low-flow cardiopulmonary bypass. Circulation. 1999;100:526.
11 Bellinger DC, Wypij D, duDuplessis AJ, et al. Neurodevelopmental status at eight
years in children with dextro-transposition of the great arteries: the Boston
Circulatory Arrest Trial. J Thorac Cardiovasc Surg. 2003;126:1385.
12 du Plessis AJ, Jonas RA, Wypij D, et al. Perioperative effects of alpha-stat versus
pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J
Thorac Cardiovasc Surg. 1997;114:991.
13 Manzar S, Nair AK, Pai MG, et al. Head size at birth in neonates with transposition
of great arteries and hypoplastic left heart syndrome. Saudi Med J. 2005;26:453.
14 Limperopoulos C, Majnemer A, Rosenblatt B, et al. Multimodality evoked potential
findings in infants with congenital heart defects. J Child Neurol. 1999;14:702.
15 Limperopoulos C, Majnemer A, Shevell MI, et al. Neurologic status of newborns
with congenital heart defects before open heart surgery. Pediatrics. 1999;103:402.
16 Limperopoulos C, Majnemer A, Shevell MI, et al. Neurodevelopmental status of
newborns and infants with congenital heart defects before and after open heart
surgery. J Pediatr. 2000;137:638.
17 Miller SP, McQuillen PS, Vigneron DB, et al. Preoperative brain injury in newborns
with transposition of the great arteries. Ann Thorac Surg. 2004;77:1698.
18 Tavani F, Zimmerman RA, Clancy RR, et al. Incidental intracranial hemorrhage
after uncomplicated birth: MRI before and after neonatal heart surgery.
Neuroradiology. 2003;45:253.
19 Kaltman JR, Di H, Tian Z, et al. Impact of congenital heart disease on
cerebrovascular blood flow dynamics in the fetus. Ultrasound Obstet Gynecol.2005;25:32.
20 Licht DJ, Wang J, Silvestre DW, et al. Preoperative cerebral blood flow is
diminished in neonates with severe congenital heart defects. J Thorac Cardiovasc
Surg. 2004;128:841.
21 Te Pas AB, van Wezel-Meijler G, Bokenkamp-Gramann R, et al. Preoperative
cranial ultrasound findings in infants with major congenital heart disease. Acta
Paediatr. 2005;94:1597.
22 van Houten J, Rothman A, Bejar R. High incidence of cranial ultrasound
abnormalities in full-term infants with congenital heart disease. Am J Perinatol.
1996;13:47.
23 Tworetzky W, Marshall AC. Fetal interventions for cardiac defects. Pediatr Clin
North Am. 2004;51:1503.
24 Tworetzky W, Wilkins-Haug L, Jennings RW, et al. Balloon dilation of severe aortic
stenosis in the fetus: potential for prevention of hypoplastic left heart syndrome:
candidate selection, technique, and results of successful intervention. Circulation.
2004;110:2125.
25 Robertson CM, Joffe AR, Sauve RS, et al. Outcomes from an interprovincial
program of newborn open heart surgery. J Pediatr. 2004;144:86.
26 Limperopoulos C, Majnemer A, Shevell MI, et al. Predictors of developmental
disabilities after open heart surgery in young children with congenital heart
defects. J Pediatr. 2002;141:51.
27 Limperopoulos C, Majnemer A, Shevell MI, et al. Functional limitations in young
children with congenital heart defects after cardiac surgery. Pediatrics.
2001;108:1325.
28 Majnemer A, Limperopoulos C, Shevell M, et al. Long-term neuromotor outcome at
school entry of infants with congenital heart defects requiring open-heart surgery.
J Pediatr. 2006;148:72.
29 Miller G, Vogel H. Structural evidence of injury or malformation in the brains of
children with congenital heart disease. Semin Pediatr Neurol. 1999;6:20.
30 Eskedal L, Hagemo P, Eskild A, et al. A population-based study of extra-cardiac
anomalies in children with congenital cardiac malformations. Cardiol Young.
2004;14:600.
31 Derbent M, Bikmaz YE, Yilmaz Z, et al. Variable phenotype and associations in
chromosome 22q11.2 microdeletion. Am J Med Genet A. 2006;140:659.
32 Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2
deletion: phenotype, incidence, and contribution to major birth defects in the
population. Pediatrics. 2003;112:101.
33 Moss E, Wang P, McDonald-McGinn D, et al. Characteristic cognitive profile in
patients with a 22q11.2 deletion: verbal IQ exceeds nonverbal IQ. Am J HumGenet A. 1995;57:20.
34 Bingham PM, Lynch D, McDonald-McGinn D, et al. Polymicrogyria in chromosome
22 deletion syndrome. Neurology. 1998;51:1500.
35 MacKenzie-Stepner K, Witzel MA, Stringer DA, et al. Abnormal carotid arteries in
the velocardiofacial syndrome: a report of three cases. Plast Reconstr Surg.
1987;80:347.
36 Mitnick R, Bello J, Shprintzen R. Brain anomalies in velo-cardiofacial syndrome.
Am J Med Genet. 1994;54:100.
37 Antshel KM, Conchelos J, Lanzetta G, et al. Behavior and corpus callosum
morphology relationships in velocardiofacial syndrome (22q11.2 deletion
syndrome). Psychiatry Res. 2005;138:235.
38 Bish JP, Pendyal A, Ding L, et al. Specific cerebellar reductions in children with
chromosome 22q11.2 deletion syndrome. Neurosci Lett. 2006;399:245.
39 Campbell LE, Daly E, Toal F, et al. Brain and behaviour in children with 22q11.2
deletion syndrome: a volumetric and voxel-based morphometry MRI study. Brain.
2006;129:1218.
40 Natowicz M, Chatten J, Clancy R, et al. Genetic disorders and major extracardiac
anomalies associated with the hypoplastic left heart syndrome. Pediatrics.
1988;82:698.
41 Schaer M, Schmitt JE, Glaser B, et al. Abnormal patterns of cortical gyrification in
velo-cardio-facial syndrome (deletion 22q11.2): an MRI study. Psychiatry Res.
2006;146:1.
42 Sugama S, Bingham PM, Wang PP, et al. Morphometry of the head of the caudate
nucleus in patients with velocardiofacial syndrome (del 22q11.2). Acta Paediatr.
2000;89:546.
43 Barnea-Goraly N, Menon V, Krasnow B, et al. Investigation of white matter
structure in velocardiofacial syndrome: a diffusion tensor imaging study. Am J
Psychiatry. 2003;160:1863.
44 Zinkstok J, van Amelsvoort T. Neuropsychological profile and neuroimaging in
patients with 22Q11.2 deletion syndrome: a review. Child Neuropsychol.
2005;11:21.
45 Lajiness-O’Neill R, Beaulieu I, Asamoah A, et al. The neuropsychological phenotype
of velocardiofacial syndrome (VCFS): relationship to psychopathology. Arch Clin
Neuropsychol. 2006;21:175.
46 Vorstman JA, Morcus ME, Duijff SN, et al. The 22q11.2 deletion in children: high
rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child
Adolesc Psychiatry. 2006;45:1104.
47 Golding-Kushner K, Weller G, Shpintzen R. Velo-cardio-facial syndrome: language
and psychological profiles. J Craniofac Genet. 1985;5:259.48 Shprintzen R, Goldberg R, Golding-Kushner K, et al. Late-onset psychosis in the
velo-cardio-facial syndrome. Am J Med Genet. 1992;42:141.
49 Bish JP, Nguyen V, Ding L, et al. Thalamic reductions in children with chromosome
22q11.2 deletion syndrome. Neuroreport. 2004;15:1413.
50 Eliez S, Barnea-Goraly N, Schmitt JE, et al. Increased basal ganglia volumes in
velo-cardio-facial syndrome (deletion 22q11.2). Biol Psychiatry. 2002;52:68.
51 Kates WR, Miller AM, Abdulsabur N, et al. Temporal lobe anatomy and psychiatric
symptoms in velocardiofacial syndrome (22q11.2 deletion syndrome). J Am Acad
Child Adolesc Psychiatry. 2006;45:587.
52 Glauser T, Rorke L, Weinberg P, et al. Congenital brain anomalies associated with
the hypoplastic left heart syndrome. Pediatrics. 1990;85:984.
53 Jones M. Anomalies of the brain and congenital heart disease: a study of 52
necropsy cases. Pediatr Pathol. 1991;11:721.
54 Cheng TO. That balloon atrial septostomy is associated with preoperative stroke in
neonates with transposition of the great arteries is another powerful argument in
favor of therapeutic closure of every patent foramen ovale. Am J Cardiol.
2006;98:277.
55 McQuillen PS, Hamrick SE, Perez MJ, et al. Balloon atrial septostomy is associated
with preoperative stroke in neonates with transposition of the great arteries.
Circulation. 2006;113:280.
56 Mahle WT, Tavani F, Zimmerman RA, et al. An MRI study of neurological injury
before and after congenital heart surgery. Circulation. 2002;106:I109.
57 McConnell JR, Fleming WH, Chu WK, et al. Magnetic resonance imaging of the
brain in infants and children before and after cardiac surgery. A prospective
study. Am J Dis Child. 1990;144:374.
58 Reddy VM, Hanley FL. Cardiac surgery in infants with very low birth weight. Semin
Pediatr Surg. 2000;9:91.
59 Volpe JJ. Intracranial hemorrhage. In Neurology of the Newborn, 4th Ed.,
Philadelphia: WB Saunders; 2001:397.
60 Glauser T, Rorke L, Weinberg P, et al. Acquired neuropathologic lesions associated
with the hypoplastic left heart syndrome. Pediatrics. 1990;85:991.
61 Young R, Liberthson R, Zalneraitis E. Cerebral hemorrhage in neonates with
coarctation of the aorta. Stroke. 1982;13:491.
62 Giuliani R, Szwarcer E, Aquino E, et al. Fibrin-dependent fibrinolytic activity
during extracorporeal circulation. Thromb Res. 1991;61:369.
63 Rudack D, Baumgart S, Gross G. Subependymal (grade 1) intracranial hemorrhage
in neonates on extracorporeal membrane oxygenation. Clin Pediatr. 1994;33:583.
64 von Allmen D, Babcock D, Matsumoto J, et al. The predictive value of head
ultrasound in the ECMO candidate. J Pediatr Surg. 1992;27:36.65 du Plessis AJ. Cerebral hemodynamics and metabolism during infant cardiac
surgery. Mechanisms of injury and strategies for protection. J Child Neurol.
1997;12:285.
66 du Plessis AJ, Johnston MV. The pursuit of effective neuroprotection during infant
cardiac surgery. Semin Pediatr Neurol. 1999;6:55.
67 Kinney HC, Panigrahy A, Newburger JW, et al. Hypoxic-ischemic brain injury in
infants with congenital heart disease dying after cardiac surgery. Acta Neuropathol
(Berl). 2005;110:563.
68 Volpe JJ. Hypoxic-ischemic encephalopathy: biochemical and physiological aspects.
In In Neurology of the Newborn, 4th Ed., Philadelphia: WB Saunders; 2001:217.
69 Volpe JJ. Hypoxic-ischemic encephalopathy: neuropathology and pathogenesis. In
Neurology of the Newborn, 4th Ed., Philadelphia: WB Saunders; 2001:296.
70 Redmond J, Gillinov A, Zehr K, et al. Glutamate excitotoxicity: a mechanism of
neurologic injury associated with hypothermic circulatory arrest. J Thorac
Cardiovasc Surg. 1994;107:776.
71 Moody D, Bell M, Challa V, et al. Brain microemboli during cardiac surgery or
aortography. Ann Neurol. 1990;28:477.
72 Casey L. Role of cytokines in the pathogenesis of cardiopulmonary-induced
multisystem organ failure. Ann Thorac Surg. 1993;56:S92.
73 Westaby S. Organ dysfunction after cardiopulmonary bypass: a systemic
inflammatory reaction by the extracorporeal circuit. Intensive Care Med.
1987;13:89.
74 Pesonen EJ, Korpela R, Peltola K, et al. Regional generation of free oxygen
radicals during cardiopulmonary bypass in children. J Thorac Cardiovasc Surg.
1995;110:768.
75 Pyles LA, Fortney JE, Kudlak JJ, et al. Plasma antioxidant depletion after
cardiopulmonary bypass in operations for congenital heart disease. J Thorac
Cardiovasc Surg. 1995;110:165.
76 Ledeist F, Menasche P, Kucharski C, et al. Hypothermia during cardiopulmonary
bypass delays but does not prevent neutrophil-endothelial cell adhesion. A clinical
study. Circulation. 1995;92:II.
77 Andersen K, Waaben J, Husum B, et al. Nonpulsatile cardiopulmonary bypass
disrupts the flow-metabolism couple in the brain. J Thorac Cardiovasc Surg.
1985;90:570.
78 Speziali G, Russo P, Davis D, et al. Hypothermia enhances contractility in cerebral
arteries of newborn lambs. J Surg Res. 1994;57:80.
79 Greeley W, Ungerleider R, Smith L, et al. The effects of deep hypothermic
cardiopulmonary bypass and total circulatory arrest on cerebral blood flow in
infants and children. J Thorac Cardiovasc Surg. 1989;97:737.80 Murkin JM, Farrar JK, Tweed WA, et al. Cerebral autoregulation and
flow/metabolism coupling during cardiopulmonary bypass: the influence of
PaCO . Anesth Analg. 1987;66:825.2
81 Coetzee A, Swanepoel C. The oxyhemoglobin dissociation curve before, during and
after cardiac surgery. Scand J Clin Lab Invest Suppl. 1990;203:149.
82 Powers W. Hemodynamics and metabolism in ischemic cerebrovascular disease.
Neurol Clin. 1992;10:31.
83 Dexter F, Hindman B. Theoretical analysis of cerebral venous blood hemoglobin
oxygen saturation as an index of cerebral oxygenation during hypothermic
cardiopulmonary bypass. Anesthesiology. 1995;83:405.
84 Forbess JM, Visconti KJ, Hancock-Friesen C, et al. Neurodevelopmental outcome
after congenital heart surgery: results from an institutional registry. Circulation.
2002;106:I95.
85 Kern JH, Hinton VJ, Nereo NE, et al. Early developmental outcome after the
Norwood procedure for hypoplastic left heart syndrome. Pediatrics.
1998;102:1148.
86 Uzark K, Lincoln A, Lamberti JJ, et al. Neurodevelopmental outcomes in children
with Fontan repair of functional single ventricle. Pediatrics. 1998;101:630.
87 Wernovsky G, Stiles KM, Gauvreau K, et al. Cognitive development after the
Fontan operation. Circulation. 2000;102:883.
88 McGrath E, Wypij D, Rappaport LA, et al. Prediction of IQ and achievement at age
8 years from neurodevelopmental status at age 1 year in children with
Dtransposition of the great arteries. Pediatrics. 2004;114:e572.
89 Kirshbom PM, Flynn TB, Clancy RR, et al. Late neurodevelopmental outcome after
repair of total anomalous pulmonary venous connection. J Thorac Cardiovasc Surg.
2005;129:1091.
90 Mahle WT, Clancy RR, Moss EM, et al. Neurodevelopmental outcome and lifestyle
assessment in school-aged and adolescent children with hypoplastic left heart
syndrome. Pediatrics. 2000;105:1082.
91 Wernovsky G, Wypij D, Jonas RA, et al. Postoperative course and hemodynamic
profile after the arterial switch operation in neonates and infants: a comparison
of low-flow cardiopulmonary bypass and circulatory arrest. Circulation.
1995;92:2226.
92 Wypij D, Newburger JW, Rappaport LA, et al. The effect of duration of deep
hypothermic circulatory arrest in infant heart surgery on late neurodevelopment:
the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg. 2003;126:1397.
93 Sorensen H, Husum B, Waaben J, et al. Brain microvascular function during
cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1987;94:727.
94 Lundar T, Lindegaard K, Froysaker T, et al. Dissociation between cerebralautoregulation and carbon dioxide reactivity during nonpulsatile
cardiopulmonary bypass. Ann Thorac Surg. 1985;40:582.
95 Bellinger DC, Wypij D, du Plessis AJ, et al. Developmental and neurologic effects of
alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass
in infants. J Thorac Cardiovasc Surg. 2001;121:374.
96 du Plessis A, Newburger J, Jonas R, et al. Cerebral oxygen supply and utilization
during infant cardiac surgery. Ann Neurol. 1995;37:488.
97 Ruvolo G, Greco E, Speziale G, et al. Nitric oxide formation during
cardiopulmonary bypass. Ann Thorac Surg. 1994;57:1055.
98 Dugan LL, Sensi SL, Canzoniero LM, et al. Mitochondrial production of reactive
oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J
Neurosci. 1995;15:6377.
99 Nathan HJ, Polls T. The management of temperature during hypothermic
cardiopulmonary bypass: 2. Effect of prolonged hypothermia. Can J Anaesth.
1995;42:672.
100 Ginsberg M, Sternau L, Globus M-T, et al. Therapeutic modulation of brain
temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev.
1992;4:189.
101 Astudillo R, van der Linden J, Ekroth R, et al. Absent diastolic cerebral blood flow
velocity after circulatory arrest but not after low flow in infants. Ann Thorac Surg.
1993;56:515.
102 Jonassen A, Quaegebeur J, Young W. Cerebral blood flow velocity in pediatric
patients is reduced after cardiopulmonary bypass with profound hypothermia. J
Thorac Cardiovasc Surg. 1995;110:934.
103 Menache CC, du Plessis AJ, Wessel DL, et al. Current incidence of acute neurologic
complications after open-heart operations in children. Ann Thorac Surg.
2002;73:1752.
104 Plum F, Posner J. Multifocal, diffuse, and metabolic brain diseases causing stupor
or coma. In The diagnosis of stupor and coma, 3rd Ed., Philadelphia: FA Davis;
1985:177.
105 Waitling S, Dasta J. Prolonged paralysis in intensive care unit patients after use
of neuromuscular blocking agents: a review of the literature. Crit Care Med.
1994;22:884.
106 Clancy RR, McGaurn SA, Wernovsky G, et al. Risk of seizures in survivors of
newborn heart surgery using deep hypothermic circulatory arrest. Pediatrics.
2003;111:592.
107 Clancy RR, Sharif U, Ichord R, et al. Electrographic neonatal seizures after infant
heart surgery. Epilepsia. 2005;46:84.
108 Gaynor JW, Jarvik GP, Bernbaum J, et al. The relationship of postoperativeelectrographic seizures to neurodevelopmental outcome at 1 year of age after
neonatal and infant cardiac surgery. J Thorac Cardiovasc Surg. 2006;131:181.
109 Mizrahi EM, Clancy RR. Neonatal seizures: early-onset seizure syndromes and
their consequences for development. Ment Retard Dev Disabil Res Rev. 2000;6:229.
110 Dietrich W, Busto R, Alonso O, et al. Intraischemic but not postischemic brain
hypothermia protects chronically following global forebrain ischemia in rats. J
Cereb Blood Flow Metab. 1993;13:541.
111 Lynch B, Rust R. Natural history and outcome of neonatal hypocalcemic and
hypomagnesemic seizures. Pediatr Neurol. 1994;11:23.
112 Satur C, Jennings A, Walker D. Hypomagnesemia and fits complicating pediatric
cardiac surgery. Ann Clin Biochem. 1993;30:315.
113 Rappaport LA, Wypij D, Bellinger DC, et al. Relation of seizures after cardiac
surgery in early infancy to neurodevelopmental outcome. Boston Circulatory
Arrest Study Group. Circulation. 1998;97:773.
114 du Plessis A, Kramer U, Jonas R, et al. West syndrome following deep
hypothermic cardiac surgery. Pediatr Neurol. 1994;11:246.
115 Yang J, Park Y, Hartlage P. Seizures associated with stroke in childhood. Pediatr
Neurol. 1995;12:136.
116 Gaynor JW. Periventricular leukomalacia following neonatal and infant cardiac
surgery. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2004;7:133.
117 Galli KK, Zimmerman RA, Jarvik GP, et al. Periventricular leukomalacia is
common after neonatal cardiac surgery. J Thorac Cardiovasc Surg. 2004;127:692.
118 Ashwal S, Holshouser B, Schell R, et al. Proton magnetic resonance spectroscopy
in the evaluation of children with congenital heart disease and acute central
nervous system injury. J Thorac Cardiovasc Surg. 1996;112:403.
119 Ashwal S, Holshouser BA, del Rio MJ, et al. Serial proton magnetic resonance
spectroscopy of the brain in children undergoing cardiac surgery. Pediatr Neurol.
2003;29:99.
120 deVeber G. Arterial ischemic strokes in infants and children: an overview of
current approaches. Semin Thromb Hemost. 2003;29:567.
121 Hutchison JS, Ichord R, Guerguerian AM, et al. Cerebrovascular disorders. Semin
Pediatr Neurol. 2004;11:139.
122 Barker PC, Nowak C, King K, et al. Risk factors for cerebrovascular events
following Fontan palliation in patients with a functional single ventricle. Am J
Cardiol. 2005;96:587.
123 Nussmeier N, McDermott J. Macroembolization: prevention and outcome
modification. In: Hilberman M, editor. Brain Injury and Protection During Cardiac
Surgery. Boston: Martinus Nijhoff; 1988:85.
124 Cromme-Dijkhuis A, Henkens C, Bijleveld C, et al. Coagulation factorabnormalities as possible thrombotic risk factors after Fontan operations. Lancet.
1990;336:1087.
125 du Plessis A, Chang A, Wessel D, et al. Cerebrovascular accidents following the
Fontan procedure. Pediatr Neurol. 1995;12:230.
126 Dobell A, Trusler G, Smallhorn J, et al. Atrial thrombi after the Fontan operation.
Ann Thorac Surg. 1986;42:664.
127 Hess J, Kruizinga A, Bijleveld C, et al. Protein-losing enteropathy after Fontan
operation. J Thorac Cardiovasc Surg. 1984;88:606.
128 Rosenthal DN, Friedman AH, Kleinman CS, et al. Thromboembolic complications
after Fontan operations. Circulation. 1995;92(suppl II):287.
129 Levy SR, Abroms IF, Marshall PC, et al. Seizures and cerebral infarction in the
fullterm newborn. Ann Neurol. 1985;17:366.
130 Ginsberg MD. Emerging strategies for the treatment of ischemic brain injury. In:
Waxman SG, editor. Molecular and Cellular Approaches to the Treatment of
Neurological Disease. New York: Raven Press; 1993:207.
131 Anderson D. Cardioembolic stroke: primary and secondary prevention. Postgrad
Med. 1991;90:67.
132 Cerebral Embolism Study Group. Cardioembolic stroke, immediate
anticoagulation, and brain hemorrhage. Arch Intern Med. 1987;147:636.
133 Hart R, Easton J. Hemorrhagic infarcts. Stroke. 1986;17:586.
134 Yatsu F, Hart R, Mohr J, et al. Anticoagulation of embolic strokes of cardiac
origin: an update. Neurology. 1988;38:314.
135 Saiman L, Prince A, Gersony W. Pediatric infective endocarditis in the modern
era. J Pediatr. 1993;122:847.
136 Bjork V, Hultquist G. Contraindications to profound hypothermia in open-heart
surgery. J Thorac Cardiovasc Surg. 1962;44:1.
137 Wong PC, Barlow CF, Hickey PR, et al. Factors associated with choreoathetosis
after cardiopulmonary bypass in children with congenital heart disease.
Circulation. 1992;86:118.
138 Curless RG, Katz DA, Perryman RA, et al. Choreoathetosis after surgery for
congenital heart disease. J Pediatr. 1994;124:737.
139 du Plessis AJ, Bellinger DC, Gauvreau K, et al. Neurologic outcome of
choreoathetoid encephalopathy after cardiac surgery. Pediatr Neurol. 2002;27:9.
140 Kupsky WJ, Drozd MA, Barlow CF. Selective injury of the globus pallidus in
children with post-cardiac surgery choreic syndrome. Dev Med Child Neurol.
1995;37:135.
141 Deleon GA, Radkowski MA, Crawford SE, et al. Persistent respiratory failure due
to low cervical cord infarction in newborn babies. J Child Neurol. 1995;10:200.
142 Levin DA, Seay AR, Fullerton DA, et al. Profound hypothermia with alpha-stat pHmanagement during open-heart surgery is associated with choreoathetosis. Pediatr
Cardiol. 2005;26:34.
143 Hamrick SE, Gremmels DB, Keet CA, et al. Neurodevelopmental outcome of
infants supported with extracorporeal membrane oxygenation after cardiac
surgery. Pediatrics. 2003;111:e671.
144 Bergman I, Steeves M, Burckart G, et al. Reversible neurologic abnormalities
associated with prolonged intravenous midazolam and fentanyl administration. J
Pediatr. 1991;119:644.
145 Petzinger G, Mayer SA, Przedborski S. Fentanyl-induced dyskinesias. Mov Disord.
1995;10:679.
146 Puntis J, Green S. Ischemic spinal cord injury after cardiac surgery. Arch Dis Child.
1985;60:517.
147 Christenson JT, Sierra J, Didier D, et al. Repair of aortic coarctation using
temporary ascending to descending aortic bypass in children with poor collateral
circulation. Cardiol Young. 2004;14:39.
148 Souza Neto EP, Durand PG, Sassolas F, et al. Brachial plexus injury during cardiac
catheterisation in children. Report of two cases. Acta Anaesthesiol Scand.
1998;42:876.
149 Liu XY, Wong V, Leung M. Neurologic complications due to catheterization.
Pediatr Neurol. 2001;24:270.
150 Mok Q, Ross-Russell R, Mulvey D, et al. Phrenic nerve injury in infants and
children undergoing cardiac surgery. Br Heart J. 1991;65:287.
151 Hwang MS, Chu JJ, Su WJ. Diaphragmatic paralysis caused by malposition of
chest tube placement after pediatric cardiac surgery. Int J Cardiol. 2005;99:129.
152 Joho-Arreola AL, Bauersfeld U, Stauffer UG, et al. Incidence and treatment of
diaphragmatic paralysis after cardiac surgery in children. Eur J Cardiothorac Surg.
2005;27:53.
153 Bolton C. Clinical neurophysiology of the respiratory system. Muscle Nerve.
1993;16:809.
154 Weese-Mayer DE, Hunt CE, Brouillette RT, et al. Diaphragm pacing in infants and
children. J Pediatr. 1992;120:1.
155 Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill
patients after long-term administration of vecuronium. N Engl J Med.
1992;327:524.
156 Danon M, Carpenter S. Myopathy with thick filament (myosin) loss following
prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve.
1991;14:1131.
157 Benzing G, Iannacone S, Bove K, et al. Prolonged myasthenic syndrome after one
week of muscle relaxants. Pediatr Neurol. 1990;6:190.158 Johnston JK, Chinnock RE, Zuppan CW, et al. Limitations to survival for infants
with hypoplastic left heart syndrome before and after transplant: the Loma Linda
experience. J Transpl Coord. 1997;7:180.
159 Bauer J, Thul J, Kramer U, et al. Heart transplantation in children and infants:
short-term outcome and long-term follow-up. Pediatr Transplant. 2001;5:457.
160 McClure CD, Johnston JK, Fitts JA, et al. Post-mortem intracranial
neuropathology in children following cardiac transplantation. Pediatr Neurol.
2006;35:107.
161 Raja R, Johnston JK, Fitts JA, et al. Post-transplant seizures in infants with
hypoplastic left heart syndrome. Pediatr Neurol. 2003;28:370.
162 Hotson J, Enzmann D. Neurologic complications of cardiac transplantation. Neurol
Clin. 1988;6:349.Chapter 5
Neurological Manifestations of Acquired Cardiac
Disease, Arrhythmias, and Interventional
Cardiology
Colin D. Lambert, David J. Gladstone
CARDIOGENIC EMBOLISM
Clinical Features
Investigations
Causes
Atrial Fibrillation and Flutter
Cardioversion in Atrial Fibrillation or Flutter
Chronic Sinoatrial Disorder
Cardiomyopathies
Myocardial Infarction and Left Ventricular Dysfunction
Rheumatic Heart Disease
Atrial Myxoma
Marantic (Nonbacterial Thrombotic) Endocarditis
Other Echocardiographic Abnormalities Linked to Stroke
Acute Medical Treatment of Cardiogenic Embolism
SYNCOPE
INTERVENTIONAL PROCEDURES
Coronary Catheterization
Percutaneous Transluminal Coronary Angioplasty and Stenting
Thrombolytic Therapy for Acute Myocardial Infarction
The neurological manifestations of acquired cardiac disease fall into several
categories:
1. The sudden onset of a focal neurological deficit due to occlusion of a cerebral or
retinal artery by an embolus that has developed within the heart (cardiogenic
embolism)
2. Transient, self-limited episodes of generalized cerebral ischemia that occur as aconsequence of brief failures of cardiac output, due to either rhythm disturbances
or outflow obstruction, resulting in presyncope or syncope
3. The complications of invasive techniques for the investigation or management
of cardiac disease
The major exceptions to these generalizations occur with atrial 7brillation (AF),
which is associated with embolus formation rather than syncope, and with chronic
sinoatrial disorder, which predisposes to both syncopal and embolic disturbances.
Topics that are the focus of other chapters are not considered here. In this
chapter, the term stroke is used to mean the sudden onset of a focal neurological
de7cit of ischemic origin. Cerebral embolus is used where the de7cit is thought to
be of embolic origin. The term cardiogenic embolism is reserved for events in which
the embolic occlusion is considered to be the result of a cardiac source of emboli.
This chapter addresses three major situations: (1) cardiogenic embolism, (2)
arrhythmias and their manifestations (syncope), and (3) interventional procedures.
CARDIOGENIC EMBOLISM
Clinical Features
Ischemic stroke or transient ischemic attack (TIA) may be classi7ed into six major
1etiological categories, which have implications for treatment and prognosis. This
is the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classi7cation, the
standard now for clinical studies. These categories are cardioembolism, large-artery
atherosclerosis, small-artery (lacunar) occlusion, stroke of other determined
etiology, stroke of undetermined etiology, and events of multiple possible etiologies.
The 7rst four categories are also subdivided into probable or possible. Strokes in
the undetermined group are classed as either completely or incompletely evaluated.
The last category accommodates those in whom more than one established cause is
present.
Cardiogenic brain embolism accounts for about 20 percent of acute ischemic
strokes overall. Coexistent pathology (i.e., arterial and heart disease in the same
patient) may be present in up to one third of patients with a potential cardiac
2source of embolism. The most common cardiac cause of ischemic stroke is AF,
3which accounts for about one sixth of all strokes. Other cardiac causes of stroke
are listed in Table 5-1.
TABLE 5-1 Established and Putative Cardiac Causes of Stroke
ArrhythmiasAtrial fibrillation
Atrial flutter
Sick-sinus syndrome
Valvular heart disease
Prosthetic
Rheumatic
Mitral valve prolapse
Calcific aortic stenosis
Aortic sclerosis
Mitral annular calcification
Myocardial infarction (acute and chronic)
Left ventricular dysfunction
Cardiomyopathy
Congestive heart failure
Other echocardiographic abnormalities
Patient foramen ovale ± atrial septal aneurysm
Left atrial thrombus
Spontaneous left atrial echo contrast
Cardiac tumors
Endocarditis
Infective
Marantic nonbacterial thrombotic
Iatrogenic causes
Cardiac surgery
Cardiac catheterization
Percutaneous coronary interventions
Thrombolytic therapy for acute myocardial infarction
Cardioversion for atrial fibrillation/flutter
In the young stroke population (generally regarded as patients who have their 7rst
stroke around the age of 15 to 45 years), 60 or so causes had to be considered in
4one study. In that study of 329 patients, cardioembolism was thought to be
responsible in 64 (just under 20 percent). There were 13 diagnoses in these 64
patients, with the top three being paradoxical embolism and prosthetic orrheumatic valve disease. No patients had AF, a feature also noted in a Swedish
5study. Strokes attributable to a cardiac source show striking diAerences in various
studies. In a Persian study of 124 patients, 54 percent were thought to be of cardiac
6origin. Rheumatic heart disease was the major culprit. In contrast, a French study
7of 296 patients attributed less than 9 percent to a cardiac cause. In Italy, the
87gure was 34 percent. This was a hospital-based study of 394 consecutive young
adults with ischemic stroke submitted to a comprehensive diagnostic protocol. Of
the 133 considered to be of cardiac origin, these were subdivided into two groups
according to TOAST criteria. The smaller group (23) had a probable cause
including recent myocardial infarction, AF, valvulopathy, patent foramen ovale
(PFO) with deep vein thrombosis (DVT) and atrial myxoma. The much larger
group (110 patients) had various possible causes: PFO with right to left shunt (60),
atrial septal aneurysm (ASA) (22), and PFO plus ASA (16). Looked at another way,
23 of 394 patients (6%) had an established cardiac cause. Attribution was less
certain in 28 percent. In Korea and Taiwan, around 18 percent of cases were
9,10attributed to a cardiac cause. Comparison of etiological factors in the
occurrence of TIAs in younger, as opposed to older, patients disclosed that only two
cardiac sources were encountered more frequently in the younger age group:
11valvular heart disease and mitral valve prolapse.
