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Geriatric Medicine An Evidence-Based Approach Fourth Edition With 186 Illustrations in 217 Parts, 8 in Full Color
Editor
Christine K. Cassel, MD Professor and Dean, Oregon Health & Science University, School of Medicine, Portland, Oregon
Deputy Editor
Rosanne M. Leipzig, MD, PhD Vice-Chair for Education, Gerald and May Ellen Ritter Professor of Geriatrics, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York
Associate Editors
Harvey Jay Cohen, MD Director, Center for the Study of Aging and Human Development, and Chief, Geriatrics Division, Duke University Medical Center; Director, Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Durham, North Carolina
Eric B. Larson, MD, MPH Director, Center for Health Studies, Group Health Cooperatives; Professor of Medicine, University of Washington Medical Center, Seattle, Washington
Diane E. Meier, MD Director, Hertzberg Palliative Care Institute; Catherine Gaisman Professor of Medical Ethics; Professor, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York
Managing Editor
Carol F. Capello, PhD Assistant Professor of Geriatric Education, Division of Geriatrics and Gerontology, Weill Medical College of Cornell University, New York, New York
1 3
Christine K. Cassel, MD, Professor and Dean, Oregon Health & Science University, School of Medicine, Portland, OR, 97201-3098, USA Rosanne M. Leipzig, MD, PhD, Vice-Chair for Education, Gerald and May Ellen Ritter Professor of Geriatrics, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA Harvey Jay Cohen, Director, Center for the Study of Aging and Human Development, and Chief, Geriatrics Division, Duke University Medical Center; Director, Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Durham, NC 27710, USA Eric B. Larson, MD, MPH, Director, Center for Health Studies, Group Health Cooperatives; Professor of Medicine, University of Washington Medical Center, Seattle, WA 98195–6330, USA Diane E. Meier, MD, Director, Hertzberg Palliative Care Institute; Catherine Gaisman Professor of Medical Ethics, Professor, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA Carol F. Capello, PhD, Assistant Professor of Geriatric Education, Division of Geriatrics and Gerontology, Weill Medical College of Cornell University, New York, New York 10021, USA
Library of Congress Cataloging-in-Publication Data Geriatric medicine: an evidence-based approach/editors, Christine K. Cassel . . . [et al.].—4th ed. p. ; cm. Includes bibliographical references and index. ISBN 0-387-95514-3 (h/c : alk. paper) 1. Geriatrics. 2. Evidence-based medicine. I. Cassel, Christine K. [DNLM: 1. Geriatrics. 2. Evidence-Based Medicine. WT 100 G36635 2002] RC952 .G393 2002 618.97—dc21 2002070548 ISBN 0-387-95514-3
Printed on acid-free paper.
© 2003, 1997, 1990 and 1984 Springer-Verlag New York, Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer-Verlag New York, Inc., 175 Fifth Avenue, New York, NY 10010, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now know or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed in the United States of America. 9 8 7 6 5 4 3 2 1
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To the dedicated caregivers of older adults and to the teachers and scientists devoted to improving the care of the older population
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Preface
Since the publication of the third edition of Geriatric Medicine, extraordinary advances have occurred in the science of aging and the potential for biomedical research to give us answers to many, if not most, of the age-related disorders that threaten the quality of life in older years. At the most basic level, the successful mapping of the human genome was declared complete in the fall of 2000. Understanding the map of the human genome is as important as understanding the map of genomes of important laboratory species, ranging from the microscopic worms and fruitflies used in most classic genetic studies to rodents such as laboratory mice, and eventually to primates, on which much of the research on the aging human brain is done. The genetic maps of all of these species, including our own, does not answer clinical questions, but it does open the door to dramatic, rapid, and efficient answers to questions about the genetic polymorphisms related to diseases in humans. The telomerase story also unfolded since the third edition. Telomerase is an enzyme responsible for maintaining the telomeres—the redundant DNA portions at the end of chromosomes—whose shortening seems to be linked directly to cell senescence, apoptosis, and the control over cell death, which, at the level of the individual cell, seems to be linked to the decline of organ function and eventually aging and death within the organism.The potential for genetic manipulations by which telomerase maintains and restores telomere length within individual tissue cultures gives great promise for potential approaches to restoring function lost through degenerative diseases, such as macular degeneration and other disorders related to epithelial aging. In addition, the maintenance of telomeres has been intriguingly associated with the malignant immortality of cancer cells, and yet it appears possible to prevent degeneration without creating uncontrolled growth or malignancy. Understanding this single genetic mechanism may give us clues not only to degenerative neurological and epithelial disease, but also perhaps to cancer,another age-related human disease. Scientists have also discovered that stem cells from embryonic and adult tissues can potentially create new tissues and new organs. Perhaps most excitingly, it appears that brain cells themselves can be replaced through this mechanism. Thus, stem cell research holds promise for treatment of Alzheimer’s and Parkinson’s disease, as well as for potentially growing new functioning organs that could be used for transplantation with much reduced risk of rejection because they are genetically fashioned to match the recipient’s immune status. Because of these and many more similar advances, it is more and more important for the practicing clinician to be conversant with the literature of basic science and to stay abreast of such developments. Our patients come to us having read about these developments or having seen television reports, and we should be able to answer their questions and share the excitement. We should also be educating them about the realistic limits, understanding that many of these developments will not provide immediate cures but are promising future developments. vii
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Secondly, we owe it to ourselves to share the excitement of our colleagues in basic science, as well as the general public, in recognizing that aging research has come into real prominence in the last decade. We also need to be well informed about the rampant marketing of bogus dreams of anti-aging potions that the marketplace is all too ready to foist onto our patients. The aging of the baby boomers has created a huge and growing market for anti-aging therapies. Many are safe, effective, and worthwhile. However, in some instances, such as vitamin supplementation or hormone replacement, controversies exist and individual patient decision should be informed by knowledgeable and free discussions based on real science. This information can come from you, the clinician. It can also come from internet sources, but internet sources increasingly are also are full of inadequate and misleading information and, thus, it becomes even more important for us to be able to relay to our patients legitimate sources of information. Some of the most useful include the following: • On terra firma, the National Institutes of Health is a complicated maze of 75 buildings. But on the Web (http://www.nih.gov), it is a snap to move from the National Cancer Institute to Mental Health to Alternative Medicine. Log on to www.clinicaltrials.gov to search for clinical trials by disease. • The National Institute on Aging, one of 25 institutes and centers of the National Institutes of Health, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. Visit http://www.nia.nih.gov/ for a description of its mission, sponsored research programs, news and calendar of events, and health information, including NIA publications and videos, a resource directory for older adults, and various internet links of Federal websites of interest to the aging community. • At their website, the Centers for Disease Control and Prevention (www.cdc.gov) provides a calendar of events, current topics, and recent reports and publications. Click on their “Data and Statistics” for CDC health data standards, scientific data, surveillance, health statistics reports, and laboratory information. The website also includes information about grant and cooperative agreement funding opportunities, as well as press releases and current health news. On their “Publications, Software, Products” link, one can order and download brochures, catalogs, publications, software, slides, and videos. Consumers can browse their “Health Topics” from A (Acanthamoeba infection) to Z (Zoster), get the latest on health “Hoaxes and Rumors” (i.e., deodorants cause breast cancer), or check out the travel section to find out if they will need vaccines for a trip abroad. Or stay close to home and find a link to your local state health department. • The Food and Drug Administration is the primary resource for information about safety alerts/recalls and product approvals of drugs, cosmetics, foods, medical devices, biologics, animal feed and drugs, and radiation-emitting products. Ongoing clinical trials are also profiled. Go to http://www.fda.gov. • HealthWeb (http://www.healthweb.org/) is a collaborative project of the health sciences libraries of the Greater Midwest Region of the National Network of Libraries of Medicine and those of the Committee for Institutional Cooperation. Currently, there are over 20 actively participating member libraries. The goals of the HealthWeb project include the development of an interface that provides organized access to evaluated noncommercial, health-related, internet-accessible resources, including those currently available, as well as new resources developed in collaboration with other organizations. The interface integrates educational information so the users has a one-stop entry point to learn skills and use material relevant to their discipline, including geriatrics and gerontology. • The National Aging Information Center (http://www.aoa.gov/NAIC/ ) serves as a central source for a wide variety of information on aging for older people, their families, and those who work for or on behalf of older persons. NAIC resources include program and policy-related materials for consumers and practitioners and
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•
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•
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•
demographic and other statistical data on the health, economic, and social conditions of older Americans. The NAIC bibliographic database contains references to program- and policy-related materials on aging not referenced in any other computer system or print resource. The GeroWeb, sponsored by the Geroinformatics Workgroup at the Wayne State University Institute of Gerontology, is designed as an online resource for researchers, educators, practitioners, and others interested in aging and older individuals. (http://geroserver.iog.wayne.edu/GeroWebd/GeroWeb.html) The Alzheimer Research Forum’s intended audience is Alzheimer researchers and other researchers whose work may bring understanding to Alzheimer’s. The site has news, holds online forums, conducts online polls (“What are your 10 most wanted research tools?”), provides information on conferences, research funding, and includes a reagent company directory. Visit them at http://www.alzforum.org/home.asp. The Federal Interagency Forum on Aging-Related Statistics was initially established in 1986, with the goal of bringing together Federal agencies that share a common interest in improving aging-related data. The Forum has played a key role by criticially evaluating existing data resources and limitations, stimulating new database development, encouraging cooperation and data sharing among Federal agencies, and preparing collaborative statistical reports. Their website (http://www.agingstats.gov/ ) provides information from their latest report. Older Americans 2000: Key Indicators of Well-Being, as well as links to aging-related statistical information on Forum Member websites, ongoing Federal data resources relevant to the study of aging, past products of forum activities, and agency contacts. AgeLine is a free searchable electronic database of 60,000 summaries of publications about older adults and aging, including books, journal and magazine articles, and research reports. Coverage is sporadic between 1966–1977, but more comprehensive coverage exists from 1978–present. http://research.aarp.org/ageline/home.html) The Centers for Medicare and Medicaid (CMS), formerly the Health Care Financing Administration (HCFA), is a federal agency within the U.S. Department of Health and Human Services. CMS runs the Medicare and Medicaid programs and the State Children’s Health Insurance Program (SCHIP), and also regulates all laboratory testing (except research) performed on humans in the U.S. By visiting the CMS website at http://cms.hhs.gov physicians and other health care professionals can gain quick access to professional publications and program forms and learn about the Medicare program and CMS contracts with Medicare health plans, as well as statistics, data, and the latest CMS research and program analysis. Consumers can find information on what Medicare covers, who is eligible, and how to enroll. They can also get a personalized report on Medicare health plans, nursing homes, dialysis facilities, participating physicians, and prescription drug programs in their area.
While we have a glut of information, we also have real ethical challenges facing us. The advances in genetic knowledge and potential alterations of genes through gene therapy have led to real caution because of highly visible adverse consequences to subjects of human studies. People are very concerned about the degree to which genetic information can be kept private and justifiably concerned that such information not fall into the hands of employers or insurers. The country will continue to be embroiled in deep disagreements about the use of human stem cells for research. The dramatic promise that they hold has come up against deep-seated religious beliefs of those who feel that embryos that are surplus and intended for discarding are indeed human life and ought not to be used for experimentation. These and other ethical issues will continue to be important as science progresses. In their chapter, Greg Sachs and Harvey Cohen discuss the ethical issues in clinical research, including the ethics of research with Alzheimer’s disease, a paradigmatic disorder where patients cannot fully make their own decisions and yet where research
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is very high stakes and needs to be offered to those suffering from the ravages of this disease. Ethical issues also continue to surround treatment decisions and, in particular, those around expensive potential life-prolonging and intrusive measures for older individuals. The challenge—especially in the United States—is how to balance the promise of these disorders with the increasing inequities in our health care system, in particular in a situation where more and more people under the age of 65 have no health insurance at all. All of these issues will continue to intensely involve the public, and thus clinicians will need every possible resource to stay informed as citizens and to provide important answers for their communities and their patients. Along these lines, we have expanded this edition by 18 chapters, devoting an entire section to the emerging field of palliative medicine and increasing our coverage on surgical issues, care management, and pharmacology. Health care providers will increasingly be called upon to practice what has come to be known as “evidence-based medicine.” So much of health care—particularly the prescribing of medications—is extremely costly and, as we know well in geriatrics, carries risks of its own. For this reason, it is more and more important that clinicians understand the evidence behind the use of any interventions, both diagnostic and therapeutic. The science of evaluating evidence is a statistical one, and the standards for doing so have been articulated by leaders in the field. One of those leaders, Rosanne Leipzig, is deputy editor of this edition of Geriatric Medicine. She has looked at every single chapter through an evidence-based lens and, whenever possible, provided up-to-date information about the quality and strength of the evidence for the diagnostic and treatment recommendations included in each chapter. We are very fortunate that Dr. Leipzig has joined the Geriatric Medicine, 4/e, team and can give us this added dimension of balance and rigor to the expertise of our world-class roster of authors. I also want to thank Harvey Cohen, Eric Larsen, and Diane Meier,Associate Editors, who have contributed enormously to the production of this book. We have worked hard together and learned a great deal from each other. Thanks also to Carol Capello in her role as Managing Editor. Carol has now taken us through two editions of Geriatric Medicine, and we hope we can persuade her to work with us on the fifth edition of Geriatric Medicine. Christine K. Cassel
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vii xvii
Part I Basics of Gerontology 1
Evidence-Based Medicine and Geriatrics . . . . . . . . . . . . . . . . . . . . . . . . . Rosanne M. Leipzig
3
2
Molecular and Biologic Factors in Aging . . . . . . . . . . . . . . . . . . . . . . . . . . Charles Mobbs
15
3
Physiology of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . George E. Taffet
27
4
The Demography of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S. Jay Olshansky
37
5
Epidemiology and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tamara B. Harris
45
6 Psychosocial Influences on Health in Later Life . . . . . . . . . . . . . . . . . . . . Elizabeth C. Clipp and Karen E. Steinhauser
53
7
Principles of Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jerry Avorn, Jerry H. Gurwitz, and Paula Rochon
65
8 Clinical Strategies of Prescribing for Older Adults . . . . . . . . . . . . . . . . . . Judith L. Beizer
83
Part II Changing Contexts of Care in Geriatric Medicine 9
Contexts of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laurence Z. Rubenstein
93
10
The Long and the Short of Long-Term Care . . . . . . . . . . . . . . . . . . . . . . . Robert L. Kane
99
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Contents
11
The Geriatrician in the Nursing Home . . . . . . . . . . . . . . . . . . . . . . . . . . . Wayne C. McCormick
113
12
Home Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sharon A. Levine and Patricia P. Barry
121
13
Acute Hospital Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert M. Palmer
133
Part III Clinical Approaches to the Geriatric Patient 14 Clinical Approach to the Older Patient: An Overview . . . . . . . . . . . . . . . Glendo L. Tangarorang, Gerard J. Kerins, and Richard W. Besdine
149
15
Chronic Disease Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Harrison G. Bloom
163
16
Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Harrison G. Bloom
169
17
Instruments to Assess Functional Status . . . . . . . . . . . . . . . . . . . . . . . . . . Brandon Koretz and David B. Reuben
185
18 Comprehensive Geriatric Assessment and Systems Approaches to Geriatric Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David B. Reuben
195
19
Neuropsychological Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marilyn S. Albert
205
20 Preoperative Assessment and Perioperative Care . . . . . . . . . . . . . . . . . . . Peter Pompei
213
21
Anesthesia for the Geriatric Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey H. Silverstein
229
22
Surgical Approaches to the Geriatric Patient . . . . . . . . . . . . . . . . . . . . . . Ronnie Ann Rosenthal
239
23
Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kenneth Brummel-Smith
259
Part IV Palliative Care 24
Old Age and Care Near the End of Life . . . . . . . . . . . . . . . . . . . . . . . . . . Diane E. Meier
281
25
Doctor-Patient Communication Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . James A. Tulsky
287
26
Care Near the End of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarah Goodlin
299
27
Sources of Suffering in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maria Torroella Carney and Diane E. Meier
311
Contents
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28
Acute and Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bruce A. Ferrell
323
29 Palliative Care in Early, Moderate, and Advanced Dementia . . . . . . . . . . Anna Monias and Diane E. Meier
343
30
351
The Value of Achieving a Peaceful Death . . . . . . . . . . . . . . . . . . . . . . . . . Daniel Callahan
Part V Medical Care Section A: Cancer in the Elderly Cancer in the Elderly: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Harvey Jay Cohen
361
31 The Science of Neoplasia and Its Relationship to Aging . . . . . . . . . . . . . . Robert E. Martell and Harvey Jay Cohen
363
32
Screening for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eugene Z. Oddone, Mitchell T. Heflin, and John R. Feussner
375
33
Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ann Partridge and Eric Winer
393
34 Colon Cancer and Other Gastrointestinal Malignancies . . . . . . . . . . . . . . Peter C. Enzinger and Robert J. Mayer
417
35
Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eric B. Haura, Susan A. Blackwell, and Jeffrey Crawford
441
36
Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Khalid Matin and Donald L. Trump
455
37
Gynecologic Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angeles A. Alvarez and Daniel L. Clarke-Pearson
469
38
Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marc Gautier, Elizabeth M. Bengtson, Edward M. Liebers, and Harvey Jay Cohen
487
Section B: Organ System Diseases and Disorders 39
Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nanette Kass Wenger
509
40
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark A. Supiano
545
41
Peripheral Arterial Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . William R. Hiatt and Mark R. Nehler
561
42
Rheumatologic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel J. Brauner, Leif B. Sorensen, and Michael H. Ellman
573
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Contents
43
Skeletal Fragility in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angela Inzerillo, Jameel Iqbal, Bruce Troen, Diane E. Meier, and Mone Zaidi
621
44
Orthopedic Problems with Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lawrence A. Pottenger
651
45
Medical Aspects of Hip Fracture Management . . . . . . . . . . . . . . . . . . . . . R. Sean Morrison and Albert L. Siu
669
46
Treatment of Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kenneth L. Minaker
681
47
Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David S. Cooper
695
48
Changes in Male Sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas Mulligan and Waleed Siddiqi
719
49
Sexual Function and the Older Woman . . . . . . . . . . . . . . . . . . . . . . . . . . . Fran E. Kaiser
727
50 Gynecologic and Urologic Problems of Older Women . . . . . . . . . . . . . . . M. Chrystie Timmons
737
51
Benign Prostatic Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catherine E. DuBeau
755
52
Nephrology/Fluid and Electrolyte Disorders . . . . . . . . . . . . . . . . . . . . . . . Sharon Anderson
769
53
Immunology of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Edith A. Burns and James S. Goodwin
783
54
Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas T. Yoshikawa
801
55
Hematologic Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gerald Rothstein
819
56
Gastroenterologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joanne A.P. Wilson
835
57
Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James R. Webster, Jr.
853
58
Dermatologic Diseases and Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amy Krupnick Freeman and Marsha Gordon
869
59
Changes and Diseases of the Aging Eye . . . . . . . . . . . . . . . . . . . . . . . . . . Bruce P. Rosenthal
883
60
Otologic Changes and Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . George A. Gates and Thomas S. Rees
893
61
Aging and the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gretchen Gibson and Linda C. Niessen
901
Contents
xv
Section C: Common Problems in Older Adults 62
Dietary Supplements for Geriatric Patients . . . . . . . . . . . . . . . . . . . . . . . . Cynthia X. Pan and Charles Mobbs
921
63
Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neil M. Resnick
931
64
Syncope in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wishwa N. Kapoor
957
65
Management of Chronic Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David R. Thomas
967
66
Falls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David C. Thomas, Helen K. Edelberg, and Mary E. Tinetti
979
67
Chronic Dizziness and Vertigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aman Nanda and Mary E. Tinetti
995
68
Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David A. Lipschitz
1009
69
Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eric B. Larson and Robert A. Bruce
1023
70
Sleep and Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tamar Shochat and Sonia Ancoli-Israel
1031
71
Herpes Zoster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kenneth Schmader
1043
72
Elder Mistreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Terry Fulmer and Maria Hernandez
1057
73
Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Linda P. Fried, Jonathan Darer, and Jeremy Walston
1067
Part VI Neurologic and Psychiatric Disorders 74
Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gary J. Kennedy
1079
75 Neurobiologic Basis of Age-Related Dementing Disorders . . . . . . . . . . . 1095 Patrick R. Hof, Thierry Bussière, Joseph D. Buxbaum, and John H. Morrison 76
Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sharon K. Inouye
1113
77
Cerebrovascular Disease and Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stanley Tuhrim
1123
78
Abnormalities of Posture and Movement . . . . . . . . . . . . . . . . . . . . . . . . . José C. Masdeu and María Cruz Rodriguez-Oroz
1139
xvi
Contents
79 Depression, Anxiety, and Other Mood Disorders . . . . . . . . . . . . . . . . . . . 1163 Harold G. Koenig and Dan G. Blazer, II 80
Late-Life Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steven C. Samuels and Deborah B. Marin
1185
Part VII Ethics and Health Policy Issues for Older Adults 81
Mechanisms of Paying for Health Care . . . . . . . . . . . . . . . . . . . . . . . . . . . Bruce C. Vladeck
1201
82 Justice and the Allocation of Health Care Resources . . . . . . . . . . . . . . . . 1213 Nancy S. Jecker 83 Medical Treatment and the Physician’s Legal Duties . . . . . . . . . . . . . . . . . 1221 Marshall B. Kapp 84
Determination of Decision-Making Capacity . . . . . . . . . . . . . . . . . . . . . . Jason H.T. Karlawish and Robert A. Pearlman
1233
85 Ethical and Policy Issues in End-of-Life Care . . . . . . . . . . . . . . . . . . . . . . 1243 Melissa A. Bottrell, Christine K. Cassel, and Emily R. Felzenberg 86 Ethical Challenges to Research in Geriatric Medicine . . . . . . . . . . . . . . . 1253 Greg A. Sachs and Harvey Jay Cohen
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1263
Contributors
Marilyn S. Albert, PhD, Professor of Psychiatry & Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA Angeles A. Alvarez, MD, Assistant Professor of Gynecology and Oncology, Division of Gynecology/Oncology, Duke University Medical Center, Durham, NC 27710, USA Sonia Ancoli-Israel, PhD, Professor, Department of Psychiatry, University of California, San Diego, San Diego, CA 92161, USA Sharon Anderson, MD, Professor of Medicine, Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR 97201-2940, USA Jerry Avorn, MD, Associate Professor of Medicine, Harvard Medical School; Chief, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, MA 02115, USA Patricia P. Barry, MD, Executive Director, Merck Institute of Aging and Health, Washington, DC 20005, USA Judith L. Beizer, PharmD, Associate Clinical Professor, College of Pharmacy and Allied Health Professions, St. John’s University, Jamaica, NY 11439, USA Elizabeth M. Bengtson, MD, Assistant Professor, Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA Richard W. Besdine, MD, FACP, Greer Professor of Geriatric Medicine; Director, Center for Gerontology and Health Care Research, Brown University School of Medicine, Providence, RI 02912, USA Susan A. Blackwell, PA-C, Senior Physician Assistant, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC 27710, USA Dan G. Blazer, II, MD, PhD, J.P. Gibbons Professor of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA Harrison G. Bloom, MD, Clinical Associate Professor of Geriatrics and Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA xvii
xviii
Melissa A. Bottrell, MPH, PhD, Project Director, National Center for Ethics in Health Care, VA Puget Sound Health Care System, Seattle, WA 98108, USA Daniel J. Brauner, MD, Associate Professor, Department of Medicine, University of Chicago, Chicago, IL 60637, USA Robert A. Bruce, MD, Professor Emeritus of Medicine, University of Washington, Seattle, WA 98133-8065, USA Kenneth Brummel-Smith, MD, Chair, Brain Center on Aging, Providence Health System, Portland, OR 97230, USA Edith A. Burns, MD, Associate Professor of Medicine, Medical College of Wisconsin, Milwaukee, WI 53295, USA Thierry Bussière, PhD, Elan Pharmaceuticals Inc., South San Francisco, CA 94080, USA Joseph D. Buxbaum, PhD, Associate Professor, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA Daniel Callahan, PhD, Director of International Programs, The Hastings Center, Garrison, NY, 10524, USA Maria Torroella Carney, MD, Assistant Professor of Clinical Medicine, State University of New York at Stony Brook School of Medicine; Mineola, NY 11501, USA Christine K. Cassel, MD, Professor and Dean, Oregon Health & Science University, School of Medicine, Portland, OR 97201-3098, USA Daniel L. Clarke-Pearson, MD, James M. Ingram Professor of Gynecologic Oncology, Duke University Medical Center, Durham, NC 27710, USA Elizabeth C. Clipp, RN, PhD, Associate Director for Research, Geriatric Research, Education and Clinical Center (GRECC), Durham VA Medical Center; Professor, School of Nursing and Professor, Department of Medicine, Division of Geriatrics; Senior Fellow in the Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC 27710, USA Harvey Jay Cohen, MD, Director, Center for the Study of Aging and Human Development, and Chief, Geriatrics Division, Duke University Medical Center; Director, Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Durham, NC 27710, USA David S. Cooper, MD, Professor of Medicine, The Johns Hopkins University School of Medicine; Director, Division of Endocrinology, Sinai Hospital of Baltimore, Baltimore, MD 21215, USA Jeffrey Crawford, MD, Professor of Medicine, Director, Clinical Research, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC 27710, USA Jonathan Darer, MD, MPH, General Medicine Fellow, The Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA Catherine E. DuBeau, MD, Assistant Professor of Medicine, Harvard Medical School, Urban Medical Group; Research Physician, Hebrew Rehabilitation Center for Aged, Jamaica Plain, MA 02130, USA
Contributors
Contributors
xix
Helen K. Edelberg, MD, Assistant Professor, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA Michael H. Ellman, MD, Professor of Medicine, Rheumatology Section, Division of Medicine, University of Chicago, Chicago, IL 60637, USA Peter C. Enzinger, MD, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115-5013, USA Emily R. Felzenberg, MPH, JD, Medical Student, New York College of Osteopathic Medicine, Old Westbury, NY 11568 USA Bruce A. Ferrell, MD, Associate Professor, Department of Medicine, Division of Geriatrics, UCLA School of Medicine, Los Angeles, CA 90095-1687, USA John R. Feussner, MD, MPH, Chief Research and Development Officer, Department of Veterans Affairs, Washington, DC 20420, USA Linda P. Fried, MD, MPH, Director, Center on Aging and Health, The Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA Terry Fulmer, RN, PhD, FANN, Professor and Director for the Center of Nursing Research, and Head, Division of Nursing, New York University, New York, NY 10013, USA George A. Gates, MD, Professor, Otolaryngology-Head and Neck Surgery; Director, Virginia Merrill Bloedel Hearing Research Center, University of Washington School of Medicine, Seattle, WA 98195, USA Marc Gautier, MD, Associate Professor of Medicine, Section of Hematology and Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA Gretchen Gibson, DDS, Director, Special Care Dental Programs, VA North Texas Health Care System, Clinical Associate Professor, Baylor College of Dentistry, Dallas, TX 75216, USA Sarah Goodlin, MD, Assistant Professor of Medicine, Geriatrics Division, University of Utah School of Medicine; Director of Supportive Care and Palliative Medicine, LDS Hospital, Salt Lake City, UT 84143, USA James S. Goodwin, MD, Professor of Medicine, Director, Geriatric Services, University of Texas Medical Branch, Galveston, TX 77555-0460, USA Marsha Gordon, MD, Professor and Vice Chairman, Department of Dermatology, Mount Sinai School of Medicine, New York, NY 10029, USA Jerry H. Gurwitz, MD, Professor of Medicine, University of Massachusetts Medical School; Executive Director, Meyers Primary Care Institute, Fallon Healthcare System, Worcester, MA 01605, USA Tamara B. Harris, MD, MS, Chief, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD 20892, USA Eric B. Haura, MD, Interdisciplinary Oncology Program, Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
xx
Mitchell T. Heflin, MD, Assistant Professor, Department of Medicine, Division of Geriatrics, Duke University Medical Center, Durham, NC 27710, USA Maria Hernandez, MD, Chief Medical Officer’s Assistant, Hospital de Clinicas Caracas, San Bernardino, Caracas, Venezuela William R. Hiatt, MD, Novartis Professor of Cardiovascular Research, Section of Vascular Medicine, Unversity of Colorado Health Sciences Center, Denver, CO 80203, USA Patrick R. Hof, MD, Associate Regenstreif Professor of Neuroscience, Kastor Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, New York, NY 10029, USA Sharon K. Inouye, MD, MPH, Professor of Medicine, Department of Internal Medicine, Yale University School of Medicine, Yale-New Haven Hospital, New Haven, CT 06504, USA Angela Inzerillo, MD, Assistant Professor of Medicine and Geriatrics, Mount Sinai School of Medicine, New York, NY 10029, USA Jameel Iqbal, BS, Research Associate, Mount Sinai School of Medicine, New York, NY 10029, USA Nancy S. Jecker, PhD, Professor, Department of Medical History and Ethics, University of Washington School of Medicine, Seattle, WA 98195, USA Fran E. Kaiser, MD, Adjunct Professor of Medicine, St. Louis University School of Medicine, St. Louis, MO 63104, USA Robert L. Kane, MD, Professor, Minnesota Chair in Long Term Care and Aging, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA Wishwa N. Kapoor, MD, MPH, Falk Professor of Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Marshall B. Kapp, JD, MPH, Professor, Departments of Community Health and Psychiatry; Director of Geriatric Medicine and Gerontology, Wright State University School of Medicine, Dayton, OH 45435-0001, USA Jason H.T. Karlawish, MD, University of Pennsylvania, Institute on Aging, Philadelphia, PA 19104, USA Gary J. Kennedy, MD, Professor of Psychiatry and Behavioral Science, Albert Einsteing College of Medicine; Director, Division of Geriatric Psychiatry and Fellowship Training Program, Montefiore Medical Center, Bronx Psychiatric Center, Bronx, NY 10024-2490, USA Gerard J. Kerins, MD, FACP, Assistant Professor of Medicine, Division of Geriatrics, University of Connecticut Health Center, Farmington, CT 06030-3956, USA Harold G. Koenig, MD, MHSc, Associate Professor of Psychiatry and Medicine, Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, NC 27710, USA
Contributors
Contributors
xxi
Brandon Koretz, MD, Assistant Clinical Professor of Medicine, Division of Geriatrics, UCLA School of Medicine, Los Angeles, CA 90024, USA Amy Krupnick Freeman, MD, Dermatology Resident, Department of Dermatology, Mount Sinai School of Medcine, New York, NY 10029, USA Eric B. Larson, MD, MPH, Director, Center for Health Studies, Group Health Cooperatives; Professor of Medicine, University of Washington Medical Center, Seattle, WA 98195, USA Rosanne M. Leipzig, MD, PhD, Vice-Chair for Education, Gerald and May Ellen Ritter Professor of Geriatrics, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA Sharon A. Levine, MD, Associate Professor of Medicine, Director of Medical Education and the Geriatric Medicine, Dentistry, and Psychiatry Fellowship Program, Geriatrics Section, Boston University Medical Center, Boston, MA 02218, USA Edward M. Liebers, MD, Clinical Fellow, Department of Medicine, Section of Hematology and Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA David A. Lipschitz, MD, PhD, Chairman, Donald W. Reynolds Department of Geriatrics; Director, Center on Aging, Donald W. Reynolds Center on Aging, Little Rock, AK, 72205, USA Deborah B. Marin, MD, Professor of Psychiatry, Vice Chair, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA Robert E. Martell, MD, PhD, Assistant Professor of Medicine, Divisions of Geriatrics and Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA José C. Masdeu, MD, PhD, Professor and Director of Neurology and the Neuroscience Center, Department of Neurology, University of Navarre Medical School, Pamplona, Spain Khalid Matin, MD, Fellow, Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA Robert J. Mayer, MD, Director, Center for Gastrointestinal Oncology; Professor of Medicine, Department of Adult Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115-5013, USA Wayne C. McCormick, MD, MPH, Associate Professor, Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington Medical Center; Program Director, Long Term Care Services, Harborview Medical Center, Seattle, WA 98104, USA Diane E. Meier, MD, Director, Hertzberg Palliative Care Institute; Catherine Gaisman Professor of Medical Ethics; Professor, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA Kenneth L. Minaker, MD, Associate Professor of Medicine, Harvard Medical School; Chief, Geriatric Medicine Unit, Massachusetts General Hospital, Boston, MA 02114, USA
xxii
Charles Mobbs, PhD, Associate Professor, Neurobiology of Aging Laboratories, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA Anna Monias, MD, Victory Springs, Inc., Premier Senior Health Care, Reisterstown, MD, 21136, USA John H. Morrison, PhD, Professor and Director, Kastor Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, New York, NY 10029, USA R. Sean Morrison, MD, Associate Professor, Brookdale Department of Geriatrics, and Adult Development; Research Director, Hertzberg Palliative Care Institute, Mount Sinai School of Medicine, New York, NY 10029, USA Thomas Mulligan, MD, AGSF, Chair, Consortium on Successful Aging, McGuire VAMC, Virginia Commonwealth University, Richmond, VA 23249, USA Aman Nanda, MD, Assistant Professor of Medicine, Division of Geriatrics, Brown Medical School, Rhode Island Hospital, Providence, RI, 02903, USA Mark R. Nehler, MD, Assistant Professor of Surgery, Section of Vascular Surgery, University of Colorado Health Sciences Center, Denver, CO 80203, USA Linda C. Niessen, DM, MPH, MPP, Vice President, Clinical Education, DENTSPLY International, York, PA 17405, USA Eugene Z. Oddone, MD, MHSc, Director, Center for Health Services Research in Primary Care, VA Medical Center; Chief, Divison of General Internal Medicine, Duke University Medical Center, Durham, NC 27710, USA S. Jay Olshansky, PhD, Associate Professor, Department of Medicine, Harris Graduate School of Public Policy Studies, University of Chicago, Chicago, IL 60089, USA Robert M. Palmer, MD, MPH, Department of General Internal Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA Cynthia X. Pan, MD, Assistant Professor and Director of Education, Palliative Care Program, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA Ann Partridge, MD, Breast Oncology Center, Dana Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA 02115, USA Robert H. Pearlman, MD, MPH, Professor, Department of Medicine, University of Washington,VA Puget Sound Health Care System, Seattle,WA 98108, USA Peter Pompei,MD, Associate Professor of Medicine,Stanford University School of Medicine,Veterans Affairs Palo Alto Health Care System, Stanford, CA 94305-5475, USA Lawrence A. Pottenger, MD, PhD, Associate Professor, Orthopaedic Surgery; Director, Surgical Arthritis Clinic, University of Chicago Medical Center Chicago IL 60637, USA Thomas S. Rees, PhD, Associate Professor of Otolaryngology-Head and Neck Surgery, University of Washington, Harborview Medical Center, Seattle, WA 98104, USA
Contributors
Contributors
xxiii
Neil M. Resnick, MD, Professor of Medicine; Chief, Geriatric Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA David B. Reuben, MD, Chief, Division of Geriatrics; Director, Multicampus Program in Geriatric Medicine and Gerontology; Professor of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1687, USA Paula Rochon, MD, MPH, Assistant Professor of Medicine, University of Toronto; Scientist, Kunin Lunenfeld Applied Research Unit, Baycrest Center for Geriatric Care; Scientist, Institute for Clinical Evaluative Sciences, Toronto, Canada María Cruz Rodriguez-Oroz, MD, Assistant Professor of Neurology, University of Navarre Medical School, Pamplona, Spain Bruce P. Rosenthal, OD, FAAO, Chief, Low Vision Programs, Lighthouse International, New York, NY 10022, USA Ronnie Ann Rosenthal, MD, Associate Professor of Surgery, Yale University School of Medicine; Chief, Surgical Service, VA Connecticut Healthcare System, West Haven, CT 06516, USA Gerald Rothstein, MD, Chief of Geriatrics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA Laurence Z. Rubenstein, MD, MPH, Professor, Department of Medicine, Division of Geriatrics, UCLA School of Medicine; Director, Geriatric Research, Education, and Clinical Center, Sepulveda VA Medical Center, Sepulveda, CA 91343, USA Greg A. Sachs, MD, Chief, Section of Geriatrics; Co-Director, Center for Comprehensive Care and Research on Memory Disorders, Department of Medicine, University of Chicago Medical Center, Chicago, IL 60637, USA Steven C. Samuels, MD, Assistant Professor, Department of Psychiatry, Mount Sinai School of Medicine; Training Director, Geriatric Psychiatry Fellowship, Bronx Veterans Affairs Medical Center, Bronx Veterans Hospital, Bronx, NY 10468, USA Kenneth Schmader, MD, Associate Professor of Medicine, Division of Geriatrics, Center for the Study of Aging, Duke University and Durham Veterans Affairs Medical Centers, Durham, NC 27710, USA Tamar Shochat, PhD, Department of Psychiatry, University of California, San Diego, San Diego, CA 92161, USA Waleed Siddiqi, MD, Staff Physician, Community Health Clinic of Clinch Valley Medical Center, Richlands, VA 24641, USA Jeffrey H. Silverstein, MD, Associate Professor, Department of Anesthesiology/ Surgery, Mount Sinai School of Medicine, New York, NY 10029, USA Albert L. Siu, MD, MSPH, Chief, Division of General Internal Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA Leif B. Sorenson, MD, Professor of Medicine, Section of Rheumatology, University of Chicago Medical Center, Chicago, IL 60637, USA
xxiv
Karen E. Steinhauser, PhD, Health Scientist, Program on the Medical Encounter and Palliative Care and Center for Health Services Research in Primary Care, Durham VA Medical Center; Research Assistant Professor, Department of Medicine, Division of General Internal Medicine, Duke University Medical Center, Durham, NC 27705, USA Mark A. Supiano, MD, Associate Professor of Internal Medicine; Director, GRECC, VA Ann Arbor Health Care System, Ann Arbor, MI 48105, USA Glendo L. Tangarorang, MD, Geriatrics Fellow, University of Connecticut Center on Aging, Farmington, CT 06030-5215, USA George E. Taffet, MD, Associate Professor, Department of Medicine, Division of Geriatrics, Baylor College of Medicine, Houston, TX 77030, USA David C. Thomas, MD, Assistant Professor, Departments of Internal Medicine and Rehab Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA David R. Thomas, MD, Professor of Medicine, Division of Geriatric Medicine, St. Louis University Health Sciences Center, St. Louis, MO 63104, USA M. Chrystie Timmons, MD, FACOG, Director, Gerigyn, P.A., Chapel Hill, NC 27514, USA Mary E. Tinetti, MD, Professor, Department of Medicine and Epidemiology and Public Health, Yale University; Chief, Section in Geriatrics, New Haven, CT 06520-8025, USA Bruce Troen, MD, Associate Professor of Medicine, University of Miami School of Medicine, Miami Veterans Affairs Medical Center, Miami, FL 33125, USA Donald L. Trump, MD, FACP, Chairman, Department of Medicine; Senior Vice President for Clinical Research, Roswell Park Cancer Institute, Buffalo, NY 14263, USA Stanley Tuhrim, MD, Estelle and Daniel Maggin Department of Neurology, Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, NewYork, NY 10029, USA James A. Tulsky, MD, Program on the Medical Encounter and Palliative Care, Durham VA Medical Center; Associate Professor of Medicine, Associate Director, Institute on Care at the End of Life, Duke University, Durham, NC 27705,USA Bruce C. Vladeck, PhD, Professor of Health Policy and Geriatrics; Director, Institute for Medical Practice, Mount Sinai School of Medicine; Senior Vice President for Policy, Mount Sinai School of Medicine, New York, NY 10029, USA Jeremy Walston, MD, Assistant Professor of Medicine; Medical Director, Terrrace Rehabilitation Unit, The Johns Hopkins Medical Institutions, Johns Hopkins Geriatric Center, Baltimore, MD 21224, USA James R. Webster, Jr., MS, MD, Gertz Professor of Medicine, Northwestern University Medical School; Director Emeritus, Buehler Center on Aging, Chicago, IL 60611, USA Nanette Kass Wenger, MD, Professor of Medicine, Division of Cardiology, Department of Medicine, Emory University School of Medicine; Chief of Cardiology, Grady Memorial Hospital; Consultant, Emory Heart and Vascular Center, Atlanta, GA 30303, USA
Contributors
Contributors
xxv
Joanne A. P. Wilson, MD, FACP, Professor of Medicine, Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA Eric Winer, MD, Director of Breast Oncology Center, Dana Farber Cancer Institute, Boston, MA 02115, USA Thomas T. Yoshikawa, MD, Chairman and Professor, Department of Internal Medicine, Charles R. Drew University of Medicine Science, Los Angeles, CA 90059, USA Mone Zaidi, MD, PhD, FRCP, Professor of Medicine, Geriatrics and Physiology, Director, Mount Sinal Bone Program, and Chief, Division of Endocrinology (VA), Mount Sinai School of Medicine, New York, NY 10029, USA
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Part I Basics of Gerontology
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1 Evidence-Based Medicine and Geriatrics Rosanne M. Leipzig
The goal of evidence-based medicine is provision of care guided by the most up-to-date, scientifically sound evidence after careful investigation of the patient’s history, physical condition, and expectations. Evidence-based medicine (EBM) is a term coined in 1992 by a group of clinical epidemiologists based at McMaster University in Hamilton, Ontario, to describe their transition from teaching clinicians how to read the medical literature1 to teaching us how to use the literature in the care of an individual patient (Fig. 1.1).2 This change emphasized three basic concepts.
Hierarchy of Evidence The first concept is that “all evidence is not created equal.” Depending on the type of clinical question—that is, therapeutic, diagnostic, prognostic, etc.—there is a hierarchy among study designs in terms of their ability to provide an accurate, less biased answer. For example, the Hormone and Estrogen Replacement Study (HERS) trial demonstrated in a randomized controlled trial (RCT) that hormone replacement therapy (HRT) given as 0.625 mg conjugated equine estrogens and 2.5 mg medroxyprogesterone acetate did not improve survival or decrease coronary events in women with existing coronary artery disease, even though several prospective cohort trials suggested that it would.3 Results from two other RCTs to support this finding.4 In the HRT observational trials, women who were offered and chose to take HRT differed systematically at baseline from those who did not; for example, they were more likely to be upper middle class, to be well educated, and to participate in more health promotion and disease prevention activities, and were therefore less at risk for death and coronary disease. These factors may account for their better outcomes after taking HRT.5,6 Randomized controlled trials are superior to prospective cohort studies of the same population because the groups being
compared are at equal risk of the outcome being studied, except for exposure to the intervention being tested. Risk factors associated with an outcome, whether they are known or not yet identified, are randomly distributed in RCTs. An observational trial can only identify known risk factors and then attempt to statistically adjust for discrepancies between them in the study groups. Most clinical questions fall into one of seven categories: clinical findings, differential diagnosis, etiology, diagnostic tests, prognosis, therapy, or prevention.62 Table 1.1 provides examples of important criteria that should be met to maximize the ability of clinical research to answer each type of clinical question. Some of these criteria have been used to create the “clinical query” search strategies on PubMed at the NLM’s website ·http://www.ncbi.nlm.nih.gov/entrez/query/static /clinical.htmlÒ and provide a filter for obtaining highquality studies relating to therapy/prevention, diagnosis, etiology, and prognosis. Similar criteria have been developed for several other types of clinical questions.7 For the past 10 years, studies that meet these validity criteria have been identified and published within the American College of Physicians (ACP) Journal Club, and are available online as well as in the print journal published by the ACP.8 Clinical Evidence and the Cochrane Library are two other sources of systematic reviews of highquality studies designed to answer specific medical questions.9,10
Clinically Meaningful Results The second concept is that clinical, not statistical, significance is what matters in medicine. Many outcomes that are statistically significant are not clinically important. Some “clinical” outcomes are really intermediate, or surrogate, endpoints, not outcomes that make a difference to the patient. When these intermediate or 3
4 1. Convert daily clinical need for information into answerable questions. 2. Find best available evidence with which to answer each question. 3. Appraise the evidence critically and systematically with particular attention to its internal and external validity. 4. Integrate the evidence with the patient’s unique biopsychosocial situation and the clinician’s own expertise. 5. Evaluate clinical performance as well as the process of acquiring, integrating, and applying the new evidence. Figure 1.1. Five tenets of evidence-based medicine. (From Ref. 62, with permission.)
surrogate outcomes are accepted, the treatment may result in an outcome that harms the patient. For example, before definitive studies using patient-oriented outcomes, suppression of ventricular premature contractions (VPB) was considered beneficial, as was increasing bone mineral density with fluoride. Yet when the studies were done, it was found that suppressing VPBs with certain agents increases patient mortality and increasing bone mineral density with fluoride increases fractures.11,12 Clinical significance also means that the magnitude of the effect is worth the costs of the intervention, including the inconvenience, adverse events, and psychologic or emotional as well as financial costs. The usual way of indicating a benefit, the relative risk reduction (RRR), may be quite large when the absolute risk reduction (ARR), or absolute benefit, is small (Table 1.2), as would be the case when, for example, a treatment reduces the risk of an outcome by 50% for an outcome that only occurs once in every million patients treated. In EBM, a term often used to define the size of the treatment benefit is the number needed to treat (NNT), which is the number of people who would need to be treated with the active intervention, rather than the control, over a specific time period to prevent one additional patient from having the bad outcome the treatment was given to prevent. These terms are illustrated in Figure 1.2, where stroke, the primary outcome of the Systolic Hypertension in the Elderly Program trial, is shown to occur in approximately 8% of control patients and 5% of treated patients.13 Here the ARR is 3%, the RRR 36%, and the NNT is 33 over 4.5 years. In other words, treating 33 patients with isolated systolic hypertension (ISH) over 4.5 years will result in one fewer stroke than would have occurred if the ISH had not been treated. Similar terms describe the results of diagnostic tests, including the likelihood ratio, which compares the probability that people with an abnormal test actually have the disease in question to the probability that they have an abnormal test result but not the disease.
R.M. Leipzig
Applicability The third concept is that studies are done on populations but clinicians need to apply them to an individual patient. This approach is relatively easy when the patient sitting in front of you meets the study inclusion and exclusion criteria, but it is far more difficult when the patient resembles those seen in most geriatric practices—old, somewhat frail, with multiple medical conditions and taking multiple medications, possibly with some cognitive, functional, or mood impairment. In geriatrics, the primary challenge to practicing evidence-based medicine is the lack of high-quality studies that include older adults. There is a paucity of evidence on treating or diagnosing common conditions in relatively healthy elderly, let alone in patients like those just described. For example, how should patients with congestive heart failure (CHF) be treated? The range of mean ages of patients in the systolic CHF clinical trial literature is 58 to 65 years, with the median range being 61,14 yet one recent population-based study found that almost 50% of new-onset CHF occurred in people age 80 or older and that approximately 50% of these had systolic CHF.15 Will 80-year-olds be able to tolerate the recent standards for systolic CHF therapy, which include the addition of three to five new medications [i.e., aspirin, beta-blocker, HMG (3-hydroxy-3-methylgluaryl)-CoA reductase inhibitor, angiotensin-community enzyme (ACE) inhibitor, diuretic, digoxin]? How should the 40% to 50% of patients over 70 whose CHF is diastolic (an ejection fraction ≥45%)16 be treated? The answer is unknown, as no large randomized trials have been published to date.
Treatment Studies: Applying Results to Older Adults Figure 1.3 depicts several of the areas where differences in older adults might impact the benefit/risk ratio of a treatment. Several of these are key principles in geriatric medicine and overlap the specific biologic, social and economic, and epidemiologic issues discussed in the User’s Guide: How to Decide on the Applicability of Clinical Trial Results to Your Patient.17 In this chapter, disease, patient, and treatment differences that can influence the application of study results to older adults, as well as the intersections of each of these, are discussed.
Patient–Disease Interactions Despite the concerns about reduced therapeutic efficacy that follow, it is important to recognize that older adults are often the group most likely to benefit from treatment
1. Evidence-Based Geriatrics
5
Table 1.1. Evidence-based medicine (EBM) criteria for evaluating studies. Criteria
Therapy/prevention
Differential diagnosis
Diagnostic tests
Harm/etiology
Prognosis
Primary validity requirements
• Was the assignment of patients to treatments randomized? • Were all patients who entered the trial properly accounted for and attributed at its conclusion? • Was follow-up complete? • Were patients analyzed in the groups to which they were randomized?
• Did the study patients represent the full spectrum of those who present with this clinical problem? • Were the criteria for each final diagnosis explicit and credible?
• Was there an independent, blind comparison with a reference standard? • Did the patient sample include an appropriate spectrum of patients to whom the diagnostic test will be applied in clinical practice?
• Were there clearly identified comparison groups that were similar with respect to important determinants of outcome, other than the one of interest? • Were the outcomes and exposures measured in the same way in the groups being compared? • Was follow-up sufficiently long and complete?
• Was there a representative and well-defined sample of patients at a similar point in the course of the disease? • Was follow-up sufficiently long and complete?
Secondary Validity Requirements
• Were patients, health workers, and study personnel “blind” to treatment? • Were the groups similar at the start of the trial? • Aside from the experimental intervention, were the groups treated equally?
• Was the diagnostic workup comprehensive and consistently applied? • For initially undiagnosed patients, was followup sufficiently long and complete?
• Did the results of the test being evaluated influence the decision to perform the reference standard? • Were the methods for performing the test described in sufficient detail to permit replication?
• Is the temporal relationship correct? • Is there a dose– response gradient?
• Were objective and unbiased outcome criteria used? • Was there adjustment for important prognostic factors?
Results
• How large was the treatment effect? • How precise was the estimate of the treatment effect?
• What were the diagnoses and their probabilities? • How precise are these estimates of disease probability?
• Are likelihood ratios for the test results presented of data necessary for their calculation included?
• How strong is the association between exposure and outcome? • How precise is the estimate of the risk?
• How large is the likelihood of the outcome event(s) in a specified period of time? • How precise are the estimates of likelihood?
Applicability
• Can the results be applied to my patient care? • Were all clinically important outcomes considered? • Are the likely treatment benefits worth the potential harms and costs?
• Are the study patients similar to those in my own practice? • Is it unlikely that the disease possibilities or probabilities have changed since this evidence was gathered?
• Will the reproducibility of the test result and its interpretation be satisfactory in my clinical setting? • Are the results applicable to the patient in my practice? • Will the results change my management strategy? • Will patients be better off as a result of this test?
• Are the study results applicable to my practice? • What is the magnitude of the risk? • Should I attempt to stop the exposure?
• Were the study patients similar to my own? • Will the results lead directly to selecting or avoiding therapy? • Are the results useful for reassuring or counseling patients?
Source: From Refs. 52–54, with permission.
Table 1.2. Glossary of evidence-based vocabulary included in the fourth edition of Geriatric Medicine. Terms relevant to study design Case-control study
Case series Cohort study
Double-blind (DB) External validity Heterogeneity
Internal validity Meta-analysis Multicenter Placebo-controlled (PC) Prospective cohort study Randomized controlled trial (RCT)
Systematic review
Terms relevant to study results Absolute risk reduction (ARR)
Case-control studies examine outcomes that are rare or take a long time to develop. Cases are identified in which the outcome occurred; controls are then selected with similar age, sex, and medical conditions excepting the target outcome. Investigators assess the relative frequency of exposure to the alleged harmful agent, controlling for differences in the variables. Descriptions of a series of patients; case series lack a control group. Involves identification of two or more groups (cohorts) of patients, one which did receive the exposure of interest, and one which did not, and following these cohorts forward for the outcome of interest. A trial in which neither the patient nor the physician knows whether drug or placebo is being taken, or at what dosage.58 How well results fit populations other than the one in which the model was generated. In a meta-analysis, results of individual studies suggest that they were performed in different populations. Can compromise the validity of a meta-analysis; significant heterogeneity indicates decreased likelihood that chance alone is responsible for any observed differences in treatment effects between studies. How well results fit the population in which the model was generated. Quantitative review of systematically chosen literature, the hallmark of which is statistical synthesis of the numerical outcomes of several trials that all asked the same question. A clinical trial conducted at more than one site, but following the same protocol at all locations. A trial in which the effectiveness of the drug is compared to that of a placebo. An observational study that follows a large group (a cohort) of people forward in time Experiment in which individual are randomly allocated to receive or not receive an experimental preventative, therapeutic, or diagnostic procedure and then followed to determine the effect of the intervention. Explicit, structured presentation of results of an unbiased literature review, using predetermined search and appraisal definitions. Based on deductive, rather than inductive, reasoning.
The difference between the control event rate (CER) and the experimental treatment event rate (EER). Use restricted to a beneficial intervention. ARR = CER - EER
95% confidence interval (CI)
Control event rate (CER) Experimental event rate (EER) Intention-to-treat (ITT) Likelihood ratio (LR)
Negative predictive value Number needed to treat (NNT)
An estimate of the precision of a measurement by determining, with 95% accuracy, that the measurement includes the “true” value for the population. The broader the CI range, the more uncertain is the true value of the measurement; CIs that cross zero do not reach clinical significance. Rate of the outcome in the control group. Rate of the outcome in the experimental treatment group. Results that include every individual originally randomized, regardless of whether or not they completed the trial. Positive LR = probability of an abnormal diagnostic or screening test result (including clinical signs or symptoms) in patients with the disorder of interest compared to the probability of the abnormal result in patients without the disorder (Sn/1 - Sp). Negative LR = probability of a normal diagnostic or screening test result (including clinical signs or symptoms) in patients without the disorder of interest compared to the probability of a normal result in patients with the disorder (Sp/1 - Sn). The proportion of patients testing negative for the disorder who are actually disease free, of all the patients testing negative. The number of patients who must be treated with this intervention (rather than the control) over a specified time period to prevent one additional bad outcome. NNT = 1/ARR (as a decimal)
Number needed to harm (NNH) Odds ratio (OR) Per protocol analysis Positive predictive value Relative risk reduction (RRR)
Sensitivity (Sn)
Specificity (Sp)
The number of patients who would need to be treated over a specific time period before one adverse side effect of the treatment will occur. The odds of an experimental patient suffering an adverse event relative to a control patient. Results that do not take into account all persons originally randomized, only those participants who followed the study protocol. The proportion of patients testing positive for the disorder who actually have the disease, of all the patients testing positive. Percent reduction in “bad” outcome events in the experimentally treated groups relative to the control groups. RRR = (CER - EER) / CER * 100 The proportion of diseased patients actually testing positive for the disorder, of all the diseased patients. SnNout: When a test has a high Sensitivity, a Negative test rules OUT the diagnosis. The proportion of disease-free patients actually testing negative for the disorder, of all the diseasefree patients. SpPin: When a test has a high Specificity, a Positive result rules IN the diagnosis.
Source: From Refs. 52, 55–60, with permission.
1. Evidence-Based Geriatrics
Figure 1.2. Stroke incidence in patients with isolated systolic hypertension. (From Ref. 13, with permission.)
7
lar event are depicted for hypertensive patients. With increasing age, fewer patients need to be treated to obtain benefit, which is not surprising because the prevalence of death and cardiovascular events resulting from hypertension increases with age. In general, older adults have a similar decrease in relative risk and the same or a smaller NNT than middle-aged or younger adults, particularly when risks of treatment are small. Table 1.4 illustrates this concept by summarizing the results of subgroup analyses by age from four RCTs of lipid-lowering agents in patients with known coronary disease.18
Disease Differences of a given disorder. Benefits are almost always greatest in the population most likely to experience the bad outcome that the treatment is intended to avoid or improve. Treatment of hypertension can be used as an example. In Table 1.3, the NNTs over 5 years to prevent one additional death or cardiovascular or cerebrovascu-
Age-related differences in disease pathophysiology or in the multifactorial nature of a condition can decrease treatment efficacy. For example, agents effective at treating pneumonia in community-dwelling adults may be less effective when treating nursing home-aquired pneumonia due to differences in the causative organisms and
Figure 1.3. Applicability of treatment study results to older adults: domains to consider.
8
R.M. Leipzig
Table 1.3. Antihypertensive treatment NNT for 5 years to prevent one event. Older (>60 years old)
Younger
Mortality Total Cardiovascular Cerebrovascular Coronary heart disease
72 58 193 88
167 205 365 NS
Morbidity and Mortality Cerebrovascular Coronary heart disease Cardiovascular
46 68 21
168 184 —
NNT, number needed to treat; NS, not statistically significant. Source: From Ref. 61, with permission.
resistance patterns.19,20 Sulfonylureas are effective in treating type II diabetes, but the lack of endogenous insulin makes them of little use in treating type I. The symptom complex of nocturia and leg edema may suggest CHF, yet diuretics will not improve nocturia caused by age-related temporal shifts in fluid elimination that are a result of loss of the circadian rhythm of antidiure-
tic hormone secretion, decreased renin-angiotensinaldosterone, increased secretion of atrial naturetic hormone, and diminished renal concentrating and sodium-conserving ability,21 or leg edema that is secondary to venous insufficiency. Classic differential diagnosis teaches us to use Occam’s razor; that is, scientists should assume no more causes than are absolutely necessary to explain their observations. A single diagnosis should be sought to account for all the patient’s signs and symptoms. Many geriatric disorders, however, are multifactorial in that several different conditions contribute to the symptom complex. With multifactorial disorders, identifying and treating a single condition may result in some but not complete improvement. Intermediate outcomes may be improved, yet patients may not be aware of any improvement. For example, the single diagnoses most responsible for dyspnea on exertion (DOE) are pneumonia, asthma or chronic obstructive pulmonary disease (COPD), angina, or CHF. Specific treatment for the correct diagnosis results in resolution of the symptom. In older patients, a number of chronic conditions may contribute to the complaint of DOE. In addition to the disorders already noted, kyphosis, intrinsic lung disease, deconditioning,
Table 1.4. Secondary prevention: effects of age on lipid lowering in patients with congestive heart disease (CHD).
Reference 4S (Lancet 1994) Subgroup analyses
Agent/no. patients Simvastatin/ 4444 1021 3423
LIPID (Engl J Med 1998) Subgroup analyses
CARE (Sacks et al., N Engl J Med 1996) Subgroup analyses
VA-HIT (Rubins et al., N Engl J Med 1999) Subgroup analysis
Mean age, years (range) 58 (35–70) 67 (≥65) 56 (55 years for
174
women) is itself an accepted risk factor for coronary artery disease. After reviewing evidence on whether identification and treatment of asymptomatic people with abnormal lipid levels can substantially reduce the risk of coronary heart disease, the U.S. Preventive Services Task Force recently extended its recommendations to include routine lipid screening for older and middle-aged persons. Neither an optimal screening interval for older adults nor an upper age limit at which to discontinue screening has been set, but the Task Force has suggested that repeated screening may be less important in older people because lipid levels are less likely to increase after age 65 years. Five-year intervals have been suggested as a benchmark for the general U.S. population, with longer or shorter intervals dictated by patient risk; intervals longer than 5 years may be sufficient for older persons who have had low-risk results on previous lipid tests whereas elderly patients showing higher-risk lipid levels should be screened more frequently. Older individuals who have never been screened should be.84 The U.S. Preventive Services Task Force strongly recommends measurement of total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but finds insufficient evidence to recommend for or against triglyceride measurement. The American College of Physicians has set ranges for total cholesterol (>240 mg/dL), LDL-C (≥160 mg/dL), and triglycerides (>400 mg/dL) that it considers associated with high risk for coronary heart disease. The National Cholesterol Education Program sets a high-risk range for HDL-C (65, patients with atypical moles, and those with >50 moles
Family history of ovarian cancer
USPSTF, The U.S. Preventive Services Task Force (1996); CTF, Canadian Task Force on the Periodic Health Examination (1997); AAFP, The American Academy of Family Physicians (2002); ACP, American College of Physicians; AMA, American Medical Association; CDC, Center for Disease Prevention and Control; Y, yes; N, no; I, insufficient evidence; *, screen high-risk patients.
180
H.G. Bloom
Table 16.5. Screening measures for which evidence does not support recommendation.
I
N
Screening for osteoporosis (bone densitometry)
I*
N*
Screening for lung cancer Screening for pancreatic cancer Screening for bladder cancer
N N N*
N N
Screening for asymptomatic carotid disease Screening for peripheral artery disease Screening for abdominal aortic aneurysm
I
N
N* I*
I*
Screening for asymptomatic bacteriuria Screening for iron-deficiency anemia
I N
I N
N*
Screening for tuberculosis
N*
N*
N*
ACP
CTF
Annual electrocardiogram
AAFP
Screening measure
USPSTF
Does not recommend
N
N N
N*
Recommends American College of Cardiologists/ American Heart Association, American College of Sports Medicine National Osteoporosis Foundation, American Academy of Clinical Endocrinologists*
Screen high-risk individuals
Women with history of fractures; loss of height with back pain; advanced age; Caucasian race; low body weight; bilateral oophorectomy before menopause; women considering estrogen prophylaxis
N
N
N
American Heart Association*
N*
Smokers; patients who worked in rubber or dye professions Patients with risk factors for cardioor cerebrovascular disease Diabetics Men over 60 who are smokers, hypertensives, claudicants, or have family history of AAA Recent immigrants from developing nations Recent immigrants from developing nations; patients from underserved, low-income populations, patients with diabetes, renal failure, HIV; substance abusers; nursing home residents
USPSTF, The U.S. Preventive Services Task Force (1996); CTF, Canadian Task Force on the Periodic Health Examination (1997); AAFP, The American Academy of Family Physicians (2002); ACP, American College of Physicians; AMA, American Medical Association; Y, yes; N, no; I, insufficient evidence; *, screen high-risk patients.
16. Prevention
interventions, with few exceptions (e.g., influenza vaccine yearly), has not been well studied. Until better evidence is available, common sense should prevail.
Conclusion As the quantity of prevention-related information increases and dissemination becomes quicker and more widespread, shared decision making between clinician and patient will become increasingly important. Availability of sites beyond the physician’s office—the Internet, the workplace, senior centers, and schools, for example—will facilitate broader access to disease prevention and health promotion measures. As more individuals live longer and more active lives, attention to lifestyle habits, quality of life issues, risk factors for diseases, and genuine health promotion activities will demand more attention in the disease prevention/health promotion arena. The medical community, however, will need to be vigilant in its surveillance of “new breakthrough prevention measures” to guard the general older public from the unscientific claims of those purporting to practice “anti-aging” medicine (see Chapter 62).
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16. Prevention 63. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281(23):2189–2197. 64. Kiningham RB. Physical activity and the primary prevention of cancer. Prim Care. 1998;25(2):515–536. 65. Flood AB, Wennberg JE, Nease RF, Fowler FJ, Ding J, Hynes LM. The importance of patient preference in the decision to screen for prostate cancer. Prostate Patient Outcomes Research Team. J Gen Intern Med. 1996;11: 342–349. 66. Friedrich MJ, Issues in prostate cancer screening. JAMA. 1999;281:1573–1575. 67. U.S. Preventive Services Task Force. Guide to Clinical Preventive Services. Baltimore: Williams & Wilkins; 1996. 68. Martinez de Hurtado J, Chechile Toniolo G, Villavicencio Mavrich H. The digital rectal exam, prostate-specific antigen and transrectal echography in the diagnosis of prostatic cancer. Arch Esp Urol. 1995;48(3):247–259. 69. De Parle N. From the Health Care Financing Administration. JAMA. 2000;283(12):1558. 70. Siegler EE. Cervical carcinoma in the aged. Am J Obstet Gynecol. 1969;103:1093–1097. 71. Mandelblatt JS, Hammond DB. Primary care of elderly women: is Pap smear screening necessary? Mt Sinai J Med. 1985;52:284–290. 72. U.S. Preventive Services Task Force. Guidelines from Guide to Clinical Preventive Services, 2nd Ed. Baltimore: Williams & Wilkins; 1996. 73. Cervical cancer. NIH Consens Statement. 1996; 14(1):1–38. 74. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000;132:810–819. 75. U.S. Preventive Services Task Force. Screening for hypertension. In: Guide to Clinical Preventive Services. Baltimore: Williams & Wilkins; 1996:39–51. 76. Gorelick PB, Sacco RL, Smith DB, et al. Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA. 1999;281:1112–1120. 77. Mulrow CD, Cornell JA, Herrera CR, Kadri A, Farnett L, Aguilar C. Hypertension in the elderly. Implications and generalizability of randomized trials. JAMA. 1994;272: 1932–1938. 78. U.S. Preventive Services Task Force. Screening for hypertension. In: Guide to Clinical Preventive Services. Baltimore: Williams & Wilkins; 1996:39–51. 79. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program. JAMA. 1991;245: 3255–3264. 80. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The National Heart, Lung, and Blood Institute (NHLBI). Bethesda: National Institutes of Health; 1997.
183 81. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program. JAMA. 1991;245:3255–3264. 82. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Dection, Evaluation, and Treatment of High Blood Pressure. NIH Pub: 93–1088. Bethesda: National Institutes of Health, 1993. 83. Corti MC, Guralnik JM, Salive ME, et al. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Ann Intern Med. 1997;126:753–760. 84. U.S. Preventive Services Task Force. Screening for Lipid Disorders: Recommendations and Rationale. Am J Prev Med. 2001;20(3S):73–76 (http://www.elsevier.com/locate/ajpmonline). 85. Guidelines for using serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as screening tests for preventing coronary heart disease in adults. American College of Physicians. Part 1. Ann Intern Med. 1996;124(5):515–517. 86. Garber AM, Browner WS, Hulley SB. Cholesterol screening in asymptomatic adults, revisited. Part 2. Ann Intern Med. 1996;124(5):518–531. 87. Leaf DA. Lipid disorders: applying new guidelines to your older patients. Geriatrics. 1994;49(5):35–41. 88. Ginsberg HN, Goldberg IJ. Disorders of lipoprotein metabolism. In: Harrison’s Principles of Internal Medicine. McGraw-Hill, New York, 2001. 89. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497. 90. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20(4):537–544. 91. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343–1350. 92. U.S. Department of Health and Human Services, Diabetes Prevention Program. Information available online: http://www.hhs.gov/news/press/2001pres/20010808a.html. 93. Goldberg TH, Chavin SI, Preventive medicine and screening in older adults. J Am Geriatr Soc. 1997;45:344– 354. 94. Butler RN, Rubenstein AH, Gracia AM, Zweig SC. Type 2 diabetes: causes, complications, and new screening recommendations. I. Geriatrics. 1998;53(3):47–50, 53–54. 95. Goldberg TH, Chavin SI. Preventive medicine and screening in older adults. J Am Geriatr Soc. 1997;45:344–354. 96. Goldberg TH. Update: Preventive medicine and screening in older adults. J Am Geriatr Soc. 1999;47:122–123. 97. Association AD. Report of expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20:1183–1197.
184 98. Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA. 2001; 286(22):2815–2822. 99. U.S. Preventive Services Task Force. Guidelines Guide to Clinical Preventive Services, 2nd Ed. Section I. Screening Part H. Musculoskeletal Disorders; Section III, Immunizations and Chemoprophylaxis. Baltimore: Williams & Wilkins; 1996. 99. Panel NCD. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785–795. 100. Hough S. Osteoporosis clinical guideline. South African Medical Association—Osteoporosis Working Group. S Afr Med J. 2000;90(9 pt 2):907–944. 101. Goldberg TH. Update: Preventive medicine and screening in older adults. J Am Geriatr Soc. 1999;47:122–123. 102. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in
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healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613. Grady D, Herrington D, Bittner V. Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA. 2002;288:49–57. Hulley S, Furberg C, Barrett-Connor E. Non-cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progenstin Replacement Study Follow-up (HERS II). JAMA. 2002;288:58–66. Reuben DB, Greendale GA, Harrison GG. Nutrition screening in older persons. J Am Geriatr Soc. 1995;43(4): 415–425.
17 Instruments to Assess Functional Status Brandon Koretz and David B. Reuben
Geriatric assessment refers to an overall evaluation of the health status of the elderly patient. The well-being of any person is the result of the interactions among a number of factors, only some of which are medical. In the geriatric population, these various factors may have become impaired at different rates. Thus, an overall functional assessment is more holistic than the traditional medical evaluation. The ultimate goal of these evaluations is to improve or maintain function. Frequently, assessment instruments are used to evaluate the various components of patients’ lives that contribute to their overall well-being. These components, or domains, include cognitive function, affective disorders, sensory impairment, functional status, nutrition, mobility, social support, physical environment, caregiver burden, health-related quality of life, and spirituality. The instrument itself can take many forms: it can be a structured interview, a self-reported questionnaire, a physical or mental task, or a blood test. Assessment instruments usually produce scores that can be compared to established normal ranges. The results from an individual patient assessment can be used to establish a baseline for future comparisons, form diagnoses, monitor the course of treatment, provide prognostic information, and screen for occult conditions. This last application is the most common use for instruments that are employed in the outpatient setting. This chapter provides an overview of geriatric assessment instruments. We begin by briefly describing some of the basic psychometric attributes that should guide the use of any instrument. Next, we discuss the strengths and weaknesses of different types of instruments. Finally, we end with a review, arranged by functional domain, of some useful instruments. The emphasis is on those instruments that are easy for a single healthcare provider to apply in the outpatient setting. A list of some suggested instruments appears in Table 17.1.
Psychometric Attributes of Instruments As there are a wide variety of assessment instruments, it is important for practitioners to chose those that have been appropriately evaluated for validity, reliability, and, if possible, responsiveness.
Validity Validity is the extent to which an assessment instrument accurately measures the quality it is intended to measure. Usually, validity is the relationship between an instrument’s performance and a “gold standard,” another instrument, or a future event. Sensitivity and specificity are both components of validity. Sensitivity is the extent to which a test is able to detect persons with a disorder.1 Specificity is the extent to which those with a negative test result do not have a disorder.1 Both these characteristics refer to the intrinsic qualities of the instrument itself and are not dependent upon disease prevalence in the population being examined. However, they are frequently combined with prevalence rates to estimate positive and negative predictive values. For screening purposes, it is appropriate to maximize sensitivity at the expense of specificity to capture as many patients with the condition as possible.
Reliability Reliability is the ability of a test to arrive at the same result with repeated measurements. The two most important types are interrater and test–retest. Interrater reliability refers to the degree of similarity between two scores obtained by two simultaneous observers. Test–retest reliability refers to the similarity between two scores obtained serially by the same observer over a time period when change is not expected.
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Table 17.1. Suggested brief geriatric assessment instruments. Domain Cognition Dementia
Delirium Affective disorders Visual impairment Hearing impairment
Dental health Nutritional status Gait and balance a b
Instrument
Sensitivity
Specificity
Time (min)
Cutpoint
MMSE7
79%–100%a
46%–100%
9
5.0 ng/mL) Aneuploidy Specific chromosomal deletion (allelic loss)
P.C. Enzinger and R.J. Mayer Table 34.4. Use of chemotherapy for colorectal cancer by age. Node positive
Metastatic
Age, years
n
Treated, %
n
Treated, %
65–69 70–74 75–79 80–84 85+
457 502 516 333 249
48 48 39 24 6
377 411 366 262 214
45 41 27 18 5
Source: From Sundararajan et al.,83 with permission.
lymphatic invasion,78 and vascular invasion79 (Table 34.3) increase the risk of recurrence substantially in this group. Therefore, many experts recommend postoperative chemotherapy to patients with these adverse prognostic factors. Current postoperative chemotherapy for high-risk resected colon cancer is based on the combination of 5-FU and leucovorin. Fluorouracil is an antimetabolite that binds to the enzyme thymidylate synthase, thereby depleting thymidine pools and inhibiting DNA synthesis.80,81 Leucovorin (also known as folinic acid) stabilizes the complex formed between 5-FU and thymidylate synthase, prolonging inhibition of this enzyme by more than 20 fold.82 Older patients receive adjuvant chemotherapy less often than their younger counterparts (Table 34.4).13,83 Although chemotherapy has become the standard of care for high-risk resected colon cancer in the general population, some controversy remains regarding the relative benefit of this treatment in patients older than 70 years of age. Recently, an intention-to-treat meta-analysis was completed, pooling 3351 patients from seven randomized trials.84 In these trials, patients with Dukes’ B2 or C (stage II or III) colon cancer had been randomized to receive surgery alone or surgery followed by 5-FU-based chemotherapy. Patients were stratified by decade of life (70), with 15% of patients older than 70 years of age. Treatment effect (i.e., overall survival and disease-free survival) and toxicity were essentially the same for all age groups. It therefore appears that postoperative chemotherapy in high-risk colon cancer is as beneficial and tolerable in patients over age 70 years as it is for younger patients.
Adjuvant Chemotherapy and Radiation Therapy: Rectal Cancer Chemoradiation after surgery reduces the local recurrence rate and increases disease-free survival in patients with deeply invasive (T3–T4) or lymph node-positive rectal cancer. In one study, 5-year disease-free survival
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increased from 46% to 70% in those patients who received chemoradiation after their surgery.85 Similarly, regional recurrences were reduced from 24% to 11% with this approach. Radiation therapy is typically given over 5 to 6 weeks. Fluorouracil-based chemotherapy may be administered during this time either as a bolus86 or as a continuous infusion.87 Additionally, at least 4 months of 5-FU based chemotherapy is generally given. Chemoradiation for rectal cancer may also be adminsitered before surgery.88,89 Preoperative chemoradiation is most often recommended if there is evidence by endoscopic ultrasound or magnetic resonance imaging of lymph node involvement or deep invasion through the rectal wall. If this approach is undertaken, patients should still receive postoperative chemotherapy following surgical resection. If imaging studies reveal superficial disease with no lymph node enlargement, surgery would seem to be the preferred initial treatment because patients with early-stage cancer do not require further therapy. There are few data to suggest that elderly patients respond any differently to chemoradiotherapy than younger patients. Older patients, however, do appear to be at increased risk for radiation-related small bowel damage.90 Therefore, particularly in this group, an effort should be made to limit the amount of small bowel in the radiation field.
Follow-Up Prospective data have failed to show any survival benefit for the use of surveillance CT scans, chest radiographs, liver function tests, and fecal occult blood tests following the resection of a colorectal cancer.91–93 However, a careful history and thorough physical examination every 3 to 6 months is recommended for the first 3 years following resection and annually thereafter.94 The use of serial determinations of the plasma carcinoembryonic antigen (CEA) level as an early indication of clinically occult recurrent disease, although not universally accepted, has been recommended at 3-monthly intervals for the first 3 postoperative years.94 Such a recommendation is based on evidence showing an elevated CEA level to be the initial indication of disease in 60% to 64% of cases and to be the most cost-effective approach to detect potentially resectable disease.91,92,95 Patients should undergo a colonoscopy within 1 year of the time of their diagnosis, with a goal of detecting other polyps or cancer within the large bowel. The purpose of this procedure is not to screen for recurrent cancer at the suture line, because such anastomotic recurrences are exceedingly rare. Colonoscopy should be repeated yearly so long as further polyps are discovered. If no polyps are detected, the interval between future examinations may be extended to every 3 to 5 years.94
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Advanced Colorectal Cancer Surgery: Advanced Colorectal Cancer Patients with anatomically isolated tumor recurrences may be candidates for an attempt at surgical resection, particularly if several years have elapsed since the time of the initial diagnosis. Five-year survival has been reported in 25% to 39% of selected patients who underwent the resection of liver or lung metastases.96,97 In a series from the Memorial Sloan-Kettering Cancer Center, 128 patients 70 years of age or older underwent liver resection for metastatic colorectal cancer between 1985 and 1994.98 Although these patients experienced a 4% perioperative mortality rate and a 42% complication rate, their median survival was 40 months and 5-year survival rate was 35%. These older patients had a similar outcome to 449 patients less than 70 years old who underwent comparable liver resections during the same time period. Similarly, studies have shown that appropriately selected octogenarians can tolerate lung resections with acceptable morbidity and mortality.99 Patients who did not initially receive postoperative 5FU-based chemotherapy for their resected colon cancer should be considered for chemotherapy after complete resection of their recurrence. In patients who have received prior chemotherapy, the benefits of further treatment after reresection are uncertain.97 The merits of hepatic arterial infusion chemotherapy (delivered by an implanted abdominal pump) after resection of hepatic metastases from colorectal cancer have been the source of debate. Such treatment clearly reduces the likelihood of recurrence in the liver but does not protect against extrahepatic recurrences and does not appear to prolong survival.100,101
Chemotherapy: Advanced Colorectal Cancer For many years, the standard treatment for advanced colorectal carcinoma has been the combination of 5-FU and leucovorin, given either for 5 consecutive days monthly or for 1 day per week. Small randomized studies have shown such chemotherapy to prolong survival when compared to best supportive care alone (11 versus 5 months; p = 0.006) and to improve quality of life.102 SEER data from 1992 demonstrated that the usage of chemotherapy in patients with advanced colorectal cancer falls with increasing age (see Table 34.4).83 Furthermore, elderly patients are underrepresented in clinical trials. Although 72% of all advanced colorectal cancer patients are 65 years or older (1992–1994 SEER data), less than 50% of patients in clinical trials sponsored by the National Cancer Institute (United States) were in this elderly age group.103,104
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The reasons for this disparity in treatment remain unclear. In a review of major trials of advanced colorectal cancer, researchers from the Royal Marsden Hospital in London found no difference in the probability of disease regression (24% versus 29%), toxicity, failurefree survival, or 1-year overall survival (44% versus 48%) between patients older and younger than 70 years of age.105 The median overall survival was shorter for the older patients (9.6 versus 11.5 months; p = 0.04), likely due to competing comorbidities. Irinotecan (CPT-11, Camptosar) is a new antitumor agent that has been recently approved for the treatment of colorectal cancer. It acts primarily by inhibition of the topoisomerase I enzyme. Once bound to the topoisomerase I–DNA complex, irinotecan blocks reannealing of the parent DNA, thereby halting nucleic acid synthesis in the cell, leading to cell death. Severe diarrhea, neutropenia, and nausea may occur with this drug in approximately 25% to 33% of patients. The administration of irinotecan leads to disease regression in 13% to 23% of patients whose disease is refractory to 5-FU.106 Compared to best supportive care alone in similar patients resistant to 5-FU, irinotecan therapy has been demonstrated to improve both survival duration and quality of life.107 In patients who have received no prior chemotherapy, the probability of response to irinotecan is higher (29%) and is similar to that of 5-FU and leucovorin.108 Weekly irinotecan can safely be added to weekly 5-FU and low-dose leucovorin. Recently, this triple combination was compared to 5-FU and leucovorin alone in a randomized trial.108 The response rate of the ironotecan/5-FU/leucovorin combination was superior to 5-FU and leucovorin (50% versus 28%; p < 0.0001) as was the median progression-free survival (7.0 months versus 4.3 months; p = 0.004). Overall toxicity and quality of life were similar with both regimens. Although these promising results have led some oncologists to consider this combination as initial therapy for patients with advanced colorectal cancer, only 40% of patients enrolled in the trial were 65 years of age or older, and the tolerance of treatment may well be poorer in the elderly. Conceivably, the same therapeutic effect may be achieved with less toxicity by giving 5-FU/leucovorin and irinotecan sequentially rather than concomitantly. Fluorouracil may also be given as a continuous infusion. This form of administration offers a moderate improvement in response rate (22% versus 14%; p = 0.0002) and a small improvement in survival (13 versus 12 months; p = 0.04) compared to bolus 5-FU in patients with advanced colorectal cancer.109 Infusional 5-FU causes less diarrhea, mucositis, and hematologic toxicity and may shrink colorectal cancers that no longer respond to bolus 5-FU therapy. The major side effect is palmarplantar dysesthesia (burning, redness, and peeling of the
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hands and feet), which is severe in approximately onethird of patients. These advantages must be balanced by the inconvenience of continuous therapy and the complications that may arise from portacath placement. To circumvent the complications and inconvenience of infusional 5-FU, orally administered forms of 5-FU have been developed. Of these, only capecitabine (Xeloda) is currently approved for use in the United States. In randomized studies, capecitabine and 5-FU/leucovorin appear to lead to equivalent outcomes.110 A number of antitumor agents are under active development for this disease. Among these, oxaliplatin111 and IMC-C225112 appear most promising. Both have demonstrated activity in 5-FU-refractory advanced colorectal cancer.
Pancreatic Cancer In the United States, the number of expected new cases (29,200) and the number of expected deaths (28,900) for pancreas cancer in the year 2001 are almost identical.1 In part, this dire prognosis is due to the advanced stage of disease at presentation. At the time of diagnosis, less than 10% of patients have localized disease.3 The other patients have nodal (30%) or metastatic (60%) spread. Overall, the probability for 5-year survival for this cancer is less than 5%. For patients undergoing a potentially curative resection, this estimate rises to approximately 17%. The median survival for this group of resected patients is 12 to 18 months verus 3 to 6 months for patients with metastatic disease. The median age at presentation is 60 years, and thus a significant proportion of patients is elderly. Both genders are equally affected, and AfricanAmericans have a slightly higher rate of disease. Smoking appears to be the greatest risk factor for pancreas cancer. In one prospective study of 167,767 patients, the proportion of pancreatic cancers attributable to cigarette smoking was 25%.113 Risk was reduced by 48% and then approached that of nonsmokers after 2 and 10 years of smoking cessation, respectively. Other risk factors are disputed. Pancreatitis and diabetes, among others, have been linked to this malignancy in some114,115 but not all116,117 studies.
Prevention and Surveillance Smoking cessation is the most important preventative step for this disease. As indicated above, risk is reduced by nearly half within 2 years of quitting and drops to normal after less than 10 years of smoking cessation.113 With the possible exception of those few individuals who have a strong family history of this cancer, serial imaging studies as a means of screening are not indicated.118
34. Colon Cancer and Other Gastrointestinal Malignancies
Diagnosis and Workup Many patients seek medical attention because of jaundice, which may be unaccompanied by any pain. Several weeks or months of epigastric or back pain, as well as weight loss, are also common. Patients may recently have been diagnosed with glucose intolerance or malabsorption syndrome. The initial diagnostic evaluation usually includes a CT scan with contrast and endoscopic retrograde cholangiopancreatography (ERCP). Often, the latter procedure not only establishes the diagnosis of cancer but also can serve to relieve the jaundice (through endoscopic stent placement) with which the patient originally presented. Additionally, the blood tumor marker CA 19-9 should be obtained; although this marker is not diagnostic for pancreatic cancer, it has been shown to independently predict resectability.119 Patients may be resectable if there is no evidence of distant disease or encasement or occlusion of the celiac axis or superior mesenteric artery. Those patients who appear resectable require further evaluation with magnetic resonance angiography (MRA) or laparoscopy but do not require a preoperative biopsy. Patients with metastatic lesions or unresectable tumors should undergo pathologic confirmation of their disease. Such a pathologic diagnosis is often not established in older patients having a clinical suspicion of pancreatic cancer. In one series, tissue confirmation was established in 88% of persons in their sixties but only in 41% of persons in their nineties.120 Patients with a clinical diagnosis of what appeared to be a locally confined pancreatic neoplasm had a 5-year survival of 27% compared to 4% for those with biopsy-proven cancer. Thus, a disproportionate number of elderly patients may be misdiagnosed with this malignancy and may be incorrectly given a poor prognosis in an attempt to spare them the discomfort of an accurate pathologic diagnosis. In experienced hands, the major complication rate for CT- or ultrasound-guided biopsy of pancreatic lesions is approximately 1%.121
Treatment Patients with pancreas cancer can be divided into three groups. The first group, with resectable disease, usually receives postoperative chemoradiation. In the second group, who have a cancer that is unresectable but has not spread to other organs, slightly different regimens of chemoradiation are offered. The third group, having metastatic disease, may be treated with chemotherapy or may receive palliative care alone.
Surgery: Resectable Pancreas Cancer Pancreaticoduodenectomy (the Whipple procedure) is the only potentially curative therapy for pancreas cancer.
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The resection includes the distal duodenum, the proximal jejunum, the neck, head, and uncinate process of the pancreas, the gallbladder, and the distal biliary tree. Historically, this procedure is associated with a high morbidity and mortality. In the last decade, however, mortality rates at hospitals at which the procedure is frequently performed have dropped to less than 3%.122,123 There is ample evidence that pancreaticoduodenectomy can be safely performed in geriatric patients. For instance, in 206 patients over 70 years of age treated at the Mayo Clinic from 1982 through 1987, operative mortality was 9% with a surgical morbidity of 28%.124 Overall survival was 19 months and 5-year survival was 4%. Similarly, the operative mortality in 138 patients older than 70 years of age who underwent pancreatic resection at Memorial Sloan-Kettering Cancer Center was 6% and the major complication rate was 45%. These results were virtually identical to those of younger patients. However, 5-year survival was slightly lower in the group of older patients (21% versus 29%; p = 0.03).98 An even older cohort was reported from the Johns Hopkins Hospital.125 At that institution, 46 patients older than 80 years of age who underwent pancreaticoduodenectomy had an operative mortality of 4.3%, compared to 1.6% for patients under 80 years (p = NS). The complication rate was 57% and 41%, respectively (p = 0.05). Other studies from Germany,126 Sweden,127 and Italy128 provide further evidence that pancreatic surgery can be safely performed in the elderly with results akin to those of younger patients.
Postoperative Chemoradiation: Resectable Pancreas Cancer Following the complete resection of pancreas cancer, the use of adjuvant postoperative chemoradiation should be considered. Trials have shown that such combined modality therapy can double the 2-year actuarial survival (43% versus 18%) and median survival (21 months versus 11 months) compared to surgery alone.129,130 In one study, 19% of patients randomized to receive chemoradiation were alive 5 to 11 years following their surgery, whereas only 5% of patients randomized to surgery alone lived to the 5-year point.130 The results of these relatively small studies have recently come under question. Two large European trials have shown no statistical benefit for postoperative chemoradiation in pancreatic cancer.131,132 It is too early to determine if these new studies will impact present practice patterns in the United States. Some investigators have advocated preoperative chemoradiation133 or intraoperative radiation therapy134 for patients with localized pancreas cancer. There are theoretical advantages for these approaches, but the available data have emerged from small patient cohorts at
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single institutions in a setting where selection bias is likely. For these reasons, the use of preoperative or intraoperative therapy should be reserved for clinical trials only.
Advanced Pancreas Cancer Patients who are found to be unresectable at the time of attempted pancreaticoduodenectomy may be candidates for surgical palliation for jaundice and pain. Typically, these patients undergo a retrocolic gastrojejunostomy, a hepatojejunostomy, and a chemical splanchnicectomy. In one series of 118 patients from the Johns Hopkins Hospital, the perioperative mortality for these procedures was 2.5%; only 3% subsequently developed gastric obstruction and only 1.6% developed jaundice.122 In a randomized trial, chemical splanchnicectomy with 50% alcohol significantly reduced or prevented pain when compared to placebo injection with saline.135
Chemoradiation: Locally Unresectable Pancreas Cancer It is unclear if chemoradiation is superior to chemotherapy alone or to supportive care in patients with locally unresectable pancreas cancer because no randomized trials have been performed in this clinical setting. However, promising results at single institutions136,137 led investigators of the Gastrointestinal Tumor Study Group to randomize patients with unresectable pancreas cancer to chemotherapy plus radiation or to radiation therapy alone.138 The median survival was 10 months for patients who received 5-FU in addition to radiation therapy versus 5.5 months for those who received radiation therapy alone (p < 0.01). Similarly, the 1-year survival was superior for the chemoradiation group (40% versus 10%). Therefore, chemoradiation is now commonly employed for this group of patients.
Chemotherapy: Metastatic Pancreas Cancer Metastatic pancreas cancer has been treated with 5-FU since the early 1960s; disease regression rates have ranged from 7% to 19%, and the median survival has varied from 4.5 to 6.0 months. The addition of other antitumor agents to 5-FU, while sometimes increasing the response rate, has had no impact on survival.139,140 In small, randomized trials, the use of these 5-FU-based regimens has, however, shown a significant survival advantage when compared to supportive care alone (30–33 weeks versus 7–15 weeks).141,142 More recently, gemcitabine, a nucleoside analogue, has been found to have antitumor activity in pancreas cancer.143,144 Partial responses have been reported in 6% to 11% of patients, with an associated median survival of
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5.6 to 6.3 months. Gemcitabine has been compared to weekly bolus 5-FU as initial therapy in patients with advanced pancreas cancer.145 Although the improvements in response (5.4% versus 0%) and median survival (5.7 versus 4.4 months) for gemcitabine were modest, improvements in symptom control led to acceptance of the drug as standard therapy for this disease. Of note, patients up to 79 years of age were included in this trial, with a median age of 62 years. Efforts to combine gemcitabine with other agents are underway.
Palliation: Metastatic Pancreas Cancer Neurolytic block of the celiac plexus and/or splanchnic nerves is an important adjunctive therapy to oral analgesia in pancreas cancer. In this procedure, ethyl alcohol is injected into the nerve via a small-gauge needle, guided by CT scan or other imaging technique. In experienced hands, this technique relieves pain in approximately 75% of patients.146 Up to 50% of patients may have minimal or no pain 15 days following their procedure, without opioid therapy.147 Effective pain relief is often attained for several months.
Gastric Cancer Worldwide, gastric cancer is the second leading cause of cancer death (after lung cancer) in both men and women.10 In East Asia, it is the most common cancer in men and the leading cause of cancer death in women. In the United States, the predicted number of new cases for 2001 was 21,700 with 12,800 deaths expected.1 Symptoms occur relatively late in the development of the disease. Thus, more than 40% of patients present with metastatic cancer and only one-fifth of patients have localized disease.3 The distribution of gastric cancers has changed over the past three decades, primarily due to an increase in the number of adenocarcinomas of the cardia and an even greater decline in cancers of the fundus, body, and antrum.148 Over the past decades, beginning in the early 1930s, the incidence of gastric cancer has shown a remarkable decline in the United States,149 probably due to improvements in refrigeration and sanitation. Consumption of preserved, smoked, or cured foods has decreased and inversely intake of fresh fruits and vegetables has increased.150 Infection with Helicobacter pylori, which increases the risk of gastric cancer by approximately twofold, has also declined.151–153 In general, it is thought that achlorhydria leading to dysplasia of the gastric mucosa, resulting from such etiologic causes as atrophic gastritis (occasionally accompanied by pernicious anemia), chronic active gastritis from H. pylori infection, and prior antrectomy for peptic ulcer
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disease, may lead to an increased risk of gastric cancer.154–157 Less firm associations with this malignancy include cigarette smoking, blood group A, prior radiation exposure, family history, and Epstein–Barr virus infection.149
Prevention and Surveillance Continued improvements in refrigeration and sanitation throughout the world will likely result in a further decrease in the prevalence of this disease. Although the eradication of H. pylori infection may further reduce the risks of this malignancy, such an appealing concept has not yet been validated in a clinical trial.151,158 Endoscopic screening for gastric cancer may be justifiable in endemic areas, such as East Asia, but is not warranted in the United States.
Diagnosis and Workup Generally, patients with epigastric pain and weight loss are first found to have a gastric cancer by the identification of an abnormality on upper GI series. Upper endoscopy usually reveals a malignant ulcer or suspicious rugal thickening. Biopsy, in most cases, demonstrates an adenocarcinoma. CT scan of the abdomen and pelvis and chest radiographs are utilized to determine the extent of disease. In contrast to colorectal cancer, which generally spreads initially to the liver, gastric cancer frequently metastasizes to the ovary (“Krukenberg tumor”), pelvic peritoneal cul-de-sac (“Blumer’s shelf”), or periumbilical area (“Sister Mary Joseph node”). Operative candidates at many centers now undergo staging laparoscopy to “rule out” such intraperitoneal spread before attempting a surgical resection.
Treatment Surgery: Resectable Gastric Cancer Gastrectomy is the only curative treatment for gastric cancer. In patients who undergo the resection of all macroscopic and microscopic tumor (R0 resection), the long-term survival is approximately 35%.159,160 Multivariate analysis reveals that the ratio of involved to removed lymph nodes, followed by depth of tumor invasion and postsurgical complications, are the most important prognostic factors for patients who have undergone a complete resection. The extent of the surgical resection required to obtain an optimal clinical outcome has been the source of controversy. At a minimum, a so-called D-1 resection should be performed.161 In this procedure, patients undergo an omentectomy and gastrectomy with complete removal of the perigastric lymph nodes. Such an operation generally
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results in the recovery of 17 lymph nodes on average.162 In addition, many surgeons, particularly from Japan, advocate a D-2 resection, which adds the removal of the omental bursa portion of the transverse mesocolon, the removal of the left gastric, celiac, and splenic lymph nodes, and occasionally the spleen to the D-1 procedure. In the D-2 operation, approximately 30 lymph nodes are recovered in the resected specimen.162 Proponents of the D-2 procedure have claimed a greater rate of surgical cure for this more radical approach while detractors have focused on a higher likelihood for perioperative morbidity and mortality. Consequently, two large prospective randomized trials have compared the D-1 and D-2 surgical procedures.162,163 Neither demonstrated a survival benefit for the D2 operation, but both documented a significantly higher rate of complications (43% versus 25%; p < 0.001) and postoperative deaths (10% versus 4%; p < 0.004) for this more radical procedure. Gastric surgery may be performed safely in patients older than 70 years of age. A prospective review of 310 elderly patients with gastric cancer found that surgery in this group was reasonably tolerated and led to a survival duration comparable to the results obtained in younger patients.164
Postoperative Chemotherapy: Gastric Cancer Since the late 1960s, numerous randomized trials have attempted to demonstrate that postoperative chemotherapy reduces the rate of recurrence and prolongs survival after the resection of a gastric cancer. Most of these trails showed no significant survival benefit as summarized in a 1993 meta-analysis.165 That review revealed a slight but nonsignificant improvement in survival for patients treated with postoperative chemotherapy (odds ratio, 0.88; 95% CI, 0.72–1.08). However, a more recent analysis, using stricter inclusion criteria and incorporating more current trials, showed a statistically significant 4% reduction in recurrence for postoperative chemotherapy in patients who had undergone R0 resections (odds ratio, 0.80; 95% CI, 0.66–0.97).166 The greatest benefit was obtained in patients with tumor spread to regional lymph nodes.
Postoperative Chemoradiations: Gastric Cancer Postoperative radiation therapy alone does not appear to offer a survival benefit in resectable gastric cancer.167 Fluorouracil-based chemotherapy, however, has been shown to be a potent radiation sensitizer in this disease.168 To explore the value of such radiosensitization, the impact of postoperative radiation therapy and 5-FU-based chemotherapy was recently compared to no postoperative therapy in a randomized trial involving more than 550 patients who had undergone a complete resection of a locally advanced adenocarcinoma of the stomach or the
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gastroesophageal junction.169,170 The patient cohort randomly allocated to receive chemoradiation experienced a significant improvement in 3-year disease-free survival (49% versus 32%; p = 0.001) and 3-year overall survival (52% versus 41%; p = 0.03). The success of this combined modality treatment program required sophisticated radiation therapy planning.171 At present, all patients with fully resected muscle-invasive or lymph nodepositive gastric cancer should now be considered for postoperative chemoradiation.
Advanced Gastric Cancer Surgery: Advanced Gastric Cancer Radical surgery is not indicated for gastric cancer patients in whom tumor has spread within the peritoneum, to other organs, the omentum, or distant lymph nodes. However, a less extreme resection or a bypass procedure may be appropriate to provide more effective palliation.172–175
Chemotherapy: Advanced Gastric Cancer The benefit of chemotherapy in the presence of unresectable or widely metastatic gastric cancer has been the topic of debate and the focus of several randomized trials. These studies, in which patients have been randomly allocated to received chemotherapy or supportive care alone, have consistently revealed a prolongation of survival176,177 and an improvement in quality of life178 in association with treatment. The choice of chemotherapy regimens in this setting is difficult. Single-agent therapy generally has less toxicity than combination chemotherapy and may be better suited for older individuals. Chemotherapeutic compounds that have significant activity (15%–20% response rate) in gastric cancer include 5-FU, cisplatin, the anthracyclines (doxorubicin and epirubicin), irinotecan, and the taxanes (paclitaxel and docetaxel). Of these, 5-FU, irinotecan, and the taxanes are least toxic. The most widely studied is 5-FU, which forms the backbone of most combination regimens in this disease. The use of chemotherapy combinations in gastric cancer has been characterized by response rates as high as 50% in uncontrolled studies that have not been confirmed in randomized trials.139,179–181 A number of randomized trials have been completed during the past decade, comparing various antitumor combinations that have been developed for the treatment of advanced gastric cancer. The most promising among these is the combination of epirubicin, cisplatin, and continuous infusion 5-FU (ECF), which has had a response rate of 41% to 45% and a median survival of 8.9 to 9.4 months.182,183 The treatment program is somewhat inconvenient be-
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cause of the cumbersome administration of 5-FU as a prolonged continuous infusion and uncertainty about the contribution of epirubicin. As a result, some oncologists continue to consider a 5-FU and cisplatin combination as the standard of care.184
Esophageal Cancer Cancers arising from the esophagus, including the gastroesophageal junction, are typically either squamous cell carcinomas or adenocarcinomas and are the sixth leading cause of cancer death worldwide.10 Eighty percent of these deaths occur in developing countries, particularly South Africa and China, where squamous cell carcinomas predominate. In contrast, esophageal cancer is less common in the United States, although it has increased significantly during the past three decades. In 2001, 13,200 new cases and 12,500 deaths from this disease were anticipated.1 Esophageal cancer is now the seventh leading cause of cancer death in American men. The rise in the incidence of esophageal cancer in the United States is primarily due to a significant increase in adenocarcinomas of the distal esophagus and, to a lesser extent, of the gastroesophageal junction. Between 1974 and 1994, adenocarcinomas of the esophagus increased dramatically in white males whereas squamous cell carcinomas of the esophagus declined slightly.148 This trend is particularly evident in older men; the appearance of esophageal adenocarcinomas has doubled in white men younger than 55 years but has quadrupled in white men ages 65 to 74 years. Smoking is thought to increase the risk of all esophageal cancers.148,185,186 Significant alcohol intake, especially when combined with smoking, greatly enhances the risk of squamous cell carcinoma but has no impact on the development of adenocarcinoma.185 The greatest risk for esophageal adenocarcinoma appears to be gastroesophageal reflux disease and the development of Barrett’s esophagus. In Barrett’s esophagus, the normal stratified squamous epithelium of the esophagus is replaced by columnar epithelium, presumably in response to chronic gastroesophageal reflux. Recurrent symptoms of reflux result in an eightfold increase in the risk of esophageal adenocarcinoma.187 Patients with Barrett’s esophagus are at even higher risk, with an annual rate of cancer development of approximately 0.8%.188 Drugs that relax the gastroesophageal sphincter and increase reflux, such as anticholinergics and aminophyllines, may contribute to the development of as many as 10% of these cancers.189,190 Obesity, which increases intra-abdominal pressure and gastroesophageal reflux, is also thought to add to the rising incidence of these tumors.190,191 The epidemiologic pattern of esophageal carcinoma does not appear different in elderly patients. In one
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series, 74% of patients 70 years or more of age were found to have adenocarcinoma and 26% had squamous carcinoma.192 In another study, the incidence of Barrett’s associated adenocarcinoma was lower in the patients 70 years or older compared to younger age groups (15.6% versus 24%; p = 0.046).193 The location of tumors in the esophagus does not, however, differ between older and younger patients. A similar distribution in early- and latestage cancers has also been reported. The overall prognosis for this cancer is poor. More than half of all patients already have metastatic disease at the time of their diagnosis.194 Five-year survival even with the earliest stages of cancer is only in the range of 60%.195 With lymph node involvement, 5-year survival drops below 25%. Patients with metastatic disease have a median survival of less than 1 year.
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obtained and typically shows a stricture or erosion of the esophagus. Upper endoscopy reveals a friable, ulcerated mass; squamous cell carcinoma and adenocarcinoma appear visually similar and can only be distinguished histologically. A CT scan of the chest, abdomen, and pelvis should be performed as a means of detecting metastatic disease. Patients with disease restricted to the esophagus may be further evaluated with endoscopic ultrasonography. This procedure is particularly effective in determining the depth of invasion of the tumor. Positron emission tomography is increasingly utilized to identify radiographically undetectable metastatic disease.204 Scanning of the head or skeleton is not routine and should be reserved for symptomatic patients only.
Treatment Prevention and Surveillance
Surgery: Resectable Esophageal Cancer
Smoking cessation and moderation of alcohol intake are important steps in reducing the appearance of squamous cell carcinoma of the esophagus. The risk for this cancer decreases substantially after a decade of smoking cessation.186 In contrast, the risk for adenocarcinoma of the esophagus does not change appreciably even 30 years after exposure to cigarettes ceases.185 Patients with Barrett’s esophagus who are otherwise in good health may be candidates for regular endoscopic surveillance. Endoscopic ablation therapy combined with proton pump inhibition may revert Barrett’s esophagus to a normal squamous mucosa in some patients.196 Small uncontrolled experiences have led to claims that endoscopic surveillance is cost-effective,197 leads to the diagnosis of earlier-stage tumors,198 and may improve survival.199 Such observations remain anecdotal in the absence of randomized data. Some experts have recommended that endoscopy be performed every 2 years in patients with Barrett’s esophagus in the absence of epithelial dysplasia and more frequently if mild dysplasia is discovered.196,200 The identification of severe dysplasia (i.e., carcinoma in situ) has been considered an indication for an esophagectomy, because many of these patients have been found to have invasive cancer in their resection specimens.201 Patients not considered surgical candidates may undergo mucosal ablation with photodynamic therapy or other techniques.202,203
Localized esophageal cancer may be resected either by a transthoracic or a transhiatal approach. Neither retrospective205 nor prospective206 trials have shown any difference in mortality or morbidity between these types of surgery. Patients who underwent surgery alone in recent, large randomized trials have had an operative mortality of 4% to 6% and perioperative morbidity of 26%.207,208 In these trials, patients had a median survival of 16 to 19 months and 5-year survival probabilities of 20% to 26%. Age does not appear to be a limiting factor in surgery of the esophagus. Although elderly patients tend to have a higher incidence of respiratory and cardiovascular complications than younger patients, this does not appear to have a significant effect on operative mortality or survival.193,209–213
Diagnosis and Workup Patients with esophageal cancer usually experience dysphagia and often complain of odynophagia at the time of diagnosis. Weight loss is also common and is an independent poor prognostic indicator if greater than 10%. Barium swallow is often the first diagnostic study
Chemoradiation: Localized Esophageal Cancer Although radiation therapy alone cannot cure esophageal cancer,214 the combination of radiation therapy with concurrent chemotherapy has led to long-term survival in about 25% of patients, similar to the results associated with surgery.215–217 Such chemoradiation therapy appears equally effective in patients 70 years of age and older as in younger individuals.215,216
Adjuvant Therapy: Localized Esophageal Cancer Preoperative radiation therapy does not appear to enhance the outcome associated with surgery.218 However, the data assessing the value of preoperative chemotherapy are conflicting: a mature, randomized trial involving 440 American patients showed no benefit,208 while the preliminary results from a seemingly similar study in 802 British patients suggested that the same treatment prolonged survival.219
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With these uncertain results, attention has focused on the combination of chemotherapy and radiation therapy before surgery.220–226 Of five randomized trials that have attempted to demonstrate a benefit for preoperative radiation therapy and concurrent chemotherapy in esophageal cancer, only one study from a single institution has shown a statistical improvement in survival.227 More recently, a larger multi-institutional trial207 demonstrated no difference in median overall survival. The other studies have had too few patients to give statistically meaningful results.228–230
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titis B or C is one to three decades, it is thought that the rising incidence of this malignancy is a result of transfusion of unscreened blood and blood products, intravenous drug abuse, needle sharing, and unsafe sexual practices during the 1960s and 1970s.243 Other risk factors for this disease in the United States include alcoholic cirrhosis, inherited hemochromatosis, and the use of hormone supplements such as oral contraceptives and exogenous androgens. In the developing world, aflatoxin B1 exposure (from the mold Aspergillus flavus on grain) and schistosomiasis are important additional etiologic factors.
Advanced Esophageal Cancer Chemotherapy
Prevention and Surveillance
Several forms of chemotherapy are effective in esophageal cancer.194,231–236 Response durations are typically brief, lasting no longer than a few months, and survival is short, rarely exceeding more than 1 year. Although combination chemotherapy regimens tend to result in higher response rates, the therapeutic value of such intensive treatment must be balanced with a greater likelihood of toxicity. Cisplatin has become the cornerstone of combination chemotherapy in esophageal cancer, generally being combined with 5-FU, or more recently with paclitaxel,237,238 irinotecan,239 vinorelbine,240 or gemcitabine.241 The combination of weekly cisplatin and irinotecan appears particularly active, with objective disease regression occurring in more than half of patients.239
Important steps in reducing the incidence of this cancer in the United States include vaccination of all children and sexually active adults for hepatitis B and the recently implemented screening techniques of the blood supply for hepatitis B and C. Approximately 75% of patients with hepatocellular carcinoma demonstrate an elevation in their serum alpha-fetoprotein level. Consequently, it has been proposed that patients at increased risk for the development of this tumor such as those with hepatitis B or C infections, alcoholic cirrhosis, or hemochromatosis undergo periodic alpha-fetoprotein testing as a form of surveillance screening.246 This strategy has thus far been shown to be effective in Alaskan Native Americans with serologic evidence to hepatitis B exposure, in whom hepatocellular carcinomas were detected more frequently at a resectable stage than had occurred previously when such testing had not been performed.247 Prospective and retrospective studies of patients with hepatitis C, treated with short periods of interferon (3–6 months), have demonstrated a 50% to 34% reduction in the incidence of hepatocellular carcinoma.248,249 Interferon therapy is less successful in the treatment of hepatitis B, and its efficacy in reducing the incidence of hepatocellular carcinoma has not been studied. The potential benefits of interferon therapy in this setting must be balanced by the numerous and often severe side effects (e.g., flu-like symptoms, fatigue, weight loss, depression, anemia, thrombocytopenia, cardiac toxicity) associated with this treatment, especially in older individuals.
Hepatocellular Carcinoma Hepatocellular carcinoma (or primary liver cancer) is the fourth most common cause of cancer death in the world, leading to almost half a million deaths annually.10 More than half of these deaths are in China and Taiwan, where the condition represents the leading cause of cancer death in men.242 In contrast, the annual incidence in the United States has been relatively low, with 16,200 cases expected in 2001.1 The incidence of hepatocellular carcinoma has nearly doubled in the United States in the past two decades, primarily due to a significant increase in hepatitis B and C infections, which, along with alcoholic cirrhosis, are the primary causes of this cancer in the developed world.243 Eighty-five percent of patients infected with hepatitis C and 5% of patients infected with hepatitis B will develop persistent, chronic disease.244,245 Cirrhosis develops in approximately 20% of chronic disease patients, and, in turn, hepatocellular carcinoma is diagnosed in 2% to 7% of patients with cirrhosis.243 Because the latency period for the development of hepatocelluar carcinoma in patients infected with hepa-
Diagnosis and Workup Patients most often seek medical attention for the development of an often painful abdominal mass in the right upper quadrant or epigastrium that is frequently accompanied by weight loss. In patients with cirrhosis, the development of hepatocellular carcinoma may be
34. Colon Cancer and Other Gastrointestinal Malignancies
heralded by ascites, portal hypertension, and relatively abrupt clinical deterioration. Abnormal levels of serum transaminases and alkaline phosphatase on standard liver function testing are observed in most cases, but normal liver tests do not exclude the diagnosis. Alpha-fetoprotein is commonly elevated and is considered diagnostic when above 500 ng/mL.250 Ultrasonography and CT scan of the liver can determine the anatomic distribution of hepatocellular carcinoma and can also provide orientation for percutaneous needle biopsy. Patients with relatively small tumors and no evidence of distant disease or malignant ascites may be evaluated for resection. Magnetic resonance imaging, angiography, and laparoscopy can determine the resectability of the cancer. Contraindications to surgery include portal or hepatic vein invasion or portal vein thrombosis.251 Relative contraindications include severe cirrhosis, active hepatitis, large or multifocal tumors, and comorbidities.
Treatment Treatment options for hepatocellular carcinoma restricted to the liver include operative resection, orthotopic liver transplantation, nonsurgical tumor ablation, or transarterial hepatic chemoembolization. Patients treated with a partial hepatectomy at specialized medical centers have a 5-year survival rate of approximately 35% to 50% and an operative mortality rate less than 5%.250 However, intrahepatic recurrences occur in up to 75% of patients252; spread to distant sites is also common. There is no evidence that postoperative treatment with chemotherapy is useful following the resection of a hepatocellular carcinoma.253 Orthotopic liver transplantation is not tolerable in the geriatric population. Localized tumor ablation with ethanol, cryotherapy, or radiofrequency has been increasingly utilized to eradicate small tumors and may be particularly appropriate for older patients, who are frequently considered poor candidates for surgery. Percutaneous ethanol injection (PEI) is the most commonly employed of these ablative techniques. Absolute or 95% ethanol is injected directly into the tumor either percutaneously or with direct visualization through a small incision. The probability of 5-year survival (32%–52%) and the rate of intrahepatic recurrence (60%–74%) are similar to those reported with surgical resection.254–257 Surgical resection and PEI have not been compared in a randomized trial. Transarterial chemoembolization (TACE) represents the most commonly used management strategy for patients with unresectable hepatocellular carcinoma.250 The rationale for this treatment approach focuses on the observation that hepatocellular tumors derive nearly their entire blood supply from the hepatic artery while normal liver tissue is also oxygenated through the portal
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vein. In patients undergoing TACE, selective branches of the hepatic artery are occluded (often with gel foam), leading to tumor necrosis without destruction of adjacent normal tissues. Additional intrahepatic chemotherapy may also be given. Although this procedure often results in dramatic tumor shrinkage and transient symptomatic palliation, randomized trials have failed to show a survival advantage when compared to observation alone.258,259 Surgery and chemoembolization in the geriatric population have been found to be tolerable in most260–262 but not all261,263 experiences. In patients with advanced hepatocellular carcinoma, the use of chemotherapy has been disappointing251; randomized trials have not demonstrated a survival advantage for treated patients.250,264
Gallbladder Cancer Cancers of the gallbladder occur infrequently in the United States.1 The incidence increases with age and reaches its peak in the seventh decade of life. Women and Native Americans, who are more prone to gallstones, have a higher risk of gallbladder cancer.265 Other risk factors include choledochal cysts, exposure to various carcinogens, gallbladder polyps, and calcification of the gallbladder (“porcelain gallbladder”).266 The 5-year probability for survival is favorable (>85%) only for those gallbladder cancers that do not invade beyond the muscular layer of the gallbladder.266 Once the tumor invades the adjacent connective tissue, the probability of 5-year survival drops sharply (to 5% Of tissue involved Diagnosed by needle biopsy, elevated PSA only Palpable nodule £Half of a lobe >Half lobe, not both Both lobes Tumor penetrates capsule Unilateral Bilateral Seminal vesicle invasion Tumor fixed or invades adjacent structures Bladder neck, sphincter, rectum Levator muscles or fixed to pelvic sidewall Regional nodes (true pelvis) One node £ 2 cm One node > 2 £ 5, multiple nodes Any node > 5 cm Metastases Nonregional nodes Bone Other
T1 T1a T1b T1c T2 T2a T2b T2c T3 T3a T3b T3c T4 T4a T4b N N1 N2 N3 M1 M1a M1b M1c
AUA, American Urologic Assoication; TNM, tumor-node-metastasis.
a 4 or 5 score. These two scores are added together and expressed as a Gleason score; for example, 4 + 3 = 7. This grade is useful in predicting the biologic aggressiveness of a tumor and correlates with prognosis and extent of disease.43–45
Management of the Patient with Prostate Cancer Once a histologic diagnosis and clinical stage have been established, patients and their physicians face several major decisions. These decisions are complicated by the variable natural history of this disease and the lack of randomized prospective trials to guide therapeutic decisions. Particularly in the older patient, the primary care physician can and should play a crucial role in this decision making because the past medical history and current condition of the patient will have a significant impact on the options to be considered. The decisions to be made differ widely based on the extent of the disease. In general, patients can be grouped into three categories: (1) those with organ-confined disease; (2) those with regionally advanced disease; and (3) those with metastatic disease.
Organ-Confined Disease This category is composed of patients with localized prostate cancer (T1–2c, N0, M0). There is controversy about
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the management of patients in this broad category. These patients range from those with well-differentiated, incidentally detected tumors involving less than 5% of the gland (T1a), to those with palpable tumor diffusely involving both lobes (T2c). These tumors have widely variable natural histories, but the unifying characteristic is that they are potentially curable by definitive therapy. Whether such therapy has an impact on overall survival, particularly for the population of men with T1a or T1b disease, is not known. Thus, there is debate as to how these patients should be managed. This debate is particularly relevant in an elderly population where life expectancy and tolerance of morbidity have considerable impact on treatment decisions. Consideration of the natural history of prostate cancer is crucial. The overall survival for patients with organconfined disease who are not treated is numbered in terms of several years.46 The two definitive therapeutic modalities that have been utilized to treat this disease are radical prostatectomy and irradiation. There are several techniques for administering irradiation: external beam irradiation administered via an increasing number of techniques that allow increase in dose intensity of irradiation [three-dimensional (3-D), conformal field treatment planning, intensity-modulated radiation therapy (IMRT), brachytherapy using intra prostatic implantation of 1125 or palladium-impregnated seeds or high-doserate, afterloading techniques]. It is beyond the scope of this chapter to discuss the variety of irradiation techniques. The greatest experience and longest follow-up data for irradiation are derived from a series of patients treated by external beam irradiation. After surgical treatment for T1 and T2 prostate cancer, the cancer-specific survival rate is 90% to 94% at 10 years and 82% to 90% at 15 years.47–49 If the PSA level is considered as an indicator of disease progression, the reported progression rate for the foregoing group is 17% to 31% at 5 years and 23% to 53% at 10 years.50,51 Treatment of localized prostate cancer with irradiation yields similar results. In a study of 313 patients with T1 disease by Hanks et al.52 with external beam radiation alone, survival was 77% at 5 years and 51% at 10 years (comparing well with 81% and 62% survival for age-matched normal males). Another study53 of 500 men mostly with T1 and T2 disease treated with irradiation revealed 80% survival at 5 years with 72% surviving without clinical evidence of any disease. The rate went down to 51% when the PSA was taken into account as an indicator of recurrence. (NB: The surgery data represent cancerspecific mortality and the radiation data overall mortality.) It is critical to realize, when examining outcomes of irradiation and prostatectomy, that surgical series usually include younger men and report results by pathologic stage. By contrast, irradiation series generally are composed of older men and results are reported as the clini-
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cal stage, which notoriously underestimates the local and regional extent of tumor. Improved results have been obtained in localized prostate cancer using a combination of external beam radiation and goserelin [a gonadotropin-releasing hormone agonist (GnRHa)].54 Bolla and colleagues54 studied 415 patients with T1–T4 prostate cancer, randomly assigned to irradiation versus radiation and goserelin. The survival in the combined therapy arm was 79% at 5 years versus 62% in the radiation-only group (p < 0.001). Eighty-five percent of the surviving patients were free of disease at 5 years. When comparing these data with those for surgery, it should be noted that the Bolla study included patients with T3 and T4 prostate cancer, which are not included in the surgery data. The Radiation Therapy Oncology Group (RTOG)has several suchongoing trials in which short-term or long-term therapy with GnRHa + antiandrogen + irradiation is being studied with respect to local control and time to progression in comparison to irradiation alone. Prostatectomy and irradiation have complications that may have a significant impact on quality of life.55 The major complications of these approaches are listed in Table 36.2. Acute radiation proctitis and cystitis are seen often in men receiving external beam radiotherapy; infrequently, chronic cystitis or proctitis may result. Following radical prostatectomy, impotence and incontinence are the complications with the most significant impact on quality of life. In addition, this procedure is associated with 1 to 2 units of blood loss and a 0.1% to 2% risk of perioperative mortality. Reported series from major centers with large experiences note impotence and incontinence rates of 30% to 40% and 5% to 10% respectively. However, a more population-based survey of Medicare patients who had undergone radical prostatectomy revealed that the vast majority were impotent and more than 40% had some problem with continence.56 Nearly one-fourth of the patients reported that they required further therapy for recurrent cancer. This survey suggests that the published estimates for the efficacy and complication rates of this procedure may be overly optimistic. There are no satisfactory trials comparing prostatectomy Table 36.2. Complications of prostate cancer treatments. Treatment External beam radiotherapy
Radical prostatectomy
Complications Acute cystitis, proctitis: 30%–40% Urinary retention: 3%–5% Chronic prostitis: cystitis 4%–7% Impotence: 40%–60% Blood loss: 1–2 units Impotence: 40%–60% Incontinence: 5%–15% Anastomotic stricture: 1%–25% Thromboembolism: 1%–12% Mortality: 0.1%–2%
36. Prostate Cancer
with radiation that has been completed.57 At this time, there is little compelling evidence to support either irradiation or prostatectomy as superior. The debate regarding radical prostatectomy and radiotherapy takes on particular significance in men with competing morbidities, particularly when there are data suggesting that no treatment at all is an acceptable approach for some men. There are published series that suggest the survival of men with localized prostate cancer who are not treated is comparable to that of men who undergo radical prostatectomy,58,59 but methodologic problems, including the lack of statistical power, limit the conclusions to be drawn from these trials. A larger trial designed to address this question is now underway in the Veterans Administration System. There are no randomized trials comparing radiation therapy with observation. Observation-only is an option for some men with organ-confined prostate cancer, and this is especially true in the elderly population with reduced life expectancy. Several studies have shown that most men with small tumors and well- or moderately differentiated cancer will have long survival without major interventions.60–66 A pooled analysis of more than 800 men with localized disease identified tumor grade as the major factor in predicting disease-specific and metastasis-free survival.46 The 10-year, disease-specific survival is 87% for men with histologic grade 1 and 2 tumors (Gleason £7) and 34% for men with grade 3 (Gleason >7) tumors. This diseasespecific survival for men with well- and moderately differentiated tumors compares favorably with the reported survival for both radical prostatectomy and external beam radiotherapy.67,68 A recent development in the therapy of localized prostate cancer is the use of ultrasound-guided cryoablation of the prostate. A preliminary report on this technique showed that 82% of the 55 men who underwent the procedure had no residual disease at 3 months of follow-up.69 The procedure is associated with significantly shortened hospital stays and overall morbidity when compared with prostatectomy. However, it has been studied in a relatively small number of men, and shortand long-term efficacy is unknown. Currently, cryoablation for localized prostate cancer is an experimental procedure. Clinical decision making in older patients with organconfined disease is largely an issue of how much and which risks patients are willing to tolerate. With observation alone, there is the risk of developing widespread metastatic disease, whereas each of the treatments has risk of side effects. In the older patient, the risk of developing metastatic disease must be weighed against the life expectancy and comorbid conditions that may limit that life expectancy and raise the risk associated with therapy. An open and frank discussion of these risks with each individual is required.
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Regionally Advanced Disease These patients have cancer that is no longer confined to the prostate gland but has not spread to the soft tissue structures or lymph nodes in the pelvis (T3,N0 or Tx,N1–3). Patients with clinical T3 tumors have 5-year survival of 64% to 72% following radical prostatectomy, external beam radiotherapy, or hormonal therapy, and 10-year survival of 29% to 47%.70–72 Recognizing the increased risk for local recurrence and development of progressive disease, most investigators do not believe that patients in this disease category are curable by either radical prostatectomy or external beam radiotherapy alone. In general, however, these patients do appear to have the potential for prolonged survival with median survival greater than 5 years in most studies no matter what therapy is given. Intuitively, pathologic stage T3 disease (microscopic penetration of the prostatic capsule or invasion of the seminal vesicles) should have a better prognosis than clinical stage T3 disease (palpable involvement of the seminal vesicles). Unfortunately, the data to support this assumption are lacking. Patients with T3 prostate cancer have been treated with radical prostatectomy, with or without additional (adjunctive) irradiation or hormonal therapy,70,73 definitive radiotherapy,71 immediate hormonal therapy,72 or observation with hormonal therapy on progression.74 Adjuvant radiotherapy has been the primary modality of treatment for patients with extracapsular spread after prostatectomy (pathologic stage C disease).75 In most studies, the 5-year survival rates range from 60% to 75% regardless of therapy. Thus, there are no convincing data to specifically recommend any of these approaches. Patients with regional nodal involvement (N1) have a much worse prognosis. Median survival is reported to be as low as 39.5 months.76 In this small study (44 patients), radical prostatectomy, adjuvant hormonal therapy, and radiotherapy seemed indistinguishable with regard to survival. However, in a large consecutive series of 120 patients with D1 disease, the 5-year prostate cancerspecific survival was 61% in a group followed with expectant management alone.77 The group at the Mayo Clinic has argued that the high risk of recurrence in N1 patients justifies adjuvant hormonal therapy. This group has reviewed data from 631 patients who underwent pelvic node dissection and were found to have D1 disease.78 Of these patients, 251 went on to radical prostatectomy and orchiectomy, with 97 receiving radiation and orchiectomy and 60 orchiectomy alone. Prostate cancer-specific survival was markedly improved in the prostatectomy patients at 5 and 10 years when compared with the orchiectomy-alone patients (5 year, 90% versus 66%; 10 year, 78% versus 39%). As with many prostate cancer studies, however, these are retrospective data; unknown, unrecognized, or unstated selection bias leading to
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treatment decisions prevent firm conclusions from such data.77
Adjunctive Androgen Deprivation Considerable data have emerged in the past 5 years regarding the use of androgen deprivation therapies (ADT) (usually GnRHa ± antiandrogen) in conjunction with irradiation and surgery for localized disease. Already referred to are the data of Bolla et al.,54 which demonstrated a substantial survival advantage for patients with T3–T4 primary tumors treated with irradiation + LHRHa compared to irradiation alone. The RTOG is conducting trials of T3, T4 and T1, T2 tumors evaluating pen-irradiation as well as prolonged androgen deprivation compared to irradiation alone. Freedom from local progression and freedom from PSA progression occur significantly more often when irradiation is accompanied by ADT in RTOG studies. In a multiinstitutional randomized trial, Messing et al.79 reported an improved survival in men with N+ disease following prostatectomy if ADT was employed. D’Amico80 and colleagues note improved survival when irradiation is combined with ADT in a retrospective, case-control study. Taken together, these data suggest that adjunctive ADT improves survival in certain subsets of patients. Although considerably more work is required to clearly define the role of “early” ADT, these observations call into question the long-held dictum that ADT does not affect survival in prostate cancer. No data are available examining the role of ADT as sole therapy for clinically localized prostate cancer. Studies demonstrating superiority of ADT + irradiation versus irradiation alone raise the question of the role of ADT alone in men with localized disease, especially, perhaps, men with competing causes of morbidity or mortality.
Metastatic Disease Approximately 30% of patients diagnosed with prostate cancer have metastatic disease at presentation.81 An additional 30%, who initially present with organ-confined or regionally advanced disease, manifest evidence of metastasis at some point in the course of their disease. Metastatic prostate cancer is a significant cause of morbidity and mortality in the elderly male population. Hormonal therapy of patients with metastatic prostate cancer is one of the most effective therapies available for the treatment of disseminated malignancy. Based on the Nobel Prize-winning work of Huggins and Hodges82 in the 1940s, ADT had been utilized with great palliative benefit in patients with disseminated prostate cancer. Response rates of 80% to 90% are reported with each of the currently available therapies: estrogens, orchiectomy, and the LHRHa.83,84 Diethylstilbestrol (DES) is the
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primary estrogen used in the therapy of prostate cancer. This agent is clearly effective in treating metastatic prostate cancer; clinical responses following DES occur as often as with orchiectomy. Unfortunately, even with low-dose regimens, this agent is associated with a significant incidence of cardiovascular side effects, including cardiovascular death.85 Orchiectomy is the “gold standard” for ADT, particularly for men at high risk for complications as indicated by extensive bony involvement, obstructive uropathy, or cord compression. Surgical castration results in a rapid, 95% reduction in circulating testosterone and is not associated with the cardiovascular complications of DES.86 GnRH analogues require 2 to 3 weeks to produce castrate levels of testosterone.81 Nonetheless, the GnRHa analogues are effective therapy for prostate cancer. The major limitations to their use are compliance and cost. The currently available analogues require monthly or every 3- or 4-month injections. The cost of these injections is approximately $400 and $1400, respectively. A once-yearly implantable form of leuprolide (Viadur) has been developed and is being tested for efficacy and safety.87 In a cost comparison analysis with the GnRHa analogues, orchiectomy is clearly more cost effective.88 In addition, GnRHa initially induces an increase in circulating levels of testosterone, which may result in tumor flare.82,89,90 This surge in testosterone can cause a significant exacerbation of bone pain, increased urinary obstruction, and potentially significant spinal cord compression in some patients. The effects of this flare can be controlled using antiandrogens such as flutamide, bicalutamide, or nilutamide.91 The antiandrogens are combined with the GnRHa analogues or orchiectomy in a strategy known as total androgen blockade (TAB). This therapeutic approach seeks to improve outcome through “totally” blocking androgenstimulated growth of prostate cancer by reducing the circulating androgens and blocking receptor binding by any remaining androgens. In uncontrolled studies, response rates as high as 97% with 2-year survival of 89% were reported.92 There are currently three antiandrogens in use in this country: flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron). Numerous trials have explored TAB with either orchiectomy or GnRHa + antiandrogens compared to orchiectomy or GnRHa alone. Flutamide was studied in a randomized controlled trial in which previously untreated patients with metastatic prostate cancer were randomized to receive the GnRHa analogue leuprolide (Lupron, daily subcutaneous injection) with or without flutamide.93 This trial enrolled more than 600 patients and demonstrated a statistically significant benefit for the combination therapy in terms of both progression-free survival and overall survival. In a subset analysis, these differences seemed particularly prominent in the patients with good
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performance status and minimal disease. In contrast, a European study of 571 patients randomized to goserelin with or without flutamide showed no advantage for the combination in terms of response rate, time to progression, or overall survival.94 Thus, the efficacy of this combination remains controversial. Metanalyses reveal either no or limited benefit of TAB versus testicular androgen suppression. An important U.S. trial randomized 1200 men to receive orchiectomy alone or orchiectomy + flutamide. No benefit of TAB was seen in this trial. Benefits of TAB, if any, seem to be limited to TAB employing LHRHa + antiandrogen. This finding may reflect the benefits of antiandrogen antagonism of the initial androgen surge that accompanies initiation of LHRHa or conceivably antiandrogens offsetting a small, but perhaps important, frequency of failure of LHRHa to completely suppress testicular androgen secretion. Orchiectomy alone an be a highly effective form of androgen suppression. If LHRHa are employed, we routinely initiate antiandrogens simultaneously and continue antiandrogens for at least 6 to 10 months. The major drawbacks to total androgen blockade are the costs and the side effects of antiandrogens. Flutamide is associated with diarrhea (possibly due to the lactose filler in the capsules) and occasional cases of hepatic toxicity.95 Preliminary preclinical and limited clinical data suggest that intermittent androgen deprivation (IAD) may have merit in prostate cancer treatment. In androgendependent animal tumor models, IAD appears to delay the emergence of androgen-independent tumor growth. In a number of pilot clinical trials IAD appears to be better tolerated than continuous androgen suppression and may be associated with a delay in development of androgen-independent disease progression. A large randomized national trial is underway comparing IAD to continuous androgen deprivation. If IAD is equivalent or superior to continuous therapy in terms of disease control, it will clearly be the preferred approach, because suppressed libido, hot flashes, and loss of bone mineralization should be less frequent with IAD. The timing of ADT has always been a controversial topic. In a randomized study of 938 patients with either locally advanced (T2–4) or asymptomatic metastatic prostate cancer, done in the United Kingdom, a significant benefit in morbidity and mortality from prostate cancer was seen in the patients who received immediate ADT (orchiectomy or LHRHa) versus the patients who did not receive ADT until clinically indicated.96 Despite the success of androgen deprivation therapy as measured by “response,” palliation of symptoms, improvement in bone scan, and reduced PSA, the median duration of response for men with metastatic prostate cancer is approximately 18 to 24 months, no matter what therapy they receive. Eventually, in all men, cells emerge that are
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able to grow despite androgen deprivation.83 Median survival, once this hormone-“independent” state is established, is approximately 1 year. It is these patients who are destined to die of their prostate cancer.To date, no therapy has been shown to improve overall survival in men with androgen-independent disease. With the increased use of PSA levels to monitor the status of disease in men with prostate cancer, evidence of tumor activity despite androgen deprivation can be ascertained earlier than symptomatic recurrence, radiographic, or physical exam would reveal. By defining survival from the date of increasing PSA, survival in the androgen-independent phase of disease may appear to be increasing; this is an artifact of earlier definition of androgen independence. Recent studies indicate that the first intervention in patients with androgen-independent prostate cancer should be withdrawal of antiandrogens in those who are taking them. Declines in PSA and decreases in the size of soft tissue masses have been documented following cessation of therapy with flutamide and bicalutamide.97–99 These responses occur primarily in men treated for a prolonged period with total androgen blockade and are usually short lived (6–9 months), but some patients may have extended periods of disease stabilization. Secondary hormonal therapy has been utilized for many years in the treatment of men with androgenindependent disease.100 Unfortunately, unlike breast cancer, a prior response to hormonal therapy does not predict for response to secondary hormonal therapy in prostate cancer. Numerous agents have been tested. A partial listing is included in Table 36.3. Objective responses (primarily reduction in PSA) occur in 15% to 20% of patients and are typically of short duration. Appetite stimulation has been demonstrated as a side effect of megestrol acetate.100,101 These agents may improve the cachexia seen in these patients but have limited benefit in treating prostate cancer.
Table 36.3. Agents used in hormonal therapy. Reduction in androgen levels Orchiectomy Adrenal suppression Aminoglutethimide Ketoconazole Direct cytotoxicity Ketoconazole Diethylstilbestrol Megestrol acetate Androgen receptor antagonists Flutamide Bicalutamide Nilutamide Multiple mechanisms PC-SPES Megestrol acetate
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Two secondary “hormonal approaches” merit special mention. 1. Several randomized trials have employed glucocorticoids alone as the “standard” therapy for androgen independent prostate cancer. These studies consistently reveal a 15% to 20% frequency of 50% or greater decrease in PSA and a similar rate of pain reduction and an improved sense of well-being. These data suggest that relatively low dose glucocorticoids provide real, albeit relatively infrequent, and temporary benefit in men with androgen-independent prostate cancer. 2. The agent PC-SPES is a commercially available, Chinese combination of eight herbs. The active component or components in PC-SPES are unclear, but preclinical studies and clinical trials indicate that PC-SPES suppresses the growth of prostate cancer cells in vitro, reduces PSA levels in men with no prior hormonal therapy, and, most intriguingly, results in subjective improvement and a 50% or greater decrease in PSA in approximately 50% of men with androgen-independent prostate cancer. This activity of PC-SPES is dependent, at least in part, on the fact that PC-SPES contains phytoestrogen compounds that suppress testicular androgen synthesis and likely have direct antiproliferative effects against prostate cancer. The toxicity of PC-SPES is the toxicity of estrogen: thromboembolic disease, fluid retention, congestive heart failure. There are no data comparing PC-SPES to other first- or second-line approaches to androgen deprivation. Cytotoxic chemotherapy has been studied extensively in men with hormone-refractory prostate cancer.102–104 Despite numerous studies, there is no evidence that cytotoxic therapy provides survival benefit. This result has led some investigators to question whether any patient with prostate cancer should receive cytotoxic chemotherapy.105 Two carefully conducted, randomized trials evaluated the role of mitoxantrone and glucocorticoids. Both studies revealed a significant improvement in palliation of bone pain and greater reduction in serum PSA in those who received the combination compared to the arm receiving only glucocorticoids. Mitoxantrone has been approved by the FDA for use in metastatic prostate cancer. Although no impact in survival has been seen with mitoxantrone therapy, these studies do indicate that limited, but real, palliative benefit is achieved with a very safe and welltolerated cytotoxic therapy.106,107 Several other studies show that taxanes (paclitaxel or docetaxel), with or without estramustine, have antitumor effects in men with androgen-independent prostate cancer. Ketoconazole + doxorubicin alternating with vinblastine + estramustine also has clear antitumor effects. Although “effective” systemic cytotoxic therapy
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for androgen-independent prostate cancer remains to be defined, considerable data suggest that we have entered an era in the care of prostate cancer patients in which the use of cytotoxic therapy will be increasingly employed.108–112
Supportive Care of the Patient with Prostate Cancer Prostate cancer is a significant cause of morbidity in elderly men, even in those destined to die of other causes. The primary care physician plays a crucial role in the management of problems with metastatic prostate cancer. The major cause of morbidity in advanced prostate cancer is bone metastasis. These metastases often involve critical structures such as the vertebral bodies and weight-bearing bones, as well as the marrow cavity itself. These patients are at risk for cord compression, major fractures, and bony pain.
Spinal Cord Compression Spinal cord compression is a true oncologic emergency that occurs in 10% to 15% of patients with prostate cancer.113 The key to the management of this complication is early recognition. Most patients develop back pain before the onset of neurologic symptoms, and any evidence of neurologic impairment consistent with either nerve root or cord compression is an indication for careful evaluation. Motor abnormalities are usually the initial neurologic manifestation, followed by sensory loss. Once motor or sphincter function in impaired, improvement is relatively uncommon. Approximately 50% of patients who are paraparetic at presentation are able to regain the ability to walk, whereas patients who present with frank paraplegia rarely regain ambulatory function. A high index of suspicion of spinal cord compression must be maintained. High-dose intravenous corticosteroid therapy (dexamethasone 6 mg q 6 h) should be instituted in cases of suspected cord compression.114 Contrast-enhanced magnetic resonance imaging or computed tomographic (CT) myelography are the diagnostic tools of choice in assessing this condition. The thoracic spine is the most commonly involved site, and multiple levels of compression are not unusual. Once the diagnosis has been established, therapy is directed at relieving the pressure on the cord exerted by the tumor mass either with external beam radiotherapy or surgery.115,116 Currently, there is no evidence that surgery yields superior results when compared with radiotherapy alone in terms of preservation or recovery of neurologic function.
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Bone Metastases Impending Fracture The management of bony metastases in patients with advanced prostate cancer presents a major challenge. Not only can these metastases result in cord compression as already noted, but they are a significant cause of morbidity and contribute to mortality, particularly when they involve the long bones. Pathologic fracture involving the femurs and hips have an even more ominous prognosis than traumatic fractures do in the healthy elderly. Pathologic fractures are relatively rare in men with prostate cancer, despite the high rate of bone involvement,117,118 likely because of the propensity for these metastases to be osteoblastic rather than osteolytic. The development of pain on weightbearing is often the first sign of an impending fracture and should be investigated promptly in patients with known metastatic disease. External beam radiotherapy and prophylactic orthopedic procedures often prevent the development of debilitating fractures and preserve function. Once a pathologic fracture has developed, the outlook for regaining function is markedly decreased, and an aggressive approach to preventing fractures is clearly waranted.119
Pain Pain due to bone metastases is a common and vexing clinical problem; effective management is often difficult.120 Pain may be a major cause of functional limitation and suffering. Several surveys have indicated that patients are extremely fearful of cancer pain and that our current approaches to pain management are marked by an underutilization of appropriate medication.121,122 Narcotic analgesics are the mainstay of the management of cancer pain.123 Sustained-release morphine preparations with shorter-acting opioids for breakthrough pain are effective in most patients. Elderly patients are reported to have a higher risk of cognitive impairment with narcotics, but they can be used safely in this population. In the case of bony metastases, narcotics are often supplemented with nonsteroidal anti-inflammatory drugs to good advantage.124 These agents were typically associated with side effects including gastric erosions and bleeding and must be used with care in an elderly population.125 (Also see Chapter 28, Acute and Chronic Pain.) External beam radiotherapy should be utilized frequently in the management of painful bone metastases.126,127 Irradiation has the advantage of providing rapid and often complete relief of pain. However, it is not unusual for patients to develop multiple areas of involvement with new areas of bony pain occurring during a course of radiotherapy. This complication often results in expansion or addition to previously existing radiotherapy
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ports with a resultant exposure of significant amounts of marrow to the toxicity of radiotherapy, which may contribute to the anemia associated with marrow infiltration by prostate cancer, thus having a significant negative impact on quality of life. Newer approaches to the management of painful bone metastases include the use of bisphosphonates and radiolabeled compounds that are incorporated into bone, including radioisotopes of strontium, samarium, and rhenium.128–130 These agents are preferentially taken up in bone and appear to have significant activity in terms of ameliorating bone pain; up to 70% to 80% of patients report decreased pain. The bisphosphonates may be useful in prostate cancer involving the bone. These agents inhibit osteoclast activity and erosion of bone. Several bisphosphonates have undergone clinical trials to assess their effect on bone pain. Encouraging results have been seen. Bisphosphonates decrease indices of bone resorption that are above normal in 50% to 80% of cancer patients.131 Recent data indicate that these drugs may also inhibit the adhesion of tumor cells to bone, thereby preventing or delaying the development of new bony, as well as extraosseus, metastases.132 The precise role of bisphosphonates in men with prostate cancer is uncertain. In patients with either breast cancer or multiple myeloma, initiation of bisphosphonates early in the evolution of metastatic disease is associated with reduced skeletal morbidity and even improved survival. Some have argued that the primarily osteoblastic nature of bone metastases in patients with prostate cancer means that bisphosphonates will have a limited role. However, osteolysis does accompany even markedly osteoblastic bone metastases. The role of bisphosphonates in men with this disease remains to be determined.
Conclusion Prostate cancer is a major health problem in the elderly male population, causing significant morbidity, mortality, and expenditure of health care dollars. This problem will only increase as the population ages. Currently, controversy exists in several key areas of prostate cancer management, including screening and treatment of localized, advanced,and androgen-independent disease.These areas are under active investigation, and new approaches to this disease are emerging.
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metastatic carcinoma of the prostate. J Urol. 1990;144:934– 941. Labrie F, Dupont A, Belanger A, et al. New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate. 1983;4:579–594. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419–424. Tyrrell CJ, Altwein JE, Lippel F, et al. A multicenter randomized trial comparing the luteinizing hormonereleasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J Urol. 1991;146:1321–1326. Wysowski DK, Freiman JP, Tourtelot JB, et al. Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med. 1993;118:860–864. The Medical Research Council Prostate Cancer Writing Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol. 1997;79: 235–246. Kelly WK, Scher HI. Prostate specific antigen decline after antiandrogen withdrawal: the flutamide in advanced prostate cancer in progression under combination therapy. J Urol. 1993;150:908–913. Dupont A, Gomez JL, Cisan L, et al. Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol. 1993;150: 908–913. Small EJ, Carroll PR. Prostate-specific antigen decline after Casodex withdrawal: evidence for an antiandrogen withdrawal syndrome. Urology. 1994;43:408–410. Smith DC, Bahnson RR, Trump DL. Secondary hormonal manipulation (prostate cancer). In: Vogelzang NJ, Scardino PT, Shipley WU, et al., eds. Comprehensive Textbook of Genitourinary Oncology. Baltimore: Williams & Wilkins; 1996;885–919. Loprinzi CL, Ellison NM, Goldberg RM, et al. Alleviation of cancer anorexia and cachexia: studies of the Mayo Clinic and the North Central Cancer Treatment Group. Semin Oncol. 1990;17:8–12. Eisenberger M. How effective is cytotoxic chemotherapy for disseminated prostatic cancer? Oncology. 1987;1:59. Eisenberger MA, Simon R, O’Dwyer PJ, et al. A reevaluation of nonhormonal cytotoxic chemotherapy in treatment of prostatic carcinoma. J Clin Oncol. 1985;3:827–841. Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer. 1993; 71:1098–1109. Tannock IF. Is there evidence that chemotherapy is of benefit to patients with carcinoma of the prostate? J Clin Oncol. 1985;3:1013–1021. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone resistant prostate cancer: a Canadian randomized trial with palliative endpoints. J Clin Oncol. 1996;14:1756–1764. Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormonerefractory prostate cancer: results of the cancer and
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leukemia group B9182 study. J Clin Oncol. 1999;17(8): 2506–2513. Oh WK. Chemotherapy for patients with advanced prostate carcinoma: a new option for therapy. Cancer. 2000; 88:3015–3021. Trivedi C, Redman B, Flaherty LE, et al. Weekly 1-hour paclitaxel clinical feasibility and efficacy in patients with hormone-refractory prostate cancer. Cancer. 2000;89(2): 431–436. Bracarda S, Tonato M, Bosi P, et al. Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study. Cancer. 2000;88(6):1438–1444. Petrylak DP. Chemotherapy for advanced hormone refractory prostate cancer. Urology. 1999;54(suppl 6A): 30–35. Millikan RE. Chemotherapy of advanced prostatic carcinoma. Semin Oncol. 1999;26(2):185–191. Pienta, KJ. Pain management in patients with advanced prostate cancer. Oncology. 1999;13:1537–1546. Vecht CJ, Haaxma-Reiche H, van Putten WLJ, et al. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology. 1989;39: 1255–1257. Smith EM, Hampel N, Ruff RL, et al. Spinal cord compression secondary to prostate carcinoma: treatment and prognosis. J Urol. 1993;149:330–333. Shoskes DA, Perrin RG. The role of surgical management for symptomatic spinal cord compression in patients with metastatic prostate cancer. J Urol. 1989;142:337–339. Dijstra S, Wiggers T, van Geel BN, et al. Impending and actual pathological fractures in patients with bone metastases of the long bones. A retrospective study of 233 surgically treated fractures. Eur J Surg. 1994;160:535–542. Nielsen OS, Munro AJ, Tannock IF. Bone metastases: pathophysiology and management policy. J Chin Oncol. 1991;9:509–524. Hardman PD, Robb JE, Kerr GR, et al. The value of internal fixation and radiotherapy in the management of upper and lower limb bone metastases. Clin Oncol (R Coll Radiol). 1992;4:244–248.
467 120. Ashburn MA, Lipman AG. Management of pain in the cancer patient. Anesth Analg. 1993;76:402–416. 121. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med. 1994;330:592–596. 122. Cherny NI, Portnoy RK. The management of cancer pain. CA Cancer J Clin. 1994;44:263–303. 123. Hammack JE, Loprinzi CL. Use of orally administered opioids for cancer-related pain. Mayo Clin Proc. 1994;69: 384–390. 124. Eisenberger E, Berkey CS, Carr DB, et al. Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol. 1994;12:2756– 2765. 125. Kantor TG. Control of pain by nonsteroidal antiinflammatory drugs. Med Clin N Am. 1982;66:1053–1059. 126. Benson RC Jr, Hasan SM, Jones AG, et al. External beam radiotherapy for palliation of pain from metastatic carcinoma of the prostate. J Urol. 1981;127:69–71. 127. Gilbert HA, Kagan AR, Nussbaum H, et al. Evaluation of radiation therapy for bone metastases: pain relief and quality of life. Am J Roentgenol. 1977;129:1095–1096. 128. Robinson RG, Preston DF, Spicer JA, et al. Radionuclide therapy of intractable bone pain: emphasis on strontium89. Semin Nucl Med. 1992;22:28–32. 129. Maxon FR III, Schroder LE, Hertzberg VS, et al. Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo. J Nucl Med. 1991;32:1844–1881. 130. Collins C, Eary JF, Donaldson G, et al. Samarium-153EDTMP in bone metastases of hormone refractory prostate carcinoma:a phase I/II trial. J Nucl Med. 1993;34:1839– 1844. 131. Bishop M, Fellow G. Urinary hydroxyproline excretion— a matter of bony metastases in prostatic carcinoma. Br J Urol. 1997;49:711–718. 132. Boissier S, Magnetto S, Frappart L, et al. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices bone extracellular matrices. Cancer Res. 1997;57:3890– 3894.
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37 Gynecologic Cancers Angeles A. Alvarez and Daniel L. Clarke-Pearson
Genital tract cancer afflicts a significant portion of postmenopausal women. These malignancies account for 13% of all cancers in women. Approximately 75,400 new cases were diagnosed and 24,700 deaths resulted from gynecologic malignancies in 1999.1 Risk of developing a gynecologic cancer increases with age.2 Figures 37.1 and 37.2 show the age-related incidence and mortality, respectively, of these malignancies. As with other cancers, early detection provides the best opportunity for successful management. Therapeutic strategies include surgery, chemotherapy, and radiation treatment. Integration of these diverse modalities is best coordinated by a gynecologic oncologist who has the skills necessary to accomplish surgical and medical treatment of these women, as well as the knowledge of appropriate circumstances for the use of radiotherapy.
Endometrial Cancer Endometrial cancer is the most common invasive gynecologic cancer, representing 5.4% of all malignancies of women, and one of the 10 most frequent cancers.3 The incidence is 72 cases per 100,000 women per year, yielding a lifetime risk of 1 in 45. Approximately 37,400 new cases and 6,470 deaths occurred in 1999.1 An estimated 39,300 cases will occur in 2002.1 Seventy-five percent of endometrial cancer patients are postmenopausal, and the average age of onset is 60 years.2 Several risk factors for endometrial cancer have been identified.4 Obesity increases the risk threefold for women 21 to 50 pounds overweight; risk is heightened to 10 fold for individuals exceeding ideal body weight by 50 pounds. Risk for nulliparous women is two times higher than primiparas and three times that of multiparous women. Late menopause (age 52 versus age 49) leads to a 2.4-fold increased incidence of endometrial cancer. Hormones significantly alter the risk of endometrial neoplastic disorders.5 “Unopposed” estrogen replace-
ment therapy in postmenopausal patients increases endometrial cancer risk 4- to 15 fold; risk is related to dose and duration of therapy.6 On the other hand, cyclic or continuous supplementation with progestins provides protection against endometrial cancer, reducing risk to below that of women without postmenopausal hormonal support.5 Tamoxifen, an antiestrogen used in the therapy of breast cancer patients, increases the risk of endometrial cancer two- to threefold. Despite this unwanted side effect of tamoxifen, it is generally accepted that the benefits of tamoxifen therapy outweigh the risks and that therapy should not, in general be halted because of fears of endometrial cancer.7 Estrogen-secreting tumors (granulosa cell tumors of the ovary) and polycystic ovarian disease increase the risk of endometrial cancer.8 Oral contraceptives decrease the risk of endometrial cancer by approximately 50%, and this effect persists for about 10 years after discontinuation of the pill.9 Hypertension has been reported to increase endometrial cancer risk onefold, and diabetes elevates the risk threefold. Ironically, smoking one pack of cigarettes a day decreases risk by about 30%, presumably due to enhanced estrogen metabolism in smokers.10 Symptoms of endometrial cancer include abnormal uterine bleeding, vaginal discharge, pelvic pressure, and manifestations of metastatic disease. Abnormal uterine bleeding is the most common clinical feature and is present in approximately 80% of women with endometrial cancer. The differential diagnosis of a postmenopausal woman who presents with abnormal vaginal bleeding includes endometrial atrophy, endometrial hyperplasia, endometrial polyps, cervical cancer, and vaginal cancer, in addition to endometrial carcinoma. Patients with suspicious symptoms should be carefully evaluated with a detailed history, with emphasis on the risk factors already discussed.11 A thorough physical examination should also be performed. The pelvic examination should include a careful assessment of uterine size and an endometrial biopsy.12 A Pap smear should 469
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A.A. Alvarez and D.L. Clarke-Pearson Figure 37.1. Annual incidence of genital tract cancers by age per 100,000 women in the United States, 1992–1996. (Adapted from Ries et al.108)
also be done as well; however, Pap smears lack sufficient sensitivity for the diagnosis of endometrial cancer and must not be substituted for biopsy of the endometrial cavity. Transvaginal ultrasound, with measurement of the endometrial stripe thickness, is a useful adjunct. Using a “normal” endometrial stripe measurement of 4 mm or less for women less than 5 years since menopause and 3 mm or less for those 5 years or more since menopause, transvaginal ultrasound demonstrated a 97% sensitivity, 76% specificity, and 99.7% negative predictive value in the detection of endometrial cancer.13 For patients receiving tamoxifen, the endometrial stripe may measure up to 10 mm and is not a reliable measurement for the detection of endometrial cancer compared to patients not receiving tamoxifen.14 Dilatation and curettage are recommended if office biopsy cannot be performed or if the clinical suspicion of cancer remains high in the face of a negative biopsy and transvaginal ultrasound. Hysteroscopy may also be performed, allowing visual inspection of the endometrial cavity, and may identify small foci of tumor missed on routine biopsy.
Figure 37.2. Annual mortality of genital tract cancers by age per 100,000 women in the United States, 1992–1996. (Adapted from Ries et al.108)
Screening for endometrial cancer has not proven to be of much clinical value. Methods such as routine endometrial biopsy and pelvic sonography have been explored. Given that a high percentage of endometrial cancer patients become symptomatic early in the course of their disease and that endometrial biopsy is readily available, screening does not improve outcome significantly if practitioners keep in mind the risk factors and diligently biopsy the endometrium in suspicious cases.15 Endometrial cancers are initially treated and staged using a surgicopathologic evaluation to document the extent of spread.16 Preoperative medical assessment should search for metastases (physical exam and chest xray), as well as assure that the patient is medically fit to undergo surgery. Table 37.1 outlines the current staging system. Standard therapy comprises exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-
Table 37.1. FIGO staging of endometrial cancer. Stagea
Definition
IA IB
Grade 1,2,3 Grade 1,2,3
IC
Grade 1,2,3
IIA IIB IIIA
Grade 1,2,3 Grade 1,2,3 Grade 1,2,3
IIIB IIIC
Grade 1,2,3 Grade 1,2,3
IVA IVB
Grade 1,2,3 Grade 1,2,3
Carcinoma confined to the endometrium Invasion of less than one-half myometrial thickness Invasion of equal to or more than one-half myometrial thickness Spread to endocervical glands Invasion of cervical stroma Invasion of serosa and/or adnexa and/or positive peritoneal cytology Vaginal metastases Pelvic and/or para-aortic lymph node involvement Invasion of bowel and/or bladder mucosa Distant metastases including spread to abdominal viscera or inguinal lymph nodes
FIGO, International Federation of Gynecology and Obstetrics. a Grade 1, 5% of less of a nonsquamous or nonmorular solid growth pattern; grade 2, 6%–50% of a nonsquamous or nonmorular solid growth pattern; grade 3, more than 50% of a nonsquamous or nonmorular solid growth pattern.
37. Gynecologic Cancers
oophorectomy, washings from the abdomen and pelvis to assess for cytologic evidence of tumor extension, and pelvic and para-aortic lymphadenectomies if poor prognostic or adverse histologic features are present.17 Clinical staging was employed before 1988 and is still utilized in the fewer than 5% of cases in which the patient is unfit to undergo surgery.18 Increased risk of recurrence and decreased survival are associated with high-grade histology, cervical extension, deep myometrial invasion, extrauterine extension, and malignant peritoneal cytology.16,19 The presence of estrogen and progesterone receptors is associated with a better prognosis and a higher response rate to progestational therapy. Progestational therapy is usually reserved for recurrent disease, salvage therapy, or the medically infirm who are poor surgical candidates.20 Postoperative management of patients with endometrial cancer varies according to the stage and grade of their tumor. Women at low risk for recurrence (stage IA, grade 1 and 2) require no additional therapy. A recent phase III randomized study of surgery versus surgery plus adjunctive radiation therapy in intermediate-risk individuals [stage IB, IC, IIA (occult) and IIB (occult)] demonstrated that the use of adjuvant pelvic radiation therapy decreased the risk of pelvic recurrence but had no significant effect on overall survival. Patients randomized to the radiotherapy group had a higher incidence of adverse effects, including hematologic, gastrointestinal (with and without obstruction), genitourinary, and cutaneous toxicities.21 Patients with stage IIB or IIIA should receive tailored treatment, which may include vaginal cuff irradiation, pelvic radiotherapy, or intraperitoneal 32P.22 Patients at high risk for persistent, recurrent, or progressive disease (stages IIIB, IIIC, IVA, and IVB, all grades) usually receive postoperative radiation treatment to the vaginal cuff, pelvic, or para-aortic regions.23,24 Whole abdominal radiation is sometimes employed in cases of intraabdominal tumor spread.25 Currently, a randomized prospective trial comparing whole abdominal radiation versus doxorubicin-cisplatin chemotherapy for patients with advanced disease is under way. Radiation as a primary means of therapy is usually reserved for poor surgical candidates. When utilized, external beam technique followed by uterine intracavitary placement of a radiation source is the usual strategy.26 Hormonal therapy is sometimes used for metastatic or recurrent endometrial cancer.8 Progestational agents have proven to be most effective, although responses to tamoxifen have been described.27 Tumors that express progesterone receptor are more sensitive to the growthsuppressive effects of progestins that those lacking receptors (70% versus 16% response rate).28 Cytotoxic chemotherapy may be used for palliation in advanced or recurrent disease.29 Doxorubicin and cisplatin are the best agents available. Response rates of 31% to 81%
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have been achieved, but long-term survivors are rare. Paclitaxel combined with platinum-based chemotherapy has demonstrated a partial response rate of 63% in recurrent disease, and this agent is currently being evaluated in phase III trials.30 Prognosis varies according to clinical stage. Five-year survival according to stage is as follows: I, 93%; II, 73%; III, 48%; IV, 25%.31 Patients with stage IA endometrial cancer have a 5-year survival of more than 95%. Multivariate analysis has demonstrated that age at diagnosis is an independent prognostic factor; survival decreases from 93% to 71% as age increased from 30 to 70+20,31 Recurrence is most likely in the first 3 years after treatment. About half of recurrences are in the vagina or pelvis. Patients should be seen every 3 to 4 months in follow-up and should be asked about spotting, bleeding, pain, or any other unusual symptoms that may portend relapse. A careful physical examination including Pap smear and pelvic assessment should be performed. Chest x-ray may be valuable for screening for pulmonary metastases. CA 125 is not routinely used to follow these patients but can be useful in isolated cases.32 Recurrent endometrial cancer is treated on an individual basis. Strategies include radiation therapy (depending on prior treatment), surgery for resection of isolated tumor, pelvic exenteration for recurrence after radiotherapy,or systemic therapy with hormonal or cytotoxic agents. Some patients with recurrent endometrial cancer, especially those localized to the vaginal cuff, can be treated successfully with radiotherapy, surgery, or a combination of the two. Patients who have metastatic recurrent disease generally have a poor survival. Hormonal therapy and chemotherapy may provide palliative benefit. Although it is labeled as contraindicated by the U.S. Food and Drug Administration (FDA), estrogen replacement given after definitive cancer treatment does not appear to influence survival for patients with early-stage disease. Provision of hormonal support for women with advanced disease must be decided on an individual basis and should be done in close consultation with a gynecologic oncologist.33
Ovarian Cancer Ovarian cancer is the leading cause of death among gynecologic malignancies. In 1999, there were 25,200 new ovarian cancers diagnosed and 14,000 deaths from this disease.1 Women have a 1 in 70 lifetime risk of developing ovarian cancer, and 1 in 100 will die of this disease.34 More than 48% of ovarian cancers occur in women over the age of 65. Age-adjusted incidence rates increase as age advances. For women under 40, the incidence is 1.4 per 100,000 women; the incidence is between 40 and 50 per 100,000 for women over age 60,2 and peaks at
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Figure 37.3. Age distribution of patients with epithelial ovarian cancer, based on data from the International Federation of Gynecology and Obstetrical (FIGO) 1988 Annual Report. (Reprinted with permission from Morley G, Reynolds RK. Gynecologic, Obstetric, and Related Surgery, 2nd Ed. Mosby, Boston, 2000.)
57.0 per 100,000 for women 70 to 74 years old35 (Fig. 37.3). Most ovarian cancers are diagnosed at advanced stage, with extensive intraabdominal spread present at the time of initial diagnosis. Many risk factors have been identified for ovarian cancer.36 The best documented of these is the relationship between the number of lifetime ovulatory cycles and ovarian cancer risk. Events or conditions that suppress ovulation protect women against this malignancy. Thus, multiparity, oral contraceptive use, and a history of breastfeeding are protective. Conversely, women who are nulliparous or who undergo a late menopause are at increased risk. Women who have undergone ovulation induction therapy for infertility may have a higher risk, but this has not yet been firmly established.37 High dietary fat consumption, use of talc in perineal regions, and mumps infections before menarche have also been implicated as factors that elevate ovarian cancer risk. Genetic influences are also important. About 5% of ovarian cancer patients have a family history of significance.38 Three familial ovarian cancer syndromes have been identified.39 Women who fall into these categories often develop ovarian cancer at a younger age than those who develop sporadic tumors. Site-specific ovarian cancer afflicts families by causing ovarian cancer in the affected kindred. In familial breast/ovarian cancer syndrome, female family members develop early-onset breast or ovarian cancers. Cancer family syndrome (Lynch type II) is characterized by nonpolyposis colon cancer and either breast, ovarian, or endometrial adenocarcinoma. All these syndromes are transmitted in an autosomal dominant pattern with variable degrees of penetrance.
A.A. Alvarez and D.L. Clarke-Pearson
Several pathologic categories of ovarian tumors exist.40 Epithelial cancer (adenocarcinoma) accounts for more than 80% of ovarian tumors and has an average age of onset over 40. These malignancies arise from coelomic epithelium; histologic subtypes of epithelial tumors include serous, mucinous, transitional cell, clear cell, and undifferentiated. Epithelial cancers are assigned grades of 1 to 3; the higher the grade, the less well differentiated the tumor. It is important to recognize tumors of low malignant potential (borderline tumors). These tumors are also of epithelial origin and are characteristically indolent and slow growing. They have cellular features of both malignancy and benignity. Because of their torpid nature, low malignant potential tumors have a more favorable prognosis than frankly invasive ovarian cancer. Another malignancy commonly misdiagnosed as ovarian cancer is primary peritoneal serous carcinoma. This cancer, arising from the peritoneum, spreads like ovarian cancer, looks histologically similar, yet minimally involves the ovary. Sex cord/stromal tumors arise from mesenchymal tissues and account for about 5% of ovarian cancers. These tumors may occur at any age; subtypes consist of granulosa cell, thecoma, fibroma, and Sertoli–Leydig histologies. Germ cell tumors make up another category. They typically afflict children and adolescents and are relatively rare in postmenopausal women. These tumors account for approximately 15% to 20% of ovarian cancers. Ovarian metastases may arise from other primary cancers such as breast, endometrial, lymphoma, colon, and stomach and may present with signs and symptoms similar to de novo ovarian cancer. Because the majority of ovarian cancers in the geriatric population are of epithelial origin, our discussion focuses on this category. Other issues specifically related to the care of elderly ovarian cancer patients are addressed next. Ovarian cancer often has an insidious onset with nonspecific symptoms, which often results in a delay in diagnosis. Gastrointestinal symptoms are common including dyspepsia, nausea, early satiety, altered bowel habits, eructation, abdominal discomfort, pain, and distension. Patients are often initially misdiagnosed with stress, depression, irritable bowel syndrome, or gastritis.41 The correct diagnosis of ovarian cancer requires a high index of suspicion. A carefully detailed history and physical examination are essential. Symptoms, family history, and risk factors should be assessed. Physical examination should include meticulous abdominal, pelvic, and lymph node examinations. Omission of the pelvic exam at the first visit is an important factor associated with delay of diagnosis.41 Examination frequently reveals a significant abdominopelvic mass accompanied by ascites. Radiographic studies are sometimes useful in securing the diagnosis and triaging patients for appropriate treatment. Ultrasound can
37. Gynecologic Cancers
help differentiate benign from malignant lesions. Benign tumors often appear as simple cysts under 10 cm in diameter with septations less than 3 mm thick. Malignant lesions often are complex with solid and cystic components or are completely solid. Other malignant features include bilaterality, multiple septations greater than 3 mm, papillations, mural nodules, excrescences, and ascites. Doppler flow studies of malignant tumors show increased vascularity, enhanced blood flow, and decreased blood flow resistance. Computed tomography (CT) scans may be helpful, especially in the evaluation of retroperitoneal structures and the upper abdomen. Magnetic resonance imaging (MRI) is expensive and thus far unproven in the evaluation of the adnexa. Barium enema is useful in cases where gastrointestinal symptoms suggestive of a colonic neoplasia are present. Abdominal plain films are beneficial for demonstrating small bowel obstruction in symptomatic patients. In cases of undiagnosed abdominopelvic masses, radiographic studies cannot replace surgical exploration for definitive diagnosis and treatment. Standard laboratory studies include complete blood count, electrolyte screen, and BUN–creatinine. Liver function analysis and coagulation panels are not usually informative in the absence of symptoms. The tumor marker CA 125 may be useful in the diagnosis and therapy of ovarian cancer.32 If serum CA 125 is elevated in postmenopausal women with a pelvic mass, cancer should be strongly suspected. However, there are many other causes of elevated CA 125, and this test should not be considered a definitive verification of the presence or absence of cancer. CA 125 is most helpful for monitoring disease status (tumor burden) during therapy.42 Paracentesis for analysis of ascitic fluid for diagnosis should be avoided. Risks of this procedure are (1) rupture of a cyst, which could release cancer cells or viscous mucoid material; (2) seeding of the needle tract with tumor; and (3)
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false reassurance may be acquired if cytology studies prove to be falsely negative. However, if the patient is experiencing intolerable symptoms, such as dyspnea due to ascites, a therapeutic paracentesis may be indicated. Spread of ovarian cancer occurs by capsular invasion, peritoneal seeding and lymphatic infiltration.40 Peritoneal spread is the most common pattern and includes most peritoneal surfaces with frequent involvement of the omentum and diaphragm. Carcinoma of the uterus and cervix usually disseminate through pelvic lymphatics, whereas ovarian cancer drains to the para-aortic nodal tissue. Distant spread to intrathoracic regions or liver parenchyma may occur when malignant cells are transported via hematogenous routes. Extraovarian spread worsens prognosis. Another prognostic factor is tumor grade, which is usually more important than histologic subtype when forecasting outcome for women with early-stage ovarian epithelial cancers. Staging of ovarian cancer employs a surgicopathologic system and is outlined in Table 37.2. Surgical staging is best accomplished by a gynecologic oncologist.43 Patients usually undergo preoperative antibiotic and mechanical bowel preparation. Exploratory laparotomy, comprehensive abdominal exploration, hysterectomy, bilateral adnexectomy, omentectomy, and tumor debulking are performed. Peritoneal washings or ascites fluid is obtained for cytology. Random peritoneal or lymph node biopsies are performed in apparent early-stage cases to uncover occult microscopic tumor foci and document their locations. Pelvic and para-aortic lymph node dissections are completed to document extent of tumor spread or to “debulk” the cancer. Bowel surgery is performed in appropriate cases to relieve obstruction or to reduce tumor volume.44 Surgical cytoreduction is performed to remove macroscopic tumor deposits because prognosis is directly related to the volume of residual disease before the initiation of adjuvant therapy. Bristow
Table 37.2. FIGO staging of ovarian cancer. Designation Stage I IA IB IC Stage II IIA IIB IIC Stage III IIIA IIIB IIIC Stage IV
Definition Cancer limited to the ovaries Growth limited to one ovary, capsule intact, no malignant ascites, no tumor on external surface Growth limited to both ovaries, capsule intact, no malignant ascites, no tumor on external surface As for IA or IB but with surface growth, ruptured capsule (before or during surgery), positive washings, or malignant ascites Growth involving one or both ovaries with pelvic extension Extension and/or metastases to the uterus and/or tubes Extension to other pelvic organs As for IIA or IIB but with surface growth, ruptured capsule (before or during surgery), positive washings, or malignant ascites Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; liver capsule involvement Tumor grossly limited to the true pelvis with negative nodes but microscopic seeding of abdominal peritoneal surfaces Abdominal peritoneal implants, but none exceeding 2 cm; nodes negative Abdominal peritoneal implants larger than 2 cm and/or positive retroperitoneal or inguinal nodes Tumor involving one or both ovaries with distant metastases; pleural effusions must be demonstrated to harbor malignant cells; liver parenchymal involvement
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et al. demonstrated that even patients with stage IV disease benefited from aggressive cytoreduction. Median survival was 50 months for patients in whom both extraand intrahepatic optimal cytoreduction had been accomplished versus only 7 months for patients who were suboptimally debulked.45 The full extent of tumor spread and amount of residual disease is documented so that appropriate therapeutic decisions can be made. Clearly surgical judgement is necessary to achieve optimal surgical and medical outcome, especially in elderly women who may have underlying medical problems. Patients with stage IA grade 1 epithelial ovarian cancer have such an excellent prognosis that postoperative adjuvant therapy is unnecessary. For those with more advanced cancers, postoperative treatment usually consists of six courses of platinum-based multiagent chemotherapy, usually cisplatin or carboplatin combined with paclitaxel. Paclitaxel and platinum-based therapy has been demonstrated in prospective randomized clinical trials to improve progression-free survival and overall survival for patients with advanced suboptimally debulked ovarian cancer.46 Carboplatin is just as efficacious as cisplatin and is associated with an improved adverse effect profile.47 Intraperitoneal chemotherapy is also under investigation, and currently clinical trials are evaluating intravenous versus intraperitoneal cisplatin and paclitaxel for patients with optimally debulked stage III ovarian cancer. Novel therapeutic agents (such as antiangiogenic agents and gene therapies) are currently being evaluated in the treatment of ovarian cancer in clinical trials. Herceptin, anti-Her2neu antibody, is available to patients with recurrent or refractory ovarian cancer who overexpress Her2neu. Chemotherapeutic treatment spawns many side effects; elderly women particularly have an elevated risk of complications with some regimens.48 Cisplatin causes nausea, irreversible renal damage, and peripheral neuropathy (which is the dose-limiting toxicity). Administration of cisplatin requires extensive hydration and antiemetic therapy but can be safely used in the elderly.49 Carboplatin differs from its congener, cisplatin, in that it is much less emetogenic, nephrotoxic, and neurotoxic. Debilitated patients tolerate carboplatin therapy better than cisplatin treatment, owing to different toxicity profiles of these agents.50 Carboplatin is better tolerated by the elderly because it does not cause renal injury or nausea. Furthermore, because aggressive hydration is not required, carboplatin administration is less likely to exacerbate congestive heart failure or cause other side effects related to volume overload. The predominant side effects of paclitaxel are neutropenia and alopecia. Age alone is an insufficient criterion to alter the dose of either carboplatin or paclitaxel.51 Radiation therapy (RT) has a limited role in treatment of ovarian cancer. Intraperitoneal 32P has sometimes been
A.A. Alvarez and D.L. Clarke-Pearson
used to treat stage IC disease or for patients with persistent microscopic tumor deposits after chemotherapy. However, there are conflicting data regarding the efficacy of 32P therapy, and one study has even demonstrated that cisplatin significantly prevented relapse in stage IC patients compared to 32P therapy.52 External beam radiation therapy is sometimes useful for local control of sizable tumor foci, or residual disease, or for treatment of extremely poor surgical candidates. Treatment of the entire peritoneal cavity with teletherapy with curative intent is impractical in most cases. However, lower-dose whole abdominal radiation may be employed in selected cases to control small-volume disease.53 Survival of patients treated for ovarian cancer varies according to the stage of their disease. Five-year survival for women with epithelial ovarian cancer has improved and is as follows: stage I, 93%; stage II, 70%, stage III, 37%; stage IV, 25%.54 Survival in ovarian cancer patients is influenced by age.31 Multivariate analysis has revealed age to be an independent predictor of outcome. Overall, 5-year survival for elderly women over the age of 75 is only 20%, compared to 70% for women under 45 years of age.35 This trend toward decreasing survival with advancing age holds true for patients with the same stage of ovarian cancer, even when adjustments for life expectancy are included.55 Older women are more likely to be diagnosed with advanced-stage disease.35 Older women are also less likely to undergo complete surgical staging, extensive debulking, or receive multimodality therapy because of overriding comorbities.35,55 Bulky residual disease often remains after surgery due to the patient’s otherwise poor health or because of limited experience of the surgeon in managing ovarian cancer patients.56 More than 40% of women 85 years or older, according to a review of hospital records, did not receive any definitive therapy.55 Older women with ovarian cancer, in general, are treated less aggressively than their younger counterparts.55 Optimal therapy should not be withheld in elderly patients unless there are overriding medical contraindications. Analysis of outcomes for patients involved with six randomized Gynecologic Oncology Group (GOG) trials revealed that those over age 69 had poorer survival rates than younger women, even after correcting for stage, residual disease, and performance status.57 A retrospective case-control investigation has confirmed this finding.58 Other studies have shown that more conservative surgery and less aggressive adjuvant therapy are contributing factors that may lead to decreased survival in elderly patients with epithelial ovarian cancer,55 which was demonstrated to be due, in part, to these women receiving their care from obstetrician-gynecologists, general surgeons, and other nononcologists who persuaded them not to seek aggressive treatments. This bias against elderly women has been shown in another report
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documenting decreased specialist referral and use of physician influence to dissuade these cancer victims from obtaining optimum therapy.59 Thus, although advanced age presages a poorer prognosis, in appropriate candidates maximal surgical debulking and aggressive chemotherapy may partially mollify the effect of age. Follow-up involves serial physical and pelvic examinations, CA 125 levels, and sometimes CT imaging. Today, “second-look” surgery is infrequently performed after initial chemotherapy to determine the status of the tumor, that is, whether microscopic or grossly evident foci exist.60 Although somewhat controversial,61 and with no evidence that this surgery improves overall survival, this procedure is generally limited to those participating in research protocols to assess the effectiveness of new treatment modalities. About 55% of patients who are clinically free of disease will have a positive (i.e., persistent tumor) second-look operation. Debate regarding second-look operation exists because of its fallibility in predicting survival. There is a 25% to 45% recurrence rate after a negative second-look procedure, and some argue that the information gained does not justify the expense and morbidity of the surgery.62 Recurrence risk is increased with advanced-stage disease, high tumor grade, and large tumor volume.31 A number of strategies may be employed to control tumor recurrences, although most are aimed at palliation rather than “cure.” Treatment with secondary surgical debulking, multiagent chemotherapy, radiation therapy, biologic response modifiers, or chemotherapy with monoclonal antibody-directed agents, intraperitoneal instillation, or systemic administration with experimental compounds have all been utilized. Therapy must be individualized based upon the site(s) of recurrence, the biology of the tumor, the patient’s performance status, her medical comorbidities, and her wishes regarding how aggressively she wants the cancer treated.63 Refractory cancer carries with it a very poor prognosis.64 Death usually occurs within 18 to 36 months as the cancer propagates and sprawls out on the splanchnic bed, causing bowel obstruction, nausea, and vomiting. Sepsis often follows bowel or ureteral obstruction. Severe electrolyte abnormalities may result from nutritional deficiencies, renal dysfunction following cisplatin treatment, and accumulation of massive peritoneal or pleural effusions. Decisions regarding management of persistent, progressive disease must be made with care and with the participation of the patient and her family.44 Relevant issues include support with total parenteral nutrition (which often can be administered at home by the patient or a family member), medical or surgical relief of bowel obstruction, intravenous hydration or antibiotics, hospice care, and pain management. It is imperative that maintaining quality of life and assuagement of pain be goals of therapy.