Features suggesting cardioembolism are usually derived from analysis of the
clinical presentation and neuroimaging features of acute ischemic strokes that
occur in patients with cardiac abnormalities thought to predispose to thrombus
12-19formation (Table 5-2). Emboli may lodge in either the anterior (carotid) or
the posterior (vertebrobasilar) circulation. The anterior circulation is aAected four
times more commonly than the posterior. Least likely to be aAected are the entire
internal carotid artery, deep branches of the middle cerebral artery, and
20brainstem. Although the posterior circulation is less commonly aAected, studies
of the mechanism of infarction in speci7c territories (e.g., those of the posterior
inferior cerebellar artery and superior cerebellar artery) implicate cardiogenic
21embolism in 50 percent of cases. A cardioembolic mechanism occurred in 67
percent of cases with isolated cerebellar infarcts (i.e., without concomitant
22brainstem or occipital infarcts). Embolism is also a common mechanism of
23infarction within the territory of the posterior cerebral artery.
TABLE 5-2 Clinical Features Suggesting Cardioembolic Rather Than
Noncardioembolic Stroke
Cortical signs (e.g., aphasia, neglect, visual field defect)Isolated global aphasia or Wernicke’s aphasia (without hemiparesis)
Impaired consciousness at stroke onset
Sudden onset, reaching maximal deficit within 5 minutes of onset
Rapid dramatic neurological recovery (“spectacular shrinking deficit”)
Simultaneous or sequential strokes in different vascular territories
Evidence of systemic embolism
Atrial fibrillation, valvular heart disease
Stroke recurrence rate and prognosis have been estimated in several studies. A
meta-analysis showed that the 3-month risk of recurrent stroke was 12 percent if
the etiology was cardioembolism, compared to 19 percent for large-vessel
atherosclerosis, 3 percent for small-vessel disease, and 9 percent for unknown
24cause. In a population-based study of 7rst stroke in Bavaria, patients with
cardioembolic stroke had the lowest 2-year survival rate (55%) and were three
times more likely to be dead at 2 years compared to those with small-artery
25occlusion.
Investigations
The 7rst neurological investigation for suspected stroke is usually a computed
tomography (CT) scan of the head to exclude intracranial hemorrhage or other
nonischemic pathological processes and to identify signs of acute infarction or
vessel occlusion. In patients at high-risk of cardioembolism, cranial CT disclosed
infarcts that were more likely to involve one half of a lobe or more, or the infarcts
12involved both super7cial and deep structures. Deep small infarcts were
underrepresented and were considered to have a predictive value of 90 percent for
12the absence of a major cardiac source. Similar conclusions were drawn in an
earlier study, namely, that the mechanism underlying lacunes is infrequently
embolic and that infarctions in the pial (super7cial) artery territory are usually
26indicative of an embolic mechanism.
The potential for embolic infarcts to develop hemorrhagic transformation
remains a concern, especially when anticoagulant therapy has to be considered. A
hemorrhagic infarct was seen on the initial CT scan of 6 percent of patients in a
12series of 244 cases, none of whom were receiving anticoagulants. In a series of
27scans performed within 48 hours of onset, the 7gure rose to 24 percent ; on
28prospective follow-up scanning, a total of 40 percent was found at 1 month.
With the more sophisticated technology of magnetic resonance imaging (MRI), the7gure rose to nearly 70 percent at 3 weeks. Both of the latter studies showed that
larger infarcts were more liable to demonstrate hemorrhagic transformation, with a
3 297gure of 90 percent for infarcts with a volume greater than 10 cm . Thus, the
key factors that determine whether hemorrhagic transformation occurs appear to
be the time of the study, size of the infarct, and technology applied. The age of the
patient may also be a factor in that patients older than 70 years may be more liable
28to hemorrhagic transformation.
Because of concerns for the complications of acute stroke treatment by
thrombolysis or anticoagulation, early pointers to hemorrhagic transformation have
been sought. The only independent predictor identi7ed in a study of 150
consecutive patients was focal hypodensity found by CT scanning within the 7rst 5
hours after stroke onset. Mortality was twice as high in the
hemorrhagictransformation group owing to the larger size of infarcts in that group. Evolution of
the transformation process was similar in anticoagulated and nonanticoagulated
29patients.
MRI is the most sensitive test for detecting early infarction. DiAusion-weighted
30images are superior to T2-weighted images and to CT. The pattern of
diAusionweighted imaging abnormalities can help to determine the most likely etiological
diagnosis. For example, a pattern of multiple acute lesions in more than one
vascular territory (bilateral lesions or lesions in the anterior and posterior
circulations) suggests a shower of cardiogenic emboli. Single cortical-subcortical
lesions are also associated with a cardiac source of emboli.
Conventional catheter angiography remains the de7nitive method for assessing
structural abnormalities of the extra- and intracranial circulation. Use of this
invasive procedure requires recognition of the associated risks. A review of 15
studies (8 prospective) concluded that the mortality rate was very low (less than
0.1%) but that the risk of a neurological complication (TIA or stroke) was
approximately 4 percent and that of a permanent neurological de7cit was 1
31percent. The characteristic angiographic appearance of an embolic occlusion is
of a proximal, meniscus-like 7lling defect in an artery that is otherwise normal and
lacks evidence of atherosclerotic change. Emboli tend to fragment. In a study of
142 patients who underwent angiography, the initial procedure, performed at a
median of 1.5 days after the precipitating event, revealed an occlusion in 82
percent. Follow-up angiography, at a median of 20 days, showed reopening of the
28vessels in 95 percent. Distal branch occlusions are often also considered to be
embolic manifestations. Conventional catheter angiography has now been largely
replaced by noninvasive contrast-enhanced CT angiography or magnetic resonance
angiography in many countries because of increased availability and lower
complication rates.Echocardiography has come to occupy a preeminent place in the structural
evaluation of the heart. Transthoracic echocardiography (TTE) is noninvasive but
has limitations that can be overcome by using the transesophageal
(transesophageal echocardiography [TEE]) route. For the latter procedure, the
patient is usually mildly sedated and topical anesthetic is applied to the posterior
pharynx. In experienced hands, the procedure was successfully accomplished in 98
32percent of instances. The complication rate was less than 1 percent. The
technique employed (TEE or TTE) depends on the area to be visualized. The two
procedures can be considered complementary; TTE images the left ventricle well,
but TEE is required for adequate assessment of the left atrium and its appendage.
TEE is also better for visualizing a PFO. TEE is the most sensitive and speci7c test
for detecting a cardiac source of embolism. For patients with AF, TEE may assist in
3risk stratification and guide cardioversion.
A review of papers published between 1966 and 1998 evaluated the yield of TTE
or TEE, or both, in various subgroups of patients with stroke. The 7gures reached
were, for TTE, an overall yield of less than 1 percent in patients without clinical
evidence of cardiac disease, rising to 13 percent in those with cardiac disease. The
33corresponding 7gures for TEE were less than 2 percent and 19 percent. The
recommendations reached highlight some uncertainties. It was concluded that
there was fair evidence to recommend echocardiography in patients with stroke
and clinical evidence of heart disease (grade B recommendation). Because the yield
from TEE is higher than that for TTE, controversy arises as to whether this should
be the 7rst intervention. Some have preferred a sequential approach with TTE
34followed by TEE, if indicated, but others have suggested that it is more
cost35eAective to proceed directly to TEE. Clearly, the area to be visualized is a major
consideration.
Cardiac MRI is emerging as a new technology for noninvasive structural imaging
of the heart. MRI is more sensitive than TTE and comparable to TEE for the
detection of cardiac thrombi.
Transcranial Doppler ultrasonography is a noninvasive tool that can be of value
in the acute stroke setting for detecting acute intracranial vascular obstruction
(e.g., due to an occlusive embolus in the middle cerebral artery) and can monitor
recanalization following treatment with thrombolysis. It can also be used to detect
right-to-left cardiac shunts due to PFO. By identifying microbubbles reaching the
middle cerebral arteries, especially following the Valsalva maneuver,
contrastenhanced transcranial Doppler ultrasonography has shown near-perfect correlation
with contrast-enhanced TEE for the detection and quanti7cation of such
36,37shunts.
It remains necessary for the clinician to balance extensive investigation againstits impact on patient management, usually the justi7cation for lifelong
anticoagulant therapy and its consequent risks. In several situations, there are no
established guidelines for management. The onus remains on the clinician to
determine the signi7cance of potential sources of emboli and their implications for
management.
Causes
Atrial Fibrillation and Flutter
Atrial 7brillation, the most common arrhythmia in medical practice, is a major risk
factor for stroke and death. This arrhythmia accounts for nearly half of all cardiac
3causes of stroke and about one quarter of strokes in the elderly. Strokes associated
38with AF are generally severe, and 1-year mortality is 50 percent. AF is also a risk
39,40factor for silent strokes and vascular dementia.
The prevalence of AF is strongly age dependent, ranging from 0.1 percent among
38adults older than 55 years to 9 percent in those 80 years or older. Over 2 million
38individuals have AF in the United States, and prevalence is rising. AF typically
occurs in patients with underlying cardiac disease (i.e., valvular heart disease,
heart failure, coronary disease, hypertension, cardiomyopathy, mitral valve
prolapse, mitral annular calci7cation, and cardiac tumors), but may also occur as
“lone AF” in young patients who have no cardiac disease. It may be paroxysmal
(self-terminating episode, lasting less than 7 days), recurrent (2 or more episodes),
persistent (more than 7 days), or permanent (cardioversion failed or not
attempted). Reversible or temporary causes include alcohol, surgery,
hyperthyroidism, acute myocardial infarction, pulmonary embolism, and
3pericarditis, among others.
The average annual risk of stroke in individuals with AF is 5 percent and is
heavily dependent on age and the presence of additional risk factors (Table 5-3). In
the Framingham Study, stroke risk was 1.5 percent in the age group 50 to 59 years
41and 23.5 percent in those 80 to 89 years.
TABLE 5-3 Two-Year Stroke Risk for Patients With Atrial Fibrillation Strati7ed by
Additional Risk Factors
It is well established that the risk of stroke in AF is related to the presence or
absence of associated structural cardiac disease and other risk factors. For example,
in the absence of rheumatic heart disease, there is a 7vefold increase in stroke
incidence, but this increases to 17-fold when associated with rheumatic mitral
42valve disease. Only in lone AF (i.e., 7brillation in the absence of overt
cardiovascular disease or precipitating illness) developing in middle age is theprognosis relatively benign. Follow-up at 15 years disclosed a rate of
43thromboembolic events of 0.55 per 100 person-years. This was equivalent to 1.3
percent of the patients experiencing a stroke on a cumulative actuarial basis.
The most important predictor of stroke risk in patients with AF is a history of
thromboembolism (i.e., previous TIA, stroke, or systemic arterial embolism). Other
independent risk factors for stroke in AF are hypertension, heart failure, increasing
age, and diabetes mellitus. Other factors that have been associated with increased
stroke risk in some studies include female sex, systolic hypertension, and left
3ventricular dysfunction.
Echocardiographic features that have been used for risk strati7cation in patients
with AF include left ventricular systolic dysfunction, atrial thrombus, dense
spontaneous echo contrast or reduced blood Low velocity within the left atrium or
left atrial appendage on TEE, and aortic atheroma. Left atrial size does not appear
44to predict risk of thromboembolism. TEE is the method of choice for evaluating
the left atrial appendage, the site at which most thrombi form, and the left atrium.
In a prospective study of patients with AF considered on clinical grounds to be at
high risk of stroke, risk was 18 percent per year in those with dense spontaneous
echo contrast who were treated with low-dose warfarin (international normalized
ratio [INR] 1.2 to 1.5) plus aspirin compared to 4.5 percent for those on
doseadjusted warfarin. Prevalence of thrombus in the left atrial appendage was similar
initially in the two treatment groups (10% to 12%) when TEE was performed more
than 2 weeks after study entry, but atrial thrombus was present in 6 percent of
those on warfarin compared to 18 percent of those on combination therapy, and
stroke rate was 13 percent per year in the latter group. Absence of thrombus
predicted a low rate of ischemic events (2.3% per year); the presence of thrombus
45predicted a high rate (18% per year).
That the risk of stroke in AF can be signi7cantly reduced by anticoagulation was
46-49clearly established by four independent studies. A 7fth, Canadian, study was
terminated prior to completion because the other studies had shown clear evidence
50 51of bene7t. A meta-analysis published in 1999 evaluated 16 trials. Six were of
dose-adjusted warfarin versus placebo. The conclusions drawn from the original
four studies were upheld. Warfarin reduced stroke risk by 62 percent overall.
Absolute risk reductions were higher for secondary prevention (8.4% per year) than
primary prevention (2.7%). These percentages translate into the numbers needed
to treat (NNT) of 12 and 37, respectively. Although more intracranial hemorrhages
(ICHs) occurred in the warfarin group (0.3% per year) compared to those on
placebo (0.1%), this was not statistically signi7cant. Major extracranial
hemorrhage occurred in 0.6 percent per year of patients on placebo, with a relative
risk of those on warfarin of 2.4 (absolute risk increase, 0.3% per year). The total
number of patients in the six trials was 2,900, with an average follow-up of 1.7years. The aforementioned risk reduction with warfarin was based on
intention-totreat analysis; the on-treatment analysis reveals more than 80 percent relative risk
reduction in stroke.
This meta-analysis also evaluated adjusted-dose warfarin compared to aspirin.
There were 7ve trials, all unblinded, totaling 2,837 individuals. Excluding one
study because the range of the INR was wide (2.0 to 4.5), the relative risk
reduction for warfarin compared to aspirin was 46 percent.
The issue of aspirin as an alternative to warfarin has also been addressed in
51several trials. Aspirin dose ranged from 25 to 1,200 mg daily. More than 3,000
patients were studied, with an average follow-up of 1.5 years. In patients receiving
placebo, the stroke rate was 5.2 percent per year for primary prevention and 12.9
percent for secondary prevention. Aspirin reduced stroke risk by 22 percent,
resulting in numbers needed to treat of 67 and 40, respectively. The trials showed
only a trend toward reduced stroke in aspirin-treated patients. All-cause mortality
was not reduced. The authors suggested that the bene7t of aspirin is to prevent
nondisabling stroke that is not of cardioembolic origin. Therefore, published
guidelines strongly recommend warfarin rather than aspirin for stroke prevention
52in individuals with AF who are at high risk.
In practice, despite the clear bene7t of warfarin in stroke prevention in patients
with AF, this therapeutic intervention is frequently underused. Many studies from
diAerent countries have demonstrated suboptimal rates of appropriate
53-55antithrombotic therapy for patients with AF. Several potential reasons
account for underuse of warfarin, including physician factors, patient factors, and
geographic practice variations. Warfarin is a diN cult medication for patients
because of the inconvenience of INR monitoring, drug and food interactions, and
bleeding risks. However, physicians frequently overestimate the bleeding risks but
56underestimate the bene7ts of warfarin and overestimate the bene7ts of aspirin.
Although major adverse bleeding events associated with warfarin occur with a
57relatively low incidence, they may profoundly bias physician prescribing
58behavior. There is often a bias against prescribing warfarin to patients of
advanced age, especially elderly women, despite the fact that safety in patients 80
59years and older has been established.
Individual patient preferences, knowledge, and attitudes aAect compliance with
long-term anticoagulation therapy. Among AF patients taking warfarin in one
study, about one half did not know that AF was a risk factor for stroke and could
not state why they were taking warfarin; ethnic diAerences in knowledge about
60their diagnosis and treatment were also identi7ed. Methods to encourage
compliance with appropriate antithrombotic prophylaxis include use of a patient
decision aid. One such tool is available for download atwww.canadianstrokenetwork.ca/research.clinicians.php and is highly
recommended for use by primary care physicians and specialists who are
counseling AF patients about the bene7ts and risks of warfarin compared to those
of aspirin for stroke prevention. A home INR 7nger-stick device for self-monitoring
61may increase the duration patients spend in the therapeutic INR range.
Bleeding is the major concern with anticoagulant therapy. The average risk of
major bleeding in the clinical trials was 1.3 percent per year with warfarin
62compared to 1 percent with aspirin or placebo. The Stroke Prevention in Atrial
Fibrillation study had a higher rate of major bleeding at 2.3 percent on warfarin
62and 1.1 percent per year on aspirin. Rates of ICH were 0.9 percent per year and
0.3 percent per year, respectively. Age older than 75 years increased the risk of
major hemorrhage to 4.2 percent per year (relative risk = 2.6) compared to 1.7
percent per year in the younger population. Of patients on warfarin, 16 were in the
therapeutic range, 4 were below, and 13 were above at the time of their bleed. All
had had therapeutic levels on their last routine prothrombin time ratios. Intensity
of anticoagulation was a risk factor for bleeding only in those older than 75 years.
62The other identified risk factor was the use of more than three prescription drugs.
Interestingly, in another study, patients with cerebral ischemia of presumed arterial
origin had a substantially higher risk of ICH than those anticoagulated for AF.
63Leukoariosis is a newly identified risk factor.
Analysis of a cohort of patients attending 7ve anticoagulation clinics
documented the cumulative risk of bleeding over an 8-year period. Serious bleeds
occurred at a rate of 7.5 events per 100 patient-years. Points that emerged were
that the incidence of bleeding and thromboembolic complications remained
approximately constant, with a prothrombin time ratio of 1.3 to 2.0, but it
increased sharply above or below those limits (i.e., thromboembolism was much
more likely with a prothrombin time ratio of less than 1.3). No increase in bleeding
complication was found related to any speci7c indication for therapy, including
cerebrovascular disease. Older patients did not have a greater risk of bleeding. The
highest risk of bleeding was seen during the 7rst 3 months of therapy, and then it
tended to plateau somewhat. Of particular note was the high risk of recurrence
(32%) in patients who experienced one serious bleed. It was also noted that
patients who had more than four dose adjustments per year bled 25 percent more
64often than those who had fewer adjustments.
With the exception of some patients with lone AF, all patients with AF (regardless
of whether this is paroxysmal, persistent, or permanent) require some form of
antithrombotic therapy unless contraindicated. It remains necessary to
individualize management strategies for speci7c patients, taking into account
compliance, risk of bleeding complications, and other medical conditions. Risk
strati7cation is essential to determine the optimal treatment, i.e., warfarin oraspirin. Many diAerent schemes have been devised for identifying patients with AF
unassociated with valvular heart disease that are at high, moderate, or low risk of
stroke. According to the 2006 American Heart Association guidelines, high risk
factors are previous stroke, TIA, or systemic embolism, mitral stenosis, and
3prosthetic heart valves. Moderate risk factors include age 75 years or older;
hypertension; heart failure; left ventricular ejection fraction 35 percent or lower;
and diabetes. Warfarin is recommended for patients with any high risk factor or
more than one moderate risk factor. This means that all patients with a previous
ischemic stroke or TIA are considered at high risk and require warfarin
anticoagulation for secondary stroke prevention, unless contraindicated. Warfarin
or aspirin (81 to 325 mg) is recommended for those with only one moderate risk
factor. Aspirin alone (81 to 325 mg) is considered suN cient for patients without
any of these risk factors.
For patients receiving warfarin, the target INR should be 2.5 (range 2.0 to 3.0).
The INR should be monitored closely: usually weekly initially and then monthly
once stable. A minimum INR of 2.0 is recommended for stroke prevention; stroke
65risk increases exponentially as the intensity of anticoagulation declines.
In addition to protecting against stroke, antithrombotics attenuate stroke
severity: patients taking warfarin at the time of stroke have less-disabling strokes
compared to individuals taking aspirin or no antithrom- botic therapy, and stroke
66,67severity is negatively correlated with INR at stroke onset. Table 5-4 gives a
summary of the indications for warfarin in secondary stroke prevention for patients
with selected cardiac conditions.
TABLE 5-4 Summary of Indications for Warfarin in Secondary Stroke Prevention for
Patients With Selected Cardiac Conditions52
Strong or Moderate Indication for Warfarin
Mechanical heart valve
Atrial fibrillation
Atrial flutter
Cardioversion in atrial fibrillation or flutter
Bioprosthetic heart valve
Rheumatic mitral valve disease
Acute myocardial infarction and left ventricular thrombusPossible/Uncertain Indication for Warfarin
Dilated cardiomyopathy
Left ventricular dysfunction
Patent foramen ovale associated with atrial septal aneurysm
Mitral annular calcification associated with mitral regurgitation
Warfarin Usually Not Indicated
Isolated patent foramen ovale
Isolated mitral valve prolapse
Isolated mitral annular calcification
Isolated aortic valve disease
The only class I evidence in support of warfarin for stroke prevention exists for atrial
7brillation and mechanical heart valves. Treatment recommendations are expected
to change over time as new evidence emerges; the reader is advised to consult
published guidelines for more detailed information.
For patients with a mechanical heart valve, the INR should be maintained above
2.5, and for secondary stroke prevention, the target INR should be 3.0 (range 2.5 to
523.5)
Dual antiplatelet therapy (aspirin plus clopidogrel) was investigated in a
randomized trial and found to be inferior to warfarin for stroke prevention in AF
68and associated with a higher rate of adverse bleeding events than warfarin.
If warfarin therapy needs to be interrupted for surgical procedures, temporary
discontinuation for up to 1 week is usually considered reasonable for patients
without mechanical heart valves. However, this practice can be associated with
increased stroke risk. Heparin may be substituted in high-risk patients.
In addition to medical therapy for stroke prevention in AF, interventional
techniques are being investigated. These include percutaneously implanted left
atrial appendage occlusive devices and surgical resection of the left atrial
69appendage, given that 91 percent of thrombi are localized at that site. Carotid
artery endovascular devices to filter emboli are also under investigation.
Cardioversion of AF to sinus rhythm (either pharmacological or electrical) does
not reduce the risk of stroke and therefore does not obviate the need for continued
70,71anticoagulation therapy for stroke prevention.AF occurring in the postoperative setting following cardiac surgery is fairly
common and usually self-limited. Anticoagulation is reasonable if AF persists for
more than 48 hours, but it may not need to be continued long-term if sinus rhythm
is restored. Similarly, other conditions associated with transient AF (e.g., alcohol,
3thyrotoxicosis) usually do not need long-term antithrombotic prophylaxis.
In patients with atrial Lutter, the risk of thromboembolism is thought to be less
than that for AF but higher than for patients in sinus rhythm. These patients
frequently go on to develop AF. For practical purposes, the antithrombotic
3treatment recommendations are similar to those for AF.
Cardioversion in Atrial Fibrillation or Flutter
Cardioversion (electrical or pharmacological) undertaken to convert AF back to
sinus rhythm is associated with an increased risk of thromboembolism. Review of
22 series published over a 30-year period showed an overall risk of embolism of 1.5
72percent. Figures have changed little in recent years, with an incidence of 1.3
73percent. It appears that up to 3 weeks may be required for atrial mechanical
74activity to recover. It is therefore recommended that warfarin (INR 2.0 to 3.0) be
given for at least 3 weeks before elective cardioversion of patients who have been
in AF for 2 days or more or when the duration of AF is unknown and that it be
3continued until normal sinus rhythm has been maintained for 4 weeks.
For patients requiring immediate cardioversion, intravenous heparin is
3recommended concurrently followed by warfarin for at least 4 weeks.
Alternatively, TEE prior to cardioversion can be performed; if no thrombus is
detected, then cardioversion can occur as soon as the patient is anticoagulated and
continue for at least 4 weeks. If a thrombus is detected on TEE, warfarin is
recommended for at least 3 weeks before and may need to be continued for a
longer duration afterward.
3The recommendations for cardioversion in atrial Lutter are the same as for AF.
Atrial Lutter has been studied less extensively than AF, but embolism can occur in
relation to cardioversion or during subsequent months. The total incidence of acute
and chronic events was found to be 7 percent over a period of 26 ± 18 months in a
75consecutive series of 191 unselected patients undergoing cardioversion. The
same percentage was found in a smaller study of 86 patients who were followed for
a longer period (mean, 4.5 years). Annual risk was estimated at 1.6 percent, one
76third of the rate for those with AF. Prior transesophageal echocardiography is not
an adequate predictor of those at risk. A total of 3 of 41 patients who had no left
atrial clot developed ischemic neurological syndromes within 48 hours of elective
77cardioversion. In another study, spontaneous echo contrast was a more common
78finding than atrial thrombosis (34% versus 11%).Chronic Sinoatrial Disorder
As with atrioventricular block, chronic sinoatrial disease (sick sinus syndrome)
presents usually with syncope and dizziness but diAers in predisposing to systemic
embolism. In a study comparing age- and sex-matched control subjects with
atrioventricular heart block to those having chronic sinoatrial disorder, prevalence
of systemic embolism was found in 16 percent of those with sick-sinus syndrome
79compared to 1.3 percent of those with atrioventricular block. Other studies have
disclosed similar 7gures; patients with the “brady-tachy” form of the disorder
80,81appear to be particularly at risk. Insertion of a pacemaker does not protect
against embolic phenomena. In one series, 6 of 10 strokes developed after
82pacemaker insertion. Only one of these patients was anticoagulated at the time.
Concern was raised that, although ventricular pacing provides symptomatic
relief, this modality may worsen the underlying disease process by increasing the
83rate at which AF, congestive heart failure, and thromboembolism occur. Many
studies relating to various pacemaker types have followed. A Cochrane review
noted poor quality of reporting but concluded that physiological (primarily
dualchamber) pacing had a statistically signi7cant bene7t in preventing the
84development of AF compared to ventricular pacing. A nonsigni7cant preference
for stroke prevention was found. A large subsequent study, also comparing
ventricular with dual-chamber pacing, concluded that clinical features were the
85key predictors of stroke. In the same year, a Danish study showed single-chamber
atrial pacing to be superior to dual-chamber pacing in the prevention of AF and
86thromboembolism. Patients in the brady-tachy group were noted to be more at
risk of developing AF and stroke. It was concluded that warfarin treatment should
be considered for these patients.
Cardiomyopathies
This continues to be a rapidly changing 7eld. A new de7nition and classi7cation
87were proposed in 2006. Cardiomyopathies are de7ned as “a heterogeneous group
of diseases of the myocardium associated with mechanical and/or electrical
dysfunction that usually ‘but not invariably’ exhibit inappropriate ventricular
hypertrophy or dilatation and are due to a variety of causes that frequently are
87genetic.” Speci7cally excluded are those diseases of the myocardium secondary
to congenital or valvular heart disease, systemic hypertension, or atherosclerotic
coronary disease. The cardiomyopathies are then divided into two major groups
based on predominant organ involvement. The primary cardiomyopathies are those
solely or predominantly con7ned to heart muscle. Genetic, mixed, and acquired
forms are recognized. Both hypertrophic and dilated cardiomyopathies are
considered primary diseases. Also now included are the ion channel disorders, inwhich there is a primary electrical disturbance without structural cardiac
pathology. These are further considered in the section devoted to syncope. The list
of secondary cardiomyopathies is extensive.
Neuromuscular or neurological causes listed are Friedreich’s ataxia, Duchenne or
Becker muscular dystrophy, Emery–Dreifuss muscular dystrophy,
neuro7bromatosis, and tuberous sclerosis. Surprisingly, the mitochondrial
cytopathies, quintessentially multisystem disorders, are listed as primary
cardiomyopathies. The secondary cardiomyopathy table classi7cation does not
include infective processes, such as Chagas’ disease or infection with human
immunodeficiency virus, although these are briefly mentioned in the text.
In North America, the most common cardiomyopathy is hypertrophic
cardiomyopathy, which is an autosomal-dominant disease aAecting 1:500 of the
88general population. The disorder is notorious as a major cause of sudden cardiac
89death in athletes but is compatible with survival until old age. Mortality rates
overall have been estimated at 1.0 to 1.5 percent for ages 16 to 65, 3.9 percent
over the next decade, and 4.7 percent for ages older than 75 years. Risk was
90generally similar in Western and Asian populations. Stroke risk in hypertrophic
91cardiomyopathy has been studied in a group of 900 patients. Stroke occurred in
44 patients over a period of 7 ± 7 years. A small number (7) of other vascular
events were noted. Age at 7rst event ranged from 29 to 86 years, with a mean of 61
± 14 years. Stroke was particularly associated with advanced age, congestive
symptoms, and AF. The cumulative incidence of events was signi7cantly higher in
nonanticoagulated patients with AF compared to those receiving warfarin. Other
studies con7rm increased risk of stroke when AF develops in hypertrophic
cardiomyopathy, but surprisingly also identi7ed a subgroup in which the course
92was largely benign. OutLow tract obstruction also increased the risk of
92,93 92stroke. The odds ratio for stroke in patients with AF was 17.7.
There are considerable geographic variations in the causes of cardiomyopathy. In
Latin America, American trypanosomiasis (Chagas’ disease) is a major cause. Stroke
has been increasingly well documented as a complication. A study of 94
consecutive stroke patients with the cardiomyopathy of Chagas’ disease compared
94these with 150 consecutive stroke patients without Chagas’ disease. A
cardioembolic basis for stroke was considered present in 56 percent of the former
compared to 9 percent of the controls. Most strokes in the group with Chagas’
disease were in the anterior circulation (85%); the posterior circulation was rarely
aAected (5%) and less than 10 percent of the patients presented with lacunar
syndromes.
In Chagasic cardiomyopathy, the apical region of the left ventricle is the typical
site for formation of thrombosis or aneurysm. Echocardiography in this studyrevealed an apical aneurysm in 37 percent and mural thrombosis in 12 percent,
but the most common 7nding was left ventricular diastolic dysfunction (49%). The
ECG was abnormal in 67 percent. The most common abnormality was a right
bundle branch block pattern (35%), followed by left His fascicular block (17%),
and AF (15%). A pacemaker had been inserted in 10. Oral anticoagulation has
been recommended for all individuals with Chagasic stroke who demonstrated risk
94factors for cardioembolism.
In Africa, the major cardiomyopathy is the dilated type, but peripartum
95cardiomyopathy is ubiquitous with an incidence ranging from 1:100 to 1:1,000.
There are regional variations: endomyocardial 7brosis is restricted to the tropical
95regions of East, Central, and West Africa. The incidence of human
immunode7ciency virus (HIV)–associated cardiac disease, including
cardiomyopathy, is increasing in contrast to developing countries where the
availability of highly active antiretroviral therapy has signi7cantly reduced the
96incidence of myocarditis.
In Japan, hypertrophic cardiomyopathy is the most common cause of
97cardiomyopathy, followed closely by dilated cardiomyopathy (DCM).
Cardiomyopathy associated with the prolonged QT interval syndrome came in a
distant third, followed by mitochondrial disease, arrhythmogenic right ventricular
97dysplasia, and Fabry’s disease of the heart.