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Epithelial ovarian cancer is not generally considered an estrogen-dependent neoplasia and, therefore, hormonal replacement therapy is not contraindicated. In fact, estrogen may augment the patient’s quality of life and be an important part of her treatment.
Cervical Cancer Cervical cancer accounts for about 20% of all gynecologic cancers. This cancer is largely preventable through screening and treatment of premalignant lesions. However, there were about 12,800 new cases and 4,200 deaths related to cervical cancer in 1999.1 More than 50,000 new cases of cervical carcinoma in situ are diagnosed each year. The incidence is 8 to 10 cases per 100,000 women per year. Average age of onset is 45 to 55, but there is a wide variation in the ages of those afflicted. Several epidemiologic risk factors have been identified.2,65–71 Advanced age increases risk twofold. Black, Hispanic, and Native American women have a two- to threefold elevation in risk. A risk about three times that of the general female population is found in women of low socioeconomic status, multiparas, those engaging in sexual activity at a young age or with multiple partners, and chronic smokers. Women with a history of sexually transmitted disease (especially herpes or genital warts) are 2 to 10 times more likely to develop cervical cancer. Lack of regular Pap screening increases risk two- to sixfold. Immunosuppressed patients have a higher risk of cervical carcinoma. Dietary deficiency of ascorbic acid and carotene has been reported to augment the development of cervical neoplasia, although this is less well documented than the other risk factors. Screening is vital for diagnosis and treatment of cervical cancer in its earliest phases.72,73 A more detailed discussion of cancer screening may be found in Chapter 32. Pathogenesis of cervical cancer has received immense scrutiny in recent years. Molecular analysis has demonstrated that the etiology of cervical cancer in older women is similar to younger women.74 Human papillomavirus is regarded as the vector that confers susceptibility to neoplastic conversion or that directly incites transmutation to a malignant phenotype in some infected epithelial cells.70,75 Neoplastic tranformation usually originates at the squamocolumnar junction of the cervix. Varying degrees of cervical intraepithelial neoplasia (CIN) exist; these are graded from 1 to 3 on the basis of increasing severity of the lesion. Carcinoma in situ designates the condition in which all epithelial layers consist of neoplastic cells that are abutting the basement membrane, poised for invasion through this delimitation. It usually takes 10 to 20 years for intraepithelial neoplasia to progress to invasive disease. Most tumors (80%–90%) exhibit squamous histology; adenocarcinoma is the
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other predominant category. Other morphologies are rare. Women with early invasive cervix cancer may have a cervix that appears normal to the naked eye, or they may have a small, ulcerated lesion that may seem to represent a benign inflammatory process. In such cases, cervical smears may be particularly effective in detecting preinvasive or early-stage disease. Most of these women are asymptomatic. On the other hand, patients with advanced cancer often experience symptoms. The most common abnormality is irregular vaginal bleeding. Postcoital spotting has long been considered a warning sign, but metrorrhagia or menorrhagia may occur as well. Some patients have a serosanguinous or yellow vaginal discharge that frequently is malodorous. Another symptom attributable to advanced cervical cancer is pain in the lower abdomen, pelvis, or back. Hematuria or rectal bleeding may occur if bladder or rectal invasion exists. Invasive cancers display two primary modes of extension: local spread and metastasis via lymphatic and hematogenous routes. Cervical cancer may exhibit an ulcerative or exophytic appearance. Local expansion usually involves extension to the endocervix or vaginal fornices, followed by progressive infiltration of parametrial tissues, uterine corpus, bladder, or rectum. Lymphatic dissemination typically occurs in a stepwise progression. Pelvic nodes become involved before common iliac and para-aortic lymph node chains. Hematogenous spread may give rise to distant implants of cancer in lungs, bones, liver parenchyma, or other tissue. In general, the likelihood of metastasis rises with increasing size and expanse of tumor.76 Spread to the pelvic nodes is present in 15%, 30%, or 47%, respectively, for tumors confined to the cervix, in the parametrium, or involving the pelvic side-
wall. The corresponding para-aortic nodal involvement for these situations is 6%, 16%, or 29%. Cervical cancer is evaluated using a clinical staging system that is shown in Table 37.3. A pelvic examination should include a through evaluation of the cervix, vagina, parametria, and pelvic sidewalls. Extrapelvic regions that should receive extra attention include the abdomen, chest, and supraclavicular lymph nodes. Chest x-ray and intravenous urography are allowable radiographic techniques (under the clinical staging guidelines) for documenting the extent of tumor spread. Cystoscopy and proctoscopy are also permitted. General or conduction anesthesia is often employed to facilitate pelvic examination, procurement of biopsies, and cystoscopic and proctoscopic evaluations. Other studies that are sometimes helpful for diagnosis and treatment planning include lymphangiography, computed tomography (CT) scan, CTdirected lymph node aspiration, magnetic resonance imaging (MRI), positive emission tomograghy (PET) scan, blood count, serum chemistry profile, and urinalysis. Treatment for cervical carcinoma may include surgery, radiotherapy and chemotherapy.77,78 The most commonly utilized modality is radiotherapy, which ideally employs one or both of two techniques. (1) Teletherapy, or external beam application, is directed to cervical, parametrial, and pelvic nodal regions (Fig. 37.4A). The field may be extended superiorly if there is suspected or documented involvement of the common iliac or para-aortic nodes.79 (2) Brachytherapy, or intracavitary treatment, is commonly done with intrauterine placement of cesium over a time period calculated to deliver a standard dose (Fig. 37.4B). The advantage of this technique is that extremely high doses of radiation can be applied to the tumor with less penetration of surrounding normal tissue. Recently, the utility of radiotherapy with concurrent cisplatin-
Table 37.3. FIGO staging of cervical cancer. Designation Stage 0 Stage I IA IA1 IA2 IB IB1 IB2 Stage II IIA IIB Stage III IIIA IIIB Stage IV IVA IVB
Definition Carcinoma in situ Cancer confined to the cervix (corpus extension is disregarded) Preclinical cancer, i.e., diagnosed by microscopy only Measured depth of stromal invasion no greater than 3.0 mm Microscopically measurable lesion with depth of invasion 12,000 mL (3) Increased leukocyte alkaline phosphatase score in absence of fever or infection (4) Serum vitamin B12 level greater than 900 pg/mL or vitamin B12-binding capacity greater than 2200 pg/mL a Diagnosis of polycythemia vera if A1 + A2 + A3 or A1 + A2 + any two factors from category B.
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patients on a diuretic or patients known to have spurious erythrocytosis. Once the red cell mass is confirmed to be elevated, other primary causes must be evaluated. Hypoxia either from lung disease or as a result of an abnormal hemoglobin variant, as well as erythropoietin-producing renal tumors, needs to be evaluated. The leukocyte alkaline phosphatase score is frequently elevated as opposed to the situation in CML. Treatment for the patient with PV needs to be individualized. Phlebotomy can reduce the hematocrit quickly. However, in elderly patients, one has to be careful to avoid inducing significant hemodynamic changes that could further compromise the circulation. Very few patients are managed with phlebotomy alone. The PV study group evaluated three common treatments: phlebotomy, 32P, and chlorambucil. None of these treatments was without shortcomings.12 Patients who were managed with phlebotomy alone had a significantly increased risk of thrombotic complications, which appears to be independent of the level of hematocrit or platelet count. Patients treated with 32P or chlorambucil had a markedly increased risk of developing acute leukemia. Hydroxyurea has emerged as a primary option for many patients. It is well tolerated, and, although not devoid of mutagenic risks, it appears to have significantly less risk than alkylating therapy for the development of acute leukemia. The goal of therapy should be to maintain the hematocrit in the range of 42% to 45%. There is a direct relationship between the level of hematocrit and the risk of vascular occlusive episodes. Other goals of therapy include control of the frequently associated pruritis with histamine antagonists. Elective surgical procedures should be delayed until counts have been controlled for at least 2 months to reduce the risk of hemorrhage or thrombosis. Aspirin and other antiplatelet agents have not been proven to reduce the risk of thrombotic events and may, in fact, increase the risk of hemorrhage and are not routinely recommended. The prognosis for patients with controlled PV is excellent as compared with the other hematologic malignancies. Long-term survival is common. Future directions for patients with polycythemia vera include the use of interferon-alpha. In early studies, it appears to be active in reducing the red cell mass and platelet counts.13 Although side effects of interferon continue to limit its use in older patients, it can be useful in patients with extreme thrombocytosis.
Essential Thrombocythemia Essential thrombocythemia (ET) is a myeloproliferative disorder defined as a persistent isolated platelet count above 600,000/mL. It is frequently accompanied by a
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marked increase in megakaryocytes in the bone marrow, and on physical examination splenomegaly is common. Patients frequently develop complications with both thrombosis and hemorrhage. The exact incidence of ET is unknown, although it is not a rare disorder. There is no known etiology. The major clinical manifestations are related to the elevated platelet count, resulting in either hemorrhagic or thrombotic episodes. Elderly patients can be particularly prone to these additional thrombohemorrhagic complications because of other comorbid conditions. The platelets in patients with ET are qualitatively abnormal, and this may explain why the frequency of thrombohemorrhagic complications is not directly related to the absolute number of circulating platelets. The diagnosis is made on the basis of a sustained and unexplianed increase in the platelet count. It is important to distinguish primary thrombocythemia from reactive thrombocytosis, as well as to consider the possibility of another myeloproliferative disorder associated with an elevated platelet count. Some of the important causes of secondary thrombocytosis that should be considered in a differential diagnosis include iron deficiency anemia, occult carcinoma, chronic inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease, and acute or chronic infections. Treatment for patients who have reactive thrombocytosis should be directed at the underlying etiology regardless of the platelet count because these patients rarely develop thrombohemorrhagic complications despite markedly elevated platelet counts.
Treatment The treatment of ET is usually with hydroxyurea, and the goal is to control the platelet count to around 500,000/mL. The important point is that many patients can be observed without therapy until the platelet count approaches 1 million. Older patients may need to be treated somewhat earlier because of their otherwise increased risk for thrombohemorrhagic complications. Previous studies using busulfan and 32P have demonstrated increased toxicities, and these therapies are no longer standard for ET. The prognosis is similar to that of PV, with prolonged survival possible. Hemorrhage or thrombotic complications frequently contribute to morbidity and mortality. Some patients will evolve to myelofibrosis or acute leukemia.
Future Directions The new antiplatelet agent anagrelide can inhibit platelet aggregation and platelet production. Interferon-alpha has some activity in this disorder. Combinations of these agents, with or without hydroxyurea, may represent an improvement in the management of patients with ET.
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Carefully controlled trials are needed to assess these issues.
Myeloid Metaplasia with Myelofibrosis (MMMF) MMMF is an unusual clonal disorder sometimes also known as idiopathic myelofibrosis. Gradual fibrosis of the marrow space with extramedullary hematopoiesis is the typical course. Splenomegaly is common. An examination of the peripheral blood film shows the presence of nucleated red blood cells and teardrop forms that are the characteristic leukoerythroblastic findings. The incidence of MMMF is unknown, but it tends to be a disease of the elderly, with an average age of approximately 60 years. The malignant transformation appears to occur at the level of the stem cells, with a dense collagen fibrosis developing in the marrow space. There is no known etiology. The clinical manifestations relate to either the presence of splenomegaly or the consequences of anemia or other cytopenia. Rarely, sites of extramedullary hematopoiesis appearing in the pulmonary, gastrointestinal, central nervous, or genitourinary systems have been the presenting finding for occult MMMF. As noted, the peripheral blood smear typically shows teardrop poikilocytes, confirming the leukoerythroblastic blood picture. Nucleated red blood cells and immature myeloid elements are also frequently seen. There are variable effects on circulating white cells and platelets. The diagnosis is made on the basis of the characteristic clinical findings and the presence of fibrotic marrow, which can be more accurately assessed histologically with the aid of a reticulin stain. Many conditions can lead to secondary fibrosis of the marrow, including lymphoma, carcinoma, and chronic diseases such as TB and histoplasmosis, as well as some of the other myeloproliferative syndromes as previously mentioned, and these need to be ruled out before a primary diagnosis is made. Therapy for MMMF is unsatisfactory. In general, a conservative management strategy is adopted, although some authors have suggested that chemotherapy early in the course of disease can be beneficial. Symptomatic patients generally require symptom-directed therapy. Thus, anemia is treated with transfusion, as well as complete evaluation for other coexistent disorders such as nutrient deficiencies. Androgen stimulation is also frequently used. Symptoms of splenomegaly, such as early satiety, are treated with measures to induce reduction in splenic size. Chemotherapy with hydroxyurea, 32P, and other agents has been used with some, at least short-term, success. Interferon has been used successfully to shrink splenomegaly but has frequently resulted in worsened cytopenias. Splenic radiation has also been used, but
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usually a short duration of response is seen. Splenectomy is a controversial issue.14 It is indicated for patients with severe thrombocytopenia, uncontrolled hemolysis, or painful splenomegaly that is refractory to other methods of control. However, there is a significant perioperative mortality rate. The prognosis for MMMF is worse than that for essential thrombocythemia and polycythemia vera. Average survival is approximately 5 years.
Lymphoproliferative Disorders Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. This prevalence is due to two factors. First, the incidence of CLL rises with advancing age with the median age in the sixties. As noted previously, the population over the age of 60 continues to grow. Second, patients with CLL can experience a long survival, with median survival approaching 6 years. Thus, the prevalence of the disease is quite high. CLL is generally a neoplasm of activated B lymphocytes. The leukemic cell morphologically resembles mature small lymphocytes normally seen in the peripheral blood. A sustained blood lymphocyte count that is greater than 10 ¥ 103/mL has been required to diagnose CLL. Additionally, 30% of nucleated cells in the bone marrow should be lymphocytes, and the peripheral blood lymphocytes should be positive for B-cell markers. In some clinical situations, CLL can be diagnosed with fewer total lymphocytes if surface markers confirms a monoclonal population of typical lymphocytes. The exact cell of origin in CLL is unknown. Although 95% of patients have a B-cell phenotype, T-cell CLL can rarely occur. The typical B-cell CLL does stain positive with antibody to CD5, which is normally a T-cell antigen, and this has been taken to imply that the malignant cell is arrested at an intermediate stage of B-cell differentiation. Other diseases, such as hairy cell leukemia, to be considered later, are thought to result from the malignant transformation of a lymphocyte at a different stage of development. The etiology of CLL is also unknown. Retroviruses and ionizing radiation, which lead to other forms of leukemia, apparently do not increase the risk for CLL. Interestingly, the incidence of CLL is far less in Japan than in Western populations. In addition, there is an increased risk of a variety of autoimmune disorders in relatives of patients with CLL, implying a genetic predisposition to the development of lymphocytic disorders.15 The lymphocytes in CLL usually express a specific surface immunoglobulin, although at low intensity. Normal control of antibody production in patients with
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Table 38.2. Staging systems for chronic lymphocytic leukemia (CLL).
Lymphocytosis Lymphadenopathy Hepatomegaly/splenomegaly Anemia Thrombocytopenia a
Rai
Binet
Expected median survival (years)
O I II III IV
A BIa BII C C
8–10 5–6 5–6 2.5 2.5
Three or more groups of lymph nodes must be positive.
CLL is disrupted. There is a marked reduction in normal antibody production manifested as a diffuse hypogammaglobulinemia, resulting in a high incidence of infections. On the other hand, there is a paradoxical increase in autoimmune complications, including hemolytic anemias. This dysregulation is an exaggeration of the phenomena seen in normal aging. The diagnosis and staging of CLL has produced two excellent classification systems, one by Binet and one by Rai. Recently, these two staging systems have been combined and are represented in Table 38.2, along with the expected median survivals. There are a few points worth making regarding the stage of CLL at the time of diagnosis. Approximately 25% of patients present with only a lymphocytosis in the peripheral blood and the marrow but no evidence of lymphadenopathy, organomegaly, or other cytopenias. These patients have an exceedingly good prognosis and in general should not undergo any therapy unless their disease progresses. The development of multiple enlarged lymph nodes, hepatomegaly, or splenomegaly mark progression to stage B disease. The development of either anemia or thrombocytopenia on the basis of marrow compromise portends a significantly worse prognosis. The treatment of CLL has, in general, been aimed at controlling the disease rather than curing it. Therapy is withheld until significant cytopenias or symptomatic lymphadenopathy or organomegaly develops. In general, treatment is initiated with an alkylating agent. Most frequently chlorambucil is used, in either low daily doses or pulses from 2 to 4 weeks. Fludarabine is an active agent for the treatment of CLL. It produces a higher rate of complete remissions and a longer duration of response than chlorambucil.16 This agent has response rates of 50% to 80% in both previously untreated as well as treated patients. Overall survival is not improved, and because fludarabine is associated with increased toxicity, especially for older patients with renal impairment, many clinicians use it only after failure of chlorambucil. Other alkylating agents such as cyclophosphamide are also effective. Prednisone is usually given with the alkylating
agent and sometimes alone for patients with manifestations of autoimmune phenomena. Unfortunately, the course of CLL is progressive despite initiation of therapy. Several attempts have been made to predict the course of patients with CLL more accurately than the current staging system. At least two criteria appear to suggest rapid progression of disease. The rate of increase of blood lymphocytes has long been recognized to be a useful indicator of prognosis. Most authors recommend a period of observation before initiating cytotoxic therapy in an effort to evaluate the pace of the disease. A doubling of lymphocytes in the peripheral blood in less than 1 year is associated with a worse prognosis. Investigators have also reported that the pattern of bone marrow infiltration with lymphocytes is prognostic. Patients with a diffuse lymphocytic infiltration have more rapid progression of their disease than patients with nodular involvement of the bone marrow.
Future Direction Recently, there has been renewed interest in immunotherapy of CLL. Recombinant monoclonal antibodies have demonstrated activity against this disease. Campath 1-H is approved for patients with CLL who have failed fludarabine. This modified antibody recognizes the CD-52 antigen on the surface of CLL lymphocytes and can initiate antibody-dependent cell-mediated cytotoxicity (ADCC), as well as activate the complement cascade causing death of CLL cells.17 There is a considerable infusion-related reaction with the drug, and patients can be immunosupressed because of the resultant lymphopenia resulting in reactivation of latent CMV. Nonetheless, this new avenue of attack may prove quite beneficial to elderly patients. Supportive therapy is very important for patients with CLL because of the many associated clinical phenomena. Autoimmune phenomena, such as anemia or thrombocytopenia, can be treated with a steroid alone without cytotoxic therapy. Pure red cell aplasia, which occasionally occurs, may respond to either cyclosporin or antithymocyte globulin (ATG). Recurrent infections with encapsulated organisms frequently result from the hypogammaglobulinemia that occurs in these patients. The mainstay of therapy is prompt initiation of appropriate antibiotics. However, intermittent intravenous gamma globulin can be effective in reducing the frequency of infections, especially in those patients with very low levels of serum immunoglobulin G (IgG).18
Hairy Cell Leukemia Hairy cell leukemia is another chronic lymphoproliferative disorder that is now known to be a clinical entity distinct from CLL. Similar to CLL, it is a proliferation of
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neoplastic B lymphocytes. Hairy cell leukemia cells also expresses the receptor for interleukin 2 known as CD-25; this suggests that the arrest in differentiation for these lymphocytes occurs later than that for CLL but earlier than that of the lymphocytes in myeloma. Most patients with hairy cell leukemia present with pancytopenia. Circulating hairy cells are seen in approximately 90% of the cases. The typical hairy cell is a large lymphocyte with an eccentric nucleus, and the cytoplasm typically has fine irregular projections. The tartaric acidresistant acid phosphatase (TRAP) stain, although not specific, is usually positive because of increased levels of an isoenzyme in these cells. The majority of patients present with complications of cytopenia, and 80% will have splenomegaly.
Treatment Therapy for hairy cell leukemia has undergone a rapid change over the last few years. In fact, the hematologist is now confronted with choosing from more than one highly effective therapy. Historically, initial therapy was splenectomy. This intervention usually improved the cytopenias but only provided transient benefits. Subsequently, interferon-alpha demonstrated significant activity with a response rate of close to 80%.19 Some patients (about 10%) achieved complete responses. Once interferon was stopped, relapses were common, but frequently patients would respond to another course of treatment with interferon. Most recently, deoxycoformycin and chlorodeoxyadenosine (2-CDA) have demonstrated remarkable activity.20 Deoxycoformycin appears to be active even in those patients who fail interferon, whereas 2-CDA has an extremely high complete response rate and, in fact, may be curative after a single course of therapy. With such impressive therapy, the indications for initiation of therapy have been reevaluated. In general, up to 20% of patients with hairy cell leukemia have a very indolent form of the disease and may never require therapy. It is important to spare these patients the potential morbidity of treatment. The indications to consider therapy include significant cytopenias, repeated infections, massive or painful splenomegaly or lymphadenopathy, or vasculitis. Close observation for those patients without these indications is warranted.
Plasma Cell Dyscrasias The lymphoproliferative disorders are malignant transformations of lymphocytes. The clinical syndromes corresponding to each diagnostic category result from the characteristic behavior of the transformed cell. The end stage of B-lymphocyte development is the plasma cell producing large amounts of immunoglobulin. The malig-
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nant transformation of cells with this degree of differentiation represents a group of diseases termed the plasma cell dyscrasias or plasma cell proliferative disorders. A spectrum of clinical conditions exists from monoclonal gammopathy of uncertain significance to multiple myeloma, Waldenstrom’s macroglobulinemia, and amyloidosis. However, it is the production of immunoglobulin by a plasma cell that ties these diseases together. Normal B-cell development involves production of one of the five classes of immunoglobulins. The earliest event in B-cell development involves rearrangement of the germline immunoglobulin genes to produce a unique immunoglobulin. Ultimately, a specific immunoglobulin of the IgM class is made. Subsequently, the cell is able to alter the class of immunoglobulin (IgG, -A, -D, -E) while retaining the unique antigenic recognition sites. Each clone of cells produces only one immunoglobulin with one heavy chain (G, A, M, E, D) and one light chain (kappa, lambda). Protein electrophoresis and immunoelectrophoresis can detect the production and secretion of these immunoglobulins or their components (a light chain or heavy chain). The abnormal accumulation of monoclonal immunoglobulin in the serum is frequently called an M spike and is usually one of the early clues to the diagnosis of plasma cell dyscrasias.
Monoclonal Gammopathy of Uncertain Significance Monoclonal gammopathy of uncertain significance (MGUS) is a relatively common condition that increases in older patients. The definition of monoclonal gammopathy of uncertain significance is somewhat problematic. In essence, it represents the presence of an M spike without an underlying diagnosis of multiple myeloma, Waldenstrom’s macroglobulinemia, or amyloidosis. Formerly known as benign monoclonal gammopathy, it is no longer called this because a significant proportion of patients ultimately will develop one of the aforementioned diseases. In this way, it can be considered one step in the multistep pathway to oncogenesis. MGUS is defined as having an M spike of IgG less than 3.5 g/dL or IgA less than 2 g/dL or the presence of a small amount of urinary light chain in the urine in 24 h. The plasma cells in the marrow cannot exceed 10%, and there can be no lytic bone lesion or other symptoms related to a lymphoproliferative disorder. Finally, a stable level of monoclonal protein characterizes MGUS. MGUS is common and, like myeloma, shows an increasing incidence with advancing age. As many as 10% to 14% of those over the age of 70 may have a detectable M spike.21 The course of monoclonal gammopathy has been well characterized by the Mayo Clinic Group. They followed 241 patients for a median of 19 years and found that only
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24% of them had a stable or “benign” monoclonal gammopathy; 22% of them developed myeloma, macroglobulinemia, or amyloidosis, and 51% died of unrelated causes. Only 3% of the patients had a progressive rise of their M protein without the development of an underlying disorder.22 The evaluation of a patient who has been found to have an M spike should be aimed at discovering a potential underlying lymphoproliferative disorder. In a report of more than 800 cases of monoclonal protein seen at a referral center during 1988, 64% were related to MGUS, with myeloma, amyloid, lymphoma, Waldenstrom’s macroglobulinemia, and CLL accounting for the remainder.23 However, it should be remembered that the incidence of MGUS far exceeds the incidence of myeloma in the general population. This referral population is markedly enriched for patients with documented lymphoproliferative disorders. A complete history and physical examination, routine CBC, electrolytes, and renal function with a serum calcium and uric acid should be obtained. Quantitative immunoglobulin, a 24-h urine for electrophoresis, and total skeletal x-rays may be required to evaluate the significance of a monoclonal gammopathy. A bone marrow aspirate and biopsy or a biopsy of a single soft tissue mass or lytic bone lesion may also be required. In the absence of identifying an underlying lymphoproliferative disorder, the patient should be diagnosed with MGUS. Follow-up electrophoresis in 3 to 6 months and then yearly should be adequate for those patients who show no progression in their M spike. Patients who have an M protein in the urine should be followed more closely.
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myeloma can evolve from a monoclonal gammopathy of uncertain significance (MGUS). The cell of origin in multiple myeloma remains unknown. Plasma cells themselves have little proliferative potential. It is likely that clonogenic pre-B cells account for the majority of proliferation in multiple myeloma. Thus, it is at the level of the pre-B cell or earlier that the transformation to malignancy occurs. Karyotypic alteration is frequently seen in myeloma, with 30% to 50% of patients having abnormalities of their chromosomes. Oncogenes and tumor suppressor gene abnormalities, such as ras, myc, bcl-1/PRAD1/cyclin D-1, bcl-2, Rb, and P53, have recently been implicated in the development of myeloma. The low proliferative potential of plasma cells has hampered the elucidation of genetic events in this disease. Clinically, the manifestations of the disease are usually caused by one or a combination of the following factors: (1) proliferation of the malignant clone causing replacement of normal structures; (2) elaboration of cytokines by the malignant plasma cells; and (3) accumulation of the M component in plasma and in tissue. The most common findings include fatigue, anemia, renal failure, hypercalcemia, hypogammaglobulinemia, and infections. Rarely, hyperviscosity or complications of amyloid infiltration of tissues can occur. The diagnosis of multiple myeloma requires a significant M spike (3.5 g/dL of IgG or 2.0 g/dL of IgA), plasmacytosis greater than 30% in the marrow, or plasmacytoma on tissue biopsy. Additionally, the presence of lytic bone lesions or low residual immunoglobulins can provide supportive evidence in the diagnosis of myeloma.
Pathophysiology
Multiple Myeloma Multiple myeloma is a common malignancy with about 12,000 cases each year in the United States and 9000 deaths. The incidence of the disease increases dramatically with advancing age. The incidence is approximately 2 per 100,000 under the age of 50, but 20 to 25 per 1000,000 of those in the seventies. The mean age of diagnosis is in the upper sixties. Given the increase in the geriatric population in the United States, we should continue to see an increasing incidence of multiple myeloma. The etiology of myeloma is unknown, but there are genetic as well as environmental factors. Controversy exists regarding the role of viral factors in the development of myeloma. Specifically, human herpesvirus 8 (HHV-8) has been associated with some patients with myeloma. The disease occurs more frequently in blacks than whites and more frequently in males than in females. Radiation exposure, as well as occupational exposure to asbestos and petroleum products, is associated with increased risk for the development of myeloma. Multiple
We now understand the pathophysiology of many of the characteristic clinical manifestations of multiple myeloma. Skeletal complications occur quite commonly. Because the lesions are typically osteoclastic with minimal osteoclastic activity, bone scans are typically negative. Plain x-ray and magnetic resonance imaging (MRI) of the bone are more sensitive than a bone scan. The excessive bone resorption that occurs has been the subject of much research. The plasma cells in the marrow secrete tumor necrosis factor (TNF) and interleukin 1 (IL-1), among other cytokines. These cytokines contain most of the activity previously referred to as osteoclastactivating factor (OAF). Further, the TNF and IL-1 secreted by the plasma cells stimulate secretion of IL-6 by marrow stromal cells. IL-6 not only adds to the osteoclastic activity but also is one of the major growth factors for the myeloma cell clone. A cascade of bone resorption and myeloma cell growth with continued secretion of cytokines can quickly result in clinical hypercalcemia.
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The hypercalcemia associated with multiple myeloma usually is multifactorial, with increased bone turnover, dehydration commonly found in the elderly, and renal insufficiency all playing a role. Inactivity secondary to debilitation or bone pain also adds to the progression of hypercalcemia. The anemia of multiple myeloma is also a multifactorial process. The major influence, however, remains the proliferation of the myeloma cell clone within the bone marrow. Renal insufficiency, chemotherapy, and shortened red cell survival also play a role. Renal insufficiency in the setting of myeloma is a bad prognostic indicator. Monoclonal light chains (known as Bence–Jones proteinuria) accounts for more than 90% of the renal dysfunction. However, amyloid, infection, Fanconi’s syndrome, and hyperuricemia can be other mechanisms for renal insufficiency. Hypogammaglobulinemia is common and frequently results in recurrent infection by encapsulated organisms. Amyloid may develop in the setting of myeloma, with light chain deposition in susceptible organs. Hyperviscosity typically occurs in the setting of IgM production but can occur with very high levels of IgG or IgA. Transfusion in the setting of subclinical hyperviscosity can precipitate symptomatic hyperviscosity because the increased hematocrit after transfusion can adversely affect the whole blood viscosity.
Staging The Durie and Salmon staging system combines easily obtainable clinical parameters and divides patients into three groups with significantly different expected survival (Table 38.3). More recently, additional prognostic factors have been evaluated. Of these, beta-2-microglobulin and plasma cell labeling index appear to be useful individual parameters. Overall, the median survival is 2 to 3 years with treatment.
Treatment Treatment for myeloma has shown marked improvements over the last several years, but cure remains elusive. In the 1960s, melphalan and prednisone were first used and improved survival from about 7 months to the current level of about 3 years. Multiple regimens combining alkylating agents, nitrosourea, doxorubicin, vincristine, and prednisone, as well as interferon, have been studied over the last 15 years. An overview analysis comparing melphalan/prednisone versus several other combination chemotherapy (CCT) regimens demonstrated there was no improvement in overall survival for those patients who received the CCT regimen.24 Although melphalan/prednisone remains an option, particularly for the majority of patients who are over the
M. Gautier et al. Table 38.3. Durie and Salmon staging system for multiple myeloma. Stage I
II III
Criteria All the following: 1. Hemoglobin >10 g/dL 2. Serum calcium 20/h), % Paroxysmal supraventricular tachycardia, % Ventricular premature complexes (>10/h), % Ventricular couplets, % Ventricular tachycardia, %
34–180 1.8–2 66 13–28 32 8–11 2–4
Source: Modified from Marcus et al. ECG indicates electrocardiographic. Reprinted with permission from American College of Cardiology (J Am Coll Cardiol. 1987;10:67A–72A), with permission.
to identify symptomatic arrhythmias, particularly when diary evidence is available to correlate symptoms with these spontaneously occurring arrhythmias. The test is indicated to identify cardiac rhythm disturbances as etiologic of otherwise unexplained lightheadedness, dizziness, giddiness, falls, frank syncope, or uncomfortable palpitations. The limitation of utility of this study is the high prevalence of both supraventricular and ventricular arrhythmias in the absence of cardiac disease or cardiac symptoms, even arrhythmias as potentially serious as nonsustained ventricular tachycardia23 (Table 39.1). Most asymptomatic arrhythmias in the absence of cardiac disease do not warrant therapy. Importantly, syncope may result from orthostatic hypotension, significant aortic stenosis, carotid sinus hypersensitivity, and ageand disease-related impairments of cerebral blood flow, as well as arrhythmias. Specific arrhythmia identification is needed to guide pharmacologic or pacemaker therapy. The increase in both supraventricular and ventricular ectopic beats with aging is more likely a consequence of aging changes in the aorta and ventricles than of intrinsic abnormalities of the conduction system.
Echocardiogram The echocardiogram is far more accurate than the chest roentgenogram in the assessment of cardiac chamber size because the kyphoscoliotic chest deformity and sternal depression common in elderly persons may cause a factitious increase in heart size on the chest roentgenogram. The echocardiogram is also more accurate for the determination of left ventricular hypertrophy, a powerful marker for coronary risk, than is the electrocardiogram; in addition to identifying left ventricular wall thickness and mass, cardiac chamber size, and valvular abnormalities, wall motion abnormalities and ventricular ejection fraction can be determined, as can pericardial effusion. However, a technically adequate echocardiogram cannot be recorded in some elderly patients because of their chest configuration.
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Doppler echocardiography is reliable for determining the aortic valve area and estimating the pressure gradient in elderly patients with significant aortic stenosis; there is a good correlation of the calculated echocardiographic valve area with cardiac catheterization data.24 Dobutamine stress echocardiography to detect myocardial ischemia has not been systematically assessed in an elderly population.
Exercise Tests and Exercise Radionuclide Studies Exercise testing can be undertaken with comparable safety and efficacy in elderly patients as in younger patients, that is, among elderly patients able to perform an adequate exercise test. Treadmill exercise testing in elderly individuals provided prognostic information incremental to clinical data.25 A normal response to exercise testing has the same favorable prognosis as in a younger population, and an abnormal response to exercise imparts comparable risk as in younger individuals; the high predictive accuracy of an abnormal exercise test at elderly age reflects the high prevalence and severity of coronary heart disease in this population.26 Few data are available regarding exercise testing in patients older than 75 years of age. Careful explanation of the test procedure, a practice session on the bicycle or treadmill before the actual test, meticulous skin preparation and electrode placement, and selection of an appropriately lowintensity exercise protocol increase the likelihood of a satisfactory exercise test. The Naughton protocol or a modification of the standard Bruce protocol is preferable for treadmill exercise testing of elderly patients with limited exercise capability. Arm ergometry can be considered for elderly patients who are unable to perform treadmill or bicycle exercise because of arthritis, claudication, or cerebrovascular or musculoskeletal disorders. The exercise test can help determine if the chest discomfort represents myocardial ischemia, can characterize risk status in the patient with angina pectoris or following myocardial infarction, can guide recommendations for a physical activity regimen, and can assess the suitability for return to work when appropriate. Exercise thallium scintigraphy is helpful when conduction abnormalities or repolarization changes on the resting ECG limit the interpretation of the exercise ECG. The presence and extent of exercise-induced reversible thallium-201 or technetium-99m scintigraphic abnormalities permit effective risk stratification in elderly patients.27,28 Exercise-induced evidence of cardiac dilation and abnormal radioisotope lung uptake indicate a high-risk status. Myocardial perfusion scintigraphy after intravenous administration of dipyridamole (Persantine) is well tolerated by aged patients and may help identify myocardial ischemia in elderly patients who are unable
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to exercise. The sensitivity, specificity, and safety appear comparable in populations older and younger than 70 years of age.29 Ventricular function can be assessed by radionuclide ventriculography; although it is more expensive than echocardiography, it is applicable to elderly patients in whom adequate echocardiographic images cannot be obtained. Contrast-enhanced computed tomography (CT), positron emission tomography (PET) scanning, and magnetic resonance imaging (MRI) require systematic study in elderly populations. Because of the progressive nonuniformity of lung function with aging, perfusion defects may occur in the absence of pulmonary embolism, rendering this test somewhat less reliable in an elderly population. Spiral CT imaging appears valuable to identify pulmonary embolism.
Invasive Diagnostic Tests Transesophageal echocardiography, used to evaluate for aortic dissection, infective endocarditis, and valvular heart disease, among others, appears well tolerated at elderly age. Cardiovascular catheterization and coronary arteriography are also well tolerated in elderly patients. Precise diagnosis may enable more successful medical and surgical therapies. Procedure-related morbidity and mortality, although relatively infrequent, are increased two- to threefold at elderly age.30,31 The number of coronary arteriograms performed annually on patients older than age 65 continues to escalate in the United States; arterial tortuousity increases the difficulty of the procedure.
Manifestations of Cardiovascular Disease Heart Failure Most of the 5 million patients with heart failure in the United States32 are elderly, and heart failure is the most frequent hospital discharge diagnosis for patients older than 65 years of age.33 Seventy-five percent of heart failure hospitalizations occur in individuals older than 65 years and 50% in patients 75 years and older. Heart failure is more common in men than in women until about age 80; an eightfold increase in heart failure among men in the seventh decade of life compared with the fifth decade was noted in the Framingham population.34 In a Medicare cohort, one-third of patients died within 1 year of initial hospitalization for heart failure.35 During the past two decades, heart failure deaths have almost doubled in the over-75 population. Most of the 400,000 new cases of heart failure diagnosed annually in the
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United States are in the geriatric population. With the continuing dramatic increases in the size of the elderly population, comparable dramatic increases in heart failure incidence and prevalence can be anticipated. The prevalence of heart failure increases with increasing age and is estimated to involve 5% of the population aged 65 to 74 years and 10% of those older than 75 years. Heart failure tends to be both underdiagnosed and overdiagnosed in elderly patients. Many elderly patients fail to report progressive easy fatigability, dyspnea, cough, and ankle edema, considering these a consequence of aging. Early manifestations of heart failure may be masked by the sedentary lifestyle of many elderly patients, whereas exertional dyspnea may reflect another common problem, chronic pulmonary disease, rather than cardiac failure. Deconditioning may also cause breathlessness. Pulmonary changes associated with aging may decrease exercise tolerance,even in the absence of heart failure. Basal lung rales and relatively large heart volumes, normal in an older population, may be mistakenly ascribed to heart failure. Owing to activity limitations, profound fatigue rather than exertional dyspnea may be the presenting feature. However, comparable fatigue, as well as exhaustion, confusion, and altered mentation, may result from excessive diuresis. Ankle edema may reflect venous stasis, decreased tissue turgor, or be a consequence of treatment with vasodilator drugs, rather than evidence for heart failure. On occasion, only anorexia,insomnia,nocturnal cough,or frequent nocturnal urination may herald heart failure. Many elderly patients with heart failure may have disordered mental function and behavior consequent to diminished cerebral blood flow. Coronary atherosclerotic heart disease, hypertensive cardiovascular disease, and hemodynamically significant calcific aortic stenosis are the most prevalent causes. Mitral regurgitation is also contributory. Pooled data from hypertension trials in elderly patients showed a 52% reduction in incident heart failure with antihypertensive therapy.36 Because of its high prevalence, occult coronary disease must be considered with otherwise unexplained systolic heart failure.32 Cardiac amyloidosis increases in prevalence with aging; the initial diastolic dysfunction is often accompanied by arrhythmias and conduction disturbances. Heart failure is more frequently precipitated or exacerbated by associated medical problems than in younger patients. These problems include atrial fibrillation and other arrhythmias, acute myocardial infarction, uncontrolled hypertension, intercurrent infections and fever, fluid overload,37 acute blood loss, pulmonary embolism, anemia, occult thyrotoxicosis, renal insufficiency, acute lower urinary tract obstruction in men, and major dietary indiscretions. Drugs causing myocardial depression (b-blocking drugs, calciumblocking drugs, and a number of antiarrhythmic agents) and/or poor compliance with the medical regimen are
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also contributory. Frequent use of nonsteroidal inflammatory agents by elderly patients, often as nonprescription drugs, can precipitate heart failure by a combination of sodium and water retention and the induction of renal dysfunction. Iatrogenic heart disease, often related to inappropriate pharmacotherapy, in hospitalized frail elderly patients portends a poor prognosis.37 Given the limited cardiac reserve and the frequent multifactorial etiology of heart failure in an elderly patient, remediable factors should be carefully identified and corrected. The occurrence of heart failure adversely affects the prognosis of most cardiovascular disorders and is an important contributor to the excessive mortality among elderly patients in the early months after myocardial infarction. Echocardiography has substantially improved the recognition of heart failure in elderly patients and is the most useful noninvasive test to differentiate systolic and diastolic ventricular dysfunction.38 Echocardiography is also useful in defining an otherwise inapparent cause of the heart failure; it can assess the characteristics of the heart valves, the size and function of the cardiac chambers, the presence of pericardial effusion, and focal wall motion abnormalities. Although ventricular systolic dysfunction with cardiac enlargement is a frequent finding in elderly patients with heart failure, diastolic dysfunction is a prominent cause of heart failure in this population; this is the case in more than half of octogenarians with heart failure.39 Among octogenarians, the predominant presentation of heart failure is in women with systolic hypertension and diastolic dysfunction with preserved ventricular systolic function. Clues to diastolic dysfunction as the mechanism for heart failure include a normal or near-normal heart size and a cause for left ventricular hypertrophy such as hypertension or hypertrophic cardiomyopathy. The characteristics of the aging heart and associated diabetes mellitus may impair ventricular diastolic distensibility. Ventricular diastolic dysfunction may be present in as many as half of all elderly patients with clinical manifestations of heart failure and has a more favorable prognosis than systolic dysfunction when correctly treated.40 The earlier descriptions of adverse outcomes of diastolic heart failure may reflect suboptimal or inappropriate therapies.41 About 40% of patients hospitalized with a diagnosis of heart failure have preserved ventricular systolic function, and this percentage increases dramatically at elderly age. The decreased ventricular compliance of aging is an important contributor to age-related exertional dyspnea, even with exercise of low to moderate intensity. Decreased ventricular compliance results in elevated left atrial and pulmonary capillary pressures and may produce pulmonary congestion, pulmonary edema, and other classic manifestations of heart failure. Differentiation from predominant systolic dysfunction is important in that therapies differ markedly. Diuretic and venodilator drugs alone
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may reduce ventricular filling volume and potentiate diastolic dysfunction; in one study, withdrawal of furosemide improved postprandial hypotension in elderly patients with heart failure and intact ventricular systolic function.42 The positive inotropic effect of digitalis may also be deleterious in diastolic dysfunction.Alleviation of heart failure symptoms in patients with ventricular diastolic dysfunction occurs with treatment with calcium channel-blocking drugs, beta-blocking drug, and angiotensin-converting enzyme (ACE) inhibitors.43,44 With verapamil, diltiazem, and beta-blocking drugs,surveillance is needed for adverse effects, including slowing of atrioventricular conduction and serious bradyarrhythmias. Patients with left ventricular systolic decompensation present with cardiac enlargement, tachycardia, gallop sounds, lung rales or pulmonary edema; dependent edema, jugular venous distension, hepatomegaly, and ascites occur when right-sided heart failure supervenes. Weight gain may be evident. The skin, particularly of the extremities, may be cool as a result of peripheral vasoconstriction. Restlessness and agitation are due, in part, to increased sympathetic activity; control of heart failure more effectively limits these symptoms than does sedation. Pulsus alternans and Cheyne–Stokes respiration are evidence for severe cardiac decompensation. As in younger patients, the major components of therapy for ventricular systolic dysfunction include restriction of dietary sodium, activity limitation until compensation is achieved, digitalis, diuretic drugs, vasodilator drugs, beta-blocking drugs, and spironolactone. These agents improve cardiac function by decreasing the cardiac workload, limiting sodium and water retention, and enhancing myocardial contractility. Vasodilator therapy, beta blockade, and spironolactone have improved the outlook for elderly patients with ventricular systolic dysfunction. Vasodilator drugs—ACE inhibitors, angiotensin receptor-blocking drugs, and hydralazine plus nitrates45–48—favorably alter the loading conditions of the heart, improve symptoms of reduced cardiac output, improve functional status, retard the spontaneous worsening of heart failure, and improve survival. Some controlled clinical trials documenting the benefits of vasodilator therapy have included elderly patients.45,49,50 In the Veterans Administration Cooperative Study of hydralazine and nitrates that randomized patients as old as 75 years,51 comparable benefit occurred in patients older and younger than 60 years. ACE inhibitor benefit has also been demonstrated at very old age.52 ACE inhibitors are superior to hydralazine plus nitrates,47 which can be used for patients intolerant to ACE inhibitors. Although a pilot study53 suggested superior survival benefit with angiotensin II receptor blockade with losartan compared with ACE inhibition with captopril at elderly age, this was not subsequently substantiated.54 Comparable benefit of ACE inhibitor
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therapy in improving exercise tolerance and left ventricular ejection fraction occurred in patients older and younger than 65 years. As in younger patients, ventricular ejection fraction correlates poorly with symptoms and with exercise tolerance in the elderly. Although experience with beta-blocking drugs in elderly patients is less extensive than at younger age, with trials excluding patients over age 75 to 80 years, both carvedilol and metoprolol given to patients with class II and III heart failure improved ventricular systolic function, exercise tolerance, and survival.55–57 Spironolactone in patients up to age 80 with severe heart failure improved symptoms and prognosis.58 These data suggest that newer therapies for heart failure should be applied to elderly patients, with careful attention to dose titration. However, these pharmacologic agents are currently underutilized in elderly patients hospitalized for heart failure.59 Digitalis improves myocardial contractility and remains an important component of management of ventricular systolic dysfunction, even when sinus rhythm is present;60 digitalis may limit the ventricular response to supraventricular tachyarrhythmias. In the DIG Trial,61 although survival was not altered, the combined endpoint of heart failure death or hospitalization was reduced in patients treated with digitalis. Lower doses are appropriate for elderly patients, such as 0.125 mg digoxin daily; because of the reduced glomerular filtration rate at elderly age that lessens drug excretion and because of the decrease in lean body mass, the volume in which digitalis is distributed, which causes an increase in plasma concentration. Dosage should be further reduced if quinidine, verapamil, or amiodarone are given concomitantly or if renal function is compromised. Digitalis overdosage should be suspected when confusion, bizarre behavior, altered mental status, fatigue, or anorexia occur, in addition to the usual nausea and vomiting. Digitalis given for heart failure precipitated by an acute problem that has resolved can be safely discontinued. Common complications of excessive diuretic therapy include dehydration and electrolyte abnormalities that often are manifest as altered mental status, increased likelihood of digitalis toxicity, and orthostatic hypotension that may result in orthopedic complications. The expected reflex tachycardia response to hypotension and hypovolemia is delayed and decreased at elderly age because of attenuation of baroreceptor reflexes. Sodium restriction improves diuresis and limits the resultant hypokalemia; however, major dietary alterations require assistance and encouragement in elderly patients. Difficulties with food purchasing and preparation, lack of interest in meals when eating alone, dental problems that impair chewing, and financial constraints often hamper dietary alterations. Preprocessed “convenience foods,” which have high sodium content, are often a sizeable component of the diet of elderly individuals.
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Although physical activity limitation is advisable when heart failure is decompensated, protracted immobilization predisposes to deep vein thrombosis and pulmonary embolism. When activity levels are increased after initial control of heart failure, the patient should be carefully observed for fatigue, breathlessness, edema, and weight gain as evidence of recurrent decompensation. Deconditioning of skeletal muscles and impaired skeletal muscle vasodilator response to exercise result in a greater impairment of functional capacity in elderly than in younger patients with systolic heart failure. Resumption of a regular physical activity regimen is recommended once compensation is achieved;38 functional capacity improves without apparent deterioration of ventricular function,62 predominantly due to adaptations of the intact skeletal musculature. Improvement in functional capacity can decrease dependency and disability.63 Functional capacity, as gauged by a 6-min walk test, is an independent marker of prognosis.64 Elderly patients with severe systolic dysfunction, particularly in association with atrial fibrillation, are candidates for oral anticoagulant therapy to limit thromboembolic complications. Reversion of atrial fibrillation or atrial flutter to sinus rhythm can substantially augment the cardiac output and improve heart failure because of the importance of the atrial contribution to ventricular filling in the poorly compliant aged ventricle. Because of the significant morbidity and mortality from cardiac failure at elderly age, patients require frequent and meticulous surveillance. An intensive multidisciplinary treatment strategy for heart failure involving specialized education, assessment, and management in a randomized clinical trial decreased readmissions and improved medication compliance. This approach has proved cost-effective in elderly populations by limiting rehospitalizations.65,66 Intensive home care surveillance resulted in improved functional status.67 Absence of emotional support was a strong independent predictor of fatal and nonfatal cardiovascular events after hospitalization in older women.68 Cardiac transplantation is uncommon in elderly patients but has been accomplished using older donor hearts. Rejection is less frequent, but the risk of infection and malignancy is higher in older than younger transplant patients.69
Arrhythmias and Conduction Abnormalities Both arrhythmias and conduction abnormalities increase in prevalence with increasing age.70–72 Reflecting agerelated changes in specialized conducting tissue and in atrial and ventricular myocardium.14
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Although arrhythmias may present as syncope or altered consciousness, many elderly patients have significant arrhythmias in the absence of these symptoms or of palpitations. Syncope may result from either tachyarrhythmias or bradyarrhythmias. Because of the ageand disease-related decreases in cerebral blood flow, a lesser severity of bradyarrhythmia or tachyarrhythmia than required in younger patients may cause an alteration of consciousness or true syncope at elderly age. Because syncope of cardiovascular origin entails an enormous 1-year mortality rate, 24%, identification of its mechanism is urgent to enable appropriate therapy; elderly patients with syncope of a noncardiac cause have a more favorable outlook, with their annual mortality approximating 3%.73,74 The prevalence of single supraventricular premature beats increases with aging. These beats are present in virtually all individuals older than 80 years of age, even in the absence of heart disease, are typically asymptomatic, and do not require treatment. There was no gender difference in the Cardiovascular Health Study.75 Atrial fibrillation also increases in prevalence with increasing age, being present in almost 10% of the population older than 80 years;76 it is a major contributor to stroke in elderly patients, even in the absence of valvular disease.77 Atrial fibrillation was present in 5% to 6% of patients in the Cardiovascular Health Study,78 predominantly in association with cardiovascular disease. In this study,78 a history of heart failure, valvular heart disease, or stroke; left atrial enlargement on echocardiogram; abnormal mitral or aortic valve function; treated hypertension, and advanced age all were independently associated with an increased prevalence of atrial fibrillation in community-dwelling elderly men and women. In the Framingham Heart Study,79 atrial fibrillation was associated with an increased risk of mortality, more so for women than for men (odds ratio of 1.5 and 1.9, respectively). The major issues relate to rate control, cardioversion, and stroke prevention. Success of cardioversion, in a prospective study, was comparable for patients older and younger than age 65.80 Chronic atrial fibrillation is associated with an increased incidence of stroke that accelerates with age. Anticoagulation81 can reduce stroke risk by almost 70%. Warfarin anticoagulation appears particularly warranted when atrial fibrillation is associated with heart failure.82 Reduction in stroke and stroke mortality has been documented with warfarin treatment, even in patients older than 75 years so treated. However, elderly patients remain undertreated with warfarin based on clinical practice guidelines for atrial fibrillation.83 Antiplatelet agents have not been effective in preventing stroke in elderly patients with nonvalvular atrial fibrillation. Ambulatory electrocardiography in elderly persons who are presumably free of cardiac disease shows that
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ventricular arrhythmias are pervasive (see Table 39.1), including frequent multiform ventricular ectopic complexes (PVCs)84 and nonsustained ventricular tachycardia (VT).72 Asymptomatic ventricular arrhythmias do not impart excess risk in healthy elderly patients and rarely require treatment in the absence of significant myocardial ischemia or ventricular dysfunction. Ventricular arrhythmias on 24-h ambulatory ECG were more common in elderly men than elderly women in the Cardiovascular Health Study.75 Nonsustained VT on 24-h ambulatory ECG in the Bronx Longitudinal Aging Study84 independently predicted death and MI. Very frequent ventricular premature beats, in excess of 1000 per 2 h, signify a poor prognosis in very old people with coronary heart disease.23 Older age independently predicted increased ventricular arrhythmia following MI in the cardiac arrhythmia suppression trial (CAST) Registry.85 Hourly PVCs increased from 0.4 in patients younger than 50 to 4.0 at 75 to 80 years, with VT prevalence increasing from 7.3% to 15.3% respectively. Electrophysiologic testing or signal-averaged ECGs offer little benefit in identifying high risk status in asymptomatic elderly patients with ventricular arrhythmias.86 Adverse antiarrhythmic drug reactions are more common in elderly patients due to their altered metabolic function and drug elimination, as well as to the frequent polypharmacy; antiarrhythmic drugs also are more likely to potentiate conduction abnormalities and ventricular dysfunction in an elderly population. In one study of antiarrhythmic drug therapy for asymptomatic complex ventricular arrhythmias in a geriatric population, the high incidence of adverse drug effects necessitated frequent discontinuation of therapy, and therapy did not improve survival, with or without ventricular systolic dysfunction.87 Elderly patients with symptomatic, refractory life-threatening ventricular tachyarrhythmias tolerate electrophysiologic testing well; this procedure can identify patients who require drug therapy or surgical intervention including Coronary Artery Bypass Graft (CABG) surgery, endocardial resection, aneurysmectomy, or cardioverter-defibrillator implantation.88 The pharmacologic management of supraventricular and ventricular arrhythmias is comparable in elderly and younger patients, except that lower doses of medication are usually indicated. Radiofrequency catheter ablation therapy is effective and safe to treat tachyarrhythmias at elderly age.89,90 Bradyarrhythmias, both the sick sinus syndrome and complete atrioventricular block, occur frequently in an elderly population; symptomatic bradyarrhythmias are the major indications for pacemaker implantation. Sick sinus syndrome does not generally require treatment in the absence of symptoms or extreme bradycardia. Digitalis and calcium- and b-blocking drugs, used to treat coronary disease and hypertension, may accentuate the
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bradycardia of the sick sinus syndrome; in elderly patients with the bradycardia-tachycardia subset of the sick sinus syndrome, pacemaker implantation may be required to permit pharmacologic treatment of the tachyarrhythmias with digitalis, b-blocking drugs, or calciumblocking drugs. Pacemaker implantation is appropriate at all ages, because pacemakers can improve symptoms and both the length and quality of life.91 Currently the median patient age of pacemaker recipients in the United States is approximately 70 years, rendering the geriatric population the major beneficiary of this therapy. Before permanent pacing, more than half of all patients with complete atrioventricular block died within 2 years. Pacemaker implantation, even at an elderly age, entails minimal morbidity and mortality. Even in octogenarians and nonagenarians, normal relative survival occurred in those without other heart disease.92 Coexisting heart disease and, in particular, preexisting heart failure adversely affect long-term survival.92 Although ventricular demand pacemakers remain the most common units in use, rate-responsive dualchambered pacemakers have advantages in alert and active elderly patients with underlying sinus rhythm in that atrial contraction contributes importantly to ventricular function when ventricular compliance is abnormal, and that the cardiac rate is proportional to the activity need.93 Disadvantages of these complex pacemakers are their higher cost and the increased skill of the physician needed for implantation and surveillance. However, dual-chamber pacemaker use in the Medicare national hospital database was associated with increased survival,94 even after controlling for potentially confounding patient characteristics. Pacing mode should be determined not by patient age but by the etiologic electrophysiologic problem. Sinus bradycardia is a common rhythm in elderly patients; when asymptomatic, it is not an indication for pacemaker implantation or other intervention. Similarly, asymptomatic complete atrioventricular block does not warrant pacing. A consensus guideline for indications for pacemaker implantation prepared by the American College of Cardiology/American Heart Association is equally appropriate for older and younger patients.95 In elderly patients with limited mobility, transtelephonic pacemaker surveillance may be helpful. Limited data are available about use of implantable cardioverter-defibrillators in elderly patients. Although these devices can be placed with minimal risk and are equally effective in preventing sudden death in older as in younger patients, nonsudden cardiac death was increased three times in one series of patients older than 75 years.96 A review of the success of cardiopulmonary resuscitation in elderly patients shows it to be less effective than
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in younger individuals. Characteristics associated with a favorable outcome include ventricular tachycardia or fibrillation as etiologic versus asystole or electromechanical dissociation and the symptom of chest pain versus that of dyspnea. Survival after cardiopulmonary resuscitation among elderly nursing home residents is extremely low.97
Atherosclerotic Coronary Heart Disease Atherosclerotic coronary heart disease (CHD) is the most prevalent cardiac disease at elderly age, involving an estimated 3.6 million patients.98 Coronary disease is responsible for more than two-thirds of all cardiac deaths among the elderly U.S. population, and morbidity and mortality from CHD increase progressively with age. In the United States, most patients with CHD, with new episodes of acute myocardial infarction, and with chronic heart failure secondary to CHD are older than 65 years of age.99 About 60% of patients hospitalized in the United States for acute myocardial infarction are older than 65 years,100 and the incidence of MI increases prominently with increasing older age.101 Not only is coronary disease highly lethal at elderly age, but disability is prominent; 50% of men and 20% of women aged 55 to 64 years with CHD have activity limitation, versus 85% and 55%, respectively, at 75 years and older. Nevertheless, there is a wide variation in the severity of coronary illness and in the functional status of elderly coronary patients. The male preponderance among younger coronary patients lessens at elderly age and gender difference in MI incidence virtually disappears by the eighth decade; clinical evidence of CHD is present in about 20% of both men and women by age 80. Although coronary atherosclerosis is almost uniformly present at autopsy examination of elderly patients, many have never had clinical manifestations of myocardial ischemia.
Angina Pectoris A recent study of nonhospitalized patients with angina pectoris102 revealed a mean age of 69 years, with 75% of the population women; although 90% described effort angina, 47% had rest angina, and 35% had angina precipitated by mental stress. The presentation of angina pectoris, both as an isolated event and following myocardial infarction, is more likely to be atypical, owing to a combination of a habitually decreased activity level, associated diseases, and possibly an altered sensitivity to pain in elderly persons. Angina is less likely to be activity induced in that arthritis, claudication, or musculoskeletal problems limit activity for many elderly patients before angina occurs. This angina
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may be misinterpreted as unstable because it occurs at rest in predominantly inactive patients. Furthermore, angina is more likely to be precipitated by a concurrent medical or surgical problem such as infection, blood loss, hypertension or hypotension, thyrotoxicosis, or arrhythmia. Dyspnea and fatigue may be the prominent manifestations of myocardial ischemia, and eating may precipitate angina. Additionally, patients with memory loss may not remember transient chest pain and those with chronic brain syndromes may not appreciate, describe, or express the occurrence of chest discomfort. Silent ischemia is highly prevalent at elderly age,103 with the risks greatest in the early morning hours or on awakening; standard anti-ischemic therapy is appropriate. Despite this high prevalence of silent ischemia, exertional chest pain independently predicts coronary death at elderly age,104 with comparable prognostic significance for men and women, although anginal severity does not define risk status. Therapy is as for younger patients, but attention must be directed to identification and remediation of precipitating or exacerbating factors. Elderly patients with stable angina, without evidence of early ischemia at exercise testing, who have a satisfactory symptomatic response to medical management are best suited for this approach. Elderly age is associated with increased fatal and nonfatal coronary events in patients with both stable and unstable angina; suboptimal pharmacologic and revascularization therapies likely contribute to the less favorable outcome.105 Severe unstable angina is common in elderly persons. When unresponsive or poorly responsive to intravenous nitroglycerin, oral aspirin, heparin, b- and calciumblocking drugs as tolerated,and IIb/IIIa glycoprotein inhibitor therapy, urgent coronary arteriography is indicated to evaluate suitability for myocardial revascularization.
Myocardial Infarction Elderly patients have a significantly different presentation, clinical course, and prognosis of MI than is the case at younger ages.99 There is a marked increase in morbidity and mortality,106 with 80% of all MI deaths occurring after age 65. Mortality from acute MI is increased 6-fold at ages 75 to 84 years and 15-fold after 85 years, compared with that at ages 55 to 64 years.107 Functional disability before MI importantly predicts MI severity and postinfarction survival.108 Although age adversely affects MI survival in part because prior MI, hypertension, and heart failure all increase with increasing age,109 the contribution of less aggressive therapies requires study.110 In the Myocardial Infarction Triage and Intervention (MITI) project, MI mortality was increased 10-fold in elderly patients (17.8% at 75 years
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or more versus 2% at less than 55 years).111 The prognosis was worse for elderly women than elderly men,112 although data from the U.S. National Registry of Myocardial Infarction-2 suggest otherwise.113 Chest pain as the presenting manifestation of acute MI is less frequent in elderly individuals.114,115 Classic chest pain is reported by only one-third of patients older than 85 years of age. Elderly patients have an increased prevalence of comorbid illness associated with painless infarction such as diabetes and hypertension. Additionally, there may be lesser or altered sensitivity to pain with aging. Although the myocardial infarction may be painless, the clinical presentation is often not asymptomatic and may include acute dyspnea, exacerbation of heart failure, or pulmonary edema; and syncope, cerebrovascular accident, vertigo, palpitations, peripheral arterial embolism, nausea and vomiting, or acute renal failure; more subtle changes involve altered mentation, including acute confusion or agitation, profound weakness or fatigue, and changes in eating pattern or in other usual behaviors. The onset of symptoms of MI is more likely to occur at rest or during sleep in elderly patients, likely reflecting their more sedentary lifestyle. Unrecognized MI has as serious a prognosis as identified episodes of MI.114 Based on Framingham data, unrecognized MI is more common in elderly women than in elderly men. Twenty-three percent and 38% of elderly men and women, respectively, with ECG evidence of MI in the Cardiovascular Health Study6 did not report a history of MI. In the Goteborg Study, 60% of patients with ECG evidence of MI gave no history of an acute episode.116 Asymptomatic or atypical presentations of MI commonly exclude elderly patients from the potential benefits of thrombolytic therapy or acute coronary angioplasty. Acute MI in elderly patients is often a nonQ-wave MI and, as is the case with angina pectoris, is more often precipitated by an intercurrent medical or surgical problem associated with hypovolemia, blood loss, infection, hypotension, and the like (Table 39.2). Atypical symptoms may partly explain the delayed hospital presentation at elderly age.117 Acute myocardial infarction, because of its atypical presentation, is more often unrecognized in aged patients, despite the fact that infarction in elderly persons characteristically is of increased severity, has a greater occurrence of complications, entails a longer hospital stay, and results in a higher mortality than in a younger age group. Elderly patients are more likely to be female; to have associated hypertension, diabetes mellitus, and cerebrovascular accident; and to have a history of prior infarction and of heart failure. In addition to the atypical presentation, the diagnosis of MI may be further obscured in that the electrocardiographic diagnosis is limited by the increased occurrence of non-Q-wave infarction,118 and elevated myocardial
N.K. Wenger Table 39.2. Atypical manifestations: acute myocardial infarction (MI) in elderly patients. Presentation Painless infarction more common Acute symptoms Dyspnea Exacerbation of heart failure Pulmonary edema Syncope Stroke Vertigo Acute confusion Palpitations Peripheral arterial emboli Nausea and vomiting Acute renal failure Subtle manifestations Altered mentation Excessive weakness or fatigue Changes in eating pattern Changes in other usual behaviors Common precipitating factors Hypovolemia Blood loss Infection Hypotension
band (MB) fractions of creatine kinase (CK) are common in the presence of a normal total CK level because of decreased lean body mass with aging.119 Pooled data from large randomized placebo-controlled trials of thrombolytic therapy for acute MI, involving more than 58,600 patients, have shown comparable benefit at young and older ages up to age 75 years, with comparable efficacy of all thrombolytic drugs tested in elderly patients.120–122 Advanced age alone (up to age 75) should not exclude patients from treatment with thrombolytic therapy.123 The ACC/AHA clinical practice guidelines for acute MI cite a class I recommendation for this treatment for patients up to age 75 and a class IIa for those 75 and older.124 Statistically significant reduction in mortality was more prominent at older than at younger age, despite the increased risk of bleeding, and in particular intracerebral bleeding, in the elderly.125–128 Improvement in ventricular function occurred at all ages studied. Because the absolute risk of MI mortality is greater at 65 to 75 years than for younger patients, the absolute benefit of successful coronary thrombolysis is also greater.129 However, even with successful thrombolysis, patients older than 75 years in GUSTO-I had more left ventricular (LV) dysfunction and greater mortality than those younger than age 75.130 Lesser use of thrombolytic therapy at advanced age is due, in part, to the later arrival at hospital of elderly patients.111,131,132 Even in elderly patients known to have CHD, delay in accessing medical care was substantially greater than at younger age.133 Elderly female patients and those with
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diabetes were treated later in the GUSTO-I trial, adding to their already substantial risk.134 Since 1990, however, data suggest increased use of thrombolytic therapy for elderly patients, particularly elderly women.135 Robust data are lacking for patients older than 75 years of age136 because these patients typically have been excluded from earlier studies of these interventions. Caution is warranted regarding coronary thrombolysis beyond age 75. An observational study derived from the Medicare database suggested significant survival disadvantage, without benefit in any clinical subgroup.137 Clearly randomized trial data are needed, given the limitations of observational studies.138 In particular, the contribution of higher-dose, nonweight-based heparin therapy to bleeding risk at elderly age was not ascertained. In GUSTO V, thrombolysis with half-dose reteplase plus abciximab (a IIb/IIIa platelet glycoprotein inhibitor) was associated with increased intracranial bleeding beyond age 75.139 In the Cooperative Cardiovascular Project, primary percutaneous transthoracic coronary angioplasty (PTCA) was associated with modestly lower short- and long-term mortality rates than coronary thrombolysis;140 there was a 16% reduction in 30-day mortality risk. Among the 80 patients older than age 80 in GUSTOIIB,141 there was no 30-day mortality difference between coronary thrombolysis and acute angioplasty, with high mortality rates in both groups. Acute coronary angioplasty (PTCA) should also be considered for elderly patients for whom coronary thrombolysis is contraindicated; up to a 90% procedural success rate was described for patients age 70 years and older,142 with favorable outcomes also described in octogenarians.143 Risk of cerebral hemorrhage is dramatically less with acute PTCA than with coronary thrombolysis in elderly patients. In-hospital mortality is greater in patients older than 70 years of age; the 30% to 40% mortality is about twice that of younger patients. Complications including hypotension and cardiogenic shock, atrioventricular block, atrial arrhythmias, heart failure, pulmonary edema, and cardiac rupture occur with increased frequency in elderly patients. In the SHOCK trial, emergency revascularization did not benefit patients with MI and cardiogenic shock older than age 75.144 Cardiac rupture during the first week after MI occurs, particularly in elderly women with hypertension. In one series, MI mortality was doubled with the occurrence of atrial fibrillation. Right ventricular infarction substantially increases hospital mortality.145 Severe mitral regurgitation due to papillary muscle infarction and cardiac rupture of either the ventricular septum or a papillary muscle usually are heralded by recurrent chest pain, pulmonary edema, and/or cardiogenic shock. Use of intraaortic balloon counterpulsation enables survival until cardiac catheterization and surgical repair can be performed. In patients
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with these surgically correctable lesions, favorable responses to surgical intervention have been described.146 Despite the high operative mortality, survivors have a satisfactory long-term outcome. Not surprisingly, elderly patients often have a more protracted hospital stay for MI. Although survival of elderly patients improved substantially from 1987 to 1990, particularly for those younger than 85 years, the decline in CHD mortality has been less prominent in elderly than in younger patients. Concomitant changes included the increased use of acute pharmacologic and invasive interventions to limit infarct size and revascularize myocardium.147,148 In one study,149 hospital complications and 30-day and 1-year mortality rates declined approximately 30% in patients aged 75 and older, with the most marked benefit in reperfused patients. Major differences still persist in the application of beneficial therapies to patients older than 75 versus younger than 55: 5% versus 39% thrombolytic therapy, 7% versus 29% PTCA, 5% versus 11% CABG, and 57% versus 82% aspirin use.111,150,151 Early beta-blocker therapy was not used for 51% of elderly patients hospitalized for acute MI in the Cooperative Cardiovascular Project,152 although this therapy was associated with a 19% reduction in mortality risk across all age groups in the Medicare cohort. Posthospital mortality is also increased following MI, due to the increased severity of infarction, often superimposed on prior infarction; this also accounts for the increased residual invalidism and increase in late deaths at elderly age. In the early years of acute coronary care, elderly patients were arbitrarily excluded from coronary or intensive care facilities on the basis of age alone. However, elderly patients benefit equally from intensive coronary care, ECG monitoring, and arrhythmia prevention and reversion. In particular, they have an equally favorable response to defibrillation as younger patients. The increased occurrence of heart failure at elderly age and other complications of infarction and frequent complicating illnesses warrant meticulous surveillance. Elderly patients with heart failure more often require monitoring of cardiac output and intracardiac pressures through a pulmonary artery catheter to guide therapy. Other problems encountered more frequently in the elderly patient with MI include difficulty with urination, particularly in men with prostatic enlargement who receive diuretic therapy; constipation and a variety of nonspecific gastrointestinal symptoms; and the precipitation of glaucoma, urinary retention, or confusion when atropine is used to reverse sinus bradycardia. The early mortality of elderly patients after MI has been reduced from an estimated 43% to 79% to as low as 25% to 27% with coronary care unit management; this difference probably is related to increased intensity of coronary care unit therapy.153
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Drug management of acute MI is comparable with that of a younger population. There is an increased propensity to adverse effects from narcotic analgesic medications; half the dosage usual for younger individuals is recommended. In general, adverse responses to drug therapy are more likely to occur and can be exacerbated by coexisting medical illnesses and related multiple-drug therapy. All drugs should be introduced at lower doses than in younger patients, with gradual dosage increases as tolerated. Intravenous administration of beta-blocking drugs in acute MI improved survival only in older patients,154–158 although data are not available for patients older than 75 years. Long-term oral beta-blocking drugs provide equal or greater long-term survival benefit and reduction of reinfarction after MI in elderly as in younger patients,159 particularly for patients with anterior MI, with data available to age 75 years.155,160,161 Contemporary data suggest underutilization of beta-blocking drugs in elderly patients after acute MI,162 with only 21% of eligible patients receiving this therapy163 in one study and 50% in another.164 Beta-blocker use was associated with a 43% decreased mortality rate and 22% decreased rehospitalizations in a Medicare cohort, with benefit also evident in patients older than age 75. Diltiazem and verapamil appear to provide comparable benefits in younger and older patients with nonQ-wave MI and preserved ventricular function, although calcium channel-blocking drugs have not improved survival and may worsen outcome in patients with ventricular dysfunction.165 However, most studies of calcium channel-blocking drugs in patients with non-Q-wave MI did not provide aged-based analysis, despite inclusion of elderly patients. Comparable reduction in mortality occurred in patients with MI older and younger than 70 years treated with aspirin during acute MI in the international study of infarct survival (ISIS-2) trial.166 Virtually no patients older than 75 years were enrolled in other clinical trials of aspirin use. Of concern is that about one-third of elderly patients with acute MI without contraindications to aspirin use failed to receive aspirin during the first 2 days of MI hospitalization.167 Aspirin use was associated with a 22% decrease in 30-day mortality risk in this Medicare population. Aspirin was not prescribed at discharge to 24% of eligible elderly patients in the Cooperative Cardiovascular Project.168 Angiotensin-converting enzyme (ACE) inhibitors likely provide comparable benefit in elderly and younger patients, particularly those with large infarctions and ventricular dysfunction. ACE inhibitor therapy in patients with a decreased ejection fraction following MI decreased fatal and nonfatal cardiovascular events, including the development of heart failure and recurrent infarction; relative risk reduction was greater for the 35% of patients older than 65 years.49 Elderly patients in the
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GISSI-3 trial also had decreased mortality and severe ventricular dysfunction associated with ACE inhibitor therapy.169 Long-term warfarin anticoagulation after acute MI reduced reinfarction in elderly patients in the Sixty-Plus Reinfarction Trial, without significant deleterious bleeding risk. The Warfarin Re-Infarction Study170 showed survival, reinfarction, and cerebrovascular benefits in patients up to age 75 randomized to warfarin, although a post hoc analysis showed attenuated benefit with increasing age.171 Data from the Cardiac Arrhythmia Suppression Trial (CAST) discourage use of antiarrhythmic drugs for MI survivors of all ages without symptomatic arrhythmia, even those with complex ventricular arrhythmia, owing to increased mortality risk from drug proarrhythmic effects.172 In CAST, ambulatory ECG data showed that age was an important independent predictor of ventricular ectopy in postinfarction patients.173 Nitrate drug use requires attention to orthostatic hypotension because of diminished baroreceptor responsiveness; elderly patients must be cautioned to sit when taking sublingual nitroglycerin for relief of angina. Among eligible patients recently hospitalized for MI, lipid-lowering drugs were used by only one-third. Age greater than 74 years was independently related to lack of lipid-lowering drug use.174 A substantial number of elderly patients have an essentially uncomplicated MI with an excellent prognosis for recovery and rehabilitation. They are ideal candidates for early ambulation to prevent the deleterious effects of prolonged immobilization. Education and counseling are important components of care. At discharge, there should be a careful review of medications, with written recommendations for diet, activity, and coronary risk reduction. Predischarge exercise testing appears safe for appropriately selected elderly patients who remain asymptomatic and offers prognostic data comparable to that reported for younger patients.175 Inability to undergo exercise testing 1 month after MI is a marker of unfavorable prognosis.176 As is the case in younger patients, the lower the exercise intensity at which ischemic ST segment abnormalities appear, the greater their severity, and the longer their persistence after cessation of exercise, the greater the risk. Failure of SBP to increase with exercise or exercise-induced hypotension also indicates a high-risk status. Evidence of residual ischemia at exercise testing, with and without radionuclide studies, or with dipyridamole-thallium imaging in elderly patients with non-Q-wave MI is associated with an increased risk of mortality and warrants consideration for invasive intervention.177,178 Elderly patients with non-Q-wave MI have greater mortality risk in the year after hospital discharge than do patients with Q-wave MI; aggressive diagnostic
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and therapeutic interventions may be of particular benefit in these patients.179 (See p. 530 for coronary risk reduction.) Lack of emotional support independently predicts mortality risk after MI.180 Although many male coronary patients 80 years and older have a spouse for social support and to assist as a caregiver, women with CHD of comparable age often have no such companion and may forfeit their independent lifestyle. Exercise test data can be used to recommend the intensity of physical activity that can be performed with safety following discharge from the hospital. Many elderly patients can exercise safely without supervision; predischarge exercise testing can identify the high-risk subset of patients for whom initially supervised exercise is appropriate. Exercise test results can also guide recommendations for return to preinfarction physical activities, including resumption of remunerative work when appropriate. Many physicians underestimate the habitual physical activity level of their older cardiac patients and inappropriately recommend restriction of physical activity.181 Excessive immobilization is associated with detrimental physical and psychologic consequences. In contrast, many elderly individuals decrease their activity levels because any submaximal task is perceived as requiring increased work; this is because of the increase in relative energy cost caused by the lessened aerobic capacity that occurs with aging. Even with usual daily activities, there is a greater increase in heart rate in elderly people. Additionally, combinations of musculoskeletal instability, emotional problems (particularly depression), and often inappropriate admonitions from family members and friends further decrease activity levels. Rehabilitative exercise training can limit the high risk of disability of elderly patients after a coronary event181 and encourage coronary risk reduction.182 The goal of rehabilitation is restoration, maintenance, and extension of a reasonably independent and active lifestyle. Although an increasing percentage of elderly patients after MI or myocardial revascularization procedures are currently enrolled in supervised exercise rehabilitation programs or prescribed an independent exercise regimen by their physicians, elderly patients (particularly elderly women) are less likely to be referred than younger patients.63 Comparable improvements in physical work capacity and in endurance occur in elderly as in younger men and women, and appropriate exercise entails no greater risk.63,183,184 Walking is an ideal exercise regimen after discharge from the hospital, with gradual increases in the pace and distance of walking. Because the energy expenditure of walking often entails a significant proportion of the aerobic capacity of elderly patients, walking even as slowly as 3.5 miles per hour is an excellent physical conditioning stimulus. The major physio-
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logic effect is a decrease in the heart rate response to submaximal work. Additional benefits of exercise training include improved neuromuscular coordination, joint mobility, coordination, and flexibility, and the potential to limit bone demineralization. Exercise testing for exercise prescription is recommended before embarking on a more intensive physical activity regimen. High-impact aerobic activities are inappropriate at elderly age as they are associated with an increase in musculoskeletal complications.185
Myocardial Revascularization Elderly patients with chronic angina unresponsive or poorly responsive to medical management, or those with persisting chest pain following MI, are candidates for coronary arteriography to assess their suitability for myocardial revascularization. Older patients with evidence of myocardial ischemia at low work loads at exercise testing also constitute a high-risk group for early recurrent coronary events and should be evaluated for myocardial revascularization. Because a high percentage of posthospital deaths in very elderly patients are either sudden or due to recurrent MI, risk stratification testing should routinely be considered for patients older than 75 years as at ages 65 to 75150 to identify the subset for whom myocardial revascularization is appropriate. Elderly patients are more likely to have multivessel coronary disease and left main coronary stenosis, and coronary lesions are more likely to be diffuse and calcified. It is thus not surprising that elderly patients undergoing CABG are more likely to have unstable angina, prior MI, and New York Heart Association class IV heart disease than younger patients. Elderly patients are also characterized by a higher percentage of women and a greater likelihood of comorbid conditions including diabetes, hypertension, heart failure, renal insufficiency, and PVD. Older age patients now constitute more than half the population undergoing cardiac catheterization, PTCA, and CABG surgery.100 CABG surgery in patients 80 years and older increased 67% between 1987 and 1990,186 providing a Medicare database of almost 25,000 such patients; in recent years, mortality rates for elderly patients undergoing revascularization procedures decreased in this Medicare database. In nonrandomized but comparable elderly patients older than 70 years undergoing myocardial revascularization procedures, there was substantially less hospital mortality, stroke, and MI with PTCA than with CABG; in the ensuing 5 years, however, PTCA patients required more repeat procedures, but 5-year mortality was comparable for PTCA and CABG patients, about 30%.187 Elderly patients (≥70 years) with unstable angina at high risk for CABG who
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were treated successfully with PTCA had long-term mortality comparable to that of age-matched subjects without diagnosed CHD.188 Recent series have described outcomes of CABG surgery in selected octogenarians and nonagenarians, usually with highly symptomatic and unstable coronary disease, who were unresponsive or poorly responsive to medical management.189–192 In addition to the more likely left main and triple-vessel coronary disease, often with ventricular dysfunction, and substantial comorbidity in elderly patients, older age is an independent risk factor for morbidity and mortality from CABG, with elderly women at highest risk.193 A recent report describes a 10% hospital mortality rate in octogenarians, with diabetes and ventricular dysfunction adversely affecting outcome.189 Despite the initial high risk and significant hospital expenses, survivors were pain-free, often with restored performance status, and with 5-year survival rates comparable to that of the general octogenarian population in the United States.186 Evaluation of elderly patients with diabetes in the CASS Registry194 showed surgical benefits comparable to those in nondiabetic elderly patients, a 44% reduction in mortality compared with medical therapy. As in younger populations, use of at least one internal mammary artery graft improved symptoms and event-free survival in patients 70 years and older.195 The symptomatic improvement and favorable late sustained improvement and quality of life among elderly survivors of CABG suggest that an optimistic approach to the management of symptomatic elderly patients with advanced obstructive CHD is reasonable,196 even for selected octogenarians and nonagenarians.190,191 Patients older than 70 years of age sustain a higher operative mortality from elective CABG than do younger individuals, as well as higher rates of postoperative cardiac and noncardiac complications, which occur in as many as 30% to 50%. These complications include greater need for prolonged ventilatory support for respiratory failure; for implanted pacemakers; for inotropic support and use of the intra-aortic balloon pump; greater reoperation for bleeding; stroke; delirium; renal failure; perioperative infarction; and sepsis. Complications are most frequent in elderly women.197 Atherosclerotic emboli from aortic atheromatous disease contribute importantly to complications; intraoperative transesophageal echocardiography can identify protruding atheromas that require modification of aortic manipulation.198 Increased age predisposes to impaired cognition after cardiac surgery unrelated to changes in cerebral blood flow autoregulation.199 Elderly patients can be anticipated to have a longer hospital stay following CABG, with more time spent in an intensive care setting.189 Emergency CABG in elderly patients entails a substantially increased mortality risk, 14.9% versus 3.6% for elective surgery in one series.200
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In elderly patients with preserved ventricular function and without major associated medical problems, 5-year survival following successful CABG approximates 90%. In the CASS, 81% of elderly patients were free of recurrent angina, MI, requirement for repeat CABG surgery, or death at 1 year, and 40% were free of such events at 5 years. These results were comparable to those in patients younger than age 65. High-risk patients older than age 65 years in the CASS201 had better survival and freedom from chest pain with surgical management than with medical management. Nevertheless, operative morbidity and mortality is greater, hospitalization is more protracted, and overall survival is less than that for younger patients.202 However, because elective CABG in patients older than 75 years resulted in an operative mortality of 3.6% in one series versus 14.9% mortality for urgent or emergency CABG surgery,200 early evaluation and referral for elective revascularization of symptomatic elderly patients may avert the excess mortality of emergency revascularization. In a study comparing CABG in patients older and younger than 75 years, actuarial 5-year cardiac event-free survival rates were comparable.203 As myocardial revascularization procedures are increasingly undertaken in highly symptomatic octogenarians and nonagenarians, the outcomes appropriate for assessment include restoration of comfort, self-sufficiency, and improved functional status, that is, meaningful long-term survival.204 Early ambulation and gradually progressive physical activity after CABG can help limit complications and improve the functional status at discharge from the hospital. Although direct comparison of the results of PTCA with those of CABG is not available, because of the increased risk of CABG at elderly age and because catheter-based interventions often are better tolerated than surgery, there has been increased application of PTCA to elderly patients. There is an equal or greater increase in PTCA application among elderly women than elderly men. However, often the coronary anatomy is unsuitable for transcatheter revascularization. The incidence of left main coronary artery disease has been estimated to be 13% to 35% in different series. Recent reports of PTCA at elderly age documented angiographic success rates of 80% to 90%, even with multivessel PICA, without excess occurrence of procedural complications and with functional improvement and patency rates comparable to those at younger age.205–207 If complete revascularization is achieved, freedom from recurrent angina and cardiac death is comparable to that in younger patients.208 Incomplete revascularization is associated with poorer long-term survival.209 In the Mayo Clinic experience, despite improved technical success and decreased short-term PTCA complication rates, event-free survival rates continued to be influenced by baseline characteristics.210 Restenosis rates, even
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among octogenarians, are comparable to those in younger patients.211 Age remains an important predictor for procedural mortality and late survival in PTCA, particularly for patients older than 80 years.206,212 However, almost threefourths of elderly survivors of PTCA do not require CABG surgery and remain free of MI at 4 to 5 years. Compared with patients 65 to 74 years, patients older than 75 years were more symptomatic, more likely to have heart failure, and more likely to require multivessel PICA.213 The increased incidence of vascular site complications reflects the high prevalence of PVD. Despite a high rate of procedural success, PTCA in patients older than 90 years involved a high rate of inhospital complications and limited clinical benefit.214 Limited data from elderly patients with high-risk lesion morphology at coronary arteriography suggest that coronary angioplasty using new devices and stenting may be a therapeutic alternative.215 Substantial changes in both surgical and transcatheter revascularization techniques mandate comparison of these contemporary approaches in the elderly population.
Systemic Arterial Hypertension and Cardiovascular Risk Hypertension is highly prevalent at elderly age, occurring in more than half of the U.S. population older than 65 years.216 Hypertension and its consequences comprise the major reason for which patients in the United States consult their physicians. In most populations, systolic blood pressure (SBP) increases into the eighth and ninth decades, whereas diastolic blood pressure (DBP) levels off in the fifties and sixties; thus, isolated systolic hypertension (ISH) is prominent in geriatric populations.217 Both reduced arterial compliance and increased cardiac output appear to contribute to ISH at elderly age.218 Pulse pressure widens in old age as a result of a continued increase in SBP and a decrease in DBP. Low DBP, particularly in association with a wide pulse pressure, appears to reflect widespread atherosclerosis at elderly age.219 The age-related increase in SBP is not invariable and is infrequent in most nonindustrialized societies. Lower rates of hypertension are described in physically active elderly women, with blood pressure progressively lower at higher levels of activity.220 The World Health Organization (WHO) definition of hypertension is a blood pressure in excess of 160/95 mmHg. Isolated systolic hypertension is defined as a SBP in excess of 150 mmHg with a DBP below 90 mmHg, and accounts for approximately two-thirds of hypertension in persons older than 65 years. In the United States, approximately one-third of elderly women and one-fifth of elderly men have ISH. Either ISH or combined sys-
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tolic and diastolic hypertension occurs in 63% of whites and more than 75% of blacks older than 65 years.216 Major elevation in DBP in excess of 110 mmHg is three times as common in elderly black patients as in elderly white patients. Hypertension remains a powerful predictor of cardiovascular mortality at all ages; even borderline systolic or diastolic hypertension doubles the risk of cardiovascular events at elderly age. Although the increase in risk is related to the severity of hypertension, systolic hypertension is more closely correlated with cardiovascular and cerebrovascular morbidity and mortality at elderly age than is diastolic hypertension.221,222 Systolic blood pressure, determined by ambulatory blood pressure monitoring, significantly predicted cardiovascular risk over and above conventional blood pressure monitoring in the Systolic Hypertension in Europe trial.223 Development of left ventricular hypertrophy (LVH), a potent independent risk factor for cardiovascular mortality, is highly correlated with systolic hypertension. In the Framingham Heart Study, even borderline ISH at elderly age was associated with increased LV wall thickness and impaired diastolic filling.224 Antihypertensive agents that can effect regression of LVH may contribute to decreasing cardiovascular complications. Elevated SBP, which increases ventricular afterload and myocardial oxygen demand, may depress cardiac function, particularly with coincident CHD. Blood pressure should be measured annually even in previously normotensive elderly persons. Because blood pressure measurements are highly variable at elderly age, two or three baseline readings on separate occasions are recommended before treatment is initiated.225 Hypertension contributes importantly to accelerated CHD, heart failure, cerebrovascular accident, renal failure, aortic dissection, and aortic aneurysm rupture in the elderly, as well as in younger populations. Although only 20% of patients in the Veterans Administration Cooperative Study on Antihypertensive Agents were older than 60 years, half of all morbidity, heart failure, and stroke occurred in this age group.226 Control of hypertension decreases the risk of complications: cardiovascular death, fatal MI, heart failure, and stroke in elderly patients.216,227 Control of isolated systolic hypertension in the Systolic Hypertension in the Elderly Program (SHEP)228 using low-dose chorthalidone as initial therapy, with low-dose beta blockade added as needed, reduced stroke by 36% and fatal and nonfatal cardiovascular events by 32%, the latter largely due to decreased fatal MI. Occurrence of heart failure was reduced approximately 50%, particularly among patients with prior MI,229 with comparable benefits in patients with and without baseline ECG abnormalities and with or without noninsulin-treated diabetes.230 In the SHEP cohort, depression was associated with a significant substantial increase in risk of death and stroke or MI.231 In the
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Swedish Trial in Old Patients with Hypertension-2 (STOP-2) study,232 outcomes were comparable with conventional drugs (beta blockers and diuretics) and the newer ACE inhibitors and calcium channel-blocking drugs. However, elderly patients receiving ACE inhibitor compared with calcium channel-blocking drugs had fewer MIs and less heart failure. Particularly in elderly patients with mild hypertension, nonpharmacologic approaches including reduction of sodium intake, weight reduction, moderation of alcohol consumption, and regular modest-intensity physical activity225 should be initially considered. In the randomized Trial of Nonpharmacologic Intervention in the Elderly (TONE), the best results were associated with combined sodium restriction and weight loss.233 Elderly patients should be cautioned that nonsteroidal antiinflammatory drugs can decrease the efficacy of antihypertensive drug treatment.234 Based on results of major randomized clinical trials that enrolled elderly patients,217,235 comparable or greater benefit of pharmacotherapy to that at younger age was documented, at least to age 80 years. The European Working Party on Hypertension in the Elderly (EWPHE) trial,222 in which 70% of patients were women, showed a favorable effect of antihypertensive therapy on cardiac mortality, fatal MI, heart failure, and overall cardiovascular mortality. In these clinical trials, there were no increased rates of therapy discontinuation resulting from adverse effects in elderly patients, and study medication adherence was comparable to younger patients. In one study, calcium antagonist drugs, compared with beta-blockers, increased the risk of gastrointestinal hemorrhage in hypertensive patients over age 67.236 Meta-analysis of antihypertensive therapy trials involving more than 15,000 patients older than 60 years showed comparable reduction in stroke risk and cardiac morbidity as in younger patients.237 Goal blood pressure should be 140/90 mmHg, with avoidance of postural hypotension and maintenance of renal function; this should be accomplished without adverse symptomatic side effects and at reasonable cost. Goal blood pressure of less than 130/85 is a costeffective intervention in elderly diabetic hypertensive patients.238 Initiation of drug therapy should involve half the usual adult dose, with gradual increments in drug dosage. However, few elderly patients achieve goal blood pressure levels with monotherapy; low doses of two drugs are often necessary. Because of impaired baroreflex control of blood pressure at elderly ages, blood pressure should be checked in the sitting and standing positions when therapy is instituted. The drugs chosen, in addition to lowering blood pressure, should be those that effect regression of left ventricular hypertrophy. Hypertension and its therapy are discussed in more detail in Chapter 40.
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Valvular Heart Disease, Congenital Heart Disease, Infective Endocarditis, and Nonvalvular Cardiovascular Infections Aortic Stenosis Hemodynamically significant symptomatic calcific aortic stenosis is the most frequent valvular heart disease that requires surgical correction in elderly patients.239 One in four patients who undergo aortic valve replacement are 70 years or older. Although more common in men in younger age groups, calcific aortic stenosis predominates in women after age 80. Frequent underdiagnosis of hemodynamically significant aortic stenosis is of concern because correct diagnosis and valve replacement surgery are associated with a favorable long-term prognosis, that is, improved symptoms and survival. Aortic stenosis in elderly patients is typically caused by calcification of a tricuspid aortic valve; 90% of aortic valves in elderly patients with calcific aortic stenosis are tricuspid. Symptomatic hemodynamically important aortic valvular stenosis is characterized by the same presentations in the elderly as in a younger population: angina pectoris, exertional dizziness or syncope, and dyspnea or heart failure; however, these symptoms are often misinterpreted as being caused by other cardiac problems, such as CHD, or by neurologic disease when the presentation is with syncope.240 Significant aortic stenosis is one of the most common anatomic causes of syncope at elderly age. Symptoms are less often activity precipitated than in younger patients because a relatively sedentary lifestyle more frequently occurs with aging. Progression of the severity and symptoms of aortic stenosis at elderly age is characteristic and often rapid. Aortic valve replacement is indicated, in that fewer than 50% of patients with hemodynamically significant symptomatic calcific aortic stenosis survive for more than 5 years after symptom onset; sudden death is common.241 Differentiation is required from the benign, but pervasive, short earlypeaking basal systolic murmur of aortic sclerosis, present in one-half to one-third of elderly patients. The classic slow-rising small-volume carotid pulse of a younger patient with aortic stenosis, occasionally associated with a thrill, may be masked by sclerosis and decreased elasticity of the carotid vessels in an elderly patient; these may also mask the usual narrow pulse pressure. The carotid bruit may be erroneously attributed to primary vascular disease. Systemic arterial hypertension, rarely seen in younger individuals with severe aortic stenosis, is not uncommon in elderly persons because of vascular stiffening. The late-peaking, harsh basal systolic murmur that radiates into the neck often has high-
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frequency components that are heard along the lower left sternal border and toward the cardiac apex throughout most of systole, mimicking the murmur of mitral regurgitation. The apical systolic murmur of associated mitral annular calcification may further complicate recognition. Hyperexpansion of the lungs and dorsal kyphosis may limit the palpatory evidence of the forceful sustained apex impulse of left ventricular hypertrophy and, at times, the basal systolic thrill; the harsh basal systolic murmur may become softer and the thrill no longer palpable as the cardiac output lessens. Lack of commissural fusion of the calcified aortic valve in elderly persons further mutes the harsh characteristics of the murmur and also explains the absence of an ejection sound. S2 is soft with occasional reversal of splitting, and an S4 is prominent when sinus rhythm is present. Atrial fibrillation rarely occurs in younger patients with aortic stenosis, but often precipitates heart failure in elderly patients, due to a loss of the atrial contribution to ventricular filling in a poorly compliant ventricle in combination with the lessened ventricular filling resulting from the rapid heart rate. Atrial fibrillation may be present in as many as one-fourth of elderly patients with severe aortic valvular stenosis. There is frequently a coexisting basal early diastolic decrescendo murmur of aortic regurgitation, but aortic regurgitation of hemodynamic significance is unusual. The ECG has characteristic changes of left ventricular hypertrophy, although concomitant emphysema may mask the increased voltage. The heart size on chest radiograph is usually normal; aortic valvular calcification may be evident and can be confirmed by echocardiography. Critical aortic stenosis virtually never occurs in the absence of echocardiographically detectable calcium deposition. An increased left ventricular wall thickness is evident in most patients. Echocardiography with Doppler studies can noninvasively assess the severity of aortic valvular obstruction. The aortic valvular pressure gradient at Doppler echocardiography correlates reasonably with the aortic valve area at cardiac catheterization. Hemodynamically severe aortic stenosis as evaluated by Doppler echocardiography in the Helsinki Aging Study242 markedly increased 4year mortality risk. Cardiac catheterization and coronary arteriography are warranted, nonetheless, because coexistent coronary disease is frequent243 and concomitant myocardial revascularization may be required if aortic valve replacement is undertaken.244 Exercise testing is hazardous if critical aortic stenosis is suspected because syncope and sudden death have been precipitated. Aortic valve replacement for symptomatic critical aortic stenosis is indicated at virtually all ages in otherwise functional elderly patients244 because of their excessive mortality after the onset of angina pectoris, heart failure, or syncope. Asymptomatic elderly patients with
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reasonable exercise tolerance with severe aortic stenosis do not warrant surgery; sudden death is very rare without antecedent symptoms.245 Symptomatic geriatric patients with severe aortic stenosis have mortality rates as high as 50% in the first year.246 Although angina and heart failure symptoms may respond to medical management, clinical deterioration is frequent, leading to urgent surgery with its increased operative mortality. Aortic valve replacement can be performed at an acceptable risk, even in octogenarians and in patients with class III and class IV disease,247 because left ventricular function is often well preserved even after the onset of heart failure. CHD, prior MI, heart failure, and atrial fibrillation all increase surgical risk.248 Aortic valve replacement dramatically improves survival, hemodynamic status, and the patient’s quality of life. However, neurologic complications are more common than at younger age. In one series, actuarial survival at 1, 3, and 5 years was 90.8%, 84.2%, and 76.0%, respectively, although concomitant surgical procedures increased the operative risk.249 In another series, perioperative mortality was 2.5% in patients below 70 years, 7.3% in those beyond 70 years, and 12.5% in those older than 80 years; among patients older than age 70, 1-year survival was 83%, and 5-year survival 52%.250 There was a favorable 10-year postoperative survival with maintenance of functional status. About 10% of patients will require permanent pacemaker implantation for perioperative heart block. Comparison of valve replacement for aortic stenosis in another series among patients older and younger than 75 years showed a surgical mortality of 12.4% versus 6.6% in the two groups.251 In another report of aortic valve replacement in octogenarians where half had concomitant CABG surgery, operative mortality was 9.8%.252 In a more recent series,253 isolated aortic valve replacement beyond age 70 entailed a perioperative mortality of 4.3%, which increased to 10% with concomitant CABG surgery. Of equal importance to survival is the resultant functional status and life quality. Among an octogenarian group with 69% of patients class III or IV preoperatively, 81% were class I or II at follow-up.254 Formal quality of life assessment in patients 70 to 89 years after aortic valve replacement showed comparable scores to age-matched population norms in most domains.255 Bioprosthetic rather than mechanical valves are often chosen for very elderly patients to avoid problems of anticoagulation and because these valves deteriorate more slowly in elderly patients.256 Concurrent CABG surgery decreased early mortality in elderly patients with significant associated CHD.244 Aortic balloon valvotomy is rarely undertaken because of the high rates of restenosis and of posthospital mortality, but it may offer limited palliation for highly symptomatic elderly patients who are not candidates for valve replacement.257–259 Despite modest decreases in
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peak pressure gradient and increases in valve area, hospital mortality was 4% to 9%, one-fourth of patients had died by 6 months, and their event-free 1-year survival was 43%.258 Balloon valvotomy may be used to improve the status of elderly patients with severe aortic stenosis and heart failure, increasing the likelihood of subsequent successful valve replacement.260
Aortic Regurgitation Aortic regurgitation, caused by myxomatous or other valvular degeneration, congenital bicuspid aortic valve, rheumatic heart disease, infective endocarditis, rheumatoid disease, aortic dissection, trauma, syphilis, systemic arterial hypertension, and a number of other disorders, is the most common cause of a diastolic murmur at old age and can usually be diagnosed by clinical examination. Echocardiography and Doppler studies can help to assess the hemodynamic severity. Aortic regurgitation is typically managed medically with dietary sodium restriction, diuretics, vasodilator drugs, and digitalis to control cardiac failure. Nifedipine therapy in asymptomatic patients with severe aortic regurgitation and normal left ventricular function may avert or delay the need for valve replacement.261 Exercise tolerance, as in younger patients, is often preserved even with advanced disease. Decrease in left ventricular contractility (ejection fraction below 50%–55%) or progressive increase in ventricular volumes (end-systolic volume greater than 55%) warrant valve replacement; surgical mortality is excessive once clinical heart failure supervenes.245 The results of aortic valve replacement for aortic regurgitation are less satisfactory than for aortic stenosis, at least in part because of the frequently severe ventricular dysfunction. Acute aortic regurgitation, as may occur with trauma or infective endocarditis, typically presents with acute pulmonary edema and requires urgent valve replacement. Patients may be misdiagnosed as having MI. The diagnosis is often overlooked because of the lack of the characteristic wide pulse pressure and cardiac enlargement and the brief or inaudible murmur due to overwhelming cardiac failure. Diagnosis is often made by echocardiography.
Mitral Regurgitation Mitral regurgitation is more common than mitral stenosis at elderly age. Common causes of mitral regurgitation in elderly patients include rheumatic heart disease, myxomatous mitral leaflet degeneration, mitral valve prolapse, mitral annular calcification, and papillary muscle dysfunction or chordal rupture, secondary to CHD. Mitral annular calcification is more frequent in women than men and can often be diagnosed by the character-
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istic C-shaped roentgenographic calcification or at echocardiography. Myxomatous degeneration of the mitral valve may cause mitral valve prolapse. Many elderly patients with chronic mitral regurgitation and sinus rhythm are asymptomatic, with the onset of atrial fibrillation precipitating hemodynamic decompensation. The diagnosis of mitral regurgitation usually can be made by clinical examination, but echocardiographic examination often suggests the cause. Medical therapy is usually appropriate unless mitral regurgitation is of major hemodynamic importance; Doppler echocardiography may help to quantify the severity of the mitral regurgitation. Assessment of exercise capacity and noninvasive documentation of left ventricular systolic function can identify symptomatic patients for whom cardiac catheterization is appropriate to assess suitability for operative intervention. Outcomes are improved with operation before deterioration of ventricular function.262 The prevalence of mitral valve prolapse in elderly patients is not well established. Mitral valve prolapse may be asymptomatic in some elderly patients and be diagnosed only by the classic auscultatory findings. In others, however, disabling chest pain occurs.263 Because of the frequently associated nonspecific repolarization abnormalities on the electrocardiogram, an erroneous diagnosis of angina pectoris may be made. Palpitations should suggest an associated arrhythmia. In contrast to younger patients, mitral valve prolapse in elderly patients, particularly elderly men, may result in severe mitral regurgitation and symptomatic heart failure. There may be complicating infective endocarditis or ruptured chordae tendineae; again, in contrast to the female predominance in the younger population, heart failure secondary to mitral valve prolapse predominates in elderly men. Mitral valve replacement in elderly patients is less satisfactory than aortic valve replacement,264 with a surgical mortality rate of 10% to 14%. This difference is due in part to urgent or emergency surgery as with MI-related severe acute mitral regurgitation, prior limited attention to papillary muscle preservation, and almost uniform associated left ventricular dysfunction. Papillary muscle integrity seems especially important in elderly patients to prevent progressive ventricular failure. Mitral regurgitation secondary to myocardial ischemia is also more frequent in elderly patients. The mortality rate of combined mitral valve replacement and CABG surgery may average 30% for patients in the eighth and ninth decades, and residual cardiac dysfunction and symptoms are more likely to be present than after aortic valve replacement. Mitral valve repair entails both lower mortality and fewer thromboembolic complications, but data are limited on mitral valve reconstruction in elderly patients.197,202,265 Extensive mitral annular calcification may complicate surgery. Requirement for anticoagulation must be considered with decision for mechanical
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valve implantation. Although bioprosthetic valves may enable freedom from anticoagulation in patients in sinus rhythm, bioprosthetic valve degeneration may necessitate reoperation at even older age. Education of elderly patients, attention to drug interactions, and contemporary lower-dose regimens can minimize bleeding complications of ambulatory anticoagulation. Antibiotic prophylaxis against infective endocarditis is needed for the frequent invasive diagnostic or surgical procedures performed in hospitalized elderly patients; recommendations apply comparably to older and younger patients.266 Acute massive mitral regurgitation, as occurs with chordal rupture or flail mitral leaflet associated with infective endocarditis or papillary muscle rupture in the setting of acute MI, typically presents with acute pulmonary edema with hypotension or cardiogenic shock and requires emergency valve replacement. Transesophageal echocardiography is valuable for clinical decision making.267 Intraaortic balloon counterpulsation support may be needed to enable cardiac catheterization and induction of anesthesia.
Mitral Stenosis Mitral stenosis, usually rheumatic in origin, rarely becomes newly symptomatic in elderly patients, except at the development of atrial fibrillation. Control of the ventricular response rate typically restores compensation. Rarely, mitral stenosis is caused by progressive mitral annular calcification. Mitral balloon commissurotomy is increasingly used for symptomatic elderly patients because of its long-term beneficial effects on symptoms, functional status, hemodynamic measurements, and exercise capacity.257,268,269 However, calcification of the mitral valve and valve apparatus limits the suitability for balloon valvuloplasty.
Congenital Heart Disease Congenital cardiac lesions rarely cause de novo hemodynamic problems in the elderly population. Most congenital cardiac lesions of hemodynamic significance have been corrected in childhood or young adulthood.270 Too few patients with corrected congenital heart disease have yet reached a very old age for determination to be made regarding their risk of arrhythmia, ventricular dysfunction, and other abnormalities. Uncorrected secundum atrial septal defect is the most frequent congenital cardiac lesion in elderly patients; these patients are characteristically asymptomatic in the absence of complicating pulmonary hypertension or supraventricular tachyarrhythmias. In patients symptomatic with dyspnea and fatigue who do not have elevated pulmonary vascular resistance, shunt closure improves
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symptoms and entails only a modestly greater risk than in a younger age group. Surgical correction is not indicated for a small calcified persistent ductus arteriosus because of the unacceptably high surgical risk without defined benefit.
Infective Endocarditis and Nonvalvular Cardiovascular Infections Although one-third of all cases of infective endocarditis occur in elderly patients, its recognition is often delayed or missed in this age group because of fewer and atypical symptoms271 and an absent or minimal febrile response. A cardiac murmur may not be prominent; the major presentations may be anemia, renal failure, hemiplegia, or unexplained coma. A high index of suspicion for endocarditis is warranted in elderly patients with otherwise unexplained fever, weight loss, embolic episodes, or confusion. Earlier recognition associated with the high diagnostic sensitivity of transesophageal echocardiography is credited in a recent report with improving clinical outcomes at elderly age, making them comparable to those for younger patients.271 Elderly individuals constitute an increasing percentage of patients with infective endocarditis, and the problem is likely to increase further in prevalence as more elderly patients are hospitalized and undergo complex invasive diagnostic and therapeutic procedures. Endocarditis is associated with a higher mortality than in younger patients,272 in part because of the delay in diagnosis and in the initiation of appropriate therapy. Invasive vascular procedures are the most common sources of infection; almost one-fourth of all episodes are nosocomially acquired. In addition to the organisms usually encountered in a younger population, enterococci, Streptococcus bovis, and coagulase-negative staphylococci occur with excess frequency in elderly patients.272 Coagulase-negative staphylococci are typically traceable to invasive vascular or skin sources. Streptococcus bovis appears due to gastrointestinal problems, and enterococcal endocarditis appears related to the increase in genitourinary procedures performed in elderly men. Aortic valve endocarditis is most common, with mitral regurgitation the second most frequent predisposing valvular lesion. Infective endocarditis often occurs in elderly patients with intracardiac prosthethic devices.273 Dosages of antibiotics may require reduction due to abnormalities of renal function and comorbid illness. Valve replacement must be addressed with hemodynamically significant abnormalities. Use of prophylactic antibiotics for appropriate invasive procedures can limit the occurrence of infective endocarditis in susceptible elderly patients.266 Nonvalvular cardiovascular infections are also more common in elderly patients, reflecting frequent use of implantable devices and prosthetic materials in a geri-
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atric population. The subtle presentations warrant a high index of suspicion to initiate diagnostic measures.274
Cardiomyopathy Hypertrophic cardiomyopathy occurs relatively frequently and is commonly underdiagnosed in elderly patients;275 it may be incorrectly labeled as aortic valvular stenosis, mitral regurgitation, or the papillary muscle dysfunction of CHD. Incorrect diagnosis, with resultant inappropriate drug therapy (e.g., digitalis and other positive inotropic drugs, diuretics, nitroglycerin, and vasodilator drugs), may exacerbate the outflow obstruction and result in serious complications. Although about one-third of individuals with hypertrophic cardiomyopathy are older than age 60, little is known about the natural history of hypertrophic cardiomyopathy in elderly patients. In some series, women predominate among elderly patients with hypertrophic cardiomyopathy. The prognosis appears to be better than in a younger population, as serious arrhythmias or sudden cardiac death are unusual.276 This prognosis may represent survival of a low-risk population, decreased physical activity with aging that limits risk, or this may be a different disease; disproportionate septal thickening and alteration in ventricular configuration occur with aging.277 It remains uncertain whether hypertension is etiologic;278 anterior displacement of the mitral valve due to mitral annular calcification may also be contributory. Left ventricular hypertrophy is described as more modest in elderly patients, involving predominantly the ventricular septum, with outflow obstruction caused by a combination of systolic anterior motion of the anterior mitral leaflet and posterior motion of the ventricular septum.279 Elderly patients characteristically have onset of symptoms late in life.279 Clinical symptoms include dizziness, palpitations,syncope,chest pain,fatigue,and dyspnea,with the latter often the prominent complaint. Severe dyspnea portends an unfavorable prognosis.276 It is uncertain whether symptoms differ from those of younger patients. Onset of atrial fibrillation may produce rapid hemodynamic deterioration, owing to dependence of the poorly compliant hypertrophied ventricle on the atrial contribution to ventricular filling to maintain stroke volume. Physical examination may pose diagnostic problems in that brisk carotid pulsations are erroneously ascribed to decreased vascular elasticity, and an S4 and nonspecific systolic murmurs are common in elderly patients. A bisferiens carotid pulse or a double cardiac apex impulse may be the clue to perform appropriate maneuvers. The left sternal border systolic murmur increases with a Valsalva maneuver and decreases on squatting. An aortic regurgitant murmur may be caused by coexisting calcific aortic valve disease.
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The electrocardiogram is that of left ventricular hypertrophy; Q waves of septal hypertrophy may mimic MI. Echocardiography can confirm the diagnosis. Free wall myocardial hypertrophy may equal that of the ventricular septum. Prophylaxis against infective endocarditis is appropriate. The majority of symptomatic elderly patients benefit from medical therapy. Calcium- or beta-blocking drug therapy can alleviate symptoms of angina and dyspnea. Hypovolemia increases risk and should be avoided. Occasionally, severely symptomatic elderly patients with a significant ventricular outflow gradient and an unsatisfactory response to medical management warrant surgical correction.280 Dilated cardiomyopathy is infrequent in an elderly population, as the majority of patients with this problem do not survive to an elderly age. Hypertension and lower educational levels are associated with dilated cardiomyopathy at elderly age.281 The management is as for ventricular systolic dysfunction and includes digitalis, diuretics, angiotensin-converting enzyme (ACE) inhibitors, and other vasodilator drugs; anticoagulation is recommended, particularly when there is associated atrial fibrillation, to prevent embolic events.282 Restrictive cardiomyopathy is unusual in elderly patients. Although senile cardiac amyloidosis has a high prevalence among the oldest old patients, atrial fibrillation, rather than restrictive cardiomyopathy, seems to be the more frequent manifestation. ECG voltage is low in patients with cardiac amyloidosis, and echocardiography may demonstrate a “sparkling” appearance to the myocardium. Hemochromatosis is another, although uncommon, cause of restrictive cardiomyopathy. Restrictive cardiomyopathy is increasingly encountered as a consequence of CABG surgery and postoperative pericarditis, as well as of radiation therapy to the chest.
Cardiac Disease Secondary to Pulmonary Disease Pulmonary embolism is a frequent and often unrecognized complication of many systemic illnesses in elderly patients.283 The combination of prolonged bed rest, a sedentary lifestyle, cardiopulmonary diseases, heart failure, and frequent surgical procedures are the major predisposing factors, as is atrial fibrillation. It is often misdiagnosed as pneumonia or heart failure. An estimated 107,000 hospitalizations annually in the Medicare population result from deep vein thrombosis and pulmonary embolism.284 The clinical presentation varies from an acute cardiovascular emergency characterized by dyspnea, orthopnea, chest discomfort, syncope, or shock, or at times may be manifest only as increased cough, mild chest discom-
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fort, transient dyspnea, or a worsening of heart failure. Sudden unexplained dyspnea should be considered to be caused by pulmonary embolism until proved otherwise. A high index of suspicion is warranted to search for evidence of deep vein thrombosis of the leg and evidence of acute cor pulmonale. Pulmonary ventilation-perfusion scanning is the initial screening procedure. However, isotopic perfusion lung scanning abnormalities may occur in the absence of pulmonary embolism because of the nonuniform perfusion of the aged lung. Spiral CT scanning appears to provide comparable diagnostic accuracy and greater safety. Pulmonary angiography, if needed, does not entail substantially greater risk than at younger age, save for the more frequent complicating renal failure.283 Clinical findings include tachypnea, tachycardia, often a low-grade fever, an accentuated pulmonic component of S2 with wide splitting, a prominent parasternal impulse, an accentuated a wave in the jugular venous pulse, and at times evidence of right ventricular decompensation. Deep vein thrombosis of the leg also may be evident. In a Medicare population, the 30-day case-fatality rates increased with increasing age. The risk of fatality was very high (25%–40%) when pulmonary embolism complicated cardiac problems, including heart failure, stroke, MI, and chronic pulmonary disease, and after CABG surgery or hip or knee replacement. These data highlight the need for deep vein thrombosis prophylaxis in these populations.285 Anticoagulation, initially with heparin and subsequently with warfarin, is the treatment of choice. Thrombolytic therapy may be indicated for massive pulmonary embolism with hemodynamic instability; the risk of bleeding is increased at elderly age. Vena caval obstruction with a transvenously inserted filter device is appropriate when anticoagulation is contraindicated. Pulmonary heart disease in elderly patients is superimposed on the decreased elastic properties of the aged lung, as well as the loss of pulmonary vascular reserve and the decrease in ventilatory function and pulmonary diffusing capacity of aging. The most common form of chronic pulmonary heart disease that causes cor pulmonale and right ventricular failure at elderly age is chronic obstructive pulmonary disease due to chronic bronchitis and emphysema. The mortality from this problem among elderly patients is related, at least in part, to their coexisting cardiovascular disease, predominantly CHD and hypertensive cardiovascular disease. Recurrent pulmonary embolism is an important etiology, especially with prolonged immobilization at bed rest. Primary pulmonary hypertension has also been described in old age.286 Smoking is a chronic contributor to the increased severity of cardiac decompensation; environmental pollutants and respiratory infections cause intermittent exacerbations.
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An accentuated pulmonic component of S2, often with wide splitting; jugular venous distension with prominent a and v waves; a parasternal cardiac impulse; a right-sided S3; the holosystolic murmur of tricuspid regurgitation that increases with inspiration; hepatomegaly and peripheral edema; and right axis deviation of the frontal plane QRS axis and evidence of right ventricular hypertrophy and right atrial abnormality on the ECG are the clinical findings of pulmonary hypertension and right ventricular decompensation. Echocardiography or radioisotope angiography may help differentiate pulmonary hypertension due to pulmonary vascular obstruction with right-sided heart failure from left-sided heart disease, pulmonary hypertension, and right-sided heart failure. Therapy includes smoking cessation, bronchodilator drugs, liquefaction of sputum, and treatment of respiratory infections. Sodium restriction and diuretic therapy may lessen heart failure. Digitalis use is controversial except for control of the ventricular response rate to supraventricular tachyarrhythmias. Digitalis toxicity is common in elderly patients with chronic lung disease. Compensation of the pulmonary status best controls supraventricular arrhythmia. There is no evidence that any pulmonary vasodilator drugs have a beneficial effect on a long-term basis, despite the demonstration of acute hemodynamic improvement. Similarly, phlebotomy to reduce blood viscosity in patients with moderate erythrocytosis remains controversial in that the oxygencarrying capacity of the blood is reduced and little hemodynamic benefit is attained. Low- to moderateintensity regular aerobic exercise can improve functional status in patients with a compensated pulmonary status. Therapeutic problems are accentuated with concomitant cardiac and pulmonary disease, in that the nonselective beta-blocking drugs used to treat CHD or hypertension may induce bronchospasm and worsen chronic lung disease; conversely, theophylline and betaagonist drugs used as bronchodilators to manage chronic obstructive pulmonary disease may worsen angina and hypertension and induce arrhythmias. Corticosteroid therapy for chronic obstructive pulmonary disease may exacerbate hypertension and heart failure. When significant hypoxemia is present, elderly patients have a favorable response, comparable with that of younger patients, to continuous low-flow oxygen therapy, if respiratory depression does not occur.
Noncardiac Surgery in Elderly Patients with Cardiovascular Disease The increasing numbers of elderly persons and the success of surgical procedures at geriatric age have increased the number of surgical interventions in this
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population. More than one-fifth of all noncardiac surgical procedures currently involves elderly patients. Cardiac complications are the major contributors to perioperative morbidity and mortality. Emergency surgery entails the highest cardiovascular risk, as cardiac problems cannot be optimally managed preoperatively or cardiac risk status is unknown. There is more heterogeneity in an elderly population than within any other age group; chronologic age poorly predicts either a patient’s physiologic age or functional capabilities. Negative stereotypes of elderly persons as being seriously ill and disabled often inappropriately bias recommendations and decisions about medical care and particularly surgical interventions for elderly cardiac patients. Age alone should not constitute a contraindication to surgical therapy; the increased complications in elderly patients relate predominantly to their associated diseases; these should prominently influence clinical decisions. Mental status, cognitive ability, and expectations from medical care are other attributes to be considered. Both overt and occult cardiovascular disease, but particularly CHD, contribute to the increased risk of perioperative cardiovascular complications. In addition to cardiac disease, noncardiovascular surgery in elderly patients is often complicated by cerebrovascular and peripheral vascular disease, atherosclerosis of the aorta and great vessels, impaired renal function, prostatic obstruction, pulmonary disease, and malnutrition. In addition to cardiac status, cardiac risk for anesthesia and surgery encompasses the baseline physiologic changes of aging and the comorbid illnesses. As with cardiac surgery, overall recovery from noncardiac surgery at elderly age is protracted, with increased needs for nursing care and more time spent in an intensive care setting. Perioperative MI is the major cause of postoperative mortality at elderly age owing to the high prevalence of known and unrecognized CHD.287 The highest risk for noncardiac surgery is within 6 months of MI; only emergency or urgent surgery should be undertaken in this period. Unstable angina, residual myocardial ischemia, uncontrolled hypertension, and decompensated heart failure also entail an adverse prognosis. Because of the high prevalence of significant CHD in asymptomatic or minimally symptomatic elderly patients, preoperative exercise or pharmacologic thallium scintigraphy or echocardiography helps evaluate CHD status, assessing the extent of myocardial ischemia and consequent risk status, suggesting the need for further evaluation.288 A normal study identifies low risk status, abnormalities in one vascular territory intermediate risk status, and reversible defects in more than one vascular territory (suggesting multivessel CHD) high risk status. Determination of anaerobic threshold at exercise testing is described to precisely assess cardiovascular reserve and surgical risk at elderly age.289 Coronary arteriography can
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define the need and suitability for myocardial revascularization before noncardiac surgery. High-risk patients with a varied age range who had CABG surgery before noncardiac surgery had a mortality risk comparable to that of patients without significant CHD.290 Risk stratification is particularly indicated before elective peripheral vascular surgery because of the substantial concordance of known and unrecognized but correctable CHD with peripheral arterial disease.291,292 Intraoperative and postoperative surveillance should highlight adequate oxygenation, electrolyte balance, and control of cardiac failure and arrhythmia. Pulmonary artery catheter monitoring is warranted for severe heart failure or suspected myocardial ischemia. Prophylactic digitalis administration and prophylactic pacemaker insertion are not indicated. Most patients with known suspected CHD should have continuous intraoperative ECG monitoring. Evaluation for an acute event by cardiac enzymes and ECG daily for at least 3 days postoperatively shows the highest occurrence of acute coronary events on postoperative days 2 and 3.
Preventive and Rehabilitative Approaches to Care As increased numbers of reasonably healthy and active individuals enter old age, more precise assessment of their functional capabilities will be required to determine suitable vocational, as well as recreational and leisure, activities. Remunerative work, continuing into the eighth decade, may soon be usual. This elderly population can be anticipated to have greater interest in and requirements for both primary and secondary preventive cardiovascular care. At the same time, an overriding concern among elderly persons is maintenance of a self-sufficient and independent lifestyle, to which loss or deterioration of functional capability is viewed as a threat. Preventive strategies are increasingly applied to the elderly population, as modifiable coronary risk factors are highly prevalent in elderly patients293 and continue to predict the occurrence and recurrence of coronary events and mortality in old age294 (Table 39.3). Elderly persons are health conscious, as shown by their disproportionate representation in most health screening programs. Given the estimated U.S. life expectancy of 16.9 years at age 65 and 10.7 years at age 75, coronary risk reduction strategies are appropriate. However, data from a Canadian study295 show that even among hospitalized patients at high risk for cardiovascular events, risk factor assessment and modification was suboptimal, particularly for women and elderly patients. Because of continued progression of coronary atherosclerotic lesions even in old age, risk intervention may arrest the progression or induce regression of atherosclerosis. Because preventive data are less
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531
Table 39.3. Impact of risk factors on cardiovascular disease incidence by age in men and women at 30-year follow-up: Framingham Study. Multivariate logistic regression coefficientsa at age: 35–64 yearsb Risk factor Systolic pressure Diastolic pressure Serum cholesterol level Blood glucose level Relative weight Vital capacity Cigarettes ECG-LVH Intraventricular block NSA-ST-T
Age, 65–94 yearsb
Men
Women
Men
Women
0.341* 0.302* 0.230*** 0.087*** 0.080**** -0.089**** 0.333* 0.121* 0.049*** 0.053*
0.361* 0.288** 0.202* 0.176*** 0.134** -0.252* 0.183* 0.112* 0.075**** 0.130*
0.410* 0.259* 0.091**** 0.146* 0.044* -0.109* 0.045* 0.142* 0.096**** 0.187*
0.207* 0.089* 0.040* 0.173* 0.052* -0.216* 0.083* 0.229* 0.096**** 0.147*
ECG-LVH, electrocardiographic evidence of left ventricular hypertrophy; NSA-ST-T, nonspecific ST segment and T-wave abnormalities. a Covariates for each variable cited in “Risk Factor” column: blood pressure, cholesterol, cigarettes, and electrocardiographic evidence of left ventricular hypertrophy. b Age at biennial examination. * p < 0.001; ** p < 0.01; *** not significant; **** p < 0.05. Source: Modified from Kannel et al. Coronary events, stroke, cardiac failure, and peripheral arterial disease. Reprinted with permission from American College of Cardiology (J Am Coll Cardiol. 1987;10:25A–28A), with permission.
robust than for younger patients, interventions should entail few risks, involve few adverse effects, and have reasonable cost. Preventive approaches include control of hypertension, weight reduction or control, dietary sodium and fat restriction, regular modest-intensity physical activity, and emphasis on smoking cessation. Although the relative importance of coronary risk factors decreases somewhat with age, the absolute or attributable risk is greater due to the excess coronary morbidity and mortality in elderly patients. In the Honolulu Heart Study smoking, hypertension, diabetes, and hypercholesterolemia conferred a comparable relative risk for CHD at middle and old age.296 In the Cardiovascular Health Study (CHS),297 noninvasively detected subclinical disease was associated with a very high risk of clinical disease, with systolic hypertension and diabetes the most powerful traditional risk factors.101 Noninvasively detected subclinical disease, that is, abnormal echocardiographic ejection fraction, increased internal carotid intima-medial thickness, and low ankle–arm index, also was an independent predictor for 5-year mortality.298 Aggressive preventive interventions appear warranted for elderly persons with subclinical disease. Higher levels of fibrinogen and factor VIII299 were associated with an increased risk for cardiovascular events and mortality in CHS, and C-reactive protein was associated with incident cardiovascular events, especially in elderly individuals with subclinical disease.300 The lesser risk relationship of cholesterol levels to coronary disease in older adults is offset by the greater occurrence of CHD in elderly persons.301 Elevated total
cholesterol levels increase risk of coronary death at elderly age; risk for coronary death decreased as cholesterol levels decreased.302 In the Zutphen Elderly Study,303 both total and HDL cholesterol were important predictors of CHD in elderly men. Vegetarians, who have lower cholesterol levels than nonvegetarians, also show lower CHD rates even in the 75- to 84-year-old age group.304 Women constitute a greater proportion of the elderly population, where the occurrence of MI is comparable in elderly men and women, so that detection and management of CHD must intensively involve elderly women. Although mean blood cholesterol levels are higher in men before the fifth decade, women subsequently have higher mean total cholesterol levels, which continue to increase at least to age 80, due to progressive increases in low-density (LDL) cholesterol, which exceeds that for men at elderly age. Recommendations for recognition and management of hyperlipidemia are comparable in younger and elderly populations, as hypercholesterolemia continues to confer increased coronary risk at elderly age. The Adult Treatment Panel of the National Cholesterol Education Program (NCEP) recommends that all adults with total blood cholesterol values above 200 mg/dL be evaluated and that those with elevated LDL cholesterol levels be treated.305 About one-third of elderly men and one-half of elderly women have elevated cholesterol levels warranting intervention, based on NCEP guidelines.306 Recommendations for cholesterol lowering in the elderly population are based predominantly on extrapolation of data derived from younger populations, although one study of postinfarction patients that included a sizeable
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elderly cohort307 described a 28% reduction in total mortality in patients treated with lipid-lowering agents. Nevertheless, few elderly patients were enrolled in most secondary prevention studies, and virtually none older than 75 years. Although intervention outcome data are limited for geriatric populations, statin drugs appear to have similar efficacy and safety in nonelderly and elderly populations.308–311 Dietary therapy is recommended for the aged adult; this consists of a diet restricted in saturated fat and cholesterol and high in fruits, vegetables, and grains; additional dietary components include lean meats, fish, and low-fat dairy products. A trained nutritionist or dietitian can often help elderly individuals initiate appropriate dietary management, while assuring adequate nutrition. This diet may confer other health benefits as well. Cigarette smoking continues to be associated with an increased risk of sudden cardiac death and fatal reinfarction,312 and smoking cessation decreases cardiovascular risk to that of nonsmoking individuals, independent of the age at smoking cessation.313 Smoking cessation decreased the risk of mortality or MI in older men and women with angiographically documented coronary disease in the Coronary Artery Surgery Study (CASS) Registry.314 Because deconditioning from inactivity occurs more rapidly at elderly age, a physically active lifestyle should be encouraged for elderly patients, incorporating a planned regimen of modest-intensity physical activity, designed to improve functional status and minimize or delay subsequent disability and dependency. A physical activity regimen, even in previously sedentary elderly patients, can enhance endurance and functional capacity. Resistance training improved walking endurance in healthy elderly individuals.315 Although the effect of exercise on coronary risk has not been examined systematically in elderly populations, high-level physical activity (>2000 Kcal weekly) in persons 65 to 79 years was associated with improved survival compared with individuals with lower physical activity levels.316 Moderate- and highintensity walking lowered blood pressure in normotensive elderly subjects;317 lower rates of hypertension are described in physically active elderly women.220 Both the physiologic characteristics of aging and the superimposed limitations due to cardiovascular disease must be addressed in formulating physical activity recommendations. Exercise recommendations must be individualized, avoiding excessive fatigue or exhaustion and limiting musculoskeletal injuries by restriction of running, jumping, and other high-impact activities.185 Brisk walking is generally recommended. Both physical activity318 and correct nutrition, including weight control, contribute importantly to the maintenance of cardiovascular function at elderly age. High-intensity resistance exercise can effectively counteract muscle weakness and physical frailty in very elderly people.319
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Hypertension, elevation of both the systolic and the diastolic blood pressures, is the dominant cardiovascular risk factor in the elderly population, with its incidence increasing with advancing age; it continues to impart risk in elderly persons. Control of blood pressure limits cerebrovascular complications and facilitates the management of angina and of heart failure. Dietary sodium restriction is important in blood pressure control. Electrocardiographic evidence of left ventricular hypertrophy, intraventricular conduction disturbances, and nonspecific repolarization abnormalities all independently predict future cardiovascular events. Control of obesity, in addition to decreasing cardiac work and cardiovascular risk, favorably affects glucose tolerance, blood pressure, and serum lipid levels. Diabetes mellitus or glucose intolerance remains an independent predictor of cardiovascular risk in old age. Postmenopausal estrogen use by women in the Cardiovascular Health Study320 was associated with a more favorable cardiovascular risk profile well into the eighth decade. Whether this improvement reflects hormone effect or the baseline characteristics of women who continue hormone therapy or both is unknown. The role of dietary and pharmacologic antioxidants remains uncertain.321 The decline in coronary mortality in the United States from 1963 to 1981 affected all ages, but was less prominent in the elderly population; because most cardiovascular risk factors can be modified in elderly persons, attention to this aspect seems to be appropriate. Based on Framingham data,99 the 10% of individuals aged 65 to 74 years with the highest multivariate coronary risk scores had a twofold greater occurrence of coronary events among men and fourfold greater occurrence among women. In the elderly Framingham cohort, elevated risk levels for cardiovascular disease were associated with increased Medicare costs.322 Benefits of risk reduction, however, must be extrapolated from intervention trials in younger-aged patients; however, conventional risk modification may favorably affect other health aspects as well. Risk status can be ascertained by standard clinical examinations and simple laboratory tests. Most preventive measures that are appropriate for older individuals constitute reasonable and relatively simple modifications of existing habits; unfavorable lifestyle behaviors can be modified to favorably affect cardiovascular risk.
Conclusion In planning for health care in the twenty-first century, the increased proportion of elderly patients, who often will have cardiovascular disease and often will require advanced technology diagnostic and therapeutic interventions, must be addressed.323 Comparison must be
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made of the resources required for and outcomes of palliative care if sophisticated techniques are not undertaken. The use of health care resources will increase not only with increasing age but with the improved expectations of older persons about their health status. At the same time, it will be necessary to avoid overzealous and redundant diagnostic and therapeutic measures. Data are needed to define interventions at old and very old age that favorably affect morbidity and mortality, functional status, and other meaningful quality of life attributes. Preventive aspects will increasingly become important components of care for elderly cardiac patients, and require the development of cost-effective preventive strategies, although it remains uncertain how much extension of years of health and decrease in disability can be anticipated in later life. The decline in premature cardiovascular mortality in recent decades appears an important component in the longevity of the elderly population; however, it is not certain whether the effect of preventive efforts in limiting or delaying cardiovascular disease will ultimately decrease overall health care costs.
Acknowledgments. With appreciation to Julia Wright and Jeanette Zahler for assistance in the preparation of the manuscript.
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542 267. Ofili EO, Rich MI, Brown P, et al. Safety and usefulness of transesophageal echocardiography in persons aged ≥70 years. Am J Cardiol. 1990;66:1279–1280. 268. Le Feuvre C, Bonan R, Lachurie M-L, et al. Balloon mitral commissurotomy in patients aged ≥70 years. Am J Cardiol. 1993;71:233–236. 269. Meneveau N, Schiele F, Seronde M-F, et al. Predictors of event-free survival after percutaneous mitral commissurotomy. Heart. 1998;80:359–364. 270. Cheitlin MD. Congenital heart disease in the adult. Mod Conc Cardiovasc Dis. 1986;55:20–24. 271. Werner GS, Schulz R, Fuchs JB, et al. Infective endocarditis in the elderly in the era of transesophageal echocardiography: clinical features and prognosis compared with younger patients. Am J Med. 1996;100:90–97. 272. Terpenning MS, Buggy BP, Kauffman CA. Infective endocarditis: clinical features in young and elderly patients. Am J Med. 1987;83:626–634. 273. Selton-Suty C, Hoen B, Grentzinger A, et al. Clinical and bacteriological characteristics of infective endocarditis in the elderly. Heart. 1997;77:260–263. 274. Kearney RA, Eisen HJ, Wolf JE. Nonvalvular infections of the cardiovascular system. Ann Intern Med. 1994;121:219– 230. 275. Krasnow N, Stein RA. Hypertrophic cardiomyopathy in the aged. Am Heart J. 1978;96:326–336. 276. Fay WP, Taliercio CP, Ilstrup DM, et al. Natural history of hypertrophic cardiomyopathy in the elderly. J Am Coll Cardiol. 1990;16:821–826. 277. Lever HM, Karam RF, Currie PJ, et al. Hypertrophic cardiomyopathy in the elderly: distinctions from the young based on cardiac shape. Circulation. 1989;79:580– 589. 278. Pearson AC, Gudipati CV, Labovitz AJ. Systolic and diastolic flow abnormalities in elderly patients with hypertensive hypertrophic cardiomyopathy. J Am Coll Cardiol. 1988;12:989–995. 279. Lewis JF, Maron BJ. Clinical and morphologic expression of hypertrophic cardiomyopathy in patients ≥65 years of age. Am J Cardiol. 1994;73:1105–1111. 280. Koch J-P, Maron BJ, Epstein ES, et al. Results of operation for obstructive hypertrophic cardiomyopathy in the elderly: septal myotomy and myectomy in 20 patients 65 years of age or older. Am J Cardiol. 1980;46: 963–966. 281. Coughlin SS, Tefft MC, Rice JC, et al. Epidemiology of idiopathic dilated cardiomyopathy in the elderly: pooled results from two case-control studies. Am J Epidemiol. 1996;143:881–888. 282. Shah PM, Abelmann WH, Gersh BJ. 18th Bethesda Conference: Cardiovascular Disease in the Elderly. Cardiomyopathies in the elderly. J Am Coll Cardiol. 1987; 10(suppl A):77A–79A. 283. Stein PD, Gottschalk A, Saltzman HA, et al. Diagnosis of acute pulmonary embolism in the elderly. J Am Coll Cardiol. 1991;18:1452–1457. 284. Kniffin WD Jr, Baron JA, Barrett J, et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med. 1994;154:861– 866.
N.K. Wenger 285. Siddique RM, Siddique MI, Connors AF Jr, et al. Thirtyday case-fatality rates for pulmonary embolism in the elderly. Arch Intern Med. 1996;156:2343–2347. 286. Braman SS, Eby E, Kuhn C, et al. Primary pulmonary hypertension in the elderly. Arch Intern Med. 1991;151: 2433–2438. 287. Mangano DT. Perioperative cardiac morbidity. Anesthesiology. 1990;72:153–184. 288. Eagle KA, Brundage BH, Chaitman BR, et al. Guidelines for perioperative cardiovascular evaluation for noncardiac surgery: report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation. 1996;93: 1278–1317. 289. Wasserman K. Preoperative evaluation of cardiovascular reserve in the elderly. Chest. 1993;104:663–664. 290. Foster ED, David KB, Carpenter JA, et al. Risk of noncardiac operation in patients with defined coronary disease: the Coronary Artery Surgery Study (CASS) Registry experience. Ann Thorac Surg. 1986;41:42–50. 291. Gersh BJ, Rihal CS, Rooke TW, et al. Evaluation and management of patients with both peripheral vascular and coronary artery disease. J Am Coll Cardiol. 1991;18:203– 214. 292. Towne JB, Weiss DG, Hobson RW II. First phase report of Cooperative Veterans Administration asymptomatic carotid stenosis study: operative morbidity and mortality. J Vasc Surg. 1990;11:252–259. 293. World Health Organization Study Group. Epidemiology and Prevention of Cardiovascular Diseases in Elderly People. WHO Technical Report Series 853. Geneva: World Health Organization; 1995. 294. Tervahauta M, Pekkanen J, Nissinen A. Risk factors of coronary heart disease and total mortality among elderly men with and without preexisting coronary heart disease: the Finnish Cohorts of the Seven Countries Study. J Am Coll Cardiol. 1995;26:1623–1629. 295. The Clinical Quality Improvement Network (CQIN) Investigators. Low incidence of assessment and modification of risk factors in acute care patients at high risk for cardiovascular events, particularly among females and the elderly. Am J Cardiol. 1995;76:570–573. 296. Masaki KH, Petrovitch H, Rodriquez BL, et al. The value of risk factor modification in old age. Cardiol Elderly. 1993;1:391–397. 297. Kuller L, Borhani N, Furberg C, et al. Prevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study. Am J Epidemiol 1994;139:1164–1179. 298. Fried LP, Kronmal RA, Newman AB, et al., for the Cardiovascular Health Study Collaborative Research Group. Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JAMA. 1998;279:585– 592. 299. Tracy RP, Arnold AM, Ettinger W, et al. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 1999;19:1776–1783.
39. Cardiovascular Disease 300. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;17:1121–1127. 301. Kannel WB, Doyle JT, Shephard RJ, et al. 18th Bethesda Conference: Cardiovascular Disease in the Elderly. Prevention of cardiovascular disease in the elderly. J Am Coll Cardiol. 1987;10(suppl A):25A–28A. 302. Corti M-C, Guralnik JM, Salive ME, et al. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Ann Intern Med. 1997;126:753–760. 303. Weijenberg MP, Feskens EJM, Kromhout D. Total and high density lipoprotein cholesterol as risk factors for coronary heart disease in elderly men during 5 years of follow-up: the Zutphen Elderly Study. Am J Epidemiol. 1996;143:151–158. 304. Snowdon DA, Phillips Rl, Fraser GE. Meat consumption and fatal ischemic heart disease. Prev Med. 1984;13:490– 500. 305. The Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3025. 306. Denke MA, Grundy SM. Hypercholesterolemia in elderly persons: resolving the treatment dilemma. Ann Intern Med. 1990;112:780–792. 307. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand. 1988;223:405–418. 308. Pacala JT, McBride PE, Grady SL. Management of older adults with hypercholesterolaemia. Drugs Aging. 1994;4: 366–378. 309. Santinga JT, Rosman HS, Rubenfire M, et al. Efficacy and safety of pravastatin in the long-term treatment of elderly patients with hypercholesterolemia. Am J Med. 1994;96: 509–515. 310. Hulley SB, Newman TB. Cholesterol in the elderly: is it important? JAMA. 1994;272:1372–1374. 311. Scandinavian Simvastatin Survival Study group. Randomised trial of cholesterol lowering in 4444 patients with
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coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. Jajich CL, Ostfeld AM, Freeman DH Jr. Smoking and coronary heart disease mortality in the elderly. JAMA. 1984;252:2831–2834. LaCroix AZ, Lang J, Scherr P, et al. Smoking and mortality among older men and women in three communities. N Engl J Med. 1991;324:1619–1625. Hermanson B, Omenn GS, Kronmal RA, et al., and participants in the Coronary Artery Surgery Study. Beneficial six-year outcome of smoking cessation in older men and women with coronary artery disease. Results from the CASS Registry. N Engl J Med. 1988;319:1365– 1369. Ades PA, Ballor DL, Ashikaga T, et al. Weight training improves walking endurance in healthy elderly persons. Ann Intern Med. 1996;124:568–572. Paffenbarger RS Jr, Hyde RT, Wing AL, et al. Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med. 1986;314:605–613. Braith RW, Pollock ML, Lowenthal DT, et al. Moderateand high-intensity exercise lowers blood pressure in normotensive subjects 60 to 79 years of age. Am J Cardiol. 1994;73:1124–1128. Wenger NK. Physical inactivity and coronary heart disease in elderly patients. Clin Geriatr Med. 1996;12:79–88. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330: 1769–1775. Manolio TA, Furberg CD, Shemanski L, et al., for the CHS Collaborative Research Group. Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. Circulation. 1993;88(part 1):2163–2171. Hertog MGL, Feskens EJM, Hollman PCH, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993;342:1007–1011. Schauffler HH, D’Agostino RB, Kannel WB. Risk for cardiovascular disease in the elderly and associated Medicare costs: the Framingham Study. Am J Prev Med. 1993;9: 146–154. Wenger NK, ed. Proceedings from the Millennium Symposium: Heart disease in the octogenarian, March 11, 2000. Am J Geriatr Cardiol. 2000;9:1–112.
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40 Hypertension Mark A. Supiano
Classification and Epidemiology Results from cross-sectional studies have shown that blood pressure, particularly systolic blood pressure (SBP), increases with increasing age.1 No age adjustment is made in setting the threshold value that defines high blood pressure. The classification of blood pressure outlined by the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNCVI), shown in Table 40.1, is the same for all adults irrespective of age.2 There were several minor modifications made in the JNC-VI revision of blood pressure classification that have major significance with respect to geriatric hypertension. The former category of isolated systolic hypertension [i.e., SBP > 160 mmHg and diastolic blood pressure (DBP) < 90 mmHg] was removed. In addition, the conjunction linking the systolic and diastolic blood pressure columns that define each stage was changed from “and” to “or.”As a consequence of this new approach to classification and because isolated diastolic hypertension is so uncommon in older individuals, the correct categorization of blood pressure among those above age 60 may be made by using the level of SBP alone in 99% of cases.3 Thus, the SBP level matters for the purposes of classification. Finally, as is discussed, treatment recommendations are stratified, based in large part on the classification strategy shown in Table 40.1. Contrary to a former point of view that held that high blood pressure is an expected normal aspect of aging, it is now evident that hypertension in older individuals defined according to these blood pressure levels should be viewed as a disease state that is associated with an increased risk for adverse outcomes [e.g., coronary heart disease, congestive heart failure (CHF), stroke, peripheral vascular disease, and renal disease) and mortality. Therefore, although common, high blood pressure in older individuals is not benign. It is also important to note that, for any level of diastolic blood pressure, the risk for
these adverse events is progressively greater at higher levels of systolic blood pressure.4,5 Thus, systolic blood pressure matters as a risk factor for cardiovascular disease. In addition, it is increasingly being recognized that a major predictor of cardiovascular risk is the pulse pressure—the difference between systolic and diastolic blood pressure.6 An analysis of data from the Systolic Hypertension in the Elderly Program (SHEP) identified that pulse pressure was a significant predictor of stroke and total mortality independent of the influence of mean arterial blood pressure.7 Therefore, the age-associated increases in systolic blood pressure and in pulse pressure are important contributors to the morbidity and mortality associated with hypertension in older individuals. Epidemiologic studies such as the National Health and Nutrition Examination Surveys have shown that the overall prevalence of hypertension in noninstitutionalized individuals above the age of 65 is between 50% and 70%. The prevalence is highest among AfricanAmericans relative to whites and Mexican-Americans. Unlike the younger hypertensive population in which there is a male predominance, there is no marked gender difference in the overall prevalence of hypertension in the elderly. Moreover, the age-associated increase in the prevalence of isolated systolic hypertension appears to be greater for women than for men.8
Pathophysiology Many age-related changes in physiology contribute to the increase in blood pressure. Lifestyle factors, such as diet, obesity, and physical activity, and the presence of comorbidities are also important contributors. A multitude of pathophysiologic mechanisms interact in the dynamic and complex regulation of arterial blood pressure. The maintenance of blood pressure homeostasis and the provision of adequate cerebral perfusion in the response to such hypotensive stimuli as volume depletion, upright 545
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Table 40.1. Classification of blood pressure. Category Normal High normal Hypertension Stage 1 Stage 2 Stage 3
Systolic (mmHg)
Diastolic (mmHg)
25) has been found to put women at increased risk for the development of OA of the knee.36 Obesity appears to provide an additive risk when combined with heavy physical activity. As yet unknown metabolic factors, possibly related to estrogen, are theorized to explain the differences in risk associated with sex, as well as the increased risk for hand OA with obesity. Because of the markedly increased prevalence of OA in women, as well as the appearance of generalized OA around the time of the menopause, several studies have addressed a possible protective role of estrogen replacement on OA. One cross-sectional study showed an association between postmenopausal estrogen replacement therapy and a reduced risk of radiographic evidence of OA of the hip, with greatest reduction among those who had taken estrogen for 10 or more years.37 The first prospective cohort study to address this question was performed on a subcohort from the Framingham Study.38 Only a modest and not statistically significant protective effect of estrogen replacement therapy on OA of the knee was observed in this particular study. Ever since orthopedic surgeons began noticing that patients undergoing surgery for hip fractures seemed to have a lower than expected prevalence of OA, the possibility of an inverse relationship between OA and osteoporosis has been suspected. The theoretical underpinning for this relationship is that subchondral bone acts as a shock absorber for overlying cartilage and that osteoporotic or softer bone may be acting as a better shock absorber and thus protect against the development of OA.39 This observation has been strengthened in epidemiologic studies, which have verified an inverse correlation between OA and osteoporosis. Women with radiographically defined knee OA had greater bone mineral density (BMD), as measured by dual-energy xray absorptiometry at the femoral neck, than did women
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without knee OA.40 An inverse relationship between OA and osteoporosis of the spine was found when comparing normal subjects with those with OA or osteoporosis of the spine.41 Radiographic hip OA was associated with increased BMD in the femoral neck compared with control subjects in a large prospective study in a cohort from the Study of Osteoporotic Fractures.42 Interestingly, the increase in BMD was not associated with a decreased risk of hip fractures, possibly related to the numbers and types of falls sustained by subjects with OA. This relationship seemingly pertains to OA involving the hand joints as well.43 Osteoarthritis was associated not only with increased BMD but with an increased rate of bone loss as well, suggesting an increased turnover.44 Crystals that are known to cause acute arthritis and periarthritis also play an important role in mediating the expression of OA. The class of crystals most commonly found in osteoarthritic joints is the calcium-containing crystals, of which calcium pyrophosphate and basic calcium phosphate are the best studied.45 Osteoarthritis is both more common and more severe in joints in which chondrocalcinosis or crystals have been demonstrated. The distribution of joints is altered in those with crystalassociated OA. Involvement of the carpus, elbow, and shoulder is significantly more common in crystalassociated OA than in primary OA. The presence of multiple knee compartment involvement is also more common in crystal-associated OA than in the absence of crystal deposition. In the only prospective study to systematically evaluate knee synovial fluid for the presence of calcium pyrophosphate crystals, the presence of crystals was found to be associated with progressive cystic changes, progressive bone attrition, and poor symptomatic and functional outcome.46 However, chondrocalcinosis was not found to be a risk factor for the development of knee OA in a subanalysis of the Framingham Study.34 Importantly, the true prevalence of crystals is probably underestimated by both x-ray and routine synovial fluid analysis as more sensitive methods have demonstrated one or both crystal types in the majority of cases of severe OA of the knee.45
The Role of Joint Instability in the Pathogenesis of OA OA is not merely a disease of cartilage but of all the tissues of the diarthrodial joint, as well as surrounding structures. There is now increasing interest in the changes that take place in the periarticular skeletal muscles, as well as other factors involved in maintaining joint stability and proprioception. Ligaments, essential components of joint stability, become more compliant with increasing age, but whether this is clinically important and related to the increasing prevalence of OA with age is not known. Ligamentous laxity is a cause of OA in animal models but
D.J. Brauner, L.B. Sorensen, and M.H. Ellman
has been less well studied in humans, although the hypermobility syndromes are known to be a risk factor for OA. Increased ligamentous laxity, as evidenced by increased varus-valgus movement, has been found to be correlated with the degree of radiologic OA of the knee.47 In patients with unilateral OA of the knee, the uninvolved knee had greater varus-valgus laxity compared with control knees. This finding supports the concept that ligamentous laxity may predate the disease and may increase the risk of knee OA, as well as contributing to its progression. The role of periarticular muscle weakness in the pathogenesis and progression of OA has sparked recent interest. Reduced quadriceps strength relative to body weight is found in women with OA of the knee compared to those without OA.48 Although it had been previously assumed that decreased quadriceps strength in OA of the knee was related to decreased use of the painful joint, recent studies point to a possible pathogenic role of quadriceps weakness. Comparing a community-based cohort of older persons (average age, 71 years), researchers found quadriceps weakness was greater in participants with radiographic knee OA compared with those without it, even in the absence of joint pain. This finding suggests that knee extensor weakness may be a risk factor for the initiation and progression of knee OA.49 Complaints referable to quadriceps weakness are one of the most common and early symptoms reported by patients with OA and are a better determinant of pain than radiographic changes.50 Muscle weakness may play a large role in the age-related increase in incidence of OA, as aging is also frequently associated with generalized weakness related to deconditioning. The phenomenon of arthrogenous muscle dysfunction (AMD) describes the decreased strength of voluntary contraction of muscle acting across a joint with OA and may, in part, explain knee extensor weakness in OA.51 The relationship between muscle weakness and OA is receiving increasing interest. Skeletal muscles are essential components of the neuromuscular protective mechanisms that provide shock absorption for the joint. Coordinated joint movement and muscle activity control joint loading so that loads applied across joints are dissipated. A well-described example of this occurs with normal gait when the knee is loaded during heel strike. Eccentric quadriceps contraction, which involves muscle lengthening but maintaining tension, cushions the impact. Weak muscles are fatigued more readily, and their voluntary and reflex motor control is slower than those of well-conditioned muscles; this compromises the neuromuscular protective mechanisms of the muscle and leads to excessive joint movement and instability that stresses innervated tissues, elicits pain, and gives rise to rapid jarring loading of the joint. This rapid loading results in microtrauma to articular cartilage and subchondral bone.
42. Rheumatologic Diseases
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Figure 42.1. The relationship between muscle weakness, subchondral bone, and osteoarthritis.
Subchondral bone becomes harder and less able to act as a shock absorber, which then creates an amplification loop in which mild trauma can result in severe joint destruction (Fig. 42.1). Problems with proprioception, the conscious and unconscious perception of limb position and movement in space, have been implicated as a risk factor for OA. In a canine model of anterior cruciate ligament (ACL) transection, OA was more severe and developed earlier when performed in combination with either a dorsal root ganglionectomy or articular neurectomy than with ACL transection alone.52 In humans, this question has been studied most extensively in the knee where proprioception derives from integration of afferents from receptors in muscles, tendons, joint capsule, ligaments, meniscal attachments, and skin. The hypermobility syndrome, a well-known risk factor for precocious OA, is associated with impaired proprioception, especially near full extension, and may result in mechanically unsound joint positions that could predispose to OA.53 Cross-sectional studies show that knee proprioception is worse in patients with knee OA than in controls. Proprioception was found to be worse in older subjects and even worse in the elderly subjects with knee OA.54 Theoretically, proprioceptive inaccuracy may contribute to gait characteristics associated with increased stress across joints that predispose toward OA. However, it is not clear whether the proprioceptive problems predispose to OA or if changes associated with OA themselves contribute to worsening in proprioception. Proprioception in older patients with unilateral knee OA was found to be worse in both the involved knee as well as the uninvolved knee compared with older control subjects.55 This finding implies that impaired proprioception is not exclusively a result of local disease in knee OA, but the relative importance of impaired proprioception in the development and progression of knee OA requires longitudinal study. Inactivity is an important risk factor for OA that has been incompletely explored in humans, although there are excellent animal models that demonstrate immobi-
lization leading to OA. Prolonged bed rest with lack of joint loading is a theoretical risk for the development of OA that should be included on the long list of adverse consequences of bed rest. Acetabular dysplasia, a very important risk factor for hip OA in younger people, is responsible for only a very small percentage of incident hip OA in the elderly.56
Genetics of OA Since the familial occurrence of Heberden’s nodes was documented 60 years ago, there has been an appreciation that genetic factors play a major role in OA. Because of the complex nature of this role and the multifactorial nature of OA, the genetics of OA is poorly understood. Primary generalized OA is the most common form of OA that is clearly associated with genetic influences. About 20% of those patients describe a positive family history. Multiple studies suggest that the inheritance is probably polygenic. Family aggregation of OA among siblings involving the DIP, PIP, and first CMC joints in a cohort from the Baltimore Longitudinal Study on Aging contributes to evidence of inheritability.57 Study of hand and knee radiographs of families from the Framingham Study cohort and Framingham Offspring Study suggests a mixed model in a Mendelian mode with a major recessive gene and a residual multifactorial component in generalized OA.58 Mutations of the genes that code for type II collagen are probably responsible for small groups of families with precocious OA. The Arg519-Cys mutation in type II collagen results in severe, precocious familial OA in 100% of carriers within the first three decades of life.59 Another area of possible genetic influence is in control of mediators such as IGF-1 that may be important in cartilage formation during development stages and remodeling of adult cartilage.60
Pathophysiology of OA Knowledge of the physiology of cartilage and the pathophysiology of OA is becoming increasingly important to
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appreciate risk factors and institute preventive measures, as well as to understand new treatment modalities.
Cartilage Hyaline articular cartilage, the main tissue of interest in OA, is composed mainly of a protein matrix and chondrocytes, which live scattered in normal cartilage in isolation. The “effete” chondrocyte comprises less than 5% by volume of the cartilage but is extremely metabolically active and responsible for maintaining the extracellular matrix (ECM). The two major components of the ECM are proteoglycans and collagen fibers. The collagen fibers (90% type II collagen) provide the tensile strength and structural integrity of the cartilage, and the proteoglycans, extremely complex glycoconjugates, are responsible for its ability to undergo reversible deformation or elasticity. The predominant proteoglycan of articular cartilage is aggrecan, which is composed largely of glycosaminoglycans. Glycosaminoglycans are longchained, repeating, sulfated, disaccharide units (the most common ones being keratin sulfate and chondroitin sulfate) that are attached to a core protein. Aggrecan molecules are synthesized and secreted into the ECM by the chondrocyte, where they form aggregates of up to 200 aggrecans attached to a hyaluronic acid core, a linear,
high molecular weight glycosaminoglycan, via a link protein. Aggrecans are highly concentrated in the ECM and compressed to approximately 20% of their extended volume by the collagen fibers that form a threedimensional network, preventing further expansion of the proteoglycans. The proteoglycans carry a high concentration of negatively charged anions at physiologic conditions and thus are highly hydrophilic, providing a swelling pressure that is restrained by the stiffness and tensile strength of the collagen fibers so that only a fraction of their hydrodynamic domain is exposed. When cartilage is loaded, it is deformed by the expulsion of fluid, which tends to move toward the load into the synovial cavity, carrying the waste products of the cells with it. As water is released from the aggrecans, negative charges are exposed. As aggrecan molecules are forced closer together by the load, increases in the density of negative charges and in the repulsive forces tend to resist further deformation. Ultimately equilibrium is reached, in which the external loading force is balanced by internal forces. When the load is removed, water, along with nutrients, is forced back into the ECM and the cartilage regains its original shape61 (Fig. 42.2). The fact that cartilage is both avascular and aneural has important clinical ramifications. Nutrients diffuse into the cartilage via the synovial fluid, but this requires
Figure 42.2. Schematic of structure and properties of proteoglycans in cartilage.
42. Rheumatologic Diseases Table 42.2. Changes in cartilage proteoglycans with aging. 1. Progressive decrease in the average length of the core protein of the aggrecan molecule 2. Decreased hydrodynamic size of the aggrecan molecule via decreased length of chondroitin sulfate chains and increase in number of keratin sulfate chains 3. Decreased proportion of aggrecans able to form aggregates with hyaluronic acid 4. Decreased size of aggregates from reduction of length of the hyaluronic acid molecule and smaller size of the aggrecan molecules
joint loading, as already described. A well-described model for inducing OA in animals involves unloading limb joints by casting for several weeks, thus disrupting the flow of nutrients to the chondrocyte. When the cast is removed and the joint is reloaded, premature cartilage damage and OA quickly ensue. Importantly, because of the lack of neural input when damage is isolated to the cartilage, there will be no associated sensation or warning. Many changes have been found to occur in cartilage with aging. The changes in cartilage proteoglycans are summarized in Table 42.2. These changes lead to a decrease in the hydration of the articular cartilage with aging, which causes a thinning and increased stiffness of the articular cartilage. Articular cartilage show a marked age-related enrichment in a different type of cross-linking product produced by nonenzymatic means (browning) that tends to stabilize it and retain its properties. Collagen has an extremely long half-life, of the order of 100 years; thus, tensile integrity should remain despite aging.
Changes in Matrix in OA Under normal physiologic conditions, chondrocytes regulate a dynamic metabolic steady state in which anabolism is balanced by catabolism. The earliest change of OA observed from animal models and ex vivo analysis of human cartilage involves increased hydration of the cartilaginous matrix; this is in distinction to the normal changes of aging, which involve a decrease in the water content of cartilage, as just described. This increase in hydration is thought to be associated with clipping of collagen fibers and consequent release of the physical restraint to the hydrophilic proteoglycans that swell with water. Early on in the process there is an increase in the rate of proteoglycan synthesis by the chondrocyte, which may be an attempt to compensate for an increase in catabolism of the matrix, causing an early hypertrophic phase preceding the later degenerative phase. The subsequent degenerative phase is associated with extensive depletion of matrix proteoglycans via digestion of their
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core proteins by proteases released from chondrocytes. In later stages, chondrocytes synthesize less matrix than normal. Matrix synthesis varies by regions, being strongly suppressed in the superficial layers of cartilage but less so in the deeper layers.62 Because chondrocytes lack cell-to-cell contact, communication between them must occur across the ECM via cytokines. Elucidating the complex interactions and effects of these cytokines in OA has been an important area of recent investigation. A number of mediators that influence chondrocyte metabolism have been elucidated, including interleukin-1-alpha and -beta (IL-1), tumor necrosis factor (TNF), and nitric oxide (NO). The cytokine IL-1 is the prototypic inducer of cartilage catabolism. IL-1 inhibits collagen production and causes collagen degradation through the induction of matrix metalloproteinases, a variety of which have been described.63 Chondrocytes are probably the major site of production of mediators of inflammation in OA showing high expression of IL-1, TNF, and NO.64 IL-1-alpha and -beta have been demonstrated in chondrocytes at the articular surface, as well as distributed throughout cartilage demonstrating OA changes.65 Cartilage exhibiting the early changes of OA had the highest intensity of staining and the highest frequency of positive cells, suggesting a role in pathogenesis. The free radical nitric oxide also appears to occupy an important mediator role. In the joint, chondrocytes are the major cell source of NO. One of the major functions of NO in cartilage is its role in the suppression of matrix synthesis. NO is at least partly responsible for IL-1induced suppression of glycosaminoglycan and collagen synthesis. Interestingly, production of NO by normal cartilage in response to IL-1 decreases with advancing age. NO may also be involved as a mediator of IL-1induced expression of matrix metalloproteinase mRNA and protein and may contribute as an activator of the latent forms of the enzymes. NO also regulates chondrocyte metabolism in response to mechanical loading.66 NO may also to have some protective effects in cartilage; it is probably involved in antimicrobial defense and may have anabolic effects stimulating proteoglycan production under certain conditions, as well as participating in wound healing and stimulating collagen production. Another response of the chondrocyte to cartilage damage is the production of matrix molecules such as type X collagen, not found in normal articular cartilage but found in developing growth plate cartilage. Although this is interpreted as a repair response, it results in the production of a mixture of fibrocartilage-like and hyalin cartilage-like matrix, in addition to matrix calcification. Besides alterations in chondrocyte metabolism, there are also changes in their growth characteristics. In normal mature human articular cartilage, there are no detectable
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levels of chondrocyte proliferation, although very low levels of proliferation are probably needed to maintain cartilage cellularity. With increasing age, there is a decline in cellularity. In osteoarthritis, once the continuity of the surface of cartilage is disrupted, the cells can divide, forming clusters of chrondrocytes, the so-called brood capsules. Another response of chondrocytes found in OA cartilage is to undergo morphologic changes characteristic of apoptosis, possibly as a result of NO production. Fibrillation is the earliest gross change of cartilage in OA seen in association with increased hydration and depletion of proteoglycan. As fibrillated cartilage is abraded, focal erosions and vertical clefts are formed. These erosions coalesce with progressive denudation of underlying sclerotic bone. Proliferation of bone occurs at the joint margins to form osteophytes and in subchondral bone, especially in areas denuded of cartilage. The term eburnation applies to the glistening appearance of the polished sclerotic bone surface. The classic morphologic changes of subchondral sclerosis in OA are thought by some to have a role in the pathogenesis of the condition. Although many authorities believe that the earliest events in OA occur in cartilage, an alternate view suggests that changes in subchondral bone precede measurable changes in the cartilage. It is postulated that the earliest lesions are trabecular fractures in cancellous bone. The healing of these fatigue fractures results in thickening of the trabeculae, leading to an increase in the density of bone with a consequent reduction in its ability to absorb energy. With loss of this functional role of bone, energy absorption is shifted toward the overlying cartilage whose collagen fibers sustain fatigue fractures, eventually leading to deterioration of cartilage. Cyst formation is commonly seen in the juxta-articular bone, probably a result of tissue breakdown related to focal areas of microfracture in the ischemic subchondral bone. Although several studies have shown evidence of increased subchondral bone turnover in early OA, there is still disagreement about whether these changes are concurrent with, primary to, or secondary to cartilage deterioration.67 Focal, chronic synovitis, characterized by lymphocyte and mononuclear cell infiltration, is frequently seen in OA; this is probably due to secretion of inflammatory mediators initiated by the release of hydroxyapatite or calcium pyrophosphate crystals or by cartilage breakdown components, or the presence of immune complexes in the surface of the cartilage.