In young adults arrhythmogenic right ventricular dysplasia/cardiomyopathy
98(ARVD/C) is another rare hereditary disorder causing sudden death. In a natural
history study of 130 patients, 100 male, age at onset of symptoms was 32 ± 14
years. The annual mortality rate was 2.3 percent; all patients who died had a
99history of ventricular tachycardia. Diagnosis requires a high index of
87suspicion.
In the dilated cardiomyopathies, a necropsy study showed a high incidence of
embolic events (systemic or pulmonary) at 60 percent of 152 cases. In the living,
once a TIA or stroke has occurred, either warfarin or antiplatelet therapy should be
52considered. There is insuN cient evidence to recommend warfarin or antiplatelet
100therapy for primary prevention, in the absence of other indications.
Myocardial Infarction and Left Ventricular Dysfunction
Patients with a history of coronary artery disease have a threefold increase in stroke
101risk. This risk is particularly high within the 7rst month after myocardial
102infarction (MI). Mechanisms include embolism from left ventricular mural
thrombosis and the development of AF (which occurs in up to 20% of patients after
103MI).A community-based study of 2,160 patients hospitalized between 1979 and 1998
found stroke risk during the 30 days after a 7rst MI to be increased 44-fold, and it
remained two to three times higher than expected during the subsequent 3
102years. Of note, the 20-year duration of the study enabled the conclusion to be
102drawn that acute MI treatment by thrombolysis did not reduce stroke risk.
Overall, stroke risk following MI is approximately 1 percent during the 7rst month
104,105and about 2 percent at 1 year. For a non-ST elevation acute coronary
106syndrome, the early stroke risk was found to be 0.7 percent at 3 months. In
large randomized trials of aspirin versus the combination of aspirin and clopidogrel
in patients with MI or acute coronary syndrome, the stroke rate ranged between 0.9
103and 1.7 percent.
In a meta-analysis, predictors of stroke following MI included advanced age,
diabetes, hypertension, previous stroke or MI, anterior MI, AF, heart failure, and
104nonwhite race. Anterior wall MI has been a predictor of stroke in some, but not
107all, studies. Left ventricular thrombus develops in about one third of individuals
108in the 7rst 2 weeks following an anterior MI. A meta-analysis of 11 studies
concluded that mural thrombus formation after an MI poses a signi7cantly
109increased risk of embolization, which is reduced by anticoagulation.
The current recommendation, in the absence of thrombolytic therapy, is that,
after acute MI, heparin should be initiated and followed by warfarin for 3 months
in patients considered to be at increased risk of embolism, either pulmonary or
systemic. High-risk patients are those with severe left ventricular dysfunction,
congestive heart failure, a history of pulmonary or systemic embolism,
echocardiographic evidence of mural thrombosis, or the presence of AF. Because of
the increased frequency of mural thrombosis in anterior as opposed to inferior
myocardial infarcts, it is also recommended that patients with an anterior Q-wave
110infarction receive heparin followed by warfarin.
In patients with TIA/ischemic stroke related to an acute MI in which LV mural
thrombus is identi7ed, oral anticoagulation is recommended for at least 3 months
and up to 1 year (INR 2 to 3) in addition to aspirin for coronary artery disease (up
52to 162 mg/day).
Stroke risk is inversely proportional to left ventricular ejection fraction (LVEF). In
a study of 2,231 patients with LV dysfunction after an acute MI, those with LVEF
less than 29 percent had a stroke risk nearly double that of patients with LVEF
exceeding 35 percent: the annual stroke rate was 1.5 percent overall. Thus,
111reduced LVEF is an independent risk factor for subsequent stroke. Another
study found a 58 percent increase in risk of embolic events for every 10 percent
112decrease in LVEF in women, but not men.Congestive heart failure carries a two- to threefold increase in the relative risk of
stroke. Among patients enrolled into heart failure trials, the overall annual stroke
risk has ranged between 1.3 to 3.5 percent; most patients were taking aspirin or
113warfarin. In the absence of clinically overt heart failure or MI, the presence of
asymptomatic left ventricular systolic dysfunction, even of mild degree, is an
114independent risk factor for stroke.
The optimal antithrombotic prophylaxis for patients with poor LV function
remains uncertain; the eN cacy of warfarin versus aspirin is the subject of ongoing
115trials.
Rheumatic Heart Disease
Extensive experience has accumulated over several decades concerning the
association of systemic embolism with rheumatic heart disease. A 1973 review
116concisely summarized relevant features. A minimum of 20 percent of patients
with rheumatic heart disease experience a thromboembolic complication at some
time, and 40 percent of these arterial emboli involve the brain. Embolic events are
the cause of death in 16 to 35 percent of adults dying of rheumatic heart disease,
and subgroups of patients having a much greater frequency of embolic
complication can be identified.
The risk of embolism is substantially increased when atrial thrombus is present
(risk increases from 16% to 41%) or AF develops (risk increases from 7% to 30%).
The proportion of patients developing left atrial thrombus increases from 9 to 41
percent when AF is present; conversely, 80 percent of patients with atrial thrombus
are in AF. Embolism is most likely to occur when the dominant valvular lesion is
that of mitral stenosis, either alone or in combination with aortic valve disease or
mitral insuN ciency. Isolated aortic valve disease is rarely associated with embolic
events. Older patients more frequently have AF, atrial thrombus, and embolic
events.
Studies of atrial thrombosis initially involved TTE, an insensitive method. Of 293
patients in one study who were to undergo open heart surgery, TTE disclosed
thrombi in the left atrium in 33. At surgery, this was con7rmed in 30 of the cases,
but the study had missed 21 additional patients, including all 11 in whom
117thrombus was located in the left atrial appendage.
Once embolization has occurred, recurrence rate is high, approaching 60
118percent. Current recommendations are therefore strongly in favor of the use of
long-term warfarin (to prolong the INR to 2.0 to 3.0) in patients with rheumatic
mitral valve disease who have a history of systemic embolism or who develop AF,
either chronic or paroxysmal. It is also recommended that the same treatment be
given to patients in normal sinus rhythm if the left atrial diameter is in excess of5.5 cm. Furthermore, if recurrent systemic embolism occurs despite adequate
119warfarin therapy, addition of aspirin should be considered. The bene7cial eAect
of adding aspirin, 100 mg daily, to warfarin has been demonstrated in the context
120of prosthetic heart valves.
Atrial Myxoma
Atrial myxomas have long been recognized as a cause of cerebral embolism. They
are uncommon. A French hospital reviewed experience with 112 cases collected
121over 40 years. Women outnumbered men 72 to 40; ages ranged from 5 to 84
years. The presenting symptoms were cardiac, constitutional, and embolic in 67,
34, and 29 percent, respectively. Younger and male patients were more liable to
have embolic events. Neurological manifestations, in 113 patients, were evaluated
122in a literature review. Ischemic stroke was the most common at 83 percent,
often at multiple sites. Syncope (28%), psychiatric presentations (23%), headache
(15%), and seizures (12%) were all encountered. In a Spanish study of 28 patients,
123it was noted that in the 9 with stroke, TIA had preceded the stroke in 7.
Treatment is surgical. A rare delayed complication is that of distal multiple
124cerebral aneurysm formation. Transient ischemic attacks led to this diagnosis 5
years after successful surgery in one person. Symptoms were controlled with
clopidogrel.
Marantic (Nonbacterial Thrombotic) Endocarditis
Although there are several causes of nonbacterial thrombotic endocarditis, a review
of 14 series, predating the era of echocardiography, found an underlying
malignancy in half. The most common tumor was lung cancer. Cancers of
gastrointestinal origin accounted for a similar number of cases. Breast cancer
appeared underrepresented. The mitral valve was most commonly aAected (43%),
followed by the aortic valve (36%). Overall, embolism occurred in 42 percent of
125patients. An autopsy series (171 cases) found cancers of the ovaries, biliary
126system, pancreas, stomach, and lung to be most common.
The widespread availability of echocardiography has facilitated recognition of
vegetations. A prospective study of 200 unselected ambulatory patients with solid
tumors found vegetations in 19 percent compared to 2 percent in controls.
Vegetations were seen in 50 percent of pancreatic cancers, 28 percent of lung
127cancers, and 19 percent of lymphomas. Only two patients had cerebral events.
On MRI, numerous lesions of various sizes may be found in multiple arterial
territories.
At one cancer center, 96 stroke patients were assessed. Echocardiography (TTE)
was performed in 61; none had TEE. An embolic mechanism was thought to becausative in 52. The heart was implicated in 14, but nonbacterial thrombotic
endocarditis in only 3. Stroke of embolic origin carried a dismal prognosis. Life
128expectancy was just over 2 months, and treatment had no apparent influence.
Other Echocardiographic Abnormalities Linked to Stroke
Patent Foramen Ovale and Atrial Septal Aneurysm
A PFO is present in about one quarter of adults and represents a potential
129mechanism for cardiogenic embolism. Case-control studies of young adults
(younger than 55 years) with cryptogenic stroke found a 7vefold increase in
130prevalence of PFO compared to control subjects without stroke.
In a French prospective study of individuals with stroke and an isolated PFO, the
4-year stroke recurrence risk was 2.3 percent. For those with both PFO and ASA,
the rate was 15.2 percent compared to 0 percent for those with ASA alone. In the
“control group” with neither PFO nor ASA, the rate was 4.2 percent. All patients in
131this study were taking aspirin. In another study, the presence of a PFO (with or
without ASA) did not confer a signi7cant increase in stroke recurrence rate over a
2-year follow-up; furthermore, recurrence rate did not diAer between patients on
132aspirin or warfarin or in those with large or small PFO.
133ASA was found in 2 percent of persons in a population-based study. In elderly
patients undergoing cardiac surgery, the incidence was nearly 5 percent. No
patient had a cerebrovascular event over a follow-up period of 70 months; most
134were receiving aspirin. It was concluded that the risk of embolic stroke was low.
The optimal management of patients with PFO is not currently known.
Treatment options include (1) antiplatelet therapy, (2) anticoagulation, (3)
percutaneous device closure, and (4) surgical closure. Opinions diAer between
specialists: neurologists are more likely to recommend medical management,
135whereas cardiologists are more likely to suggest device closure. Randomized
trials are currently under way to compare the eN cacy and safety of medical
therapy with percutaneous closure. For patients with cryptogenic stroke and
136isolated PFO, antiplatelet therapy is usually recommended. For patients with
PFO and ASA, anticoagulation or device closure may be considered, although
evidence to support these treatments is lacking.
Left Atrial Spontaneous Echo Contrast
Left atrial spontaneous echo contrast (smoke) may be detected by TEE and is
thought to represent stasis of blood within the atrium. The 7nding may thus
indicate a predisposition to thrombus formation. It is most commonly encountered
in patients with either AF or mitral stenosis and has been found to be highly137associated with previous stroke or peripheral embolism in this context.
Mitral Annular Calcification
Mitral annular calci7cation (MAC) has been suggested as a potential source of
calci7c or thrombotic emboli to the cerebral and retinal circulations, but the
evidence has been conLicting on whether it is an independent risk factor for stroke.
A Framingham study documented a doubled stroke risk in those with MAC
compared to those without, but it was unclear whether this relationship is causal or
a marker for other risk factors; for example, in MAC, the risk of developing AF is
138,139increased 12-fold. Although one study found MAC to be an independent
140 141,142predictor of stroke, two others did not. One of these involved nearly
1426,000 patients followed over 6 to 7 years. MAC appears to be a marker of
generalized atherosclerotic disease including carotid stenosis, calci7ed aortic
143,144plaque, and coronary disease.
Mitral Valve Prolapse
Mitral valve prolapse (MVP) is the most frequent valve disease in adults, with a
145prevalence of about 2 percent. Initially postulated as a cause of stroke/TIA in
146 147,148the young, this has not been con7rmed in more recent studies. Stroke
risk is increased with older age and the development of cardiac conditions: AF,
149mitral valve thickening, left atrial enlargement, and mitral regurgitation. In
those with an auscultatory diagnosis of MVP alone, con7rmed by
150echocardiography, no increase in risk was found. In the Framingham cohort, no
signi7cant diAerence was found in the prevalence of stroke/TIA in those with or
151without MVP.
Treatment guidelines are therefore (1) no antithrombotic therapy for primary
151prevention in individuals with MVP who have not experienced embolic events
and (2) long-term antiplatelet therapy for secondary prevention in MVP patients
52who have had ischemic stroke or TIA. If other cardiac abnormalities develop,
these are treated according to their own merits.
Aortic Valve Sclerosis and Stenosis
Systemic embolism in patients with aortic valve disease is uncommon in the
absence of AF or other risk factors. Aortic sclerosis (valve thickening without
outLow obstruction) is a common 7nding in the elderly and is associated with
generalized atherosclerotic vascular disease and increased cardiovascular
152mortality.
A prospective study of patients with echocardiographically documented aortic
valve calci7cation showed no statistically signi7cant diAerence in stroke risk inpatients with calci7cation without stenosis (8%) compared to those with stenosis
153(5%) or control subjects (5%). Additionally, aortic valve disease was not
associated with the presence of silent brain infarcts in this study. A larger study
compared stroke risk in those with stenosis to those with sclerosis. Over a mean
follow-up of 5 years, stroke risk was 12 percent in those with stenosis and 8 percent
in those with sclerosis compared to 6 percent in those with a normal aortic valve.
After adjusting for other variables, there was no statistically signi7cant increase in
152stroke risk in those with aortic sclerosis. A similar conclusion was found in
153another cohort study. With regard to aortic stenosis, only if severe was it an
154independent predictor of stroke in addition to age and AF.
Acute Medical Treatment of Cardiogenic Embolism
The landmark study comparing thrombolysis of acute ischemic stroke with
intravenous tissue plasminogen activator (t-PA) against placebo showed improved
155clinical outcome at 3 months for all stroke subtypes. Cardioembolism accounted
for 28 percent of the patients. Therefore, this acute intervention should be
considered for stroke of cardioembolic origin. The two fundamental eligibility
criteria are (1) treatment initiated within 3 hours of stroke onset (therefore the time
of stroke onset must be clearly defined) and (2) absence of hemorrhage on CT brain
scan. Prompt assessment and treatment are required because the odds of a
favorable outcome with t-PA decline rapidly the longer the interval to t-PA
injection time.
156A series of inclusion and exclusion criteria exist. The purpose is to minimize
the risk of intracerebral hemorrhage, the major complication of intravenous t-PA,
and to avoid treating minor or rapidly resolving processes such as TIAs, or
nonischemic events. The dose of t-PA for stroke thrombolysis (0.9 mg/kg) is lower
than that for acute MI. The risk of intracerebral hemorrhage in the treated group
155(6.4%) was 10 times higher than that of the placebo group in one report. This
risk appears increased if the treatment window is extended beyond 3 hours.
Patients treated with t-PA cannot receive heparin, warfarin, or aspirin for the 7rst
24 hours after infusion. Subsequently, long-term anticoagulation for secondary
stroke prevention must be considered.
Other interventional approaches to achieve recanalization include direct intraclot
lysis via a microcatheter and mechanical clot disruption, but availability of such
procedures is limited. Mechanical clot removal devices may especially have a role
in the acute treatment of patients with severe stroke in whom thrombolysis is
157contraindicated (e.g., recent cardiac surgery).
Some embolic infarcts undergo secondary hemorrhagic transformation, which
may lead to clinical deterioration. Factors found to increase this possibility in onestudy were large infarct size and initiation of early anticoagulation (less than 12
158hours from presentation).
The optimal timing of initiation of anticoagulation after cardioembolic stroke is
not known. One recommendation is that nonhypertensive patients without evidence
of hemorrhage on CT scan performed 24 to 48 hours after stroke can start
anticoagulation. Anticoagulation is usually delayed for about 7 days in those with
large infarcts. The American Stroke Association states that initiation of warfarin is
generally recommended within 2 weeks after a stroke, but longer delays may be
52appropriate in patients with large infarcts or uncontrolled hypertension.
Decisions must be individualized.
SYNCOPE
Transient self-limited interruptions of cardiac output result in generalized cerebral
ischemia, a condition that is termed syncope when it results in a loss of
159consciousness. Syncope is discussed in Chapter 8 but is considered further here
with particular regard to its occurrence in patients with acquired cardiac disease
and arrhythmias.
A study of syncope induced in 14 patients with pacemakers noted that
consciousness was lost 9 or more seconds after induction of a ventricular
160arrhythmia (7brillation or tachycardia). Patients felt distant, dazed, or as if
they were “fading out” before loss of consciousness. Motor activity was noted in 10
of 15 episodes, with generalized tonic contraction of axial muscles followed or
accompanied by irregular jerking of the extremities, generalized rigidity without
clonic activity, or irregular facial movement or eyelid Lutter without tonic activity.
None of the patients bit their tongue or was incontinent. During the recovery phase,
tonic Lexion of the trunk was seen in three patients. Patients remained dazed or
confused for up to 30 seconds or more after restoration of the circulation. This
study con7rmed that motor phenomena occur in association with syncope without
corresponding electroencephalographic (EEG) evidence of epileptic discharges. The
authors noted variability in EEG 7ndings and poor correlation of these changes
160with the clinical ones.
Videometric analysis of syncope lasting on average 12 seconds induced in 42
healthy volunteers showed that myoclonic activity occurred in 90 percent. Head
turns, oral automatisms, and writhing movements were common. Upward eye
deviation was also common, and eyes remained open in three quarters of the
subjects. Visual hallucinations occurred in 60 percent and were associated with
161auditory hallucinations in 36 percent, although never with intelligible speech.
Focal neurological symptoms are rare with cardiac arrhythmia. Evaluation of
290 patients who required pacemaker insertion disclosed that only 4 had focalneurological symptoms or signs; among these, only 2 had focal symptoms that
162could be related to a speci7c episode of cardiac dysfunction. Rarely, features
suggestive of complex partial seizures are seen.
The clinical spectrum of abnormalities that occur with generalized cerebral
hypoperfusion is thus an extended one, ranging from nonspeci7c “dizziness”
through a variety of sensory disturbances, including paresthesias and alterations of
vision to loss of consciousness, sometimes with convulsive features. This has long
been recognized in the context of blood donation, where 12 percent of syncopal
163reactions were shown to have some convulsive features. Confusion may occur
upon recovery. These observations highlight potential diN culties in distinguishing
syncope from seizure.
A collaborative study between cardiologists and neurologists identi7ed historical
criteria to identify seizure patients among those presenting with presumed syncope:
waking with a lacerated tongue, loss of consciousness with emotional stress, head
turning to one side during loss of consciousness, and postictal confusion or
164abnormal behavior. Of note, syncopal events indistinguishable from seizures
have been observed in the context of cardiac arrhythmias. Additionally, seizures
may cause arrhythmias.
Syncope is common, especially in the elderly, who show a high recurrence
165rate. Of the many causes, it is important to identify those of cardiac origin
because mortality is signi7cantly increased in this group of patients. A cardiac
basis, in diAerent studies, ranged from 1 to 8 percent for organic heart disease and
1594 to 38 percent for arrhythmias. In addition to common structural causes, aortic
tract outLow stenosis or intermittent obstruction to outLow may occur, for
example, by a mobile thrombus or tumor in the left atrium. Echocardiography is
the test of choice. In the case of arrhythmias, the prime objective is to document a
relevant abnormality during an episode.
In the past, no cause for syncope was found in about one third of patients, but
diagnostic yields as high as 76 percent have been achieved, for example, in a Swiss
166study of 788 patients presenting to an emergency department. Evaluations were
completed in 650 of those patients. History and clinical examination led to a
diagnosis in 38 percent. In 10 percent, a possible cause for syncope was identi7ed,
and in about 3 percent this was refuted. In 21 percent, the cause of syncope was
not initially determined, and the majority of this group underwent an extensive
work-up. A probable cause of syncope was found in only 30 of the 122 patients in
this group. Among the 650 patients, 69 (11%) were considered to have a cardiac
cause, and arrhythmias were most prominent (44 patients). A sinus bradycardia or
pause was seen in 15, as was atrial ventricular block, whereas 4 showed a
supraventricular tachycardia and 1 had a pacemaker malfunction. Acute coronarysyndromes were found in 9, aortic stenosis in 8, and pulmonary embolism in 8. The
18-month mortality in the cardiac group, noncardiac group, and group with
unidentified cause was 26, 6, and 7 percent, respectively.
A relatively common disorder predisposing to paroxysmal supraventricular
tachycardia is the WolA–Parkinson–White syndrome, usually a sporadic disorder,
167with a prevalence of up to 1 in 1,000 persons. AF may develop. Dizziness,
syncope, and, rarely, sudden death may occur. The characteristic
electrocardiographic (ECG) hallmarks are a short PR interval and a slowly rising
prolonged QRS complex.
It is those patients with an apparently normal heart that present a special
168challenge and raise the possibility of disorders of the conducting tissues. The
long QT syndrome is seen throughout the world. A recessive form is associated with
deafness, whereas the more common form, without deafness, has
autosomaldominant inheritance. Acquired forms, often drug related, are more common.
Exertion or emotion may trigger events. The characteristic feature, as the name
implies, is a prolonged QT interval (corrected for heart rate) on a standard ECG.
The disorder predisposes to polymorphic ventricular tachycardia, which in turn
87predisposes to syncope and sudden death.
169Recently, a short QT interval syndrome has been identi7ed. Especially
aAected are the young, including infants. It is rare and predisposes to paroxysmal
AF and episodes of ventricular 7brillation, which may lead to syncope and sudden
death. It has been suggested that the disorder may be responsible for some cases of
170sudden infant death.
Sudden death in males from Southeastern Asia attributable to ventricular
7brillation has been recognized for more than 20 years. Episodes indistinguishable
from generalized seizures may occur in sleep, and the sudden death is presumed
171due to ventricular 7brillation. It is now known as SUNDS (sudden unexplained
nocturnal death syndrome) and has been linked to the Brugada syndrome, which is
172said to be phenotypically, genetically, and functionally the same. However, the
Brugada syndrome has been described in Europe and in females. The Brugada
syndrome is also characterized by sudden death due to malignant arrhythmias. The
baseline ECG may be abnormal in showing ST elevation in leads V1, 2, and 3,
together with the presence of a right bundle branch block pattern. However, this
pattern may be concealed and require unmasking by the use of sodium channel
blockers.
Another disorder, but one in which the resting ECG is unremarkable, although it
may show a sinus bradycardia and prominent U waves in some patients, is
173catecholamine-induced polymorphic ventricular tachycardia. This is a disorder
of childhood with an average age at symptom onset of 8 years. Syncope or eventsindistinguishable from seizures are triggered by exercise or emotional stress.
Evaluation of syncope therefore requires attention to family history, age at onset,
unexplained sudden deaths, note of apparent epileptic disorders, relation of events
to exertion and distress, and eAects of postural change. In the presence of an
apparently normal heart, evaluation of the standard ECG may suggest a cause, as
indicated previously. In the context of a normal ECG or with intermittent events,
prolonged recordings may be required in order to capture an episode. With daily
events, a Holter monitor may suN ce. More prolonged recording techniques are
available, as are sophisticated electrophysiological studies. Details are beyond the
scope of this chapter; a useful modern overview of an approach to the investigation
174of syncope is available.
Cardiac arrhythmias may also result from epileptic events. Tachycardia is the
175most commonly observed rhythm disturbance. Sinus bradycardia, complete
atrioventricular block, and cardiac arrest all have been documented as epileptic
176-178effects. Asystole secondary to an epileptic event, often a partial seizure, has
179been documented to last for up to 60 seconds. It should be noted that
180carbamazepine can cause heart block, especially in elderly women.
INTERVENTIONAL PROCEDURES
Coronary Catheterization
Coronary angiography carries a small (0.2%) risk of central nervous system (CNS)
complications. An unexplained observation is the preponderance of embolic events
181within the posterior circulation, regardless of the route of catheterization. The
corresponding clinical features are visual disturbances that may be migrainous,
182,183transient, or persistent; confusion may also occur. For patients experiencing
an iatrogenic ischemic stroke in the context of coronary catheterization,
184thrombolytic therapy is a potential treatment option that should be considered.
Percutaneous Transluminal Coronary Angioplasty and Stenting
Percutaneous transluminal coronary angioplasty had an overall mortality of 0.1
percent in a large series of more than 12,000 patients. Of the 121 who died,
lowoutput failure was the most common cause (66% of deaths); stroke was responsible
185for 4 percent. Another study showed that in the presence of peripheral vascular
disease the risk of any major complication (stroke included) was higher: 12 versus 8
186percent.
Angioplasty has also been compared to coronary stenting. Stroke rate (0.2%) was
187equal in the two groups. To prevent stent thrombosis, an antithrombotic
regimen is required. The addition of clopidogrel to aspirin reduces stroke incidence188both before and after percutaneous coronary intervention. In a study of more
than 18,000 patients with a non–ST-segment elevation acute coronary syndrome,
the 6-month stroke risk was 1.3 percent (1.1% for those not undergoing coronary
artery bypass graft surgery) and the 6-month mortality in these patients was 27
189percent. Independent predictors of stroke risk were coronary bypass surgery
(especially when performed early), previous stroke, diabetes, and older age, among
others. Percutaneous coronary intervention was not associated with an increased
risk of stroke in this group.
In a study of 12,407 percutaneous coronary interventions (1990 to 1999), the
190periprocedural risk of stroke and TIA was 0.38 and 0.12 percent, respectively.
More than 90 percent of patients in this study underwent balloon angioplasty, and
nearly half also underwent coronary stenting. Independent predictors of stroke
were advanced age, use of an intra-aortic balloon pump, and need for saphenous
190vein graft intervention.
Primary angioplasty, compared to thrombolysis, has been noted to decrease
191signi7cantly the risk of stroke, but when used as a rescue therapy, stroke risk
192was marginally increased. In a review of 23 randomized trials involving more
than 7,000 patients with acute MI and ST-segment elevation who were randomly
assigned to either primary percutaneous transluminal coronary angioplasty or
thrombolysis, the overall stroke rate was 1 percent with angioplasty compared to 2
percent with thrombolysis (a statistically signi7cant reduction in favor of
193angioplasty).
Thrombolytic Therapy for Acute Myocardial Infarction
Concern that the introduction of thrombolytic therapy for MI would result in an
increase in stroke was not substantiated by the results of the initial large Italian
trial of nearly 12,000 patients. Stroke rate was 0.77 percent in the streptokinase
group compared to 0.92 percent in the control group. An excess of stroke was
evident only during the 7rst day after randomization to streptokinase. After this
time, patients in the control group had more stroke or TIA events. The study did
194not include CT scan results. Extended experience from this group, speci7cally
stressing stroke risk, found that stroke occurred in 236 (1.14%) of 20,768 patients.
Autopsy or CT scanning enabled the cause of stroke to be identi7ed in 74 percent.
Perhaps surprisingly, infarction was more common (42%) than hemorrhage (31%).
Patients receiving recombinant t-PA showed a small but signi7cant excess of
195stroke. Comparison of four thrombolytic strategies con7rmed a slight excess of
hemorrhagic stroke in those receiving t-PA and in those receiving combined
thrombolytic agents. This excess risk was on the order of 2 to 3 per 1,000
196treated. In the four groups, stroke risk rate ranged from a low of 1.22 percent inthose treated with streptokinase and subcutaneous heparin to 1.64 percent in those
treated with intravenous heparin and both t-PA and streptokinase. These
percentages are equal to or less than those documented in recent large
prethrombolytic studies of acute MI.
The risk of ICH following thrombolytic therapy has been linked to the intensity of
heparin anticoagulation and timing of partial thromboplastin time (PTT)
monitoring. Recent trials that have used reduced-dose heparin regimens and 3-hour
197PTT monitoring have reduced ICH rates.
When ICH does occur, it is likely to be large in size, supratentorial in site, and
more often lobar than deep. Mass eAect is common, and blood may extend into the
ventricles or subarachnoid space. Of the 244 cases in the study referred to earlier,
symptoms emerged within 8 hours of treatment in 55, after 30 hours in 58, and
194between these times in the remainder. A small percentage (3%) of hemorrhages
were subdural. Syncope within 48 hours of treatment, or facial or head trauma
within 2 weeks of treatment were disproportionately noted, but numbers were
198small (7).
Review of risk factors in 150 patients with documented ICH identi7ed four
factors as independent predictors: age older than 65 years, body weight less than
70 kg, hypertension on hospital admission, and administration of alteplase. The
same risk factors for ICH were identi7ed in the GUSTO-I trial; additional predictors
included a history of cerebrovascular disease or hypertension, and elevated systolic
199and diastolic blood pressure on admission.
If ICH is suspected, immediate brain CT scan and discontinuation or reversal of
thrombolytic or antithrombotic therapy are recommended. Neurosurgical
200consultation should be considered.
REFERENCES
1 Goldstein LB, Jones MR, Matchar DB, et al. Improving the reliability of stroke
subgroup classification using the Trial of ORG 10172 in Acute Stroke Treatment
(TOAST) criteria. Stroke. 2001;32:1091.
2 Cardiogenic brain embolism. The second report of the Cerebral Embolism Task
Force. Arch Neurol. 1989;46:727.
3 Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the
Management of Patients with Atrial Fibrillation: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines and
the European Society of Cardiology Committee for Practice Guidelines (Writing
Committee to Revise the 2001 Guidelines for the Management of Patients With
Atrial Fibrillation): developed in collaboration with the European Heart Rhythm
Association and the Heart Rhythm Society. Circulation. 2006;114:e257.4 Adams HPJr, Kappelle LJ, Biller J, et al. Ischemic stroke in young adults. Experience
in 329 patients enrolled in the Iowa Registry of stroke in young adults. Arch
Neurol. 1995;52:491.
5 Kristensen B, Malm J, Carlberg B, et al. Epidemiology and etiology of ischemic
stroke in young adults aged 18 to 44 years in northern Sweden. Stroke.
1997;28:1702.
6 Ghandehari K, Moud ZI. Incidence and etiology of ischemic stroke in Persian young
adults. Acta Neurol Scand. 2006;113:121.
7 Ducrocq X, Lacour JC, Debouverie M, et al. Cerebral ischemic accidents in young
subjects. A prospective study of 296 patients aged 16 to 45 years. Rev Neurol
(Paris). 1999;155:575.
8 Rasura M, Spalloni A, Ferrari M, et al. A case series of young stroke in Rome. Eur J
Neurol. 2006;13:146.
9 Lee TH, Hsu WC, Chen CJ, et al. Etiologic study of young ischemic stroke in Taiwan.
Stroke. 2002;33:1950.
10 Kwon SU, Kim JS, Lee JH, et al. Ischemic stroke in Korean young adults. Acta
Neurol Scand. 2000;101:19.
11 Giovannoni G, Fritz VU. Transient ischemic attacks in younger and older patients.
A comparative study of 798 patients in South Africa. Stroke. 1993;24:947.
12 Kittner SJ, Sharkness CM, Sloan MA, et al. Features on initial computed
tomography scan of infarcts with a cardiac source of embolism in the NINDS
Stroke Data Bank. Stroke. 1992;23:1748.
13 Kittner SJ, Sharkness CM, Sloan MA, et al. Infarcts with a cardiac source of
embolism in the NINDS Stroke Data Bank: neurologic examination. Neurology.
1992;42:299.
14 Knepper LE, Biller J, Tranel D, et al. Etiology of stroke in patients with Wernicke’s
aphasia. Stroke. 1989;20:1730.
15 Hanlon RE, Lux WE, Dromerick AW. Global aphasia without hemiparesis: language
profiles and lesion distribution. J Neurol Neurosurg Psychiatry. 1999;66:365.
16 Timsit SG, Sacco RL, Mohr JP, et al. Early clinical differentiation of cerebral
infarction from severe atherosclerotic stenosis and cardioembolism. Stroke.
1992;23:486.
17 Arboix A, Oliveres M, Massons J, et al. Early differentiation of cardioembolic from
atherothrombotic cerebral infarction: a multivariate analysis. Eur J Neurol.
1999;6:677.
18 Arboix A, Garcia-Eroles L, Massons JB, et al. Atrial fibrillation and stroke: clinical
presentation of cardioembolic versus atherothrombotic infarction. Int J Cardiol.
2000;73:33.
19 Minematsu K, Yamaguchi T, Omae T. ‘Spectacular shrinking deficit’: rapid recoveryfrom a major hemispheric syndrome by migration of an embolus. Neurology.
1992;42:157.
20 Bogousslavsky J, Van MG, Regli F. The Lausanne Stroke Registry: analysis of 1,000
consecutive patients with first stroke. Stroke. 1988;19:1083.
21 Kase CS, Norrving B, Levine SR, et al. Cerebellar infarction. Clinical and anatomic
observations in 66 cases. Stroke. 1993;24:76.
22 Bogousslavsky J, Regli F, Maeder P, et al. The etiology of posterior circulation
infarcts: a prospective study using magnetic resonance imaging and magnetic
resonance angiography. Neurology. 1993;43:1528.
23 Yamamoto Y, Georgiadis AL, Chang HM, et al. Posterior cerebral artery territory
infarcts in the New England Medical Center Posterior Circulation Registry. Arch
Neurol. 1999;56:824.
24 Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic
stroke in population-based incidence studies. Neurology. 2004;62:569.
25 Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke
subtypes according to TOAST criteria: incidence, recurrence, and long-term
survival in ischemic stroke subtypes: a population-based study. Stroke.
2001;32:2735.
26 Ringelstein EB, Koschorke S, Holling A, et al. Computed tomographic patterns of
proven embolic brain infarctions. Ann Neurol. 1989;26:759.
27 Weisberg LA. Computerized tomographic findings in cardiogenic cerebral
embolism. Comput Radiol. 1985;9:189.
28 Okada Y, Yamaguchi T, Minematsu K, et al. Hemorrhagic transformation in
cerebral embolism. Stroke. 1989;20:598.
29 Toni D, Fiorelli M, Bastianello S, et al. Hemorrhagic transformation of brain
infarct: predictability in the first 5 hours from stroke onset and influence on
clinical outcome. Neurology. 1996;46:341.
30 Gonzalez RG, Schaefer PW, Buonanno FS, et al. Diffusion-weighted MR imaging:
diagnostic accuracy in patients imaged within 6 hours of stroke symptom onset.
Radiology. 1999;210:155.
31 Hankey GJ, Warlow CP, Sellar RJ. Cerebral angiographic risk in mild
cerebrovascular disease. Stroke. 1990;21:209.
32 Daniel WG, Erbel R, Kasper W, et al. Safety of transesophageal echocardiography.
A multicenter survey of 10,419 examinations. Circulation. 1991;83:817.
33 Kapral MK, Silver FL. Preventive health care, 1999 update: 2. Echocardiography for
the detection of a cardiac source of embolus in patients with stroke. Canadian
Task Force on Preventive Health Care. CMAJ. 1999;161:989.
34 Thompson CR. Echocardiography in stroke: which probe when? CMAJ.
1999;161:981.35 McNamara RL, Lima JA, Whelton PK, et al. Echocardiographic identification of
cardiovascular sources of emboli to guide clinical management of stroke: a
costeffectiveness analysis. Ann Intern Med. 1997;127:775.
36 Belvis R, Leta RG, Marti-Fabregas J, et al. Almost perfect concordance between
simultaneous transcranial Doppler and transesophageal echocardiography in the
quantification of right-to-left shunts. J Neuroimaging. 2006;16:133.
37 Sloan MA, Alexandrov AV, Tegeler CH, et al. Assessment: transcranial Doppler
ultrasonography: report of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology. Neurology. 2004;62:1468.
38 Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in
adults: national implications for rhythm management and stroke prevention: the
AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA.
2001;285:2370.
39 Feinberg WM, Seeger JF, Carmody RF, et al. Epidemiologic features of
asymptomatic cerebral infarction in patients with nonvalvular atrial fibrillation.
Arch Intern Med. 1990;150:2340.
40 Ott A, Breteler MM, de Bruyne MC, et al. Atrial fibrillation and dementia in a
population-based study. The Rotterdam Study. Stroke. 1997;28:316.
41 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor
for stroke: the Framingham Study. Stroke. 1991;22:983.
42 Wolf PA, Dawber TR, Thomas HEJr, et al. Epidemiologic assessment of chronic
atrial fibrillation and risk of stroke: the Framingham study. Neurology.
1978;28:973.
43 Kopecky SL, Gersh BJ, McGoon MD, et al. The natural history of lone atrial
fibrillation. A population-based study over three decades. N Engl J Med.
1987;317:669.
44 Echocardiographic predictors of stroke in patients with atrial fibrillation: a
prospective study of 1066 patients from 3 clinical trials. Arch Intern Med.
1998;158:1316.
45 Transesophageal echocardiographic correlates of thromboembolism in high-risk
patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial
Fibrillation Investigators Committee on Echocardiography. Ann Intern Med.
1998;128:639.
46 Petersen P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomised trial of
warfarin and aspirin for prevention of thromboembolic complications in chronic
atrial fibrillation. The Copenhagen AFASAK study. Lancet. 1989;1:175.
47 Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation.
1991;84:527.
48 The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic
atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial FibrillationInvestigators. N Engl J Med. 1990;323:1505.
49 Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke
associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke
Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med.
1992;327:1406.
50 Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation
Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991;18:349.
51 Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke
in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131:492.
52 Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients
with ischemic stroke or transient ischemic attack: a statement for healthcare
professionals from the American Heart Association/American Stroke Association
Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and
Intervention: the American Academy of Neurology affirms the value of this
guideline. Stroke. 2006;37:577.
53 Paciaroni M, Agnelli G, Caso V, et al. Atrial fibrillation in patients with first-ever
stroke: frequency, antithrombotic treatment before the event and effect on clinical
outcome. J Thromb Haemost. 2005;3:1218.
54 Indredavik B, Rohweder G, Lydersen S. Frequency and effect of optimal
anticoagulation before onset of ischaemic stroke in patients with known atrial
fibrillation. J Intern Med. 2005;258:133.
55 Waldo AL, Becker RC, Tapson VF, et al. Hospitalized patients with atrial fibrillation
and a high risk of stroke are not being provided with adequate anticoagulation. J
Am Coll Cardiol. 2005;46:1729.
56 Bungard TJ, Ghali WA, McAlister FA, et al. Physicians’ perceptions of the benefits
and risks of warfarin for patients with nonvalvular atrial fibrillation. CMAJ.
2001;165:301.
57 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.
Analysis of pooled data from five randomized controlled trials. Arch Intern Med.
1994;154:1449.
58 Choudhry NK, Anderson GM, Laupacis A, et al. Impact of adverse events on
prescribing warfarin in patients with atrial fibrillation: matched pair analysis.
BMJ. 2006;332:141.
59 Kagansky N, Knobler H, Rimon E, et al. Safety of anticoagulation therapy in
wellinformed older patients. Arch Intern Med. 2004;164:2044.
60 Lip GY, Kamath S, Jafri M, et al. Ethnic differences in patient perceptions of atrial
fibrillation and anticoagulation therapy: the West Birmingham Atrial Fibrillation
Project. Stroke. 2002;33:238.
61 Matchar DB, Jacobson AK, Edson RG, et al. The impact of patient self-testing of
prothrombin time for managing anticoagulation: rationale and design of VACooperative Study #481—the Home INR Study (THINRS). J Thromb Thrombolysis.
2005;19:163.
62 Bleeding during antithrombotic therapy in patients with atrial fibrillation. The
Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med.
1996;156:409.
63 Gorter JW. Major bleeding during anticoagulation after cerebral ischemia: patterns
and risk factors. Stroke Prevention In Reversible Ischemia Trial (SPIRIT).
European Atrial Fibrillation Trial (EAFT) study groups. Neurology. 1999;53:1319.
64 Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic
anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up
Study Group. Ann Intern Med. 1993;118:511.
65 Hylek EM, Skates SJ, Sheehan MA, et al. An analysis of the lowest effective
intensity of prophylactic anticoagulation for patients with nonrheumatic atrial
fibrillation. N Engl J Med. 1996;335:540.
66 O’Donnell M, Oczkowski W, Fang J, et al. Preadmission antithrombotic treatment
and stroke severity in patients with atrial fibrillation and acute ischaemic stroke:
an observational study. Lancet Neurol. 2006;5:749.
67 Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on
stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349:1019.
68 Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral
anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial
with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised
controlled trial. Lancet. 2006;367:1903.
69 Nageh T, Meier B. Intracardiac devices for stroke prevention. Prev Cardiol.
2006;9:42.
70 Cordina J, Mead G. Pharmacological cardioversion for atrial fibrillation and flutter.
Cochrane Database Syst Rev. 2005. CD003713
71 Mead GE, Elder AT, Flapan AD, et al. Electrical cardioversion for atrial fibrillation
and flutter. Cochrane Database Syst Rev. 2005. CD002903
72 Stein B, Halperin JL, Fuster V. Should patients with atrial fibrillation be
anticoagulated prior to and chronically following cardioversion? Cardiovasc Clin.
1990;21:231.
73 Arnold AZ, Mick MJ, Mazurek RP, et al. Role of prophylactic anticoagulation for
direct current cardioversion in patients with atrial fibrillation or atrial flutter. J
Am Coll Cardiol. 1992;19:851.
74 Manning WJ, Leeman DE, Gotch PJ, et al. Pulsed Doppler evaluation of atrial
mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll
Cardiol. 1989;13:617.
75 Seidl K, Hauer B, Schwick NG, et al. Risk of thromboembolic events in patients withatrial flutter. Am J Cardiol. 1998;82:580.
76 Wood KA, Eisenberg SJ, Kalman JM, et al. Risk of thromboembolism in chronic
atrial flutter. Am J Cardiol. 1997;79:1043.
77 Mehta D, Baruch L. Thromboembolism following cardioversion of “common” atrial
flutter. Risk factors and limitations of transesophageal echocardiography. Chest.
1996;110:1001.
78 Irani WN, Grayburn PA, Afridi I. Prevalence of thrombus, spontaneous echo
contrast, and atrial stunning in patients undergoing cardioversion of atrial flutter.
A prospective study using transesophageal echocardiography. Circulation.
1997;95:962.
79 Fairfax AJ, Lambert CD, Leatham A. Systemic embolism in chronic sinoatrial
disorder. N Engl J Med. 1976;295:190.
80 Bathen J, Sparr S, Rokseth R. Embolism in sinoatrial disease. Acta Med Scand.
1978;203:7.
81 Simonsen E, Nielsen JS, Nielsen BL. Sinus node dysfunction in 128 patients. A
retrospective study with follow-up. Acta Med Scand. 1980;208:343.
82 Fisher M, Kase CS, Stelle B, et al. Ischemic stroke after cardiac pacemaker
implantation in sick sinus syndrome. Stroke. 1988;19:712.
83 Camm AJ, Katritsis D. Ventricular pacing for sick sinus syndrome—a risky
business? Pacing Clin Electrophysiol. 1990;13:695.
84 Dretzke J, Toff WD, Lip GY, et al. Dual chamber versus single chamber ventricular
pacemakers for sick sinus syndrome and atrioventricular block. Cochrane Database
Syst Rev. 2004. CD003710
85 Greenspon AJ, Hart RG, Dawson D, et al. Predictors of stroke in patients paced for
sick sinus syndrome. J Am Coll Cardiol. 2004;43:1617.
86 Kristensen L, Nielsen JC, Mortensen PT, et al. Incidence of atrial fibrillation and
thromboembolism in a randomised trial of atrial versus dual chamber pacing in
177 patients with sick sinus syndrome. Heart. 2004;90:661.
87 Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification
of the cardiomyopathies: an American Heart Association Scientific Statement from
the Council on Clinical Cardiology, Heart Failure and Transplantation Committee;
Quality of Care and Outcomes Research and Functional Genomics and
Translational Biology Interdisciplinary Working Groups; and Council on
Epidemiology and Prevention. Circulation. 2006;113:1807.
88 Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA.
2002;287:1308.
89 Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349:1064.
90 Pokorski RJ. Hypertrophic cardiomyopathy: risk factors for life and living benefits
insurance. J Insur Med. 2002;34:43.91 Maron BJ, Olivotto I, Bellone P, et al. Clinical profile of stroke in 900 patients with
hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;39:301.
92 Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical
course of hypertrophic cardiomyopathy. Circulation. 2001;104:2517.
93 Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract
obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.
2003;348:295.
94 Carod-Artal FJ, Vargas AP, Horan TA, et al. Chagasic cardiomyopathy is
independently associated with ischemic stroke in Chagas disease. Stroke.
2005;36:965.
95 Sliwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy
in Africa. Circulation. 2005;112:3577.
96 Barbaro G. HIV-associated cardiomyopathy etiopathogenesis and clinical aspects.
Herz. 2005;30:486.
97 Matsumori A, Furukawa Y, Hasegawa K, et al. Epidemiologic and clinical
characteristics of cardiomyopathies in Japan: results from nationwide surveys.
Circ J. 2002;66:323.
98 Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations
of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter
study. J Am Coll Cardiol. 1997;30:1512.
99 Hulot JS, Jouven X, Empana JP, et al. Natural history and risk stratification of
arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation.
2004;110:1879.
100 Sirajuddin RA, Miller AB, Geraci SA. Anticoagulation in patients with dilated
cardiomyopathy and sinus rhythm: a critical literature review. J Card Fail.
2002;8:48.
101 Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to
stroke. The Framingham study. JAMA. 1983;250:2942.
102 Witt BJ, Brown RDJr, Jacobsen SJ, et al. A community-based study of stroke
incidence after myocardial infarction. Ann Intern Med. 2005;143:785.
103 Dutta M, Hanna E, Das P, et al. Incidence and prevention of ischemic stroke
following myocardial infarction: review of current literature. Cerebrovasc Dis.
2006;22:331.
104 Witt BJ, Ballman KV, Brown RDJr, et al. The incidence of stroke after myocardial
infarction: a meta-analysis. Am J Med. 2006;119:354.
105 Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for
fibrinolytic therapy in suspected acute myocardial infarction: collaborative
overview of early mortality and major morbidity results from all randomised trials
of more than 1000 patients. Lancet. 1994;343:31.106 Kassem-Moussa H, Mahaffey KW, Graffagnino C, et al. Incidence and
characteristics of stroke during 90-day follow-up in patients stabilized after an
acute coronary syndrome. Am Heart J. 2004;148:439.
107 Bodenheimer MM, Sauer D, Shareef B, et al. Relation between myocardial infarct
location and stroke. J Am Coll Cardiol. 1994;24:61.
108 Fuster V, Halperin JL. Left ventricular thrombi and cerebral embolism. N Engl J
Med. 1989;320:392.
109 Vaitkus PT, Barnathan ES. Embolic potential, prevention and management of
mural thrombus complicating anterior myocardial infarction: a meta-analysis. J
Am Coll Cardiol. 1993;22:1004.
110 Cairns JA, Theroux P, Lewis HDJr, et al. Antithrombotic agents in coronary artery
disease. Chest. 1998;114:611S.
111 Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke
after myocardial infarction. N Engl J Med. 1997;336:251.
112 Dries DL, Rosenberg YD, Waclawiw MA, et al. Ejection fraction and risk of
thromboembolic events in patients with systolic dysfunction and sinus rhythm:
evidence for gender differences in the studies of left ventricular dysfunction trials.
J Am Coll Cardiol. 1997;29:1074.
113 Pullicino PM, Halperin JL, Thompson JL. Stroke in patients with heart failure and
reduced left ventricular ejection fraction. Neurology. 2000;54:288.
114 Hays AG, Sacco RL, Rundek T, et al. Left ventricular systolic dysfunction and the
risk of ischemic stroke in a multiethnic population. Stroke. 2006;37:1715.
115 Pullicino P, Thompson JL, Barton B, et al. Warfarin versus aspirin in patients with
reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J
Card Fail. 2006;12:39.
116 Abernathy WS, Willis PWIII. Thromboembolic complications of rheumatic heart
disease. Cardiovasc Clin. 1973;5:131.
117 Shrestha NK, Moreno FL, Narciso F, et al. Two-dimensional echocardiographic
diagnosis of left-atrial thrombus in rheumatic heart disease. A clinicopathologic
study. Circulation. 1983;67:341.
118 Carter AB. Prognosis of cerebral embolism. Lancet. 1965;2:514.
119 Levine HJ, Pauker SG, Salzman EW, et al. Antithrombotic therapy in valvular
heart disease. Chest. 1992;102:434S.
120 Turpie AG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in
patients treated with warfarin after heart-valve replacement. N Engl J Med.
1993;329:524.
121 Pinede L, Duhaut P, Loire R. Clinical presentation of left atrial cardiac myxoma. A
series of 112 consecutive cases. Medicine (Baltimore). 2001;80:159.
122 Ekinci EI, Donnan GA. Neurological manifestations of cardiac myxoma: a reviewof the literature and report of cases. Intern Med J. 2004;34:243.
123 Alvarez-Sabin J, Lozano M, Sastre-Garriga J, et al. Transient ischaemic attack: a
common initial manifestation of cardiac myxomas. Eur Neurol. 2001;45:165.
124 Jean WC, Walski-Easton SM, Nussbaum ES. Multiple intracranial aneurysms as
delayed complications of an atrial myxoma: case report. Neurosurgery.
2001;49:200.
125 Lopez JA, Ross RS, Fishbein MC, et al. Nonbacterial thrombotic endocarditis: a
review. Am Heart J. 1987;133:773.
126 Steiner I. Nonbacterial thrombotic endocarditis—a study of 171 case reports. Cesk
Patol. 1993;29:58.
127 Edoute Y, Haim N, Rinkevich D, et al. Cardiac valvular vegetations in cancer
patients: a prospective echocardiographic study of 200 patients. Am J Med.
1997;102:252.
128 Cestari DM, Weine DM, Panageas KS, et al. Stroke in patients with cancer:
incidence and etiology. Neurology. 2004;62:2025.
129 Kizer JR, Devereux RB. Clinical practice. Patent foramen ovale in young adults
with unexplained stroke. N Engl J Med. 2005;353:2361.
130 Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a
metaanalysis of case-control studies. Neurology. 2000;55:1172.
131 Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated
with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med.
2001;345:1740.
132 Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke
patients with patent foramen ovale: Patent Foramen Ovale in Cryptogenic Stroke
Study. Circulation. 2002;105:2625.
133 Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors
for stroke assessed by transesophageal echocardiography and carotid
ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a
Community. Mayo Clin Proc. 1999;74:862.
134 Burger AJ, Sherman HB, Charlamb MJ. Low incidence of embolic strokes with
atrial septal aneurysms: a prospective, long-term study. Am Heart J.
2000;139:149.
135 Messe SR, Cucchiara B, Luciano J, et al. PFO management: neurologists vs
cardiologists. Neurology. 2005;65:172.
136 Messe SR, Silverman IE, Kizer JR, et al. Practice parameter: recurrent stroke with
patent foramen ovale and atrial septal aneurysm: report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology. 2004;62:1042.
137 Chimowitz MI, DeGeorgia MA, Poole RM, et al. Left atrial spontaneous echo
contrast is highly associated with previous stroke in patients with atrialfibrillation or mitral stenosis. Stroke. 1993;24:1015.
138 Benjamin EJ, Plehn JF, D’Agostino RB, et al. Mitral annular calcification and the
risk of stroke in an elderly cohort. N Engl J Med. 1992;327:374.
139 Savage DD, Garrison RJ, Castelli WP, et al. Prevalence of submitral (anular)
calcium and its correlates in a general population-based sample (the Framingham
Study). Am J Cardiol. 1983;51:1375.
140 Kizer JR, Wiebers DO, Whisnant JP, et al. Mitral annular calcification, aortic
valve sclerosis, and incident stroke in adults free of clinical cardiovascular
disease: the Strong Heart Study. Stroke. 2005;36:2533.
141 Boon A, Lodder J, Cheriex E, et al. Mitral annulus calcification is not an
independent risk factor for stroke: a cohort study of 657 patients. J Neurol.
1997;244:535.
142 Gardin JM, McClelland R, Kitzman D, et al. M-mode echocardiographic predictors
of six- to seven-year incidence of coronary heart disease, stroke, congestive heart
failure, and mortality in an elderly cohort (the Cardiovascular Health Study). Am
J Cardiol. 2001;87:1051.
143 Allison MA, Cheung P, Criqui MH, et al. Mitral and aortic annular calcification
are highly associated with systemic calcified atherosclerosis. Circulation.
2006;113:861.
144 Tunca A, Karanfil A, Koktener A, et al. Association between mitral annular
calcification and stroke. Jpn Heart J. 2004;45:999.
145 Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of
mitralvalve prolapse. N Engl J Med. 1999;341:1.
146 Barnett HJ, Boughner DR, Taylor DW, et al. Further evidence relating mitral-valve
prolapse to cerebral ischemic events. N Engl J Med. 1980;302:139.
147 Gilon D, Buonanno FS, Joffe MM, et al. Lack of evidence of an association
between mitral-valve prolapse and stroke in young patients. N Engl J Med.
1999;341:8.
148 Petty GW, Orencia AJ, Khandheria BK, et al. A population-based study of stroke in
the setting of mitral valve prolapse: risk factors and infarct subtype classification.
Mayo Clin Proc. 1994;69:632.
149 Avierinos JF, Brown RD, Foley DA, et al. Cerebral ischemic events after diagnosis
of mitral valve prolapse: a community-based study of incidence and predictive
factors. Stroke. 2003;34:1339.
150 Orencia AJ, Petty GW, Khandheria BK, et al. Risk of stroke with mitral valve
prolapse in population-based cohort study. Stroke. 1995;26:7.
151 Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart
disease–native and prosthetic: the Seventh ACCP Conference on Antithrombotic
and Thrombolytic Therapy. Chest. 2004;126:457S.152 Otto CM, Lind BK, Kitzman DW, et al. Association of aortic-valve sclerosis with
cardiovascular mortality and morbidity in the elderly. N Engl J Med.
1999;341:142.
153 Boon A, Lodder J, Cheriex E, et al. Risk of stroke in a cohort of 815 patients with
calcification of the aortic valve with or without stenosis. Stroke. 1996;27:847.
154 Petty GW, Khandheria BK, Whisnant JP, et al. Predictors of cerebrovascular
events and death among patients with valvular heart disease: a population-based
study. Stroke. 2000;31:2628.
155 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study
Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med.
1995;333:1581.
156 Adams HP, del Zoppo G, Alberts MJ, et al. Guidelines for the early management
of adults with ischemic stroke. A guideline from the American Heart
Association/American Stroke Association Stroke Council, Clinical Cardiology
Council, Cardiovascular Radiology and Intervention Council, and the
Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in
Research Interdisciplinary Working Groups. Stroke. 2007;38:1655.
157 Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical
embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke.
2005;36:1432.
158 Cardioembolic stroke, early anticoagulation, and brain hemorrhage. Cerebral
Embolism Study Group. Arch Intern Med. 1987;147:636.
159 Kapoor WN. Syncope. N Engl J Med. 2000;343:1856.
160 Aminoff MJ, Scheinman MM, Griffin JC, et al. Electrocerebral accompaniments of
syncope associated with malignant ventricular arrhythmias. Ann Intern Med.
1988;108:791.
161 Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of
transient cerebral hypoxia. Ann Neurol. 1994;36:233.
162 Reed RL, Siekert RG, Merideth J. Rarity of transient focal cerebral ischemia in
cardiac dysrhythmia. JAMA. 1973;223:893.
163 Lin JT, Ziegler DK, Lai CW, et al. Convulsive syncope in blood donors. Ann Neurol.
1982;11:525.
164 Sheldon R, Rose S, Ritchie D, et al. Historical criteria that distinguish syncope
from seizures. J Am Coll Cardiol. 2002;40:142.
165 Savage DD, Corwin L, McGee DL, et al. Epidemiologic features of isolated
syncope: the Framingham Study. Stroke. 1985;16:626.
166 Sarasin FP, Louis-Simonet M, Carballo D, et al. Prospective evaluation of patients
with syncope: a population-based study. Am J Med. 2001;111:177.
167 Al-Khatib SM, Pritchett EL. Clinical features of Wolff-Parkinson-White syndrome.Am Heart J. 1999;138:403.
168 Goldschlager N, Epstein AE, Grubb BP, et al. Etiologic considerations in the
patient with syncope and an apparently normal heart. Arch Intern Med.
2003;163:151.
169 Brugada R, Hong K, Cordeiro JM, et al. Short QT syndrome. CMAJ.
2005;173:1349.
170 Wolpert C, Schimpf R, Veltmann C, et al. Clinical characteristics and treatment of
short QT syndrome. Expert Rev Cardiovasc Ther. 2005;3:611.
171 Otto CM, Tauxe RV, Cobb LA, et al. Ventricular fibrillation causes sudden death in
Southeast Asian immigrants. Ann Intern Med. 1984;101:45.
172 Hong K, Berruezo-Sanchez A, Poungvarin N, et al. Phenotypic characterization of
a large European family with Brugada syndrome displaying a sudden unexpected
death syndrome mutation in SCN5A. J Cardiovasc Electrophysiol. 2004;15:64.
173 Leenhardt A, Lucet V, Denjoy I, et al. Catecholaminergic polymorphic ventricular
tachycardia in children. A 7-year follow-up of 21 patients. Circulation.
1995;91:1512.
174 Strickberger SA, Benson DW, Biaggioni I, et al. AHA/ACCF scientific statement on
the evaluation of syncope: from the American Heart Association Councils on
Clinical Cardiology, Cardiovascular Nursing, Cardiovascular Disease in the Young,
and Stroke, and the Quality of Care and Outcomes Research Interdisciplinary
Working Group; and the American College of Cardiology Foundation: in
collaboration with the Heart Rhythm Society: endorsed by the American
Autonomic Society. Circulation. 2006;113:316.
175 Blumhardt LD, Smith PE, Owen L. Electrocardiographic accompaniments of
temporal lobe epileptic seizures. Lancet. 1986;1:1051.
176 Constantin L, Martins JB, Fincham RW, et al. Bradycardia and syncope as
manifestations of partial epilepsy. J Am Coll Cardiol. 1990;15:900.
177 Wilder-Smith E. Complete atrioventricular conduction block during complex
partial seizure. J Neurol Neurosurg Psychiatry. 1992;55:734.
178 Liedholm LJ, Gudjonsson O. Cardiac arrest due to partial epileptic seizures.
Neurology. 1992;42:824.
179 Rocamora R, Kurthen M, Lickfett L, et al. Cardiac asystole in epilepsy: clinical and
neurophysiologic features. Epilepsia. 2003;44:179.
180 Takayanagi K, Hisauchi I, Watanabe J, et al. Carbamazepine-induced sinus node
dysfunction and atrioventricular block in elderly women. Jpn Heart J.
1998;39:469.
181 Keilson GR, Schwartz WJ, Recht LD. The preponderance of posterior circulatory
events is independent of the route of cardiac catheterization. Stroke.
1992;23:1358.182 Vik-Mo H, Todnem K, Folling M, et al. Transient visual disturbance during cardiac
catheterization with angiography. Cathet Cardiovasc Diagn. 1986;12:1.
183 Kosmorsky G, Hanson MR, Tomsak RL. Neuro-ophthalmologic complications of
cardiac catheterization. Neurology. 1988;38:483.
184 Serry R, Tsimikas S, Imbesi SG, et al. Treatment of ischemic stroke complicating
cardiac catheterization with systemic thrombolytic therapy. Catheter Cardiovasc
Interv. 2005;66:364.
185 Malenka DJ, O’Rourke D, Miller MA, et al. Cause of in-hospital death in 12,232
consecutive patients undergoing percutaneous transluminal coronary angioplasty.
The Northern New England Cardiovascular Disease Study Group. Am Heart J.
1999;137:632.
186 Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary
angioplasty and intravenous thrombolytic therapy for acute myocardial
infarction: a quantitative review. JAMA. 1997;278:2093.
187 Grines CL, Cox DA, Stone GW, et al. Coronary angioplasty with or without stent
implantation for acute myocardial infarction. Stent Primary Angioplasty in
Myocardial Infarction Study Group. N Engl J Med. 1999;341:1949.
188 Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment
before percutaneous coronary intervention in patients with ST-elevation
myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA.
2005;294:1224.
189 Cronin L, Mehta SR, Zhao F, et al. Stroke in relation to cardiac procedures in
patients with non-ST-elevation acute coronary syndrome: a study involving
>18000 patients. Circulation. 2001;104:269.
190 Fuchs S, Stabile E, Kinnaird TD, et al. Stroke complicating percutaneous coronary
interventions: incidence, predictors, and prognostic implications. Circulation.
2002;106:86.
191 Cucherat M, Bonnefoy E, Tremeau G. Primary angioplasty versus intravenous
thrombolysis for acute myocardial infarction. Cochrane Database Syst Rev. 2003.
CD001560
192 Patel TN, Bavry AA, Kumbhani DJ, et al. A meta-analysis of randomized trials of
rescue percutaneous coronary intervention after failed fibrinolysis. Am J Cardiol.
2006;97:1685.
193 Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous
thrombolytic therapy for acute myocardial infarction: a quantitative review of 23
randomised trials. Lancet. 2003;361:13.
194 Maggioni AP, Franzosi MG, Farina ML, et al. Cerebrovascular events after
myocardial infarction: analysis of the GISSI trial. Gruppo Italiano per lo Studio
della Streptochinasi nell’Infarto Miocardico (GISSI). BMJ. 1991;302:1428.
195 Maggioni AP, Franzosi MG, Santoro E, et al. The risk of stroke in patients withacute myocardial infarction after thrombolytic and antithrombotic treatment.
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico II
(GISSI-2), and The International Study Group. N Engl J Med. 1992;327:1.
196 An international randomized trial comparing four thrombolytic strategies for
acute myocardial infarction. The GUSTO investigators. N Engl J Med.
1993;329:673.
197 Giugliano RP, McCabe CH, Antman EM, et al. Lower-dose heparin with
fibrinolysis is associated with lower rates of intracranial hemorrhage. Am Heart J.
2001;141:742.
198 Gebel JM, Sila CA, Sloan MA, et al. Thrombolysis-related intracranial hemorrhage:
a radiographic analysis of 244 cases from the GUSTO-1 trial with clinical
correlation. Global Utilization of Streptokinase and Tissue Plasminogen Activator
for Occluded Coronary Arteries. Stroke. 1998;29:563.
199 Gore JM, Granger CB, Simoons ML, et al. Stroke after thrombolysis. Mortality and
functional outcomes in the GUSTO-I trial. Global Use of Strategies to Open
Occluded Coronary Arteries. Circulation. 1995;92:2811.