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to events that occurred earlier in life. Studies have shown associations between recreational physical activity performed years ago and radiographic OA.68 The level of activity appears to correlate with risk; however, it is also well known that some loading, as well as maintenance of muscle strength, is also important in preventing OA. The ideal level of activity to minimize OA development has not been established and probably is quite variable between individuals. In a 9-year longitudinal study of recreational runners compared with nonrunners (average age, 66 at the end of the study), Lane et al. found no increase in the rate of development of hip or knee OA.69 Much more attention should be paid to the activities, especially sports, in which even very young children are participating, and the potential risks they pose for later development of OA. Well-designed long-term studies of programs to determine if prophylactic exercises can prevent OA or diminish its severity are needed to answer these questions. Although obesity is an important risk factor, from a prevention perspective, early intervention is important because it appears that cumulative exposure is important, with increased body mass index (BMI) in young men 20 to 29 being more predictive of subsequent knee OA than at ages 30 to 39 or 40 to 49.70 Observational data from the Framingham OA Study suggest that weight loss of approximately 5 kg will reduce a person’s risk for the development of knee OA over the subsequent 10 years by 50%.71 The role of micronutrients in prevention is a frequently asked question. An analysis of the Framingham data found no significant association of incident radiographic knee OA with any micronutrient.72 However, a threefold reduction in risk for progression of radiographic OA was noted for those in the middle and upper thirds of vitamin C intake; those in the upper third for vitamin C intake also had a reduced risk of developing knee pain during the course of the study. The theoretical explanation for the possible effects of vitamin C on OA comes from its involvement in collagen metabolism. Vitamin C acts as an electron donor in the synthesis of type II collagen and is involved in the hydroxylation of proline to form hydroxyproline. It also plays a role in glycosaminoglycan synthesis through its role as a carrier of sulfate groups. Its role as an antioxidant may also have some effect.73 Interest in vitamin D increased when investigators reported that a relative deficit of vitamin D intake predisposes to progression of preexisting OA.74 Both lower intake of vitamin D and decreased serum levels have been well documented in older people.
Prevention As with other chronic diseases for which there is no cure, priority needs to be given to measures that can prevent the condition. Although OA is commonly thought of as a disease of older people, consideration needs to be given
Treatment The goals of therapy for OA are to reduce pain, slow progression, and improve function and quality of life. As for many other chronic diseases, lifestyle modifications
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play an important part of the therapeutic approach of OA. Nonpharmacologic approaches are by far the most important therapies for OA. An important goal of therapy is to reduce stress on joints by weight reduction if indicated, strengthening of the muscles around involved joints, improving flexibility and proprioception, and joint protection strategies, including improving joint mechanics and the use of assistive devices and orthotics. In managing osteoarthritis, it is important to establish and communicate realistic objectives for each patient. It is critical to focus the patient’s attention on enhancement and preservation of functional ability, such as walking, dressing, and living independently. Many patients who present with hand involvement need only reassurance that the disease process is not likely to become generalized or crippling.
Exercise in the Treatment of OA “Exercise may be the most effective, malleable, and inexpensive modality available to achieve optimal outcomes for people with OA.”75 There is a growing recognition that health and fitness are achievable with less intense regimens than previously thought and that these regimens are feasible for people with a variety of chronic and disabling conditions. For more information on this subject, the interested reader is referred to the American College of Sports Medicine Guide to Exercise Testing and Prescription for People with Chronic Diseases and Disabilities.76 Rehabilitation that increases muscle strength has been shown to be associated with decreased joint pain and disability without exacerbation of knee OA pain. Reeducation of neuromuscular skills can decrease reaction times and improve functional joint stability and proprioception, which are important in restoring shock absorption function of muscle and protecting against further joint damage. OA changes found in one joint frequently affect other joints with range of motion and strength deficits generally found in adjacent joints and bilaterally. A poorly appreciated but consistent finding in people with unilateral knee OA is not only decreased range of motion of the involved knee, but of the hip and ankle as well, and significant limitation of motion of all three joints of the uninvolved contralateral limb. Older people with knee OA have been found to decrease range of motion in all the major joints of the lower extremities.77 Decreased range of motion of the hip and knee increases the risk for injury and falls, in part because it becomes much more difficult to recover balance from a stumble. To prevent a fall after a stumble, one must produce rapid changes in hip and knee flexion angles while weightbearing.78 Maintaining or improving the compliance of periarticular soft tissue is also thought to protect joints from damaging
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peak forces as part of the neuromuscular protective system. Stretching and flexibility exercises are therefore key elements in exercise programs for people with OA. In the first large multicenter controlled study of its kind, investigators sought to answer several important questions about the potential benefits of exercise for people with OA. They found that both aerobic and resistance exercise programs over an 18-month period resulted in modest but consistent improvement in self-reported pain and disability and better scores on performance measures of function compared with controls participating in a health education program. Importantly, they found that the subgroup of older participants, those over 70, experienced the same beneficial effects. They also showed that moderate exercise did not worsen the disease in terms of either pain or x-ray scores.79 Improved proprioceptive accuracy has also been demonstrated following muscle training. Knee orthoses have been shown to improve knee proprioception. Use of an elastic knee bandage improves proprioception, probably because the bandage stimulates superficial skin receptors, free nerve endings, and hair end organs that would react strongly to bandage movement on skin.80 This increase in proprioception may, in part, explain the improvement, especially the sense of safety patients report with elastic bandages, which do not provide significant mechanical support. A modality intimately linked with exercise but also found to be an important adjunct in itself for the treatment of OA is education. Self-care education for OA resulted in notable preservation of function and control of resting knee pain in one large study.81 The cost of such a program was shown to be defrayed by a drop in the number of clinic visits but had no significant effects on the utilization and cost of pharmaceutical, laboratory, or radiology services.82
Biomechanical Approaches to Therapy Simple interventions directed toward reducing the load in affected joints include the use of walking aids, wedged insoles that change the angle of the legs, shock-absorbing footwear that reduces impact, and a heel lift if one leg is shorter than the other. Viscoelastic inserts may be effective in relieving pain and disease progression or even prevention, as they have been found to reduce the amplitude of the shock waves at heel strike with walking by 42%.83 If hip or knee involvement is unilateral, a cane held in the contralateral hand is helpful. If involvement is bilateral, crutches or a walker are more desirable. Biomechanical principles provide a rationale for prescribing adaptive devices such as an elevated toilet seat and high chairs. Knee cages around the knee may provide some stability when ligamentous laxity is pronounced. Pillows should never be placed under the knees at night because of the risk of devloping flexion contracture.
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Flexion contracture of the hip may be prevented and mild contractures may be corrected by having the patient lie prone for 30 min twice daily. Occupational therapy to modify activities of daily living can reduce unnecessary overloading of the joints of the upper and lower extremities. Other nonpharmacologic approaches include thermal modalities, transcutaneous electrical nerve stimulation (TENS), exercise programs, weight loss programs, patellar taping, tidal irrigation, and programs to improve coping skills and social support. Sexual function is often affected in persons with arthritis. It is important for the physician to evaluate problems in this area and to advise the patient of measures aimed at overcoming handicaps. Patients with osteoarthritis of the hips, knees, or spine frequently have problems with sexual intercourse due to pain or mechanical problems. Despite these limitations, sexual activity can be undertaken with the use of analgesics beforehand. Patients should be encouraged to try a variety of positions that allow the successful, pain-free performance of intercourse. The Arthritis Foundation’s pamphlet “Living and Loving with Arthritis” describes a variety of sexual problems and suggested solutions.
Drug Therapy Although the future holds promise for the development of disease-modifying modalities for the treatment of OA, the current pharmacologic approach to treating OA is palliative rather than curative. The primary objective of drug therapy is to reduce pain. Pain is generally undertreated in older patients, and the pain of OA is no exception. On the other hand, pain may be an important signal to prevent certain types of use that might result in further damage to the joint. Analgesic arthropathy, in which the relief of pain causes accelerated joint damage because of increased joint loading, needs to be kept in mind with any successful therapy. Guidelines for management of OA suggest a stepwise approach, starting with simple analgesic medication, which is usually acetaminophen. Despite its lack of antiinflammatory properties, acetaminophen has been shown to perform well in double-blind placebo-controlled trials against the nonsteroidal anti-inflammatory drug, ibuprofen.84 These data suggest that pure analgesics should be considered as first-line drugs in OA much more frequently than is the case today. For patients without liver disease, doses of 1 g acetaminophen up to four times daily are recommended. For the management of moderately severe pain, viz., acute radicular pain of spinal osteoarthritis, tramadol HCl (Ultram) has comparable efficacy to acetaminophen with codeine #3. Ultram is a centrally acting agent with low potential for addiction. For pain associated with acute or chronic conditions, the dose is one or two 50-mg tablets every 4 to 6 h, as needed,
D.J. Brauner, L.B. Sorensen, and M.H. Ellman
to a maximum of 400 mg/day. For patients over 75 years of age, the maximum dose should not exceed 300 mg/day. Individualization of dose is necessary for patients who have renal or hepatic impairment. Propoxyphene is no better than acetaminophen and should be avoided in older patients. For patients not receiving adequate relief, the addition or switch to a nonsteroidal anti-inflammatory drug (NSAID) is the next step. NSAIDs are among the most widely used therapeutic agents today, with nearly $2 billion spent in the United States yearly on prescription NSAIDs alone.85 These agents provide analgesia and suppress inflammation by inhibiting the cyclooxygenase enzymes that catalyze the formation of prostaglandins from arachidonic acid. Cyclooxygenase (COX) exists in two distinct isoforms, which display important differences in their patterns of distribution as well as their regulation. COX-1 is constitutively expressed in virtually all tissues. COX-1-mediated prostaglandins regulate renal and platelet function, protect the gastric mucosa, and promote hemostasis. COX-2-mediated prostaglandins play a role in pain, inflammation, and fever, and in the regulation of cell growth, apoptosis, and angiogenesis. COX-2 is constitutively found in small amounts in such dissimilar tissues as the brain, endometrium, and the kidneys, as well as in certain neoplasms. A characteristic feature of the COX-2 enzyme is its presence in an inducible form and its upregulation at sites of inflammation and in some tumors. Stimulation by inflammatory cytokines, endotoxin, or growth factor leads to a 10- to 80-fold increase in COX-2 levels in such cells as macrophages, fibroblasts, chondrocytes, synovial cells, and endothelial cells. It is a widely held view that the anti-inflammatory properties of NSAIDs are mediated through COX-2 inhibition, whereas most of their adverse effects occur as a result of the inhibiting effects on COX-1. Conventional or traditional NSAIDs, such as ibuprofen and naproxen, suppress both COX-1- and COX-2-mediated prostaglandins. More recently, a new class of NSAIDs, termed coxibs, has been added to the therapeutic armamentarium. The actions of coxibs are more specific to COX-2. The traditional NSAIDs include the timehonored aspirin and other salicylates, and a large number of NSAIDs that have been developed over the past 30 years in the hope of enhancing efficacy and reducing side effects. These drugs have in common analgesic effects at a lower dosage and anti-inflammatory effects at a higher dosage. At therapeutically equivalent dosages, most traditional NSAIDs have not proven to be much safer than aspirin. No significant differences in efficacy or side effects are apparent among the different classes of traditional NSAIDs. The choice between the various traditional NSAIDs becomes largely empirical, and it is often necessary to go through a sequential trial of several
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different NSAIDs to arrive at the one that best suits the patient. Intermittent rather than continuous use of NSAIDs is preferable. In the elderly, compounds with a short biological half-life, such as ibuprofen and ketoprofen, are preferable to those with prolonged half-lives. Concomitant administration of two NSAIDs is not generally recommended because of the potential for added adverse effects. If the decision has been made to prescribe a traditional NSAID to an older patient, it is important to keep in mind that the starting dose should be lower than that recommended for younger adults, and stepwise adjustments should be made until an optimal therapeutic response is obtained. Patients with OA generally obtain effective analgesia at about half the daily dose given to patients with rheumatoid arthritis. There is a vast body of literature on the evils of NSAIDs for older patients who are more prone to their side effects, especially gastrointestinal toxicity and renal dysfunction. Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with conventional NSAIDs. Gastroduodenal ulcers can be demonstrated by endoscopy in 10% to 20% of patients who take NSAIDs on a regular basis, and the annual incidence of clinically important GI complications approaches 2%.86 It has been conservatively estimated that 16,500 NSAID-related deaths occur among patients with rheumatoid arthritis and osteoarthritis every year in the United States. If deaths from gastrointestinal toxic effects of NSAIDs were tabulated separately in the National Vital Statistics reports, these effects would constitute the fifteenth most common cause of death in the United States. Advanced age has been consistently found to be a primary risk factor for adverse gastrointestinal (GI) events. The risk increases linearly with age.87 The very essence of this debate, especially as regards GI side effects, has been altered by the recent release of the new class of NSAIDs, the selective COX inhibitors. At the time of this writing, two specific COX-2 inhibitors are available, rofecoxib and celecoxib. Additional coxibs are currently undergoing clinical trials. The recommended daily dose of rofecoxib is 12.5 to 25 mg and that of celecoxib 100 to 200 mg. Several investigators have concluded that rofecoxib 12.5 mg qd is equipotent to celecoxib 200 mg qd. Although rofecoxib is the more selective of the two, both agents appear to be as effective as traditional NSAIDs in suppressing inflammation and providing analgesia, while reducing the incidence of endoscopic ulcers to levels similar to those seen with placebo.86 In a double-blind, placebo-controlled study, specific inhibition of COX-2 by rofecoxib, administered once daily, resulted in clinically meaningful improvements in patients with OA, confirming that COX-2derived prostanoids are important mediators of pain and
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other symptoms of knee OA and that inhibition of COX1 is not required for clinical benefit.88 Celecoxib has similarly been shown to be associated with a lower incidence of upper GI ulcer complications in a recent randomized controlled study.89 Another important benefit of the coxibs is that, in contrast to the nonselective NSAIDs, they do not inhibit thromboxene B2 levels or the antiplatelet effects of low-dose acetylsalicylic acid (ASA), nor do they increase bleeding time.90 Although coxibs do reduce the risk of ulcers, a cost–benefit analysis is useful for putting the benefits into perspective. Peterson and Cryer considered patients at higher risk for ulcer complications, such as those aged 75 years or older with a prior history of ulcer and gastrointestinal tract bleeding, who have about a 5% risk of developing a complicated ulcer while taking a traditional NSAID. Assuming that COX-1-sparing agents reduce the risk by approximately 50% (i.e., to 2.5%), 40 patients would need to be treated with a COX-1-sparing NSAID instead of a nonselective NSAID to prevent one ulcer complication. The yearly incremental cost of this approach to preventing one complicated ulcer would be about $30,000, a cost that was thought to justify switching such patients to COX-1-sparing NSAIDs. This approach also would be less costly than prescribing cotherapy for a generic NSAID with misoprostol or a proton pump inhibitor, although the occurrence rate of complicated ulcers with these two strategies has not been compared in a head-to-head study.85 Because COX-2 is expressed in both a constitutive and inducible fashion in the kidney, it is not surprising that renal adverse effects may result from treatment with coxibs as they do with nonselective NSAIDs. In general, renal adverse effects of NSAIDs include reductions in glomerular filtration rate (GFR) and renal blood flow, sodium retention, and increases in serum potassium. These effects can lead to fluid retention, edema, mild elevations of the blood pressure, and hyperkalemia. Obviously, these effects are more likely seen in frail patients, such as the elderly and those with chronic illnesses. Supportive of this notion is a study in elderly subjects demonstrating that COX-2 inhibition resulted in renal effects similar to those observed with nonselective NSAIDs.91 Systemic adrenal corticosteroid analogues are not usually recommended in the management of osteoarthritis. Clinical results with these drugs are equivocal and are outweighed by their potential side effects. However, in the patient with severe debilitating pain in whom other therapies have not helped sufficiently, a brief course of low-dose prednisone (5 mg a.m.) may give remarkable palliation. Topical application of creams containing a NSAID or capsaicin appears to have analgesic effects. Local application of capsaicin, which depletes substance P from
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sensory nerve endings, caused a 30% reduction in pain in OA of the knee.92 If pain relief is still not adequate, then Tylenol with codeine or oxycodone, which has been shown to be effective in OA, should be tried in carefully selected patients. Controlled-release oxycodone or in fixed combination with acetaminophen added to NSAIDs have been compared in patients with OA with similar significant effectiveness in reducing pain and improving sleep found over placebo. The controlled-release preparation was found to produce fewer side effects with significantly less nausea and dry mouth.93
Nutraceuticals as Therapeutic Agents in OA Two compounds that are receiving increasing attention are the nutraceuticals glucosamine and chondroitin sulfate. These compounds have been used in various forms for OA in continental Europe for more than a decade and have recently acquired substantial popularity in this country because of several lay publications. The medical community in the United Kingdom and the United States, on the other hand, has paid little attention to the potential benefits of these compounds, largely due to concerns about the validity of clinical trials. The theoretical considerations for the possible effectiveness of glucosamine in OA stems from its status as a principal component of glycosaminoglycan (GAG), a key constituent of the matrix of all connective tissues. It is formed by the addition of an amino group to glucose that is then acetylated to acetyl-glucosamine. More than 50% of the glucosamine is nonionized at a pH of the small intestine, thus allowing significant and rapid absorption. Glucosamine has a special tropism for cartilage and is incorporated by the chondrocyte into proteoglycans, which are secreted into the extracellular matrix. In rats, 14 C-labeled glucosamine appears in rat cartilage 4 h after ingestion. When glucosamine is added to cultured human chondrocytes from osteoarthritic cartilage, a dosedependent increase in proteoglycan synthesis occurs.94 Most clinical studies have been conducted on glucosamine. In some preparations glucosamine is combined with chondroitin sulfate. Glucosamine and chondroitin are prepared by extraction from animal products, including bovine and calf cartilage. More than 90% of ingested glucosamine is absorbed, while less than 10% of chondroitin sulfate is absorbed. In short-term studies, glucosamine and chondroitin preparations have proven to be safe, but long-term toxicity studies remain to be done. The concern about the quality of clinical trials led McAlindron et al. to perform a meta-analysis combined with systematic quality assessment of 15 double-blind, placebo-controlled clinical trials of these preparations in knee and/or hip OA.95 In summing up the results, the
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authors found that the clinical trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects but exhibit methodologic problems that have been associated with exaggerated estimates of benefit. The overall impression was that the compounds did show some benefit in treating OA symptoms. Given their excellent safety profile, glucosamine and chondroitin are likely to be useful in the treatment of OA even though they may be only modestly effective. Glucosamine and chondroitin are available in pharmacies and health food stores. The amounts generally administered are glucosamine 1500 mg/day and chondroitin sulfate 1200 mg/day, with an average cost of about $30 to $45 per month.
Joint and Bursa Injections Aspiration and joint injections with corticosteroids have been one of the mainstays for the palliative therapy of painful joints. When effusions are large, especially in the knee, relief of symptoms often occurs with simple aspiration of the joint fluid. However, the fluid will quickly reaccumulate unless corticosteroids are also injected. A singe intra-articular injection of triamcinolone hexacetonide in knee OA provides short-term pain relief compared with placebo, with best results seen in those with clinical evidence of joint effusion and successful aspiration of synovial fluid at the time of injection.96 The mechanism for alleviating pain besides decreasing inflammation, which is usually minimal in OA, is unclear. Because of earlier experience with frequent injections of corticosteroids leading to an accelerated rate of joint damage, it is recommended to limit the frequency of joint injections to once every 3 months and not to exceed three injections in a given joint per year. The joint damage seen with multiple corticosteroid injections over shorter periods of time has been attributed to a direct effect of steroids on chondrocyte metabolism, possibly combined with a component of analgesic arthropathy. In weightbearing joints, decreased loading should be recommended for at least 2 days. Response to steroid injections is highly variable, and repeat injections should be limited to those who have a significant response that lasts several months. Steroid injections are also useful adjuncts in the treatment of inflamed bursae. Observational studies have demonstrated both short- and long-term response to steroid injection, with a majority of patients showing improvement when assessed 26 weeks after injection.97
Viscosupplementation In recent years, viscosupplementation has begun to emerge as an alternative or supplement to analgesics and NSAIDs in the management of patients with OA of the knee. Viscosupplementation for the management of OA
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was first used and tested on race horses in the early 1970s and shortly thereafter in people with OA of the knee. The rationale for this therapy stems from the unique properties of hyaluronic acid (HA). The synovial lining of the diarthrodial joint is composed of one to two layers of cells that produce a highly viscous lubricating fluid, which contains high molecular weight substances, such as HA and lubricin. These substances coat the surface of the articular cartilage, providing lubrication as the articular cartilage surfaces move across each other during movement. The highly viscous nature of the synovial fluid is important for normal joint function, providing a nearly frictionless surface for joint movement. Arthritis is associated with elaboration of enzymes and free radicals that degrade both HA and lubricin. Breakdown of HA leads to a decrease in the viscosity of the synovial fluid with loss of smooth movement of the articular surfaces, leading to further joint deterioration. It has been known for many years that synovial fluid from OA joints is lower in elasticity and viscosity than that from normal joint joints. This decrease in rheologic properties of the synovial fluid is due to reductions in the molecular size and concentration of hyaluronan and results not only from increased degradation but also from decreased synthesis and an inferior quality of synthesized hyaluronan. In early clinical studies with hyaluronan products (1–2 million in molecular weight), viscosupplementation was shown to be a safe treatment in osteoarthritis. However, 6 to 10 injections were often required to show any efficacy because the elastoviscous properties of the early hyaluronan preparations were inadequate and the injected hyaluronan was eliminated too quickly. Because of this limitation, hylans were developed to produce a more highly elastoviscous fluid with rheologic properties similar to those of synovial fluid in the knee joint of healthy young persons.98 Hylans are cross-linked forms of purified hyaluronan to form polymers of high molecular weight (6 million). Hylan preparations have a longer residence time in the joint space, and because of cross-links, they become more resistant to free radical degradation. A treatment regimen consisting of three injections of hylan given 1 week apart has been shown to provide optimal pain relief in people with OA of the knee. In one study comparing hylan G-F 20 with a lower molecular weight hyaluronon, hylan was found to yield significantly better results at 12 weeks in all the primary outcome measure, which included weightbearing pain and overall treatment response.99 Systemic adverse events have been reported rarely with viscosupplementation and have not occurred with repeat injection, but mild to moderate transient local pain and swelling occur in 2% to 3% of intra-articular injections of hylan G-F 20.
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There is some speculation that hylan may act as a DMOAD, but no studies are yet available to confirm this. Theoretically, the introduction of replacement HA preparations of sufficiently high molecular weight might delay, if not halt, the progression of OA. More studies are needed to assess long-term effects of this therapy. Some skepticism is warranted in view of recent findings in a canine model of OA. In this study, a series of intraarticular injections of HA did not alter the development of osteophytosis or fibrillation, and, in addition, prostaglandin concentration in the cartilage of treated knees was significantly reduced, suggesting that HA therapy may adversely affect cartilage.100
Joint Replacement Surgical intervention, mostly in the form of total knee and hip arthroplasty, is recommended for patients in whom pain and disability cannot be controlled by other means. Many recent studies have established the effectiveness and safety of total joint arthroplasty. However, these studies have tended to include mostly younger patients. Brander et al. looked specifically at subjects 80 years of age and older who were undergoing either hip or knee arthroplasty and compared their outcome with a younger, otherwise matched control group. They found that the older group had similar dramatic improvements in pain and function, as well as similar complication rates and length of stay in acute care facilities, compared with the younger group. The most dramatic postoperative functional gains were seen in the most disabled people.101 The decision to perform a total hip arthroplasty (THA) for patients with OA is based largely on patient reports of pain and disability and not on the radiographic findings of OA. Fox et al. reviewed the x-rays of elderly patients who had undergone unilateral THA and found that this group tended to have the contralateral THA performed with less severe x-ray findings.102 This finding suggests that if patients had a better understanding of the procedure and its benefits, they would opt for earlier surgical intervention. Besides alleviating pain and improving function, elective THA has consistently resulted in improved health-related quality of life, which was often dramatic and was most likely to occur within the first 3 to 6 months after THA.103 Loosening remains a major complication following total joint replacement. Infection needs to be ruled out whenever loosening occurs. However, the rate of prosthetic joint infection has decreased to less than 1% with improvements in the operating room environment and the use of prophylactic antibiotics. Recent studies suggest inflammatory reactions directed against the implanted materials may contribute to aseptic loosening. Elevated
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immune cell proliferation responses to both acrylic and cobalt/chromium were observed in patients with aseptically loosened prostheses.104 Like many other procedures, the outcome of elective hip replacement bears a relationship to the volume of procedures performed by surgeons and hospitals, with low-volume providers tending to have higher rates of adverse events and serious complications.105
Treatment of Low Back Pain Besides the usual therapies already discussed, therapy for low back pain may include a course of physical therapy, with special attention to body mechanics, and epidural injections in selected cases. Osteopathic manual therapy (i.e., spinal manipulation) is a frequently used method of treatment for patients with chronic and subchronic back pain that has only recently been systematically studied. A randomized controlled trial comparing standard allopathic therapies with osteopathic manual therapy, albeit in subjects between 20 and 59 years of age with low back pain that had lasted at least 3 weeks but less than 6 months, found that both groups improved similarly during the 12-week follow-up. The allopathic treatment included analgesics, anti-inflammatory medication, active physical therapy, or therapies such as ultrasonography, diathermy, hot or cold packs (or both), use of a corset, or TENS. The osteopathic group required significantly less medication and used less physical therapy.106
Surgical and Nonsurgical Treatment of Spinal Stenosis Conservative treatment of lumbar spinal stenosis consisting of exercise programs and pain medication is recommended for those with tolerable symptoms or in whom surgery is too risky or not desired. Caudal epidural blocks are a reasonable therapeutic option in some patients with lumbar stenosis, especially those who are poor surgical risks or have refused surgery. For those with progressive neurologic impairment, decompressive lumbar laminectomy with or without posterior spinal fusion may be indicated. A prospective cohort study assessed 4-year outcomes for patients with lumbar stenosis treated surgically or nonsurgically.107 For the patients with severe lumbar spinal stenosis, surgical treatment was associated with greater improvement in patient-reported outcomes than nonsurgical treatment at 4-year evaluation, even after adjustment for differences in baseline characteristics among treatment groups. The relative benefit of surgery declined over time but remained superior to nonsurgical treatment. Outcomes for the nonsurgically treated patients improved modestly and remained stable over 4 years. In a study with a longer evaluation
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period, Amundsen et al. followed a cohort of 100 patients with symptomatic stenosis for 10 years who received either surgical or conservative treatment.108 Those patients selected for surgery had better outcomes than those treated conservatively. Importantly, Amundsen et al. found that many improved with conservative therapy and, in those who did not, that a delay in surgery of from 3 to 27 months did not appreciably alter their outcomes compared with those who had surgery initially, suggesting that an initial conservative approach is prudent. There has been limited systematic study of surgical outcomes in older patients; however, two recent studies evaluated the efficacy of surgical treatment in patients who were older than 70 and 75 years of age, respectively.109,110 These studies found that with appropriate preoperative selection and evaluation, the surgical treatment of elderly patients with lumbar spinal stenosis can produce significant improvement with acceptable levels of morbidity. Katz et al. found that the most powerful predictors for positive outcomes after surgery for degenerative lumbar stenosis was the patient’s report of good or excellent health before surgery.111
Role of Acupuncture Acupuncture appears to be a safe and effective adjunctive therapy for short-term relief of symptoms of OA involving the knee. The benefit of treatment shows some decline at 4 weeks after cessation.112 The response to acupuncture appears to be quite variable among patients. Efforts to relate differences in response to psychosocial factors have not been rewarding in predicting response.
Experimental Therapies The recent appreciation of the active metabolic life of the chondrocyte has led to an interest in biologically based therapies for OA. The potential use of doxycycline in the treatment of OA is based on its inhibition of protease activity against collagen in vitro at concentrations achieved in serum after oral dosing.113 Oral administration of doxycycline significantly inhibited collagenase and gelatinase activity in human OA cartilage that was removed for THA.114 Much more work is needed before therapy with doxycycline can be recommended for OA. Other potential biologic agents include inhibitors of IL-1 and NO, which are known to suppress synthesis of cartilage matrix. The administration of NO synthase inhibitors in experimentally induced arthritis have resulted in reduction of both synovial inflammation and destruction of cartilage and bone. Another avenue of future potential treatment is gene therapy, specifically manipulation of those genes whose products stimulate chondrogenesis or inhibit breakdown of cartilaginous matrix.115
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Crystal Deposition Disease Deposition of crystals in and around joints may be associated with acute or chronic arthritis. Crystals implicated in arthritis include monosodium urate monohydrate (MSU), calcium pyrophosphate dihydrate (CPPD), and HA and other basic calcium phosphates. The prevalence of crystal deposition diseases increases with age. Deposits of calcium pyrophosphate and hydroxyapatite are often seen in association with OA. Articular manifestations of this group of diseases are extremely common in the geriatric population, presenting a wide range of clinical responses.
Deposition of Crystals: Relationship to Aging and Osteoarthritis The precise mechanisms by which crystals are deposited are imperfectly understood, but increased concentrations of metastable calcium salts and sodium urate, the unmasking of activators of crystal nucleation and crystal growth, or a decrease in concentration of inhibitors of crystal nucleation may act singly or together to promote crystal formation. In idiopathic or sporadic CPPD deposition disease seen in the elderly, isolated elevation of pyrophosphate in synovial fluid is due to local abnormalities. Increased pyrophosphate production has been demonstrated in osteoarthritic cartilage and probably results from enhanced breakdown of nucleotides mediated by the chondrocytic ectoenzymes, 5¢-nucleotidase and nucleoside triphosphate pyrophosphohydrolase. The increased activity of these metabolic processes is an attempt by chrondrocytes to repair damaged cartilage. Ultrastructural studies have demonstrated deposits of CPPD in chondrocyte lacunae in areas of damaged matrix and activated chondrocytes. Aggregated proteoglycans are potent inhibitors of crystal formation. Deaggregation of proteoglycans in aged and osteochondritic cartilage would lead to a loss of natural calcium crystal inhibitor. It would appear that deposits of CPPD and MSU can form in the absence of osteoarthritis. The familial cases of chondrocalcinosis and gout in younger persons are examples of deposition of crystals in seemingly normal cartilage. On the other hand, biochemical changes in osteoarthritic cartilage may predispose to crystal deposition, which in turn may contribute to further joint deterioration. In this latter setting, crystal deposition is a secondary, opportunistic process in damaged cartilage. Aging alone appears to be the major factor leading to formation of CPPD in fibrocartilaginous structures. The simultaneous finding of mixtures of crystal deposits in the same joints of elderly patients is further evidence of their susceptibility to intraarticular and periarticular
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crystal deposition. A positive association exists between gout and CPPD deposition disease and between CPPD and hydroxyapatite formation.
Crystal-Induced Synovitis It is generally believed that preformed microcrystals are shed from cartilage or synovium. Crystals that are associated with arthritis possess a negative surface charge and avidly bind proteins, including immunoglobulins, albumin, lysosomal enzymes, complement, and lipoproteins. Urate crystals have a strong affinity for IgG. The molecular orientation of IgG on the crystal surface leaves the Fc portion exposed and free to interact with Fc cell membrane receptors on leukocytes, monocytes, synoviocytes, and platelets. The interaction between cells and crystals causes the cells to become activated with release of a host of inflammatory mediators. Coating of the crystal surface with IgG greatly enhances phagocytosis and complement activation. Monocytes and polymorphonuclear leukocytes release a potent chemotactic factor that causes rapid accumulation of polymorphonuclear leukocytes. Phagocytosis induces release of oxygen radicals and lysosomal enzymes. MSU crystals induce release of interleukin-1 from monocytes, an observation that may explain the fever of acute gouty arthritis. Some crystals, for example, MSU, are membranolytic. After digestion of their protein coating in the phagolysosome, the uncoated crystal causes rupture of the phagolysosome with release of its enzymes into the cytoplasm, resulting in cellular autolysis, increased permeability of the cell wall, and release of intracellular enzymes into the surrounding medium. Coating of the crystals with hyaluronic acid and certain proteins, such as albumin or lipoprotein, may inhibit or prevent crystalinduced inflammation, which may explain the occurrence of crystals in joint fluid after the inflammatory reaction has subsided or even in the absence of any detectable inflammation. Study of synovial fluid by polarized light microscopy provides clinicians with a precise method of identifying MSU and CPPD when the crystals are more than 1 mm in size. Using a first-order red plate compensator allows one to determine the sign of birefringence and further differentiate between crystal types. Nonbirefringent apatite and other basic calcium phosphate crystals are so minute that they cannot be identified by ordinary light microscopy; they tend to aggregate into nonbirefringent microspherules that are difficult to distinguish from cell detritus and fat droplets. Definitive identification of apatite and other basic calcium phosphates requires sophisticated techniques. Plain radiographs identify macroscopic deposits of radiopaque calcium containing salts. Hydroxyapatite deposits are frequently seen in periarticular and capsular
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distribution, whereas CPPD deposition disease is associated with characteristic punctate and linear calcifications in fibrocartilaginous and hyaline cartilage.
Gout New onset of gouty arthritis is common among the elderly. Most of these patients have hyperuricemia on the basis of decreased urinary excretion of uric acid, related to the effects of diuretic therapy, mild renal failure, hypertension, or hypertriglyceridemia. It has been estimated that about half of all patients who present with their initial attack of acute gouty arthritis are taking a diuretic. With the widespread use of these drugs in the elderly population, it is hardly a surprise that diuretic use is a major cause of gout in this age group. Less commonly, gout is secondary to overproduction of uric acid due to increased turnover of cells, as in myeloproliferative disorders. The presentation of gout in the elderly differs from the more classic picture in younger men. The pattern is frequently polyarticular, subacute or chronic, and men and women appear to be affected with the same frequency. In women, the first manifestations of gout may be acute arthritis in finger joints, sometimes presenting as inflamed Heberden’s or Bouchard’s nodes. Elderly women are particularly prone to develop diuretic-induced polyarticular gout. Many have underlying osteoarthritis, and concomitant tophi and osteoarthritic changes in the same joint have been described. The appearance of asymptomatic tophi in Heberden’s and Bouchard’s nodes in elderly women as the initial manifestation of gout has been highlighted in several recent reports.116,117 Chronic polyarticular gout with tophi can be misdiagnosed as rheumatoid arthritis with rheumatoid nodules, resulting in improper treatment and otherwise preventable disability. To add to the confusion, rheumatoid factor tests are positive in about 30% of patients with tophaceous gout, a finding that relates to the coating of urate crystals by IgG. The diagnosis of gout can be readily established by studying synovial fluid or tophaceous material by polarized light microscopy. Needle-shaped negatively birefringent crystals of MSU are seen in 95% of patients with acute gouty arthritis and are a sine qua non for establishing a definitive diagnosis. Hyperuricemia, common in the elderly, is less reliable as a diagnostic test. Furthermore, serum urate levels are within normal limits at the time of the acute attack in 7% of the cases. Calcium pyrophosphate dihydrate crystals can coexist with urate crystals, and isolated cases of bacterial arthritis superimposed on gouty arthritis have been reported. If the clinical picture is suspicious of a septic joint, synovial fluid must be cultured.
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The management of gout in the elderly is guided by the same principles that apply to a younger age group. The acute attack is treated with colchicine or one of the NSAIDs. The cautious use of NSAIDs has been discussed under osteoarthritis. A patient with decreased renal function, whose gout is precipitated by administration of a diuretic, is at risk of developing renal insufficiency if a NSAID is used to treat acute gouty arthritis. Colchicine has a low therapeutic margin and should be administered with caution. It is given in hourly doses of 0.6 mg, for a total of four to eight doses with decreases in dosage for hepatic or renal disease. The drug must be stopped promptly at the first sign of loose stools to avoid the consequences of dehydration and potassium loss. Renal, hepatic, and myocardial impairment, and the presence of cardiac arrhythmias, enhance the risk for colchicine toxicity. Chronic usage in patients with renal insufficiency has been associated with myoneuropathy syndrome. Colchicine may be administered slowly into a large vein in a dose of 2 mg. Great caution must be exercised to avoid extravasation, which may result in tissue necrosis and sloughing of the skin. Intra-articular injection of corticosteroid is helpful when gout involves an accessible joint. Oral administration of corticosteroids is also useful in older patients, but because of a tendency of gouty arthritis to rebound, concomitant administration of a maintenance dose of colchicine or a NSAID is necessary. Drugs to lower serum urate should be initiated once the acute attack has subsided. Because acute gouty arthritis may occur during the initial treatment with a hypouricemic drug, it is advisable to use colchicine prophylactically in a dose of 0.6 mg twice daily for several weeks. Uricosuric drugs are effective so long as the creatinine clearance exceeds 50 mL/min. Probenecid and sufinpyrazone are the principal uricosuric drugs. Diflunisal in a dose of 500 mg two times daily is weakly uricosuric and may be worth trying in a patient who also requires an analgesic drug for symptomatic OA. Aspirin abolishes the effect of uricosuric drugs and should not be given concomitantly. Allopurinol is the drug of choice for patients with overproduction of uric acid or with significant reduction in renal function or those who require continuous treatment with aspirin, diuretics, or other drugs that interfere with the tubular secretion of urate. The dose of allopurinal in elderly patients with diminished uric acid excretion is smaller than in overproducers of uric acid. The goal is to prescribe the lowest dose of allopurinol that will maintain serum urate between 5 and 6 mg/dL. Frequently, 100 or 200 mg allopurinol given in a single morning dose will suffice. Serious toxicity includes agranulocytosis, granulomatous hepatitis, and exfoliative dermatitis. Many cases of prolonged hypersensitivity reactions characterized by an erythematous maculopapular rash, eosinophilia, fever, liver function
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abnormalities, and progressive renal failure have been recorded. Another concern in using allopurinol is the observation of an increased incidence of severe hypersensitivity reactions from coadministered drugs, for example, penicillin and ampicillin. Asymptomatic hyperuricemia is not an indication for long-term uratelowering therapy; the risks of drug toxicity outweigh any benefit.
Calcium Pyrophosphate Dihydrate Deposition Disease Calcium pyrophosphate dihydrate (CPPD) causes the most common crystal-associated arthritis in the elderly. In 1962, McCarty reported an acute arthritis mimicking gout, and therefore termed pseudogout, in elderly patients with chondrocalcinosis.118 He further identified the crystals in synovial fluid and cartilage as calcium pyrophosphate dihydrate (Ca2P2O7·2H2O). CPPD crystal deposition disease is a heterogenous disorder. Familial or hereditary cases have been reported from several countries. A small fraction are associated with underlying metabolic disorders, including hyperparathyroidism, hypothyroidism, hypophosphatasia, hypomagnesemia, hemochromatosis, ochronosis, gout, Wilson’s disease, and senile amyloidosis. CPPD crystal deposition disease associated with genetic disorders has an early onset. In the elderly, the idiopathic or sporadic form is by far the most common type of CPPD deposition disease. The prevalence increases in stepwise fashion with age. It is rare before age 50 and increases from 10% to 15% in those aged 65 to 75 to 30% to 60% in those over 85 years. Ellman et al. studied the prevalence of knee chondrocalcinosis in hospital and clinic patients older than 50 years and found an overall prevalence of 9.6%.119 In a representative sample of 79-year-olds in Gothenburg, radiographic evidence of chondrocalcinosis in knees or hands was present in 16%.120 The majority of patients with chondrocalcinosis are free of symptoms. Radiopaque densities are noted in fibrocartilage (especially menisci, radiocarpal joint, symphysis pubis, shoulders, and hips and in the midzonal layer of hyaline cartilage), giving rise to punctate of linear calcification. Acute synovitis, or pseudogout, is the most dramatic clinical manifestation. It presents as an acute monoarthritis, most often located to the knee, but also commonly seen in the wrist, shoulder or ankle. As in gout, surgery, trauma or serious medical illness may trigger an acute attack. About 10% of patients have oligoarticular involvement or a migratory pattern involving several joints successively, sometimes over a course of many weeks or months. About half of symptomatic patients present with clinical and radiographic features that are reminiscent of low-grade osteoarthritis, except that joint
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involvement is that of pseudogout rather than generalized OA. The patients complain of chronic pain, stiffness and restricted movement of knees, wrists, shoulders, elbows, metacarpophalangeal joints, hips, and ankles. Minor acute attacks may be superimposed on chronic symptoms. Acute and chronic tenosynovitis may be present. Wrist involvement may produce a carpal tunnel syndrome. The chronic polyarticular arthropathy seen in 5% of the patients may be confused with rheumatoid arthritis. A number of reports have described a severe destructive arthropathy similar to a Charcot joint and affecting almost exclusively elderly women in association with calcium pyrophosphate deposition, involving the shoulder, elbow, or wrist, in addition to knees or hips.121 In addition to the typical x-ray findings of calcifications in articular cartilage already described, calcifications may be seen in the joint capsule, synovium, and bursae and in tendons, especially the Achilles, triceps, quadriceps, and supraspinatus tendons. The diagnosis is confirmed by presence of weakly positively birefringent calcium pyrophosphate crystals in synovial fluid and characteristic radiologic findings. In acute arthritis, polymorphonuclear leukocytes predominate. Total synovial fluid WBC counts range from 4000 to 50,000/mm3. Triclinic (crystals with three axes, all unequal and none at right angles), rhomboid crystals are found within leukocytes and extracellularly. In chronic arthritis, the leukocyte count is lower and mononuclear cells are more numerous. CPPD synovitis is a prevalent disease, and one should always keep in mind the possible coexistence of another joint disease. The screening for rare metabolic disorders is unrewarding in the elderly, but measurement of serum calcium, iron, and ironbinding capacity should be obtained, and screening for hypothyroidism in a geriatric population is always worthwhile. Treatment of acute synovitis is with nonsteroidal anti-inflammatory drugs, aspiration of joint fluid, and intra-articular injection of corticosteroid. The effect of colchicine is less reliable than in acute gouty arthritis. Chronic CPPD arthritis is managed in much the same way as osteoarthritis. The principles and potential hazards of using NSAIDs have been discussed in the section on OA.
Hydroxyapatite Deposition Disease Hydroxyapatite (HA) and other basic calcium phosphates, which comprise the mineral phase of bone and teeth, make up the majority of ectopic or extraskeletal calcifications. Ectopic calcifications can be divided into dystrophic types, which occur in tissue that has been injured, and metastatic calcifications, which are related to increased calcium and phosphate concentration. Examples of dystrophic lesions are calcifications, which may
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occur in scleroderma, dermatomyositis, ochronosis, and tophi and following local injections of corticosteroids. Metastatic calcifications may be seen in hyperparathyroidism, sarcoidosis, and end-stage renal disease managed with chronic hemodialysis. Idiopathic periarticular HA deposition occurs commonly in bursae and tendons. More recently, HA crystals have been found in synovial fluid in a high percentage of patients with osteoarthritis, and less often in patients with other types of arthritis. Because of their minute size (75–250 Å in diameter), individual HA crystals cannot be identified by ordinary or polarized light microscopy. Their precise identification requires electron microscopic techniques or microprobe or x-ray diffraction analysis. HA crystals can cause acute inflammation of tendons and bursae. The common rotator tendon is one typical site. The etiology of calcific tendinitis is unknown; presumably trauma leads to tissue damage with calcium deposition in the form of HA occurring at the site of tissue injury. In calcific periarthritis, the skin is often warm and red over the affected joints and the tissues are boggy and tender, but effusion is absent. Periarthritic calcification is visible on radiographs. HA crystals, detected by electron microscopy, were present in synovial fluid from more than half of patients with OA of the knee.122 The crystals were associated with more severe disease but did not correlate with the concentrations of putative markers of cartilage such as keratan sulfate. HA crystals have been shown to have phlogistic properties and have been implicated as a cause of the flares of synovitis seen in osteoarthritis, in which cases there is a tendency to higher synovial fluid cell count and a more severe course. HA-associated destructive arthritis is an unusual form of rapidly progressive destructive OA of the large joints in elderly patients that is associated with HA crystals in the synovial fluid. Although the shoulder is a typical site (so-called Milwaukee shoulder),123 it is well recognized that similar destructive changes can occur in other larger joints such as the knee, hip, and ankle and even in small joints. The overwhelming majority of patients with HAassociated destructive arthritis have been elderly women. Rapid joint destruction leading to instability and large, noninflammatory, often hemorrhagic effusions, containing large amounts of HA particles and joint detritus, are cardinal clinical features. Radiographs show characteristic changes, such as marked attrition of bone and cartilage on both sides of the joint, scalloping pressure defects, and periarticular calcifications. Osteophytosis, subchondral sclerosis, and cyst formation are either absent or are minor findings. The pathogenesis of this destructive arthropathy has not been fully delineated, but activated collagenase and neutral protease play a major role in accelerating chondrolysis and joint destruction.
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Other Crystals and Particles A variety of other birefringent materials may occasionally cause synovitis. Calcium oxalate crystal deposition can be seen in elderly patients with end-stage renal disease who are receiving chronic hemodialysis. Positively birefringent bipyramidal and polymorphic calcium oxalate crystals have been demonstrated in cartilage, synovium, and synovial fluid. Radiographically, deposits in cartilage cannot be distinguished from calcium pyrophosphate deposition. Involvement of metacarpophalangeal and proximal interphalangeal joints is common. Joint disease in chronic renal failure may be associated with either HA or calcium oxalate deposition. Cryoglobulins found in essential cryoglobulinemia and multiple myeloma can precipitate in crystalline form in a variety of tissues, including the synovium. Rare cases of cryoglobulin crystal-associated arthritis have been reported. Cholesterol crystals are mainly seen in chronic inflammatory effusions. Crystalline depot corticosteroid preparations may occasionally induce a transient inflammation hours after intra-articular injection (postinjection flare). Corticosteroid crystals can appear as positively or negatively birefringent rods, similar in size to urate or CPPD, as granules, or as irregular debris. Finally, particles of wearing surgical articular implants can be associated with a chronic detritic synovitis in elderly patients who have undergone partial or total joint replacement.
Polymyalgia Rheumatica and Giant Cell Arteritis Temporal arteritis and polymyalgia rheumatica are closely related diseases that primarily affect the elderly, frequently occur in the same individual, and usually are associated with constitutional symptoms in the form of malaise, fatigue, weight loss, anemia, and elevated levels of acute-phase reactants. Furthermore, in both syndromes, a rapid response to glucocorticoids is seen regularly. Temporal arteritis and polymyalgia rheumatica are nosologic terms used to define typical clinical syndromes, whereas giant cell arteritis denotes a specific pathologic process. The question of the relationship between temporal arteritis and polymyalgia rheumatica is still a valid one. Some consider the two to be syndromes at either end of the spectrum of one disease, with temporal arteritis the more severe and polymyalgia rheumatica the less severe expression of an underlying giant cell arteritis. Others believe that a common etiologic agent produces either a proximal synovitis leading to symptoms of polymyalgia rheumatica, or a giant cell arteritis leading to symptoms of vasculitis and occlusion of elastic arteries originating from the aortic arch.
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The association of polymyalgia rheumatica with giant cell arteritis is striking. Most series have shown that 40% to 60% of patients with giant cell arteritis have symptoms of polymyalgia rheumatica, which may be the initial presentation in one-third of patients. Conversely, biopsy of the temporal artery has demonstrated giant cell arteritis in 15% to 30% of patients with polymyalgia rheumatica who had no symptoms or signs of arteritis. The term polymyalgia rheumatica was coined by Barber in 1957 to describe a syndrome characterized by myalgias and stiffness of the shoulder and pelvic girdles, neck, or torso for a duration of 1 month or more, accompanied by constitutional symptoms and an elevated erythrocyte sedimentation rate in patients who have no underlying disease to explain the symptoms. The syndrome is extremely rare in people under the age of 50 years. Despite widespread awareness of the condition in the United States, the first report in the American literature did not appear until 1963. Giant cell arteritis, clinically also known as temporal arteritis or cranial arteritis, is a form of granulomatous vasculitis, typically containing giant cells, that most often causes occlusion of the branches of the external and internal carotids but may involve many medium- and large-sized arteries throughout the body, including the aorta.
Epidemiology Polymyalgia rheumatica and giant cell arteritis are relatively common diseases in the elderly. The incidence rate has been shown to be highest in northern Europe and in populations of the same ethnic background in the northern United States. Epidemiologic studies of these entities have been conducted in Olmstead County, Minnesota, which comprises an urban population in Rochester and a surrounding rural population.124,125 The mean annual incidence of polymyalgia rheumatica over a 10-year span (1970–1979) was 53.7 per 100,000 population 50 years of age and older; this may be compared to an incidence of rheumatoid arthritis of 77 per 100,000 in the same age group. The prevalence of polymyalgia rheumatica was estimated at 550 per 100,000 aged 50 and older. The average annual incidence of giant cell arteritis in the period between 1950 and 1983 was 16 per 100,000 population 50 years and over, with a slightly higher figure of 21.7 for the period between 1975 and 1983. The agespecific incidence rate rose, from 1.4 per 100,000 population aged 50 to 59 years, to a maximum of 44.7 per 100,000 population older than 80 years. In 1984, the prevalence of persons with a history of temporal arteritis was 234 per 100,000 population aged 50 and older. Two prospective studies from Denmark and Norway found incidence rates that were higher than those reported in prior retrospec-
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tive studies;126,127 the annual incidence of giant cell arteritis, which was the term used to encompass temporal arteritis and polymyalgia rheumatica, occurring either together or alone, was 76.6 and 141.7 per 100,000 population aged 50 years or more, respectively. The annual incidence of biopsy-proven giant cell arteritis in persons 50 years and older was 23.3 and 29.0 per 100,000, respectively. All studies have found the incidence rates of polyalgia and giant cell arteritis to be significantly higher for women than for men. Autopsy studies suggest that giant cell arteritis may be even more prevalent. In a prospective study, Östberg examined sections of the temporal arteries and two transverse sections of the aorta and found giant cell arteritis in 1.6% of 889 consecutive postmortem cases.128
Etiology and Pathogenesis The causes of polymyalgia rheumatica and giant cell arteritis is not known, nor has its striking prevalence in older people been elucidated. However, during the past few years, remarkable progress has been achieved in the understanding of the pathogenic mechanisms that lead to inflammation and damage of the vessel wall in giant cell arteritis.129,130 The cellular infiltrate is dominated by macrophages, a heterogenous population of CD-4+ T lymphocytes, a smaller number of CD-8+ T cells, and nucleated giant cells. B lymphocytes are usually absent. The CD-4+ T lymphocytes accumulate preferentially in the adventitia of the artery in close proximity to TGF-b1and IL-1-producing macrophages. A small population of CD-4+ T cells takes on the phenotype of an activated Tcell blast and undergoes clonal expansion with associated production of interferon-g. These findings suggest recognition of an antigen that resides in the adventitia. This location is apart from the internal elastic membrane and adjoining tissue that bears the brunt of injury and which is characterized by infiltration by a population of macrophages that have undergone functional differentiation to produce collagenase and inducible nitric oxidase synthase. The nature of the antigen in giant cell arteritis has not been identified. The fragmentation of the elastic lamina observed in pathologic specimens has long led to speculation that elastic fibers represent a target antigen. Support for this view has come from a recent report suggesting release of elastase-derived elastin peptides that serve as the putative autoimmune targets in this disease.131 On the other hand, the sudden onset of giant cell arteritis in some patients and the finding that the peaks of incidence of giant cell arteritis correlate with peaks of incidence of respiratory diseases have raised questions of an infectious agent triggering the autoimmune process. A viral etiology has been suspected but never proven.
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Two recent studies have suggested that a virus may play a role in the pathogenesis of giant cell arteritis. The Mayo group found a statistically significant association between histologic evidence of giant cell arteritis and the presence of parvovirus B19 DNA in temporal artery biopsies.132 A strong association of IgM directed against parainfluenza virus type 1 and biopsy-verified temporal arteritis, with a significant rise in positivity rate between the onset of symptoms and diagnosis, was found in a multicenter, prospective study.133 This finding suggested that reinfection with parainfluenza virus type 1 is linked to the onset of giant cell arteritis in a subset of patients. Although vasculitic lesions are absent in polymyalgia rheumatica, it may nevertheless represent a forme fruste of arteritis. Analysis of tissue cytokines by molecular techniques has demonstrated the presence of proinflammatory cytokines such as TGF-b1, IL-1, and IL-6 in temporal artery specimens from patients with polymyalgia rheumatica who had no obvious findings for arteritis on histologic examination.134 Epidemiologic evidence supports a genetic role in the pathophysiology of the disease. Although no association with class I HLA antigens has been detected, susceptibility and disease severity appear to be linked to certain class II antigens. Studies of northern European populations have shown an association with the HLA-DR4 haplotype, but not as strong as that observed in rheumatoid arthritis. The incidence of HLA-DR4 in patients with giant cell arteritis seen at the Mayo Clinic was 60% compared with 24% for a normal control group. An analysis of the functionally most important locus of the HLA class II complex, the HLA-DRB1 locus, in patients with biopsy-proven giant cell arteritis revealed an overrepresentation of three allelic variants of the HLA-DRB1 *04 family.135 In this particular study, the clinical findings were similar in DR4+ and DR4- patients. Relapses occurred in both subsets, and associated polymyalgia rheumatica was observed with similar frequency. The frequency of molecularly defined HLA alleles varies greatly among different ethnic groups. The lower incidence of polymyalgia rheumatica and giant cell arteritis among blacks and in southern Europe can be explained, at least in part, by the lower prevalence of the HAL-DR4 haplotype in these populations. In addition, recent studies from Spain and Italy show that susceptibility and severity of these diseases are more closely associated with other, nonDR4, HLA class II alleles.
Pathology The pathologic diagnosis of giant cell arteritis is based on the presence of typical histology changes in each arterial layer. The changes tend to affect the arteries in a patchy fashion with abnormal segments of the artery interspersed with normal segments. A distinctive fibromyxoid
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intimal proliferation causing variable degrees of luminal compromise with or without thrombus formation is seen in almost all patients. Giant cells are often closely associated with elastic lamina fragmentation. The media shows patchy degeneration, dropout of smooth muscle cells, and granulomas containing lymphocytes, histiocytes, epithelioid cells, and multinucleated giant cells. Giant cells are not seen in all sections, and their presence is not required to make the diagnosis if other histologic findings are characteristic. Giant cell arteritis has a predilection for elastic arteries that originate from the arch of the aorta, but involvement of almost every medium- and large-sized artery has been reported. The intracranial arteries are involved less often. It has been suggested that the relative sparing of the intracranial arteries is related to the small amount of internal elastic lamina in this vascular bed. In polymyalgia rheumatica, muscle biopsies have been normal or at most have shown nonspecific type II muscle atrophy, but a number of ultrastructural abnormalities have been observed. Arthroscopy and biopsy of shoulder and knee joint have demonstrated synovitis, characterized histologically by mild inflammation with lymphocytes and a few polymorphonuclear leukocytes, but without vasculitis. Granulomatous myocarditis and hepatitis have also been reported.
Clinical Picture The mean age of onset of both giant cell arteritis and polymyalgia rheumatica is about 70 years. Both diseases occur twice as often in women as they do in men. In terms of diagnosis and treatment, it is useful to recognize four patient groups: (1) patients with polymyalgia rheumatica; (2) patients with temporal arteritis; (3) patients with symptoms of both polymyalgia rheumatica and temporal arteritis; and (4) patients without local symptoms of arteritis or muscular symptoms but with systemic symptoms such as fever, malaise, and weight loss. The onset of polymyalgia rheumatica usually is insidious but can be abrupt. The most common symptoms are aches and stiffness involving the proximal muscle girdles and the neck. The discomfort usually extends to the proximal portion of the arms and thighs and to the axial musculature. The stiffness is prominent in the morning and after prolonged inactivity. Pain is accentuated by movements of the joints. Pain and stiffness may be so incapacitating that the patient cannot get out of bed in the morning without the assistance of another person. Generalized systemic complaints may include low-grade fever, night sweats, anorexia, weight loss, and depression. Peripheral musculoskeletal symptoms occur in approximately half the cases of polymyalgia rheumatica; these include a mild, usually asymmetric arthritis that predominantly involves wrists and knees, and inflammatory
42. Rheumatologic Diseases
involvement of distal tenosynovial structures that may cause a carpal tunnel syndrome or swelling of the distal extremities, with and without pitting edema. In the absence of peripheral manifestations, physical signs are conspicuously few. Muscular strength is not impaired. Tenderness, when present, is felt mostly around the shoulders. Active range of motion may be limited due to elicitation of pain, but passive motion is normal. Giant cell arteritis is also often insidious in onset and is associated with symptoms and signs that are dictated by the anatomic involvement. Most of the clinical features can be related to vasculitis and occlusion of the cranial branches of arteries originating from the aortic arch. The most common symptom is a headache, which is usually boring or lancinating in nature. Scalp tenderness along the course of the superficial temporal, posterior auricular, or occipital arteries is a telltale sign. The temporal artery may be swollen and pulseless. Tender nodules are sometimes felt. Rarely, occlusion leads to areas of gangrene of the scalp. Jaw claudication is often considered pathognomonic but occurs in less than half of patients. Giant cell arteritis may present with unusual manifestations, and the diagnosis should be considered in elderly patients who complain of pain with deglutination, throat or tongue pain, hoarseness, cough, ear pain, or sudden loss of hearing when no obvious cause for these symptoms can be found. A well-recognized and serious complication of giant cell arteritis is ocular involvement, leading to partial or complete visual loss in 15% to 20% of the patients. An even lower incidence rate of permanent loss of vision (8%) was found in the Mayo Clinic series of 166 patients with biopsy-proven giant cell arteritis.136 This incidence is lower than the incidence found in older studies and may reflect earlier recognition and treatment of the disease. Even though the dramatic manifestations of ocular involvement may appear abruptly, most patients have various complaints relating to the eyes for some time before loss of vision occurs, that is, transient blurring, amaurosis fugax, and diplopia, ptosis, or other manifestations of ophthalmoplegia. Both eyes can be affected, but loss of vision in one eye usually precedes loss of vision in the other by 1 to 12 days. Impaired visual acuity is caused by ischemic optic neuritis that is secondary to involvement of the opthalmic or the posterior ciliary arteries that supply the optic nerve. Occlusion of the central retinal artery is rarely a cause of blindness in temporal arteritis. Opthalmoplegia is a common ocular manifestation, and, as mentioned, it may precede more classical symptoms of giant cell arteritis. Occasionally, patients may complain of diplopia in the absence of detectable opthalmoplegia. Other opthalmologic complications of giant cell arteritis include episcleritis and scleritis. Clinical evidence of involvement of large arteries occurs in 15% of cases. Arteritic lesions of the aorta
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may lead to aortic valve incompetence or a dissection aneurysm and rupture of the aorta. Several reports have called attention to the increased incidence of aortic aneurysm and dissection in patients with giant cell arteritis. A population-based study from Olmsted County, Minnesota, revealed aneurysm of the thoracic aorta in 11.5% of their cases, a 17-fold higher rate than observed in the general population.137 Aortic aneurysm rupture was the cause of death in 8% of their patients. Upper extremity claudication, Raynaud’s phenomenon, paresthesias, bruits over the large proximal arteries, and decreased or absent pulses and blood pressure are common manifestations of vasculitis of the large arteries to the upper extremities. Lower extremity involvement, when it occurs, presents as leg claudication. Rare cases of involvement of the vasculature of the foot, leading to pedal gangrene, have been reported. Visceral manifestations include myocardial infarction, abdominal angina, and neurologic symptoms due to vertebral arteritis. Fever and high erythrocyte sedimentation rate in patients with myocardial infarction, cerebrovascular accident, or aortic aneurysm may signal giant cell arteritis. Acute neurologic problems were observed in 51 of 166 patients with biopsy-proven giant cell arteritis.136 This group excluded patients with opthalmologic problems and large artery abnormalities on physical examination. Of these 51 patients, 23 had peripheral neuropathies and 12 had transient ischemic attacks or strokes related to carotid or vertebral artery involvement. A multitude of neurologic manifestations can be seen when the vertebrobasilar artery system is involved, including ataxia, lateral medullary syndrome, hemianopsia, hearing loss, and dementia. Instead of the classic symptoms of arteritis, patients may present with prominent constitutional symptoms, such as fever, weight loss, malaise, and depression. In a retrospective study of 100 patients with biopsy-proven temporal arteritis, 15 fulfilled the criteria for fever of unknown origin.138 In 11 of the 15 patients, manifestations suggesting giant cell arteritis were eventually recognized, but in 4 patients the giant cell arteritis was discovered only after a random temporal artery biopsy. Therefore, temporal artery biopsy must be considered strongly in an elderly patient who presents with fever or unexplained anemia. The prognosis for giant cell arteritis is generally favorable once the condition has been recognized and treatment is under way. In most studies, the survival rate for patients with giant cell arteritis was found to be the same as for the general population of the same age. A recent follow-up study of the more than 200 patients in the 1990 American College of Rheumatology giant cell arteritis classification criteria cohort found survivorship to be virtually identical to that of the general population.139 However, large artery involvement resulting in a fatal
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outcome does occur,140 and a study from Sweden showed an increase in mortality during the first 4 months after diagnosis in 284 patients with biopsy-proven giant cell arteritis.141 Thereafter, the death rate was equal to that of the general population. Fatal outcome was usually seen in patients who were insufficiently treated with corticosteroids. It is important that all patients with giant cell arteritis be examined carefully for large artery lesions, because early recognition and treatment may prevent arterial occlusion, rupture, and death.
Diagnostic Studies Polymyalgia rheumatica and giant cell arteritis characteristically are associated with a very high erythrocyte sedimentation rate and elevation of other acute-phase reactants, such as C-reactive protein, fibrinogen, platelet count, and complement level. Westergren’s sedimentation rate in giant cell arteritis is frequently more than 100 mm in 1 h. It should be appreciated that a normal sedimentation rate does not completely rule out a diagnosis of polymyalgia rheumatica. A subgroup of polymyalgia rheumatica with low sedimentation rate (10%) losses or gains of bone mineral density, serial measurements may help identify nonresponders or patients requiring a change in therapy. Serial measurements over relatively short intervals are not useful in assessing bone mass response to preventive measures such as estrogen replacement, because expected rates of change are small by comparison with the precision variability of the technique. There are no prospective data supporting the ability of serial measures of bone loss rates to predict fracture risk. When a serial measurement fails to show a significant increase, or reveals a decrease in BMD, should this finding institute a change in therapy? A recent study attempted to address the question of regression to the mean.46 This principle predicts that patients with unusual responses to treatment are likely to have more typical responses if treatment is continued.47 The study groups
A. Inzerillo et al.
consisted of patients from the Fracture Intervention Trial (FIT) and Multiple Outcomes of Raloxifene Evaluation Trial (MORE) trials who appeared to lose BMD after the first year of active treatment. The study demonstrated that those who lost more during the first year of treatment with alendronate or raloxifene were more likely to gain in the second year of treatment. Therefore, treatment should be continued in patients who appear to lose BMD early in treatment.
Techniques Commonly Used Dual-Energy X-Ray Absorptiometry (DEXA) DEXA utilizes a beam of x-ray photons passing through the bone region of interest. The amount of beam passing through the bone and detected by the scintillation counter is inversely proportional to the bone mass. This technique measures the sum of cortical and trabecular bone at the midradius (95% cortical bone), lumbar spine, femoral neck, total hip, and total body with a precision of approximately 1% to 3%, depending on the operator and skeletal site measured.44 Radiation exposure is low (1– 3 mSv per site), and patient acceptability is high. The high reproducibility and low radiation dose of DEXA, and freedom from the error introduced by radioisotopic decay seen with older photon absorptiometry techniques, have resulted in virtual elimination of the photon absorptiometric method in recent years (Table 43.7). For the diagnosis of osteoporosis with DEXA, measurement of at least two skeletal sites is preferable, usually PA spine and hip (Fig. 43.4 A,B). Falsely elevated bone mineral density on DEXA is important to recognize while interpreting results. Reasons for such artifacts include degenerative joint or disk disease, compression fractures, vascular calcifications, or scoliosis occurring in the path of the measurement beam. Use of femoral neck, total hip, and forearm measurement sites is usually preferable under these clinical circumstances.44 Lateral spine measurement may also be useful in this clinical circumstance. A midradius measurement, which consists primarily of cortical bone, may be useful in hyperparathyroidism, as these patients tend to have greater cortical bone loss. DEXA values are reported by comparison to age and gender reference groups with T scores (standard deviations above or below values for young normals) and Z scores (standard deviations above or below age-matched values).44 A T score more than 2 SD below young normals indicates an increased risk of fracture and should lead to consideration of antiresorptive therapy to prevent further bone loss. A Z score of more than 1 to 2 SD below the age-matched mean value should prompt a thorough evaluation for secondary causes of bone loss (see Tables 43.2, 43.3).
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Table 43.7. Comparison of modalities in bone mass measurement. Major site
Precision error (%)
DXA
PA lumbar spine Lateral lumbar spine Hip Distal 1/3 forearm Total body
1–2 5–15 1.5–3 1 1
pDXA
Radius Phalanges Calcaneus
QCT
L1–L3 spine
pQCT
Method
Benefits
Problems
Serial Exams
Radiationa
1. Low radiation 2. Expensive 3. Precise
1. Requires a skilled technician 2. Subject to artifacts, particularly the spine
Yes
1–3 mSv
1–2
1. 2. 3. 4. 5. 6.
Portable Screening Low radiation Easy to operate Shorter scan times Inexpensive
1. 2. 3. 4.
Able to scan one site only Different normative database False negative Measure site unresponsive to treatment
No
100, 100, 100, 100, 1,000, 1,000, 1,000, 0.05)].41,43 Two studies that compared dextran to low-dose unfractionated heparin observed no significant differences between the two groups in the development of thromboembolic complications.41,42 However, both these studies were quite small, and it is questionable whether they had
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adequate power to detect a true difference. In contrast, two larger studies that compared dextran to low molecular weight heparin observed a significant reduction in thromboembolic events in the heparin groups [odds ratios, 0.25 ( p < 0.001) and 0.49 (p < 0.005)] as compared to the dextran groups.44,45 In summary, dextran appears to provide protection against the development of thromboembolic events at a level comparable to aspirin. It is probably less efficacious, however, than warfarin or heparin. The potential for dextran administration to cause volume overload resulting in congestive heart failure or renal insufficiency, and the small risk of anaphylaxis associated with this agent argues against its routine use in the geriatric population, particularly given the availability of equally or more efficacious agents. Typically, dextran is administered as a 10% solution in 500 to 1000 mL normal saline per day. Pneumatic sequential leg compression devices have been shown to decrease the incidence of postoperative deep vein thrombosis in urologic, neurosurgical, and general surgical patients.50 Compression stockings have also been recently evaluated in patients with hip fracture and have been shown to significantly reduce the incidence of thromboembolic events as compared to no treatment.46 Given these data, we recommend the routine use of intermittent pneumatic compression devices until the patient is ambulating on a routine basis. When to begin and how long to continue anticoagulation therapy following fracture is currently not known, and there are no data available with respect to hip fracture that address this issue. Most of the studies have begun anticoagulant therapy on admission, although this has not been studied in a systematic manner. Two autopsy series involving hip fracture patients suggest a role for continuing prophylaxis following hospitalization. In a group of patients who did not receive any form of prophylaxis, the rate of fatal pulmonary embolism declined from 1% at 30 days to 0.4% at 60 days and 0.2% at 90 days.51 Conversely, in a second autopsy series of patients, all of whom received prophylactic thromboembolic agents, the majority of fatal pulmonary embolisms were observed 30 days or more following fracture repair.52 The results of these two studies suggest that prolonged prophylaxis might be helpful in some patients, although which patients and for how long need to be empirically studied. At present, it seems reasonable to begin anticoagulation on admission and continue prophylaxis until the patient is fully ambulatory and to extend prophylaxis further in patients in whom the risk of deep venous thrombosis may be increased (patients who experienced prolonged immobility postrepair or patients in whom surgery was delayed). In summary, there is strong evidence supporting the use of either low-dose heparin or low molecular weight heparin as prophylaxis for deep venous thrombosis. The latter may be slightly more effective but is more expen-
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sive and has been associated with bleeding or hemorrhage in the spinal cord following epidural anesthesia in nonhip fracture populations. For these reasons, and until further data are available, low-dose heparin is probably the preferred agent. Aspirin also appears to have some benefit but to a lesser extent and may be considered in patients at high risk for hemorrhagic complications. Several studies support the use of low-dose warfarin; however, the required INR monitoring and risk of over- or underanticoagulation are potential drawbacks. Some patients, however, might strongly prefer weekly INR monitoring to the twice-daily injections required for heparin or low molecular weight heparin. Compression stockings appear to impart benefit with negligible risk and should be utilized. No data are yet available as to the timing of prophylactic thromboembolics and the optimal duration of therapy.
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p < 0.01)) as compared to controls. Tube-fed patients achieved independent mobility significantly faster than nontube-fed patients. One-fifth of patients could not tolerate the nocturnal feedings. Hartgrink and colleagues60 examined the effect of supplemental nocturnal tube feeding on the development of pressure ulcers, serum protein, and serum albumin. No significant differences were found in any of the three outcome measures, although only 26% percent of patients tolerated the tube feedings for the 2-week study period. Oral protein supplementation appears to be beneficial in reducing minor postoperative complications, preserving body protein stores, and reducing overall length of stay. Patients with evidence of moderate to severe malnutrition may benefit from nocturnal enteral tube feeding if tolerated.
Urinary Tract Management Nutritional Management Malnutrition has been associated with increased surgical morbidity and mortality,53,54 increased hospital length of stay,54 and poorer functional outcomes.54 It has been reported that as many as 20% of patients experiencing a hip fracture suffer from severe malnutrition.55 Interventions to improve nutritional status might therefore improve outcomes and decrease complications. To date, there have been five randomized controlled trials of nutritional supplementation in patients undergoing surgery for hip fracture. Three of the studies examined oral protein supplementation56–58 and two studies examined supplemental nasogastric tube feeding.59,60 All the studies suggest that oral protein supplementation can improve outcomes following fracture. Stableforth58 compared hip fracture patients randomized to protein supplementation versus usual care and reported significantly improved nitrogen and calorie balance in the supplemented group. Delmi and colleagues57 and Tkatch and colleagues56 randomized hip fracture patients to receive either protein supplementation or usual care57 or placebo.58 Patients receiving protein supplementation were found to have significantly fewer complications at 6 months, significantly higher albumin levels, and significantly shorter overall lengths of stay than nonsupplemented subjects. Bastow and colleagues59 examined the effect of nocturnal nasogastric tube feeding in 122 patients at increased risk for nutritional compromise (arm and trifold skin circumference less than 1 SD below the mean) for home and hospitalized elderly patients.61 Patients were randomized to usual care or nocturnal tube feedings. There were no significant differences in mortality, although the study lacked statistical power to detect this difference. Very thin patients had a significant reduction in overall length of stay and had significant increases in weight (+4.2 kg;
Urinary retention, incontinence, and urinary tract infections are commonly observed in postoperative hip fracture patients.62 Because of the frequency of postoperative bladder problems, successful strategies to reduce voiding problems might lead to decreased morbidity. There have been two randomized controlled trials of urinary bladder management in patients undergoing orthopedic surgery.63,64 One study examined patients with recently sustained hip fracture and the other examined patients undergoing hip or knee replacement. Michelson and colleagues64 randomized 100 patients with knee or hip replacement to removal of their indwelling urinary catheter immediately postoperatively or the morning following surgery. The group whose indwelling catheter was removed the morning after surgery had significantly lower rates of urinary retention. Skelly and colleagues63 randomized 67 hip fracture patients to receive an indwelling catheter for 48 h postoperatively, followed by intermittent straight catheterization or intermittent straight catheterization immediately postoperatively. Spontaneous voiding occurred significantly earlier in the intermittent catheterization group. There were no significant differences in the incidence of urinary tract infections in either of the two studies between control and intervention subjects. Indwelling catheters should probably be removed within 24 h of surgery and patients managed by intermittent straight catheterization. Evidence does not exist regarding the management of patients who continue to experience urinary retention following 48 h of intermittent catheterization.
Delirium Delirium, a transient global disorder of cognition and attention characterized by concurrent disorders of atten-
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tion, perception, thinking, memory, psychomotor behavior, and the sleep–wake cycle,65,66 may be the most frequent medical complication observed following hip fracture.67 Delirium occurs in an estimated 11% to 30% of elderly general medical patients68 and in 13% to 61% of patients with hip fracture.69 The occurrence of delirium in hospitalized patients has been shown to increase length of stay, risk of complications, mortality, and institutionalization.70–74 Further, the majority of patients who develop delirium have at least some persistent symptoms as much as 6 months later. In patients with hip fracture, delirium has been associated with poorer functioning in physical, cognitive, and affective domains 6 months postfracture and with slower rates of recovery.75,76 In this section, we focus specifically on the problem of delirium following hip fracture. A more thorough review of delirium may be found in Chapter 76. For this discussion, we focused on three types of investigations. First, we identified studies that employed multivariate methods to identify risk factors that, if modified, might prevent delirium; 15 studies met these criteria.69,74,77–89 Second, because the treatment of the underlying etiology is a cornerstone of the management of delirium, we reviewed studies that systematically described the frequency of different etiologies for this syndrome. We found 4 cohort studies,79,90,91 1 of which involved exclusively hip fracture patients. Finally, we identified studies that focused on the prevention and management of delirium in hip fracture patients. We found 2 nonrandomized studies that examined supportive treatment of delirium.92,93 The findings with regards to baseline risk factors for delirium appear to be fairly consistent across most studies. Advanced age, history of cognitive impairment, greater illness severity, and history of alcohol use appear to place hospitalized medical and surgical patients at increased risk for the development of confusion. In the two studies of hip fracture patients, only age, dementia, and prefracture functional status predicted the development of delirium.69,77 Precipitating risk factors have been more difficult to identify and, with few exceptions, a clear understanding of the iatrogenic conditions that place elderly patients at increased risk for delirium has yet to emerge. Although many risk factors have been proposed in the literature (e.g., metabolic disturbances, dehydration, alcohol withdrawal, urinary retention, changes in environment, psychosocial factors, and medications),94 only a few factors have been consistently identified as precipitating factors in prospective trials, and even these relationships are not consistent across studies. One particularly noteworthy finding, however, has been that two recent studies88,89 have suggested that untreated or undertreated postoperative pain places patients at increased risk for delirium and that, in this setting, opioid analgesic use does not increase the risk of delirium. No precipitat-
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ing factors were identified in the two studies of hip fracture patients.77,93 Regarding the etiology of delirium, there have been three case series79,90,91 that examined this issue in medical and surgical patients and one study that examined the etiology of delirium in hip fracture.95 Delirium in hip fracture appears to result from different etiologies and appears to follow a different clinical course from that observed in the medically ill. Brauer and colleagues95 found that in more than 60% of observed cases of delirium following hip fracture, the etiology could not be determined. In the majority of cases (74%), the delirium resolved or was nearly resolved at the time of hospital discharge without active intervention. These findings are in contrast to data in the medically ill that suggest that an etiology for delirium can be determined in the majority of circumstances, that delirium tends not to resolve spontaneously but improves only after therapeutic intervention.72,74 The management of delirium has been based largely on clinical experience because few systematic and controlled studies have been performed.94 There have been two nonrandomized studies involving hip fracture patients. Williams and colleagues92 conducted a time sequence trial using pre- and postoperative nursing interventions (e.g., environmental manipulation, reorientation, reassurance) in hip fracture patients. The incidence of delirium was 44% in the treatment group as compared to 52% in the control (p < 0.02). Gustafson and colleagues93 compared 103 treatment subjects with 111 historical controls admitted 2 to 5 years before the intervention cohort. The intervention in this study consisted of pre- and postoperative geriatric assessments, oxygen therapy for hypoxia, early surgery (performed as soon as patients were medically stable), and aggressive treatment of perioperative blood pressure falls. The incidence of delirium was 61% in the historical controls and 48% in the treatment group (p < 0.05). Subjects in the treatment group were less likely to be confused for more than 7 days (9% versus 28%) and had a shorter length of stay (11.6 versus 17.4 days). The individual contributions of each of the various components of the intervention to the reduction in delirium are unknown. In summary, although many cohort studies have examined the risk factors for developing delirium, most analyses have not specifically focused on hip fracture patients and many studies have lacked adequate statistical power. Nevertheless, the assembled studies indicate a number of recurring potentially modifiable risk factors for developing delirium including electrolyte and metabolic laboratory abnormalities, medications with psychoactive properties, and infection. Environmental manipulation and supportive reorientation appear to reduce the incidence of delirium and benefit the acutely delirious patient, although more research addressing the optimal symptomatic management is needed.
45. Medical Aspects of Hip Fracture Management
Rehabilitation Rehabilitative services for hip fracture patients may include limb and joint mobilization and progressive exercises; physical and occupational therapy to regain mobility and independence in activities of daily living; physician oversight of the therapy; psychologic counseling; social work; restorative nursing services; and recreational services. For the purposes of this chapter, we focused on selected aspects of rehabilitation that are particularly salient to the primary care provider (e.g., internist, family practitioner, nurse practitioner), recognizing that rehabilitation is a shared responsibility with the surgeon who, depending on the fracture and type of surgery, may have specific recommendations about mobilization and weightbearing. Specifically, we address the value of (a) early mobilization, (b) intensified interdisciplinary rehabilitation approaches, and (c) intensity and frequency of therapy. There have been a number of reports of programs that employed early mobilization or early weightbearing policies. From these reports, we excluded studies, primarily from the 1960s through 1970s, that reviewed the experience of “early weightbearing” initiated many days or weeks after the perioperative period and focused only on those studies that reported on early mobilization in the first 24 to 48 h. For this group of interventions, we identified one randomized trial96 that included early mobilization as part of a larger program of accelerated rehabilitation; we also identified a large number of trials that employed early mobilization policies in the first 24 to 48 h for all subjects.97–108 In the case of intensified interdisciplinary rehabilitation programs, we identified four randomized trials.109–112 For the intensity and frequency of physical therapy, we identified two small randomized trials102,112 and three cohort studies that attempted to control for potential confounding between patient characteristics and receipt of services.8,26,113 The one randomized trial that evaluated early mobilization (usually within 24 h of surgery) did so as part of a program that also included early discharge from the hospital and a comprehensive rehabilitation program during and after hospitalization.96 Although that trial of 252 patients found no differences in physical independence of patients at 4 months, it showed that so-called accelerated rehabilitation could reduce health care costs. Other studies97–108 have shown that policies on early mobilization from the first postoperative day can be implemented without an increased risk of surgical complications,97–99 change in discharge destination,97,101 poorer functional outcomes,97,100,102 and increased mortality.99,101 There have been four, relatively small, randomized trials that evaluated the benefits of geriatric interdisciplinary rehabilitation.109–112 Two of the studies found no differences in functional outcomes,112 mortality, or
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placement.110 Two studies, however, found positive effects associated with these programs. Kennie and colleagues,109 in a study of 112 patients, reported improved functional status and found that patients were more likely to be discharged to their own home than to a nursing home following interdisciplinary rehabilitation. Additionally, a randomized trial of geriatric assessment and rehabilitation in which hip fracture was the most common diagnosis (occurring in 18% of the patients) found that geriatric rehabilitation improved the chances of returning to the community.111 Two randomized trials have evaluated intensified physical therapy (e.g., therapy sessions twice rather than once a day or supplemental individualized educational sessions).102,112 Both trials failed to show any benefit in functional outcomes; however, they were both quite small. For that reason, we sought additional evidence of efficacy from cohort studies that attempted to control for potential confounding between patient characteristics and receipt of services. In a cohort study of 162 hospitalized patients, Guccione and colleagues113 found that more than one physical therapy session per day was associated with improved functional outcome after adjusting for age, prefracture ambulation, and length of stay. In another study of 536 patients, Magaziner and colleagues8 reported that the number of physical therapy sessions (after adjustment for prefracture and other hospital care variables) was associated with improved physical independence at 1 year but did not affect walking ability or ability to perform instrumental activities of daily living. Finally, in a multisite study involving 284 acute care hospitals in five states, Hoenig and colleagues26 found that more than five physical therapy/occupational therapy (PT/OT) sessions per week was associated with earlier ambulation [odds ratio (OR), 1.76; 95% confidence limits (CL), 1.50, 2.07), and patients who ambulated earlier had shorter lengths of stay (6.5 fewer days; p < 0.001) were more likely to return to the community (OR, 1.45; 95% CL, 1.16, 1.81) and had better than a 6-month survival (OR, 2.8; 95% CL, 2.06, 3.88). In summary, the available data suggest that early mobilization can be done safely in selected patients, although the potential benefits of early mobilization have not been well studied and quantified. In the case of interdisciplinary rehabilitation featuring geriatric assessment, there is some suggestion from randomized trials that these programs can improve functional outcome and increase the likelihood of patients returning to the community. These trials, however, have been small and limited to programs with personnel with special interests in orthogeriatrics. For physical therapy services, cohort studies that have adjusted for potential confounders suggest that the frequency of physical therapy is likely to have an important impact on outcome and that more than one session per day is probably beneficial.
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Falls Assessment Patients who have fractured a hip have an increased risk of a subsequent fracture.114 Interventions to reduce the likelihood and number of subsequent falls might therefore have beneficial effects on outcome. A comprehensive review of fall assessment and prevention may be found in Chapter 66. To date, there have been a number of randomized controlled trials115–121 and one preplanned meta-analysis122 of clinical and social interventions to reduce falls. None of the studies were specifically targeted to hip fracture patients. Two of the six studies116,117 focused on patients at risk for falling on the basis of other factors. Four studies115,119–121 focused on older persons in the community who were otherwise unscreened for fall risk, and one study focused on frail nursing home residents.118 The meta-analysis122 included eight trials, two of which are cited above,116,118 and examined the impact of exercise and balance on fall prevention. The five studies115,118–121 that focused on subjects previously unscreened for fall risk randomly assigned either nursing home residents,118 senior centers, or households to interventions that included low-intensity exercises, counseling on risk factor reduction, and efforts to identify and correct environmental hazards. Two of the studies115,119 showed that the intervention slightly reduced the risk of falling (but not that of fractures or falls requiring medical attention). The interventions that targeted older persons at risk of falling were more efficacious. Rubenstein and colleagues117 randomly assigned ambulatory nursing home residents to either usual care or detailed clinical and environmental assessments within a week of the fall. The intervention did not significantly reduce the risk of subsequent falls, but the intervention group was hospitalized less frequently over the next 2 years. Tinetti and colleagues116 identified communitydwelling older persons with specific risk factors (e.g., postural hypotension or difficulty in transferring) for falling and randomly assigned them to either social visits or a targeted multifactorial intervention that featured medication adjustment, behavioral instruction, and exercise activities targeted to the patient’s risk factors. This intervention reduced the risk of falling (relative risk = 0.69) and the prevalence of targeted risk factors. Province and colleagues122 performed a meta-analysis of eight trials involving diverse patient populations and several different interventions, all of which, however, included an exercise component. These eight trials demonstrated an adjusted fall incidence rate of 0.90 (95% confidence limits, 0.81–0.99). An adjusted fall incidence rate of 0.83 (95% confidence limits, 0.70–0.98) was observed for treatment groups that included balance training as compared to controls. No specific exercise component was signifi-
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cant for injurious falls, but the studies did not have adequate power to detect this outcome. These studies suggest that interventions to reduce the incidence of falls are more likely to be beneficial if they focus on persons at risk for falls and if the interventions target specific risk factors or behaviors. Exercise and balance training also appear to be somewhat effective in decreasing fall risk. Because persons who have sustained hip fractures are at higher risk of subsequent falls, these findings may be generalizable to this population.
Conclusion Hip fracture is a common disorder that results in death or significant loss of function for more than 150,000 Americans annually. Furthermore, the number of hip fractures occurring annually in this country is expected to double by the year 2040.6,123 Clinical outcomes of hip fracture patients should be improvable by evidence-based medical care. This chapter has identified processes of medical care for which the data are unambiguous (e.g., prophylactic antibiotics and antithrombotics) and others for which the data are less clear and for which more research is needed (e.g., management of delirium, prevention of falls, duration of prophylactic thromboembolics, and cost-effectiveness of low molecular weight heparin as compared to other agents). The recommendations proposed in this chapter should enhance our ability to predict and manage the common complications of hip fracture, improve function and quality of life, and improve the quality of medical care afforded these patients.
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hospital discharge for hip fracture: a prospective study. J Gerontol. 1990;45:M101–M107. Ray NF, Chan JK, Thamer M, Melton LJ III. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;12(1): 24–35. Brainsky A, Glick H, Lydick F, et al. The economic cost of hip fractures in community-dwelling older adults: a prospective study [see comments]. J Am Geriatr Soc. 1997; 45(3):281–287. Office of Technology Assessment. Hip Fracture Outcomes in People Aged 50 and Over: Mortality, Service Use, Expenditures, and Long-Term Functional Impairment. Washington, DC: U.S. Government Printing Office; 1993. Chrischilles E, Shireman T, Wallace R. Costs and health effects of osteoporotic fractures. Bone. 1994:15(4):377– 386. Zuckerman J. Hip fracture. N Engl J Med. 1996;334:1519– 1525. Zuckerman JD, Schon LC. Hip fractures. In: Zuckerman JD, ed. Comprehensive Care of Orthopaedic Injuries in the Elderly. Baltimore: Urban & Schwarzenberg; 1990. pp. 23–111. Morrison RS, Siu AL. Survival in end-stage dementia following acute illness. JAMA. 2000;284(1):47–52. Morrison RS, Siu AL. A comparison of pain and its treatment in advanced dementia and cognitively intact patients with hip fracture. J Pain Symptom Manag. 2000;19:240– 248. Parker M, Pryor G. The timing of surgery for proximal femoral fractures. J Bone Joint Surg. 1992;74B:203–205. Dolk T. Operation in hip fracture patients—analysis of the time factor. Injury. 1990;21(6):369–372. Villar R, Allen S, Barnes S. Hip fractures in healthy patients: operative delay versus prognosis. Br Med J. 1986;293:1203–1204. Bredhal C, Nyholm B, Hindsholm K, Mortensen J, Olesen A. Mortality after hip fracture: results of operation within 12 hours of admission. Injury. 1992;23:83–86. Holmberg S, Kalen R, Thorngren KG. Treatment and outcome of femoral neck fractures. An analysis of 2418 patients admitted from their own homes. Clin Orthop. 1987;218:42–52. Kenzora J, McCarthy R, Lowell J, Sledge C. Hip fracture mortality, relation to age, treatment, preoperative illness, time of surgery, and complications. Clin Orthop Relat Res. 1984;186:45–46. Rogers F, Shackford S. Keller M. Early fixation reduces morbidity and mortality in elderly patients with hip fractures from low impact falls. J Trauma Inj Infect Crit Care. 1995;39:261–265. Todd CJ, Freeman CJ, Camilleri Ferrante C, et al. Differences in mortality after fracture of hip: the east Anglian audit. Br Med J. 1995;310(6984):904–908. Zuckerman J, Skovoron M, Koval K, Aharonoff G, Frankel V. Postoperative complications and mortality associated with operative delay in older patients who have a fracture of the hip. J Bone Joint Surg. 1995;77A:1551–1556.
677 26. Hoenig H, Rubenstein L, Sloane R, Horner K, Kahn K. What is the role of timing in the surgical and rehabilitative care of community-dwelling older persons with hip fracture. Arch Intern Med. 1997;157:513–520. 27. Davis FM, Woolner DF, Frampton C, et al. Prospective, multi-centre trial of mortality following general or spinal anaesthesia for hip fracture surgery in the elderly. Br J Anaesth. 1987;59(9):1080–1088. 28. Perez J, Warwick D, Case C, Bannister G. Death after proximal femoral fracture—an autopsy study. Injury. 1995;26:237–240. 29. Handoll HHG, Farrar MJ, McBirnie J, et al. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Review. The Cochrane Library, 4th Ed. Oxford: Update Software; 2000. 30. Morrison R, Chassin M, Siu A. The medical consultant’s role in caring for patients with hip fracture. Ann Intern Med. 1998;128:1010–1020. 31. Classen DC, Evans KS, Pestotnik SL, Horn SD, Menlove KL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326(5):281–286. 32. Boxma H, Broekhuizen T, Patka P, Oosting H. Randomised controlled trial of single dose antibiotic prophylaxis in surgical treatment of closed fractures. Lancet. 1996;347:1133–1137. 33. Albers B, Patka P, Haarman H, Kostense P. Kosteneffektivat einer antibiotikaprophylaxe bei senkung des infectionsrisikos um 0.25% [Cost effectiveness of antibiotic prophylaxis for closed fractures]. Unfallchirurg. 1994;97: 625–628. 34. Abramowicz M, ed. Handbook of Antimicrobial Therapy. New Rochelle: Medical Letter; 1998. 35. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med. 1988;318:1162–1173. 36. Lassen M, Borris L, Christiansen H, et al. Clinical trials with low molecular weight heparins in the prevention of postoperative thromboembolic complications: a metaanalysis. Semin Thromb Hemost. 1991;l7:284–290. 37. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Br Med J. 1994;308:235–246. 38. Powers P, Gent M, Jay R, et al. A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip. Arch Intern Med. 1989:149:771–774. 39. Morris G, Mitchell J. Preventing venous thromboembolism in elderly patients with hip fractures: studies of low-dose heparin, dipyridamole, aspirin, and fluriprofen. Br Med J. 1977;1:535–537. 40. Gerhart TN, Yett HS, Robertson LK, Lee MA, Smith M, Salzman EW. Low-molecular-weight heparinoid compared with warfarin for prophylaxis of deep-vein thrombosis in patients who are operated on for fracture of the
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R.S. Morrison and A.L. Siu hip. A prospective, randomized trial. J Bone Joint Surg Am. 1991;73(4):494–502. Bergqvist D, Efsing H, Hallbook T, Hedlund T. Thromboembolism after elective and post-traumatic hip surgery—a controlled prophylactic trial with dextran 70 and low-dose heparin. Acta Chir Scand. 1979;145(4):213–218. Pini M, Spadini E, Carluccio L, et al. Dextran/aspirin versus heparin/dihydroergotamine in preventing thrombosis after hip fracture. J Bone Joint Surg. 1985;76B:305– 309. Feldman D, Zuckerman J, Walters I, Sakales S. Clinical efficacy of aspirin and dextran for thromboprophylaxis in geriatric hip fracture patients. J Orthop Trauma. 1993;7: 1–5. Bergqvist D, Kettunen R, Fredin H, et al. Thromboprophylaxis in patients with hip fractures: a prospective, randomized, comparative study between Org 10172 and dextran 70. Surgery. 1991;109(5):617–622. Oertli D, Hess P. Durig M, et al. Prevention of deep vein thrombosis in patients with hip fractures: LMWH versus dextran. World J Surg. 1992;16:980–984. Fisher CG, Blachut PA, Salvian AJ, et al. Effectiveness of pneumatic leg compression devices for the prevention of thromboembolic disease in orthopaedic trauma patients: a prospective, randomized study of compression alone versus no prophylaxis. J Orthop Trauma. 1995;9(1): 1–7. Gent M, Hirsh J, Ginsberg JS, et al. Low-molecular-weight heparinoid orgaran is more effective than aspirin in the prevention of venous thromboembolism after surgery for hip fracture. Circulation. 1996;93(1):80–84. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000;355(9212):1295–1302. Nightingale SL. From the Food and Drug Administration. JAMA. 1998;279:346. Coe NP, Collins RE, Klein LA, et al. Prevention of deep vein thrombosis in urological patients. A controlled, randomized trial of low-dose heparin and external pneumatic compression boots. Surgery. 1978;83:230–234. Schroder HM, Andreassen M. Autopsy-verified major pulmonary embolism after hip fracture. Clin Orthop. 1989; 293:196–203. Bergqvist D, Fredin H. Pulmonary embolism and mortality in patients with fractured hips—a prospective consecutive series. Eur J Surg. 1991;157:571–574. Patterson BM, Cornell CN, Carbone B, Levine B, Chapman D. Protein depletion and metabolic stress in elderly patients who have a fracture of the hip. J Bone Joint Surg Am. 1992;74(2):251–260. Koval KJ, Maurer SG, Su ET, Aharonoff GB, Zuckerman JD. The effects of nutritional status on outcome after hip fracture. J Orthop Trauma. 1999;13(3):164–169. Bastow M, Rawlings J, Allison S. Undernutrition, hypothermia, and injury in elderly women with fractured femur; an injury response to altered metabolism? Lancet. 1983;1983(i):143–146. Tkatch L, Rapin CH, Rizzoli R, et al. Benefits of oral protein supplementation in elderly patients with fracture of the proximal femur. J Am Coll Nutr. 1992;l1(5):519–525.
57. Delmi M, Rapin CH, Bengoa JM, Delmas PD, Vasey H, Bonjour JP. Dietary supplementation in elderly patients with fractured neck of the femur. Lancet. 1990;335(8696): 1013–1016. 58. Stableforth PG. Supplement feeds and nitrogen and calorie balance following femoral neck fracture. Br J Surg. 1986;73(8):651–655. 59. Bastow MD, Rawlings J, Allison SP. Benefits of supplementary tube feeding after fractured neck of femur: a randomised controlled trial. Br Med J Clin Res Ed. 1983; 287(6405):1589–1592. 60. Hartgrink HH, Wille J, Konig P, Hermans J, Breslau PJ. Pressure sores and tube feeding in patients with a fracture of the hip: a randomized clinical trial. Clin Nutr. 1998; 17(6):287–292. 61. Vir S, Love A. Anthropometric measurements in the elderly. Gerontology. 1980;26:262–268. 62. Smith NK, Albazzaz MK. A prospective study of urinary retention and risk of death after proximal femoral fracture. Age Ageing. 1996;25(2):150–154. 63. Skelly JM, Guyatt GH, Kalbfleisch R, Singer J, Winter L. Management of urinary retention after surgical repair of hip fracture. Can Med Assoc J. 1992;146(7):1185–1189. 64. Michelson JD, Lotke PA, Steinberg ME. Urinary-bladder management after total joint-replacement surgery. N Engl J Med. 1988;319(6):321–326. 65. Lipowski Z. Delirium in the elderly patient. N Engl J Med. 1989;32:278–303. 66. Lipowski Z. Transient cognitive disorders (delirium, acute confusional states in the elderly). Am J Psychiatry. 1983; 140:1426–1436. 67. Gillick M, Serell N, Gillick L. Adverse consequences of hospitalization in the elderly. Soc Sci Med. 1982;16:1033– 1038. 68. Rummans T, Evans J, Krahn L, et al. Delirium in elderly patients: evaluation and management. Mayo Clin Proc. 1995;70:988–989. 69. Gustafson Y, Berggren D, Brannstrom B, et al. Acute confusional states in elderly patients treated for femoral neck fracture. J Am Geriatr Soc. 1988;36(6):525–530. 70. Cole M, Primeau F, McCusker J. Effectiveness of interventions to prevent delirium in hospitalized patients: a systematic review. Can Med Assoc J. 1996;155:1263–1268. 71. Francis J, Kapoor WN. Prognosis after hospital discharge of older medical patients with delirium. J Am Geriatr Soc. 1992;40(6):601–606. 72. Levkoff S, Evans D, Liptzin B, et al. Delirium: the occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med. 1992;152:334–340. 73. Murray AM, Levkoff SE, Wetle TT, et al. Acute delirium and functional decline in the hospitalized elderly patient. J Gerontol. 1993;48(5):M181–M186. 74. Rockwood K. Delays in the discharge of elderly patients. J Clin Epidemiol. 1990;43:971–975. 75. Dolan MM, Hawkes WG, Zimmerman SI, et al. Delirium on hospital admission in aged hip fracture patients: prediction of mortality and 2-year functional outcomes. J Gerontol A Biol Sci Med Sci. 2000;55(9):M527–M534. 76. Marcantonio ER, Flacker JM, Michaels M, Resnick NM. Delirium is independently associated with poor functional
45. Medical Aspects of Hip Fracture Management
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recovery after hip fracture. J Am Geriatr Soc. 2000;48(6): 618–624. Williams M, Campbell E, Kaynor W, Musholt M, Mlynarczyk S, Crane L. Predictors of acute confusional states in elderly persons. Res Nurs Health. 1985;8:31–40. Foreman M. Confusion in the hospitalized elderly. Res Nurs Health. 1989;12:21–29. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990;263(8):1097– 1101. Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA. 1996; 275(11):852–857. Inouye S, Viscoli C, Horwitz R, Hurst L, Tinetti M. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med. 1993;119:474–481. Jitapunkul S, Pillay I, Ebrahim S. Delirium in newly admitted elderly patients: a prospective study. Q J Med. 1992;300:307–314. Marcantonio E, Goldman L, Mangione C, et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA. 1994;271(2):134–139. Rogers M, Liang M, Daltroy L. Delirium after elective orthopedic surgery: risk factors and natural history. Int J Psychiatry Med. 1989;19(2):109–121. Schor JD, Levkoff SE, Lipsitz LA, et al. Risk factors for delirium in hospitalized elderly. JAMA. 1992;267(6):827– 831. Pompei P, Foreman M, Rudberg M, Inouye S, Braund V, Cassel C. Delirium in hospitalized older persons: outcomes and predictors. J Am Geriatr Soc. 1994;42:809– 815. Williams Russo P, Urquhart BL, Sharrock NE, Charlson ME. Post-operative delirium: predictors and prognosis in elderly orthopedic patients. J Am Geriatr Soc. 1992;40(8): 759–767. Duggleby W, Lander J. Cognitive status and postoperative pain: older adults. J Pain Symptom Manag. 1994;9:19– 27. Lynch EP, Lazor MA, Gellis JE, Orav J, Goldman L, Marcantonio ER. The impact of postoperative pain on the development of postoperative delirium. Anesth Analg. 1998;86:781–785. Moses HD, Kaden I. Neurologic consultations in a general hospital. Spectrum of iatrogenic disease. Am J Med. 1986; 81(6):955–958. Purdie FR, Honigman B, Rosen P. Acute organic brain syndrome: a review of 100 cases. Ann Emerg Med. 1981; 10(9):455–461. Williams M, Campbell E, Raynor V, Mlynarczyk S, Ward S. Reducing acute confusional states in elderly patients with hip fractures. Res Nurs Health. 1985;8:329–337. Gustafson Y, Brannstrom B, Berggren D, et al. A geriatricanesthesiologic program to reduce acute confusional states in elderly patients treated for femoral neck fractures. J Am Geriatr Soc. 1991;39(7):655–662. Francis J. Delirium in older patients. J Am Geriatr Soc. 1992;40:829–838.
679 95. Brauer C, Morrison RS, Silberzweig SB, Siu AL. The cause of delirium in patients with hip fracture. Arch Intern Med. 2000;160(12):1856–1860. 96. Cameron ID, Lyle DM, Quine S. Cost-effectiveness of accelerated rehabilitation after proximal femoral fracture. J Clin Epidemiol. 1994;47(11):1307–1313. 97. Zuckerman J, Sakales S, Fabian D, Frankel V. Hip fractures in geriatric patients: results of an interdisciplinary hospital care program. Clin Orthop. 1992;274:213–225. 98. Stromqvist B, Hansson LI, Nilsson LT, Thorngren KG. Hook-pin fixation in femoral neck fractures. A twoyear follow-up study of 300 cases. Clin Orthop. 1987;218: 58–62. 99. Arnold WD. The effect of early weight-bearing on the stability of femoral neck fractures treated with Knowles pins. J Bone Joint Surg Am. 1984;66(6):847–852. 100. Jarnlo GB. Hip fracture patients. Background factors and function. Scand J Rehabil Med Suppl. 1991;24:1–31. 101. Ceder L, Stromqvist B, Hansson LI. Effects of strategy changes in the treatment of femoral neck fractures during a 17-year period. Clin Orthop. 1987;218:53–57. 102. Karuumo I. Intensive physical therapy after fractures of the femoral shaft. Ann Chir Gynaecol. 1977;66(6):278– 283. 103. Skinner P, Riley D, Ellergy J, Beaumont A. Displaced subcapital fractures of the femur: a prospective randomized comparison of internal fixation, hemiarthroplasty and total hip replacement. Injury. 1989;20:291–293. 104. Sorenson J, Varmarken J, Bomler J. Internal fixation of femoral neck fractures. Dynamic hip and Gouffon screws compared in 73 patients. Acta Orthop Scand. 1992;63:288– 292. 105. Elmerson S, Andersson G, Irstam L, et al. Internal fixation of femoral neck fracture. No difference between Rydell four-flanged nail and Gouffon’s pin. Acta Orthop Scand. 1988;59:372–376. 106. Olerud C, Rehnberg L, Hellquist E. Internal fixation of femoral neck fractures. Two methods compared. J Bone Joint Surg Br. 1991;73:16–19. 107. Nungu S, Olerud C, Rehnberg L. Treatment of intertrochanteric fractures: comparison of ender nails and sliding screw plates. J Orthop Trauma. 1991;5:452– 457. 108. Dalen N, Jacobsson B, Eriksson P. A comparison of nailplate fixation and enders nailing in pertrochanteric fractures. J Trauma. 1988;28:405–406. 109. Kennie D, Reid J, Richardson I, Kiamari A, Kelt C. Effectiveness of geriatric rehabilitative care after fractures of the proximal femur in elderly women: a randomised clinical trial. Br Med J. 1988;297:1083–1086. 110. Gilchrist W, Newman R, Hamblen D, Williams B. Prospective randomised study of an orthopaedic geriatric inpatient service. Br Med J. 1988;297:1116–1118. 111. Applegate WB, Miller ST, Graney MJ, Elam JT, Burns R, Akins DE. A randomized, controlled trial of a geriatric assessment unit in a community rehabilitation hospital. N Engl J Med. 1990;322(22):1572–1578. 112. Jette AM, Harris BA, Cleary PD, Campion EW. Functional recovery after hip fracture. Arch Phys Med Rehabil. 1987; 68(10):735–740.
680 113. Guccione AA, Fagerson TL, Anderson JJ. Regaining functional independence in the acute care setting following hip fracture. Phys Ther. 1996;76(8):818–826. 114. Finsen V, Benum P. The second hip fracture: an epidemiologic study. Acta Orthop Scand. 1986;57:431–433. 115. Wagner EH, LaCroix AZ, Grothaus L, et al. Preventing disability and falls in older adults: a population-based randomized trial. Am J Public Health. 1994;84(11):1800– 1816. 116. Tinetti M, Baker D, McAvay G, et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med. 1994;331: 315–320. 117. Rubenstein L, Robbins A, Josephson K, Schulman B, Osterweil D. The value of assessing falls in an elderly population. Ann Intern Med. 1990;113:308–316. 118. Mulrow CD, Gerety MB, Kanten D, et al. A randomized trial of physical rehabilitation for very frail nursing home residents [see comments]. JAMA. 1994;271(7):519–524.
R.S. Morrison and A.L. Siu 119. Hornbrook M, Stevens V, Wingfield D, Hollis J, Greenlick M, Ory M. Preventing falls among community dwelling older persons: results from a randomized trial. Gerontologist. 1994;34:16–23. 120. Reinsch S, Macrae P, Lachenbruch P, Tobis J. Attempts to prevent falls and injury: a prospective community study. Gerontologist. 1992;32:450–456. 121. Vetter N, Lewis P, Ford D. Can health visitors prevent fractures in elderly people. Br Med J. 1992;304:888– 890. 122. Province MA, Hadley EC, Hornbrook MC, et al. The effects of exercise on falls in elderly patients. A preplanned meta-analysis of the FICSIT Trials: Frailty and Injuries: Cooperative Studies of Intervention Techniques. JAMA. 1995;273(17):1341–1347. 123. Cummings S, Rubin S, Black D. The future of hip fractures in the United States: number, costs, and potential effects of postmenopausal estrogen. Clin Orthop. 1990:252:163– 166.
46 Treatment of Diabetes Kenneth L. Minaker
Sites of Care Care of the older diabetic patient, similar to the care of other complex geriatric patients, has become a multidisciplinary issue with very high stakes in terms of vascular, renal, and ocular disability. Recent studies have demonstrated the value of careful management on the improvement in patient outcomes, and large-scale studies are under way to deter or prevent the emergence of clinical disease. Increasingly, the focus of care is planning a comprehensive, multidisciplinary treatment and assessment program designed to prevent end-organ injury and to intervene early in the course of illness. It is an encouraging time to be involved in the treatment of diabetic patients, particularly outpatients treated early in the course of their illness. Improved care of the vascular and renal complications in those with advanced disease has also produced promise for their higher quality of life.
diabetes mellitus is approximately 2 per 1000 among those older than 45 and increases for those individuals more than 75 years old.4 Prevalence is much higher in older Hispanics, African Americans, Native Americans (Indians), Scandinavians, Japanese, and Micronesians. Individuals with diabetes mellitus who are older than 65 usually have noninsulin-dependent diabetes (NIDDM). Insulin-dependent diabetes mellitus (IDDM) accounts for only 5% to 10% newly diagnosed diabetes mellitus in late life.5 In addition, a small proportion of older individuals who initially have NIDDM appear to become insulin dependent over time. A few clues as to who will require insulin exist. Ketosis at the time of diagnosis suggests that insulin therapy will be necessary. However, some elderly individuals with diabetes and ketosis can subsequently be treated with oral agents. The human leukocyte antigen (HLA)-DR3 serotype is more common in older adults who require insulin treatment. The frequency of antibodies to islet cells in older diabetic patients is not increased.5
Demographics, Epidemiology, and Risk Factors
Specific Clinical Patterns with Aging
Diabetes mellitus prevalence increases with age, and the numbers of older persons with diabetes are expected to grow as the elderly population increases in number1–3 (Fig. 46.1). The National Health and Nutrition Examination Survey (NHANES III) demonstrated that, in the population over 65 years old, almost 18% to 20% have diabetes. Of great diagnostic and clinical significance is that one-half of those with diabetes mellitus are not aware they have the disease. Other abnormalities in carbohydrate metabolism that have been observed include an additional 20% to 25% older patients meeting the criteria for impaired glucose tolerance. These unknown diabetic individuals and those potentially at risk were uncovered using glucose tolerance tests, which are very sensitive to abnormalities in carbohydrate economy. The incidence of
A variety of metabolic, sensory, and cardiovascular conditions accompany the widespread prevalence of diabetes in the elderly and contribute to the reduced life expectancy that occurs with diabetes. Life expectancy reductions in diabetic individuals at ages 50 to 59 are 6 to 7 years, at ages 60 to 69 are 4 to 5 years, and at age 70 and above life expectancies are reduced by 3 years. In addition, the longer diabetes has been present, the greater the life expectancy reduction. Hypertension occurs in 30% to 50% of those with diabetes in 45- to 64-year-olds but is present in 70% of diabetic patients aged 65 to 74. Diabetic ketoacidosis mortality is greater in individuals over age 75 (50 per 100,000 diabetic patients) than age 65 to 74 (20 per 100,000 diabetic patients). Hyperosmolar nonketotic 681
682
K.L. Minaker Figure 46.1. Prevalence of diabetes in men and women in the U.S. population age 20 years or older, based on NHANES III. Reproduced with permission from Ref. 3.
25
21.1 20.2 20
Percent of population
17.8
17.5
15 12.9
12.4
10 8.4 6.8
7.7
6.1
5 1.6 1.7 0 Men Women Men Women 20–39 40–49
Men Women Men Women 50–59 60–74 Sex and Age (years)
Men Women 75+
coma is essentially a disorder of the elderly diabetic.6 Twenty-four percent of all cases of legal blindness occur in diabetic individuals over age 65 years. Peripheral neuropathy, the most common diabetic neuropathy, has a prevalence of 25% to 35% in diabetic patients between 65 and 74 years of age. Absent pulses are twice as frequent in diabetic versus nondiabetic individuals (20% versus 13%) in the age group 55 to 74 years. The risk of leg amputations is 15 to 40 times greater for a person with diabetes. Renal failure requiring dialysis occurs most often from the pool of patients with diabetes mellitus, and recent evidence suggests progression to renal failure is more rapid in older patients. The incidence of stroke is almost twice as great in diabetic individuals at all ages. Stroke incidence increases with advancing age to incidence rates four times greater: the rate at age 45 to 49 is 30 per 1000 and at age 65 to 69 is 133 per 1000. Between the ages of 45 and 64, 8.4% of diabetic individuals have had a stroke, a prevalence that increases to 12.7% in individuals more than 65 years of age.7 The incrementally greater impact of the number of risk factors for stroke in the elderly diabetic population has been studied in the Framingham Heart Study. With increasing numbers of risk factors, including hypertension, hypertension treatment, diabetes mellitus, cigarette smoking, preexisting heart disease, atrial fibrillation, and ECG changes compatible with left ventricular hypertrophy, 10-year stroke probability increases geometrically.8
Men Women age-std
Advancing age in diabetic individuals is associated with increasing prevalence of a host of gastrointestinal diseases including hiatus hernia, ulcers, and gallstones, trends that are more apparent in females than males with diabetes mellitus (NHANES II). Infection rates, particularly urinary tract infections and viral pneumonia, are twice as frequent in diabetic individuals than nondiabetic individuals. Current evidence suggests no age-related increase in infection rates. Periodontal disease shows a linear increase with age in diabetic individuals.9 The overall impact of comorbid disease, being more prevalent in older diabetic individuals, is substantial. Although hospital discharges primarily for diabetes mellitus decrease with advancing age, those for associated diseases increase dramatically. Hospitalization rates are 40% to 80% higher in diabetic patients than nondiabetic patients depending on age.10 Advancing age is also associated with a progressive increase in length of hospital stay with diabetes mellitus.
Pathogenesis of Age-Associated Glucose Intolerance Glucose intolerance associated with aging itself may predispose to the development of overt diabetes mellitus. Glucose intolerance is present even in very healthy older individuals. Postprandial blood glucose increases by
46. Treatment of Diabetes
5.3 mg/dL per decade after the age of 3011,12 (Fig. 46.2). Age-related changes in fasting blood glucose levels are 1 to 2 mg/dL (0.05–0.09 mM) per decade after age 30.13,14 Several factors appear to contribute to age-associated glucose homeostatic changes. Glucose absorption slows with increasing age, and hepatic glucose production shuts down after food and glucose is delayed, most likely as a result of delayed insulin secretion.15 Subtle age-related changes in regulation of insulin secretion have been described.16 The presence of insulin resistance in the elderly has been confirmed in multiple studies.14,17,18 It is a result of postreceptor events, the specific site(s) of which are not yet understood.19–21 Other factors may contribute to glucose intolerance. Both the decline in lean body mass and the increase in body fat that accompany aging may contribute to insulin resistance.22 Reduced levels of physical activity and altered diet may cause these changes in body composition.23 Studies of master athletes suggest that some of these changes can be either prevented or modified with exercise.24 High-carbohydrate, low-fat diets improve insulin sensitivity in older individuals.25 Drugs commonly used by older individuals, including diuretics, tricyclic antidepressants, estrogen, sympathomimetics, glucocorticoids, niacin, and phenytoin may adversely affect glucose metabolism. Stress states such as myocardial infarction, infection, burns, and surgery may also worsen glucose tolerance. Impaired glucose tolerance is a risk factor for the development of cardiovascular disease and diabetes mellitus. The Honolulu Heart Study demonstrated that fatal myocardial events among older nondiabetic men were 2.4 times higher in those in the highest quintile for 1 h postchallenge glucose levels than in those in the lowest quintile.26 The risk of development of diabetes mellitus among those over age 70 who are glucose intolerant is
Figure 46.2. Changes in blood glucose levels with age.
683
2% per year, as compared with a risk of 0.04% per year for those with normal glucose tolerance.27 The reduction in glucose tolerance associated with aging is correlated with insulin resistance, obesity, hyperlipidemia, and hypertension. The pathogenesis of these associated and interrelated conditions is referred to as the metabolic syndrome or syndrome X. Although the pathogenesis is currently under detailed study, the emergence of insulin resistance as a central feature of diabetes mellitus in the elderly appears secure.
Pathogenesis of Diabetes Mellitus in the Elderly A strong genetic predisposition to type 2 diabetes in middle-aged and elderly patients exists. The specific genes responsible have not been discovered.3 Patients with a family history of diabetes are more likely to develop the illness as they age.4 Elderly patients with peripheral insulin resistance and reduced glucoseinduced insulin release are more likely to develop type 2 diabetes than those without.28 In elderly identical twins discordant for type 2 diabetes, subjects without diabetes have evidence of impaired glucose metabolism.29 Physiologic and environmental factors compound genetic predisposition. Lower testosterone levels in men30 and higher testosterone levels in women31 are risk factors for diabetes development. Elderly individuals who have a high intake of fat and sugar and a low intake of complex carbohydrates are more likely to develop diabetes.32–35 Physical inactivity and central fat distribution predispose to diabetes in the elderly.36–46 Unlike younger patients, fasting hepatic glucose production is normal in elderly patients with type 2 diabetes.47 Elderly type 2 diabetes patients have specific alterations in carbohydrate metabolism. The primary metabolic defect in lean elderly subjects is an impairment in glucose-induced insulin release; the primary abnormality in obese elderly subjects is resistance to insulin-mediated glucose disposal.47,48 Glucose uptake occurs by insulin-mediated and noninsulin-mediated mechanisms. Recently, it has been demonstrated that nonmediated glucose uptake (glucose effectiveness) is markedly impaired in elderly patients with type 2 diabetes. The mechanism for this defect is unclear, but impaired glucose effectiveness is a contributing factor to elevated glucose levels in elderly diabetes patients. Given that several interventions, including glucagon-like peptide 1 (GLP-1), have been shown to enhance glucose effectiveness in younger patients, these findings may have important therapeutic relevance for elderly patients with diabetes.49–51 Few studies have evaluated molecular biologic abnormalities in elderly patients with diabetes and more are
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required. The glucokinase gene is the glucose sensor for the b-cell. Some studies have found that this gene acts as a marker for abnormal glucose tolerance in the elderly, but others have not.52,53 Insulin receptor number and affinity are normal in elderly patients, but insulin receptor tyrosine kinase activity in skeletal muscle is reduced.54
Clinical Presentation Classic symptoms of polyuria or polydipsia are rarely present. Glucose is not spilled into the urine until the plasma glucose is markedly elevated because the renal threshold for glucose increases with age. Polydipsia is also less common, because thirst is impaired. When symptoms are present, they are generally atypical (falls, failure to thrive, urinary incontinence, or delirium). Diabetes may present for the first time in elderly individuals as a result of a fasting screening glucose level or be concurrent with the presentation at the time of illness with a complication of illness, such as a myocardial infarction or stroke. Finally, nonketotic hyperosmolar coma may be the first sign of diabetes in older individuals, particularly in older nursing home patients; this results from decreased access to water associated with osmotic diuresis, impaired thirst, and cognitive dysfunction. Unusual clinical findings also develop in older patients with established diabetes.55,56 Intradermal bullae of the feet that resolve spontaneously have been described.57 Painful limitation of the shoulder joints occurs frequently and may be related to nonenzymatic glycation of proteins.58 Diabetes increases the risk for accidental hypothermia in older individuals.59 Malignant otitis externa is a necrotizing infection caused by Pseudomonas, occurring almost exclusively in elderly patients with diabetes.56 Renal papillary necrosis can occur in association with urinary tract infections. Diabetic amyotrophy causes asymmetric and painful weakness of the muscles of the pelvic girdle and thigh, and usually resolves spontaneously in a few months. It is most prevalent in older males.56 Diabetic neuropathic cachexia occurs in older patients with diabetes, causing weight loss, depression, and painful peripheral neuropathy.60
Diagnosis and Differential Diagnosis of Diabetes Mellitus in the Elderly The diagnosis of diabetes mellitus is made primarily through the findings of elevated glucoses on fasting laboratory samples, random glucoses during outpatient or inpatient care, and, much less commonly now, after formal oral glucose tolerance testing (OGTT). In 1997, the American Diabetes Association (ADA) revised its diagnostic criteria61 to rely solely on a fasting plasma
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glucose value greater than 126 mg/dL (7.0 mmol/L), rather than on a fasting glucose over 140 mg/dL or a 2-h oral glucose tolerance test plasma glucose value over 200 mg/dL, as had been recommended by the 1980–1985 World Health Organization (WHO) diagnostic criteria62 and the ADA 1979 criteria for diabetes.63 The new ADA criteria also recommended two other diagnostic classes. Impaired fasting glucose (IFG) is defined as a fasting plasma glucose (FPG) between 110 mg/dL (6.1 mmol/L) and 126 mg/dL (7.0 mmol/L); normal fasting glucose is defined as a fasting plasma glucose less than 110 mg/dL. The OGTT is not recommended for routine diagnosis of glucose intolerance or diabetes. The 1998 preliminary report of WHO essentially endorses the ADA 1997 recommendation, with the exception that they advocate the use of OGTT.64 The new ADA 1997 criteria change the incidence of diabetes by age, sex, and ethnicity, resulting in a significant increase in the number of individuals diagnosed with diabetes mellitus while perhaps excluding significant numbers of individuals who would have gained the diagnosis through postchallenge glucose elevations.61 From all the population data available, the criteria of a 2-h plasma value greater than 200 mg/dL (11.1 mmol/L) would be met by almost all patients who met the older fasting value of 140 mg/dL (7.8 mmol/L). However, it would also be met by many individuals with a lower fasting value. The new fasting value of 126 mg/dL (7 mmol/L) is reported to be more in agreement with the diagnosis of diabetes by the 2-h post-OGTT plasma glucose value of 200 mg/dL. However, the data suggest this may not be the case. At least 25 studies have examined the impact of the new 1997 ADA criteria with the older 1985 WHO criteria. These reports indicate that 11% to 80% of the individua1s diagnosed with diabetes mellitus by the WHO criteria will be missed if the diagnosis is solely based on the lower FPG, which appears to particularly include the elderly. The observations leading to the use of 200 mg/dL level and the difficulties with this level suggest further revisions may be needed. Using data from the NHANES III survey, comparisons of the results of FPG with the 2-h post-OGTT plasma glucose level are more than 50% discrepant.65 The ADA’s 1997 report has stated that the justification for the cut point for the 2-h post-OGTT glucose level of 200 mg/dL is derived, in part, from the evidence that the prevalence of microvascular complications increases dramatically at this point. In addition, the 2-h plasma glucose value following an OGTT from many large populations has a bimodal distribution. The nadir intersection of the two modes is known as the antimode and it shifts to the right with advancing age.66 The 200 mg/dL level represents the average level of the antimodes from several large population studies (Pima Indians, Naruans, Samoans, Mexican-Americans, and East Indians). However, the antimodes from these pop-
46. Treatment of Diabetes
ulations arc quite variable (range, 143–310 mg/dL) and do not support the average 200 mg/dL level. They do, however, increase with age. Many of the reported studies show that the 1997 ADA diagnosis standards do not result in equal sensitivity for fasting and 2-h glucose levels, especially in older individuals. Although the use of fasting plasma glucose alone for diabetes diagnosis may simplify testing, the WHO criteria would identify a much greater percentage of elderly subjects with diabetes or impaired glucose testing and move ahead the diagnosis by 5 to 8 years over criteria based on fasting glucose levels. As diabetes prevention efforts increase, a move to a more sensitive bias in diagnosis may be needed. The majority of newly diagnosed diabetic patients (>90%) emerge from the population with impaired glucose tolerance (IGT), no matter how it is defined, and are at higher risk for cardiovascular disorders.27
Prognosis and Course of Illness It had been hoped for many years that intensive treatment of diabetes mellitus would reverse or defer significantly its major complications of microvascular and macrovascular disease, stroke, and heart attack, and be compatible with a healthy lifestyle. While a general impression indicating that intensive and aggressive therapy was potentially a benefit, two major studies have recently provided much greater justification and clarification for control of diabetes mellitus. These two studies, the Diabetes Control Complications Trial research group and the United Kingdom Prospective Diabetes Study Group investigations, are reviewed in detail here to establish more clearly the rationale for close control of diabetes.
Glucose Control The Diabetes Control and Complications Trial (DCCT)67 was a randomized, controlled trial of individuals with type 1 diabetes mellitus (aged 13–39 years) comparing the effect of intensive blood glucose management to conventional management on diabetic outcomes over a mean 6.5-year follow-up. Subjects in general were in good health and had diabetes for 1 to 15 years. Patients were stratified by the presence of retinopathy into a primary prevention cohort (no baseline retinopathy) and a secondary prevention cohort (mild retinopathy), and then randomized to either intensive insulin management consisting of three or more insulin doses per day to keep glucose levels as close to normal as possible or to conventional therapy consisting of standard insulin therapy to keep glucoses within accepted guidelines (A1c < 7.0). For primary prevention, the adjusted relative risk of retinopathy was reduced by 76% (95% CI, 62%–85%) in
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the intensively treated group compared to the conventionally treated group. For secondary prevention, the risk of retinopathy progression was reduced by 54% (CI, 39%–66%) in the intensively treated group. In both cohorts, the reduction in risk increased with time and was not evident until 36 months into the treatment. When the two cohorts were combined, intensive therapy reduced severe retinopathy and need for laser treatment by 47% and 51%, respectively, clinical neuropathy by 60% (CI, 38%–74%; p £ 0.002), microalbuminuria ( p £ 0.002), and albuminuria ( p < 0.04). Severe hypoglycemia was more common (62 versus 19), as were coma (16 versus 5) and emergency room admission (9 versus 4 cases per 100 patient-years) in the intensively managed group. No significant differences in mortality were observed between the two groups (7 intensive versus 4 conventional). The DCCT resulted in a number of important recommendations. Intensive therapy with a goal of achieving glucose levels as close to the nondiabetic range as possible should be employed in most IDDM patients. Intensive therapy should be implemented in centers with the requisite nursing, dietary, behavioral, and clinical expertise to ensure safe and effective therapy. Although most diabetes in late life is not of the type 1 variety, this study provided important principles and hopes for improving the long-term prognosis for diabetes patients. The most comprehensive study of type 2 diabetes to date has been the United Kingdom Prospective Diabetes Study Group.
United Kingdom Prospective Diabetes Study (UKPDS 33) The UKPDS 3368 investigated whether tight control of blood glucose in type 2 diabetic patients reduced the risk of microvascular or macrovascular disease. Patients over age 65 were excluded from this multicenter RCT; mean age was 54. Of the 3867 patients, 2729 were randomized to open-label intensive drug therapy with either chlorpropamide, glibenclamide, or insulin, with the goal of lowering FPG to less than 108 mg/dL. The 1138 other patients were randomized to conventional therapy that aimed for the lowest FPG possible with diet alone (although drugs were added if FPG reached as high as 270 mg/dL or in the presence of hyperglycemic symptoms). Compared to conventional therapy, intensive therapy significantly reduced the risk of microvascular complications, but not macrovascular complications or macrovascular subclinical surrogate endpoints over the 10-year study period. Median hemoglobin A1c levels were significantly lower in the intensive group (7%) than in the conventional group (7.9%). Three grouped endpoints
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were assessed: all-cause mortality, diabetes-related deaths [myocardial infarction (MI), stroke, peripheral vascular disease, renal disease, hyperglycemia or hypoglycemia, and sudden death], and any diabetes-related endpoint (death from any of the preceding, as well as nonfatal MI, angina, heart failure, stroke, renal failure, amputation, vitreous hemorrhage, retinopathy, blindness, or cataract). Only diabetes-related endpoints were significantly reduced with intensive therapy, with a risk reduction of 12% (95% CI, 1%–21%). Most of this reduction was due to reduction in microvascular outcomes, especially the need for retinal photocoagulation, which was reduced 25% (95% CI, 7%–40%). All three intensive drug regimens reduced microvascular endopoints equally. Neither all-cause mortality nor diabetes-related deaths differed by intensity of treatment, although a nonsignificant trend ( p = 0.052) toward reduction in risk of myocardial infarction was observed in the intensive therapy group, with an RRR of 16% (95% CI, 0–29%). Compared to conventional treatment, intensive therapy was associated with a mean 6.4-pound weight gain (most prominently in the insulin group) and an increased risk of hypoglycemia. Treatment for hypertension was more common with chlorpropamide than with any other regimen, including conventional therapy. A substudy examined 342 newly diagnosed obese diabetic patients randomized to metformin during UKDPS 33 and compared them to the overweight patients who were included in the UKDPS 33 study already discussed [conventional treatment (411) or intensive treatment (951)]. Based on absolute risk (events per 1000 patientyears) and relative to conventional therapy, metformin treatment reduced risk of any diabetes-related endpoint by 32% (NNT, 10; CI, 6–32), diabetes-related deaths by 42% (NNT, 19; CI, 10–97), and all-cause mortality by 36% (NNT, 15; CI, 8–83). Relative risk of myocardial infarction was also significantly reduced. Metformin was also significantly better than all other drugs used in the intensively treated group in reducing risk of reaching any diabetes-related endpoint, stroke, and all-cause mortality. In these already overweight patients, weight gain was less common with metformin than with other intensive therapies, as were hypoglycemic episodes.69 Metformin/Sulfonylurea combined therapy was found to perhaps have less benefit than either drug alone. This observation is important as the popularity of combined drug therapy is increasing.
Blood Pressure Control and Complications in Type 2 Diabetes UKPDS 38 evaluated the effect of hypertension control on diabetic outcomes. The study involved the randomization of 1148 hypertensive patients (mean age, 56.4
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years), to either tight blood pressure control (blood pressures less than 150/85) with either an angiotensinconverting enzyme (ACE) inhibitor (captopril) or a beta-blocker (atenolol), or to less tight control (blood pressures less than 180/105) without these drugs. The actual mean blood pressures obtained were 144/82 in the tight control group and 154/87 in the “less tight.” Endpoints were identical to those in the main study just described. Mean follow-up time was 8.4 years. Tight blood pressure control reduced diabetes-related endpoints by 24% (95% CI, 8%–38%; p = 0.0046), diabetesrelated deaths by 32% (CI, 6%–51%; p = 0.019; NNT = 15), and stroke by 44% (CI, 11%–65%; p = 0.013) compared to less tight control. Microvascular endpoints were reduced by 37% (CI, 11%–56%; p = 0.0092), with 35% reduction in risk of retinal photocoagulation ( p = 0.023). There was no difference in all-cause mortality. There were also no differences between captopril or atenolol in terms of treatment benefits.70 The DCCT and UKPDS give us important information related to the rationale for treatment of diabetes mellitus in late life. It is clear that microvascular and macrovascular events can be influenced by careful control of diabetes mellitus. As a result, the management of both blood pressure and blood sugar in diabetes mellitus has a sound rationale. The use of ACE inhibitor therapy in minimizing the development of and the progress of renal damage as measured by micro- and clinical-grade albuminuria has now become an important standard of care in the management of type 2 diabetes. Whether ACE inhibitor itself or blood pressure reduction alone is the factor reducing albuminuria is not fully answered. Additionally, the importance of high lipids as a strong risk factor for future cardiovascular disease in diabetic individuals is gaining attention, and aggressive treatment is becoming the norm.
Treatment and Management of Diabetes Mellitus The benefits of aggressive treatment in terms of delaying or preventing complications in the elderly diabetic are clear. Life expectancy for the older diabetic person is approximately two-thirds that of a healthy elderly individual. This fact is not an argument against aggressive treatment; in fact, reductions in life expectancy are in large part because most older diabetics have adequate time to develop and suffer from chronic complications of diabetes mellitus. Recent studies confirm that many of the vascular and renal complications of diabetes develop at a relatively similar rate in types 1 and 2 diabetes.69 Other diabetic complications are aggravated by changes inherent in aging. Creatinine clearance declines with
46. Treatment of Diabetes
normal aging71 and may accelerate or enhance risk for diabetic renal failure. Age is also an independent risk factor for the development of peripheral neuropathy, a common condition in diabetes mellitus.72,73 The initial approach to the older adult with diabetes mellitus requires assessment of the patient’s current medical status and estimated life expectancy. Motivation and commitment of the patient and family also play a large role in determining what level of treatment is appropriate. Support services available in the community and financial status should also be considered. Following evaluation, one of two levels of care can be recommended: symptom-preventing care or aggressive care. The decision is made jointly by the patient and the primary caregiver. Family members and consultants such as geriatricians, diabetologists, cardiologists, and nephrologists may be helpful. These consultants provide a clearer picture of the current medical condition and estimates of life expectancy. Symptom-preventing care is indicated for those individuals for whom the primary goal of treatment is avoidance of metabolic complications. The average glucose levels necessary to achieve this goal are approximately 200 mg/dL (11 mM) or the glucose level at which glycosuria is minimal. The elimination of glycosuria removes the risk of volume depletion and the risk of secondary problems related to hypotension and poor tissue perfusion. Hyperglycemic hyperosmolar nonketotic coma due to dehydration and glycosuria is the most dramatic expression of this phenomenon. Glycosuria also is associated with weight loss caused by the loss of calories in the urine. The resultant catabolic state leads to a loss of lean body tissue. The long-term consequences of poor nutrition include increased risk of infections. Aggressive care has prevention of long-term complications as its goal. Euglycemia is defined as (1) a fasting glucose level lower than 115 mg/dL (6.4 mM), (2) a mean glucose level between 110 and 140 mg/dL (6–8 mM), and (3) normal levels of glycosylated hemoglobin. Prevention of long-term complications in type I patients results from this level of control. These benefits are believed to extrapolate to elderly patients within NIDDM. Aggressive management programs for older adults with diabetes require high levels of skill, commitment, and diabetes education. Most older individuals are fully able to learn the complicated concepts and tasks required.74–76 Older adults lead a less hectic, more ordered life than younger adults. Consequently, making the adjustments in lifestyle necessary for adherence to a good diabetes treatment program may at times be easier. All older adults with diabetes mellitus should receive a standard basic care program regardless of the treatment goal chosen. These standards77 (Table 46.1) include a complete history and physical examination to detect any complications of diabetes mellitus and any risk factors for
687 Table 46.1. Minimum standards of care for older adults with diabetes mellitus. Initial evaluation Complete history and physical examination Geriatric assessment Laboratory examination: fasting blood glucose, glycosylated hemoglobin, fasting lipid profile, creatinine, urinalysis, electrocardiogram Ophthalmologic examination Dietary assessment Continuing care Use of treatment as needed to meet target glucose levels: diet, oral agents, or insulin Assessment of blood glucose levels as frequently as needed to ensure that treatment goals are being met Annual assessment for diabetes complications Annual review of geriatric assessment
complications. A geriatric assessment, emphasizing a functional assessment, should be performed at the time of diagnosis. Skills in the basic activities involved in daily life (bathing, grooming, dressing, feeding, toileting, and transferring) and the instrumental activities of daily life (e.g., shopping, telephoning, finances, and housework) should be assessed. Social support systems and financial and insurance status often should also be assessed, by nursing and social work staff. Laboratory evaluation at diagnosis includes determinations of fasting serum glucose level, glycosylated hemoglobin (to assess previous level of control and to be used as a baseline), fasting lipid profile, and serum creatinine; urinalysis with examination for proteinuria; and an electrocardiogram. Ophthalmologic evaluation at the time of diagnosis is recommended by the American Diabetes Association for all patients with NIDDM.78 This recommendation is particularly relevant for elderly patients who are at high risk for ocular diseases including cataract and glaucoma. Dietary assessment provides an initial dietary therapy for the diabetic patient. Standard diabetes therapy includes diet, exercise, and if necessary use of oral hypoglycemic agents or administration of insulin.
Oral Hypoglycemic Agents Increasingly, therapy for type 2 diabetes builds on diet and exercise and has become more mechanistically focused. Single or combination chemotherapy is used. A significant amount of improvement can be expected with improved therapy. Currently, 54% of elderly diabetic patients have hemoglobin A1c levels above normal and 27% of the total had A1c levels greater than 8. Thus, nearly a quarter have “poor” control.79 Current best practices require a normal hemoglobin A1c, certainly less than 7. For those individuals in whom the demands of therapy are too great, medication side effects are too great, or
688 Table 46.2. Dietary therapy: special considerations for older adults with diabetes. Financial difficulty Difficulty with shopping because of transportation or mobility problems Poor food preparation skills (particularly elderly widowed men) Ingrained dietary habits Difficulty following dietary instruction because of impaired cognitive function Decreased taste Increased frequency of constipation
access to monitoring is not possible, a reduction in expectations and greater complication rates will be higher. Medications currently available can promote insulin secretion, increase insulin sensitivity, or slow the digestion/processing of complex carbohydrates.
Diet Diet alone has varying degrees of success. Elderly patients with diabetes are able to improve diabetes control with diet and weight loss.80 However, they may find it difficult to adhere to a strict dietary regimen and maintain weight loss. Older adults with mobility problems may find exercise to increase caloric expenditure impossible. If dramatic dietary restriction is employed to reduce weight, nutrient and vitamin deficiencies may develop. Aggressive dietary management cannot be recommended under these circumstances. Other considerations specific to older adults may limit the effectiveness of dietary therapy (Table 46.2).18 A diabetic diet is relatively high in carbohydrates (50%–60% of total calories), low in fat (30 mg), iodide inhibits thyroid hormone release and blocks thyroidal iodide uptake. Iodide also causes a transient decrease in thyroid hormone biosynthesis, the so-called Wolff–Chaikoff effect. These actions of iodide are probably important in protecting the organism against hyperthyroidism in the event of large iodide loads. Because of its inhibitory effects on thyroid function, iodide occasionally is used to treat hyperthyroidism, but, as is discussed here, it also can cause either hyperthyroidism (the Jod–Basedow phenomenon) or hypothyroidism, given the appropriate clinical substrate.
Thyroid Hormone Synthesis and Transport Thyroid hormone synthesis is a multistep process that begins with the trapping of iodide by the thyroid follicular cell. Iodine is an essential nutrient and is abundant in the diet of most Western countries. In the United States, the average daily urinary iodine excretion, which reflects dietary iodine intake, has fallen from a mean of 32 mg/dL in 1971 to 1974 to 14.5 mg/dL in 1988 to 1994.6 Fifteen percent of women over age 60 had low urinary iodine levels (99.9%) to transport proteins, principally thyroid-binding globulin (TBG), thyroid-binding prealbumin, and albumin. It is believed that only the unbound, or free, hormone is available to enter cells and exert its metabolic effects. Because of the tight binding of thyroid hormones to serum proteins, their clearance is prolonged significantly: the half-life of T4 is approximately 7 days; because it is less firmly bound, T3 has a shorter half-life, approximately 1 day. It is important to emphasize that quantitative and qualitative changes in the binding proteins alter the serum total T4 and T3 concentrations but do not affect free thyroid hormone levels. Thus, situations in which thyroid-binding proteins are altered may be confused with true thyroid dysfunction if only total thyroid hormone concentrations are considered.
Thyroid Hormone Metabolism Although thyroid hormones are metabolized in a variety of ways, the deiodination pathway is the most relevant clinically (Fig. 47.2). Via this route, approximately 50% of the daily T4 production is converted to T3 by removal of a single iodine atom from the outer ring of the T4 molecule. This reaction is catalyzed by a ubiquitous enzyme, 5¢- or outer-ring deiodinase, which also degrades the nonbiologically active compound, reverse T3 (rT3), to another inert product, T2. About 80% of the daily T3 production derives from T4 deiodination in the peripheral tissues. Because T3 is the more metabolically active hormone and binds to nuclear thyroid hormone receptors with far greater affinity than does T4, it is likely that T4 is merely a “pro-hormone” for T3. In fact, virtually all the biologic effects of thyroid hormone can be accounted for by the actions of T3 alone. A variety of clinical states can decrease the conversion of T4 to T3 via inhibitory effects on outer-ring deiodinase activity. Starvation, systemic illness, and certain drugs (propranolol, amiodarone, iodinated contrast agents) all cause a fall in serum T3 concentrations and a reciprocal rise in serum rT3, resulting from a fall in T4 to T3 conversion and in rT3 degradation. The fall in T3 concentration reduces protein catabolism and tissue oxygen consumption, which may be beneficial to the organism during periods of illness or decreased caloric intake.
47. Thyroid Disorders
697
Figure 47.2. Peripheral metabolism of T4 and factors that influence the tissue conversion of T4 to T3.
Age-Related Changes in Thyroid Function and Metabolism A number of studies have examined possible changes in thyroid function with advancing age. Most studies show little, if any, change in circulating T4 or free T4 levels in the blood. Plasma iodide levels increase, due to a decrease in thyroidal iodine accumulation. This fall in thyroidal iodine uptake is accompanied by a decrease in T4 secretion. However, decreased T4 secretion in the elderly is not necessarily indicative of thyroid failure because it is not accompanied by elevations in serum TSH. Studies of elderly men7 have also revealed reductions in the T4 metabolic clearance rate resulting from possible decreases in outer-ring deiodinase activity, lean body mass, or both.8 Thus, there are two distinct changes in T4 economy that occur with aging: a decrease in T4 secretion counterbalanced by a decrease in T4 degradation, with no net change in T4 concentrations in the blood. Possible alterations in serum T3 concentrations are more controversial. Although several studies have shown age-related reductions in serum T3 and free T3 levels, particularly after age 90 years,9 others have found no significant decline during the fifth through the ninth decade.10,11 One potential explanation for the discrepancies among the various reports is the inclusion of individuals with subclinical illness in the study populations. Thus, the reported decline in serum T3 noted by some investigators may be secondary to the presence of subtle or occult infirmities associated with aging, rather than being caused by the aging process itself. Despite the tentative conclusion drawn by many investigators that serum T3 levels do not fall with age, it is clear that T3 levels often are low in randomly selected elderly individuals without obvious illness. Because the major source of daily T3 production derives from outer-ring
deiodination of T4, one possible explanation for the low T3 levels in some aged individuals is the well-established decrease in the T4 secretion rate. Another possible reason is a decline in the T4 deiodination rate, which is the hallmark of systemic illness or decreased caloric intake. If a fall in deiodination were the explanation, a reciprocal rise in rT3 would be expected; this has recently been reported in a group of healthy centenarians.9 Thus, the fall in serum T3 may be due to the decrease in T4 production by the thyroid gland or a decrease in peripheral T4 deiodination or both. As noted earlier, the decline in thyroidal T4 secretion is not accompanied by an elevated serum TSH level, which is the most sensitive indicator of thyroid hypofunction. Indeed, some studies using highly sensitive TSH assays have shown a decline in mean TSH levels with age.10,12 However, other reports suggest that mean TSH levels in the elderly are higher than values observed in younger individuals.13 Because most studies have shown that elderly women more often have high-normal or frankly elevated TSH levels, and antithyroid antibodies are often (although not always) present in such patients, it is reasonable to conclude that the slight elevation in mean TSH noted in most reports results from the inclusion in the study population of patients with subclinical autoimmune thyroiditis.2 Thus, the normal range for TSH should not differ between younger and older individuals.
Thyroid Hormone Action Thyroid hormones enter the cell by diffusion and bind to specific receptors located in the nucleus. The thyroid hormone receptor was recently discovered to be a homologue of the protein product or products of a family of oncogenes (erb-A), and shares common structural features with the steroid hormone and retinoic acid
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receptors.14 The thyroid hormone receptor protein acts to modify DNA transcription and the synthesis of new proteins by the cell (e.g., angiotensin-converting enzyme, sex hormone-binding globulin, the beta-adrenergic receptor, factor VIII). while it inhibits the transcription and synthesis of other proteins (e.g., TSH and TRH). Future studies of thyroid hormone receptors will undoubtedly enhance our understanding of thyroid hormone action, particularly the reasons why older thyrotoxic individuals have few or no symptoms or signs of thyroid hormone excess (see following). Virtually all tissues contain thyroid hormone receptors in varying amounts; the degree to which a tissue responds to thyroid hormone is proportional to the thyroid hormone receptor density within that tissue. Clinical observations suggest that elderly persons have decreased responsiveness to thyroid hormones, which is particularly striking in the older patient with thyrotoxicosis, as discussed in the next section. Experimentally, the thyroid hormone response of erythrocyte Ca2+/adenosine triphosphatase (a nonreceptor-mediated activity) falls with age,15 and in aging rats there is a decrease in hepatic malate dehydrogenase mRNA induction by T3 compared to young rat.16 There may also be an age-related decrease in lymphocyte nuclear thyroid hormone receptors.17 Despite these intriguing data, the decrease in thyroid hormone action that is obvious clinically has yet to be explained at the molecular level.
The many recent advances in the laboratory measurement of thyroid function have greatly simplified the evaluation of thyroid dysfunction. Even subtle forms of hypoand hyperthyroidism can be diagnosed easily, and thyroid hormone therapy can be adjusted with great precision.
Measurement of Thyroid Hormone Concentrations Radioimmunoassays for T4 and T3 are routinely available, with rapid turnaround times. It must be recalled that alterations in TBG affect the total T4 and T3 concentrations but not the circulating free thyroid hormone concentrations. Thus, patients with TBG excess or deficiency Table 47.1. Clinical situations associated with abnormal TBG concentrations. Estrogen therapy Acute hepatocellular disease
TBG, thyroid-binding prealbumin.
Increased T4 Hyperthyroidism Increased protein binding TBG excess Anti-T4 antibodies Abnormal binding proteins Acute illness (transient) Decreased T4 catabolism Amiodarone High-dose propranolol
Decreased T4 Hypothyroidism TBG deficiency Serious illness Anticonvulsant therapy
have high or low T4 and T3 concentrations, respectively, but are clinically and biochemically euthyroid (Table 47.1). It behooves the clinician to determine the true thyroid status of the patient to avoid erroneous diagnoses and inappropriate therapy. Direct measurement of free T4 has become more popular due to improved costeffectiveness; it has rapidly replaced the free thyroxine index (FTI), which is the product of total T4 and the T3 resin uptake (T3RU). The T3RU is an indirect approximation of TBG binding capacity, and, when used in concert with the total T4 concentration, it permits distinguishing true thyroid disease from perturbations in TBG concentration. It is important not to confuse the T3RU, which uses radioactive T3 in vitro, with the direct assay of serum T3 (the T3 radioimmunoassay).
Low Serum Total T4 Levels
Thyroid Function Testing
TBG excess
Table 47.2. Major causes of abnormal serum T4 concentrations in elderly patients.
TBG deficiency Androgen therapy Chronic liver disease Severe catabolic illness Congenital X-linked deficiency
Hypothyroxinemia is characteristic of hypothyroidism, but other conditions also must be considered (Table 47.2). A decrease in serum total T4 often results from TBG deficiency or inhibition of T4 binding to TBG by drugs (salsalate, high-dose salicylates) or endogenous factors. A circulating inhibitor of T4 binding to TBG has been described in nonthyroidal illness and may account for the often extraordinarily low total serum T4 values (80 years a
References: 9, 18, 51, 57, 58, 68–71, 74, 80, 87, 107–109. Number of studies with significant odds ratio or relative risk ratio in univariate analysis/total number of studies that included each factor. c Relative risk ratios (RR) calculated for prospective studies–odds ratios (OR) calculated for retrospective studies. Source: Modified and used with permission: J Am Geriatr Soc. 49(5): 665. b
Table 66.2. The relationship between falls and medication use.
Multifactorial Etiology
Medication classa
The epidemiologic model of host, activity, and environmental factors addresses the multifactorial etiology of most falls. Under this model, there is a reciprocal relationship among host, activity, and environmental factors. The importance of these three categories of factors varies with individual falls. Host factors contributing to falls can best be understood by considering that postural stability requires input from sensory, central integrative, and effector neuromuscular components in a highly integrated manner.36 These components are overlapping and compensatory. Cardiac, circulatory, respiratory, metabolic, and other conditions may further influence the functioning of these three primary components. Postural instability and predisposition to falling may not be evident until several contributing components are impaired. A related and clinically useful method for explaining fall etiology is to consider both predisposing as well as situational factors. Predisposing risk factors are those intrinsic characteristics of the individual that chronically impair stability and render the individual vulnerable to new insults. Situational factors are those host, activity, and environmental factors that are present at the time of the fall (Tables 66.1 and 66.2).
Psychotropics Neuroleptics Sedative/hypnotics Any antidepressant Tricyclic antidepressants Benzodiazepines Diuretics Digoxin Class IA antiarrhythmics Three or more medications Four or more medications
Predisposing Risk Factors As noted, stability depends on the intricate functioning of sensory, central integrative, and musculoskeletal effec-
Number of studies
Pooled OR
95% CI
20 23 23 28 13 14 27 18 11 11 9
1.73 1.5 1.54 1.66 1.51 1.48 1.08 1.22 1.59 —b —b
1.52–1.97 1.25–1.79 1.40–1.70 1.4–1.95 1.14–2.00 1.23–1.77 1.02–1.16 1.05–1.42 1.02–2.48 —b —b
a
References: 48, 50. Pooled odds ratio and 95% confidence interval not calculated due to heterogeneity in the definition of medication, however or significantly increased in recurrent fallers.
b
tor components. Accumulated impairments and diseases affecting these components, superimposed on age-related physiologic changes or lifestyle factors (e.g., past physical activity), result in a predisposition to falling.37 The major sensory modalities responsible for orienting the individual in space and identifying hazards include the visual, auditory, vestibular, and proprioceptive systems. These modalities have multiple interconnections with one another. Age-related visual changes include decreased visual acuity, contrast sensitivity, dark adaptation, and accommodation. In addition, ocular diseases that are common in older persons, such as macular degeneration, glaucoma, and cataracts, may adversely affect visual functioning. Visual acuity, contrast sensitivity, and
982
depth perception, a visual function involved in spatial orientation, have been shown to be especially relevant to postural stability and falling.38–40 An age-related decline in vestibular function has been suggested as an explanation for increased postural sway as well as dizziness and perhaps falling in elderly persons.41 The vestibular system contributes to spatial orientation at rest as well as during acceleration and is responsible for visual fixation during head and body movements. An age-related decline in vestibular function has been attributed to changes in the otoconia. Predisposing factors include past aminoglycoside use as well as present use of aspirin, furosemide, quinine, quinidine, and perhaps tobacco and alcohol. Head trauma, mastoid or ear surgery, and middle ear infections are other possible predisposing factors. Elderly persons with vestibular problems complain of worsening stability in the dark because of increased reliance on visual input. Hearing contributes directly to stability through the detection and interpretation of auditory stimuli, which help localize and orient the individual in space, particularly when other sensory modalities are impaired. More than 50% of elderly persons have some hearing loss.42 The proprioceptive system provides spatial orientation during position changes, while walking on uneven ground, or when other modalities are impaired.36 The proprioceptive system includes peripheral nerves, apophyseal joint mechanoreceptors, and the posterior columns, as well as multiple central nervous system connections. It is unclear whether age-related changes occur in peripheral nerves. Nevertheless, peripheral neuropathy from a variety of different causes is common among elderly persons. The contribution of cervical mechanoreceptors to proprioception is not well appreciated.43 Predisposing factors for cervical disorders include whiplash injuries and cervical degenerative diseases such as rheumatoid arthritis or spondylosis. Older adults with proprioceptive problems complain of worsening difficulties in the dark or on uneven ground. They may complain of true vertigo. Gait often improves in these individuals with even minimal support. The central nervous system channels inputs from the sensory modalities to the appropriate efferent components of the musculoskeletal system. Given the multiple connections and their complexity, virtually any central nervous system disorder can contribute to instability and falling. Specific diseases such as Parkinson’s disease, normal pressure hydrocephalus, and stroke are associated with an increased risk of falling. Central nervous system processes that adversely affect cognition further impede stability because problem solving and judgment are needed to interpret and respond appropriately to environmental stimuli. Individuals with impaired mental status or dementia have consistently been found to have an increased incidence of falling, even in the absence of
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a clinical gait disorder. Additional studies have demonstrated the relationship between white matter disease, even in the absence of cognitive impairment, and gait disorders.44 Any impairment within the musculoskeletal system, including joints, muscles, and bones, will decrease stability and increase fall risk. Arthritis, myopathies, and hemiparesis are all associated with falling. Arthritis likely increases the risk of falling through several mechanisms including pain, periarticular muscle weakness, and compromised proprioception due to deterioration of joint mechanoreceptors. Hip, knee, and ankle weakness have all been found to significantly increase risk of falling.45 Reciprocal flexion and extension of lower extremity muscles appears essential to postural stability. Ankle dorsiflexion weakness may explain the tendency of some elderly persons to fall backward with even minimal displacement. Alternatively, the predisposition to falling backward may result from a smaller posterior than anterior base of support. Foot abnormalities such as calluses, bunions, and deformed toes and nail abnormalities may provide incorrect proprioceptive information and adversely affect gait patterns. Systemic diseases may contribute to instability by impairing sensory, neurologic, or musculoskeletal functioning or by causing a reduction in cerebral oxygenation or perfusion, fatigue, or confusion. Common examples include anemia, electrolyte disturbances, hypoglycemia or hyperglycemia, acid–base disturbances, or hypothyroidism. Postural hypotension may result in instability by compromising cerebral blood flow.46 The prevalence of postural hypotension ranges from 10% to 30% in community-dwelling persons over 65 years of age. As is falling, postural hypotension is frequently multifactorial. Contributing factors include age-related autonomic changes, decreased baroreceptor sensitivity, decreased renin-angiotensin response to upright position, decreased venous and lymphatic return, and salt and water depletion. The effects of diseases such as diabetes or Parkinson’s disease and of medications such as antidepressants, neuroleptics, antihypertensives, nitrates, and diuretics are further contributing factors. Postural hypotension should be considered if the fall occurred while moving from a lying or sitting to a standing position, after prolonged standing, or during exertion. Another abnormality in blood pressure homeostasis is postprandial hypotension.46 The mechanisms and mediators of postprandial hypotension remain unknown, although inability to compensate for splanchnic blood pooling after the meal has been postulated as a possible etiology. Medications may contribute to gait instability through a variety of mechanisms, including impairment of cognitive functioning, postural hypotension, dehydration, impaired balance, fatigue, or electrolyte disturbance.
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(Table 66.2) Centrally acting medications, including sedative-hypnotics, tranquilizers, antidepressants, and neuroleptics have repeatedly been associated with an increased risk of falls and injuries.47,48 Both selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants have been implicated in falls and hip fractures.49 Other classes of medications associated with falls in older adults include diuretics, type 1A antiarrhythmics, and digoxin.50 In addition to specific medications, recent changes in dose and the total number of medications have been associated with an increased risk of falling.51 Conversely, evidence suggests that postural instability, as manifested by impaired balance, dizziness, and falling, is one of the most frequent presentations of adverse drug effect in an older population.52,53
falls by community-dwelling older adults occur at home. About 10% of falls occur on stairs, well out of proportion to time spent on them, with descending being more hazardous than ascending.9,54 The most commonly mentioned environmental hazards include carrying heavy or bulky objects, and negotiating obstacles that can be tripped over, slippery floors, and poor lighting.55 Slippery or improperly fitting shoes are another potential hazard. Finally, patterns on floors or walls, depending on their quality, may either distort or improve visual perception.56
Situational Factors
As in community-based studies, investigators have attempted to identify the “most likely cause” of individual falls by nursing home residents.57 Studies of nursing home residents have found a higher incidence of falls caused by gait, balance, or strength disorders (25%; range, 20%–39%), by dizziness (25%; range, 0%–30%) and by confusion (10%; range, 0%–14%).29 Only 16% (range, 6%–27%) of falls are primarily attributed to an environmental factor.29 Visual disorders (4%; range, 0%–5%), postural hypotension (2%; range, 0%–16%), and drop attacks (0.3%; range, 0%–3%) are other less frequently cited causes. Other causes such as acute illness, drugs, and pain were believed to account for 12% of falls among nursing home residents. Although investigators have attempted to identify the “most likely cause of individual falls,” falling among nursing home residents, as among community-living residents, most often results from the accumulated effect of multiple specific impairments and diseases.51,58 The predisposing impairments are the same as those cited for community-dwelling older adults. The prevalence of the impairments is higher among nursing home than among community residents, which may partially explain the higher frequency of falling.29 Similar to community studies, studies of nursing home residents have identified an increased risk of falling with an increased number of impairments and diseases possessed.51,58
Falling is well recognized as a nonspecific presentation of acute illness in older adults. Acute febrile illnesses (e.g., pneumonia or urinary tract infections) and chronic disease exacerbations (e.g., congestive heart failure or diabetes mellitus) likely precipitate falls by temporarily impairing stability.9 Some cardiac dysrhythmias cause a decrease in cerebral blood flow and loss of consciousness, resulting in a fall.53 Carotid baroreceptor hypersensitivity may contribute to syncopal, as well as nonsyncopal, falls. One type of fall, mentioned most frequently in the British literature, is the drop attack.3 This term refers to a sudden loss of postural tone without loss of consciousness. Drop attacks may occur while walking, while turning the neck, while looking up, or without an obvious precipitating movement. Some individuals note that their knees buckled or “just gave out.” It is likely that at least some of those who report their knees buckling have impaired mechanoreceptors secondary to arthritic joint changes. Difficulty getting up is often reported. The etiology and frequency of drop attacks are unknown. Although reported in up to 25% of falls in the earlier literature,3 more recently “just going down” without any obvious intrinsic or environmental cause is reported in less than 5% of falls.9,29 The majority of falls by community-living elderly persons occur during the course of usual, relatively nonhazardous activities such as walking, changing position, or performing basic activities of daily living. Only a small percentage of falls occur during clearly hazardous activities such as climbing on chairs or ladders or participating in sports activities.9 Although major environmental hazards account for few falls, environmental factors probably contribute to the majority of falls by community-dwelling older adults. The precise role of environmental factors is difficult to ascertain because studies lack control data on nonfallers or fallers at times other than their fall. Over 70% of
Nursing Homes Immediate Causes and Predisposing Factors
Situational Factors Host factors such as acute illness, postural hypotension, dizziness, or medications have been described. Environmental factors are thought to be less important among institutionalized than community-dwelling older adults. The greater frailty and larger number of impairments predispose institutionalized elderly persons to fall in situations where healthier persons would not. Also, by and large, institutions are safer environments than the community because many potential hazards have been
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removed. Further, institutionalized elderly persons have fewer opportunities to engage in such hazardous activities as climbing stairs, walking on ice, or climbing on ladders. Even so, environmental factors do contribute to falls among institutionalized older adults.29 Examples include ill-fitting shoes, untied shoelaces, long pants, or slippery floors.59 Furniture may be hazardous; beds that are either too high or too low, bed rails that can be climbed over, and chairs that are too low or soft may also be dangerous. Walking aids are an unappreciated fall hazard. Canes and footrests can be tripped over, and the added weight of a walker may displace an individual backward. Many residents are able to remove their restraints. In addition, restrained persons may take their wheelchairs or chairs over with them in a fall. As one study points out, falls are a possible, but not inevitable, outcome in the nursing home setting. Through the implementation of a standardized and structured safety program, the impact of these falls can be minimized.60
Risk Factors for Serious Fall Injury Recent interest has focused on factors that increase the risk of serious injury, particularly fractures, during a fall. The likelihood of suffering a serious injury during a fall has been postulated to depend on factors such as the velocity of the fall, the energy-absorbing capacity of the surface landed on, the protective responses of the faller, the injury threshold of the tissue, and the direction and location of impact.61,62 Characteristics of fallers shown to be independently associated with serious injury include older age, female gender, white race, decreased bone mineral density, decreased body mass index, cognitive impairment, the use of certain medications, abnormal neuromuscular findings such as decreased reaction time and balance disturbance, poor visual acuity, history of previous falls and fall injuries, and the presence of specific chronic diseases, such as diabetes, and stroke.12,18,63–74 Increased physical activity level has been associated with both an increased and a decreased risk of suffering a serious fall injury event.12,72 Circumstances of the fall that increase likelihood of serious injuries such as fractures include the direction and impact of the fall, the height of the fall, and the hardness of the landing surface, as well as low body mass index (BMI).73–75 A discussion of the risk factors and medical aspects of hip fracture management are covered in Chapter 45.
Evaluation and Management The goal of a fall evaluation and prevention strategy is to minimize the risk of falling without compromising mobil-
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ity or functional independence. Given the inherent tradeoffs between safety and independence, this goal may be difficult to achieve in some individuals. Perhaps a better goal, rather than to prevent all falls, would be to prevent relevant fall-related morbidities such as serious injury, fear, and the inability to get up. As the ability to identify the subset of fallers at risk for these fall sequelae improves, evaluative and preventive efforts can be better targeted. A recent report by an expert panel provides an evidence-based approach to the management and prevention of falls:The Quality Indicators for Assessing Care of the Elderly (ACOVE) project.75–77 As already described, the etiology and risk factors for falls are similar in nursing home and community residents, but the relative frequency and modifiability of contributing risk factors may differ in these two populations. Therefore, the recommended evaluation and preventive strategies are discussed separately for community and nursing home residents. The American Geriatrics Society and British Geriatrics Society Panel on Falls in Older Persons has published the most up-to-date guidelines for the prevention of falls in older persons, and the reader is referred there for a discussion of these guidelines.78
Community The first step in evaluating individuals who have experienced a fall or who are at risk for falling is to identify possible contributing factors.79,80 The following components of the evaluation provide complementary information: (1) a thorough assessment of predisposing risk factors and diseases; (2) a balance and gait assessment; and (3) a review of previous fall situations.
Predisposing Risk Factor Assessment History and Examination The risk assessment begins with a careful history and physical examination aimed at identifying all predisposing risk factors. It is important to bear in mind that the multiple diseases and disabilities suffered by many older individuals may render the signs and symptoms of specific conditions obscure, vague, or nonspecific. For example, nonvestibular disorders may present with vertigo, whereas individuals with vestibular dysfunction may complain only of vague dizziness or unsteadiness. Therefore, a thorough systematic assessment of all possible contributing factors is essential. The governing concept in fall assessment is that it may be possible to decrease fall risk by ameliorating as many contributing factors as possible. The neurologic diseases that predispose to falls can be diagnosed from a thorough neurologic history and exam-
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ination. Although most neurologic diseases associated with falling result in postural instability and pathologic gait patterns, these findings are not disease specific. Common features of gait seen in persons with central neurologic diseases include flexed posture, step-to-step variability, path deviation, decreased step height that results in shuffling if severe, instability on turning, and easy displacement backward.36,81 Many of these findings, however, can also be seen in individuals with sensory abnormalities and may represent compensatory, rather than primary, changes. Thus, in diagnosing neurologic diseases, gait findings must be considered in association with findings from other components of the neurologic examination including cranial nerve findings, sensation, tone, muscle strength, and coordination. The neurologic examination is helpful not only in diagnosing specific diseases but also in identifying other contributing factors to fall risk such as decreased sensation or muscle weakness. Other important components of the risk assessment are included in Table 66.3. Simple screening tests such as the Snellen chart can be used to measure near and distant visual acuity. If there are any questions concerning visual function, the individual should be referred to an ophthalmologist or optometrist for a full evaluation. Portable audiometry or the Whisper Test82 can be used to screen for hearing problems. Although vestibular dysfunction is difficult to diagnose from simple clinical tests, a vestibular contribution to instability should be suspected if the individual complains of vertigo, worsening stability in the dark or with specific head positions, or provides a history of predisposing factors including past aminoglycoside use, use of aspirin, furosemide, quinine, or quinidine, or has a past history of head trauma, mastoid or ear surgery, or middle ear infections. If vestibular problems are suspected, attempts should be made to provoke vertigo with the Dix–Hillpike maneuver (see Chapter 67). Selected patients should be referred to audiology for a complete hearing evaluation or to otolaryngology for full vestibular testing. Individuals with proprioceptive impairments complain of worsening stability in the dark, on uneven ground, on inclines, or on thick rugs. Decreased position and vibration sense are noted on examination. During gait testing, individuals with decreased proprioception may markedly improve their gait pattern simply by holding on to the examiner’s finger or using a straight cane. If a cervical disorder is the cause of the proprioceptive problem, the complaints will be similar to those for peripheral neuropathy, but the individual will also complain of worsening symptoms with head turning or true vertigo. In some cases, the examination may reveal signs of radiculopathy or myelopathy; there may be clumsiness with fine motor tasks and even mild spastic quadriparesis. Many elderly individuals will, on examination of neck range of motion while standing, exhibit decreased neck range of motion
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and complaints ranging from vague dizziness to marked instability. It may be difficult to determine whether these individuals suffer from a mechanoreceptor-related cervical disorder or whether the decreased neck range of motion is secondary to vestibular dysfunction and inadvertent avoidance of neck movements that precipitate the symptoms. It is important to distinguish between the two because a decrease in neck movements will exacerbate the underlying vestibular disorder by impeding compensation by the central nervous system. The musculoskeletal examination may reveal various patterns of muscle weakness. As noted earlier, all of hip, knee, and ankle strength and range of motion are essential to postural stability and the response to perturbations. Thus, any arthritic or musculoskeletal process may contribute to fall risk. Individuals with knee arthritis may complain of falls because their “knee gave out.” Individuals with proximal muscle weakness may report difficulty getting in and out of chairs, in and out of the bathtub, and climbing stairs, whereas individuals with distal weakness will complain of frequent tripping. The contribution of upper extremity arm movements to postural stability and response to perturbation is unappreciated and needs to be considered. Foot problems, including bunions, calluses, and deformity, can affect gait patterns and decrease proprioception and thus should be identified. Although postural hypotension has not been identified as a frequent risk factor for falls among communitydwelling elderly persons, this is likely because it is not feasible to assess blood pressure change at the time of a fall. Blood pressure change with position change should be part of the risk factor assessment. Individuals may complain of lightheadedness or other vague sensations on position change, prolonged standing, or walking, although many individuals with significant postural hypotension may be asymptomatic and thus unaware of the blood pressure drop. Many, but not all, of these individuals may have concomitant diseases such as Parkinson’s syndrome or diabetes. In addition, as noted next, many medications can contribute to the risk of falling by causing postural hypotension. Particularly important medications to ask about include nitrates, antihypertensives, and antidepressants. The screen for depressive symptoms may reveal vegetative complaints, poor concentration, or apathy. Finally, a careful medication review is an essential component of a fall risk assessment. The assessment should involve the direct recording of all prescription medications from the original containers and verification of the dose and timing of each medication. Over-the-counter medications, particularly sedative-hypnotics, cold preparations, and nonsteroidal anti-inflammatory agents, must be ascertained as well. In addition, possible medication side effects including confusion, lightheadedness, fatigue,
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Table 66.3. Predisposing and situational factors associated with risk of falling. Predisposing factors with contribution to falling Sensory Vision: acuity, perception Impaired hazard recognition; distorted environmental signals; spatial disorientation Hearing Spatial disorientation; balance impairment; distorted environmental signals (auditory) Vestibular dysfunction Spatial disorientation at rest; impaired visual fixation; balance impairment especially with head or body turning Proprioceptive: cervical disorders; peripheral neuropathy Spatial disorientation during position changes or while walking on uneven surfaces or in dark Central neurologic Central nervous system diseases Impaired problem solving, strength, sensation, balance, gait, tone, or coordination
Dementia/cognitive impairment Impaired problem solving, impaired gait Musculoskeletal Muscle weakness: upper and lower extremity, Impaired postural stability Arthritides Impaired postural stability Feet Impaired proprioception; impaired postural instability; altered gait pattern Back Impaired ability to regain stability Other Postural hypotension Impaired cerebral blood flow leading to fatigue, weakness, postural instability; syncope if severe
Depression ? accident-proneness; ? poor concentration Medications: especially sedatives, phenothiazines, antidepressants; total number and dose of medications Impaired alertness; postural hypotension; postural instability; fatigue Situational factors Acute host factors Acute illness; new or increased medications Transiently impaired alertness; postural hypotension; fatigue Displacing activity Increased opportunity to fall Environmental hazards Slipping or tripping hazards (e.g., loose rugs, wet floors, ice, small objects) stairs, lighting, and furniture Nursing home: movable tables; inappropriate bed or chair height; ill-fitting shoes or pants; restraints
Possible interventions Medical: refraction; cataract extraction Rehabilitative: balance and gait training Environmental: good lighting; home safety assessment; architectural design that minimizes distortions and illusions Medical: cerumen removal; audiologic evaluation with hearing aid if appropriate Rehabilitative: training in hearing aid use Environmental: decrease background noise Medical: avoid vestibulotoxic drugs; surgical ablation Rehabilitative: habituation exercises Environmental: good lighting (increased reliance on visual input); architectural design that minimizes distortions and illusions Medical: diagnose and treat specific disease (e.g., spondylosis, B12 deficiency) Rehabilitative: balance exercises; correct walking aid Environmental: good lighting (increased reliance on visual input); appropriate footwear; home safety assessment Medical: diagnose and treat specific diseases (e.g. Parkinson’s syndrome, Normal Pressure hydrocephalus) Rehabilitative: physical therapy; balance and gait training; correct walking aid Environmental: home safety assessment; appropriate adaptations (e.g. high, firm chairs, raised toilet seats, grab bars in bathroom) Medical: minimize sedating or centrally acting drugs Rehabilitative: supervised exercise and ambulation Environmental: safe, structure, supervised environment Medical: diagnose and treat specific diseases Rehabilitative: balance and gait training; Tai Chi, muscle-strengthening exercises; back exercises; correct walking aid; correct footwear; good foot care (nails, bunions) Environmental: home safety assessment; appropriate adaptations
Medical: diagnose and treat specific disease; avoid offending drugs; rehydrate; replenish salt Rehabilitative: tilt table if severe; reconditioning if component of deconditioning; graded pressure stockings; dorsiflexion and hand flexion exercises before arising Environmental: elevate head of bed Medical: ?antidepressants associated with increased risk of falling; ? select least anticholinergic Medical: lowest effective dose of essential medications; readjust or discontinue when possible
Possible interventions Medical: diagnose and treat specific diseases; start medications low and increase slowly Environmental: increase supervision during illnesses or with new medication Rehabilitative: recommend avoiding only clearly hazardous and unnecessary activities (e.g., climbing on chairs); balance and gait training Environmental: home safety assessment with appropriate adaptive or structural changes (see Ref. 7)
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weakness, or postural hypotension should be elicited from the patient. Carotid hypersensitivity should be suspected if the individual gives a history of “just going down” or falling with head turning or with looking up. Carotid sinus massage should be performed if carotid sinus syndrome is suspected, if there is no evidence of cerebrovascular disease or cardiac conduction abnormality, and if the procedure is judged safe in the individual patient. The carotid sinus syndrome is defined as greater than a 3-s sinus pause or more than a 5 mmHg drop in systolic blood pressure. Laboratory Evaluation All elderly persons who have experienced falls should undergo routine laboratory screening including a complete blood count, thyroid function tests, electrolytes, including blood urea nitrogen (BUN) and creatinine, and serum glucose, as well as a determination of vitamin B12 levels. These tests are warranted to screen for anemia, thyroid dysfunction, electrolyte abnormalities, dehydration, hyperglycemia or hypoglycemia, and B12 deficiency because of the prevalence, nonspecific presentation, and potential for modification of underlying diseases by these diagnoses. Drug levels, for example, should be measured in individuals taking anticonvulsants, tricyclic antidepressants, antiarrhythmics, and high-dose aspirin. History and examination should guide other laboratory investigations. As already noted, in approximately 10% of cases falls by community-dwelling older adults are a nonspecific manifestation of an acute illness. In these situations the laboratory and diagnostic evaluation in these situations should be dictated by the suspected etiology. Examples of potentially useful tests include the electrocardiogram, cardiac enzymes, chest x-ray, urine analysis and culture, and blood cultures. Brain imaging with computed tomography or magnetic resonance imaging is indicated only when focal abnormalities are noted on the neurologic examination. Cervical spine films may be helpful in individuals with impaired gait, lower extremity spasticity, and hyperreflexia suggestive of cervical spondylosis. A lateral dimension of the spinal canal of less than 12 mm is suggestive of a significant encroachment on the cervical cord. Magnetic resonance imaging should be pursued to confirm this finding only if the individual is deemed a candidate for neurosurgery. A 24 h ambulatory cardiac monitor (Holter) is not warranted for the routine evaluation of nonsyncopal falls. The yield of ambulatory electrocardiographic monitoring is very low in these individuals. In addition, the results may be difficult to interpret because of the high prevalence of asymptomatic arrhythmias in older adults.