200 Mahaffey KW, Granger CB, Sloan MA, et al. Neurosurgical evacuation of
intracranial hemorrhage after thrombolytic therapy for acute myocardial
infarction: experience from the GUSTO-I trial. Global Utilization of Streptokinase
and tissue-plasminogen activator (tPA) for Occluded Coronary Arteries. Am Heart
J. 1999;138:493.Chapter 6
Neurological Manifestations of Infective Endocarditis
Linda S. Williams, Bradley L. Allen
HISTORICAL OVERVIEW
EPIDEMIOLOGY OF NEUROLOGICAL COMPLICATIONS
PATHOPHYSIOLOGY OF NEUROLOGICAL COMPLICATIONS
RISK FACTORS FOR NEUROLOGICAL COMPLICATIONS
Site of Infection
Infecting Organism
Acuteness of Infection
Valvular Vegetations
Hematological Risk Factors
ISCHEMIC STROKE
Clinical Presentation
Seizures
Evaluation of Patients
Treatment of Ischemic Stroke
Anticoagulation in Native Valve Endocarditis
Anticoagulation in Prosthetic Valve Endocarditis
Surgical Treatment
HEMORRHAGIC STROKE
Clinical Presentation
Evaluation
Treatment of Hemorrhagic Stroke
Intraparenchymal Hemorrhage
Mycotic Aneurysms
CEREBRAL INFECTION
Clinical Presentation
Evaluation
Treatment of Cerebral Infection
OTHER NEUROLOGICAL COMPLICATIONS
SUGGESTED MANAGEMENT ALGORITHM
PROGNOSIS
CONCLUDING COMMENTSHISTORICAL OVERVIEW
The relationship between infection of the heart valves and arterial embolization was . rst
1recognized by Rudolf Virchow in the mid-1800s and the classic clinical triad of fever, heart
murmur, and hemiplegia was described 30 years later by Osler in his Gulstonian Lectures of
21885. The understanding of infective endocarditis has evolved since these early descriptions to
a concept of the disease having di9erent predisposing conditions, di9erent propensity for sites of
valve infection, di9erent infecting organisms, and di9erent treatments, but the proportion of
patients with neurological manifestations has remained relatively constant. It is important to
recognize any neurological complications not only because they are frequent but also because
they may require alterations in treatment and are often associated with increased morbidity and
mortality in infective endocarditis. Although the key to treating neurological complications is
appropriate antibiotic therapy, the presence of neurological manifestations often alters
concomitant medical or surgical treatment of infective endocarditis. This chapter reviews the
most common neurological manifestations of infective endocarditis, detailing their epidemiology
and clinical presentations, suggesting appropriate diagnostic evaluations, and discussing
treatment options.
EPIDEMIOLOGY OF NEUROLOGICAL COMPLICATIONS
Neurological events have long been recognized as frequent and severe complications of infective
endocarditis. In series of patients from the 1950s onward, the overall frequency of neurological
complications has remained relatively constant at approximately 20 to 40 percent (Table
63-151). One reason for the similarity of these reports is that cerebral emboli are almost always
symptomatic; the only study to date that has systematically performed cerebral and abdominal
imaging in patients with infective endocarditis regardless of symptoms showed that the overall
proportion of cases with cerebral embolization was 34 percent and that more than 90 percent of
9these cerebral emboli were symptomatic. Nevertheless, because of the high overall incidence of
stroke in the general population, infective endocarditis is an unusual cause of stroke.
Neurological complications of infective endocarditis can be divided into three major types:
ischemic stroke, hemorrhagic stroke, and cerebral infection (Table 6-1). Ischemic stroke is by far
the most common, occurring in 20 to 30 percent of patients and accounting for 50 to 75 percent
of all neurological complications. Primary cerebral hemorrhage, usually intraparenchymal or
subarachnoid, is less common, reported in 2 to 17 percent of patients. Secondary hemorrhagic
transformation of an ischemic stroke, however, is not uncommon and is estimated to occur in 20
to 40 percent of ischemic strokes. Cerebral infections may manifest without previous clinical
evidence of ischemic or hemorrhagic stroke in less than 10 percent of cases; typical infections
include cerebritis, meningitis, and microabscesses or macroabscesses. Other neurological
symptoms, including seizures, headache, mental status changes, and neuropsychological
abnormalities, sometimes occur but are usually secondary to one of the three major
complications. Rarely, endocarditis has been associated with spinal cord infarction or abscess,
discitis, retinal ischemia, and ischemic cranial and peripheral neuropathies.
TABLE 6-1 Common Neurological Complications in Patients With Infective EndocarditisPATHOPHYSIOLOGY OF NEUROLOGICAL COMPLICATIONS
Almost all the neurological complications of infective endocarditis have embolization as their
primary cause. Although cerebral emboli are probably not more common than extracerebral
9emboli, they are more often symptomatic and thus more frequently reported, and they are
associated with an increased morbidity and mortality compared to other systemic emboli.
Cerebral emboli most often a9ect the middle cerebral artery (MCA) territory and may be septic
or nonseptic; either type can cause ischemic stroke. Septic emboli may also lead to hemorrhagic
stroke through the development of arteritis or mycotic aneurysm, to cerebral microabscess or
macroabscess, usually by seeding of ischemic tissue, and to cerebritis or meningitis by seeding of
the meninges (Fig. 6-1). Although the term bacterial intracranial aneurysm has been suggested as
16more appropriate, the term mycotic aneurysm continues to be widely used and is therefore used
here.
FIGURE 6-1 Embolization to various cerebral structures is responsible for most of the
neurological complications of infective endocarditis. Emboli that lodge in the lumen of cerebral
vessels may lead to ischemic stroke and can lead to arteritis or mycotic aneurysm formation withresultant vessel rupture and cerebral hemorrhage. Emboli to the meninges may produce
meningitis, and emboli to the brain parenchyma, especially when associated with cerebral
ischemia, may result in meningoencephalitis or abscess.
(Reprinted with permission from Solenski NJ, Haley EC Jr: Neurological complications of infective
endocarditis. p. 331. In Roos KL [ed]: Central Nervous System Infectious Diseases and Therapy. Marcel
Dekker, New York, 1997.)
Most primary intracerebral hemorrhages in infective endocarditis result from septic embolism,
followed by septic necrosis and rupture of the vessel wall; less commonly, they result from
5,17-19rupture of mycotic aneurysms. Masuda and colleagues found that 10 of 16 patients with
infective endocarditis and intracerebral bleeding had pyogenic arteritis, in 5 of whom rupture
occurred without evidence of concomitant mycotic aneurysm; 13 of the 16 had either septic
18emboli or arteritis, or both. Intracerebral hemorrhage may also occur owing to a secondary
hemorrhage into an ischemic infarct. In one histopathological series of 17 patients, it was due to
secondary transformation of ischemic infarction in 24 percent of cases, necrotic arteritis in 24
percent, mycotic aneurysm in 12 percent, and other causes in 11 percent; in 29 percent it was of
17unknown etiology.
Mycotic aneurysm formation has been related to (1) septic embolization to the arterial lumen,
20producing intraluminal wall necrosis and outward extension of infection, and (2) septic
embolization to the adventitial layer of the artery, resulting in destruction of the adventitia and
21,22muscularis layers and subsequent aneurysmal dilation. Mycotic aneurysms are usually
small, located at distal arterial bifurcations, rather than on the circle of Willis, and can be single
or multiple. Branches of the MCA are the most common location for mycotic aneurysms; in one
23series, almost 40 percent of all mycotic aneurysms involved distal MCA vessels. Rarely,
mycotic aneurysms involve extracranial vessels, including the internal carotid artery (Fig. 6-2).
FIGURE 6-2 This patient with fungal endocarditis developed headache, confusion, and
decreased level of consciousness without focal de. cits. A, Head computed tomography (CT)showed subarachnoid hemorrhage (increased density) in the perimesencephalic cistern, left more
than right, and dilatation of the temporal horns of the lateral ventricles. B, Digital subtraction
angiography showed a large aneurysm of the cavernous portion of the left internal carotid
artery. The aneurysm was treated with endovascular coils to occlude the carotid artery.
Brain macroabscesses account for less than 1 percent of all neurological complications of
infective endocarditis and may occur secondary to ischemic infarction from a septic embolus or
to extension of infection from adjacent arteritis or mycotic aneurysm. Brain microabscesses are
more common than macroabscesses and usually occur in cases with multiple ischemic infarctions
as a result of distal migration of septic embolic fragments. Microabscesses have been associated
most commonly with Staphylococcus aureus infections. Meningoencephalitis is usually a result of
embolization to meningeal vessels, with subsequent parenchymal or cerebrospinal Euid (CSF)
invasion of the infecting organism. Aseptic meningitis may also occur with subarachnoid
hemorrhage due to a necrotic arteritis or ruptured mycotic aneurysm.
RISK FACTORS FOR NEUROLOGICAL COMPLICATIONS
A variety of clinical and laboratory variables have been associated with an increased risk of
neurological complications (Table 6-2), including site and type of valve infection, virulence of
the infecting organism, acuteness of infection, presence of valvular vegetations, increased size
and mobility of vegetations, and certain hematological factors.
TABLE 6-2 Suggested Risk Factors for Embolization in Infective Endocarditis
Risk Factor Proposed Mechanism
Mitral valve Increased valve mobility and left-sided position predispose to systemic
infection embolization
“Virulent” More rapid endothelial invasion leads to more friable, unstable valve surface
organism
Acuteness of More rapid endothelial invasion leads to more friable, unstable valve surface
infection
Valvular Increasing vegetation size and vegetation mobility may predispose to
vegetations embolism
Hematological Increased endothelial cell activity, platelet aggregability, and
factors antiphospholipid antibodies may be associated with increased risk of
embolization
Site of Infection
Neurological complications are more common with left-sided than with right-sided valve
11,24,25involvement, although some series have found increased embolism in patients with
26,27right-sided infective endocarditis. Cerebral embolization in right-sided endocarditis may
occur via embolization through a patent foramen ovale or a pulmonary arteriovenous
28,29fistula. Mitral valve infection has been associated most commonly with neurological
complications; in one series, mitral valve infection was found in 76 percent of cases with30neurological complications compared to 37 percent of other cases (P and this association has
3,10,31-33also been reported by others. However, Wong and colleagues reported associations
between aortic valve infection and stroke, with 44 percent of those with stroke having large
34aortic valve vegetations compared with a 9 percent prevalence in those without stroke. Some
authors have found no relationship between the site of infection and the occurrence of
4,13,26,35 36,37neurological complications. Although disagreement exists, most reports
comparing native valve and prosthetic valve endocarditis indicate no significant difference in the
proportion of patients with neurological complications. Among patients with prosthetic valve
endocarditis, however, mechanical valves may be associated with complications more often than
38bioprosthetic valves.
Infecting Organism
Several important changes in the type and characteristics of the infecting organism in infective
endocarditis have become evident in the past few years. Although streptococci, staphylococci,
and enterococci remain the three most prevalent infecting organisms, some recent studies report
that staphylococcal is now more common than viridans group streptococcal infective endocardi
12,39tis. More problematic than a shift in type of infecting organism is the growing prevalence of
antibiotic resistance among these organisms, especially resistant viridans group streptococci and
40,41methacillin- and van-comycin-resistant S. aureus. This changing resistance pattern is
reEected in updated guidelines from the American Heart Association on diagnosis, antimicrobial
42treatment, and management of complications in patients with infective endocarditis.
It is unclear whether antibiotic susceptibility changes have an impact on the risk of embolic
complications, although an infection with a resistant organism that takes longer to control might
well be associated with an increased risk of embolization. Previous studies have linked an
3,4,30,33,35,43increased risk of cerebral embolization to endocarditis due to S. aureus,
3 3 44 3enterococci, Escherichia coli, Streptococcus bovis, various fungi, enterobacteriaceae, and
3,45anaerobic bacteria. Several studies have shown that, even after adjusting for other factors, S.
14,15 14aureus and S. bovis were independently associated with embolism. In prosthetic valve
endocarditis, speci. cally, Staphylococcus epidermidis has been associated with more neurological
46complications than S. aureus. Endocarditis due to Streptococcus pneumoniae has been
47,48associated with an increased risk of meningitis (50% to 90% of cases), and S. aureus
49endocarditis has been associated with brain abscess. The current summation of these varied
reports is that the virulence of the organism, the availability of e9ective antimicrobial therapy,
and the potential development of large, friable vegetations all contribute to the propensity for
embolization.
Acuteness of Infection
There is a higher risk of neurological complications with acute endocarditis than with subacute
endocarditis. This probably relates to the typical etiological agents noted in acute disease (S.
aureus and beta-hemolytic streptococci), the potential for large vegetations or valve damage, and
the subsequent increased risk of cerebral embolization. Many authors have observed that the risk
of cerebral embolization is highest in the . rst 1 to 2 weeks of infection, with most patients either
presenting with a neurological complication or experiencing an acute event in the . rst 48 hours
3,5,10,13,14,33,50after diagnosis. Similarly, the risk of embolization decreases as the duration ofe9ective antibiotic treatment increases, with most events occurring in the . rst 2 weeks of
14,33,50therapy.
Valvular Vegetations
Valvular vegetations are detected by two-dimensional echocardiography in 50 to 80 percent of
patients with infective endocarditis and by transesophageal echocardiography (TEE) in more
32,36,51-53than 90 percent of cases. Because of its increased sensitivity and ability to evaluate
the more posteriorly located aortic valve, transesophageal echocardiography appears to be
cost54,55e9ective as the initial study if clinical suspicion of infective endocarditis is high. Although
some older clinical series revealed no signi. cant di9erence in the development of neurological
4,8,50,56-58complications between patients with and without vegetations, most recent studies
have linked either the presence of vegetations, increased vegetation size, or vegetation mobility
13,26,27,32,59-63to an increased risk of embolization. The emergence of this relationship may be
related to greater access and improved technical capabilities of echocardiography in the more
recent series. A prospective study of 384 patients with infective endocarditis, all of whom had
transesophageal echocardiography, found that vegetation length greater than 10 mm and
vegetation mobility increased the risk of embolism and that vegetation length greater than 15
14mm independently increased 1-year mortality. The signi. cance of changes in vegetations on
serial echocardiography remains unclear: some investigators report that morphological changes
64in vegetation size or consistency are not associated with complications, whereas others . nd
that an increase in vegetation size during antibiotic treatment is associated with increased
33,65,66complications. A . nal echocardiographic variable that may be related to complications
is the presence of spontaneous echo contrast imaging. In a multivariate analysis, Rohmann and
colleagues found that spontaneous echo contrast on transesophageal echocardiography was an
independent predictor for embolization and hypothesized that this . nding signi. ed increased
67spontaneous platelet aggregation. Current recommendations suggest that repeat
echocardiography may be useful if clinical changes that suggest treatment failure occur during
antibiotic therapy and that it should be performed urgently for unexplained progression of heart
42failure, new heart murmurs, or the development of atrioventricular block.
Hematological Risk Factors
In addition to spontaneous echo contrast, some reports also present evidence of an association
13,68-71between coagulation system activation and embolic events. In a series of 91 patients
with infective endocarditis, antiphospholipid antibodies were present in 62 percent of patients
with embolic events compared to 23 percent of those without such events (P = 0.008) and were
also positively correlated with other markers of endothelial cell activation, thrombin generation,
69and impaired . brinolysis. Antiphospholipid antibodies have also been reported to decrease
70after successful treatment of infective endocarditis. Whether antiphospholipid antibodies
independently increase the risk of embolism or this risk results from the association of these
antibodies with increased numbers and size of vegetations remains to be determined. Similarly,
soluble adhesion molecules have also been reported to independently increase the risk of
13,71embolism. At present, however, these hematological studies do not clearly aid in risk
prediction for patients with infective endocarditis.
ISCHEMIC STROKEIschemic stroke secondary to embolization of friable valvular material is the most common
neurological complication of infective endocarditis. Most cerebral emboli are symptomatic, but
9they can be asymptomatic in as many as 35 percent of patients. Ischemic stroke is the
3,30presenting symptom of infective endocarditis in up to 20 percent of cases and is most
common in the acute stage of the infection, that is, before antibiotic treatment is begun or
4,5,10during the . rst several days of treatment (median time, 4 to 10 days). Because of this
clustering of symptoms in the acute phase, transient focal neurological symptoms in a febrile
patient, especially in the presence of a regurgitant murmur, should always raise suspicion for
infective endocarditis.
Clinical Presentation
In accordance with their embolic etiology, the majority of ischemic strokes involve the cortex,
rather than being con. ned to subcortical brain tissue. One series found that 62 percent of strokes
a9ected the cerebral or cerebellar cortex (with or without additional subcortical involvement),
5and only 16 percent were exclusively subcortical. Brainstem strokes account for 10 percent or
3less of all strokes in infective endocarditis.
Because of their cortical involvement, ischemic strokes often present with aphasia, if the
dominant hemisphere is involved, or visual or spatial neglect, if the nondominant hemisphere is
a9ected. If the embolus lodges in the posterior cerebral artery, homonymous hemianopia can
result. In addition to the more typical focal cerebral hemispheric or brainstem syndromes,
3multiple microemboli are clinically manifest in as many as 11 percent of cases and in more
72than 50 percent of cases systematically evaluated with neuroradiological studies. Patients with
microemboli can present with nonlocalizing symptoms, including diminished level of
consciousness, encephalopathy, or psychosis.
Clinical worsening of ischemic stroke may result from a variety of mechanisms, including
development of cerebral edema, recurrent embolization and stroke, secondary hemorrhage into
the ischemic area, and development of cerebral abscess. Cerebral edema may occur regardless of
ischemic stroke mechanism, is more likely to be symptomatic in larger strokes and younger
patients, and is typically maximal between 72 to 96 hours after stroke. Recurrent embolization
should be suspected if new focal de. cits develop; this complication is most likely to occur early
in the course of treatment or if infection is uncontrolled. Hemorrhagic transformation of an
ischemic stroke occurs in 18 to 42 percent of all patients with ischemic stroke and has been
73reported to be more common in cardioembolic strokes. An autopsy series of patients with
neurological complications of infective endocarditis found hemorrhagic transformation of an
18ischemic infarct in 9 of 16 patients. Hemorrhagic transformation of an ischemic stroke is often
asymptomatic, although development of intrainfarct hematoma is more likely to be symptomatic
73than is the development of petechial hemorrhage. The term septic infarction has been used
when, several days to weeks after an ischemic stroke, a cerebral abscess develops within the
72infarcted tissue (Fig. 6-3). The frequency with which this occurs is not known.FIGURE 6-3 This patient presented with left hemiparesis and mitral valve endocarditis. A,
Noncontrast head CT showed a focal low-density lesion in the right internal capsule and
lentiform nucleus with a central area of hemorrhage (increased density) and cortical hemorrhage
in the insula. B, With contrast, large conEuent areas of enhancement representing leaky blood–
brain barrier can be seen in the right caudate and lentiform nuclei, the insula, and the temporal
cortex. C, Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). MRI 2
days after the head CT showed di9use increased signal in the regions of CT enhancement and the
right thalamus. D, After gadolinium, ring-like enhancement in the area of a previous infarct can
be seen, representing possible secondary infection. This pattern is sometimes referred to as a
“septic infarction.” This enhancement pattern resolved with antibiotic treatment and without
development of a macroabscess.
Seizures
Although seizures can occur in patients with infective endocarditis as a result of toxic or
metabolic disturbances (e.g., hypoxia, antibiotic toxicity), most often seizures are secondary to
ischemic or hemorrhagic stroke. The proportion of patients with seizure as the presentingsymptom of infective endocarditis was 2 percent in one large series; 11 percent of patients had
3seizures during the course of their illness. Seizures that are secondary to focal brain injury are
usually focal in nature, with or without secondary generalization, whereas seizures due to
metabolic or toxic factors are more often primarily generalized. The development of seizures
during antibiotic treatment often signi. es clinical worsening from either recurrent stroke,
hemorrhagic transformation, or abscess formation. Thus, new onset of seizures should always
prompt an urgent neuroimaging study. Rarely, seizures are secondary to antibiotic therapy, with
imipenem the antibiotic having the greatest seizure proclivity.
Evaluation of Patients
All patients with acute focal neurological de. cits should have a noncontrast head computed
tomography (CT) scan or brain magnetic resonance imaging (MRI). Noncontrast CT allows for
the most accurate distinction between hemorrhagic and ischemic events and can be done more
quickly than MRI in most settings. If infective endocarditis is known or suspected, head CT with
and without contrast may be useful; areas of increased contrast enhancement, representing
possible cerebral abscess may then be distinguished from areas of ischemia (Fig. 6-3). Although
published radiological series are few, brain MRI appears to be more sensitive than CT in
detecting the multiplicity of neurological lesions seen in infective endocarditis. In one series,
multiple lesions were found in 10 of the 12 patients studied, with embolic branch infarction (8),
multiple emboli and microabscesses (7), and hemorrhagic stroke (4) being the most common
72findings. MRI . ndings have been categorized into four patterns: (1) embolic infarction, (2)
multiple patchy infarctions (nonenhancing), (3) small nodular or ring-enhancing white matter
lesions (probably microabscesses), and (4) hemorrhagic infarctions (intraparenchymal or
74subarachnoid). Microabscesses usually develop several days after the ischemic stroke and can
75be asymptomatic or associated with clinical deterioration. Multiple microabscesses are often
responsible for nonfocal encephalopathy. MRI is superior to CT for symptoms referable to the
brainstem or cerebellar regions.
Once cerebral embolism has occurred, serial neuroimaging studies or subsequent angiography
can be performed to assess the presence of secondary complications such as microabscess or
macroabscess formation, hemorrhagic transformation of ischemic stroke, or development of a
mycotic aneurysm. Most authors agree that patients without neurological symptoms do not
require cerebral angiography and that those with intracerebral hemorrhage do require
76angiography, but whether to perform cerebral angiography after ischemic stroke in patients
with infective endocarditis is especially controversial. The 2005 AHA statement on diagnosis and
treatment of infective endocarditis suggests that diagnostic pursuit of mycotic aneurysms should
be considered in patients with severe headache, erythrocytes or xanthochromia in CSF, or focal
42neurological signs.
Based on the evidence that subarachnoid hemorrhage can occur without previous symptoms in
more than 50 percent of patients with mycotic aneurysm, some authors recommend that all
patients with cerebral embolism have arterial imaging performed at some time beyond 48 hours
77after the initial event. The basis for the timing of this recommendation is that mycotic
aneurysm formation after septic embolization takes at least 48 hours to develop, and
angiography immediately after embolization may therefore be negative. Although some studies
suggest a more rapid angiographic evaluation based on early mycotic aneurysmal rupture within
7824 hours of the onset of neurological symptoms, others argue that a mycotic aneurysm
develops in so few patients that angiographic complications present a greater risk. Using thepublished literature, van der Meulen and colleagues estimated the probability of 12-week
survival in patients with infective endocarditis and ischemic stroke and found no added survival
bene. t for patients who had angiography, largely owing to the low prevalence of mycotic
76aneurysms and the low risk of their rupture in patients with adequate antibiotic therapy. Since
so few patients with infective endocarditis harbor mycotic aneurysms, the need to perform initial
or serial angiography depends on the clinical presentation and proposed treatment. Patients with
hemorrhagic stroke or hemorrhagic transformation of an ischemic stroke should have
angiography to delineate mycotic aneurysm from arteritis because this distinction often
inEuences subsequent evaluation and treatment. Patients with ischemic or hemorrhagic stroke
who require long-term anticoagulation for mechanical valves or treatment of systemic
thromboembolism, for example, may also bene. t from angiography to exclude a mycotic
aneurysm. Patients with ischemic stroke without hemorrhagic transformation or any indication
for long-term anticoagulation probably do not bene. t from repeated neuroimaging studies or
conventional angiography.
The diagnosis of infective endocarditis depends on the documentation of an infecting organism
on serial blood cultures and, in part, on the presence of valve abnormalities on
42echocardiography. Echocardiography is also important in assessing valve function and
excluding conditions such as valve thrombosis or abscess formation that would change clinical
management. Transesophageal echocardiography is more sensitive to mitral and aortic valve
pathology and has been reported to change patient management in as many as one third of
79cases. Whether serial echocardiography provides data that reliably predict risk of subsequent
thromboembolism or otherwise influence management is not known.
CSF examination is regarded by some authors as part of the standard evaluation of patients
with infective endocarditis and neurological symptoms. The manner in which the CSF results will
inEuence therapy, however, is not clear. The interpretation of CSF . ndings as a diagnostic tool
for infective endocarditis in patients with acute stroke is complicated by the tendency for
patients with cerebral embolism unrelated to endocarditis also to have mild to moderate
increases in either white blood cells, red blood cells, or protein concentration in the CSF shortly
80,81after stroke. In one large series, CSF was abnormal in 48 of 69 patients with infective
3endocarditis in whom it was examined. Of these, 28 percent had a purulent pro. le, 25 percent
were aseptic, 13 percent were hemorrhagic, and 30 percent were normal. With the exception of
purulent CSF in patients with meningismus, the type of neurological event in these patients did
not correlate with the CSF pattern. For these reasons, CSF examination does not usually aid in
the diagnosis or management of patients with neurological symptoms and infective endocarditis.
Treatment of Ischemic Stroke
The cornerstone of treatment of infective endocarditis is appropriate antibiotic therapy directed
at the infecting organism. Numerous studies have shown that the risk of either initial or recurrent
thromboembolism decreases sharply after the . rst few days of adequate antibiotic
4-7,33,51therapy. Although this association may result in part from an ascertainment bias, it is
critical to ensure that antibiotics are begun empirically, immediately after drawing initial blood
for cultures (preferably three sets from separate sites) in febrile patients with stroke in whom
infective endocarditis is among the di9erential diagnoses. Since e9ective long-term antimicrobial
therapy will be required to treat infective endocarditis, the isolation and susceptibility testing of
the pathogen are of critical importance. Involvement of an infectious diseases consultant is
recommended. Thorough discussion of a current approach to diagnosis and antimicrobial42treatment in various clinical scenarios can be found in the 2005 AHA guideline statement.
Recent studies have addressed the question of whether acute antiplatelet therapy is bene. cial
in reducing the risk of thromboembolism in infective endocarditis. In animal models of the
disease, aspirin or aspirin plus ticlopidine has been found to reduce vegetation weight,
echocardiographic evidence of vegetation growth, bacterial titer of vegetations, or systemic
82-84 85emboli. Although one pilot study con. rmed this . nding, a larger randomized controlled
trial found no reduction of embolic events in patients treated with 325 mg aspirin compared to
those given placebo, and there was a nonsigni. cant trend toward increased bleeding in the
86aspirin-treated group. Based on this study, routine use of antiplatelet therapy for the purpose
42of decreasing embolic risk in patients with acute infective endocarditis is not recommended.
Anticoagulation in patients with infective endocarditis remains a controversial and
complicated topic. Hemorrhagic complications are clearly more common in anticoagulated
patients, with one retrospective study . nding that 50 percent of the hemorrhages occurred in the
8713 percent of subjects receiving anticoagulation. However, patients with mechanical
prosthetic valves may be receiving long-term anticoagulation, and the decision as to whether
and for how long to withhold anticoagulants in this setting is especially diK cult. Given the
divergent management strategies required, it is useful to consider anticoagulation in native and
prosthetic valve endocarditis separately.
Anticoagulation in Native Valve Endocarditis
Many authors have documented an increased risk of hemorrhagic complications in
anticoagulated patients with native valve endocarditis and ischemic stroke, and the risk of
recurrent embolism is low in patients receiving appropriate antibiotic therapy. Accordingly,
there appears to be little bene. t to anticoagulating patients with native valve endocarditis.
Whether lower-level anticoagulation (e.g., for prevention of deep venous thrombosis) is safe in
patients with stroke and infective endocarditis is unknown. Because other strategies, such as
using sequential compression devices, have been shown to be equally eK cacious, a conservative
approach is to use these nonpharmacological methods of prevention of venous thrombosis.
Anticoagulation in Prosthetic Valve Endocarditis
Patients with bioprosthetic valves are typically not on long-term anticoagulation and have a
38,46lower risk of stroke in infective endocarditis than patients with mechanical valves ; thus, the
same rationale applies to them as for patients with native valve endocarditis. Patients with
mechanical prostheses who have endocarditis and stroke, however, present especially diK cult
management dilemmas. Most studies indicate that the proportions of patients with native and
4,5prosthetic valves having endocarditis and cerebral embolism are similar ; initiating
anticoagulation in a previously nonanticoagulated patient with infective endocarditis and a
mechanical valve thus appears unwarranted.
If a patient with a mechanical valve is receiving long-term anticoagulation and develops a
cerebral embolus as a complication of infective endocarditis, the decision as to whether to
continue anticoagulation or temporarily withhold it depends on several factors, including the
size of the stroke and type of mechanical valve. Some authors have suggested that
anticoagulation decreases the risk of cerebral embolism and should be instituted in all patients
87,88with newly diagnosed prosthetic valve endocarditis. Because larger strokes, especially those
76secondary to emboli, may be more likely to develop secondary hemorrhagic complications,other authors favor withholding anticoagulation for several days in patients with acute cerebral
embolism and mechanical valve endocarditis, especially when S. aureus is the infecting
89,90organism.
Regardless of the timing of anticoagulation, it is safer to convert the patient from oral
anticoagulation to the more controlled intravenous route of therapy during the acute phase of
infective endocarditis. Some authors have not found a decrease in cerebral emboli in patients
46with acute prosthetic valve endocarditis anticoagulated with warfarin or have documented a
88rate of hemorrhagic complications as high as 36 percent in this subgroup of patients, thus
leading to the position that anticoagulants should not be initiated and perhaps should be
temporarily discontinued in previously anticoagulated patients with prosthetic valve
5,91endocarditis. If temporary discontinuation of anticoagulation is considered, determination of
the patient’s type of mechanical valve and consultation with a cardiologist or a cardiothoracic
surgeon concerning the risk of valve thrombosis with that valve type will help guide the decision
about how long the patient can safely remain o9 anticoagulation. Although the use of
anticoagulants remains controversial, converting to the most controllable (i.e., intravenous) form
of therapy and frequent monitoring of anticoagulation parameters (activated partial
thromboplastin time or international normalized ratio [INR]) are recommended. Solenski and
Haley recommend that large cerebral infarctions, hemorrhage on CT scan, presence of mycotic
aneurysm, uncontrolled infection or infection with S. aureus, history of bleeding diathesis, and
possibly advanced patient age are factors arguing against the use of anticoagulation in patients
92with neurological complications of mechanical valve endocarditis.
Surgical Treatment
Valve replacement is not usually recommended as a therapy for preventing initial or recurrent
stroke, although multiple emboli, infection with a “virulent” organism, and the presence of large
26,61vegetations may be relative indications for surgery. Typically, surgery is reserved for
patients with acute or refractory congestive heart failure, perivalvular abscess, unstable valve
prosthesis, continued embolism, infection with a pathogen resistant to e9ective antimicrobial
agents, or inability to clear the infection. If surgery is required, the timing of the procedure in a
patient with ischemic or hemorrhagic stroke is controversial. If surgery is contemplated to
prevent embolization, early surgery is associated with greatest bene. t since the risk of
embolization is greatest in the . rst 2 weeks of the infection. If stroke has occurred, the . rst 72 to
120 hours after stroke are the period of maximal risk of cerebral edema and disruption of
cerebral autoregulation; thus, most authors recommend delaying cardiac surgery for at least 1
week after stroke if possible. One retrospective assessment of 247 patients operated on for
leftsided native valve endocarditis found that operation at approximately 3 weeks after the
neurological de. cit appeared was as safe for patients with previous neurological complications
93as for those without neurological manifestations of endocarditis.
HEMORRHAGIC STROKE
Intracerebral hemorrhage in infective endocarditis may be primary or secondary to ischemic
stroke or other pharmacological or hematological conditions (Table 6-3; Fig. 6-4). Of the
primary hemorrhages, intraparenchymal and subarachnoid hemorrhage are most common.
Secondary transformation of an ischemic stroke is the most common form of intracerebral
hemorrhage in infectious endocarditis, accounting for 24 to 56 percent of all hemorrhages in this17,18condition. Intracerebral hemorrhage is a much less common complication than ischemic
stroke, accounting for 2 to 17 percent of all neurological complications. In one recent series, only
8 cases of subarachnoid hemorrhage occurred among 489 patients with infective endocarditis; in
946 of these, no cause for the hemorrhage was identi. ed by autopsy or angiography. The
prevalence of asymptomatic mycotic aneurysms in patients with infective endocarditis is not
17known, but seems to be small.
TABLE 6-3 Causes of Intracerebral Hemorrhage in Infective Endocarditis
Primary Intracerebral Hemorrhage
Arterial rupture secondary to arteritis
Rupture of a mycotic aneurysm
Secondary Intracerebral Hemorrhage
Hemorrhagic conversion of ischemic stroke
Anticoagulation
Hematological disorder
Disseminated intravascular coagulopathy
Thrombocytopenia
Vitamin K deficiency
Preexisting central nervous system lesion (e.g., aneurysm, arteriovenous malformation)
FIGURE 6-4 This patient had tricuspid valve endocarditis secondary to intravenous drug abuse.
Initially, the patient had no neurological symptoms but left the hospital against medical advice
after completing 6 days of antibiotic therapy. He returned 2 days later with a decreased level ofconsciousness and a right gaze preference. A toxicology screen was positive for cocaine.
Noncontrast axial head CT at that time showed an approximately 3 × 4-cm hemorrhage in the
right frontal lobe with intraventricular extension and subfalcial herniation. Cerebral angiography
did not show a mycotic aneurysm. Echocardiography showed a large patent foramen ovale with
right-to-left shunting and vegetations on the tricuspid valve. This case underscores several clinical
points: (1) neurological complications of endocarditis are more common during uncontrolled
infection; (2) neurologically asymptomatic patients may have silent cerebral emboli, particularly
in the nondominant hemisphere; and (3) patients with right-sided endocarditis may develop
cerebral embolization via a right-to-left shunt.
As described previously, in at least 40 percent of patients, septic embolization is the . rst event
3,17,77leading to intracerebral hemorrhage. Depending on the location of the embolus, arteritis
with secondary vessel rupture or development of a mycotic aneurysm may occur. Several series
have documented that hemorrhagic complications are more common in anticoagulated patients,
with one third of patients with endocarditis and subsequent intracerebral hemorrhage either
17anticoagulated or having an underlying bleeding diathesis. In one series, 23 percent of all
3intracerebral hemorrhages occurred in the 3 percent of anticoagulated patients ; in another, 50
87percent of all such bleeds occurred in the 13 percent of patients who were anticoagulated.
These observations have led to the consensus to avoid anticoagulation in native valve
endocarditis and to a judicious approach to its use in prosthetic valve endocarditis. Other
conditions that sometimes accompany infective endocarditis may also predispose to bleeding
complications, including disseminated intravascular coagulation, thrombocytopenia, and
vitamin K deficiency.
Although mycotic aneurysms are most commonly found in the intracranial vessels, rarely these
95-97aneurysms may involve the extracranial carotid (Fig. 6-1), thoracic, or abdominal vessels.
Management in these cases should be individualized but may include surgical or endovascular
interventions or vessel ligation.
Clinical Presentation
Intracerebral hemorrhage usually presents with focal neurological symptoms as in ischemic
stroke, but nonlocalizing symptoms, such as headache and decreased level of consciousness, may
also predominate. Seizures may occur at the onset of the hemorrhage or later in its course. If
subarachnoid hemorrhage occurs, either from rupture of an arteritic vessel or from a mycotic
aneurysm, meningismus may be a prominent feature. Headaches may be more di9use and
94subacute than is typical with saccular aneurysm rupture. A transient ischemic attack (TIA)
may precede intracerebral hemorrhage in as many as 25 percent of patients or may be the
98presenting symptom.
Evaluation
As in ischemic stroke, noncontrast head CT is the best initial neuroimaging procedure. The
hematoma appears as an increased-density signal on CT (Fig. 6-4) and can be localized to the
intraparenchymal, subarachnoid, subdural, or intraventricular space. Hemorrhagic
transformation of an ischemic infarct is most often patchy and may follow the contour of the
gyri (Fig. 6-3A), but may appear as a homogeneous hematoma within an infarct. MRI is also
useful and can better delineate stroke in the posterior fossa, although the signal change of blood
products over time may make MRI more diK cult to interpret in hemorrhagic stroke. A clue tothe presence of an underlying mycotic aneurysm may be a focal area of cortical enhancement
99adjacent to an area of hemorrhage.
All patients with intracerebral hemorrhage complicating infective endocarditis should have
imaging of the cerebral vasculature to visualize any underlying mycotic aneurysm. Since
mycotic aneurysms tend to be small and to occur distally, rather than at the more proximal
arterial branch-points as do saccular aneurysms, conventional cerebral angiography is preferred
over magnetic resonance angiography (MRA) or CT angiography (CTA) for aneurysm detection.
Although the resolution of these techniques continues to improve, at present they are adequate
for screening in patients with infective endocarditis and ischemic stroke but should not be the
primary diagnostic tool for evaluating patients with infective endocarditis and hemorrhagic
stroke. They may be useful, however, for serial monitoring of aneurysm size following
conventional angiography. One study reported the utility of monitoring mycotic aneurysms with
serial thin-slice CT or MRI and found that all of six aneurysms identi. ed with conventional
100angiography could be successfully followed for 6 to 8 weeks. Repeat angiography at the end
of antibiotic treatment con. rmed the resolution (in 2) or persistence (3 enlarged, 1 unchanged)
of the aneurysms.
Treatment of Hemorrhagic Stroke
Intraparenchymal Hemorrhage
The mainstay of treatment for either primary or secondary intracerebral hemorrhage in patients
with infective endocarditis is the same as that for cerebral emboli: e9ective treatment of the
underlying infectious organism. This is especially true for patients with pyogenic arteritis but is
also critical for the treatment of mycotic aneurysms. Some patients with intracerebral
hemorrhage and progressive neurological deterioration, either from expanding hematoma or
edema, may bene. t from surgical evacuation of the clot, but no . rm guidelines exist for assisting
with management in these cases. Similarly, although recombinant factor VIIa has been used
successfully to reduce hematoma growth and improve outcomes in patients with intracerebral
101hemorrhage, no data are available for its use in patients with infective endocarditis and
cerebral hemorrhage. The increased risk of thrombosis and stroke associated with its use would
be of concern in this population. As discussed previously, patients with mechanical valves and
receiving anticoagulation therapy may have their anticoagulant discontinued temporarily or
converted to an intravenous form. All patients should have close neurological monitoring in an
intensive care setting because deterioration from recurrent hemorrhage or edema is not
uncommon.
Mycotic Aneurysms
The natural history of mycotic aneurysms is that approximately one third resolve with 6 to 8
weeks of antibiotic treatment, one third remain unchanged in size, and the remaining one third
17,78,100,102,103are equally divided among those that increase and those that decrease in size.
Because of their propensity to resolve with antibiotic therapy, the evaluation and treatment of
mycotic aneurysms are controversial. Aspects of care that remain unclear are whether serial
angiography is needed in patients with mycotic aneurysms and the indications for surgical
therapy.
Because more than one third of mycotic aneurysms either are unchanged in size or enlarge
during antibiotic therapy, some authors recommend serial angiography every 2 weeks during77,104,105antibiotic treatment. If an aneurysm enlarges, surgical treatment to prevent rupture
104-106may be advocated. Late hemorrhage from a ruptured mycotic aneurysm in patients who
have completed adequate antibiotic therapy is rare, occurring in none of 122 patients with a
77 17,107mean 40-month follow-up, but it has been reported. As discussed previously, the need
for ongoing or subsequent long-term anticoagulation is another factor that may favor
angiographic surveillance and surgical treatment, especially in patients with known cerebral
embolization.
Once an aneurysm is discovered, controversy also exists about its treatment. Asymptomatic
aneurysms are often treated medically, with surgical intervention reserved for those that either
105,106enlarge or do not resolve after antibiotic therapy is completed. Although symptomatic
aneurysms may also resolve with antibiotic treatment and the risk of rebleeding is low, some
authors favor surgical treatment of symptomatic mycotic aneurysms in addition to antibiotic
105,106therapy. This recommendation is usually based on the fear of recurrent bleeding, the
associated increased morbidity and mortality, and the potential development of new aneurysms.
Aneurysm accessibility and number are other features that inEuence the decision for surgical
treatment; single aneurysms in a peripheral location are more likely to be treated surgically.
Inaccessible aneurysms may be successfully treated endovascularly, although the management
108-111and outcomes in these cases are highly individualized. Whether to undertake surgery at
presentation or to wait until the completion of antibiotic therapy is debatable. For unruptured
mycotic aneurysms, some authors have suggested serial angiography every 2 weeks during
77,104,105antibiotic therapy, although the proportion of aneurysms that enlarge and thus may
require urgent surgery is small. Since at least half of mycotic aneurysms persist after adequate
antibiotic treatment and since new aneurysms can appear, it seems reasonable to repeat
angiography, either conventional or MRA, at the conclusion of antibiotic therapy (usually 4 to 6
weeks) or to undertake serial imaging with a noninvasive procedure, such as MRA.
Accessible aneurysms that persist after adequate antibiotic therapy or that enlarge during
therapy are usually treated surgically. Because mycotic aneurysms often lack a de. ned neck
amenable to clipping, other surgical techniques, including wrapping, excision, or endovascular
obliteration, may be necessary. Because mycotic aneurysms are often diK cult to locate at the
112time of surgery, new techniques, including stereoscopic brain-surface imaging with MRA and
113stereotactic angiographic localization, are sometimes used to aid in aneurysm localization.
CEREBRAL INFECTION
Cerebral infection, most commonly abscess or meningitis, has been reported as a primary
complication in 6 to 31 percent of cases, although these cases typically represent less than 10
percent of the entire population of patients with endocarditis and neurological complications
(Table 6-1). These infections most typically occur after cerebral embolism; infection arising
without clinical evidence of prior cerebral embolization is unusual. Encephalitis has also been
reported, although the usual pathology in these cases is multiple emboli with microabscess
formation.
Meningitis accounts for 4 to 7 percent of all neurological manifestations of infective
endocarditis and is reported to be more common with either S. aureus or S. pneumoniae
3,114,115infections. When meningitis is associated with involvement of the cerebral cortex,
evidenced by gyral enhancement on MRI, the terms cerebritis and meningoencephalitis are used.
Rarely, cerebritis can lead to the development of a parameningeal abscess in the cortex.Meningitis typically results from septic emboli to the meningeal vessels with subsequent CSF
colonization. Less commonly, meningitis is nonseptic, resulting from sterile inEammation of the
meninges due to blood products or circulating immune complexes in the CSF.
Cerebral abscesses are rare, accounting for approximately 2 percent of all neurological
116complications in infective endocarditis. Small “microabscesses,” often de. ned as abscesses
3smaller than 1 cm , are more common than “macroabscesses” but still account for less than 4
percent of all neurological complications. Cerebral abscess usually develops as the result of septic
embolus and is not necessarily preceded by clinical symptoms. Radiographically,
infarctionrelated abscesses are usually small and multiple and demonstrate areas of nodular or ringlike
72,74enhancement in an area of prior ischemic stroke (Fig. 6-3D). Abscess has also been
117reported as a consequence of mycotic aneurysm or septic arteritis.
Clinical Presentation
Although the clinical diagnosis of meningitis is infrequent in infective endocarditis, symptoms of
meningitis are not. In one series, meningeal symptoms or signs occurred in more than 40 percent
31of 84 patients with endocarditis. In addition to meningismus, headache, encephalopathy,
cranial neuropathies, seizures, and increased intracranial pressure may occur. These symptoms
may be subtle, especially in the elderly, and, when associated with fever, elevated white blood
cell count, and regurgitant murmur should prompt an urgent evaluation for infective
endocarditis.
Evaluation
All patients with known or suspected infective endocarditis and neurological symptoms, whether
focal or nonfocal, should have imaging with noncontrast head CT prior to lumbar puncture. This
is critical because multiple embolic strokes, intracerebral hemorrhage, and abscess may all
present with nonfocal symptoms and can also cause signi. cant compartmental increases in
intracranial pressure, thus increasing the risk of cerebral herniation. Lumbar puncture should not
be done in any patient with a focal lesion and evidence of mass e9ect on neuroimaging studies.
Because patients with endocarditis have a propensity toward hematological abnormalities,
coagulation tests, including a platelet count and INR, are especially important before one
performs a spinal tap.
Treatment of Cerebral Infection
As for any type of meningitis, the goal of treatment is adequate antibiotic therapy to which the
infecting organism is sensitive and that has good CSF penetration and activity in brain abscesses.
Both microabscesses and macroabscesses usually respond to antibiotic treatment, although
macroabscesses may occasionally produce signi. cant mass e9ect and thus require stereotactic
aspiration or surgical drainage.
OTHER NEUROLOGICAL COMPLICATIONS
Other extracerebral neurological complications may rarely occur. Although cerebral and
9systemic emboli appear to occur with similar frequency, cerebral neurological complications
predominate over extracerebral complications, probably because the brain receives more blood
Eow than peripheral neurological tissues and because cerebral complications are more likely to
be symptomatic.Mononeuropathy simplex or multiplex has been reported in as many as 1 percent of patients
118with infective endocarditis. Both peripheral and cranial nerves may be involved, and viridans
streptococci appear to be an especially prominent infectious organism in these cases. Discitis,
occasionally with associated abscess or osteomyelitis, has also been reported and is more
common with S. aureus infection. Other rare sites of embolization include the spinal cord and the
retina.
SUGGESTED MANAGEMENT ALGORITHM
The management of neurological complications of infective endocarditis is not standardized and
substantial variations in care may be necessary based on the individual patient’s characteristics.
Nonetheless, it is helpful to consider a treatment algorithm that includes pathways for the major
neurological manifestations of the disease (Fig. 6-5). This algorithm di9ers from some proposed
previously in that cerebral angiography is not suggested for all patients with ischemic stroke,
lumbar puncture is not recommended for all patients with neurological complications, and serial
92,105angiography every 2 weeks is optional. As many other authors have suggested, the two
keys to managing patients, regardless of any neurological complications, are (1) a high level of
suspicion for the possibility of infective endocarditis and (2) prompt initiation of appropriate
antibiotic therapy after obtaining multiple sets of blood cultures.FIGURE 6-5 Suggested management algorithm for patients with focal neurological de. cits and
known or suspected infective endocarditis. Factors favoring either surgical or medical treatment
of mycotic aneurysms are presented; management of these cases is highly individualized. Repeat
angiography at the conclusion of medical therapy is suggested for all patients with known
mycotic aneurysms and may be considered either for patients with intracerebral hemorrhage and
a negative initial angiogram or for patients with ischemic stroke who require long-term
anticoagulation. LP, lumbar puncture, MRA, magnetic resonance angiography.
PROGNOSIS
Among patients with infective endocarditis, mortality is increased in those with neurological
3,4,9,10complications compared to those without. Estimates of in-hospital mortality in various
clinical series range from 16 to 58 percent compared with 14 to 20 percent for patients with and
without neurological complications, respectively, although a population-based study from France
12reported 16 percent in-hospital mortality in 1999. Mortality is higher in infections with more
virulent organisms, with several large cohort studies showing an association between S. aureus
14,15,39,119and mortality. Intracerebral hemorrhage appears to confer added risk, as mortality
17,30,119in these patients is reported to be 40 to 90 percent. Although rare, mycotic aneurysm
106rupture is associated with even higher mortality. Mortality in patients with unruptured
mycotic aneurysms appears no di9erent from the aggregate mortality rate in all patients with
16neurological manifestations of endocarditis. A multicenter, prospective study of 384 patients
with infective endocarditis found that increasing age, female gender, serum creatinine greater
than 2.0 mg/L, moderate to severe congestive heart failure, infection with S. aureus, increased
medical comorbidity, and vegetation length greater than 15 mm were all independently
14associated with 1-year mortality. Another study of factors related to in-hospital death also
found an association with S. aureus infection and comorbidity as well as embolic events and
119diabetes.
3,5,6,77The risk of recurrent neurological events, either embolic or hemorrhagic, is quite low.
5Recurrent ischemia has been documented in less than 0.5 percent of cases per day and
77recurrent hemorrhage in less than 1 percent of all cases. Elimination of recurrent events
33,46,50appears to depend more on effective antibiotic treatment than on other specific therapy.
CONCLUDING COMMENTS
Although infective endocarditis has evolved over the past several decades with regard to
frequency of involvement of di9erent valves and prevalence and susceptibility of infecting
organisms, the proportion of patients with neurological manifestations and the type of
neurological complications remain remarkably consistent. Most neurological complications are
caused by embolization of friable valvular material resulting in either ischemic or hemorrhagic
stroke. A high index of suspicion for infective endocarditis as the cause of stroke is critical
because common treatments for acute stroke, such as thrombolysis or anticoagulation, are
contraindicated in patients with native valve endocarditis and ischemic stroke. Management of
patients with endocarditis and mechanical prosthetic valves is complicated, and decisions about
continued anticoagulation in these patients must be individualized. Similarly, decisions about
medical or medical plus surgical treatment of mycotic aneurysms must also be individualized
because a number of clinical factors may inEuence treatment. Although many clinical decisionsin patients with neurological manifestations of infective endocarditis must be individualized, it is
clear that the cornerstone of prevention and treatment of all neurological complications is rapid
delivery of appropriate antibiotic therapy.
ACKNOWLEDGMENTS
Dr. Williams is supported by grants from the Department of Veterans A9airs and the National
Institutes of Health.
REFERENCES
1 Virchow R. Uber die akute Entzündung der Arterien. Virchows Arch. 1847;1:272.
2 Osler W. Malignant endocarditis (Gulstonian Lecture). Lancet. 1885;1:415.
3 Pruitt AA, Rubin R, Karchmer A. Neurologic complications of bacterial endocarditis. Medicine.
1978;57:329.
4 Salgado AV, Furlan AJ, Keys TF, et al. Neurologic complications of endocarditis: a 12-year
experience. Neurology. 1989;39:173.
5 Hart RG, Foster JW, Luther MF, et al. Stroke in infective endocarditis. Stroke. 1990;21:695.
6 Paschalis C, Pugsley W, John R, et al. Rate of cerebral embolic events in relation to antibiotic and
anticoagulant therapy in patients with bacterial endocarditis. Eur Neurol. 1990;30:87.
7 Matsushita K, Kuriyama Y, Sawada T, et al. Hemorrhagic and ischemic cerebrovascular
complications of active infective endocarditis of native valve. Eur Neurol. 1993;33:267.
8 Weng MC, Chang FY, Young TG, et al. Analysis of 109 cases of infective endocarditis in a tertiary
care hospital. Chung-Hua I Hsueh Tsa Chih (Taipei). 1996;58:18.
9 Millaire A, Leroy O, Gaday V, et al. Incidence and prognosis of embolic events and metastatic
infections in infective endocarditis. Eur Heart J. 1997;18:677.
10 Roder BL, Wandall DA, Espersen F, et al. Neurologic manifestations in Staphylococcus aureus
endocarditis: a review of 260 bacteremic cases in nondrug addicts. Am J Med. 1997;102:379.
11 Heiro M, Nikoskelainen J, Engblom E, et al. Neurologic manifestations of infective endocarditis:
a 17-year experience in a teaching hospital in Finland. Arch Intern Med. 2000;160:2781.
12 Hoen B, Alla F, Selton-Suty C, et al. Changing profile of infective endocarditis: results of a 1-year
survey in France. JAMA. 2002;288:75.
13 Durante ME, Adinolfi LE, Tripodi MF, et al. Risk factors for “major” embolic events in
hospitalized patients with infective endocarditis. Am Heart J. 2003;146:311.
14 Thuny F, Disalvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis:
prognostic value of echocardiography. A prospective multicenter study. Circulation.
2005;112:69.
15 Miro JM, Anguera I, Cabell CH, et al. Staphylococcus aureus native valve infective endocarditis:
report of 566 episodes from the International Collaboration on Endocarditis Merged Database.
Clin Infect Dis. 2005;41:507.
16 Bohmfalk GL, Story JL, Wissinger JP, et al. Bacterial intracranial aneurysms. J Neurosurg.
1978;48:369.
17 Hart RG, Kagan-Hallet K, Joerns SE. Mechanisms of intracranial hemorrhage in infective
endocarditis. Stroke. 1987;18:1048.
18 Masuda J, Yutani C, Waki R, et al. Histopathological analysis of the mechanisms of intracranial
hemorrhage complicating infective endocarditis. Stroke. 1992;23:843.19 Cerebral Embolism Task Force. Cardiogenic brain embolism—the second report of the cerebral
embolism task force. Arch Neurol. 1989;46:727.
20 Katz RI, Goldberg HI, Selzer ME. Mycotic aneurysm: case report with novel sequential
angiographic findings. Arch Intern Med. 1974;134:939.
21 Molinari GF, Smith I, Goldstein MN, et al. Pathogenesis of cerebral mycotic aneurysm. Neurology.
1973;23:325.
22 Nakata T, Shinoya S, Kamiya K. The pathogenesis of mycotic aneurysm. Angiology. 1968;19:93.
23 Weir B. Special aneurysms (nonsaccular and saccular). In: Brown C, Eckhart C, editors.
Aneurysms Affecting the Nervous System. Baltimore: Williams & Wilkins; 1987:134.
24 Hubbel G, Cheitlin MD, Rapaport E. Presentation, management, and follow-up evaluation of
infective endocarditis in drug addicts. Am Heart J. 1981;102:85.
25 Levine DP, Crane LR, Zervos MJ. Bacteremia in narcotic addicts at the Detroit Medical Center. II.
Infectious endocarditis: a prospective comparative study. Rev Infect Dis. 1986;8:374.
26 Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective
endocarditis. J Am Coll Cardiol. 2001;37:1069.
27 Macarie C, Iliuta L, Savulescu C, et al. Echocardiographic predictors of embolic events in
infective endocarditis. Kardiol Pol. 2004;60:535.
28 Jones HRJr, Caplan LR, Come PC, et al. Cerebral emboli of paradoxical origin. Ann Neurol.
1983;13:314.
29 Stagaman DJ, Presti C, Rees C, et al. Septic pulmonary arteriovenous fistula: an unusual conduit
for systemic embolization in right-sided valvular endocarditis. Chest. 1990;97:1484.
30 Le Cam B, Guivarch G, Boles JM, et al. Neurologic complications in a group of 86 bacterial
endocarditis. Eur Heart J. 1984;5(suppl C):97.
31 Kanter MC, Hart RG. Neurologic complications of infective endocarditis. Neurology.
1991;41:1015.
32 Rohmann S, Erbel R, Gorge G, et al. Clinical relevance of vegetation localization by
transoesophageal echocardiography in infective endocarditis. Eur Heart J. 1992;12:446.
33 Vilacosta I, Graupner C, San Roman JA, et al. Risk of embolization after institution of antibiotic
therapy for infective endocarditis. J Am Coll Cardiol. 2002;39:1489.
34 Wong D, Chandraratna AN, Wishnow RM, et al. Clinical implications of large vegetations in
infectious endocarditis. Arch Intern Med. 1983;143:1874.
35 Garvey GJ, Neu HC. Infective endocarditis—an evolving disease. Medicine (Baltimore).
1978;57:105.
36 Schulz R, Werner GS, Fuchs JB, et al. Clinical outcome and echocardiographic findings of native
and prosthetic valve endocarditis in the 1990’s. Eur Heart J. 1996;17:281.
37 Carpenter JL, McAllister CK. Anticoagulation in prosthetic valve endocarditis. South Med J.
1983;76:1372.
38 Keyser DL, Biller J, Coffman T, et al. Neurologic complications of late prosthetic valve
endocarditis. Stroke. 1990;21:472.
39 Cabell CH, Jollis JG, Peterson GE, et al. Changing patient characteristics and the effect on
mortality in endocarditis. Arch Intern Med. 2002;162:90.
40 Gordon KA, Beach ML, Biedenbach DJ, et al. Antimicrobial susceptibility patterns of
betahemolytic and viridans group streptococci: report from the SENTRY Antimicrobial Surveillance
Program (1997–2000). Diagn Microbiol Infect Dis. 2002;43:157.41 Salgado CD, Farr BM, Calfe DP. Community-acquired methicillin-resistant Staphylococcus aureus:
a meta-analysis of prevalence and risk factors. Clin Infect Dis. 2003;36:131.
42 Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial
therapy, and management of complications: a statement for healthcare professionals from the
Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Stroke, and
Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious
Diseases Society of America. Circulation. 2005;111:294.
43 Gransden WR, Ekyn SJ, Leach RM. Neurological presentations of native valve endocarditis. QJM.
1989;73:1135.
44 Kupferwasser I, Darius H, Muller AM, et al. Clinical and morphological characteristics in
Streptococcus bovis endocarditis: a comparison with other causative microorganisms in 177
cases. Heart. 1998;80:276.
45 Felner JM, Dowell VRJr. Anaerobic bacterial endocarditis. N Engl J Med. 1970;283:1188.
46 Davenport J, Hart RG. Prosthetic valve endocarditis 1976–1987: antibiotics, anticoagulation, and
stroke. Stroke. 1990;21:993.
47 Powderly WG, Stanley SL, Medoff G. Pneumococcal endocarditis: report of a series and review of
the literature. Rev Infect Dis. 1986;8:786.
48 Straus AL, Hamburger M. Pneumococcal endocarditis in the antibiotic era. Arch Intern Med.
1966;118:190.
49 Watanakunakorn C, Tan JS, Phair JP. Some salient features of Staphylococcus aureus
endocarditis. Am J Med. 1973;54:473.
50 Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the prognostic
value of echocardiography. Ann Intern Med. 1991;114:635.
51 Mügge A, Daniel WG, Frank G, et al. Echocardiography in infective endocarditis: reassessment of
prognostic implications of vegetation size determined by the transthoracic and the
transesophageal approach. J Am Coll Cardiol. 1989;14:631.
52 Daniel WG, Schroder E, Mügge A, et al. Transesophageal echocardiography in infective
endocarditis. Am J Card Imaging. 1988;2:78.
53 Erbel R, Rohmann S, Drexler M. Improved diagnostic value of echocardiography in patients with
infective endocarditis by transesophageal approach: a prospective study. Eur Heart J. 1988;1:43.
54 Reynolds HR, Jagen MA, Tunick PA, et al. Sensitivity of transthoracic versus transesophageal
echocardiography for the detection of native valve vegetations in the modern era. J Am Soc
Echocardiogr. 2003;16:67.
55 Heidenreich PA, Masoudi FA, Maini B, et al. Echocardiography in patients with suspected
endocarditis: a cost-effectiveness analysis. Am J Med. 1999;107:198.
56 Jung HO, Seung KB, Kang DH, et al. A clinical consideration of systemic embolism complicated
to infective endocarditis in Korea. Korean J Intern Med. 1994;9:80.
57 Heinle S, Wilderman N, Harrison JK, et al. Value of transthoracic echocardiography in predicting
embolic events in active infective endocarditis. Duke Endocarditis Service. Am J Cardiol.
1994;74:799.
58 De Castro S, Magni G, Beni S, et al. Role of transthoracic and transesophageal echocardiography
in predicting embolic events in patients with active infective endocarditis involving native
cardiac valves. Am J Cardiol. 1997;80:1030.
59 Wann LS, Hallam CC, Dillon JC, et al. Comparison of m-mode and cross-sectional
echocardiography in infective endocarditis. Circulation. 1979;60:728.60 Buda AJ, Zotz RJ, LeMire MS, et al. Prognostic significance of vegetations detected by
twodimensional echocardiography in infective endocarditis. Am Heart J. 1986;112:1291.
61 Sanfilippo AJ, Picard MH, Newell JB, et al. Echocardiographic assessment of patients with
infectious endocarditis: prediction of risk for complications. J Am Coll Cardiol. 1991;18:1191.
62 Lancellotti P, Galiuto L, Alert A, et al. Relative value of clinical and transesophageal
echocardiographic variables for risk stratification in patients with infective endocarditis. Clin
Cardiol. 1998;21:572.
63 Deprele C, Berthelot P, Lemetayer F, et al. Risk factors for systemic emboli in infective
endocarditis. Clin Microbiol Infect. 2004;10:46.
64 Vuille C, Nidorf M, Weyman AE, et al. Natural history of vegetations during successful medical
treatment of endocarditis. Am Heart J. 1994;128:1200.
65 Rohmann S, Erbel R, Darius H, et al. Prediction of rapid versus prolonged healing of infective
endocarditis by monitoring vegetation size. J Am Soc Echocardiogr. 1991;4:465.
66 Rohmann S, Erbel R, Darius H, et al. Effect of antibiotic treatment on vegetation size and
complication rate in infective endocarditis. Clin Cardiol. 1997;20:132.
67 Rohmann S, Erbel R, Darius H, et al. Spontaneous echo contrast imaging in infective
endocarditis: a predictor of complications? Int J Cardiac Imaging. 1992;8:197.
68 Kupferwasser LI, Taha TH, Durrant S, et al. Hemostatic studies in patients with infective
endocarditis: a report on nine consecutive cases with evidence of coagulopathy. Heart Vessels.
1991;6:102.
69 Kupferwasser LI, Harner G, Mohr-Kahaly S, et al. The presence of infection-related
antiphospholipid antibodies in infective endocarditis determines a major risk factor for embolic
events. J Am Coll Cardiol. 1999;33:1365.
70 Lydakis C, Apostolakis S, Lydataki N, et al. Stroke-complicated endocarditis with positive lupus
anticoagulant—a case report. Angiology. 2005;56:503.
71 Korkmaz S, Ileri M, Hisar I, et al. Increased levels of soluble adhesion molecules, E-selectin and
P-selectin, in patients with infective endocarditis and embolic events. Eur Heart J. 2001;22:874.
72 Bakshi R, Wright PD, Kinkel PR, et al. Cranial magnetic resonance imaging finding in bacterial
endocarditis: the neuroimaging spectrum of septic brain embolization demonstrated in twelve
patients. J Neuroimaging. 1999;9:78.
73 Moulin T, Crepin-Leblond T, Chopard J-L, Bogousslavsky J. Hemorrhagic infarcts. Eur Neurol.
1993;34:64.
74 Kim SJ, Lee JY, Kim TH, et al. Imaging of the neurological complications of infective
endocarditis. Neuroradiology. 1998;40:109.
75 Bertorini TE, Laster RE, Thompson BF, et al. Magnetic resonance imaging of the brain in
bacterial endocarditis. Arch Intern Med. 1989;149:815.
76 van der Meulen JHP, Weststrate W, van Gijn J, et al. Is cerebral angiography indicated in
infective endocarditis? Stroke. 1992;23:1662.
77 Salgado AV, Furlan AJ, Keys TF. Mycotic aneurysm, subarachnoid hemorrhage, and indications
for cerebral angiography in infective endocarditis. Stroke. 1987;18:1057.
78 Brust JC, Taylor Dickinson PC, Hughes JEO, et al. The diagnosis and treatment of cerebral
mycotic aneurysms. Ann Neurol. 1990;27:238.
79 Ellis CJ, Waite ST, Coverdale HA, et al. Transoesophageal echocardiography in patients with
prosthetic heart valves and systemic emboli: is it a useful investigation? N Z Med J.
1995;108:376.80 Merritt HH, Fremont-Smith F. The Cerebrospinal Fluid. Philadelphia: WB Saunders, 1938.
81 Sornas R, Ostlund H, Muller R. Cerebrospinal fluid cytology after stroke. Arch Neurol.
1972;26:489.
82 Nicolau DP, Freeman CD, Nightingale CH, et al. Reduction of bacterial titers by low dose aspirin
in experimental aortic valve endocarditis. Infect Immun. 1993;61:1593.
83 Nicolau DP, Tessier PR, Nightingale CH. Beneficial effect of combination antiplatelet therapy on
the development of experimental Staphylococcus aureus endocarditis. Int J Antimicrob Agents.
1999;11:159.
84 Kupferwasser LI, Yeaman MR, Shapiro SM, et al. Acetylsalicylic acid reduces vegetation bacterial
density, hematogenous bacterial dissemination, and frequency of embolic events in
experimental Staphylococcus aureus endocarditis through antiplatelet and antibacterial effects.
Circulation. 1999;99:2791.
85 Taha TH, Durrant SS, Mazeika PK, et al. Aspirin to prevent growth of vegetations and cerebral
emboli in infective endocarditis. J Intern Med. 1992;231:543.
86 Chan KL, Dumesnil JG, Cujec B, et al. A randomized trial of aspirin on the risk of embolic events
in patients with infective endocarditis. J Am Coll Cardiol. 2003;42:775.
87 Leport C, Vilde JL, Bricaire F, et al. Fifty cases of late prosthetic valve endocarditis: improvement
in prognosis over a 15-year period. Br Heart J. 1987;58:66.