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Balance and Gait Evaluation Balance and gait represent end products of the accumulated effects of disease, age-related and lifestyle changes, and impairments in sensory, neurologic, and musculoskeletal functioning. Therefore, a careful assessment of balance and gait is an essential component of the fall evaluation. There is strong epidemiologic evidence to support balance and gait assessment as the single best means of identifying individuals at increased risk of falling.9,10,13,18,83,84 Simple but reliable methods for observing an individual’s balance and gait performance are available for use in clinical practice.58,85 Tests of balance and gait typically reproduce the position changes, postural responses, and gait maneuvers used during daily activities. The “Get Up and Go” test and the Performance-oriented Assessment of Mobility are two examples of clinical observation tests of balance and gait that have been used extensively in clinical practice.58,85 Both assessments involve observing the individual perform various combinations of maneuvers such as getting up from a chair, reaching up, turning, bending over, assuming various narrowed stances, walking at a usual and rapid pace, and sitting in a chair. The examiner watches for instability or difficulty with performing each maneuver. Components of a simple balance and gait assessment are included in Table 66.4. The assessment may help to identify not only individuals at risk for falling but the circumstances in which falls are most likely to occur. As discussed next, combinations of medical, rehabilitative, and environmental interventions can be recommended based on the simple observations of balance and gait. The role of computerized posturography in the clinical evaluation and treatment of balance and falling disorders remains to be determined. Posturography may be helpful in determining the relative contribution of visual, vestibular, and proprioceptive abnormalities to postural instability.83 Posturography may further reveal the method by which the individual responds to postural perturbations. Although still under investigation, preliminary studies suggest that these findings may help in the development of effective rehabilitative interventions.86 Review of Fall Situations The fourth component of the fall evaluation is a careful review of recent fall situations. In determining the contribution of possible intrinsic factors, the clinician should obtain information on premonitions; feelings of lightheadedness, vertigo, or unsteadiness; recent medications, particularly focusing on recent changes; preceding alcohol consumption; or symptoms of acute illness, postural hypotension, or dysrhythmias. A precise description of activity at the time of the fall is important as well.87 Was the individual standing still, performing a simple
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Table 66.4. Position changes, balance maneuvers, and gait components included in performance-oriented mobility assessment. Position change or balance maneuver Getting up from chaira Sitting down in chair Withstanding nudge on sternum or pull at waist Side by side standing with eyes open and shut Neck turning Bending over
Observation: fall risk if Does not get up with single movement; pushes up with arms or moves forward in chair first; unsteady on first standing Plops in chair; does not land in center Moves feet; begins to fall backward; grabs object for support; feet not touching side by side Same as above; eyes closed tests patient’s reliance on visual input for balance Moves feet; grabs object for support; feet not touching side by side; complains of vertigo, dizziness, or unsteadiness Unable to bend over to pick up small object (e.g., pen) from floor; grabs object to pull up on; requires multiple attempts to arise
Gait component or maneuver b
Initiation Step height (raising feet with stepping) Step continuity Step symmetry Path deviation Turning
Observation: fall risk if Hesitates; stumbles; grabs object for support Does not clear floor consistently (scrapes or shuffles); raises foot too high (more than 2 in.) After first few steps, does not consistently begin raising one foot as other foot touches floor Step length not equal (pathologic side usually has longer step length; problem may be in hip, knee, ankle, or surrounding muscles) Does not walk in straight line; weaves side to side Stops before initiating turn, staggers; sways; grabs object for support
a
Use hard, armless chair. Other more difficult balance maneuvers include tandem, semitandem, and one-leg standing. Patient walks down hallway at “usual pace,” turns and comes back using usual walking aid. Repeat at “rapid pace.” Examiner observes single component of gait at a time (analogous to heart examination). Other gait observations include heel–toe sequencing; armswing; trunk sway; stepping over objects. Source: Modified with permission from JAMA. 1988; 259: 1191. “Copyright 1988, American Medical Association.”
b
activity of daily living such as getting dressed, or walking? If walking, on what type of surface? Was the individual getting up or sitting down, arising from a lying position, going up or down stairs or curbs? If the fall occurred during routine and relatively nonhazardous activities, the goal of intervention will be to improve the safety and effectiveness of the maneuver during which the fall occurred. If, on the other hand, the fall occurred while performing more hazardous activities such as climbing on chairs or ladders, substitution of safer activities or avoidance should be recommended. Environmental details that should be ascertained include obstacles in the immediate area of the fall; the volume and intensity of lighting; the floor or ground surface; objects being carried; footwear, including the fit, heel height, and type of sole; and walking aids used at the time of the fall. A home safety evaluation as well as careful review of specific fall situations may reveal remedial environmental hazards. While common sense dictates eliminating obvious hazards such as throw rugs and obstacles, these have not been shown to be independent risk factors. Still, a recent Cochrane review supports interventions to reduce home hazards, particularly by a trained professional for patients in the immediate posthospitalization period.88,90
Prevention and Therapy The appropriate intervention strategy depends on the health status and fall history of the individual. For
healthy individuals who have not suffered falls, the treatment goal is to maintain or improve balance, gait, flexibility, and endurance to decrease the risk of falls and to maintain mobility and functional independence. Recent clinical trials suggest that strength and balance training are effective in increasing lower extremity strength in healthier, more vigorous elderly persons.91 In a casecontrol study, older persons who perform vigorous physical activity at least three times per week and have no limitations in their ADLs may be at a lower risk for fallrelated fractures.92 Recent evidence suggests that older adults who participate in a program of resistance exercise training once or twice weekly demonstrate improved neuromuscular performance and achieve muscle strength gains similar to those training 3 days per week.93 Further studies are needed to define the longterm effectiveness, optimal combination of exercise components, and minimal intensity required. In a recent randomized controlled trial, a low-cost multifactorial intervention based at a community organization was shown to be effective in reducing slips by 61%, trips by 56%, and falls by 29% in a group of healthy older adults during 1 year.94 Evidence is emerging that among “healthier,” less-impaired persons, exercise seems to have as strong an effect on falls as does the multifactorial approach in the less healthy.95 The aim of treatment in older individuals who have already experienced falls or who suffer from chronic diseases and impairments is to reduce the rate of subsequent falls and decrease the incidence of fall-related morbidity such as injury, fear,
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inability to get up, functional decline, and immobility. The treatment strategy should be guided by the results of the assessment.96–98 The governing concept should be that it is possible to reduce the risk of falls and fall sequelae by eliminating or modifying as many contributing factors as possible. Because of the overlapping, compensatory nature of the systems affecting stability as described earlier, simple interventions may result in major improvements, even if the interventions are not targeted at the systems believed to be most impaired. As most of the factors contributing to fall risk are chronic diseases or impairments that may be modifiable, but only rarely curable, the treatment strategy should combine appropriate combinations of medical, surgical, rehabilitative, and environmental interventions. These interventions are summarized in Table 66.3. Similarly, the balance and gait assessment is useful not only for identifying individuals at risk for falling and the situations under which falls are likely to occur but can also be used to determine rehabilitative and environmental interventions that may decrease risk. Examples of using the results of balance and gait examination to guide treatment are outlined in Table 66.4. Rather than targeting one area of risk, an individualized, interdisciplinary, multifactorial approach to modifying all risk factors was shown to be most beneficial in reducing falls in older adults.90 The withdrawal of psychotropic medications in association with a home-based exercise program had a relative hazard for falls of 0.34 (95% CI, 0.16–0.74) compared with maintaining the psychoactive medications and the exercise program.99 As can be seen from reviewing Tables 66.3 and 66.4, physical therapy is an integral part of any fall assessment and treatment program.97 A home safety evaluation with recommendations for modification and adaptation, prescription of and training in the appropriate use of assistive devices, transfer and gait training, and instruction in muscle-strengthening and balance exercises are examples of fall preventive interventions carried out by a trained physical therapist.97 The physical therapist may also help in treating the consequences of falls by teaching strategies for how to fall, or for getting up from the floor after a fall, and by encouraging confidence in performance of activities of daily living without falling. Recent evidence suggests that a home exercise program may reduce falls, but further evidence is needed to determine the longterm effects of this intervention.100 A randomized controlled trial of thrice-weekly progressive resistance exercises, walking, and balance training in a group of high-risk community-dwelling male fallers resulted in improved endurance and lower extremity strength and decreased fall rates.101 A preplanned meta-analysis of the seven federally funded Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) Trials showed a 10% reduction in
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the adjusted fall incidence ratio for studies that included endurance, resistance, and flexibility exercise programs and a 17% reduction for those that only used balance.102 After adjusting for fall risk factors, a moderate Tai Chi training program was found to reduce the risk of multiple falls by 48%.103 Promising treatment modalities for the prevention of fall-related fractures include treatment of osteoporosis, discussed in Chapter 43. Additionally, an assessment of falls is recommended for those patients who have already sustained a hip fracture.104 Providing extra padding, through the use of various types of hip protectors, appears to be a promising approach for the prevention of hip fractures, one of the most serious consequences of falls among elderly persons.105 These devices were recently shown to improve self-efficacy in high-risk community-dwelling older adults and to reduce the risk of hip fracture in a group of frail ambulatory elderly.106
Nursing Home The first step to developing and implementing a fall evaluation and prevention program for institutionalized older adults is to establish appropriate goals. Not only are institutionalized older adults more likely than their community-dwelling counterparts to be frail, they are also more likely to have readily available alternatives to walking as a means of mobility. It is important to carefully assess the trade-offs of safety versus functional independence and mobility in institutionalized older adults, as an increase in physical activity may increase the risk of injury. Although the components of a fall evaluation are the same in nursing home and community-dwelling older adults, the relative contribution of chronic or situational risk factors may differ.
Predisposing Risk Factor Assessment A thorough clinical evaluation aimed at identifying all contributing risk factors is the cornerstone of the evaluation among nursing home residents.107 As with communityliving elderly persons, the risk of falling increases with the number of impairments, suggesting again that ameliorating or eliminating as many risk factors as possible may decrease risk.51,58,108 A careful examination of the risk factors noted in Table 66.3 is essential as the number and severity of impairments and diseases is greater among nursing home than community residents, and nonspecific and vague presentations, particularly among the large number of nursing home residents with cognitive impairment, render the clinical history less reliable.109
Laboratory Evaluation As among community-living elderly persons, routine laboratory testing should be targeted toward conditions
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that are common and treatable. Additional testing should be considered on an individual resident basis, guided by the history and examination. There is no role for routine ambulatory cardiac monitoring for nonsyncopal falls among nursing home residents.
Balance and Gait Evaluation Balance and gait assessment plays the same role in nursing home as in community residents. Reliable and validated assessments have been developed specifically for use among frail nursing home residents and hospital patients.110
Review of Fall Situations Although many falls among nursing home residents are unwitnessed, there is greater opportunity to identify acute intrinsic and environmental contributors to falling among nursing home residents compared with community residents.29,57 Symptoms experienced near the time of the fall such as dizziness may suggest postural hypotension, hypoglycemia, dysrhythmia, or a medication side effect. Chest pain may suggest angina or myocardial infarction. The immediate postfall physical examination should include a careful evaluation of postural blood pressure and pulse changes at both 1 and 3 min, focal neurologic signs, and signs of any acute illnesses that may present as a fall. Environmental factors that are particularly relevant to nursing home residents include the presence of side rails, inappropriate use of walking aids such as walkers or wheelchairs, and the presence and application of vest, belt, or other restraints. Among nonambulatory nursing home residents, injurious falls are more likely to occur while seated or during transfers from the chair or bed level and to involve ill-fitting or poorly maintained equipment such as wheelchairs, shower chairs, or commodes.111
Prevention and Therapy Although earlier studies demonstrated that careful assessment and intervention among nursing home residents who fall reduces the risk of hospitalization, there was little evidence that it prevents subsequent falls.112 A recent randomized controlled trial of a nursing home consultation service demonstrated a reduction in the proportion of nursing home residents who were recurrent fallers, especially among those who adhered to the recommendations. These interventions included targeting environmental and personal safety issues, wheelchair use, transferring, and ambulation, along with psychotropic drug use.60 The specific role of physical therapy in fall prevention among nursing home residents remains to be determined. Although on the one hand studies have not found physical therapy interventions to be effective,
D.C. Thomas, H.K. Edelberg, and M.E. Tinetti
other studies have shown that intense strength training results in increased strength, balance, and gait in even very frail elderly nursing home residents.113,114 These seemingly conflicting results suggest that the optimal cost-effective strategy is to identify and treat those elderly persons most likely to benefit from a multifactorial intervention to prevent falls. At the very least, a physical therapy evaluation is warranted to prescribe and ensure the correct use of assistive devices, including walkers, canes, crutches, orthotics, and shoe modification. Although researchers have failed to establish a causal link between medications and falls by nursing home residents, the strong association between medications and falling and the contribution of polypharmacy to other adverse events warrants frequent medication review and adjustment. The goal should be to reduce the total number and dosage of medications taken by nursing home residents. On the strength of the current evidence it is suggested that efforts to prevent falls in nursing homes should focus on decreasing the use of psychoactive medications, training staff members to perform safe transfers, and repairing broken equipment such as wheelchairs.
Environmental Assessment In addition to assessing the environment at the time of a fall, ongoing environmental assessment aimed at removing potential hazards and modifying the environment to improve mobility and safety should be an ongoing practice in nursing homes. The provision of adequate lighting without glare; dry, nonslippery floors that are free of obstacles; high, firm chairs with arms; beds at appropriate heights for individual residents (feet should touch the floor with the knees bent at 90°); beds without upper side rails; and raised toilet seats with arms are preventive measures that should be implemented for all nursing home residents. Movable bed trays, which are often used by residents for support, should be considered a serious fall hazard. Footwear should be scrutinized; shoes that are ill fitting, have worn soles or heels, or are left untied are unsafe for nursing home residents. Slippers without backs, with soles that are either too slippery or have too high friction, or which provide little foot and ankle support are particularly hazardous, as is wearing stockings without shoes.
Restraints Recent efforts, guided by federal regulations as well as by the results of several studies, have aimed at reducing the use of physical restraints. Although controlled studies are lacking, observational evidence suggests that physical restraints may contribute to falls, injuries, and death through strangulation as well as to other adverse outcomes such as withdrawal and depression.30,115,116 One
66. Falls
prospective study showed a 25% to 40% reduction in restraint use in a nursing home with restraint education with consultation compared to restraint education or control alone.117 Increasingly, nursing homes are implementing alternative measures such as increased nurse-toresident ratio, alternative seating, lowered side rails and bed heights for residents who climb out of bed, and alarms that are activated when residents try to get out of bed or move unassisted.29 Although the effectiveness of these various techniques and devices remains to be determined, restraint reduction does appear to decrease the injury rate in those who fall.33 As noted for community-living elderly persons, injury prevention alternatives such as hip protectors are currently being tested.105,118 It has been proven that hip protectors can be particularly effective in preventing hip fractures. At this point, however, patients complain about the discomfort and practicality of the device, thereby resulting in only a small percentage of at-risk patients wearing them. As a result, nursing home patients should be encouraged to use hip protectors to prevent injury from falls.119
Summary Falling is a common event among community and nursing home residents. These falls may result in considerable morbidity, ranging from self-imposed activity restriction to serious injury and death. Until methods are available for accurately identifying those falls or fallers at risk for serious morbidity, all fallers should be assumed to be at risk. A small percent of falls result from a single, overwhelming intrinsic event such as a stroke, from the effects of a single disease process such as Parkinson’s disease, or from overwhelming environmental hazards. The majority of falls are multifactorial, resulting from various combinations of intrinsic, activity-related, and environmental factors. Recent studies suggest that careful assessment and interventions aimed at identified risk factors and well-designed exercise programs may decrease the risk of falling. Most often, the goal of fall prevention programs should be to minimize the risk of falls and injuries without compromising function or mobility. As with all older individuals, however, the goals and priorities may be different for individual persons.
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D.C. Thomas, H.K. Edelberg, and M.E. Tinetti dwelling older adults. J Am Geriatr Soc. 1985;33(5): 330–333. 41. Hazell JW. Vestibular problems of balance. Age Ageing. 1979;8(4):258–260. 42. Woolf SH, Kamerow DB, Lawrence RS, Medalie JH, Estes EH. The periodic health examination of older adults: the recommendations of the U.S. Preventive Services Task Force. Part II. Screening tests. J Am Geriatr Soc. 1990; 38(8):933–942. 43. Wyke B. Cervical articular contribution to posture and gait: their relation to senile disequilibrium. Age Ageing. 1979;8(4):251–258. 44. Masdeu JC, Wolfson L, Lantos G, Tobin JN, Grober E, et al. Brain white-matter changes in the elderly prone to falling. Arch Neurol. 1989;46(12):1291–1296. 45. Whipple RH, Wolfson LI, Amerman PM. The relationship of knee and ankle weakness to falls in nursing home residents: an isokinetic study. J Am Geriatr Soc. 1987;35(1): 13–20. 46. Lipsitz LA. Orthostatic hypotension in the elderly. N Engl J Med. 1989;321:952–957. 47. Ray WA, Griffin MR. Prescribed medications, and the risk of falling. Top Geriatr Rehabil. 1990;5:12–20. 48. Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and meta-analysis: I. Psychotropic drugs. J Am Geriatr Soc. 1999;47(1):30–39. 49. Liu B, Anderson G, Mittmann N, To T, Axcell T, et al. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet. 1998;351(9112):1303–1307. 50. Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and meta-analysis: II. Cardiac and analgesic drugs. J Am Geriatr Soc. 1999;47(1): 40–50. 51. Robbins AS, Rubenstein LZ, Josephson KR, Schulman BL, et al. Predictors of falls among elderly people. Results of two population-based studies. Arch Intern Med. 1989; 149(7):1628–1633. 52. Gray SL, Mahoney JE, Blough DK. Adverse drug events in elderly patients receiving home health services following hospital discharge. Ann Pharmacother. 1999;33(11): 1147–1153. 53. Kapoor WN. Syncope in older persons. J Am Geriatr Soc. 1994;42(4):426–436. 54. Startzell JK, Owens DA, Mulfinger LM, et al. Stair negotiation in older people: a review. J Am Geriatr Soc. 2000;48(5):567–580. 55. Stevens M, Holman CDJ, Bennett N. Preventing falls in older people: impact of an intervention to reduce environmental hazards in the home. J Am Geriatr Soc. 2001;49:1442–1447. 56. Owen DH. Maintaining posture and avoiding tripping. Optical information for detecting and controlling orientation and locomotion. Clin Geriatr Med. 1985;1(3):581–599. 57. Lipsitz LA, Jonsson PV, Kelley MM, et al. Causes and correlates of recurrent falls in ambulatory frail elderly. J Gerontol. 1991;46:M114–M122. 58. Tinetti ME, Williams TF, Mayewski R. Fall risk index for elderly patients based on number of chronic disabilities. Am J Med. 1986;80(3):429–434.
66. Falls 59. Donald IP, Pitt K, Armstrong E, et al. Preventing falls on an elderly care rehabilitation ward. Clin Rehabil. 2000; 14(2):178–185. 60. Ray WA, Taylor JA, Meador KG, et al. A randomized trial of a consultation service to reduce falls in nursing homes. JAMA. 1997;278(7):557–562. 61. Melton LJ, Riggs BL. Risk factors for injury after a fall. Clin Geriatr Med. 1985;1(3):525–539. 62. Cummings SR, Nevitt MC. A hypothesis: the causes of hip fractures. J Gerontol. 1989;44(4):M107–M111. 63. Lord SR, McLean D, Stathers G. Physiological factors associated with injurious falls in older people living in the community. Gerontology. 1992;38(6):338–346. 64. Kelsey JL, Browner WS, Seeley DG, et al. Risk factors for fractures of the distal forearm and proximal humerus. The Study of Osteoporotic Fractures Research Group. Am J Epidemiol. 1992;135(5):477–489. 65. Ryynanen OP, Kivela SL, Honkanen R, et al. Recurrent elderly fallers. Scand J Prim Health Care. 1992;10(4): 277–283. 66. Greenspan SL, Myers ER, Maitland LA, et al. Fall severity and bone mineral density as risk factors for hip fracture in ambulatory elderly. JAMA. 1994;271(2):128–133. 67. Grisso J. Risk factors for falls as a cause of hip fracture in women. N Engl J Med. 1991;324(19):1326–1331 68. Myers AH, Baker SP, VanNatta ML, et al. Risk factors associated with falls and injuries among elderly institutionalized persons. Am J Epidemiol. 1991;133(11): 1179–1190. 69. Campbell AJ, Borrie MJ, Spears GF. Risk factors for falls in a community-based prospective study of people 70 years and older. J Gerontol. 1989;44(4):M112–M117. 70. Mahoney J, Sager M, Dunham NC, et al. Risk of falls after hospital discharge. J Am Geriatr Soc. 1994;42(3):269–274. 71. Oliver D, Britton M, Seed P, et al. Development and evaluation of evidence based risk assessment tool (STRATIFY) to predict which elderly inpatients will fall: case-control and cohort studies [see comments]. Br Med J. 1997;315(7115):1049–1053. 72. Sorock GS, Bush TL, Golden AL, et al. Physical activity and fracture risk in a free-living elderly cohort. J Gerontol. 1988;43(5):M134–M139. 73. Schwartz AV, Kelsey JL, Sidney S, et al. Characteristics of falls and risk of hip fracture in elderly men. Osteoporos Int. 1998;8(3):240–246. 74. Davis JW, Ross PD, Nevitt MC, et al. Risk factors for falls and for serious injuries on falling among older Japanese women in Hawaii. J Am Geriatr Soc. 1999;47(7):792–798. 75. Wenger NS, Shekelle PG. Assessing care of vulnerable elders: ACOVE project overview. Ann Intern Med. 2001;135(8 pt 2):642–646. 76. Shekelle PG, MacLean CH, Morton SC, et al. ACOVE quality indicators. Ann Intern Med. 2001;135(8 pt 2): 653–667. 77. Rubenstein LZ, Powers CM, MacLean CH. Quality indicators for the management and prevention of falls and mobility problems in vulnerable elders. Ann Intern Med. 2001;135(8 pt 2):686–693. 78. Guideline for the prevention of falls in older persons. American Geriatrics Society, British Geriatrics Society,
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D.C. Thomas, H.K. Edelberg, and M.E. Tinetti people living in the community. N Engl J Med. 1994; 331(13):821–827. Koch M, Gottschalk M, Baker DI, et al. An impairment and disability assessment and treatment protocol for community-living elderly persons. Phys Ther. 1994;74(4): 286–294; discussion 295–298. Lipsitz LA. An 85-year old woman with a history of falls. JAMA. 1996;276(1):447–454. Campbell AJ, Robertson MC, Gardner MM, et al. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc. 1999;47(7):850–853. Lord SR, Ward JA, Williams P, et al. The effect of a 12-month exercise trial on balance, strength, and falls in older women: a randomized controlled trial. J Am Geriatr Soc. 1995;43(11):1198–1206. Rubenstein LZ, Josephson KR, Trueblood PR, et al. Effects of a group exercise program on strength, mobility, and falls among fall-prone elderly men. J Gerontol A Biol Sci Med Sci. 2000;55(6):M317–M321. Province MA, Hadley EC, Hornbrook MC, et al. The effects of exercise on falls in elderly patients. A preplanned meta-analysis of the FICSIT Trials. Frailty and Injuries: Cooperative Studies of Intervention Techniques [see comments]. JAMA. 1995;273(17):1341–1347. Wolf SL, Barnhart HX, Kutner NG, et al. Reducing frailty and falls in older persons: an investigation of Tai Chi and computerized balance training. Atlanta FICSIT Group. Frailty and Injuries: Cooperative Studies of Intervention Techniques [see comments]. J Am Geriatr Soc. 1996;44(5): 489–497. Morrison RS, Chassin MR, Siu AL. The medical consultant’s role in caring for patients with hip fracture. Ann Intern Med. 1998;128(12 pt 1):1010–1020. Lauritzen JB, Petersen MM, Lund B. Effect of external hip protectors on hip fractures. Lancet. 1993;341(8836):11–13. Kannus P, Parkkari J, Niemi S, et al. Prevention of hip fracture in elderly people with use of a hip protector. N Engl J Med. 2000;343(21):1506–1513. Kiely DK, Kiel DP, Burrows AB, et al. Identifying nursing
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67 Chronic Dizziness and Vertigo Aman Nanda and Mary E. Tinetti
Dizziness is a subjective sensation of postural instability or of illusory motion. It is a nonspecific term that includes vertigo, disequilibrium, lightheadedness, spinning, giddiness, faintness, floating, feeling woozy, and many other sensations. As the etiologies differ, dizziness is often classified on the basis of duration as acute (present for less than 1–2 months) or chronic (present for more than 1–2 months). Because the causes of acute dizziness are usually identical for patients of all ages, this chapter is therefore limited to a discussion of chronic dizziness.
Prevalence and Morbidity Dizziness is one of the most common presenting complaints in primary care practice for persons aged 65 years and older.1 The prevalence of dizziness ranges from 4% to 30% in this age group.2–4 Dizziness increases with age, with a 10% increase every 5 years. After adjusting for age, women are 30% more likely than men to report dizziness.3 Chronic dizziness has been associated with an increased risk of falls, syncope, functional disability, and, in some studies, strokes and death.4–12 It is strongly associated with fear of falling and reduced confidence in performing daily activities.13 In one study, 47% of patients with dizziness expressed a fear of falling compared to only 3% of the controls.14 It has also been associated with worsening of depressive symptoms, self-rated health, and participation in social activities.15
Types of Dizziness There is no universally accepted classification of dizziness. Dizziness has been categorized by either duration (acute/chronic) or types of sensations. Drachman and Hart16 categorized dizziness into four subtypes based on sensations: vertigo, presyncope, disequilibrium, and other.
Vertigo is a spinning or rotational sensation, either of the patient with respect to the environment (subjective vertigo) or of the environment with respect to the patient (objective vertigo). The key element is the perception of motion. Vertigo often begins instantaneously, is episodic, and when severe may be associated with nausea, vomiting, and a staggering gait. Vertigo is considered to result from a disturbance within the vestibular system or its connections. However, the lack of a spinning sensation may not be used to exclude vestibular diseases, as patients with vestibular problems can describe dizziness as an imbalance, disequilibrium, or other sensation. Also, etiologies outside the vestibular system (e.g., cervical causes of dizziness) may result in vertigo. Presyncope is a feeling of lightheadedness or impending faintness or a feeling that one is about to pass out. It is usually considered to result from a hypoperfusion of the brain. A number of cardiovascular conditions may cause presyncope and syncope. Disequilibrium is a feeling of imbalance or unsteadiness usually not associated with any abnormal head sensations. The patient feels as if he or she is going to fall. Disequilibrium usually results from abnormalities in the proprioceptive system. The category “other” is defined as a vague feeling other than vertigo, presyncope, or disequilibrium. The patient may describe “floating,” “wooziness,” “spaciness,” “whirling,” and other nonspecific sensations. A person may have a combination of two or more of these four types of dizziness; this is the most common type of dizziness reported by older persons17,18 and is believed to result from systemic disorders such as anemia, electrolyte imbalances, diabetes, and hypothyroidism, or from the presence of combinations of diseases affecting the vestibular, central nervous, visual, or proprioceptive system. These sensations as noted here have diagnostic specificity among persons of all ages with acute dizziness and among younger persons with chronic dizziness. Among 995
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older persons with chronic dizziness, however, there is a less consistent correlation between the type of sensation and specific organ systems.
Mechanisms of Equilibrium Given that dizziness is a sensation of postural instability, a review of the mechanisms determining balance and equilibrium may help in understanding the pathophysiology of dizziness. Maintenance of balance and equilibrium results from a complex integration of sensory information obtained from the visual, auditory, vestibular, and proprioceptive systems by the cerebral cortex and cerebellum and the use of this information for the appropriate motor response. The visual system helps in maintaining balance by providing signals from the retina to the occipital cortex, necessary for providing a stable retinal image during head movement. The vestibulo-ocular reflex (VOR) controls the position of the eyes, enabling maintenance of a stable visual image during head movement. The VOR depends on the information relayed by the vestibular nucleus to the sixth (abducens) cranial nerve nucleus in the pons and, via the medial longitudinal fasciculus, to the third (oculomotor) and fourth (trochlear) cranial nerve nuclei in the midbrain. Binocular vision and depth perception also are important visual signals for spatial orientation. Hearing assists in stability by detecting and interpreting auditory stimuli, which enables one to localize and be oriented in space. Hearing is particularly helpful when other sensory modalities are impaired. Hearing impairment, common in older persons, may be secondary to aging, to disease processes, or to the presence of excess cerumen. Although impaired hearing may be a marker of vestibular dysfunction as both sensory modalities operate through the eighth cranial nerve, studies have reported an independent association between decreased hearing and dizziness.4,18 The vestibular system contributes to spatial orientation at rest, as well as during acceleration, and is responsible for visual fixation during head and body movements. The vestibular system includes the semicircular canals, utricle, saccule, vestibular nerve, and vestibular nucleus in the brainstem. The semicircular canals respond to changes in angular acceleration, and the utricle and saccule respond to linear acceleration. The sensory epithelium of the semicircular canals, utricle, and saccule consists of hair cells. The afferents from these hair cells relay information to the vestibular nuclei in the brainstem. The vestibular nuclei relay this information to the nuclei of the third, fourth, and sixth cranial nerves, spinal cord (vestibulospinal tract), and cerebellum (vestibulocerebellar pathway).
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The proprioceptive system provides information about changes in position and movements and helps maintain equilibrium during changes in position. The components of the proprioceptive system are mechanoreceptors in the joints, peripheral nerves, posterior columns in the spinal cord, and multiple central nervous system connections. The afferent impulses relay information to the cerebral cortex via the thalamus and to the cerebellum via the spinocerebellar tract. The cerebral cortex, cerebellum, and brainstem integrate information received from the visual, auditory, vestibular, and proprioceptive systems and direct the musculoskeletal system via efferent pathways toward the response appropriate for maintaining balance and equilibrium. Lesions in the brain may cause disordered integration of information from these systems, resulting in imbalance/dysequilibrium.
Effects of Aging on Sensory Systems Evidence suggests that age-related changes occur in each of the vestibular, visual, auditory, and proprioceptive systems. Although these age-related changes do not likely cause clinical disease, they may predispose older persons to the occurrence of dizziness by making them more vulnerable to the effects of superimposed impairments and diseases. Degenerative changes and reductions in the number of sensory cells (hair cells) in the semicircular canals, saccule, and utricle have been reported with aging.19,20 Richter noted a significant decrease in the number of cells in Scarpa’s ganglion.21 Bergstrom found a 37% reduction in the number of nerve fibers in the vestibular nerves of five people over age 75.22 Age-related visual changes include a decrease in visual acuity, dark adaptation, contrast sensitivity, and accommodation.23,24 Age-related decline in proprioception has not been extensively studied. Skinner et al. reported a significant deterioration in joint-position sense in older individuals, but Kokemen et al. concluded that there is no major decline in joint-position sensation with aging.25,26
Causes of Chronic Dizziness Dizziness results from either discrete or combined effects of disorders or impairments in the multiple systems responsible for maintaining equilibrium. Acute and, to a lesser extent, chronic dizziness result when a disorder in one of these systems causes abnormal or decreased sensory input, resulting in a mismatch of information about the movements of the head or body. Discrete causes of chronic dizziness can be divided into central nervous system disorders, vestibular disorders, psychogenic causes, systemic causes, medications, and
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miscellaneous. The relative frequency of these causes is unclear, as there has been a wide variability in their reported prevalences.9,10,16–18,27–31
Discrete Diseases Causing Dizziness Central Nervous System Causes Cerebrovascular diseases have been identified as a primary or contributing cause of dizziness in 4% to 70% of older patients.9,10,16–18,28–32 Vertebrobasilar ischemia results from an obstruction of the blood flow in the vertebrobasilar arteries, most commonly caused by arteriosclerosis leading to either transient ischemic attacks (TIA) or infarction. Because the basilar artery is responsible for the blood supply to the eighth nerve and vestibular nuclei, dizziness is one of the cardinal signs of basilar artery insufficiency. Apart from acute dizziness, which is usually in the form of prodromal symptoms in patients with vertebrobasilar TIA, patients may complain of chronic dizziness following a brainstem infarct. Dizziness may also result from anterior or posterior inferior cerebellar artery ischemia but is uncommon with internal carotid cerebral artery disease.32 Other central nervous system disorders such as parkinsonism, acoustic neuroma, and basilar artery migraine (rare in older persons) may also cause dizziness.33–35
Vestibular Causes Vestibular diseases have been identified as a primary or contributing cause in 4% to 71% of cases of dizziness.9,16,17,27,28,30,31 Common vestibular diseases causing chronic dizziness in older persons include benign paroxysmal positional vertigo, Meniere’s disease, recurrent vestibulopathy, and acoustic neuroma. Ototoxic medications may also lead to complaints of dizziness. Benign paroxysmal positional vertigo (BPPV), reportedly responsible for between 4% and 34% of cases of recurrent episodes of dizziness,9,16,17,27,28,30 is characterized by brief bouts (seconds) vertigo of sudden onset that is provoked by certain changes in the head position (e.g., rolling over in bed into a lateral position, gazing upward, or leaning forward). Another characteristic feature of BPPV is an accompanying rotational nystagmus. The vertigo is often associated with nausea or vomiting. Patients typically experience recurrent bouts of positional vertigo over days to months, with quiescent periods between episodes. Most BPPV cases have no identifiable cause. The most common known causes are a history of head trauma and viral neurolabyrinthitis.36 The currently accepted pathophysiologic mechanism of BPPV is the presence of free-floating particulate matter, most likely dislodged otoconia (tiny calciferous granules that form part of the
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receptor mechanism in the otolith apparatus) in the endolymph of the posterior semicircular canal. The exact mechanism by which free-floating particulate matter causes paroxysmal vertigo and nystagmus is unknown, but presumably it is the result of the movement of the debris causing alterations in endolymphatic pressure.37–39 The otoconia have been shown to undergo degenerative changes with aging, which might also be responsible for their dislodgment from the utriculus.40 A definitive diagnosis of benign paroxysmal positional vertigo can be made by the Dix–Hallpike test (discussed here).41 Meniere’s disease is an idiopathic inner ear disorder characterized by episodic vertigo, tinnitus, fluctuating hearing loss, and a sensation of fullness in the inner ear. The frequency of this disease has been reported to be 2% to 8% in dizziness cases.9,16,17,27,28,30 Males and females are affected equally, with onset usually occurring during the fifth decade of life. The main pathologic finding in patients with Meniere’s disease is an excess of endolymph within the cochlea and vestibular labyrinth. The patient develops a varying degree of sensations of fullness or pressure, along with hearing loss, and tinnitus in the affected ear. Vertiginous episodes usually last from 1 to 24 h. The patient may complain of a sense of unsteadiness after the acute episode. In the early stages, the hearing loss is completely reversible, but in later stages, partial or complete hearing loss occurs in about 90% of the patients.42 The hearing loss has a sensorineural pattern, with hearing at the lower frequencies tending to be worse. Recurrent vestibulopathy was first described by LeLeiver and Barber in 1981.43 This clinical entity is characterized by recurrent episodes of vertigo, usually lasting from 5 min to 24 h, without auditory or neurologic signs or symptoms. The exact cause is not known.44 The absence of auditory symptoms differentiates it from Meniere’s disease. Spontaneous recovery has been reported in 62% of patients over an 8.5-year follow-up.45 An acoustic neuroma is a benign tumor of the eighth cranial nerve, characterized by tinnitus and progressive unilateral sensorineural hearing loss that is greater for higher frequencies. This tumor has been reported in 2% to 3% of older persons with dizziness.17,28 Vertigo is a complaint of 19% of patients, whereas 48% complain of imbalance or disequilibrium.46 As the tumor grows, patients may complain of parasthesias or pain in the trigeminal nerve distribution. A large tumor can cause cerebellar ataxia.
Postural Hypotension In various studies, postural hypotension has been identified as a primary or contributing cause in 2% to 15% of dizziness cases.18,27–29 Postural hypotension has commonly been defined as a drop in systolic arterial blood pressure
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of at least 20 mmHg or a fall in diastolic blood pressure of 10 mmHg after standing up from a supine position. However, there are no uniform criteria for postural hypotension in older persons, and at least 15 different definitions exist for postural hypotension.47,48 Blood pressure is commonly measured at 1 and 3 min after standing, but in some older persons a significant orthostatic drop occurs only after 10 to 30 min (delayed orthostatic hypotension).49 Some older persons complain of dizziness on standing, but their blood pressure changes do not meet the criteria of postural hypotension. In one study of 9672 elderly women, postural hypotension was reported in 14% of the participants, but only 3% of these patients complained of dizziness, whereas 16% of the subjects reported dizziness on standing without any postural blood pressure changes.6 In another study, 9% of patients with postural blood pressure changes complained of dizziness, while 31% complained of dizziness on standing with no postural blood pressure changes.29 These results suggest that a postural drop in blood pressure is not always symptomatic and that, conversely, not all dizziness with postural changes is the result of orthostatic blood pressure changes. Postprandial hypotension, usually defined as a decrease in systolic blood pressure of 20 mmHg or more in a sitting or standing posture within 1 to 2 h of eating a meal, may also cause dizziness.50,51 A recent study showed that the effects of postprandial hypotension and orthostatic hypotension are additive but not synergistic, suggesting that the two entities have different pathophysiologic mechanisms.52 Postprandial reductions in blood pressure may result in falls, syncope, weakness, or dizziness.
Systemic Causes Systemic disorders may contribute to instability or dizziness by affecting the sensory, central, or effector components. In addition, systemic disorders may result in decreased cerebral perfusion or oxygen delivery, fatigue, or confusion, many of which in turn may result in instability or dizziness. Common examples include anemia, hypothyroidism, congestive heart failure, and diabetes mellitus with anatomic dysfunction. Carotid sinus hypersensitivity or carotid sinus syndrome can also cause dizziness, falls, or syncopal episodes. Wearing tight collars can precipitate dizziness, syncopal episodes, or falls upon sudden head turning or looking up. Carotid sinus syndrome is defined as a sinus pause of more than 3 s or a drop in systolic blood pressure of more than 50 mmHg following carotid sinus massage for 5 s. In one study, carotid sinus syndrome was reported in 45% of patients with dizziness, falls, and syncope.53 However, this high percentage is likely because the study population was a select group referred to a syncope clinic.
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The prevalence of dizziness in patients with systemic disorders is not known, but studies have found a significant association between dizziness and a history of angina, myocardial infarction, hypertension, or diabetes mellitus and with the total number of chronic conditions.4,17,18,54
Psychogenic Causes Psychogenic causes of dizziness have been reported in the range of 0% to 57% in older persons with dizziness.9,16–18,29–31,54,55 The most common conditions in older persons are depressive and anxiety disorders, either the primary cause or a contributing factor. Patients usually present with a vague sensation of dizziness, along with other somatic complaints and with symptoms of psychologic disorders. Studies have reported an independent association between dizziness and depression or anxiety.3,4,17,54
Cervical Causes The reported frequency of dizziness caused by cervical spine disorders ranges from 0% to 65%.16,27,29,30 Disorders of the cervical spine should be suspected when dizziness worsens with head turning or walking on uneven surfaces. Both proprioceptive and vascular mechanisms have been postulated.56,57 Proprioceptive deficits in the cervical spine can cause dizziness secondary to the impaired information from proprioceptive receptors present in the facet joints of the cervical spine. In older persons, cervical osteoarthritis most likely causes dizziness via this mechanism. The patient usually complains of pain in the neck on movement, along with a worsening of dizziness. There is often a history of arthritis or whiplash injury. Further examination may reveal a decreased range of motion of the neck or signs of radiculopathy or myelopathy or spastic gait. A vascular mechanism causing cervical dizziness is thought to result from an obstruction to the vertebral arteries. One theory is that when there is an extensive blockage of one vertebral artery, rotation of the head can sufficiently obstruct the other vertebral artery to cause brainstem ischemia.56 Another theory is that when a person turns their head or neck, an osteoarthritic spur may press upon the nearby vertebral artery, causing a transient disruption of the blood flow.57
Medications Medications have frequently been reported to cause or contribute to chronic dizziness.17,18,28 Several classes of medications, such as anxiolytic drugs, antidepressants, antihypertensive drugs, aminoglycosides, chemotherapeutic agents, and nonsteroidal anti-inflammatory drugs, are known to produce dizziness as a side effect.58
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Medications may cause dizziness through various mechanisms. Antihistamines and tricyclic antidepressants trigger dizziness through their anticholinergic side effects. Aminoglycosides have direct ototoxic effects when used in high dosages or for longer durations, especially when renal function is impaired. Other ototoxic agents include nonsteroidal anti-inflammatory agents such as aspirin, quinine, loop diuretics, and erythromycin and vancomycin analogues.59 Meclizine, often prescribed for dizziness, has anticholinergic properties and may even exacerbate the dizziness caused by nonlabyrinthine disease.57 When taking a medication history, one should also inquire about over-the-counter drugs such as cold preparations, which are prone to cause dizziness. In addition to specific medications, an independent association between the use of multiple medications and dizziness has been reported.18,54
Diseases Causing Impairment of Vision Diseases such as cataracts, glaucoma, and macular degeneration, which are common in older persons, may cause dizziness by impairing the visual functions. Davis, in his study of 117 patients with complaints of dizziness, reported that 26% suffered from disorders of the visual system, but he concluded that it was the major cause of dizziness in only 1% of the cases.28 In this study, 13% of the patients had cataracts. Other studies have also reported an association between poor vision or cataracts and dizziness.4,54
Chronic Dizziness as a Geriatric Syndrome In the previous section, dizziness in older persons was considered a symptom of one or more discrete diseases. The results of recent studies, however, suggest the possibility of a multifactorial etiology of dizziness.3,4,18,30 In these studies, chronic dizziness has been associated with risk factors such as angina, myocardial infarction, stroke, arthritis, diabetes, syncope, anxiety, depressive symptoms, impaired hearing, alcohol consumption, smoking, nervousness, and the use of several classes of medications. In a recent cohort study of a large community sample, the authors found an association between factors in multiple domains and the occurrence of chronic dizziness. The factors that were independently associated with chronic dizziness included anxiety, depressive symptoms, decreased hearing, postural hypotension, impaired balance and gait, the use of five or more medications, and a past history of myocardial infarction. A person with more than five of the risk factors was five times more likely to report chronic dizziness than a person with fewer than two factors.18 These findings were validated
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in a cohort of patients seen in a geriatric assessment center.54 An association among the characteristics in multiple domains and dizziness suggests that dizziness may be considered as a geriatric syndrome, similar to delirium and falls.18 Geriatric syndromes are health conditions experienced more frequently by older than by younger persons and result from the accumulated effect of impairments and diseases involving multiple systems. The importance of considering chronic dizziness a geriatric syndrome is that a multifactorial assessment and intervention strategy, as described in the following section, may be more effective at alleviating the symptom than the standard disease-oriented approach. The concept of a geriatric syndrome does not preclude the possibility that a single disease may be primarily responsible for impairment in a subset of persons. Rather, it acknowledges that many symptoms such as dizziness in older persons cannot be explained adequately on the basis of a single disease.
Evaluation Dizziness is a challenging problem for physicians who take care of older persons. The differential diagnosis as presented in the previous section is broad. The potential workup is extensive and expensive. The goal should be to eliminate the cause of the dizziness, if possible. If not, the goal should then be to alleviate the dizziness to the extent possible and to avoid the adverse consequences such as falls, functional disability, and increased depressive symptoms. Based on these goals and on the available evidence, a stepwise approach to the evaluation of chronic dizziness seems warranted. The existence of discrete diseases is usually suggested by the results of the history, physical examination, and routine laboratory evaluation. Only in the subset of patients in whom discrete diagnosis is suggested by their routine evaluation should a targeted battery of expensive tests be pursued, and only if the results of these tests are likely to influence treatment or prognosis. For the majority of older persons in whom a routine evaluation does not suggest a single discrete cause, the clinician should identify the various factors contributing to dizziness, some of which may be amenable to treatment. This approach is based on the fact that identifying and ameliorating one or more of these contributors might help alleviate the dizziness and its adverse consequences. Table 67.1 lists the possible causes of chronic dizziness, the salient history and examination findings, relevant investigations, and treatment. An evaluation of dizziness begins with the clinical history. The patient should be asked to be as precise as possible about the sensations of dizziness, an often difficult task because patients may experience more than one
Possible causes Central nervous system Brainstem (vertebrobasilar) and/or cerebellar infarcts/ hemorrhages
Cerebellopontine angle tumor: acoustic neuroma, schwanomma, etc. Parkinson’s disease
Vestibulocochlear system Benign paroxysmal positional vertigo
Meniere’s disease
Peripheral nerves Diabetes; vitamin B12 deficiency; hypothyroidism; syphilis; idiopathic
Vision Presbyopia, cataract; glaucoma; macular degeneration
Examination
Investigations
Treatment
History of dizziness (e.g., vertigo, near fainting, wooziness) usually associated with slurred speech; visual changes; one-sided weakness and/or gait ataxia; truncal ataxia History of vertigo or dysequilibrium; unilateral hearing loss; tinnitus Dysequilibrium; imbalance; slow motor activities; slow walking, etc.
Detailed neurologic examination, localizing the lesion
CT or MRI scan; MRI is preferred
Low-dose aspirin or ticlopidine or clopidigel if infarct; rehabilitation therapy
Detailed neurologic examination
Audiometry reveals asymmetric hearing loss; which may be further evaluated by MRI Diagnosis is made by history and examination
Surgical excision
Sudden and fleeting episodes of intense vertigo with specific head position (e.g., rolling over in bed into lateral position; looking upward; bending forward); episodes last days to months and are often recurrent Episodic vertigo for a few hours; there are no symptoms between episodes; tinnitus; fluctuating hearing loss; sensation of fullness in ears
History of episodic vertigo; nystagmus; confirmed by Dix– Hallpike maneuver; along with absence of signs suggesting other pathology, especially central involvement
None
Epley maneuver is helpful in treatment provided the side of the vertigo is known; vestibular rehabilitation and sometimes a short course of vestibular suppressants
If unilateral, then bedside vestibulo-ocular reflex test will be abnormal
An audiogram revealing a sensorineural hearing loss (low more than high frequencies) is confirmatory; MRI scan to rule out retrocochlear lesions
Salt restriction and diuretics are the mainstay; during acute attacks vestibular suppressants may be helpful to relieve vertigo; surgical interventions, including endolymphatic decompression, gentamicin perfusion, vestibular nerve section, and labyrinthectomy should be considered only in severe cases
Disequilibrium; worse in dark or on uneven surfaces
Decreased vibration or position sense; steppage gait
Serum glucose; B12 levels; thyroid function test; VDRL
Treatment of the underlying disease; good lighting; appropriate walking aid and footwear; gait and balance training exercises
Neck pain, usually episodic dizziness secondary to change in position of the neck, history of trauma or arthritis
Decreased neck range of motion; decreased vibratory or joint position sense; signs of radiculopathy or myelopathy or vertebrobasilar ischemia
Cervical spine series
Treatment of underlying disease; cervical or balance exercises; cervical collar; consider surgery
Difficulty in vision; use of bifocals or trifocals
Abnormalities in near/distant acuity
Vision testing; referral to ophthalmologist
Good lighting without glare; appropriate refraction; consider avoiding bifocals or trifocals; drugs for glaucoma; surgery
Increased muscular rigidity; bradykinesia; tremor; orthostatic hypotension
Antiparkinson treatment
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Cervical spine Degenerative or inflammatory arthritis, spondylosis, whiplash injury
History
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Table 67.1. Evaluation and treatment of chronic dizziness
Hypotension Orthostatic volume/salt depletion; drugs; vasovagal attack; autonomic dysfunction; diabetes; parkinsonism; deconditioning
Postprandial
Systemic diseases Cardiac/metabolic/respiratory: e.g., cardiac arrhythmias, valvular lesions, coronary artery disease, cardiomyopathy; heart failure; COPD; diabetes; thyroid disorders; renal disorders; anemia Psychiatric disorders Anxiety, depression
Medications Ototoxic: aminoglycosides, diuretics, nonsteroidal antiinflammatory drugs, vestibular suppressants Others: antihypertensives, antianxiety drugs, anticholinergics, antidepressants, anticonvulsants, antipsychotics
Difficulty in hearing in social situations; unilateral or bilateral deafness
Otoscopy: cerumen; abnormal findings with whisper test, Rinne’s test, Weber’s test
Audioscopic examination; audiometry
Cerumen removal; ear wax drops; hearing aid; surgery (for otosclerosis); hearing rehabilitation; listening devices
Near fainting: worse when getting up, walking, exercising; may be asymptomatic; complaints consistent with predisposing diseases; medication history
Blood pressure and heart rate; signs of predisposing diseases
Investigations relevant to predisposing diseases
Same as orthostatic hypotension except the onset is within 1 h of eating
Postprandial blood pressure and heart rate measurement
None
Salt and water repletion; dosage adjustment or removal of the offending drugs; treatment of relevant diseases; ankle pumps; slow rising; elevate head of bed; graduated stockings; reconditioning exercises; drug therapy, fludrocortisone, midodrine, if needed Frequent small meals; avoid exertion after meals; have caffeine with meals; slow rising; avoid antihypertensive drugs with or near meal time
Symptoms of the underlying diseases
Signs of the underlying diseases
Relevant investigations
Usually continuous nonspecific dizziness; fatigue; poor appetite; sleep problems; somatic complaints; poor concentration
Positive results on anxiety or depression screening
Psychotherapy; antidepressant therapy after considering risks and benefits
Vestibulocochlear symptoms (as discussed above)
Presence of nystagmus, bedside vestibular function test can be abnormal, abnormal caloric test
Eliminate, substitute, or reduce specific offending medication if possible; reduce the drugs to lowest possible dose
H/o fatigue; confusion; dizziness often vague, can be continuous, dizziness can be postural
May have postural hypotension
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Hearing Cerumen; presbycusis; otosclerosis
Variable, depending on the underlying disease
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manifestation or a vague sensation. The frequency and duration of dizziness, as well as any associated symptoms such as hearing loss, ear fullness, tinnitus, diplopia, dysarthria, and syncopal episodes, are all important. Recurrent episodes of dizziness lasting less than 1 min are seen in BPPV, whereas recurrent episodes of dizziness associated with fluctuating hearing loss or tinnitus and ear fullness are suggestive of Meniere’s disease. The clinician should ask the patient whether the dizziness is episodic or continuous. For example, in BPPV, Meniere’s disease, or CNS disorders, the dizziness is episodic whereas psychogenic dizziness is usually continuous. The patient should also be asked about any precipitating or provoking factors, such as standing from a supine or sitting position, rolling over in bed, or changing the position of the head or neck (i.e., looking up or from side to side). One should inquire as to whether dizziness occurs after eating meals, which can be caused by postprandial hypotension. The physician should also ask about comorbid conditions, such as cardiac diseases, diabetes, renal disorders, anxiety, or depression, which can predispose or exacerbate dizziness. A careful review of all medications, including over-the-counter drugs, is also important. All patients with complaints of dizziness should be evaluated for depressive symptoms or anxiety disorders. The physical examination should include measurements of orthostatic changes in blood pressure. Blood pressure and heart rate measurements should be taken after at least 5 min of quiet lying and then at 1 to 2 min after standing. The patient’s ears should be examined for excessive wax or structural abnormalities in the external ears. Hearing should be tested by either a whisper test or an audioscope. Near and distant vision should also be tested. The examiner should look for spontaneous nystagmus. The nystagmus in peripheral vestibular lesions is usually horizontal or rotatory and is suppressed by visual fixation, whereas that in central lesions is vertical and is not suppressed by visual fixation. Frenzel glasses (highdiopter lenses in a frame with a light source) should be used, if available. These lenses eliminate visual fixation and magnify nystagmus. Another possible method of detecting vestibular dysfunction is to do a one-leg or tandem stand on thick foam with the eyes closed, which eliminates visual and proprioceptive input to maintain balance. However, the sensitivity and specificity of this method have not been determined. In the examination of cranial nerves, diplopia, dysarthria, dysphagia, or facial weakness are suggestive of vertebrobasilar involvement. One should look for cerebellar signs, such as gait ataxia, truncal ataxia, or dysmetria, which suggest etiologies such as a cerebellar stroke or cerbellopontine angle tumors. In the latter,
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patients may present with unilateral hearing loss, tinnitus, absence of corneal reflex, and facial parasthesias and ataxia as well as dizziness. Gait and balance examinations should be performed. A poorer performance with eyes closed rather than open suggests a vestibular or proprioceptive etiology. A steppage gait suggests a proprioceptive etiology, as does an improvement in gait when the patient places a fingertip on the examiner’s fingertip. Vibration sense testing is a more sensitive test of proprioception than is testing for joint position sense. Range of neck motion, preferably in a standing position, should be assessed. A decrease in the range of motion, with or without symptoms of dizziness, may be due to a cervical process or, secondarily, to vestibular dysfunction. (The sensation of dizziness on head turning leads to a voluntary restriction in head turning, which, in turn, may lead to a decreased range of neck motion.) Because decreased head turning can interfere with central compensation, recognizing it in patients with vestibular dysfunction is important because vestibular rehabilitation is helpful. A detailed history and physical examination should help the physician in identifying one or more causes responsible for dizziness. Apart from the history and physical examination, certain provocative tests can be done at bedside to evaluate the vestibular system.
Provocative Tests 1. To see if the vestibulo-ocular reflex (VOR), which helps to maintain visual stability during head movement, is intact, the following three tests can be done. The sensitivities, specificities and predictive values of these tests for vestibular lesions in older persons have not been established. a. In the head-thrust test, the patient is asked to fixate on the examiner’s nose, and the head is moved rapidly by the examiner about 10° to the left or right. In a normally functioning VOR, the eyes will be fixed on the target. In patients with a vestibular deficit, the eyes are carried away from the target along with the head, followed by a corrective saccade back to the target. For example, in a patient with a right-sided vestibular lesion, head thrusts to the right will produce a slipping away of the pupils from the target, followed by a corrective movement back to the target, whereas head thrusts to the left will produce a normal response of the eyes.60,61 b. In the postheadshake test, with fixation eliminated by Frenzel lenses, the head is rotated either passively by the examiner or actively by the subject at a frequency of about 2 Hz in the horizontal plane for about 10 s, and then the examiner looks for nystagmus when the head is stopped. In unilateral peripheral vestibular lesions, there
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is a horizontal nystagmus with the fast phase usually beating toward the stronger ear, whereas in central lesions the nystagmus may be vertical.60,62 2. Dynamic visual acuity testing is done by asking the patient to read a fixed eye chart while the examiner moves the head horizontally at a frequency of 1 to 2 Hz. A drop in acuity of two rows or more from the baseline is suggestive of an abnormal vestibulo-ocular reflex.63 This test is sometimes difficult to perform because patients may be able to read at times when the head is not in motion (i.e., at turnaround points or by resisting movements).60 These tests are more helpful in detecting unilateral than bilateral vestibular dysfunction. It is important to remember that compensatory mechanisms may mask a vestibular deficit when these maneuvers are used in patients with long-standing vestibular loss.60 If the findings of these tests are abnormal, then the patient can be referred for more sophisticated vestibular testing, such as electronystagmography and rotational testing. 3. The Stepping Test, originally described by Unterberger64 and later modified by Fukuda,65 is positive when there is a lesion in the vestibulospinal system. The patient is asked to stand at the center of a circle drawn on the floor. The circle is divided into sections by lines passing at 30° angles. The patient is blindfolded and is asked to outstretch both arms at 90° to the body. The patient is then asked to flex and raise high first one knee and then the other and to continue stepping forward at a normal walking speed for a total of 50 or 100 steps. The examiner notes body sway while the patient marches in place with the eyes closed. In a unilateral vestibular lesion or in acoustic neuroma, there will be a gradual rotation of the body (more than 30°) toward the affected side.60,65,66 4. The Dix–Hallpike Maneuver41 can definitively establish a diagnosis of BPPV.37 The patient is seated on an examination table with the head rotated 30° to 45° to one side. The patient is asked to fix his vision on the examiner’s forehead. The examiner holds the patient’s head firmly in the same position and moves the patient from a seated to a supine position with the head hanging below the edge of the table and the chin pointing slightly upward. The examiner should note for the direction, latency, and duration of the nystagmus and the latency and duration of vertigo, if present. The diagnostic criteria for BPPV are (1) vertigo associated with a rotatory nystagmus; (2) a latency (typically of 1–2 s) between the completion of the maneuver and the onset of vertigo and nystagmus; (3) a paroxysmal nature of the vertigo and nystagmus (lasting for 10–20 s); and (4) fatigability (decrease in the intensity of the vertigo and nystagmus with repeated testing).37
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Routine Laboratory Evaluation A small battery of laboratory tests should be performed on all patients with chronic dizziness because the prevalence of undetected abnormalities is high and because results often lead to effective treatment. Hematocrit, glucose, blood urea nitrogen, electrolytes, thyroid function tests, and vitamin B12 levels should be ordered in all patients complaining of dizziness. If a cardiovascular etiology is suspected, an ECG to evaluate for the presence of cardiac arrhythmia is indicated. Holter monitoring and tilt table testing are indicated only if there is a strong suspicion of transient/intermittent cardiac arrhythmia or unexplained syncope. Audiometry, which includes pure tone assessment, speech discrimination, impedance measurement, and evoked responses, is recommended for evaluating dizzy patients with hearing loss. Gradual hearing loss is characteristic of acoustic neuroma, while Meniere’s disease typically presents with fluctuating hearing loss. Also, in acoustic neuroma an audiogram reveals a sensorineural hearing loss, which is more for higher than for lower frequencies, whereas in Meniere’s disease sensorineural hearing loss is more for lower frequencies.
Specialized Testing Vestibular Function Tests Several tests for vestibular function that might be considered in patients with a history and physical examination finding suggestive of vestibular disease include electronystagmography, rotational testing, and computerized posturography. Electronystagmography is the most established and widely used test. Eye movements are recorded with electrodes that record changes in scalp potential produced by the corneal–retinal potential. The procedure consists of a battery of tests designed to record eye movements in response to visual and vestibular stimuli, including oculomotor evaluation, positional testing, and caloric testing.67 The oculomotor evaluation involves saccade testing, pursuit testing, optokinetic nystagmus, and spontaneous and gaze-evoked nystagmus. The positional testing is designed to detect nystagmus evoked when the head is held in different positions. The caloric testing assesses the symmetry of vestibular functions. This test can indicate the side of involvement in unilateral vestibular lesions. Each ear is stimulated first with warm (44°C) and then cool water (30°C), each instilled over 30 s. The temperature change stimulates or suppresses the respective horizontal semicircular canals, resulting in nystagmus.68 A decreased response will occur on the ipsilateral side in peripheral vestibular disorder. Patients
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with suspected bilateral vestibular loss should undergo rotational chair testing to confirm the finding.67 Aging minimally affects responses to the caloric test.69 The rotational chair test uses a series of well-controlled rotational stimuli to provoke nystagmus. The patient is seated on a chair in a dark, soundproof room. The patient is asked to fixate on an imaginary visual target while the chair is oscillated at different frequencies and the eye movements are recorded. This test reflects the function of the vestibulo-ocular system. Findings can reveal the degree of peripheral or central vestibular dysfunction; serial measurements can be used to detect improvement or worsening of the dysfunction. The effects of aging on the rotational chair test are not well documented because inconclusive results have been produced by too few studies that lack standardization.69 Computerized posturography provides information related to functional ability of the patient to maintain balance. It quantifies the functions of the vestibulospinal system. The patient stands on a platform that is embedded with four sensors to monitor sway. This test has two components, a sensory organization test (SOT) and a motor control test (MCT). The SOT measures the ability of the patient to maintain her balance when visual and somatosensory inputs are systematically disrupted, whereas in the MCT the patient experiences abrupt changes in the center of gravity produced by horizontal movements and rotations of the platform.67 Rather than providing localizing information, this test provides information regarding which types of stimuli (visual, vestibular, and proprioceptive) the patient can or cannot use to maintain balance.67 This test is useful in providing additional information when peripheral vestibular pathology is suggested by the vestibular function test, but the results are inconclusive.70 Effects of aging on posturography have been documented and consist of an inability to perform well with reduced visual or somatosensory information and a general reliance on a hip strategy to maintain balance.71
Neuroimaging Not all patients with dizziness need neuroimaging. Magnetic resonance imaging scans should be done if the history or physical examination is suggestive of a stroke or cerebellopontine angle tumor.
Treatment Treatment is ideally directed toward a specific cause. However, investigators have acknowledged the limitations of a diagnosis-oriented approach for the evaluation and management of chronic dizziness.18,72 Also, the presentation sometimes does not permit identification of a
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specific cause. Therefore, if the history, examination, and routine laboratory testing do not suggest a discrete cause, therapeutic trials are often the best way to determine significant contributors. Older persons often have multiple comorbid diseases and impairments that contribute to dizziness. The most effective treatment, therefore, may be to ameliorate one or more potential etiologic factors.73
Medical Therapy Medical therapy for individual diseases is discussed in Table 67.1. Patients should be treated for anxiety or depression. If there is impairment of vision or hearing, it should be corrected. Medication-associated dizziness responds to dosage adjustment or to medication withdrawal. One should try to reduce all drugs to the lowest possible dosages. Vestibular suppressants, including antihistamines (e.g., meclizine) and anticholinergic agents (scopolamine), are commonly used for symptomatic relief. These agents are effective for acute dizziness but play little role in managing chronic dizziness. Meclizine is a weak antihistaminic agent usually taken orally in doses of 12.5 to 25 mg three times a day, as needed. Vestibular suppressants should not be used long term because of their CNS side effects and because they suppress central and vestibular adaptation and thus may worsen or exacerbate dizziness.74 Benzodiazepines (e.g., diazepam) may be beneficial to patients with severe unilateral peripheral vestibular dysfunction. Scopolamine should not be used in older persons due to its anticholinergic side effects such as urinary retention and deficits in cognition.
Rehabilitation Vestibular rehabilitation therapy is an important and effective management strategy for patients with peripheral and central vestibular causes of dizziness. Studies have shown a reduction in symptoms and disability following rehabilitation therapy.75–78 Vestibular rehabilitation includes combinations of exercises involving head and eye movements (while sitting and standing) designed to provoke vertigo and unsteadiness. It also involves various dynamic balance exercises and exercises to improve gait stability during head movement, visual and vestibular interactions, and vestibular spinal responses. The movements are repeated until they can no longer be tolerated, and the number of repetitions are gradually increased over a period of 6 to 8 weeks.79 Initially, the exercises may worsen the dizziness, but over time (weeks to months) movement-related dizziness improves, likely because of central adaptation. Generally, a good functional recovery can be achieved by patients with peripheral vestibular disorders, but rarely does complete recovery occur in patients with central vestibular
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dysfunction, although they can experience considerable functional improvement.80 Vestibular rehabilitation can be administered in a classroom setting or one-to-one with a physical therapist. Also, patients can perform exercises independently at home after being instructed by a physical therapist. This therapy also has been shown to alleviate dizziness in patients who have anxiety, probably by educating them about their dizziness and by encouraging them to cope actively with their problem.81 The canalith repositioning procedure, introduced by Epley,82 is a currently recommended treatment for benign positional vertigo.37 The purpose of this bedside maneuver is to move free-floating debris by the effects of gravity from the posterior semicircular canal into the utriculus of the vestibular labyrinth, where it will no longer affect the dynamics of the semicircular canals.82 In this procedure, a Dix–Hallpike maneuver is performed with the patient’s head rotated 45° toward the affected ear and hanging below the edge of the table, and a vibrator is applied to the ipsilateral mastoid process. After the cessation of the provoked vertigo and nystagmus, the head, which is hanging below the edge of the table, is rotated 45° to the opposite side. This maneuver may induce a brief episode of vertigo. The examiner should hold the head in this position and wait for about 10 to 15 s or until the vertigo ceases. Then the head and body are further rotated until the head is in a facedown position. This maneuver may again induce a brief vertigo. The patient should be kept in the final facedown position for about 10 to 15 s or until the vertigo ceases. Then, with the head kept in the same position, the patient is brought to a seated position. Once the patient is upright, the head is turned forward with the chin tilted slightly downward. The patient should be instructed not to lie flat and to keep the head relatively upright for the next 24 to 48 h. Another option would be to instruct the patient to wear a cervical collar and neither to lie supine nor to tilt the head upward, downward, or to the right or left more than 30°.83 These strategies are to prevent the loose debris from gravitating back to the posterior semicircular canal. There are no data available to support these recommendations. Investigators have tried gentle manual vibration of the head instead of using a vibrator during the treatment and have found it effective; 60% of the patients reported improvement with this procedure without using a vibrator and 92% reported improvement with the use of the vibrator.83 In patients who cannot keep their head in a relatively upright position for 1 to 2 days, a different maneuver described by Brandt and Daroff84 can be used.85 The patient is asked to sit on a table sideways with eyes closed and to rotate the head horizontally about 45°. Then the patient should rapidly lie on their side in the opposite direction and should wait in the same position until the vertigo has resolved or for 30 s. The patient should then
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sit up rapidly and wait for another 30 s. The movement is then repeated in the opposite direction.85 This maneuver can be repeated every 3 h while awake and can be terminated if the patient is symptom free for 2 consecutive days.84 The patient can perform these exercises at home. It usually takes 1 to 2 weeks for the symptoms to be resolved. These exercises likely work either by habituation or by dislodging debris from the posterior semicircular canals.85 Physiotherapy in the form of cervical exercises and relaxation techniques has been found to be effective for patients with cervical dizziness.86 Progressive, competency-based balance exercises have proved effective in enhancing a sense of stability and may be useful for patients with dizziness related to sensory or motor deficits.
Surgery Surgical therapy is needed in a small group of dizzy patients. Surgical excision is the treatment of choice for cerebellopontine angle tumors. Surgery is reserved for disabling unilateral peripheral disease unresponsive to medical therapy. Surgical procedures can be ablative or nonablative. Ablative procedures include transmastoid labyrinthectomy and partial vestibular neurectomy. The primary indication for either procedure is uncontrolled Meniere’s disease or peripheral vestibulopathy.87 Nonablative procedures include endolymphatic sac decompression and posterior canal occlusion. Endolymphatic sac decompression is confined to cases of Meniere’s disease but its role is controversial.87,88 Surgery is indicated for only those disabled patients of BPPV who are refractory to the canalith repositioning procedure despite multiple attempts. The two procedures used to disable the posterior semicircular canal include singular neurectomy or occlusion of the posterior semicircular canal.87,89,90
Patient Education Patients should be given basic education concerning the functioning of the balance system and the pathophysiology of dizziness. This knowledge enables patients to understand the body movements responsible for these symptoms and also alleviates their anxiety about this problem.81 They should be instructed on modifying their activities; for example, if orthostatic hypotension is detected, patients should be instructed to rise slowly from sitting or supine positions. Movements such as looking up, reaching up, or bending down are to be avoided, in part by storing items at home strategically. However, patients should be cautioned not to habitually avoid other movements such as head turning because doing so may compromise central adaptation, thereby exacerbating dizziness. Patients should be instructed to avoid
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walking in the dark. They should be reminded to avoid over-the-counter drugs that may exacerbate dizziness.
References 1. Sloane PD. Dizziness in primary care. Results from the national ambulatory medical care survey. J Fam Pract. 1989: 29:33–38. 2. Hale WE, Perkins LL, May FE, Marks RG, Stewart RB. Symptom prevalence in the elderly. An evaluation of age, sex, disease, and medication use. J Am Geriatr Soc. 1986:34: 333–340. 3. Colledge NR, Wilson JA, Macintyre CCA, MacLennan WJ. The prevalence and characteristics of dizziness in an elderly community. Age Ageing. 1994:23:117–120. 4. Sloane P, Blazer D, George LK. Dizziness in a community elderly population. J Am Geriatr Soc. 1989:37:101–108. 5. Tilvis RS, Hakala S-M, Valvanne J, Erkinjuntii T. Postural hypotension and dizziness in a general aged population: a four-year follow-up of the Helsinki Aging Study. J Am Geriatr Soc. 1996:44:809–814. 6. Ensrud KE, Nevitt MC, Yunis C, Hulley SB, Grimm RH, Cummings SR. Postural hypotension and postural dizziness in elderly women. Arch Intern Med. 1992:152: 1058–1064. 7. Boult C, Murphy J, Sloane P, Mor V, Drone C. The relation of dizziness to functional decline. J Am Geriatr Soc. 1991:39: 858–861. 8. Sixt E, Landahl S. Postural disturbances in a 75 year old population: prevalence and functional consequences. Age Ageing. 1987:16:393–398. 9. Kroenke K, Lucas CA, Rosenberg ML, et al. Causes of persistent dizziness: a prospective study of 100 patients in ambulatory care. Ann Intern Med. 1992:117:898– 904. 10. Grimby A, Rosenhall U. Health related quality of life and dizziness in old age. Gerontology. 1995:41:286–298. 11. O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S. Incidence of and risk factors for falls and injurious falls among the community-dwelling elderly. Am J Epidemiol. 1993:137: 342–354. 12. Tinetti ME, Doucette J, Claus E, Marottoli R. Risk factors for serious injury during falls by older persons in the community. J Am Geriatr Soc. 1995:43:1214–1221. 13. Tinetti ME, Mendes de Leon CF, Doucette JT, Baker DI. Fear of falling and fall-related efficacy in relationship to functioning among community-living elders. J Gerontol. 1994:49:M140–M147. 14. Burker EJ, Wong H, Sloane PD, Mattingly D, Preisser J, Mitchell CM. Predictors of fear of falling in dizzy and non dizzy elderly. Psychol Aging. 1995:10:104–110. 15. Tinetti ME, Williams CS, Gill TM. Health, functional and psychological outcomes among older persons with chronic dizziness. J Am Geriatr Soc. 2000:48:417–42l. 16. Drachman DA, Hart CW. An approach to the dizzy patient. Neurology. 1972:22:323–334. 17. Sloane PD, Baloh RW. Persistent dizziness in geriatric patients. J Am Geriatr Soc. 1989:37:1031–1038.
A. Nanda and M.E. Tinetti 18. Tinetti ME, Williams CS, Gill TM. Dizziness among older adults: a possible geriatric syndrome. Ann Intern Med. 2000: 132:337–344. 19. Johnson LG. Degenerative changes and anomalies of the vestibular system in man. Laryngoscope. 1971:81: 1682–1694. 20. Rosenhall U. Degenerative patterns in the aging human vestibular neuro-epithelia. Acta Otolaryngol. 1973:76: 208–220. 21. Richter E. Quantitative study of human Scarp’s ganglion and vestibular sensory epithelium. Acta Otolaryngol. 1980:90:199–208. 22. Bergstrom B. Morphology of the vestibular nerve. The number of myleinated vestibular nerve fibers in man at various ages. Acta Otolaryngol. 1973:76:173–179. 23. Sekuler R, Hutman LP. Spatial vision and aging. 1: Contrast sensitivity. J Gerontol. 1980:35:692–699. 24. Hutman LP, Sekuler R. Spatial vision and aging. 2: Criterion effects. J Gerontol. 1980:35:700–706. 25. Skinner HB, Barrack RL, Cook SD. Age-related decline in proprioception. Clin Orthop Relat Res. 1984:184:208–211. 26. Kokmen E, Bossemeyer RW, Williams WJ. Quantitative evaluation of joint motion sensation in an aging population. J Gerontol. 1978:33:62–67. 27. Lawson J, Fitzgerald J, Birchall J, Aldren CP, Kenny RA. Diagnosis of geriatric patients with severe dizziness. J Am Geriatr Soc. 1999:47:12–17. 28. Davis LE. Dizziness in elderly men. J Am Geriatr Soc. 1994: 42:1184–1188. 29. Colledge NR, Barr-Hamilton RM, Lewis SJ, Sellar RJ, Wilson JA. Evaluation of investigations to diagnose the cause of dizziness in elderly people: a community-based controlled study. Br Med J. 1996:313:788–792. 30. Katsarkas A. Dizziness in aging. A retrospective study of 1194 cases. Otolaryngol Head Neck Surg. 1994:110:296–301. 31. Hoffman RM, Einstadter D, Kroenke K. Evaluating dizziness. Am J Med. 1999:107:468–478. 32. Fisher CM. Vertigo in cerebrovascular disease. Arch Otolaryngol. 1967:85:529–534. 33. Harker LA, Rassekh CH. Episodic vertigo in basilar artery migraine. Otolaryngol Head Neck Surg. 1987:96:239–250. 34. Reichert WH, Doolittle J, McDowell FH. Vestibular dysfunction in Parkinson disease. Neurology. 1982:32:1133– 1138. 35. Hitselberger WE. Tumors of the cerebellopontine angle in relation to vertigo. Arch Otolaryngol. 1967:85:539–541. 36. Baloh RW, Honrubia V, Jacobson K. Benign positional vertigo: clinical and oculographic features in 240 cases. Neurology. 1987:37:371–378. 37. Furman JM, Cass SP. Benign paroxysmal positional vertigo [review article]. N Engl J Med. 1999:341:1590–1596. 38. Welling DB, Parnes LS, O’Brien B, Bakaletz LO, Brackmann DE, Hinojosa R. Particulate matter in the posterior semicircular canal. Laryngoscope. 1997:107:90–94. 39. Parnes LS, McClure JA. Free-floating endolymph particles: a new operative finding during posterior semicircular canal occlusion. Laryngoscope. 1992:102:988–992. 40. Ross MD, Peacor D, Johnson LG, et al. Observations on normal and degenerating human otoconia. Ann Otol Rhinol Laryngol. 1976:85:310–326.
67. Chronic Dizziness and Vertigo 41. Dix MR, Hallpike CS. The pathology, symptomatology and diagnosis of certain common disorders of the vestibular system. Proc R Soc Med. 1952:45:341–354. 42. Green DJ, Blum DJ, Harner SG. Longitudinal follow-up of patients with Meniere’s disease. Otolaryngol Head Neck Surg. 1991:104:783–788. 43. LeLiever WC, Barber HO. Recurrent vestibulopathy. Laryngoscope. 1981:91:1–6. 44. Wallace IR, Barber HO. Recurrent vestibulopathy. J Otolaryngol. 1983:12:61–63. 45. Rutka JA, Barber HO. Recurrent vestibulopathy: third review. J Otolaryngol. 1986:15:105–107. 46. Selesnick SH, Jackler RK, Pitts LW. The changing clinical presentation of acoustic tumors in the MRI era. Laryngoscope. 1993:103:431–436. 47. Ooi WL, Barrett S, Hossain M, Kelly-Gagnon M, Lipsitz LA. Patterns of orthostatic blood pressure change and their clinical correlates in a frail, elderly population. JAMA. 1997: 277:1299–1304. 48. Mader SL. Aging and postural hypotension. An update. J Am Geriatr Soc. 1989:37:129–137. 49. Sloane PD. Dizziness. In: Cobbs EL, Duthie EH, Murphy JB, eds. Geriatric Review Syllabus: A Core Curriculum in Geriatric Medicine, 4th Ed. Iowa: Kendall/Hunt, for the American Geriatric Society; 1990:149–151. 50. Jansen RWMM, Lipsitz LA. Postprandial hypotension: epidemiology, pathophysiology, and clinical management. Ann Intern Med. 1995:122:286–295. 51. Lipsitz LA, Fullerton KJ. Postprandial blood pressure reduction in healthy elderly. J Am Geriatr Soc. 1986:34: 267–270. 52. Maurer MS, Karmally W, Rivdeneira H, Parides MK, Bloomfield DM. Upright posture and postprandial hypotension in elderly persons. Ann Intern Med. 2000:133: 533–536. 53. Mcintosh S, Costa DD, Kenny RA. Outcome of an integrated approach to the investigations of dizziness, falls and syncope in elderly patients referred to a syncope clinic. Age Ageing. 1993:22:53–58. 54. Kao A, Nanda A, Williams CS, Tinetti ME. Validation of dizziness as a possible geriatric syndrome. J Am Geriatr Soc. 2001:49:72–75. 55. Sloane PD, Hartman M, Mitchell CM. Psychological factors associated with chronic dizziness in patients aged 60 and older. J Am Geriatr Soc. 1994:42:847–852. 56. McClure JA. Vertigo and imbalance in the elderly. J Otolaryngol. 1986:15:248–252. 57. Sloane PD. Evaluation and management of dizziness in the older patient. Clin Geriatric Med. 1996;12:(4):785–801. 58. Kerstin W, Carsten W. Drug-related dizziness. Acta Otolaryngol Suppl. 1998:455:11–13. 59. Rybak LP. Ototoxicity. Otolaryngol Clin North Am. 1993:26:705–845. 60. Walker MF. Zee DS. Bedside vestibular examination. Otolaryngol Clin North Am. 2000;33(3):495–506. 61. Halmagyi GM, Curthoys IS. A clinical sign of canal paresis. Arch Neurol. 1988:45:737–739. 62. Takahashi S, Fetter M, Koenig E, Dichgans J. The clinical significance of head-shaking nystagmus in the dizzy patient. Acta Otolaryngol (Stockh). 1990:109:8–14.
1007 63. Longridge NS, Mallinson AI. The dynamic illegible E-test. A technique for assessing the vestibulo-ocular reflex. Acta Otolaryngol (Stockh). 1987:103:273–279. 64. Unterberger S. Neue objective registrierbare vestibularisdrehrealktion, erhalten durch treten auf der stelle. Der “Tretversuch.” Arch Ohren Nasen Kehlopfheilkd. 1938:145: 478–492. 65. Fukuda T. The stepping test. Acta Otolaryngol (Stockh). 1958:50:95–108. 66. Moffat DA, Harries MLL, Baguley DM, Hardy DG. Unterberger’s stepping test in acoustic neuroma. J Laryngol Otol. 1989:103:839–841. 67. Ruckenstein MJ, Shepard NT. Balance function testing. A rational approach. Otolaryngol Clin North Am. 2000:33: 507–517. 68. Hart CW. Caloric tests. Otolaryngol Head Neck Surg. 1984: 92:662–670. 69. Sloane PD, Baloh RW, Honrubia V. The vestibular system in the elderly: clinical implications. Am J Otolaryngol. 1989: 10:422–429. 70. Rubin W. How do we use state of the art vestibular testing to diagnose and treat the dizzy patient? An overview of vestibular testing and balance system integration. Neurol Clin. 1990;8(2):225–234. 71. Manchester D, Woollacott M, Zederbauer-Hylton N, Marin O. Visual, vestibular and somatosensory contributions to balance control in the older adult. J Gerontol. 1989:44: M118–M127. 72. Sloane PD, Dallara J. Clinical research and geriatric research: the blind men and the elephant [editorial]. J Am Geriatr Soc. 1999:47:113–114. 73. Tinetti ME. Chronic dizziness and postural instability. In: Beers MH, Berkow R, eds. The Merck Manual of Geriatrics, 3rd Ed. Whitehouse Station: Merck Research Laboratories; 2000:181–194. 74. Zee DS. Perspective on the pharmacotherapy of vertigo. Arch Otolaryngol. 1985:11:609–612. 75. Shepard NT, Smith-Wheelock M, Telian SA, Raj A. Vestibular and balance rehabilitation therapy. Ann Otol Rhinol Laryngol. 1993:102:198–205. 76. Cowand JL, Wrisley DM, Walker M, Strasnick B, Jacobson JT. Efficacy of vestibular rehabilitation. Otolaryngol Head Neck Surg. 1998:118:49–54. 77. Norre ME, Beckers A. Benign paroxysmal positional vertigo in the elderly. Treatment by habituation exercises. J Am Geriatr Soc. 1988:36:425–429. 78. Yardley L, Beech S, Zander L, et al. A randomized controlled trial of exercise therapy for dizziness and vertigo in primary care. Br J Gen Practice. 1998:48: 1136–1140. 79. Isaacson JE, Rubin AM. Otolaryngologic management of dizziness in the older patient. Clinics in Geriatric Medicine. 1999:15:179–191. 80. Whitney SL, Rossi MM. Efficacy of vestibular rehabilitation. Otolaryngol Clin North Am. 2000:33:659–672. 81. Yardley L, Luxon L. Treating dizziness with vestibular rehabilitation (editorial). BMJ. 1994:308:1252–1253. 82. Epley JM. The canalith repositioning procedure: for treatment of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg. 1992:107:399–404.
1008 83. Li JC. Mastoid oscillation: A critical factor for success in the canalith repositioning procedure. Otolaryngol Head Neck Surg. 1995:112:670–675. 84. Brandt T, Daroff RB. Physical therapy for benign paroxysmal positional vertigo. Arch Otolaryngol. 1980:106:484–485. 85. Tusa RJ. Episodic vertigo. In: Conn HF, et al, eds. Conn’s Current Therapy, 2000 Ed. Philadelphia: Saunders; 2000: 884–892. 86. Karlberg M, Magnusson M, Malmstrom EM, Melander A, Mortiz U. Postural and symptomatic improvement after physiotherapy in patients with dizziness of suspected cervical origin. Arch Phys Med Rehabil. 1996:77:874–882.
A. Nanda and M.E. Tinetti 87. Goebel JA. Management options for acute versus chronic vertigo. Otolaryngol Clin North Am. 2000:33:483–493. 88. Ruckenstein MJ, Rutka JA, Hawke M. The treatment of Meniere’s disease: Torok revisited. Laryngoscope. 1991:101: 211–218. 89. Parnes LS, McClure JA. Posterior semicircular canal occlusion for intractable benign paroxysmal positional vertigo. Ann Otol Rhinol Laryngol. 1990:99:330–334. 90. Gacek RR. Technique and results of singular neurectomy for the management of benign paroxysmal positional vertigo. Acta Otolaryngol (Stockh). 1995:115:154–157.
68 Nutrition David A. Lipschitz
Human aging may be defined as a complex interaction between an individual and the environment over time. In relation to external variables that affect aging, perhaps none is more important than nutrition. Evidence obtained from animal studies has shown that life expectancy can be significantly extended by restricting food intake. Nutritional factors have been shown to contribute substantively to many diseases that occur in late life. With advancing age, the risk of developing serious nutritional deficiencies also increases because of agerelated reductions in total food intakes combined with the presence of debilitating disease. The presence of malnutrition increases functional dependency, morbidity, mortality, and use of health care resources. This chapter discusses the relevance of these findings and describes rational approaches to the diagnosis and management of nutritional problems in the elderly.
The Role of Caloric Restriction in Aging Many animal studies have shown that nutritional deprivation delays maturation and significantly prolongs life expectancy.1 These investigations have shown that caloric restriction causes delays in virtually every biomarker of aging. Classic studies have shown delays in the appearance of the well-described age-related declines in cell-mediated and humoral immunity. This effect has been suggested as the mechanism by which dietary restriction results in the later appearance of neoplasms. Food restriction also leads to a marked reduction in the generation of free radicals postulated to result in many declines in cellular function that occur with age. The mechanism by which food restriction results in prolongation of life span is still not clear. It appears that total calorie intake is a more important variable than are either total protein or fat intakes. Caloric restriction results in the presence of leaner and more active animals who utilize energy very efficiently. Overall meta-
bolic requirements are markedly reduced. This lifelong diminution in metabolic activity has recently been suggested as an important factor in prolonging life. The importance of these observations in relation to humans remains unclear. Affluent societies who frequently consume high-caloric, high-fat diets usually demonstrate the longest life expectancy. It must be emphasized, however, that the shorter life span noted in the less affluent can be ascribed to pathologic malnutrition, diminished sanitation, and the increased prevalence of communicable diseases. In industrialized societies, high-fat, high-calorie diets are associated with high prevalence rates of age-related diseases, such as atherosclerosis, hypertension, and colon and breast cancer. For these reasons,recent dietary recommendations have focused on the need for a prudent diet that not only restricts total and saturated dietary fats but also avoids excessive calorie intake. These recommendations may be important in the minimization of the role of nutrition in the common cancers that occur in the Western world.
Energy Requirements Aging results in a significant decrease in energy needs.2 The major mechanism is a decrease in resting energy expenditure as a consequence of declines in muscle mass. Reduced thyroid function does not appear to contribute to the reduced energy needs of the elderly. Diminished energy needs also result from age-related declines in physical activity, which has been demonstrated longitudinally in men and confirmed in women. Decreased activity is the result primarily of coexisting diseases, such as bone and joint disorders, loss of postural stability, and chronic diseases that may limit activity, such as angina pectoris and intermittent claudication. However, reduced strength as a consequence of declines in muscle mass does contribute to reductions in mobility. Total caloric (food) intake is determined primarily by energy needs. Thus, a 30% reduction in energy need will 1009
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be accompanied by a 30% reduction of food intake. This reduced caloric intake has been confirmed in both crosssectional and longitudinal studies. As compared with younger subjects, individuals over the age of 70 consume a third fewer calories. The importance of this effect relates to the fact that the average intake of all nutrients is reduced in parallel. Yet the requirements for virtually every other nutrient, with the exception of carbohydrates, do not decline significantly with age (see following). As a consequence, epidemiologic studies of dietary intakes of healthy elderly individuals reveal deficient intakes. In contrast, biochemical assessments of nutritional status indicate that significant deficiencies of both macro- and micronutrients (vitamins and minerals) are quite rare in ambulatory healthy elderly. This is explained by the fact that inadequate dietary intake of a nutrient is determined by the comparison of the actual intake with the recommended dietary allowance (RDA) for that nutrient. The RDA is generally much higher than an intake that would result in a nutritional deficiency. Nevertheless, decreased intake results in reduced reserve capacity. In the presence of disease with increased nutritional requirements or because of declining intake caused by anorexia, severe nutritional deficiencies are very common in hospitalized or institutionalized elderly individuals with acute or chronic diseases.
Protein Requirements On first principles it seems likely that, because of declines in muscle mass, aging should result in decreased protein needs. At the current time, the RDA for protein for younger subjects is 0.8 g/kg body weight. Studies in the elderly have shown that, even in healthy elderly subjects, the requirements for protein are modestly increased.3 At the current time a protein intake of 1 g/kg body weight is recommended in healthy elderly. Most importantly, the presence of acute or chronic diseases further increases protein requirements. In this circumstance, protein intake in the older patient is frequently grossly inadequate. This is particularly important in wound healing and in decubitus ulcer, where inadequate protein intake adversely affects outcome. Although aging results in significant declines in muscle mass, protein synthetic and degradation rates are only minimally compromised. Visceral protein stores and turnover are generally unchanged with aging so that no significant reductions are noted in serum albumin, retinol binding protein, or prealbumin, which reflect visceral protein stores.
Fat Requirements Aging does not alter any of the specific requirements for any of the essential lipids. Advancing age is generally
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associated with an increase in the proportion of body weight as fat, which is the result of decreases in muscle mass accompanied by an increase in fat mass. Body fat stores increase until the seventh decade, after which reductions in total weight and fat stores are frequently noted. Although obesity is not as common a problem in the elderly as it is in younger individuals, approximately 20% of subjects over the age of 65 are significantly overweight. Studies have shown that even in the very old obesity is associated with increased mortality. Furthermore, there is evidence that the risks of atherosclerotic heart disease and stroke in the elderly can be reduced by consuming a diet low in saturated fats and cholesterol. These facts make dietary recommendations in the elderly difficult. For older individuals, a palatable acceptable diet is very important. Recommending drastic changes in dietary intake should therefore be undertaken with caution and with careful clinical judgment. For individuals in their late sixties and early seventies who are very healthy and ambulatory but significantly overweight, hypercholesterolemic, and perhaps hypertensive, an effort to reduce calories, fat, and sodium intake is warranted. In many circumstances, drastic reductions in diet may not be beneficial; this particularly applies to institutionalized elderly where medically prescribed diets are frequently not palatable, are not adequately consumed, and may result in weight loss. It must be noted that the value of serum or high-density lipoprotein (HDL) cholesterol in the prediction of coronary artery disease is less for the elderly than it is for younger subjects.3 For this reason, the efficacy of aggressive dietary or pharmacologic attempts to lower cholesterol in subjects over the age of 70 is far from clear.
Water Requirements In the elderly, fluid balance is extremely important because of the propensity of the elderly to develop dehydration and the ease at which overhydration can occur in elderly individuals with compromised renal function or other disorders associated with fluid retention. As a general rule, water intake should be 1 mL/kcal or 30 mL/kg body weight. Dehydration is extremely prevalent in hospitalized elderly and is the single most common cause of an acute confusional state in the elderly; this is primarily related to the well-described age-related decline in thirst drive. Studies have demonstrated a decreased ability of the elderly to respond to fluid deprivation, which becomes a particularly serious problem in frail elderly who develop a minor pathologic insult, such as a respiratory or urinary tract infection, resulting in fever, increased metabolism, and fluid loss. If fluid intake does not readily replace fluid lost, dehydration rapidly develops. This leads to confusion, worsening dehydration, and the rapid development of a serious disease that may
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be life threatening, warrant hospitalization, and necessitate a prolonged period of recuperation. For these, aggressive attempts at assuring adequate hydration are essential in the elderly. Furthermore, this must commence soon after the development of a minor or major pathologic stress. Patients and their families must be educated to emphasize the importance of maintaining adequate fluid intake at all times and to carefully monitor intake if a minor illness develops or if fluid requirements are increased, as occurs during heat waves. In the hospitalized older patient, the possibility that confusion or delirium is caused by dehydration should be high on the differential diagnosis list. Physicians must assure that their patients have adequate access to water. Furthermore, total fluid intake should be carefully monitored by frequent weight and intake and output measurements.
Mineral Requirements Numerous studies indicate that, for a wide variety of minerals and vitamins, intake is significantly lower than the RDA for a large proportion of ambulatory elderly.4
Calcium Of most importance is the evidence that lifelong inadequate intakes of calcium contribute to the high prevalence of osteoporosis in the elderly. It is generally recommended that calcium intake in the elderly be between 1.0 and 1.5 g/day.
Zinc The prevalence of zinc deficiency is important because of the role that this mineral plays in food intake and in wound healing. In elderly subjects with chronic debilitating diseases, modest zinc deficiency may contribute to anorexia. Although not clinically proven, there is also evidence that zinc supplementation aids in wound healing in general and in the healing of pressure ulcers in particular.5 Zinc supplementation has also been shown to improve immune function and impede the rate of development of macular degeneration in the elderly.
Iron In younger patients, iron deficiency is the most common cause of anemia and the most common global deficiency leading to widespread morbidity and decreased work performance. Aging is associated with a gradual increase in iron stores in both men and women. As a consequence, iron deficiency is rare in the elderly and invariably is caused by pathologic blood loss. It is important to emphasize that the anemia of chronic disease, which is associated with iron-deficient erythropoiesis, including a low serum iron concentration and a reduced transferrin sat-
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uration, is frequently misdiagnosed as iron-deficiency anemia in the elderly. This error results in the inappropriate administration of oral iron therapy and unnecessary invasive investigative procedures to identify the source of iron loss. The anemia of chronic disease is associated with an impaired ability of the reticuloendothelial system to recirculate iron obtained from the breakdown of phagocytosed senescent red cells. Thus, in the anemia of chronic disease, iron stores are normal or increased, whereas in iron deficiency iron stores are absent. Recent studies indicate a correlation between increased iron stores and risks of neoplasia and coronary artery disease. Because aging is associated with increasing iron stores, supplementation with oral iron may not be desirable in older persons. Consuming a multivitamin with minerals containing the RDA for iron, combined with adequate intake from the diet, may result in inappropriately high intakes. If current evidence confirms adverse effects of iron stores, the use of iron-containing supplements in the elderly may well be unwise.
Selenium There is suggestive evidence that selenium deficiency may contribute to age-related declines in cellular function. The mineral may be involved in minimizing free radical accumulation, as it is essential for the normal function of glutathione peroxidase. Significant selenium deficiency has been reported frequently in the elderly, although syndromes associated with selenium deficiency are very rare (cardiomyopathy, nail abnormalities, and myopathies). There is some evidence that selenium deficiency may contribute to a greater neoplastic risk and declines in immune function.
Copper Aging generally is associated with increases in serum copper concentrations, although the significance of this increase is unknown. Copper deficiency is very rare and has been reported only in total parenteral nutrition.
Chromium Recent evidence has suggested an important role for chromium in carbohydrate metabolism. Studies have shown age-related declines in tissue chromium levels. It is possible that chromium deficiency may contribute to glucose intolerance in the elderly, although the therapeutic efficacy of chromium replacement is controversial.
Vitamin Requirements Studies have shown that dietary intake of many vitamins is inadequate in the elderly, including an intake of 50% or less for folic acid, thiamine, vitamin D, and vitamin E. In other studies intakes were shown to be less than 66%
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of the RDA for most vitamins. It must be emphasized again that deficiencies identified on the basis of inadequate intake are invariably significantly higher than the prevalence of biochemical deficiency of most vitamins.
Water-Soluble Vitamins Vitamin C Studies have indicated inadequate dietary intake of vitamin C in the elderly. Others have shown a high prevalence of vitamin C supplementation in the elderly. There is no evidence, however, that vitamin C deficiency is of any clinical relevance in healthy elderly or that replacement with megadoses of vitamin C is of any clinical value. In elderly subjects with chronic debilitating diseases, there is some evidence that vitamin C supplementation improves the rate of wound and pressure ulcer healing. There is little evidence that megadoses of vitamin C have any relevant side effects, although falsely negative occult bloods have been reported, as have inaccuracies in serum and urine glucose determinations. Thiamine Clinically relevant deficiencies of the B vitamins are very rare in the elderly. Thiamine deficiency, however, is common in elderly alcoholics and can be an important contributing factor in the development of disordered cognition, neuropathies, and perhaps cardiomyopathies. Relevant deficiencies of this vitamin are relatively common in institutionalized elderly. Folate Acid Like thiamine, folate deficiency in the elderly is predominantly found in alcoholics. It is also common in elderly subjects who are taking drugs that interfere with folate metabolism (trimethoprim, methotrexate, and Dilantin) or in disorders associated with increased folate needs (hemolytic anemia and ineffective erythropoiesis). Folate deficiency may result in cognitive loss or significant depression and should always be evaluated in the workup of elderly subjects with a memory disorder.
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workup of any elderly patient with disordered cognition or depression, and replacement therapy should be given to any patients in whom low serum levels are found. The lower limit of normal varies in different laboratories, but a value below 150 pg/mL is highly suspect and should always result in the commencement of replacement therapy.
Fat-Soluble Vitamins Recent evidence has suggested that vitamin A is one of the only nutrients in which requirements decrease with advancing age. Studies have shown that aging is associated with an increase in absorption of vitamin A from the gastrointestinal tract, accompanied by a reduction of hepatic uptake. These effects make the elderly susceptible to toxicity if excessive amounts of the vitamin are consumed as a supplement. Side effects of daily intakes in excess of 50,000 IU include headaches, lassitude, reduction in white cell counts, impaired hepatic function, and bone pain. The vitamin plays an important role in visual acuity. However, there is no evidence that vitamin A supplements improve age-related declines in eyesight. Vitamin A and its precursor beta-carotene have been suggested as exerting a protective effect against an array of neoplasms. Recent large-scale controlled trials have, however, failed to definitively prove a beneficial effect of beta-carotene in the development of skin cancers. Vitamin D Recent studies suggest that vitamin D deficiency may be a serious concern in the elderly. In addition to the vitamin’s known role in bone metabolism, it also affects macrophage function in general and pulmonary macrophages in particular. Vitamin D deficiency increases susceptibility to the development of pulmonary tuberculosis by compromising macrophage function. This has been suggested as contributing to the high prevalence of tuberculosis in nursing home patients in whom deficiencies are common and aggravated by diminished exposure to sunlight. In any patient with severe osteoporosis, fracture, or bone pain, vitamin D-induced osteomalacia must be excluded.
Vitamin B12 Low serum vitamin B12 concentrations have been shown to occur in as many as 10% of otherwise healthy elderly subjects. Many comprehensive workups indicate early pernicious anemia, the commonest cause of vitamin B12 deficiency, whereas in others no obvious cause can be identified. B12 deficiency classically causes a severe megaloblastic anemia. Not uncommonly, the nonhematologic manifestations of B12 deficiency can occur in the absence of anemia; these include gait disorders, sensory and motor neurologic deficits, and highly significant memory loss. This vitamin should be measured routinely in the
Vitamin E Vitamin E (alpha-tocopherol) is abundant in the diet and deficiencies of the vitamin virtually never occur. It is involved in the function of the enzyme glutathione peroxidase, which is involved in free radical generation. The vitamin also affects the biophysical properties of the cell membrane, reducing the age-related increase in membrane microviscosity. It also influences immune function, and recent evidence indicates that administration of the vitamin enhances immune function in the elderly and may minimize infectious risk. Despite these effects, which
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may be of benefit in improving age-related declines in cellular function, no good evidence exists indicating a beneficial effect of vitamin E supplementation in subjects of any age. Vitamin K Vitamin K is essential for the production of a number of factors involved in both the intrinsic and extrinsic clotting cascade. There is evidence that vitamin K administration is beneficial in elderly people who have an unexplained prolongation of their prothrombin time. Although dietary intake is adequate, deficiencies can result from the administration of drugs that interfere with the vitamin’s absorption or interfere with bacterial flora.
A Practical Approach to Nutritional Assessment General Considerations on History and Physical Examination A high index of suspicion of nutritional problems is very important in patients who have a primary diagnosis associated with malnutrition, such as chronic alcoholism, disorders of cognition, chronic myocardial, renal, or pulmonary insufficiency, malabsorption syndromes, and multiple medication use.6 In addition, particular attention should focus in the history on evidence of anorexia, early satiety, nausea, change in bowel habits, fatigue, apathy, or memory loss. Physical findings that may also provide clues to the presence of nutritional deficits include poor dentition, cheilosis, angular stomatitis, and glossitis, which is common in a number of vitamin deficiencies. Pressure ulcers or poorly healing wounds, edema, dehydration, and poor dental status are common physical findings in severely malnourished patients. Clinically, a number of important questions must be addressed in the nutritional assessment. Increased risk of malnutrition can usually be identified from the history and physical examination. Commonly recognized risk factors are listed in Table 68.1. Generally, factors leading to malnutrition can be categorized into disorders resulting in anorexia, inadequate or inappropriate nutrient intake, and social or economic isolation.
Has the Patient Lost Weight? Weight loss is perhaps the most important finding indicating the presence of malnutrition. Recent studies have clearly indicated that this finding in patients with serious disease is a very poor prognostic sign and is associated with increased morbidity and mortality.7 To be significant, weight loss must be involuntary. It has often been said
1013 Table 68.1. Causes of weight loss in the elderly. Anorexia Depression Medications Digoxin Serotonin reuptake inhibitors Diseases Cancer Chronic organ failure (cardiac, renal, pulmonary) Chronic infections Tuberculosis Polymyalgia rheumatica and other collagen vascular diseases Single nutrient deficiencies that affect taste and appetite Vitamin A Zinc Malabsorption Intestinal ischemia Celiac disease Swallowing disorders Neurologic Esophageal candidiasis Web stricture Dental disease Metabolic Thyroid disease Diabetes Liver disease Social Isolation Poverty Caregiver fatigue Neglect Abuse Physical Alcohol Food preference not met Inappropriate food choices Physical Inability to purchase or cook food Decreased activity No cause identified
that to be significant, weight loss must have exceeded 10% or more of body weight in 6 months, 7.5% or more in 3 months, or 5% or more in 1 month. In older persons, any weight loss that clearly cannot be ascribed to alterations in fluid balance (common in older persons receiving diuretic therapy) should be taken seriously. It must be emphasized that significant malnutrition can be present in individuals who are not underweight. Any significant weight loss that is involuntary indicates that nutritional intake is inadequate and that the patient’s needs are not being met.
Is the Patient Underweight? To determine if the patient is underweight or has lost weight requires an evaluation of body composition.8 In
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this regard, virtually every anthropometric measure of body composition employs height as the reference point. In both males and females, height decreases by approximately 1 cm per decade after the age of 20. This is caused by vertebral bony loss, increased laxity of vertebral supportive ligaments, reductions in disk spaces, and alterations in posture. Historical estimations of height are also frequently inaccurate in the elderly, and its measurement is difficult in bedridden patients or in those with significant postural abnormalities. For this reason, it has been suggested that alternatives to height should be used in the development of standards for body composition for the elderly. Options suggested include arm length and kneeheight measurements. In general, a gradual increase in weight occurs with advancing age, peaking in the early forties in males and a decade later in females. After age 70, reductions in weight are not uncommon. Lean body mass decreases by approximately 6.0% per decade after the age of 25. By the age of 70, lean body mass has decreased an average of 5 kg for females and 12 kg for males. Thus, in the elderly, fat constitutes a far greater percentage of total weight than it does in subjects of younger ages. Fat distribution also alters with aging. Truncal and intrabdominal fat content increase while limb fat diminishes. Skinfold measurements are often employed to estimate fat and muscle stores. Although the triceps skinfold thickness is the most frequently obtained, multiple skin folds are much more reliable than single measurements. In the elderly, subscapular and suprailiac skinfolds are the best predictors of fat stores in males, while the triceps skinfold and thigh measurements are of greater value in females. Total body water is also decreased in parallel to declines in lean body mass. Evaluating ideal body weight for height can be employed to determine if a patient is underweight. Tables are available for older persons that provide a guide to their ideal body weight. These are based upon an assessment of height, weight, and body frame. On the basis of these tables, being significantly underweight is defined as being 15% below the ideal weight for that individual patient. Unfortunately, current tables are based upon relatively small samples and often are not representative of the individual being evaluated. A more accurate assessment is the determination of the body mass index (BMI), which is the ratio of weight to height squared. This obviates the need to create gender tables, although the confounding effect of age remains to be determined and the problems with assessing height persist. A standard nomogram is available from which BMI can be calculated from height and weight. It is generally recommended that persons over the age of 65 have a BMI between 24 and 29. As a general rule, a BMI below 22 is a cause for concern and indicates that the patient is significantly underweight, while a value above 29 indicates obesity.
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Does the Patient Have Protein-Energy Malnutrition? This condition is best described as a metabolic response to stress that is associated with increased requirement for energy and protein. The pathophysiologic events leading to this disorder are illustrated in Figure 68.1. The metabolic response to a stress such as injury or infection is characterized by hormonal changes and the release of cytokines that lead to the development of anorexia, despite the presence of increased nutrient needs. In older persons, the negative sequelae of this response can develop quickly. Protein-energy malnutrition (PEM) is associated with marked depletion of visceral protein stores characterized by the presence of hypoalbuminemia. Inadequate supply of protein leads to liver dysfunction, which contributes to the low serum albumin. Decreased clearance of drugs and toxins also occurs, increasing the risk of toxicities and adverse drug reactions. Inadequate supply of protein primarily affects organ systems with the highest turnover of cells, which are the skin, immunohematopoietic system, and gastrointestinal tract. Thus, PEM is characterized by a dry skin and “flaky paint” dermatitis. Impaired immune responses lead to compromised host defenses, increasing the risk of life-threatening infections. Malabsorption also develops as a result of impaired jejunal and ileal mucosal cell proliferation, creating a vicious cycle of malnutrition causing malabsorption and worsening malnutrition. As a result of disease and deficiencies of taste-related nutrients, anorexia is usually present. The disorder is also referred to as hypoalbuminemia malnutrition and is usually diagnosed by the presence of a serum albumin level of less than 3.0 g/dL. In the elderly, relatively minor stress of short duration can result in PEM. Thus, PEM is common in elderly patients who develop minor pulmonary and urinary infections and is often found soon after an elective surgical procedure. The problem of PEM in the elderly is compounded by the ease at which these patients develop severe dehydration as a consequence of an age-related decline in thirst drive.9 This leads to the development of confusion, hypotension, and a vicious cycle in which the patient’s overall condition can deteriorate very rapidly. Furthermore, in contrast to younger people, the positive benefits of this disorder in the elderly are limited to a very short period. If nutritional needs are not met within 2 to 3 days of the onset of the acute illness, the declines in immune, hepatic, and gastrointestinal function appear to contribute significantly to increased morbidity, mortality, and prolonged hospital stays. In the nursing home, PEM should be suspected in any patient who develops an acute medical problem. It is also frequently seen in patients with chronic infections and in those with decubitus ulcers. Any patient presenting with
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Figure 68.1. Pathophysiology of protein-energy malnutrition. ADH, antidiuretic hormone; ESR, erythrocyte sedimentation rate.
confusion, lassitude, anorexia, decreased activity, or greater functional dependence may have developed an acute medical problem such as an infection, which, if not treated, will result in the development of significant PEM. Does the Patient Have Isolated Nutrient Deficiencies? These are quite rare in older persons but should be considered in special circumstances. Zinc deficiency has been reported to be increased in patients with pressure ulcers and may contribute to decreased rates of healing. For this reason, zinc supplementation is frequently prescribed in patients with pressure ulcers. Vitamin D deficiency is relatively common in homebound and institutionalized older persons and may contribute to declines in host defense mechanisms in the elderly. Frank osteomalacia has also been reported. Folate deficiency is limited to patients with malabsorption and to older alcoholics (not uncommon). Vitamin B12 deficiency has been reported to be frequent in older persons. Its level should be measured in any patient being evaluated for memory loss. Low levels warrant replacement. Whether this affects memory is not clear. Significance of Malnutrition in Older Persons There is compelling evidence indicating that malnutrition is highly significant in older persons. Being underweight or losing weight is associated with increased morbidity and mortality in older persons. There is even suggestive
evidence that voluntary weight loss may be associated with an increased adverse outcome in older persons. In the acute care hospital setting, the presence of proteinenergy malnutrition has been shown to be an independent predictor of increased morbidity and mortality in older persons. This information is important, as studies have shown that the nutritional status of hospitalized patients is often ignored and that nutritional therapy is inadequate with a high complication rate.
Management of Nutritional Problems in Older Persons Weight Loss and Being Underweight As indicated, a major predictor of increased morbidity and mortality makes being underweight or losing a significant amount of weight highly relevant clinically. While no study has shown that correcting the decline in weight improves survival in this patient population, it is obvious that every attempt must be made to identify and treat the cause. The initial approach to management should be a careful attempt to identify the cause of the weight loss and, if found, to aggressively attempt correction. Table 68.1 lists the common causes of weight loss in older persons, highlighting potentially correctable causes. Figure 68.2 lists an approach to treatment of weight loss
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Figure 68.2. A rational approach to the treatment of weight loss in the elderly.
in the elderly. Identifying a potentially treatable cause such as drug use (digoxin, fluoxytene), thyrotoxicosis, and depression can usually result in weight gain if the underlying condition is corrected with appropriate medical interventions. Other conditions that may well contribute to weight loss that are potentially improvable include social or economic isolation, difficulties with cooking or feeding as a consequence of physical disability, dental or swallowing problems, and not providing palatable or preferred foods. Failure to identify a cause for weight loss is generally accompanied by a poor prognosis despite aggressive medical and nutritional interventions. Older persons who have experienced weight loss are consuming inadequate calories to meet their needs. Thus nutritionally the aim must be to increase caloric intake. This can be achieved by assuring the use of palatable meals, often recommending diets high in both protein and fats. All too frequently the underweight older person may, for apparent health reasons, be consuming a low-fat, low-protein diet that may well contribute to or minimize the chances of weight gain. In these patients, risks of hypercholesterolemia are small compared with those from losing weight. For this reason, in underweight older persons we often recommend high-fat diets, including red meats, pork, full cream milk, and ice cream, all of which are dense in both calories and proteins. Frequent small meals should be recommended, using nutritional supplements that are calorie dense and high in protein as meal
replacements or late night snacks. Providing supplements with meals is not recommended, as total caloric intake will not be improved. The importance of a comprehensive rehabilitation program cannot be overemphasized. Recent evidence has shown that increased caloric intake can only be achieved when nutritional supplementation is accompanied by an aggressive and proactive program of exercise and physical therapy (Fig. 68.3).10 Patients who fail to respond to treatment of their underlying medical condition and fail to gain weight despite nutritional and physical rehabilitation carry a very poor prognosis.
Management of Nutritional Problems in the Acute Care Setting Protein Energy Malnutrition Figure 68.4 summarizes a rational approach to the management of nutritional problems in the acute care setting. Once a diagnosis of PEM has been made, clinical judgment is extremely important in deciding the appropriate time to commence nutritional support. In the acutely ill patient, attention should first be directed at correcting the major medical abnormalities. Thus, management of infections, control of blood pressure, and the restoration of metabolic, electrolyte, and fluid homeostasis must assume
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priority. During this period, fluid and nutrient intake should be recorded so that an assessment of future needs can be made. Once the acute process has stabilized, daily calorie counts should be performed and the patients should be encouraged by the staff to voluntarily consume as much of their food as possible. If fluid overload is not a major concern, the use of polymeric dietary supplements between meals and in the late evening should be considered. The aim is to obtain a caloric intake of approximately 35 kcal/kg, based upon an ideal rather than the actual body weight. It is our experience that by encouragement alone only 10% of elderly subjects with PEM can consume sufficient food voluntarily to correct their nutritional deficiency. Thus, most subjects require a more aggressive form of nutritional intervention. As a general rule, more aggressive attempts to assure adequate nutrient intake must commence within 48 h of admission. The approach taken depends upon the clinical presentation of the patient and whether or not short-term or more long-term nutritional support is required. For those patients requiring shortterm support (fewer than 10 days), peripheral hyperalimentation is the method of choice. Using this approach it is possible, through a peripheral vein, to provide adequate calories and protein to meet the patient’s needs using amino acid solutions, 10% dextrose, and intralipid. Nasogastric feeding should be avoided in any confused older patient because of the risk of aspiration and the need for restraints to prevent the patient from pulling out the uncomfortable and irritating tubes. For those who are
Figure 68.3. Effect of nutritional supplementation with and without exercise on daily increase in energy (food) intake in underweight older persons. (Adapted from Fiatarone et al., with permission.10)
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not confused and who have a normal gastrointestinal tract, enteral hyperalimentation through a small-bore nasogastric polyethylene catheter should be considered. These tubes are nonirritating and do not interfere with patient mobility or the ability to swallow food. It is extremely important that after the tube is passed, placement in the stomach be confirmed before commencing nutritional feedings. For patients likely to require nutritional support for periods of 6 weeks or longer, a feeding gastrostomy or jejunostomy is recommended. For both nasogastric feeding gastrostomies, infusions should begin with an undiluted, commercially available polymeric dietary supplement at a continuous rate of 25 mL/h. The supplement should contain no more than 1 kcal/mL, as caloric-dense fluids are too viscous to pass through the tube with ease. The rate can gradually be increased so that after 48 h the total daily protein and calorie requirements of the patient are met by this route. Enteral hyperalimentation has major side effects of which the attending physician must be aware. One of the most commonly encountered side effects is excessive fluid retention. When nutritional support begins, weight gain is invariably noted within the first 2 to 3 days. This almost certainly reflects fluid retention, as the weight gain is associated with significant reductions in the serum albumin and hemoglobin levels. The average increase in weight during this time in our patients is 1.3 kg, while the level of the serum albumin falls from a mean of 2.8 g/dL in patients before nutritional support to a value of 2.3 g/dL at day 3. Occasionally, and particularly in elderly
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Figure 68.4. An approach to the nutritional support of malnourished hospitalized elderly patients.
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subjects with inadequate renal function, excessive retention of fluid can result in peripheral edema or even heart failure. When this occurs, diuretic therapy can correct the underlying problem or the use of calorie-dense supplements should be considered. Major alterations in circulating electrolytes have also been described. Hyponatremia and hypocalcemia occur frequently. In addition, hypophosphatemia and decreased magnesium levels can occur, resulting in worsening confusion and delirium. Hyperglycemia and glycosuria are occasionally noted, and frank diabetic coma can develop. An additional problem seen occasionally is severe diarrhea. The risk of diarrhea can be minimized if supplements are given by slow infusion. Bolus administration of dietary supplements through a nasogastric tube increases the risk of diarrhea and, particularly in the elderly, enhances the possibility of vomiting and aspiration pneumonia. Nutritional management requires a great deal of clinical skill, particularly when frail aged subjects are being supported. With suitable training and monitoring, the side effects of enteral hyperalimentation can be minimized and, when they occur, easily corrected.
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Although anecdotal evidence has demonstrated that aggressive nutritional intervention can result in weight gain (Fig. 68.5), improved immune and hematologic functions, as well as the return of serum albumin, transferrin, and other parameters of visceral protein stores to the normal range, increases in muscle mass, as measured by anthropometric measurements, usually do not occur.11 Because a major goal of any geriatric rehabilitation is to improve functional independence and improve strength, strategies aimed at improving muscle mass are particularly important. For this reason, the recent observation that administration of recombinant growth hormone can improve muscle mass and performance in frail elderly is particularly significant. It may well be that this will become a useful tool as an adjunct to nutritional support in older patients receiving rehabilitation. A similar beneficial effect of appropriate exercise has also been recently reported. These studies emphasize the need for a comprehensive approach to the management of elderly malnourished patients. Aggressive nutritional intervention is only a part of a complete strategy aimed at restoring, in the appropriate patient, functional independence.
Figure 68.5. Response to enteral hyperalimentation in 10 elderly patients with protein-energy malnutrition. Changes in weight and serum albumin are shown.
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Nutritional Support of Patients with Pressure Ulcers Debility, immobility, and prolonged pressure are wellknown contributors to the development of pressure ulcers.5 There is also good evidence that treatment and prevention of nutritional deficiencies can decrease the risk of developing pressure ulcers and aid in the rate of healing. There is some evidence to suggest that the rate of pressure ulcer healing can be improved by administration of relatively large doses of zinc and vitamin C. In addition, total protein intake has been shown to affect the rate of pressure ulcer healing. In a recent study, we examined the effects of dietary protein intake on pressure ulcer healing in a group of geriatric patients receiving enteral hyperalimentation. A significant increase in pressure ulcer healing rates was found in subjects fed a very high protein formula containing 25% of calories as protein as compared with a group receiving 16% of calories as protein. The percent improvement averaged 76% in the very high protein formula as compared with 36% in the group fed 16% protein diet. This finding was also observed in a recent report that demonstrated a correlation between dietary protein intake and pressure ulcer healing.
Nutritional Support of Long-Term Tube Feeders Most long-term care facilities have a number of bedbound older patients who are receiving long-term nutritional support either via a nasogastric tube, or more common at the current time, via feeding gastrostomies or jejunostomies. In bedbound patients, energy requirements are determined exclusively via resting metabolic rate and, as such, are generally lower than ambulatory older persons. In our experience, weight gain can be maintained when as little as 25 kcal/kg body weight is provided on a daily basis.12 This amount will increase if an active disease process is present, such as an infection or a pressure ulcer. As a general rule, supplements with the highest protein content are favored. This is based on studies in which we have demonstrated that nitrogen balance is only maintained when more than 20% of total calories are provided in the form of protein. It is important to assure that the water needs of patients receiving enteral hyperalimentation are being met. Water needs average 35 mL/kg, even in the bedbound patient. Thus in patients receiving supplements containing 1 or more cal/mL, fluid needs may not be met without the provision of free water, in addition to the dietary supplement.
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Paying attention to fluid status is critically important because of the well-known negative sequelae of dehydration in older persons.
Summary Management of nutritional problems in the elderly constitutes an important challenge. Few health care professionals pay much attention to the nutritional status of their patients, which may have adverse effects on morbidity, mortality, and quality of life. While overnutrition is a common problem in younger persons, aging is associated with increases in the incidence of weight loss, being underweight, and having protein-energy malnutrition. Identifying and appropriately treating the underlying cause is a critical component of nutritional rehabilitation. However, it is important to simultaneously assure that the patient’s energy and protein needs are met, which can be done by dietary manipulation and by the use of dietary supplements. In the hospitalized setting, the presence of anorexia and inadequate voluntary food intake may necessitate the need for nutritional hyperalimentation. Peripheral hyperalimentation is recommended for the older confused patient requiring short-term nutritional support and who is unlikely to tolerate nasogastric feeding. For long-term nutritional support, feed via nasogastric tube or percutaneous endoscopic gastrostomy (PEG) placement should be considered. It is important to emphasize that nutritional care is a critical component of comprehensive rehabilitation program that must include physical and occupational therapy if overall improvement of the patient and functional independence are to be achieved.
References 1. McCarter RJM. Role of caloric restriction in prolongation of life. Clin Geriatr Med. 1995;11:553–565. 2. Shock NW, Gruelich RC, Andres R, et al, eds. Normal Human Aging: The Longitudinal Study of Aging. NIH Pub 84-2450. Washington, DC: National Institutes of Health; 1984. 3. Gersovitz M, Motil K, Munro H, et al. Human protein requirements: assessment of the adequacy of the current recommended dietary allowance for dietary protein in elderly men and women. Am J Clin Nutr. 1982;35:6–14. 4. Chernoff R. Effects of age on nutrient requirements. Clin Geriatr Med. 1995;11(4):641–651. 5. Allman R. Pressure sores among the elderly. N Engl J Med. 1989;320:850–853. 6. Ham RJ. The signs and symptoms of poor nutritional status. Prim Care. 1994;21:33–67.
68. Nutrition 7. Sullivan DH, Walls RC. Impact of nutritional status on morbidity in a population of geriatric rehabilitation patients. J Am Geriatr Soc. 1994;42:471–477. 8. The Nutrition Screening Initiative. Incorporating Nutrition Screening and Interventions into Medical Practice: A Monograph for Physicians. Washington, DC: The Nutrition Screening Initiative; 1994. 9. Silver AJ, Morley JE. Role of the opioid system in the hypodypsia associated with aging. J Am Geriatr Soc. 1992;40:556–560.
1021 10. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplements for physical frailty in very elderly people. N Engl J Med. 1994;330:1769– 1775. 11. Lipschitz DA, Mitchell CO. The correctability of the nutritional, immune and hematopoietic manifestations of protein calorie malnutrition in the elderly. J Am Coll Nutr. 1982;1:17–25. 12. Lipschitz DA. Approaches to the nutritional support of older patients. Clin Geriatr Med. 1995;11:715–724.
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69 Exercise Eric B. Larson and Robert A. Bruce
Introduction The health benefits of exercise, particularly for a sedentary society, have gained an increasingly compelling evidence base in the past decade. For earlier generations of seniors, exercise was a regular feature of everyday life. Beginning sometime after the industrial revolution and culminating in today’s most advanced societies, there is a seemingly inevitable tendency leading to everyday lives that require progressively less energy expenditure through exercise. Exercise in the last half of the twentieth century was viewed primarily as recreation, and especially recreation for younger people. The therapeutic benefits of exercise were initially explored for younger people—in whom the principal benefits are for cardiovascular risk reduction. We believe that the health benefits of exercise may be even greater in older persons. Younger adults have considerably more physiologic reserve, both muscular strength and cardiovascular capacity. Older individuals, by contrast, experience a progressive decline in many physiologic functions, including muscular strength and cardiovascular capacity.1,2 Habitual exercise, by. improving strength and maximum aerobic capacity (VO2 max) as a result of conditioning effects, can provide added physiologic reserve as well as enhance well-being by reducing effort and fatigue associated with activities of daily living.3 Most importantly, habitual exercise in moderation can slow development of disability and thereby prolong active life expectancy.4,5 In addition to habitual exercise for conditioning, there is increasing evidence that resistance exercise to improve muscle strength along with more tailored exercise therapies, including those designed to improve balance, and rehabilitate persons with various chronic disease and acute ailments, may be of particular value for older patients.6–8 Thus, exercise should be considered an important part of general care of so-called healthy agers as well as for persons with age-related illnesses.9
Society should focus health promotion on the elderly as well as the young. Life expectancy at age 65 averages at least 15 years for men and 19 years for women,10 long periods during which risk reduction and health promotion can provide beneficial effects. Most older people in advanced countries have grown older during an era when advancing technology at home and in the workplace has promoted a lifestyle characterized by progressively less habitual physical activity. A physically active lifestyle (before today’s ongoing exercise craze) was usually associated with lower socioeconomic manual labor or the considerable activity provided by raising children. As people aged, they typically became progressively more sedentary. Leisure time was for resting, and heavy physical activity was not viewed as desirable. Thus, it may come as a surprise to many older patients when a physician recommends habitual exercise as a “treatment” or when tailored exercise programs are prescribed as part of a care plan for managing ongoing chronic diseases. There is now a growing evidence base that exercise programs offer measurable health benefits, ranging from increased life expectancy to mitigation of adverse sequelae of aging and of many chronic diseases. Nowadays, the greatest challenge with regard to achieving the health benefits of exercise is caused by limited access to effective programs and poor compliance.11
Exercise and Aging Dynamic aerobic exercise is commonly defined as the rhythmical alternating flexion and extension of large muscle masses for pleasure or improved fitness and stamina.3 Aerobic metabolism of muscle increases in proportion to the mass of muscles involved and the intensity of exertion. The functional limits are determined by the body’s ability to circulate oxygen and substrates and remove CO2, metabolites, and heat from the muscles, which is determined by cardiac output and arterial-mixed 1023
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venous oxygen (a-v O2) differences at symptom-limited maximal exercise.12 Beyond these limits, additional energy for a short interval is achieved by anaerobic metabolism with release of lactate. A variety of acute changes occur during dynamic aerobic exercise. Knowledge of the physiology of exercise was originally derived from studies of young, typically athletic male volunteers; however, subsequent work has been directed to other adults, including the elderly.13 The circulatory response to dynamic exercise is most prominent in the exercising muscle. Blood flow increases from 4 to 7 mL/100 g/min up to 50 to 70 mL/100 g/min due to decreased vascular resistance and opening of capillary beds in working muscles.14 The muscle itself generates adenosine triphosphate (ATP), increases oxygen consumption, and consumes more substrates, especially free fatty acids. Oxygen extraction at the tissue level increases from 5 to 15 mL/100 mL of nutrient flow.15 Overall, total oxygen uptake increases 10- to 20-fold in well-trained athletes. Cardiac output increases linearly with oxygen uptake, and heart rate increases linearly with cardiac output.15 Stroke volume increases to a lesser extent as a result of enhanced systolic emptying. The increase in cardiac output, however, is not sufficient to account for all the increase in oxygen uptake. Increased extraction of oxygen at the tissue level occurs also. There is a prominent rise in systolic blood pressure as well as a modest increase in mean arterial pressure. Diastolic blood pressure usually is unchanged or decreases. Arterial vasoconstriction during exercise restricts regional blood flow to the hepatosplanchnic and renal circulations to transfer more blood flow to working skeletal muscle groups and to a lesser extent the coronary circulation. In the working muscle, heat is generated up to 41°C at maximal effort. A maximum of about 25% of the chemical energy produced is turned into work; 75% is given off as heat and must be dissipated. The most important mechanism for handling excess heat is circulatory; adequate blood flow is required to allow heat to flow from the contracting muscle to the surface for dissipation through the skin. In the lungs, the minute ventilation increases in proportion to the generation of carbon dioxide14 and aids in heat dissipation. Most people perform dynamic aerobic exercise repeatedly for a training or conditioning effect. The training effect consists of an increase in the capacity for maximal effort and decrease in circulatory and relative metabolic changes at any given level of submaximal . effort. The increase in maximum aerobic capacity (VO2 max) that occurs is related to the person’s baseline, limitations imposed by the presence of any disease, and the intensity and consistency of duration. and frequency of training.14 Physical training increases VO2 max, and because capac-
E.B. Larson and R.A. Bruce
ity is greater, the effort required for any . given level of submaximal exertion as a percent of VO2 max, cardiac output, and heart rate is reduced. Approximately half the increase occurs as a result of peripheral changes, that is, an increase in the capacity of aerobic metabolism and extraction of substrate and oxygen at the tissue level. These peripheral changes include an increased density of mitochondria in the muscle, increased amount of mitochondrial enzymes, and therefore an increased capacity to oxidize fat, carbohydrate substrates, and ketones; the amount of myoglobin is increased as is the ability to generate ATP. The net result is an increased capacity for oxygen extraction and a decrease in lactate production during submaximal exercise.16 The other half of the training effect occurs primarily in the cardiovascular system.15,17 Thus, skeletal muscles are more efficient and myocardial oxygen requirements are actually less due to the reduction in afterload. Dynamic exercise may be sustained for hours without fatigue if activity is below 50% . of the individual’s maximum oxygen consumption (VO2 max).18 To obtain physiologic adaptation, training should begin .at lower levels, gradually increasing to 58% to 78% of VO2 max or to 70% to 85% of the individual’s maximal heart rate.18,19 Exertion at this level, 20 to 40 min three times per week, for several weeks is required for physical conditioning to occur. If not maintained, deconditioning occurs. Thus, an active life is necessary to maintain the benefits of such training. Strenuous exertion or training activities sustained above 85% of maximal heart rate can trigger adverse effects such as heart attacks, especially in sedentary persons with coronary heart disease.20,21 Aging alters structures and reduces . functions of cells and tissues of all organ systems. VO2 max defines the functional limits of aerobic metabolism and the cardiovascular system that occur with aging.1,18 In the absence of bronchopulmonary disease or anemia, . neither ventilation nor arterial oxygen content limits VO2 max before the cardiovascular limits are obtained. of . Much research has focused on the relationship . VO2 max and age. The general results are that VO2 max increases with age during growth and in childhood development, reaches a peak with. adolescence, and then declines with advancing age.1,22 VO2 max is higher in men than women in proportion to differences in amount of skeletal muscle mass. For both men and women, higher values are found in physically active persons . compared to those who are sedentary. After adjusting VO2 max for weight, the highest value for aerobic capacity is observed during the first decade of life, and a roughly linear decline then follows throughout life. The relationship follows the 23 declining maximal heart rate . with age. The rate of decline in VO2 max with aging is lower, based on cross-sectional selective sampling of healthy individuals of different ages, compared to the rate of
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decline found in longitudinal studies of the same persons over time. In cross-sectional studies, the coefficient for this rate of change averages -0.4 ml min-1 kg-1 yr-1 compared to -0.9 ml min-1 kg-1 yr-1 observed in longitudinal studies.23 Extrapolations based on cross-sectional data result in implausibly long-lived preservation of aerobic capacity due to selective survival effects whereas, using longitudinal data, the age at which basal or minimal oxygen uptake is intersected (minimal aerobic requirement for survival) corresponds to observed survival of healthy persons.18,23 Longitudinal measurements are . needed to describe the effects of aging on VO2 max; such data are difficult to obtain. The critical observation with regard to exercise and . aging is that the rate of decline in weight-adjusted VO2 max with aging is not identical in habitually active compared to sedentary men who remain healthy. Regression lines computed for aerobic capacity and age from longitudinal reports of aerobic capacity and aging show separation for active and sedentary men. The slopes were remarkably similar for the same categories of men, even though data24–26 were derived from different population samples over different durations between measurements. The slopes of the regression lines calculated were -0.54 ± 1.5 mL min-1 kg-1 yr-1 for physically active men compared to -1.32 ± 0.85 ml min-1 kg-1 yr-1 for sedentary mean23; thus, . there is a twofold difference in the rate of decline in VO2 max based on habitual activity levels. For men in the 50- to 59-year-old range, this is equivalent to a 10-year difference in the intersection of the extrap-
Figure 69.1. Age-related decline in physiologic . function, as measured by maximum oxygen consumption (VO2 max). Solid lines represent regression lines based on longitudinal studies of . VO2 max; dotted segments are extrapolations based on regression line (decline) observed. Extrapolation of this decline in persons who have been followed longitudinally and classified as . habitually active or sedentary suggests that minimum VO2 min (3.5 ml/kg/min) occurs at a later age in the habitually active group.
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Figure 69.2. The relationship between functional aerobic capacity, aging, and functional reserve. D functional reserve is the difference between functional reserve for active and sedentary persons at ages 40, 60, and 70, respectively.
. olated regression lines with the VO2 min necessary to maintain life (Figure 69.1).3,18 The consequences of a difference in the rate of declining aerobic capacity are obviously important for aging persons. One important consequence is expressed by the concept of functional reserve.27,28 Functional aerobic reserve can be defined as the amount of reserve . between maximum aerobic capacity (VO2 max) and the weight-adjusted resting oxygen requirement of about 3.5 ml/kg/min, which is the minimal aerobic requirement for survival. Figure . 69.2 shows that at age 40 the difference in rates of VO2 max and minimal functional capacity associated with survival (or the functional aerobic reserve) is considerable.27 Furthermore, the relative difference between conditioned and unconditioned persons is small. As the two curves diverge and one approaches age 60, there still is considerable functional aerobic reserve but the difference between active and sedentary persons’ functional reserve is greater. By the time a person reaches age 70, the functional reserve in the sedentary group becomes much less as aerobic capacity approaches the minimum aerobic requirements for survival, and thus there is more likely to be a clinically significant difference in functional aerobic reserve. The clinical importance of the difference between sedentary and active groups may be manifest as improved ability to withstand the stress of illness, more rapid recovery from illness or injury, and greater likelihood to have the ability to perform activities of daily living during the course of an acute illness or during exacerbations of chronic illnesses.3,27 These data form the theoretical basis for postulating that aerobic exercise and conditioning may not only prolong life but, more importantly, prolong active life expectancy,3,5 the health benefit most desired by patients.
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Exercise Programs for Older Persons It is tempting (and probably justified) to simply prescribe exercise as a general tonic for all older persons. However, there are special benefits for older persons with chronic disease and disabilities for whom more focused prescriptions should be considered. Current evidence supports exercise programs for persons with ischemic heart disease, including those with congestive heart failure, osteoporosis, osteoarthritis, spinal stenosis, degenerative central nervous system diseases such as Parkinson’s disease, diabetes, hypertension, peripheral vascular disease, and possibly psychiatric illnesses, such as depression and anxiety disorders.8,9,29,30–35 In general, current evidence indicates that older adults with chronic diseases enjoy benefits from exercise. If anything, we believe exercise offers relatively more benefits to older adults in whom the baseline level of risk is higher, and thus the opportunity to reduce risk is greater. We now know that the underlying plasticity of the muscles, autonomic nervous system, bones, and joints exists in both young and old persons and is amenable to the effects of conditioning and therapeutic exercise.6,36–39 Habitual exercise in older adults has been shown to produce as much conditioning effect as in younger persons.13,40 The most important concern with regard to the overall health benefits of exercise in older persons is the risk of exercise.41 Except for the risks, exercise is essentially a “low-cost” intervention and may require relatively little in the way of health care resources. If the individual has time that is not encumbered with other activities (work, raising a family, etc.), the marginal cost to the individual of time spent exercising is low. Thus, the key element to the question of efficacy in older persons is risk and injuries.41 The hazards of exercise are related to extremes of intensity and duration. When exercise is excessively intense and/or prolonged, extreme fatigue, exhaustion, or delayed recovery is experienced. In addition, more prolonged or intense exercise is associated with increased risk of injury.42 Injuries and sudden death are the most important complication for elderly persons.3 The risk of injury has been documented in numerous studies to be directly related to the intensity of training.3,41,43 For example, for participants in the Peach Tree Road Race in Atlanta, Georgia, there was a nearly linear relationship between miles run per week and likelihood of suffering an injury in the previous year. At the highest level of training, more than 70% of participants had at least one injury the preceding year.42 On the other hand, studies of a “runners’ club” from Stanford demonstrate that habitual exercise need not be associated with increased overall utilization of health service.43 In this group of patients with mean age of 58.6 years who ran approximately 27 miles per week, visits to physicians, dis-
E.B. Larson and R.A. Bruce
ability days, and disability levels were more favorable in the running group compared to a group of community controls. Nonetheless, 35% of the visits to physicians in the runners’ club were for running-related injuries.43 The risk of sudden death and nonfatal myocardial infarction is quite small, but detectable, during unsupervised activity.44 Risk factors for sudden death among those participating in exercise programs include attaining a heart rate in excess of 85% of that individual’s maximum; marked ST depression with exercise despite the absence of chest pain; poor adherence. to limiting heart rate; and attainment of above-average VO2 max for gender and age due to peripheral mechanisms.20 Overall, however, the risk of primary cardiac arrest in more active individuals is less.44 The incidence of primary cardiac arrest attributable to lack of exercise was greatest in older, hypertensive, or obese males.45 Bouts of heavy exertion in sedentary people appear to pose a threat.21 Thus, any general exercise program should be moderate in intensity and duration and should minimize risk of injury, cardiac arrest, and nonfatal myocardial infarction, as well as excessive fatigue. It may also be important to maintain adequate hydration to counteract fluid losses of sweating. Four goals should be a part of an exercise program established for older individuals.27 First, the program should increase conditioning, especially endurance. Second, the intervention should improve muscle strength, especially lower extremity strength, given the importance of walking to independent functioning. Both these goals are likely to improve a person’s ability to perform activities of daily living, decrease fatigue associated with the day’s activity, improve a sense of well-being, and perhaps forestall such adverse events as falls by improving muscle strength. The third goal of an exercise program should be to minimize risk of injury due to the program, and a fourth goal should be to promote enjoyment without causing excessive fatigue. The components of the exercise program include two essentials: the first is dynamic aerobic exercise3,19 in the form of walking, swimming, cycling, jogging, and so forth; the second is a program that promotes lower extremity strengthening. Also desirable are a period to warm up and cool down and muscle and tendon stretching. The exercise program should be tailored, especially so for older individuals. The program should take account of an individual’s physical capacities and coexistent disabilities as well as mitigating social, psychologic, and economic factors.19 Among all forms of exercise available to the elderly, brisk walking is one of the most ideal and has, in fact, been recommended by a number of groups.46–48 Brisk walking does produce a training response in many older individuals. More vigorous exercise may be required for persons to obtain a conditioning effect if they start from higher baseline fitness levels. Physicians
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and other health professionals should be prepared to give appropriate guidelines for exercise.19 In particular, habitually sedentary persons may need to be advised of the normal responses to exercise, which include increased heart rate and breathing; mild perspiration; an increased awareness of one’s heartbeat; and, at least initially, mild muscle aches. Such responses are normal and do not indicate that a person should stop exercising.27 The warning signs of excessive exercise include severe dyspnea, wheezing, coughing; any form of chest discomfort; excessive perspiration; syncope or near syncope; prolonged fatigue and exhaustion lasting at least half an hour after exercise; and local muscle or joint discomfort. Heart rate guidelines are most appropriate for persons with coexistent cardiac disease. An exercise tolerance test will allow one to calculate the desired heart rate based on the observed or extrapolated maximal heart rate. The typical target heart rate for achieving a conditioning effect is 70% to 80% of maximal heart rate.2 There also are tables listing average exercise heart rates for various age groups; however, such tables may be less useful given the wide variation in baseline and maximal aerobic capacity seen in the elderly. In our own experience, it is perhaps more useful to teach individual guidelines for pacing. One guideline is the so-called talk test in which persons know they are not exercising excessively when they can carry on a normal conversation while exercising. For many elderly persons, a reliable heart rate guide is to aim for an exercise heart rate 15 to 20 beats per minute over their resting heart rate.48 Most persons who have not exercised excessively will also find that their pulse returns to resting levels or nearly so within 20 min after stopping exercise. Finally, it is important to emphasize that exercise for conditioning is not “competition.” Many people associate exercise with competition and thus need to be counseled to avoid external comparisons. Competitive urges can be focused on the goal of making progress or minimizing decline over time. Perhaps the most important pacing guide is to emphasize starting a program slowly and increasing activity by small increments. Many older persons abandon exercise programs because they expect too much too fast, become discouraged, and thereby give up their programs before benefits are achieved (Table 69.1). The duration to be prescribed is driven by the amount of time required to produce the conditioning effect. In general, a minimum of 20 to 30 min of aerobic exercise three times per week at 70% to 80% of maximum heart rate is required to achieve a conditioning effect, which will begin approximately 2 weeks after commencing an exercise program. Moderate exercise (such as brisk walking) is more likely to produce a conditioning effect at levels of 30 to 40 min for 5 days per week, which is the level recommended by the U.S. Prevention Services Task
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Force. Deconditioning begins as soon as a program is abandoned. Deconditioning is dramatic and malignant when persons “take to bed.”49 Table 69.1 demonstrates two programs recommended by advisory groups for elderly individuals.48 Both plans begin at extremely modest levels (5 min of walking three times per week or 1/4 mile walking three times per week) and eventually proceed to a brisk walking pace lasting 30 to 60 min. Compliance, along with low levels of physician counseling, is the major barrier to successful exercise programs in the elderly.11,50 This is a common issue for many health promotion activities. More research is required to define strategies for improving compliance with habitual exercise recommendations. A related issue is the relative lack of social and community resources for habitual activity. Much of our advancing technology consists of “labor-saving” devices. In our large northern cities, especially, there may be few opportunities and almost no facilities for older persons to get habitual exercise. During the prolonged cold or wet winters, the opportunity for outside activity is particularly restricted. The social issues involved in creating facilities that provide a range of exercises at reasonable costs have yet to be solved. Walking in shopping malls is a solution that works in some communities. Older adult living communities are beginning to “invest” in exercise facilities containing a treadmill, bicycling, and cross-country skiing and other exercise machines. Recent work on the feasibility of high-intensity resistance exercise training has demonstrated that rather vigorous, supervised progressive resistance training exercise designed to improve strength is both feasible and effective.6,37,38,39,51 Muscle dysfunction is an important factor in the development of falls, fractures, dependence in activities of daily living, and need for institutionalization.52.53 The feasibility and effectiveness of strength training represents an important advance, which could lead to effecTable 69.1. Two examples of brisk walking programs. Week 1 2 3 4 5 6 7 8 9 10 11 12
Program 1: miles of walking46 1 a 4 1 4 1 2 1 4
/ / / / 1 1 1 (20 min) 11/2 (30 min) 2 (40 min) 2 (20 min) 21/2 (50 min) 3 (60 min)
a Three times weekly. Source: From Ref. 46, with permission.
Program 2: minutes of walking47 5 7 9 11 (approx. 1/2 mile) 13 15 18 20 (approx. 1 mile) 23 26 28 30 (approx. 11/2 mile)
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tive programs to reverse frailty. The results also demonstrate that aged, wasted, and unused muscles retain their plasticity at virtually any age. What emerges as this chapter goes to press is that habitual exercise and tailored exercise programs are important components in the therapeutic armamentarium of geriatric medicine. Habitual moderate intensity exercise is a proven way to reduce risk of death from heart disease53 and will also improve bone density, strength, stamina, and balance, which reduces risk of falling and injury, hypertension, glucose control, sleep, depression, constipation, and other common maladies.3,27 Age-related decline in exercise capacity and functional reserve is attenuated by habitual exercise. The development of specifically tailored programs is likely best accomplished with the assistance of specially trained physical therapists or in group programs often found in senior centers, through voluntary groups such as YMCAs in some residential facilities or in some medical centers. We recently established a program at the University of Washington Medical Center (Strong and Steady), whose purpose is to provide seniors with the tools to maintain or increase their level of independent physical function and enhance their health through exercise. The Strong and Steady Program uses a combination of exercise and education to accomplish these goals. The services provided through the Strong and Steady Program include individual therapy sessions, group classes, and individualized fitness programs. Education focuses on the importance of exercise to health maintenance and measures that can be taken to maintain safe mobility function. The program includes a comprehensive evaluation and the development of an individualized exercise program. The evaluation performed by a physical therapist focuses on assessment of balance, mobility and fall risk, and components of function such as strength, range of motion, and coordination. The tools of the program include strengthening exercises, balance retraining, aerobic conditioning, flexibility exercises, and gait retraining. More information on the Strong and Steady Program can be found on the University of Washington Medical Center Web site, http://www.washington.edu/medical/uwmc/uwmc_ clinicals/bonejo/strong.html. We believe that programs like Strong and Steady should help address the challenge of providing access to facilities, therapeutic expertise, and programs for older adults—both those with good health and those with chronic disease. The need for such services likely exceeds supply in most communities. Geographic access is often a problem for many patients. Financial viability of the programs themselves is a critical issue. The Strong and Steady Program was started with a small grant from the UWMC Service League to cover modest startup costs. The Program receives most of its revenue from billed charges and is expected to cover operational costs in 2 to
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3 years, when it reaches its expected clinical capacity. The services are charged as physical therapy evaluation, therapeutic exercise, balance training, and gait training. Most charges are to Medicare, with supplemental or private pay covering the other 20%. Group classes are all private pay. We believe evidence strongly supports such efforts by clinicians, provider institutions, geriatric self-help activist groups, and older persons in general to promote exercise—both habitual and tailored programs—for long periods of time to maintain strength, fitness, health, and function.
References 1. Astrand PO. Physical performance as a function of age. JAMA. 1968;205:729–733. 2. Larson EB, Bruce RA. Exercise and aging. Ann Intern Med. l986;105:793–785. 3. Larson EB, Bruce RA. Health benefits of exercise in an aging society. Arch Intern Med. 1987;147:353–356. 4. Fries JF, Singh G, Morfeld D, Hubert HB, Lane WE, Brown BW. Running and the development of disability with age. Ann Intern Med. 1994;121:502–509. 5. Katz S, Branch LG, Branson MH, Papsidero JA, Beck JC, Greer DS. Active life expectancy. N Engl J Med. 1983;309: 1218–1224. 6. Fiatarone MA, Marks EC, Ryan ND, et al. High intensity strength training in nonagenarians. JAMA. 1990;263:3029– 3034. 7. Buchner DM, Cross ME, de Lateur BJ, et al. The effect of strength and endurance training on gait, balance, fall risk and health services use in community-living older adults. J Gerontol Med Sci. 1997;52A:M218–24. 8. Wolff J, van Croonenborg JJ, Kemper HC, Kostense PJ, Twisk JW. The effect of exercise training on bone mass: a meta-analysis of published clinical trials in pre- and postmenopausal women. Osteoporos Int. 1999;9:1–12. 9. Girolami B, Bernardi F, Prinz MH, et al. Treatment of intermittent claudication with physical training, snacking cessation, pentoxifylline, or nafronyl: a meta-analysis. Arch Intern Med. 1999;159:337–345. 10. Van Nostrand JF, Furner SE, Suzman R, eds. Health Data on Older Americans: United States, 1992. Vital Health Statistics, Series 3. US Department of Health and Human Services, Hyattsville, MD; 1993. 11. Elward K, Larson EB, Wagner EH. Factors associated with regular aerobic exercise in an elderly population. J Am Board Fam Pract. 1992;5:467–474. 12. Mitchell JN, Sproule BJ, Chapman CV. The physiological meaning of the maximal oxygen intake tests. J Clin Investig. 1958;37:538–547. 13. Posner JD, Gorman KM, Windsor-Landsberg L, et al. Low to moderate intensity endurance training in healthy older adults: physiological responses after four months. J Am Geriatr Soc. 1992;40:1–7. 14. Clausen JP. Circulatory adjustments to dynamic exercise and effect of physical training in normal subjects and
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patients with coronary artery disease. Prog Cardiovascular Dis. 1976;18:459–495. Wallace AG. Cardiovascular adaptations to exercise. In: Smith LH, Their SO, eds. Pathophysiology: The Biological Principles of Disease. Philadelphia: Saunders; 1981;1136– 1142. Holloszy JO. Adaptations of muscular tissue to training. Prog Cardiovasc Dis. 1976;18:445–458. Detry JR, Russeau M, Vanderbrouche G, Kasumi F, Brasseur LA, Bruce RA. Increased arteriovenous oxygen differences after physical training in coronary heart disease. Circulation. 1974;44:109–118. Bruce RA. Exercise, functional aerobic capacity and aging— another viewpoint. Med Sci Sports Exerc. 1984;16:8–13. Goldberg L, Eliot EL. Prescribing exercise. West J Med. 1984;141:383–836. Hossack KF, Hartwig R. Cardiac arrest associated with supervised cardiac rehabilitation. J Cardiac Rehabil. 1982; 2:402–408. Curfman GD. Is exercise beneficial or hazardous to your heart? N Engl J Med. 1993;329:1720–1731. Robinson S. Experimental studies of physical fitness in relationship to age. Arbeitsphysiologie. l938;10:251–323. Dehn MM, Bruce RA. Longitudinal variations in maximal oxygen intake with age and activity. J Appl Physiol. 1972; 33:805–807. Dill DB, Robinson S, Ross JC. A longitudinal study of 16 champion runners. J Sports Med. 1967;7:4–32. Hollman W. Korperliches Training als Pravention von Herz Kreislauf-Krankheiten. Stuttgart: Kippokrates-Verlag; 1965. Irving JB, Kusumi F, Bruce RA. Longitudinal variations in maximal oxygen consumption in healthy men. Clin Cardiol. 1980;3:134–136. Larson EB. A general approach to health promotion and disease prevention in the older adult. Geriatrics 1988;43: 31–39. Williams MA. Clinical implications of aging physiology. Am J Med. 1984;76:1049–1054. Arroll B, Baeglehole R. Exercise for hypertension. Lancet. 1993;34:1248–1249. Hambrecht R, Wolf A, Grelen S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med. 2000;342:454–460. Kasch FW, Boyer JL, Schmidt DK, et al. Aging of the cardiovascular system during 33 years of aerobic exercise. Aging 1999;28:531–536. Paluska SA, Schwenk TL. Physical activity and mental health: current concepts. Sports Med. 2000;29:167–180. Singh NA, Clements KM, Fiatarone MA. A randomized trial of progressive resistance training in depressed elders. J Gerontol A Biol Sci Med. 1997;52:27–35. Wei M, Gibbons LW, Kampert JB, Nichamon MZ, Blair SW. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med. 2000;132:605–611. Walker RD, Nawaz S, Wilkinson CH, Saxton JM, Pockley AG, Wood RF. Influence of upper- and lower-limb exercise program on cardiovascular function and walking distances
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in patients with intermittent claudication. J Vasc Surg. 2000;31:662–669. Beere PA, Russell SD, Morey MC, Kitzman DW, Higginbotham MB. Aerobic exercise training can reverse age-related peripheral circulation changes in healthy older men. Circulation. 1999;100:1085–1094. Pyka G, Lindenberger E, Charette S, Marcus R. Muscle strength and fiber adaptations to a yearlong resistance training program in elderly men and women. J Gerontol. 1994;49:M22–M27. Fiatarone MA, Evans WJ. The etiology and reversibility of muscle dysfunction in the aged. J Gerontol. 1993;48:77–83. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330:1769–1775. De Vries HA. Physiological effects of an exercise training regimen upon men aged 52 to 88. J Gerontol. 1970;25: 325–336. Koplan JP, Siscovick DS, Goldbaum GM. Risks of exercise: public health view of injuries and hazards. Public Health Rep. 1985;100:189–194. Koplan JP, Powell KE, Sikes RK, Shirley RW, Campbell OC. An epidemiologic study of the benefits and risks of running. JAMA. 1982;248:3118–3121. Lane NE, Bloch DA, Woud PD, Fries JF. Aging, longdistance running and the development of musculoskeletal disability. Am J Med. 1987;82:772–780. Siscovick DS, Weiss NS, Fletcher RH, et al. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med. 1984;311:874–877. Siscovick DS, Weiss NS, Fletcher RH, Schoenbach VJ, Wagner EH. Habitual vigorous exercise and primary cardiac arrest: effect of other risk factors on the relationship. J Chron Dis. 1984;37:625–631. President’s Council on Physical Fitness and Sports. Pep Up Your Life—A Fitness Book for Seniors. Washington, DC: American Association for Retired Persons. Exercise and Your Heart. Bethesda, MD: U.S. Dept. of Health and Human Services, Public Health Services, National Institutes of Health; 1981. Mielchen SD, Larson EB, Wagner E, et al. Getting started: a guide to physical activity for seniors. Seattle: Center for Health Promotion, Group Health Cooperative; 1987. Clark LP, Dion DM, Barker WH. Taking to bed: rapid functional decline in an independently mobile older population. J Am Geriatr Soc. 1990;38:967–972. Wee CC, McCarthy EP, Davis RB, Phillips RS. Physician counseling about exercise. JAMA. 1999;282:1583–1588. Mulrow CD, Gerety MD, Kanton D, et al. A randomized trial of physical rehabilitation for very frail nursing home residents. JAMA. 1994;271:519–524. Tinetti ME, Baker DI, McAvay MS, et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med. 1994;331: 821–827. Paffenbarger RS Jr, Hyde RT, Wing AL, Lee IM, Jung DL, Kampert JB. The association of changes in physical activity level and other lifestyle characteristics with mortality among men. N Engl J Med. 1993;328:538–545.
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70 Sleep and Sleep Disorders Tamar Shochat and Sonia Ancoli-Israel
The prevalence of sleep complaints increases dramatically with age and is estimated to be about 40% in the elderly population.1 These complaints include difficulty falling asleep, waking up at night, waking up too early in the morning, not feeling well rested, and needing to nap during the day. In an epidemiologic study of more than 9000 participants aged 65 and over, more than half reported at least one sleep complaint occurring most of the time.2 Women were more likely to report nighttime complaints but were less likely to nap during the day compared to men. The most common complaint was waking up at night (30%), followed by daytime naps (25%) and difficulty falling asleep (19%). Less than 20% reported rarely or never having any sleep complaint. Sleep complaints were associated with coexisting health disorders, including poor self-perceived health, depressive symptoms, respiratory symptoms, physical disabilities, chronic medical conditions, and medication use. However, of the healthy minority in this study, over one-fourth reported at least one chronic sleep complaint. Although age-related changes do occur in normal sleep, sleep problems in the elderly are not a consequence of the aging process per se but are strongly related to medical and psychiatric comorbidity as well as psychosocial changes in later life. Furthermore, some specific sleep disorders such as sleep disordered breathing, periodic limb movements in sleep, and REM sleep behavior disorder are more prevalent with age, although not exclusive to this age group.
Physiologic Sleep and Its Measurement In the 1950s, scientists discovered that sleep is an active process, not, as formerly believed, a passive state not worthy of scientific investigation. By recording brainwave activity (the electroencephalogram, EEG), eye movements, and muscle tension, it was determined that sleep is broken down into two major states, rapid
eye movement (REM) and nonrapid eye movement (NREM). NREM sleep is further subdivided into sleep stages 1 through 4, which represent a continuum from light sleep (stage 1) to deep sleep (stages 3 and 4). REM sleep is characterized by rapid eye movements similar to those seen in the waking state, as well as muscle atonia. Healthy human individuals show stable and distinct patterns of sleep architecture, that is, the cyclic alternations of the different sleep stages. Sleep is entered through the transitional stage 1, and followed by stages 2, 3, and 4, respectively. After about 90 min, through stage 2 sleep, REM sleep begins. The first appearance of REM sleep during the night is termed REM latency. This 90- to 100-min cycle repeats itself typically four to five times during the night. However, the internal temporal structure changes, so that at the beginning of the night stages 3 and 4 are long while REM sleep is short, and as the night progresses, the amount of stages 3 and 4 decreases, while the amount of REM sleep increases. Both REM sleep and non-REM sleep stages 3 and 4 are homeostatically driven; that is, selective deprivation of each of these states subsequently causes a rebound in their appearance once the person is allowed to sleep. This finding leads to the ubiquitous assumption that both are essential in the sleep process and its many functions.3 REM sleep may also be driven by a circadian oscillator, as studies have shown that REM is temporally coupled with the circadian rhythm of temperature.4
Specific Clinical Patterns in Aging Because the prevalence of several medical and psychiatric conditions that affect sleep, as well as the prevalence of specific sleep disorders, is high in the elderly population, it is extremely difficult to portray the picture of the “normal” elderly sleeper. Nevertheless, studies of agerelated changes in sleep architecture have found some common characteristics. Sleep efficiency, defined as the 1031
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amount of time asleep relative to the amount of time in bed, is decreased to 70% to 80%,5 compared to 90% or more in younger adults. Total sleep time is reduced, particularly in the later part of the sleep episode.6 The amount of stage 1 sleep, which is the transitional state between wake and sleep, is increased, while the amount of stages 3 and 4 (also termed slow-wave sleep or delta sleep) is much decreased.4,7 Specifically, the amplitude of slow-wave activity is significantly reduced.8 Therefore, older people spend more of the night in light sleep and are more likely to arouse (awaken) in response to external stimuli during the night. Changes in the amount of REM sleep and latency of REM (time from sleep onset to the first REM sleep period) in the elderly are controversial.5 While some studies report a reduction in the percentage of REM,4 others report few or no changes in REM with aging.9 Feinberg7 reported a shorter REM latency and longer duration of REM sleep in the first sleep cycle. Reynolds et al.10 reported a “flat” temporal distribution of REM, with no changes in the percentages of REM sleep throughout the night, unlike the increase in REM sleep in the second half of the night typically seen in young adults. Some studies have shown shorter REM latencies in the elderly; however, this may be due to the decrease in the amount of non-REM sleep in stages 3 and 4. Alternatively, as REM sleep is coupled to the circadian rhythm of core body temperature, which has been found to be phase advanced in the elderly population, it is possible that changes in circadian timing account for the reduced REM latency compared to young adults.4 Studies looking at gender differences have shown that despite the tendency for women to complain about their sleep more often than men, older women sleep somewhat better than older men.11 This conclusion is consistent with polysomnographic findings showing that slow-wave sleep is more preserved in older women than it is in older men.10,12 Sleep maintenance, particularly in the last part of the night, was also reported to be poorer in older men than women.10 Although sleep disruption in elderly women may be milder compared to elderly men, women tend to report their sleep problems and seek help more often than their male counterparts.
Sleep Disordered Breathing Definition and Prevalence Sleep disordered breathing (SDB) or sleep apnea is characterized by complete or partial cessation of breathing, lasting at least 10s, that occurs repeatedly throughout the night. The respiratory disturbance index (RDI) represents the number of complete pauses (apnea) and partial pauses (hypopnea) in respiration per hour of sleep.
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There are two types of apnea: obstructive and central. Obstructive apneas are caused by an anatomic obstruction of the airway during sleep. Patients attempt to breathe and may appear to be choking or gasping for breath; however, despite their respiratory effort the airway is shut down. The obstruction may be located in different areas, but most often it is in the lower pharynx, between the base of the tongue and the larynx. Many patients with obstructive sleep apnea are heavy, loud snorers, as snoring in itself is also a result of a partial obstruction of airflow. In mild to moderate cases, obstructive apnea may be related to body position.13 Sleeping in a supine position may increase the frequency and severity of the apnea, as the tongue falls back to the anterior neck and oropharynx. Respiratory events may occur in all sleep stages; however, in some patients the length and severity of the events increases during REM sleep.14 Central apneas are caused by failure of the central nervous system respiratory centers. Respiratory neurons fail to stimulate the motor neurons that activate the respiration process, resulting in an absence of respiratory effort. Central apnea is common in patients with heart failure or stroke. Many patients have mixed apneas, with both central and obstructive components. Ancoli-Israel et al.15 have reported the prevalence of SDB with RDI greater than 10 in 70% of elderly men and 56% of elderly women, respectively, compared to only 15% and 5% of younger men and women, respectively.16
Consequences of the Disorder Patients with SDB stop breathing in their sleep. To start breathing again, they must awaken. Often these awakenings are so brief that they are not recalled the next morning. However, these short repetitive arousals may cause sleep fragmentation, which in turn may lead to excessive sleepiness during the day. The respiratory events may cause oxyhemoglobin desaturation, which may cause morning headaches and decreased cognitive functioning. SDB is also an independent risk factor for hypertension17 and is associated with obesity and cardiac arrhythmias.18,19 In severe cases, SDB has been linked to increased mortality.20,21 However, in a review of the literature, Wright et al.22 claimed that evidence for an association between SDB and morbidity and mortality was not sound, and other confounding factors such as age, body mass index, smoking, and alcohol use were often not properly considered. Epidemiologic studies have linked SDB in the elderly with cognitive impairment and dementia.23,24 AncoliIsrael et al. found significant associations between SDB and cognitive functioning in communitydwelling elderly,25 as well as in the nursing home, where
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severe apnea was significantly correlated with severe dementia.26
Clinical Presentation The two chief complaints of the apnea patient are loud snoring (usually the spouse suffers from this and is motivated to seek help) and excessive daytime sleepiness. Patients usually do not complain of sleep disruption, as they do not remember the nighttime arousals. However, the daytime sleepiness may have extreme consequences, as some patients may fall asleep at work or while driving. Morning headaches, confusion, and cognitive impairment are also common, particularly in the elderly. Some studies have linked these disturbances to the hypoxemia or to the excessive sleepiness.27,28
Risk Factors Patients with SDB are often obese, although this is less true in the elderly. Smoking has been implicated as a risk factor.29
Diagnosis Sleep disordered breathing (SDB) must be evaluated by an all-night sleep recording. Traditionally, this is done in a sleep laboratory, with a full EEG montage, including a nasal thermistor that records airflow and chest and abdomen movements, and oximetry, to determine oxyhemoglobin level. Portable equipment that can be set up in the patient’s home is also available. This alternative is particularly appropriate for elderly individuals who may become confused or disoriented or simply uncomfortable while sleeping away from home. Based on the sleep recording, the RDI is computed and treatment options are evaluated. SDB is diagnosed slightly differently in the various sleep clinics, but generally the cutoff point is an RDI greater than 10 to 15.
Treatment and Management Weight loss in obese patients with SDB can significantly reduce or eliminate the respiratory events.30 For positional apnea, sewing a pocket to the back of a nightshirt and placing a tennis ball inside the pocket is a simple, noninvasive method to avoid lying in a supine position.31 Alcohol and sedating medications should be avoided, as these may exacerbate the severity of the apnea.32,33 Smoking cessation may help.29 The treatment of choice for obstructive sleep apnea is continuous positive airway pressure (CPAP).34 This machine is connected by a hose to a face mask worn over
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the patient’s nose. Positive pressure is administered continuously at an appropriately titrated level, acting as a splint to keep the airway from collapsing during sleep. When used appropriately, CPAP is extremely effective in eliminating the respiratory events, the oxygen desaturations, the snoring, and the excessive daytime sleepiness. CPAP has also been found to improve measures such as mood, general health, fatigue, and functional status even in mild cases of SDB.35 However, CPAP does not cure SDB, and it must be worn every night unless another solution, such as weight loss or surgery (see following), is achieved. Compliance is therefore an important issue, and initial acceptance rate has been found to be 70% to 80%. Long-term compliance has been found to be 80% to 90%.36,37 Surgical procedures for the correction of anatomic abnormalities of the airway have been developed for the treatment of obstructive sleep apnea. Obstructions are most often found in three major regions, including the nose, the soft palate, and the base of the tongue. Usually patients have multiple obstructions. The goal of surgery is to cure the apnea or to obtain results comparable to those observed with CPAP treatment.38 Nasal reconstruction is used for the correction of obstruction in the nasal airway. Pharyngeal reconstruction, or uvulopalatopharyngoplasty (UPPP), is indicated for the correction of excess tissue in the soft palate, a large uvula, and enlarged tonsillar adenoidal tissue. Unfortunately, UPPP is only effective in about 50% of the cases.39 Laser-assisted uvulopalatoplasty (LAUP) is a similar procedure mostly used for the treatment of snoring. Its success rate for obstructive sleep apnea is lower than that of UPPP.39,40 Genioglossus advancement is used for obstruction at the base of the tongue, with the tongue being moved forward to enlarge the airway. UPPP combined with genioglossus advancement has a success rate of 61%.41 Maxillomandibular advancement is indicated for patients who do not respond to other forms of surgery. It is relatively contraindicated in the elderly population as they tend to have more risk factors such as heart disease, for example, atherosclerosis, placing them at risk for complications from this invasive surgical procedure. Tracheostomy was one of the first procedures for obstructive sleep apnea. Today it is used only for severe cases, when all else has failed, or in conjunction with UPPP. Drug treatments for SDB have generally been only marginally successful. For central sleep apnea, respiratory stimulants such as progesterone and acetazolamide may be appropriate. For SDB associated with REM sleep, tricyclic antidepressants may be indicated, as they reduce the amount of REM, thus indirectly reducing the number of respiratory events. Oral appliances have been developed for both obstructive sleep apnea and snoring, including the tongue-
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retaining device and the mandibular advancement device. Both devices are designed to enlarge the airway at the base of the tongue by advancing the tongue or the mandible forward. Although compliance rates are estimated to range between 50% and 100%, success rates (i.e., achieving a RDI < 10) are only about 50%.42 Thus, oral appliances are indicated for patients who do not respond to behavioral treatment such as weight loss or body position, who are intolerant to CPAP, or who are not candidates for surgery.43 Treatment options are based on the severity of the apnea, the patient’s medical status, the level of urgency in treating the apnea, and the patient’s own preference.
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Risk Factors A related disorder that occurs during the relaxed, awake state often just before sleep onset is restless leg syndrome (RLS). Patients report unpleasant sensations in their legs and irresistible movement of the legs. The disagreeable, sometimes painful leg sensations are alleviated by rubbing or squeezing the legs or simply by walking. The prevalence of RLS is not well defined. Most patients with RLS also suffer from PLMS, suggesting that these disorders may be related. Furthermore, many patients with PLMS also suffer from other sleep disorders, including SDB and REM sleep behavior disorder.46,47
Diagnosis and Differential Diagnosis
Periodic Limb Movements in Sleep Definition and Prevalence Periodic limb movements in sleep (PLMS) is a disorder of unknown etiology, in which patients involuntarily kick their limbs (most often it is their legs) in short, clustered episodes lasting between 0.5 and 5 s and occurring about every 20 to 40 s. The kicks are often accompanied by arousals. These episodes occur repeatedly throughout the night. The myoclonus index (MI) represents the number of kicks with arousals per hour of sleep. The prevalence of PLMS seems to increase with age. Ancoli-Israel et al.44 reported that 45% of randomly selected elderly adults aged 65 years and older had PLMS, compared to 5% to 6% of the younger adult population.45
Consequences of the Disorder As with SDB, the nighttime arousals are often too short to be recalled. However, patients with PLMS may complain of insomnia, as they may have difficulty falling asleep as well as settling back to sleep following these episodes. PLMS occur most often in the first half of the night, during sleep stages 1 and 2. Sleep is fragmented, with reduced amounts of stages 3 and 4 and REM.
Clinical Presentation In addition to complaining of difficulty falling asleep, patients may also complain of excessive daytime sleepiness, as they suffer from sleep fragmentation throughout the night. They may also note that the bedding is disorganized or jumbled when they wake up in the morning. Bed partners often complain of the leg kicks disturbing their sleep as well, and often it is important to obtain information from the bed partner in diagnosing and assessing the disorder.
PLMS is diagnosed in a full night sleep recording in the sleep clinic, which includes the recording of the anterior tibialis muscles to establish the MI. The muscular jerks are often accompanied by EEG signs of arousal, which may appear following the leg jerks. As with SDB, ambulatory equipment is available to record sleep in the comfort of one’s own home. PLMS is diagnosed with a MI greater than 5. PLMS and RLS may be associated with some medical conditions, including uremia, anemia, chronic lung disease,myelopathies,and peripheral neuropathies. Use of medications, such as tricyclic antidepressants and lithium carbonate, and withdrawal from benzodiazepines and anticonvulsants may all induce these disorders. Other movement disorders that should be differentiated from PLMS include the hypnic myoclonus, nocturnal leg cramps,and jerks associated with long-term use of l-dopa.48
Treatment and Management PLMS is treated by medications aimed at reducing or eliminating the leg jerks or the arousals. Dopaminergic agents such as carbidopa/levodopa, pergolide,49 and a newer drug, pramipexol, are the treatment of choice for PLMS, as they decrease or eliminate both the leg jerks and the arousals. These medications are also successful for the treatment of RLS.49 In one study, carbidopa/ levodopa was superior to propoxyphene in decreasing the number of leg kicks and the number of arousals per hour of sleep.50 However, carbidopa/levodopa and, to a lesser extent, pergolide may shift the leg movements from the nighttime to the daytime.49 Benzodiazepines, such as clonazepam and temazepam, are sometimes used to treat PLMS. These drugs do not eliminate the limb movements but do decrease the arousals, so that the patient sleeps more continuously throughout the night.51 Triazolam has been shown to be effective in older patients,52 although because of agerelated changes in pharmacokinetics and the need to
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avoid daytime sedation, it is recommended that low doses of triazolam be prescribed in this population.53 Furthermore, caution should be used in prescribing a sedative hypnotic to elderly patients who might have SDB, because sedatives exacerbate the severity of the respiratory events. Some of the longer-acting medications, particularly clonazepam, may not be eliminated by morning, particularly in older adults, causing daytime sedation. Opiates such as propoxyphene or Tylenol with codeine are effective in decreasing the leg kicks; however, the arousals may continue to occur.54
REM Sleep Behavior Disorder Definition and Prevalence REM sleep behavior disorder (RBD) is a disorder in which the muscle atonia typical of the REM state is absent, causing motor disinhibition presenting as vigorous movements that may be violent or aggressive toward the patient or the bed partner. Vivid dreams are often remembered on awakening and are consistent with the observed behavior. Most often the patients report not being the aggressors in the dream, but being the defenders of themselves or their family members. The harmful behavior is uncharacteristic of the waking individual. RBD is considered a neuropathologic disorder, although most often it is idiopathic. It has been associated with neurodegenerative impairments such as dementia, parkinsonism, Guillain–Barre syndrome, olivo-pontocerebellar degeneration, and subarachnoid hemorrhage.55 Some patients exhibit other sleep disorders, including narcolepsy and PLMS. It is also associated with psychiatric disorders such as depression and drug and alcohol abuse and withdrawal. The prevalence of REM behavior disorder (RBD) in the population has not been estimated; however, those diagnosed with the disorder are predominantly older men.56
Consequences The majority of the patients report injuries to themselves and to their spouses, including ecchymoses, lacerations, and fractures.56
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many as four episodes a night for several nights in a row. Some experience a nightly episode. There have been no reports of spontaneous remission. One-fourth of the patients report a prodrome in their history,which involved behavioral disinhibition of dreams, or other parasomnias, including sleeptalking, yelling, and limb jerks. Sleep recordings show elevated percentages of REM sleep, as well as a shortened REM latency.
Diagnosis and Differential Diagnosis A detailed history of the sleep disorder, from both the patient and the bed partner, should include the timing and frequency of the episodes and the type of the behavioral disturbance. Mahowald and Schenck57 have suggested minimal criteria for diagnosing RBD, including a history or videotape recording of abnormal sleep behavior, with an EMG recording showing elevated muscle tone and/or phasic limb twitching. Differential diagnoses include night terrors and sleepwalking, which are also disruptive behavioral enactments during sleep; however, unlike RBD, these are parasomnias that occur during non-REM sleep, often in the early part of the night. Another differential diagnosis is parkinsonism, as 30% of patients with this disease who are treated with l-dopa may exhibit similar sleep disturbance.58 In a longitudinal follow-up study of 29 male patients initially diagnosed with idiopathic RBD, 38% were subsequently diagnosed with a parkinsonian disorder.59 Compared with the idiopathic RBD group, those who developed parkinsonism had significantly elevated PLMS in non-REM sleep, as well as elevated REM sleep percentage. The authors implicate the pathology of the pedunculopontine nucleus in these combined disorders.
Treatment and Management Clonazepam is remarkably efficient in the treatment of both the vivid dreams and the disruptive behaviors in RBD. It can be taken at low doses for extended periods of time with minimal side effects.56 Alprazolam may be used when clonazepam is not well tolerated.58 However, benzodiazepines may be contraindicated in cases of SDB or excessive daytime sleepiness. Other treatment options include tricyclic antidepressants such as desipramine55,60 and carbamazepine.61
Clinical Presentation Episodes usually begin during the second half of the night when REM is most abundant, but usually no earlier than 60 to 90 min after sleep onset, which is when the first REM period is expected to occur. RBD may become more frequent over time. Patients may experience an episode once every 2 to 3 weeks, or as
Insomnia Definition and Prevalence Unlike SDB, PLMS, or RBD, insomnia is not considered a sleep disorder in itself, but rather a complaint of insuf-
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ficient and nonrestorative sleep. There are several possible causes for the insomnia complaint, including medical, psychiatric, drug and medication use, changes in circadian rhythms, and psychophysiologic issues. Insomnia may be short or transient, lasting only a few days to a few weeks. Most often, transient insomnia may be related to a specific event, such as taking an exam, moving to a new house, starting a new job, divorce, or loss of a loved one. The anxiety associated with the stressful event may interfere with sleep and, if not resolved effectively, poor sleep habits may turn into long-term psychophysiologic insomnia. The prevalence of insomnia increases with age.62 In a survey of more than 9000 elderly adults 65 years and older, 28% complained of difficulty initiating sleep, and 42% reported difficulty in both initiating and maintaining sleep.2 In a study done in the general practice, more than 50% of elderly patients reported insomnia, with 80% of those reporting that the insomnia was a chronic condition.63 Insomnia was associated with poor sleep hygiene and with depression. Women complained of insomnia more than men.64,65 The annual incidence rate of insomnia in the elderly was found to be 5% and was associated with depressed mood, respiratory symptoms, poor perceived health, physical disabilities, widowhood, and use of sedatives.66 Remission was estimated as 15% annually and was associated with improved self-perceived health, no new medical conditions such as heart disease and stroke, and improved physical functioning.66 AfricanAmerican women were found to have a higher incidence of insomnia than either African-American men or Caucasian men and women.67
Clinical Presentation Insomnia may present as a difficulty in falling asleep, which is referred to as sleep onset insomnia, or as a difficulty in maintaining sleep throughout the night, which is called sleep maintenance insomnia. In sleep onset insomnia, the patient may lie in bed without falling asleep from 30 min to a few hours. With sleep maintenance insomnia, falling asleep is achieved easily, but the patient awakens one to several times during the night and has difficulty falling back to sleep. Some patients have both sleep onset and sleep maintenance insomnia. In the elderly, waking up too early in the morning and having difficulty getting back to sleep is particularly prevalent, often secondary to advanced sleep phase syndrome (ASPS). ASPS is a common circadian rhythm sleep disorder in the elderly, in which the timing of the sleep period is advanced to an earlier hour and wake-up time is correspondingly advanced as well.
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Risk Factors Long-term or chronic insomnia may be caused by chronic medical conditions, such as cerebrovascular disease, arthritis, chronic obstructive pulmonary disease, and neurologic disorders.68 The pain and discomfort associated with these disorders may interfere with sleep. Psychiatric disorders are strongly related to the insomnia complaint.69 Depression is one of the most common causes of insomnia, and depressive symptoms are very common in the elderly population70 (see Chapter 79). Alerting or stimulating medications may cause insomnia, such as CNS stimulants, decongestants, beta-blockers, calcium channel blockers, corticosteroids, bronchodilators, and stimulating antidepressants.31 Substances such as alcohol, caffeine, and nicotine can all cause insomnia. Sedating medications may cause daytime drowsiness, which may lead to daytime napping, which subsequently may also lead to insomnia at night. Circadian rhythm changes with age may also present as an insomnia complaint.
Diagnosis and Differential Diagnosis Unlike the specific sleep disorders already discussed, a sleep recording in the sleep clinic is usually not warranted for complaints of insomnia because insomnia may not occur every night and often patients experience insomnia in their own bed but not in new environments. As multiple factors may contribute to the insomnia complaint, a comprehensive history should be taken with the patient and, when possible, with the bed partner. This information should include medical and psychiatric history and current medication use, including dosage and time of administration. Possible sleep disorders may present as insomnia, including PLMS and SDB. Identification of the underlying problem causing the insomnia is the key to successful treatment. A history should also include sleep-related habits such as napping, sleep–wake patterns on weekends versus weekdays, exercise regimens, timing and duration of bright light exposure, and caffeine or alcohol intake. Much of the sleep patterns and habits information can easily be obtained by asking the patient to fill out a sleep log for 1 or 2 weeks. An example of a typical sleep log can be seen in Table 70.1. Some sleep clinics also use a wrist activity monitor, called an actigraph, which reliably distinguishes sleep from waking based on level of activity,71,72 to diagnose insomnia. Patients wear this watchlike device and fill out a sleep log for about a week. Contrasting the objective actigraphic-based information with the subjective reports may reveal some misperceptions of the patient regarding their sleep. For example, insomnia patients may overestimate their sleep latency, that is, the amount of time that
70. Sleep and Sleep Disorders Table 70.1. Sleep diary. Day: __ Date: __ Patient ID: Complete before bedtime: 1. Time actigraph removed for bathing: __ : __ am/pm Time put back on: __ : __ am/pm 2. How many naps did you take today? Times: From: __ : __ am/pm To: __ : __ am/pm From: __ : __ am/pm To: __ : __ am/pm 3. How many cups of coffee or other beverages with caffeine did you drink? Times: __ : __ am/pm __ : __ am/pm 4. How many alcoholic beverages did you drink? Time: __ : __ am/pm __ : __ am/pm Complete in the morning: 1. What time did you go to bed? __ : __ am/pm 2. What time did you turn out the lights and go to sleep? __ : __ am/pm 3. How long did it take you to fall asleep? __ hours and __ minutes 4. How many awakenings did you have during the night? 5. What time did you wake up in the morning? __ : __ am/pm 6. What time did you get out of bed? __ : __ am/pm 7. Did you feel refreshed when you got up? yes/no
it takes them to fall asleep73,74 and underestimate their sleep efficiency.74 Abnormal sleep–wake patterns may indicate a circadian rhythm sleep disorder. These disorders occur when the physiologic propensity for sleep is misaligned with the environmental light–dark cycle. Thus, although sleep may not be disrupted, its timing is inappropriate with respect to the normal environment. Elderly patients often complain of early morning awakenings, which may be caused by advanced sleep phase, that is, they are tired early in the day and they wake up early in the morning, due to an advancement of their sleep–wake cycle. Duffy et al.6 have suggested that older individuals have a narrow window of time in which sleep is efficiently maintained, and this window is at an advanced clock time relative to younger adults. It is important to stress that although advanced sleep phase may present as insomnia, there is no sleep disruption associated with it, and only the timing of sleep is inappropriate or inconvenient. The differential diagnosis is important in terms of modes of treatment.
Treatment and Management As many factors may contribute to the insomnia complaint, identifying and treating the underlying cause is the key for a successful outcome. If insomnia is caused by a painful medical problem, successful treatment of the medical disorder will improve the insomnia as well. If depression is causing the insomnia, treatment of the depression will help resolve the insomnia.
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Changing the timing of medication administration may be important for resolving the insomnia. Ideally, stimulating medications should be taken early in the day, while sedating medications should be taken near bedtime. Some behavioral modification techniques have proven successful for the alleviation of psychophysiologic or primary insomnia. In a recent review by Morin et al.,75 70% to 80% of patients with primary chronic insomnia benefited from nonpharmacologic treatments. Sleep hygiene76 is a set of guidelines aimed at maintaining healthy sleep habits. Commonsense rules include avoiding or limiting naps, particularly late in the day, as daytime napping may interfere with nighttime sleep; avoiding substances that interfere with sleep, such as alcohol, caffeine, and nicotine; maintaining a stable sleep–wake pattern throughout the week; and exercising regularly, but not late in the day (physical or mental stimulation at night may interfere with sleep). For a summary of sleep hygiene rules for the elderly, see Table 70.2.77 Stimulus control therapy78 is another behavioral technique designed to remove all negative associations from the bedroom environment. The patient is instructed to go to bed only when sleepy. If unable to fall asleep in 15 to 20 min, the patient must leave the bedroom and engage in a relaxing activity, such as reading a magazine or writing a letter. Only when patients feel sleepy again can they return to bed. This procedure should be repeated as needed, until sleep is achieved in less than 15 min. For a summary of stimulus control therapy, see Table 70.3. Stimulus control therapy is appropriate for patients who feel stress, tension, or anxiety that are conditioned to the bedroom or the bed. They are caught in a vicious cycle, in which negative thoughts and feelings disrupt their ability to fall asleep, leading to more intensified adverse thoughts and feelings associated with the bedroom. Learning to associate the bedroom with relaxing feelings of sleepiness breaks the cycle and allows the patient to regain control over their sleep. Sleep restriction therapy79 is based on reducing time in bed to improve sleep efficiency. Many insomniacs try to
Table 70.2. Rules of sleep hygiene in the elderly. 1. 2. 3. 4. 5. 6. 7. 8. 9.
Maintain a regular sleep/wake schedule. Take no more than one nap per day. Limit nap time to less than 60 min early in the day. Exercise regularly. Spend time in bright outdoor light. Avoid caffeine, especially after lunch. Avoid alcohol and nicotine. Check the effects of medications on sleep. Limit liquid intake in the evening.
Source: From Martin J, Shochat T, Ancoli-Israel S. Assessment and treatment of sleep disturbances in older adults. Clin Psychol Rev. 2000;20:783–805, with permission.
1038 Table 70.3. Instructions for stimulus control therapy. 1. Patient goes to bed only when sleepy. 2. If not asleep within about 20 min, patient gets out of bed and engages in relaxing activity. 3. Patient returns to bed only when sleepy. 4. If patient again does not fall asleep within 20 min, repeat as necessary. 5. Wake-up time remains the same every day (regardless of number of hours asleep). 6. Daytime naps must be avoided. 7. Bed is used only for sleeping (not for reading, paying bills, or watching television). Source: From Bootzin RR, Nicassio PM. Behavioral treatments for insomnia. In: Hersen M, Eisler RM, Miller PM, eds. Progress in Behavior Modification, vol 6. New York: Academic Press; 1978:1–45,78 with permission.
get more sleep by going to bed early and spending more time in bed, when in fact this only worsens the problem. Thus, patients are instructed to stay in bed only for the amount of time that they actually sleep, plus 15 min. Actual sleep time is assessed by a subjective sleep log or an actigraph.80,81 When sleep efficiency reaches 85% or above, time in bed may be increased by 15 min. The procedure is repeated until the desired amount of time in bed is reached. Sleep restriction therapy was found to be superior to relaxation techniques80 and comparable to sleep hygiene therapy81 for the treatment of insomnia in communityresiding elderly after a 3-month follow-up. Bright light therapy is an effective treatment for circadian rhythm sleep disorders. The light–dark cycle is the most important synchronizer of our internal biologic clock, and changes in the timing of bright light exposure effectively shift altered circadian rhythms to a more appropriate phase. In the elderly, who most commonly have advanced sleep phase syndrome, exposure to bright light in the evening hours on a daily basis delays the sleep episode to a later phase, so that they no longer experience the early morning awakenings that often present as an insomnia complaint. Avoidance of bright light in the early morning hours is also important, as light exposure early in the day causes an advancement of the sleep episode. There is growing evidence that institutionalized elderly patients receive disturbingly low levels of illumination during the day, and this has been associated with poor sleep at night.82–84
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be determined to establish the appropriate type of sedative; that is, a short-acting, fast-absorbing hypnotic would be appropriate for sleep-onset insomnia (e.g., zolpidem or zaleplon), whereas a medium-acting hypnotic should be used for sleep maintenance insomnia (e.g., temazepam). Long-acting hypnotics are usually contraindicated, as they are bound to create excessive daytime sleepiness and diminished performance the following day, and may increase the risk of car accidents.85 Ultra-short-acting hypnotics, such as zaleplon, may be used both at the beginning of the night and again, if needed, in the middle of the night, without residual sedation in the morning.86,87 Pharmacologic treatment should be used in combination with behavioral therapy. In a small trial, Morin et al.88 compared the effectiveness of behavioral, pharmacologic, and combined behavioral and pharmacologic treatment for insomnia in the elderly. All three modes of treatment were effective compared to placebo in the short term, and the combined approach was slightly better than the behavioral or pharmacologic approaches alone. However, long-term follow-up revealed that those who received pharmacologic treatment alone showed a worsening of their sleep, whereas those who received behavioral treatment alone maintained their gains from posttreatment. For the combined approach group, followup results were more variable, that is, some patients maintained their gains in the long run while some did not. The use of melatonin for the alleviation of insomnia in the elderly has received much attention both in the scientific community and in the general media. Melatonin is a natural hormone that is secreted during the nighttime and is associated with sleep promotion and circadian rhythm regulation. The amount of melatonin secreted at night has been found to drop in the elderly, and this has been associated with the decline in sleep quality in older adults.89 Melatonin replacement in elderly insomniacs has been found to improve sleep efficiency.90 In a recent study, insomnia patients were able to discontinue benzodiazepine treatment and maintain good sleep quality with melatonin substitution.91 However, melatonin may be effective only in those insomnia patients whose melatonin levels are particularly low or depleted. Furthermore, caution should be used, as there is still much debate regarding the correct dosage and timing of administration. Finally, melatonin is currently sold as a food supplement and lacks proper quality control.
Pharmacologic Treatment
Sleep Disorders in Dementia
The use of sedative-hypnotics in the elderly population must be approached with caution. Because of changes in metabolic and elimination rates, the lowest effective dose must be used. The specific type of sleep disturbance should
Definition and Prevalence Dementia is highly associated with sleep disruption. Sleep–wake patterns in dementia are often polyphasic,
70. Sleep and Sleep Disorders
with frequent nighttime awakenings and redistribution of sleep episodes throughout the day.92 Ancoli-Israel and colleagues have reported that many institutionalized demented patients were neither awake nor asleep for a full hour in the day or night,93 and that while the mildly to moderately demented patients had extremely fragmented sleep at night, the severely demented patients were extremely sleepy during the day and night.94
Clinical Presentation Sleep structure is also altered in demented patients compared to healthy elderly individuals, with significantly lower amounts of stages 3 and 4 and REM sleep and significantly more awakenings, as well as more time spent awake during the night.92 Increased stage 1 sleep and decreased sleep efficiency have also been reported.95 REM latency has been found to increase in dementia patients, possibly due to the general reduction in the amount of REM found in these patients.96 The neuronal degeneration seen in Alzheimer’s disease is most likely the cause of these sleep changes. Neuronal structures that are damaged in this population and are implicated in sleep regulation include the basal forebrain and the reticular formation of the brainstem.96 As sleep changes are already evident in the early, mild stages of dementia, they may serve as markers of early dementia in clinical assessment. Nocturnal awakenings, often accompanied by agitation, confusion, and wandering, are typical in demented patients. These events are often referred to as “sundowning” behaviors, and as they typically occur at the same time of day, it has been suggested that they are related to a circadian rhythm disorder.97 Support for this hypothesis has come from studies using bright light treatment for circadian rhythm disorders. Satlin et al.98 used bright light therapy in the evening to improve sleep and behavioral disturbances in Alzheimer’s disease patients. Mishima et al. found similar results using morning bright light therapy.99 Lovell et al.100 reported that bright light therapy in the morning hours decreased agitated behaviors in the late afternoon in a group of institutionalized demented patients. In a recent study, Martin et al.101 challenged the idea of sundowning by showing that peak levels of agitation occur during various times of the day, but more often in the afternoon, rather than in the evening or night. However, they did find associations between circadian rhythms of activity, agitation, and light exposure, indicating that sleep disruption in demented individuals may be amenable to treatment using bright light exposure.
Risk Factors Ancoli-Israel et al.26 have reported a strong relationship between demented patients and sleep apnea, with the
1039
most severe apnea in the most severely demented group of patients. This positive association has been confirmed by several research studies, as summarized by AncoliIsrael and Coy.102 In a review of the literature, the prevalence of SDB in demented patients ranged between 33% and 70%.103 In a recent study of institutionalized Alzheimer’s disease patients, the prevalence of SDB was 80% with RDI of 10 or more and 48% with an RDI of 20 or more.104 Cognitive impairment is a common symptom in both dementia and SDB patients. In SDB, cognitive impairment is associated with the nocturnal hypoxemia, as well as the sleep fragmentation.27,28 In an epidemiologic study, Dealberto et al. (24) found a strong relationship between symptoms of SDB and cognitive impairment. Bliwise has suggested that SDB may contribute to cognitive decline in demented elderly, together with cerebrovascular disease and hypertension.5,105 Furthermore, he suggests that treatment of SDB may reverse the cognitive decline in demented patients or at least slow the dementia process. In a pilot study, Shochat et al.106 examined the possibility of treating demented patients with SDB using CPAP. They concluded that CPAP may be tolerated and may partially reverse cognitive decline (e.g., global mental functioning and memory) in some mildly demented patients. In summary, severe sleep disturbance is commonly found in the demented elderly population, which may be the result of neurodegenerative processes in areas in the brain that regulate sleep/wake and possibly circadian rhythm mechanisms.The high presence of SDB in this population may indicate that neuronal damage is also contributing to the respiratory difficulties during sleep, and these respiratory disturbances may be contributing to the cognitive impairment associated with the dementia.
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70. Sleep and Sleep Disorders 42. Schmidt-Nowara WW, Lowe A, Wiegand L, Cartwright R, Perez-Guerra F, Menn S. Oral appliances for the treatment of snoring and obstructive sleep apnea: a review. Sleep. 1995;18:501–510. 43. An American Sleep Disorders Associations Report. Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances. Sleep. 1995; 18:511–513. 44. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Periodic limb movements in sleep in community-dwelling elderly. Sleep, 1991;14(6):496–500. 45. Bixler EO, Kales A, Vela-Bueno A, Jacoby JA, Scarone S, Soldatos CR. Nocturnal myoclonus and nocturnal myoclonic activity in a normal population. Res Commun Chem Pathol Pharmacol. 1982;36:129–140. 46. Guilleminault C, Crowe C, Quera-Salva MA, Miles L, Partinen M. Periodic leg movement, sleep fragmentation and central sleep apnoea in two cases: reduction with Clonazepam. Eur Respir J. 1988;1(8):762–765. 47. Mahowald MW, Schenck CH. REM sleep behavior disorder. In: Thorpy MJ, ed. Handbook of Sleep Disorders. New York: Dekker; 1990:567–593. 48. Montplaisir J, Godbout R, Pelletier G, Warnes H. Restless leg syndrome and periodic limb movements during sleep. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine, 2nd Ed. Philadelphia: Saunders; 1994:589–597. 49. Earley CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep. 1996;19:801–810. 50. Kaplan PW, Allen RP, Buchholz DW, Walters JK. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levidopa and propoxyphene. Sleep. 1993;16(8):717–723. 51. Mitler MM, Browman CP, Menn SJ, Gujavarty K, Timms RM. Nocturnal myoclonus: treatment efficacy of clonazepam and temazepam. Sleep. 1986;9:385–392. 52. Bonnet MH, Arand DL. The use of triazolam in older patients with periodic leg movements, fragmented sleep, and daytime sleepiness. J Gerontol. 1990;45(4):M139– M144. 53. Greenblatt DJ, Harmatz JS, Shapiro L, Engelhardt N, Gouthro TA, Shader RI. Sensitivity to triazolam in the elderly. N Engl J Med. 1991;13:1691–1698. 54. Kavey N, Walters AS, Hening W, Gidro-Frank S. Opioid treatment of periodic movements in sleep in patients without restless legs. Neuropeptides. 1988;11(4):181–184. 55. Schenck CH, Bundlie SR, Ettinger M, Mahowald MW. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep. 1986;9:293–308. 56. Schenck CH, Mahowald MW. Polysomnographic, neurologic, psychiatric, and clinical outcome report on 70 consecutive cases with the REM sleep behavior disorder (RBD): sustained clonazepam efficacy in 89.5% of 57 treated patients. Clevel Clin J Med. 1990;57:S10–S24. 57. Mahowald MW, Schenck CH. REM sleep behavior disorder. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine, 2nd Ed. Philadelphia: Saunders; 1994:574–588.
1041 58. Sforza E, Krieger J, Petiau C. REM sleep behavior: clinical and physiopathological findings. Sleep Med Rev. 1997; 1:57–69. 59. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology. 1996;46:388–393. 60. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW. Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. JAMA. 1987;257:1786– 1789. 61. Bamford CR. Carbamazepine in REM sleep behavior disorder. Sleep. l993;16:33–34. 62. Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment. Prevalence and correlates. Arch Gen Psychiatry. 1985;42:225–232. 63. Hohagen F, Kappler C, Schramm E, et al. Prevalence of insomnia in elderly general practice attenders and the current treatment modalities. Acta Psychiatr Scand. 1994; 90:102–108. 64. Morgan K, Dallosso H, Ebrahim S, Arie T, Fentem PH. Characteristics of subjective insomnia in the elderly living at home. Age Ageing. 1988;17:1–7. 65. Chui HFK, Leung T, Lam LCW, et al. Sleep problems in Chinese elderly in Hong Kong. Sleep. 1999;22:717– 726. 66. Foley DJ, Monjan A, Simonsick EM, Wallace RB, Blazer DG. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6800 persons over three years. Sleep. 1999;22:S366–S372. 67. Foley DJ, Monjan A, Izmirlian G, Hays JC, Blazer DG. Incidence and remission of insomnia among elderly adults in a biracial cohort. Sleep. 1999;22:S373–S378. 68. Wooten V. Medical causes of insomnia. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia: Saunders; 1994:456–475. 69. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention? JAMA. 1989;262(11):1479–1484. 70. Blazer D, Burchett B, Service C, George LK. The association of age and depression among the elderly: an epidemiologic exploration. J Gerontol. 1991;46(6): M210–M215. 71. Hauri PJ, Wisbey J. Wrist actigraphy in insomnia. Sleep. 1992;15(4):293–301. 72. Sadeh A, Sharkey KM, Carskadon MA. Activity-based sleep-wake identification: an empirical test of methodological issues. Sleep. l994;17:201–207. 73. Bootzin RR, Wyatt JK, Valdiserri M, Ludwig C. Assessment of insomnia at home with wrist actigraphy and sleep diaries. Sleep Res. 1993;22:355. 74. Brooks JO III, Friedman L, Bliwise DL, Yesavage JA. Use of the wrist actigraph to study insomnia in older adults. Sleep. 1992;16(2):151–155. 75. Morin CM, Hauri PJ, Espie CA, Spielman AJ, Buysse DJ, Bootzin RR. Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep. 1999;22:1134–1156. 76. Hauri P, Linde S. No More Sleepless Nights. New York: Wiley; 1990:1–262.
1042 77. Hauri P. Case Studies in Insomnia. New York: Plenum; 1991: 1–268. 78. Bootzin RR, Nicassio PM. Behavioral treatments for insomnia. In: Hersen M, Eisler RM, Miller PM, eds. Progress in Behavior Modification, vol 6. New York: Academic Press; 1978:1–45. 79. Glovinsky PB, Spielman AJ. Sleep restriction therapy. In: Hauri PJ, ed. Case Studies in Insomnia. New York: Plenum; 1991:49–63. 80. Friedman L, Bliwise DL, Yesavage JA, Salom SR. A preliminary study comparing sleep restriction and relaxation treatments for insomnia in older adults. J Gerontol. 1991; 46(1):P1–P8. 81. Friedman L, Benson K, Noda A, et al. An actigraphic comparison of sleep restriction and sleep hygiene treatments for insomnia in older adults. J Geriatr Psychiatry Neurol. 2000;13:17–27. 82. Ancoli-Israel S, Klauber MR, Jones DW, et al. Variations in circadian rhythms of activity, sleep and light exposure related to dementia in nursing home patients. Sleep. 1997; 20:18–23. 83. Martin J, Shochat T, Marler M, Ancoli-Israel S. Circadian activity rhythms, sleep/wake and light exposure in nursing patients. Sleep. 2000;23:A216. 84. Martin J, Shochat T, Gehrman P, et al. Light, sleep and agitation in Alzheimer’s disease patients. Soc Light Treat BioRhythms. 2000;12:13. 85. Hemmelgarn B, Suissa S, Huang A, Boivin JF, Pinard G. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA. 1997;2:27–31. 86. Walsh JK, Pollack CP, Scharf MB, Schweitzer PK, Vogel GW. Lack of residual sedation following middle-of-thenight zaleplon administration in sleep maintenance insomnia. Clin Neuropharmacol. 2000;23:17–21. 87. Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M, Zaleplon Clinical Study Group. Zaleplon, a novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Comp J Clin Psychiatry. l999;1:114–120. 88. Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late life insomnia. JAMA. 1999;281:991–999. 89. Haimov I, Laudon M, Zisapel N, et al. Sleep disorders and melatonin rhythms in elderly people. Br Med J. 1994;309: 167. 90. Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18(7):598–603. 91. Garfinkel D, Zisapel N, Wainstein J, Laudon M. Facilitation of benzodiazepine discontinuation by melatonin: a
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new clinical approach. Arch Intern Med. 1999;159:2456– 2460. Prinz PN, Peskind ER, Vitaliano PP, et al. Changes in the sleep and waking EEGs of nondemented and demented elderly subjects. J Am Geriatr Soc. 1982;30:86–92. Jacobs D, Ancoli-Israel S, Parker L, Kripke DF. Twentyfour hour sleep-wake patterns in a nursing home population. Psychol Aging. 1989;4(3):352–356. Pat-Horenczyk R, Klauber MR, Shochat T, Ancoli-Israel S. Hourly profiles of sleep and wakefulness in severely versus mild-moderately demented nursing home patients. Aging Clin Exp Res. 1998;10:308–315. Bliwise DL. Sleep in dementing illness. Annu Rev Psychiatry. 1994;13:757–777. Prinz PN, Vitaliano PP, Vitiello MV, et al. Sleep, EEG and mental function changes in senile dementia of the Alzheimer’s type. Neurobiol Aging. 1982;3:361–370. Bliwise DL, Carroll JS, Lee KA, Nekich JC, Dement WC. Sleep and sundowning in nursing home patients with dementia. Psychiatry Res. 1993;48:277–292. Satlin A, Volicer L, Ross V, Herz L, Campbell SS. Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer’s disease. Am J Psychiatry. 1992; 149:1028–1032. Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia. Acta Psychiatr Scand. 1994;89:1–7. Lovell BJ, Ancoli-Israel S, Gevirtz R. The effect of bright light treatment on agitated behavior in institutionalized elderly. Psychiatry Res. 1995;57:7–12. Martin J, Marler MR, Shochat T, Ancoli-Israel S. Circadian rhythms of agitation in institutionalized Alzheimer’s disease patients. Chronobiol Int. 2000;17:405–418. Ancoli-Israel S, Coy T. Are breathing disturbances in elderly equivalent to sleep apnea syndrome? Sleep. 1994; 17:77–83. Ancoli-Israel S. Epidemiology of sleep disorders. In: Roth T, Roehrs TA, eds. Clinics in Geriatric Medicine. Philadelphia: Saunders; 1989:347–362. Ancoli-Israel S, Poceta JS, Stepnowsky C, Martin J, Gehrman P. Identification and treatment of sleep problems in the elderly. Sleep Med Rev. 1997;1:3–17. Bliwise DL. Is sleep apnea a cause of reversible dementia in old age? J Am Geriatr Soc. 1996;44:1407–1409. Shochat T, Cohen-Zion M, Ancoli-Israel S. The effects of CPAP treatment on cognitive function in dementia: a pilot study. Sleep. 2000;23:A21.
71 Herpes Zoster Kenneth Schmader
Herpes zoster is a neurocutaneous disease caused by the reactivation of varicella-zoster virus (VZV) from a clinically latent state in dorsal sensory or cranial ganglia. VZV reactivation preferentially affects elderly persons and usually results in dermatomal pain and a vesicular skin eruption. Zoster has been recognized since ancient times, but only recently have large numbers of persons experienced the disease, owing to population aging and increasing numbers of immunosuppressed hosts. Although a scourge for the patient, zoster is a remarkable phenomenon for clinical observers. Dr. HopeSimpson said it best when lecturing the Royal College of Physicians in England: “Herpes zoster is fascinating because it arrives unpredictably, is readily diagnosed—a rare pleasure for most of us—and difficult to explain.”1
Epidemiology Risk Factors
greater than 75 years.3 Donahue et al. confirmed this relationship in Boston where they reported an incidence of 1.9, 2.3, 3.1, 5.7, and 11.8 per 1000 person-years for the age groups 25 to 34, 35 to 44, 45 to 54, 55 to 64, and 65 to 75+ years, respectively.5
Cellular Immunity The other strong risk factor for zoster is cellular immune dysfunction. In vitro lymphoproliferative responsiveness to VZV antigens is significantly diminished in immunosuppressed patients and in the elderly. In vivo, zoster is more frequent and severe in patients with hematologic malignancies, organ transplants, HIV infection, immunomediated diseases, and immunosuppressive therapies.6–10 Patients with solid tumors are at lesser risk for zoster, but in one large series treated patients of any age with lung, breast, or gynecologic cancers were more likely to have zoster than those with other solid tumors.6 Conversely, zoster is not a risk factor for cancer, so the presence of zoster in an elderly patient should not trigger a diagnostic search for a presumed underlying malignancy.10
Aging The cardinal epidemiologic feature of herpes zoster is its striking relationship to aging. Primary VZV infection usually occurs during childhood and adolescence in temperate zones (childhood to young adulthood in tropical zones), and VZV establishes a latent infection in more than 95% of the adult population (Fig. 71.1).2 However, the likelihood of symptomatic VZV reactivation increases sharply with aging.1–5 For example, HopeSimpson’s study of zoster cases in England showed an incidence of 0.74 per 1000 per year in children under 10 years old, 2.5 per 1000 per year in adults aged 20 to 50 years, and 7.5 per 1000 per year in those older than 60 years old.1 Ragozzino et al. found a similar dramatic increase with aging in Minnesota, where the incidence of zoster was less than 1 per 1000 per year under 44 years old but peaked at 4 to 4.5 per 1000 per year at ages
Other Factors Other potentially important but less well-established risk factors include physical trauma, radiation therapy, psychologic stress, and white race. In a case-control study of stressful life events and zoster in the elderly, cases experienced negative life events significantly more often than controls at 2 months before zoster onset [odds ratio (OR) 2.64, 95% confidence interval (CI) 1.13, 6.27] and 3 months before onset (OR 2.64, 95% CI 1.20, 6.04).11 In the Duke Established Populations for the Epidemiological Studies of the Elderly (EPESE), stressful life events increased the risk of zoster but the result was borderline for statistical significance [adjusted relative risk (RR) = 1.38, 95% CI 0.96–1.97, p = 0.078], and methodologic limitations precluded definitive conclusions about these results.12 Regarding race, in the Duke EPESE, blacks 1043
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Figure 71.1. Age-related activity of varicella-zoster virus in a population in a temperate region. (Reprinted by permission of the New England Journal of Medicine 1983;309:1366.2)
were four times less likely than whites to develop zoster over their lifetimes, after adjusting for age, cancer, sex, and education (adjusted OR 0.25, 95% CI 0.18–0.35).13 In a follow-up prospective study of the incidence of zoster in blacks and whites in the Duke EPESE, blacks were significantly less likely than whites to develop zoster (adjusted risk ratio 0.35, 95% CI 0.24–0.51).12 Gender, education, residence, season, and exposure to zoster or to chickenpox do not predict zoster.1,3,13,14
Incidence The incidence of herpes zoster in Western populations of all ages is estimated to be between 1.3 and 3.4 per 1000 person-years.1,3,5,15 Estimates of the incidence of zoster in the elderly vary from 3.9 to 11.8 cases per 1000 personyears.1,3,5,13,15 The incidence of zoster in populations limited to immunosuppressed patients is substantially higher. For example, the incidence of zoster in HIVinfected individuals ranges from 29 to 51 per 1000 personyears.8,16,17 Investigators have used these data to calculate an overall lifetime incidence of zoster of 10% to 20% and to estimate the total number of cases in the United States each year to be at least 600,000.18 Elderly patients usually experience zoster only once, but second attacks occur in 1% to 5% of zoster victims. With population aging, the total number of zoster cases worldwide will increase significantly in the future.
Transmission The potential infectivity of the elderly zoster patient is an important component of the disease. Viable, cell-free,
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infectious VZV is present in vesicular lesions. Although less infectious than varicella patients, an elderly zoster patient can transmit varicella to an uninfected susceptible host. There is no evidence that the elderly zoster patient transmits varicella or herpes zoster to latently infected individuals.14 Regarding infection control, susceptible, seronegative persons should avoid contact with the zoster patient until the rash has crusted over. To protect susceptible staff and patients, the Centers for Disease Control recommends a private room and standard precautions for immunocompetent hospital patients with localized zoster. For immunocompromised patients in hospital with localized zoster or any patient with disseminated zoster, the recommendations are a private room with special ventilation and airborne and contact precautions. The risk of VZV transmission is thought to be higher in these patients.19 Similar measures are advocated for zoster patients in long-term care facilities but modified for the special problems and limited resources of these facilities.20 For example, private rooms may be available only for the patient with disseminated zoster. These precautions no longer apply when the rash has crusted over because VZV is very difficult to recover and the patient is no longer contagious.
Pathogenesis Varicella-Zoster Virus The causative agent is a double-stranded DNA virus of the herpesvirus family. The VZV genome contains approximately 125,000 nucleotide base pairs and encodes about 70 gene products.21,22 These products include glycoproteins located in the viral envelope that bind to host cell receptors, initiate cellular infection, and stimulate the host immune response. Other protein products include the enzymes thymidine kinase and viral DNA polymerase. Viral thymidine kinase catalyzes the transformation of nucleoside analogues such as acyclovir to the triphosphate form that inhibits VZV DNA polymerase and viral replication.
Primary and Latent Infection VZV causes primary infection when it invades the respiratory tract of a VZV-naive individual. From the respiratory tract, VZV disseminates in the blood and infects the skin, causing the rash of chickenpox. During this time, VZV also infects dorsal sensory and cranial nerve ganglia where it establishes a latent, lifelong infection. The persistence of VZV in asymptomatic adults has been confirmed by the detection of VZV DNA and RNA in spinal and trigeminal ganglia by in situ hybridization and by amplification of VZV DNA using the polymerase chain
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reaction (PCR).23,24 The virus is present in both neurons and satellite cells during latency.22 VZV appears to evade the immune system during latency by limiting expression of viral proteins and downregulating the expression of MCH class I antigens.
immunity and the age-related increase in herpes zoster are coincidence or cause and effect is unknown.
Reactivation
Acute Herpes Zoster
The molecular mechanisms responsible for VZV reactivation are poorly understood. Available evidence suggests that VZV sporadically replicates throughout life but the host immune response prevents clinical manifestations. As host immunity wanes, the likelihood of reactivated VZV causing zoster increases.25 As with other herpesviruses, cell-mediated immunity is much more important than humoral immunity in defending VZV reactivation. For example, patients with agammaglobulinemia do not have an increased risk for zoster whereas diseases and therapies that affect T cells (hematologic malignancies, AIDS, cancer chemotherapy) markedly increase the incidence and severity of zoster. Age-related decline in the number and function of Tcell responders to VZV plays a role in the development of zoster in old age. Studying lymphocytes from young (n = 14) and old (n = 15) subjects, Miller first demonstrated that the proliferative response of these cells to VZV antigen in vitro was significantly less in the elderly.26 Berger et al. confirmed age-related differences in VZV antigen-dependent lymphocyte proliferation by demonstrating a low or absent stimulation index in lymphocytes from 33 of 100 (33%) healthy elderly and 0 of 43 (0%) persons aged 20 to 40 years.27 Burke et al. studied lymphocyte proliferation and skin test reactivity to VZV antigen in 157 healthy, latently infected subjects of all ages.28 Mean stimulation indices declined steadily by decade from a peak mean of 6.28 in 1- to 10-year-olds (n = 24) to 2.10 in 60- to 70-year-olds (n = 12), 1.56 in 70to 80-year-olds (n = 12), and 1.39 in 90- to 100-year-olds (n = 13). In addition, the percent of positive skin test responses to VZV progressively decreased with aging, starting at 89% in 30- to 40-year-olds to 18% in 60- to 70-year-olds, 8% in 70- to 80-year-olds, and 0% in 80- to 100-year-olds. Finally, Hayward et al. used lymphoproliferative responses to VZV antigens to estimate the frequency of VZV-responsive lymphocytes in blood from healthy old (n = 6) and young (n = 6) subjects.29 Mean responder cell frequency was 1 : 14,300 ± 2000 (one VZV-responsive lymphocyte per 14,300 lymphocytes) in young volunteers and 1 : 78,000 ± 6600 in elderly subjects (p = 0.002). Further studies by Hayward et al. have confirmed these findings in larger numbers of subjects.30 Although these studies were limited by cross-sectional design and small sample size, they demonstrated consistent results using similar methodologies. Whether the age-related decline in tests of in vitro VZV cellular
Prodrome
Clinical Features
As VZV spreads in the dorsal ganglion and afferent nerve, the patient usually experiences a prodrome of pain, discomfort, or paresthesias in the affected dermatome. This distressing prelude bewilders patients, caregivers, and physicians because the cause is not readily apparent and it masquerades as many other conditions in the elderly, such as biliary colic, appendicitis, kidney stones, pleuritis, myocardial infarction, acute musculoskeletal pain, trigeminal neuralgia, and migraine headaches. One potentially useful clue to the diagnosis is tender or hyperesthetic skin in the affected dermatome during this prodrome. The experienced clinician should keep herpes zoster in the differential diagnosis of any acute, unilateral, localized pain syndrome in the elderly, particularly if unexplained after the history and examination.
Rash After a few days of the prodrome, the rash erupts and the diagnosis of zoster becomes apparent (see Fig. 59.4). The rash begins as an erythematous maculopapular eruption that is unilateral and dermatomal. Within a day or two, vesicles form on this erythematous base. The exanthem may be confluent or scattered about the dermatome and a few satellite lesions may be found in adjoining dermatomes. It appears most frequently on the areas of the trunk innervated by T3 to L3 and on the areas of the face innervated by the ophthalmic division of the trigeminal nerve.1,3,31 Typically, the vesicles crust over in 7 to 10 days (2–3 weeks in immunocompromised individuals) and the crusts persist for 2 to 3 weeks. The impact of the rash ranges from an uncomfortable nuisance to serious problem in the elderly, including dissemination to other areas of skin, secondary bacterial infection, scarring, embarrassment and social withdrawal when on the face, and inaccessibility for proper care when on the back.
Pain The acute neuritis produces significant pain in most elderly patients but the pain experience is remarkably variable, reflecting the variability of many conditions in geriatrics. A small percentage (~10%) of elderly zoster patients undergo little or no pain.32 For those with pain or discomfort, the severity ranges from mild to severe; the
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quality includes terms like burning, deep aching, tingling, itching, and stabbing; and the temporal aspects vary from constant to intermittent. The acute zoster pain experience can have a tremendous effect on the patient’s quality of life and functional status by interfering with personal care, mobility, sleep, energy, mood, and socialization.
Atypical Presentations Zoster is no different from other conditions in geriatrics in its ability to present atypically. The rash may be small and inconspicuous or it may be disseminated over several dermatomes. In AIDS patients, chronic, indolent VZV replication can generate a hyperkeratotic, verrucous rash.33 In other clinical scenarios, the rash may not be present as a diagnostic guide. For example, investigators have described prodromal pain for a month or more before the appearance of the rash, so-called preherpetic neuralgia.34 Typical unilateral, dermatomal, neuralgic pain due to zoster can occur without a rash, an event entitled zoster sine herpete.35 Besides dermatomal pain, acute facial palsy, hearing loss, vertigo, and/or dysgeusia (cranial polyneuritis); blurred vision and a painful eye (acute retinal necrosis); fever, delirium, and meningismus (meningoencephalitis); back pain, leg paraparesis and ascending paresthesias (myelitis); and hepatitis may be the first manifestations of zoster without a rash.36–39
Postherpetic Neuralgia Postherpetic neuralgia (PHN) is the most debilitating and feared feature of zoster in the elderly. A common definition of PHN is pain 1 month after the onset of the rash, although alternative definitions include pain after the rash has healed or pain 3 months after rash onset.40,41 Like zoster, the overriding epidemiologic feature of PHN is its striking relationship to aging. For example, deMoragas and Kirkland reported pain greater than 1 month in 10% of zoster patients less than 40 years old, 42.3% of those 40- to 59 years old, and 68% of those greater than 60 years old.32 Other risk factors include greater severity of the acute pain, greater rash severity, the degree of sensory impairment in the affected dermatome, and a painful prodrome.42–44 In the placebo group of a large acyclovir trial in zoster patients over 60 years old, 61% of patients had pain 1 month after rash onset.45 PHN victims describe their suffering with words like burning, throbbing, stabbing, shooting, sharp, aching, gnawing, tiring, and tender.46 These descriptors and clinical studies have revealed that PHN pain is spontaneous and/or stimulus evoked.47 The spontaneous pain usually involves constant pain and/or brief, intermittent shocklike pain. Patients may also note distracting tingling or
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itching. Stimulus-evoked pain consists of allodynia or hyperpathia. Allodynia is pain elicited by an innocuous stimulus, but that definition does not convey how terrible this can be for the elderly patient. The touch of bedsheets or clothing may be so unbearable that patients remain partially naked, effectively trapped in their home. Hyperpathia is an exaggerated pain after a mildly painful stimulus. For example, a minor bump of the affected dermatome against an object can send the patient to bed with severe pain that lasts for hours. Cutaneous scarring and disordered sensation is not uncommon in the affected dermatome. Careful sensory testing often reveals a discrete area of tenderness in the affected dermatome but absent or diminished thermal, touch, vibration, or pinprick sensation.48 These findings are curious because PHN is a “positive” neurologic phenomenon (pain) but the exam shows “negative” findings (decreased or absent sensation). PHN profoundly affects the elderly patient’s quality of life and functional status. Patients can suffer from a variety of constitutional symptoms including chronic fatigue, anorexia, weight loss, and insomnia. PHN is a well-known cause of depression in the elderly. The social activities of many patients and their spouses are often curtailed by the illness, and the patient’s social role may change from a vital member of the community to an inactive individual in a household. Furthermore, PHN can interfere with dressing, bathing, grooming, eating, and mobility. For example, the patient with allodynic skin may be forced to avoid bathing or clothing around the affected area. Instrumental ADLs commonly affected include traveling, shopping, cooking, and housework.
Other Complications Ocular VZV reactivates in the ophthalmic division of the trigeminal nerve in 10% to 15% of zoster patients.3,40 The appearance and location of the facial rash do not necessarily predict the location and extent of eye involvement. Rash on the tip of the nose, indicating involvement of the nasociliary branch, appears to increase the likelihood of inflammation of the eye. The uvea and the cornea are the most common sites of inflammation, but any part of the eye is vulnerable.49,50 VZV-induced damage to these structures can result in glaucoma, optic neuritis, optic atrophy, corneal anesthesia and ulceration, cataract, eyelid scarring and retraction, compromised vision, and blindness.51 In one study of the natural history of ophthalmic zoster in untreated patients, 50% of patients developed ocular complications and 28% had active ocular disease 6 months or more after rash onset.49
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VZV can also cause acute retinal necrosis, which is characterized by destructive retinal inflammation and affects adults of any age.51–53 Patients do not exhibit facial rash; instead, they present with blurred vision and a painful eye. The fundus shows peripheral yellow-white patches indicative of retinal inflammation. These changes are not specific for VZV but VZV is frequently found in the lesions. The inflammation usually persists for 4 to 5 weeks and is followed by retinal scarring and detachment. Years later, the unaffected eye can develop the same pathology.
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cent to the ophthalmic division of the trigeminal nerve and cause granulomatous angiitis with resultant thrombosis. Weeks to months after zoster, patients present with fixed or transient motor deficits contralateral to the zoster-affected side. The delayed manifestation may preclude the clinician from making the link between the stroke and the prior occurrence of ophthalmic zoster. These patients show segmental narrowing or occlusion of cerebral arteries next to the affected ophthalmic division on a cerebral arteriogram.
Visceral Neurologic Considering the focus and spread of VZV within the peripheral and central nervous system, it is not surprising that zoster is associated with several neurologic complications along with PHN.54 Up to 5% of zoster patients develop focal motor pareses involving muscle groups innervated by ventral horn neurons in proximity to dorsal horn neurons of the affected dermatome. The most commonly affected muscles are those of the extremities with zoster of the accompanying dermatome and the face with zoster of the seventh cranial nerve. Oculomotor weakness (cranial neuritis), unilateral diaphragmatic paralysis (cervical zoster), bladder and anorectal dysfunction (sacral zoster), and intercostal muscle weakness (thoracic zoster) have also been reported. These deficits usually occur at the time of or within a few weeks after the onset of the rash. Full or partial recovery of motor function occurs in 65% to 85% of patients within months of the onset of weakness, but VZV-induced facial palsy has a much lower rate of recovery (30%–40%).55,56 Other important neurologic complications include cranial neuropathy, meningoencephalitis, transverse myelitis, and cerebral stroke. Zoster-induced cranial nerve symptoms include facial weakness with involvement of cranial nerve (CN) V or VII; hearing loss, imbalance, hyperacusis, and tinnitus with CN VIII; dysgeusia and mouth lesions with CN V, mandibular branch, and CN IX; and pharyngitis and laryngitis with CN IX, X.54,57 The patient may have multiple symptoms because more than one cranial nerve can be involved in an attack. Cephalic herpes zoster (Ramsay Hunt syndrome) refers to VZV-induced facial palsy and otic vesicles, often in association with CN VIII and/or other cranial nerve symptoms.54 Clinically overt meningoencephalitis rarely occurs in the elderly. The clinical manifestations of fever, delirium, headache, and meningismus may occur days or weeks before, during, or up to 2 months after the rash.58 Most patients survive and regain premorbid cognitive functioning. Cerebral stroke or transient ischemic attacks are a recognized complication of ophthalmic zoster in older patients.59,60 VZV appears to infect cerebral arteries adja-
Under conditions of severe immunosuppression, reactivated VZV can cause pneumonitis, hepatitis, esophagitis, gastritis, cystitis, and arthritis.25 These complications are unusual in the typical elderly zoster patient.
Diagnosis Clinical The clinical diagnosis of herpes zoster in the elderly is ordinarily unmistakable and sufficient. Burns and contact dermatitis may infrequently resemble zoster, but the history and clinical course will lead to the diagnosis. The principal condition in the differential diagnosis is zosteriform herpes simplex. The differentiation is most challenging in the elderly when the herpes simplex virus (HSV) reactivates in sacral and trigeminal dermatomes and produces lesions on the buttocks or face that are indistinguishable from zoster. HSV commonly produces a short, mild prodrome; generates smaller, closely grouped vesicles; recurs many times; affects younger adults; and very rarely causes postherpetic neuralgia.25 However, the appearance of the rash and the clinical situation may make it impossible to distinguish the two conditions and lead to misdiagnosis.61,62
Laboratory Diagnostic testing is useful for differentiating herpes zoster from herpes simplex, for suspected organ involvement, and for atypical presentations. Available tests can provide a definitive diagnosis of herpes zoster by detecting (1) VZV antigens using immunofluorescent antibody (IFA) techniques, (2) VZV replication in culture, (3) VZV antibody by serology, or (4) VZV DNA by the polymerase chain reaction (PCR) in the target specimen (vesicle fluid/scrapings, involved tissue, CSF, or blood) (Table 71.1). Of these options, IFA is the most expedient and useful test because it is rapid, specific, and sensitive.63 A rash specimen is easily prepared by scraping or swabbing the base of an unroofed vesicle, placing the material on a slide, and fixing it by air-drying or acetone. The slide
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Table 71.1. Laboratory diagnostic tests for herpes zoster. Test
Sensitivity
Specificity
Turnaround
Comment
IFA Culture Serology PCR
Very high Low Moderate Very high
High High Moderate High
Hours Days Weeks Hours
Preferred test in most patients Positive test needs confirmatory test Retrospective diagnosis Limited availability, expensive
IFA, immunofluorescent antibody (direct or indirect); PCR, polymerase chain reaction.
is stained with an anti-VZV monoclonal antibody that is tagged with an immunofluorescent label. The microscopic detection of fluorescence indicates the presence of VZV antigen and confirms the diagnosis. Cell culture of infected specimens can isolate VZV. A positive culture shows the typical cytopathic effects (CPE) of in vitro herpes virus infection—distinct foci of enlarged, fused cells that appear multinucleated and contain intranuclear inclusions. However, VZV culture is limited by the slow time for a result (usually several days but as little as 1–2 days with the shell vial technique), the nonspecific nature of CPE (a positive culture requires immunologic confirmation), and significant insensitivity (VZV is very labile).64 Serologic tests can provide a retrospective diagnosis if acute and convalescent sera are obtainable and show a fourfold or greater increase in VZV IgG titers. The most sensitive and specific tests are fluorescent antimembrane antibody (FAMA), enzyme-linked immunofluorescent antibody (ELISA),latex agglutination,and radioimmunoassays (RIA).25 Although not useful for acute infection, serologic tests are occasionally helpful for atypical syndromes such as zoster sine herpete. The PCR detects VZV DNA by repeated amplification of target segments of the VZV genome. The PCR is a powerful, extremely sensitive, specific technique that can produce results in a day. Researchers have used the PCR to detect VZV DNA in the rash, conjunctiva, synovial fluid, cerebrospinal fluid, a variety of tissues, and in the air surrounding patients with chickenpox and zoster and in mononuclear cells of asymptomatic elderly persons.65–69 The principal disadvantage of the PCR is its extreme sensitivity and potential for false positives.
Prognosis The prognosis of herpes zoster is related to the duration and severity of pain. The duration and severity of zoster pain is significantly greater in older patients than younger patients. In general, the number of elderly zoster patients with pain declines over weeks to months from rash onset. Specific data on pain duration in elderly zoster patients is limited by the lack of population-based studies of this phenomenon. Nonetheless, data from patient groups and recent clinical trials provide some useful information.
Studies of predominantly older adults in the preantiviral era found that the percentage of patients with any pain 6 months after rash onset was 41% to 46% and one year after rash onset was 28% to 41%.1,32 The upper figures in these ranges are partly elevated by referral bias. In a meta-analysis of acyclovir trials, the percent of patients 50 years of age or older with any pain in the placebo group was 54% at 3 months and 35% at 6 months after rash onset (12-month data not available).70 These data indicate that a substantial subset of elderly zoster patients have a poor prognosis with respect to pain. Many of these patients are refractory to all treatments, and some may actually get worse over time.71 Furthermore, some patients have pain-free intervals of weeks or even months only to note the return of their pain. Nonetheless, the geriatrician can offer hope to the acute zoster pain sufferer because the majority of elderly zoster patients note the loss of pain in the weeks or months after rash onset. Furthermore, some patients with long-lasting pain eventually have a good outcome. In a study of 88 patients with PHN of 1 year or more, 31 (35%) had mild pain and no disability after an average of 2 years of follow-up.71
Treatment Acute Herpes Zoster Rash Recommended treatments for the rash are empirical because there are no clinical trials of topical therapy. The stage of the rash determines the choice of therapy. For an uncomplicated rash, soap and tap water are sufficient to keep the wound clean and provide some comfort. For the patient with multiple, oozing vesicles, wet dressings with aluminum acetate (Burow’s solution), acetic acid, or zinc sulfate dry lesions and prevent secondary infection. Calamine lotion, cornstarch, or baking soda are said to be useful by some patients in this phase. The typical rash heals in 3 to 4 weeks. Oral antiviral therapy reduces the time of rash healing by a mean of 1 to 2 days.45
Pain The principal goal of the treatment of herpes zoster in the elderly is the reduction or elimination of pain. Anti-
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viral therapy, anti-inflammatory drugs, and analgesics are three strategies to achieve that goal.
Antiviral Therapy (Table 71.2) Available anti-VZV drugs are nucleoside analogues that are converted first by VZV thymidine kinase and then cellular kinases to the nucleoside triphosphate form. This compound stops VZV from replicating by inhibiting VZV DNA polymerase and by incorporation into the VZV DNA chain. In general, these drugs are safe and well tolerated in the elderly. The most common side effects are nausea and/or vomiting, diarrhea, and headache in about 8% to 17% of patients.45,72,73 To be effective, the drugs must be used early during zoster. The beneficial effects occur most when the drugs are begun within 48 to 72 h of rash onset. They are all renally excreted.
Acyclovir When used early, oral acyclovir can reduce acute zoster pain.74 The effect of acyclovir on chronic pain is less apparent because clinical trial data conflict. It is difficult to combine data from available studies because of differences in study methods and definitions of postherpetic neuralgia. Nonetheless, a recent meta-analysis combined the results of five randomized, placebo-controlled trials of oral acyclovir and used any pain at 6 months as the outcome.75 None of these studies reported significant differences in the proportion of treated or placebo patients with pain at 6 months, but there was a trend favoring acyclovir in four of the studies. When the data were combined, the summary odds ratio for the incidence of any pain at 6 months for patients treated with acyclovir was 0.54 (95% CI, 0.36–0.81). Acyclovir is useful for ophthalmic zoster, visceral, and central nervous system infections, and for the immunosuppressed host. Oral acyclovir reduced keratitis, uveitis, and ocular complications significantly in placebocontrolled trials of older patients with ophthalmic zoster.76 Depending on the nature of the pathology, some ophthalmologists employ topical corticosteroids to reduce severe inflammation and mydriatics to reduce pupillary sphincter and ciliary body muscle spasm and prevent anterior lens and pupil synechiae.77 Intravenous (i.v.) acyclovir, at doses of 10 mg/kg every 8 h for 7 to 10 days, is recommended in severely immunosuppressed patients
with localized zoster and for any patient who develops serious VZV-induced disease such as meningoencephalitis, pneumonitis, acute retinal necrosis, generalized dissemination, or other organ system complications.78 Acyclovir i.v. does not appear to affect PHN but it does reduce the likelihood of cutaneous, visceral, or central nervous system complications in the immunosuppressed host.79 Oral acyclovir is sufficient for localized zoster in mildly immunosuppressed patients. Acyclovir-resistant VZV, mediated by the lack of thymidine kinase, has been reported only in AIDS and transplant patients on prolonged acyclovir therapy and not in elderly patients.80,81
Famciclovir Famciclovir is a prodrug that is well absorbed in the gastrointestinal tract and metabolized in the liver to penciclovir. Penciclovir has a chemical structure very similar to that of acyclovir. A placebo-controlled trial of famciclovir in immunocompetent zoster patients more than 18 years old (mean, 51 years old) demonstrated a significantly shorter overall duration of zoster pain in the treated group.73 The proportion of patients with pain at rash healing (the study definition of PHN) was the same in both groups. Of the patients with pain at rash healing (about 54% of the total group), the median duration of PHN was significantly less in the treated group (median time to loss of pain, 60–63 days with famciclovir and 120 days with placebo group, 500-mg dose versus placebo, p = 0.02). Similar results were reported in a subgroup analysis of patients over 50 years old. In another trial of immunocompetent zoster patients greater than 18 years old, famciclovir (at doses of 250 mg, 500 mg, or 750 mg three times daily for 7 days) was compared to standard doses of acyclovir.82 Famciclovir and acyclovir were equally effective in reducing acute pain and the duration of zoster-associated pain. The efficacy of famciclovir in ophthalmic zoster and the immunosuppressed host is unknown. Famciclovir dosage must be decreased when the creatinine clearance falls below 60 ml/min.
Valacyclovir Valacyclovir is well absorbed in the gastrointestinal tract and metabolized in the liver to acyclovir, thereby bypassing the poor absorption of acyclovir. Valacyclovir, at 1 g for 7 days (n = 384) or 14 days (n = 381) was compared to acyclovir in standard doses (n = 376) in immuno-
Table 71.2. Oral anti-varicella-zoster virus medications. Name Acyclovir Famciclovir Valacyclovir
Active agent
Reduce zoster pain?
Oral dose
Form
Acyclovir Penciclovir Acyclovir
Yes Yes Yes
800 mg five times daily 500 mg three times daily 1 g three times daily
Tablet, liquid Tablet Tablet
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competent zoster patients over 50 years old (mean, 68 years old).72 Median days to pain cessation for 7-day valacyclovir was 38 days; for 14-day valacyclovir, 44 days; and for acyclovir, 51 days. The recommended dose is 1 g three times a day, with downward adjustments for renal insufficiency when the creatinine clearance falls below 50 ml/mm. A thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome has been reported in severely immunosuppressed patients while taking valacyclovir.83 In summary, antiviral therapy appears to reduce acute pain and the duration of pain in elderly zoster patients who are treated within 72 h of rash onset. The longer the patient presents after 72 h of rash onset, the less sense it makes to prescribe antiviral therapy, unless the patient continues to form new vesicles or has ocular involvement. Acyclovir reduces ocular complications in ophthalmic zoster and organ system complications in the severely immunosuppressed host. The disadvantages of antiviral therapy are marginal or no effect on PHN in some patients, gastrointestinal side effects, and cost. The very early use of antiviral therapy is paramount because days of VZV replication, neuronal destruction, and inflammation have occurred by the time the patient reaches the doctor. Currently available data suggest that acyclovir, famciclovir, or valacyclovir are acceptable agents with factors other than efficacy determining the choice.
Anti-inflammatory Agents Several well-designed clinical trials of corticosteroids compared to placebo or acyclovir in zoster have shown no significant effect on chronic zoster pain and argue against routine treatment of elderly zoster patients for preventing PHN.84,85 The most common adverse effects were gastrointestinal symptoms (dyspepsia, nausea, vomiting), edema, and granulocytosis. Interestingly, corticosteroids reduced acute zoster pain from 2 to 8 weeks after rash onset in most of these trials, although that beneficial effect was not sustained. In the most recent trial, Whitley et al. studied acyclovir plus prednisone (n = 51), acyclovir plus prednisone placebo (n = 48), prednisone plus acyclovir placebo (n = 50), and placebos for acyclovir and prednisone (n = 52) in immunocompetent zoster patients of median age 60 to 63 years.86 Standard doses of acyclovir were given for 21 days and prednisone was given as 60 mg/day for the first week and tapered over the next 2 weeks. There were no significant differences between the four groups or between prednisone versus noprednisone groups (hazard ratio, l.26; 95% confidence interval, 0.91–1.75) in time to cessation of zosterassociated pain. However, time to uninterrupted sleep, return to daily activity, and cessation of analgesic therapy was significantly accelerated in the prednisone versus no-
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prednisone groups in this relatively healthy group of 60year-olds. Therefore, oral corticosteroids may be considered for otherwise healthy older adults with moderate to severe pain and no contraindications to corticosteroids. Some clinicians use corticosteroids for VZV-induced facial paralysis and cranial polyneuritis to improve motor outcomes and pain.
Analgesics Clinicians should employ analgesics to reduce acute zoster pain regardless of effects on chronic zoster pain. The choice of nonopiate or opiate analgesics depends on the patient’s pain severity, underlying conditions, and response to the drug. The principles of excellent pain management, such as scheduled analgesia, use of standardized pain measures, and close follow-up, should be applied to acute zoster pain management as with any other painful condition. If pain control from antiviral agents and analgesics is inadequate, then regional or local anesthetic nerve blocks should be considered. Although there are no randomized controlled trials of this approach for the treatment of acute pain or the prevention of PHN, several published case series have consistently reported acute pain relief from a variety of anesthetic techniques.87,88 The effectiveness of well-managed opiates, regional anesthetic nerve blocks, anticonvulsants, and tricyclic antidepressants in reducing chronic zoster pain is not known but needs to be tested in rigorous clinical trials. In one randomized double-blind study of amitriptyline or placebo during acute zoster in 72 elderly patients, the percentage of patients who were pain-free at 1 and 3 months after rash onset was not significantly different. However, at 6 months after rash onset, 32 (84%) patients in the amitriptyline group were pain-free compared to 22 (65%) patients in the placebo group ( p = 0.05).89 This study was small, the use of acyclovir was unbalanced between the groups, and amitriptyline is a hazardous drug in the elderly. These points argue against using amitriptyline acutely in elderly zoster patients, but the result is interesting and deserves better study with less toxic alternatives. Nonpharmacologic approaches to zoster pain are also important. Elderly zoster victims need education and reassurance because shingles myths and fears are commonplace. Social support, mental and physical activity, adequate nutrition, and a caring attitude go a long way toward coping with this illness.
Postherpetic Neuralgia No one treatment is uniformly effective in all elderly PHN patients. Clinicians have employed many treatments for
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PHN, but few of these treatments have been evaluated in randomized, double-blind, placebo-controlled trials. However, recent clinical trials indicate that topical lidocaine, gabapentin, opiates, and tricyclic antidepressants can significantly reduce pain in PHN patients.
Topical Therapies Topical therapies are low-risk interventions that include topical lidocaine, capsaicin, and nonsteroidal antiinflammatory (NSAID) drugs. The topical lidocaine patch and the topical anesthetic cream EMLA (eutectic mixture of lidocaine and prilocaine) have produced significant pain relief in PHN patients in uncontrolled and controlled clinical trials.90–93 Galer et al. enrolled PHN patients who were successfully treated with topical lidocaine patches and randomized them to continue the topical patch or receive a vehicle patch for 2 weeks and then cross over to the opposite treatment for 2 weeks.94 Patients were allowed to exit either treatment period if their pain relief scores decreased by 2 or more on a 6-item pain relief scale for 2 consecutive days. The lidocaine patch exit time was 14 days and the vehicle patch exit time was 3.8 days (p < 0.001), indicating that vehicletreated patients wanted the active ingredient after a few days. At study completion, 25 of 32 (78.1%) of subjects preferred the lidocaine patch compared to 3 of 32 (9.4%) of vehicle patch recipients. Hence, the topical lidocaine patch provided significantly more pain relief than a placebo patch. The 10 by 14 cm patch contains 5% lidocaine base and other ingredients on a polyester backing. One or more patches are applied over the affected area for 12 h/day. It may take up to 2 weeks to determine whether it is effective. Systemic lidocaine toxicity has not been reported with topical lidocaine preparations. The disadvantages of the patch are application site reactions such as skin redness or rash and substantial cost. Capsaicin (0.025% or 0.075%), the active principle in hot peppers, has had divergent results in controlled clinical trials and in systematic reviews.95–97 It is difficult to blind patients and investigators because of the burning associated with the treatment. An adequate trial requires 6 weeks of therapy of either the 0.025% or 0.075% concentration applied to the affected area three to four times per day. The utility of the drug is limited by intense burning that becomes tolerable for some patients and unbearable for many others. NSAID creams and aspirin or indomethacin in solution [chloroform, ether, dimethylsulfoxide (DMSO)] are reported to reduce pain in limited studies.98–101 The extent of clinical benefit from these treatments is uncertain, but these agents deserve further study in large, controlled clinical trials. All topical therapies may be impractical when the involved area of skin is too large or difficult to reach.
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Anticonvulsants Clinicians have used phenytoin and carbamazepine for PHN, but there is little evidence for their effectiveness and they can have significant adverse effects in the elderly. However, there is evidence that gabapentin is effective in reducing the severity of PHN. Rowbotham et al. conducted a randomized, placebo-controlled trial of gabapentin in 229 patients with PHN over an 8-week period.102 Study participants received an initial dose of 300 mg, and the dose was titrated over a 4-week period to 300 mg tid, 600 mg tid, 900 mg tid, and 1200 mg tid or until intolerable adverse effects. On an 11-point pain scale (0–10), the average daily pain score of treated patients declined from 6.3 to 4.2 compared with a decline from 6.5 to 6.0 in the placebo group ( p < 0.001). Fortythree percent of the treated group rated their pain as moderately or much improved compared to 12% of the placebo group. On average, treated patients experienced significant improvement in health-related quality of life, sleep, and mood compared to placebo recipients. The adverse effects of gabapentin included somnolence (27%), dizziness (24%), and ataxia (7%). These adverse effects will limit the use of gabapentin in the frail elderly and elderly patients with falls and gait disturbance.
Tricyclic Antidepressants (TCAs) Five randomized controlled clinical trials of amitriptyline, one trial of desipramine, and one trial of nortriptyline have demonstrated moderate to good pain relief in 44% to 67% of elderly PHN patients.103–108 Nortriptyline and desipramine are preferred alternatives to amitriptyline because they cause less sedation, cognitive impairment, orthostatic hypotension and constipation in the elderly. Given the adverse effects of amitriptyline in the elderly and the data supporting its use, Watson et al. compared amitriptyline and nortriptyline in PHN patients using a double-blind crossover design.108 The two agents reduced pain in roughly 55% of patients but nortriptyline was better tolerated. A conservative dosing regimen of nortriptyline begins with 10 mg at night and increases the dose every 4 to 7 days by the same amount until reduction in pain or intolerable side effects. At least 4 weeks of therapy is required (4–8 weeks recommended) and therapy should be continued for 3 to 6 months if adequate pain reduction.
Opiates There is increasing evidence that a subset of PHN patients respond to chronic opioid therapy. Small studies of intravenous morphine and oral opioids have reported significant pain relief in PHN.109–112 Watson and Babul conducted a randomized, placebo-controlled, double-
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blind, crossover trial of sustained release oxycodone in 38 PHN patients over an 8-week period.113 The initial dose of controlled-release oxycodone was 10 mg every 12 h. The dose was increased weekly to 20 mg every 12 h and to a possible maximum of 30 mg every 12 h. The results showed significant pain relief in constant, intermittent, and allodynic pain as measured by visual analogue scale and a numerical-verbal 6-point pain scale. Sixty-seven percent of patients expressed marked preference for oxycodone compared to 11% for placebo. The most frequently reported adverse effects were constipation, nausea, and sedation.
Other Modalities Transcutaneous electrical nerve stimulation (TENS) may be beneficial in some patients and it has little risk.114 The ideal candidate for a TENS trial has truncal or extremity PHN and adequate cognition, vision, and manual dexterity. Some patients derive short-term relief from the application of cold to the affected area. Acupuncture has been used in PHN, but there is little evidence to support its efficacy.115,116 Ablative surgical procedures are usually considered for the desperately ill PHN patient who has failed all attempts at medical management. The literature is restricted to case reports or series of limited quality.117 In general, the likelihood of success from surgical procedures appears to be very small whereas the risks are significant. Chronic pain coping strategies, social support, physical activity as tolerated, and a supportive doctor–patient relationship are beneficial for elderly PHN patients. In summary, available evidence indicates that the lidocaine patch, gabapentin, tricyclic antidepressants (preferably nortriptyline or desipramine), and opiates (e.g., oxycodone) are effective in providing pain relief in a significant number of elderly patients with PHN. The choice for initial treatment depends on patient comorbidity, the drug’s adverse event profile, patient preference, and cost. If an adequate trial of the first choice is not effective, then the other agents may be employed. Whether combinations of these agents are superior to single drug therapy is unknown. The chances of pain reduction are likely to be increased if nonpharmacologic principles of chronic pain management are employed. In particular, the value of regular follow-up and a supportive relationship cannot be overstated. If these widely available therapies show no pain reduction after adequate trials, then more specialized treatments are available. Those treatments include regional neural blockade (best if tried 29
Cutoff for grip strength (kg) criterion for frailty: £29 £30 £30 £32 £17 £17.3 £18 £21
Summary for frailty: a subject is frail if he/she has 3, 4, or 5 components identified as frail. Intermediate subjects have 1 or 2 components, and subjects with 0 positive frailty factors are considered not frail. Source: From Ref. 4, with permission of the authors.
Part VI Neurologic and Psychiatric Disorders
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74 Dementia Gary J. Kennedy
Dementia is a syndrome of progressive, global decline in cognition that is severe enough to degrade the individual’s well-being and social function. Persons with dementia have learning and memory problems, plus at least one of the following: impairments in communication (aphasia), reasoning, and planning (executive function); recognition and manipulation of objects in space (agnosia, apraxia); orientation; and the regulation of emotion and aggression. Dementia is the most common cause of disability among older Americans.1 With the number of dementia cases projected to double over the next 40 years,2 even modestly effective interventions will have substantial benefits if achieved in the population at large. However, rates of underrecognition and undertreatment are considerable.3 A comprehensive approach combining proven interventions can have a major impact on the patient and family’s well-being and on the costs of long-term care.
Epidemiology and Costs There were 360,000 new cases of Alzheimer’s dementia diagnosed in 1997, with prevalent cases from all forms of dementia approaching 4 million Americans.4 Costs of dementia care provided by professionals, institutions, and agencies total $100 billion a year. Yet, most persons with dementia are cared for in the community rather than institutions. The expense to the family members providing community-based care is estimated to be an additional $100 billion. Alzheimer’s disease alone affects 8% to 15% of persons 65 and older. The prevalence of dementia increases exponentially, doubling every 5 years at least to age 85, at which point the incidence may decline.5 Among individuals 85 and older with a demented first-degree relative, however, the prevalence approaches 50%.6 And, despite improved survival rates associated with cardiovascular disease, an increase in vascular dementia may be expected.7 Pathogenesis of
primary neuronal degeneration and genetic and other risk factors are discussed in the next chapter. What follows here is a commonsense, evidence-based approach to treatment.
Differential Diagnosis Table 74.1 characterizes the various cognitive disorders, as well as the specific dementias. The diagnosis is challenging in the early stage because there are no definitive biologic markers, the onset is often insidious, and other reversible causes of cognitive impairment either resemble or accompany dementia. Clinical history from patient and family, physical examination, mental status assessment, and laboratory procedures are carried out to detect reversible or partially reversible disease. Although few dementias are reversible, most have elements that will partially remit.8 Delirium (see Chapter 76) is perhaps the most common cognitive disorder and often complicates dementia. The hallmarks are fluctuating level of awareness, impaired attention, disorganized thinking, and demonstrable physiologic disturbance. Symptoms should remit once the disturbance is reversed, but recovery may be delayed in older persons. Delirium can also be chronic and difficult to distinguish from dementia.9 Cognitive impairment due to depressive disorders is distinguished by the patient’s prominent complaints of difficulty with memory and concentration. Apathy, irritability, and reluctance to complete cognitive testing are apparent. Aphasia is usually absent.10 However, there is a growing body of evidence that late-life depression accompanied by cognitive impairment often heralds the onset of dementia, even when the initial impairment remits with antidepressant therapy.11 Age-associated memory impairment (AAMI) is characterized by memory complaints in persons age 50 or older whose performance falls 1 SD below the mean on 1079
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Table 74.1. Differential diagnosis of cognitive impairment in adults. Condition
Distinguishing features
Dementia
Progressive decline, global cognitive impairment with learning and memory deficits (recent > remote), aphasia, apraxia, agnosia, executive dysfunction; patients tend to minimize deficits Childhood onset without progressive decline; history of diminished educational and work attainment; attention unimpaired Sudden onset and fluctuating course with inattention, disorganized thinking, and altered level of awareness; impairment reversible but recovery may be prolonged by advanced age Memory and concentration complaints prominent; aphasia absent, apathy or irritability present; cooperation with testing difficult, risk of subsequent dementia elevated Age >50, memory complaints prominent; performance below 1 SD from the mean on tests normed with young adults, information retrieval slowed; learning, orientation, communication intact; functional independence preserved Age >50, memory complaints prominent; performance below 1.5 SD from the mean on tests compared to age mates, information retrieval slowed; learning, orientation, communication intact; functional independence preserved Insidious onset with smooth, inexorable decline, cortical atrophy; apolipoprotein E, e4 allele, and cardiovascular disease elevate risk; more rapid decline in middle-stage onset; mood disturbance early, psychosis and behavioral disturbance later in the course Sudden onset, fluctuating course with temporary improvements or prolonged plateau; multiple infarcts, diffuse white matter lesions, diabetes, cardiovascular disease present; focal neurologic exam Autosomal dominant but incomplete penetrance inheritance pattern; atrophic caudate nuclei; premorbid DNA testing quantifies risk, age of onset, severity Characteristic tremor with unilateral onset, bradykinesia, bradyphrenia, cognition may be spared Focal neurologic exam; circumscribed rather than global cognitive deficits may improve significantly over 6 months
Developmental disorder Delirium Major depressive disorder with cognitive impairment Age associated
Mild cognitive impairment
Alzheimer’s disease
Vascular dementia Huntington’s disease Parkinson’s disease Acute cognitive impairment due to stroke, traumatic brain injury Frontal lobe degeneration, Pick’s disease Lewy body dementia Corticonuclear degeneration Creutzfeldt–Jakob disease Alcohol-related dementia Normal pressure hydrocephalus AIDS dementia
Personality, sociability, executive function prominently impaired; disinhibition, impaired judgment, and social indifference significant; aphasia, apraxia, amnesia, loss of calculation less notable Sudden onset, fluctuating level of awareness, psychosis (visual and auditory hallucinations more often than delusions) prominent, parkinsonian signs and falls; adverse response to typical antipsychotic Marked visuospatial impairment, substantial apraxia, memory behavior disturbance less prominent Rapid progression, death in 6–12 months, characteristic EEG, myoclonic jerks Massive, prolonged abuse; may remit with abstinence Gait disturbance (“magnetic gait”), incontinence, ventricular enlargement disproportionate to cortical atrophy HIV positive, may present with behavioral disturbance, parkinsonian features
Source: Used with permission from Kennedy GJ. Geriatric Mental Health Care: A Treatment Guide for Health Professionals. New York: Guilford; 2000:48.
tests normed for younger adults. Although lower memory scores are predictive of dementia, only 1% to 3% of these individuals will experience global cognitive decline in the ensuing 12 to 24 months.12 In contrast, 5% to 15% of persons with mild cognitive impairment (MCI) will develop dementia within the year. MCI is characterized by performance between 1 and 1.5 SD below the mean on tests of memory. As with AAMI, persons with MCI have memory complaints but do not meet diagnostic criteria for dementia; they exhibit slowed information retrieval, but orientation and communication are usually intact.13 Although a histologic examination of brain tissues sets the criteria for “definite” Alzheimer’s disease, the diagnosis of “probable” Alzheimer’s dementia can be accurately made in 90% of cases by history from the patient and family and clinical examination.1 “Possible” cases may have atypical features but no identifiable alternative
diagnosis. Alzheimer’s disease is the most frequent dementia. The onset is insidious; the decline is smooth, but more rapid in the middle stage in which behavioral disturbances emerge. Individuals with Alzheimer’s disease often minimize their deficits, unlike persons with MCI or depression. Alzheimer’s and Pick’s disease represent cortical dementias in which there is primary neuronal degeneration.14 Huntington’s and Parkinson’s disease represent the subcortical dementias. Dementia associated with Lewy bodies overlaps with both Parkinson’s and Alzheimer’s disease in presentation and distribution of pathology. The secondary neuronal degeneration of the vascular dementias is caused by angiopathic disorders, most commonly ischemic heart disease and arrhythmias, hypertension, and diabetes. Hemiparesis, gait disorder, and other signs of past stroke also suggest vascular dementia. However, the pathology of vascular dementia is fre-
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quently of a mixed type (cortical and subcortical) with diverse presentations in which the loss of brain volume, ventricular dilatation, bradykinesia, and the cognitive deficits are difficult to distinguish from Alzheimer’s disease. Although perceptual distortions are common in dementia, when visual or auditory hallucinations are prominent, signs of Parkinson’s disease are evident, the onset was abrupt, and the course characterized by lucid moments alternating with confusion, Lewy body disease may be diagnosed.15 Paranoid delusions, falls, and depression are also characteristic of diffuse Lewy body dementia. More importantly, patients with diffuse Lewy body disease experience marked disruptions in dopaminergic systems, accounting for their exquisite sensitivity to antipsychotic medications.16 Alzheimer’s, vascular, and Lewy body disease make up the majority of dementia diagnoses. Table 74.2 offers a simplified algorithm that will capture 95% of the dementias encountered by the average practitioner. The rare dementias would be easy to overlook were it not for their distinctive features. Marked deficits in visual perception and praxis out of proportion to memory impairment suggest corticonuclear degeneration. Changes in affect, typically depression but also hypomania and irritability preceding signs of dementia, suggest a non-Alzheimer’s diagnosis.17 Early deterioration in personality, loss of social inhibitions, and frontal lobe atrophy indicate Pick’s dementia.18 Physical signs such as the tremor and bradykinesia of Parkinson’s disease, the choreoathetoid movements of Huntington’s disease, the myoclonic twitching of Creutzfeldt–Jakob disease, or the pseudobulbar palsy of vascular dementia may not present before intellectual deterioration is observed. Huntington’s disease is typical of the subcortical dementias in that various cortical functions, including communication,
praxis, and visual perception, are generally spared. Emotional disturbances and personality change are regular features of Huntington’s disease and are frequently the first signs of the illness.19 Normal pressure hydrocephalus is characterized by incontinence, abnormal (“magnetic”) gait, and ventricular atrophy out of proportion to cortical loss. Dementia may also be secondary to infectious systemic disease such as syphilis or acquired immunodeficiency syndrome.20 Transmissible disorders of the prion type (Creuztfeldt–Jakob disease) may also cause dementia through exposure to infected foodstuffs or transplanted tissues or extracts.21
Diagnostic Procedures Routine diagnostic laboratory procedures include complete blood count, blood chemistries, liver function studies, serologic test for syphilis, thyroid-stimulating hormone and vitamin B12 and folate levels, and cardiogram. In less than 1% of patients will these procedures detect a reversible cause of dementia. However, the identification of comorbid conditions whose less than optimal treatment compounds the disability or worsens the prognosis of the dementia will be more substantial. Chest x-ray, human immunodeficiency virus (HIV) test, and test of Lyme disease may also be included, based on physical examination and history. For patients with syncope or suspected seizures, an electroencephalogram may be ordered. A review of prescribed and over-the-counter medications and intake of alcohol and tobacco products is mandatory. Medications may be the most common cause of reversible dementia. Imaging studies are used to confirm the diagnosis when clinical findings are equivocal, to distinguish one demen-
Table 74.2. Simplified algorithm for the differential diagnosis of dementia. Insidious onset with smooth decline and motor function minimally impaired? YES NO
Æ
Abrupt onset or fluctuating course, little if any psychosis?
Ø Alzheimer’s dementia History of stroke or significant ischemic brain injury on CAT scan or MRI? YES NO
Æ
Ø vascular dementia
Marked fluctuation in cognitive impairment, hallucinations prominent, signs of Parkinson’s syndrome evident, falls YES
Ø Lewy body disease Source: Used with permission from Kennedy GJ. Geriatric Mental Health Care: A Treatment Guide for Health Professionals. New York: Guilford; 2000:51.
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tia from another, and to detect reversible causes. Because the incidence of irreversible dementia is age related, the detection rate for reversible causes with imaging declines with advancing age. Computerized tomography of the brain, without contrast, should be performed when focal neurologic signs are present, when change in mental status is sudden, or when trauma or mass effects are suspected. Magnetic resonance imaging may be indicated when vascular dementia is suspected. However, the white matter changes seen on T2-weighted images are not necessarily indicative of dementia.1 Functional imaging studies with positron emission tomography or single photon emission computerized tomography may detect the temporoparietal metabolic deficits of Alzheimer’s disease or the diffuse irregular deficits of vascular dementia when objective signs of memory impairment are equivocal.22 Functional imaging is far from being a routine clinical procedure. As treatments become available for early intervention, however, the desire for early detection may yet bring functional imaging into everyday practice.
Cognitive Assessment Cognitive assessment should be conducted without family present to avoid distractions and any potential embarrassment over failed items. Because the patient is asked to actively demonstrate errors, considerable care is required to place the person at ease and accurately administer the exam. It is useful to discuss findings and recommendations in the individual interview and then gain the patient’s permission to share the information with family. A premium is placed on openness and disclosure. However, certain individuals will be too anxious or suspicious to be examined alone or to accept a discussion of findings and recommendations in their presence. In such cases, tact and ingenuity are required to obtain consent for disclosure to the family. The use of a cognitive screening instrument allows the clinician to demonstrate the presence and, with longitudinal administrations, the course of deficits objectively. A number of factors may influence cognitive performance yet not be indicative of dementia. These aspects include inefficient learning strategies, slowed processing capacity, reduced attention, sensory deficits, and ageassociated memory impairment.23 Age, education, and other demographic factors also alter performance.24 Language, visuospatial ability, and abstract reasoning are less affected by age than memory and learning. Longterm and procedural memories are relatively preserved, whereas recent and episodic recall decline.25 For example, the older musician may perform pieces from early life with both facility and feeling but not recall what was played the next day. New music will be impossible to master, despite good command of the instrument.
G.J. Kennedy
The Mini-Mental State Examination (MMSE) is the most widely used screening exam for impaired cognition in the United States and has been translated to a number of languages and normed for age and education. Molloy and Standish26 have standardized the administration procedures for the MMSE to reduce test time and uncertainty about scoring (Table 74.3). Their techniques also reduce test anxiety. A perfect score is 30, with mild to moderate impairment falling between 18 and 24. For persons with fewer than 9 grades of education, a score of 17 or less is evidence of at least mild impairment. The average decline in MMSE scores among Alzheimer’s patients is 2 to 4 points per year. In the study by Kelman et al. of 1855 older community residents, an impaired MMSE score whether mild, moderate, or severe was a stronger predictor of mortality than physical disability, number of conditions, or age.27 MMSE scores of 19 and above, memory loss and disorientation, repetitiousness, loss of interests, and change in personality characterize mild Alzheimer’s dementia.28 Although depression may appear early, delusions, agitation, sleep disturbance, and wandering are more characteristic of moderate dementia. Persons with moderately advanced dementia have MMSE scores ranging between 10 and 19. They require supervision to complete tasks of daily living, such as dressing, and to be safe from dangerous wandering. Severe dementia is evidenced by marked aphasia, loss of capacity to recognize family, incontinence, and dependency in all aspects of daily living. Of the widely used screens for cognitive impairment, the Clock Drawing Test is the briefest, requiring less than 5 min to complete. The patient is asked to draw a clock face with all the numbers and hands and then to state the time as drawn. The number 12 must appear on top (3 points), there must be 12 numbers present (1 point), there must be two distinguishable hands (1 point), and the time must be identified correctly (1 point) for full credit. A score less than 4 is considered impaired.29 The Free and Cued Selective Reminding may be useful to distinguish age-associated memory impairment from dementia. The Free and Cued Selective Reminding test reduces the agerelated decrements in learning and processing to elicit genuine deficits in recall, which are characteristic of dementia. The measures may also be less sensitive to educational attainment.23 For intellectually gifted persons, those with higher educational attainment, and when decline is subtle, referral to a neuropsychologist is warranted. For annual screening of seniors in primary care without signs or symptoms of dementia, the MMSE combined with the Clock Drawing Test provides adequate sensitivity and specificity.29 Serial assessments at 6-month intervals are helpful when the diagnosis remains suspect. However, like imaging studies, none of the cognitive screening or neuropsychologic batteries can be considered diagnostic.
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Table 74.3. Standardized Mini-Mental State Examination. Preparations Ensure that the patient is willing and that vision and hearing aids if needed are in place. Ask “Would it be all right to ask you some questions about your memory”? Ask each question a maximum of 3 times. If the patient does not respond score the item as 0. If the answer is incorrect, score 0. Do not hint, prompt, or ask the question again once an answer has been given. If the patient answers, “What did you say?” do not explain or engage in conversation—merely repeat the same directions up to a maximum of 3 times. If the patient interrupts or wanders from the task, redirect the person by saying “I will explain in a few minutes when we are finished. Now if we could just proceed please . . . we are almost finished.” Begin by saying I am going to ask you some questions and give you some problems to solve. 1. (Allow no more than 10 seconds for each reply) Max Score a) “What year is this?” (Accept exact answer only) 1 b) “What season is this?” (In the last week of the old season or first of the new, accept either) 1 c) “What month of the year is this?” (On the first day of the new month or last day of the previous, accept either month) 1 d) “What is today’s date?” (The day before of after is acceptable, e.g., on the 7th accept the 6th or 8th) 1 e) “What day of the week is this?” (Exact day only) 1 2. (Allow no more than 10 seconds for each reply) a) “What county/borough are we in?” 1 b) “What province/state/country are we in?” 1 c) “What city/town are we in?” 1 d) If in the clinic, “What is the name of this hospital/building?” (Exact name of hospital/institution/building only) 1 If in the patient’s home “What is the street address of this house?” (Street name and house number or equivalent in rural areas) e) If in the clinic “What floor of the building are we on?” (Exact answer only) 1 If in the home “What room are we in?” (Exact only) 3. “I am going to name 3 objects. After I have said all 3, I want you to repeat them. Remember what they are because I am going 3 to ask you to name then again in a few minutes.” (Say the objects slowly at 1-second intervals) “BALL (1 second) CAR (1 second) MAN. Please repeat the 3 items for me.” (Score 1 point for each reply on the first attempt. Allow 20 seconds for the reply, if the patient cannot repeat all 3 on the first attempt, repeat until they are learned but no more than 5 times) 4. “Now please subtract 7 from 100 and keep subtracting 7 from what’s left until I tell you to stop.” (May repeat 3 times if the 5 patient pauses—allow 1 minute for answer. Once the patient starts do not interrupt until 5 subtractions have been completed. If the patient stops, repeat “keep subtracting 7 from what’s left” for a maximum of 3 times. See scoring examples below) 5. “Now what were the 3 objects that I asked you to remember?” (Score 1 point each regardless of the order; allow 10 seconds) 3 BALL CAR MAN 6. Show the patient a wristwatch and ask; “What is this called?” (Accept “wristwatch or “watch” but not “clock” or “time”) 7. Show a pencil and ask; “What is this called?” (Do not accept “pen”) 8. I’d like you to repeat a phrase for me: say “no if’s, and’s, or but’s.” (Exact reply only) 9. “Read the words on the page and then do what it says.” (Hand the patient the sheet with CLOSE YOUR EYES on it. Instructions may be repeated 3 times but patient must close eyes for correct score) 10. Ask if the patient is right or left handed. The paper is held in front of the patient and should be taken with the nondominant hand. “Take this paper in your right/left hand, fold it in half, and place it on the floor.” Takes paper with nondominant hand = 1 Folds it in half = 1 Places it on the floor = 1 11. Give the patient a pencil and paper and say “Write any complete sentence on this piece of paper.” (Allow no more than 30 seconds. Sentence should make sense. Ignore spelling.) 12. Place intersecting pentagons design, pencil, and paper in front of the patient. Say: “Please copy this design.” Allow multiple attempts up to 1 minute. To be correct the patient’s copy must show a 4-sided drawing within two 5-sided figures. Ignore rotation and distortions.)
1 1 1 1 3
1 1
Scoring serial sevens: 93, 86, 79, 72, 65 93, 88, 81, 74, 67 92, 85, 78, 71, 64 93, 87, 80, 73, 64
5 points 4 points 4 points 3 points
Scource: Adapted with permission from the author, Dr. D.W. Molloy, McMaster University. Also see Molloy DW, Alemayehu E, Roberts R. (1991) A standardized Mini-Mental State Examination (SMMSE): its reliability compared to the traditional Mini-Mental Sate Examination (MMSE). American Journal of Psychiatry. 148:102–105.
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Table 74.4. Evolution of Alzheimer’s disease (AD) as measured with the Functional Assessment Staging/Global Deterioration Scale (FAST/GDS), Clinical Dementia Rating (CDR) Scale, and Mini-Mental State Examination (MMSE). FAST/GDS stage
CDR stage
MMSE score
1 2
0 0.5
29
3
0.5
4 5 6a 6b 6c 6d 6e 7a 7b 7c 7d 7e 7f
0.5 1 2 2 3 3 3 3 3 3 3 3 3
Diagnosis
Elapsed Time 0
25
Normal Age-associated memory impairment Mild cognitive impairment
19 14 5
Mild AD Moderate AD Moderately severe AD
7 years 9 years 10.5 years
Severe AD
13 years
0
Progression of Disability No difficulties either subjectively or objectively Complaints of forgetting location of object, subjective work difficulties Decreased job functioning evident to co-workers; difficulty in traveling to new locations Decreased ability to perform instrument ADL’s Requires assistance in choosing proper clothing Difficulty putting clothing on properly Unable to bathe properly; may develop fear of bathing Inability to handle mechanics of toileting Urinary incontinence Fecal incontinence Ability to speak limited (1 to 5 words a day) All intelligible vocabulary lost Nonambulatory Unable to sit up independently Unable to smile Unable to hold head up
Source: Adapted from Reisberg B. Alzheimer’s disease. In: Sadavoy J, Lazarus LW, Jarvik LF, Grossberg GT, eds. Comprehensive Review of Geriatric Psychiatry—II, 2nd Ed. Washington, DC: American Psychiatric Press; 1996:401–458, with permission.
Assessment of Functional Impairment
Reduction of Excess Disability
Although the examination of cognition occurs between patient and practitioner, functional impairment is more reliably assessed with collateral informants, most often family.30 An assessment of activities of daily living not only covers the maintenance of physical hygiene and grooming, but also the more instrumental tasks such as management of finances, property, and household chores. Patients may appear in immaculate condition as a result of attentive caregivers, yet not be able to shop, cook, bathe, dress, or pay the bills without total assistance. The Global Deterioration Scale and Functional Assessment Staging (Table 74.4) is a widely used measure of dementia-related dependency.31
Beyond recognition of the specific dementia, the optimal treatment of associated conditions is critical. One-half of persons with dementia have a concurrent physical or mental illness that contributes to their functional impairments. Half that number will experience at least temporary benefits from treatment of the comorbid condition. And, in half that group, the benefits will last a year or more.32 Weight control, exercise, elimination of tobacco use, and minimizing alcohol intake represent good preventive health at any age, perhaps more so for individuals with dementia. However, some persons would rather not forgo real pleasures in the present for the promise of potential benefits in the uncertain future. For patients with suspected vascular dementia, the use of 325 mg aspirin daily should be recommended.33
Treatment The comprehensive approach to dementia care seeks to preserve the patient’s independence by delaying disability to the end of the natural life span. There are five elements to the comprehensive approach. First is accurate diagnosis of the specific dementia and recognition of other conditions that contribute excess disability. Second is caregiver education, counseling, and support. The third element is the pharmacologic palliation of cognitive impairment. Fourth are interventions, both pharmacologic and environmental, to lessen behavioral and psychologic disturbances. Fifth is early advance care planning in anticipation of late-stage and end-of-life care issues.
Counseling and Coaching the Caregiver The cornerstones of caregiver counseling are education, emotional support, and telephone availability. When combined with support groups, these techniques delayed nursing home admission an average of 9 months without increasing the caregiver’s burden.34 The majority of dementia care is provided by female family members who vary widely in their capacity to adapt to the burdens of the illness.35 Rehabilitation of the patient should always include consultation with the family, and failure of the family to appear should alert the clinician to future problems. Most families are remarkably creative in providing care. Others seem enmeshed, trapped in maintaining
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conflict rather than resolving it.36 Clinical depression is a problem for 20% to 60% of the primary family caregivers.37,38 The focus of care in these instances shifts to the family member and includes supportive psychotherapy or antidepressant medication. In rare instances, elder abuse, most often in the form of neglect, will require involvement of community agencies. Caregivers should be instructed to modify the physical environment to be safe and predictable. A regular schedule of activities including rising, meals, medications, and exercise lessens the burden on memory. Unfamiliar people, places, and events require accommodation for which the patient is poorly equipped. Travel that disrupts the person’s routine will be disorienting. Cherished holidays are better celebrated in the patient’s home. The withdrawal of firearms, opportunities to cook or smoke unsupervised, and automobile driving requires compassion and at times imagination. Psychotic and affective disturbances occur in as many of 80% of patients and account for much of the needed caregiver counseling. Behavioral disturbances are more distressing than forgetfulness or incontinence. Aggression, assault, accusations, nighttime wandering, and loss of capacity to recognize the caregiver predict nursing home admission.39,40 Pharmacologic improvement of cognition will help, but behavioral and other measures often need to be instituted, as discussed in subsequent sections.
Pharmacologic Palliation of Impaired Cognition Brietner predicts that medications emerging in the next two decades will significantly reduce the morbidity of Alzheimer’s disease.41 Simply delaying the onset of dementia by 5 years would reduce the prevalence by onethird.42 Until those agents have been administered to a generation at risk, however, the pharmacologic alternative will continue to be drugs that may palliate but cannot prevent the disability of dementia (Table 74.5). Because the common dementias overlap diagnostically, every patient with the diagnosis of dementia should be offered a trial of a cholinesterase inhibitor.43 In mild to moderately impaired persons, cholinesterase inhibitors may improve cognition, delay decline, lessen the disability in activities of daily living,44 improve psychologic and behavioral disturbances including psychosis,45,46 and forestall nursing home admission.47 Using randomized controlled trials of cholinesterase inhibitors, Livingston and Katona48 performed a number needed to treat analysis to calculate the number of patients receiving active treatment needed to demonstrate a beneficial effect compared to placebo. For example, 29 patients with atrial fibrillation would need to be treated with coumadin to prevent stroke in 1. In contrast, with 10 mg donepezil, 6 (95% confidence interval, 4–12) Alzheimer’s patients need to be treated to stabilize
Table 74.5. Agents used to palliate the cognitive impairment of dementia. Trade name
Initial dose
Aricept
Rivastigmine
Galantamine
Generic name Anticholinesterases Donepezil
Antioxidants Selegiline
Alpha-tocopherol Others Extract of Ginkgo biloba
Final dose
Arrhythmia potential
Hypotensive potential
Sedative potential
5 mg qd
10 mg qd
Bradycardia
Low
Low
Exelon
1.5 mg bid
6 mg bid
Low
Low
Low
Reminyl
4 mg bid
16 mg bid
Bradycardia
Low
Low
Eldepryl
5 mg qd
5 mg bid
Low
Moderate
Low
Vitamin E
30 IU qd
1000 IU bid
NA
NA
NA
Ginkgold Tebonin forte
60 qd
60 qid
Low
Low
Low
Precautions
Advantages
Transient, initial GI upset, abrupt withdrawal leads to abrupt decline, may interact with paroxitine Transient, initial GI upset, titrated up at 2-week intervals, abrupt withdrawal leads to abrupt decline, bid dosing Transient, initial Gl upset, titrated up at 4-week intervals, abrupt withdrawal leads to abrupt decline, bid dosing
Once a day dosing, safety
Potentially life-threatening diet and drug interactions are rare at recommended doses Liver toxicity, coagulopathy
Available as a transdermal patch Low toxicity, OTC
Wider dose range, no drug interactions Wider dose range, nicotinic receptor modulation
qid dosing, an “herbal” not Low toxicity, subject to FDA quality controls, OTC few data available at max dose
T1/2, half life; OTC, over the counter; FDA, U.S. Food and Drug Administration; NA, not applicable; AD, Alzheimer’s disease; VaD, vascular dementia. Source: Used with permission from Kennedy GJ. Geriatric Mental Health Care: A Treatment Guide for Health Professionals. New York: Guilford; 2000:58.
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or reverse cognitive decline by 1 year in 1 person; with 12 mg rivastigmine, 5 (95% confidence interval, 4–7) patients need to be treated. On average, cholinesterase inhibitors restore the person to a level of impairment seen 6 months previously. Although the effect is palliative, the less impaired time and delay in nursing home admission may be precious, particularly for patients whose improvement is marked. The side effects of cholinergic enhancement are nausea, diarrhea, sweating, bradycardia, and insomnia; these are most often are transient, occurring in 10% to one-third of patients at the initiation of treatment depending on the agent. To lessen adverse reactions, the cholinesterase inhibitors should be taken with meals and not at bedtime. Promethazine may be administered to counter nausea and vomiting but should not be required beyond the initial phase. The medication should be titrated up at 2- to 4-week intervals to the maximum recommended or tolerated dose. Phasing in the increase on an every other day schedule may enhance tolerability. Roughly one patient in four will experience improvement readily noticeable to family and practitioner within weeks of beginning the drug. That number increases to one in three by the third month of treatment.49 However, the majority of those who are not obviously better will experience less decline in the coming months with medication than without. As a result, the identification of genuine nonresponders who might be offered an alternative cholinesterase inhibitor is a real dilemma. Also, there is as yet no evidence for or against switching from one cholinesterase inhibitor to another. In theory, use of serial MMSE assessments might demonstrate a stabilizing effect of the medication. In practice, patients and families who find the benefits trivial compared to the burden of side effects, cost, and pill taking will opt to withdraw from treatment. However, cholinesterase inhibitors should not be withdrawn simply because the patient has been admitted to a nursing home. When withdrawn, the cognitive impairment of genuine responders will fall to that of patients treated with placebo. However, once the patient is bedbound, free of behavioral disturbances, and no longer recognizes family or caregivers, the benefits of the drug are questionable. Two cholinesterase inhibitors are approved and a third is under consideration (galantamine) by the FDA for mild to moderate Alzheimer’s disease. Donepezil possesses a prolonged action and specificity for brain tissue. The starting dose is 5 mg once daily and should be increased to 10 mg. Although it is metabolized by the cytochrome P-450 system, drug interactions are rare. Many practitioners find it has an alerting effect in latestage patients.43 Rivastigmine (Exelon) is a brain-specific cholinesterase inhibitor administered twice daily. The dose ranges from 1.5 to 6 mg bid.50 Patients able to tolerate the gastrointestinal difficulties of higher doses may
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benefit more. It is not metabolized by the cytochrome P450 system, and drug interactions are thought to be rare. Rivastigmine also inhibits butylcholinesterase, which may be more active in the latter stages of dementia, but the clinical significance of this property is uncertain.51 The acetylcholinesterase inhibitor galantamine (Reminyl) is a plant-derived alkaloid with nicotinic receptormodulating activities. Its capacity to allosterically modulate nicotinic receptors avoids the undesirable cardiovascular effects of direct nicotinic stimulation.52 However, the clinical significance of this property is uncertain. Galantamine is taken twice daily at doses ranging from 4 to 16 mg. Because multiple enzymes of the cytochrome P-450 system metabolize galantamine, drug interactions should be rare.53 Although the cholinesterase inhibitors should not be prescribed together, many practitioners combine them with vitamins C (500 mg) and E (400–1000 IU bid). Both are antioxidants and appealing in theory, but evidence of benefit in dementia exists only for vitamin E. The author generally discourages patients from adding extract of Ginkgo biloba to the foregoing regimen for reasons of minimal benefit, cost, and possible coagulopathy, particularly in the presence of high-dose vitamin E. Selegiline, a selective monoamine oxidase-B inhibitor, and vitamin E (a-tocopherol) reduce the rate of functional decline and delay nursing home placement in moderately impaired persons with dementia. However, cognitive performance is not enhanced, and the combination of the two agents is no more beneficial than vitamin E alone.54 Estrogen is associated with lesser prevalence of dementia among more highly educated women in epidemiologic studies. It also has a trophic effect on cultured neurons. However, the use of estrogen to treat established cases of or prevent Alzheimer’s disease has not yet been convincingly demonstrated.55
Management of Behavioral and Psychologic Symptoms Mental and behavioral disturbances are prevalent, occurring in more than half of community-residing elders who meet diagnostic criteria for dementia.56 Their relative prevalence is displayed in Table 74.6 with significant differences between vascular dementia and Alzheimer’s disease noted. The causes of behavioral symptoms are usually multiple, including the caregiving context, the caregiver’s capacities and tolerance, as well as the patient’s disease. Intervention to make the disturbed behavior less disruptive is a more realistic goal than outright elimination. A wait-and-see attitude may be reasonable when transient depression occurs, but agitation and psychosis are more likely to be persistent and disruptive.28 The key to behavioral intervention is improved communication and patient perception. Adequate time
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Table 74.6. Prevalence of specifica behavioral or psychologic symptoms among community-residing persons with dementia. Apathy Depression (Vascular > Alzheimer’s) Agitation/Aggression Irritability Delusions (Alzheimer’s > vascular) Anxiety Hallucinations Pacing, wandering
25% 24% 24% 20% 18% 17% 14% 14%
a More than half of diagnosed persons exhibited one or more symptoms. Source: Data from Lyketsos et al. Am J Psychiatry. 2000;157:708–714, with permission.
must be allowed to communicate. Visual cues and verbal suggestions should be coupled. Caregivers should stay at eye level with the patient, avoid provocative stances or gestures, speak softly and slowly, use “sound bite”-size statements or instructions, check that the patient understands and is ready, eliminate visual distractions, reduce ambient noise, and attend to one thing at a time. Glasses and hearing aids should be available, and they will need to be replaced when lost. Characterization of the three-point sequence or ABC’s of problematic behavior is central to the task of management.57 First, the caregiver is asked (A) to identify the “Antecedents” or triggering events such as changes in daily routine, interpersonal conflict, emotional or physical stressors. The antecedents can then be removed or minimized as a preventive measure. (B) The caregiver should describe the “Behavior” in detail, how often it occurs, when and where it is most likely to happen, and how long it lasts. Caregivers may need to step back and observe or take note to provide sufficient detail and to set the baseline for objective measurement of improvement. This observation period also refines recognition of antecedents and how the problem behavior fits into other aspects of the patient’s life. (C) The caregiver identifies the “Consequences” of the behavior, how the caregiver or others react to reinforce or deter the activity, and what happens when the activity ceases. Roca58 advocates a different three-part approach to behavioral disturbances of encompassing empathic, behavioral, and medical perspectives. The patient’s point of view, the environmental precipitants, and the extent to which unrecognized or undertreated diagnoses contribute to the disturbances are each assessed to arrive at effective interventions. The male resident of the facility who is occasionally combative and wanders out of the home provides an example of each perspective. The man may have been a boxer early in life who is now protecting himself from the intrusion of unfamiliar nursing staff. Staff should be alerted to his characteristic defense. He may have a bed near the entrance to the facility and simply be following others out as a result of echopraxia. Or, he may have a past history of bipolar illness with
untreated mania as the explanation for his behavior. The intervention should be tailored to the individual characteristics of each patient.
Agitation Behavioral disturbances naturally cluster into predominantly psychotic or affective groups, with agitation occurring in both.59 Agitation is a common, persistent problem, and the etiology varies. Delirium may be the most frequent acute cause. However, environmental stressors such as sleep deprivation and unfamiliar or chaotic surroundings can induce confusion indistinguishable from toxic delirium. Patients may be “talked down” and reoriented, but attempts to flee or remove intravenous lines or life supports as a result of delirium require medication, most often an antipsychotic agent such as haloperidol. Depression, psychosis, anxiety, boredom, and pain also contribute to agitation.60 Mania in dementia may also cause agitation, particularly when elevated mood, irritability, and hyperactivity appear. Frontal lobe degeneration impairs the person’s judgment and capacity to sequence steps to gain attention or comfort. Patients whose needs cannot be accurately expressed because of aphasia may also become agitated. Their inability to comprehend spoken cues may compromise staff efforts to reassure them. Recognizing the impediments to communication will lessen the caregiver’s frustration and justify the time and patience required to reduce, if not prevent, agitation. Impairments in hearing and vision add to the problem.
Psychotic Symptoms: Delusions, Hallucinations, Paranoia, Suspicions It is important to distinguish persistent false beliefs or perceptions from transitory illusions that result from impairments in vision, hearing, and cortical deficits.61 Similarly, if antecedents can be identified, they may be manipulated to reduce the problem to manageable proportions. Change in routine and caregiving personnel should be minimized. Better lighting to reduce shadows, correct sensory deficits, a modulated level of activity, and attention may also be effective. The suspicious person may be set at ease by reassurance or redirection to a less threatening theme or activity. Distraction, physical activity, or gentle touch (the elbow is neutral territory) may also restore trust. Attention provided when suspicions are silenced will lay a foundation for trust and reassurance at more problematic times. However, when patients act on their delusions through reclusiveness, threats, accusations, or assault, antipsychotic medication is necessary. Suspicious patients may retain enough regard for an empathic physician that they will consent to medication to restore sleep, alleviate
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stress, or help control their temper. Patients can be informed that family or nursing staff will place liquid medication in their juice or cereal each morning if they agree. Consent need not be renewed with each dose.
Affective Symptoms: Apathy, Depression, Anxiety, Sleep Disturbance Loss of interest, initiative, and responsiveness are seen in at least one-quarter of persons with dementia.56 For patients who sleep too much, exercise, coffee, or tea may be useful. Other patients who are apathetic or nap too frequently may benefit from low-dose methylphenidate (5–15 mg after breakfast and lunch). Transient depressive symptoms are not uncommon in dementia, but persistent depressed mood and suicidal behaviors are less frequent. Depressed expressions may be evoked when the patient is reminded of sad events, when frustration overwhelms, or when the person feels neglected or alone. To lessen depressive expressions as well as apathy, caregivers should focus on pleasant memories, avoid or minimize frustrating, unpleasant circumstances, and increase pleasurable activities and social interaction. Teri et al.62 found that combined behavioral and psychoeducational approaches significantly improved depressive symptoms in the majority of dementia patients and their caregivers. However, when there is a prior history of major depressive episodes, an antidepressant may be indicated. Sleep disturbance is common in dementia and disrupts both the patient’s and the caregiver’s rest. A brief assessment of the sleep pattern, time spent in bed, and daytime activities can identify the need for changing the sleep schedule, adding exercise, or prescribing medication. If physical discomfort awakens the patient, an analgesic at bedtime may help. Holding fluids after 6:00 p.m. may reduce the frequency of nighttime urination. Sedation will solve the problem, but predisposes the patient to falling and increased daytime confusion.
Verbally Disruptive Behaviors Verbally disruptive behaviors include screaming, abusive language, and repetitive verbalizations. These behaviors disturb others and may signal the person’s unmet needs. In theory, screaming may result from cortical disinhibition or be reinforced by attention. However, it more often results from undiagnosed and untreated pain, physical discomfort, sensory deprivation, or social isolation. Often the behavior can be reduced in frequency and volume without resorting to sedation. Individual social interaction is most effective. Examples include simple conversation, range of motion exercises, and sensory stimulation with photos, fabrics, fragrances, and occupational therapy games.63
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Family and staff generally prefer a little unpleasant vocalization to a patient made inaccessible with psychotropics. However, risk to the patient and risk to others must be parceled out. The concept of negotiated autonomy helps to avoid futile power struggles over patient rights. Negotiated autonomy means that once the patient is dependent on others, the autonomy of those others becomes a shared concern. Behavior that is disagreeable to others with whom the patient resides or on whom the patient depends is a justified focus of intervention. Thus, accommodation rather than autonomy is the issue.
Sundowning Increased confusion at evening time can usually be managed by recognizing that change in the environmental routine triggers the problem. Patients who become troubled at change of shift in the nursing home or hospital may be responding to the increase in stimulation. Others may be bothered by the reduction in stimulation as daylight fades. In either situation, providing the optimum of stimulation is preferable to medication. Food, brief personal contact, music, or improved hearing or vision are only some of the alterations in the care routine that reduce sundowning.63
Indiscreet or Unwelcome Sexual Behavior Demented persons seeking sexual gratification should not be labeled pathologic even though they may disturb caregivers and facility staff. However, when sexual advances are unwelcome or when self-stimulation is not managed discreetly, more may be required than directing the patient to a private area. The problem should be discussed directly with the patient at the time of the behavior and disapproval indicated for the circumstances surrounding the act, not the impulse. A matter-of-fact approach with family and staff also helps alleviate their reluctance to discuss the issue. Pathologic sexuality in dementia is more often seen with frontal lobe disease and represents disinhibition rather than willfulness. Staff and family will be less morally outraged once the neurologic basis of the behavior is explained.
Difficulties Accepting Personal Care Efforts to assist with feeding, bathing, or transfer from bed to chair or toilet are sometimes met with assaultive behavior, particularly when the caregiver is not familiar with the patient. Assaultiveness results from protective reflexes and disinhibition directly related to the dementia. Apraxia, aphasia, and agnosia, made worse by impairment in vision and hearing, reduce the patient’s ability to complete or comprehend simple tasks or to recognize the caregiver. It is helpful to educate staff that the
74. Dementia
objectionable behavior is the result of neurologic deficits and protective responses rather than malice. With time, staff become accustomed to the patient’s needs and, through perseverance and intuition, develop an effective routine of care. Two persons may be required for bathing to prevent assault. The time saved by team approach to “problem bathers” more than compensates for the added personnel. Nonetheless, for some patients, a low dose of risperidone, olanzapine, or the short-lived benzodiazepine lorazepam is necessary to counter combativeness.
Willful Behavior and Personality Disorders Despite accusations that objectionable behavior is “done on purpose,” most often staff and family are mistaken in attributing willfulness to the demented person’s behavior. However, individuals with personality disorders may also become demented. Problematic interpersonal relations across adult life are the key indicator that psychotropic medications may not be beneficial. Limit setting and confrontation are more effective. Because the behavior is part of an established pattern, staff should adjust their expectations accordingly.
Falls, Wandering, Pacing Gait disturbance due to apraxia, quadriceps weakness, rigidity, sedatives, and poor vision predispose the patient to falls, soft tissue injury, and fractures. Physical therapy, if the patient will actively engage and sustain the benefits, may reduce the risk but not eliminate it. A change in medications may help, but environmental modifications are more likely needed. Restraints are usually employed to reduce the risk of falls. However, they degrade the patient’s quality of life, cause soft tissue injury, and have led to documented cases of strangulation. As a result, there has been a national effort to reduce if not eliminate restraints in long-term care.64 The dilemma of balancing safety and freedom should be shared with staff and family to reach a consensus. The substituted judgment of family in an informed or negotiated model of consent is most helpful.65 Faced with the progressive decline in a loved relative, the family may choose near-term freedom from restraints and sedation rather than long-term freedom from injury. The patient who walks about the backyard or enclosed garden of a nursing home presents no problem. However, when someone with dementia becomes lost in the neighborhood or wanders into traffic, safety becomes the issue. In the acute care setting, where wandering poses a more imminent risk, placing the patient under close observation may be necessary. In nursing facilities, an ankle bracelet set to electronically trip an exit alarm can help staff to redirect the patient to a safe destination. A family
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member may volunteer to provide supervised walking. Alternatively, physical therapy or other forms of low-risk exercise may be substituted. Exercise for the demented person is an underutilized modality to remedy behavioral disturbance. Caregivers should seek to determine whether there is a temporal or event-related pattern to the wandering. Do reminders of leaving (hat, coat) need to be removed? Pictures of family prominently displayed in the patient’s room may assist when helping the patient to “go home.” Pacing or wandering may also signal unmet needs or discomfort. Staff may need to experiment with toileting, snacks, or analgesics to find the right solution.
Catastrophic Reactions Persons with dementia can be transiently overwhelmed, displaying anxious confusion, unwarranted suspicions, or tearful self-reproach. This catastrophic response follows overstimulation and a sense of failure or threat. An overbearing attitude, rapid questions, excessive commands, or too much noise or activity can provoke the response. Criticism, whether real or implied, such as intrusive efforts to correct or reorient the person, may also contribute. Patient fatigue or conflict with certain individuals may also be to blame. To counter a catastrophic reaction, it is helpful to change the subject or defer the task to a less distressing time. A soothing tone, with empathic comments spoken slowly with eye contact, may abort the response. At times it will be necessary to create a distraction or to remove the patient from the source of conflict or supply a pleasurable alternative.
Medications for Behavioral and Psychologic Disturbances “Start low, go slow” is the catchphrase of prescribing for older adults. However, the most common error when using medication to control behavioral disturbance is failure to follow through, to monitor the effects, and to adjust doses accordingly. A short-acting benzodiazepine (lorazepam 0.5 mg oral or intramuscular) can help the patient through procedures such as a CAT scan or MRI. For sleep disturbance, however, low doses of the sedating antidepressant trazodone (25–50 mg) may be effective. Hypotension may ensue as the dose is increased.66
Antipsychotics Haloperidol (0.5 mg), and risperidone (0.5 mg) are available in liquid form, which allows the dose to be given in food or a beverage for patients who have difficulty swallowing or accepting pills. Haloperidol, because of its lengthy track record, lack of cardiovascular effects, and availability of an intramuscular injection, may be pre-
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ferable for short-term use in acute care settings. Although more expensive, the atypical antipsychotics are preferable for longer-term treatment. Risperidone, a mildly sedative atypical antipsychotic, does not induce movement disorders or hypotension at low doses (1–2 mg daily). Katz et al.67 found it superior to placebo for the treatment of suspiciousness and aggressive behavior in dementia; however, at 2 mg, extrapyramidal signs began to appear. Olanzapine (2.5–10 mg) is less likely to induce extrapyramidal effects than resperidone but may cause somnolence, gait disorder, and elevated fasting blood glucose. It rarely lowers blood pressure, and the weight gain associated with its use may be desirable for some individuals. It also reduces agitation, aggression, and other manifestations of psychosis, as well as reducing their impact on caregivers.68 Quetiapine (Seroquel) is more sedative than olanzapine but less likely to cause extrapyramidal effects. It is also relatively free of interactions with other drugs. At a mean dose of 100 mg (25 mg initially then up to 50 mg bid), it reduces behavioral disturbances, most notably hostility.69 In summary, both the typical and atypical antipsychotic medications are modestly effective for psychosis in dementia. They exhibit a therapeutic window in which low doses are ineffective and high doses are either ineffective or induce intolerable side effects. Based on the controlled trials, ease of administration, and duration in clinical practice, risperidone is the initial choice, followed by olanzapine then quetiapine. If these agents fail, either a typical antipsychotic or clozapine would be next in line. If extrapyramidal side effects appear with risperidone, another atypical antipsychotic should be substituted. Although antipsychotics have been the main treatment of aggression, valproate (125 mg twice daily to start) has gained increasing recognition as an antiaggression agent, as well as a mood stabilizer. It is relatively safe, and not amnestic, arrhythmogenic, or hypotensive, but should be monitored with the same therapeutic levels used for anticonvulsant therapy.70
Antidepressants For the agitated or sleep-deprived depressed patient, trazodone is an effective antidepressant but is hypotensive and very sedative (25 mg initial dose). Nefazadone (50 mg twice daily to begin) is virtually free of amnestic and arrhythmic effects and is less sedative than trazodone. Sertraline (25 mg to begin) is not sedative and improves the signs of depression among nursing home residents in the late stages of dementia.71 Citalopram (20–40 mg), which is FDA approved for recurrent depression, is somewhat longer acting than sertraline. Paroxetine (10–20 mg daily) is a more calming selective serotonergic reuptake inhibitor. Like sertraline and citalopram, it is free of cardiovascular and amnestic risk but may cause
G.J. Kennedy
nausea and jitteriness in a minority of persons. For the frail patient in whom no risk of side effects can be tolerated, buproprion (75–150 mg twice daily), which is selectively noradrenergic, is reasonable. In similar instances, methylphenidate (5–15 mg after breakfast and lunch) may be prescribed and has the advantage of rapid onset of therapeutic response for the apathetic or somnolent patient).72 Venlafaxine (25– 100 mg twice daily) has the advantage of lacking sedative and hypotensive properties but may impair appetite.73 In contrast, mirtazapine (7.5–30 mg) will improve sleep and appetite.74 Antidepressants are frequently effective in combating anxiety. Sertraline, venlafaxine, and paroxetine are each FDA approved for one or more of the anxiety disorders and are less sedating than the benzodiazepines. Some practitioners also use nefazadone for this purpose.
Preparations for Late-Stage and End-of-Life Care In the early stage of the disease, when incapacity is minimal, the practitioner should anticipate the need for supportive services and urge referral before the need becomes acute. Arrangements for home health aides, day treatment, respite care, and residence in nursing facilities can be patched together with a good deal of continuity. However, providing these arrangements exceeds the capacity of any one individual and is best coordinated by a social worker or other professional functioning as a case manager. Legal advice for the management of financial assets is another important area of consideration for the family. Nursing home placement will devastate even substantial estates, and prolonged care at home is also expensive.75 Durable power of attorney assigned to a family member while the patient is still capable of exercising the necessary judgment will ensure adequate access to resources once the person is no longer able to manage financial decisions. Cost considerations aside, patients and families need assistance throughout the treatment process to confront end-of-life care issues early, while the patient can still participate in appointing a surrogate decision maker and expressing preferences about future care. The appointment of a durable power of attorney for health care decisions (health care proxy) is the first step. A backup proxy may also be appointed. Some ethicists prefer the appointment of a health care proxy over the designation of advance directives. The proxy is empowered to act across an array of contingencies, which may be difficult to anticipate. However, the use of “feeding tubes” (gastrostomy or nasogastric tube), “breathing machines” (respirators), and “artificial kidney” (hemodialysis) for reasons beyond treatment of acute illness will be rejected by most older patients under circumstances of irreversible loss of mental ability. Late-stage dementia patients become so
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impaired that they are unable to allow others to feed them or to swallow without aspiration. Difficulty with feeding may signal terminal decline. Artificial nutrition and hydration through a gastrostomy tube has not been demonstrated to reduce suffering or prolong life in advanced dementia.76 Further, feeding tubes are associated with aspiration pneumonia, fecal and urinary incontinence, cellulitus at the tube site, and other morbidities. Placement of a feeding tube also signals loss of the human contact gained through spoon-feeding. Given the real risks and scant benefits of feeding tubes, their use is considered an option rather than an imperative. When those who care for the person are at odds about placing a feeding tube it is helpful to determine by consensus the specific goal to be achieved by the treatment. Typical examples include decubitus healing or a return to oral feeding. The involved parties can then agree to a time limited trial of tube feeding and, if the desired goal is not met the tube can be removed once proven to be ineffective.77 (Also see Chapter 29.) Cardiac resuscitation should also be carefully discussed before the indication arises. Late in the stage of dementia, when the patient has lost awareness of caregivers and surroundings, the use of antibiotics or hospitalization for acute illness has not been shown to prolong life and is associated with significant distress and agitation. These are difficult decisions, but they are more easily approached when the practitioner anticipates the need and is experienced in the discussion.77
Medical Legal Issues Physicians are increasingly being called upon to provide affidavits and expert testimony regarding the capacity of an older individuals to manage assets and property and to make essential life decisions. A credible evaluation should include a diagnostic assessment that emphasizes the evaluation of functional capacity and is substantiated by validated measures of cognitive impairment and functional deterioration. Ideally, the evaluation should include a visit to the allegedly incapacitated person’s home where the ability to manage personal documents, mail, medications, financial transactions, and telephone can be directly observed. A history of functional decline from collateral informants and a review of medical assessments to ensure that reversible causes of mental impairment have not been neglected are mandatory. The report should delineate life skills that are preserved, as well as those that are deficient. For example, an individual may take pride in keeping house and preparing meals but not be able to balance the checkbook or make change in the market. A court-ordered financial guardian and assistance with shopping are required, but a housekeeper is not. (See also Chapter 84.)
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Summary A comprehensive approach based on evidence from the scientific literature promises to reduce the disability of dementia substantially in the near future. However, the use of medications and modifications in staff or family’s approach to the patient still requires ingenuity and perseverance. Even modest individual benefits, when spread over the large numbers of older Americans who will become demented, means sizable reductions in projected costs of care.
How to Contact Community-Based Services National Association of State Units on Ageing: 202-898-2578 Alzheimer’s Association: 800-621-0379, www.alz.org National Association of Home Care: 202-547-7424, www.nahc.org ABA Commission on Legal Problems of the Elderly: 202-662-8690, www.abanet.org Assisted Living Federation of America: 703-691-8100, www.alfalorg National Academy of Elder Law Attorneys: 520-881-4005, www.naela.org Eldercare Locator: 800-677-1116, www.aqeinfo.org/elderloc
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in patients undergoing programmed electrical stimulation of cardiac arrhythmias. Psychosom Med. 1987;49:410–421. Katzman R. Alzheimer’s disease. N Engl J Med. 1986;314: 964–973. Inouye SK, Bogardus ST, Charpentier PA, et al. A clinical trial of a multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999,340:669– 676. Reifler BV. Mixed cognitive-affective disturbances in the elderly: a new classification. J Clin Psychiatry. 1986;47:354– 356. Jost BC, Grossberg GT. Evolution of psychiatric symptoms in Alzheimer’s disease: a natural history study. J Am Geriatr Soc. 1996;44:1078–1081. Richards M, Touchon J, Ledesert B, Richie K. Cognitive decline in ageing: are AAMI and AACD distinct entities? Int J Geriatr Psychiatry. 1999;14:534–540. Peterson R, Smith G, Waring S, et al. Mild cognitive impairment; clinical characterization and outcome. Arch Neurol. 1999;56:303–308. Huber SJ, Paulson GW. The concept of subcortical dementia. Am J Psychiatry. 1985;142:1313–1317. McKieth LG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996; 47:1113–1124. Luis CA, Barker WW, Gajaraj K, et al. Sensitivity and specificity of three clinical criteria for dementia with Lewy bodies in an autopsy-verified sample. Int J Geriatr Psychiatry. 1999;14:526–533. Mahendra B. Depression and dementia: the multi-faceted relationship. Psychol Med. 1985;15:227–236. Heston LL, White JA, Mastri AR. Pick’s disease; clinical genetics and natural history. Arch Gen Psychiatry. 1987;44: 409–411. Folstein SE, Folstein MF. Psychiatric features of Huntington’s disease. Psychiatr Dev. 1983;2:193–206. Koenig S, Gendelman HE, Orenstein JM, et al. Detection of AIDS virus in macrophages in brain tissues from AIDS patients with encephalopathy. Science. 1986;233:1089–1093. Harrington MG, Merril CR, Asher DM, Gajdusek DC. Abnormal proteins in the cerebrospinal fluid of patients with Creutzfeldt–Jakob disease. N Engl J Med. 1986;315: 279–283. Cutler NR, Haxby JV, Duara R, et al. Brain metabolism as measured with serial assessment in a patient with familial Alzheimer’s disease. Neurology. 1985;35:184. Grober E, Lipton RB, Hall C, et al. Memory impairment on free and cued selective reminding predicts dementia. Neurology. 2000;54:827–832. Folstein M, Anthony JC, Parhad I, Duffy B, Gruenberg EM. The meaning of cognitive impairment in the elderly. J Am Geriatr Soc. 1985;33:228–235. Sherwin BB. Mild cognitive impairment: potential pharmacological treatment options. J Am Geriatr Soc. 2000;48:431– 441. Molloy DW, Standish TIM. A guide to the standardized Mini-Mental State Examination. Int Psychcogeriatr. 1997;9: 87–94.
G.J. Kennedy 27. Kelman HR, Thomas C, Kennedy GJ, Chen J. Cognitive impairment and mortality among older community residents. J Am Public Health. 1994;84:1255–1260. 28. Devanand DP, Jacobs DM, Tang M-X, et al. The course of psychopathology in mild to moderate Alzheimer’s disease. Arch Gen Psychiatry. 1997;66:205–210. 29. Stahelin HB, Monsch AU, Spiegel R. Early diagnosis of dementia via a two-step screening and diagnostic procedure. Int Psychogeriatr. 1997;9:123–130. 30. Kasper JD. Cognitive impairment among functionally limited elderly people in the community: future considerations for long-term care policy. Milbank Q. 1990;68: 81–109. 31. Auer S, Reisberg B. The GDS/FAST system. Int Psychogeriatr. 1997;9:167–171. 32. Reifler BV, Larson E. Excess disability in demented elderly outpatients: the rule of halves. J Am Geriatr Soc. 1988;36: 82–83. 33. Nyenhuis DL, Gorelick PB. Vascular dementia: a contemporary review of epidemiology, diagnosis, prevention, and treatment. J Am Geriatr Soc. 1998;46:1437–1448. 34. Mittelman MS, Ferris SH, Shulman E, Steinberg G. The effects of a multicomponent program on spouse-caregivers of Alzheimer’s disease patients: results of a treatment/ control study. In: Heston LL, ed. Progress in Alzheimer’s Disease and Similar Conditions. Washington, DC: American Psychiatric Association Press; 1995:259–270. 35. Butler RN. Sounding board; on behalf of older women. N Engl J Med. 1996;334:794–796. 36. Boss P, Caron W, Horbal J, Mortimer J. Predictors of depression in caregivers of dementia patients: boundary ambiguity and mastery. Fam Process. 1990;29:245–254. 37. Cohen D, Eisdorfer C. Depression in family members caring for a relative with Alzheimer’s disease. J Am Geriatr Soc. 1988;36:885–889. 38. Gallagher D, Rose J, Rivera P, et al. Prevalence of depression in family caregivers. Gerontologist. 1989;29:449–456. 39. Coleridge PT, George LK. Predictors of institutionalization among caregivers of patients with Alzheimer’s disease. J Am Geriatr Soc. 1986;34:493–498. 40. Gwyther LP. Care of Alzheimer’s Patients: A Manual for Nursing Home Staff. Washington, DC: American Health Care Association and the Alzheimer’s and Related Disorders Association; 1988. 41. Breitner JCS. The end of Alzheimer’s disease? Int J Geriatr Psychiatry. 1999;14:577–586. 42. Rosenberg RN. The molecular and genetic basis of AD: the end of the beginning. The 2000 Wartenberg lecture. Neurology. 2000;54:2045–2054. 43. Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry. 2000;157:4–15. 44. Rogers SE, Friedhof LT, Apter JT, et al. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multi-center, randomized, double-blind, placebo controlled trial. Dementia. 1996;7:293-303. 45. Kaufer DI, Cummings JL, Christine D. Effect of tacrine on behavioral symptoms in Alzheimer’s disease: an open label study. J Geriatr Psychiatry Neurol. 1996;9:1–6. 46. Becker RE, Colliver JA, Markwell SJ, et al. Effects of metrifonate on cognitive decline in Alzheimer’s disease: a
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1093 62. Teri L, Logsdon R, Uomoto J, et al. Behavioral treatment of depression in dementia: a controlled trial. J Gerontol. 1997;32B:P159–P166. 63. Cohen-Mansfield J, Werner P. Management of verbally disruptive behaviors in nursing home residents. J Gerontol Med Sci. 1996;52:M369–M377. 64. Swauger KC, Tomlin C. Moving toward restraint-free patient care. J Nurs Admin. 2000;30:325–329. 65. Moody HR. From informed consent to negotiated consent. Gerontologist. 1988;28:64–70. 66. Houlihan DJ, Mulsant BH, Sweet RA, et al. A naturalistic study of trazodone in the treatment of behavioral complications of dementia. Am J Geriatr Psychiatry. 1994;2:78–85. 67. Katz IR, Jeste VD, Mintzer JE, et al. Comparison of resperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, doubleblind trial. J Clin Psychiatry. 1999;60:107–115. 68. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer’s disease in nursing care facilities: a doubleblind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry. 2000;57:968–976. 69. McManus DQ, Arvantis LA, Kowalcyk BB. Quetiapine, a novel antipsychotic: experience in elderly patients with psychotic disorders. Seroquel Trial 48 Study Group. J Clin Psychiatry. 1999;60(5):292–298. 70. Maletta GJ. Treatment of behavioral symptomatology of Alzheimer’s disease, with emphasis on aggression: current clinical approaches. Int Psychogeriatr. 1992;4:117–130. 71. Magai C, Cohen C, Kennedy GJ, Gomberg D. A controlled clinical trial of sertraline in the treatment of depression in nursing home residents. Am J Geriatr Psychiatry. 2000;8:66– 75. 72. Salzman C. Practical considerations for the treatment of depression in elderly and very elderly long-term care patients. J Clin Psychiatry. 1999;60(suppl 20):30–33. 73. Clerc GE, Ruimy P, Verdeau-Palles J. A double blind comparison of venlafaxiine and fluoxitine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol. 1994;9:139–143. 74. Burrows G, Kremer C. Mirtazapine: clinical advantages in the treatment of depression. Psychopharmacology. 1997; 17(suppl 1):34S–39S. 75. Overman W, Stoudemire A. Guidelines for legal and financial counseling of Alzheimer’s disease patients and their families. Am J Psychiatry. 1988;145:1495–1500. 76. Gillick MR. Rethinking the role of tube feeding in patients with advanced dementia. N Engl J Med. 2000;342:206–210. 77. Karlawish JH, Quill T, Meier DE. A consensus-based approach to providing palliative care to patients who lack decision-making capacity. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians— American Society of Internal Medicine. Ann Intern Med. 1999;130:835–840.
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75 Neurobiologic Basis of Age-Related Dementing Disorders Patrick R. Hof, Thierry Bussière, Joseph D. Buxbaum, and John H. Morrison
Over the past decade, we have witnessed a remarkable increase in our knowledge of the structural, molecular, and biochemical determinants of Alzheimer’s disease (AD). Alzheimer’s disease is the most common form of dementia, as it affects approximately 11% of the population over age 65, and up to 50% of individuals over 85 can be diagnosed as having “probable AD.”1 The exact pathogenetic events that lead to dementia are not yet known, although numerous hypotheses regarding the formation of the typical lesions of AD have been proposed and many risk factors have been identified. The current knowledge of the pathologic changes that occur in AD suggests that structurally and functionally AD is predominantly a disease of the cerebral cortex. However, it is not a generalized loss of cortical function: it involves only certain populations of neurons that share specific regional and laminar distribution and connectivity patterns, whereas other neuron types are spared.2 Thus, different degrees of neuronal vulnerability exist in AD that can be related to the morphologic and biochemical characteristics of select neuronal populations and connections. In this context, neuroanatomic analyses of nonhuman primate brain have considerably expanded our knowledge of the organization of the major afferent and efferent systems of the cerebral cortex, as well as its intrinsic organization. These analyses have fostered the development of an organizational scheme for the cerebral cortex that relates various molecules of interest to specific groups of neurons or circuits and have been particularly illuminating in regard to the organization of neocortical connectivity and interactions between the neocortex and the hippocampus. Furthermore, specific histochemical techniques have made it possible to investigate issues such as neuronal typology, connectivity, and localization within the context of their neurochemical identity. Certain neuron types within the cerebral cortex and some of the major cortical afferent systems have now been characterized as to the presence of structural proteins and neurotransmitters, and the extension of these studies
to the human cerebral cortex is currently on its way. There are obvious limitations as to the application of such experimental paradigms to the study of the human brain, and it should be kept in mind that the human brain has become the object of intensive analyses with chemically specific techniques only relatively recently. However, many of the histochemical procedures work very reliably in the postmortem human brain, and to some extent it is possible to draw certain correlations across species that have allowed for the application to the human brain of organization principles described in several species of nonhuman primates. Such correlations have been particularly useful in regard to issues pertaining to the neuropathology of AD, as well as to the normal functional anatomy of the human cerebral cortex, although caution must be used when transposing information extracted from analyses of the monkey to the human brain.
Overview of Neuronal Vulnerability in Dementia It is instructive to consider briefly the links between the distribution of pathologic changes in AD and related dementing conditions and the localization of specific elements of the cortical circuitry that are affected by these alterations. The current state of knowledge on the molecular components of the principal neuropathologic lesions observed in AD can be considered in the context of observations that relate the neurochemical phenotype of a given neuron to its relative vulnerability or resistance to the degenerative process. Selective neuronal vulnerability has been particularly well studied in AD but is a cardinal feature of all the major age-related neurodegenerative disorders.2 The notion of differential vulnerability can be best understood in the context of an inclusive and integrative definition of neuronal typology that includes single cell morphology, regional and laminar location, connectivity, and neurochemical phenotype. This approach is useful 1095
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Figure 75.1. Examples of neurofibrillary tangles (NFT) (A) and senile plaques (SP) (B) from the hippocampus of a severe Alzheimer’s disease (AD) case. Note the flameshape morphol-
ogy of NFT and the more variable features of SP. In (B), several SP stained with an antiamyloid protein antibody are visible. Bar (on B) 100 mm (A); 200 mm (B).
to explore the cellular organization of the neocortex, as well as the cellular pathologic changes in diseases such as AD, as it considers the complex relationships among these morphologic and functional parameters. In a very general sense, the most vulnerable group of cortical neurons includes large pyramidal cells, and more specifically those providing long corticocortical projections between association neocortical areas and hippocampal projections. These systems utilize the excitatory amino acid neurotransmitter glutamate and are driven by glutamatergic input. The occurrence of modifications in the expression during aging or dementia of some of the various subunit proteins that constitute the glutamate receptors, in particular those subunits regulating calcium permeability through the receptor channels, may determine susceptibility to calcium-mediated toxicity, which may play an important role in the degenerative processes leading to neuronal death in dementing illneses. For example, neurons that express high cytoplasmic levels of certain calcium-binding proteins may have an increased calcium-buffering capacity and are likely to resist the toxic effects of abnormal intracellular calcium concentrations. Other neurons, in particular, pyramidal cells, are not equipped with such molecular mechanisms and demonstrate enhanced vulnerability to a variety of noxious stimuli that may lead to the formation of the neurofibrillary tangles (NFT), one of the cardinal pathologic changes of AD. It appears, therefore, that specific neurochemical and morphologic characteristics of certain pyramidal neurons may predispose them to degeneration, as well as NFT formation. Because only certain neuronal circuits are affected in AD, the relevance and impact of pathologic alterations in AD are best understood within the context of the organized systems that underlie neocortical function. For example, integrated processing in a given sensory modality such as vision involves the simultaneous activity of numerous distinct
cortical domains that have extensive, ordered interconnections establishing a distributed, hierarchical system and subserving the proper integration of the visual information. Similarly, cognition and language, not modalityspecific functions, presumably rely on more complex networks. Such corticocortical circuits are provided by the particular neurons that degenerate in AD, leading in turn to a global neocortical disconnection syndrome that presents clinically as dementia.2,3
Lesion Types and Distribution in Alzheimer’s Disease Alzheimer’s disease is a neurodegenerative disorder classically characterized by the presence of two major types of histopathologic lesions, neurofibrillary tangles (NFT) and senile plaques (SP), in the cerebral cortex (Fig. 75.1). The distribution and density of NFT and SP have been analyzed in great detail and constitute the basis of the neuropathologic diagnosis of AD.4 NFT are characterized by the accumulation of abnormal components of the neuronal cytoskeleton that form paired helical filaments, whereas SP are composed of dystrophic neurites and glial elements with or without a central amyloid core.3,5,6 These lesions are consistently observed throughout the brain but predominate in the cerebral cortex, where NFT are located in the soma of large pyramidal neurons, and SP are distributed throughout the cortical regions but are particularly numerous in association areas.7 Tangles are also found in a number of subcortical structures connected with the cerebral cortex, such as the amygdala and the thalamus, as well as cholinergic and aminergic nuclei in the basal forebrain and brainstem. Variable densities of SP are also observed in other subcortical structures, such as the cerebellum and basal ganglia. Other pathologic alterations commonly seen in the brain of AD
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patients include neurophil threads, which also contain paired helical filaments and appear early in the course of the disease, granulovacuolar degenerations, diffuse amyloid deposits, and amyloid angiopathy. Severe neuronal loss in the hippocampal formation and association regions of the neocortex, leaving primary sensory and motor areas relatively spared, is commonly observed in the brain of AD patients, involving the large cortical neurons, and correlated with the presence of NFT in neocortical association areas.2 Also, synapse loss, together with increased synaptic size, is an early marker of the dementing process because a strong association
between loss of neocortical synapses estimated by immunolabeling for the synaptic protein synaptophysin and cognitive impairment has been reported, which appears to be a better correlate of cognitive deficit than NFT densities.8 Synaptic damage and synapse loss have also been reported in the neocortex of elderly nondemented individuals, suggesting an age-dependent mechanism for the loss or remodeling of synapses in the neocortex.9 At the regional level, NFT are more numerous in the temporal cortex, followed in descending order by the frontal cortex, the parietal cortex, and the occipital cortex (Fig. 75.2).3,4,7 NFT are observed primarily within layers
Figure 75.2. Regional distribution of NFT and amyloid deposition in the cerebral cortex in normal aging compared to very mild AD and severe AD.2–4,7,10–12 NFT appear first in the hippocampal formation and entorhinal cortex. Cases with incipient dementia show low numbers of NFT in the inferior temporal cortex and prefrontal cortex. During subsequent stages in the progression of AD, NFT are found throughout the cerebral cortex, although generally lower densities are present in primary sensory and motor cortices compared with association regions. Senile plaques are present principally in the hippocampal formation and temporal neocortex in normal aging, but it should be noted that the primary visual cortex may contain relatively high levels of amyloid deposition as well. In AD cases, amyloid is present throughout the neocortex. In terms of regional densities it is interesting to note that the hippocampal formation shows somewhat less amyloid deposition than the association neocortex. It should be kept in mind that these patterns are inferred from typical cases and provide a generic overview of the distribution of these lesions from a neuropathologic standpoint, but do not serve as a quantitative measure that can be used as a correlate of the severity of the dementing process, and do reflect the considerable caseto-case variability in numbers of lesions.
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III and V in the neocortex, although their density varies considerably among cortical regions, primary sensory and motor regions having many fewer NFT than association areas.7,10,11 Similar differences are found in other sensory systems. In addition, considerable differences in laminar NFT distribution exist among neocortical regions. With a few exceptions, SP show a generally comparable distribution among neocortical areas.11,12 In the medial temporal lobe, layer II of the entorhinal cortex, the subiculum, and the CA1 field of the hippocampus represent particularly vulnerable cortical domains that consistently display very high NFT densities in AD (Fig. 75.2, 75.3).2,7,13 The distribution of SP in the hippocampal formation is variable, with certain zones displaying high SP densities and amyloid deposition, such as layer III of the entorhinal cortex, the molecular layer of the dentate gyrus, and the superficial layer of the subiculum.14 There are strong correlations between the distribution of SP, NFT, and neuron loss among regions and layers of the cerebral cortex and the neurons of origin of certain long corticocortical and hippocampal projections.10–13,15–17 The neurons of origin of corticocortical projections can be ascribed to three categories, feedforward, feedback, and lateral connections, based on their localization in the cortical layers and the distribution of their axonal terminals in the regions where they project (Fig. 75.4).18,19 In this scheme, feedforward connections ascend within the hierarchy of a given modality (i.e., from a primary sensory area to an association area), feedback projections descend the same hierarchy, and lateral connections link cortical regions at the same hierarchical level. Feedforward connections originate mostly from neurons located in the superficial layers of the cortex and terminate in the deep portion of layer III and in layer IV of the target cortical region, feedback projection neurons are located principally in layers V and VI and project to layers I and VI, and lateral connections originate from layers V and VI and project to layers III to VI (Fig. 75.4). The distribution of NFT indicates that elements of feedforward, lateral, and feedback projections can all be affected by the degenerating process of AD. Considering that layer V contains generally higher NFT densities than layer III in association areas suggests that feedback as well as lateral projections may be at higher risk in AD than feedforward systems. Interestingly, most of the projection neurons from the occipital and temporal association cortex to the frontal and from the occipital cortex to the temporal cortex are located in layer III. The regional and laminar distribution of SP suggests that they may be related to NFT formation (see Figs. 75.2, 75.4), in that their distribution appears to reflect the degeneration of the terminations of projections from neurons affected by NFT formation,10 although multiple neuronal systems are involved in SP formation.20 The distribution of NFT and SP in the hip-
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Figure 75.3. Regional and laminar NFT formation and neuronal loss in normal aging and AD. The flameshaped structures represent a semiquantitative assessment of NFT densities. An estimate of the percent of neuronal loss is shown by the gray scale (see % equivalent at bottom). In normal aging (CDR 0), a few NFT are consistently observed in layer II of the entorhinal cortex (EC) and the superior frontal cortex (SFC) remains devoid of NFT. There is no neuronal loss in normal aging. In contrast, very early AD (CDR 0.5) is characterized by higher NFT densities in the EC. Very rare NFT are observed in SFC. The neocortical areas show no neuronal loss, but a significant degree of neuronal loss is present in layer II of the EC. In definite AD (CDR 2), NFT are found in very high densities in layer II of the EC, but in moderately high densities in SFC. The degree of neuronal loss parallels NFT densities in these regions. The size of boxes reflects tissue shrinkage, due to neuronal loss, in AD.
pocampal formation also outlines specific projections. The perforant pathway that projects from layers II and III of the entorhinal cortex is affected severely and early during AD, and the presence of NFT in the neurons of origin of this pathway and its termination in the dentate
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gyrus are correlated with high densities of SP in the molecular layer of the dentate gyrus.21 High densities of NFT in layer V of the entorhinal cortex are correlated with the degeneration of connections to the amygdala and association cortical areas part of the limbic lobe, and the projections from the hippocampus to the entorhinal cortex, amygdala, and neocortical areas, originating from the CA1 field and the subiculum, are consistently affected, as are amygdala nuclei projecting to the entorhinal cortex and hippocampus.21
The presence of intracellular fibrillar aggregates in certain cerebral regions is a common feature of several neurodegenerative disorders, as well as of aging. Neurofibrillary tangles have been extensively studied as a neuropathologic signature for AD. The molecular dissection has shown that the microtubule-associated proteins (MAP) tau are the main components of these aggregated structures in AD. Tau proteins are derived from a unique human tau gene located on chromosome 17q21–22 (see details in Fig. 75.5). Importantly, exons 2, 3, and 10 are
alternatively spliced, giving rise to six different isoforms in the adult human brain.22 The expression of these isoforms is developmentally regulated, as only the shortest isoform is present in the fetal brain (called fetal isoform) and all the six tau variants are present in the adult brain. Moreover, the isoforms are differentially distributed among neuronal populations. Also, tau proteins undergo some posttranslational modifications, which is important in the context of pathologic conditions.22 Tau proteins belong to the family of the microtubuleassociated proteins (MAP), together with MAP1, MAP2, MAP3, and MAP4 in the nervous system. These microtubule-associated proteins are involved in the formation of the cytoskeleton by enhancing the polymerization of tubulin monomers and stabilizing microtubule bundles (Fig. 75.6).23 The amino-terminal part of tau proteins is referred to as the projection domain, as it forms extensions from the microtubule core. These extensions are able to make connections with cytoskeletal components, such as neurofilaments, and with cytoplasmic elements or the neural plasma membrane. The projection domain is also involved in signal transduction pathways. The carboxy-terminal part of the molecule binds to microtubules through a flexible array of distributed weak sites and is referred to as the microtubule-binding
Figure 75.4. The laminar distribution of NFT and SP (black triangles and black disks, respectively, in the center panels) matches the distribution of corticocortically projecting neurons along neocortical hierarchies. Feedforward projection ascend the hierarchy, originating from a region involved in primary processing (such as the primary visual cortex), and terminating in an association cortex dealing with more complex types of information (such as a visual region located in the parietal lobe and integrating visual motion). The feedback projections are reciprocal to the feedforward projection and descend the same
hierarchy.18,19,40 Not shown on this diagram are lateral connections that interconnect cortical regions located at the same functional level in the hierarchy. The NFT are found in the same cortical layers in which the neurons providing feedforward and feedback corticocortical projections are located, and they are slightly more numerous in the deep layers, suggesting a stronger correlation with feedback projections. Senile plaques are observed in higher densities in layer IV and the lower portion of layer III, which corresponds to the zone of termination of feedforward projection.
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P.R. Hof et al. Figure 75.5. Schematic representation of the human Tau gene and the six tau isoforms present in the human brain. The human tau gene is located on the long arm of chromosome 17 at position 17q21. It contains 16 exons, with exon 1 a part of the promoter (upper panel ). Exons 4A, 6, and 8 are not transcribed in humans (middle panel). Exons 1 and 14 are transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, and 13 are essential constitutive elements of the gene, and exons 2, 3, and 10 undergo alternative splicing, giving rise to 6 different mRNAs, translated in 6 different tau isoforms (lower panel). These isoforms differ by the absence or presence of one or two 29-amino-acid inserts encoded by exon 2 (light box) and 3 (dotted box) in the aminoterminal part, in combination with either three (R1, R3, and R4) or four (R1–R4) repeat regions (black boxes) in the carboxy-terminal part. The fourth microtubule-binding domain is encoded by exon 10 (hatched box; lower panel ). The number of amino acid varies between 441 (longest tau isoform) and 352 residues (fetal tau isoform).
Figure 75.6. Neurofilaments and microtubules are the major components of the neuronal cytoskeleton. Microtubules constitute the network responsible for the axonal transport of soluble proteins and vesicles between the neuronal cell body and the synapses (anterograde transport), or between the synapses and the cell body (retrograde transport). In physiologic conditions, a dynamic equilibrium exists such that polymerization of tubulin monomers occurs at one end of the microtubules and
depolymerization occurs at the opposite end. Finally, polymers of tubulin are stabilized by specific proteins called microtubuleassociated proteins (MAPs). Tau proteins belong to this class. Nonphosphorylated tau proteins promote the polymerization of tubulin monomers into microtubules and also stabilize the bundles of newly formed microtubules. Conversely, phosphorylation of tau proteins abolishes their binding to microtubules and results in depolymerization and eventually NFT formation.
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domain. It regulates the rate of microtubule polymerization, stabilizes the forming microtubules, and is also involved in interaction with functional proteins such as protein phosphatase 2A or presenilin 1.22 Tau proteins exhibit about 70 potential phosphorylation sites, and at least 30 of them have been described by using different biochemical or immunohistochemical techniques. At any given time, the phosphorylation state of the sites results from the regulated activity of kinases and phosphatases. The binding between tau proteins and microtubules and the subsequent microtubule stabilization depends partially on the phosphorylation state. Hyperphosphorylated tau proteins aggregates have been described in AD, as well as in several other neurodegenerative diseases, the so-called “tauopathies.”22 Extensive studies have shown that a specific distribution of the tau lesions, as well as different electrophoretic patterns of tau proteins, could discriminate among these disorders (Fig. 75.7). In AD, the filamentous tau inclusions are known as paired helical filaments (PHF), based on their ultrastructural appearance. These PHF exhibit specific biochemical properties that distinguish them from the normal tau proteins. PHF form insoluble polymers that are not found in normal samples obtained from biopsy materials. The electrophoretic profile of abnormally phosphorylated tau proteins shows a triplet of bands at 55, 64, and 69 kDa, and a minor band at 72 to 74 kDa. Dephosphorylation of PHF tau proteins before their electrophoretic migration
shows that this triplet results from the aggregation of the six tau isoforms.22 In addition to AD, NFT are observed in a variety of neurodegenerative disorders. Remarkably, these disorders can be identified on the basis of their biochemical profile of tau isoforms. Figure 75.7 summarizes the typical tau profiles in postencephalitic parkinsonism (PEP), Guamanian amyotrophic lateral sclerosis/parkinsonism– dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Neurofibrillary tangles are found in variable densities in the brain of patients who survived the influenza pandemic in the years 1916 to 1926 and who later developed PEP. The biochemical analyses have shown that the six isoforms of tau proteins are hyperphosphorylated, aggregate into NFT, and display an AD-like electrophoretic pattern (triplet tau55, tau64, and tau64).24 Nevertheless, the distribution of these proteins, predominantly in association cortices and subcortical brain regions but also in primary motor cortex and basal ganglia, differs from that in AD, where the triplet of tau proteins is mostly restricted to the hippocampal formation and association neocortex. It should be mentioned that heterogeneity exists among cases. A similar electrophoretic profile of tau proteins has been described in cases with Guamanian ALS/PDC. The regional and laminar distribution of the tau triplet differs
Figure 75.7. Schematic representation of the different electrophoretic profiles of pathological tau proteins using a phosphorylation-dependent monoclonal antibody (in frames), with their isoforms composition (right of each frame). The six tau isoforms are involved in the formation of the tau55, tau64, tau69 AD triplet with the minor tau74 variant. This pattern is also described in postencephalitic parkinsonism (PEP), Guamanian amyotrophic lateral sclerosis/parkinsonism–dementia
complex (ALS/PDC), and some families with FTDP-17 (left panel). The typical progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) doublet tau64, 69 is related to the aggregation of hyperphosphorylated tau isoforms with exon 10. The FTDP-17 families with mutations in exon 10 or intron 10 exhibit the same profile (middle panel). Hyperphosphorylated tau proteins without exon 10 that aggregate in Pick’s disease are detected as a tau55, 64 doublet (right panel ).
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from that in AD cases, as both cortical and subcortical areas are affected, and cortical layers II and III are preferentially involved.25 In contrast to these two conditions, the electrophoretic pattern of tau proteins in CBD and PSP has been described as two major bands with an apparent molecular weight of 64 and 69 kDa (PSP/CBD tau doublet), although a minor 74-kDa band is also detected.26–29 The characteristic lesions described in the brains of patients affected by Pick’s disease, the so-called Pick bodies, are also detected with antibodies against phosphorylated sites present within tau proteins. By Western blotting, these antibodies reveal two bands with an apparent molecular weight of 55 and 64 kDa (Pick tau doublet) and a minor band at 69 kDa.30–32 The importance of tau proteins as the major component of fibrillar lesions has been emphasized by the emergence of a new class of neurologic syndromes called frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).33–35 This designation includes different disorders sharing some clinical and pathologic features and for which a genetic linkage with chromosome 17q21–22 has been demonstrated.36 The neuropathologic features are frontal and temporal atrophy, severe neuronal loss, gliosis affecting both the gray and white matter, and superficial spongiosis. The presence of filamentous inclusions in neuronal cells, or in both neuronal and glial cells, has been described. The presence of these lesions is caused by mutations on the Tau gene that always segregate with the pathology, underlining the direct role of tau proteins in the pathogenic mechanism. At least 17 mutations on the Tau gene have been described in different families. Some mutations result in a tau profile similar to that observed in PSP and CBD (tau64, tau69), whereas others are resolved as a typical AD tau triplet. These diseasespecific tau profiles highlight well the fact that various etiopathogenic mechanisms can lead to a comparable neurodegenerative process resulting in the formation of NFT, which can be understood as a general response to neuronal injury.
Neuronal Types Prone to Neurofibrillary Tangle Formation The number of NFT does not account for the total population of pyramidal neurons, indicating that only certain subpopulations of pyramidal neurons are selectively susceptible to paired helical filament aggregation. The large neocortical pyramidal cells in layers III and V represent the most affected cell class, whereas smaller pyramidal neurons in layers II, VI, and the upper part of layer III are more resistant to NFT formation. Also, the spiny stellate cells and small pyramidal cells in layer IV are not
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affected by this process as are the many morphologic types of inhibitory interneurons. The large pyramidal neurons in layers II, III, and V of the entorhinal cortex and those in CA1 field and subiculum are all severely affected. Considering the morphology and connectivity of the vulnerable neurons, it is interesting to note that all are efferent cells that send long projections to other cortical regions or to subcortical structures, and all are large pyramidal neurons.16,17 However, other cellular characteristics are also linked to vulnerability to the degenerative process because certain large efferent neurons, such as the principal cells in the CA3 field and the large neurons of the dentate hilus, are generally relatively resistant to degeneration in AD, and in subcortical structures, NFT appear in several nuclei that project to the cerebral cortex, such as catecholaminergic cell groups in the brainstem and cholinergic neurons in the nucleus basalis of Meynert. Certain pyramidal neurons in the human and monkey neocortex have been shown to be enriched in neurofilament protein.16,17,37 Neurofilament protein immunoreactivity in the primate neocortex is restricted to the perikaryon and dendrites of a subpopulation of large pyramidal neurons. Interestingly, neurofilament proteins, as well as other cytoskeletal proteins, have been implicated in NFT formation,2,38 and pyramidal cells expressing high levels of nonphosphorylated neurofilament protein appear to be highly susceptible to NFT formation. The distribution of neurofilament proteincontaining neurons corresponds to the distribution of corticocortically projecting cells, as demonstrated by studies in the macaque monkey.39 The correlation between origins of long corticocortical projections and neurofilament protein-containing neurons is particularly visible in the primary visual cortex of monkeys and humans, where layer IVB cells and the Meynert cells are the only large, strongly immunoreactive neurons. These neurons form well-established connections to the parietal lobe and susberve visuomotor functions known to be affected during aging and AD.40 These observations on visual projections therefore demonstrate the existence of a neurochemically defined neuronal subpopulation that is vulnerable in AD and can be correlated with a functionally characterized projection system. We have also reported in the macaque monkey that many long association corticocortical projections originate from neurofilament protein-containing neurons, and, in some of them, 90% to 100% of the neurons of origin of the projection contain neurofilament protein,39 which is particularly the case of projections from the temporal to the prefrontal and parietal neocortex that are known to be involved in networks subserving many aspects of the cognitive functions.41 In fact, the laminar distribution of neurofilament protein-containing neurons in visual association, prefrontal, and anterior cingulate in
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Figure 75.8. Involvement of neurofilament protein-immunoreactive pyramidal neurons in layer III of the area 9 in an AD case. In this sample labeled for neurofilament protein and tau protein, a few normal neurons are labeled (arrows) and an intracellular NFT is seen developing within a neurofilament protein-immunoreactive neuron (arrowhead). Bar 30 mm.
human cerebral cortex is very similar to the distribution of NFT in that the layers that have high NFT density in an AD brain no longer contain a high density of neurofilament protein-immunoreactive neurons.16,17 A comparable situation exists in the hippocampal formation where layers II, III, and V of entorhinal cortex and the pyramidal neurons of the subiculum have a very high density of neurofilament protein-immunoreactive neurons in the normally aging human brain and present with a dramatic loss of these neurons in AD.2 These observations demonstrate that neurofilament protein-containing neurons are highly vulnerable in AD, and quantitative analyses have demonstrated a severe loss of neurofilament protein-containing neurons in layers III and V in the inferior temporal and superior frontal cortex (Fig. 75.8). The severity of the loss correlates with the size of these neurons in that the neurofilament protein-containing neurons larger than 6000 mm3 of perikaryal volume are the most affected, with up to 60% cell loss, whereas the smaller-size neurons (2000– 6000 mm3 of perikaryal volume) are not affected.16 In addition to regional distribution and relationship to connectivity, NFT identified by antibodies to neurofilament and tau proteins have revealed dynamic cellular alterations in vulnerable neuronal populations during normal aging. Layer II of the entorhinal cortex contains neurofilament protein-immunoreactive neurons and also displays
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immunoreactivity to tau protein, suggesting the existence of transitional forms of NFT during aging.2 In AD cases, most NFT in the entorhinal cortex progress to an end stage and are no longer immunoreactive to neurofilament protein, and transitional forms of NFT are observed in the frontal cortex, indicating that a time-dependent process takes place in the formation of NFT in certain neurofilament protein-containing neurons (Fig. 75.9).2,6,20 Interestingly, certain neurons, such as the pyramidal neurons of the CA1 field, do not normally express detectable levels of neurofilament protein in young adults but do form NFT in AD. Such neurons show increasing levels of neurofilament protein immunoreactivity during aging before accumulation of tau protein, suggesting that high levels of neurofilament protein are a necessary substrate for the formation of NFT.42 Thus, one of the neurochemical characteristics of the vulnerable neurons in AD is the presence of high somatic and dendritic concentrations of nonphosphorylated neurofilament proteins, even though this may be only one aspect of the phenotype associated with selective neuronal vulnerability. In addition, when the monkey data are considered together with the distribution of neurofilament protein-containing neurons and NFT in humans, it is likely that the human homologues of the neurofilament protein-containing, corticocortically projecting neurons of the macaque monkey are those that are highly vulnerable in AD. These neuronal networks use glutamate as their neurotransmitter. Disruption of glutamate metabolism and glutamate receptor-mediated excitotoxicity represents one of the major mechanisms of neuron death in many neurodegenerative disorders. Glutamate receptor-mediated excitotoxicity presumably results from increased calcium flux leading to toxic intracellular concentrations of this ion, and this mechanism is likely associated with all types of ionotropic glutamate receptors that are involved in facilitating or regulating calcium fluxes. Although the N-methyl-d-aspartate (NMDA) receptor has been the receptor subtype primarily associated with calcium flux into the neuron, it is now clear that both kainate and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors also modulate calcium influx.43 Thus, the glutamate receptor profile of cortical neurons and related circuits has emerged as an important parameter when correlating identified neurons and circuits with susceptibility for vulnerability to degeneration through excitotoxicity, because the defining characteristics of a given glutamatergic projection with respect to ion fluxes depends on the subunit composition of the receptors that dominate that system. Abnormal functioning of glutamatergic receptors and resulting increases in intracellular calcium concentration are also linked to a variety of pathologic molecular events, such as production of free radicals, increased
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Figure 75.9. Mechanisms through which an imbalance in excitatory neurotransmission can induce a molecular cascade resulting in neuronal damage and death. Impaired energy metabolism can result in abnormally elevated stimulation of ionotropic glutamate receptors through depolarization of membranes (A) as well as increasing intracellular calcium. Elevated calcium can trigger the generation of free radicals by activating a number of calcium-dependent enzymatic reactions (B). Free
radicals are extremely reactive products that will induce direct damage to cellular structure and result in neuronal death. Free radicals also affect glutamate receptors by further increasing the release of excitatory amino acids (C) as well as energy metabolism by inducing mitochondrial dysfunction (D). It is likely that all these pathways participate in the formation of NFT in the AD brain.
release of excitatory amino acids, destabilization of lipid membranes, and damage to the cytoskeleton, that are all involved in the final processes leading to NFT formation and cell death (see Fig. 75.9). Autoradiographic, immunocytochemical, or in situ hybridization studies have demonstrated severe alterations in the distribution and density of several glutamate receptor subunits in the cerebral cortex in normal aging and AD.44 In addition, changes in the expression of specific glutamate receptor subunits leading to functional decline without neuronal degeneration are known to occur during normal aging.45,46 For instance, in aged monkeys, compared to juvenile and young adult monkeys, the NMDA receptor levels decrease specifically and consistently in the outer molecular layer of the dentate gyrus in the hippocampal formation, where the perforant path terminates, but there are no significant differences in expression of AMPA or kainate glutamate receptor subunits and no morphologic reflection of degeneration of the perforant path.45,46 These data also suggest that the intradendritic parcellation of a particular neurotransmitter receptor is modifiable in an age-related and circuit-specific manner and that such changes may be an underlying condition for age-related memory impairment.2,45 It should be noted that several classes of GABAergic
interneurons containing the calcium-binding proteins parvalbumin, calbindin, and calretinin, as well as a variety of neuropeptides, are largely resistant to the degenerative process, even in severe cases displaying very high densities of NFT and SP.3 The cellular distribution of calcium-binding proteins is largely coextensive with that of GABA in cortical interneurons, and these proteins subdivide the GABAergic neurons into nonoverlapping morphologic subtypes that together account for the vast majority of the GABAergic cells.47 Moreover, parvalbumin-immunoreactive neurons have been shown to be resistant to degeneration in the cerebral cortex of Huntington’s disease, Pick’s disease, Guamanian ALS/PDC, PEP, PSP, CBD, and frontal lobe dementia, but not in Down syndrome and Creutzfeldt–Jakob disease. Calbindin- and calretinin-containing cells are also resistant in most of these disorders, except in frontal lobe dementia, where calbindin-immunoreactive neurons are vulnerable.3 The combination of factors such as high cytoplasmic levels of calcium-binding proteins, certain neuropeptides, and GABA with the morphologic features of locally projecting interneurons may confer some resistance to these neurons in many neurodegenerative illnesses and contrasts sharply with the morphologic phenotype of the vulnerable cells.