88 Wilson WR, Geraci JE, Danielson GK, et al. Anticoagulant treatment and central nervous system
complications in patients with prosthetic valve endocarditis. Circulation. 1978;57:1004.
89 Delahaye JP, Poncet P, Malquarti V, et al. Cerebrovascular accidents in infective endocarditis:
role of anticoagulation. Eur Heart J. 1990;11:1074.
90 Tornos P, Almirante B, Mirabet S, et al. Infective endocarditis due to Staphylococcus aureus:
deleterious effect of anticoagulant therapy. Arch Intern Med. 1999;159:473.
91 Salgado AV. Central nervous system complications of infective endocarditis. Curr Concepts
Cerebrovasc Dis Stroke. 1991;26:19.
92 Solenski NJ, Haley ECJr. Neurological complications of infective endocarditis. In: Roos KL,
editor. Central Nervous System Infectious Diseases and Therapy. New York: Marcel Dekker;
1997:331.
93 Gillinov AM, Shah RV, Curtis WE, et al. Valve replacement in patients with endocarditis and
acute neurologic deficit. Ann Thorac Surg. 1996;61:1125.
94 Chukwudelunzu FE, Brown RDJr, Wijdicks EF, et al. Clinical features and etiology of
subarachnoid hemorrhage associated with infectious endocarditis. Neurology. 1999;52(suppl
2):A503.
95 Jebara VA, Acar C, Dervanian P, et al. Mycotic aneurysms of the carotid arteries—case report
and review of the literature. J Vasc Surg. 1991;14:215.
96 Mansur AJ, Grinberg M, Leao PP, et al. Extracranial mycotic aneurysms in infective endocarditis.
Clin Cardiol. 1986;9:65.
97 Heyd J, Yinnon AM. Mycotic aneurysm of the external carotid artery. J Cardiovasc Surg (Torino).
1994;35:329.
98 Sikert RG, Jones HRJr. Transient cerebral attacks associated with subacute bacterial endocarditis.
Stroke. 1970;1:178.
99 Simmons KC, Sage MR, Reilly PL. CT of intracerebral haemorrhage due to mycotic aneurysms:
case report. Neuroradiology. 1980;19:215.
100 Ahmadi J, Tung H, Giannotta SL, et al. Monitoring of infectious intracranial aneurysms bysequential computed tomographic/magnetic resonance imaging studies. Neurosurgery.
1993;32:45.
101 Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral
hemorrhage. N Engl J Med. 2005;352:777.
102 Corr P, Wright M, Handler LC. Endocarditis-related cerebral aneurysms: radiologic changes with
treatment. AJNR Am J Neuroradiol. 1995;16:745.
103 Morawetz RB, Karp RB. Evolution and resolution of intracranial bacterial (mycotic) aneurysms.
Neurosurgery. 1984;15:43.
104 Bingham WF. Treatment of mycotic intracranial aneurysms. J Neurosurg. 1977;46:428.
105 Barrow DL, Prats AR. Infectious intracranial aneurysms: comparison of groups with and without
endocarditis. Neurosurgery. 1990;27:562.
106 Monsuez JJ, Vittecoq D, Rosenbaum A, et al. Prognosis of ruptured intracranial mycotic
aneurysms: a review of 12 cases. Eur Heart J. 1989;10:821.
107 Schold C, Earnest MP. Cerebral hemorrhage from a mycotic aneurysm developing during
appropriate antibiotic therapy. Stroke. 1978;9:267.
108 Scotti G, Li MH, Righi C, et al. Endovascular treatment of bacterial intracranial aneurysms.
Neuroradiology. 1996;38:186.
109 Frizzell RT, Vitek JJ, Hill DL, et al. Treatment of a bacterial (mycotic) intracranial aneurysm
using an endovascular approach. Neurosurgery. 1993;32:852.
110 Chapot R, Houdart E, Saint-Maurice JP, et al. Endovascular treatment of cerebral mycotic
aneurysms. Radiology. 2002;222:389.
111 Sugg RM, Weir R, Vollmer DG, Cacayorin ED. Cerebral mycotic aneurysms treated with a
neuroform stent: technical case report. Neurosurgery. 2006;58:E381.
112 Kato Y, Yamaguchi S, Sano H, et al. Stereoscopic synthesized brain-surface imaging with MR
angiography for localization of a peripheral mycotic aneurysm: case report. Minim Invasive
Neurosurg. 1996;39:113.
113 Cunha e Sa M, Sisti M, Solomon R. Stereotactic angiographic localization as an adjunct to
surgery of cerebral mycotic aneurysms: case report and review of the literature. Acta Neurochir
(Wien). 1997;139:625.
114 Grandsden WR, Eykyn SJ, Leach RM. Neurological presentations of native valve endocarditis.
QJM. 1989;73:1135.
115 Wolff M, Regnier B, Witchitz S, et al. Pneumoccocal endocarditis. Eur Heart J. 1984;5:C7780.
116 Tunkel AR, Kaye D. Neurologic complications of infective endocarditis. Neurol Clin.
1993;11:419.
117 Pozzati E, Tognetti F, Padovani R, et al. Association of cerebral mycotic aneurysm and brain
abscess. Neurochirurgia (Stuttg). 1983;26:18.
118 Jones HRJr, Siekert RG. Embolic mononeuropathy and bacterial endocarditis. Arch Neurol.
1968;19:535.
119 Chu VH, Cabell CH, Benjamin DK, et al. Early predictors of in-hospital death in infective
endocarditis. Circulation. 2004;109:1745.Chapter 7
Neurological Complications of Hypertension
S. Claiborne Johnston, Jacob S. Elkins
EPIDEMIOLOGY
PATHOPHYSIOLOGY
EVALUATION and TREATMENT
STROKE
CEREBRAL ANEURYSMS
Unruptured Cerebral Aneurysms
Subarachnoid Hemorrhage
INTRACEREBRAL HEMORRHAGE
LACUNAR INFARCT
PERIVENTRICULAR WHITE MATTER DISEASE
BINSWANGER’S DISEASE
CADASIL
CAROTID ARTERY STENOSIS
INTRACRANIAL ATHEROSCLEROSIS
AORTIC ARCH ATHEROSCLEROSIS
CARDIAC EMBOLUS
DEMENTIA
PERIPHERAL NEUROPATHY
HYPERTENSIVE ENCEPHALOPATHY
ECLAMPSIA
IMMUNOSUPPRESSION
Blood pressure was , rst measured in 1707 by an English divinity student, Stephan Hales,
1using a glass tube attached directly into the arteries of animals. Methods of measurement
improved slowly over the next 200 years, with Nikolai Korotko7 describing the modern
cu7-andstethoscope technique in 1905. Hypertension was recognized as an indicator of poor prognosisby Theodore Janeway, who published a case series of 7,872 hypertensive patients gathered from
1903 to 1912, in which hypertension was de, ned as a systolic blood pressure greater than 160
mmHg. He found a mean survival of 4 to 5 years after the development of symptoms of
hypertension, with stroke being an important cause of death.
Hypertension was initially considered a compensatory phenomenon rather than a disease in
itself. Even into the 1940s, physicians were concerned that lowering blood pressure would
exacerbate end-organ damage, particularly in the kidneys. Treatment options were not available
until 1925, when surgical sympathectomy was shown to reduce blood pressure without
impairment in renal function. The , rst antihypertensive medication, tetraethylammonium, was
used in a patient in 1946, but the agent was poorly tolerated because of severe anticholinergic
side e7ects. A tolerable oral agent was not available until 1957, when chlorothiazide was shown
to reduce blood pressure in patients with essential hypertension and rapidly became the most
commonly prescribed medication.
Both acute hypertension and chronic hypertension produce neurological disease. Acute
hypertension is associated with hypertensive encephalopathy, an uncommon presentation since
the widespread identi, cation and treatment of hypertension. Chronic hypertension is associated
with stroke, which is its most important neurological complication. All stroke subtypes are linked
to hypertension, including ischemic infarction, intraparenchymal hemorrhage, and aneurysmal
subarachnoid hemorrhage. Chronic hypertension is also associated with dementia and with
peripheral neuropathy in those with diabetes.
EPIDEMIOLOGY
Both systolic and diastolic blood pressures are distributed approximately normally in the
population. For convenience, physicians have de, ned pathological states such as hypertension
based on speci, c blood pressure thresholds, typically a systolic blood pressure of 140 mmHg or
greater or a diastolic blood pressure of 90 mmHg or greater, or both. Thus de, ned, hypertension
is common, a7ecting approximately 50 million individuals in the United States and as many as 1
2billion worldwide. In the Framingham study, individuals who were normotensive at age 55 had
3an approximately 90 percent lifetime risk of developing hypertension. Despite the frequent
division of blood pressure into diagnostic categories such as hypertension and normotension,
there is no obvious threshold at which higher blood pressure begins a7ecting the risk of
complications, and even patients with diastolic blood pressures of 80 to 90 mmHg are at
4increased risk of stroke compared with those with blood pressures of 70 to 80 mmHg (Fig. 7-1).
ReDecting a growing awareness of the continuous risk associated with blood pressure, blood
pressures in the range of 120–140/80–90 mmHg, once considered to be “normal,” are now
2labeled as “prehypertensive.” Throughout much of the twentieth century, blood pressure risk
was assessed according to the diastolic blood pressure, and it was not until 1993 that systolic
5blood pressure was formally incorporated into the de, nition of hypertension in U.S. guidelines.
Since that time, however, it has been increasingly recognized that systolic blood pressure is
somewhat more informative than diastolic blood pressure at predicting future cardiovascular
6events.FIGURE 7-1 Relative risks of stroke. Estimates of the usual diastolic blood pressure (DBP) in
each baseline DBP category are taken from mean DBP values 4 years after baseline in the
Framingham study. Solid squares represent disease risks in each category relative to risk in the
whole study population; sizes of squares are proportional to the number of events in each DBP
category; and 95 percent con, dence intervals for estimates of relative risk are denoted by vertical
lines.
(From MacMahon S, Peto R, Cutler J, et al: Blood pressure, stroke, and coronary heart disease. Lancet
335:764, 1990, with permission.)
PATHOPHYSIOLOGY
In the brain, the primary pathophysiologic process of hypertension is related to increases in
vasomotor tone and peripheral arterial resistance. Acute elevation in blood pressure results in
constriction of small arteries in the brain in a compensatory response termed autoregulation.
Brain blood-Dow is maintained at a relatively constant level over a range of pressures. At high
pressures, vasoconstriction is thought to be protective by reducing pressure at smaller, more
distal vessels. Acute severe hypertension overwhelms normal autoregulation at a mean arterial
pressure of approximately 150 mmHg, with increased cerebral blood-Dow occurring above this
pressure threshold. Vasoconstriction in acute hypertension is patchy, and some small vessels are
exposed to high pressures, which may lead to endothelial injury and focal breakdown of the
7blood–brain barrier. Acute hypertensive encephalopathy is a fulminant presentation of this
process. Fibrinoid necrosis of small vessels may also occur, lowering the threshold for future
ischemic and hemorrhagic events.
Chronic hypertension results in cerebral vascular remodeling. The media hypertrophies, and
8the lumen becomes narrowed. These changes are protective, with reduction in wall tension and
9shifting of the autoregulation curve to allow compensation at higher blood pressures. However,
vascular remodeling is accompanied by endothelial dysfunction, with impaired relaxation and
poor compensation for hypoperfusion. The result is greater susceptibility to ischemic injury due
7to reduced collateral flow.
Hypertension also predisposes to atherosclerosis. Hypertension is proinDammatory and is
10accompanied by increased plasma oxygen free radicals. Free radicals induce vascular smooth
muscle cell proliferation and may oxidize low-density lipoproteins, which in turn promotesmacrophage activation and monocyte extravasation. Angiotensin II is elevated in many
hypertensives and may play a direct role in atherogenesis independent of its e7ects on blood
11pressure. It directly stimulates smooth muscle cell growth, hypertrophy, and lipoxygenase
10activity, with resultant inDammation and low-density lipoprotein oxidation, thus accelerating
atherosclerosis. Angiotensin II also stimulates the production of transforming growth factor β
(TGF- β), a cytokine that is linked to , brosis in a number of disease states. In animal models,
transforming growth factor β appears to play a causal role in the development of hypertension
12and pathological vessel remodeling.
EVALUATION AND TREATMENT
The gold standard of blood pressure measurement is auscultation using a mercury
sphygmomanometer. Newer devices can provide accurate readings but require calibration. Blood
pressure should be measured in the seated position after a 5-minute rest with the patient’s feet
resting on the Door and the arm supported at heart level during the measurement. Accurate
readings depend on the use of an appropriate-sized cu7 with the bladder covering at least 80
percent of the arm. The classi, cation of blood pressure into speci, c diagnostic categories is
13based on the average of two or more readings on each of two or more oK ce visits. A complete
history and physical examination with basic laboratory measurements are essential to evaluate
for identifiable causes of hypertension and assess risk. Several patient characteristics may suggest
an identi, able cause of hypertension including young age, severe hypertension, hypertension
that is refractory to multiple interventions, and physical or laboratory , ndings suggestive of
endocrinological disorders, such as truncal obesity or hypokalemia. Abdominal bruits or
decreased femoral pulses may also be an indicator of renovascular disease or coarctation of the
14aorta.
Lifestyle modi, cation is recommended as an initial therapy for patients with blood pressure of
2120/80 mmHg or higher. E7ective lifestyle interventions include weight loss, limited alcohol
intake, aerobic physical activity, adequate potassium intake (approximately 90 mmol/day),
reduction in sodium intake, and dietary regimens such as the Dietary Approaches to Stop
15Hypertension (DASH) eating plan. Antihypertensive medications are recommended in addition
to lifestyle measures for patients with blood pressure of 140/90 mmHg or higher, and when the
blood pressure is 130/80 mmHg or higher in those with diabetes and chronic kidney disease.
For subjects without a history of cardiovascular disease or other compelling indication,
initiating therapy with a thiazide diuretic such as chlorthalidone, is generally recommended. In
the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT), involving
more than 33,000 participants, therapy with chlorthalidone was either equivalent or superior to
lisinopril and amlodipine for the primary prevention of cardiovascular endpoints, with a
16particular benefit for African American subjects both in terms of safety and efficacy. When the
blood pressure is 160/100 mmHg or higher, initiating therapy with two-drug combinations is
2generally recommended.
There are many bene, ts to treating hypertension, especially reductions in myocardial
infarctions, congestive heart failure, retinopathy, renal failure, and overall mortality. The focus
of the remainder of this chapter is on speci, c neurological complications of hypertension and the
unique aspects of treatment that they necessitate.
STROKEOf all the identi, ed modi, able risk factors for stroke, hypertension appears to be the most
important, owing to its high prevalence and its associated three- to , vefold increase in stroke
17risk. Based on epidemiological data, approximately 50 percent of strokes could be prevented if
18hypertension were eliminated (Table 7-1). Even small reductions in blood pressure result in
large reductions in stroke risk. For example, in a meta-analysis of 37,000 hypertensive subjects
from 14 studies, a reduction of 5 to 6 mmHg in diastolic blood pressure with active treatment
19was associated with a 42 percent reduction in stroke risk. The bene, ts of blood pressure
reduction on stroke risk extend similarly to the elderly with isolated elevations in systolic blood
pressure. In the Systolic Hypertension in the Elderly Program (SHEP) trial of 4,736 subjects 60
years and older, a 36 percent reduction in stroke was seen with a 12-mmHg decline in systolic
20,21pressure, a , nding con, rmed in other large randomized trials. Although there is still some
uncertainty surrounding the treatment of blood pressure in the oldest old (>85 years), the best
22available data suggest that bene, ts will be comparable with those seen in younger individuals.
Stroke rates have generally declined worldwide, especially throughout the 1970s and 1980s,
23although more recently they appear to have plateaued (Figs. 7-2 and 7-3). Although these
historic trends are not entirely explained by better control of blood pressure, the rates of decline
have roughly paralleled increased use of antihypertensive medications, suggesting that bene, ts
of blood pressure therapy observed in randomized trials have been at least partially realized in
24community practice.
Estimated Impact of Modifiable Risk Factors on Stroke in the United States*TABLE 7-1FIGURE 7-2 Percent change in stroke mortality, men aged 35 to 74, 1972 to 1982.
(From Thom TJ: Stroke mortality trends: an international perspective. Ann Epidemiol 3:509, 1993.
Copyright 1993, with permission from Elsevier Science.)
FIGURE 7-3 Age-adjusted death rates for stroke among men and women in the United States,
1900 through 1990.
(From Higgins M, Thom T: Trends in stroke risk factors in the United States. Ann Epidemiol 3:550,
1993. Copyright 1993, with permission from Elsevier Science.)
Hypertension contributes to each of the major intermediate causes of both ischemic and
hemorrhagic stroke including carotid stenosis, intracranial atherosclerosis, small-vessel
arteriosclerosis, and both macroscopic and microscopic aneurysms. Each of these conditions is
considered separately in this chapter. In part because of the heterogeneity of its manifestations in
the brain, there continues to be some uncertainty about the optimal management of blood
pressure in both the acute and chronic phases after stroke.
In the acute phase of cerebral ischemia, hypertension may play a compensatory role in
25maintaining cerebral perfusion to viable but threatened areas of the brain. Loss of normal
cerebral autoregulation has been demonstrated in areas of ischemic brain. When autoregulationis lost, blood Dow to the brain becomes directly proportional to mean arterial pressure, and
therefore, in theory, pharmacological increases in blood pressure could have salutatory e7ects in
26preserving hypoperfused regions of the brain. In some small studies, rapid pharmacological
reductions in blood pressure have predicted worse outcomes, and there are numerous anecdotal
27,28reports of the recrudescence of stroke symptoms after a decrease in blood pressure.
Therefore, most stroke guidelines recommend withholding pharmacological treatments of blood
pressure in acute stroke in the absence of acute end-organ injury or administration of
29thrombolytics, unless the blood pressure exceeds 220/120 mmHg. It is also possible, however,
to make physiological arguments that would be supportive of acute blood pressure reduction,
30such as stabilization of an intra-arterial thrombus or to reduce edema formation. Ongoing
trials in this area will provide key data to help resolve this debate.
Although historically there has been concern about lowering blood pressure even in the
chronic phases after stroke, there is now overwhelming evidence to support the use of
pharmacological interventions to lower blood pressure for secondary stroke prevention. In 6,105
subjects with a history of stroke, the Perindopril Protection Against Recurrent Stroke Study
(PROGRESS) demonstrated a 43 percent relative risk reduction for secondary stroke prevention
when subjects were randomized to the combination of the angiotensin-converting enzyme (ACE)
31inhibitor perindopril and the thiazide diuretic indapamide. Combination therapy with the ACE
inhibitor and thiazide, which resulted in a mean blood pressure reduction of 12.3/5 mmHg,
demonstrated a substantially more robust bene, t for stroke prevention than monotherapy with
ramipril (relative risk reduction 5%), which produced only a 4.9/2.8-mmHg average reduction
in blood pressure (P for heterogeneity between treatments <_0.00129_. combination=""
therapy="" with="" an="" ace="" inhibitor="" and="" a="" thiazide="" is="" now=""
commonly="" recommended="" for="" secondary="" stroke="" _prevention2c_="" bene, ts=""
appearing="">to be similar regardless of whether measured blood pressure is above or below
32the traditional cut points for hypertension. Although other studies have supported the , nding
that therapy with renin-angiotensin system antagonists and diuretics provides especially strong
33bene, ts for stroke prevention, particularly when compared with β -blockers, the degree of
hypertension control that is achieved is usually the best predictor of protection against recurrent
stroke. Therefore, response to therapy and other comorbidities, such as heart failure, diabetes,
asthma, and arrhythmia, should be considered when deciding on an appropriate
2antihypertensive drug regimen. There is still debate about how soon after stroke to initiate
therapy, as the majority of patients in trials of blood pressure therapy after stroke have been
randomized months after their qualifying event. Early initiation of therapy is increasingly
practiced to improve patient compliance, and current guidelines recommend consideration of
32,34treatment once the “hyperacute” period has ended.
CEREBRAL ANEURYSMS
Cerebral aneurysms are focal dilations of blood vessels. Subarachnoid hemorrhage, an important
form of hemorrhagic stroke, occurs when a cerebral aneurysm ruptures (Fig. 7-4). Hypertension
is associated with cerebral aneurysm formation and with subarachnoid hemorrhage. In a large
sample of Medicare patients, hypertension was listed as a secondary diagnosis in 43 percent of
patients admitted with unruptured aneurysms and in 34 percent of hospitalized control
35subjects. In a meta-analysis, the risk of subarachnoid hemorrhage was 2.8 times greater in
36those with a history of hypertension.FIGURE 7-4 A ruptured anterior communicating artery aneurysm producing acute
subarachnoid hemorrhage. A, Head computed tomography (CT) shows a large amount of blood at
the base of the brain and a small amount of intraventricular blood. B, Angiogram reveals a
complex saccular aneurysm.
The cause of the development and rupture of cerebral aneurysms is probably multifactorial.
Epidemiological studies have found several environmental risk factors for subarachnoid
hemorrhage other than hypertension. Cigarette smoking increases the risk of subarachnoid
36hemorrhage by 100 percent or more, perhaps by increasing the release of proteolytic enzymes
37that a7ect blood vessel integrity. Heavy alcohol consumption increases subarachnoid
hemorrhage risk with a pooled odds ratio of 1.5 in case control studies and relative risk of 4.7 in
36cohort studies. Alcohol-induced hypertension, relative anticoagulation, or increased cerebral
37blood-Dow may be responsible. Oral contraceptives are associated with a small but signi, cant
38excess risk of subarachnoid hemorrhage, with a relative risk of 1.4 in current and past users.
The source of the association is unknown.
Genetic factors are also important to aneurysm formation and subarachnoid hemorrhage. The
risk of subarachnoid hemorrhage is three to seven times greater in patients with an a7ected ,
rst39degree relative, and the prevalence of unruptured aneurysms is probably at least twice as high
40as without a family history. Females are twice as likely to have an aneurysm or present with
subarachnoid hemorrhage. African Americans have twice the rate of subarachnoid hemorrhage
41as whites. Polycystic kidney disease, Ehlers–Danlos syndrome type 4, and α -antitrypsin1
de, ciency are also associated with increased risk. Marfan’s syndrome has been considered a risk
42factor for aneurysm formation, but this association has recently been questioned.
The pathology of aneurysms reveals little about the underlying etiology. Two major
morphological subtypes are recognized: fusiform and saccular or berry aneurysms. Fusiform
aneurysms more commonly occur in children and in the elderly. The childhood form is thought
43to represent a genetic or early developmental abnormality in vessel wall structure. Fusiform
44aneurysms in the elderly are often associated with intracranial atherosclerosis. Saccular
aneurysms commonly occur at vessel branch points at the base of the brain, with the middle
cerebral artery bifurcation and origins of the anterior communicating artery and posterior
45communicating artery representing the most frequent locations. Turbulent Dow may be
responsible for this tropism.Unruptured Cerebral Aneurysms
Estimates of the prevalence of unruptured aneurysms vary widely. A recent meta-analysis of
prospective studies in adults reported 3.6 percent prevalence in four autopsy series and 6.0
46percent in nine angiographic studies. Prevalence was 2.3 percent in those without a known
risk factor. Approximately 90 percent of these aneurysms were less than 10 mm in diameter, and
70 percent were less than 6 mm. Based on the prevalence from angiographic studies, an
estimated 11 million American adults have an unruptured aneurysm, and these are being
detected more frequently with advances in imaging studies. Annual cost for unruptured
47aneurysms in the United States was estimated at $522 million in the 1980s and is probably
significantly greater now.
Unruptured aneurysms are often asymptomatic, discovered incidentally in a work-up for an
unrelated problem. Some aneurysms produce symptoms by compressing neighboring structures.
Presentation with a new cranial neuropathy is considered a worrisome sign for imminent rupture
and often prompts urgent treatment. New headaches are also a presenting sign of unruptured
aneurysm. Although migraine may simply represent an unrelated occurrence prompting head
imaging, some headaches may be due to the aneurysm itself. A sudden, severe “thunderclap”
headache may herald rapid aneurysm growth or a small leak without evidence of subarachnoid
48hemorrhage.
Catheter angiography is the gold standard for detection of aneurysms. Magnetic resonance
(MR) angiography is approximately 85 percent sensitive for detecting aneurysms larger than 3
49mm, with 85 percent speci, city. Head computed tomography (CT) does not reliably detect
unruptured aneurysms.
Prognosis of unruptured aneurysms, as reDected in the rate of rupture, is a subject of
controversy. In the largest prospective cohort study, the International Study of Unruptured
Intracranial Aneurysms, 1,692 subjects with unruptured aneurysms who did not undergo surgery
or endovascular treatment, were followed prospectively for an average of 4.1 years. The size of
the aneurysm (≥7 mm in maximal diameter) and location at the basilar tip or posterior
communicating artery were independent predictors of hemorrhage. Among 1,077 subjects with
no history of subarachnoid hemorrhage, the annual risk of hemorrhage for an aneurysm less
than 7 mm in diameter in the anterior circulation was 0 percent; it was 0.5 percent when the
50aneurysm was located in the posterior circulation.
The standard of care for treatment of aneurysms has historically been surgical clipping, in
which a metal clip is placed over the neck of the aneurysm, isolating it from the circulation. Coil
embolization is an alternative therapy and involves packing platinum coils into an aneurysm
through a microcatheter in an angiographic endovascular procedure. The relative merits of the
51two procedures have been argued. Coil embolization appears to provide a safer approach but
may not reduce subsequent rupture rates as effectively as surgical clipping.
Whether a given aneurysm requires treatment depends on the anticipated rupture rate. For
asymptomatic aneurysms smaller than 7 mm with no history of subarachnoid hemorrhage,
treatment may not be justi, ed, particularly when in the anterior circulation, given the risks of
52surgery and endovascular therapy. Treatment of unruptured aneurysms appears to be
coste7ective when they are larger or symptomatic or when there is a history of subarachnoid
hemorrhage from a different aneurysm.
Controlling or eliminating risk factors, such as hypertension, smoking, and alcohol abuse, mayreduce rupture rates, but this has not been systematically studied.
Subarachnoid Hemorrhage
Subarachnoid hemorrhage accounts for approximately 5 percent of all strokes, but it tends to
occur at a younger age than other stroke subtypes, with median age at death being 59 years for
subarachnoid hemorrhage, 73 years for intracerebral hemorrhage, and 81 years for ischemic
53stroke. Subarachnoid hemorrhage accounts for nearly one third of the years of potential life
lost before age 65 due to stroke. Case fatality rates approach 50 percent, and another 10 to 20
54percent remain disabled and dependent at follow-up. Approximately 25,000 Americans
55present with subarachnoid hemorrhage each year, with total costs estimated at $5.6 billion.
Presentation with subarachnoid hemorrhage generally involves sudden onset of severe
headache, sometimes accompanied by neck pain. Alteration of consciousness occurs in a
minority of patients, but it may be severe enough to produce coma or sudden death outside the
hospital. Head CT often shows blood surrounding the base of the brain. Intraventricular and
intraparenchymal hemorrhage may be present and can provide clues as to the location of the
ruptured aneurysm. Lumbar puncture may rarely show signs of hemorrhage when there is no
evidence of it on head CT. Blood in the spinal Duid that does not clear is suggestive of
subarachnoid hemorrhage. Xanthochromia is present in nearly all cases and may persist for more
than 3 weeks, but its appearance is delayed by more than 12 hours in 10 percent of cases.
Angiography is required for the characterization of the aneurysm and to plan treatment.
Prognosis depends on the ability to treat the underlying aneurysm and on the patient’s
condition at presentation. Recurrent hemorrhage occurs in more than 4 percent of untreated
patients during the , rst day and then in 1 to 2 percent per day for the next 2 weeks and is
45associated with even greater fatality and morbidity than primary rupture. Regardless of
treatment and recurrent hemorrhage, the level of consciousness is the major predictor of
56mortality (Table 7-2). The World Federation of Neurological Surgeons developed a Universal
Subarachnoid Hemorrhage Grading Scale, similar to the older Hunt and Hess scale, which has
been widely adopted but o7ers little advantage over determinations of level of consciousness
57alone.
TABLE 7-2 Overall Outcome After Subarachnoid Hemorrhage by Consciousness Level on
Admission*
To reduce the risk of recurrent hemorrhage, aneurysms are generally rapidly identi, ed and
repaired with surgical clipping or endovascular coil embolization. Controversy continues aboutoptimal timing of treatment in high-risk patients. Early surgery may be technically more
challenging when a large amount of subarachnoid clot is present, but early surgical treatment
reduces the risk of recurrent rupture more quickly than does later surgery. Most neurosurgeons
45therefore recommend early treatment.
Hydrocephalus from obstruction of the cerebral aqueduct or the meninges by blood clot may
require external drainage. Vasospasm is a common complication that produces cerebral ischemia
due to blood vessel constriction in areas with aneurysmal subarachnoid clot. It becomes
symptomatic in one third of cases, usually 3 to 14 days after hemorrhage, and results in cerebral
58infarction or death in 15 to 20 percent. Transcranial Doppler ultrasonography can detect
59vasospasm before it becomes symptomatic and is helpful in monitoring patients. Oral
nimodipine, a calcium-channel antagonist, reduces poor outcomes from vasospasm and should
be given as soon as possible after the initial bleed in all cases. Hypertension induced with
pressors and hydration with intravenous Duids may reduce the risk of infarction, but these
measures have never been studied in trials. They should not be used in patients with untreated
ruptured aneurysms because of the risk of precipitating further episodes of bleeding.
Vasodilatation through angioplasty or intra-arterial verapamil (or other vasodilators)
immediately reverses angiographic vasospasm in many cases, but it requires further study before
clinical benefits are proven.
INTRACEREBRAL HEMORRHAGE
Bleeding directly into the substance of the brain is termed intraparenchymal or intracerebral
hemorrhage (Fig. 7-5). It may occur as a complication of ischemic stroke, termed hemorrhagic
conversion, or as the primary injury without preceding ischemia. Hypertension is the most
important identi, ed risk factor for intracerebral hemorrhage. More than 70 percent of patients
with intracerebral hemorrhage have a history of hypertension, and the risk of hemorrhagic stroke
60is elevated 9.5-fold in the highest compared with the lowest quintile of systolic blood pressure.FIGURE 7-5 Head CT of an acute basal ganglia intracerebral hemorrhage with mass e7ect
compressing the ventricles.
Intracranial hemorrhage is responsible for 10 to 15 percent of all stroke deaths but for more
than one third of the years of life lost before age 65 due to the younger age distribution of
53intracerebral hemorrhage. Case fatality rates are high, with 35 to 50 percent dead at 1 month
61and only 20 percent returning to independence at 6 months. In the United States, an estimated
37,000 cases of intracerebral hemorrhage occur each year, with the total estimated cost of care
55exceeding $6 billion annually.
Other risk factors for intracerebral hemorrhage include age, race, substance abuse,
anticoagulation, platelet dysfunction, and vascular and structural anomalies. Rates of
intracerebral hemorrhage increase with age. African Americans have 40 percent higher rates
41than those of whites, with larger di7erences at younger ages. Cocaine and amphetamines are
associated with increased risk, particularly acutely, possibly because of transient severe
60hypertension. Abnormalities in clotting may account for an increased incidence of
intracerebral hemorrhage with heavy alcohol use. Excessive warfarin anticoagulation and
62,63antiplatelet therapy also increase the risk of intracerebral hemorrhage. Thrombolytic agents
used for ischemic stroke and myocardial infarction cause intracerebral hemorrhage in some
cases. It may also occur with severe thrombocytopenia and platelet dysfunction.