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Molecular Biology of Amyloid and Its Role in Alzheimer’s Disease
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In addition to the intraneuronal accumulation of PHF, AD is characterized histopathologically by the presence of extracellular deposits of an amyloid peptide (Ab) in plaques.48 Plaques are spherical structures 15 to 20 mm in diameter, consisting of a peripheral rim of abnormal neuronal processes and glial cells surrounding a core of deposited materials. Brain Ab has both soluble and insoluble species, with aggregation states from monomer to higher molecular weight oligomers. Soluble brain Ab is predominantly a random coil and a-helical folded peptide. Insoluble Ab is b-sheeted and forms either fibrillar or amorphous deposits. These Ab fibrillar aggregates are thought to act as a nidus for subsequent deposits of other proteins, including a-antichymotrypsin, components of the complement cascade, and apolipoproteins E and J (apoE, apoJ).49 Ab production and release are normal physiologic events. Ab peptides are normally present in the media of amyloid protein precursor(APP-) expressing cultured cells and in human and rodent cerebrospinal fluid.50–53 Recently, there have been reports showing evidence there could be two distinct
pools of intracellularly generated Ab: a pool that is eventually secreted and a pool that is destined to remain within the cell.54,55 The relative importance of intracellular versus extracellular Ab has not been determined at this point. Level of Ab, as determined by ELISA, correlates exceptionally well with AD progression.56 Ab is proteolytically derived from a larger integral membrane protein, the amyloid precursor protein (APP). APP is an integral membrane glycoprotein containing the Ab region, which includes 28 amino acids of the ectodomain and 11 to 14 amino acids of the adjacent transmembrane domain.48,57 The APP gene is localized on chromosome 21 at 21q21.2.58,59 APP can be processed by at least three secretases, namely a-, b-, and g-secretase (Fig. 75.10). In the nonamyloidogenic pathway, asecretase cleaves the amyloid precursor protein within the Ab domain, releasing an extracellular portion. The cleavage within the Ab domain prevents deposition of the intact amyloidogenic peptide. a-Secretase generates a soluble N-terminal fragment of APP known as sAPPa, and its C-terminal counterpart of about 10 to 11 kDa remains embedded in the membrane. The 10- to 11-kDa C-terminal product may undergo an additional cleavage by a protease g-secretase activity. The protease termed “b-secretase” initiates Ab generation by creating an
Figure 75.10. The amyloid protein precursor (APP) is a single transmembrane domain protein that exists as eight different isoforms transcribed by an alternative splicing mechanisms from a single gene located on chromosome 21. The normal function of APP is still unknown. The differential proteolytic cleavage of APP by a-, b-, or g-secretase leads to the formation of different proteolytic products, which are involved in two differ-
ent pathways called the nonamyloidogenic and the amyloidogenic pathway. a-Secretase cleaves APP within the Ab domain (black box), and the consecutive cleavage by g-secretase gives rise to the nonamyloidogenic p3 fragment. Conversely, bsecretase cleaves APP before the Ab domain, and the consecutive cleavage by g-secretase generates the amyloidogenic Ab peptides that will aggregate into senile plaques.
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approximately 12-kDa C-terminal fragment.60 This 12kDa fragment may then undergo “g-secretase” cleavage within the hydrophobic transmembrane domain to release the 40-, 42-, or 43-residue Ab peptides.52 The varying C-terminal of Ab may be a feature of crucial importance because Ab peptides display distinct physical properties and, in particular, exhibit aggregation behavior that can vary according to their length.61 It has been shown recently in fibroblasts with a disrupted TACE (tumor necrosis factor a-converting enzyme) gene that two classes of a-secretase exist, one involved in the basal secretion and the other involved in regulated secretion.62–64 TACE, a member of the ADAM family (a disintegrin and metalloprotease family) of proteases, has been demonstrated to play a central role in regulated asecretase cleavage of APP. Four groups have now identified a candidate for b-secretase (BACE), also known as Asp-2.65–68 Interestingly, presenilin 1 (PS1) appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP by g-secretase.69 It is possible that presenilins are g-secretase or that they facilitate gsecretase activity through some other mechanism. Genes may be related to disease in two ways: through autosomal dominant mutations, by themselves sufficient to cause the disease (i.e., deterministic mutations), or, alternatively, through gene variations (polymorphisms) that may increase disease risk without being sufficient by themselves to cause the disorder. This latter group is referred to as susceptibility genes. Although it is currently thought that most cases of AD occur sporadically, autosomal dominant transmission has been identified in families with early-onset AD, defined as beginning before the age of 65 years. These cases are relatively rare; worldwide, only several hundred families are currently known that carry deterministic mutations.70 Extensive research carried out during the past two decades has isolated a number of genes that when mutated cause AD, that is, APP on chromosome 21,71,72 the presenilin 1 (PS1) gene on chromosome 14, and the presenilin 2 (PS2) gene on chromosome 1.73 Mutations in these genes lead to earlyonset AD and only explain a small proportion (5%–10%) of total AD cases. Furthermore, trisomy 21 (Down syndrome) increases the risk of AD, perhaps due to the tripled genetic dosage of APP. In addition, a number of susceptibility genes are also currently being studied, with polymorphisms of the apolipoprotein E gene receiving the most attention. The presence of the apolipoprotein E4 (apoE4-) allele has been identified as a genetic risk factor for sporadic and familial AD with late onset. Several different pathogenic mutations have been found in exons 16 and 17 of the APP gene to date. These mutations are missense mutations. The early-onset AD mutations are located outside the Ab amyloid sequence, close to the C-terminal g-secretase cleavage site,71 within the transmembrane domain, or at the N-terminal b-
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secretase cleavage site within the extracellular part of APP.74 One mutation is located inside the Ab amyloid sequence next to the a-secretase cleavage site.75,76 The localization of mutations led to the hypothesis that they might influence the activity of the respective secretases, resulting in the aberrant processing of APP.77 Indeed, mutations at codons 716 and 717 lead to a selective increase in the production of Ab peptides ending at residue 42/43.78–82 The mutations at codons 670 to 671, on the other hand, appear to augment the production of both Ab40 and Ab42(43),83 whereas the mutation at codon 692 has a more complicated effect on APP processing, causing impaired a-secretase cleavage, increased heterogeneity of secreted Ab species, and increased hydrophobicity of the Ab.80 This mutation also has clinical features in some cases similar to those of cerebral hemorrhage with amyloidosis of the Dutch type and in other cases more similar to AD. The homologous membrane proteins presenilin 1 (PS1) and presenilin 2 (PS2) were identified in 1995 as the genes responsible for a substantial fraction of earlyonset, autosomal dominant AD.73,84 Mutations in the PS1 gene on chromosome 14 are the most common cause for autosomal dominant familial AD (FAD)73; these account for 30% to 50% of all early-onset cases85 and are the primary cause of AD with onset before the age of 55 years. To date, more than 50 PS1 mutations and 2 PS2 mutations have been reported in FAD. All mutations in the PS are missense mutations, except for the mutation of a splice acceptor site resulting in the deletion of exon 9. Pathogenic mutations in PS modify APP processing, thereby leading to an augmentation of Ab42(43) secretion. AD patients carrying PS1 or PS2 mutations have significant increase of plasma Ab42(43) level together with deposition of Ab42 in the brain.86–88 In fibroblasts from such patients, the APP metabolism is shifted toward an increase of Ab42(43) production. Similarly, the presence of mutated PS1 increases Ab42(43) in transfected cells and in transgenic mice.89–92 How the mutant PS influences the production of Ab42(43) peptides remains uncertain. In neurons of PS1-knockout mice, secretion of Ab is drastically reduced, leading to the accumulation of a- and bcleaved C-terminus stubs of APP.69,93 This finding gives evidence that PS1 is obligatory for proteolysis of APP at the g-secretase cleavage site. In addition to the deterministic genetic mutations found in APP are the presenilins, genetic factors that modify the risk of getting AD. ApoE alleles on chromosome 19 are considered important risk factors for the development of late-onset AD. ApoE is a 34-kDa component of various lipoproteins, including chylomicrons, very low density lipoproteins (VLDL), and a subset of highdensity lipoproteins (HDL).94 These lipoproteins regulate plasma–lipid transport and clearance by acting as ligand for lipoprotein receptors such as LDLR and low density
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receptor-related protein (LRP).95,96 ApoE is polymorphic and is encoded by three alleles (ApoE2, -3, and -4) that differ in two amino acid positions. In general, it seems that E4 allele increases the risk for developing AD by about threefold, and that the E2 allele decreases the risk.97 The presence of one or two E4 alleles is associated with earlier onset of disease and an enhanced amyloid burden in brain but has little effect on the rate of progression of dementia.98 Thus, the homozygous E4/E4 subjects have an earlier onset (mean age, >70 years) than heterozygous E4 subjects (mean age of onset for E2/E3, over 90 years).99 The most obvious hypothesis is that ApoE E4/E2 polymorphisms might influence the production, distribution, or clearance of Ab. This hypothesis is supported by observations that first, the subjects with one or more ApoE4 alleles have a higher burden than do subjects with no E4 alleles.100 Second, there is evidence that both ApoE and Ab may be cleared through the lipoprotein-related (LRP) receptor and that ApoE4 and Ab peptide may compete for clearance through the LRP receptor.95 Third, transgenic mice that overexpress APP develop a significantly lower number of Ab deposits when bred to an ApoE knockout background.101 These findings strongly support a role of ApoE in the aggregation or clearance of Ab in the brain. It should be noted that the ApoE genotype influences the onset of AD in patients with Down syndrome and in those with APP mutations but not in families with presenilin mutations.101 In summary, biochemical studies in postmortem tissue support a role for Ab in AD. In addition, all available genetic evidence support a role for this peptide in AD. For these reasons, therapies targeting Ab represent important therapeutic avenues for AD.
taining significant compromise of hippocampal circuits and may rely more on neocortical than on hippocampal circuits for memories essential for daily activities.103 Healthy elders may present with difficulties in learning and retrieving new information, and their major limitation may be the amount of new information they can learn within a given period of time in comparison to younger individuals. Unlike patients with early AD, healthy elders are able to retain the new information after some delay, whereas patients with mild cognitive impairment retain little of it.103 This impairment in information retention that characterizes the very early stages of AD is correlated to neuronal loss in the entorhinal cortex and to volumetric changes in the temporal lobe. Similarly, the volume of the temporal horn of the lateral ventricle increases in these patients, which may correlate with the selective loss of projections from the entorhinal cortex.2,3,103–105 In fact, normal brain aging may be defined as intact cognitive abilities in the presence of scarce neurofibrillary pathology in the entorhinal cortex, which may represent a stable age-related asymptomatic AD-like neurofibrillary pathology. This idea points to the differential involvement of hipocampal and neocortical circuits between aging and dementia and indicates that whereas normal brain aging presents as a minimal pathology of discrete medial temporal regions, AD is a disease of the neocortical circuits (see Figs. 75.2, 75.3, 75.4). This interpretation of the pathologic features of AD suggests that the debilitating effects of dementia result from changes restricted to the association neocortex. Considerable hippocampal alterations may occur in absence of neocortical involvement and with only minor disruptions in activities of daily living of the individual that are not sufficient for a diagnosis of dementia. The cells that provide the most vulnerable projections appear to be highly specialized neurons that share identifiable morphologic and neurochemical features. As the elements of the biochemical and anatomic phenotype that are linked to differential cellular vulnerability in AD are increasingly recognized, functional correlations are likely to emerge between cellular changes, neurochemical characteristics of vulnerability, and affected cortical pathways. It is hoped that this understanding will make it possible to design therapeutic strategies to protect or rescue the neurons at risk in AD. The protection of these neurons appears to be an attractive avenue for intervention in the management of AD and may be more practical than the development of a cure.
Conclusions Clearly, other degenerative processes play an important role in AD, and they may also contribute to the clinical characteristics of the disease. Some cortical networks may be more sensitive to the effects of additional deleterious factors known to be involved in AD, such as inflammation free radicals, and potential amyloid toxicity, which may act in a synergistic manner with their morphologic and molecular phenotype to render them particularly vulnerable.102 However, the generalized loss of long corticocortical projections emerges functionally as the most devastating component of AD and that most directly related to dementia. Thus, the degeneration of presumed corticocortical circuits within the neocortex appears therefore to be the necessary factor for the clinical expression of the dementia in AD.2,3 It should be kept in mind, however, that in sharp contrast to AD patients, many elderly individuals maintain near-normal levels of cognitive performance while sus-
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1108 2. Morrison JH, Hof PR. Life and death of neurons in the aging brain. Science. 1997;278:412–419. 3. Hof PR, Bouras C, Morrison JH. Cortical neuropathology in aging and dementing disorders: neuronal typology, connectivity, and selective vulnerability. In: Peters A, Morrison JH, eds. Neurodegenerative and Age-Related Changes in Cerebral Cortex, Cerebral Cortex, vol 14. New York: Kluwer–Plenum; 1999:175–312. 4. Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer’s disease—a primer for practicing neuropathologists. Arch Pathol Lab Med. 1993;117:132–144. 5. Brion JP. Molecular pathology of Alzheimer amyloid and neurofibrillary tangles. Semin Neurosci. 1990;2:89–100. 6. Vickers JC, Dickson TC, Adlard PA, et al. The cause of neuronal degeneration in Alzheimer’s disease. Prog Neurobiol. 2000;60:139–165. 7. Arnold SE, Hyman BT, Flory J, et al. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex. 1991;1:103–116. 8. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–580. 9. Masliah E, Mallory M, Hansen L, et al. Quantitative synaptic alterations in the human neocortex during normal aging. Neurology. 1993;43:192–197. 10. Pearson RCA, Esiri MM, Hiorns RW, et al. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci USA. 1985;82:4531–4534. 11. Lewis DA, Campbell MJ, Terry RD, et al. Laminar and regional distribution of neurofibrillary tangles and neuritic plaques in Alzheimer’s disease: a quantitative study of visual and auditory cortices. J Neurosci. 1987;7:1799– 1808. 12. Rogers J, Morrison JH. Quantitative morphology and regional and laminar distributions of senile plaques in Alzheimer’s disease. J Neurosci. 1985;5:2801–2808. 13. Hyman BT, Van Hoesen GW, Kromer LJ, et al. Perforant pathway changes and the memory impairment of Alzheimer’s disease. Ann Neurol. 1986;20:472–481. 14. Thal DR, Rüb U, Schultz C, et al. Sequence of Ab-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol. 2000;59:733–748. 15. Duyckaerts C, Hauw JJ, Bastenaire F, et al. Laminar distribution of neocortical senile plaques in senile dementia of the Alzheimer type. Acta Neuropathol. 1986;70:249– 256. 16. Hof PR, Cox K, Morrison JH. Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease. I. Superior frontal and inferior temporal cortex. J Comp Neurol. 1990;301:45–54. 17. Hof PR, Morrison JH. Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease. II. Primary and secondary visual cortex. J Comp Neurol. 1990;301:55–64. 18. Felleman DJ, Van Essen DC. Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex. 1991; 1:1–47.
P.R. Hof et al. 19. Barbas H. Pattern in the laminar origin of corticocortical connections. J Comp Neurol. 1986;252:415–422. 20. Vickers JC. A cellular mechanism for the neuronal changes underlying Alzheimer’s disease. Neuroscience. 1997;78: 629–639. 21. Hyman BT, Van Hoesen GW, Damasio AR. Memoryrelated neural systems in Alzheimer’s disease: an anatomic study. Neurology. 1990;40:1721–1730. 22. Buée L, Bussière T, Buée-Scherrer V, et al. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev. 2000;33:95–130. 23. Weingarten MD, Lockwood AH, Hwo SY, et al. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA. 1975;72:1858–1862. 24. Buée-Scherrer V, Buée L, Leveugle B, et al. Pathological tau proteins in postencephalitic parkinsonism: comparison with Alzheimer’s disease and other neurodegenerative disorders. Ann Neurol. 1997;42:356–359. 25. Buée-Scherrer V, Buée L, Hof PR, et al. Neurofibrillary degeneration in amyotrophic lateral sclerosis/ parkinsonism–dementia complex of Guam. Immunochemical characterization of tau proteins. Am J Pathol. 1995;146:924–932. 26. Flament S, Delacourte A, Verny M, et al. Abnormal Tau proteins in progressive supranuclear palsy. Similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol. 1991;81:591–596. 27. Ksiezak-Reding H, Morgan K, Mattiace LA, et al. Ultrastructure and biochemical composition of paired helical filaments in corticobasal degeneration. Am J Pathol. 1994; 145:1496–1508. 28. Sergeant N, Wattez A, Delacourte A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J Neurochem. 1999;72:1243–1249. 29. Schmidt ML, Huang R, Martin JA, et al. Neurofibrillary tangles in progressive supranuclear palsy contain the same tau epitopes identified in Alzheimer’s disease PHF-tau. J Neuropathol Exp Neurol. 1996;55:534–539. 30. Delacourte A, Robitaille Y, Sergeant N, et al. Specific pathological Tau protein variants characterize Pick’s disease. J Neuropathol Exp Neurol. 1996;55:159–168. 31. Probst A, Tolnay M, Langui D, et al. Pick’s disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol. 1996;92:588– 596. 32. Sergeant N, David JP, Lefranc D, et al. Different distribution of phosphorylated tau protein isoforms in Alzheimer’s and Pick’s diseases. FEBS Lett. 1997;412:578– 582. 33. Foster NL, Wilhelmsen K, Sima AA, et al. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol. 1997;41:706–715. 34. Lynch T, Sano M, Marder KS, et al. Clinical characteristics of a family with chromosome 17-linked disinhibitiondementia-parkinsonism-amyotrophy complex. Neurology. 1994;44:1878–1884. 35. Wilhelmsen KC, Lynch T, Pavlou E, et al. Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22. Am J Hum Genet. 1994;55:1159–1165.
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36. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol. 1998;8:387– 402. 37. Hof PR, Morrison JH. Neurofilament protein defines regional patterns of cortical organization in the macaque monkey visual system: a quantitative immunohistochemical analysis. J Comp Neurol. 1995;352:161–186. 38. Trojanowski JQ, Schmidt ML, Shin RW, et al. Altered tau and neurofilament proteins in neurodegenerative diseases: diagnostic implications for Alzheimer’s disease and Lewy body dementias. Brain Pathol. 1993;3:45–54. 39. Hof PR, Nimchinsky EA, Morrison JH. Neurochemical phenotype of corticocortical connections in the macaque monkey: quantitative analysis of a subset of neurofilament protein-immunoreactive projection neurons in frontal, parietal, temporal, and cingulate cortices. J Comp Neurol. 1995;362:109–133. 40. Hof PR, Vogt BA, Bouras C, et al. Atypical form of Alzheimer’s disease with prominent posterior cortical atrophy: a review of lesion distribution and circuit disconnection in cortical visual pathways. Vision Res. 1997;37: 3609–3625. 41. Goldman-Rakic PS. Topography of cognition: parallel distributed networks in primate association cortex. Annu Rev Neurosci. 1988;11:137–156. 42. Vickers JC, Riederer BM, Marugg RA, et al. Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer’s disease. Neuroscience. 1994;62:1–13. 43. Gasic GP, Heinemann S. Determinants of the calcium permeation of ligand-gated cation channels. Curr Opin Cell Biol. 1992;4:670–677. 44. Mishizen A, Ikonomovic M, Armstrong DM. Glutamate receptors in aging and Alzheimer’s disease. In: Hof PR, Mobbs CV, eds. Functional Neurobiology of Aging. San Diego: Academic Press; 2001:283–314. 45. Gazzaley AH, Siegel SJ, Kordower JH, et al. Circuitspecific alterations of N-methyl-d-aspartate subunit 1 in the dentate gyrus of aged monkeys. Proc Natl Acad Sci USA. 1996;93:3121–3125. 46. Gazzaley AH, Thakker MM, Hof PR, et al. Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys. Neurobiol Aging. 1997;18:549–553. 47. De Felipe J. Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28k, parvalbumin and calretinin in the neocortex. J Chem Neuroanat. 1997;14:1–19. 48. Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–890. 49. Snow AD, Mar H, Nochlin D, et al. The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer’s disease. Am J Pathol. 1988;133:456–463. 50. Busciglio J, Gabuzda DH, Matsudaira P, et al. Generation of b-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci USA. 1993;90:2092– 2096.
51. Haass C, Schlossmacher MG, Hung AY, et al. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322–325. 52. Seubert P,Vigo-Pelfrey C, Esch F, et al. Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature. 1992;359:325–357. 53. Shoji M, Golde TE, Ghiso J, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258:126–129. 54. Cook DG, Forman MS, Sung JC, et al. Alzheimer’s Ab(1–42) is generated in the endoplasmic reticulum/ intermediate compartment of NT2N cells. Nat Med. 1994; 3:1021–1023. 55. Skovronsky DM, Doms RW, Lee VMY. Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J Cell Biol. 1998;141: 1031–1039. 56. Naslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000;283:1571– 1517. 57. Masters CL, Simms G, Weinman NA, et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985;82:4245– 4249. 58. Kang J, Lemaire HG, Unterbeck A, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cellsurface receptor. Nature. 1987;325:733–736. 59. Tanzi RE, Gusella JF, Watkins PC, et al. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987;235:880– 884. 60. Citron M, Teplow DB, Selkoe DJ. Generation of amyloid beta protein from its precursor is sequence specific. Neuron. 1995;14:661–670. 61. Burdick D, Soreghan B, Kwon M, et al. Assembly and aggregation properties of synthetic Alzheimer’s A4/ beta amyloid peptide analogs. J Biol Chem. 1992;267:546– 554. 62. Buxbaum JD, Liu KN, Luo Y, et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem. 1998;273:27765– 27767. 63. Parvathy S, Hussain I, Karran EH, et al. Cleavage of Alzheimer’s amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells. Biochemistry 1999; 38:9728–9734. 64. Lammich S, Kojro E, Postina R, et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA. 1999;96:3922–3927. 65. Hussain I, Powell D, Howlett DR, et al. Identification of a novel aspartic protease (Asp 2) as b-secretase. Mol Cell Neurosci. 1999;14:419–427. 66. Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999;402:537–540. 67. Vassar R, Bennett BD, Babu-Khan S, et al. b-Secretase cleavage of Alzheimer’s amyloid precursor protein by the
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76 Delirium Sharon K. Inouye
Delirium, defined as an acute alteration in attention and cognition, is a common, serious, and potentially preventable source of morbidity and mortality for older persons. Delirium is a clinical diagnosis, based on observation of the patient at the bedside. Although the exact diagnostic criteria continue to evolve, the criteria for delirium appearing in the Diagnostic and Statistical Manual Version IV (DSM-IV) of the American Psychiatric Association are widely used as the current diagnostic standard1 (Table 76.1). However, these criteria were based on expert opinion, and their diagnostic performance has not been tested. The Confusion Assessment Method (CAM)2 provides a validated tool, which is currently in widespread use for rapid identification of delirium (see Table 76.1). The CAM algorithm, which is based on the presence of the features of acute onset and fluctuating course, inattention, and either disorganized speech or altered level of consciousness, has a sensitivity of 94% to 100%, specificity of 90% to 95%, positive predictive accuracy of 91% to 94%, and negative predictive accuracy of 90% to 100% for delirium.2 Although it can occur in any setting, delirium is most common in settings where the frailty and illness acuity of patients are most severe. The incidence of delirium increases with age, cognitive impairment, frailty, illness severity, comorbidity, and other risk factors for delirium (see following). The emergency room and acute hospital have the highest overall rates of delirium. Acute alteration in mental status represents a leading presenting symptom for acutely ill older persons, accounting for at least 30% of emergency evaluations of older persons. In the hospital setting, the intensive care and postoperative settings have the highest rates of delirium.3 Although not well studied, delirium occurs with some frequency in nursing home and rehabilitation settings. Although less frequent in the community setting, delirium is an important presenting symptom to community physicians, and can serve as a barometer for underlying health status of elderly persons, often heralding serious underlying disease.
Epidemiology and Risk Factors Because of its frequency in this setting, most of the epidemiologic studies of delirium have involved hospitalized older patients. Previous studies have measured the prevalence of delirium, that is, cases present at the time of hospital admission, as 14% to 24%, and the incidence of delirium, that is, new cases arising during hospitalization, as 6% to 56%.4–16 The rates of postoperative delirium range from 10% to 52%.4–16 Hospital mortality rates in patients with delirium range from 25% to 33%, as high as mortality rates associated with acute myocardial infarction or sepsis.4,5,10,11,17–24 Delirium has not been well examined in nursing home or community settings. In terms of the costs of delirium, it has been estimated that each year delirium complicates hospital stays for more than 2.3 million older persons, involving more than 17.5 million inpatient days and accounting for more than $4 billion (1994 dollars) of Medicare expenditures related to hospitalization.25 Moreover, delirium is associated with substantial additional costs after hospital discharge because of the increased need for institutionalization, rehabilitation services, home health care, rehospitalization, and other health care services. Delirium is usually a multifactorial syndrome,14 as are many other common geriatric syndromes, such as falls, incontinence, and pressure sores. In some cases, delirium may be caused by a single factor, but more often delirium is the result of the interrelationship between patient vulnerability at the time of admission (i.e., predisposing factors) and the occurrence of noxious insults during hospitalization (i.e., precipitating factors). For example, patients who are highly vulnerable to delirium at baseline (e.g., such as cognitively impaired or severely ill patients), can be pushed into delirium by the presence of only a mild insult, such as a single dose of a sedative medication for sleep. By contrast, patients who are not vulnerable would be relatively resistant, with delirium resulting only after repeated exposure to multiple 1113
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Table 76.1. Diagnostic criteria for delirium. Diagnostic and Statistical Manual Version IV (DSM-IV) diagnostic criteria A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia. C. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. D. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition. The Confusion Assessment Method (CAM) Diagnostic Algorithma Feature 1. Acute onset and fluctuating course This feature is usually obtained from a family member or nurse and is shown by positive responses to the following questions: Is there evidence of an acute change in mental status from the patient’s baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or increase and decrease in severity? Feature 2. Inattention This feature is shown by a positive response to the following question: Did the patient have difficulty focusing attention, for example, being easily distractible, or having difficulty keeping track of what was being said? Feature 3. Disorganized thinking This feature is shown by a positive response to the following question: Was the patient’s thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject? Feature 4. Altered level of consciousness This feature is shown by any answer other than “alert” to the following question: Overall, how would you rate this patient’s level of consciousness? (alert [normal], vigilant [hyperalert], lethargic [drowsy, easily aroused], stupor [difficult to arouse], or coma [unarousable]). a The diagnosis of delirium by CAM requires the presence of features 1 and 2 and either 3 or 4. Source: Adapted with permission from Inouye SK. Delirium and other mental status problems in the older patients. In: Goldman L, Bennett JC. Cecil Textbook of Medicine, 4th Ed. Philadelphia: Saunders; 1999:19–22.
noxious insults, such as general anesthesia, major surgery, multiple psychoactive medications, immobilization, and infection. Moreover, the effects of multiple risk factors appear to be cumulative. Clinically, the importance of this multifactorial etiology is that removing or treating one factor alone often is insufficient to resolve the delirium. Attention should be paid to the multifactorial predisposing and precipitating factors that may be contributing to the delirium. Predisposing or vulnerability factors for delirium include preexisting cognitive impairment or dementia, severe illness, high number of comorbid diseases, functional impairment, advanced age, chronic renal insufficiency, dehydration, malnutrition, depression, and vision or hearing impairment.8,13,24,26–30 Dementia is a leading risk factor for delirium, consistently identified across studies. Patients with dementia have a two- to five-fold increased risk for delirium. Moreover, one-third to onehalf of delirious patients have an underlying dementia. Nearly any chronic medical illness can predispose to delirium, including diseases involving the central nervous system (e.g., Parkinson’s disease, cerebrovascular disease, mass lesions, trauma, infection), as well as diseases outside the central nervous system, such as infectious, metabolic, cardiac, pulmonary, endocrine, and neoplastic conditions. The occult presentation of systemic disease— sometimes presenting only with delirium—is an important tenet of geriatric medicine. One validated predictive model,15 developed to determine delirium risk at the time
of hospital admission, identified the following independent predisposing factors: severe underlying illness, vision impairment, baseline cognitive impairment, and high BUN/creatinine ratio (used as an index of dehydration). Medications, the most common precipitating factors for delirium, contribute to at least 40% of delirium cases.14,31,32 Many medications can lead to delirium; the most common are those with recognized psychoactive effects, such as sedative-hypnotics, narcotics, H2-blockers, and medications with anticholinergic effects. In previous studies, use of any psychoactive medication was associated with a 4-fold increased risk of delirium.8,14 Sedativehypnotic drugs have been associated with a 3- to 12-fold increased risk of delirium; narcotics with a 3-fold risk; and anticholinergic drugs with a 5- to 12-fold risk.24,28–30,33,34 Delirium increases in direct proportion to the number of medications prescribed, an effect that is likely caused by adverse effects of the medications themselves, as well as the increased risk of drug–drug and drug–disease interactions. Recent studies provide strong evidence that inappropriate use and overuse of psychoactive medications are common in older patients, and that many cases of delirium and other related adverse drug events may be preventable.35–38 Other precipitating factors for delirium include medical procedures or surgery, intercurrent medical illnesses, infections, immobilization, use of indwelling bladder catheters, use of physical restraints, dehydration, malnutrition, iatrogenic events, electrolyte or metabolic
76. Delirium
derangement, alcohol or drug intoxication or withdrawal, environmental influences, and psychosocial stress.10,19,22,26,39–44 Immobilization can lead to delirium and functional decline within just a few days, yet physicians routinely order bedrest or no activity in 57% of patientdays of hospitalization, often without medical justification.45,46 Moreover, medical devices (e.g., indwelling bladder catheters and physical restraints) can contribute to immobilization, as well as other adverse effects. Iatrogenic events, occurring in 29% to 38%47–49 of older patients, include complications of diagnostic or therapeutic procedures, transfusion reactions, bleeding due to overanticoagulation, and the like. Insufficiency of any major organ system can precipitate delirium, particularly renal, hepatic, or respiratory failure. Occult respiratory failure is an increasing problem in older patients, who often lack the typical signs and symptoms of dyspnea and tachypnea, and who are easily overlooked by measuring oxygen saturation alone. Acute myocardial infarction or congestive heart failure commonly present as delirium in an elderly patient, without the expected symptoms of chest pain or dyspnea. Occult infection represents another noteworthy cause of delirium, because older patients frequently fail to mount the expected febrile or leukocyte response to severe systemic infections, including pneumonia, urinary tract infection, endocarditis, abdominal abscess, or septic arthritis. Metabolic disorders are important contributors to delirium: these include hyper- or hyponatremia, hypercalcemia, acid–base disorder, hypo- and hyperglycemia, and thyroid or adrenal disorders. A validated predictive model14 for delirium risk based on exposure to precipitating factors during the course of hospitalization identified the following five independent precipitating factors: physical restraint use, malnutrition, more than three medications added during the previous day (70% of these were psychoactive medications), indwelling bladder catheter, and any iatrogenic event.
Pathogenesis To date, the fundamental pathophysiologic mechanisms of delirium remain unclear. Delirium has been thought to represent a functional rather than structural lesion, with characteristic electroencephalographic findings demonstrating global functional derangements and generalized slowing of cortical background (alpha) activity.50,51 Delirium is considered to be the final common pathway of many different pathogenic mechanisms, culminating in the widespread reduction of cerebral oxidative metabolism with failure of cholinergic transmission. Proposed mediators have included adenosine, betaendorphin, histamine, somatostatin, lymphokines, tryptophan, phenylalanine metabolites, various neuropeptides,
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and cortisol.52–55 A recent study56 has found that changes in large neutral amino acids, which are precursors of several neurotransmitters, may play a role in delirium. Although delirium has been considered a transient syndrome, several of these basic mechanisms may not be completely reversible, particularly those resulting in hypoxic brain injury. In addition, the dose and duration of the insult, as well as the presence of preexisting cognitive impairment, may greatly influence the reversibility of the delirium.
Clinical Presentation The key features of delirium are acute onset and inattentiveness. Determining the acuity of onset requires accurate knowledge of the patient’s previous level of cognitive functioning. With delirium, the mental status typically changes over hours to days, as distinguished from dementia in which the changes occur more insidiously over weeks to months. Extra effort may be required to ascertain baseline information from a reliable source, such as a family member, caregiver, or nurse. Another key feature is the fluctuating course of delirium, with symptoms tending to come and go or increasing and decreasing in severity over a 24-h period. Lucid intervals are characteristic, and can be misleading even to experienced clinicians. Inattention is recognized as difficulty focusing, maintaining, and shifting attention. Delirious patients appear easily distracted, have difficulty following commands or maintaining a conversation, and often perseverate with an answer to a previous question. On cognitive testing, patients may manifest difficulty with simple repetition tasks, digit spans, or reciting months backward. Other key features include a disorganization of thought and altered level of consciousness. Disorganization of thought is a manifestation of underlying cognitive or perceptual disturbances, and is recognized by disorganized or incoherent speech, rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject. Altered level of consciousness is typically manifested by lethargy, with reduced awareness of the environment. Although not cardinal elements, features frequently associated with delirium include disorientation, cognitive deficits (e.g., memory impairment, dysnomia), psychomotor agitation or retardation, perceptual disturbances (e.g., hallucinations, misperceptions, illusions), paranoid delusions, emotional lability, and sleep–wake cycle disruption. Clinically, delirium can present in either hypoactive or hyperactive forms. The hypoactive form of delirium, which is characterized by lethargy and reduced psychomotor activity, is the most common form in older patients. This form of delirium is often unrecognized and is associated with a poorer overall prognosis.57–59 The
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hyperactive form of delirium, in which the patient is agitated, vigilant, and often hallucinating, is rarely missed. Importantly, patients can fluctuate between the hypoactive and hyperactive forms—the mixed type of delirium. Moreover, partial or incomplete forms of delirium have been recognized to be common,60,61 particularly during the resolution stages of delirium, and have been shown to adversely influence long-term prognosis.
Diagnosis and Differential Diagnosis Delirium is a clinical diagnosis, relying on astute observation at the bedside, careful cognitive assessment, and history taking from a reliable informant to establish the patient’s baseline functioning. Previous studies have documented that clinicians may fail to detect delirium in up to 70% of affected patients.62–64 Identifying the potentially multifactorial contributors to the delirium is of critical importance, because many of these factors are treatable and, if left unaddressed, may result in substantial morbidity and mortality. Because the potential contributors are innumerable, the search requires keen clinical judgment combined with a thorough medical evaluation. The challenge is enhanced by the frequently nonspecific or atypical presentation of the underlying illness in older persons. In fact, in the elderly population, delirium may be the only sign of life-threatening illness such as sepsis, pneumonia, or myocardial infarction. The first step in evaluation should include formal cognitive assessment and determination of any acute change from the patient’s baseline level of cognition. Because cognitive impairment is readily missed during regular conversation, a brief cognitive screening test, such as the Mini-Mental Status Examination,65 is recommended. Attention should be assessed with simple tests, such as a forward digit span (inattention indicated by inability to repeat five digits forward) or reciting the days of the week or the months backward. A comprehensive history and physical examination remain the cornerstones of the evaluation of delirium. The history should be directed toward establishing the patient’s baseline level of cognitive functioning and the course of any mental status changes, as well as obtaining clues about potential precipitating factors or insults, such as recent medication changes, new infections, or medical illnesses. The physical examination should include a detailed neurologic examination for focal deficits and a careful search for signs of falls or head trauma, infection, or other acute medical processes. Because of the frequent contribution of medications to delirium, review of the medication list, including overthe-counter medications, should be carried out in every patient. The majority of older patients will be on at least several medications during hospitalization, heightening
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the potential for adverse events as well as drug–drug or drug–disease interactions. In older patients, medications may cause adverse effects even at recommended dosages and at measured serum levels that are within the “therapeutic range.” Thus, medications with psychoactive effects should be removed or minimized whenever possible. When these medications cannot be removed, dosage reductions or substitution of less toxic alternatives should be considered. The side effects and interaction profiles of all current drugs should be reviewed. Finally, chronic medication and alcohol use should be assessed specifically to evaluate for any potential withdrawal risk. In older patients, substance use is commonly unrecognized or overlooked, particularly during the early phase of hospitalization. Evidence-based strategies estimating the predictive value of laboratory tests in delirium assessment are lacking. Thus, the laboratory evaluation must be based on clinical judgment, and should be tailored to the individual situation. An astute history and physical examination, review of medications, targeted laboratory testing (e.g., complete blood count, chemistries, glucose, renal/liver function tests, urinalysis, oxygen saturation), and search for occult infection should assist with identification of the majority of potential contributors to the delirium. The need for further laboratory testing (such as thyroid function tests, B12 level, cortisol level, drug levels or toxicology screen, ammonia level) will be determined according to the individual patient’s clinical picture. In patients with cardiac or respiratory diseases, or with related symptoms, an electrocardiogram, chest radiograph, and/or arterial blood gas determination may be warranted. The indications for cerebrospinal fluid examination, brain imaging, or electroencephalography remain controversial. Overall, the diagnostic yield for these procedures are low, and they are probably indicated in less than 10% of delirium cases. Cerebrospinal fluid examination is indicated for the febrile delirious patient where meningitis or encephalitis must be excluded. Brain imaging (such as computed tomography or magnetic resonance imaging) should be reserved for cases with new focal neurologic signs, with history or signs of head trauma, or without another identifiable cause of the delirium. Electroencephalography, which has a false-negative rate of 17% and false-positive rate of 22% for distinguishing delirious and nondelirious patients,51,66 plays a limited role and is most useful to detect occult seizure disorders and to differentiate delirium from nonorganic psychiatric conditions. The differential diagnoses for delirium include a variety of conditions associated with confusion and altered mental status, most commonly dementia, depression, and nonorganic psychotic disorders. The paramount challenge in differential diagnosis is distinguishing dementia, a chronic confusional state, from delirium
76. Delirium
alone or delirium superimposed on dementia. The differential diagnosis is crucial, however, because of the prognostic significance of delirium, which often represents a medical emergency. Obtaining the clinical history is critical to making the distinction between delirium and dementia. These two conditions are distinguished by the acuity of symptom onset in delirium (dementia is much more insidious), and the impaired attention and altered level of consciousness associated with delirium. Disorientation and memory impairment, while commonly recognized features, are not useful in differential diagnosis because they may be present with both conditions and may be absent in delirium. Differentiating depression and nonorganic psychotic disorders from delirium can pose other challenges for the clinician. Although paranoia, hallucinations, and affective changes can occur with delirium, the presence of key delirium features of acute onset, inattention, altered level of consciousness, and global cognitive impairment will assist with the diagnosis of delirium. In cases involving an uncooperative patient or where an accurate history is unavailable, establishing the diagnosis with certainty may not be possible. In these cases, because of the potentially life-threatening nature of delirium and its high occurrence rate in the older hospitalized population, the recommendation is to manage the case as a presumptive delirium and search for reversible causes (e.g., intercurrent illness, metabolic derangements, drug toxicity), until further information can be obtained. Figure 76.1 presents an algorithm for the evaluation of altered mental status in the older patient. The first step in the evaluation is to establish the patient’s baseline cognitive functioning and the time-course of any cognitive changes. Chronic impairments, developing or progressing over months to years, are most likely attributable to a dementia, which should be evaluated accordingly (see Chapter 74). Acute alterations occurring over hours to weeks, which may be superimposed on an underlying dementia, should be further evaluated with cognitive assessment to determine whether delirium is present. If delirium features are not present (see Clinical Presentation section above), then further evaluation for major depression, acute psychotic disorder, or other psychiatric disorders (see Chapters 78 and 79) is indicated.
Clinical Course and Prognosis Delirium has been previously considered to be a transient, reversible condition; however, recent studies60,61 have documented that delirium may be more persistent than previously believed. A delirium duration of 30 days or more is typical in older patients, and a prolonged transitional phase characterized by cognitive, affective, or behavioral abnormalities is quite common. In fact, as few
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as 20% of patients had complete resolution of all delirium symptoms at 6-month follow-up in one study.60 Delirium appears to have greater deleterious effects on long-term cognitive functioning in patients with underlying cognitive impairment or dementia. Long-term detrimental effects are likely related to the duration, severity, and underlying cause(s) of the delirium. Whether delirium itself leads to permanent cognitive impairment or dementia remains controversial; however, previous studies document that at least some patients never recover their baseline level of cognitive functioning. Delirium had been documented to be an important prognostic determinant.67 Previous studies8,10,18,21,28,29,34,60, 68–79 have shown that delirium is an independent predictor of prolonged length of hospital stay, increased morbidity and mortality, and higher rates of institutionalization and functional and cognitive decline, even after controlling for age, gender, dementia, illness severity, and baseline functional status.
Prevention and Management Prevention of Delirium Primary prevention of delirium, that is, preventing delirium before it occurs, is the most effective strategy to reduce delirium and its attendant complications. Table 76.2 indicates well-documented delirium risk factors and tested preventive interventions for each risk factor. These risk factors were selected because current evidence supports both the clinical relevance and the remediable nature of each risk factor with practical interventions. A controlled clinical trial80 demonstrated the effectiveness of a delirium prevention strategy targeted toward these risk factors. Implementation of these preventive interventions resulted in a 40% risk reduction for delirium in hospitalized older patients.
Nonpharmacologic Management Nonpharmacologic approaches should be used for management of every delirious patient. These approaches include strategies for reorientation and behavioral intervention, such as ensuring the presence of family members, orienting influences, use of sitters, and transferring a disruptive patient to a private room or closer to the nurse’s station for increased supervision. Personal contact and communication are critical, incorporating reorientation strategies, simple instructions, and frequent eye contact. Patients should be encouraged to participate in decision making about their care as much as possible. Eyeglasses and hearing aids (if needed) should be worn as much as possible to reduce sensory deficits. Mobility, self-care, and independence should be enhanced;
Figure 76.1. An algorithm for the evaluation of suspected delirium in the older adult. TFT, thyroid function tests; B12, vitamin B12 assay; CT, computed tomography; MRI, magnetic resonance imaging; mg, milligrams; IM, intramuscular injection;
po, oral administration; Q, every. (Adapted with permission from Inouye SK. Delirium and other mental status problems in the older patients. In: Goldman L, Bennett JC. Cecil Textbook of Medicine, 4th Ed. Philadelphia: Saunders; 1999:19–22.)
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76. Delirium
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Table 76.2. Delirium risk factors and potential interventions. Risk factor Cognitive impairment Sleep deprivation Immobilization Psychoactive medications
Vision impairment Hearing impairment Dehydration
Interventions Therapeutic activities program Reality orientation program (reorienting techniques, communication) Noise reduction strategies Scheduling of nighttime medications, procedures, and nursing activities to allow uninterrupted period of sleep Early mobilization (e.g., ambulation or bedside exercises) Minimizing immobilizing equipment (e.g., bladder catheters) Restricted use of prn sleep and psychoactive medications (e.g., sedative-hypnotics, narcotics, anticholinergic medications) Nonpharmacologic protocols for management of sleep and anxiety Provision of vision aids (e.g., magnifiers, special lighting) Provision of adaptive equipment (e.g., illuminated phone dials, large-print books) Provision of amplifying devices Repair of hearing aids Early recognition and volume repletion
Source: Adapted with permission from Inouye SK. Delirium and other mental status problems in the older patients. In: Goldman L, Bennett JC. Cecil Textbook of Medicine, 4th Ed. Philadelphia: Saunders; 1999:19–22.
physical restraints should be avoided because of their adverse effects of immobility and increased agitation and their potential to cause injury. Clocks, calendars, and the day’s schedule should be provided to assist with orientation. Room and staff changes should be kept to a minimum. A quiet environment with low-level lighting is optimal for the delirious patient. Allowing an uninterrupted period for sleep at night is of key importance in the management of the delirious patient; this requires coordination and scheduling of nursing and medical procedures, such as medications, vital signs, intravenous fluids, and treatments. Hospital-wide changes may be needed to ensure a low level of noise at night, including hallway noise and conversations. Nonpharmacologic approaches for relaxation, including music, relaxation tapes, and massage, can be effective for management of agitation in delirious patients.
Pharmacologic Management Pharmacologic approaches should be reserved for patients with severe agitation, which may result in the interruption of essential medical therapies (e.g., intubation, intraaortic balloon pumps, dialysis catheters) or which may endanger the safety of the patient, other patients, or staff. However, clinicians must be aware that any drug used for the treatment of delirium will have psychoactive effects and may further cloud mental status and obscure efforts to follow the patient’s mental status. Thus, the drug should be given in the lowest possible dose for the shortest duration. Neuroleptics are the preferred agents of treatment, with haloperidol representing the most widely used and tested treatment for delirium.81 Although newer neuroleptics are available, fewer data are available to support their use. If parenteral adminis-
tration is required, intravenous haloperidol results in rapid onset of action with short duration of effect, whereas intramuscular use will have a more optimal duration of action. The recommended starting dose of haloperidol is 0.5 to 1.0 mg orally or parenterally, repeating the dose every 20 to 30 min after vital signs have been checked, until sedation has been achieved. The endpoint should be an awake but manageable patient, not a sedated patient. The average elderly patient who has not previously been treated with neuroleptics should require a total loading dose not exceeding 3 to 5 mg haloperidol. Subsequently, a maintenance dose of one-half the loading dose should be administered in divided doses over the next 24 h, with tapering doses over the next few days. The leading side effects of haloperidol include sedation, hypotension, acute dystonias, extrapyramidal side effects, and anticholinergic effects (e.g., anticholinergic delirium, dry mouth, constipation, urinary retention). Benzodiazepines are not recommended for treatment of delirium because of their tendency to cause oversedation, respiratory depression, and exacerbation of the confusional state. However, they remain the drugs of choice for treatment of withdrawal syndromes from alcohol and sedative-hypnotic drugs. For geriatric patients, lorazepam (starting dose, 0.5–1.0 mg) is the recommended agent of this class, because of its favorable half-life (10–15 h), lack of active metabolites, and availability of a parenteral form.
Terminal Phase Management of delirium at the end of life poses particular challenges for the clinician. Because delirium occurs in more than 80% of patients at the end of life, establishing the goals of care with the patient and family is
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a crucial step, including discussions about the potential causes of the delirium, intensity of medical evaluations considered appropriate, and—in some cases—the need for titration between alertness and adequate control of pain and agitation. Even in the terminal phase, many causes of delirium are potentially reversible; however, the burdens of evaluation (e.g., invasive testing) or definitive treatment (e.g., surgery for brain metastasis or reduction in narcotic dose) may not be consistent with the goals for care. In all cases, symptom management should begin immediately, while evaluation is under way. Nonpharmacologic approaches should be instituted in all patients, with pharmacologic approaches for selected cases. Haloperidol remains the first-line therapy for delirium in terminally ill patients. In end-of-life care, there is a lower threshold for the use of sedative agents. Sedation may be indicated as an additional therapy for management of severe agitated delirium in the terminally ill patient, which can cause considerable distress for the patient and family. Because sedation poses the risks of decreased meaningful interaction with family, increased confusion, and respiratory depression, this choice should be made in conjunction with the family according to the goals for care. If sedation is indicated, an agent that is short acting and easily titrated to effect is recommended. Lorazepam (starting dose, 0.5–1.0 mg p.o., i.v., s.q.) is the recommended agent of choice; however, midazolam (starting dose, 0.5–1.0 mg i.v. or s.q.) may be useful for short-term sedation where rapid onset and titration are required. Because the risks of respiratory suppression and hypotension with midazolam are great, the patient must be closely monitored.
System-Wide Changes The optimal management of delirium requires systemwide changes to improve the quality of hospital care for older patients.82 Interventions needed to reduce delirium rates include education of physicians and nurses to improve recognition and heighten awareness of the clinical implications; encouragement of cognitive assessment of all elderly hospitalized patients; provision of incentives to change practice patterns that lead to delirium (e.g., immobilization, overuse of psychoactive medications, bladder catheters, and physical restraints); and creation of systems that enhance high-quality geriatric care (e.g., geriatric expertise, case management, clinical pathways, and quality monitoring for delirium). With its common occurrence, its frequently iatrogenic nature, and its close linkage to the processes of care, incident delirium serves as a valuable marker for the quality of hospital care and provides an opportunity for overall improvement in care for the older population.
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S.K. Inouye 74. Brannstron B, Gustafson Y, Norberg A, et al. ADL performance and dependency on nursing care in patients with hip fractures and acute confusion in a task allocation care system. Scand J Caring Sci. 1988;5:3–11. 75. Rockwood K. Delays in the discharge of elderly patients. J Clin Epidemiol. 1990;43:971–975. 76. Koponen H, Stenback U, Mattila E, et al. Delirium among elderly persons admitted to a psychiatric hospital: clinical course during the acute stage and one-year follow-up. Acta Psychiatr Scand. 1989;79:579–585. 77. Magaziner J, Simonsick EM, Kashner M, et al. Survival experience of aged hip fracture patients. Am J Public Health. 1989;79:274–278. 78. Levkoff SE, Safran C, Cleary PD, et al. Identification of factors associated with the diagnosis of delirium in elderly hospitalized patients. J Am Geriatr Soc. 1988;36:1099– 1104. 79. Thomas RI, Cameron DJ, Fahs MC. A prospective study of delirium and prolonged hospital stay: exploratory study. Arch Gen Psychiatry. 1988;45:937–940. 80. Inouye SK, Bogardus ST, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999;340:669–676. 81. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry. 1996;153:231–237. 82. Inouye SK, Schlesinger MF, Lydon TJ. Delirium: a symptom of how hospital care is failing older persons and a window to improve quality of hospital care. Am J Med. 1999;106: 565–573.
77 Cerebrovascular Disease and Stroke Stanley Tuhrim
Stroke is a major public health problem afflicting primarily older adults. It is the third leading cause of death in the United States and is surpassed only by heart disease worldwide.1,2 In the United States, more than 700,000 new strokes occur annually.3 Stroke is also the leading cause of disability in the United States, with an estimated 4 million stroke survivors in this country living with strokerelated deficits.1 Over 70% of stroke survivors remain vocationally impaired, over 30% require help with activities of daily living, and 20% walk only with assistance.4 Approximately half of stroke survivors return to some form of employment, but this figure declines with age.5 The incidence of stroke doubles in each successive decade after age 55 and occurs approximately twice as often in African-Americans as in whites at all ages. It is more common in men under age 75 but is equally common among older men and women.3,6,7 Stroke is actually a heterogeneous group of diseases. There are two main categories, hemorrhage and infarction, which result from different pathophysiologic mechanisms: extravasation of blood from a damaged vessel in hemorrhage and ischemia or insufficient blood perfusing brain tissue in infarction. These categories can be further subdivided pathophysiologically. Subarachnoid hemorrhage is leakage of blood at the brain surface into the cerebrospinal fluid, usually the result of rupture of an aneurysm in an artery at the base of the brain (circle of Willis). Less often, the bleeding may be caused by rupture of a vascular malformation or trauma to a surface vessel. Intracerebral hemorrhage (ICH) usually is caused by rupture of a small artery or arteriole with leakage of blood into the brain parenchyma.
Subarachnoid Hemorrhage Subarachnoid hemorrhage (SAH) accounts for 5% to 10% of all strokes. Incidence rates vary from 6 to 16 per 100,000, with the highest rates reported from Japan and
Finland.8–10 Women are affected more often than men by a ratio of 3 : 2, and incidence increases with advancing age.8,11 SAH patients in the Framingham Study averaged 63 years of age.12 Tobacco use and heavy alcohol consumption have been identified as risk factors for SAH.13,14 Hypertension does not play as important a role in SAH risk as in other forms of stroke, although use of cocaine and other noradrenergic stimulants has been associated with SAH, possibly by precipitating rupture of an aneurysm during an acute hypertensive espisode.15 Arteriovenous malformations (AVMs) can also cause SAH, but frequently produce intraparenchymal hemorrhage as well. They are rarely the cause of SAH in the elderly. Bleeding is less brisk than with ruptured saccular aneurysms, and symptoms may develop more slowly. AVMs usually present in adolescence or early adulthood, causing headache, seizures, or hemorrhage. In the elderly, the cause of SAH is more often undetermined than in younger patients. Amyloid angiopathy or unrecognized head trauma is often thought to be responsible. Morbidity and mortality are high in SAH. About 12% of SAH patients die before receiving medical attention.16,17 The 90-day mortality rate among those who do reach medical attention is about 25%, and 40% of survivors suffer residual cognitive, motor, and sensory deficits.17 Early mortality results from the direct effects of the initial or recurrent bleeding, whereas medical complications or ischemia, secondary to vasospasm induced by subarachnoid blood, are responsible for most deaths beyond the first week. The Hunt and Hess Scale is widely used to grade the severity of SAH (Table 77.1).18 Grade 1 and 2 patients have a good prognosis, while grade 4 and 5 patients usually do poorly and are usually not considered candidates for surgical intervention. Grade 3 patients have the most variable outcomes. The Glasgow Outcome Scale (see Table 77.1), originally developed for head trauma, is frequently used to grade outcomes in SAH.19 The majority of patients with SAH harbor saccular aneurysms as 1123
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S. Tuhrim
Table 77.1. Global measures in subarachnoid hemorrhage (SAH). Hunt and Hess Scale Grade 1 2 3 4 5
Neurologic status Asymptomatic Severe headache, stiff neck, no neurologic deficit except cranial nerve palsy Drowsy, minimal neurologic deficit Stuporous, moderate or severe hemiparesis Deep coma, decerebrate
Glasgow Outcome Scale Category 1 2 3 4 5
Outcome
Good recovery, independent lifestyle Moderate disability, independent lifestyle Severe disability, conscious but not independent Vegetative Dead
the cause of bleeding. Saccular aneurysms form at the bifurcation of large arteries and are probably caused by a combination of congenital and degenerative changes in arteries. Hemodynamic stresses at arterial bifurcations lead to degenerative changes in the internal elastic lamina, weakening of the arterial wall, and aneurysmal outpouching. The most common sites for aneurysm formation are within the anterior circulation, at the junction or bifurcation of the major cerebral arteries. Posterior circulation aneurysms are less common, the most common sites being the bifurcation of the basilar artery and the vertebral artery–posterior interior cerebellar artery junction.
Diagnosis of SAH Most aneurysms remain asymptomatic until they bleed, but some larger aneurysms compress adjacent nerves, brain tissue, or meningeal structures, causing headache and neurologic dysfunction. When aneurysms rupture, they leak blood into the cerebrospinal fluid (CSF) under arterial pressure. Patients usually describe a sudden onset of severe headache, often “the worst headache of my life.” There is usually some alteration in consciousness, ranging from deep coma with massive bleeding to sleepiness or agitation with lesser amounts of bleeding. Unless bleeding also occurs directly into brain, patients do not have major focal neurologic signs. When a patient presents with the abrupt onset of severe headache, with or without meningismus or subtle neurologic signs, SAH must be considered. The differential diagnosis may include other causes of headache, such as migraine or infectious meningitis, but if SAH is considered, a computerized tomographic (CT) scan should be obtained; this can show the presence of blood in the subarachnoid space, confirming the diagnosis. The
location of blood may indicate the likely location of the aneurysm and the amount, and the thickness of blood indicates the likelihood of subsequent vasospasm.20 Because of variability in magnetic resonance scanning techniques and interpretation skills, for the present, CT scan remains more accurate than MR imaging in most centers, with a yield approaching 95% if done within 24 h of stroke onset.21 If a CT scan cannot be performed or fails to confirm the diagnosis of SAH, a lumbar puncture should be performed to allow examination of the CSF.22 All patients with SAH have blood in the CSF when tapped within 48 h. Some patients have a small “warning leak” before massive aneurysmal rupture. These small hemorrhages are often missed by CT and will be detected only by lumbar puncture. No patient in whom SAH is suspected should leave the hospital without a lumbar puncture. Findings diagnostic of SAH include the constant red or pink appearance of the CSF on collection. In this instance, the presence of xanthochromia in the supernatant after prompt centrifugation distinguishes pathologic SAH from leakage induced by trauma during the spinal tap. Centrifugation should be performed immediately after collection to avoid hemolysis of red blood cells ex vivo. Red blood cells in the fluid with a cell count that remains constant from the first tube collected to the last, and the presence of white blood cells in greater proportion than that found in the periphery, are also indicative of true SAH. Xanthochromia may not be present if the CSF is collected within 6 h of ictus and may be the only abnormality remaining if lumbar puncture is delayed several days. Unless the patient’s condition precludes treatment, angiography should be performed to determine the cause of bleeding. Conventional (catheter) angiography will detect approximately 95% of aneurysms and all AVMs. If an initial angiogram is negative, a repeat study, usually performed 1 to 2 weeks later, will detect an aneurysm in about 2% of cases.23 Magnetic resonance angiography (MRA) and CT angiography are useful as complements to conventional angiography and as screening tests in high-risk, asymptomatic individuals, but are not as sensitive in imaging small (3 ¥ 3 cm) hematomas and those with a decreased level of consciousness or clinical evidence of brainstem compression require early craniectomy because greater benefit is observed in patients who undergo surgery before deterioration of consciousness. Studies of surgical evacuation of unselected supratentorial ICH have not
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demonstrated significant efficacy, although selected patients with large superficial hematomas may be candidates for evacuation. Recent studies have focused on developing surgical approaches allowing evacuation of clot with minimal damage to overlying normal tissue including stereotactic and endoscopic approaches. Techniques to liquefy the clot by irrigation with fluid at a high pressure or thrombolytics are under investigation. Repeated injection of fibrinolytic agents, usually at 6- or 12-h intervals using a stereotactically placed catheter can result in complete removal of hematoma.76,77 The observed risk of inducing rebleeding is less than 5%. These efforts have been supplemented by high-pressure ultrasound irrigation systems and special drills to break the clot into easily removable fragments.78 A recent pilot study of 12 patients whose mean age was 69 years (range, 55–82) demonstrated this approach leads to a 50% clot volume reduction in 3 days with a low rate of additional bleeding or death. This approach may produce successful clot reduction with less morbidity, especially in the elderly or unstable patient, than open craniotomy, but has yet to undergo full evaluation.79
Seizures and Epilepsy Most seizures associated with ICH occur at the onset of intracerebral hemorrhage or within the first 24 h.80,81 Seizures are most frequently associated with lobar hematomas, with an incidence ranging from 24% to 54%. Recurrent seizures (epilepsy) develop in 13% to 15% of ICH patients. Because there is no clear association between the use of prophylactic anticonvulsants and the subsequent development of epilepsy in these patients, prophylactic anticonvulsants for all patients are not advisable. Anticonvulsants should generally only be administered to patients who have already suffered a seizure or undergo a neurosurgical procedure.80,81 Anticonvulsants can usually be discontinued after the first month in patients who have had no further seizures, although patients who have a seizure after 2 weeks of onset of ICH are at higher risk for recurrence.82
Cerebral Amyloid Angiopathy Cerebral amyloid angiopathy (CAA) occurs exclusively in older adults (age >60 years), affecting the cerebral vasculature selectively, favoring the superficial lobar regions, and generally sparing deeper structures typically affected in hypertensive ICH. Amyloid deposition can be demonstrated by Congo red or other stains in the small and medium-sized cortical and leptomeningeal vessels. The incidence of CAA rises dramatically with age; in an autopsy series, CAA was present in 5% of those 60 to 69
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years of age but rose to 50% in those over age 80.83 In addition to the lobar location, the other distinctive feature of CAA is the tendency for recurrence, uncommon in hypertensive ICH. As many as eight distinct hemorrhages have been reported in a single individual.84 CAA occurs with increased frequency in patients with Alzheimer’s disease, and at least 40% of patients with CAA-related ICH have histologic changes of Alzheimer’s disease at autopsy.85
Ischemic Stroke Infarction accounts for about 80% of strokes. There are three main subcategories of infarction: (1) cardioembolic, (2) large vessel atherothrombotic, and (3) small vessel or lacunar stroke.
Cardioembolic Infarction Embolism from thrombi that form in the heart or that occur in large veins and pass through the heart via a rightto-left shunt account for approximately 30% of ischemic strokes. A variety of cardiac sources of embolism have been identified including valvular lesions, hemostasis secondary to rhythm disturbances, hypokinesis of the left ventricle, either globally as in a cardiomyopathy or focally secondary to infarction, or rarely tumors. Atrial fibrillation is the most widely recognized cardiac abnormality associated with ischemic stroke. It is a condition of the elderly, occurring in 0.1% of those 50 to 59 years of age and increasing gradually to 4% of those over age 80. The proportion of strokes attributed to atrial fibrillation also increases with age, rising from 7% of strokes in the sixth decade to 36% for those in the ninth decade.86 The development of transesophageal echocardiography has provided additional insight into the source of cerebral emboli. With this technique it is possible to detect thrombus in the left atrial appendage, which is generally the site that harbors clot in a fibrillating atrium but is not visible on transthoracic echocardiogram. Spontaneous echo contrast (“smoke”) is often seen in a fibrillating atrium (and sometimes in other situations) and is thought to represent platelet–fibrin aggregates that are a precursor to thrombus formation. A patent foramen ovale (PFO), the most common conduit for paradoxical emboli, is also readily diagnosed by this procedure. Transesophageal echocardiography has also led to appreciation of atherosclerotic plaque in the ascending aorta and aortic arch, especially in elderly patients. These plaques can be ulcerated and serve as a nidus for clot formation or protrude into the lumen as a highly mobile peduncle, likely to embolize to more distal arteries. The thickness of this plaque has been correlated with the risk
S. Tuhrim
of stroke.86–88 Because it is a somewhat invasive procedure, transesophageal echo is not done routinely in most centers, but patients who have no obvious source of stroke should undergo transesophageal echocardiography to determine if one of these embolic sources is present.
Lacunar Infarction Lacunes are small, deep infarcts caused by degenerative changes within small penetrating arteries that bring blood to the internal capsule, basal ganglia, cerebral white matter, thalamus, and pons. Hypertension is the most important cause of lipohyalinosis, the most common mechanism of disease within the media of these microscopic arteries. Sometimes microatheroma originating at the orifice of these penetrating arteries leads to occlusion. Lacunar infarcts are the most common vascular lesions found within the brain at necropsy. In various series and registries, they account for at least 25% of ischemic strokes. The neurologic symptoms depend on the region of ischemia. The most common clinical presentations are (1) pure motor stroke, due to infarction in the pons or internal capsule, characterized by weakness of the face, arm, and leg on one side of the body; (2) pure sensory stroke, due to infarction in the lateral part of the thalamus and/or posterior limb of the internal capsule, characterized by numbness or paresthesia of the face, arm, leg, and trunk on one side of the body without weakness; (3) ataxic hemiparesis, due to infarction in the subcortical white matter or pons, characterized by a combination of incoordination and weakness on one side of the body without other major findings; and (4) clumsy hand-dysarthria due to pontine infarction, characterized by markedly slurred speech and difficulty with fine motor control of one hand.89 Patients suffering from these syndromes do not demonstrate prominent visual, cognitive, or behavioral abnormalities. The diagnosis of lacunar infarction is based on the presence of risk factors, the nature of the clinical signs and symptoms, and the results of neuroimaging tests. Most often, patients with lacunar infarction have a history of hypertension or diabetes. The presence of prominent headache, vomiting, or a decreased level of alertness makes lacunar infarction unlikely. The clinical symptoms and signs should be compatible with a small, deep lesion. Aphasia, hemianopia, and signs of anosognosia or inattention are strong evidence against lacunar disease. CT or MRI should show a small, deep infarct or be normal. In some cases, the clinical and neuroimaging tests are equivocal and do not establish a lacunar cause. In these patients, a search for other ischemic causes, such as coagulopathy, an embolism of cardiac origin, and large artery ischemic disease, is warranted.
77. Cerebrovascular Disease and Stroke
Large Artery Occlusive Disease The large vessels that bring blood into the brain are prone to atherosclerotic narrowing most commonly at sites of origin or bifurcation, especially the bifurcation of the common carotid into the internal and external carotid arteries in the neck. Atherosclerotic stenosis leads to infarction by reducing blood flow distal to the point of stenosis and by acting as a nidus for adhesion and aggregation of platelets producing either thrombosis at that location or embolization to and occlusion of more distal, narrower arteries. The neurologic symptoms will depend on the artery affected. In general terms, symptoms of cerebral ischemia can be divided into those that arise from the anterior circulation, supplying the anterior three-fourths of each hemisphere, and the posterior circulation, supplying the occipital lobes, posterior thalamus, cerebellum, and brainstem. The anterior circulation consists of the paired internal carotid arteries that give off the ophthalmic arteries and then branch into anterior and middle cerebral arteries. Atherosclerotic lesions are most common at the origin of the internal carotid arteries in the neck and the middle cerebral stem. The posterior circulation consists of the paired vertebral arteries, which give rise to the posterior inferior cerebefiar arteries before joining to form the basilar artery that gives off the paired anterior inferior and superior cerebellar arteries and penetrating branches supplying the brainstem before bifurcating into paired posterior cerebral arteries. Symptoms and signs of posterior circulation ischemia are highly variable and overlap with those of the anterior circulation, but vertigo, diplopia, nausea, and vomiting are common complaints heard in brainstem or cerebellar disease; nystagmus, disconjugate eye movement abnormalities, gait or limb ataxia, crossed (i.e., ipsilateral face and contralateral limb or body) sensory or motor deficits, and hemianopic visual field loss are indicative of posterior circulation ischemia. Confusion and memory loss can be seen, especially in embolic occlusion of the basilar artery, blocking penetrating branches that supply the thalamus.90
Diagnosis and Treatment In June 1996, the FDA approved the use of tissue plasminogen activator (t-PA) in acute ischemic stroke, if given within 3 h of symptom onset. This decision signaled a virtual revolution in the diagnosis and management of acute stroke. For the first time, a proven safe and effective treatment was available, but the time frame for its use required a much more expeditious response than was customary for patients, emergency medical services, doctors, and hospitals. The public needed to be educated to recognize a stroke and react appropriately (only onethird of patients experiencing a stroke recognize it as
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such), and care providers needed to be educated to respond to stroke as an emergency. When signs or symptoms are recognized, emergency medical services should be contacted and the patient brought to the nearest hospital capable of caring for stroke as an emergency. Once at the hospital, prompt triage is necessary because of the possibility of life-threatening cardiorespiratory effects. Assessment should begin with evaluation of the patient’s airway, breathing, and circulation, followed by a general medical and neurologic history and physical assessment. Determining the time of symptom onset and presence of signs of trauma or medical conditions that would predispose to a particular stroke type or preclude the use of t-PA are crucial. Ancillary tests should include a complete blood count, prothrombin and activated partial thromboplastin times, serum glucose and electrolytes, electrocardiogram, and chest x-ray. A CT scan should be performed as quickly as possible to exclude intracranial hemorrhage or a nonischemic cause of the patient’s symptoms. Conditions that may mimic a stroke include encephalitis, hypoglycemia, seizure, brain tumor, subdural hematoma, and migraine. If these conditions are excluded by history, physical, and imaging findings, most patients who arrive within 3 h will be candidates for intravenous thrombolysis. Exclusion criteria are listed in Table 77.2. The only exclusion criterion that may be altered by treatment is the patient’s blood pressure. Consideration for thrombolysis is one of the very few clinical circumstances in which elevated blood pressure should be treated in the setting of acute ischemic stroke. Before Table 77.2. Characteristics of patients with stroke who may be eligible for intravenous tissue plasminogen activator therapy. Age >18 years Diagnosis of ischemic stroke causing clinically apparent neurologic deficit Onset of symptoms 80% inhibition of MAO
+
++
+++
150–600 250–1250
0.4–0.7 mmol/L 50–100 ng/mL
++ ++
0 0
0 0
5–30
NA
0
0
?
Drug Heterocyclics Doxepin Nortriptyline Desipramine Trazodone Nefazodone
Mood stabilizers Lithium carbonate Valproic acid Stimulants Methylphenidate
NA, not applicable; four plus signs, strong; three plus signs, moderate; two plus signs, weak; one plus sign, negligible; zero, none; MAO, monoamine oxidase; SSRI, selective serotonin reuptake inhibitor; S/NRI, serotonin/norepinephrine reuptake inhibitor.
endogenous depressions. If used today, lower doses than those for younger adults are preferred, because high blood levels may occur even at reduced dosages.77 Doses of 10 to 50 mg of nortriptyline or 25 to 75 mg of desipramine at bedtime are often adequate to relieve symptoms, although blood levels should be followed to ensure a therapeutic dose. For patients with an agitated depression who need sedation, trazodone at doses from 50 to 300 mg/day or nefazodone at doses of 100 to 300 mg/day may be tried. Because they are virtually devoid of anticholinergic side effects, trazodone and nefazodone are attractive drugs for use in elderly patients. Nevertheless, their antidepressant potency is questionable at doses that elders can usually tolerate, and side effects such as excessive drowsiness, orthostasis, and priapism are reasons for caution (although less so for nefazodone than for trazodone). Bupropion is another antidepressant that may have special advantages in certain patients. Elders who have psychomotor retarding (slowed down in physical movements and mental activity), or are unmotivated, fatigued, frail, and at high risk for falling, may find bupropion helpful. Doses beginning at 75 mg/day and increasing to 225 or 300 mg/day are recommended; any single dose should not exceed 150 mg, usually requiring bid (twice a day) or tid (three times a day) dosing. Toxicity at the higher doses may be manifested by tremor, unpleasant
gastrointestinal side effects, or visual hallucinations. Stopping or reducing the dose readily reverses these symptoms. Bupropion has also been associated with an increased risk of seizures, especially in patients with anorexia nervosa or bulimia; thus, a history of seizures should be ruled out before starting this drug. Combinations of an SSRI and a tricyclic antidepressant, bupropion, or trazadone may help in resistant depressions. For instance, 10 to 20 mg of fluoxetine, 25 to 50 mg of sertraline, or 10 to 20 mg of paroxetine may be used with 10 to 50 mg of nortriptyline or 25 to 50 mg of trazodone at night to achieve the desired antidepressant effect and minimize side effects such as insomnia. Note that all SSRIs interfere with the hepatic metabolism of tricyclics and will increase their blood levels; thus, if an SSRI is added to a regimen that includes a tricyclic antidepressant, the dose of the latter should be reduced by one-half or greater and blood levels carefully monitored. Much attention has been directed toward the cytochrome P-450 group of enzymes and the potential for toxic drug–drug interactions secondary to the effects of the SSRIs upon these enzymes. In general, commonly used medications when used in moderation do not result in side effects. Nevertheless, the clinician should review the specific medications prescribed to the patient, perhaps with a computer-assisted program, to avoid these drug–drug interactions.
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St. John’s wort is a natural herb that has been used for the treatment of depression, particularly in Europe. The preparations that can be bought over the counter in health food stores in the United States are of uncertain composition and purity. These preparations should not be used for a patient with a clinical diagnosis of depression, because there are known effective treatments that have been tested (antidepressants already described), approved by the FDA, and have careful guidelines and requirements for their preparation. St. John’s wort is currently being evaluated in a multisite study funded by the NIH’s Office of Alternative Medicine. Before starting therapy with an antidepressant, the older patient should undergo a thorough history and physical examination to identify contraindications. When using tricyclics, special effort should be employed to elicit a history of closed-angle glaucoma, difficulty with urination, severe dizziness with standing, seizure disorder, severe hypertension, recent myocardial infarction, or unstable angina. The physical examination should include measurement of orthostatic blood pressure changes, as well as examination of the liver and prostate for enlargement. Baseline liver and kidney function test results should also be obtained because most antidepressants are metabolized in the liver and excreted in the urine. An electrocardiogram should be obtained before starting therapy with antidepressants, especially tricyclics or tetracyclics; even patients on SSRIs may be at increased risk for developing cardiac complications, particularly in the presence of atrial arrhythmias. If a left bundle branch block, bifascicular block, second-degree heart block, or prolongation of the QT interval (>480 ms) are present, antidepressants should not be started until a cardiac consultation has been obtained or the patient is under careful observation in the hospital. Patients with atrial fibrillation may experience an acceleration in heart rate due to anticholinergic side effects that enhance conduction through the atrioventricular (AV) node. Simple firstdegree AV block or bundle branch block does not increase the risk of cardiac complications. A follow-up electrocardiogram, after the start of treatment, is essential in all patients with heart disease. The dose should be decreased or the drug should be stopped if there is a marked prolongation of the PR, QT, or QRS durations or if AV block worsens or ventricular arrhythmias increase. Use of tricyclic antidepressants concurrently with quinidine, procainamide hydrochloride (Pronestyl), or other type I antiarrhythmics may produce additive cardiac effects. To ensure compliance, patients should be informed of possible side effects, such as dizziness with sudden standing, difficulty with urination, dry mouth, and constipation for tricyclic antidepressants, and side effects such as nausea, headache, weight loss, agitation, insomnia, and loss of sexual interest for SSRIs. These effects are often
H.G. Koenig and D.G. Blazer, II
experienced soon after starting the drug therapy, but often gradually improve after a couple weeks of therapy. patients should also be warned that antidepressant effects may not occur before 6 to 8 weeks of treatment. When there is concern over the patient’s suicidal potential, no more than 1 g of a tricyclic antidepressant should be dispensed at any one time; fatal overdose with the SSRIs, bupropion, velafaxine, mirtazapine, and nefazodone is much more difficult. Once a response is achieved, antidepressants should be continued for 6 to 9 months and then gradually tapered. Given the high rate of relapse in older adults, some experts are now recommending longterm maintenance therapy at the same dose that achieved a therapeutic response, especially if the elder has experienced a recurrence of a successfully treated episode. Lifelong treatment may be indicated for those with a history of one or more relapses.78 Monoamine oxidase inhibitors are an alternative to the heterocyclic antidepressants and SSRIs, although they are not easy to use in the treatment of depression in older patients. Lithium carbonate may be useful in preventing the recurrence of unipolar depression, although its efficacy in this regard is not as established as for bipolar disorder. Although lithium alone is a poor antidepressant, it may be used to augment the antidepressant effects of tricyclics. Lithium may sensitize postsynaptic adrenergic receptors, thereby enhancing the effects of tricyclic antidepressants. Anticonvulsants such as carbamazepine or valproic acid are especially useful in treating older patients who rapidly cycle between depressed and manic or agitated moods. In general, the use of lithium or anticonvulsants by nonpsychiatric physicians in the treatment of depression or management of bipolar disorder in older patients is not recommended. In general, benzodiazepines should not be used to treat geriatric depression as these can induce excessive sedation and may even worsen the depressive state.79,80 The possible exception is alprazolam, which has been reported to have antidepressant, as well as antianxiety, effects. At doses of 2 to 4 mg/day, the antidepressant effects of this drug have been reported to equal those of imipramine. Nevertheless, elders may easily become dependent on alprazolam, and it is difficult to get them off the drug once started. Low doses of stimulants such as methylphenidate (5–15 mg two or three times/day) may enhance the appetite and mood of an apathetic older adult. At such doses, side effects are rare (especially if the last dose is given before 2 p.m.), and abuse or addiction is seldom encountered; nevertheless, blood pressure should be monitored and these drugs avoided in patients with unstable angina. Furthermore, tolerance may occur, requiring an escalation of dose to achieve the desired effect. Stimulants have been used to treat depression in medically ill older patients,10 although it remains unclear
79. Depression, Anxiety, and Other Mood Disorders
whether they actually treat the mood disorder or simply activate retarded patients. Major depression in patients with dementia should be treated with antidepressant medication. Start with an SSRI, bupropion, or mirtazapine (if sleep is a problem). Avoid tricylics if possible. The starting dose of tricylics, if used, should be low (e.g., 10 mg nortriptyline, increasing slowly to a maximum of 50 mg/day). Anticholinergic effects can worsen dementia and may precipitate an acute delirium. The treatment of acute mania is best accomplished with lithium carbonate; supplementation with benzodiazepines or phenothiazines may be necessary. The anticonvulsant valproic acid is increasingly being utilized as a first-line agent to control both manic episodes and agitation/aggression in elderly patients. In rare circumstances, a manic episode will respond only to ECT. Recent studies have demonstrated the effectiveness of combined use of tricyclic antidepressants (specifically nortryptiline) and IPT in both the treatment of a depressive episode and the prevention of relapse once the episode remits.81 The combination of medications and psychotherapy was especially beneficial in decreasing the likelihood of recurrence once an episode responded to therapy, even in the most severely depressed sample members.
Electroconvulsive Therapy For severe depressions that are persistent and refractory to psychotherapy and pharmacotherapy, ECT is the most effective treatment.82 It is particularly effective in major depression with either melancholic or psychotic features. Of the 1400 ECT treatments per year given to psychiatric inpatients at Duke Hospital, 70% are for patients age 60 or over. Despite its remarkable effectiveness and general safety, ECT is still usually performed only after other methods of treatment have failed. In cases where the patient becomes suicidal or attempts to starve to death, ECT is the treatment of choice because of its rapid effect. For an adequate therapeutic response, treatments are usually given three times per week for a total of 8 to 12 times; this can be done as an inpatient or outpatient. A marked improvement usually is noted after one of the treatments. Following this improvement, two or three further treatments are usually given. The overall success rate for ECT in drug nonresponders is about 80%, a rate similar in both younger and older patients. In the absence of prophylactic drug therapy, the relapse rate 1 year following ECT exceeds 50%. Maintenance ECT (weekly or monthly) or concurrent use of antidepressants decreases the relapse rate to around 20% in the year following ECT. Confusion following ECT varies from patient to patient, depending on underlying level of cognitive
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impairment. There is less confusion after unilateral than bilateral electrode placement during ECT and also less confusion after brief pulse stimulation than after sine wave stimulation. It is difficult to evaluate the effects of ECT on memory, because depression itself affects memory. Significant cognitive impairment is not a contraindication to ECT, because if this impairment is caused by depression, it may improve as the depression improves.83 Most memory impairment induced by ECT disappears by 6 months after treatment.84
Prognosis The natural history of major depression follows a pattern of remission and relapse. Until recently, most followup studies indicated that one-third of depressed elders recovered completely from an index episode, one-third experienced a partial recovery or relapsed soon after recovery, and one-third remained continuously ill.11 The results from follow-up studies, however, depend largely on the sample. British investigators Baldwin and Jolley,85 however, reported that 60% of depressed elders remained continuously well or had further episodes with complete recovery during a 3- to 8-year follow-up period. Factors associated with better outcome are female sex, current employment, and high level of subjective social support.3,86 Other positive prognostic factors include an extraverted personality style, absence of severe symptomatology, a family history of depression, a history of recovery from previous episodes, no substance or alcohol abuse, no other comorbid major psychiatric illness, minimal intercurrent life changes, and religious coping style.38,85,86 On the other hand, poor outcomes have been associated with delusions, significant cognitive impairment, and physical illness.85,87,88 More recent studies indicate that when antidepressant therapy is combined with psychotherapy or ECT, a remission can be achieved in about 80% of cases (similar to the response rate in younger depressed patients).89–92 Little is known concerning the outcome of bipolar disorders in older persons. There is some information to suggest that early-onset bipolar disorder may “burn out” with time. Shulman and Post93 found that few of their sample of elderly persons with bipolar disorder had the early-onset variety. When mania occurs for the first time in an elder who previously had unipolar depression, the illness may have a poorer prognosis than unipolar depression; the strong association between late-onset mania and progressive neurologic disorders (such as Alzheimer’s disease and other dementias) accounts for this.94
Suicide and Its Prevention Cross-sectional epidemiologic studies have shown that suicide rates in later life are higher than at younger ages,
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and suicide ranks among the top 10 causes of death in persons over age 65.95 After nearly 40 years of declining suicide rates in the elderly, since 1980 these rates have begun to increase. Risk factors for suicide include sex (male), race (white), marital status (divorced or separated), economic status (low), mental illness, previous suicide attempts, and health. Although men of all ages have a higher suicide rate than women, older men have a higher rate than any other age by sex group;15 in fact, the higher rate of suicide in the elderly results largely from the higher risk in older white males. Elderly patients with mental illness, particularly depression and schizophrenia, are at high risk for suicide. When depression coexists with other mental disorders, the risk increases further. The presence of alcohol abuse or dependence is a major risk factor for suicide, especially among elderly white males; this is particularly true for late-onset alcoholics, who often drink in response to psychosocial stressors. Thus, an inquiry about alcohol use is essential when evaluating safety risk in older patients with depression. Poor health status is another major risk factor for suicide in later life. In 1928, Cavan noted that physical illness led to suicide when a person’s capacity to endure severe pain was exceeded.96 In a review of 391 cases of suicide, she found that 23% had physical illness; in two-thirds of this group, the suicide was directly related to the illness. The close relationship between physical illness and suicide has been repeatedly demonstrated by other investigators, particularly in men and in patients with coexisting depression or organic brain syndrome. MacKenzie and Popkin provide an excellent review of the association between medical illness and suicide.97 Involvement of family in helping to monitor an elderly suicidal patient at home is vital in preventing suicide. Inquiry about a “plan” often reveals the means by which the act might be attempted; the family should be instructed to remove from the house weapons such as guns, large knives, and all but necessary medications. If the family cannot assure the physician that at least one family member can be with the patient at all times until the risk of suicide has passed, then hospitalization is the safest course. If hospitalized, the patient should be placed in an environment with windows of shatter-proof glass or safety screens and should not have access to open stairwells or laundry chutes. Potentially harmful devices, such as razors, scissors, knives, forks, ropes, and breakable glass bottles or glasses, should also be removed from the patient’s environment. Adequate doses of psychotropic medication should be utilized for the confused or psychotic patient. The quickest and safest form of treatment in the severely depressed and suicidal elder is ECT.
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Anxiety Disorders Anxiety is a common symptom experienced by elderly persons, particularly those with physical health problems.98 Clinicians evaluating an elderly person with a complaint of anxiety must first decide if the symptom is due to some underlying medical illness. If not, then the clinican must determine whether the anxiety is a result of psychiatric illness or represents a normal response to life events. The signs and symptoms of anxiety are both cognitive and physical, and include difficulty with concentration, dizziness or faintness, tremulousness, insomnia, fears of “going crazy” or dying, tachycardia, diaphoresis, and shortness of breath. Many of these signs and symptoms are also seen in a wide range of medical and other psychiatric disorders from which they must be distinguished.
Epidemiology Anxiety syndromes typically begin in early life and decrease in frequency after the age of 65. The ECA surveys found that 6% of persons over age 65 fulfilled criteria for an anxiety disorder within the past month.99 Other studies have reported rates of clinically significant anxiety as high as 20% in some elderly populations.100 Phobia is the most common psychiatric disorder in elderly women, who are also more likely than men to be diagnosed with any of the anxiety disorders.99 Medical illnesses that increase the vulnerability of older persons to anxiety include Parkinson’s disease, chronic obstructive pulmonary disease, and early dementia, where rates of anxiety disorder range from 8% to 38%.101–103 Elderly persons with anxiety disorder tend to be high utilizers of health services, and therefore commonly come into contact with medical personnel.
Diagnostic Evaluation Anxiety disorders seldom present for the first time in later life, although generalized anxiety disorder or panic disorder are known to do so.104 The general rule is that lateonset anxiety is presumed to have a medical cause until proven otherwise. Table 79.3 presents psychiatric and medical causes for anxiety in older patients. Evaluation consists of a comprehensive history, physical examination, and battery of laboratory tests, including electrolytes, thyroid studies, and an electrocardiogram. A history of caffeine intake—tea, colas, or coffee—should be elicited, as well as over-the-counter drug use. Prescription medications that cause anxiety include sympathomimetics, corticosteroids, theophylline, calcium channel blockers, opiates, and amphetamines. Withdrawal from chronic benzodiazepine use may cause a prolonged withdrawal
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Table 79.3. Medical and psychiatric causes of anxiety in the elderly. Medical disorders Cardiovascular Myocardial infarction Paroxysmal atrial tachycardia Hypothermia Mitral valve prolapse Hyperkalemia Dietary Caffeine Vitamin deficiencies Drug-related Anticholinergic toxicity Akathisia (antipsychotics) Antihypertensive side effects Digitalis toxicity Theophylline Thyroid replacement therapies Antidepressants (SSRIs, bupropion) Neurologic Central nervous system infections Central nervous system masses Postconcussion syndrome Temporal lobe epilepsy Parkinson’s disease
Psychiatric disorders Anxiety disorders Panic disorder Agoraphobia Social phobia Simple phobia Obsessive-compulsive disorder Posttraumatic stress disorder Generalized anxiety disorder Other psychiatric disorders Major depression Dementia Psychosis Adjustment disorder to negative life events Sleep disorder Somatoform pain disorder Somatization disorder Personality disorders Substance abuse, dependence, withdrawal Alcohol Sedative/hypnotics Prescription drugs Over-the-counter drugs (decongestants, diet aids)
Endocrinologic Insulinoma Hypoglycemia Hypo- or hyperthyroidism Hypo- or hypercalcemia Pheochromocytoma Cushing’s disease Carcinoid syndrome Pulmonary Chronic obstructive lung disease with hypoxia Pneumonia with hypoxia Miscellaneous Anemia Systemic lupus erythematosus Toxins
syndrome in the elderly associated with anxiety. All patients should be asked about alcohol use and when the last drink was taken. When physical and psychiatric symptoms of anxiety overlap in patients with medical problems, a diagnosis of anxiety disorder should be reserved for those who either had anxiety symptoms before the onset of the medical illness or continue to have symptoms after the physical condition has been treated. Diagnostic assessment is often complicated by a heavy overlap between anxiety disorders and depressive disorders. Although only 2% of older psychiatric inpatients have an isolated anxiety disorder, nearly 40% with major depression fulfill criteria for anxiety disorder.105
Clinical Features The major anxiety disorders noted in DSM-IV include generalized anxiety disorder, panic disorder with and without agoraphobia, posttraumatic stress disorder, obsessive-compulsive disorder, and phobia (social or simple). Because of their prevalence in later life and impact on functioning, we focus here on generalized anxiety disorder (GAD), panic disorder, and obsessivecompulsive disorder (OCD). To meet the DSM-IV criterion for GAD, the person must have experienced excessive or unrealistic anxiety nearly every day for 6 months or longer and have had at least 6 of 18 possible symptoms during that period of time. The 18 symptoms
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are grouped into symptoms of muscle tension, autonomic hyperactivity, and vigilance or scanning. The 1980–1981 ECA surveys found that the 1-year prevalence of GAD among 5700 persons aged 65 or over was 2.2%, the highest of any anxiety disorder except phobias.106 To meet DSM-IV criteria for panic disorder, a person must experience recurrent episodes of severe anxiety or fear, accompanied by at least four of the following symptoms: shortness of breath, palpitations, sweating, dizziness, nausea, choking, depersonalization, numbness or tingling, hot flashes, and chest pain, all usually accompanied by a fear of dying or going crazy; at least four such episodes must have occurred within a 4-week period. These intense periods of anxiety usually occur spontaneously, without warning, and typically last only about 5 to 10 min. Panic disorder may or may not be associated with agoraphobia (the fear of being in public places or situations from which escape may be difficult). The 1-year prevalence of panic disorder in persons over age 65 in the ECA studies was 0.04% in men and 0.41% in women.107 Although usually a chronic illness that develops in early adulthood, late-onset panic disorder can occur and is characterized by fewer symptoms and less avoidance.108 Panic disorder in older adults with heart disease is both prevalent and underdiagnosed.109 Almost one-third of older persons with chest pain and no evidence of coronary artery disease are reported to have late-onset panic disorder.110 OCD is characterized by recurrent obsessive thoughts or compulsive behaviors that cause a significant disruption in social or occupational functioning. The person has little control over the obsessive thoughts, which are recurrent and persistent; he or she is often compelled to perform repetitive behaviors or rituals (washing hands, counting, checking locks, etc.) to avoid feeling overwhelmingly anxious. Epidemiologic studies report a 1year prevalence between 0.9% and 1.5% in the geriatric populations.111,112 Many older persons with this disorder resist hospitalization for medical problems because it may disrupt their compulsive activities. Other psychiatric diagnoses, particularly alcoholism, can lead to complaints of anxiety in older patients. Anxiety can be part of an alcohol withdrawal syndrome that occurs when alcohol use is temporarily halted; alternatively, alcohol may be used to self-medicate an underlying anxiety disorder. There is also considerable overlap between the anxiety disorders and dementia, where it may be difficult to distinguish anxiety from agitation.113
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treatment largely involves supportive, problem-focused counseling to help the patient choose a healthy coping strategy. If an anxiety disorder is diagnosed, then more specific therapies are indicated.
Behavioral Therapies Behavioral therapies are commonly used to treat anxiety disorders in both younger and older adults (Table 79.4). Progressive muscle relaxation is commonly used for patients with GAD, panic disorder, or social phobia.114 This therapy involves the systematic tensing and relaxing of muscle groups, beginning first with the facial muscles and gradually moving down to the neck, upper arms, abdomen, legs, and feet. This technique is often combined with rhythmic breathing and visualization. Studies have shown that progressive muscle relaxation is effective in relieving the anxiety of patients with chronic pulmonary diseases and with cancer.115,116 Another behavior technique is called graded exposure; it is used to treat phobias and compulsive behaviors. The person is repeatedly exposed to the feared stimulus until the fear of that stimulus is gradually lost. Systematic desensitization combines progressive muscle relaxation with breathing and visualization; it prevents the stimulus from arousing anxiety by associating it with a deeply relaxed state.117 Other behavioral techniques include biofeedback, meditation, social skills training, assertiveness training, and participant modeling. Studies have now demonstrated the effectiveness of behavioral therapies for treating anxiety disorders in older adults.118 Cognitive therapy is commonly used with behavioral techniques to achieve better outcomes. Table 79.4. Management of anxiety disorders in the elderly. Condition Panic disorder (with or without agoraphobia)
Agoraphobia without panic disorder Social phobia
Simple phobia Generalized anxiety disorder
Management After treating reversible medical problems and arriving at a specific psychiatric diagnosis, the clinician must choose from a wide range of psychotherapeutic and drug treatment options. If the anxiety symptoms are minor and associated primarily with stressful life circumstances,
Obsessive-compulsive disorder
Posttraumatic stress disorder
Treatment Desipramine, clonazepam, alprazolam, phenelzine, exposure therapy, cognitivebehavioral therapy Cognitive-behavioral therapy, exposure therapy Cognitive-behavioral therapy, exposure therapy, beta-blockers, phenelzine, serotonin-reuptake inhibitors Graded exposure and systematic desensitization Buspirone, clonazepam, b-blockers, behavioral therapy, psychotherapy Serotonin-reuptake inhibitors, behavioral therapy, psychodynamic therapy Psychotherapy, behavior therapy, nortriptyline, clonazepam, phenelzine
79. Depression, Anxiety, and Other Mood Disorders
Benzodiazepines The pharmacologic management of anxiety disorders is most successful when used in combination with cognitive and behavioral therapies. Antidepressants and benzodiazepines are the mainstay of pharmacologic treatment for anxiety disorders. Between 17% and 50% of all older adults use benzodiazepines for problems with anxiety or medical problems.119 All benzodiazepines work equally well in relieving anxiety; only the side effect profiles of these drugs differ. Elderly persons often respond to low doses of medication. Furthermore, elders are at greater risk for the development of toxicity because of pharmacokinetic changes with aging, such as slowed hepatic metabolism and reduced glomerular filtration rate. Because they bind tightly with plasma albumin (reduced in some elders) and distribute preferentially to fatty tissue (increased in elders), benzodiazepines with a long half-life tend to accumulate and have toxic side effects. The half-lives of diazepam and chlordiazepoxide in older adults is nearly three times that in younger persons.114 For this reason, short-acting benzodiazepines such as lorazepam and oxazepam arc the drugs of choice. These drugs are conjugated in the liver, eliminated in the urine, and have no active metabolites (as do alprazolam and diazepam). Oxazepam is typically started at a dose of 7.5 mg (1/2 a 15-mg tablet) given three times per day, which can then be gradually increased up to a maximum of 45 mg/day. Lorazepam is usually initiated at a dose of 0.25 mg (1/2 a 0.5-mg tablet) three times per day and tapered upward to a maximum of 3 mg/day. Alprazolam is a benzodiazepine with an intermediate half-life of 12 to 15 h in the elderly. At a single dose of 0.5 to 2.0 mg, alprazolam is effective for the immediate relief of severe anxiety, particularly during a panic attack. However, it has an active metabolite that can build up in the elderly and cause toxic reactions.120 As noted earlier, alprazolam can induce dependence, particularly in those with a history of alcohol or benzodiazepine abuse, and is difficult for some elders to discontinue (see following). It is generally best to use short-acting benzodiazepines in elderly patients; however, there are some indications for using longer-acting agents such as diazepam, chlordiazepoxide, or clonazepam. One indication is where anxiety is constant throughout the day and night and is clearly interfering with ability to function. Many elderly persons have taken these drugs for years and do not abuse them.121 Of the longer-acting agents, clonazepam is the safest; doses of 0.25 to 1.0 mg twice a day is usually effective, although some patients will do well on a once a day or even once every other day regimen. Clonazepam, however, has been reported to be depressogenic, so it must be used with caution in mixed anxietydepression states.
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When discontinuing benzodiazepines that have been taken regularly for several months or more, the clinician must gradually taper these compounds to avoid inducing seizures or delirium. Alprazolam, in particular, can produce severe dysphoria and psychotic-like symptoms if the drug is tapered too rapidly. The discontinuation of this medication should be accomplished over several months. Alternatively, one might switch to clonazepam (on a mg/mg basis), and then gradually discontinue the clonazepam. Benzodiazepines can induce a number of side effects about which clinicians must educate their patients. Side effects include oversedation, confusion, memory loss, and disorientation, particularly when used with other CNS suppressants. Benzodiazepines have been shown to cause disequilibrium in older adults and increase the risk of falling and hip fractures; antidepressants and neuroleptics, however, are equally as dangerous in this regard.122 Benzodiazepines can also impair ventilation during sleep, which may worsen sleep-related breathing disorders such as chronic obstructive pulmonary disease, congestive heart failure, and sleep apnea.123 Cognitive impairment may also be induced or exacerbated by these drugs.124 Other problems include disinhibition (particularly in demented elders), impaired driving, and paradoxical agitation.
Antidepressants Antidepressants are effective and safe treatments for anxiety disorders in older adults. When initiating therapy, we start patients on both antidepressants and benzodiazepines, gradually tapering off the benzodiazepine once the antidepressant has had a chance to take effect. This approach is particularly effective because of the heavy overlap between depressive and anxiety syndromes in later life.105 We start patients on a low dose of an SSRI and gradually increase the dosage to adults over a period of weeks. All the new SSRIs are effective antianxiety agents if taken at an adequate dose for a sufficient period of time (6–8 weeks). Initially, however, these drugs may exacerbate the patient’s symptoms, and therefore should be used concurrently with a benzodiazepine. We typically begin patients on clonazepam at a dose of 0.25 to 1.0 mg twice per day. An alternative to beginning an SSRI is to start 25 mg desipramine per day and increase by 25 mg every 4 days until a therapeutic serum level is achieved (>125 ng/ml). Regardless of antidepressant used, after 6 to 8 weeks, the clonazepam is gradually tapered off over a 4-week period. Clomipramine, fluoxetine, and fluvoxamine are specifically indicated for obsessive-compulsive disorder. The side effects associated with clomipramine (orthostatic and anticholinergic effects), however, limit its use in the elderly. Fluoxetine, on the other hand, may be associated
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with gastrointestinal symptoms that make it intolerable unless initiated at a very low dose (10 mg every other day) and gradually increased to 20 or 40 mg per day (if tolerated). Fluvoxamine may be the drug of first choice for older adults with symptoms of OCD. It is typically begun at 25 mg twice daily and increased up to a maximum of 100 mg three times per day as tolerated. Headache can be a problem if the dose is not gradually increased. Unfortunately, fluvoxamine is quite expensive at the doses needed to treat OCD.
Other Drugs Other treatments for anxiety disorders include buspirone, beta-blockers, and sedating antihistamines. Buspirone is a serotonin agonist that has no cross-tolerance with the benzodiazepines. It has a slow onset of action, and initially may even exacerbate anxiety because of its activating effects. Buspirone is a safe drug to use over the long term given its lack of addictive potential and lack of psychomotor impairment, and it interacts with virtually no other medications. It is specifically indicated for generalized anxiety disorder. At least one study in elderly patients with chronic health problems has demonstrated a significant improvement of anxiety with this drug.125 A major drawback is cost; the usual dosage of 10 mg three times per day costs about $90 to $180 per month, which may be prohibitive for some elders. Also, buspirone is rarely effective in patients who have taken benzodiazepines previously or have a history of substance abuse. Beta-blockers are effective in blocking the autonomic symptoms that accompany anxiety (palpitations, sweating, trembling); they do not, however, affect the cognitive aspects of anxiety. Because of this, beta-blockers are not effective in panic disorder, because they do not diminish the psychologic anxiety associated with panic. Propranolol can be very helpful at doses from 10 mg twice a day to 40 mg three times per day in patients with social phobia, performance anxiety, or generalized anxiety disorder. Note, however, that beta-blockers have been associated with depression, and may exacerbate depression if present concurrently with anxiety; furthermore, there are a number of medical contraindications that limit its use in elderly patients. Antihistamines are frequently used both over-thecounter and by prescription to reduce anxiety. In general, these drugs should not be used to treat anxiety disorders in older adults because of their anticholinergic, drying, and nonspecific sedative effects. Neuroleptics should only be used if anxiety is associated with psychotic symptoms.
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Acknowledgment. This work was supported by an NIMH grant R01 MH57662-01 (Dr. Koenig), the Clinical Research Center for the Study of Depression in Late Life (MH40159), and an NIA grant R01 AG12765-03 (Dr. Blazer).
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1180 61. Shulman KI. Mania in old age. In: Murphy E, ed. Affective Disorders in the Elderly. Edinburgh: Churchill Livingstone; 1986. 62. Post F. Functional disorders. II. Treatment and its relationship to causation. In: Levy R, Post F, eds. The Psychiatry of Late Life. London: Blackwell; 1982. 63. Shulman KI. The influence of age and ageing on manic disorder. Int J Geriatr Psychiatry. 1989;4:63–65. 64. Young RC, Klerman GL. Mania in late life: focus on age at onset. Am J Psychiatry. 1992;149:867–876. 65. Tohen M, Shulman KI, Satlin A. First-episode mania in late life. Am J Psychiatry. 1994;151:130–132. 66. Sweer L, Martin DC, Ladd RA, et al. The medical evaluation of elderly patients with major depression. J Gerontol. 1988;43:M53–M58. 67. Koenig HG. Aging and God. New York: Haworth Press; 1994. 68. Koenig HG, Breitner J. Antidepressant use in the medically ill older person. Psychosomatics. 1990;31:22–32. 69. Beck AT, Rush J, Shaw B, et al. Cognitive Therapy of Depression. New York: Guilford; 1979. 70. Lewinsohn P. A behavioral approach to depression. In: Friedman R, Katz M, eds. The Psychology of Depression: Contemporary Theory & Research. New York: Wiley; 1974: 157–176. 71. Klerman GL, Weissman MM, Rounsaville BJ, et al., eds. Interpersonal Psychotherapy of Depression. New York: Basic Books; 1984. 72. Horowitz M, Kaltreider N. Brief therapy of the stress response syndrome. Psychiatr Clin Am. 1979;2:365–377. 73. Thompson LW, Gallagher D, Breckenridge JS. Comparative effectiveness of psychotherapies for depressed elders. J Consult Clin Psychol. 1987;55:385–390. 74. Arean PA, Pen MG, Nezu AM, et al. Comparative effectiveness of social problem-solving therapy and reminiscence therapy as treatments for depression in older adults. J Consult Clin Psychol. 1993;61:1003–1010. 75. Myers WA. New Techniques in the Psychotherapy of Older Patients. Washington, DC: American Psychiatric Press; 1991. 76. Marmar CR, Horowitz MJ, Weiss DS, et al. A controlled trial of brief psychotherapy and mutual-help group treatment of conjugal bereavement. Am J Psychiatry. 1988;145: 203–209. 77. Nies A, Robinson DS, Friedman MJ, et al. Relationship between age and tricyclic antidepressant pharmacokinetics and plasma levels. Am J Psychiatry. 1977;134:790– 793. 78. Greden JF. Antidepressant maintenance medications: when to discontinue and how to stop. J Clin Psychiatry. 1993;54(suppl 8):39–45. 79. Tyrer P, Murphy S. The place of benzodiazepines in psychiatric practice. Br J Psychiatry. 1987;151:719–723. 80. Greenblatt DJ, Shader RI, Abernathy DR. Current status of benzodiazepines: clinical use of benzodiazepines. N Engl J Med. 1983;309:410–405. 81. Reynolds C III, Frank B, Perel I, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA. 1999;281:39–45.
H.G. Koenig and D.G. Blazer, II 82. Abrams R. Electroconvulsive Therapy, 2nd Ed. New York: Oxford University Press; 1992. 83. Salzman C. Electroconvulsive therapy in the elderly. Psychiatr Clin Am. 1982;5:191–197. 84. Zervas IM, Calev A, Jandorf L. Age-dependent effects of electroconvulsive therapy on memory. Convulsive Ther. 1993;9:39–42. 85. Baldwin RC, Jolley DJ. The prognosis of depression in old age. Br J Psychiatry. 1986;149:574–583. 86. Post F. The management and nature of depressive illness in late life: a follow-through study. Br J Psychiatry. 1972; 121:393–404. 87. Murphy E, Smith R, Lindesay J, et al. Increased mortality rates in late-life depression. Br J Psychiatry. 1988;152:347– 353. 88. Koenig HG, Goli V, Shelp F, et al. Major depression in hospitalized medically ill men: documentation, treatment, and prognosis. Int J Geriatr Psychiatry. 1992;7:25– 34. 89. Reynolds CF, Frank B, Perel JM, et al. Combined pharmacotherapy and psychotherapy in the acute and continuation treatment of elderly patients with recurrent major depression: a preliminary report. Am J Psychiatry. 1992; 149:1687–1692. 90. Hinrichsen GA. Recovery and relapse from major depressive disorder in the elderly. Am J Psychiatry. 1992;149: 1575–1579. 91. Stoudemire A, Hill CD, Morris R, et al. Long-term affective and cognitive outcome in depressed older adults. Am J Psychiatry. 1993;150:896–900. 92. Hughes DC, Demallie D, Blazer DG. Does age make a difference in the effects of physical health and social support on the outcome of a major depressive episode? Am J Psychiatry. 1993;150:728–733. 93. Shulman K, Post F. Bipolar affective disorder in old age. Br J Psychiatry. 1980;136:26–32. 94. Shulman K, Tohen M, Stalin A, et al. Mania compared with unipolar depression in old age. Am J Psychiatry. 1992;149: 341–345. 95. Conwell Y. Suicide in elderly patients. In: Schneider LS, Reynolds CF, Lebowitz BD, Friedhoff AJ, eds. Diagnosis and Treatment of Depression in Late Life: Results of the NIH Consensus Development Conference. Washington, DC: American Psychiatric Press; 1994. 96. Cavan RS. Suicide. Chicago: University of Chicago Press; 1928:279–287. 97. MacKenzie TB, Popkin MK. Suicide in the medical patient. Int J Psychiatry Med. 1987;17:3–22. 98. Blazer DG. Generalized anxiety disorder and panic disorder in the elderly: a review. Harvard Rev Psychiatry. 1997; 5:18–27. 99. Regier DA, Boyd JH, Burke JD, et al. One month prevalence of mental disorders in the United States. Arch Gen Psychiatry. 1988;45:977–986. 100. Sheikh JI. Anxiety and its disorders in old age. In: Birren J, Sloane R, Cohen G, eds. Handbook of Mental Health & Aging, 2nd Ed. San Diego: Academic Press; 1992:409–432. 101. Stein MB, Heuser IJ, Juncos JL, et al. Anxiety disorders in patients with Parkinson’s disease. Am J Psychiatry. 1990; 147:217–220.
79. Depression, Anxiety, and Other Mood Disorders 102. Karajgi B, Rifkin A, Doddi S, et al. The prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease. Am J Psychiatry. 1990;147:200–201. 103. Wands K, Merskey H, Hachinski V, et al. A questionnaire investigation of anxiety and depression in early dementia. J Am Geriatr Soc. 1990;38:535–538. 104. Jenike MA. Anxiety disorders of old age. In: Jenike MA, ed. Geriatric Psychiatry and Psychopharmacology. Chicago: Year Book; 1989:248–271. 105. Alexopoulas GS. Anxiety and depression in the elderly. In: Salzman C, Uebowitz B, eds. Anxiety Disorders in the Elderly: Treatment and Research. New York: Springer; 1991:131–150. 106. Blazer DG, Hughes D, George LK, et al. Generalized anxiety disorder. In: Robins LN, Regier DA, eds. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York: Free Press; 1991:180–203. 107. Eaton WW, Dryman A, Weissman MM. Panic and phobia. In: Robins LN, Regier DA, eds. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York: Free Press; 1991:155–179. 108. Sheikh J, King R,Taylor CB. Comparative phenomenology of early-onset versus late-onset panic attacks: a pilot survey. Am J Psychiatry. 1991;148:1231–1233. 109. Beitman BD, Mukerji V, Alpert M, et al. Panic disorder in cardiology patients. Psychiatr Med. 1990;8:67–81. 110. Beitman BD, Kushner M, Grossberg GT. Late onset panic disorder: evidence from a study of patients with chest pain and normal cardiac evaluations. Int J Psychiatry Med. 1991; 21:29–35. 111. Blazer DG, George LK, Hughes D. The epidemiology of anxiety disorders: an age comparison. In: Salzman C, Lebowitz B, eds. Anxiety Disorders in the Elderly: Treatment and Research. New York: Springer; 1991:17–30. 112. Karno M, Golding JM. Obsessive compulsive disorder. In: Robins LN, Regier DA, eds. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York: Free Press; 1991:204–219.
1181 113. Abrams R. Anxiety and personality disorders. In: Sadavoy J, Lazarus U, Jarvik L, eds. Comprehensive Review of Geriatric Psychiatry. Washington, DC: American Psychiatric Association; 1991:369–376. 114. Jacobsen E. Progressive Relaxation, 2nd Ed. Chicago: Chicago University Press; 1938. 115. Gift AG, Moore T, Soeken K. Relaxation to reduce dyspnea and anxiety in COPD patients. Nurs Res. 1992;41:242–246. 116. Holland JC, Morrow GR, Schmale A, et al. A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms. J Clin Oncol. 1991;9:1004–1011. 117. Wolpe J. The Practice of Behavior Therapy, 2nd Ed. New York: Pergamon Press; 1973. 118. Hussian RA. Geriatric Psychology: A Behavioral Perspective. New York: Van Nostrand Reinhold; 1981. 119. Salzman C, Lebowitz BD. Anxiety in the Elderly. New York: Springer; 1991:149–173. 120. Salzman C. Treatment of anxiety. In: Salzman C, ed. Clinical Geriatric Psychopharmacology, 2nd Ed. Baltimore: Williams & Wilkins; 1992:189–212. 121. Pinsker H, Suljaga-Petchel K. Use of benzodiazepines in primary care geriatric patients. J Am Geriatr Soc. 1984;32: 595–598. 122. Ray WA, Griffin MR, Schaffner W, et al. Psychotropic drug use and the risk of hip fracture. N Engl J Med. 1987;316: 363–369. 123. Guilleminault C. Benzodiazepines, breathing, and sleep. Am I Med. 1990;88(3A):25S–28S. 124. Salzman C. Anxiety in the elderly: treatment strategies. J Clin Psychiatry. 900;51(suppl 10):18–21. 125. Bohm C, Robinson DS, Gammans RE, et al. Buspirone therapy in anxious elderly patients: a controlled clinical trial. J Clin Psychopharmacol. 1990;10(suppl 3):47S– 51S. 126. Abernathy DR, Greenblatt DJ, Divoll M, et al. Pharmacokinetics of alprazolam. J Clin Psychiatry. 1983;44:45– 47.
Appendix 11-Item Abbreviated Duke Social Support Index (Self-Administered) 1. Other than members of your family, how many persons in this area within one hour’s travel (of your home/from here) do you feel you can depend on or feel very close to?
Number None
00
None Once Twice Three times Four Five Six Seven or more
00 01 02 03 04 05 06 07
[scoring 0 = 1, 1-2 = 2, >2 = 3] 2. (Other than at work) How many times during the past week did you spend some time with someone who does not live with you, that is, you went to see them or they came to visit you, or you went out together?
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[scoring 0 = 1, 1-2 = 2, >2 = 3] 3. (Other than at work) How many times did you talk to someone—friends, relatives or others—on the telephone in the past week (either they called you, or you called them)?
None Once Twice Three times Four Five Six Seven or more
00 01 02 03 04 05 06 07
None Once Twice Three times Four Five Six Seven or more
00 01 02 03 04 05 06 07
Hardly ever Some Most
1 2 3
Hardly ever Some Most
1 2 3
Hardly ever Some Most
1 2 3
Hardly ever Some Most
1 2 3
Hardly ever Some Most
1 2 3
Hardly ever Some Most
1 2 3
[scoring 0 or 1 = 1, 2-5 = 2, >5 = 3] 4. (Other than at work) About how often did you go to meetings of clubs, religious meetings, or other groups that you belong to in the past week?
[scoring 0 or 1 = 1, 2-5 = 2, >5 = 3] 5. Does it seem that your family and friends (i.e., people who are important to you) understand you most of the time, some of the time, or hardly ever?
6. Do you feel useful to your family and friends (i.e., people important to you) most of the time, some of the time, or hardly ever?
7. Do you know what is going on with your family and friends most of the time, some of the time, or hardly ever?
8. When you are talking with your family and friends, do you feel you are being listened to most of the time, some of the time, or hardly ever?
9. Do you feel you have a definite role (place) in your family and among your friends most of the time, some of the the time, or hardly ever?
10. Can you talk about your deepest problems with at least some of your family and friends most of the time, some of the the time, or hardly ever?
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11. How satisfied are you with the kinds of relationships you have with your family and friends—very dissatisfied, somewhat dissatisfied, or satisfied?
Very dissatisfied Somewhat dissatisfied Satisfied
1 2 3
If NO FAMILY OR FRIENDS: Would you say that you are very dissatisfied, somewhat dissatisfied, or satisfied with not having any of these relationships?
Brief Koenig Depression Scale Please answer yes or no to the following statements/questions about how you have been feeling in the past week. 1. I often became bored.
1 Yes
0 No
2. I often became restless and fidgety.
Yes
No
3. I felt in good spirits.
No
Yes
4. I felt I had more problems with memory than most.
Yes
No
5. I could concentrate easily when reading the papers.
No
Yes
6. I preferred to avoid social gatherings.
Yes
No
7. I felt downhearted and blue.
Yes
No
8. I felt happy most of the time.
No
Yes
9. I often felt helpless.
Yes
No
10. I felt worthless and ashamed about myself.
Yes
No
11. I often wish I were dead.
Yes
No
Scoring: Scores of 3 or higher suggest that further evaluation is necessary for the diagnosis of possible clinical depression. (Source: Koenig HG, Blumenthal J, Moore K. New version of brief depression scale. J Am Geriatr Soc. 1995;43:1447, with permission.)
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80 Late-Life Psychosis Steven C. Samuels and Deborah B. Marin
Five percent of community elders have paranoid delusions at any given time,1 and 20% will develop a psychotic episode at some point in their lifetime.2 Epidemiologic data are limited for late-life psychosis because aged subjects were not included or diagnostic criteria excluded late-onset cases. Females tend to develop psychosis at a later age of onset than males.3 Psychosis, defined as a delusion or a hallucination, is a symptom rather than a specific disease. A delusion is a fixed false belief, and a hallucination is a sensory perception devoid of any actual stimulus. In the elderly, psychosis is associated with significant morbidity and mortality and negatively affects the quality of life for the patient and caregiver. Patients with psychosis routinely present to health care providers at more advanced stages of disease. The presence of psychosis is associated with increased behavioral disturbance, risk of institutionalization, and health care costs. The elderly patient with psychosis may have a broad range of diagnoses including delirium, dementia, affective disorders, schizophrenia, delusional disorder, general medical conditions, or substance use. Less common causes of psychosis in the elderly include posttraumatic stress disorder and brief reactive psychosis. Parkinson’s disease, chronic obstructive pulmonary disease (COPD), and severe pain are examples of medical conditions that may be complicated by psychosis. Dopaminergic agents, anticholinergic drugs, opiates, and steroids are some of the medications that may cause these symptoms. Psychosis may be related to intoxication or withdrawal from prescription or over-the-counter drugs, herbal preparations, street drugs, and alcohol. Misuse of prescription and over-the-counter drugs is more common in the elderly than illicit drug abuse. Moreover, psychosis attributed to medical conditions or medication is more common in the aged than primary psychiatric causes of psychosis. The astute geriatrician is able to recognize psychosis, determine potential etiologies, initiate a diagnostic workup, and begin treatment. Consultation with a
geriatric psychiatrist may be helpful as the interaction between medical illness, brain disease and psychopathology is often complex in the patient with late-life psychosis. Table 80.1 lists the differential diagnosis of psychosis in late life. Common examples of medical conditions that have been associated with psychosis are listed in Table 80.2. Medications and substances associated with psychosis are listed in Table 80.3.
Sites of Care The patient’s treatment setting (inpatient, outpatient, home care, long-term care) may assist the clinician in determining the diagnosis and allocating the available resources when establishing a care plan. For example, in the acute medical, surgical, and intensive care units, psychosis is frequently seen in the context of a delirium. In any setting, a newly diagnosed psychosis should be viewed as a delirium until proven otherwise. The basic principles of delirium management are to determine and treat the underlying cause of the acute confusional state and maintain patient safety. This approach may require symptomatic management with judicious use of antipsychotic agents in combination with environmental modification and reorientation4 (also see Chapter 77). The reason for an acute admission may give significant clues as to the etiology of the psychosis. For example, a temporal relationship between the onset of the psychosis and initiation or change in a medical condition suggests that the medical condition may be aggravating or causing the psychosis. The presentation of psychosis in the outpatient setting may falsely lead the clinician to view the psychosis as less serious than in the acute care setting. However, the acute presentation of psychosis in the ambulatory setting still obligates the clinician to consider a general medical condition or substance as potential contributors. The patient’s psychoses may fluctuate in relationship to the 1185
1186 Table 80.1. Differential diagnosis of psychosis in late life. Delirium Schizophrenia Schizophreniform psychosis Schizoaffective disorder Dementia with psychosis Depression with psychosis Bipolar disease with psychosis Posttraumatic stress disorder Delusional disorder Brief reactive psychosis Psychosis secondary to a substance Psychosis secondary to a medical condition
Table 80.2. Examples of medical conditions that are associated with psychosis. Infections (e.g., urinary tract, meningitis, abscess) Neoplasms (e.g., primary and metastatic, also paraneoplastic syndromes) Endocrinopathies (e.g., diabetes, thyroid disease) Traumatic injury (e.g., subdural; ophthalmologic injury) Vasculopathies (e.g., CVA, vasculitis) Degenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease) Nutritional (e.g., vitamin deficiciencies, malnutrition) Severe pain Special sense impairment (e.g., decreased acuity, prolonged isolation) Cardiac disease (e.g., hypoperfusion, postcardiac surgery) Pulmonary pathology (hypoxia, COPD) Hepatic failure Renal disease (e.g., uremia) Hematologic (e.g., anemia, DIC) Gastrointestinal (e.g., impaction, obstruction) Autoimmune diseases
status of the primary psychiatric disorder, medical comorbidity, or medication change. In addition, environmental change, illness, or hospitalization of the caregiver, or nonadherence to medication are psychosocial factors that may contribute to psychosis. Another common scenario in the outpatient setting is the misuse of over-the-counter preparations including herbal remedies. These compounds may have problems with quality control and have significant potential for neuropsychiatric side effects such as psychosis.5 The home setting may be the primary site to find psychotic patients, yet it is often difficult for the clinician to make entry into the home. Often, the more severely psychotic patients will not voluntarily visit primary care physicians unless they have somatic delusions. Severely paranoid patients may refuse entry to any “strangers,” including home care workers. In the home care setting, psychosis is common and a significant predictor of disability.6–8 The reported rates of psychosis in the home setting may be artificially low, however, because the more severely psychotic patients may refuse to participate in the surveys that generate these data.
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The physical state of a patient’s residence provides an exceptional opportunity to infer psychosis in patients who may otherwise go undiagnosed. For example, a severely paranoid patient may have “extra locks” on the door or may have altered the environment in such a way as to imply psychosis. Shades may be drawn, the phone disconnected, or the number changed. The patient who believes “my house is not my home” or “that man is not really my husband” or “someone stole my money” (when it was actually misplaced) are some common scenarios of demented patients with psychosis. In the context of a psychotic patient refusing evaluation, emergency psychiatric evaluation by a mobile crisis team or emergency room team may be necessary. The logistics of getting the patient evaluated are dependent on local ordinances. Most localities allow the patient’s individual liberty to be usurped by societal protection with the caveat that the judicial system must review the case. Psychotic patients who remain in the community may benefit from aggressive use of antipsychotic agents, as the presence of psychosis is a consistent predictor of institutionalization in elderly patients with dementia and psychosis.9 Long-term care facilities include nursing homes, assisted living facilities, adult homes, and state psychiatric hospitals. The prevalence of psychosis in the nursing home is approximately 10%,10 including patients with delirium, dementia with psychosis, or affective disorders with psychosis. The relatively high rate of psychopathology in the nursing home aged may result from the transfer of patients from the state psychiatric hospitals to nursing homes and the high percentage of dementia patients who reside in these settings. Nursing homes are mandated by regulation to follow specific guidelines for assessment and documentation regarding antipsychotic medication use. Proper assessment requires quantifying and objectively identifying the symptoms that are being targeted with the antipsychotic agent. Center for Medicare & Medicaid Services (formerly Health Care Finance Administration) guidelines have been established to defined disruptive behaviors that will justify the use of antipsychotics in the nursing Table 80.3. Examples of substances associated with psychosis. Steroids H2 blockers Quinolones Analgesics (opiates, NSAIDs) Alcohol Benzodiazepines Anticholinergics Antihistamines Dopaminergics Cardiac (e.g., digoxin) Heavy metals Poisons Other drugs of abuse (cocaine, methamphetamine)
80. Late-Life Psychosis
home.11,12 The guidelines suggest objective documentation of symptoms, quantification of symptoms, persistence of symptoms, a search for a preventable cause, and that symptoms cause a danger to self or others. Other acceptable justifications for antipsychotic use per HCFA guidelines include psychosis that impairs function or causes distress, as continuous yelling, screaming, or pacing that result in functional impairment. Behavioral disturbance and psychosis in nursing home patients is episodic, tend to be mild, and do not worsen over time,13 suggesting that an empiric attempt at trials of or reduced doses of antipsychotics in these patients makes clinical sense. The HCFA guidelines have resulted in reduction of antipsychotic use in the nursing home.14 Adult homes and assisted living facilities are other long-term care facilities that provide less intensive nursing care than nursing homes. Private payment is the most common payment structure for assisted living, whereas nursing or adult homes are increasingly dependent on state-funded entitlements. Prevalence data for psychosis in assisted living facilities and adult homes are sparse, but the prevalence rates of psychosis in the adult home would be expected to be higher than the assisted living facility on the basis of patient mix. Psychosis associated with dementia or depression is expected to be the more common diagnosis in assisted living facilities, whereas severe and persistent mental illness (schizophrenia, schizoaffective disorder) is expected to be the more common diagnosis in the adult homes. One may hypothesize that residents of assisted living facilities have a relatively high functional level before admission compared with the adult home patient, who often has a diagnosis of schizophrenia or schizoaffective disorder. If the patient requires skilled nursing, they may receive care either in the nursing home or in a residence with constant nursing care. State psychiatric hospital patients have severe functional impairment secondary to psychiatric illness and are unable to survive safely in the community. The “state hospitals” have dramatically decreased in size from a peak in the 1950s due to deinstitutionalization initiatives. The patients who remain are the “sickest of the sick,” with prevalence rates of psychosis approaching 75%. Patients in these facilities often receive multiple antipsychotic agents and have relatively high rates of tardive dyskinesia and moderate to severe functional impairment.15,16 The poor prognosis for schizophrenic and schizoaffective patients who reside in the state hospitals is that they are at advanced risk of developing a progressive dementia after age 65. Risk factors for development of this dementia are low education and high rates of positive (psychosis) and negative symptoms (apathy, amotivation, withdrawal). The cognitive loss correlates with functional impairment and loss of ability to attend to activities of daily living.17–21
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The following sections review psychosis associated with schizophrenia, dementia, and affective disorders in later life.
Schizophrenia The community prevalence rates of schizophrenia in individuals over age 65 ranges from 0.1% to 0.5%,22 and incidence rates in those patients over age 60 years suggest an increase of 11% for each 5-year incremental age increase.23 One model of differentiating elderly schizophrenic patients is based upon age at disease onset.24 Late-onset schizophrenia is defined as onset over age 40 and very late onset schizophrenia is defined as onset over age 60. Late-onset schizophrenia is more likely than earlier age onset schizophrenia to present with visual or olfactory hallucinations, persecutory delusions, partition delusions (beliefs that others in a neighboring space are controlling the patient), third-person running commentary, and derogatory auditory hallucinations.25,26 Compared with earlier-onset schizophrenia, late-onset forms of schizophrenia are less likely to have formal thought disorder, negative symptoms, or soft neurologic signs.25–28 In contrast, late-onset disease is associated with a higher likelihood of organic causes and sensory impairment.24 When the geriatrician is considering a diagnosis of schizophrenia in a patient, careful evaluation of cognition and neurologic status including the special senses is warranted. The practicing geriatrician is likely to treat patients with schizophrenia. The notion that most elderly schizophrenic patients are institutionalized is a myth that probably results from the term dementia praecox used by Kraepelin. This term implied deterioration in cognition for the patients described, and later studies did not confirm this belief.29 In fact, although most elderly schizophrenic patients have significant symptoms and functional disability, they do not demonstrate significant cognitive impairment or live in an institution.
Dementia Psychosis may co-occur with several forms of dementia. Psychosis occurs in up to one-third of Alzheimer’s disease (AD) patients at any given time30,31 and has also been associated with vascular dementia, Parkinson’s disease, dementia with Lewy bodies, Pick’s disease, prion-related dementia, substance-induced persisting dementia, and dementia secondary to medical conditions such as anoxia or head trauma.32–34 Psychosis in dementia needs to be differentiated from misidentification or confabulation. An example of misidentification is when a patient with dementia
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believes that her reflection in the mirror is another person or that individuals in a picture hanging on a wall or on the television are “real.” In the first example, the patient may refuse to enter a room with these objects for fear of experiencing these events. Misidentification is best treated with nonpharmacologic interventions rather than antipsychotic medications. Removing the offending structure (mirror, wall hanging, or television) may be effective. Confabulation is defined as making up an answer or explanation to compensate for deficits in cognition. Distinct from psychosis, confabulation is exemplified by the man who has misplaced his keys and now states “my wife stole them.” Misidentification and confabulation may be found in many of the dementia subtypes and appears to be most common in the early to middle stages of AD. Similar to confabulation, psychosis is more common in the early to middle stages of AD. Although psychosis is a predictor of institutionalization, the intensity of an individual’s psychosis may vary. A patient who is neither a danger to themselves or others, nor significantly functionally impaired, may not require the more restrictive setting of an institution.
Psychosis and Alzheimer’s Disease Patients with psychosis and Alzheimer’s disease (AD) have a more rapid rate of decline than those AD patients without psychosis.35 The incidence of psychosis in AD ranges from 5% to 50%, depending on age and the population studied. Although the range of hallucinations and delusions overlaps, the mean rate of hallucinations appears to be less common than delusions.36 In one large community sample of patients with probable AD, 22% had delusions, 3% had hallucinations, and 9% had both.37 The patients with hallucinations had less education, increased stage and duration of dementia, and were more likely to be African-American. Hallucinations were associated with falls and anxiolytic use. Delusions were associated with increased age, antihypertensive use, depression, a more impaired health status, and aggression. Compared to early- or middle-stage patients, the advanced-stage AD patients may be unable to report their psychosis. Behavioral disturbances in the advancedstage patient may be related to psychosis, although instrumentation to measure psychosis in the advanced-stage AD patient is lacking. Agitation in advanced-stage patients may reflect pain, bladder outlet obstruction, fecal impaction, incontinence, hunger, feeling cold, or overstimulation. Identification of these unmet needs can help delineate the optimal pharmacologic and nonpharmacologic treatment approaches. For example, the advancedstage AD patient who is in pain may benefit from an
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empiric trial of analgesic, or the poorly nourished patient who may be hungry should be fed more frequently.
Psychosis in Parkinson’s Disease Psychosis in the context of Parkinson’s disease (PD) poses special challenges. Although psychoses occur in 10% to 15% of PD patients, proper attribution of the psychosis to the PD or its treatment may be difficult. The subcortical circuitry that is dysfunctional in PD may also be responsible for the generation of psychotic symptoms in the disease.38 Anticholinergic and dopaminergic agents, both utilized to treat PD, are notorious for causing psychosis.39 Because conventional antipsychotic agents may worsen the motor symptoms of PD, atypical antipsychotics have become the choice for treating psychosis associated with PD. Clozaril is the best studied with a clinical trial supporting its use.40,41 A mean dosage of 25 mg clozaril was significantly better than placebo for drug-induced psychosis in PD. Parkinsonism was not worsened by the medication; in fact, tremor improved in the clozaril-treated group. Clozaril did not significantly change cognitive status during the 4 weeks of the study. Limitations of clozaril include the potential for agranulocytosis and the requirement for blood monitoring. Case reports have described the benefit of risperdal, olanzapine, and quetiapine for psychosis associated with PD, although the motor effects of these medications has not been predictable.42,43
Psychosis and Dementia with Lewy Bodies Much recent press has focused on dementia with Lewy bodies (DLB), with some suggesting that it is the second most common progressive degenerative dementia.44 Psychosis has been associated with DLB and is one of the proposed core clinical features. Consensus groups have proposed clinical criteria that include parkinsonism, dementia, cognitive fluctuation, and visual hallucinations.44,45 We recently challenged the validity of these criteria.46 Visual hallucinations may not be useful in differentiating DLB from other dementia subtypes.47 In the DLB sample, as in PD, visual hallucinations may be related to medication use. For example, in our review of the DLB literature, 85% of those patients with visual hallucinations were receiving either dopaminergic or anticholinergic medication and 29% of those without visual hallucinations were receiving these medications.46 Medications and over-the-counter preparations may be related to the psychosis in any elderly patient. The medication list should be carefully reviewed so nonessential medications may be decreased or eliminated.
80. Late-Life Psychosis
Psychosis Associated with Vascular Dementia Hallucinations occur in 1% to 10% of stroke patients and are most commonly associated with right-sided temporoparietal lesions, cerebral atrophy, seizures.48–50 Other neuroimaging studies suggest that vascular lesions may be important in the pathogenesis of late-life paranoid psychosis.51 Patients with vascular dementia may be more susceptible to adverse effects (including psychosis) from medications and to subtle changes in chronic medical conditions. Empirical evidence to support one pharmacologic agent over another is lacking for vascular dementia with psychosis. Our practice is the empiric use of atypical antipsychotics such as risperdal, olanzapine, and quetiepine.
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elderly patients with delusional disorder to aid in the management principles for these patients. If delusions are interfering with the patient’s social, occupational, or other areas of functioning, we offer a trial of an atypical antipsychotic agent while attempting to build a therapeutic alliance.
Affective Disorders with Psychosis
Jeste and Finkel recently compared AD with psychosis to late-life schizophrenia.52 Highlights of the comparison between these conditions revealed that the incidence of AD with psychosis (30%–50%) is much more frequent than the incidence of elderly schizophrenia (less than 1%). Bizarre and well-systematized delusions are rare in psychosis associated with AD whereas they occur frequently in late-life schizophrenia. Hallucinations are more commonly visual in AD and auditory in schizophrenia. Schneiderian first-rank symptoms such as thought insertion, thought broadcasting, or thought withdrawal are more common in schizophrenia than in AD. The misidentification of caregivers is frequent in AD but rare in schizophrenia. A past history of psychosis is very common in schizophrenia, yet rare in AD with psychosis. Psychosis usually remits as AD advances, compared with schizophrenia, where it usually persists. Therefore, the need for years of maintenance antipsychotic use is uncommon in AD with psychosis but common in schizophrenia. Active suicidal ideation is rare in AD with psychosis but present in up to half of schizophrenia patients. Approximately 10% of elderly schizophrenics complete suicide.53
Affective disorders with psychosis include major depression, bipolar disease, and schizoaffective disorder. Severely depressed patients with psychosis commonly have delusional themes about excessive guilt, being punished, or somatic problems. Manic patients often have grandiose delusions. Elderly patients are at increased risk for completing suicide compared with younger patients,54 and psychosis is a risk factor for suicide completion.53 Therefore, psychotic patients should be carefully assessed for suicidal intent and plan. Patients with major depression and psychosis should be treated with antidepressants and antipsychotics. The specific antidepressant choice is beyond the scope of this chapter. Antidepressants with anticholinergic load or cardiotoxicity should be avoided in elderly patients. After the resolution of psychotic symptoms, the patient may be tapered off the antipsychotic, but should remain on the antidepressant for continuation and maintenance treatment. If the patient’s psychosis reappears on removal of the antipsychotic, it may be necessary to continue the patient on an antipsychotic and attempt to reduce or remove this at a later date. The atypical antipsychotic, olanzapine, has been approved as a stand-alone agent for acute mania but has not been studied in bipolar patients over age 65 for this indication.55 Electroconvulsive therapy (ECT) is a very effective treatment alternative in elderly patients with affective disorders and psychosis. Although ECT suffers from stigma in the medical and lay communities, it is a safe alternative treatment for affective disorder with psychosis that offers the advantage of a more rapid rate of response than pharmacotherapy. Psychiatric evaluation will assist the patient and the clinician in determining the feasibility of ECT for a particular patient.56
Delusional Disorder
Specific Clinical Patterns with Aging
Delusional disorder appears to be a distinct diagnostic entity from schizophrenia, schizoaffective disorder, bipolar disease, and dementia with psychosis. This disorder is characterized by nonbizarre delusions of at least 1-month duration. A nonbizarre delusion is a delusion that could happen in real life, such as being followed or loved from a distance. There are no controlled trials of
As patients age, the quantity and severity of medical comorbidities and medication use increase and adherence to treatment regimens may decrease. These complexities are compounded by the pharmacokinetic and pharmacodynamic changes that occur with age and the potential for drug–drug interactions.57,58 Brain changes that occur with aging may contribute to the development
Comparison of AD with Psychosis and Late-Life Schizophrenia
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or course of the disease associated with psychosis. Additionally, the aging brain may be more susceptible to additional environmental or biologic stressors. The combination of one or several of these factors may contribute to specific clinical patterns of psychosis seen with aging.
S.C. Samuels and D.B. Marin
patient.52 Atypical antipsychotics appear to be preferential to conventional antipsychotic agents but are not free from potential adverse effects. Medication treatment in combination with psychological education, environmental manipulation, and behavioral modification appear to be the standard of care in treating elderly patients with psychosis.
Pathogenesis The pathogenesis of psychosis remains unclear. Theories abound, and there may be several final common pathways leading to psychosis. For example, neurochemical, in vivo imaging, and neuropathologic studies support the relationship between basal ganglia abnormalities and psychosis. Studies attempting to explain the pathophysiology of psychosis are limited by lack of uniformity in patient selection, clinical and neuropathologic diagnoses, psychotic rating methodology, medication and substance use, and medical comorbidity.
Approach to Differential Diagnosis After the history and examination reveal the presence of hallucinations or delusions, the evaluation should focus on whether medical conditions, their treatments, or other substances (e.g., medications, toxins, over-the-counter preparations, herbal compounds) are contributing factors. The psychosis may also result from substance intoxication or withdrawal. The next step is to determine whether the active phase symptoms of schizophrenia are present, the duration of symptoms, and their relationship to mood symptoms. Figure 80.1 is a decision tree for the differential diagnosis of psychotic disorders based on the DSM-IV.59
Treatment Approaches Treatment for psychosis in late life involves some core principles. The newly diagnosed psychosis in a patient should be viewed as a potential delirium until proven otherwise. General medical conditions and offending substances should be sought as probable contributors. Management should focus on problem behaviors and functional status rather than on the severity or duration of the psychotic symptom per se. Goals of treatment should be realistically defined and reviewed with the patient and caregivers. Adequate time should be given to test whether an intervention is realizing the therapeutic goals set. In general, the older patient with psychosis requires lower doses of antipsychotic medication compared with the younger patient, with some authors recommending a dosage 15% to 25% of that of a young schizophrenic
Pharmacologic Agents Traditional Antipsychotics: Do They Still Have a Role? Haloperidol is the most commonly prescribed antipsychotic agent, and thioridazine is commonly prescribed for agitation because of its sedating effects. These “traditional” agents may no longer be the ideal choices for the management of psychosis in later life. Cardiac conduction irregularities such as prolongation of QTC and polymorphic ventricular tachycardia (torsades de pointes) have been associated with intravenous haloperidol60 and oral thioridazine.61,62 A recent “Dear Doctor” letter issued by the FDA and labeling changes in the product information warn of thioridazine’s adverse cardiac conduction profile. These is a black box warning label about the thioridazine’s dose-dependent risk of QTC prolongation and the recommendation that EKGs and serum potassium levels be obtained at baseline and periodically monitored.63 The traditional antipsychotic agents have variable degrees of dopaminergic, alpha-adrenergic, anticholinergic, and histamine effects. The dopaminergic effects (primarily D2 blockade) are presumed to result in the therapeutic effects and the extrapyramidal side effects such as tremor, bradykinesia, akathisia, rigidity, and dystonic reactions. The higher potency agents (e.g., haloperidal, fluphenazine) have relatively higher ratios of dopaminergic blockade to adrenergic, anticholinergic, and histaminic effects. The lower-potency agents have higher ratios of anticholinergic, histaminic, and adrenergic effects relative to dopaminergic effects. Adrenergic blockade increases the risk of orthosatatic hypotension. The histaminic blockade results in sedation and weight gain. The peripheral and central anticholinergic effects may lead to dry mouth, blurry vision, urinary retention, constipation, and confusion. Aging-related brain changes and disease-related brain changes (e.g., from AD, PD, stroke) place elderly patients at increased risk of side effects from the traditional antipsychotic agents. In one metaanalysis of 16 double-blind controlled studies using conventional antipsychotics for dementia, 20% of patients had a significant side effect (i.e., sedation, orthostatic hypotension, or extrapyramidal effects).64 The lower-potency agents should be avoided in elderly
80. Late-Life Psychosis Figure 80.1. Differential diagnosis of psychotic disorders. (Adapted from DSM IV.)
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Is psychosis present?
Continue to assess clinical status
N
Y Is the cause a medical condition?
Psychotic disorder secondary to a general medical condition
Y
N Is the cause a medication or substance?
Substanceinduced psychotic disorder
Y
N Are the active phase symptoms of schizophrenia present?
Y
Are major depression or manic symptoms present concurrent with active phase symptoms of schizophrenia?
N
Y
N
Are mood symptoms brief relative to psychosis?
Y
Y
Is duration at least 6 months?
N Schizophreniform disorder
N Has psychosis lasted at least 2 weeks in the absence of prominent mood symptoms?
Are nonbizarre delusions present for at least 1 month?
Y
N
Is duration of mood symptoms brief relative to delusions?
Y
N Do delusions occur only during mood episodes?
Schizophrenia
Is functional impairment limited to delusions?
Y
N
Y
Schizoaffective disorder Mood disorder with psychotic features
Delusional disorder
N N
Psychotic disorder not otherwise specified
Y Mood disorder with psychotic features
Is the duration more than 1 day but less than 1 month?
Y N
Brief psychotic disorder
Psychotic disorder not otherwise specified
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patients who are at increased risk of side effects from these agents. A meta-analysis of antipsychotic agents used for inpatients with behavioral disturbance associated with dementia or other neurologic conditions demonstrated an effect size of 18%.65 The placebo group had a 41% response rate and the treatment group had a response rate of 59%. The relatively high placebo response rate may have underrepresented the true differences between groups. Other limitations of the study include heterogeneous groups, generalizability only to inpatients, and dated nature of the study as conventional agents were the only antipsychotics available. Despite their widespread use, there is not a substantial evidence base from which to recommend conventional antipsychotics for behavioral disturbance associated with dementia. One placebo-controlled crossover study compared fixed low-dose haloperidol (0.5– 0.75 mg/day) to standard dose haloperidol (2–3 mg/day) for 6 weeks in AD patients with psychosis.66 Patients receiving standard doses of haloperidol performed superior to low-dose haloperidol or placebo, although there was increased extrapyramidal risk in the standard-dose haloperidol group.
Tardive Dyskinesia Tardive dyskinesia (TD) is a significant problem in the elderly, leading to functional disability and social stigma. All antipsychotic agents, regardless of potency, carry the risk of tardive dyskinesia. Jeste et al. estimated the 12month incidence of TD in patients over age 55 years to be 25%, the 2-year incidence to be 34%, and the 3-year cumulative incidence to be 53%.67 Age, female gender, length of exposure to neuroleptic medication, and the presence of extrapyramidal signs appear to be significant risk factors for TD.66,68,69 There was great hope that the introduction of atypical agents would reduce or eliminate the risk of TD from antipsychotic agents. Few studies have compared typical to atypical agents in the risk of TD. Jeste et al. compared haloperidal to risperidone in schizophrenic patients (mean dose, 1 mg/day for both agents) and found that TD was significantly more likely to occur with haloperidol than risperidone.69 Case reports of TD associated with atypicals are in the literature.70 Comparing long-term effects of atypical agents to typical ones is not practical because the atypicals have not been available to patients as long. Short-term incidence studies of TD reveal only part of the story. The short-term studies may reveal the development of mild to moderate TD, but moderate to severe TD may develop over the longer term, and the atypical agents have not yet been used long enough. Hence, longer-term studies of the atypical agents are required to determine the rates of side effect development for the atypical agents in the elderly.
S.C. Samuels and D.B. Marin
Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is a rare but lifethreatening event that has been associated with both typical and atypical antipsychotic agents.71 Clinical evidence suggestive of the syndrome includes fever, rigidity, mental state changes, autonomic instability, elevated CPK, and previous administration of an antipsychotic agent. The prognosis from NMS is good, with most patients recovering within 2 weeks.72 Complications arise from prolonged fevers, electrolyte abnormalities, and hypoxia. Treatment for NMS is primarily supportive with conflicting evidence regarding the utility of dopaminergic agonists such as dantroline. The pathophysiology of NMS remains elusive.
Clozapine Clozapine is primarily indicated for patients with schizophrenia who have not responded to two previous antipsychotic trials. The agent has increased D2-receptor affinity and specificity for mesolimbic and mesocortical circuits. Agranulocytosis, a rare but fatal side effect from clozapine, is found more commonly in the older than younger patients.73 The risk of agranulocytosis requires a weekly evaluation of white blood cell and neutrophil counts. The more common side effects from clozapine include sedation, hypersalivation, hypotension, constipation, sweating, nausea/vomiting, urinary incontinence, fever, tachycardia, and weight gain.74 Discontinuation rate from side effects in elderly patients has approached 25% in some series.74,75 The emergence of side effects and discontinuation rate from the medication appear related to the rate of dose titration. Starting doses of 6.25 mg clozapine are recommended for elderly patients with slow titration rates (e.g., increase by 6.25 mg q 3–7 days). The doses needed for psychosis associated with dementia appear to be lower than that required for psychotic mood disorders, which are lower than the doses required for primary psychotic disorders.76 The monitoring requirements for clozapine prevent its use as a first-line agent.
Risperidone Risperdone is a 5-HTA receptor antagonist in addition to D2 blocker. It has low histaminic, alpha-1-, and alpha-2adrenergic effects. This altered mechanism of action may explain its wider therapeutic index compared with conventional antipsychotic agents. Although there are many case reports, open trials, and chart reviews on the effects of risperidone in the elderly,77 there are only a few controlled double-blind studies with risperidone for agitation and psychosis in the elderly persons with dementia. In one 12-week study of 625 patients with dementia (73% Alzheimer, 15% vascular, and 12% mixed), risperidone
80. Late-Life Psychosis
at 0.5, 1.0, and 2 mg each day was compared with placebo.78 The dose of 1 mg per day was optimal for the treatment of psychosis and aggression in patients with dementia and behavioral disturbance. The most common side effects from risperidone included extrapyramidal side effects (EPS), peripheral edema, and somnolence. Hypotension has also been observed in the elderly. Although there was a dose response for therapeutic efficacy with risperidone (2 mg/day > 1 mg/day > 0.5 mg/day), the higher dose (2 mg/day) was associated with elevated dropout rates (42% versus 27% for placebo) from side effects such as EPS and falls. In a pooled analysis of phase 3 data using risperidone in approximately 1000 demented elderly patients, EPS occurred in 9% of placebo-treated patients, 14% of risperidone-treated patients, and 24% of haloperidoltreated patients.79 The same group found risperidone to be effective (and superior to haloperidol) in a 13-week trial of 344 patients with behavioral disturbance associated with dementia. The dosage of 1 mg/day was optimal in reducing the severity and frequency of aggression.80 Taken together, the evidence for using risperidone for behavioral changes associated with dementia suggests an initial dosage of 0.25 to 0.5 mg per day titrated to 1 mg per day. The half-life of 20 h allows for once daily dosing. Risperidone is available in tablets, oral solution, and orally disintegrating tablets, which may facilitate administration to select elderly persons with dementia.
Olanzapine Olanzapine is an antagonist of dopamine and serotonin and has affinity for histaminic, alpha-1-adrenergic, and M-1 muscarinic receptors.81 The incidence of parkinsonian side effects is less than 10%. Olanzapine is efficacious in treating both positive symptoms (hallucinations and delusions) and negative symptoms (amotivation, withdrawal, apathy) of schizophrenia. There are limited controlled data in elderly patients with delirium, affective disorder with psychosis, or psychosis associated with Parkinson’s disease. The most common side effects associated with olanzapine are somnolence, dizziness, weight gain, and agitation. Other common side effects are constipation, rhinitis, dry mouth, and dyspepsia. Approximately 10% of patients treated with olanzapine have increases in their ALT and GGT that are dose related and reverse after drug discontinuation. Dysarthria and decreased ADLs have been reported in a case series of four elderly patients who received 5 to 10 mg olanzapine. Their conditions improved after olanzapine was stopped.82 Dosing adjustments are not required for renal impairment or based solely on age. It appears that the combination of factors that decrease clearance of the drug, such as age, cigarette smoking, and gender, are necessary before a dosing reduction. Weight gain is a
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significant problem associated with the use of olanzapine. Patients with a low body mass index are more likely to gain weight than those with high pretreatment body mass index.83 One case series reported a mean gain of 10 kg in 7 months.84 Increased blood sugar levels and triglyceride levels have also been associated with olanzapine. Olanzapine is 93% protein bound, primarily to alpha-lglycoprotein and albumin. Time to peak concentration is 6 hours and the elimination half-life is 52 h in those over age 65 years. Careful monitoring is recommended in conjunction with drugs that prolong the QT interval. There have been no cases of agranulocytosis with olanzapine, although long-term use of this agent is limited. Olanzapine has the potential to interact with other medications. For example, carbamezepine, rifampin, and omeprazole increase the clearance of olanzapine, necessitating dosage adjustments. Ciprofloxacin inhibits the metabolism of olanzapine, increasing the risk of toxicity when the two drugs are coadministered. When olanzapine is added to haloperidol (perhaps in the context of a planned substitution of agents), there appears to be an increased risk of parkinsonism,85 possibly due to inhibition of cytochrome P-450-2D6 or increased D2 blockade. Clozapine and olanzapine have not been directly compared in controlled clinical trials in the elderly. One recent study compared olanzapine (5, 10 or 15 mg) to placebo for agitation in AD.86 Olanzapine was superior in measures of delusions, hallucinations and agitation as measured by the neuropsychiatric inventory (NPI). There was no significant difference in vital signs between the groups.
Quetiapine Quetiapine, an atypical antipsychotic that is structurally similar to clozapine and olanzapine, has demonstrated efficacy for the positive and negative symptoms of schizophrenia. The agent has high affinity for serotenergic (5HT-2) and moderate affinity for dopaminergic (D2) receptors, purportedly related to its relatively low potential for parkinsonism. Clinical trials have reported no difference in EPS severity between patients treated with quetiapine or placebo. The agent also has affinity for alpha-1-adrenergic and alpha-2-adrenergic and H1 histaminic receptors but not muscarinic receptors. The most common side effects observed with quetiapine are dizziness, somnolence, constipation, postural hypotension, dry mouth, dyspepsia, and headache. Additional side effects include agitation, insomnia, tachycardia, and peripheral edema. The elimination half-life of quetiapine is 6 h, necessitating dosing two to three times per day. The peak concentration occurs 1.5 h after administration, and food increases absorption. The drug is 83% protein bound and hepatically metabolized with several active metabolites. Antipsychotic efficacy has been demonstrated in a dose
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Table 80.4. Comparison of antipsychotic agents used in the elderly. D2 receptor antagonism
5HT2a receptor antagonism
Anticholinergic effects
Clozapine (dibenzodiazepine)
Low
High
Very high
Risperidone (benzisoxazole)
High
High
Olanzapine (thienbenzodiazepine)
High
Quetiapine dibenzothiazepine Haloperidol
Drug name (chemical class)
Sedation
Parkinsonism
High
Very high
Rare
None
Low
Moderate
Low
Low
None
High
Low
Moderate
Moderate
Very low
None
Mode rate
High
Very low
Moderate
Moderate
Rare
Increases
High
None
Low
Low
Moderate
High
Decreases
range of 150 to 750 mg per day, and clinical trials for schizophrenia have shown effectiveness in dosages of 300 to 400 mg with a maximum dosage of 750 mg per day. Renal impairment does not necessitate dosage adjustment. In contrast, patients with hepatic impairment require a decrease in dosage. Transient serum transaminasemia may require discontinuation of the agent. The levels normalize after medication discontinuation, and there are no reports of irreversible hepatic damage associated with quetiapine. Patients over age 65 have diminished clearance of quetiapine, and a reduction in dosage may be necessary. Patients who have predisposition to hypotension should have a slower titration schedule to a lower target dose. Leukopenia but not agranulocytosis has been reported with quetiapine. Weight gain of greater than 7% above baseline has occurred in one-quarter of patients.87 A possible association between quetiapine and cataract formation necessitates ophthalmologic examination at initiation of therapy, shortly therafter, and at 6 months. Potential drug–drug interactions with erythromycin, fluconazole, phenytoin, and ketoconazole (increased quetiapine levels by P-450 3A4 inhibition) justify a reduction in quetiapine dosing. Close monitoring of international normalized ratio (INR) is required in patients taking warfarin with quetiapine. There are no published clinical trials specific to elderly patients comparing quetiapine to placebo. The response to quetiapine in published clinical trials has been variable; up to one-third of patients have dropped out from studies because of lack of efficacy, and sustained efficacy has been called into question.88–90 Case reports support the use of quetiapine for psychosis associated with Parkinson’s disease
Orthostasis
Effect of food on absorption
without worsening motor symptoms,43 perhaps suggesting a therapeutic niche. For agent comparisons, see Table 80.4.
Symptom Treatment in Addition to the Usual Management Several additional approaches complement pharmacotherapy in the treatment of psychosis in later life. All medical conditions have the potential to aggravate psychosis in a direct or indirect manner. Focus on stabilizing and maintaining patient overall health with preventive screenings, thorough histories, and examinations should have a positive effect on reducing the severity and duration of psychosis in late life. Treatments for medical problems pose another possible contributing factor. For example, a flare-up of a chronic condition or a new acute medical condition may lead to changes in the medication profile of a patient. The medications list should be frequently reviewed and the clinician should ask, “Are any of these medications nonessential?” An affirmation will lead to a medication adjustment that may substantially reduce the psychosis or even prevent its initiation. Pragmatic nonpharmacologic approaches for psychosis may include cognitive behavioral approaches to minimize the effect of the psychosis on the patient’s interpersonal relationships. For example, a patient may be “coached” to not spontaneously offer the content of a delusional system to others or use the technique of “thought stopping” to temporarily eliminate an internal psychotic
80. Late-Life Psychosis
Hepatic metabolism
1195
Protein binding
T1–2 (h)
Dosing
Dose/day (mg)
Extensive
97%
8–12
Twice daily
50–900
High
500 mg $22 brand $14 generic
Agranulocytosis; decreased dose in elderly
Extensive P-450
88%
20–30
Once or twice daily
0.25–6
Low
2 mg $3 brand
Decreased dose in elderly; prolactin increase
Weak P-450
93%
31
Once daily
5–20
Significant
10 mg $8.50 brand
Decreased dose in elderly
Extensive P-450
83%
7
Twice daily
100– 800
Moderate
600 mg $13 brand
Decreased dose in elderly
Extensive P-450
90%
21
Once or twice daily
0.5–8
Low
3 mg 18 cents (generic)
Decreased dose in elderly; prolactin increase
stimuli. Other general health maintenance measures such as optimal nutrition and exercise regimens may also have benefit, although the evidence base is very limited. Education about late-life psychosis may improve patient adherence to prescribed treatment regimens and offer needed support to overwhelmed caregivers who are at increased risk of excess morbidity and mortality.
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psychosis following traumatic brain injury. Int Clin Psychopharmacol. 1998;13(6):273–275. Meyendorf R. Psychopatho-ophthalmology, gnostic disorders, and psychosis in cardiac surgery. Visual disturbances after open heart surgery. Arch Psychiatr Nervenkr. 1982; 232(2):119–135. Snow RE, Arnold SE. Psychosis in neurodegenerative disease. Semin Clin Neuropsychiatry. 1996;1(4):282–293. Stern Y, Albert M, Brandt J, et al. Utility of extrapyramidal signs and psychosis as predictors of cognitive and functional decline, nursing home admission and death in Alzheimer’s disease: prospective analysis from the predictors study. Neurology. 1994;44:2300–2307. Wragg RE, Jeste DV. Neuroleptics and alternative treatments. Management of behavioral symptoms and psychosis in Alzheimer’s disease and related conditions. Psychiatr Clin Am. 1988;11(1):195–213. Bassiony MM, Steinberg MS, Warren A, Rosenblatt A, Baker AS, Lyketsos CG. Delusions and hallucinations in Alzheimer’s disease: prevalence and clinical correlates. Int J Geriatr Psychiatry. 2000;15(2):99–107. Cummings JL. Vascular subcortical dementias: clinical aspects. Dementia. 1994;5(3–4):177–180. Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry. 2000;5(2):132–148. Parkinson’s study group. Low dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med. 1999;340:757–763. Cummings JL. Managing psychosis in patients with Parkinson’s disease. N Engl J Med. 1999;340(10):801–803. Friedman JH, Factor SA. Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Movement Disord. 2000;15(2):201–211. Parsa MA, Bastani B. Quetiepine (Seroquel) in the treatment of psychosis in the treatment of Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 1998;10:216–219. McKeith IG, Perry RH, Fairbairn AF, Jabeen S, Perry EK. Operational criteria for senile dementia of Lewy body type (SDLT). Psychol Med. 1992;22(4):911–922. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996; 47(5):1113–1124. Serby M, Samuels SC. Diagnostic criteria for dementia with Lewy bodies reconsidered. Am J Geriatr Psychiatry. 2001;9: 212–216. Serby M, Samuels SC. Visual hallucinations and dementia with Lewy bodies. Arch Neurol. 2000;57(12):1792. Brust JC, Behrens MM. “Release hallucinations” as the major symptom of posterior cerebral artery occlusion: a report of 2 cases. Ann Neurol. 1977;2(5):432–436. Levine DN, Finklestein S. Delayed psychosis after right temporoparietal stroke or trauma: relation to epilepsy. Neurology. 1982;32(3):267–273. Peroutka SJ, Sohmer BH, Kumar AJ, Folstein M, Robinson RG. Hallucinations and delusions following a right temporoparietooccipital infarction. Johns Hopkins Med J. 1982; 151(4):181–185.
80. Late-Life Psychosis 51. Tonkonogy JM, Geller JL. Late-onset paranoid psychosis as a distinct clinicopathologic entity: magnetic resonance imaging data in elderly patients with paranoid psychosis of late onset and schizophrenia of early onset. Neuropsychiatry Neuropsychol Behav Neurol. 1999;12(4):230–235. 52. Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria for a distinct syndrome. Am J Geriatr Psychiatry. 2000;8(1):29–34. 53. Finkel SI, Rosman M. Six elderly suicides in a 1-year period in a rural midwestern community. Int Psychogeriatr. 1995; 7(2):221–230. 54. De Leo D, Conforti D, Carollo G. A century of suicide in Italy: a comparison between the old and the young. Suicide Life Threat Behav. 1997;27(3):239–249. 55. Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry. 1999;156(5):702–709. 56. Klapheke MM. Electroconvulsive therapy consultation: an update. Convuls Ther. 1997;13(4):227–241. 57. Zubenko GS, Sunderland T. Geriatric psychopharmacology: why does age matter? Harv Rev Psychiatry. 2000;7(6): 311–333. 58. Catterson ML, Preskorn SH, Martin RL. Pharmocodynamic and pharmacokinetic considerations in geriatric psychopharmacology. Psychiatr Clin N Am. 1997;20:205– 218. 59. Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. Washington, DC: American Psychiatric Association; 1994:694–695. 60. Hunt N, Stern TA. The association between intravenous haloperidol and torsades de pointes. Three cases and a literature review. Psychosomatics. 1995;36(6):541–549. 61. Reilly JG. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients [see comments]. Lancet. 2000;355(9209):1048–1052. 62. Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH. Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans. Clin Pharmacol Ther. 1996;60(5):543–553. 63. Thioridazine package insert. Novartis, East Hanover, NJ, June 2000. 64. Lanctot KL, Best TS, Mittmann N, et al. Efficacy and safety of neuroleptics in behavioral disorders associated with dementia. J Clin Psychiatry. 1998;59(10):550–561. 65. Schneider LS, Pollock VE, Lyness SA. A meta-analysis of controlled trials of neuroleptic medication in dementia. J Am Geriatr Soc. 1990;38:553–563. 66. Devanand DP, Marder K, Michaels KS, et al. A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer’s disease. Am J Psychiatry. 1998;155(11):1512–1520. 67. Jeste DV, Lacro JP, Palmer B, et al. Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients. Am J Psychiatry. 1999;156: 309–311. 68. Saltz BL, Woerner MG, Kane JM, et al. Prospective study of tardive dyskinesia incidence in the elderly. JAMA. 1991; 266:2402–2406. 69. Jeste DV, Lacro JP, Bailey A, et al. Lower incidence of tardive dyskinesia with risperidone compared to halo-
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peridal in older patients. J Am Geriatr Soc. 1999;47:716– 719. Ghelmer D, Belmaker RH. Tardive dyskinesia with quetiepine [letter]. Am J Psychiatry. 1999;156:796–797. Burkhard PR, Vingerhoets FJG. Olanzapine-induced neuroleptic malignant syndrome. Arch Gen Psychiatry. 1999;56:101–102. Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998;49(9): 1163–1172. Lacro JP, Eastham JH, Jeste DV, et al. Newer antipsychotics and antidepressants for elderly people. Cur Opin Psychiatry. 1996;9:290–293. Package insert for clozaril. Oberholzer AF, Hendriksen C, Monsch AU, et al. Safety and effectiveness of low dose clozapine in psychogeriatric patients: a preliminary study. Int Psychogeriatrics. 1992;4: 187–195. Chengappa KNR, Baker RW, Kreinbrook SB, et al. Clozapine use in female geriatric patients with psychoses. J Geriatr Psychiatry Neurol. 1995;8:12–15. Maixner SM, Mellow AM, Tandon R. The efficacy, safety and tolerability of antipsychotics in the elderly. J Clin Psychiatry. 1999;60(suppl 8):29–41. De Deyn PP, Katz IR. Control of aggression and agitation in patients with dementia: efficacy and safety of risperidone. Int J Geriatr Psychiatry. 2000;15(suppl 1):S14–S22. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbance associated with dementia: a randomized, double-blind trial. J Clin Psychiatry. 1999;60:107–115. De Deyn PP, De Smedt G, Brecher M. Efficacy and safety of risperidone in elderly patients with dementia: pooled results from Phase III controlled trials. Presented at the 11th Congress of the European College of Neuropsychopharmacology, Oct 31–Nov 4, 1998, Paris, France. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology. 1999;53:946– 955. Beasley CM Jr, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperizizdol: acute phase results of North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14:111–123. Gaile S, Noviasky JA. Speech disturbance and marked decrease in function seen in several older patients on olanzapine [letter]. J Am Geriatr Soc. 1998;46:1330– 1331. Tollefson GD, Beasley CM Jr, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry. 1997; 154:457–465. Gupta S, Droney T, Al-Samarrai S, et al. Olanzapine: weight gain and therapeutic efficacy [letter]. J Clin Psychopharmacol. 1999;19:273–275. Gomberg RF. Interaction between olanzapine and haloperidol [letter]. J Clin Psychopharmacol. 1999;19:272– 273.
1198 87. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry. 2000;57(10):968–976. 88. Borison RL, Arvanitis LA, Miller BG, et al. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo controlled trial in patients with schizophrenia. J Clin Psychopharmacol. 1996;16:158–169.
S.C. Samuels and D.B. Marin 89. Fulton B, Goa KL. ICI-204,636: an initial appraisal of its pharmacological properties and clinical potential in the treatment of schizophrenia. CNS Drugs. 1995;4:68– 78. 90. Wetzel H, Szegedi A, Hain C, et al. Seroquel (ICI 204,636), a putative “atypical” antipsychotic, in schizophrenia with positive symptomotology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters. Psychopharmacology. 1995;119:231–238.
Part VII Ethics and Health Policy Issues for Older Adults
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81 Mechanisms of Paying for Health Care* Bruce C. Vladeck
Although they account for less than 13% of the population of the United States, persons 65 and older incur almost 40% of this nation’s total health expenditures, because the burden of illness increases as people age and, on average, older Americans have better access to needed health services than any other age group. The overall levels of health care spending in the United States are so high, and the U.S. population so large, that this also means more money is spent on health care of older people in the United States than is spent on the health care of the entire population of any other nation in the world.1 Yet the $400 billion we are now spending annually on health services for older Americans still falls far short of providing older people with all the services they need and has clearly not produced a system of care that is entirely satisfactory either to patients or to physicians. Older Americans are the only class of citizens of this country with an entitlement to universal health insurance, through Medicare. For all its virtues and undeniable successes, however, Medicare has some significant shortcomings, both as a health insurance mechanism and as a major source of financing for the health care delivery system. Thus, any examination of payment for health services for the elderly in America must address what Medicare does and how it does it, what it has accomplished, what it does not do, and the mechanisms that fill in some, but certainly not all, of the gaps. This chapter follows that sequence.
implications for health insurance coverage and often for health service arrangements. The significance of age 65 arises, in turn, from Medicare’s roots in the Social Security system, from which it arose and to which it remains organically connected. The identification of 65 as “normal” retirement age arose, in turn, from the historical accident of its use in Germany’s social insurance scheme implemented in the late nineteenth century, the progenitor of other national social insurance programs. Medicare Hospital Insurance, generally known as Part A, parallels Old Age and Survivors Insurance (what is generally called Social Security) in that it is a compulsory, universal social insurance program, financed by payroll taxes on all wage and salary earners (and a parallel tax on the self-employed), and paying benefits to anyone with a work history or, under differing circumstances depending on the particular program, their dependents or survivors (in the case of Medicare, that includes spouses or widows over age 65 and disabled minor children). Medicare also contains Part B, or Supplemental Medical Insurance, which legally is a purely voluntary insurance program, one-quarter of which is financed by monthly premiums paid by beneficiaries, the balance by general federal revenues. Medicare’s connection to Social Security is also reflected in its coverage of roughly 5 million nonelderly disabled persons, who qualify because they receive Social Security Disability Income (SSDI) benefits and have passed the 2-year waiting period between SSDI eligibility and Medicare coverage.
Medicare: Background Considerations A logical place to begin a discussion of Medicare in a textbook on geriatrics is to acknowledge that an individual’s 65th birthday generally tends to be without any particular clinical significance, although it has major
* Prepared with the assistance of Maureen Furletti, MHS
What Medicare Covers—and Does Not Cover As is widely recognized, Medicare provides health insurance for those services covered in a typical private health insurance package at the time Medicare was enacted in 1965. Due to fiscal constraint, those benefits have not 1201
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B.C. Vladeck Figure 81.1. Medicare benefits. (Source: HCFA. Medicare and You 2000, beneficiary handbook available on www.medicare.gov.)
been significantly improved since, although understanding of the medical needs of the elderly, patterns of medical care, the organization of the health system, and private insurance have all changed dramatically in that same period. Thus, although Medicare provides reasonably extensive coverage of acute inpatient hospitalization, for example, it provides essentially no coverage at all for most dental services, correction of refractive error, or hearing aids (Fig. 81.1). The fact that Medicare does not, with a few exceptions, cover outpatient prescription drugs is a problem of such magnitude in itself that it is discussed separately.
Because of these and other limitations on Medicare coverage, because there are such substantial deductibles and copayments, and because—like most private health insurance policies of the 1960s but hardly any today— there is no cap or limit on the total out-of-pocket expenses of beneficiaries, Medicare currently covers, on average, barely half the total medical care costs of its beneficiaries. Thus, essentially every Medicare beneficiary who can seeks some additional or supplemental form of insurance (Fig. 81.2). Medicare beneficiaries can obtain supplemental coverage in one of four ways. The most fortunate have sup-
81. Mechanisms of Paying for Health Care
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Figure 81.2. Type of supplemental health insurance held by Medicare beneficiaries, 1998. (Source: HCFA. Medicare 2000: 35 Years of Improving Americans’ Health and Security, July 2000.)
plemental insurance provided as a retirement benefit by a former employer; in 1997, about a third of beneficiaries had such coverage, but that proportion is dwindling rapidly, as employers seek to cut back on retiree health benefits. Another 27% purchases individual supplemental or “Medigap” policies, the provisions of which are summarized in Figure 81.3. Although the characteristics of the Medigap market differ dramatically from one state to another, premiums for Medigap plans have been rising sharply in most of the nation in the past decade. About 15% of Medicare beneficiaries have sufficiently low incomes to qualify for either full or partial coverage under Medicaid, the state-administered, federal–state health insurance program for the poor. About the same proportion of beneficiaries is enrolled in Medicare managed care plans, which are permitted considerable freedom in establishing their own premiums, copayments, and deductibles, but which universally have lower out-of-pocket expenses than “traditional” fee-for-service Medicare. Approximately 12% of beneficiaries, or some 4.5 million individuals, are left with Medicare coverage only. Those “Medicare-only” beneficiaries are highly concentrated in the income range just above Medicaid eligibility and tend to have the highest out-of-pocket costs even though their incomes are relatively limited. In general, the costs of supplemental insurance, in addition to the costs of all those services that are covered neither by Medicare nor by supplemental policies, leaves a significant burden of out-of-pocket expense. The median elderly household spends slightly more than 20% of its income on out-of-pocket health expenses, and even
the most affluent beneficiaries, those in the upper 4% of the income distribution, spend roughly the same proportion of their income on out-of-pocket health costs as the median nonelderly family (Fig. 81.4).
Effects of Medicare The dramatic improvements in life expectancy, health status, and quality of life among elderly Americans in the past three decades are the result of multiple, interactive factors. Improvements in medical knowledge and technology, in the training and expertise of physicians and other health professionals, and in incomes, education, and nutrition among both the elderly and nonelderly have all played a part. But Medicare has played an independent role as well. Before the enactment of Medicare, persons over the age of 65 actually used fewer hospital and physician services than younger people, despite their greater burden of illness; now, of course, they use substantially more. People 65 and over are now much more likely to have a usual source of medical care—and much less likely to have to rely on clinics or emergency rooms— than other age groups in the population.2 Also, many medical advances that have helped transform the practice of medical care for the elderly, such as joint replacement, angioplasty, and the use of lasers in ophthalmic surgery, required significant financial investments by hospitals and physicians that were in turn financed, at least in part, by the availability of Medicare reimbursements for the services.
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Figure 81.3. Ten standardized Medigap plans. (Source: HCFA. Guide to Health Insurance for People with Medicare, available on www.medicare.gov.) *Plans F and J also have a high deductible option. **Basic benefits include payment of the Part
A coinsurance, coverage for 365 additional days during lifetime after Medicare benefits end, payment of Part B coinsurance (generally 20% of Medicare-approved expenses), and coverage of the first three pints of blood.
One of the more interesting attempts to identify the causes of improved health among America’s elderly was that of Manton and Vaupel, who noted that the United States had historically done quite poorly on international comparisons of life expectancy, determined from birth or early adulthood, but seemed to catch up as people aged. Using data from five countries with excellent longevity
statistics, they then found that, measured from age 80, the United States had the longest life expectancy. They attributed this finding to greater relative and absolute access to medical care for older Americans than their counterparts in other countries, a phenomenon they attributed in part to Medicare policies.3
Figure 81.4. Elderly health spending as a percentage of income, 1998. (Source: HCFA. Medicare 2000: 35 Years of Improving Americans’ Health and Security, July 2000.)
81. Mechanisms of Paying for Health Care
Medicare and Providers Medicare is not only a critical force in the life of its beneficiaries, providing them with their major vehicle of access to medical care, it is also a critical force in the professional life of most providers of medical care in the United States. It is the single largest source of revenue for most American hospitals, home care agencies, clinical laboratories, durable medical equipment suppliers, and practitioners in many medical specialties, including of course, internal medicine and geriatrics, and a significant source of revenue for other physicians, many nursing homes, and other health care organizations as well. Medicare’s facility and operational standards, data and reporting requirements, and quality-of-care measures are pervasive not only because of Medicare’s importance in itself but because other insurers and public agencies often rely on or defer to them. Because so much money is involved, and because it is believed that provider behavior and beneficiary access to care are affected not only by the absolute level of payment but also by what is paid for and how it is paid, the mechanisms of Medicare payment receive considerable attention from providers themselves, policy makers, academics, and policy analysts. Medicare’s principal payment systems are summarized in Figure 81.5. The mores of politics essentially require every provider group to insist that its level of payment is woefully inadequate. There is probably no platonically correct level in any event, but where data are available, they permit drawing the following conclusions. Since the Prospective Payment System was adopted in 1993, on average general hospitals have been paid more than their costs for treating Medicare patients, although private insurers frequently paid an even larger premium over costs;4 before the Balanced Budget Act of 1997, most skilled nursing facilities and home care agencies prospered under Medicare payment arrangements; many have lost money since, although their finances appeared to have stabilized by calendar year 2000;5 specialty psychiatric and rehabilitation facilities have also done reasonably well; and the provision of clinical laboratory and durable medical equipment services to Medicare has been an extremely profitable business. As for physicians, Medicare has traditionally paid less than private insurers, but the ratio of Medicare payments to average private payments rose rather dramatically during the latter half of the 1990s, more because private payers squeezed their payments than because of Medicare increases. The Physician Fee Schedule was implemented for Medicare in 1992, with the principal objective of shifting a substantial share of Medicare physician payments away from surgery and procedure-intensive specialty care toward more generalist,“cognitive” services. There has been some reallocation of physician spending as a result, but perhaps less than
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family practitioners, general internists, and geriatricians might have hoped, at least in part because of the inadequacies of the coding/categorization system for Medicare evaluation and management services and the political skills of procedure-oriented specialists.6 Roughly half of all the physician services for which Medicare pays fall into the fivefold classification of “Evaluation and Management,” yet that system fails to adequately capture or describe the full range of noninterventional physician services.7
Medicare Managed Care In the 1990s, when the growth of managed care arrangements dominated the private health insurance sector in the United States, much attention was paid to the relatively smaller role managed care plans continued to occupy in the Medicare program. In fact, health maintenance organizations (HMOs) had been included in Medicare since the program’s inception, as traditional prepaid group practices (the term HMO was not even invented until the early 1970s) such as KaiserPermanente and Group Health of Puget Sound. These programs were permitted to retain enrollees who had been members before retirement and were paid on a cost-reimbursement method, at a time when cost reimbursement was the dominant mode of payment for all Medicare providers. Beginning in 1985, Medicare began to pay HMOs on a full-risk basis; that is, a flat capitated monthly rate was established by formula for every county in the United States by a formula that, in principle, established the equivalent of 95% of per beneficiary costs in the conventional fee-for-service program. HMOs that were able to provide the basic Medicare benefit package at lower cost were given the option of returning the excess to the government (an option that was never exercised), establishing a stabilization fund, or providing additional benefits—the option that was most widely chosen. Beneficiaries retained the option of enrolling or disenrolling from HMOs at will, thus making it necessary for the plans to offer significant additional benefits to get beneficiaries to forsake free choice of providers and agree to having their access to care ‘‘managed.” Medicare enrollments in HMOs grew from roughly 1 million, at the time risk contracting was introduced, to more than 6 million by 1997, although that growth was characterized by peaks and valleys rather than a steady increment. Medicare managed care was highly concentrated in a few areas of the country, notably the West Coast, which has always had higher levels of managed care enrollments since the creation of Kaiser-Permanente during World War II, and south Florida, which has long been characterized by extremely high fee-for-service
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PART A
PART B
Figure 81.5. Medicare payment systems. (Sources: Medpac June 2000 Report to Congress; Ways and Means 1998; Green Book; Medicare Explained 1999; and conversations with HCFA staff.) 1 In 1998, Medicare payment to cost ratios for inpatient and outpatient hospital services was 102.6%. Private payers payment to cost ratio was 113.6% for hospital services in 1998.
(Source: Medpac Report to Congress, June 2000.) 2 Until their PPS implementation dates, rehabilitation and psychiatric hospitals are paid on a reasonable cost basis within TEFRA limits. 3 Until implementation of PPS in October 2000, home health agencies receive payment under a cost-based reimbursement system, referred to as the interim payment system.
81. Mechanisms of Paying for Health Care
costs. Extensive study of Medicare managed care plans during this period revealed that they did indeed use fewer days of inpatient hospitalization and more office visits than were typical in fee-for-service arrangements, and that they provided an overall quality of care comparable or in some cases superior to that prevailing in the feefor-service community in the same areas, but that they probably undersupplied services to the sickest and most chronically ill enrollees.8 Surveys of beneficiaries showed that the overwhelming proportion of Medicare managed care beneficiaries were highly satisfied with their plans— not a surprising finding when one remembers that dissatisfied beneficiaries were always free to disenroll at will—but the great majority of those not enrolled in HMOs did not want to be—hardly a surprising finding either.9 For a growing share of for-profit HMOs, Medicare managed care proved a profitable venture because, although payment was set at 95% of the average costs for fee-for-service enrollees, the HMOs almost invariably enrolled relatively healthier beneficiaries. Some of this risk selection resulted from carefully designed marketing strategies of the HMOs (so-called “cherry-picking”), but most of the phenomenon was attributable to the fact that beneficiaries with the greatest burden of chronic illness were more likely to have established relationships with particular physicians or hospitals who may not have participated in particular HMOs, while restrictions of freedom of provider choice were most acceptable to beneficiaries without established physician relationships, especially those who had recently relocated to retirement areas in Florida, Arizona, or California.10 The Balanced Budget Act of 1997 sought to achieve a substantial expansion of Medicare managed care enrollment by creating a new Medicare Part C for capitated plans (renamed “Medicare + Choice”), expanding the types of managed care plans that would be eligible to enroll beneficiaries and receive capitated payments, and establishing an annual open enrollment period with extensive concomitant beneficiary education. At the same time, however, the U.S. Congress fiddled with the payment formula for Medicare + Choice plans to eliminate some of the windfalls from risk selection, to reduce some of the geographic inequities that arose from discrepancies in fee-for-service costs across communities, and to provide incentives for plans to enter more rural communities. The net result was a significant constraint on increases in payment rates in most metropolitan areas that already had considerable Medicare managed care enrollment. Combined with difficult times for the HMO industry in its private business, rapidly rising pharmaceutical costs, and a continuing inability among the plans to effectively manage utilization, this led to a substantial contraction, rather than expansion, of Medicare managed care (Fig. 81.6).
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Medicare: Long-Term Financing Issues During the 1990s, the long-term financing of Medicare became a major political issue. There were several reasons: preoccupation of political leadership with federal budget deficits at a time when Medicare accounted for roughly 10% of the total budget and was the most rapidly growing component; growing recognition of the longer-term implications for Medicare and Social Security financing of the aging of the “baby boom” generation, reinforced by a well-organized and wellfinanced campaign to convince policy elites and the general public of the existence of a serious impending “entitlements crisis” that required an immediate scalingback of the national commitment to income support and health insurance programs; and the very rapid rate of increase in Medicare costs in the first 6 years of the 1990s. Most concretely, and most immediately, the Hospital Insurance Trust Fund appeared to be about to run out of money. In the spring of 1997, it was projected that the Fund would be insolvent by 2001 unless major policy changes were undertaken.11 The Balanced Budget Act of 1997 reduced future Medicare expenditures by more than $200 billion (although at the time it was enacted it was projected to save only half that much) and created a National Bipartisan Commission on the Future of Medicare to address the long-term financing problems and report back to the Congress. In the period immediately following enactment of the Balanced Budget Act, Medicare expenditures actually fell for the first prolonged period in the program’s history. These reductions caused considerable turmoil and financial stress for many nursing homes, teaching hospitals, and especially home health agencies.12 However, the savings achieved by the Balanced Budget Act and other administrative initiatives, and, more importantly, the enormous economic boom of the late 1990s to which the Balanced Budget Act is believed to have contributed, have combined to dramatically improve the long-term financial prospects of Medicare. By the spring of 2000, the Hospital Insurance Trust Fund was projected to remain solvent for another 25 years, and the financial well-being of the program continued to improve throughout the year.13 Thanks in small part to the very rapidity with which Medicare’s financial circumstances changed after the Balanced Budget Act was enacted, and in much larger part to serious ideological and philosophical divisions among its members, the National Bipartisan Commission was unable to reach any agreement and issued no report. The recommendations of its cochairmen, however, have subsequently become the basis for further discussions of Medicare “reform” in the early years of the twenty-first century. That “reform,” supported by many conservatives who favor a smaller role for government progress, would
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Figure 81.6. Medicare risk contracts, 1990–2000. (Source: Zarabozo C. “Is the sun setting over Medicare managed care?” presentation at Institute for Medicare Practice, Medicare Seminar, February 2000. Note: Number of contracts from December of that year, except in 2000, when June numbers are used. Medicare managed care enrollment, 1990–2000.) (Source:
Zarabozo C. “Is the sun setting over Medicare managed care?” presentation at Institute for Medicare Practice, Medicare Seminar, February 2000. Note: Enrollment numbers are for December of the preceding year, except in 1999, when January 1999 data are used.)
transform Medicare from a defined-benefit, governmentoperated insurance program to one in which the government annually made a defined contribution toward purchase of a private health plan, with the size of that contribution determined by a bidding process. If private plans offered prices lower than Medicare’s current costs, premiums for “traditional” Medicare would increase. Under such a system, the government’s contribution to Medicare coverage for any given beneficiary would be determined not by the costs of the services that beneficiary actually consumed, but by some fraction of the average price bid by private insurance plans. Beneficiaries would either have to opt to enroll in low-cost plans, which would likely have very restrictive provider networks or utilization limitations, or pay higher out-ofpocket premiums to maintain their current coverage. There are many practical and conceptual, as well as philosophical, objections to such a scheme, but in the current political environment its adoption remains a possibility.14
What Medicare Does Not Cover: Prescription Drugs When Medicare was enacted in 1965, outpatient prescription drugs played a much smaller role in medical therapeutics than they do today, and they were much less expensive. As a result, most private insurance plans offered limited, if any, coverage for pharmacy, and the failure to include a pharmacy benefit in Medicare was hardly noted. By now, however, the absence of prescription drug coverage in Medicare has become a real crisis. Total spending on prescription drugs for Medicare beneficiaries now averages roughly $1000 per year.15 Two-thirds of beneficiaries have at least some insurance coverage for prescription drugs through employersponsored or individual Medicare supplemental policies, through Medicaid, or through HMO enrollment, but few of those policies cover the full cost of pharmaceuticals,
81. Mechanisms of Paying for Health Care
Figure 81.7. Distribution of Medicare beneficiaries by drug coverage status and source of coverage, 1996. (Source: Davis M, Poisal J, Chulis G, Zarabozo C, Cooper B. Prescription drug coverage, utilization, and spending among Medicare beneficiaries. Health Affairs. 1999;18(1)231–243, with permission.)
and thus more than 40% of those expenditures come directly out of pocket. Perhaps more importantly, there is very strong evidence that, although beneficiaries who lack insurance coverage for prescription drugs have poorer health status than those with coverage, they obtain significantly fewer prescriptions—almost 25% fewer. Absence of coverage is thus a significant barrier to access to needed pharmaceuticals, especially among lowand moderate-income beneficiaries (Fig. 81.7). As of this writing, proposals to provide prescription drug coverage to Medicare beneficiaries are the subject of heated political discussion, but it is not clear what policies will emerge from that process.
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At any given time, about 4% of all Americans 65 and older reside in nursing homes, but Medicare pays less than 10% of the total costs of nursing home care. Some relatively affluent patients, or those with affluent families, pay for nursing home services entirely from private resources, but for the great majority of nursing home patients, Medicaid is the primary source of financing. Medicaid currently pays for just under half of all national nursing home expenses, but that figure is misleading, for two reasons. First, Medicaid, which by law is always a payor of last resort, pays nursing homes only the difference between the approved Medicaid rate for nursing home care and the beneficiary’s contribution, generally defined as the person’s entire income less $32.50 per month for a “personal needs” allowance. The beneficiary contribution, which generally consists of a monthly Social Security check, is considered “private” expenditure in the National Health Accounts. Second, many long-stay nursing home residents attain Medicaid eligibility only after having exhausted their private resources in the first part of their nursing home stay; nursing homes are thus free to charge particularly high prices to “private” patients, with the perverse effect that that accelerates their spending down to Medicaid eligibility. Since policy analysts first recognized, some 20 years ago, that Medicaid, which was originally thought of primarily as health insurance for low-income children and their mothers, was spending the lion’s share of its money on nursing home care for frail seniors, many of whom had become poor only as a result of their need for long-term care, there has been widespread recognition that something should be done to rationalize the financing of longterm care services, especially as the population continues to age and the number of people in their late seventies and
What Medicare Does Not Cover: Long-Term Care As significant as the problem of prescription drug coverage is for many Medicare beneficiaries, the single largest share of out-of-pocket expenditures is attributable not to drugs but to long-term care. Medicare does provide some coverage for skilled nursing facility services, and rather more expansive coverage for home health care, but both were clearly intended to apply only to limited, short-term, postacute episodes, and although a considerable loosening in the definitions of the home health benefit in the 1990s permitted its application to a growing share of real long-term cases, that loosening was largely ended by the Balanced Budget Act (Fig. 81.8).
Figure 81.8. Long-Term Care Financing, 1998. (Source: Graves TN, Kassner E, Mullen F, Coleman B. Long term care fact sheet. Washington, DC: AARP Public Policy Institute; 2000.)
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eighties living alone—the population most at risk for needing long-term care services—continued inexorably to increase. But, although there has been a considerable shift in patterns of formal long-term care services away from institutions and toward community-based care,neither the division of responsibility for financing those services nor the intellectual framework within which one could fully reconstitute those financing patterns has changed very much. Solving the problem of financing long-term care thus remains very much a long-term problem.
Medicare’s Safety Net Although Medicaid pays for the greatest share of nursing home costs for the elderly, its role in assisting other Medicare beneficiaries should not be overlooked. Of the 6 million people who are dually eligible for Medicare and Medicaid, perhaps a quarter are receiving formal longterm care services. For the rest, Medicaid is an essential supplemental insurer, covering not only the copayments and deductibles for Medicare, but also those services for which Medicare does not pay at all, including outpatient prescription drugs, dental, vision, and hearing services and medically necessary transportation. Because of the way most states maintain their Medicaid data, it is almost impossible to tell how spending on behalf of dually eligible beneficiaries is allocated between long-term care and acute services, but given the interrelationships among age, poverty, and ill health, it is reasonable to assume that the community-dwelling dual eligibles are relatively high users of acute care services—as are individuals in the long-term care system. The rules for achieving Medicaid eligibility are bewilderingly complex and vary considerably from one state to another. The relevant point is that, although almost all individuals legally entitled to Medicare have either enrolled or consciously chosen not to, many individuals, including many Medicare beneficiaries, who are legally entitled to Medicaid benefits are not enrolled. Reasons for failure to utilize Medicaid benefits include lack of awareness, the rigors of the enrollment process, and difficulties meeting documentation and other requirements associated with enrollment or because state eligibility officials, themselves confused, fail to enroll individuals who in fact are eligibile. Medicaid is thus a very effective safety net for those it catches, but many still fall through the holes.
Conclusions America’s elderly are the beneficiaries of enormous public expenditures for their health care, which has produced, on average, a level of access to modern, high-
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technology care unparalleled in the world. At the same time, elderly persons in the United States remain more at risk for crippling out-of-pocket medical expenses or the inability to obtain access to needed care for financial reasons than their counterparts in other industrial nations. The United States spends so much on health care for its elderly because its services are so expensive, not because its public programs are especially generous in design or philosophy. Within the next 30 years, the number of persons 65 and older in the United States, who are thereby eligible for Medicare, will double. Assuming that health care costs continue to grow more rapidly than general inflation, that means that the real costs of supporting the Medicare program, even as currently defined, may triple. During the same time, the costs of health services that Medicare does not cover, such as outpatient prescription drugs, can be expected to increase even more rapidly than other health care costs. One is reminded of the old joke concerning the review of a bad restaurant: there are only two problems—the food is lousy and the portions are too small. For Medicare, the benefit package is woefully inadequate, but maintaining only those benefits will be increasingly expensive in the years to come. On the other hand, all those people 65 and over are going to be here 30 years from now, regardless of how Medicare is constituted or whether it exists at all. One can assume, at least for purposes of discussion, that ours will continue to be a society that is generous and socially concerned enough to be unwilling to deny needed health services to elderly people who could benefit from them. Someone, in other words, is going to have to pay. The only real question is who. Policy debates about the long-term direction and configuration of Medicare touch on many putative subjects. and take many different forms, but the central underlying question is how responsibility for the costs of medical care for the elderly are to be shared. If one believes that the elderly are already bearing an excessive share of their medical costs (especially when compared to younger. more affluent groups in society), then one set of future directions for Medicare is implied. However, that does not appear to be a view that currently controls the commanding heights of the American political debate. Whatever the outcome, the future of Medicare is ultimately and essentially a political question, and the outcome will be politically determined.
References 1. Author’s calculations. 2. Medicare Payment Advisory Commission. Report to the Congress: Medicare Payment Policy. Washington, DC: U.S. Government Printing Office; 2000:Table 10-2.
81. Mechanisms of Paying for Health Care 3. Manton KG, Vaupel JW. Survival after the age of 80 in the United States, Sweden, France, England and Japan. N Engl J Med. 1995;333(18):1232–1235. 4. Medicare Payment Advisory Commission. Report to the Congress: Selected Medicare Issues. Washington, DC: U.S. Government Printing Office; 2000: Figure 5-3. 5. Medicare Payment Advisory Commission. Health Care Spending and the Medicare Program: A Data Book. Washington, DC: MedPAC; 1998:Charts 4–15, 4–20. 6. Physician Payment Review Commission. Annual Report to the Congress. Washington, DC: U.S. Government Printing Office; 2000:Chapter 13. 7. Iezzoni LI. The demand for documentation for Medicare payment. N Engl J Med. 1999;341(5):365–367. 8. Luft HS. Medicare and managed care. Annu Rev Public Health. 1998;19:459–475. 9. Medicare 2000: 35 Years of Improving Americans’ Health and Security. Washington, DC: Health Care Financing Administration; 2000: Figure 17.
1211 10. Physician Payment Review Commission. Annual Report to the Congress. Washington, DC: U.S. Government Printing Office; 1997: Chapter 3. 11. 1997 Annual Report of The Board of Trustees of the Federal Hospital Insurance Trust Fund. Washington, DC: U.S. Government Printing Office; 1997. 12. Vladeck BC. The storm before the calm before the storm: Medicare home care in the wake of the Balanced Budget Act. Care Manag J. 2000;2(4)232–237. 13. 2000 Annual Report of the Board of Trustees of the Federal Hospital Insurance Trust Fund (corrected). Washington, DC: U.S. Government Printing Office; 2000. 14. Vladeck BC. Sounding board: plenty of nothing—a report from the Medicare Commission. N Engl J Med. 1999;340: 1503–1506. 15. Calculated by author from data in: The Medicare Program: Medicare and Prescription drugs. Henry J. Kaiser Family Foundation; 2000.
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82 Justice and the Allocation of Health Care Resources Nancy S. Jecker
There is growing concern in the United States, and in many other developed nations, that health care expenditures are too high and are growing too rapidly. Between 1950 and 1990, U.S. health expenditures grew 3% per annum, faster than expenditures for other goods and services. Economists forecast that if health spending in the United States continues to outpace other areas of the economy at this rate, by 2030 health care will consume almost one-third of the gross national product.1 One of several factors responsible for increasing health care costs is the changing demographics of populations in most developed countries. Since 1900, the proportion of older people relative to younger people has increased, and demographers predict that this trend will continue well into the twenty-first century. An aging population significantly affects health care costs because elderly individuals, as a group, consume health care at higher levels than other age groups. In the United States, persons 65 and over account for approximately 12% of the population, but they use one-third of the nation’s total personal health care expenditures (exclusive of research costs).2 If present levels of disability remain stable, future spending increases will occur primarily in the areas of chronic, supportive care needed by frail and disabled elderly persons.3 Although it is sometimes assumed that the high cost of caring for the elderly is due to an “excessive” use of hightechnology services at the end of life, recent studies cast doubt on this assumption.4 As efforts to reduce health care expenditures are implemented, the impact on patients and physicians is becoming more apparent. Increasingly, physicians must attempt to balance the twin goals of providing the best possible care for patients while simultaneously limiting the use of costly tests and procedures.5,6 Rationing, often thought to be an inevitable feature of future reforms, is being discussed with growing frequency. This chapter addresses the general problem of justice in the allocation of scarce health care resources. It looks first at the question of current health care allocation and
asks, “According to what criteria are scarce health care resources currently distributed?” Next, it explores proposals for more justly distributing health care resources. The chapter closes by relating decisions about allocating health care to the more general goal of establishing a just society.
De Facto Rationing Health care rationing refers to the denial of beneficial health care under conditions of fiscal or resource scarcity. Although it is often assumed that rationing is a problem looming in the future, in fact, in the United States, health care is already rationed in many unplanned and informal ways.
Poor and Uninsured Populations First and foremost, rationing of care occurs for patients who are poor or uninsured. Thus, patients who lack access to mainstream providers often receive health care through an emergency department.7 There, physicians may be encouraged, for purely economic reasons, either to treat those who have an undesirable reimbursement status as outpatients or to transfer such patients to public hospitals. These policies and other factors place patients without health insurance at greater risk for suffering medical injury due to delayed diagnosis or treatment or otherwise substandard medical care.8 Such factors may also help to explain why the poor and poorly educated die at higher rates than those with higher incomes or better education.9,10 Unplanned rationing also takes place when long waits at emergency departments cause persons in need of urgent care to leave without receiving care.11–14 In a recent survey of 277 public and private hospitals, 38% reported that overcrowding sometimes required holding admitted patients in the emergency department for 24 h or longer until beds in appropriate care units 1213
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became available. Among responding hospitals, 40% acknowledge diverting ambulances to other hospitals for reasons of overcrowding.15
Geographic Variations in Utilization of Health Care Resources In addition to de facto rationing based on ability to pay for care, unplanned rationing also may occur on the basis of geographic location. Wennberg demonstrates substantial geographic variations in utilization of health care resources, primarily related to differences in the capacity of the local health care system and the practice style of local physicians.16 For example, capacity influences the intensity of terminal care for Medicare enrollees, with residents of areas with high per capita supplies of acute care beds more likely to die as inpatients in hospitals and more likely to be admitted to intensive care units during their last 6 months of life.17 Although it is commonly assumed that geographic variations occur as a result of physicians failing to conform their practice to standards of scientific medicine, this assumption is not borne out. Geographic variations are equally present in communities served primarily by academic medical centers. For example, populations living in Boston and New Haven, served by some of the nation’s most distinguished teaching hospitals, utilize strikingly different per capita amounts of hospital care, despite remarkable similarities in demographic features and other factors that predict the need for care.18 For several decades, the per capita amount of care provided to residents of Boston has been about 60% higher than the per capita amount provided to residents of New Haven. These differences are driven by Boston’s relatively greater per capita supplies of hospital beds. These findings reinforce the notion that capacity, not medical science, drives the rate of hospitalization. The phenomenon of geographical variation does not necessarily demonstrate that health care is rationed to patients who reside in geographic areas where medical resources and personnel are less abundant. This disparity occurs because “rationing” does not simply mean reduced access; instead, it implies reduced access to beneficial treatments. There is no evidence to suggest, however, that more intensive medical treatments always yield benefits for patients. As Wennberg noted, “There is no scientific evidence that more is always better. There are few studies of the outcomes of hospitalization versus less intensive ways of treating patients with the same disease profiles; and those that have been done show no advantage from more intensive care.”19 For example, outcomes in terms of life expectancy are no different for populations living in Boston and New Haven, despite Boston’s greater hospital capacity and despite the fact that Bostonians are more likely to die in the hospital.
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What can we conclude about the ethical implications of geographic variability? Certainly, geographic variation makes evident that the distribution of health care occurs in a morally arbitrary and unplanned fashion. The flow of resources often takes place in an unconscious rather than a deliberate and thoughtful manner. Not only do individual patients tend to be unaware of the influence of geographic location, but the influence of supply on utilization occurs without clinicians’ explicit knowledge of the relative level of available resources. For example, clinicians serving populations in hospital referral regions where the supply of acute care hospital resources is relatively low do not appear to be aware of constraints on their practice of medicine.20 In addition, geographic variation highlights the importance of creating a more explicit, publicly accountable approach to health care allocation because, to the extent that health care allocation occurs in an unplanned fashion, whatever rationing this entails will not be applied consistently. De facto rationing raises serious questions of fairness because it fails to treat patients who are similarly situated in a similar fashion. Therefore, whatever benefits and burdens medical services confer are distributed on the basis of a morally arbitrary fact—where persons happen to live. A more deliberate system can better approximate the ideal of fairness by attempting to specify morally relevant differences between persons and make these the basis for rationing. For example, the quality, length, or likelihood of medical benefit a patient is expected to receive represents more sound criteria for rationing than do morally arbitrary factors, such as whether a patient happens to live in Boston or New Haven. No one would suggest that Bostonians are morally more deserving of medical services by virtue of living in Boston.
Other Examples Other examples of unplanned rationing include slowing reimbursement and use of health care resources by means of bureaucracies that impede, inconvenience, and confuse providers and patients. The impact of bureaucracy is evident, for example, in statistics revealing that 59.7% of Medicaid or welfare denials result from problems with paperwork or documentation.21 Rationing also may be an unplanned outcome of the culture of modern medicine, which trains physicians to cure disease and prolong life while downplaying the significance of care-oriented, low-technology therapies aimed at providing comfort and improving the quality of patients’ lives.22 For example, evidence suggests that adequate palliative care is frequently unavailable for dying patients,23 infants24 and children,25,26 burn patients,27 cancer patients,28 postoperative patients, and elderly patients.29 To the extent that physicians lack the knowl-
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edge or skill to offer palliative care services, rationing occurs by default rather than by a deliberate decision for which any individuals are held accountable.30,31 Within palliative care, more costly, high-technology modalities of pain management are sometimes favored over low-technology modalities, such as oral medication, without differences in patient outcomes.32,33 Access to palliative care is also restricted for patients who are not terminally ill because needed services have traditionally been reserved for end-of-life care rather than made available to patients and families throughout the illness trajectory.34 To the extent that society at large devalues the lives of ethnic minorities, women, the elderly, or other groups, there is every reason to think that this will be reflected, perhaps unconsciously, in health care decisions. Thus, agebased rationing of health care may occur when patient age is discretely factored into decisions to admit patients to the hospital, provide intensive care, terminate therapy, or initiate vigorous treatment.35 Discrimination based on group membership can also occur as the result of inattention to the differential effects that policies have for different segments of society. For example, although age-based rationing appears gender neutral, it would, in fact, have a disproportionate effect on women because more women than men fill the ranks of older age groups.36 Likewise, although the jobbased insurance system is not explicitly gender based, it more negatively affects women as a group because women are more likely than men to work on a parttime, part-year, or temporary basis, or in nonunion or low-wage jobs—job categories that offer health care benefits less frequently.37 Women who work outside the paid labor force, whether caring for children or tending to disabled elderly relatives, are also disadvantaged under a workplace insurance system. Although many women receive workplace health insurance through spouses, this factor can lead to economic dependence and places women at risk of losing coverage through divorce or widowhood. Likewise, limited awareness of the effects of policies on racial groups may contribute to racial differences in health insurance coverage,38 infant mortality,39,40 life expectancy,41 access and outcome in organ transplantation,42–44 use of revascularization procedures after coronary angiography,45 survival following cardiac arrest,46–48 inadequate emergency department analgesia,49 and drug therapy for human immunodeficiency virus (HIV) disease.50 In summary, although rationing of health care is rarely put forward and defended in a public manner, rationing of health services nonetheless occurs. Unplanned and informal rationing often reflects morally arbitrary criteria, such as geographic location, or medically irrelevant factors, such as the ability to pay.
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Proposals for Explicit Health Care Rationing The problem with the de facto rationing described here is that it does not even aspire to meet ethical standards. Thus, implicit rationing is typically not thought through, not applied consistently, not accountable to the public, not decided democratically, and not insulated from arbitrary and unfair manipulation. In light of these concerns, most would prefer a planned and public system of allocating health care over the present approach. While critics cast doubt on the idea that explicit rationing constitutes proper public policy,51 most agree about the value of openly debating health care policies and reaching agreement about fundamental principles of justice in health care. In North America, Europe, and other developed countries, public opinion has been solicited regarding rationing of health care and the need to set limits in health coverage. These efforts enable public opinion to become visible and play a role in health policy deliberations.52,53
The Oregon Proposal Various proposals for explicit rationing of health care have been defended as ethically sound. Perhaps the most well known is Oregon’s plan to deny Medicaid reimbursement for certain categories of medical services.54 Oregon’s plan was the outgrowth of the 1989 Oregon Basic Health Services Act, a central goal of which was to extend Medicaid to all Oregonians falling below the federal poverty level. The means proposed to pay for this included restricting medical services to current Medicaid eligibles. The Oregon Health Services Commission was responsible for determining the relative priority of medical services. In the Commission’s initial plan, a computer generated a list of diseases rated by a formula taking into account the cost of treatment, length of benefit, and quality of well-being after treatment. How far down the list treatments were covered would depend on the availability of funds in each biennium. At some point along the list, a line would be drawn and diseases and injuries that fell below it would not be covered. After coming under intense criticism, the Commission formed an Alternative Methodology Subcommittee to develop an alternative approach to prioritizing services.55 The revised approach excluded cost as a significant factor in prioritizing services; instead, it considered the perceived benefit of various treatment categories to individuals and society, as well as their perceived necessity. The revised plan emphasized preventive care and treatable, life-threatening conditions that affect many, rather than conditions that are minor or are fatal and incurable. For example, organ transplants were moved from the bottom
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to near the middle of the priority list, and familiar ailments, such as pneumonia, were placed near the top.56 Oregon’s proposal explicitly incorporates rationing, most notably rationing based on the likelihood, quality, or length of medical benefit that a patient will receive from treatment, and rationing based on the imminence of a patient’s death. A number of ethical arguments have been adduced in support of each proposal. Rationing based on medical benefit is defended on utilitarian grounds, by arguing that services that generate the greatest amount of benefit merit the highest priority. According to this approach, payoff to patients, and to people generally, is the measure of justice in health care allocation. Medical benefit is also defended on nonutilitarian grounds. For example, it is argued that if people were to devise a just distribution scheme without knowing how such a scheme would affect them, or what their health care needs would be, they would prefer a distribution that assigned people the greatest entitlement to resources when they would have the greatest chance of actually benefiting.57 Various ethical reasons can also be advanced in support of rationing based on the imminence of a patient’s death. Such an approach arguably has the advantage of saving the greatest number of lives. Alternatively, the justification for applying this criterion may rest on the belief that a patient whose death is imminent is in greater need of health care and that health care should be given first to those with the greatest need.58 Critics of both a medical benefit and an imminent death criterion express the concern that these approaches may have adverse effects on elderly persons.59 As older persons, on average, have a lower life expectancy than younger persons, rationing that takes into account the duration of medical benefit will disproportionately affect older persons. Likewise, to the extent that advanced age correlates with poorer outcomes for medical procedures, rationing based on medical benefit will adversely affect the elderly as a group. Regarding the criterion of imminent death, the elderly are at greater risk of being denied treatment if, as a group, they are found to be at increased risk of mortality for various medical interventions. Thus, although medical benefit and imminent death are age blind, they may be found to have adverse effects on the geriatric population.
Age-Based Rationing Age is also put forward as an explicit basis for allocating limited health care resources. Perhaps the most prominent proponent of age-based rationing is Daniel Callahan, who argues that “government has a duty, based on our collective social obligation, to help people live out a natural life span, but not actively to help extend life beyond that point.”60 According to this approach, public-
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funded life-extending care should not be available to older persons. Instead, government should pay only for medical services intended to improve the quality of life of elderly persons. Ethical arguments favoring age-based rationing often appeal to society’s duty to younger age groups. For example, it is argued that unless age-based limits to health care are set, we will cheat our children and future generations out of adequate health care or other essential goods, such as education.61,62 Alternatively, age-based rationing is defended by arguing that although it initially appears to favor one group of people over another, in fact it affects all persons equally over time.63 This reasoning applies because, over time, each person ages. Therefore, over time, all persons experience both the advantage of greater access when they are young and the disadvantages of reduced access during old age. Age-based rationing is also justified on utilitarian grounds, by arguing that investing health care dollars in younger persons represents, on average, a better return on investment because the young generally have a greater number of years ahead to live. Another utilitarian defense of age-based rationing points out that a great financial gain could be obtained by limiting health care to the elderly because the elderly use a disproportionate share of health care dollars. According to one estimate, more than 50% of patients hospitalized for myocardial infarction are over age 65.65 If treatment for this condition were rationed on the basis of age, a major reduction in health care expenditures would be achieved. Opponents of age-based rationing hold that a just distribution of health care requires meeting the essential needs of all persons, irrespective of age.65 Thus, if older persons have, on average, a greater need for health care resources, then they are entitled to receive a greater share of such resources. Alternatively, opponents claim that the allocation of health care should depend more on the quality of benefit that medical interventions can produce than on the number of years a patient lives.66 In addition, critics of age-based limits maintain that society has special duties to older persons that forbid placing age-based limits on medical care. Such duties may stem from the belief that older persons are more deeply embedded within the fabric of social life. According to this position, “The more personally interwoven a person becomes with others through time, the greater the damage done to the social fabric when that person is torn away by death.”67 Alternatively, special duties may spring from the contributions that older persons as a group have made to the creation of social goods, such as science, technology, medicine, and culture.68 Proper recognition of these contributions requires ensuring that the elderly themselves reap the benefit that these social goods offer.
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Finally, as already noted, age limits on health care adversely affect women because the population of older adults includes more women than men.69 Among the population aged 65 and over, there are only 68 men per 100 women. The disparity in the numbers of men and women is greatest within the oldest age groups. Thus, for the group aged 85 and over, there are a mere 45 men per 100 women.70 Denying lifesaving medical care to older women also harms women disproportionately, as women have more future years to live. At age 65, a woman can anticipate living about 18 more years, whereas a man at this age can expect only 14 more years. Women who reach age 75 can look forward to 12 more years of life; by contrast, men at this age will live an average of 9 more years.71
National Health Insurance Age-based rationing focuses on a personal quality of individuals and uses this as a basis for distinguishing between persons, whereas other approaches emphasize similarities rather than differences between persons. For example, those who advocate applying a principle of equality to the distribution of health care insist that, morally speaking, it is not possible to discriminate between individuals and assign people different rights to health care. Instead, whenever anyone enjoys access to a health care service, justice requires making that service equally available to everyone with similar health care needs.72 The more precise interpretation of an egalitarian principle depends upon how the concept of “need” is elaborated.73 Thus, to say that resources must be equally available to everyone who needs them may mean that people should have equal access to every service from which they stand to benefit. Understood in this sense, a principle of equality applies to all areas of health care. Alternatively, if “need” refers only to services that provide especially important benefits, then the principle of equality applies only to “basic” or “essential” services. On the latter interpretation, although nonessential services may be unequally distributed, services that provide very important benefits to people must be equally accessible. The goal of making basic health care equally available to everyone, irrespective of factors such as a person’s income or geographic location, was one of the central aims of the Canadian health care system. The Canadian health care system is a publicly funded system based on the philosophy that health is a right, not a commodity.74 Thus, in Canada, universal access to provincial health insurance solves the problem of the uninsured by preventing it from occurring. The 1984 Canada Health Act was the first to explicitly state the principles that have become the cornerstone of the Canadian health care
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system: accessibility, portability, comprehensiveness, universality, and public administration. Because the Canadian Constitution specifies that health care coverage will be a matter of provincial jurisdiction, to be implemented by individual provinces, these five principles have served as the federal government’s criteria for judging the eligibility of provincial health plans to receive federal funding. In Ontario, for example, the criterion of universality is met by provincial regulation establishing that all who “make their home and are ordinarily present in Ontario are eligible for coverage,” so long as they reside in the province for 3 months.75 Like the United States, Canada’s health care system is facing increasing demands that stretch the limits of the public sector. The federal government has reduced its financial contribution, leaving the Canadian provinces that administer health insurance plans in financial crises. These economic limits will challenge the principles of universality and comprehensiveness that form the cornerstone of the Canadian approach to justice in health care. Whether Canada’s system of universal coverage can withstand future challenges will depend, in large part, on the strength of its ethical and social foundations. Specifically, the ability to meet future challenges will require restating and reaffirming the reasons for commitment to a principle of equality in health care. It will also call upon Canadians to prioritize competing values, such as universality and comprehensiveness. For example, if limiting benefits and rationing health services is necessary to place the goal of universality on surer footing, are such limits ethically and socially acceptable? In Canada, support for a principle of equality in health care is generally articulated by emphasizing altruistic and humanitarian concern for others.76 First, government shoulders the social and ethical responsibility to secure the general social welfare. Thus, Canadian policymakers tend to take for granted that government is responsible to protect the most vulnerable members of the society, even when doing so imposes a cost on other citizens. As expressed by the federal Advisory Committee on Health Insurance, universal access recognizes “the need for the mutual insurance of all members against the more serious dangers, a compulsory insurance so that the more secure cannot stand aside and leave the risks to be loaded on the shoulders of the less secure.”77 Second, the ethical principle of humanitarianism, or care and concern for fellow citizens, is evident in the historical development of Canada’s system of universal health insurance. Reflecting this ethical premise, the Royal Commission on Health Service identifies the factors that support public, as opposed to purely private, interest in health care as including, “A deepening of our humanitarian concern for our fellows,” together with, “A recognition of the well-being of members of the population and that the well-being of a proportion of the
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population at any given time is seriously curtailed because of mental or physical disease.”78 Generally speaking, support for applying a principle of equality to the distribution of basic health care comes from a variety of sources. First, it can be said that basic health care services provide a very special and important kind of benefit.79 Unlike other benefits, the preservation of life and health (and the resources necessary to achieve this) is a prerequisite for whatever else a person wants to do in life. Therefore, even if inequalities are ethically tolerable in other areas, they should not be within health care. Furthermore, although we may consider ourselves as exerting control over many important aspects of our lives, we often lack control over our health and need for health services.80 For instance, whether one inherits a gene predisposing the person to breast or ovarian cancer, or a gene for Huntington’s disease, is the result of the “natural lottery” rather than the result of individual decisions. Likewise, the fact that an individual is born with fetal alcohol syndrome, is injured in a flood, or experiences kidney failure from contaminated meat is not the result of that individual’s conscious choices. To the extent that disease is genetically based, or is influenced by choices others make, or occurs as the result of natural disaster, there is no basis for holding people “accountable” for having diseases. In these kinds of cases, allocating health care on the basis of merit lacks ethical underpinning, and a system of treating people equally gains ethical support. Even if merit-based allocation is suitable in other spheres, such as distributing the benefits and burdens associated with offices and positions in a society, it often does not fit the circumstances leading to ill health and the need for health care services. It is also argued that the value of equal respect requires applying a principle of equality to basic services. Gutmann, for example, maintains that inequality of access to basic health care conveys to people that they are not equally worthy human beings.81 It is analogous, she argues, to tolerating inequalities in other fundamental areas, such as the right to vote or access to police protection, which are essential to liberty and security. One reason that showing equal respect for persons is important is that it has a profound effect on people’s capacity to develop and maintain self-respect. Self-respect, in turn, determines an individual’s sense of their own worth; it affects their self-confidence and ability to carry out the important goals they set for themselves.
Summary and Conclusions In summary, this chapter addressed the problem of how to allocate scarce health care resources between different individuals and groups in society. It demonstrated
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that competing conceptions of justice lead to very different distributive approaches. Moreover, the problem of health care rationing is hardly a problem that looms in the future. Instead, rationing occurs as a pervasive feature of present health care systems. Creating a more just health care system will require societies to engage in open debates about the rationing of health care services. At a deeper level, the choice societies face must be founded on a more fundamental vision of a just society.82 To what extent does a just society emphasize equality between persons? To what extent must it stress the value of individual freedom? How does a just society balance the value of health with other values, such as the environment or education? These questions lie at the very heart of contemporary health care debates.
References 1. Fuchs V. No pain, no gain: perspectives on cost containment. JAMA. 1993;269:631–633. 2. U.S. Senate Special Committee on Aging. Aging America: Trends and Projections. Washington, D.C.: Public Health Service, U.S. Department of Health and Human Services; 1985–1986. 3. Schneider EL, Guralnik JM. The aging of America. JAMA. 1990;263:2335–2340. 4. Temkin-Greener HA, Meiners MR, Petty EA, Szydlowski JS. The use and cost of health services prior to death: a comparison of the Medicare-only and the Medicare-Medicaid elderly populations. Milbank Q. 1992;70:679–701. 5. Angell M. Cost containment and the physician. JAMA. 1985;254:1203–1207. 6. Leaf A. The doctor’s master. JAMA. 1984;311:1573–1575. 7. Stern RS, Weissman JS, Epstein AM. The emergency department as a pathway to admission for poor and highcost patients. JAMA. 1991;266:2238–2243. 8. Burstin HR, Lipsitz SR, Brennan TA. Socioeconomic status and risk for substandard care. JAMA. 1992;268:2283–2287. 9. Pappas G, Queen S, Hadden W, Fisher G. The increasing disparity in mortality between socioeconomic groups in the United States, 1960 and 1986. N Engl J Med. 1993;329: 103–109. 10. Angell M. Privilege and health. N Engl J Med. 1993;329: 126–127. 11. Baker DW, Stevens CD, Brook RH. Patients who leave a public hospital emergency department without being seen by a physician. JAMA. 1991;266:1085-1090. 12. Kellerman AL. Too sick to wait. JAMA. 1991;266:1123– 1125. 13. Bindman AB, Grumbach K, Keane D, Rauch L, Luce JM. Consequence of queuing for care at a public hospital emergency department. JAMA. 1991;266:1091–1096. 14. Olson CM. Hospital admission through the emergency department: an obstructed pathway. JAMA. 1991;266:2274. 15. Kellerman AL, Andrulis DP, Hackman BB. Emergency department overcrowding. Ann Emerg Med. 1990;19:447.
82. Justice and the Allocation of Health Care Resources 16. Wennberg JE. The Dartmouth Atlas of Health Care in the United States: A Report on the Medicare Program. Dartmouth: Dartmouth Medical School, Center for the Evaluative Clinical Sciences; 1999. 17. Wennberg JE. The Dartmouth Atlas of Health Care in the United States: A Report on the Medicare Program. Dartmouth: Dartmouth Medical School, Center for the Evaluative Clinical Sciences; 1999:85. 18. Wennberg JE. The Dartmouth Atlas of Health Care in the United States: A Report on the Medicare Program. Dartmouth: Dartmouth Medical School, Center for the Evaluative Clinical Sciences; 1999:88. 19. Wennberg JE. The Dartmouth Atlas of Health Care in the United States: A Report on the Medicare Program. Dartmouth: Dartmouth Medical School, Center for the Evaluative Clinical Sciences; 1999:93. 20. Wennberg JE. The Dartmouth Atlas of Health Care in the United States: A Report on the Medicare Program. Dartmouth: Dartmouth Medical School, Center for the Evaluative Clinical Sciences; 1999:93. 21. Grumet GW. Health care rationing through inconvenience. N Engl J Med. 1989;321:607–611. 22. Jecker NS, Reich WT. Contemporary ethics of care. In: Reich WT, ed. Encyclopedia of Bioethics. New York: Simon & Schuster/Macmillan; 1995:336–344. 23. Miettinen TT, Tilvis RS, Karppi P, Arve S. Why is the pain relief of dying patients often unsuccessful? Palliat Med. 1998;12(6):429–435. 24. Stevens B, Koren G. Evidence-based pain management for infants. Curr Opin Pediatr. 1998;10(2):203–207. 25. Beyer JE. Judging the effectiveness of analgesia for children and adolescents during vaso-occlusive events of sickle cell disease. J Pain Symptom Manage. 2000;19(1):63–72. 26. Here’s the latest research in pediatric pain control. ED Manag. 1999;11(11):128–129. 27. Ulmer JF. Burn pain management: a guideline-based approach. J Burn Care Rehabil. 1998;19(2):151–159. 28. Portenoy RK, Lesage P. Management of cancer pain. Lancet. 1999;353(9165):1695–1700. 29. Brockopp D, Warden S, Colclough G, Brockopp G. Elderly people’s knowledge of and attitudes to pain management. Br J Nurs. 1996;5(9):556–558, 560–562. 30. Miner TJ, Tavaf-Motamen H, Shriver CD. Decision making on surgical palliation based on patient outcome data. Am J Surg. 1999;177(2):150–154. 31. Higginson IJ. Evidence-based palliative care. There is some evidence—and there needs to be more. Br Med J. 1999; 319(7208):462–463. 32. Bailes JS. Cost aspects of palliative cancer care. Semin Oncol. 1995;22(2 suppl 3):64–66. 33. Warde P, Murphy T. Measuring the cost of palliative radiotherapy. Can J Oncol. 1996;6(suppl 1):90–94. 34. Pickett M, Cooley ME, Gordon DB. Palliative care: past, present, and future perspectives. Semin Oncol Nurs. 1998 May;14(2):86–94. 35. Barondess JA, Kalb P, Weil WB, Cassel C, Ginzberg E. Clinical decision-making in catastrophic situations: the relevance of age. J Am Geriatr Soc. 1988;36:919–937. 36. Jecker NS. Age-based rationing and women. JAMA. 1991; 266:3012–3015.
1219 37. Jecker NS. Can an employer based health insurance system be just? J Health Polit Policy Law. 1993;18:657– 674. 38. Trevino FM, Moyer E, Valdez B, Stroup-Benham CA. Health insurance coverage and utilization of health services by Mexican Americans, Mainland Puerto Ricans, and Cuban Americans. JAMA. 1991;265:233–237. 39. Davidson EC, Fukushima T. The racial disparity in infant mortality. N Engl J Med. 1992;327:1022–1024. 40. Becerra JE, Hogue CJR, Atrash HK, Perez N. Infant mortality among Hispanics. JAMA. 1991;265:217–221. 41. Hilts PJ. Growing gap in life expectancies of blacks and in whites is emerging. New York Times. 9 October 1989:Al. 42. Kasiske BL, Neylan JF, Riggio RR, et al. The effect of race on access and outcome in transplantation. N Engl J Med. 1991;324:302–307. 43. Kjellstrand CM. Age, sex, and race inequality in renal transplantation. Arch Intern Med. 1988;148:1305–1309. 44. Gaston RS, Ayres I, Dooley LG, Dietheim AG. Racial equity in renal transplantation: the disparate impact of HLA-based allocation. JAMA. 1993;270:1352–1356. 45. Ayanian JZ, Udvarhelyi S, Gatsonis CA, Pashos CL, Epstein AM. Racial differences in the use of revascularization procedures after coronary angiography. JAMA. 1993; 269:2642–2646. 46. Becker LB, Han BH, Meyer PM, et al., and CPR Chicago Project. Racial differences in the incidence of cardiac arrest and subsequent survival. N Engl J Med. 1993;329:600–605. 47. Whittle J, Conigliaro J, Good CB, Lofgren RP. Racial differences in the use of invasive cardiovascular procedures in the department of Veterans Affairs medical system. N Engl J Med. 1993;329:621–626. 48. Ayanian JZ. Heart disease in black and white. N Engl J Med. 1993;329:656–658. 49. Todd KH, Samaroo N, Hoffman JR. Ethnicity as a risk factor for inadequate emergency department analgesia. JAMA. 1993;269:1537–1539. 50. Moore RD, Stanton D, Gopalan R, Chaisson RE. Racial differences in the use of drug therapy for HIV disease in an urban community. N Engl J Med. 1994;330:763–768. 51. Marmor TR, Boyum D. Medical care and public policy: the benefits and burdens of asking fundamental questions. Health Policy. 1999;49(1–2):27–43. 52. Mossialos E, King D. Citizens and rationing: analysis of a European survey. Health Policy. 1999;49(1–2):75–135. 53. King D, Maynard A. Public opinion and rationing in the United Kingdom. Health Policy. 1999;50(1–2):39–53. 54. Strosberg MA, Wiener JM, Baker R, Fein IA. Rationing America’s Medical Care: The Oregon Plan and Beyond. Washington, DC: Brookings Institution; 1992. 55. Hadorn D. Setting health care priorities in Oregon. JAMA. 1991;265:2218–2225. 56. Egan T. Oregon shakes up pioneering health plan for the poor. New York Times. 22 February 1991. 57. Winslow G. Triage and Justice. Berkeley: University of California Press; 1982. 58. Kilner J. Who Lives? Who Dies? Ethical Criteria in Patient Selection. New Haven: Yale University Press; 1990. 59. Jecker NS, Pearlman RA. An ethical framework for rationing health care. J Med Philos. 1992;17:79–96.
1220 60. Callahan D. Setting Limits. New York: Simon & Schuster; 1987:137. 61. Lamm RD. Ethical care for the elderly. In: Smeeding TM, ed. Should Medical Care Be Rationed by Age? Totowa, NJ: Rowman and Littlefield; 1987:xi–xv. 62. Preston S. Children and the elderly. Sci Am. 1984;251:44–49. 63. Daniels N. Am I My Parents’ Keeper? New York: Oxford University Press; 1988. 64. Wenger NK, O’Rourke RA, Marcus FI. The care of elderly patients with cardiovascular disease. Ann Intern Med. 1988; 109:425–428. 65. Jecker NS, Pearman RA. Ethical constraints on rationing medical care by age. J Am Geriatr Soc. 1989;37:1067– 1075. 66. Jecker NS. Disenfranchising the elderly from life-extending medical care. Public Aff Q. 1988;2:51–68. 67. Kilner J. Age as a basis for allocating lifesaving medical resources. J Health Polit Policy Law. 1988;13:405. 68. Jonsen A. Resentment and the rights of the elderly. In: Jecker NS, ed. Aging and Ethics. Clifton, NJ: Humana Press; 1991:341–352. 69. Jecker NS. Age-based rationing and women. JAMA. 1991; 266:3012–3015. 70. Cassel CK, Neugarten BL. A forecast of women’s health and longevity. West J Med. 1988;149:712–717. 71. Verbrugge LM. An epidemiological profile of older women. In: Haug MR, Amasa B, Ford MS, eds. The Physical and Mental Health of Aged Women. New York: Springer; 1985: 41–64. 72. Gutmann A. For and against equal access to health care. In: President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Securing Access to Health Care, vol 2. Washington, DC: U.S. Government Printing Office; 1983:51–66.
N.S. Jecker 73. Buchanan A. An ethical evaluation of health care in the United States. In: Sass HM, Massey R, eds. Health Care Systems. Boston: Kluwer; 1988:39–58. 74. Kluge EH. The Canadian health care system: an analytic perspective. Health Care Anal. 1999;7(4):377–391. 75. Health and Welfare Canada. 1984–1985 Canada Health Act: Annual Report. Ottawa: Minister of Supply and Service; 1986:58–59. 76. Jecker NS, Meslin EM. United States and Canadian approaches to justice in health care: a comparative analysis of health care systems and values. Theor Med. 1994;15: 181–200. 77. Advisory Committee on Health Insurance. Heagarty Report. Order in Council; p.s., 836, February 5, 1942:143. As cited in Taylor MG. Health Insurance and Public Policy: The Seven Decisions That Created the Canadian Health Insurance System and Their Outcomes, 2nd Ed. Montreal: McGill-Queen’s University Press; 1988:18. 78. Hall EM, Chair. Report of the Royal Commission on Health Services. Ottawa: Queen’s Printer, 1964:5. 79. Daniels N. Just Health Care. New York: Cambridge University Press; 1985. 80. Outka G. Social justice and equal access to health care. In: Gorovitz S, Macklin R, Jameton AL, O’Connor JM, Sherwin S, eds. Moral Problems in Medicine, 2nd Ed. Englewood Cliffs: Prentice-Hall; 1983:544–557. 81. Gutmann A. For and against equal access to health care. In: President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Securing Access to Health Care, vol 2. Washington, DC: U.S. Government Printing Office; 1983:51–66. 82. Jecker NS, Meslin EM. United States and Canadian approaches to justice in health care. Theor Med. 1994;15: 181–200.
83 Medical Treatment and the Physician’s Legal Duties Marshall B. Kapp
Older patients enter into relationships with physicians and other members of the health care team to obtain medical care. These relationships can be characterized as both contractual (i.e., based on a mutual exchange of explicit or implicit promises) and fiduciary (i.e., based on the trust the dependent patient must invest in relying on the more knowledgeable and powerful health care provider). Within either of these frameworks, the resulting relationships implicate a variety of legally enforceable obligations on the part of the physician. Thus, some familiarity with treatment-related legal requirements and associated potential liabilities is essential to the practicing geriatrician. Additionally, geriatricians often have the opportunity, and sometimes may be required, to contribute medical expertise to the resolution of legal issues, as in cases where a physician’s affidavit or testimony is the central piece of evidence regarding mental competence in a contested guardianship or will probate proceeding. Many legal issues affecting geriatric practice are basically generic. For instance, physicians must be aware of the legal doctrines of informed consent and confidentiality regardless of their patients’ age.1 There is nothing inherently distinctive about older patients from a legal perspective. Many generic legal issues, however, take on unique twists or special urgency when applied to older patients. This difference may be related to a particular older person’s physical or mental decline, impaired sensory perception, well-developed life history and set of values, outliving of concerned family members or presence of intermeddling family members, and increased risk of institutionalization. Further, there exists a subset of medically related issues that pertain exclusively to elderly patients, because in some situations legislators have consciously made chronologic age by itself a relevant criterion for some specific purpose. For example, achieving age 65 by itself qualifies one for Social Security retirement benefits,2 and a person gains protection under the Age Discrimination in Employment Act (ADEA) auto-
matically at age 40.3 This chapter outlines a few of the most salient legal issues arising within the physician– older patient relationship.
Medical Malpractice The quality of medical practice is regulated through several means. Important forms of regulation include professional licensure and disciplinary requirements, oversight by Peer Review Organizations (PROs)4 and other public and private (e.g., Joint Commission on Accreditation of Healthcare Organizations) agencies that audit the quality of care provided to Medicare beneficiaries and others, mandatory reporting of certain adverse actions against physicians to the National Practitioner Data Bank (NPDB),5 extensive federal and state statutes and regulations governing nursing facilities and home health agencies, and in extreme cases (e.g., when gross neglect is charged), criminal prosecution. Physicians ordinarily are particularly apprehensive about civil medical malpractice tort lawsuits brought by individual patients seeking monetary damages for allegedly negligent care, even though older patients tend to sue their physicians less often than their younger counterparts and with less success. Much attention has been paid recently to the prevalent phenomenon of medical errors.6 There have been calls for mandatory reporting of serious errors to a government agency, but fears have been expressed by physicians about the potential ramifications of such reporting in terms of generating an increased rate of malpractice lawsuits.7 Another relatively recent development with possible litigation-related implications is the expanding enrollment of Medicare beneficiaries in various forms of managed care organizations (MCOs). This enrollment has been encouraged by the Medicare + Choice (Medicare Part C) program created by the Balanced 1221
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Budget Act (BBA) of 1997.8 Much political discussion has taken place regarding the right of individuals who obtain medical coverage as a fringe benefit of present or prior employment to personally sue their MCO as well as, or instead of, their own physician for alleged negligence;9 the future of lawsuits brought by Medicare beneficiaries against MCOs for negligence in denying payment for services is, at present, uncertain but bears close watching.
Informed Consent The fundamental ethical principle of autonomy or self-determination is embodied in the legal doctrine of informed consent. There are three essential elements that must be present for a patient’s choices about treatment to be considered legally valid. First, the patient’s participation in the decision-making process and the ultimate decision must be voluntary. The usual definition of voluntariness in the context of consent is that the person giving or withholding consent must be so situated as to be able to exercise free power of choice without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion. It means simply that the person must be free to reject participation in the proposed intervention. The physician must do all possible to minimize any intimidation that might unfavorably affect the quality of the patient–physician relationship, and the patient–institution or patient–agency relationship when applicable, and to make sure that advice and recommendations are conveyed in as nonpressured and empathetic a manner as possible. The second bedrock requirement for valid consent is that the patient’s agreement be sufficiently informed. The informed consent doctrine commands that the health care provider, before undertaking an intervention, must disclose certain information to the person who is the subject of the proposed intervention (or that person’s authorized surrogate; see following). The disclosure standard enforced in a slight majority of American jurisdictions is referred to as the “professional,” “reasonable physician,” or “community” standard. Under this test, the adequacy of disclosure is judged against the amount and type of information that a reasonable, prudent physician would have disclosed under similar circumstances. A substantial minority of states have adopted a more expansive standard of information disclosure: the “reasonable patient” or “material risk” standard. This standard dictates that the physician communicate the information that a “reasonable patient” in the same situation would need and want to make a voluntary and knowledgeable decision. Under this approach, the
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patient must be told about all material risks, that is, those factors that might make a difference to a reasonable, average patient under comparable circumstances. The patient’s age may affect what information is material to that person’s decision-making calculations. For instance, a likely side effect that will not manifest itself for another 20 years may not be very important to an older person. However, the probability that a particular intervention will be accompanied by a great amount of physical pain or discomfort may make quite a difference to an old, frail individual. Physicians always should take into account the physical and mental effects of aging, among numerous other factors, when deciding what information regarding an intervention might be material to the specific person and how to communicate that information most usefully. Within these standards of disclosure,the following informational items have usually been enumerated as essential components of the ideal informed consent process: (1) diagnosis; (2) the general natural and purpose of the proposed intervention; (3) the reasonably foreseeable risks, consequences, and perils of the intervention; (4) the probability of success; (5) reasonable alternatives; (6) the result anticipated if nothing is done; (7) limitations on the professional or health care facility; and (8) advice (i.e., the physician’s recommendation). The third essential element of legally effective consent is that the patient must be mentally able to engage in a rational decision-making process. The topic of evaluating a patient’s decisional capacity is discussed in Chapter 84. When the patient lacks sufficient present cognitive and emotional capacity to make medical choices, a proxy or surrogate decision maker must be involved (see following).
The Research Context The issue of participation by older persons, particularly those residing long term within nursing facilities, in biomedical and behavioral research protocols is a growing ethical (see Chapter 86) and legal concern. Legal questions are especially vexing when the problem being clinically investigated is mental impairment and the proposed human subjects are institutionalized as well as cognitively and emotionally compromised. The policy and practice challenge is to protect impaired elderly persons from exploitation and avoidable harm, while facilitating the conduct of important, high-quality research on problems (such as dementia) that affect older persons disproportionately. Most biomedical and behavioral research conducted in the United States is regulated under federal law that seeks to protect the rights and well-being of potential human subjects.10 The Office of Protection from Research
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Risks (OPRR) within the Department of Health and Human Services (DHHS) has—and has exercised—the authority to suspend an institution’s human subjects research activities for noncompliance with applicable regulations. At present, there are no particular legal restrictions unique to older research subjects; thus, participation by the elderly in research protocols is governed by the same law that applies to subjects of all ages. For incapacitated persons, consent for research participation may be obtained legally from those individuals who are empowered to make other decisions on the older person’s behalf; federal regulations refer to the use of a “legally authorized representative” for consent to research activities.11 However, a 1998 report by the National Bioethics Advisory Commission (NBAC) contained a number of recommendations for specially protecting potential human research subjects (of all ages) who have impaired capacity to personally consent to their own research participation.12,13 Among other items, NBAC recommended: • Institutional Review Board (IRB) membership should include at least two persons familiar with mental disorders • A special standing panel of DHHS should be created to handle especially troubling research protocols • Research using mentally impaired subjects should be disapproved if people without such impairments could be used • For protocols involving greater than minimal risk, there should be an independent assessment of a potential subject’s capacity, and the protocol must detail the assessment process These recommendations will likely set the agenda for policy discussion in this arena for the foreseeable future. The endeavor of conducting legally defensible geriatric research, particularly with demented, institutionalized subjects, presents a variety of challenges concerning site and subject selection, capacity evaluations, comprehension and retention of relevant information, choice and authority of proxy decision makers, and minimization of coercive influences. Nonetheless, the geriatric research enterprise is an essential one, and the legal challenges must be met appropriately.
Surrogate Decision Making As noted, proxy decision making concerning an older person’s participation in a research protocol sometimes is necessary when the person lacks sufficient capacity to make their own decisions rationally. Similarly, physicians involved in the diagnosis and treatment of older patients frequently must confront substitute decision makers responsible for intervening on behalf of patients whose
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cognitive or emotional deficits are so severe that they prevent the patient from personally making and communicating autonomous choices.14 The topic of surrogate decision making by third parties acting for the incapacitated patient is a complex and legally inexact one. There are several alternative ways to delegate legally what would ordinarily be the patient’s authority to make decisions for the proxy or surrogate to exercise that power on behalf of the incapacitated patient. These delegation mechanisms may be characterized as follows: (1) delegation of authority beforehand by the patient, through methods of advance planning; (2) delegation of authority by operation of statute, regulation, or broad judicial precedent; (3) informal delegation of authority by custom; and (4) delegation of authority by a court order in the specific case. The two most important current devices for advance health care planning are the living will (in some jurisdictions called a “declaration”) and the durable power of attorney for health care.15 The Patient SelfDetermination Act (PSDA) passed by Congress as part of the Omnibus Budget Reconciliation Act (OBRA) of 1990,16 in the aftermath of the United States Supreme Court’s decision in Cruzan v. Director, Missouri Department of Health,17 imposes a number of requirements on hospitals, nursing homes, health maintenance organizations, preferred provider organizations, hospices, and home health agencies that participate in the Medicare and Medicaid programs. Among these are mandates that the provider create and distribute to new patients or their surrogates a written policy on advance directives, consistent with applicable state law; the provider inquire at the time of admission or enrollment whether the patient has previously executed an advance directive; and, if no advance directive has been executed previously and the patient currently retains sufficient decisional capacity, the provider inquire whether the patient wishes to execute such a directive now.18,19 In some circumstances, particular facets of decisionmaking authority may devolve or pass from the patient to someone else by operation of a statute, regulation, or judicial precedent. One well-known example of this form of substitute decision making is the representative payee concept that is utilized to manage regular government benefit payments, including pension and disability checks from the Departments of Veterans Affairs and Defense, Railroad Retirement Board, and Civil Service; Old Age, Survivors, and Disability Insurance benefit payments under Title 2 of the Social Security Act; and Supplemental Security Income benefit payments to the aged, blind, or disabled under Title 16 of the Social Security Act. As another example of this type of power delegation is found in the federal Medicare-Medicaid requirements for nursing facilities. These regulations provide that, for a facility resident who is (1) adjudicated incompetent in
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accordance with state law or (2) found by the physician to be medically incapable of understanding his or her rights, the right to make decisions devolves to the resident’s guardian, next of kin, sponsoring agencies, or representative payee. It is in the area of decision making about care of the critically ill patient that statutory, regulatory, and judicial guidance about substitute decision making is clearest. Twenty-seven states and the District of Columbia had enacted legislation generally lumped under the rubric “family consent” or “default” statutes.20 These statutes set forth legal authority empowering designated relatives, and sometimes others, to make particular kinds of medical decisions on behalf of incapacitated persons who have not executed a living will or durable power of attorney. In addition, courts in many jurisdictions have formally recognized the family’s authority to exercise an incapacitated person’s rights on his or her behalf and, just as importantly, most of these judicial decisions explicitly establish legal precedent for families to act in future cases without the need for prior court authorization in individual cases. As a general matter, in the absence of a specific statute, regulation, or court order delegating authority to a substitute decision maker, or a court order finding an individual mentally incompetent and appointing another named person to act as guardian or conservator, neither the family as a whole nor any of its individual members (nor nonrelatives, for that matter) has any automatic legal authority to make decisions on behalf of patients who cannot speak for themselves. Nevertheless, it has long been a widely known and implicitly accepted medical custom or convention to rely on families as decision makers for incompetent persons, even in the absence of express legal power. Even when there is no explicit judicial or legislative authorization in one’s own state, the legal risk for a physician or health care institution for a good faith treatment decision made in conjunction with an incompetent patient’s family is very slight. In fact, the few courts that have been presented with the question in the context of litigation have virtually unanimously ratified the family’s authority. In some cases, however, informal substitute decision making—that is, the extralegal “muddling through” process that governs a great deal of medical, and especially geriatric, practice—by the physician and family members may not work satisfactorily. The family members may disagree among themselves. They may make decisions that seem to be at odds with the earlier expressed or implied preferences of the patient or that clearly appear not to be in the patient’s best interests (e.g., a family’s financially or psychologically driven selfish choices). The family may request a course of conduct that seriously contradicts the physician’s or facility’s own sense of ethical integrity.
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When such situations occur, judicial appointment of a guardian or conservator empowered to make decisions on behalf of an incompetent ward may be practically and legally advisable.21 However, because guardianship usually entails an extensive deprivation of the individual’s basic rights, may be imposed in the absence of meaningful procedural safeguards, and involves substantial financial, time, and emotional costs, the “least restrictive alternative” doctrine dictates that it be pursued only as a last resort when less formal mechanisms of substitute decision making have failed or are unavailable. Additionally, when guardianship is sought, consideration should be paid to the possibility of strictly limiting such guardianship in terms of both duration and extent of transferred powers. Because courts possess the authority to impose such limitations, under either specific state “partial or limited guardianship” statutes or the courts’ inherent equity powers, physicians who deal with substitute decision makers who purport to be the patient’s legal guardian should request to see a copy of the official court order creating the guardianship, to verify the existence and extent of the guardian’s authority.
Institutional Ethics Committees Standards of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) require that hospitals have “a mechanism” in place for resolving ethical disputes. One such mechanism is the institutional ethics committee (IEC), variants of which have now been established in many hospitals, as well as nursing homes,22 hospices, and home health agencies. The IEC is an internal interdisciplinary body that helps an institution or agency and its professional staff to make difficult treatment decisions in an ethically acceptable manner. Institutional ethics committees differ among institutions and agencies in terms of precise size, composition, structure, procedures, and organizational placement. IEC functions may include policy drafting, staff and public education, and/or case consultation on a concurrent or retrospective basis. Consultation with an IEC probably exerts a legal prophylactic effect, in terms of reducing unnecessary guardianship petitions, deterring possible lawsuits against the institution or agency and its staff, and making it easier to defend against the very rare malpractice cases that might be filed in this context.
“Do Not” Orders “Do Not” orders from the attending physician to other members of the health care team are predicated on prospectively made decisions to withdraw or withhold certain types of medical interventions from specified
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patients. Most attention has been devoted, especially in the acute hospital environment, to “do not resuscitate” (DNR) orders (also called “No Codes”), or instructions by the physician to refrain from attempts at cardiopulmonary resuscitation (CPR) in the event of a cardiac arrest. However, other kinds of “do not” orders also are important, particularly in the long-term care environment. Among these are “do not hospitalize” and “do not intubate” orders. Legally, deciding about implementing “do not” orders should be handled according to the same substantive principles and procedural guidelines that apply to other treatment decisions. In fact, by allowing and encouraging certain decisions to be made prospectively, before a crisis develops, “do not” orders probably reduce any potential legal risk and certainly should curtail legal anxiety. The legal status of “do not” orders when the patient is mentally competent is unambiguous. It parallels the situation of medical intervention generally, including intervention that would be life prolonging or even lifesaving. In other words, a competent adult patient has the constitutional, common law, and (in many states) statutory right to voluntarily and knowingly refuse basic (e.g., CPR) or advanced cardiac life support or any of its specific components, hospitalization, or any other form of medical intervention and to demand a precisely written “do not” order. Courts have not ordered competent elderly patients to endure medical interventions over their stated objections. The wishes of close family members should be considered by the physician (assuming the competent patient has expressly or by implication authorized family participation in their medical care), but should never be permitted to override the decision of a competent patient. Under the PSDA, acute and long-term settings should have a written policy statement regarding the institutional or agency philosophy and any relevant technologic and staffing limitations concerning various “do not” situations. A copy of this statement should be presented to every decisionally capable patient or an incapacitated patient’s most likely substitute decision maker at or before the time of admission. Extensive, regular staff education should be carried out concerning the provider’s policies. Physicians customarily should discuss treatment preferences and objectives openly and honestly with patients who are capable of participating in such decisions. As a matter of course, physicians should document the results of these discussions; such documentation might provide useful evidence later on of the patient’s wishes and the good faith quality of the decision-making process. When a capable patient has made a “do not” decision, he or she must be able to reevaluate and reconsider that decision continually in light of any change in physical or mental condition that materially affects (i.e., that might
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really make a difference in) the possible benefits and burdens of different treatment alternatives. A “do not” decision can be revoked or modified at any time. It is part of the physician’s duty to continually update the patient with new information pertinent to “do not” decisions. For the mentally incapacitated patient, clarification of respective rights and responsibilities may be available from the patient’s previously executed advance directive or from the expressions of a legislatively or judicially designated proxy. Even in the absence of a valid advance directive or explicitly legally authorized proxy, “do not” orders are still permissible for incapacitated patients according to the same general legal principles governing other kinds of decisions about life-sustaining medical treatment, that is, balancing—from the perspective of the patient—the likely benefits and burdens of the particular intervention. The only pertinent distinction between “do not” orders and other decisions to limit the use of lifeprolonging medical interventions lies in the prospective nature of the former. In an effort to clarify this area further, a number of state legislatures have passed specific legislation on this subject. JCAHO standards also address “do not” orders explicitly. Moreover, at least 42 states have in place protocols for writing and implementing Do Not Resuscitate orders pertaining to out-of-hospital situations.23,24 The physician’s and health care institution’s responsibility to adopt, educate about, and communicate concerning a clear policy on “do not” orders applies with full force when presently incapacitated patients are involved. When a patient is not presently capable of participating fully in decision making, the communication and negotiation about potential “do not” management strategies must encompass available, interested family members. The family has the same legal authority to make “do not” decisions for an incapacitated relative as to make other types of medical decisions. Even in the absence of specific legal authorization, in this sphere as elsewhere it is the medical custom or convention to involve families in “do not” decisions. From a practical risk management perspective, extensive interaction with family members concerning such decisions is a prudent, protective practice. Conversely, whether or not the family possesses the legal authority to veto a physician’s proposed “do not” decision has emerged as a controversial issue, as part of the larger “futile treatment” debate.25,26 Proceeding with entry and implementation of a “do not” order in the face of family opposition entails, from a practical standpoint, a certain risk of legal challenge after the fact. However, the realistic risk of being held liable for this conduct is small when the “do not” order was appropriate in terms of expressed patient wishes, the clinical prognosis, and the imbalance between the likely benefits and burdens of the intervention for the patient.
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A communication and negotiation process that is marked by compassion, clarity, and patience should resolve family–physician disagreement peacefully in most situations. When serious disagreement between physician and family or among family members themselves does surface and persist, consultation with an IEC may be advisable; a judicial declaratory judgment and injunction may be sought, but should be considered only as a last resort.27 During the communications process, the family should be informed that the continuing propriety of a “do not” order will be reevaluated regularly and that it can be rescinded or modified if prognosis or other factors materially change. As would be true for any clinical action predicated on an inaccurate factual basis, a physician or health care institution might be found legally liable for basing a “do not” order on an incorrect evaluation of the patient’s condition and prognosis. The attending physician should make appropriate use of available professional consultations with relevant clinical specialists, while retaining ultimate medical control and responsibility for the patient. The insight of nurses and other team members who are familiar with the patient also should be sought out and considered. The wishes of the patient (if ascertainable), the family, and significant others should all be recorded. The judgments of involved health care professionals, as well as the reasoning underlying those judgments, should be documented completely and candidly, as well as any attempts to change the mind of the patient or family. Honesty and accuracy in record keeping is the best defense for the physician and health care facility against any subsequent allegations of negligence or malevolent intent. Failure to put decisions and orders in writing not only exposes the physician to greater legal risk but also engenders possible inappropriate responses by other team members based on the mixed and confused signals that they are given. Once a “do not” order has been entered into a medical record, it should remain a permanent part of that document. If it is later modified or rescinded, the modification or rescission also should be noted in the record. Along with documentation, there is the need for communication among appropriate health care team members and institutions once a “do not” order has been written. A decision to refrain from certain interventions needs to be made known to those responsible for carrying out the order because, in the absence of such an order, the health care team normally is obligated to treat the patient with the full medical arsenal available. Communication is chiefly an organizational responsibility, and each hospital, nursing home, and home health agency should have a provision in its written policies detailing its procedures for assuring that all pertinent members of the health care team are informed accurately and promptly
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of “do not” orders or other treatment limitations concerning particular patients. Regular interdisciplinary case reviews on various institutional units are one means of communication that should be considered. Special markings on the outside of the medical chart, discreetly but clearly signifying particular treatment restrictions, are also a valuable communicative tool. Even when a long-term care facility resident needs to be, and with the resident’s or surrogate’s permission is, transferred to an acute care hospital for treatment of a specific remediable problem (such as acute infection), other treatment limitations may remain appropriate because of the person’s other, underlying, nonremediable deficits. In those circumstances, the transferring facility should have a clear, effective, ongoing mechanism in place for communicating “do not” orders directly to hospital personnel. Especially because hospital medical staff (and even more particularly house staff) may have strong preconceptions about resuscitation and other aggressive therapy for older persons who reside in long-term care facilities, it is the facility’s duty to transmit to the receiving hospital, at or before the time of the transfer, as much background as feasible concerning preferences, values, and instructions that should guide treatment for that person. The transfer agreement between the long-term care facility and any other health care facility should contain a written provision addressing the communication of this sort of information. Finally, decisions to limit specific elements of treatment should not signify total disregard or the “writing off” of an older person. Physicians in the past often have been intimidated from providing sufficient pain relief to critically ill patients because they feared criminal prosecution or professional disciplinary action for the overprescription of controlled substances. In the past decade, a number of legal initiatives have been aimed at changing this climate of apprehension to encourage the more appropriate prescribing of pain medications,28 including the enactment in many states of “Intractable Pain Statutes.” Indeed, it is widely recognized today that neglect of continuing palliative care, including effective pain management, could alienate patient and family and expose the physician and health care facility to lawsuits charging abandonment, neglect, or even abuse. Alleviating suffering is a basic goal of medical care and a part of the standard of care legally and ethically owed by health care professionals, even when “cure” of underlying disease is no longer possible. Management goals should consist of the following: remaining in physical and emotional contact with the dying person; relieving terminal symptoms (such as pain, confusion, anxiety, or restlessness); providing nourishment and hydration so long as they are palliative; skin care, bowel and bladder care, and personal grooming; and supporting the family through the period of dying, death, and bereavement. High-dose
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narcotic agents and sedatives can be used despite the possible risk of suppressed cerebral function and respiratory depression (there is controversy about how real this risk actually is), because the therapeutic intention is to control the symptoms of human suffering, not to precipitate an earlier death. One disturbing development in 1999 was the introduction in Congress of the Pain Relief Promotion Act (PRPA) (the Hyde–Nickels bill). The bill was designed to override Oregon’s physician-assisted suicide law (discussed next), by making it a violation of the federal Controlled Substances Act to administer opioids or other drugs to hasten a patient’s death. However, the most likely effect—unintended but foreseeable—of this bill if it were passed and signed into law would be to “chill” responsible pain management by discouraging, for reasons of apprehension about criminal prosecution, all physicians from adequately treating the suffering of their dying patients.29,30
Physician-Assisted Suicide Current U.S. law is unambiguous in its condemnation, particularly through state homicide statutes, of health care providers engaging in active (voluntary, positive) euthanasia (i.e., actively and intentionally doing something such as administering a lethal injection to hasten the death of a patient). In addition, almost all states explicitly legislatively condemn physician-assisted suicide (i.e., actively helping a patient to purposely take his or her own life), through either a specific statute on the subject or judicial interpretations of their general homicide statutes. In 1997, the U.S. Supreme Court unanimously upheld the validity of state laws making it criminal for physicians or other health care professionals to assist a patient to commit suicide. In these decisions, the Court rejected the notion of any federal constitutional right to physicianassisted sucide.31,32 Although the federal Constitution does not require it, the door is open legally for particular states to choose, as a matter of their own respective public policies and politics, to decriminalize physician-assisted suicide or even active euthanasia. Thus far, Oregon is the only state that has accepted this invitation.33–35
Adult Protective Services Every state has assembled an array of programs under the general rubric of adult protective services (APS). The traditional definition of this concept is a system of preventive, supportive, and surrogate services provided to adults living in the community, enabling them to maxi-
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mize independence and to avoid abuse and exploitation. APS are characterized by two elements that can be mixed in several different ways: the coordinated delivery of services to adults at risk and the actual or potential authority to provide substitute decision making concerning these services. The services feature consists of an assortment of health, housing, and social services, such as homemaker, house repair, friendly visits, and meals. Ideally, these services are coordinated by a caseworker who is responsible for assessing an older individual’s needs and bringing together the available responses. Many state APS statutes mandate that social service agencies undertake both casework coordination and delivery of services. The second component of an APS system is authority to intervene on behalf of the client. Ordinarily, the client (if capable of making autonomous decisions), with the encouragement of the physician will consent to a proposed service plan. Alternatively, the decisionally capable client may delegate decision-making authority to someone else through a durable power of attorney instrument. However, if the client refuses offered assistance but some form(s) of intervention appears necessary, the legal system may be invoked to authorize appointment of a surrogate decision maker over the person’s objections. In some states, APS offices rely, in the case of recalcitrant individuals, on the traditional methods of legal intervention in the lives of elderly persons, namely, involuntary commitment and guardianship. Legislation has been enacted in several jurisdictions, however, that creates special procedures to obtain court orders for protective services, for placing the client in an institution, for emergency orders when there is imminent danger to the client’s health or safety, or for orders authorizing entry into an uncooperative client’s home. These special procedures may be in addition to, or in place of, the existing guardianship apparatus and usually bypass the procedural protections that have been gradually built into extant guardianship laws. Court orders obtained under an APS statute often are time limited; upon expiration, the APS agency must pursue standard guardianship to continue imposing services over the client’s objection. However, during its duration, a court order authorizing APS intervention may be very broad. If the court does not limit it, for example, a protective services order may result in the placement of a person in a hospital, nursing home,36 assisted living complex, boarding home, hospice, or mental institution. As a matter of standard practice, physicians should ascertain carefully the exact nature and scope of a protective services order before accepting as legally effective the purported informed consent of a public or private social service agency offered on behalf of a patient-client. Those states that have created new court processes to authorize unconsented-to intervention, on either an
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emergency or a longer-term basis, also have established standards for identifying candidates for protective services or protective placement. Most of these states follow the same general statutory pattern. First, certain behavioral disabilities are enumerated, such as the inability to care for oneself adequately or to protect oneself from abuse and exploitation by others. Next, a number of causes for this incapacity are listed, most of which involve impairment of mental functioning. “Infirmities of aging,” “senility,” and “advanced age” were terms often used in earlier statutes to denote impairment in older persons, but such statutory language is rare today. In a very few states, physical impairment alone is considered a sufficient basis for intervention when the condition is likely to lead to self-neglect or victimization by others, even when there is no evidence of mental incompetence; most of these provisions have been invalidated by the courts on constitutional grounds or amended by state legislatures. In the context of APS, physicians frequently are called on to contribute their expertise and skills in (1) identifying candidates for services; (2) providing evidence if guardianship or commitment litigation takes place; (3) exploring voluntary alternatives; and (4) planning and placement. Physicians often are in a unique, central position to identify initially those individuals who meet the eligibility criteria for, and could significantly benefit from, the intervention of an APS program. Notifying a designated APS agency of the existence and identity of such patients is incumbent on the physician in the more than 40 states with mandatory reporting statutes for suspected adult abuse and neglect (including self-neglect). In states without mandatory reporting laws, physicians making good faith voluntary reports to APS are immune from any liability connected with that reporting.37 Just as written reports and live courtroom testimony are sought from physicians in routine guardianship cases, so too is this form of evidence highly valued in special protective services proceedings. The deference paid to physician opinion may be even greater in the latter situation, where less stringent eligibility criteria and procedural formalities often empower the presiding judge with even broader discretion in making findings and fashioning remedies. As noted, it frequently is best for APS interventions to be accepted voluntarily by older persons who need help to maximize self-control over their lives. The physician has a duty to counsel decisionally capable patients about available long-term care alternatives—both institutional and home- and community based—and their relative advantages and disadvantages, or at least to direct patients to appropriate information sources. Finally, the physician’s potential contribution to service planning and placement activities for the nonindependent elderly patient should not be forgotten. The ultimate
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goal is not simply to obtain protective services, whether on a voluntary or involuntary basis. Rather, the key is to assure the quality and appropriateness of the services actually provided for the older individual involved. Identification, referral, and evidence presentation should not be the end of physician involvement. Social service agencies are not merely a convenient place to deposit unwanted elders, and it is just as possible for an older person with limited personal resources to be “dumped” harmfully into the community as into a nursing home or public mental institution. Older individuals are entitled to receive reasonable continuity of care from their physicians. If an older person changes placement (e.g., moves from a private home to an assisted living complex or a nursing facility), the principle of nonabandonment legally obligates the physician to facilitate continuity of medical care either by continuing to treat the patient personally or by making a referral to another competent, willing physician whose services are acceptable to the older person.
Confidentiality In the course of performing their professional activities, physicians every day learn very personal, intimate information about their older patients. This knowledge of personal patient information imposes certain duties of confidentiality on the physician. Fulfilling these duties can, in specific factual situations, raise substantial legal questions. As a general legal precept, physicians have the duty to hold in confidence all personal patient information entrusted to them. This obligation has been enforced through civil damage suits based on both statutory (legislative) and common (judge-made) law and embodied in virtually all state professional practice acts and implementing regulations. Some states have enacted statutes that provide monetary damages for physician breach of confidentiality even if the patient is unable to prove any tangible injury. State medical practice acts provide that violation of the duty of confidentiality is a potential ground for revoking, denying, or suspending a physician’s license to practice medicine. Detailed federal regulations38 are being developed to safeguard the privacy of medical records, based on a mandate in the Health Insurance Portability and Accountability Act of 1996.39 The patient’s reasonable expectation of privacy extends to all members of the health care team. The difficulty in applying this general legal principle to concrete situations involving older patients is that the physician’s duty to maintain as confidential the disclosures and medical records of the patient is not an absolute, inflexible obligation. The fact that a duty is not absolute does not mean it is not important. However,
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when a duty is only prima facie, or presumptively applicable, one must consider whether there are relevant factors present that justify or even compel overriding that prima facie obligation in a particular case. The first exception to the usual rule of confidentiality is that a patient may waive, or give up, the right to confidentiality if this is done in a voluntary, competent, and informed manner. This is accomplished daily in the health care area to make information available to third-party payers such as the Health Care Financing Administration that operates Medicare40 and Medicaid, quality-of-care evaluators and auditors such as JCAHO inspectors or reviewers from the state’s Peer Review Organization (PRO), and other public and private entities including long-term care ombudsmen and the patient’s legal representatives. The physician has an obligation to cooperate fully in the patient-requested release and transfer of medical information. The patient’s waiver of confidentiality and request for release of information should be honored only if it has been documented thoroughly in writing. Further, the identity and legitimate authority of the record seeker should be verified satisfactorily. Second, when the rights of innocent third parties are jeopardized, the general requirement of confidentiality may yield. For instance, the expressed threat of a dangerous psychiatric patient to kill a specific victim, coupled with the patient’s apparent present ability (not hard to imagine even for an elderly person in today’s climate of easy handgun availability) and intent to make good on the threat, arguably should be reported to the intended victim and to law enforcement officials.41 Questions about confidentiality versus disclosure will arise increasingly in the context of automobile driving by older persons.42 Once the patient has developed agerelated neurodegenerative illness and sensory impairments, the decision to stop driving may develop into an area of tension between patient and physician if informal and noncoercive attempts at persuasion fail to bring about voluntary abstention from the roads.43 Physicians must be knowledgeable about relevant mandatory reporting requirements regarding unfitness for driving; the law on this point varies among the states.44 Only a few jurisdictions presently have statutes that expressly mandate physicians to report impaired drivers to public authorities.45 Even in the absence of a mandatory reporting statute, some physicians have been held civilly liable when they should have foreseen a patient’s dangerous driving but did nothing to prevent it and the patient then harmed an innocent third party in a motor vehicle accident.46 Further, physicians should inform drivingimpaired patients of the patients’ own legal responsibility to notify the state concerning their impairment. Third, the patient’s expectation of confidentiality must yield when the physician is mandated by state law to report to specified public health authorities the existence
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of certain enumerated conditions reasonably suspected in a patient. The physician should be familiar with the content of mandatory reporting statutes and regulations in force in their own jurisdiction. Such requirements may be based on the state’s inherent police power to protect the health, safety, and welfare of society as a whole. This rationale would support, for example, reporting requirements concerning infectious diseases or vital statistics (e.g., birth and death). Alternatively, reporting of certain conditions may be obligatory under the state’s parens patriae (“father of the country”) power to protect those individuals who are unable to care for their own needs. Mandatory reporting of elder abuse or neglect would be justified on this ground (see Chapter 73). Finally, the physician may be compelled to reveal otherwise confidential patient information by the force of legal process, that is, by a judge’s issuance of a court order requiring such release. This order is a possibility in any type of lawsuit in which the patient’s physical or mental condition is in dispute. The Health Insurance Portability and Accountability Act (HIPAA) of 199647 stipulated that if Congress did not enact comprehensive requirements regarding standards with respect to privacy of individually identifiable health information by August 1999, DHHS should issue regulations on this subject. On November 3, 1999, DHHS published proposed comprehensive rules setting federal standards in this sphere48 after the close of the public comment period on February 17, 2000, DHHS had an opportunity to modify the regulations before they would be issued in final, binding form. Once adopted, the federal rules will supersede state medical records confidentiality laws, unless a state law is more stringent in its protections of patient privacy than the federal requirements. The right of privacy may be particularly important to today’s older individuals who, as part of a cohort predating computers and modern mass communication technologies, often assign an even higher value to personal privacy than do members of subsequent generations. The right of privacy too often is compromised in treating older patients, particularly those with cognitive or emotional deficits. An older person who has significant mental capacity may, nonetheless, through appearance or demeanor leave the impression that it is appropriate to discuss his or her clinical problems and management with relatives or friends. Every safeguard should be employed to adhere to the ordinary standards of confidentiality unless there is express, or at least unambiguously implied, permission from the patient to do otherwise or the mental condition of the patient is so disabling as to dictate involving relatives or friends within the decision-making circle. Particularly in situations of marginal or questionable patient capacity, the physician should be scrupulous in making sure that the patient has no objection to family or friend
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involvement. When the family or others with appropriate authority are involved, confidential communications about the patient should be carefully handled to avoid unauthorized disclosure beyond those with a right and a need to have access to the information.
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19.
20.
Conclusion 21.
In some respects, as older patients as a group tend to bring disproportionately few malpractice claims against their physicians, legal liability concerns are less of a factor in geriatrics than in many other branches of medicine. In many ways, however, the elderly offer physicians a set of complex and unique legal challenges. This chapter has outlined some of the more salient legal considerations confronting and guiding physicians who care for older patients, in the hope of raising awareness of these issues in a way that will be beneficial both to physicians and to the older individuals who depend on them.
22.
23. 24.
25.
References 1. Liang BA. Health Law & Policy: A Survival Guide to Medicolegal Issues for Practitioners. Boston: ButterworthHeinemann; 2000. 2. 20 Code of Federal Regulations Part 404. 3. 29 United States Code § 621 et seq. 4. 42 United States Code § 1320c. 5. 42 United States Code § 11133–34. 6. Kohn L, Corrigan J, Donaldson M. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000. 7. Liang BA. Error in medicine: legal impediments to U.S. reform. J Health Polit Policy Law. 1999;24:27–58. 8. Public Law 105–33. 9. Noble AA, Brennan TA. The stages of managed care regulation: developing better rules. J Health Polit Policy Law. 1999;24:1275–1305. 10. 45 Code of Federal Regulations Part 46. 11. 45 Code of Federal Regulations § 46.102(d). 12. National Bioethics Advisory Commission. Research Involving Persons with Mental Disorders that May Affect Decisionmaking Capacity. Washington, DC: available at www.bioethics.gov/capacity. 13. Kapp MB. Regulating research for the decisionally impaired: implications for mental health professionals. J Clin Geropsychol. 2000. 14. Dubler NN, ed. Symposiun on the doctor–proxy relationship. J Law Med Ethics. 1999;27:5–86. 15. King NMP. Making Sense of Advance Directives, rev ed. Washington, DC: Georgetown University Press; 1996. 16. Public Law 101–508, §§ 4206, 4751. 17. 110 S.Ct. 2841 (1990). 18. Bradley EH, Blechner BB, Walker LC, et al. Institutional efforts to promote advance care planning in nursing homes:
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27. 28. 29. 30.
31. 32. 33. 34.
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38. 39. 40.
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challenges and opportunities. J Law Med Ethics. 1997;25: 150–159. Molloy DW, Guyatt GH, Russo R, et al. Systematic implementation of an advance directive program in nursing homes: a randomized controlled trial. JAMA. 2000;283: 1437–1444. Sabatino CP. The legal and functional status of the medical proxy: suggestions for statutory reform. J Law Med Ethics. 1999;27:52–68. Zimny GH, Grossberg GT. Guardianship of the Elderly: Psychiatric and Judicial Aspects. New York: Springer; 1998. Hoffmann DE, Boyle P, Levenson SA. Handbook for Nursing Home Ethics Committees. Washington, DC: American Association of Homes and Services for the Aging; 1995. Sabatino CP. Survey of state EMS-DNR laws and protocols. J Law Med Ethics. 1999;27:297–315. Leon MD, Wilson EM. Development of a statewide protocol for the prehospital identification of DNR patients in Connecticut including new DNR regulations. Ann Emerg Med 1999;34:263–274. Council on Ethical and Judicial Affairs, American Medical Association. Medical futility in end-of-life care. JAMA. 1999;281:937–941. Leonard CT, Doyle RL, Raffin TA. Do-not-resuscitate orders in the face of patient and family opposition. Crit Care Med. 1999;27:1045–1047. Zuckerman C. Looking beyond the law to improve endof-life care. Generations. 1999;13:30–35. Johnson SH, ed. Symposium, on legal and regulatory issues in pain management. J Law Med Ethics. 1998;26:265–352. Angell M. Caring for the dying—Congressional mischief. N Engl J Med. 1999;341:1923–1925. Orentlicher D, Caplan A. The Pain Relief Promotion Act of 1999: a serious threat to palliative care. JAMA. 2000;283: 255–258. Vacco v. Quill, 117 S. Ct. 2293 (1997). Washington v. Glucksberg, 117 S. Ct. 2302 (1997). Or. Rev. Stat. §§ 127.800–.897. Chin AE, Hedberg K, Higginson GK, et al. Legalized physician-assisted suicide in Oregon—the first year’s experience. N Engl-J Med. 1999;340:577–583. Ganzini L, Nelson HD, Schmidt TA, et al. Physicians’ experiences with the Oregon Death With Dignity Act. N Engl J Med. 2000;342:557–563. Kapp MB. The “voluntary” nature of nursing facility admissions: legal, practical, and public policy implications. N Engl J Crim Civil Confine. 1998;24:1–35. Quinn MJ, Tomita SK. Elder Abuse and Neglect: Causes, Diagnosis, and Intervention Strategies, 2nd Ed. New York: Springer; 1997. 64 Federal Register 59,918 (November 3, 1999). 42 United States Code §§ 1320d through 1320d-8. U.S. General Accounting Office. Medicare: Improvements Needed to Enhance Protection of Confidential Health Information. GAO/HEHS-99-140. Washington, DC: USGAO; 1999. Tarasoff v. Regents of the University of California, 17 Cal.3d 425, 551 P.2d 334, 131 Cal.Rptr. 14 (1976).
83. Medical Treatment and the Physician’s Legal Duties 42. Council on Ethical and Judicial Affairs. Impaired Drivers and Their Physicians. Chicago: American Medical Association; 1999. 43. Johnson JE. Urban older adults and the forfeiture of a driver’s license. J Gerontol Nurs. 1999;25:12–18. 44. Marottoli RA. New laws or better information and communication? J Am Geriatr Soc. 2000;48:100–102.
1231 45. Reuben DB, St. George P. Driving and dementia: California’s approach to a medical and policy dilemma. J Am Geriatr Soc. 1996;164:111–121. 46. Weintraub MI. Driving and Alzheimer disease [letter]. JAMA. 1996;275:182. 47. Public Law No. 104–191, 110 Stat. 1936 (1996). 48. 64 Federal Register 59918 (Nov. 3, 1999).
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84 Determination of Decision-Making Capacity Jason H.T. Karlawish and Robert A. Pearlman
An older person’s decision-making capacity determines their ability to direct his or her care. They can choose whether to receive a test or a treatment, and even direct others to make choices for them. If the patient lacks decision-making capacity, however, they may not be able to exercise their autonomous choices. Other people may need to decide for them. Decision-making capacity and the related concept of competency have received extensive conceptual development in bioethics and the law.1,2 This development has occurred largely because decision-making capacity is one of the essential components of the theory of informed consent. This theory is a robust guide for difficult decisions such as determining whether a person should be hospitalized against their will, have a surrogate assume authority over their own care, or even be enrolled in potentially risky research. Unfortunately, clinical medicine has been slow to adopt this theory into the day-today practice of medical decision making.3 Two clinical conditions emphasize the need for geriatricians to understand these concepts and to know how to apply them in clinical practice. First, elderly people are more likely than younger adults to experience illnesses that impair their ability to make decisions.4–6 These illnesses include neurodegenerative dementias, psychiatric illnesses, delirium, and impairments in hearing and vision. In fact, the initial diagnostic clue that a patient has one of these potentially treatable medical problems may be the discovery of the ethically challenging problem that a patient has difficulty making a decision. Second, an appreciable number of elderly people refuse lifesustaining treatment that their health care providers recommend. Although refusing treatment may be a reasonable clue that a patient has impaired decisionmaking capacity, disagreement with a physician’s recommendation is not the sole grounds for finding a patient incompetent.7 A physician who is skilled at assessing decision-making capacity will find this clinical circumstance an ideal opportunity to assess the patient’s
decision-making capacity and to discuss options of care, including palliative care. Collectively, these points illustrate that the ability to assess decision-making capacity is not simply a matter of reluctantly accommodating the dictates of law into the practice of medicine. It is actually part of the competent and ethical practice of geriatric medicine. A physician who can efficiently practice the skills of assessing how a patient makes a decision has effective skills to foster communication with a patient and to identify clinically significant impairments in a patient’s cognition and emotion. In this way, the physician fulfills the roles of the “doctor” as teacher and healer. The purpose of this chapter is to summarize the importance of determining decision-making capacity and to explain the standards for assessing it and judging competency. Following this introductory material, the chapter discusses particularly challenging situations and proposes mechanisms for physicians to improve the quality of their skills.
The Concepts of Competency and Decision-Making Capacity The terms competency and decision-making capacity are often used interchangably, or they are distinguished on the basis of the person’s profession. A common and technically correct distinction is that a judge determines whether a person is competent while a physician determines whether the person has decision-making capacity. Clinical practice, however, illustrates that this distinction collapses. The consequences of a physician’s judgment that a patient lacks decision-making capacity are that the patient is not competent to make the decision.8 Regardless of who is assessing a person’s ability to make a choice, however, the terms competency and decision-making capacity do have meaningful differences. The difference between “decision-making capacity” and “competence” is that the former describes a person’s 1233
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abilities to make a decision. It is assessed according to a number of standards, described next. In contrast, competency describes the judgment that a person’s decisionmaking capacity is adequate to make a particular decision. The former is a condition of a person, whereas the latter is a judgment that integrates information which describes a person’s capacities and the context and consequences of the decision.9 Competency and decision-making capacity are distinct concepts. It is entirely possible that a physician could determine that a person lacks decision-making capacity but is competent to make a decision, as might happen frequently if physicians took the time to examine, in detail, their patients’ choices. For example, a patient who agrees to take hypertension treatment may fail to understand certain facts about that treatment. (“The pills work because they reduce stress.”) But, although this misunderstanding represents impaired decision-making capacity, it has harms that are essentially nil. Hence, given the context and consequences, any reasonable practitioner (or judge) would conclude that the person is competent to take the medication. A less common scenario is the patient who has decision-making capacity but is not competent, as would occur in the case of a legal criterion that establishes who is competent. For example, a very bright 12-year-old may fulfill the standards of decisionmaking capacity but, as a child, as a matter of law, is not competent.
The Importance of Assessing Decision-Making Capacity The essential attributes that a person needs to make a decision are cognitive skills and a set of values that allow the person to categorize and weigh the importance of information. A number of medical diseases and geriatric syndromes can impair these attributes. These diseases include neurodegenerative dementias such as Alzheimer’s disease and frontotemporal dementia, psychiatric diseases such as major depression and anxiety, and medical illnesses that precipitate the common clinical syndrome of delirium. Data document notable prevalence of incompetency and impairments in decision-making capacity among patients with some of these disorders. Among patients with Alzheimer’s disease who have a Mini-Mental Status Examination score between 12 and 30, the inability to understand information needed to make a decision about medical care is extremely common (nearly 90%). Nearly half these patients may retain the ability to appreciate information, however.10 Moreover, a patient’s competency will vary depending upon the decision at hand. In one study, 20% of Alzheimer’s disease patients were competent to complete an advance directive.11 Psychiatric illnesses can also affect decision-making capacity and lead
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to incompetency. A study that compared the competency of hospitalized patients with depression and schizophrenia found that the prevalence of incompetency varied from 52% of the patients with schizophrenia to 24% of the patients with depression.12 Finally, patients without clinically significant impairments in cognition or affect can be incompetent. For example, 12% of hospitalized patients with angina were not competent to make a treatment choice,12 and among studies of cognitively normal, community-dwelling elderly, 22% were not competent to complete an advance directive11 and 7% to consent to treatment of a hip fracture.13 Three key conclusions can be drawn from these data. First, not all patients with diagnoses that classically affect cognition have impaired decision-making capacity. Second, an affective disorder such as depression can affect decision-making capacity. Finally, some patients with a diagnosis that typically affects cognition may have impaired decision-making capacity. For the clinician, this means that the model of using risk factors to generate pretest probabilities of a diagnosis can be adapted into the practice of assessing decision-making capacity. A patient with an illness such as major depression or mild dementia is more likely to have impaired decisionmaking capacity than one who does not. The importance of assessing a patient’s decision-making capacity rests in the need to balance two simultaneous ethical commitments to adult patients—to respect an adult person’s autonomy and to promote that person’s health and well-being. When a person has decision-making capacity, their autonomy is generally honored and decision making occurs in light of medical recommendations and patient values and preferences. In short, a patient gives an informed consent. Patient well-being is assured because a patient who understands a clinical situation and participates in decision making is more likely than the physician to know what is best for their well-being. For example, when a patient refuses a life-sustaining treatment because they give greater weight to quality of life than to the potential quantity of life, this personal choice reflects their assessment of the trade-offs between quality and quantity of life. However, a patient who cannot think through such trade-offs lacks decision-making capacity and may not be competent. If the patient is not competent, respecting that patient’s choice as autonomous is both an ethical and medical error. In this situation, the physician’s duty is to seek the decision of others, in particular, family or a surrogate, to make the decision. In summary, it is important to assess decision-making capacity because it serves as a means to balance a physician’s simultaneous commitments to respecting a patient’s autonomy and promoting their well-being.14 Having assessed a patient’s decision-making capacity, a physician then judges whether the patient is competent to make the decision.
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The Standards for Assessing Decision-Making Capacity At least one of five standards constitutes decision-making capacity.15 These standards were developed in law and bioethics, and they are intuitively sensible elements of how a rational person ought to make a decision. They provide the foundation for the judgment of a patient’s competence. The physician assesses the patient’s performance on each standard and then uses the results of these assessments to decide whether a patient’s decisionmaking capacity is inadequate to make the decision. The five standards of decision-making capacity are listed in Table 84.1. The first is the ability to communicate a choice, which describes a patient’s ability to consistently state a choice (“I do not want the surgery.”). Unlike the other standards, this standard makes no claim upon the patient’s reasons. In a sense, it is the simplest standard. A physician assesses this by asking the patient “What would you like to do?” Much of the day-to-day practice of clinical medicine relies upon this standard or even a weaker version of it, namely, a patient’s nonverbal acquiescence to an intervention such as checking their blood pressure. Diseases that can impair a patient’s ability to fulfill this standard include communication disorders and extreme states of anxiety that cause a patient to rapidly change choices. The second standard is the ability to make a reasonable choice. Like the first, this standard is quite simple but unlike the first it introduces content to the choice. The content is the “reasonableness” of the choice in which reasonableness is not necessarily defined by the patient’s values but the values a “reasonable person” has; this is obviously a blunt standard to apply. For example, a physician who relies solely upon this standard would likely find that an otherwise healthy patient who refuses a lowrisk and likely beneficial intervention such as surgery for a noninvasive breast cancer would have impaired decision-making capacity. Hence, adherence to this standard alone risks a paternalistic practice of medical decision making. Diseases that can impair a patient’s ability to fulfill this standard include those that cause delusions and marked deficits in judgment such as dementia and schizophrenia. Standards three through five are more substantive than the first two because they require the physician to assess
Table 84.1. The standards for assessing decision-making capacity. The ability to make a choice The ability to make a reasonable choice The ability to appreciate The ability to reason The ability to understand
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the patient’s functional cognition. The third standard, appreciation, describes a patient’s ability to recognize that, regardless of her choice, the facts of the decision apply to her. These facts include the diagnosis (“I know you said I have cancer and that’s what this is.”) and the options for treatment (“I can leave it alone or have the surgery.”). This standard requires that the patient recognize the relevance of the facts regardless of how the patient values those facts. Diseases that cause delusions or disassociation are likely to impair a patient’s ability to fulfill this standard. The fourth standard of decision-making capacity is reasoning. The ability to reason describes a patient’s ability to generate consequences and compare them. (“If I have the surgery, I will have given up on my faith in my ability to heal myself. If I do not have the surgery, I’ll take a chance the cancer could spread.”) To fulfill this standard a patient has to recognize the different options, generate the consequences of each, and compare them. The ability to achieve this standard is impaired by conditions that reduce executive function, which means the ability to attend to and compare more than one concept. Diseases that impair attention such as delirium and frontal dementia can impair a patient’s ability to fulfill this standard. The fifth standard of decision-making capacity is understanding, the patient’s ability to paraphrase back the meaning of the information that the physician disclosed to her. (“A surgery will involve cutting into my skin, removal of my gallbladder, and a 3-week period of recovery.”) To fulfill this standard a patient has to “say back” or paraphrase the information the physician disclosed. In doing this, the patient demonstrates that they grasp the meaning of the information. Obviously, the more facts the physician discloses, the more difficult it becomes for the patient to achieve understanding. Indeed, a physician could set the fact content so complex that even a colleague would “fail.” Clearly, a judgment is required as to what facts are essential for making the decision. Understanding is most dependent on a patient’s memory and language. Hence, diseases that impair memory and language such as Alzheimer’s disease and aphasias can significantly impair a patient’s ability to fulfill this standard. In theory, the five standards exist along a continuum from the simplest (communicating a choice) to the hardest (understanding). One study of patients with Alzheimer’s disease suggests that this is in fact true.10 However, patients with depression and schizophrenia have a different pattern of complexity.12 The significance of this is that the physician cannot simply rely upon the “hardest standard” as a screen for decision-making capacity. Instead, a physician can consider these standards as generally falling into two categories: the first two standards are simpler and the last three are more stringent.
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How to Assess Decision-Making Capacity The standards of decision-making capacity provide structure to the physician’s assessment. The physician uses the results of the assessment to decide what degree of performance on which of the standards is adequate to decide that a patient has decision-making capacity. A physician needs to have set routines to assess the standards and to use the results of the assessment. General rules to assess decision-making capacity are to use open-ended questions that allow the patient to think aloud, to use silent pauses rather than a battery of questions, and to sit faceto-face with a patient rather than at an unequal posture such as standing at the foot of the patient’s bed. To begin an assessment it is sensible to inform the patient of the purpose of the questions that will follow. A useful opening script might be as follows. “I’d like to take some time to go over the options of treating your breast cancer. One of my roles as doctor is as teacher. I’m a doctor of medicine, so my responsibility is to teach you about your health and options for taking care of it.” To then focus on the issue of assessing decision-making capacity a physician might say, “I’d like to go over the decision you face. Can we talk about what you see as your medical problems and the options for taking care of them?” Table 84.2 describes scripted lines to demonstrate how to assess each of the standards. Assessing the abilities to make a choice and a reasonable choice are relatively straightforward. Little skill is needed to assess these standards beyond giving the patient the opportunity to actually make a choice. As simple as this is, in the conduct of a busy office practice, a physician can forget to ask the patient the simple questions listed in Table 84.2. Table 84.2. How to assesses decision-making capacity. The ability to make a choice: “So those are the options. What would you like to do?” The ability to make a reasonable choice: Same as ability to make a choice. Physician judges whether the decision is “reasonable.” The ability to appreciate: Appreciate illness: “Can you tell me in your own words what you see as your problem?” Appreciate treatments: “Can you tell me in your own words what you see as your options for your problem?” The ability to reason: Comparative reasoning: “Regardless of whether you want to try surgery or medicine, how would taking the medicine be different from having the surgery?” Consequential reasoning: “Regardless of whether you want to try surgery or medicine, how would having the surgery affect your daily life? What about the medicine?” The ability to understand: “Can you tell me in your own words what I told you about the reasons for and against having the stress test?”
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A key point in the assessment of appreciation is to have the patient separate their choice from their appreciation of its direct relevance to their situation, which is not an immediately obvious task to most patients. Hence (see Table 84.2), a physician asks the patient to separate the choice from appreciation of the options. Open-ended probes can be useful to allow a patient to clarify an an swer. A physician assesses reasoning by asking the patient to compare options and generate consequences of options. To assess the ability to understand, the physician should ask the patient to say in their own words the information the physician has disclosed. In the case of complex information, it is sensible to disclose just parts of the information at a time. It is generally not useful to disclose information and then ask a person “Do you understand?” Most people avoid admitting their misunderstanding. The assessment of decision-making capacity occurs throughout the daily practice of medicine. When a patient participates in the decision, does not evince any cognitive impairment or affective disorders, and agrees to a recommended treatment that has benefits and minimal risk compared with alternative treatments, it is reasonable for the physician to presume that the patient has decisionmaking capacity. This scenario describes much of outpatient practice. Conversely, when a patient is comatose, delirious, severely demented, or severely psychotic, it is reasonable for the physician to either observe that the patient does not have the capacity to make decisions or decide that further simple questions are needed to assess decision-making capacity. However, between these two points there is an enormous middle ground. The principal question for a physician is what circumstances or clinical data should suggest an evaluation of a patient’s decision-making capacity. Physicians should question a patient’s decision-making capacity when the patient’s cognition or affect appears out of the ordinary,16 such as described in Table 84.3. These conditions fall into several categories: cognitive impairment, behavioral abnormalities, affective disorders, “unreasonable” or unusual choices, and a choice that is antithetical to previously held values and preferences.2,17,18 These conditions do not signify the lack of decision-making capacity or incompetency, but they do signify clues that there may be impairments in decisionmaking capacity and even incompetence. For example, a Mini-Mental State score that suggests cognitive impairment does not of itself describe impaired decisionmaking capacity, and a physician who uses it to do so would produce both false-positive and false-negative assessments of decisional capacity.7,19 Similarly, problems with behavioral functions may indicate problems that interfere with decisional capacity, yet the link between these two constructs has not been validated.20 After one of these triggering cues, the physician needs to consider whether to assess the patient’s decision-making capacity.
84. Determination of Decision-Making Capacity Table 84.3. Clues that may warrant an evaluation of decision-making capacity. Cognition and neurobehavioral functions Mini-Mental State examination score suggesting marked cognitive impairment Disorientation Change in preferences each time patient is approached Attention deficits (e.g., somnolence) Disability with language Impaired short-term memory Impaired reasoning Impaired recognition Acute change in functional status Diminished independence in activities of daily living Functional decline in social activities Acute change in behavior Psychologic modifiers of cognition and reasoning Untreated depression Distorted patient assessment of self, world, and future Anxiety Delusions Paranoia False beliefs Unreasonable or unusual choices Wanting high-burden (e.g., side effects, risks)/low-benefit treatment when available, alternative treatments seem to have better profiles Refusing high-benefit/low-burden treatment when available, alternative treatments seem to have worse profiles Inability to express a reason for such a choice Shift in values or preferences Expressing a preference for or against treatment that conflicts with long-standing values or previously expressed preferences Family members communicate that the patient is not evincing a choice that makes sense according to the patient’s history
How to Make the Judgment of Incompetence All adult patients are competent until proven otherwise. The burden of proof that the patient is not competent rests upon the physician. The general approach to assessing whether a patient lacks decision-making capacity and is not competent is to use a sliding scale concept of competency assessment.21 The concept describes the physician’s judgment about the adequacy of a patient’s decision-making capacity in the context of the consequences of the various alternatives. The physician must categorize the consequences of the various alternatives. Then, given these potential consequences, the physician judges whether the patient has adequate decision-making capacity to make the decision. With treatments that are relatively safe and likely to provide large benefits, it is reasonable to set a simple standard for assessing the decision-making capacity of a patient who agrees with this treatment. For example, agreement to receive antibiotics for an acute and reversible bacterial infection may be sufficient evidence of capacity to make a competent choice. However, the
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refusal of this treatment would warrant a close assessment of the patient’s appreciation, reasoning, and understanding. Assessing these higher standards is not meant to challenge the patient’s decision, but to assure the patient and the physician that the patient’s choice respects their values. In general, a high standard should be applied when a patient refuses a high-benefit and lowrisk intervention or needs to make a decision about an intervention with high risks. As in all medical judgments, physicians can make falsepositive or false-negative errors. A false-positive error describes judging that a patient is incompetent when, in fact, they are competent. In contrast, a false-negative error describes judging that a patient is competent when, in fact, the person is incompetent. These errors have unique consequences. A false-positive error causes the patient to experience a loss of autonomy, respect, and dignity that can lead to feelings of frustration and loss of control to the degree that a patient feels imprisoned. Second, this type of error threatens trust in the doctor. Third, family members and physicians who are making the decisions for the patient are often inclined to “overtreat” when compared to the preferences of patients.22,23 This tendency increases the likelihood of iatrogenic complications and unnecessary health care costs. Fourth, it is possible that surrogate decision makers may choose to undertreat the patient. This attitude also may augment the patient’s feelings of loss of respect and may result in significant harm, especially if the treatment under consideration is life sustaining and the patient dies as a result. Fifth, this error may result in unnecessary court proceedings and costly delays in treatment. In contrast, a false-negative error undermines the principle of beneficence. This type of error increases the risk of an incoherent treatment policy. For example, patients with decisional capacity usually make medical choices that conform with personal values about the goals of their health care. When patients who have lost decisional capacity are still making decisions, this coherence is seriously threatened. Finally, false-negative errors undermine the desired societal protections afforded by surrogate decision makers. To minimize these kinds of errors, physicians should appreciate the value of instruments that measure the patient’s ability to perform each of the standards. These instruments can aid the assessment of decision-making capacity and the judgment of competency. In general, these instruments rely upon scoring a patient’s answers to questions. There are two possible standards to describe what is a normal score: matching scores to the independent judgment of a clinician who is expert in assessing competency24–27 or setting a cutoff score based on some degree of deviation from the scores of cognitively normal persons10,12 or the scores of the subject population.28 Instruments exist to assist in assessing a patient’s ability
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to execute an advance directive,11,24,28 enroll in research,29 refuse emergent medical care,25 and consent to hospitalization30 or to treatment of a medical illness.10,27 Although the value of these instruments has not been demonstrated in day-to-day clinical practice, research suggests that an instrument as simple as operationalized definitions of the standards for assessing decision-making capacity can produce moderate interrater agreement.31 Clinicians will find these instruments particularly useful in the care of patients who face a common decision such as a geriatrician who cares for nursing home patients who need to execute an advance directive. The value of instruments is that they can structure an assessment and limit the variability between physicians. In this way, patients are assured a fair assessment, which is particularly important because physicians have poor interrater reliability when they assess a patient’s competency.32 Another potential advantage of instruments is that the range of scores on the instrument can be correlated with scores on a brief and standardized measure of cognition. Knowing this relationship, a patient’s score on a measure of cognition allows the physician to estimate the likelihood that the patient is competent. A score that falls below a cutoff signals the need to scrutinize the patient’s decision-making capacity. A final advantage of scales is that they formalize the concept of “marginal competence.” The term describes the patient whose performance is impaired but not so much as to be obviously incompetent. In psychometric terms, this is the patient who lies just a few points above the cutoff of incompetence. The clinical significance of this concept is that it identifies a patent who may have limited capacity to make some decisions or who needs particular attention during follow-up care. It also identifies a patient who needs alternative or additional approaches to imparting information and trying to ensure comprehension.
What About When . . . ? Case 1: Fluctuating Mental Status History A physician enters a 76-year-old female patient’s room before morning rounds to obtain informed consent for a diagnostic procedure. The physician finds the patient to be somewhat confused. Her Mini-Mental State examination score is 24.
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Mini-Mental State score suggests cognitive impairment, but it is an insensitive measure of decisional capacity. An interview is required to assess both the patient’s decisionmaking capacity and the cause of the confusion. If the physician judges that the patient lacks decision-making capacity and is not competent at this time, the nonemergency procedure should be deferred. It would be premature to proceed by obtaining proxy consent.
Case 2: Decisional Capacity for Executing an Advance Directive History An older person desires an advance directive. Another physician has communicated that the purpose of a directive is to avoid overtreatment and abuses by the health care “system” near the end of life. The patient states that she wants a directive to avoid any unnecessary treatment.
Considerations Decisional capacity to choose a treatment is not the same as capacity to complete an advance directive.33 Choosing a treatment involves a real and immediate decision in the present time. Choosing treatment in a directive is more complicated. Patients need to understand and appreciate that the choices articulated in a directive will be used in the future when they are no longer capable of participating in decision making, that some choices involve medical treatments and designating a proxy, and that their choices may change over time, and if they do, the patient should change their directive. The patient should also be able to reason through the consequences of different treatments and health states.
Case 3: Patient Refusal of Psychiatric Consultation for Evaluation of Competency History An older man who resides in a nursing home is refusing oral antibiotics for a lower extremity cellulitis. In preliminary discussions with the physician, he refuses to discuss his problem or the reasons for the treatment. The patient refuses to see a psychiatrist for an evaluation of his competency.
Considerations Considerations The patient’s subtle confusion is both a clinical and ethical clue of a potential problem. The patient may have a delirium and may lack decision-making capacity. The
Refusal of a minimal risk and beneficial treatment signals a need to examine decision-making capacity. The reasons for the refusal should be explored. The patient may express legitimate concerns that have nothing to do
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with decision-making capacity. The reasons may extend beyond the nature of the specific decision and pertain to mistrust or loss of autonomy and control in the nursing home. The patient should be informed that the use of a second opinion minimizes the risk of errors in judgment. This communication should not convey a threat; instead, it is information about options. If the patient continues to refuse the assessment, the physician should recalibrate the usual balance between competency and incompetency. Instead of the default case of favoring competency, the physician should set them in equilibrium and seek substantial evidence of decision-making capacity from sources such as caregivers.
Case 4: Depression and Treatment Refusal History An 88-year-old female patient involved in a home care program has long-standing depression. Multiple treatment trials have not provided appreciable benefit. She is refusing admission to the hospital for intravenous antibiotics for cellulitis of her lower extremity.
Considerations The blanket use of a psychiatric diagnosis to determine impaired decision-making capacity is not appropriate. The physician must determine whether the diagnosis is directly affecting the patient’s decision making. For example, if the patient does not have any hope, feels worthless, or cannot envision a better future, then this likely would modify their ability to rationally weigh the benefits and burdens of a recommended treatment. It would further suggest that the depression is affecting the patient’s decision making and be grounds for the determination of incompetency. On the other hand, if the depression is not severe or due to its chronicity has become an authentic part of the patient’s personality, then decision-making capacity might not be compromised.34,35
Case 5: Requesting Cardiopulmonary Resuscitation Despite Terminal Illness History An older patient with disseminated breast cancer has failed the previous course of chemotherapy. Her physician decides that it would be sensible for the patient to have a “Do Not Resuscitate Order” on the chart. The physician asks the patient whether she would want them to try to restart her heart after it stops. Much to the physician’s surprise, the patient states that she wants cardiopulmonary resuscitation (CPR). The physician wonders whether the patient is competent.
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Considerations Many patients consider CPR to be more effective than it is. In the physician–patient interview to assess decisionmaking capacity, the physician should review the patient’s understanding of the likelihood of successful cardiopulmonary resuscitation in their circumstances. If the patient continues to desire CPR despite the likelihood of its failure, the basis for their preference should be explored. Reliance upon hope is not evidence of impaired decisionmaking capacity.
How Should Physicians Assure Quality Improvement? The determination of a patient’s decision-making capacity is a linchpin to the practice of quality medicine because it promotes patient self-determination and attempts to ensure beneficent outcomes. In general, physician skills and responsibilities have not been subjected to formal quality assurance. However, studies suggest that physicians’ knowledge and skills in assessing decision-making capacity and competency may be highly subjective and arbitrary.36 Thus, physicians need mechanisms to develop their knowledge and skills to determine decision-making capacity and competency.37 Physicians and physicians in training have several mechanisms to ensure the quality of their skills to assess decision-making capacity. Education should focus on knowledge of the standards for assessing decision-making capacity and the skills to assess the standards and the patient’s cognitive abilities and affect. Physician training of these skills should involve faculty mentoring and role modeling and expert critique from physicians such as psychiatrists. Routine clinical encounters with patients can serve as an opportunity to refresh skills in assessing decision-making capacity. Periodically, a physician should take the time to assess an evidently competent patient’s decision using the methods outlined in Table 84.2. After a physician determines that a patient has impaired decision-making capacity, if the clinical circumstances are nonemergent and the decision can be deferred, opportunities exist to improve a patient’s decision-making capacity. Stopping or changing medications, repeating the assessment, or providing decision aids may improve the patient’s decision-making capacity.38 This process of managing decisional incapacity offers opportunities for quality assurance monitoring. At the level of the hospital or nursing home, quality determinations of decision-making capacity can be ensured by clear policies that define who is responsible for these determinations, how it should be done, where the data should be documented, who should be involved if the determination is ambiguous, and how to resolve conflicting impressions by any of the stakeholders
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(patient, family, surrogate, physician). Policies should stress the attending physician’s responsibility and participation because the determination is grounded, in part, on understanding the patient’s situation, prognosis, and psychologic issues. Policies also can support witnessing the information provided in the process of informed consent. The mistaken judgment that a patient is competent may occur when a physician discloses limited information. Audits can promote quality assurance by reviewing similar cases and situations and identifying and evaluating lack of consistency. Random audits also can ask patients about their understanding of a current or recent treatment. Little attention is given to assessing decisional capacity when a patient or family is not objecting to a recommendation. In other words, there may be unrecognized problems with determination of decisional incapacity in circumstances when all stakeholders in the decision are in agreement.39 When this type of audit was used in a psychiatric hospital, half the respondents who assented to treatment appeared to have impaired decision-making capacity.40 Audits that characterize problems determining decision-making capacity can serve as catalysts for educational activities.
Summary Decision-making capacity is a central determinant of an older person’s ability to direct their own care. When a patient has decision-making capacity, patient autonomy and self-determination are generally honored. Decision making occurs in light of medical recommendations, patient preferences, and professional standards. When a patient lacks decision-making capacity, however, the substituted judgment and best interests of the patient are brought to bear.41 The risks of physical and ethical harms to the patient are substantial if a patient receives treatment without competent consent. In between these situations are patients who have difficulties making a decision but are likely competent. For these patients, assessing decision-making capacity structures the practice of effective communication and will likely reduce encounters with “difficult” or “demanding” patients. All physicians in clinical practice should be comfortable with assessing decision-making capacity. The physician needs to remember three important considerations: (1) the purpose of assessing decision-making capacity and competency is to resolve the tension between respect for the patient’s self-determination and the promotion and protection of their well-being; (2) decision-making capacity and competency both refer to a patient’s ability to make a specific decision; and (3) the patient is presumed to be competent unless something triggers a question of impaired decision-making capacity.
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When a decision involves choices between interventions that are relatively safe and likely provide large benefits, it is reasonable to accept a low standard of decisional capacity, such as the mere evidence of a choice. However, refusal of these interventions or a decision that involves greater than minimal risks or only marginal benefits should require a higher standard, such as requiring the patient to demonstrate understanding, appreciation, and reasoning. In general, this process will serve the interests of both the patient and physician because it fosters effective communication. The need for a combination of clinical judgment and common sense in the determination of decision-making capacity raises the possibility of wide variations in clinical practice. Educational programs, role modeling, use of second opinions, provision of advisory feedback from ethics committees, and other quality assurance mechanisms should be implemented to minimize this occurrence.
References 1. Faden RR, Beauchamp TL. Foundations in moral theory. In: A History and Theory of Informed Consent. New York: Oxford University Press; 1986:3–22. 2. Appelbaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med. 1988;319:1635–1638. 3. Braddock CH, Edwards KA, Hasenberg NM, Laidley TL, Levinson W. Informed decision making in outpatient practice: time to get back to basics. JAMA. 1999;282:2313– 2320. 4. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the impact of delaying disease onset. Am J Public Health. 1998;88: 1337–1342. 5. Berry K, Fleming M, Manwell L, Copeland L, Appel S. Prevalence of and factors associated with current and life depression in older adult primary care patients. Fam Med. 1998;30:366–371. 6. Flint AJ. Epidemiology and comorbidity of anxiety disorders in the elderly. Am J Psychiatry. 1994;151:640–649. 7. Buchanan AE, Brock DW. Deciding for Others: The Ethics of Surrogate Decision Making. Cambridge: Cambridge University Press; 1989:58. 8. Grisso T, Appelbaum PS. Thinking about competence. In: Assessing Competence to Consent to Treatment. A Guide for Physicans and Other Health Professionals. New York: Oxford University Press; 1998:17–30. 9. White BC. Current confusion surrounding the concept of competence. In: Competence to Consent. Washington, DC: Georgetown University Press; 1994:44–81. 10. Marson DC, Ingram KK, Cody HA, Harrell LE. Assessing the competency of patients with Alzheimer’s disease under different legal standards. Arch Neurol. 1995;52:949–954. 11. Fazel S, Hope T, Jacoby R. Dementia, intelligence, and the competence to complete advance directives [research letter]. Lancet. 1999;354:48.
84. Determination of Decision-Making Capacity 12. Grisso T, Appelbaum PS. Comparison of standards for assessing patients’ capacities to make treatment decisions. Am J Psychiatry. 1995;152:1033–1037. 13. Schmand B, Gouwenberg B, Smit JH, Jonker C. Assessment of mental competency in community-dwelling elderly. Alzheimer Dis Assoc Disord. 1999;13:80–87. 14. Faden RR, Beauchamp TL. The nature and degrees of competence. In: A History and Theory of Informed Consent. New York: Oxford University Press; 1986:288–293. 15. Grisso T, Appelbaum PS. Abilities related to competence. In: Assessing Competence to Consent to Treatment. A Guide for Physicians and Other Health Professionals. New York: Oxford University Press; 1998:31–60. 16. Culver C, Gert B. The inadequacy of incompetence. Milbank Q. 1990;68:619–643. 17. Sullivan MD, Youngner SJ. Depression, competence, and the right to refuse lifesaving medical treatment. Am J Psychiatry. 1994;151:971–978. 18. Searight H. Assessing patient competence for medical decision making. Am Fam Physician. 1992;45:751–759. 19. Folstein M, Folstein S, McHugh P. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychol Res. 1975;12:189–198. 20. Alexander M. Clinical determination of mental competence: a theory and a retrospective study. Arch Neurol. 1988;45:23–26. 21. Beauchamp TL, Childress JF. The sliding-scale strategy. In: Principles of Biomedical Ethics, 4th Ed. New York: Oxford University Press; 1994:138–141. 22. Bedell S, Delbanco T. Choices about cardiopulmonary resuscitation in the hospital: when do physicians talk to patients. N Engl J Med. 1984;310:1089–1093. 23. Uhlmann R, Pearlman R, Cain K. Ability of physicians and spouses to predict resuscitation preferences of elderly patients. J Gerontol. 1988;43:M115–M121. 24. Molloy DW, Silberfeld M, Darzins P, et al. Measuring capacity to complete an advance directive. J Am Geriatr Soc. 1996; 44:660–664. 25. Kaufman DM, Zun L. A quantifiable, brief mental status examination for emergency patients. J Emerg Med. 1995; 13:449–456. 26. Bean G, Nishisato 5, Rector NA, Glancy G. The psychometric properties of the competency interview schedule. Can J Psychiatry. 1994;39:368–376. 27. Etchells E, Darzins P, Silberfeld M, et al. Assessment of patient competency to consent to treatment. J Gen Intern Med. 1999;14:27–34.
1241 28. Mezey M, Teresi J, Ramsey G, Mitty E, Bobrowitz T. Decision-making capacity to execute a health care proxy: development and testing of guidelines. J Am Geriatr Soc. 2000;48:179–187. 29. Miller CK, O’Donnell DC, Searight R, Barbarash RA. The Deaconess informed consent comprehension test: an assessment tool for clinical research subjects. Pharmacotherapy. 1996;16:872–878. 30. Billick SB, Bella PD, et al. Competency to consent to hospitalization in the medical patient. J Am Acad Psychiatr Law. 1997;25:191–196. 31. Marson DC, Earnst KS, Jamil F, Bartolucci A, Harrell LE. Consistency of physicians’ legal standard and personal judgments of competency in patients with Alzheimer’s disease. J Am Geriatr Soc. 2000;48:911–918. 32. Marson DC, McInturff B, Hawkins L, Bartolucci A, Harrell LE. Consistency of physician judgments of capacity to consent in mild Alzheimer’s disease. J Am Geriatr Soc. 1997; 45:453–457. 33. Silberfeld M, Nash C, Singer P. Capacity to complete an advance directive. J Am Geriatr Soc. 1993;41:1141– 1143. 34. Ganzini L, Lee M, Heintz R. The effect of depression treatment on elderly patients’ preferences for life-sustaining medical therapy. Am J Psychiatry. 1994;151:1631–1636. 35. Lee M, Ganzini L. The effect of recovery from depression on preferences for life-sustaining therapy in older patients. J Gerontol. 1994;49:M15–M21. 36. Markson L, Kern D, Annas G, Glantz L. Physician assessment of patient competence. J Am Geriatr Soc. 1994;42: 1074–1080. 37. Kutner J, Ruark J, Raffin T. Defining patient competency for medical decision making. Chest. 1991;100:404–409. 38. Krynski MD, Tymchuk AJ, Ouslander JG. How informed can consent be? New light on comprehension among elderly people making decisions about enteral tube feeding. Gerontologist. 1994;34:36–43. 39. Kapp M. Liability issues and assessment of decision-making capability in nursing home patients. Am J Med. 1990;89:639– 642. 40. Appelbaum P, Mirkin 5, Bateman A. Empirical assessment of competency to consent to psychiatric hospitalization. Am J Psychiatry. 1981;138:1170–1176. 41. Karlawish JHT, Quill T, Meier DE. A consensus-based approach to practicing palliative care for patients who lack decision-making capacity. Ann Intern Med. 1999;130: 835–840.
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85 Ethical and Policy Issues in End-of-Life Care Melissa M. Bottrell, Christine K. Cassel, and Emily R. Felzenberg
Clinical medical ethics combines the disciplines of philosophy, behavioral science, law, and medicine to resolve moral issues and value conflicts in medicine. All physicians face ethical dilemmas, but the practice of geriatric medicine is particularly rich and ethically complex with respect to end-of-life care. Elders often face chronic illnesses for which treatments are costly or risky, have uncertain outcomes, or are unable to offer meaningful disease modification or prolongation of life.1 The ambiguity regarding beneficial outcomes colors decisions about often difficult trade-offs between treatments that may offer potentially significant reductions in quality of life versus treatments that may not extend life but may increase comfort and thus quality of life. Decisions to change the focus of care from curative interventions to more palliative care can produce anxiety for patients and family members. Additionally, many elders may have conditions that profoundly impair communication and cognition. The result is often uncertainty about who should make health care decisions, what constitutes informed consent, and how to ascertain what decision should be made. Finally, in the broadest sense, care for elders accounts for the largest segment of health care spending, half of which comes from public programs, leading to questions about the relative value of health care compared with other goods available in the market and the value of marginally effective or futile treatments when survival is not likely to be long. Such issues pose ethical questions about intergenerational resource transfers and ultimately moral issues related to rationing of medical resources. Approaching these difficult ethical issues requires both an awareness of how these concerns intersect the practice of geriatric medicine and a systematic approach to examine the issues. Bioethics offers numerous systematic approaches to ethical analysis of moral dilemmas, for which examples and training can be found in numerous texts.1–3 Many of these approaches use a set of basic principles that undergird both attitudes of the public as well
as personal values of physicians.4 These principles commonly include beneficence, respect for persons, fidelity, and justice. For purposes of this chapter, discussion of issues in geriatric medicine and end-of-life care is focused through the lenses provided by these principles. Discussion and implementation of decisions surrounding end-of-life care are critical. Attempts to improve endof-life care often focus on enhancing the role of patients (and when appropriate, family members) as partners in the decision-making process and resolving conflicts that interfere and may even prevent health care providers from creating a good dying experience for patients and their families.5 Using the principles of respect for persons, beneficence, fidelity, and justice together with the systematic approach offered by clinical medical ethics, the clinician can better address and resolve issues of ethical importance in end-of-life care, including understanding and appropriately managing ethical conundrums brought forth by issues of patient autonomy, withholding and withdrawing life-sustaining treatment, futility, do not resuscitate (DNR) orders, and physician-assisted suicide.
Transition Decisions: From Life-Sustaining Treatment to Palliative Management Decisions to forgo life-sustaining treatment occur under a multitude of conditions. They can be provoked when it is decided not to resuscitate a patient with advanced dementia, to maintain a resident in a nursing home rather than transfer them to the hospital for diagnostic or treatment interventions, to replace chemotherapeutic treatments focused on curing cancer with palliative radiation, or not to administer antibiotics to a bedbound elder with severe chronic obstructive pulmonary disorder (COPD). In each case, the decision-making process must use a benefit/burden analysis comparing the benefits of 1243
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treatment options against potential burdens of the treatment and potential side effects. Such decisions also take place within a larger social context such that benefit/burden analyses may differ for an older patient compared with a younger patient because of personal fears about aging and disability or stereotypes of aging.6 Some authors claim that advanced age may give persons a different perspective on what remains of life and the so-called closing biography—suggesting greater acceptance of mortality. Yet, providers cannot assume this stance simply because of patient age and must approach each patient individually. Within that analysis, the decision-making team of patient, family, and clinical professionals must consider how to respect the patient’s autonomy within their cultural context, support the family, and, to the extent possible, relieve the burden while also recognizing that some treatment courses may be futile.
Respecting Patient Autonomy Because freedom is so central to our philosophy as a nation, it follows that autonomy is an integral part of medicine in the United States. Mechanisms to respect patient autonomy run throughout the health care endeavor, from patient education materials regarding particular treatments or diseases, to physician training in how to communicate with patients, to forms for informed consent and advance directives. These tools aim to create an environment in which it is possible for the clinician to ascertain the beliefs, perspectives, and concerns of the patient so as to focus health care decisions in a manner that enhances patient autonomy. Autonomy may also conflict with beneficence, as for example, when a patient refuses a proposed treatment despite the physician’s best recommendation. Further, in this multicultural nation, not all individuals or families expect to express their autonomy in medical decisions in the manner most typically expected in legal contexts, especially when making the emotionally and technically fraught decisions at the end of life.
Advance Directives The practical difficulties and ethical dilemmas surrounding patient autonomy can be most obviously seen through examination of advance directives. In the United States, estimates of the percentage of persons who have executed advance directives range from 4% to 20%. Highly educated Caucasians are generally more receptive than other groups to advance directives and tend to forgo life-sustaining treatment at a higher greater rate. Those who are poor and nonwhite, particularly Hispanics and
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blacks, may feel apprehensive about treatment limitation because they already feel that they have restricted access to care, and thus are hesitant to give the health care system an additional reason to withhold care.7 Further, elders commonly do not complete an advance directive because they feel they can rely on others, in particular, their families, to make decisions for them, and, in fact, expect family members to help make complex health care decisions. Thus, for many elders, the particularly Western view of autonomy that stems from the individual and is expressed through a legal document does not apply to their expression of autonomy. For these elders, respect for persons may flow from a broader family perspective that includes considerations of family burdens of care or expectations that a particular family member (i.e., a son or daughter) is the appropriate decision maker.8 When an elder is cared for by family at home or is a longtime nursing home resident, specialized knowledge of the patient that comes from being surrounded by family members and clinicians who know the patient further helps to ensure that the patient’s vision of autonomy is supported. In practice, however, modern medical practice often involves myriad transitions between settings, through which neither the knowledge of the patient nor explicit directives about the patient’s end-of-life care preferences through advance directives are transferred. Inconsistencies in care between settings often result from the patient’s inability to communicate, lack of uniformity in advance directives or advance directive policies, fear of liability on the part of the institution, physician, and other health care providers, and absence of an advance directive. Even when advance directives exist and are accessible, they have limitations because the language is often ambiguous or lacks specific directions for the situation at hand. In unclear situations of patient preferences, nursing home staff may transfer residents to hospitals, and emergency medical technicians (EMTs) may administer cardiopulmonary resuscitation (CPR), although this may be contrary to patient wishes. A number of strategies are available to combat the lack of continuity of care and breaches of support for patient autonomy. Physicians should encourage patients to designate a specific health care proxy or surrogate who, depending on state law, can be empowered to speak for the patient when the patient is unable to do so. Further, improved communication between health care professionals and institutions is necessary. For example, hospital physicians and other clinicians should meet staff in nursing homes that regularly admit patients to their service. Doing so could provide contacts to which the clinician could turn when context is missing regarding the preferences or concerns of a particular patient or family and thus provide alternatives means by which to clarify patient’s wishes.
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As another approach, Oregon developed the Physician Orders for Life-Sustaining Treatment (POLST), a comprehensive, one-page order form to convey preferences for life-sustaining treatments during patient transfer from one care setting to another. The form specifies four categories of care, including (1) do not resuscitate (DNR) orders, (2) comfort care, (3) antibiotic use, and (4) tube feeding.9 Studies show use of the POLST leads to consistent respect for patient preferences to limit lifesustaining interventions.9,10 The POLST attempts to overcome problems regarding lack of availability of advance directives, failure to comply with the patient’s DNR order because the patient’s wishes are not known, and physician fear in signing DNR orders because care may be compromised or cannot be implemented without translation into a physician’s order. A high degree of respect for patient wishes is implied in the POLST. Several features contribute to the form’s effectiveness and consistency, including its statewide standardization, the pink color that makes it hard to ignore, easily locatable and clearly stated orders, acceptable and understandable language about the orders, and language specific to comfort care for pain and suffering. Specifically, the POLST, unlike an advance directive, limits specific treatments according to patient wishes and concurrently implements the preferences by putting them into the form of physician orders. The POLST offers a promising way to ensure patient end-of-life treatment preferences are respected. In addition to the POLST, several state legislatures are considering policies allowing EMTs to accept DNR (do not resuscitate) orders of patients being transferred to hospitals, hospitals are honoring advance registration of DNR orders to ensure compliance of out-of hospital DNR orders (i.e., those written in nursing homes), and advocates are supporting wallet cards, bracelets, or other forms of DNR order identification to increase compliance with patient wishes.
Withholding or Withdrawing Life-Sustaining Treatment Although patient preferences as expressed in advance directives may provide an outline of how to approach a patient’s care, at some point, decisions about treatment plans include hard choices of more than simply adding comfort care but also whether to withhold or withdraw life-sustaining interventions. Patients have a right to refuse treatment even if it is life sustaining.4 Withholding life support is defined as not providing a patient with medical interventions, such as CPR—the procedure most frequently withheld. Withdrawing life support is defined as removing previously initiated medical interventions, such as mechanical ventilation—the procedure most fre-
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quently withdrawn.11 In the clinical setting, definitional distinctions between withholding and withdrawing are often made. In some cases, it may seem morally and conceptually easier to withhold a particular procedure, such as mechanical ventilation when the outcome of beginning the procedure is less certain, than to withdraw treatment, because although a treatment may not provide meaningful outcomes, treatment withdrawal would result in death. Moreover, the timing of decisions often makes the distinctions between withdrawal and withholding seem relevant. Withholding can occur relatively suddenly if the patient goes into cardiac arrest. Withdrawing is often a gradual process and may involve administering analgesics and sedatives to the patient while removing a treatment. In practice, withdrawing is documented more frequently than withholding.11,12 Physicians often become morally, legally, and even psychologically committed to a treatment’s completion, once started,12 especially when the patient has been receiving the intervention for a long time. Thus, intervention withdrawal tends to occur more commonly for treatments that are invasive, expensive, scarce, or lead to a quick death once withdrawn, and tends to occur less often when treatments have been in place for a period of time or for the management of iatrogenic complications.13 Physicians may be “committed” to the ventilation or dialysis support that they initiated, even though the treatment fails to clearly benefit the patient. Treatment continuation may even cause patients to receive unwanted treatments despite their ethical and legal rights or that of their surrogates to refuse life-prolonging interventions. Health care professionals, including physicians and nurses, often lack training with regard to the clinical aspects of withdrawing intensive life-sustaining treatment, such as palliation of dyspnea. Such skills are necessary to provide effective end-of-life care. Despite the common use of the terms in practice, the definitional distinction between withholding and withdrawing lacks logical validity and moral relevance. All treatment decisions contain some of the elements of a withhold or withdrawal decision—the morally and legally relevant distinction between treatment decisions is that, irrespective of whether a life-sustaining treatment was withheld or withdrawn, the outcome is the patient’s death. The patient’s right to remove or not initiate lifesustaining treatments has both a moral and a legal grounding.
Legal Protections for Patient Autonomy The legal basis for respecting patient decisions at the end of life stems from a variety of sources—most famously from two cases that involved the withdrawal of life
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support. Karen Ann Quinlan and Nancy Cruzan were young women in persistent vegetative states whose families wished to have their life support removed. In Quinlan, the New Jersey Supreme Court recognized the right to withdraw medical interventions from an incompetent patient in accordance with the family’s belief that the patient would have wanted treatment withdrawn.12,14 In Cruzan, the U.S. Supreme Court affirmed the right to withdraw artificial life-sustaining treatments once the incompetent patient’s wishes are known with relative confidence.12,14 Many similar cases involve elderly people who lacked capacity because of dementia and in which the family sought to limit life-sustaining interventions. With very few exceptions, the cases all were upheld so long as the decision to limit treatment was consistent with the patient’s values. Philosophically, because the state has an interest in protecting and ensuring the continued life of its citizens, these cases validate the state’s legal interest and right in interpreting an individual’s preference, including those who are incompetent, to forgo lifesustaining treatment.12
Artificial Nutrition and Hydration Within the context of decisions to withdraw or withhold care, decisions regarding forgoing artificial nutrition and hydration often raise special concerns. Legally, intravenous lines or tubes are considered medical procedures and thus are subject to the same benefit to burden analysis as any other technical intervention, such as dialysis or mechanical ventilation; surrogates and patients have the right to refuse them as with any medical treatments.15 At the same time, providing food and water is felt by some to be a moral duty and an essential form of supportive care.16 The idea of food and water is also emotionally comforting to a family in their caring for a dying patient.4 Decisions to forgo nutrition and hydration typically commonly concern patients with moderate to severe loss of cognitive function due to Alzheimer’s disease or dementia, strokes resulting in loss of ability to swallow, endstage diseases (e.g., metastatic cancer), end-stage organ failure, and treatment complications (e.g., infection, aspiration pneumonia).4 Such situations, in which a family already carries a heavy emotional burden, are only made worse by the emotional feelings often connected to food and water. However, the eating process is a human contact quite different from intravenous, gastrostomy, or jejunostomy feedings. Continued intervention may result in fluid overload and significant discomfort whereas death after withdrawal may be more comfortable. Therefore, understanding and evaluating the reasons offered to forgo artificial hydration and nutrition and thus withhold or withdraw life-sustaining treatment are essential to pro-
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viding effective end-of-life care. Clinicians, patients and family members must consider when artificial nutrition and hydration may prolong dying and patient suffering, acknowledge that these treatments may lead to poor quality of life, and thus make the more humane choice to allow the patient to die.
Do Not Resuscitate Orders DNR (do not resuscitate) orders are recommended for most terminally ill patients17 and so require consideration in end-of-life care. People of very advanced age or with multiple advanced chronic illnesses who suffer an unwitnessed, out-of-hospital, cardiac arrest have restorative success approaching zero. Even for witnessed arrests, a return to earlier functioning is unlikely, making the success rate of CPR administered in nursing homes 0% to 5%.9 A DNR orders clinicians to not pursue efforts to restore cardiac function if the heart stops beating or lungs stop functioning.17 For patients with primary lung disease, patients may also elect to forgo intubation and mechanical ventilation because it is painful and unlikely to lead to a return to an acceptable quality of life. For these patients, cardiac arrest may be reversed with a quick attempt at resuscitation, such as defibrillation, but the patient may want a DNI (do not intubate) order. For patients with very end stage disease, a DNR/DNI order covers both. The DNR order does not exclude or prohibit use of other medically suitable interventions. As with other medical decisions to forgo life-sustaining treatment, deciding whether to administer CPR requires evaluation of the ethical considerations such as the potential likelihood of clinical benefit and the patient’s preferences. Unlike most medical treatments, however, a presumption in favor of sustaining life exists legally, ethically, and medically, making CPR the correct course of treatment unless a DNR order is in place, or unless the treatment is refused or deemed medically futile. Unlike many treatments, CPR does not require a physician’s order but does require a contrary order in the form of a DNR order to withhold it. It is the only medical treatment of this sort, because success depends on immediate response.1 Because current policy dictates CPR be attempted for every patient in cardiac arrest who does not have a DNR order, CPR raises unique challenges with regard to decisions to forgo life-sustaining treatments. First, a CPR decision is conditional, depending on whether cardiac arrest actually occurs within a health care setting. Further, the success of CPR depends on factors such as how quickly it is administered after cardiac arrest, the skill of the resuscitation providers, access to a cardiac monitor, the patient’s general health and well-being, and the underlying medical conditions. Although CPR may
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restore life with effective circulation after a cardiac arrest in some patients, CPR is often unsuccessful in patients with advanced disease and contravenes the concept of a gentle or dignified death. With DNR orders, as for other medical interventions, informed choices are required and must be based on clear information about the benefits, risks, and alternatives available to the patient. In practice, many elders have mistaken perceptions of the effectiveness of CPR as well as mistaken understandings of the procedure based on television or popular media. Some studies have shown that when elders are fully informed about the low probability of restorative success and the actual steps that occur in CPR, such as chest compression and the potential for cracked ribs in frail elders, they opt for DNR status over CPR.18 Yet, clinicians often fail to comprehensively discuss CPR.18 Fully informed communication about end-of-life care options must include comprehensive discussion of CPR, other medical interventions, and palliative care options. Recommendations about CPR should be clear and definitive so the patient or surrogate, their families, and other health care providers (such as nursing home nurse aides) understand the decision and have the opportunity to ask questions. To the extent possible, a DNR decision should be made with the support and assistance of the geriatric care team as well as family members to stave off potential conflicts at the last moment. The DNR order must reflect the patient’s preferences, values, and beliefs and be careful not to impose the physician’s value judgments or the surrogate’s wishes. Finally, consulting with social workers, spiritual guidance counselors, or ethics committees can support sound and just decisions and ensures that the patient’s wishes are respected.19
Futility Decisions to withhold or withdraw care may be prompted not only by desires to focus on quality of life but also by recognition that some treatments may be futile. Considerations of treatment futility may be more common in geriatrics because older people have limited life expectancies.20 In terms of justice, ethicists argue that physicians have a responsibility to avoid harm to patients that may result from providing futile treatment, as well as larger social concerns that providing futile treatments limits the availability of scarce resources for use by others for whom treatments would be effective. If futility were a straightforward empirical assessment, many end-of-life decisions could be easier. Many authors have thus examined the concept and proposed decision criteria. Unfortunately, although some futility judgments are justified, applying the concept in practice may not be an appropriate tactic because futility judgments are often fraught
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with “confusion, inconsistency and controversy.”1 Nevertheless, the concept is worthy of discussion because the term and the concerns about futile treatments often inform considerations about end-of-life care in the elderly.
Strict and Loose Definitions of Futility Strict definitions of futility, which could be applied to fairly and uniformly guide decisions to withhold or withdraw life-sustaining treatments, are based on objective criteria and the medical expertise of physicians.1 Lo proposed three strict criteria, which include the following. (1) The treatment lacks a pathophysiologic basis—no ethical or legal justifications can be offered to continue treatment when there is no physiologic benefit for the patient. (2) Despite maximal treatment, cardiac arrest occurs— when optimal therapy fails, treatment is medically futile to continue. For example, CPR is ineffective when it would fail to effectively restore circulation to a patient in cardiopulmonary arrest. (3) When the treatment has already failed for the patient, it is deemed futile and lacks a medical, ethical, or legal reason to continue repeating failed interventions. For example, the patient does not respond to CPR and remains asystolic even 30 min after CPR was initiated. Lo also offered four looser definitions for futility that could be applied to end-of-life care for elders. (1) A small probability of success exists with the treatment.1 The difficulty is determining an appropriate cutoff point (i.e., 1% versus 5%) for futility in this probabilistic approach. Even if a quantitative threshold is stated, disagreement between patients and their surrogates may result because no single probability can be applied to define an unacceptable risk in every potential set of circumstances. In addition, although a probability may be small, it still may be considered worthwhile. The concern then becomes how to measure a small probability of survival, especially as data regarding effectiveness of clinical interventions in elders and especially the oldest-old are often unavailable. (2) Physicians do not believe the treatment will succeed in achieving any desired goals.1 This determination raises controversial value judgments. Patients or family members may desire treatment to achieve nonmedical, short-term goals, such as allowing family from far distances to see the patient before death. In such circumstances, physicians may have a moral duty to act with compassion and sustain life despite the lack of a legal duty to do so. Experts generally agree that patients should be informed in a comforting matter if even a small chance of success exists because of the need to support fully autonomous decision making on the part of patients or health care proxies. This definition of futility, however, can be used to guide treatment choices for patients when
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palliative care becomes the most humane treatment approach.6 (3) The patient’s quality of life is not acceptable.1 Treatments may be termed futile when patients, family members, or clinicians judge the patient’s quality of life unacceptable, such as when the patient is permanently unconscious and will never regain cognitive functioning. However, use of this definition by physicians exclusively to guide end-of-life decision making runs the risk of paternalistically imposing the physician’s values upon patients. Advocates for the disabled and other vulnerable populations, such as the elderly, oppose the quality of life criterion suggestions as being discriminatory and disguised value judgments about the value of the lives of those less able bodied. Moreover, competent elderly patients, having learned to cope with chronic illness and find ways to enjoy life, tend to more highly regard their own quality of life than their family does. Patients with Alzheimer’s disease who are incompetent and cannot communicate, but who do not appear to be suffering, create complex quality of life judgments for their family and physician.1 (4) The expected efforts and resources required outweigh prospective benefits.1 The issue is whether the benefits to the patient are worth the costs to society as a whole. This consideration recognizes arguments about rationing in which cost rather than benefit becomes the deciding factor and in which treating patients with poor prognoses of survival may deny treatment to other patients with better prognoses.21 Use of this criterion may appear to have an objective basis, but moral implications implicit in the definition make it a poor definition to use for final determination of when treatments should or should not be applied for particular patients. The difficulties inherent in each and every one of the strict and loose definitions and the disagreement among physicians that persist in its application to patient care means that futility, at this time, is only one of many points to consider in making decisions for patients at the end of life. The principle of beneficence speaks to the physician’s obligation to do what is best for the patient. Beneficent care requires attention to technical expertise as well as compassionate care, and allows for greater leniency in the physician’s response to patient or surrogate requests for interventions decided to be futile, especially when death is imminent. In geriatrics, adequate knowledge of clinical medicine and biomedical science is as important as a caring approach to the patient. In practice, physicians who are concerned that they are being asked to support futile treatment should focus on ongoing communication, consultation with ethics committees, and second opinions from colleagues to help minimize potential mistakes in futility judgments, keep value judgments in check, and simultaneously protect the professional and moral integrity of physicians and patient
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autonomy. Keeping the patient informed and discussing the intervention’s futility with the patient or surrogate is an important ethical and legal obligation and the best approach. Such discussions are usually beneficial to patients or surrogates and reinforce the principles of care, including respect for patients. Most patients or surrogates will eventually support the physician’s judgment1 and appreciate unambiguous and compassionate communications and recommendations.
Euthanasia and Physician-Assisted Suicide In the broadest sense, euthanasia, physician-assisted suicide (PAS) and decisions to withhold or withdraw lifesustaining treatment share common objectives such as relief of pain and suffering and respect for patient autonomy. The importance of these issues in end-of-life care for elders is highlighted by ethical, legal, political, and societal trends that frame the debate, along with religious and philosophical beliefs.22,23 Active euthanasia, also called mercy killing, causes death and ends suffering by intentionally administering medication directly to end the patient’s life.17 Euthanasia is generally categorized in three ways: that is, voluntary when a patient requests it, involuntary when a patient expresses opposition, and nonvoluntary when a patient has lost capacity and cannot make decisions or express his or her wishes.1,23 Involuntary euthanasia, although practiced in the form of lethal injections for death row inmates, is always immoral if considered as part of a health care plan. As respect for patient autonomy is potentially the only acceptable justification for active assistance in dying, nonvoluntary euthanasia is not an acceptable practice.1 The fine distinction between euthanasia and physicianassisted suicide involves the physician providing to the patient a lethal dose of medication, on the patient’s request, with the intent to allow the patient to end his or her own life.17 The patient independently must perform the final act. Physician assistance in dying may range from providing the patient with information about committing suicide to prescribing medication. Because the patient must carry out the deed, concerns about compelling a patient against his or her wishes and abusing the powers associated with being a physician and the physician’s role are lessened, although still a potential consideration. Still, being relieved of the moral responsibility for the suicidal act does not relieve the physician of further moral responsibility in physician-assisted suicide. Each situation necessitates careful consideration of the intent, motivation, justification, and results of the decision. Again, as with most end-of-life decisions, discussion with the patient and his or her family is critical and
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allows for more effective and meaningful palliative care practices.1 In practice, a physician is not, however, assisting with suicide if the physician is providing treatments to relieve pain and suffering even if the patient’s death might be hastened.17 In such circumstances, the underlying illness, not the treatment provided or withheld, is the cause of the patient’s death. The distinction between “killing” in the sense of euthanasia or PAS versus “allowing to die” in the sense of withholding or withdrawing care, or providing high doses of narcotics or sedatives to relieve pain but that also may result in patient death, is useful in practice. However, many philosophers consider the distinction problematic. These authors find the distinction between “killing” and “letting die” to not be a sound basis for moral judgment. Second, the idea that the disease causes the patient’s death rather than the withholding/withdrawing of treatment may not be tenable because death may not have occurred in the absence of this factor. Third, assisted suicide and letting die cannot be distinguished by the intent of the patient. A patient who is refusing treatments and who has had adequate informed consent also recognizes death as an outcome and thus the distinction lacks moral weight. Conversely, the U.S. Supreme Court has held that there is a rational distinction between killing and letting die,24,25 and that those who ask their doctors to commit assisted suicide and those who forgo treatment are not similarly situated.26 Concerns about active euthanasia and assisted suicide should not make physicians reluctant to relieve distressful symptoms in terminally ill patients. Indeed, fears that terminal distress will not be adequately relieved impel some people to seek active euthanasia and assisted suicide. Physicians should continue to partner with patients and families to ensure that patients are fully informed of consequences and feel more assured that they will not be abandoned when the plan of care moves from curative to palliative.
Physician-Assisted Suicide and Conflict with the Physician’s Role Physician-assisted suicide and euthanasia cause conflicts for the physician’s healing role, because, traditionally, a physician has a duty to preserve life.1 Arguments against physician-assisted suicide emphasize the sanctity of life,1 debate the passive (e.g., withholding treatment) versus active (e.g., physician-assisted suicide) killing distinction, discussed earlier, and examine the potentials for abuse, especially with vulnerable populations.1,25,27 Other authors argue that the physician’s professional ethics and integrity may be jeopardized by performing PAS.25,27 The trust in the physician–patient relationship
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could be breached, and patients may forgo seeking a physician’s care. Lack of diligence in ensuring that the patient’s requests are voluntary and that the appropriate patient receives physician-assisted suicide,1 as well as inevitable mistakes,25 are additional concerns. Important, but often inarticulated, are the religious beliefs of ethicists and policymakers on this issue. Respect for religious freedom requires allowing individual choice even if it conflicts with one’s own values.
Justifying Physician-Assisted Suicide Arguments in favor of physician-assisted suicide focus on showing respect for individual autonomy,1 recognizing the right of competent people to choose the course of their life and death, the importance of comfort and relief of suffering, and a justice argument for treating “like cases alike.” If competent, terminally ill patients can refuse treatment and thus hasten death, suicide becomes the only option for patients when treatment refusal will not suffice to hasten death. Physician-assisted suicide then serves as a compassionate alternative to unbearable suffering, because physical and emotional suffering cannot always be relieved.1 Although society has a strong interest in preserving life, that interest may diminish when a person is terminally ill and has reached his or her “closing biography,” has said good-bye to family, and wishes to exit “on his or her own terms,” usually described as death with dignity, Personal liberty is limited when there is a complete prohibition on assisted death, warranting the allowance of physician-assisted suicide in certain cases. In circumstances where suicide would happen with or without assistance, PAS allows a more humane and controlled method of end-of-life decision making.1 Religious tolerance requires respect for personal objections to all killing, but religious tolerance also requires us to respect those whose beliefs support a right to end their own lives, especially in the context of intractable suffering and ultimately terminal illness. The political debates in numerous states and in the U.S. Congress demonstrate the depth of feeling on both sides.
Legal Issues and Physician-Assisted Suicide Voluntary euthanasia and physician-assisted suicide have been openly condoned in the Netherlands for more than 10 years. Although critics argue that abuses occur, such as euthanasia of disabled infants and elderly persons with dementia, popular support in the Netherlands remains high. In the United States, Oregon has legalized a very limited form of PAS. The U.S. Supreme Court has unanimously ruled that no constitutional right to physician-
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assisted suicide exists. Statutes prohibiting physicians from providing lethal medication for use by competent, terminally ill patients do not violate the Due Process or Equal Protection Clauses of the Constitution. The Court found no fundamental liberty interest in committing physician-assisted suicide, protected by the Due Process Clause of the 14th Amendment.24,25,27 The Court also implied a right to adequate palliative care and held state laws constitutionally valid in distinguishing between prohibiting intentional acts to hasten death and permitting acts to relieve pain while unintentionally hastening death. States considering legalization of PAS are required to ensure palliative care is adequate and effectively implemented.24
Safeguards and Guidelines for Performance of PAS Consideration of legalized PAS must include guidelines to balance a humane response to a patient’s individual values with providing adequate protection to vulnerable populations. Such guidelines must clarify that a tolerable death and well-controlled pain and suffering should result from comfort care.28 Thus, physician-assisted suicide is only acceptable for terminally ill patients with incurable conditions whose illnesses are accompanied by severe pain and unrelenting suffering. Adequate palliative care must be provided. The patient’s decision must be voluntary and informed, and asking for assistance in dying must be a continuous, clear, and convincing request to end suffering. The patient’s ability to make sound decisions must be demonstrated, including identification and treatment of depression. The doctor–patient relationship should have been maintained over a period of time and be meaningful to best understand the patient’s desire for physician-assisted suicide. More than one physician should evaluate the patient to confirm that the choice is voluntary, informed, and rationally reached. The concept of such careful guidelines lies behind Oregon’s legalizing a narrowly defined form of the practice.28
Physician-Assisted Suicide in Oregon Physician-assisted suicide became an option for terminally ill patients in Oregon with the passage of Oregon’s Death with Dignity Act. A terminally ill person can request a prescription to end his or her life if he or she qualifies under the law’s requirements.29 Because care for terminally ill patients is also considered the purview of hospice care, however, conflicts between hospice care philosophy and physician-assisted suicide continue to be the subject of debate.30 In the first 2 years after the Supreme Court upheld the law, 56 persons received pre-
M.M. Bottrell et al.
scriptions for a lethal dose. Of those 56, 43 died of the lethal dose, 11 died of the underlying disease, and 2 remained alive as of January 2000.31 Requesters were, on average, in their early seventies, and cancer was the most common illness. Patients expressed concern over inadequate pain control, losing autonomy due to illness, and losing control over bodily functions. The number of requesters remains small and has not resulted in an overwhelming rise in physician-assisted suicide, as initially anticipated and feared. Moreover, in some local communities, fears that clinicians would be faced with requests for PAS have prompted regional improvements in pain management and other end-of-life care services.32
Physician-Assisted Suicide and the Elderly As life expectancy grows, many older people face years of isolation and decline. Some may want to assert a right to a dignified death on their own terms, making PAS an option. This phenomenon may be responsible for the increase in suicide rates among elderly men in the United States. On the other hand, abuses could occur in this vulnerable population. Pressure could result, including influencing elderly people to choose physician-assisted suicide rather than more expensive palliative care options. Families may choose physician-assisted suicide to relieve caregiving burdens and even encourage physicians to impose value judgments in quality of life on the patient or surrogate. In one study comparing attitudes of elderly outpatients and their families toward PAS, family members held more favorable attitudes toward PAS than patients in cases of terminal illness (59.3% versus 39.9%), in cases of chronic illness (25.3% versus 18.2%), and in cases of mental incompetence (55.6% versus 34.0%).33 Moreover, family members poorly predicted patient attitudes toward PAS. Thus, focusing on the patient’s interests rather than family preferences or a physician’s moral judgments becomes an important direction and goal for end-of-life care decisions.
Conclusion The particular ethical quandaries posed by geriatric care at the end of life require that physicians, patients, and families candidly discuss and consider end-of-life care. Decisions to withhold and or withdraw life-sustaining treatment are grounded in respect for patient autonomy, beneficence, and considerations of medical futility. Artificial nutrition and hydration and DNR orders pose particular concerns but can be managed by partnering with patients in their care. Physician-assisted suicide may be a
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final option for some patients in some states but should be approached with awareness of important guidelines for protecting patients against potential abuses. Even without formal ethics training, the practitioner who cares for elders daily manages personal dilemmas brought about by the sensitive issues inherent in end-of-life care. By applying the principles of medical ethics to the thoughtful care of older adults, geriatricians can set an example in the care of patients with difficult ethical problems generally and in end-of-life care specifically.