Intracerebral hemorrhage may result from and occur in brain tumors, such as glioblastoma
multiforme and metastatic melanoma, choriocarcinoma, renal cell carcinoma, and bronchogenic
carcinoma. Congophilic amyloid angiopathy, a vasculopathy common in the elderly, is
associated with lobar hemorrhages, often centered at the gray-white junction. Other punctate
hemorrhages may be apparent on gradient-echo MR images (Fig. 7-6), supporting the diagnosis.
Arteriovenous malformations, abnormal complexes of arteries and veins in brain parenchyma,
60account for 5 percent of intracerebral hemorrhage. Cavernous malformations are dense
collections of thin-walled vascular channels and appear to be the cause of intracerebral
63hemorrhage in 5 percent of autopsies ; they are not apparent on angiography but have a
“popcorn” appearance in T2-weighted MR images, with a hyperintense core surrounded by
hypointense hemosiderin from previous small hemorrhages (Fig. 7-7). Aneurysms may produce
intracerebral hemorrhages when blood is directed into the brain, and these rarely are mistaken
for primary hypertensive hemorrhages.FIGURE 7-6 Imaging , ndings of amyloid angiopathy, with no evidence of hemorrhage on CT
(A) but multiple punctate hypointensities at the gray-white junction on T2-weighted multiplanar
gradient-recalled (MPGR) magnetic resonance imaging (MRI) (B), suggesting old hemorrhage
(two lesions are apparent on this image in the parieto-occipital region).FIGURE 7-7 A cavernous malformation with a small amount of acute, intracerebral
hemorrhage surrounding it on CT (A). T2-weighted MRI (B) shows a lesion with a focal area of
high signal intensity surrounded by a thick rim of hypointense siderin. T1-weighted MRI (C)
showing the typical “popcorn” appearance. The high signal intensity represents methemoglobin.
Primary hypertensive intracerebral hemorrhage was thought to be caused by chronic vascular
injury, resulting in formation of microscopic aneurysms, , rst characterized by Charcot and
Bouchard in 1868. Advances in pathological tissue preparation have raised doubts about the
frequency and importance of microscopic aneurysms, attributing the appearance to complex
64vascular coils. More recently, , brinoid necrosis of small arteries has been proposed as the
65initial step in intracerebral hemorrhage. When acute hypertension or clotting abnormality
precipitates rupture, blood dissects into the brain parenchyma, sometimes producing a
hematoma. Brain injury occurs because of compression of surrounding tissue and from the direct
toxic e7ects of blood. Mass e7ect from the hematoma may lead to uncal, subfalcine, tonsillar, or
transtentorial herniation, depending on location, and death may ensue.
Clinical presentation depends on the location and size of the hemorrhage (Table 7-3). Nearlyall intracerebral hemorrhage is characterized by sudden onset of neurological de, cits,
progressing over minutes and accompanied by headache, often with alteration of consciousness.
Deterioration due to surrounding edema, hydrocephalus, or continuing or recurrent hemorrhage
often occurs within the first 24 hours but may be delayed by days.
TABLE 7-3 Clinical Presentation of Intracerebral Hemorrhage
Prognosis is multifactorial. Hemorrhage volume, most easily measured by halving the product
of the length, width, and depth on axial head CT images, is a powerful predictor of mortality,
with 80 percent 30-day mortality in those with volumes greater than 60 ml and 22 percent
66mortality in hemorrhages less than 30 ml. Mortality is much greater in those with
67intraventricular extension of blood. Hydrocephalus due to intraventricular extension or
cerebrospinal Duid (CSF) outDow obstruction predicts in-hospital mortality: 51 percent of those
68with and 2 percent of those without hydrocephalus died in one series. Lower Glasgow Coma
Scale scores, greater age, location, and blood pressure or pulse pressure are other independent
predictors of mortality. Simple multivariable prediction models have been developed and
69,70validated.
Urgent head CT is required in patients with suspected intracerebral hemorrhage. MR imaging
(MRI) is probably as sensitive as CT for detecting hemorrhage and is more sensitive for detecting
an underlying structural etiology, but the rapidity, availability, and ease of interpretation of CT
favor its initial use. Contrast-enhanced head CT scan may show evidence of persistent
71hemorrhage at the time of presentation, a sign associated with poor prognosis. Urgent catheter
angiography is required whenever aneurysmal subarachnoid hemorrhage is possible, such as in
cases with a large amount of subarachnoid blood, and should be considered for all patients
without a clear etiology who would be surgical candidates. Early MRI may be indicated if a
structural etiology is suspected, but , ndings are often obscured by the hemorrhage, and a scan
delayed by 4 to 8 weeks may provide more useful information if urgent diagnosis is unnecessary.
MRI is useful in diagnosing cavernous malformations and may suggest congophilic amyloid
angiopathy.
Treatment is generally supportive, although surgical intervention is indicated in some cases.
Severe hypertension is common after intracerebral hemorrhage, in part because it is a response
to elevated intracranial pressure and brain injury. No clinical studies are available for
determining optimal blood pressure control after intracerebral hemorrhage. Theoretically,
persistent hypertension could increase the risk of ongoing hemorrhage, but antihypertensive
treatment may reduce blood Dow to ischemic brain surrounding a hematoma or reduce cerebral
72perfusion pressure. Consensus guidelines have recommended antihypertensive medications forsystolic blood pressure greater than 180 mmHg or diastolic blood pressure greater than 105
mmHg, and fluids or pressors for systolic blood pressure less than 90 mmHg, but these thresholds
61for treatment are frequently debated. Increased intracranial pressure may lead to coma and is
treated with extraventricular drainage, osmotherapy, or hyperventilation.
Surgical evacuation of primary intracerebral hemorrhages is commonly performed when there
is posterior fossa hemorrhage with a risk of brainstem compression or when there is evolving
neurological deterioration in patients with lobar hemorrhages and other prognostic signs are
favorable. A large, international trial randomized 1,033 subjects with supratentorial hemorrhage
to receive early surgical evacuation of the hematoma or initial conservative treatment followed
by surgical evacuation only if it was necessitated by neurological deterioration. There was a
favorable outcome at 6 months in 26 percent of those allocated to early surgery as compared
with 24 percent in those allocated to initial conservative treatment (P = 0.89). In subgroup
analysis, it appeared that early surgery was more e7ective than conservative therapy when the
hematoma was 1 cm or less from the cortical surface. Additional trials will be needed to resolve
73the issue of early surgical benefit for superficial hematomas.
After the acute period, aggressive treatment of hypertension is indicated. In addition to
reducing cardiovascular disease and ischemic stroke, one study has shown that treating
74hypertension reduces the risk of intracerebral hemorrhage by more than 50 percent.
LACUNAR INFARCT
The term lacune was , rst introduced in 1843 by M. Durand-Fardel to describe small, subcortical
areas lacking gray and white matter. These lesions were attributed to infarct and associated with
particular clinical presentations by P. Marie and J. Ferrand more than 50 years later. In the
751950s C. Miller Fisher reintroduced the term into modern neurology. In a rapid succession of
articles, he described the clinical and pathological presentation, recognized the importance of
hypertension as an etiology, and developed a theory of pathogenesis that survives today.
Less than 2 cm in diameter, lacunes are small infarcts that result from occlusion of small
penetrating branches arising from large arteries (Fig. 7-8). There is general agreement about the
de, nition of lacune, but much argument about the interrelationship between lacunar infarcts,
lacunar strokes (symptomatic lacunes), lacunar syndromes (symptom complexes often associated
with lacunar strokes), and lacunar disease (lacunes due to intrinsic small-vessel changes).
Arguments arise from imperfect correlations between these entities. First, not all lacunes produce
lacunar strokes because some are silent. Second, lacunar syndromes are sometimes associated
with large-vessel strokes. Third, lacunes are produced by intrinsic small-vessel disease and by
other etiologies. These issues are discussed in greater detail later.FIGURE 7-8 An acute right thalamocapsular lacunar stroke producing left sensorimotor
syndrome. The lesion was hypodense in noncontrast head CT (A). With MRI, it was hyperintense
on T2-weighted images (B), inconspicuous on T1-weighted images (C), and hyperintense on
diffusion-weighted images (D).
More than 50 percent of lacunes are located in the basal ganglia and thalamus, with the
remainder in the internal capsule, pons, cerebellum, and subcortical white matter.
Approximately 20 to 30 percent of ischemic strokes are due to lacunes. In a recent study, 23
percent of randomly selected subjects 65 years or older had a lacune on MR scanning, and 89
76percent of those with a lacune denied a history of stroke or transient ischemic attack. These
“silent” lacunes were associated with impairment in cognitive and functional tasks, suggesting
that the overall clinical burden of lacunes may be greater than previously suspected.
Hypertension is an important risk factor for development of lacunes, ranking as the most
76,77important identi, ed risk factor in multivariable models. However, the strength of the
78association may be no greater for lacunes than for other forms of ischemic stroke, and
79hypertension is not always present. Nonetheless, since other risk factors are less important forlacunes, eliminating hypertension would be expected to have a greater impact on the occurrence
of lacunar infarction than other forms of ischemic stroke. Elevation in the level of serum
creatinine is independently associated with lacunar infarction, perhaps because it is a marker for
76chronic end-organ damage from hypertension.
Diabetes mellitus is a risk factor for symptomatic lacunes, approximately doubling the risk.
However, the inDuence of diabetes on lacunar stroke does not appear to di7er from its e7ect on
78other ischemic stroke subtypes. This is also true for cigarette smoking, which doubles the risk
of all ischemic strokes, including lacunes. Carotid artery stenosis is associated with an increased
risk of lacunar stroke, with more than twice the risk of a symptomatic lacune above a 50 percent
76or greater stenosis. Cardiac disease is less common in patients with lacunes (20%) than in
78those with other ischemic stroke types (47%).
The etiology of lacunes has been argued bitterly. Some have suggested that the vast majority
of lacunes is due to changes within small penetrating vessels, primarily because of chronic
80hypertension, but others have argued that emboli to small vessels and intracranial
79atherosclerosis are responsible for a significant number of lesions. Fisher produced much of the
data supporting intrinsic small-vessel disease. He found degenerative changes in small vessels he
termed lipohyalinosis and 4brinoid degeneration, characterized by layers of connective tissue
81within the vascular media, obstructing the lumen. These changes were proximal to infarcts in
some cases. Atherosclerosis at the origin appeared responsible for other infarcts. Fisher
81recognized that emboli may be responsible for some lacunes. Animal models have shown that
82particles may embolize to small penetrating arteries, producing lacunes.
Risk factor pro, les have been used to argue against hypertension and intrinsic small-vessel
79disease as the sole etiology of lacunes. As discussed previously, the risks imparted by
hypertension, diabetes, and cigarette smoking are similar for lacunes and for other forms of
ischemic stroke, and carotid and cardiac disease appear to be independent risk factors for
lacunes. However, carotid and cardiac disease are much more commonly associated with
large83vessel infarctions than with lacunes. The etiology of lacunes is almost certainly multifactorial.
Intrinsic small-vessel disease may predominate, but emboli and intracranial atherosclerosis
almost certainly account for a significant minority of cases.
Several classic presentations of lacunar strokes have been described, termed the lacunar
syndromes. Pure motor hemiparesis is the most common, accounting for 45 percent of cases.
Motor functions involving face, arm, and leg are impaired, but other neurological functions are
spared. The appearance is di7erent from that with cortical strokes, in which de, cits in sensation
or cognition often accompany motor changes. Pure motor hemiparesis is not always due to a
lacune, with 10 to 20 percent of cases attributed to a cortical stroke. When a lacune is
responsible, it is most often located in the posterior limb of the internal capsule or in the basis
pontis, but any other site along the path of corticospinal fibers can produce the syndrome.
Sensorimotor syndrome is the second most common lacunar syndrome, accounting for 20
78percent of cases. Weakness and numbness are present in varying degrees, usually involving the
face, arm, and leg. Other neurological de, cits are absent. The syndrome is most commonly
produced by a lacune involving the lateral thalamus and internal capsule, but 13 percent of
78cases are not due to lacunes.
78,84Ataxic hemiparesis accounts for 10 to 18 percent of lacunar syndromes. In the a7ected
limbs, pyramidal weakness is combined with elements normally attributed to cerebellar ataxia.Intention tremor, exaggerated rebound, and irregular rapid alternating movements are
superimposed on ipsilateral weakness. The , ndings are highly suggestive of a lacunar stroke,
78with 95 percent attributable to lacunes. Infarct locations are identical to those that cause pure
motor hemiparesis.
78,84Among patients with lacunar syndromes, 7 percent have a pure sensory stroke,
characterized by impaired sensation without other accompanying neurological de, cits. When
the face, arm, and leg are involved, the lesion is nearly always a lacune in the contralateral
thalamus. A lesion in the medial lemnicus in the midbrain or rostral pons may occasionally
produce an identical syndrome. Pain and dysesthesia in the a7ected region may accompany the
lesion acutely or may be delayed by weeks to months.
Many other lacunar syndromes have been described, including clumsy-hand dysarthria,
hemiballism, and pure motor hemiparesis combined with various eye movement
81abnormalities. Although lacunes occur more commonly in certain regions of the brain, they
79can occur anywhere, producing an in, nite number of potential syndromes. Even signs
generally attributed to cortical lesions may be produced by lacunes, including aphasia, abulia,
confusion, and neglect.
Prognosis for recovery after a lacunar stroke is generally more favorable than for ischemic
85strokes due to occlusion of major vessels. Recurrent stroke and mortality rates are also lower
86than for other stroke subtypes.
Lacunar syndromes may be produced by cortical strokes or even by small hemorrhages. Also,
some lacunes may be associated with carotid disease or intracranial atherosclerosis, and
knowledge of this could alter treatment decisions. Therefore, diagnostic imaging has been
recommended for all those presenting with lacunar syndromes. An immediate head CT scan will
rule out hemorrhage as an etiology but may not distinguish lacunes from large-vessel infarctions.
The absence of changes on a head CT scan delayed by more than 6 hours has been used as
con, rmatory evidence of lacunar infarction. MRI provides more de, nitive con, rmation, and MR
angiography may suggest intracranial atherosclerosis. For lacunar strokes in the internal carotid
distribution, duplex ultrasonography or neck MR angiography should be performed because a
stenosis proximal to the lacune would generally be considered symptomatic.
Acute therapy for lacunes has not been well studied. Most studies of ischemic stroke have not
examined this subtype separately, except in post hoc analyses with numbers too small to , nd
signi, cant treatment e7ects. There has been much debate about whether lacunar strokes should
be treated with tissue plasminogen activator (t-PA). Some have argued that the predominant
etiology of lacunar syndromes is intrinsic small-vessel disease, which would not be expected to
respond to thrombolytics, so that patients would be exposed to an increased risk of hemorrhage
without a good chance for bene, t. In the National Institute of Neurological Disorders and Stroke
t-PA trial, t-PA was e7ective in the subgroup of patients judged to have small-vessel occlusive
85strokes prior to randomization. In fact, absolute di7erences in favorable outcomes were
greater for small-vessel strokes than for large-vessel occlusive and cardioembolic strokes, and
di7erences in two indices reached statistical signi, cance despite small numbers. Some have
argued that the , nal stroke occurs suddenly, implying that acute thrombosis in a diseased small
vessel may account for a lacunar infarction and that this explains the eK cacy of thrombolysis.
Others have argued that the correlation between lacunar stroke and lacunar syndrome is so poor
that a diagnosis of nonthrombotic small-vessel occlusion cannot be made with accuracy and that
all patients with stroke should receive t-PA because of its overall bene, t in ischemic stroke. TheAmerican Heart Association guidelines do not recommend avoiding t-PA in lacunar
87syndromes. Although treatment is not recommended for patients with mild neurological
de, cits, including isolated hemisensory de, cits, a patient with a pure motor hemiparesis is
considered an appropriate candidate for thrombolysis. Other acute treatment for lacunar strokes
is supportive.
Aspirin appears to reduce the risk of subsequent ischemic strokes, regardless of etiology.
Although di7erences in e7ectiveness in stroke subgroups have not been carefully studied, the
Chinese Acute Stroke Trial found that aspirin’s e7ect on stroke recurrence was similar in patients
88with lacunar strokes and those with other ischemic stroke subtypes. Clopidogrel and the
combination of dipyridamole/aspirin are alternatives for secondary prevention in those who
cannot tolerate aspirin or who have recurrent strokes despite aspirin. Control of hypertension
reduces subsequent ischemic stroke risk, and risk reduction may be even greater for lacunes.
Treatment of isolated systolic hypertension in elderly patients halved the risk of lacunar stroke, a
74more dramatic effect than that seen for other ischemic strokes.
A lacune was considered evidence that a carotid stenosis was symptomatic in previous
89studies. Whether the risk–bene, t ratio for endarterectomy in patients with lacunes is di7erent
from that in those with large-vessel strokes is not known.
PERIVENTRICULAR WHITE MATTER DISEASE
With improvements in head imaging, changes in the white matter surrounding the lateral
ventricles were recognized frequently in the elderly, prompting Vladimir Hachinski to coin the
term leukoaraiosis for the , nding. Head CT shows a periventricular mantle of hypodensity, often
most profound at the frontal and occipital horns, which is hyperintense on T2-weighted MRI
(Fig. 7-9). Age is the most important risk factor, with 96 percent of those older than 65 years
90showing at least some evidence of such change. Clinically, the changes are most frequently
associated with insidious declines in cognitive and motor performance, particularly on tests that
90,91depend on reaction time and speed.
FIGURE 7-9 Imaging , ndings of periventricular white matter disease, with hypodensity on
head CT (A) and T2-weighted hyperintensities on MRI (B).The etiology of white matter lesions is believed to be related to several distinct pathological
processes, including hypoperfusion injury, cerebral amyloid angiopathy, dilated perivascular
spaces, axonal loss, astrocytic gliosis, and loss of ependymal integrity with resulting
cerebrospinal Duid extravasation. Lesions contiguous with the ventricles show fewer histological
and molecular markers of ischemia than lesions in the deep subcortical areas, where they
92resemble areas of “incomplete” infarction on pathological examination. Loss of vasomotor
reactivity and autoregulation due to small-vessel vasculopathy is hypothesized to be a frequent
93cause of the ischemic changes. Leukoaraiosis may be an important clinical indicator of
endorgan injury from hypertension, integrating information about cumulative exposure to high
blood pressure as well as susceptibility to injury. Individuals with white matter lesions in the
94brain are at high risk of incident stroke and other clinical cardiovascular events. White matter
burden is also one of strongest predictors of incident brain infarction de, ned by serial cranial
95MRI.
BINSWANGER’S DISEASE
In 1894, Otto Binswanger described a form of early dementia distinguishable from syphilitic
96general paresis and large-vessel vascular dementia by its subcortical involvement.
Hypertension is an important risk factor for the disease, existing in 94 percent of cases in one
97series. Diabetes also appears to be a risk factor. Multiple lacunar infarctions are combined
with di7use and focal myelin loss, particularly in periventricular areas, producing a pathological
picture consistent with a combination of multiple lacunes and periventricular white matter
disease. Patients present with a stepwise and gradual progression of motor, cognitive, and
behavioral de, cits, generally over 5 to 10 years. Periods of symptom stabilization or
improvement may occur. Imaging studies show patchy periventricular white matter hypodensity
or hyperintensity on T2-weighted MRI, with superimposed focal, subcortical lesions consistent
with lacunes. Aspirin and control of hypertension are expected to slow progression, but this has
not been shown systematically.
CADASIL
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) is a recently recognized dementing illness caused by mutations in the NOTCH3 gene,
98which encodes a transmembrane receptor protein of unclear function. Clinical presentation is
similar to that of Binswanger’s disease, with stepwise decline in cognitive and motor functions.
However, onset is earlier, beginning at 30 to 50 years of age, and it is often preceded by
migraines with aura. Hypertension and diabetes are not associated. Head imaging shows
99multiple lacunes superimposed on periventricular white matter disease. Degeneration of
vascular smooth muscle cells and granular deposits characterize vessels in the brain and in other
regions. Involvement of the dermis allows confirmation by skin biopsy. No treatment is available.
CAROTID ARTERY STENOSIS
The , rst comprehensive description of carotid occlusion and stroke is attributed to J. R. Hunt,
who in 1914 described a patient with decreased carotid pulsation contralateral to a
100hemiparesis. Autopsy con, rmed a hemispheric infarct and showed patent intracranial
vessels. With the advent of angiography and surgical exploration, internal carotid artery
occlusion with recent thrombus was confirmed in the 1940s.The importance of internal carotid artery stenosis as a cause of stroke is unclear because it is
diK cult to de, nitively attribute a stroke to the stenosis. The Stroke Data Bank of the National
Institute of Neurological Disorders and Stroke classi, ed 69 of 1,273 ischemic stroke cases as
101,102atherothrombotic and 41 as embolic due to severe carotid stenosis or occlusion. Based on
these numbers, approximately 9 percent of ischemic strokes are due to internal carotid stenosis
or occlusion. In the Atherosclerosis Risk in Communities Study, 34 percent of randomly selected
103subjects aged 45 to 64 years had evidence of carotid plaque on ultrasonography. An
asymptomatic carotid stenosis of more than 60 percent is found in approximately 5 percent of
10465-year-olds and increases with age.
Hypertension is an important risk factor for carotid stenosis. In the Framingham study, systolic
hypertension was a powerful predictor of subsequent carotid stenosis, with twice the odds for
105each 20-mmHg increase in systolic blood pressure. Systolic pressure is also a predictor of
106progression in patients with asymptomatic stenoses. Cigarette smoking, high serum
105cholesterol level, and increased homocysteine are other risk factors for carotid stenosis.
Internal carotid artery stenosis is produced by atherosclerosis just distal to the common carotid
bifurcation. The pathophysiology of carotid artery stenosis is complex. Hypertension induces
vascular remodeling, resulting in medial thickening, luminal narrowing, and impaired smooth
8muscle relaxation. These changes are concentrated in areas of nonlaminar Dow, such as the
common carotid bifurcation. Atherosclerotic plaques are thought to develop in these areas as a
response to injury produced by hypertension, blood-Dow abnormalities, lipids, and possibly
10infection. This initiating injury induces endothelial cell expression of cell adhesion molecules
that mediate local extravasation of mononuclear cells. Vessel wall inDammation results, with
foamy, lipid-laden macrophages and T lymphocytes. Chronic injury leads to intimal hyperplasia
and formation of complex plaques that may include a lipid core. When a plaque ruptures into
the vessel lumen, thrombosis is induced, which may produce local occlusion, distal embolus, or,
after organization, progressive luminal stenosis. Shear forces associated with a severe stenosis
may induce platelet activation and thrombus formation without plaque rupture.
Clinically, symptomatic patients present with large-vessel ischemic strokes or transient
ischemic attacks in the distribution of the ophthalmic, middle, or anterior cerebral artery.
Transient monocular blindness (amaurosis fugax), weakness, numbness, aphasia, or neglect may
occur, depending on the a7ected region of the anterior circulation. Border-zone ischemia due to
distal hypoperfusion in the anterior and middle cerebral artery territories presents with proximal
upper and lower extremity weakness and numbness (“man-in-the-barrel” syndrome) and may
indicate a critical stenosis or occlusion with inadequate collateral blood-Dow. Artery-to-artery
emboli classically appear as cortical wedge-shaped infarcts, indistinguishable from emboli from
other sources. Lacunar infarcts, often attributed to intrinsic small-vessel disease, probably
represent embolic events from carotid artery stenoses in some instances because endarterectomy
107appears to reduce the risk of ipsilateral lacune.
A cervical bruit may be a sign of carotid stenosis, but it is absent in 25 to 40 percent of cases
later con, rmed to have a greater than 70 percent stenosis and is present in 25 to 40 percent of
108those without a severe stenosis. Therefore, carotid imaging studies are generally indicated for
patients with anterior circulation ischemic strokes or transient ischemic attacks.
Carotid Doppler ultrasonography, neck MR angiography, or catheter angiography is required
for the determination of whether an internal carotid stenosis is present. All three tests are good109predictors of the degree of stenosis determined at surgery. Catheter angiography is considered
the gold standard but is limited to producing two-dimensional projections and carries a 1
percent risk of stroke. Therefore, it is generally preferable to perform carotid Doppler
ultrasonography or neck MR angiography , rst. Carotid Doppler ultrasonography is more widely
available and usually less expensive. MR angiography provides three-dimensional views and can
incorporate the intracranial vasculature. When the , ndings on either Doppler ultrasonography
or MR angiography are positive, performing the other study provides con, rmation of degree of
stenosis and may obviate the need for catheter angiography.
From the perspective of society, it does not appear cost-e7ective to screen patients for
104asymptomatic carotid stenoses. Because of the limited bene, t of surgery and the costs of
carotid ultrasonography, the pretest probability of , nding a stenosis must be greater than 40
percent before it is cost-e7ective to screen those without symptoms. Carotid ultrasonography
probably is not cost-e7ective even in asymptomatic elderly patients with bruits because the
pretest probability of , nding a high-grade stenosis is only approximately 15 percent, given the 5
percent prevalence of a high-grade stenosis in those older than 65 years and a threefold
108increased likelihood of stenosis in those with a bruit.
Aspirin has been shown to reduce risk of stroke and myocardial infarction in patients with
110ischemic stroke or transient ischemic attacks, with a risk reduction of about 20 percent. Some
clinicians use anticoagulation with heparin or warfarin to treat symptomatic carotid stenosis, but
there are no reliable data supporting this approach. Based on results in coronary artery disease, a
process with similar pathophysiology, and on overall risk reduction of ischemic stroke, treatment
with cholesterol-lowering agents may be of benefit even in those without hypercholesterolemia.
Surgical removal of the obstructing plaque by endarterectomy is the established standard of
therapy for symptomatic patients with carotid artery stenosis of at least 70 percent (Table
789,1114). Endarterectomy also reduces recurrent stroke rates in patients with symptomatic
carotid stenoses of 50 to 69 percent, but the number needed to treat (NNT) to prevent one
recurrent stroke is considerably higher in this group when compared with those with stenoses
exceeding 70 percent (∼15.4 to prevent one stroke over 5 years in those with 50% to 69%
107stenosis versus ∼5.8 to prevent one stroke over 2 years in those with 70% to 99% stenosis).
Endarterectomy is not bene, cial in patients with stenosis less than 50 percent and is generally
impractical in those with carotid artery occlusion. The risk of stroke with medical therapy is
greater in those with cerebral events compared with ocular events, with plaque surface
irregularity consistent with ulceration, with a symptomatic event within 2 weeks of presentation,
112and with greater degrees of stenosis. The risk of surgery is greater in females, in those with
severe hypertension, and in those with peripheral vascular disease. These prognostic factors may
be useful in fine-tuning patient selection for endarterectomy.
TABLE 7-4 Yearly Ipsilateral Stroke Rates With Carotid Artery Stenosis Based on 5-Year
FollowupFor patients with asymptomatic carotid artery stenosis, endarterectomy also prevents stroke
when there is stenosis of at least 60 percent as assessed by carotid ultrasonography, but again
the number needed to treat to prevent one stroke over 5 years remains large (∼20), and,
therefore, current guidelines recommend consideration of endarterectomy for asymptomatic
stenosis for patients with a surgical risk less than 3 percent and life expectancy of at least 5
32,113years.
Endovascular angioplasty and stenting are an evolving approach to treatment of carotid
stenosis, and stenting has been shown to be not inferior to endarterectomy in patients with both
symptomatic and asymptomatic stenoses who have comorbidities associated with high surgical
risk during endarterectomy. Large-scale trials comparing endarterectomy and stenting in more
representative patient populations are ongoing.
High-grade stenoses of the carotid arteries could impair distal cerebral blood-Dow in some
patients without adequate collateral supply. When endarterectomy is planned for the near
future, physicians will routinely allow higher than normal blood pressures to reduce the risk of
symptomatic hypoperfusion. Whether such a practice is truly justi, ed when compared to the risk
of plaque rupture associated with hypertension has not been addressed in clinical trials.
INTRACRANIAL ATHEROSCLEROSIS
Atherosclerosis involving the large intracranial vessels causes about 8 percent of ischemic
114strokes. African Americans, Hispanics, and Asians have a higher prevalence of intracranial
atherosclerosis, and relatively low prevalence of extracranial carotid artery stenosis compared
114,115with whites. Extracranial carotid atherosclerosis is associated with a higher prevalence of
114peripheral vascular and coronary artery disease, but intracranial atherosclerosis is not. Given
racial and risk factor distribution di7erences, it seems appropriate to consider intracranial
atherosclerosis an entity distinct from carotid artery disease rather than as an additional
manifestation of widespread atherosclerotic changes.Hypertension is an important risk factor for intracranial atherosclerosis, with a two- to
116threefold higher risk of disease in those with a history of hypertension. Smoking may be the
most important risk factor, with a 50 percent increase in odds of disease for every 10 years of
smoking. Diabetics have about three times the risk of developing intracranial atherosclerosis.
Hypercholesterolemia also increases risk, but probably to a lesser degree. The relative
contribution of these factors to intracranial atherosclerosis as opposed to other stroke subtypes is
unclear. Distribution of known risk factors probably accounts for some of the racial
114differences.
There are intriguing di7erences in the pathophysiology of intracranial atherosclerosis and
other forms of vascular disease. Intracranial arteries are less susceptible to hypercholesterolemia
117than are extracranial arteries, and atherosclerotic plaque rupture appears to be less
118common. Release of endothelial adhesion molecules is greater with intracranial
atherosclerosis than in other ischemic stroke subtypes, suggesting that inDammation is
119particularly important in its pathogenesis. There is no accepted unifying theory on the
etiology of intracranial atherosclerosis.
Clinical presentation is characterized by large-vessel or penetrating artery ischemia. The
middle cerebral artery is most commonly involved, followed in order by the basilar, intracranial
114internal carotid, anterior cerebral, and posterior cerebral arteries. Thrombosis at the site of
the stenosis may lead to hypoperfusion in the entire distal territory or artery-to-artery embolus
indistinguishable from events caused by extracranial carotid artery stenosis or cardiac embolus.
Basilar thrombosis may result from underlying atherosclerosis in the basilar or vertebral arteries
or after cardiac embolus. It is a life-threatening, often delayed diagnosis characterized by coma,
quadriplegia, and cranial nerve , ndings. Involvement of the origin of penetrating small vessels
may produce lacunar infarctions. Presentation with transient ischemic attack prior to infarction
is more common with intracranial atherosclerosis than with other stroke subtypes.
Intracranial MR angiography may reveal narrowing or occlusion of large vessels. However,
artifacts may suggest a stenosis where none is present, and sensitivity is low for medium-sized
and smaller vessels. Transcranial Doppler ultrasonography shows increased blood Dow velocities
in large stenotic vessels. Its sensitivity and speci, city are also low, so it may be most useful as an
adjunct to MR angiography. Catheter angiography is the gold standard for establishing the
diagnosis, but it is associated with a 1 percent stroke risk that is probably even higher in the
population being evaluated for intracranial atherosclerosis. Given the risk of angiography, it is
only justified if results will alter treatment decisions.
Prognosis in symptomatic patients is poor. Stenosis generally becomes more severe with time,
but regression in some segments may occur. In the largest randomized trial of treatment for
symptomatic intracranial atherosclerosis, the Warfarin-Aspirin Symptomatic Intracranial Disease
(WASID) trial, 569 subjects were randomized to aspirin (1,300 mg/day) and warfarin (target
120international normalized ratio, or INR, of 2.0 to 3.0). The trial was stopped early because of
safety concerns among subjects randomized to warfarin, and there was no signi, cant di7erence
in the primary endpoint of stroke, brain hemorrhage, or vascular death (P = 0.83). The 2-year
rates of ischemic stroke were 19.7 percent in the aspirin group and 17.2 percent in the warfarin
group (P = 0.29), indicating that intracranial atherosclerosis is a high-risk condition for
recurrent stroke. For comparison, the 2-year risk of ischemic stroke was 26 percent among
individuals with symptomatic carotid stenosis between 70 and 99 percent assigned to medical
therapy in the North American Symptomatic Carotid Endarterectomy Trial and approximately