References 1. Lo B. Resolving Ethical Dilemmas: A Guide for Clinicians. Baltimore: Williams & Wilkins; 1995. 2. Purtillo R. Ethical Dimensions in the Health Professions, 2nd Ed. Philadelphia: Saunders; 1993. 3. Jonsen AR, Siegler M, Winslade WJ. Clinical Ethics. New York: McGraw-Hill; 1998. 4. Ackerman RJ. Withholding and withdrawing life-sustaining treatment. Am Fam Physician. 2000;62(7):1555–1560. 5. Basile CM. Advance directives and advocacy in end-of-life decisions. Nurse Pract. 1998;23(5):44–60. 6. Cassel CK. Philosophical and ethical issues in geriatrics. In: Kelley WN, ed. Textbook of Internal Medicine, 4th Ed. Philadelphia: Lippincott Williams & Wilkins; 2000:3127– 3131. 7. Culigari AM, Miller T, Sobol J. Race and health care: an American dilemma? N Engl J Med. 1996;155:1893–1898. 8. Wolf SM, ed. Feminism and Bioethics: Beyond Reproduction. New York: Oxford University Press; 1996. 9. Tolle S, Tilden VP, Nelson CA, Dunn PM. A prospective study of the efficacy of the physician order form for life-sustaining treatment. J Am Geriatr Soc. 1998;46(9): 1097–1102. 10. Lee MA, Brummel-Smith K, Meyer J, Drew N, London MR. Physician orders for life-sustaining treatment (POLST): outcomes in a PACE program. J Am Geriatr Soc. 2000;48 (10):1219–1225. 11. Luce JM. Withholding and withdrawal of life support: ethical, legal, and clinical aspects. New Horiz. 1997;5(1): 30–37. 12. Ahronheim JC, Moreno J, Zuckerman C. Ethics in Clinical Practice, 1st Ed. Boston: Little, Brown, 1994. 13. Brody H, Campbell ML, Faber-Langendon J, Ogle KS. Withdrawing intensive life-sustaining treatment— recommendations for compassionate clinical management. N Engl J Med. 1997;336(9):652–657. 14. In Re. Quinlan. 70 N.J. 10. 355. A.2d 647: N.J., 1976. 15. Annas GJ, Law SA, Rosenblatt RE, Wing KR. American Health Law. Boston: Little, Brown; 1990.
1251 16. Pearlman RA, Back AL. Ethical issues in geriatric care. In: Hazzard WR, Blass JP, eds. Principles of Geriatric Medicine and Gerontology, vol 40, 4th Ed. New York: McGraw-Hill; 1999:557–570. 17. Basta LL. A Graceful Exit: Life and Death on Your Own Terms. New York: Plenum Press; 1996. 18. Levin JR, Wenger NS, Ouslander JG, et al. Life-sustaining treatment decisions for nursing home residents: who discusses, who decides and what is decided? J Am Geriatr Soci. 1999;47(1):82–87. 19. Agich GJ, Arroliga AC. Appropriate use of DNR orders: a practical approach. Clevel Clin J Med. 2000;67(6):392–400. 20. van der Steen JT, Muller MT, Ooms ME, van der Wal G, Ribbe MW. Decisions to treat or not to treat pneumonia in demented psychogeriatric nursing home patients: development of a guideline. J Med Ethics. 2000;26(2):114–120. 21. Schneiderman LJ, Jecker JS, Jonsen AR. Medical futility: its meaning and ethical implications. Ann Intern Med. 1990; 112:949–954. 22. Scanlon C. Assisted suicide: the wrong answer. Home Care Provider. 1997;2(4):159–161. 23. Young EWD. Physician-assisted suicide: where to draw the line. Camb Q Healthcare Ethics. 2000;9:407–410. 24. Burt RA. The Supreme Court Speaks—not assisted suicide but a constitutional right to palliative care. N Eng J Med. 1997;337(17):1234–1236. 25. Annas GJ. The bell tolls for a constitutional right to physician-assisted suicide. N Eng J Med. 1997;337(15):1098–1103. 26. Sulmasy DP, Ury WA, Ahronheim JC, et al. Publication of papers on assisted suicide and terminal sedation. Ann Intern Med. 2000;133(7):564–566. 27. Gostin LO. Deciding life and death in the courtroom. From Quinlan to Cruzan, Gluksberg, and Vacco—a brief history and analysis of consitutional protection of the “right to die.” JAMA. 1997;278(18):1523–1528. 28. Quill TE, Cassel CK, Meier DE. Care of the hopelessly ill: proposed clinical criteria for physician assisted suicide. N Engl J Med. 1992;327:1380–1384. 29. Miller PJ. Life after death with dignity: the Oregon experience. Soc Work. 2000;45(3):263–271. 30. Mesler MA, Miller PJ. Hospice and assisted suicide: the structure and process of an inherent dilemma. Death Studies. 2000;24(2):135–155. 31. Roscoe LA, Malphurs JE, Dragovic LJ, Cohen D. A comparison of characteristics of Kevorkian euthanasia cases and physician assisted suicide cases in Oregon. Gerontologist. 2001;41(4):439–446. 32. Mezey MD, Mezey, Mathy D. Oregon Pain Practice Improvement Cluster Initiative. [e-mail to Melissa M. Bottrell,
[email protected]]. 1 July 2001. 33. Koenig HG, Wildman-Hanlon D, Schmader K. Attitudes of elderly patients and their families toward physician assisted suicide. Arch Intern Med. 1996;156(19):2240–2248.
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86 Ethical Challenges to Research in Geriatric Medicine Greg A. Sachs and Harvey Jay Cohen
For many years, one of the main items on the agenda of advocates for improved health care for older people has been the promotion of research on the medical problems that affect the elderly. Until the 1980s, it was quite common for people over age 65 to be excluded from clinical trials, even from studies of disease that disproportionately affect the elderly, such as heart disease and cancer. Many clinical problems of older people received little or no research funding. Clearly, great strides have been made in the past two decades. There is a National Institute of Aging at the National Institutes of Health, geriatric medicine fellowships train investigators in research around the country, journals specializing in geriatric medicine and gerontology are flourishing, general medical journals abound with articles related to the care of the elderly, and clinical trials include older subjects, many even focusing specifically on older adults. Yet, as research involving older human subjects has gone forward, many important ethical challenges to the conduct of this research have either emerged or resurfaced. In this chapter, we discuss three main aspects of the ethical challenges to research in geriatrics. First, we briefly review the principles of research ethics of the past 50 years as applied to human subjects of all ages. Second, we highlight the ways in which geriatric research presents special challenges. Third, we discuss the most recent developments and controversies in research ethics, many of which challenge the traditional model of research ethics.
Historical Overview Discussions of the ethics of research involving human subjects for at least the first 40 years following World War II were dominated by concerns about informed consent. This attitude is not surprising, given that, starting with the Nazi experiments on concentration camp prisoners, many
of the most egregious abuses of research subjects and most ethically suspect research involved either nonconsenting or uninformed subjects. Table 86.1 lists some of the most important of these troubling cases, as well as many of the international and U.S. responses in terms of guidelines and regulations for the ethical conduct of research involving human subjects. It is worth noting that the amount of activity in the last few years, especially with respect to federal oversight and both proposed and actual regulatory action, is greater than at any time since the development of the U.S. research oversight structures in the 1970s. We address many of these regulatory developments in the final sections of this chapter. In the United States, much of the current institutional review board (IRB) apparatus and attention to informed consent and consent forms flows from federal regulations that were adopted following the reports of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (the National Commission).1 Although formulating standards relating to informed consent was an important part of the work of the National Commission, it is important to recognize (as the National Commission did) that many other ethical principles need to be addressed when evaluating research.2 First, informed consent is not a primary level ethics principle, per se. The fundamental principle that gives rise to the attention on informed consent is the principle of respect for persons. This principle, as stated by the philosopher Immanuel Kant, requires treating people as ends rather than as means to an end. To some extent, researchers use their subjects as a means rather than an end, as a means to obtain an answer to their research question. Using people in this fashion becomes ethically permissible only when the individuals are autonomous (“capable of deliberation about personal goals and of acting under the direction of such deliberation”) and they give their competent, voluntary, informed, and comprehending consent or permission to be used in this fashion. Another equally important ethical conviction found by 1253
1254 Table 86.1. Important events in ethics and regulation of research: 1945–2000. 1945: Uncovering of details of Nazi war crimes, including experimentation on prisoners 1949: Nuremberg Code on medical experimentation 1964: Helsinki Declaration of the World Medical Association on biomedical research involving human subjects 1966: Henry Beecher New England Journal of Medicine paper on “unethical or questionably ethical procedures” in the research literature 1972: Story of the Tuskegee Syphilis Study breaks 1974: Federal regulations on research published (45 CFR 46); National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research established 1978: Belmont Report (and other U.S. guidelines and regulations emanating from the work of the National Commission) 1980: President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research formed; worked through 1983 1995: Advisory Committee on Human Radiation Experiments Final Report; National Bioethics Advisory Commission (NBAC) created; Presidential Tuskegee apology 1999: Research suspended at several institutions by FDA or Office of Protection for Research Risks (OPRR); gene therapy trial death; calls for new research ethics regulation, training and certification
the National Commission that flows from the principle of respect for persons is that individuals who have diminished autonomy, whether their capacity for selfdetermination is diminished by mental illness or by incarceration in a prison, are in need of and should receive special protection. Several of the National Commission’s reports specifically address the needs of various vulnerable populations, such as children and prisoners. Importantly, the National Commission and subsequent federal regulations did not specifically address the needs of the two vulnerable populations of most concern in geriatrics research: subjects with dementia and subjects who reside in long-term care facilities. Two other fundamental ethical principles were identified by the National Commission as central to research: beneficence and justice. Sometimes beneficence is divided into two principles, nonmaleficence and beneficence, the former meaning not inflicting harm on others and the latter referring to the obligation to promote good. Clearly, although investigators do not set out to intentionally harm their subjects, some clinical trials involve invasive testing, drugs, or new surgical procedures that do carry the risk of harm to subjects. Thus, consideration of whether a trial should be done (or for an individual, whether or not they choose to consent to participate), often involves a complex consideration of potential benefits to participants, to others with the condition under study, or to the state of scientific knowledge, weighed against the trial’s risks or burdens. Clinicians, of course, are familiar with these concepts in terms of both
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the Hippocratic dictum “do no harm” and the general orientation toward doing what will help one’s patients. The National Commission discussed an additional obligation for researchers to promote the public good when they accept public support for their research endeavors. Justice has to do with treating people fairly, giving each individual what is due or owed to him or her. In the research arena, as discussed by the National Commission and others since, the primary concern has been the fair or equitable distribution of both the burdens and benefits of research. There is a general concern about disadvantaged or vulnerable populations being used as research subjects because of convenience or ease of recruitment, resulting in these populations being subjected to a disproportionate amount of the risks of research. Many disadvantaged populations, particularly those without regular access to health care, are simultaneously at risk of not gaining access to the fruits of the research endeavor, such as new and expensive medications or the latest diagnostic testing and surgical procedures. Justice calls for the equitable distribution of research burdens and benefits within the society. An interesting development in this area in the 1990s that was discussed in the third edition of this text was new federal regulations mandating the inclusion of minorities and women in clinical studies to overcome what has been deemed inadequate representation in trials conducted over the past few decades—quite different from the approach that views these groups as vulnerable populations needing special protection from research risks or from exploitation and overuse as subjects.
What Is Different About Research on Older People? This question is not a trivial one. If one believes that older people are not inherently very different from younger people, why should there be any special concerns, recourse to different ethical principles, or need for special regulations in considering the conduct of research involving older people? In fact, as part of an effort to overcome ageist stereotypes, much has been written about successful aging and the ways in which the vast majority of older people are cognitively intact, functionally independent, and active. Focusing for a moment on this view of aging and older people, one would have to say that there really should be no difference between research on younger subjects and research on older subjects. For research on older subjects, one still needs competent, voluntary, informed, and comprehending consent for a subject to participate. One would still expect investigators to minimize the risk to older subjects and maximize the potential benefits. One would still look for an equitable
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distribution of the benefits and burdens of the research involving older subjects. Although some potential older subjects may be vulnerable and in need of special protection, most are not. Indeed, one would hope that IRB consideration of studies involving older subjects would focus on expectations of possible harm to subjects based on knowledge of their circumstances and clinical or physiologic condition, not age per se.
Lack of Research on Older People On the other hand, there are matters relating to the history of clinical investigation, the clinical realities of geriatric medicine and research, and the presence of special populations within the general older population that we argue merit special attention and consideration. The first of these, the history of clinical investigation involving older people, is probably one of the most obvious to clinicians eager to practice what has been called evidence-based medicine, focusing on what the research literature can tell us about the diagnosis, evaluation, and treatment of diseases and clinical syndromes. Quite simply put, there has been little information from clinical trials on older people, especially the oldest-old (those over age 85). It was quite common even in the 1960s and 1970s for large clinical trials on diseases common in older people, such as diabetes mellitus or hypertension, to exclude subjects over the age of 65.3 It is only in the last several years that many larger clinical trials have enrolled sufficient numbers of older subjects, or, alternatively, that separate trials focusing specifically on older people have been conducted, to be able to answer whether results found in younger populations generalize to older people. Some of the more gratifying outcomes of many of these trials are findings, as in the Systolic Hypertension in Elderly Program (SHEP) study, demonstrating that older subjects not only often benefit from the same interventions tried in younger patients but that sometimes the marginal benefit is greatest in the oldest.4 Another recent example is the North American Symptomatic Carotid Endarterectomy Trial (NASCET), a study of carotid endarterectomy that demonstrated the greatest benefits for many severities of carotid stenosis accrued to the oldest subjects, including those over age 85.5 The relative lack of research information is even more apparent when one considers some conditions that affect predominantly older people or those who reside in nursing homes. It is not clear whether the lack of attention to research on older people was due to practical difficulties in conducting geriatric research (discussed in more detail following), a lack of interest in older people and their problems per se, or other causes. Regardless of the cause, from the perspective of the ethical principle of justice discussed
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earlier, older people were not receiving their fair share of either the burdens or the benefits of clinical research. Although this has been changing for the better in recent years, considerable room for improvement remains. A review of the recent experience of the Southwestern Oncology Group, one of the major cancer coperative study groups in the United States still found the typical cancer protocol subject to be much younger than the typical patient with cancer.6
Clinical Realities Making Geriatric Research More Difficult A priori, there may not be major differences in the ethical principles guiding research on older and younger subjects, but it is clear that the clinical realities of geriatric medicine and the older population have a major impact on the actual conduct of research.7,8 First, because older people are more likely to have comorbid conditions and to be on multiple medications, there is increased tension between selecting subjects who have only the condition of interest (yielding fewer confounding factors) and selecting subjects who will be more representative of typical older adults who have other health problems in addition to the condition under study (yielding results that are more generalizable to the broader population of the elderly). Second, trying to screen, recruit, and formally enroll older subjects may be more complicated because of communication and cognitive problems, such as hearing deficits, strokes, and dementia. Third, several studies, especially population-based studies involving subjects of all ages, suggest that older people have lower participation rates than do younger people. That is, even when eligible and approached for recruitment into a research study, older people may be more likely to refuse. Last, once people are enrolled in a study, there is a greater risk of attrition due to illness or death. Taken together, these clinical realities suggest that conducting research using older human subjects is indeed likely to be more time consuming, more expensive, and more difficult.7,8 There is an important caveat to the foregoing formulation. One should not assume that older patients are less willing to participate in research. A recent study of older and younger breast cancer patients found that older women were less likely to be offered the option of participating in clinical trials than younger women. For those who were offered enrollment, however, the older and younger women participated in similar proportions.9 We must be careful not to let the biases of physicians or researchers drive research participation. The cohort of aging Baby Boomers may have different attitudes toward research from preceding cohorts of older potential subjects.
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Special Population No. 1: People with Cognitive Impairment As discussed earlier, the competent, voluntary, informed, and comprehending consent of an individual is crucial to making that person a research subject. Unfortunately, older people are at considerable risk for conditions in which an altered mental status calls into question the ability to give informed consent. Impaired decisionmaking capacity and an inability to give informed consent may be a temporary condition, as with a postoperative delirium, or it may be permanent, as with severe Alzheimer’s disease. Geriatric medical research is not unique in its need to confront this consent dilemma; researchers in neurosurgery,10 intensive care medicine,11 and emergency medicine12 often want to study potential subjects who are not capable of giving informed consent at the time the study is to be conducted. Researchers in these other fields, however, often do not encounter their potential subjects until they have already lost decisionmaking capacity. Providers in geriatric medicine and some geriatric researchers, on the other hand, often know patients or potential subjects before the loss of decisionmaking capacity, raising additional interesting questions about the assessment of decision-making capacity, advance consent for research, and proxy consent. The greatest ethical dilemma arises from cases in which the ultimate choice is between forgoing promising research because informed consent cannot be obtained or making do without the ideal informed consent, perhaps accepting some creative alternatives. In looking at research on people with cognitive impairment, we restrict our discussion to the consideration of the paradigm presented by research on Alzheimer’s disease or other progressive dementias. We choose to limit our discussion to this area because the ethical dilemma is starkest when the condition to be studied is the same as the condition causing the loss of decisionmaking capacity. While it is true that individual investigators, patients, and families may face challenging decisions, for example, regarding proposed use of an investigational chemotherapy for a cancer that has occurred in a patient with dementia, it is clear that research on cancer could proceed even if it were to be limited to patients who can give informed consent for themselves. Research on Alzheimer’s disease, at least studying subjects beyond the earliest stages of the illness, requires using people who cannot give informed consent. The assessment of individuals’ capacity to give informed consent for themselves is an important first step in deciding whether or how to enroll potential subjects in research protocols. It is important to emphasize that declaring someone unable to make decisions or to give consent should not be based on diagnostic labels or categories. That is, giving someone the diagnosis of
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Alzheimer’s disease does not automatically confer the status of incompetence upon that individual. Rather, one should take the approach that the ability to give informed consent for research, like clinical decision-making capacity, is task specific.13 More complex information and more complicated decisions require greater degrees of cognitive function. For example, a patient with moderate Alzheimer’s disease still might be able to give consent for a study involving an interview on symptoms of depression, but it is likely that this patient would not be capable of understanding and giving consent for a protocol involving a reservoir for the intraventricular infusion of a nerve growth factor into the cerebrospinal fluid. Unfortunately, although it is easy to describe the task-specific or “sliding scale” concept of decision-making capacity assessment, at this time there are no standard or widely accepted scales for operationalizing this concept in the conduct of research. The assessment simply must be carried out on a case-by-case basis with each research protocol and each potential subject. Importantly, standard measures of cognition and severity of dementia should not be taken as direct measures of the ability to give consent. Even people with Mini-Mental State Exam scores as low the 10 to 20 range may be able to give valid consent for some projects. In clinical practice, providers are becoming more familiar with advance directives and the concept of advance care planning for clinical decision making in the event of patient incapacity. Formal advance directives are legal documents that allow patients to indicate specific treatment preferences (living wills, medical directives) or to appoint a proxy to make decisions (durable powers of attorney for health care, health care proxies). It has been suggested that a similar approach be taken with consent for research on dementia.14–16 Cognitively intact older people or patients with the very earliest stages of Alzheimer’s disease, for example, could be encouraged to execute advance directives for research purposes. Similar to clinical advance directives, a research advance directive could indicate the kinds of research projects in which someone would or would not want to participate in the future or could designate a proxy to make research enrollment decisions. Such an approach appears logical and consistent with clinical decision-making practices, but there are at least three important concerns about research advance directives.16 First, because it is not clear how helpful clinical advance directives are proving to be and because there has been even less experience with research advance directives, one hesitates to recommend wide adoption of such an unproven policy. Second, the legal status of research advance directives is not clear because most state laws creating advance directives focus on clinical decisions, especially those pertaining to the use of life-sustaining treatments.15 Third, although information
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contained in a research advance directive might be useful, there is the concern that promoting their use might create the impression (or even lead to regulations or laws) that they are required to do research on dementia. Because a minority of adults execute clinical advance directives, and one can assume that even fewer would execute research advance directives, one can envision a scenario in which research advance directives actually end up inhibiting rather than promoting dementia research.16 What then should be done for cases in which the potential subject is impaired so that informed consent cannot be obtained and research advance directives are either not an option or not present? The current model for obtaining permission to do research on cognitively impaired subjects involves what sometimes is called proxy consent plus subject assent.17,18 Informed consent is sought from a proxy, usually a close relative, who speaks on behalf of the impaired individual. Ethical support for this part of the process is based on the belief that a family member or other proxy is best suited for giving consent because (1) he or she knows the potential subject best and is most likely to make a decision that would be in keeping with the subject’s values and what that subject might have decided for him or herself (making a substituted judgment); (2) the proxy has the best interests of the subject at heart and will make the “best decision”; or (3) as a closely involved family member, the proxy is the person most likely to be affected by the decision, other than the subject, and thus has a stake in making the decision.19,20 Clearly, in clinical practice, there is a long-established tradition of turning to family members when a patient cannot make decisions. Concerns about proxy consent center on potential conflicts of interest (proxies volunteering subjects because the proxy hopes to benefit in the future from the research) or data from clinical decision-making studies that demonstrate significant discord between what patients say they would decide for life-sustaining treatment vignettes and what their proxies predict the patients would want.21,22 In general, it is probably safe to presume that the number of cases in which families will knowingly act contrary to the wishes or interests of a subject are very few in number and one can trust proxy decision making. In addition, because there are other reasons to support proxy decision making besides the ability to construct a substituted judgment, the data on patient–proxy discord need not eliminate proxy consent as a viable option.20 The assent of the subject is the other half of the model that is coupled with proxy consent. Assent refers to the willingness of a subject to agree to go along with a research protocol even if the subject cannot provide informed consent. This concept also has been applied to consent for research involving children.23 This is a
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particularly useful construct for approaching dementia research if one thinks of it as an opportunity to try and obtain useful information from a potential subject about their values and preferences that can help guide research participation decisions, rather than just thinking of assent as the lack of objection to research procedures. One empirical study on research decision making for dementia supports the ability of even very impaired subjects with dementia to give strikingly revealing and informative reports on their values and preferences when given information about specific dementia research protocols.24 Ethical issues in research on subjects with cognitive impairment received a great deal of attention in the latter part of the 1990s, including position statements by the American Geriatrics Society and the Alzheimer’s Association and a report and proposed regulations from the National Bioethics Advisory Commission (NBAC).25–27 The NBAC report and proposed regulations generated a great deal of controversy. NBAC called for such matters as assessment of potential subjects’ decision-making capacity by independent assessors; continued use of a two-tiered approach to risk assessment (minimal risk and greater than minimal risk); significant restrictions on research that does not hold out the potential of direct benefit to subjects; and limited use of advance consent for research.27 The NBAC proposals were criticized by some as not going far enough in protecting a vulnerable population and by others for potentially inhibiting or prohibiting important research.28,29 Being assailed from both sides of the debate has contributed to NBAC’s proposals not being implemented to date.
Special Population No. 2: Residents of Long-Term Care The second population that sharply focuses some of the ethical concerns specific to research in geriatric medicine and gerontology is the long-term care population, especially people residing in nursing homes. Because of the high prevalence of dementia in nursing homes, some of the concerns about research in these facilities are identical to the concerns about research on dementia already discussed. There are distinct concerns about research in nursing homes, however, that relate to the nature of life within these institutions.30 First, although nursing homes are increasingly used as sites for research, unlike academic hospitals they are not research institutions, nor are they solely medical care delivery sites. Indeed, efforts are made in many nursing homes to emphasize the social nature of the institution, the “nursing home as home,” rather than seeing them as stepdown units from hopitals. The bulk of care in nursing homes is provided by nurses’ aides and the role of physicians is somewhat limited with respect to day-to-day life. Most of the staff is unlikely to be familiar with stan-
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dard research procedures and may be uncomfortable with research. Considerable education and encouragement may be needed to gain the trust and cooperation of a nursing home’s staff for a research project. Second, much has been written about the issue of nursing homes as environments in which individual autonomy may be limited.31,32 Even seemingly simple things such as choosing a roommate or deciding when to get out of bed in the morning or what to eat often are out of the control of a nursing home resident.33 Life within any “total institution” certainly challenges the ability of even cognitively intact and healthy people to make decisions freely, let alone people who are ill or frail. Thus, it is easy to see why there would be concerns about the ability to obtain voluntary and uncoerced consent in a nursing home, even if it is informed and comprehending consent. Specifically, one wonders if nursing home residents, who are dependent on staff for so much, feel truly free to refuse to participate in research conducted on site. Obviously, these concerns are heightened when nursing home staff or physicians are themselves participating in a research project, especially if they are helping to recruit and enroll subjects. In addition, even if the consent process can be made voluntary and uncoerced, concerns remain about privacy and confidentiality in the research process because nursing homes are places where these two commodities often are in short supply. A third area of ethical concern in nursing home research relates more to the principles of beneficence and justice than to autonomy and informed consent. Although great progress has been made in the past several years in improving conditions in nursing homes, much remains to be accomplished, and a large gulf exists between the best and worst facilities. An interesting ethical question arises in deciding where to do nursing home research. Should research be limited to only the best facilities, where the residents’ needs all are being met, thus avoiding the possibility of exploiting the most vulnerable and needy residents who receive inferior daily care? From the research standpoint, a superb facility probably facilitates efficient conduct of a study, but it may limit the generalizability of one’s results to similar top-notch nursing homes. From an ethics standpoint, restricting research to the best facilities may avoid exploiting the most vulnerable, but it also prevents residents in other nursing homes from sharing in the benefits of research participation as well as its burdens. By this we mean not only the benefits derived from the knowledge generated by research studies, but also the benefits provided by research participation that include increased social interaction, increased attention, and the feeling of contributing to something important. Clearly, a balance must be struck between these competing concerns in deciding which nursing facilities to select for research projects.30
G.A. Sachs and H.J. Cohen
Evolving Ethical Controversies Within the Research Community Much of what has been discussed to this point fits within a model of research ethics that was quite stable through most of the 1980s and 1990s: trustworthy researchers interacting with individual subjects, guided by the principles of respect for persons (with a heavy emphasis on autonomy and informed consent), beneficence, and justice. More recently, several problems or concerns have arisen, some of which represent challenges within the foregoing framework and others that challenge the framework itself. We discuss four of these evolving ethical challenges in research at large: (1) trust and the research community; (2) confidentiality in research; (3) research and the private sector; and (4) likely future research ethics challenges. These developments are not unique to research in geriatric medicine, but we believe that they are of such importance that they warrant discussion here.
Trust and the Research Community In the late 1990s, the Office of Protection for Research Risks (OPRR; subsequently replaced by OHRP, the Office for Human Research Protection) and the Food and Drug Administration (FDA) temporarily suspended the clinical research operations at several universities and medical centers.34–36 While several of these research suspensions were thought by some in the research community to have been due to technical noncompliance with institutional review board (IRB) and other regulations, and that no research subjects were placed at risk of harm, some cases clearly were more serious. IRB members from one institution, for example, complained of a lack of support and resources for their work, and an audit provided examples of research being conducted without IRB review and of protocols being reviewed by panels that included the researcher. Following shortly on the heels of several of these research suspensions, a research subject participating in a gene therapy study at the University of Pennsylvania died.37 This case received significant attention initially because of the death being the first one associated with a gene therapy trial. Subsequent investigations uncovered a host of research protocol irregularities at the University of Pennsylvania and other universities conducting gene therapy trials. These irregularities included deviations from protocols, changes being made in protocols without approval by IRBs or other supervising bodies, and adverse events not being reported to appropriate authorities. Coupled with the Office of the Inspector General’s (OIG) report citing deficiencies in the existing research
86. Ethical Challenges to Research in Geriatric Medicine
oversight structure and process,38 many additional actions and proposals for strengthening research regulation have come from the federal government. These measures have included new requirements for education and certification in research ethics for investigators, research staff, and IRB members; directives to IRBs to take a more active role in monitoring of ongoing research; and NBAC’s most recent report proposing a complete overhaul of the federal structure supervising the nation’s IRBs.39 In response to these developments, many research and professional organizations have made public statements reaffirming their commitment to the ethical conduct of research involving human subjects. Although geriatrics researchers have not played a prominent role in the cases just mentioned, the American Geriatrics Society is one of the organizations that promulgated a position statement on the ethical conduct of research.40 At the heart of these efforts is the desire to reassure the public that the research community still deserves the trust that it has enjoyed in the past several decades. Some investigators believe that if that basic trust is lost, no amount of regulation or oversight will make up for the harm that will come to the research enterprise.
Confidentiality in Research Privacy and confidentiality are two things that researchers have always been required to respect in their dealings with their subjects. In the past, this did not place too many demands on most researchers. Most research was conducted at a single institution; investigators controlled the (mostly hard copy) data relating to their own subjects; subjects were promised that their identity would be kept confidential; and separate sheets with subject code numbers and names and locked file cabinets often sufficed. Today, most clinical trials are multicenter studies, sponsored by pharmaceutical or biotechnology firms, with data transmitted to coordinating centers to be reviewed by other investigators and statisticians, a data monitoring and safety board, and eventually the FDA or other regulators. Electronic transmission of research data is becoming commonplace. In addition, medical records in clinical practice are more routinely being kept in electronic formats. The electronic medical record is not only allowing clinicians to more readily communicate important clinical information to all involved in a patient’s care, but it is also allowing health services researchers and other clinical investigators to assemble data sets and identify potential subjects in a fraction of the time required previously. By linking data from existing clinical records, research data sets, and administrative data sources such as Medicare claims, researchers are able to ask and answer questions using information on thousands or even hundreds of thousands of subjects.
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Clearly, multicenter studies, electronic data transmission, and electronic records all hold great promise for research. Simultaneously, however, they greatly increase the potential for violations of confidentiality for subjects. As of this writing, new federal regulations governing medical records, including stronger requirements for written consent before allowing access to any records, have just been implemented. These controversial regulations, like many other efforts to regulate research, attempt to balance access to the potential benefits of research against the potential harms that might ensue. It remains to be seen if these new restrictions on the flow of medical data result in the proper balance or if research is inhibited excessively.
Research and the Private Sector One trend in research mentioned in the section immediately above has been the increasing role of for-profit pharmaceutical firms, equipment manufacturers, and biotechnology companies. Not only are these entities financing more of the nation’s research than in the past, more research is being conducted, directed, and supervised by commercial research organizations (CROs) outside academic centers. The combination of commercial interests driving research, private control and oversight of research, and increasingly complex relationships between researchers and commercial entities has raised a number of ethical concerns. First, there is concern that the desire of commercial firms to keep information from competitors may inhibit the free exchange of information that is an integral part of how research usually proceeds. Second, there is the concern that commercial firms profit motives will unduly influence the research process. For example, will they be less willing to publish negative studies, an already important challenge in the existing clinical trials literature? Will CROs and private IRBs be less thorough in their scrutiny of protocols because of a conflict of interest? Will this perceived conflict of interest further challenge the public’s trust of the research enterprise? Third, many concerns have been raised about the impact of relationships with industry and the potential conflicts of interest created for researchers, clinicians, and academic centers.41,42 Some concerns exist that greater commercial ties lead to potentially biased presentations of research, such as in review articles or journal supplements. Surveys suggest that most academic centers have not yet formulated adequate policies for dealing with these potential conflicts of interest.43,44 Another way in which ethical concerns have been raised by the commercialization of research relates to how many academic researchers and centers have learned to follow many of the practices formerly reserved to the for-profit sector. Researchers have created for-
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profit biotechnology firms to try and reap the financial gains from results of their work that might lead to successes in the marketplace. Most academic centers have offices or departments devoted to similar ventures and more aggressive patenting practices. International controversy exists around the patenting of genes and gene products. Lawsuits have been filed seeking access to financial gains that may have resulted from research findings. Marcia Angell has argued that these ethical issues surrounding academic centers and the for-profit sector are one of the greatest challenges to the very soul of academic medicine.41,42
Likely Future Challenges Many of the coming ethical dilemmas for research in geriatric medicine are identifiable today. Some of these will certainly be continuations of the issues already discussed, including debates over tighter regulation of human subject research and the evolving relationship between industry and academia. Others may be existing controversies that will take center stage in the public debate. Controversies that we would place in this category would include the use of stem cells in clinical trials (especially relevant for geriatrics as many of the diseases targeted for this kind of work are age-associated diseases such as Alzheimer’s disease, Parkinson’s disease, and stroke), and debates over both who will pay for research and who will have access to expensive technologies and drugs that result from research successes. Finally, other ethical dilemmas will arise because of advances in technology and the debate over whether we ought to do the things that become possible because of science. Similar to the debate over human cloning, it is likely that the field of aging will face concerns over whether we should pursue research that may extend the life span. We may very well find ourselves in debates over whether it is “right” to pursue antiaging interventions, arguments over the impact on society if such interventions work, and competing claims for access to these therapies versus efforts to protect individuals and society from potential harms.
Conclusion Research in geriatric medicine is growing in important ways at this time in history. Ethical issues particular to geriatrics research, as well as those challenges facing the broader research community, also loom large at this time. For research on geriatric medicine to continue to make inroads on the health problems of older adults, it is essential that these ethical issues continue to be addressed in a thoughtful and effective manner.
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References 1. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. DHEW (OS) 78-0012. Appendix I. DHEW (OS) 78-0013, Appendix II. DHEW (OS) 78-0014. Washington, DC: Department of Health, Education and Welfare; 1978. 2. Levine RJ. Ethics and Regulation of Clinical Research, 2nd Ed. New Haven: Yale University Press; 1986. 3. Sachs GA, Cassel CK. Biomedical research involving older human subjects. Law Med Health Care. 1990;18:234–243. 4. The Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older patients with isolated systolic hypertension: final results of SHEP. JAMA. 1991; 265:3255–3264. 5. Alamowitch S, Eliasziw M, Algra A, Meldrum H, Barnett HJM, for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group. Risk, causes, and prevention of ischaemic stroke in elderly patients with symptomatic internal-carotid-artery stenosis. Lancet. 2001; 357:1154–1160. 6. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341: 2061–2067. 7. Zimmer AW, Calkins E, Hadley E, et al. Conducting clinical research in geriatric populations. Ann Intern Med. 1985; 103:276–283. 8. Applegate WB, Curb JD. Designing and executing randomized clinical trials involving elderly persons. J Am Geriatr Soc. 1990;38:943–950. 9. Kemeny M, Muss HB, Kornblith AB, Peterson B, Wheeler J, Cohen HJ (CALGB). Barriers to participation of older women with breast cancer in clinical trials. Proc ASCO. 2000;19:abstract 2371. 10. Prentice ED, Antonson DL, Leibrock LG, et al. IRB review of a phase II randomized clinical trial involving incompetent patients suffering from severe closed head injury. IRB Rev Hum Subjects Res. 1993;15(5):1–7. 11. Fost N, Robertson JA. Deferring consent with incompetent patients in an intensive care unit. IRB Rev Hum Subjects Res. 1980;2(7):5–6. 12. Olson CM. The letter or the spirit: consent for research in CPR. JAMA. 1994;271:1445–1447. 13. Applebaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med. 1988;319:1635–1638. 14. Fletcher JC, Dommel FW Jr, Cowell DD. Consent to research with impaired human subjects. IRB Rev Hum Subjects Res. 1985;7:1–6. 15. High DM. Research with Alzheimer’s disease subjects: informed consent and proxy decision making. J Am Geriatr Soc. 1992;40:950–957. 16. Sachs GA. Advance consent for dementia research. Alzheimer Dis Assoc Disord. 1994;8(suppl 4):19–27. 17. American College of Physicians. Cognitively impaired subjects [position paper]. Ann Intern Med. 1989;111:843–848.
86. Ethical Challenges to Research in Geriatric Medicine 18. Melnick VL, Dubler NN, Weisbard A, Butler RN. Clinical research in senile dementia of the Alzheimer type: suggested guidelines addressing the ethical and legal issues. J Am Geriatr Soc. 1984;32:531–536. 19. Hardwig J. What about the family? Hastings Cent Rep. 1990; 20(2):5–10. 20. Nelson HL, Nelson JL. Preferences and other moral sources. Hastings Cent Rep. 1994;24(suppl 6):S19–S21. 21. Seckler AB, Meier DE, Mulvihill M, et al. Substituted judgment: how accurate are proxy predictions? Ann Intern Med. 1991;115:92–98. 22. Uhlmann RF, Pearlman RA, Cain KA. Physicians’ and spouses’ predictions of elderly patients’ resuscitation preferences. J Gerontol Med. 1988;43:M115–M121. 23. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Research Involving Children: Report and Recommendations. DHEW (OS) 78-0004, Appendix. DHEW (OS) 78-0005. Washington, DC: DHEW; 1977. 24. Sachs GA, Stocking CB, Stern R, et al. Ethics of dementia research: informed consent and proxy consent. Clin Res. 1994;42:403–412. 25. Sachs CA, AGS Ethics Committee, American Geriatrics Society. Informed consent for research on human subjects with dementia. J Am Geriatr Soc. 1998;46:1308–1310. 26. Alzheimer’s Association. Ethical issues in dementia research (with special emphasis on “informed consent”). Position statement adopted by Alzheimer’s Association, May 1997. Available at www.alz.org/aboutus/overview/statements.htm#ethical. Accessed 6/24/01. 27. National Bioethics Advisory Commission. Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity, vol I. Report and Recommendations of the National Bioethics Advisory Commission. Rockville, MD: National Bioethics Advisory Commission; 1998. 28. Michels R. Are research ethics bad for our mental health? N Engl J Med. 1999;340:1427–1430. 29. Capron AM. Ethical and human-rights issues in research on mental disorders that may affect decision-making capacity. N Engl J Med. 1999;340:1430–1434.
1261 30. Sachs GA, Rhymes J, Cassel CK. The Ethics of Biomedical and Behavioral research in Nursing Homes: Guidelines for Investigators. J Am Geriatr Soc. 1993;41:771–777. 31. Hofland B. Autonomy in long term care: background issues and a programmatic response. Gerontologist. 1988;28 (suppl):3–9. 32. Collopy BJ. Autonomy in long term care: some crucial distinctions. Gerontologist. 1988;28(suppl):10–17. 33. Kane RA, Caplan AL, eds. Everyday ethics: resolving dilemmas in nursing home life. New York: Springer; 1990. 34. Weiss R. U.S. halts research on humans at Duke University. Can’t ensure safety, probers find. Washington Post. May 12, 1999;A1. 35. Hilts PJ. VA Hospital is told to halt all research. New York Times. March 25, 1999. 36. Greenberg DS. Sham oversight. Washington Post. May 31, 1999;A23. 37. Stotberg SG. The biotech death of Jesse Gelsinger. New York Times Sunday Magazine. November 28, 1999. 38. Department of Health and Human Services, Office of the Inspector General. Institutional Review Boards: A Time for Reform. OE1-01-97-00193. Washington, DC: DHHS; 1998. 39. National Bioethics Advisory Commission. Ethical and policy issues in research involving human participants. Final recommendations, May 18, 2001. Available at http://bioethics.gov/pubs.html#final. Accessed 6/24/01. 40. American Geriatrics Society. The responsible conduct of geriatrics research [position statement]. In press, J Am Geriatr Soc. 41. Angell M. The pharmaceutical industry—to whom is it accountable? N Engl J Med. 2000;342:1902–1904. 42. Angell M. Is academic medicine for sale? N Engl J Med. 2000;342:1516–1518. 43. Lo B, Wolf LE, Berkeley A. Conflict-of-interest policies for investigators in clinical trials. N Engl J Med. 2000;343:1616– 1620. 44. Van McCrary S, Anderson CB, Jakovljevic J, et al. A national survey of policies on disclosure of conflicts of interest in biomedical research. N Engl J Med. 2000;343:1621– 1626.
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Index
A Absolute risk reduction (ARR), as an indication of benefit, 4 Absorption defective, in B12 deficiency, 822 of drugs, independence of age, 65 Abuse in caregiving relationships, 60 of elders, 1057–1065 in nursing homes, predictors of, 1059 Acantholytic dermatosis, transient, 872 Acceptance, of death, 353 Accountability, for long-term care outcomes, 110 Accreditation of Healthcare Organizations, Joint Commission on, on physical restraints for hospitalized patients, 136 ACE inhibitor. See Angiotensinconverting enzymes inhibitor Acetabular dysplasia, 581 Acetaminophen determination of toxicity of, 844 for mild pain, side effects of, 332 for osteoarthritis, 654 double-blind trials, 586 Acetylcysteine, for acetaminophen toxicity, 844 Achalasia, in old age, 837 Acid-base balance, disorders of, 774 Acitretin, for psoriasis treatment, 873 Acoustic neuroma, dizziness accompanying, 997 Acquired immunodeficiency syndrome (AIDS), Kaposi’s sarcoma associated with, 878 Actinic keratosis, 876 Activated thromboplastin time (aPTT), 830 Activities of daily living (ADLs) ability to perform, and postoperative outcomes, 242
assessing in the home setting, 130 help with, in the home, 122–123 as a measure of recovery from anesthesia and surgery, 229 Activities of Daily Vision Scale, 188 Activity, voluntary restriction of, after a fall, 980 Acupuncture, for osteoarthritis of the knee, 590 Acute care in a hospital setting evaluation in, 153 rehabilitation services provided in, 263 as a phase of stroke rehabilitation, 265–266 setting of, management of nutritional problems in, 1016–1020 stroke units, 1131 Acute Care of Elders (ACE) Unit intervention with, 139–143, 200 study of, 9 Acute illness, nutritional requirements in, 137 Acute lymphocytic leukemia (ALL), 487 drugs for treating, 489 Acute myelocytic leukemia (AML), differentiating from acute lymphocytic leukemia, 487 Acute nonlymphocytic leukemia (ANLL), acute lymphoblastic leukemia, 487–489 Acute pain defined, 323–324 management of, 329–330 Acute Physiology and Chronic Health Evaluation (APACHE) score on predictive of 2-year mortality, 133 predictive of mortality in myxedema coma, 708
severity of illness scales, for verifying the homeostenosis model, 27 Acute promyelocytic leukemia (APL), chromosomal translocation in, 489 Acute renal failure in the elderly, 775–776 postoperative, 221 Acyclovir, reduction of herpes zoster pain with use of, 1049 Addiction, to opioid analgesics, 335–336 Adenocarcinomas esophageal, increase in incidence of, 428–430 ovarian, 472 Adenomas, premalignant, colorectal cancers evolving from, 384 Adenosine, for sinus rhythm restoration, 218 Adjustment disorder with depressed mood, mood disorder, 1167 Adjuvant therapy for breast cancer, 401–405 for esophageal cancer, localized, 429–430 for pancreatic cancer, 425–426 Adnexa assessing in the aging woman, 742 assumption of malignancy on finding a mass, 158 Adominal examination, 158 b-Adrenergic antagonists for hypertension therapy, 552–553 for lymphocytic thyroiditis, 701 a-Adrenergic blocking drugs, for benign prostatic hyperplasia management, 761–762 b-Adrenergic blocking drugs, for thyrotoxicosis management, 702 a1-Adrenergic receptor antagonists, for hypertension therapy, 554 1263
1264 Adult protective services (APS), 1227–1228 Adult Use of Tobacco Survey (AUTS), 441 Advance care, planning for, communication skills needed in, 291–295 Advanced activities of daily living (AADL), defined, 189 Advanced glycosylation end products (AGE), and vasodilation in diabetic impotent men, 723 Advance directive, 1244–1245 consent for research on dementia, 1256–1257 decisional capacity for executing, 1238 Advanced sleep phase syndrome (ASPS), insomnia secondary to, 1036 Adverse drug events (ADEs) in corticosteroid treatment, 599–600 in finasteride treatment, 762 renal, of coxibs, 587 studies in nursing homes, 83 See also Side effects Adverse drug withdrawal events (ADWEs), studies in Veterans Administration populations, 83 Aerobic exercise, defined, 1023 Affect, role of, in communication, 288–289 Affective disorders detecting, 188 with psychosis, 1189 Age-1 gene, mutation of, effect on rate of mortality in Caenorhabditis elegans, 23 Age/aging and cancer, 366 cardiovascular changes in, 509–510 and changes in thyroid function and metabolism, 697 and crystal deposition diseases, 591 defined, 15, 38, 1009 effects of on midazolam dosage required for sedation, study, 232 on the surgical patient, 242–248 median, at death, in the United States, 281 and Medicare expenditures in the last two years of life, 300 and peripheral arterial disease, 561 postmenopausal osteoporosis in, 623 primary osteoporosis in, 623 Age-associated memory impairment (AAMI), 1079–1080 Age-based rationing, 1216–1217 Age effect, explanation of depression rates in the elderly, 1164
Index Age-entitlement programs, effect of population aging on funding of, 41 Agency for Health Care Policy and Research (AHCPR) algorithm for choice of a rehabilitation unit, 263 guidelines for intervention by nurses in home care, 122 guidelines for urodynamic testing, 760 Age-period-cohort issue, in evaluating factors impacting health, 55 Age pyramid, historic and projected, for human populations, 39–40 Aggressive behavior, in dementia patients, 346 Agitation, managing in dementia, 1087 Agranulocytosis, from clozapine, 1192 Akinesia, in Parkinson’s disease, 1148 Alcohol abuse of chronic pancreatitis from, 845 by older persons, 155 and suicide, 1174 cerebellar degeneration due to use of, 1145–1146 levels of use of, and risk of stroke, 1132 and liver disease, 844 Alcoholism depression associated with, 1168 impairment of erectile function in, 724 preoperative evaluation of, 224 Alendronate for osteoporosis glucocorticoid-induced, 638 postmenopausal, 634 for Paget’s disease, 643 for prevention of fractures, 49 Alginates, as wound dressings, 971 Algorithm for developing care plans in elder mistreatment, 1061–1062 for evaluating delirium, 1118 for rehabilitation placement decisions for stroke patients, 267 Alkaline phosphatase leukocyte in chronic myelogenous leukemia, 491 in polycythemia vera, 493 serum, in Paget’s disease, 643 All-inclusive care, for the frail elderly, 1074 Allopurinal, for gout treatment, 592–593 Allostatic load, in compensation to maintain homeostasis, 33
All-trans-retinoic acid (ATRA), for remission of acute promyelocytic leukemia, 489 Alopecia, in chemotherapy, 404 Alpha-fetoprotein, level of, associated with hepatocellular carcinoma, 430 Alprazolam dependence on, 1177 for depression, 1172 for REM sleep behavior disorder, 1035 Alprostadil, for penile injection, 724–725 Alternative medicine/therapies cultural influence on use of, 150–151 for pain management, 340 Alzheimer’s and Related Disorders Society, for patients with dementia, 303 Alzheimer’s disease age-specific incidence of, 20, 1095 amyloid associated with, 1105–1107 as a cause of dementia, 343 cerebral amyloid angiopathy associated with, 1128 cognitive impairments characteristic of, 210 decision-making capacity in, 1234–1235 diagnosis of, 1080 involvement of caregivers in management of, 165 lesion types and distribution in, 1096–1099 and psychosis, 1188 research on, dilemmas in informed consent, 1256–1257 Alzheimer’s Disease Assessment Scale, 209 Alzheimer’s Disease Assessment ScaleCognitive subspace, use to evaluate ginkgo biloba, 923 Amantadine chemoprophylaxis with, after influenza A exposure, 170 for control and treatment of influenza type A, 812 for Parkinson’s disease, gait freezing in, 1150 Ambulation, after hip fracture repair, 270–271 Ambulatory care services, use of, 96 American Academy of Dermatology, estimate of timing of UV-induced photoaging, 870 American Cancer Society (ACS) data on smokers’ risk of lung cancer, 441 recommendation of on breast self-examination, 379
Index on colorectal cancer screening, 171, 385 on mammograms for older women, 739 on skin cancer screening, 388 American College of Cardiology/American Heart Association cautions about Sildenafil use, 724–725 guideline for pacemaker implantation, 516 on tilt testing methods, 963 American College of Obstetricians and Gynecologists, recommendation on mammograms for older women, 739 American College of Physicians on assessing and managing the risk of perioperative cardiac complications, 215 on pain control near the end of life, 336 on ranges for acceptable lipid levels, 174 on screening for hypothyroidism, 707 on screening for lipid disorders in older patients, 173–174 on screening for ovarian cancer, 382 American College of Physicians-Journal Club, 3 American College of Preventive Medicine, on screening for skin cancer, 389 American College of Rheumatology on glucosamine and chondroitin sulfate for osteoarthritis, 925 guidelines for diagnosing fibromyalgia, 577–578 on survivorship in giant cell arteritis, 597–598 American Dental Association, on antibiotic prophylaxis for preventing bacterial endocarditis, 914 American Diabetes Association (ADA), diagnostic criteria for diabetes, 684 American Foundation for the Blind, estimate of number of blind in the United States, 883 American Geriatrics Society, 172 on ethical conduct of research, 1259 on pain control near the end of life, 336 Panel on Chronic Pain, 324 position statement on rehabilitation, 259
1265 American Heart Association (AHA) on echocardiographic features and the need for surgery in infective endocarditis, 811 guidelines for antibiotic prophylaxis, 914 guidelines in intracerebral hemorrhage, 1126 American Joint Committee on Cancer, breast cancer staging, 399 American Medical Association guidelines for screening and assessment of elder mistreatment, 1061 on pain control near the end of life, 336 suggested categories of medical care at home, 121 American Psychiatric Association, Diagnostic and Statistical Manual Version IV, definition of delirium, 1113 American Society of Anesthesiologists (ASA) classification of patients preoperatively, 213–214, 229 Physical Status Classification, for predicting postoperative mortality, 242–243 practice guideline development for sedation, 235–236 American Thoracic Society, criteria on reversibility of airflow obstruction, 855 American Thyroid Association, recommendation on screening for hypothyroidism, 707 American Urological Association (AUA), symptom score for lower urinary tract symptoms, 758 a-Amino-3-hydroxy-5-methyl-4isoxazole-propionic acid receptors, association with calcium flux into the neuron, 1103–1104 g-Aminobutyric acid (GABA) receptor complex, site of action for barbiturates, 231 Aminoglycosides, dizziness caused by, 999 Amiodarone hypothyroidism induced by, 705 inhibition of T4 to T3 conversion by, 701 thyrotoxicosis induced by, 702 Amitriptyline, for herpes zoster pain, 1050 Amplification, of sound, hearing aid for, 897–898
Amputation due to complicated foot ulcers, 968 lower extremity, 271–273 in peripheral arterial disease, 567 Amygdala, social relationships mediated through, and health, 57 Amyloid arthropathy associated with, 612 differentiating from rheumatoid arthritis, 603 distribution of depositions, in Alzheimer’s disease, 1097 molecular biology of, 1105–1107 multiple myeloma associated with, 498 Amyloid angiopathy cerebral, 1127–1128 in subarachnoid hemorrhage, 1123 in white matter disease, 1147 Amyloidosis, 500, 612–613 cardiac, 513 Amyloid precursor protein (APP), 1105 Anabolic steroids, as antiresorptives, 639 Anagrelide, antiplatelet agent, for essential thrombocythemia therapy, 493 Analgesia in anesthesia, 229–230 medications for, 331–332 for pain in herpes zoster, 1050 Analgesic arthropathy, defined, 586 Anaplastic thyroid cancer, 713 Anatomy lower urinary tract, 931 male sexual, 720 ocular, 884 Androgens adjunctive deprivation of, in prostate cancer therapy, 460 levels of and benign prostatic hyperplasia, 756–757 and risk of prostate cancer, 455–456 role in erections, 723 Anemia in the aging, 819, 820–826 of chronic disease, 1011 in multiple myeloma, 497–498 Anesthesia choice of technique, 236 for the geriatric patient, 229–238 regional, 234 Anesthetics local, for treating postoperative pain, 253 for treating neuropathic pain, 338 volatile, 230–231
1266 Aneurysm aortic, in giant cell arteritis, 597 obliteration of, in subarachnoid hemorrhage, 1124–1125 Angina pectoris, 517 competency of hospitalized patients with, study, 1234 Angiogenesis, inhibitors of, to treat cancer, 371 Angiography pulmonary, for diagnosis of pulmonary embolism, 859–860 in subarachnoid hemorrhage, 1124 Angiokeratomas of Fordyce, 874 Angiomas, cherry, 875 Angioplasty for claudication management, 566 coronary, for myocardial revascularization in elderly patients, 523 Angiosarcoma, 878 Angiotensin-converting enzyme (ACE) inhibitors chronic cough induced by, 934–935 comparison with hydralazine plus nitrates, for heart failure, 514 in diabetes type-2 management, 686 hyperkalemia induced by, 774 for hypertension, 553–554 for myocardial infarction therapy, 520 for stroke prevention, 1132 Ankle-brachial index (ABI) for hemodynamic assessment, 563 to identify peripheral arterial disease (PAD), 561 Ankle edema, causes of, 513 Ankle-foot orthosis, in osteoarthritis, 653 Ankylosing hyperostosis of Forestier, spinal osteophytosis form, 577 Anogenital disease, in the aging skin, 873–874 Anorexia in dying patients, 305 in small cell lung cancer, 452 Antacids, for peptic ulcer disease, 840 Antiandrogens for prostatic hyperplasia, 762–763 for treating prostate cancer, 460 Antibiotics in chronic obstructive pulmonary disease, 856–857 for demented patients, advantages and disadvantages of, 348 for meningitis, 811–812 prophylactic administratiaon of in arthroplasty, 656 perioperative, in hip fracture, 670–671
Index perioperative, to prevent bacterial infections, 219–220, 250–251 for treating pneumonia, 807–808 for treating urinary tract infections, 806 See also Drugs; Medications Antibodies antimicrosomal, in autoimmune thyroiditis, 704–705 antithyroid in Hashimoto’s thyroiditis, 710 in patients with goiter, 711–712 in subclinical hypothyroidism, 707 ovarian-cancer specific, CA 125, 382 in Sjögren’s syndrome, anti-Ro(SS-a) and anti-La(SS-B), 607 in systemic lupus erythematosus, SS-A and SS-B, 608–609 See also Immunoglobulins Antibody-dependent cell-mediated cytotoxicity (ADCC), from Campath 1-H therapy for chronic lymphocytic leukemia, 495 Anticholinergic therapy, for focal dystonias, 1157 Anticoagulation therapy adverse drug events due to, in long-term care facilities, 71 considerations in surgical dental procedures, 915 education in self-management of, 163–164 to prevent cardiac disease secondary to pulmonary disease, 529 to reduce deep venous thrombosis and pulmonary embolism during hospitalization, 249–250 to reduce stroke risk and stroke mortality in chronic atrial fibrillation patients, 515 risk factors associated with use of, 69–70 for systolic dysfunction, 515 See also Antiplatelet therapy Anticonvulsants, for herpes zoster treatment, 1051 Antidepressants for agitated patients with dementia, 1090 for anxiety disorders, 1177–1178 doses and side effects, list, 1171 for managing vulvodynia, 747 novel, for depression, 1170–1173 for treating pain, 336 underutilization of, in nursing facilities, 87 Antidiuretic hormone (ADH), response to, in the aging, 771–772 Antigen, influenza, response of T lymphocytes to, 785
Antihistamines for anxiety disorders, 1178 dizziness caused by, 999 for nausea and vomiting in end-of-life care, 306 Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), on doxazosin and congestive heart failure, 554 Antihypertensive therapy in nonsteroidal antiinflammatory drug users, 74 selection of, 552 See also Hypertension Anti-idiotypes, accumulation of, on aging, 786 Antimicrosomal antibodies, in autoimmune thyroiditis, 704–705 Antinuclear antibodies (ANA), in systemic lupus erythematosus, 609–610 Antioncogenes, role in aging, 794 Antioxidants, for antiaging treatments, 793 Antiphospholipid antibody syndrome, 611 Antiplatelet therapy, 565, 1131 for stroke prevention, 1133 Antiplatelet Trialists’ Collaboration, 565 Antipsychotic drugs comparison of, table, 1194–1195 prescribing in dementia, 1089 prescribing in nursing homes, 87–88 risk for tardive dyskinesia from, 1192 Antipyrine, as a marker for evaluating hepatic metabolizing capacity, 66 Antitetanus toxoid antibody production, study of, in the aging, 786 Antithrombotic therapy, 1130 Antiviral therapy, in herpes zoster, 1049 See also Thrombolytic therapy Antral gastritis, 839 Anxiety about aggressive therapy, 354 association with pain, 327 in dementia, managing, 1088 disorders associated with, 1174–1178 in dying patients, 304 medical and psychiatric causes of, list, 1175 about transitions, 319 Aortic balloon valvotomy, outcomes of, 525–526 Aortic regurgitation, 526 Aortic sclerosis, association with cardiovascular mortality and myocardial infarction, 510–511
Index Aortic stenosis, 524–526 assessing the need for valve replacement in, 218 calcific, as a cause of heart failure, 513 identifying in the older patient, 158 Aortic valve endocarditis, 527 Aortofemoral bypass, for claudication, 566 APACHE. See Acute Physiology and Chronic Health Evaluation Apathetic thyrotoxicosis, hyperthyroidism presenting as, 152 Apathy, in dementia, managing, 1088 Aphthous ulcerations, 910 Apnea central, 1032–1034 in propofol anesthesia, 232 Apolipoprotein E gene, association with Alzheimer’s disease, 1106 Apoptosis impairment of, and cancer, 369 induction of, in cancer therapy, 370–371 Appendages, age related dermatologic changes in, 869 Applicability criteria in evaluating evidence-based studies, 5 of study outcomes to individual patients, 4 Appreciation of a situation, as an indicator of decision-making capacity, 1235 Aqueous fluid, role in glaucoma, 885 Arginine, effect of, on wound healing, 248 Aromatase inhibitors, for treating metastatic breast cancer, 406 Arrhythmias, 515–517 syncope in, 960, 962 Ars moriendi, 354–358 Arterial compliance, change with aging, 546 Arterial disease ischemic ulcers, 967 of the skin, 879 peripheral, 561–571 Arteriography coronary to assess myocardial revascularization before noncardiac surgery, 530 indications for, in myocardial infarction, 521 indications for, in unstable angina, 517 in gastrointestinal bleeding, 842
1267 Arteriovenous malformations (AVMs), subarachnoid hemorrhage due to, 1123 Arthritis disability resulting from, 260 drugs prescribed for, evaluating, 74 oral problems associated with, 912 rehabilitation in, 274 See also Rheumatoid arthritis Arthritis Foundation, educational material available from, 274 Arthrogenous muscle dysfunction (AMD), 580 Arthropathy, amyloid, 603, 612 Arthroplasty, total joint, 655–656 Arthroscopic joint debridement, 654 Articular cartilage, loss of, in early osteoarthritis, 578 Aspirin for bone pain management, 644 for colorectal cancer prevention, studies, 419–420 effect on antibody production after influenza immunization, 793 for myocardial infarction treatment, effect on mortality, 520 for secondary stroke prevention, 1131 for thromboembolic prophylaxis in hip fracture surgery, 672–673 Assent to treatment questioning decision-making capacity in, 1240 without the capacity for informed consent, 1257 See also Informed consent Assessment comprehensive, of geriatric patients, 53, 195–203 of decision-making capacity, 1234–1237 evaluation of instruments used for, 186–187 of pain components addressed in, 312–319 in the elderly, 326–329 of rehabilitation potential, 264 See also Evaluation Assets and Health Dynamics Among the Oldest Old (AHEAD), 59 Assisted living setting medication use in, 88 prevalence of psychosis in, 1187 scope of care in, 106–107 See also Site of care Assistive listening devices (ALDs), 898 Asteototic eczema, 871 Asthma, late-onset, 854 Asymptomatic Carotid Artery Stenosis trial, lacunar strokes identified in, 1146
Asymptomatic Carotid Atherosclerosis Study, 1133 Ataxic hemiparesis, 1128 Atelectasis, postoperative, 862–863 Atenolol, for thyrotoxicosis management, 702 Atherosclerotic disease/atherosclerosis perioperative management of, 217 risk of, in vasectomized monkeys, 791 stenosis leading to infarction, 1129 subclinical hypothyroidism as a risk factor for, 707 vascular, gait disorders associated with, 1143 Atrial fibrillation (AF) in aortic stenosis, 525 association of with ischemic stroke, 1128 with thyrotoxicosis, 701 in cardiomyopathy, 528 effects of treatment with betablockers, 9 response to control of thyrotoxicosis, 703 reversion to sinus rhythm, 515 risk of stroke related to, 1132–1133 and anticoagulant therapy, 69–70 Atrial natriuretic peptide (ANP) changing levels of, with aging, 771 as a marker for myocyte hypertrophy, 32–33 Atrial septal defect, in elderly patients, 527 Atrioventricular block, mortality associated with, 516 Atrophic urethritis/vaginitis, incontinence associated with, 933 Attention interpersonal, as an intervention for agitated patients, 76 tests for evaluating, 208 Atypical parkinsonism, 1152–1153 Atypical presentation of herpes zoster, 1046 Audiologist, qualifications of, 897 Audiometry, portable, in screening for hearing problems, 985 Autoantibodies increase with age, role of T cells in, 785–786 relationship with atherosclerosis, 792 rheumatoid factors as, 601 Autocrine growth factors, 788–789 Autoimmune disorders hearing loss from, recovery with corticosteroid treatment, 897 Sjögren’s syndrome, 606–608, 907–910 and thyroid changes with aging, 695 thyroid failure, 704–705
1268 Autolysis, for wound debridement, 971 Autonomy, patient’s, respect for, 1244 Average life span, defined, 37 Axillary lymph node assessment, in breast cancer, 400–401 5-Azacytidine, for treating myelodysplastic syndromes, 491 Azathioprine for rheumatoid arthritis, 604 for systemic lupus erythematosus, 611 B Back, osteoarthritis of, 576–577 Bacteremia, association with pressure ulcers, 968 Bad news, communicating, 290–291 Balance, in providing long-term care, 109–110 Balanced Budget Act of 1997 constraints on home health care payments in, 106, 121, 124 effect on revenues of health care organizations, 1205 incentives for managed care enrollment in, 1207 increase in rehabilitation services in nursing homes under, 263–264 Balance impairment assessment of, in fall, 987 performance-based assessment of, 190 in nursing homes, 989–990 training to improve, in Parkinson’s disease, 273 Balanitis xerotica obliterans, 874 Baltimore Longitudinal Study of Aging creatine clearance measurement variability among individuals in, 27, 47 on inheritability of osteoarthritis, 581 regression equation for maximum heart rate with age, 28–32 Barbiturates, pharmacology of, in the elderly, 231 Baroreceptor reflex, diminishing sensitivity of, with aging, 957 Baroreceptor responsiveness, change with aging, 510, 546 Barrett’s esophagus and prevention of esophageal cancer, 429 and risk of esophageal cancer, 428, 838 Barriers to home care, 127 Barthel index, for measuring progress in rehabilitation, 264 Bartholin glands, examining, 740 Basal cell carcinoma from chronic exposure to ultraviolet light, 877 of the eyelids, 884
Index Basal ganglia, gait impairment due to lacunes of, 1146 Basement membrane, inhibition of enzymes degrading, in cancer therapy, 371 Basic activities of daily living (BADL), defined, 189 Basophilia, conditions associated with, 829 Beck Depression Inventory, decrease in self-reported symptoms by the aging, 150 Beers criteria, for identifying potentially inappropriate medications for the elderly, 88 Behavior, in older adults, in health and disease, 149–152 Behavioral disturbances, in dementia, 1085–1087 Behavioral therapy (BT), 1170 for anxiety disorders, 1176 pharmacologic treatment in combination with, for insomnia, 1038 Bence-Jones proteinuria, in multiple myeloma, 498 Beneficence, principle of, considering in research, 1254 Benign paroxysmal positional vertigo (BPPV), 997 Benign prostatic hyperplasia, 755–768 Benign prostatic hypertrophy, estimating five-year mortality following, 214 Benton Visual Retention Test, 209 Benzodiazepines for anxiety disorders, 1177 for dyspnea, 304 effects of, on nursing home patients, 75–76 for focal dystonias, 1157 habituation to, 73 for periodic limb movements in sleep, 1034–1035 as sedative hypnotic agents, 231–232 side effects of, in the elderly, 69 treating alcoholic patients with prior to surgery, 224 volume distribution of, in older patients, 66 Bereavement, communicating with patients in, 295, 307 Beta-2 agonists, for symptomatic relief in chronic obstructive pulmonary disease, 856 Beta-adrenergic blockers, interaction with inhalation anesthetics, 216–217 Beta-blocker therapy for anxiety disorders, 1178
in heart failure, 514 in isolated systolic hypertension, 523–524 in myocardial infarction, effect on mortality rate and rehospitalization, 520 in myocardial infarction survivors, studies of dosage, 74 for sinus rhythm restoration, 218 Beta carotene, effect on lung cancer incidence in smokers, 793 Bezoars, managing, 841 Bicalutamide (Casodex), antiandrogen for treating prostate cancer, 460 Bicipital tendinitis, 663 Bier block, for administering intravenous regional anesthesia, 234 Biochemical markers of bone turnover, 631 of malnutrition, 190 Bioequivalence, of generic and proprietary drugs, 84 Biofeedback, for urinary incontinence and prolapse management, 751 Biologic limit to life, 41–42 Biology of breast cancer in the elderly, 396–397 of cancer, 363 of cancer therapy, 370–371 of aging, 15–26 Biomechanical interventions, in osteoarthritis, 585–586 Biomembranes, for wound dressings, 971 Biopsy temporal artery, for diagnosing giant cell arteritis, 598 transrectal ultrasound-guided, for diagnosing prostate cancer, 457 Biopsychosocial Model, application to the elderly cancer patient, 361 Bipolar disorder defined, 1169 rate of, in nursing homes, 1164 Bismuth salts, effect of Helicobacter pylori, 841 Bisphosphonate therapy for bone metastasis management, in prostate cancer, 463 for hypercalcemia in multiple myeloma, 499 for hyperparathyroidism, negative effects, 641 for metastatic breast cancer, reduction of skeletal complications due to, 407 for osteoporosis, 633–634 for Paget’s disease, 643–644 Bladder infection, 744–745
Index Bladder outlet obstruction (BOO), related to benign prostatic hyperplasia, 757 Bleeding cerebellar, 1145–1146 deep, from a defect in coagulation, 829 gastrointestinal, 841–842 in hip fracture, 659, 670 postmenopausal, 747–748 risk of, in thrombolytic therapy for myocardial infarction, 518 Blepharospasm, 1157 Blessed Dementia Scale (BDS), 206–207 Blindness defined, 883 in older diabetic individuals, 682 Blister lesions, in cartilage, 652 Block Design, subtest of the Wechsler Adult Intelligence Scale-III, 209 Blood cells, regulation of production of, 819–820 Blood pressure control of, and complications in type 2 diabetes, 686 decrease in, from propofol anesthesia, 232 fluctuations in, during surgical manipulations, 216–217 increase in, and counteraction of slow renal response to sodium load, 771 after intracerebral hemorrhage, management of, 1126–1127 measuring, during surgery, 236–237 reducing before thrombolysis, 1129–1130 See also Hypertension Blood transfusion, in arthroplasty, knee or hip, 656 Blood urea nitrogen (BUN) increase with aging, 770–774 limitations of measurements of, 66–67 B lymphocytes, 786–787 in chronic lymphocytic leukemia, 494–495 neoplastic, in Waldenstrom’s macroglobulinemia, 499 stimulation of differentiation and antibody production of, by interleukin-10, 790 Body mass index, for assessing nutritional status, 190, 243, 1014 Bone anatomy and physiology of, 621–622 density of, and risk of fracture, 625–626 effect of estrogen on mass of, 635 effect of hyperthyroidism on, 700 loss of
1269 serial measurements to assess rate of, 628 types of, 622–624 resorption of, in multiple myeloma, 497–498 See also Osteo- entries Bone marrow changes during aging, 819 defects in precursors of, in the elderly, 820 evaluating, in anemia, 823 precursor cells, ability to generate B cells, in old mice, 786 transplantation of in acute leukemias, 489–490 in chronic myelogenous leukemia, 492 in multiple myeloma, 498–499 Bone mineral density (BMD) as an indirect indicator of breast cancer risk, 377 in older women, 174 Boston Diagnostic Aphasia Exam, 209 Boston Naming Test, 209 Botulinum A exotoxin to reduce wrinkles, 880 for focal dystonia treatment, 1157 Bouchard’s nodes, defined, 575 Bowel management in end-of-life care, 306 obstruction, in the elderly, 315–316 preparation before colon resection, 251 Bowen’s disease, 876 Braces, lumbrosacral, in arthritis of the spine, 657 Brachytherapy, for cervical cancer, 476–477 Bradyarrhythmias, 516 Bradycardia, in hypothyroidism, 705 Bradykinesia, in Parkinson’s disease, 1148 effect of music therapy on, 273 Breast cancer, 393–416 effect of estrogen replacement therapy on risk of, 636 screening for, 172, 377–379 Breast Cancer Demonstration Project, on risk of breast cancer with estrogen replacement therapy, 636 Breast-conserving treatment, comparison with mastectomy, studies, 399 Breast examination for older women, 739–740 physical, 157 Breast self-examination (BSE), screening for breast cancer with, 378
Breathing patterns of, postoperative, 863 sleep disordered, 1032–1034 Breslow thickness, of skin tumors, 388 Bright light therapy in circadian rhythm sleep disorders, 1038 in disordered sleep of Alzheimer’s patients, 1039 Bronchitis acute and chronic, 806–807 antibiotics for treating, 856–857 Bronchoscope, fiber optic, for observing neoplastic lung lesions, 445–446 Bullous pemphigoid, 873 Bunion (hallux valgus), 665 Buproprion for depression treatment, 1171 for treating agitated or sleep-deprived patients with dementia, 1090 Bureaucracy, effective rationing as an unplanned outcome of, 1214–1215 Burning mouth, 911 Bursitis, joint involvement mimicked by, 577 Buspirone, for anxiety disorders, 1178 Butyrophenones, for nausea and vomiting, 305–306 C CA 125, as a marker for ovarian cancer, 473 Caenorhabditis elegans, senescence in, 23 CAGE questionnaire, for evaluating alcoholism, 155 Calcific periarthritis, hydroxyapatite deposition in, 594 Calcilytics, effect of, on parathyroid hormone secretion, 639 Calcimimetic therapy, for hyperparathyroidism, 642 Calcitonin effects of, on bone, 636–638 for Paget’s disease, 644 serum level measurement, for evaluating thyroid nodules, 709–710 for treating pain associated with osteoporosis, 338 as a tumor marker in medullary cancer of the thyroid, 713 Calcium and cardiac relaxation impairment, 33 and disorders of balance in the aging, 774 high levels of, to inhibit bone resorption, 622
1270 Calcium (cont.): influx into the neuron, regulation of, 1103–1104 for reduction of bone loss physiologic roles in the body, 631–632 vitamin D administered with, 625, 638 requirement for, in the aging, 1011 Calcium channel antagonists/calcium channel blockers effects of, in myocardial infarction, 520 for hypertension, 552 after cataract surgery, 217 incontinence caused by, 934–935 interaction with inhalation anesthetics, 216–217 for sinus rhythm restoration, 218 Calcium oxalate crystal deposition, 594 Calcium pyrophosphate dihydrate, deposition of, 593 in osteoarthritic joints, 580, 591 California Verbal Learning Test, 209 Caloric restriction, role of, in aging, 1009–1013 Canada Health Act, humanitarianism, 1217 Canadian health care system, goal of, equal access to basic health care, 1217 Canalith repositioning procedures, for benign positional vertigo, 1005 Cancer age-specific incidence of, 377 in the elderly as a failure of cellular immunity, 792–794 overview, 361–362 as a major source of heterogeneity in the older population, 45 oral, 387–388, 909 of the ovaries, 471–475 pancreatic, 424–426 screening for, 375–391 thyroid, 712–713 See also Cervical disorders, cancer; Colorectal cancer; Endometrial cancer; Lung cancer; Malignant disease; Prostate cancer Cancer and Leukemia Group B, trial testing radiation therapy, 400 Cancer Prevention Study II, on aspirin use and colorectal cancer prevention, 420 Candida albicans, overgrowth of, in the mouth, 903 Candidiasis, infection by, of the aging skin, 875
Index Can-do factor, and cognitive functioning, 61 Cane, to relieve weightbearing in osteoarthritis, 653 Capacity assessment, advantages and disadvantages of, 186–187 Capsaicin, topical application of, to reduce pain in osteoarthritis, 587–588 Capsular hemorrhage, gait impairment due to lacunae, 1146 Carbamazepine, for treating trigeminal neuralgia, 336 Carbohydrates, agents slowing processing of, in the gut, 689 Carboplatin, for treating advanced ovarian cancer, 474 Carcinoembryonic antigen (CEA) follow-up determination of, 423 and prognosis in colorectal cancer, 421 as a tumor marker in medullary cancer of the thyroid, 713 Carcinoma in situ (CIS), identification of, in cervical cancer, 379 Carcinomatous neuromyopathy, symptoms of, 613 Carcinomatous polyarthritis, 613 Cardiac amyloidosis, 513 Cardiac arrest acute physiologic assessment scores after, and age, 27–28 due to lack of exercise, 1026 Cardiac Arrhythmia Suppression Trial (CAST) on mortality risk from proarrhythmmic effects of drugs, 520 ventricular arrhythmias after myocardial infarction, 516 Cardiac complications antidepressants associated with, 1172 and resuscitation, decisions about, 1091 of surgery, assessing the risk of, 214–216 rhythm disturbances, perioperative, 218 syncope, 960 Cardiac examination, in aged patients, special features of, 158 Cardiac ischemia, emergency room visits in, 150 Cardiac output changes with aging, 509 relationship with oxygen uptake, 1024 Cardiac relaxation, impaired, due to change in cellular calcium flux, 33 Cardioembolic infarction, 1128
Cardiogenic emboli, gait disorders associated with, 1143 Cardiolipin, antibodies to, in antiphospholipid antibody syndrome, 611 Cardiomyopathy, 528 Cardiopulmonary resuscitation (CPR) outcomes of, 516–517 in nursing homes, 1246–1247 patients’ preferences about, 301 request for, in terminal illness, 1239 Cardiovascular disease, 509–543 association with glucose tolerance impairment, 683 cardiotoxicity, in anthracycline-based therapy, 404 and estrogen treatment for osteoporosis, 49 hearing deterioration in, 894 Cardiovascular Health Study (CHS) on the ankle-arm index to assess peripheral arterial disease, 511 assessment criteria for defining frailty, 1068 on asymptomatic ventricular arrhythmias, 516 detection of subclinical disease in, 531–532 on functional status of the elderly, 509, 532 on gender and supraventricular premature beats, 515 on orthostatic hypotension, 510 Cardiovascular system (CVS) age-related changes in, and syncope, 957 catheterization of, in the elderly, 512 changes in, with aging, 33 examination findings, and syncope, 962 response to thyrotoxicosis, 700–701 See also Cardiovascular disease (CHS); Cardiovascular Health Study Cardioverter-defibrillators, implantable, effects on sudden and nonsudden cardiac death in older patients, 516 Care near the end of life, 299–309 questions about, for assessing geriatric patients, 62 strategies for providing for frail older adults, 1073–1074 Caregivers, 59 assessing on a home visit, 128 burned out, and risk of elder mistreatment, 1060 counseling and coaching, in dementia, 1084–1085
Index evaluation of, in pain management, 327 family burden of increasing disability on, 260 difficulties in administering medications, 86 for in-home care, 123–124 professional, for people needing help with activities of daily living, 124 risk of death of, 155, 283 stress on assessing, 191 in managing dementia patients, 343, 791 reducing, in advanced dementia, 347 support for, effect on time Alzheimer’s patients remain at home, 165 Care Plan Oversight, physician billing for, 125 Care sites. See Site of care CARE trial, evaluation of pravastatin, 76 Carotid hypersensitivity and dizziness, 998 and risk of falling, 987 syncope in, 958–959 Carotid stenosis, and risk of stroke, 1133 Carpal tunnel syndrome, 664 association with amyloidosis, 613 Carpometacarpal (CMC) joint, involvement in osteoarthritis, 575 Cartilage accumulation of injuries to, with age, 651–656 assessing, with magnetic resonance imaging, 578 structure and properties of, 582–583 Cartilage oligmeric protein, as a serum marker of osteoarthritis, 579 Carvedilol, for ventricular systolic function improvement, 514 Case management, 200–201 Catalase, effect on aging, 17 Cataracts prevalence of, by age, 887 removal of, example of comorbidities affecting treatment outcomes, 9 Catastrophic reaction managment, in dementia, 1089 Catheters, indwelling, 950–951 Causes of death, Medicare data on, 299 See also Mortality Cavernosal tissue, changes in men with erectile dysfunction, 722 Ceiling effect of an instrument, 187
1271 Celecoxib, cyclooxygenase-2 inhibitor for osteoarthritis treatment, 587 side effects of use of, 70 Cell biology bone cell types, 621 of cancer, 366–370 culture, for diagnosis of herpes zoster, 1048 Cell cycle anticancer drugs designed to disrupt, 370 cell division in, role of telomerase in limiting, 22–23 impaired control of, in cancer, 367–369 Cellular changes activation steps in response to stimuli, 788–789 cancer-causing, 363–366 immune response functions of, 783 in reactivation of herpes zoster, 1043 role of interleukin 12 in, 790 in senescence, 22–24 surface markers, in hematologic malignancies, 487 Cellulitis, 808–809 vulvar, 747 Census Bureau, U.S., models of life expectancy at birth, 41 Center for Epidemiologic Studies Depression Scale, for measuring quality of life in breast cancer patients, 407 Center for Medicare and Medicaid Services (CMS) decisions about funding chronic disease management at, 166 guidelines to define disruptive behaviors justifying antipsychotic medication, 1186–1187 Centers for Disease Control guidelines for preventing surgical site infection, 250 recommendations of on chemoprophylaxis for tuberculosis, 810 on management of herpes zoster patients, 1044 on tetanus vaccination, 171 Central auditory dysfunction, as a cause of hearing loss, 895 Central myelin antigen (CMA), in GALOP syndrome, 1142–1143 Central nervous system, functioning of, and risk of falling, 982 Central processing, postural disorders related to, 1140–1141
Central venous pressure, monitoring in surgery, 236–237 Cephalosporin, for meningitis treatment, 811 Cerebellar disorders, 1145–1146 hematomas, 1127 Cerebellopontine angle tumors, surgical management of, 1005 Cerebral amyloid angiopathy (CAA), 1127–1128 Cerebral function effect on, of metabolic changes in surgery, 223 symptoms of ischemia, 1129 Cerebrovascular disease, 1123–1137 chorea in, 1156 chronic dizziness accompanying, 997 mean hospital length of stay for, 94 Certified Outpatient Rehabilitation Facilities (CORF), 263 Cerumen, accumulation of, managing, 895 Cervical disorders cancer, 475–479 screening for, 173, 379–381 dizziness accompanying, 998 intraepithelial neoplasia (CIN), grading, 475–476 myelopathy, 1144–1145 spondylotic, 657 osteoarthritis, dizziness in, 998 Cervix atrophic, 743–744 changes in aging women, 738, 741–742 Chance and luck, in achieving a peaceful death, 352 Channeling Project, evaluation of in home care, 122 Character traits, relating to the pathogenesis of coronary artery disease, 56 Charlson index, for measuring comorbidity, and short-term operative survival, 214 Cheilitis, angular, 872 Chemoprevention of cancer, 370 colorectal, 419–420 of influenza type A, 813 Chemoradiation in cervical cancer, 476–477 for inoperable stage III lung cancer, 449 in localized esophageal cancer, 429 postoperative in gastric cancer, 427–428 in resectable pancreatic cancer, 425–426 in unresectable pancreatic cancer, 426
1272 Chemoradiation (cont.): preoperative, in rectal cancer, 423–424 Chemotherapy for acute lymphocytic leukemia and acute nonlymphocytic leukemia, 489 adjuvant in breast cancer, 403–404 in rectal cancer, 422–424 for advanced colorectal cancer, 423–424 for advanced endometrial cancer, 471 for advanced esophageal cancer, 430 for gastric cancer, advanced, 428 for Hodgkin’s disease therapy, 504 for metastatic breast cancer, study of the effect of age, 406–407 for metastatic pancreatic cancer, 426 for non-Hodgkin’s lymphoma, 502 oral complications of, 915 for ovarian cancer, complications of, 474 postoperative in colon cancer, 422 in gastric cancer, 427 preoperative, in lung cancer stage III, 449 for prostate cancer, 462 resistance to, in multiple myeloma, 499 single-agent versus multiagent regimens, 407 for small cell lung cancer, 451 for tuberculosis, 809–810 Chest pain, exertional, as a predictor of coronary death, 517 Chinese Acute Stroke trial, on aspirin therapy, 1131 Chlorambucil for chronic lymphocytic leukemia therapy, 495 for polycythemia vera therapy, 493 for Waldenstrom’s macroglobulinemia therapy, 500 Chlorodeoxyadenosine (2-CDA) therapy, for hairy cell leukemia, 496 Choice ability to make, as a standard of decision-making capacity, 1235 reasonable, as a standard of decisionmaking capacity, 1235 Cholangiopancreatography (ERCP), in gallstone pancreatitis, 845 Cholecalciferol, with calcium, effect on fracture rate, 639 Cholecystectomy, estimating the risk of 30- and 90- day mortality following, 214 Choledocholithiasis, 844–845
Index Cholelithiasis, 844–845 Cholestatic jaundice, 844–845 Cholesterol, levels of benefits of reducing, 9 and risk for coronary death in the elderly, 531 Cholesterol Education Program, National, on lipid levels, 174 Cholinesterase inhibitors for treating early and moderate Alzheimer’s dementia, 344 for treating early and moderate dementia, 1085–1086 Chondrocalcinosis, in osteoarthritis, 580 mimicking gout, 593 Chondroitin sulfate, for osteoarthritis treatment, 588 Chorea, 1156 Choroidal neovascularization, loss of visual loss in, and treatment of, 888 Chorthalidone, for isolated systolic hypertension in the elderly, 523–524 Chromium, role of, in carbohydrate metabolism, 1011 Chromosomes 1, presenilin 2 gene of, associated with Alzheimer’s disease, 1106 1q, potential link with prostate cancer, 455 9:22 translocation in chronic myelogenous leukemia, 491 14, presenilin 1 gene of, associated with Alzheimer’s disease, 1106 14:18 translocation in non-Hodgkin’s lymphoma, 501 15:17 translocation in acute myeloid leukemia, 489 17, potential link with prostate cancer, 455 17q21–22, tau protein gene, 1099–1102 19, apolipoprotein E alleles on, and risk of late-onset Alzheimer’s disease, 1106 21q21.2, amyloid precursor protein at, 1105 abnormalities of, in multiple myeloma, 497 alterations of, in myelodysplastic syndromes, 490 X, increasing fragility with aging, 787 Xq, potential link with prostate cancer, 455 Chronic Care Clinics, of the Group Health Cooperative of Puget Sound, 199–200 Chronic idiopathic ataxic neuropathy, 1142
Chronic inflammatory demyelinating polyneuropathy, gait impairment in, 1143 Chronic lymphocytic leukemia (CLL), 487, 494–495 Chronic myelogenous leukemia (CML), 491–492 Chronic myelomonocytic leukemia (CMML), as a myelodysplastic syndrome, 490 Chronic obstructive pulmonary disease (COPD), 529 chronic bronchitis as prelude to, 807 in the elderly, 854–858 example of advance care planning for a patient with, 292 Chronic pain defined, 324 management of, 330–331 Chronic phase, of stroke rehabilitation, 269–270 Chronic wounds, 967–977 Cigarette smoking effect of, on respiratory complications following surgery, 220 and peripheral arterial disease, 562 as a risk factor for lung cancer, 386–387 for sudden cardiac death, 532 Cilostazol, for claudication treatment, 566 Circadian rhythm of core body temperature, coupling of REM sleep to, 1032 sleep disorder related to, 1037 Cisplatin for treating lung cancer, 449 for treating ovarian cancer, complications of, 474 Citalopram, for treating agitated or sleep-deprived patients with dementia, 1090 Class, social, and health, 54–55 Classification of dizziness, 995–996 of falls, 980–981 of Hodgkin’s disease forms, 503 of hypertension, 545 of leukemias, 488 of myelodysplastic syndromes, 490 of non-Hodgkin’s lymphoma, 501 Claudication interventional therapy for, in peripheral arterial disease, 566–567 medical and drug therapy for, 565–566 in peripheral arterial disease, 562 Claw toes, 665
Index Clinical assessment of elder mistreatment, 1060–1061 of hearing loss, 895–897 of malignancy, with thyroid nodules, 709–711 Clinical breast examination (CBE), screening for breast cancer with, 378 Clinical classification, of syncope, 957–960 Clinical Dementia Rating Scale, evolution of Alzheimer’s disease as measured with, 1084 Clinical features of anxiety disorders, 1175–1176 of cardiovascular disease, 512–515 of chronic myelogenous leukemia, 491 in diabetes in older individuals, 684 of giant cell arteritis and polymyalgia rheumatica, 596–598 of herpes zoster, 1045–1047 of infectious diseases, 804–805 of intracerebral hemorrhage, 1125–1126 of non-Hodgkin’s lymphoma, 501 of Parkinson’s disease, 1147 of primary hyperparathyroidism, 640 of rheumatoid arthritis, 601–602 of thyrotoxicosis, 700–701 of valvular heart disease, 218 of Waldenstrom’s macroglobulinemia, 499 See also Symptoms Clinical patterns in aging, 1031–1032 in delirium, 1117 in diabetes, changes with aging, 681 in infection, 803–804 in psychosis with aging, 1189–1190 stability of hospitalized patients at discharge, 138 Clinical practice approach to the older patient, 149–159 contributions of epidemiology to, 47–48 Clinical prediction rules, applying results to older adults, 11–12 Clinical presentation of anemia, 820–821 of benign prostatic hyperplasia, 757–758 cardiac disease secondary to pulmonary disease, 528–529 of delirium, 1115–1116 of diabetes in the elderly, 684 in Hodgkin’s disease, 503 of insomnia, 1036 of lung cancer, 444–445 of osteoporosis, 626–627
1273 of Paget’s disease, 642 of periodic limb movements in sleep, 1034 of REM sleep behavior disorder, 1035 in Sjögren’s syndrome, 606–607 of sleep disordered breathing, 1033 of sleep disorder in demented patients, 1039 of systemic lupus erythematosus, 608–609 See also Symptoms Clinical strategies, for prescribing medication for elderly patients, 83–89 Clinical syndrome, frailty as, 1067–1068 Clinical trials of models of care, improving functioning during hospitalization, 139–143 realities in research including geriatric patients, 1255 on treatment of hypertension, 549–550 underrepresentation of elderly women with breast cancer in, 409 Clinician, initiatives in preventing adverse drug events, 73–75 Clobetasol, for lichen sclerosus treatment, 746 Clock-Drawing Test, 176, 188 for screening in cognitive impairment, 1082 Clonazepam for anxiety disorders, 1177 for blepharospasm, 1157 for REM sleep behavior disorder, 1035 Clopidogrel versus Aspirin for the Prevention of Ischemic Events (CAPRIE) trial, 565 Clostridium difficile, infection by, 812, 848 Clozapine for managing disturbances in dementia, 1090 for schizophrenia, 1192 Clozaril, for treating psychosis in Parkinson’s disease, 1188 Clumsy hand-dysarthria, 1128 Coagulation, inhibitors of, 830–831 See also Anticoagulation therapy Cochlea, damage to, in sensorineural hearing loss, 894–895 Cochlear implants, 898 Cochrane Collaboration metanalysis of relative risk reduction in breast cancer due to mammograms, 378 on prophylactic antibiotics in hip fracture, 670–671
Cochrane Library, systematic reviews of studies from, 3 Cochrane Review, of randomized controlled trials of mammography, 172 Cockcroft-Gault formula for creatine clearance, 822–823 for estimating renal function, 67 Code status, regarding cardiopulmonary resuscitation, 116–117 Cognition/cognitive function blunted, in depressed older patients, 152 and compliance with drug prescription, 85 effect on, of ginkgo biloba EGB761 preparation, 923 and surgical outcome, 244–245 Cognitive assessment, 187–188 in dementia, 1082–1084 and depression in stress, 1165 at home versus the clinic, 129 Cognitive-behavioral therapy, for pain management, 340 Cognitive changes, onset of, and the nature of disorders, 208 Cognitive history, 207–208 Cognitive impairment differential diagnosis of, table, 1080 disorders secondary to psychiatric syndromes, 205 drug-induced, 68–69 examining a patient with, 154 as a major source of heterogeneity in the older population, 45 pain assessment in persons with, 327–329 and participation in research, 1256–1257 as a predictor of posthospital outcomes, 134 reclassification as a disease state, 47 and sleep disordered breathing, 1032–1033, 1039 Cognitive therapy (CT) for depression, 1169–1170 provision of retraining programs, by occupational therapists, 262 Cohort effect, to explain rates of depression in the elderly, 1163–1164 Cohort studies, prospective, 3 Colchicine, for acute gout attacks, 592 Cold, effect of, on aging skin, 871 Colectomy, laparoscopic, in the elderly, studies, 252 Collagen injection of, to reduce wrinkles, 879–880 replacement of, with scar tissue, 660
1274 Collagenase, for wound debridement, 971–972 Colle’s fracture, 626–627 Colloid milium, 870 Colon, disorders of, 845–848 Colon cancer, 417–440 genetic changes traced in, 363–364 screening for fecal occult blood to detect, 158 Colon carcinoma, risk of, in inflammatory bowel disease, 847–848 Colonization methicillin-resistant Staphylococcus aureus, 804 by microorganisms, defined, 802 Colorectal cancer, 417–422 advanced, surgery for, 423 screening for, 171–172, 384–386 Combat exposure, and health, 56 Combative patient, physical examination for, 742–743 Combination drug therapy in diabetes, 689 in osteoporosis, hormone replacement with etidronate, 634 in rheumatoid arthritis, 605 Combined modality therapy, in advanced Hodgkin’s disease, 504 Comfort for demented patients, providing for, 305 versus prolonged life, patients’ choices about, 301–302 See also Palliation; Quality of life Commercial research organizations (CROs), ethical concerns about, 1259–1260 Communication with agitated patients in dementia, 1087 doctor-patient issues in, 287–297, 361 with the hearing-impaired, 899 naming suffering as a step in intervention, 311 about transitions, 294 Communication disorders specialists, 262 Community-based care, 105–107 elder abuse in, 1058 falls of individuals in, 979–980, 984–989 Community health care services, use of, by older adults, 96 Comorbid conditions association with frailty, 1068–1069 effect of on treatment offered, in breast cancer, 408 on treatment outcomes, 9
Index on treatment outcomes in colorectal cancer, 419 and mortality in breast cancer, 398 in myocardial infarction, 518 problems in geriatric care, 136–137 and treatment of lung cancer, 451–452 of prostate cancer, 459 Co-morbidity Damage Index score, 968 Compensatory mechanisms failure of, in disability, 46 model in long-term care, 99 Competency, concept of, 1233–1240 Competing risks, and decline in early mortality, 42 Competitive antagonists, for muscle relaxation, 234 Complementary/alternative medicine (CAM), increasing use of, 921–929 Compliance, in drug usage, 84–85 methods for improving, 85–86 Complications of Coronary Artery Bypass Graft surgery in older patients, 522 of herpes zoster, 1046–1047 of illness, in older patients, 801 of indwelling catheterization, 951 of inflammatory bowel disease, 847–848 long-term, preventing with aggressive care in diabetes, 687 neurologic, of aortic valve replacement, 525 postoperative, 213 reserves for overcoming, 240 of transurethral resection of the prostate, 763 posttreatment, of vulvar cancer, 481 Components, of rehabilitation, 260–261 Comprehensive discharge planning, from the hospital, 137–138 Comprehensive geriatric assessment (CGA), teams providing, 195 Comprehensive Geriatric Model, 361 Compression of morbidity hypothesis, effect on population aging, 39–40 Compression stockings, for thromboembolic prophylaxis, 672 Computed tomography (CT) scan for diagnosis of cervical myelopathy, 1145 of dementia, 1081–1084 of ovarian cancer, 473 of pancreatic cancer, 425 of subarachnoid hemorrhage, 1124 quantitative, 629 role of, in staging of lung cancer, 447
Computerized systems, to reduce medical errors in hospitals, 136 Conduction abnormalities, 515–517 Conductive hearing loss, 894 Confabulation, in dementia, 1188 Confidentiality physician’s obligations in, 1228–1230 in research, 1259 Confusion, in dying patients, 305 Confusion Assessment Method (CAM) for assessing risk of delirium, 143, 188 for identification of delirium, 1113 Congenital heart disease, in elderly patients, 527 Congestive heart failure (CHF) applicability of study data to elderly patients, 4 hypervolemic hyponatremia in management of surgical patients with, 217–218 increase in antidiuretic hormone levels in, 773 nurse-directed intervention in home care after hospitalization, 122 and response to beta-blockers, 217 studies of management of, in the patient’s home, 164–165 Conjunctiva, aging of, 885 Constipation defined, 845–846 in the elderly, managing, 314–315 as a side effect of opioid drugs, 335–336 Contact dermatitis, 873 Contact inhibition, effect on cell division, 22–23 Contexts of care, 93–97 See also Site of care Continuity of care, obligations of the physician in changes of placement, 1228 Continuous infusion, of fluorouracil in colorectal cancer treatment, 424 in gastric cancer treatment, 428 Continuous positive airway pressure (CPAP), in obstructive sleep apnea, 1033–1034 Contractures development of, on cessation of activity, 260–261 of the hip and knee, after amputations, 273 Contraindications to estrogen replacement therapy, 636 to surgery in hepatocellular carcinoma, 431 Contrast sensitivity function (CSF), as a measure of functional visual performance, 883–891
Index Control coping with loss of, at the end of life, 355 patient’s, through advance care planning, 292 Cooperative Cardiovascular Project beta-blocker therapy data, for myocardial infarction in the elderly, 519 evaluation of Percutaneous Transthoracic Coronary Angioplasty in older patients, 519 Cooperative Health Care Clinics, Kaiser-Permanente, 200 Coping, and depression, 1165–1166 Copper, nutritional, 1011 Core body temperature, circadian rhythm of, 1032 Cornea, structure of, 885 Coronary artery bypass, cognitive decline following, 245 Coronary Artery Bypass Graft (CABG) outcomes of, in the elderly, 521–522 in ventricular tachyarrhythmias, 516 Coronary artery disease (CAD) links with impairment of immunocompetence and health risk behaviors, 56 treating hypothyroidism patients with, 707 Coronary Artery Surgery Study (CASS) Registry, on risk of mortality after smoking cessation, 532 Coronary atherosclerosis, association of periodontal disease with, 904 Coronary heart disease (CHD), atherosclerotic, 517 as a cause of heart failure, 513 Corticobasal degeneration (CBD) ganglionic, 1151–1152 tau profiles in, 1101 Corticobasal-ganglionic-thalamocortical mechanisms, in gait impairment, 1140–1141 Corticocortical projections, neurons of origin of, categories of, 1098–1099 Corticosteroid analogues, in osteoarthritis, 587 Corticosteroids for the asthmatic component of chronic obstructive pulmonary disease, 856 for carpal tunnel syndrome, 664 for herpes zoster pain, study, 1050 for hypothyroid patients perioperatively, 223 injection of in acute tendinitis, 661 for painful joint therapy, 588
1275 for nausea and vomiting in end-of-life care, 306 for osteoarthritis, 654 for rheumatoid arthritis, 604–605 for rotator cuff, 663 for systemic lupus erythematosus, 611 for vulvodynia, topic application, 747 Cortisol, in the elderly, and insulin resistance, 1070 Cosmetic treatment, of aging skin, 879–880 Cough, as a source of suffering, 312–313 Coumarin, sensitivity of thyrotoxic patients to, 703 Cranial dystonia, 1157 Craniocervical dystonia, 1157 C-reactive protein association with clinical severity of osteoarthritis of the knee, 579 levels of, and giant cell arteritis and polymyalgia rheumatica, 598 Creatinine clearance, decline with age, 47, 66–67 formula for, 769 Creutzfeldt-Jakob disease, 343 symptoms of, 1081 Cricopharyngeal incoordination, in oropharyngeal dysphagia, 836 Criteria, for screening strategies, 375–376 Critical care, issues in, 864 Crohn’s disease, 847–848 Crush fractures, effects of, 626 Cruzan v. Director, Missouri Department of Health, 1223 Cryoablation, ultrasound-guided, of the prostate, 459 Cryoglobulinemia, 594 Crystal deposition disease, 591–594 Cued Selective Reminding Test, 209 Culture and definition of abuse, 1060–1061 of dying, 357–358 and responses to death, 319 and responses to disease, 150–151 Cushing’s syndrome, secondary osteoporosis in, 623 Custodians, as abusers of the elderly, 1059–1060 Cutaneous metastases, 878 Cutis rhomboidalis nuchae, 870 Cyclooxygenase inhibition of by nonsteroidal anti-inflammatory drugs, 70, 586 and risk of ulcers, 839 production of, by old macrophages, 789
Cyclophosphamide, for diffuse proliferative glomerulonephritis, 611 Cyclosporin A, interaction with hypericum extracts, 925 Cyclosporine, for systemic lupus erythematosus, 611 Cycloxygenase-2 inhibitors, for treating osteoarthritis, 653–654 Cystometry (CMG), 944 Cytarabine, for remission induction in acute myelocytic leukemia, 489 Cytokines and cancer, 366 changing cellular responsiveness to with aging, 246, 790 involvement in cancers, 370 See also Interleukins Cytoreduction, surgical, in ovarian cancer, 473–474 Cytoscopy, information obtained from, 759 Cytoskeleton, role of microtubuleassociated proteins in formation of, 1099–1100 Cytotoxic drugs, drug-induced lupus associated with, 610 D DAF-1 gene, effect on life span, in Caenorhabditis elegans, 23 Dartmouth Atlas of Health Care, 300 Daunorubicin, for remission induction in acute myelocytic leukemia, 489 Deaths association with impairments in the activities of daily living, 123 peaceful, the value of achieving, 351–358 at younger ages, causes of, 41 See also Mortality rate Death with Dignity Act (Oregon), 1250 Debridement, of pressure ulcers, 971–972 Decision-making capacity determining, 1233–1241 as an issue in informed consent, 1222 Deconditioning, clinical due to excessive bed rest, 274 recovery from, after surgery, 242 Deep venous thrombosis (DVT) in the elderly, 858–861 prophylaxis to prevent in arthroplasty, 656 in recovery from hip surgery, 659 reducing the risk of, with anticoagulation therapy, 249–250 Degeneration, in senescence, 16 Degenerative disk disease, defined, 576–577
1276 Dehydration, outcomes of, 1010–1011 Dehydroepiandrosterone (DHEA) decline in levels of, with aging, 925–926 role of, in antibody production, 793 Dehydroxyepiandrosterone (DHEA-S), decline in levels of, and frailty, 1070 Delegation of decision-making authority, living will, 1223–1224 Delirium, 1113–1122 agitation caused by, 1087 assessing, 188 chronic, differentiating from dementia, 1079 Confusion Assessment Method for evaluating risk of, 143 defined, 1113 in dying patients, 305 following hip fracture, 673–674 in hospitalized patients, 137 as a predictor of surgical outcome, 245 psychosis in the context of, 1185–1187 incontinence associated with, 932 postoperative, in thoracic procedures, 253 as a risk factor to elder mistreatment, 1058 in surgical patients, 223–224 Delirium Prevention consultation team, effect on functional change, 9 Delusion, defined, 1185 Delusional disorder, 1189 Dementia, 1079–1093 advanced, 346–347 age-related, neurobiologic basis of, 1095–1111 aspiration in the late stages of, 302 early, 344–345 effects of ginkgo biloba on, 923 history of, evaluating, 155 major depression in patients with, 1173 managing, in dying patients, 305 moderate, 345–346 oral diseases associated with, 913 prevalence of, in the population over 65, 205, 223 psychosis in, 1187–1188 relationship with sleep disordered breathing, 1032–1033 as a risk factor for delirium, 1114 for elder mistreatment, 1058 screening for, 175–176 sleep disorders in, 1038–1039 in victims of self-neglect, 1059
Index Demographics of aging, 37–44 of cancer in the elderly, 363–373 of diabetes, 681 of disability, 260 of dying and death in the United States, 281–282 of Sjögren’s syndrome, 606 of subarachnoid hemorrhage, 1123 of systemic lupus erythematosus, 608–609 Dental health assessing, 189 candidiasis associated with dentures, 905 caries, 903 oral lesions associated with dentures, 911–912 problems in primary hyperparathyroidism, 640 Dentatorubrothalamic projection, action tremor from pathology in, 1156 Deoxycoformycin, for hairy cell leukemia therapy, 496 Dependency accepting, in dying, 355 on opioid analgesics, 335 suffering associated with being cared for by others, 319–320 Dependency theory, of elder mistreatment, 1060 Depolarizing agents, for muscle relaxation, 233–234 Deposition diseases, renal disease secondary to, 775 See also Amyloid entries Depression, 1163–1174 in Alzheimer’s disease, 345 association with mortality in isolated systolic hypertension, 523–524 in caregivers, 283 in chronic dizziness, 995 in chronic obstructive pulmonary disease, 855 and chronic pain, 326–327 accentuation by aging, 651–667 clinical, in caregivers in dementia, 1085 cognitive impairment due to, 1079 competency of hospitalized patients with, study, 1234 in dementia, managing, 1088 in dying patients, 304–305 in elderly patients in hospital, 137 evaluating a family history of, 155 exacerbation by acute illness or hospitalization, 223 in frailty, 1069 insomnia caused by, 1037–1038 management of, in terminal care, 864
in patients with lung cancer, 453 poststroke, 266–269 screening for, 175 in fall risk assessment, 985–986 and treatment refusal, assessment of decision-making capacity in, 1239 underreporting of by patients, 150 use of hypericum extracts to treat, 925 in victims of self-neglect, 1059 Depression not otherwise specified, defined, 1167 Depressive symptoms as a predictor of posthospital outcomes, 134 remission from, and religiosity, 138 and socioeconomic status, 55 Dermatochalasis, eyelid, 884 Dermatoheliosis, 870 Dermatologic diseases, 869–881 Dermatomyositis, 611–612 Dermatophytes, infection of the toenail plate by, 874–875 Dermatoses, inflammatory, in aging skin, 871–872 Dermis, changes with aging, 869 Detection, Evaluation, and Treatment of High Blood Pressure, Joint National Committee on, 545 Detrusor hyperactivity with impaired contractility (DHIC), 937 Detrusor overactivity (DO) cellular level changes in, 936 differentiating from obstruction, in men, 943–944 incontinence or precipitancy associated with, 939 treating, 945–948 Detrusor underactivity, 950–951 as a cause of incontinence, 938 Development, comparison with senescence, 15 Developmental tasks, at the end of life, 319 Dextran, for thromboembolic prophylaxis in hip fracture surgery, 672 Diabetes Association, American, screening level for fasting glucose, 174 Diabetes Control and Complications Trial (DCCT), study of type 1 diabetes mellitus in the 13–39 age group, 685 Diabetes mellitus control of, and peripheral arterial disease, 563–564 dysphagia associated with smooth muscle wasting in, 837 effect of calcium channel antagonists for hypertension in, 552
Index erectile dysfunction in, 722–723 foot problems associated with, 666 foot ulcers in infection of, 968 prevalence of, 967 as a major source of heterogeneity in the older population, 45 management of surgical patients with, 222–223 noninsulin-dependent, 174 and risk of peripheral arterial disease, 561 skin infection associated with, diagnosing, 808–809 treatment of, 681–694 Diabetes Prevention Program, lifestyle modification outcomes, study, 691 Diabetic retinopathy, 888 Diabetic ulceration, 879 antimicrobial therapy for, in infection or osteomyelitis, 973 debridement of wounds in, 972 surgical management of, 974 Diagnosis of antiphospholipid antibody syndrome, 611 of anxiety disorders, 1174–1175 applying study results to older adults, 11–12 of benign prostatic hyperplasia, 758–760 of cardiac disease secondary to pulmonary disease, 528–529 of causes of incontinence, 938–945 of cervical myelopathy, 1144–1145 of chronic lymphocytic leukemia, 495 of chronic myelogenous leukemia, 491 of chronic obstructive pulmonary disease, 855 of chronic ulcers, 967 of colorectal cancer, 420–421 of community-acquired pneumonia, studies for, 807 of delirium, 1116–1117 of dementia, 1081–1084 of depression, 1166–1167 of diabetes mellitus in the elderly, 684–685 of elder mistreatment, 1060–1061 of esophageal cancer, 429 of frailty, 1071 of gallbladder cancer, 431–432 of gastric cancer, 427 of giant cell arteritis, 599 of hepatocellular carcinoma, 430–431 of herpes zoster, 1047–1048 of herpes zoster in the elderly, 1047 of hip fracture, 669–670 of Hodgkin’s disease, 503–504
1277 and hospitalization, of older persons in the United States, 94–95 of hypertension, 547–549 of hypothyroidism, 705 of infectious disease, 805 of infective endocarditis, 810 of insomnia, 1036–1037 of intracerebral hemorrhage, 1126 invasive tests for cardiovascular disease in the elderly, 512 laboratory of anemia, 822, 823–826 for assessing thyroid nodules, 709–710 of hypothyroidism, 705–706 of osteoporosis, 623 of systemic lupus erythematosus, 609–610 of thyrotoxicosis, 701 of large artery occlusive disease, 1129–1131 of lung cancer, 445–446 of mitral regurgitation, 526 of monoclonal gammopathy of uncertain origin, 497 of mood disorders in later life, 1169 of multiple system atrophy, 1153 of myxedema coma, 708 noninvasive tests for cardiovascular disease in the elderly, 511–512 of osteoarthritis, 578–579 of osteomyelitis with pressure ulcers, 968 of osteoporosis, 627–628 in men, 625 World Health Organization criteria, 627–628 of ovarian cancer, 472 of Paget’s disease, 643 of pancreatic cancer, 425 of periodic limb movements in sleep, 1034 of polycythemia vera, 492–493 of polymyalgia rheumatica and giant cell arteritis, 598 and postacute care, 102–103 of primary hyperparathyroidism, 640–641 of prostate cancer, 457 of REM sleep behavior disorder, 1035 of respiratory infections, 806–807 of rheumatic diseases in the elderly, factors complicating, 574 of Sjögren’s syndrome, 607 of skin and soft tissue infections, 808–809 of sleep disordered breathing, 1033 of spinal cord compression in prostate cancer, 462 of subarachnoid hemorrhage, 1124
in syncope, 960–964 of tuberculosis, 809 of urinary tract infection, 805–806 of venous thromboembolic disease, 859 See also Differential diagnosis Diagnosis-Related Groups, Medicare payments based on, effect on long-term care, 101–102 Diagnostic tests age of the patient, and relevance of, 12 selective use of, 961–964 See also Computed tomography (CT) scar; Diagnosis, laboratory; Instruments, for competency assessment; Magnetic resonance imaging; Positron emission tomography Diarrhea infectious, morbidity and mortality from, 812 managing in end-of-life care, 306–307 managing in the elderly, 315 Diastolic blood pressure, relationship with cardiovascular mortality, 550 Diastolic dysfunction, as a cause of heart failure, 513 Diazepam, pharmacodynamics of, 68 Diet and breast cancer, 395 calcium supplementation and bone mineral density, 631–632 caloric restriction and life span, explaining, 33 in diabetes, 688 fiber in, to manage constipation, 846 and incidence of dental caries, 903 and physiologic changes with aging, 28 and primary prevention of colorectal cancer, 171–172, 420 See also Malnutrition; Nutrition; Vitamins Dietary Approaches to Stop Hypertension (DASH), 551 Dietary restriction, and life span, 15, 20–21 Dietary supplementation with calcium, to prevent fractures, 49 for geriatric patients, 921–929 Diethylstilbestrol (DES), for treating prostate cancer, 460 Differential diagnosis of chronic ulcers, 967 of corticobasal ganglionic degeneration, 1152 of delirium, 223–224, 1116–1117 of dementia, 1079–1081 of depressive symptoms, 1167–1169 of essential thrombocythemia, 493
1278 Differential diagnosis (cont.): of frailty, 1071–1072 of insomnia, 1036–1037 of ischemic stroke, 1129 of leg symptoms, 562–563 of lung cancer, 446 of multiple system atrophy, 1153 of myeloid metaplasia with myelofibrosis, 494 of Paget’s disease, 643 of Parkinson’s disease, 1149 of polymyalgia rheumatica, 598–599 of primary hyperparathyroidism, 640–641 of progressive supranuclear palsy, 1151 of psychosis, 1190 algorithm, 1191 late in life, 1186 of REM sleep behavior disorder, 1035 of rheumatoid arthritis, 602–603 of spinal osteoarthritis, 577 of subarachnoid hemorrhage, 1124 of thyroid nodules, 709–711 of thyrotoxicosis, 701–702 use of Occam’s razor in, 8–9 Differentiation cellular, impairment in cancer, 369 mediating, in cancer therapy, 371 Diffuse esophageal spasm (DES), 837 Diffuse idiopathic skeletal hyperostosis, 577 Digital hearing aids, 897 Digitalis, for myocardial contractility improvement in heart failure, 514 Digital rectal examination (DRE) for assessing lower urinary tract symptoms, 759 for detecting prostate cancer, 383 Digit span test, 208–209 Dignity and death, 356 maintaining at the end of life, 299 Digoxin, studies of effects of withdrawal of, 74 DIG Trial, of digitalis, 514 Dimensions, of geriatric assessment, 187–191 Diminution in function, from medication, 73 Disability association with frailty, 1068–1069 defined, 259–260 excess, reducing in dementia, 1084 in the population over age 65, 45–46, 259 Discharge from hospital, disposition of patients, table, 139
Index Discharge planning, comprehensive, from the hospital, 137–138 Discrimination, in offering health care, 1215 Disease avoidance of, in successful aging, 60–61 chronic link to long-term care, 99–100 management of, 163–167 underreporting of by patients, 149–150 chronic dizziness caused by, 997–999 and complications of surgery, 213–214 defined, 259 impact of aging on, 149–152 management of, comprehensive geriatric assessment model, 200 presentation and natural history of, effect of age on, 248–249 reduction in, nineteenth century, 38–39 Disease differences, and effectiveness of treatments, 7–8 Disease-disease interactions, in the elderly, 151 Disease-modifying antirheumatic drugs (DMARDS), 603 Disease-modifying osteoarthritis drugs (DMOADs), 578–579 Disease-treatment interaction, in multiple pathologies, 151 Disequilibirum, defined, 995 Disorganized thought, in delirium, 1115 Disseminated intravascular coagulation (DIC), consumption of coagulation factors in, 831 Distal interphalangeal (DIP) joints, involvement of, in osteoarthritis, 575 Distal radius fracture, 626–627 Diuretic therapy benefits of, in older hypertension populations, 552 complications of, 514 gout, 592 study of withdrawal in elderly patients, 83 Diverticula right colon, hemorrhage in, 847 urethral, association with recurrent urinary tract infections, 745 Diverticulitis, association with nonsteroidal anti-inflammatory drugs, 847 Diverticulosis, 847 of the small bowel, symptoms of, 843 Dix-Hallpike test, for diagnosis of benign paroxysmal positional vertigo, 997, 1003
Dizziness chronic, 995–1008 in the elderly, managing, 317–318 DNA lymphocyte, 787–789 repair of breaks in, 787 DNA viruses, tumorigenic, 366 Docetaxel, for androgen-independent prostate cancer therapy, 462 Doctor’s bag, supplies for home care, 127 Documentation of “do not” orders, 1224 objective, about nursing home care, 108 Domestic violence, 1057 Donepezil dosage, in dementia, 1086 for managing early and moderate Alzheimer’s disease, 344 side effects of, 68 “Do not hospitalize” (DNH), patient request, 117 “Do not intubate” (DNI) order, 1246 “Do not” orders, 1224–1227 “Do not resuscitate” (DNR) orders, 1224, 1245–1247 Dopamine, declining excretion of, with aging, 771 Dopamine agonists, for early treatment of Parkinson’s disease, 1149 Dopaminergic agents, for periodic limb movements in sleep, 1034 Dopaminergic cells, loss of, in Parkinson’s disease, 1147 Dose adjustment of chemotherapeutic agents for elderly women, 407 and adverse drug reactions, 74 of propofol, 232 of thyroxine, calculation for elderly patients, 706–707 Down syndrome, risk of Alzheimer’s disease in, 1105–1107 Doxazosin, risk for congestive heart failure, trial data, 762 Draloxifene, for osteoporosis treatment, 636 Dressings, monitoring and treating in diabetic ulcer patients, 969–971 Drop attack, defined, 982–983 Drug clearance, and aging, 66 Drug-drug interactions, of quetiepine, 1194 Drug eruptions, cutaneous, 873 Drug-induced lupus (DIL), 610–611 Drug resistance, to amantadine or rimantadine, 170
Index Drugs administration route, 331–332 adverse events related to oral, 914 in antiarrhythmic therapy, 516 recognizing and preventing, 68–69 anesthetic, spectrum of activity for, 231 for anxiety, in dying patients, 304 as a cause of geriatric incontinence, 933 cerebellar disturbances of stance and gait from, 1146 chorea induced by, 1156 for claudication, 566 clinical strategies of prescribing for older adults, 83–89 continuous infusions of, 339 for depression in dying patients, 304–305 development and testing of, 76–77 effects of, on glucose metabolism, 683 erectile dysfunction induced by, 723 for essential tremor, 1155 for focal dystonias, 1157 frequency of adverse events by type, 72 for gout, 592–593 inhibiting thyroid function, 707 interactions with dietary supplements, 921 liver disease induced by, 844 for myocardial infarction management, 520 for nausea and vomiting, 314 for osteoarthritis, 586–588 parkinsonism induced by, 1149 for rheumatoid arthritis, 603–605 risk of acute renal failure due to, 776 for sleep disordered breathing, 1033 steady-state concentration of, 67 target range for, adjusting with changes due to aging, 9–10 for treating dyspnea, 312 See also Combination drug therapy; Medications; Nonsteroidal antiinflammatory drugs (NSAIDs); particular drugs; Psychoactive drugs; Substance abuse Dry eye, effect of, on the cornea, 885 Dry mouth, as a source of discomfort in the elderly, 316–317 Dry type, of macular degeneration, 888 Dual energy x-ray absorptiometry (DEXA), for assessing bone loss, 628–630 Ductal carcinoma in situ (DCIS), treatment of, 398–399 Duke Social Support Index, 1179–1183
1279 Duodenal ulcers, 840 Duodenum, disorders of, 838–839 Durable power of attorney for health care, 1223 assigning to a family member, 1090 Dying, the art of, 354–358 See also End-of-life care Dysarthria, from olanzapine, 1193 Dyspareunia, due to vaginal atrophy, 743 Dysphagia, 836–837 Dyspnea drugs to relieve, 304 management of, 312 Dyspnea on exertion (DOE) diagnosis of, 8–9 and heart failure, 513 Dysthymia defined, 1166 evaluating a family history of, 155 Dystonia, 1156–1157 E Early Breast Cancer Trialists’ Collaborative Group, analysis of adjuvant therapies, 402 Early Lung Cancer Action Project (ELCAAP), 445 positive predictive value of spiral computed tomography for lung cancer detection, 386 Early Lung Cancer Detection Program, National Cancer Institute, 444 Early mobilization, in hip fracture, studies, 675 Eastern Cooperative Oncology Group study of therapy for metastatic breast cancer, 406 study of therapy for non-small cell lung cancer, 450 Eating behaviors, in moderate dementia, 345 Eaton-Lambert syndrome, association with small cell carcinoma of the lung, 613 Echocardiogram/echocardiography to assess aortic stenosis, 525 to assess cardiac disease secondary to pulmonary disease, 529 to assess cardiovascular disease in the elderly, 511–512 to assess pulmonary embolism, 859 to confirm cardiomyopathy diagnosis, 528 to differentiate systolic from diastolic ventricular dysfunction, 513 for endocarditis diagnosis, 810 transesophageal to evaluate cardiovascular disease in the elderly, 512
intraoperative, 217–218 Economics of calcitonin therapy, 638 of congestive heart failure management, savings per patient, 165 cost-effectiveness of tetanus vaccination for all older individuals, 813 costs of Alzheimer’s disease, 343 of care in the last year of life, 300 of skin grafting for leg ulcers, 974 of delirium complication hospital stays, 1113–1115 of dementia, 1079 of drug therapy, 84 cost of drugs and drug-related problems in long-term care, 87 finasteride versus surgery in benign prostatic hyperplasia, 762 of end-stage renal disease, 776 estimated value of uncompensated care for the seriously ill at home, 282–283 funding for home care, 124–125 of health care, mechanisms for paying for, 1201–1211 of health service utilization, with increase in the older population, 93 health spending as a percentage of income, in elderly households, 1204 of hip fracture, 669–680 of long-term care, 100–103 Medicare costs and risk levels for cardiovascular disease, 532 of osteoporosis, cost of fractures, 625–626 of prophylactic antibiotic administration, before hip surgery, 671 reimbursement to agencies for Medicare hospice care, 303 of surgical versus medical management of pressure ulcers, 973 Ectropion effect of, on the cornea, 884 results of, 884 Edmonton Symptom Assessment Scale (ESAS), 312 Education about Alzheimer’s disease, to facilitate patient and family planning, 344 in a chronic disease self-management program, 165 correlation with health, 55
1280 Education (cont.): of patients about medications, 85–86 and scores on tests of cognitive ability, 206 Effectiveness, of home care, 121–122 Ejaculation, reflex of, 721 Ejection fraction, changes with aging, 509 Elder Life Program, 143 Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS), on supportive care in non-small cell lung cancer, 450 Elder mistreatment (EM), 60, 1057–1065 questions about, for assessing geriatric patients, 62 Electrocardiogram ambulatory long-term, abnormalities in the elderly, 511 for assessing syncope, 962 in cardiomyopathy, 528 changes of left ventricular hypertrophy, in aortic stenosis, 525 resting, abnormalities in the elderly, 511 during surgery, 236–237 Electroconvulsive therapy for affective disorders with psychosis, 1189 for psychotic depression, 1166, 1173 Electrolyte homeostasis, 770–774 Electromyography (EMG), for evaluating the distal urethral sphincter, 945 Electronystagmography, 1003–1004 Electrophysiologic studies, in syncope, 963 Electrostimulation, for urinary incontinence and prolapse management, 751 Emergency hypertensive, 555 psychiatric evaluation, 1186 surgical, risks in, 239 Emergency departments (EDs), screening for elder mistreatment in, 1058 Emission, in response to genital stimulation, 721 Emotional support effect on mortality risk after myocardial infarction, 521 versus instrumental support, effects on the elderly, 61 Emotional vitality, and quality of life in disability, 46 Empathy in handling emotion, 289–290 physician’s
Index and patient anxiety, 287, 295 and a peaceful death, 355 Empowerment of patients, comprehensive geriatric assessment model, 198 Enalaprilat, for control of postoperative hypertension, 217 Encephalopathy metabolic, insecure gait in, 1147 thyrotoxic, 700 Endarterectomy, effect of, on stroke risk, random trials, 1133 Ending an encounter with a patient, support and reassurance in, 291 Endocarditis infective, 527, 810–811 risk factors for, 218 Endocrine disorders hearing loss accompanying, 895 perioperative management of, 222–223 Endocrine system, role of, in frailty, 1072 End-of-life care, 281–285, 299–309 discussing with patients, 138 managing delirium, 1119–1120 preparation for, 1090–1091 Endometrial cancer, 469–471 risk of from estrogen therapy, 636 in tamoxifen therapy, 397 Endometrial pathology, identifying on physical examination, 743–744 Endometrial polyps, postmenopausal bleeding caused by, 748 Endoscopic retrograde cholangiopancreatography (ERCP), for diagnosis of pancreatic cancer, 425 Endoscopy to diagnose peptic ulcer disease, 840 to evaluate gastrointestinal bleeding, 842 Endothelial-derived relaxing factor (EDRF), 547 Endpoints, for gauging anesthesia adequacy, 230 End-stage renal disease, 776–777 Energy requirements, in the elderly, 1009–1010 Engagement with life, in successful aging, 60–61 Entacapone, for managing Parkinson’s disease, 1149 Enteral tube feeding for dementia patients, 347–348 for malnourished surgical patients, 223 for underweight patients, 1017–1020
Entorhinal cortex, vulnerability to neurofibrillary tangle formation, 1098–1099, 1103 Entropic process, in senescence, 16 Entropic theories of aging, 17 Environment adaptation of, to a disabled person, 261 barriers in taking a history in the home setting, 128 cellular, and cancer, 365–366 for communication with patients, 288 effect of on delirium, 1119 on mortality rate, expressed in the Gompertz Curve, 18 effects of physical elements on aging skin, 870–871 hazards in, 191 risk of falls in community life, 980, 983 risk of falls in nursing homes, 990 residential, and infection in the elderly, 803–804 See also Site of care Enzymatic debridement, 971–972 Eosinophil count, reduction in, conditions associated with, 828 Eosinophilia, conditions associated with, 829 Epidemiologic Catchment Area (ECA), on prevalence of depression in the elderly, 1163–1164 Epidemiologic transition, fourth stage of, reduction in old-age mortality, 41 Epidemiology and aging, 45–51 of anxiety disorders, 1174–1178 of benign prostatic hyperplasia, 755 of breast cancer, 393–394 data linking autoimmunity and atherosclerosis in humans, 791 of delirium, 1113–1115 of dementia, 1079 of depression, 1163–1164 of diabetes, 681 of herpes zoster, 1043–1044 of hospitalization, 133 of hypertension, 545 of infectious diseases, 801–803 of intracerebral hemorrhage, 1125 of lung cancer, 441–443 of osteoporosis, 624–625 of Paget’s disease, 642 of pain complaints, 325–326 of Parkinson’s disease, 1147 of peripheral arterial disease (PAD), 561
Index of polymyalgia rheumatica and giant cell arteritis, 595 of postural disorders, 1140 of rheumatoid arthritis, 600 of vision loss, 883 Epidermal resurfacing, agents promoting or delaying, lists, 970 Epidermis, changes with aging, 869 Epidural administration, of opioids to control pain, 253 Epilepsy, in intracerebral hemorrhage patients, 1127 Equality, in distribution of health care, 1217–1218 Equilibrium, mechanisms of, 996 Erection dysfunction in, and aging, 722–724 mechanism of, 720–721 Erosive inflammatory osteoarthritis, 575 Erotic stimulation, effect of, on neural components of erection, 720–721 Erythema ab igne, 871 Erythroplakia, as a precursor of squamous cell carcinoma, 387 Erythroplasia of Queyrat, 876 Erythropoietin for anemia associated with multiple myeloma, 499 managing, 826 measurement of, in anemia, 822 for myelodysplastic syndrome treatment, with granulocyte colony-stimulating factor, 490 recombinant, effect on quality of life chemotherapy for nonmyeloid malignancies, 452 Esophageal disorders, 835–838 cancer, 428–430 medication-induced esophagitis, 837 Essential thrombocythemia (ET), 493–494 Essential tremor, 1155 Established Populations for Epidemiologic Studies of the Elderly (EPESE), 509 on mortality risk and hypertension, 550 on stress and risk of herpes zoster recurrence, 1043 Estradiol, vaginal, to reduce urinary tract infections, 745 Estring (17b-estradiol) slow release device, 743 for treating urinary tract infections, study, 745 Estrogen receptors in tumors, and response to tamoxifen therapy, 401
1281 of the urethral and bladder mucosa, 738 Estrogen therapy for atrophic vaginitis, 933 and bone loss with aging, 49, 623, 634–636 in hyperparathyroidism, 641–642 and colorectal cancer prevention, 420 effect of on the cardiovascular risk profile, 532 on peripheral arterial disease, 565 for postmenopausal bleeding, 748 risk of endometrial cancer related to, 469 vaginal, accompanying pessary therapy, 752 for vaginal atrophy, 743 Etanercept, for decreasing TNF-a activity, for rheumatoid arthritis therapy, 604 Ethical implications of decision-making capacity in patients, 1234 in end-of-life care, 1243–1251 of geographic variability in utilization of health care, 1214 of informed consent, 1222 institutional ethics committees, 1224 of the Oregon plan, 1216 of research, controversies within the research community, 1258–1260 of research in geriatric medicine, 1253–1261 Ethnicity and caregiving arrangements, 59 and health, 54 questions about, for assessing geriatric patients, 61 See also Culture Etidronate for Paget’s disease, 643 for resorptive bone disease management, 633 Etiology of acute renal failure in the elderly, 776 of anemia, determining, 821–822 of dental caries, 903 of depression in later life, 1164–1165 of hypothyroidism, 704–705 multifactorial, in falls, 981 of Paget’s disease, 642 of polymyalgia rheumatica and giant cell arteritis, 595–596 of postural disorders, 1140–1141 of rheumatoid arthritis, 601 of syncope, 958 Etomidate, as a sedative hypnotic agent, 231–232
Etretinate, for psoriasis treatment, 873 European Carotid Stenosis Trial (ECST), 1133 European Isolated Systolic Hypertension Study, 48 European Working Party on High Blood Pressure in the Elderly (EWPHE) Trial, on treatment of hypertension, 550 European Working Party on Hypertension in the Elderly (EWPHE) trial, 524 Euthanasia, 1248–1249 Evaluation of dizziness, 999–1004 of drugs for treating psychosis in the elderly, 1190–1192 of falls, 984–991 of gastrointestinal bleeding, 841 of incontinence, 938–942 of low vision, 889 of patients, 153–159 in pulmonary disease, 853–854 of patients at home, identification of problems through, 126–127 See also Assessment Evidence hierarchy of, 3 for pursuing selected screening measures, 180 Evidence-based medicine criteria for evaluating studies, 5–6 developing a disease management program, 163–167 focus on use of specific categories of medications, 75 and geriatrics, 3–14 pharmacologic therapies for Alzheimer’s disease based on, 344 select resources, table, 11 strategies in delirium assessment, 1116 Evolutionary theory of aging, 16–17 of osteoarthritis development, 575 Excessive movement disorders, 1154–1158 Excretion, of fluid intake, timing of in the elderly, 932 Executive function, tests of, 209 Exenteration, for refractory or recurrent cervical cancer, 478 Exercise, 1023–1029 and bone loss, 632–633 for hospitalized patients, 136 and management of underweight conditions, 1015–1016 for osteoarthritis, 585, 653 as a pain management strategy, 340
1282 Exercise (cont.): pelvic muscle, to decrease incontinence, 948–949 and physiologic changes with aging, 28 as a preventive intervention, 177 in diabetes, 688 programs for older persons, 1026–1028 in prolapse, 751 and risk of breast cancer, 395 and risk of falling, 988 supervised walking program, for managing claudication, 567–568 in tendinitis/bursitis syndromes, 661 and vestibular disorders, 1004–1005 Exercise testing in aortic stenosis, risk in, 525 in the elderly, 512 in myocardial infarction patients, 520 Exercise tolerance, as a predictor of cardiac and pulmonary complications after surgery, 242–243 Exercise training as claudication therapy, 565–566 rehabilitative, after a coronary event, 521 in rheumatoid arthritis, 603 Expansion of morbidity hypothesis, effect on population aging, 39–40 Expenditures for health care, by age, 93–94 for long-term care, by source of funds, 102 for nursing home care, by source of funds, 102 See also Economics Extracellular fluid volume ability to maintain, 957 depletion of, in the elderly, 772–773 Extracellular matrix of bone, composition of, 621 changes in osteoarthritis, 583–584 Extrapyramidal side effects, from risperdal, 1193 Eye changes in and diseases of, in aging, 883–891 movements of, in progressive supranuclear palsy, 1151 ocular involvement complications in herpes zoster, 1046–1047 ocular involvement in giant cell arteritis, 597 ophthalmic treatment for cataract, 887 ophthalmopathy, in hypothyroidism, 705
Index See also Vision; Visual entries Eyelids, changes with aging, 884 F Factor VIII inhibitors, association with bleeding and activated thromboplastin time, 830–831 Failure to thrive, in the elderly, 1070–1071 Falls, 979–994 assessment of, after hip fracture, 676 contribution to risk of fracture, 49 frequency of, in the aging, 33 due to postural instability, 1140 due to prescription drug use, 68 reduction of with interventions based on in-home care, 121–122 with interventions based on in-home care education, 165 Famciclovir, for treating herpes zoster pain, 1049 Familial adenomatosis polyposis (FAP), 419 Familial Alzheimer’s disease (FAD), presenilin 1 gene associated with, 1106 Familial hypocalciuric hypercalcemia (FHH), 640–641 Family as caregivers, 59, 261 long-term care, 100–103 cognitive history from, 207–208 cultural differences in responsibility for end-of-life care, 1244–1245 spiritual suffering of, 318 study of attitudes toward physicianassisted suicide, 1250 support for, at the end of life, 299, 303, 307 Family consent, laws covering medical decisions, 1224 Family history abuse in, and elder mistreatment, 1060 in evaluating an older patient, 155 See also Heredity Fat central distribution of, and diabetes predisposition, 683 nutritional requirement for, 1010 Fatigue, causes of, in the elderly, 513 3w-Fatty acids, effects of on blood pressure and triglycerides, 923 Favre-Racouchot Syndrome, 870 Fear about death, managing, 352 of falling avoiding activity due to, 980
chronic dizziness contributing to, 995 Fecal incontinence, managing, 846 Fecal occult blood tests (FOBT), 171 for screening for colorectal cancer, 384 Feeding tube. See Tube feeding Felty’s syndrome, neutrophil supply in, 828 Femoral neck fractures, 670 Femoral popliteal bypass, for claudication treatment, 566 Fentanyl dose of, age related, 233 for relieving respiratory symptoms, 304 Ferritin, serum, for evaluating iron stores, 823 Fever, as a symptoms of infectious disease, 804 Fibrillation, of cartilage in osteoarthritis, 584 Fibrils, of primary amyloidosis, 612–613 Fibrinogen, association with risk for cardiovascular events, 531 Fibroblast growth factor, basic (bFGB), effect on diabetic neurotrophic foot ulcers, 972 Fibroblasts, changes in, with aging, 246 Fibromyalgia, 577–578 Fibrous hyperplasia, from dentures, 912 Finances considerations in long-term care, 108–109 review of, on a home visit, 129 Financial dependency, and elder mistreatment, 1060 Finasteride for increasing hair count in men, 869 for reducing prostate volume, 762 Fine-needle aspiration, for biopsy of thyroid nodules, 710 Fish oils, reduction in blood pressure from, 923 Flavinoids, effect of, on bone loss, 639 Flexible sigmoidoscopy (FSIG), 171 for colorectal cancer screening, 384–385 Floor effect, of an instrument, 187 Fluconazole, for oral candidiasis, 905 Fludarabine, for chronic lymphocytic leukemia therapy, 495 Fluid and electrolyte disorders, 769–782 Flumazenil, as a competitive antagonist for the benzodiazepine receptor, 233 Fluoride studies of bone mineral density increase with, patient-oriented outcomes of studies, 4
Index for treating osteoporosis, 638 Fluoroquinolones, for treating urinary tract infection, 806 Fluorouracil for advanced gastric cancer, 428 for colorectal cancer chemotherapy, 423–424 Flurazepam, comparison of half-life in elderly and young men, 67 Flutamide (Eulexin), antiandrogen for treating prostate cancer, 460 Fluvoxamine, for treating obsessivecompulsive disorder, 1178 Focal dystonias, 1157 Folate, and cancer prevention, 420 Folic acid effects of deficiency of, 1012, 1015 macrocytic anemia from deficiency of, 820 measuring in hospital patients, 822 to reduce side effects of methotrexate, 604 for treating anemia, 826 Follicular carcinoma, thyroid, 712 Food and Drug Administration (FDA) approval of calcitonin for osteoporosis treatment, 638 guideline on testing of drugs in the elderly, 76–77 suspension of clinical research operations at some universities, 1258 Foot problems, in the elderly, 664–666 Foot ulcers, diabetic, infection in, 968 Forced expiratory volume (FEV), 807 improvement of, in chronic obstructive pulmonary disease, 855 Fracture Intervention Trial (FIT), 49 study of bone mass loss, 628 Fractures femoral neck, 659, 670 intratrochanteric, 659, 670 vertebral, due to osteoporosis, 626 See also Hip fractures Fragmentation, of sleep in patients with periodic limb movements, 1034 in patients with sleep disordered breathing, 1032 Frailty, 1067–1076 and adverse drug effects, 71–72 and care required, 283–284 defined, 28, 1076 dynamic nature of, 33 and need for long-term care, 100–101 and openness to risk, 108 preventing, 177–179 proportion of the older population exhibiting, 45–46
1283 Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) Trials, 989 Framingham Eye Study, on cataracts, 887 Framingham Heart Study on atrial fibrillation and mortality, by gender, 515 on evidence of osteoarthritis by age, 574 on hearing loss, 893 on heart failure rates, by age, 512 on mortality risk among the elderly, 510 correlation with systolic hypertension, 523 on physical activity and risk of knee osteoarthritis, 579 on risk factors for stroke in the elderly diabetic population, 682 on stroke risk and hypertension, 1131–1132 Framingham Offspring Study, on inheritability of osteoarthritis, 581 Framingham Osteoarthritis Study, on weight loss and risk of knee osteoarthritis, 584 Framingham Study on back symptoms in the elderly, 576 on radiographic changes of osteoarthritis versus symptomatic disease, 578 on relationship of cigarette smoking and stroke, 1132 on subarachnoid hemorrhage, 1123 on thyroid nodules, by sex and age, 708–709 Free and Cued Selective Reminding test, 1082 Free radicals association with cancer, 364–365 implication in aging, loose cannon theory, 17 Froment’s rigidity sign, in Parkinson’s disease, 1148 Frontotemporal dementia, with parkinsonism, linked to chromosome 17, 1101–1102 Frozen shoulder, 663–664 Fuch’s dystrophy, 885 Fulmer Elder Assessment Instrument, 1060 Functional Assessment of Cancer Therapy-Breast instrument, for measuring quality of life in breast cancer patients, 407 Functional Assessment Staging/Global Deterioration Scale (FAST/GDS), evolution of
Alzheimer’s disease as measured with, 1084 Functional impairment assessment of, 1084 and disease, 152 of fine motor skills, in osteoarthritis, 575 after intracerebral hemorrhage, 1126 subsequent to hospitalization, 133–134 Functional Independence Measure (FIM), 264–265 Functional Reach test, 190 Functional reserve aerobic, defined, 1025 reduction in, antibiotics following surgery, 219–220 Functional status assessing in peripheral arterial disease, 563 determining in neuropsychological examination, 208 individual differences in, 45–46 instruments to assess, 185–194 and long-term care use, 99 maximizing in end-of-life care, 302 restoring in rehabilitation, 261 self-reported, 189 data supporting validity of, 156 and surgery in the aging, 242–243 Functional trajectory, to evaluate patient requirements after hospital discharge, 137–138 Function capacity, rapid change in, as a sign of infection, 804–805 Fundal gastritis, 839 Futility, of treatment judgments about, 1247 loose definitions of, 1247 strict definition of, 1247 Future, of comprehensive geriatric assessment in health care delivery, 201 G GABA agonists, for oromandibular dystonia, 1157 receptor complex site of action for barbiturates, 231 GABAergic interneurons, resistance of, to degenerative processes, 1104 Gabapentin, for herpes zoster treatment, 1051 Gail Model, breast cancer risk score in, 397 Gait assessment of in fall evaluation, 987 in fall evaluation in nursing homes, 990
1284 Gait (cont.): freezing in Parkinson’s disease, response to levodopa therapy, 1149 impairment of in osteoarthritis, of the hip, 576 in Parkinson’s disease, 1148 performance-based assessment of, 190 Gait claudication, 1144 Gait training, in Parkinson’s disease, 273 Galantamine, for mild to moderate Alzheimer’s disease, 1086 Gallbladder cancer, 431–432 GALOP syndrome (gait disorder; autoantibody; late-age onset; polyneuropathy), 1142–1143 Garlic (Allium sativum), studies of health effects of, 922 Gastrectomy, for gastric cancer, 427 Gastric cancer, 426–428 Gastritis, atrophic, types of, 839 Gastroenterologic disorders, 835–851 Gastroesophageal reflux disease (GERD), symptoms of, 838 Gastrointestinal diseases in diabetic individuals, 682 effect of nonsteroidal anti-inflammatory drugs on, 70 malignancies, 417–440 Gastrointestinal symptoms bleeding, 841–842 managing at the end of life, 305–307 as a source of suffering, 313–316 Gastrointestinal Tumor Study Group, randomized trial of chemoradiation for unresectable pancreatic cancer, 426 Gastrojejunostomy, for palliation in pancreatic cancer, 426 Gelhorn pessary, 752 Gemcitabine for metastatic pancreatic cancer, 426 for non-small cell lung cancer, 451 Gemtuzumab ozogamicin (Mylotarg), for treating acute myeloid leukemia, research on, 489 Gender and health status, 54 questions about, for assessing geriatric patients, 61 General intelligence, testing in patient evaluation, 209 Generalized anxiety disorder (GAD), 1175–1176 Genes/genetics BRCA1 and BRCA2, and risk of breast and ovarian cancer, 395–396
Index constraint by, on maximum life span, 16 effect on mortality rate change with aging, expressed by the Gompertz curve, 18 and longevity, 21 in osteoarthritis, 581 and risk of breast cancer, 395–396 See also Heredity Gene therapy, protocol irregularities associated with, 1258 Genetic instability association with cancer, 365 effect on tumors’ resistance to therapy, 371 Genetic integrity, disruption of, on aging, 363–365 Genioglossus advancement, 1033 Genitalia, external of aging women, 738 examining, 740 Geographic variations, in utilization of health care resources, 1214 Geriatric Care Program, 143 Geriatric Depression Scale (GDS), 175, 188 Geriatrician, in the nursing home, 113–119 Geriatric Pharmacy, Commission for Certification in, 87 Geriatric Quality of Life Questionnaire (GQLQ), Medical Outcomes Short Study Form-36, 191 Geriatric rehabilitation units, 263 Geriatric Review Syllabus, 60 Geriatrics, 15 Geriatric syndromes, 152 chronic dizziness, 999 Germ cell tumors, 472 Gerontogenes in fruit flies, yeast and mice, 23–24 normal function of, 22 Gerontological Society of America, 348 Gerontology, 15 goals of, assigning values to the constants of the Gompertz curve, 18 Get Up and Go test, for assessing balance and gait, 987 Giant cell arteritis, 594–600 Ginger (Zingiber officinale), reduction of nausea by, 924 Gingivitis, 901 preventing, 903 Ginkgo biloba, as a nutritional supplement, 922–923 Ginseng, 923–924 Glasgow Coma Scale (GCS) score, 1126
Glasgow Outcome Scale, for grading subarachnoid hemorrhage, 1123–1124 Glaucoma, 885–886 screening for, 176 Gleason grade, for describing histologic patterns in prostate cancer, 457 Gleevec, tyrosine kinase inhibitor, for chronic myelogenous leukemia treatment, 492 Glioblastoma, gait disorder in, 1154 Globus pallidus (GPi), surgical therapy for Parkinson’s disease involving, 1150 Glomerular basement membrane (GBM) permeability, changes in, with aging, 769 Glomerular diseases, secondary to systemic disease, 775 Glomerular filtration rate (GFR), 769 decrease in with aging, 221 rate of, 66–67 longitudinal study of, individual variability found in, 27 reduced, and impaired natriuresis in the aged, 771 Glucocorticoids for androgen independent prostate cancer treatment, 462 osteoporosis as a consequence of long-term treatment with, 638 osteoporosis associated with administration of, 623 Glucosamine, for osteoarthritis, 588, 925 Glucosamine/chondroitin, for osteoarthritis, 654 Glucose, implication in aging loose cannon theory, 17 in yeast, 24 Glucose intolerance, age-associated, 547 pathogenesis of, 682–683 a-Glucosidase inhibitors, for slowing carbohydrate processing in the gut, 689 Glutamate, disruption of the metabolism of, and neuron death, 1103 Glutamate receptor-mediated excitotoxicity, disruption of, leading to cell death, 1103 Gluten-sensitive enteropathy (celiac sprue), in the elderly, 843 Glycolic acid, to improve sun-damaged skin, 879–880 b2-Glycoprotein 1, antibodies to, in antiphospholipid antibody syndrome, 611 Goals of advance care planning, 291–292 of care, 311
Index for cardiovascular disease in the elderly, 509 clarifying, 300–302 in moderate dementia, 345 of communication about transitions due to disease progression, 294 in diabetic treatment, 687 of disease management programs, 163 of an exercise program for older individuals, 1026 of managing dizziness, 999 realistic, for nursing home patients, 119 in rheumatoid arthritis treatment, 603 Goiter, 711–712 toxic multinodular, 700 Goldman index, for risk of cardiac complications in surgery, 215 Gompertz curve, 15, 18–19 Goserelin, therapy with, combined with radiation in prostate cancer, 458–459 Gout, in the elderly, 592–593 G proteins (GTP-binding proteins), mutations of, in cancer, 369 Graded exposure, for phobia management, 1176 Granulocyte colony-stimulating factor (G-CSF), 490 recombinant, for myelodysplastic syndromes, 826 supportive use of, in treating acute leukemias, 489 Granulocyte-macrophage colonystimulating factor (GM-CSF) impaired production of, in the elderly, 820 for supportive therapy in induction for acute leukemias, 489 Graves’ disease, 700–701 Grief following diagnosis of dementia, 345 normal symptoms of, 1167 Grover’s disease, 872 Growth factors effect of, on osteoblasts and osteoporosis, 639 for managing anemia, 826 overexpression of, and cancer, 368 receptors for, and cancer, 368–369 role in wound healing, 972 Growth hormone administration of, to increase muscle mass in rehabilitation, 1017–1020 decline in, in frailty, 1070 effect of in the aging, 926 on natural killer cell activity, 787 immunoenhancing effects of, 793 and life span, in mice, 17, 23–24 and wound healing, in mice, 248
1285 Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC), tau protein profile in, 1101 Guardianship, for making decisions for critically ill patients, 1224 Guidelines, for physician-assisted suicide, 1250 Guillain-Barré syndrome (GBS), gait impairment in, 1143 Gynecologic cancers, 469–485 Gynecologic Oncology Group (GOG), randomized trials in ovarian cancer, analysis of outcomes by age, 474–475 Gynecologic problems examination of the older woman, 738–743 of older women, 737–754 H Hair age-related changes in, 869 transplants of, 869 Hairy cell leukemia, 495–496 Half-life, for drug elimination, 67 Hallucination, 1185 Haloperidol for managing dementia, 1089 for psychosis, evaluation of, 1190 Halothane, association with hepatitis, 231 Halstead Reitan Battery, 208 Handbook of Aging and the Social Sciences, 53 Handbook of the Psychology of Aging, 53 Handicapped, defined, 260 Happiness versus satisfaction with life, 60 Hashimoto’s thyroiditis, 704–705 goiter caused by, 711–712 Hayflick phenomenon, defined, 22 Hazards of exercise in the aging, 1026–1028 of hospitalization and surgery, 249 See also Safety Headache, postspinal, treating with an epidural blood patch, 235 Head and neck, physical examination of, 157 Health criteria for describing, and age, 22 poor, as a risk factor for suicide, 1174 self-reported status of, and dizziness, 318 Health care mechanisms for paying for, 1201–1211 mismatches in the system of, for the dying, 283
movement of the elderly population through the system of, 96 Health Care Financing Administration (HCFA) on costs of Medicare and long-term care in the future, 281 on physical restraint of hospitalized patients, 136 on sources of funding for home care, 124 Health care proxy, appointing, 1090 Health insurance, lack of, and rationing of health care, 1213–1214 Health Insurance Plan of Greater New York, study of mammography for reducing disease-specific mortality, 378 Health Insurance Portability and Accountability Act (HIPAA), 1229 on confidentiality of medical records, 1228 Health Policy Research, U.S. Agency for, 96 Health Professionals Follow-Up Study, on aspirin use and colorectal cancer prevention, 420 Healthy life expectancy, defined, 40–41 Healthy People 2010, goals of, 1057 Hearing contribution of postural stability, 981, 996 loss of, types of, 894–895 otologic changes with aging, 893 otoxic agents dizziness caused by, 999 hearing loss from, 895 physical examination of, 157 screening for impairment of, 176, 188–189 Hearing aids, implantable, 898 Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-s), 176, 189, 896–897 Heart, changes in, with aging, 510 See also Cardiac entries Heart and Estrogen/Progestin Replacement Study on the effects of estrogen therapy on urinary incontinence, 744 on hormone therapy for peripheral arterial disease management, 565 Heart disease as a major source of heterogeneity in the older population, 45 mean hospital length of stay for, 94 reduction in mortality with moderate exercise, 1026–1027 Heart failure, symptoms of, in the elderly, 512–515
1286 Heart Outcomes Prevention Evaluation Study, on hypertension and peripheral arterial disease, 565 Heart rate, maximum tolerable, 18, 8–32 Heat dissipation of, during exercise, 1024 effect of, on the skin, 871 Heberden’s nodes, defined, 575 Heel spur, 665–666 Helical computerized tomography (HCT), for assessing pulmonary embolism, 859 Helicobacter pylori infection and gastric function in the elderly, 838–839 in peptic ulcer, 840 and risk of gastric cancer, 426 therapy for, 841 Helper T cells, changes in function with age, 785 Helplessness, of nursing home staff caring for declining patients, 108 Helsinki Aging Study, aortic stenosis evaluated by echocardiography in, 525 Hematogenous infection, pyogenic osteomyelitis, 658 Hematologic problems, 819–833 malignancies, 487–506 toxicity from chemotherapy, in elderly patients, 407 Hematoma in intracerebral hemorrhage expansion of, 1126 surgical evacuation of, 1127 subdural, gait disturbance in, 1154 Hematometrium, management of, 744 Hematopoietic response, of the elderly, 820 Hemianopia, 884 causes of, 889 Hemiarthroplasty, in femoral neck fracture, 659 Hemochromatosis, restrictive cardiomyopathy caused by, 528 Hemocyanins, responses to, contrast between older adults and young controls, 786 Hemodialysis, age of patients, 776 Hemodynamic assessment, in peripheral arterial disease, 563 Hemodynamic instability, association with anesthetic agents as muscle relaxants, 233–234 Hemoglobin, iron in, 819–820 Hemorrhage. See Bleeding Hemostasis, disorders of, 829–832 in response to tissue injury, 246
Index Heparin low molecular weight, for venous thromboembolic disease, 860 thrombocytopenia induced by, 830 for thromboembolic prophylaxis in hip fracture surgery, 671–673 for thromboembolic therapy, 1130 Heparin in Acute Embolic Stroke Trial (HAEST), 1130 Hepatitis C, development of chronic disease in, 430–431 Hepatobiliary disorders, 844–845 Hepatocellular carcinoma, 430–431 Hepatojejunostomy, for palliation in pancreatic cancer, 426 Her-2/neu-positive tumors treating with herceptin, 474 treating with trastuzumab, 404 Herceptin, for treating advanced ovarian cancer, 474 Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu) disease, gastrointestinal bleeding in, 844 Hereditary nonpolyposis colorectal cancer (HNPCC), 419 and risk of ovarian cancer, 472 Heredity autosomal dominant transmission of early-onset Alzheimer’s disease, 1106 cancer syndromes, examples of, 365 contribution of, to depression and bipolar disorders, 1165 and giant cell arteritis, 596 in Huntington’s disease, 1156 hypercoagulable states, 832 and incidence of chronic lymphocytic leukemia, 494–495 of colorectal cancer, 419 of Fuch’s dystrophy, 885 of ovarian cancer, 472 ischemic leukoencephalopathies attributable to, 1147 and osteoporosis, 626 and rheumatoid arthritis, 600 in Sjögren’s syndrome, 606 in type 2 diabetes, 683–684 See also Genes/genetics Herniated disks, surgery for, 657 Herpes simplex virus infection, differentiating from herpes zoster, 1047 Herpes zoster (shingles), 809, 874, 1043–1056 Heterogeneity, effects of, on views of age-related changes, 46–47 Hierarchy of influence, in the nursing home, 113–115
High blood pressure, screening for, 173 See also Hypertension High-risk case management, 165 Hip, osteoarthritis of, 576 radiation of pain to the knee in, 655–656 Hip fractures, 658–659, 1140 association with psychotropic drugs, 69 effect of estrogen replacement therapy on, 635 epidemiology and the geriatric perspective on, 48–49 mean hospital length of stay for, 94–95 medical aspects of management of, 669–680 morbidity and mortality associated with, 626 rehabilitation in, 270–271 risk of, and disability, 260 Hippocampal formation, neuronal loss in, 1097, 1103 Hip protectors, use of, 989 in nursing homes, 991 Historical influences, questions about, for assessing geriatric patients, 61 History, patient describing dizziness, 999–1002 in diagnosis of delirium, 1116 for evaluating hearing, 895–897 for evaluating lower urinary tract symptoms, 759 findings associated with risk of nutritional deficiency, 243–244 for the geriatric woman, 738 in incontinence, 938–941 limitations of, in diagnosing cardiovascular disease in the elderly, 510–511 medications taken, 83 miscellaneous indications of wellbeing, 155 pain assessment and physical examination, 326–327 risk assessment beginning with, 984–987 setting for obtaining, 153–156 in syncope, 960–964 HLA-DR-4 haplotype, association with giant cell arteritis, 596 HMG-Co A reductase inhibitors, effects of, on osteoporosis, 639 Hodgkin’s disease, 503–505 Home modification of for Parkinson’s disease patients, 274 for stroke patients, 269–270 providing rehabilitation services in, 263
Index Home- and community-based services (HCBS), expenditures for, by state, 109 Home care, 105–107, 121–131 defined, 121 Medicare provision for, 303 for psychotic patients, 1186 Home care services, use of, 96 Home health aide services, defined, Medicare, 125 Home health care, defined, 121 Homemaking services, funding for, 106 Home medical call (house call), defined, 121 Home Medical Service, Boston University Medical Center Hospital, study of patients enrolled in, 123 Homeostasis and acid-base balance, 774 maintaining during and after surgery, 230 perturbation of, in the elderly, 152, 1070 Homeostenosis, effects on outcomes of interventions, 9 Home visit conducting, 128–129 value in evaluating a patient, 153 Homocysteine alteration in metabolism of, and risk of peripheral arterial disease, 562 levels of, and risk of stroke, 1132 reducing levels of with diet supplements, 565 Honolulu Heart Study, on impaired glucose tolerance and fatal myocardial events, 683 Hope, maintaining in the context of truthfulness, 291, 295 Hopelessness, link to sudden death, carotid atherosclerosis and coronary artery disease, 56 Hormone and Estrogen Replacement Study, 3 Hormones and growth of cancers, 366 relationship with immune function, 792 See also Dehydroepiandrosterone (DHEA); Thyroid-stimulating hormone (TSH) Hormone therapy for metastatic breast cancer, factors predicting response to, 406 to prevent osteoporosis, 174 relationship with breast cancer, 394–395 See also Estrogen therapy Horner’s syndrome, gait disorders associated with, 1143
1287 Hospice Medicare benefit for, 282, 299, 303, 348–349 studies about nutrition and hydration, 302 Hospice care comparison with nursing home care, 117–118 provision of benefits for at-home care, 125–126 Hospital care, acute, 133–145 Hospital Elder Life Program, management of risk factors for delirium in, 245 Hospital Insurance Trust Fund, estimates of solvency, 1207–1208 Hospitalization rates by age, 133 for alcohol-related conditions, 155 and duration, in older patients, 801 readmission reduction by intervention in in-home care, 166 Hospitalized diabetic patients, management of, 690 Hospitalized elderly longitudinal project (HELP), 133 Hospitals, utilization of by capacity, 1214 and cost of health care, 94–95 Host, age of, and tumor aggressiveness, 397 Hostility, and coronary artery disease, 56 Host-microorganism interaction, in defense against infectious diseases, 802 Hour of Our Death, The (Ariès), 351 Housing, as part of long-term care, private responsibility for, 108–109 See also Site of care Human herpesvirus 8, associated with Kaposi’s sarcoma, 878 Humanitarianism, the ethical principle of, in Canada’s universal health insurance, 1217–1218 Human leukocyte antigen (HLA), role in defense against cancer, 365–366 Human papilloma virus (HPV) testing for, to detect cervical neoplasia, 381 vulvodynia caused by, 747 Human recombinant thyrotropin, for assessing recurrent papillary carcinoma of the thyroid, 712 Human T-cell leukemia virus 1 (HTLV-1), 501 Humoral immune system, functions of, 783
Hunt and Hess Scale, for grading subarachnoid hemorrhage, 1123–1124 Huntington’s disease age-specific incidence of, 20 chorea in, 1156 symptoms of, 1081 Hurley Discomfort Scale, for evaluating discomfort in patients with dementia, 327–329 Hürthle cell carcinoma, 712 Hyaluronic acid, for osteoarthritis management, 654 Hydralazine, drug-induced lupus associated with, 610 Hydration end-of-life decisions about, 302, 347–348 to promote wound healing in the elderly, 247 Hydrocephalus, late-life, gait disorders in, 1153–1154 Hydrocolloid dressings, 970–971 Hydrogels, as wound dressings, 970 Hydrogen ion receptor antagonists, for treating peptic ulcer disease, 840 Hydroxyapatite (HA) in crystal deposition disease, 591–592 deposition disease, 593–594 Hydroxychloroquine for rheumatoid arthritis, 604 for Sjögren’s syndrome, 607–608 for systemic lupus erythematosus, 611 Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, 1132 Hydroxyproline, urinary elevation of, as a measure of osteoclastic activity, 643 Hydroxyurea compared with interferon-alpha, for treating chronic myelogenous leukemia, 492 for essential thrombocythemia therapy, 493 Hylans, for osteoarthritis therapy, 589 Hyperactive delirium, 1116 Hyperalimentation, means of attaining, 1017–1020 Hypercalcemia diagnostic of hyperparathyroidism, 640 due to hyperparathyroidism, 639–642 of malignancy, effect of calcitonin on bone resorption in, 637 in multiple myeloma, 497–498 Hypercarbia, in minimal access surgery, control of, 252 Hypercoagulable states, 832
1288 Hypercortisolism, secondary osteoporosis in, 623 Hyperglycemia control of, in patients in nursing homes, 690 fasting, Metformin for improving, 689 monitoring and treating in diabetic ulcer patients, 969 monitoring and treating in surgical patients, 222 Hyperkalemia, with angiotensinconverting enzyme inhibitors, 553–554, 774 Hyperlipidemia correlation with glucose tolerance reduction, 683 management of, 531, 1132 in peripheral arterial disease, 564–565 monitoring and treating in diabetic ulcer patients, 969 and risk of peripheral arterial disease, 562 Hypermobility syndrome, 581 Hypernatremia, 773 Hyperosmolar nonketotic coma as the first sign of diabetes in the elderly, 684 hyperglycemic, in hospitalized diabetic individuals, 690 in older diabetic individuals, 681–682 Hyperosmolar state, diabetes presenting as, in older patients, 152 Hyperparathyroidism, primary, 639–642 Hyperphosphorylation, of tau proteins, in neurodegenerative diseases, 1101 Hyperprolactinemia, erectile dysfunction in, 723–724 Hypersensitivity skin testing, allergy to, in older adults, 783 as a predictor of mortality, 791 Hypertension, 545–559 and cardiovascular risk, 532 control of, in old age, 47–48 in diabetic individuals, 681 effect on outcomes, 686 in hypothyroidism, 705 lipohyalinosis caused by, 1128 as a major source of heterogeneity in the older population, 45 as a modifiable stroke risk factor, 1131–1132 number needed to treat as a function of age, 7 perioperative management of, 216–217 postoperative, drugs for controlling, 217
Index as a risk factor in intracerebral hemorrhage, 1125 in peripheral arterial disease, 562 secondary, causes of, 548 sleep disordered breathing as a risk factor for, 1032 systemic arterial, and cardiovascular risk, 523–524 treating and incidence of heart failure, 513 in peripheral arterial disease, 565 Hypertensive cardiovascular disease, as a cause of heart failure, 513 Hyperthyroidism erectile dysfunction in, 723–724 prevalence in older patients, 222–223 secondary osteoporosis in, 623–624 severe, treatment of, 703 subclinical, 703–704 Hyperthyroxinemia, 698–699 Hypertrophic gastropathy, 839 Hypertrophic pulmonary osteoarthropathy, symptoms and diagnosis of, 613 Hypervolemic hyponatremia, in congestive heart failure, 773 Hypnosis (amnesia), in anesthesia, 229–230 Hypnotic agents, sedative, 231–233 Hypoalbuminemia and drug dosage, 65 malnutrition, 1014 and surgical outcome, 214 Hypochondriasis distinguishing from depression, 1168 stereotypical image of older patients in terms of, 150 Hypogammaglobulinemia in chronic lymphocytic leukemia, 495 in multiple myeloma, 498 Hypoglycemic agents, oral, for type 2 diabetes, 687–688 Hypogonadism, and erectile dysfunction, 723–724 Hypokalemia, due to diuretic therapy, 774 Hypokinesia, in Parkinson’s disease, 1148 Hyponatremia, 772–773 Hypotension, with spinal anesthesia in older patients, 234–235 Hypothalamic-pituitary-adrenal (HPA) axis, changes associated with frailty, 1070 Hypothalamic-pituitary-thyroid axis, 695–696 Hypothermia in hypothyroidism, 705 following surgery, 236
Hypothyroidism, 704–708 diagnosing in older patients, 152 erectile dysfunction in, 723–724 prevalence in older patients, 222–223 screening for, in calcium pyrophosphate dihydrate deposition disease, 593 subclinical, 707–708 Hypothyroxinemia, 698 Hypoxemia, nocturnal, in sleep disordered breathing, 1039 Hysterectomy, for cervical cancer treatment, 477–478 Hysteroscopy, for endometrial assessment, 748 I Iatrogenic effects, of hypericum extracts, 925 Iatrogenic illness heart disease in hospitalized frail patients, 513 hyperthyroidism, associated with bone loss, 706–707 hypothyroidism, 705 following radioiodine therapy, 702–703 risk of, during hospitalization, 134–136 secondary osteoporosis due to glucocorticoid administration, 623 Ibuprofen, for pain in the elderly, 587 Idiopathic pulmonary fibrosis (IPF), mortality in, 862 Illinois Cancer Center, on age and response to non-small cell lung cancer treatment, 450 Illness course of, for chronic wound, 967–968 debilitating, and senescence, 21 serious, effect on patients and their families, 282–283 Immobility/immobilization delirium subsequent to, 1115 and functional decline after hospitalization, 136–137, 274 postoperative, contribution of preoperative functional deficits to, 242 in the presence of untreated pain, 253 Immune surveillance, theories of, 792–794 Immune system enhancing, in cancer therapy, 371 immunodeficiency associated with non-Hodgkin’s lymphoma, 501 impairment of, and war stress, 56 organization of, 783–784
Index response of and cancer, 365–366 effect of stress on, 791 reversal of age-related immunodeficiency, 792–794 in the weak link theories of aging, 17 Immunization, 812–814 flagellin, response to in older subjects, 786 against Streptococcus pneumoniae, 813 in chronic obstructive pulmonary disease, 858 Immunofluorescent antibody (IFA) techniques, for diagnosis of herpes zoster, 1047–1048 Immunoglobulins IgG, affinity of urate crystals for, 591–592 IgM reactive with central myelin antigen, 1142–1143 in Waldenstrom’s macroglobulinemia, 499–500 production of, in plasma cell dyscrasias, 496 Immunology, of aging, 783–800 Immunomediated disorders, affecting gait, 1142–1143 Immunoregulation, factors for, production of, 789–790 Immunosuppression, and incidence of herpes zoster, 1044 Immunotherapy for treating chronic lymphocytic leukemia, research on, 495 for treating leukemias, research in, 489 Impact of Event Scale, for measuring quality of life in breast cancer patients, 407 Impairment, defined, 259–260 Implementation, of comprehensive geriatric assessment recommendations, 196–197 Inactivity, as a risk factor for osteoarthritis, 581 Inappropriate secretion of antidiuretic hormone (ADH), from selective serotonin reuptake inhibitor use, 1170–1173 Inappropriate thyroid-stimulating hormone syndromes, Jod-Basedow phenomenon, 702 Inattention, in delirium, 1115 Incentive spirometry, to increase functional residual capacity, 863
1289 Incidence age-specific, of gastrointestinal malignancies in the United States, 418 of breast cancer, 393–394 of disease defined, 19 exponential increase with aging, 19–20 of herpes zoster, 1044 of multiple system atrophy, 1152 of ovarian cancer, age-adjusted rates, 471–472 of progressive supranuclear palsy, 1150 of prostate cancer, in men over 65, 383 of subarachnoid hemorrhage, 1123–1125 Incidentalomas, of the thyroid, 710 Income correlation with functional decline, 55 in elderly households, 1204 Incompetence, judgment of, 1237–1238 Incontinence effect of age on, 931–932 screening for, 176 transient, causes of, 932–935 urinary, effects of estrogen on, 744 Indirect costs, of dementia, 343 Individual aging, 41–42 defined, 37 variability in, 21 Indomethacin, effect of, on immune response, 793 Indy, gene coding for dicarboxylate cotransporter, 24 Infarction, gait disorders associated with, 1143 Infections, 801–817 in aging skin, 87–88 bacterial, of the salivary glands, 907–908 of chronic wounds, 97 in diabetic individuals, 682 in dying patients, 307 in nursing homes, preventing, 690 foot ulcer prevalence in diabetes, 968 impaired wound healing in, 247 nonvalvular cardiovascular, 527–528 occult, delirium associated with, 1115 of the oral cavity, 902–903 in patients with dementia, 348 precipitation of myxedema coma by, 708 risk of, and neutrophil count, 82 with varicella-zoster virus, 1044–1045 Infective endocarditis, 810–811
Inflammation, in response to tissue injury, 246 Inflammatory bowel disease, 847–848 Infliximab for decreasing TNF-a activity, for rheumatoid arthritis therapy, 604 development of antinuclear autoantibodies in response to, 610 Influenza, preventing, 170–171 immunization of chronic obstructive pulmonary disease patients, 858 immunization of the elderly, 812–813 Influenza pandemic, postencephalitic parkinsonism in survivors of, 1101 Influenza vaccine, efficacy of, 9, 170–171 Informal Caregivers Survey, data from, 123–124 Information for patients about illness and advance care planning, 292 prognostic, providing to patients and their families, 265 Informed consent for “do not resuscitate” orders, 1247 ethical principle of autonomy in, 1222 importance of decision-making capacity in, 1233 See also Assent to treatment Inhaled aerosols, for chronic obstructive pulmonary disease management, 855–856 In-hospital settings, for comprehensive geriatric assessment, 200 Initiation, of carcinogenesis, 367 Injections, joint and bursa, for osteoarthritis therapy, 588 Injury, risks of, in exercise, 1026 Inoculation, direct, pyogenic osteomyelitis due to, 658 Insomnia, 1035–1038 defined, 1035–1036 Institute for the Future, on barriers to change in health care, 201 Institute of Medicine, report on nursing home care, 107 Institutional ethics committee (EIC), 1224 Institutional setting appropriate, in elder mistreatment, 1061 clinical decision making in, 75–76 elder mistreatment in, 1060 Instrumental activities of daily living (IADL), 189 assessing, in the home setting, 130 help with, in the home, 123 recovery of, after surgery, 229
1290 Instrumental support versus emotional support, for the elderly, 61 Instruments, for competency assessment, 1238 Insulin increasing action of, 689 increasing secretion of, 688–689 resistance to, in the elderly, 683 Insulin-dependent diabetes (IDDM), 681 Insulin-like pathway, and increase in life span, 23–24 Insulin receptor, homologue of, DAF-2 gene coding for, 23 Intensely-modulated radiation therapy (IMRT), for treating prostate cancer, 458–459 Intensive care unit (ICU), deaths in, 300 Intensive therapy, for diabetes, controlled trial, 685 Interdisciplinary rehabilitation, in hip fracture, studies, 675 Interdisciplinary teams, for home care, 127–128 Interferon a for chronic myelogenous leukemia therapy, 492 for essential thrombocythemia therapy, 493 for hairy cell leukemia, 496 g effects of, on natural killer cell activity, 790 production of, by activated T cells, 789 for maintenance therapy in multiple myeloma, 499 for preventing hepatocellular carcinoma in patients with hepatitis C, 430 Interleukins IL-1 role in immune response, 789 role in osteoarthritis, 583 IL-2 in cell activation, 788–789 in cellular immunity, 789 effect on gastrointestinal cancer, in combination with melatonin, 792–793 T lymphocyte production stimulated by, 827 IL-4, production of, by activated T cells, 789–790 IL-6 effect on bone resorption, 622 increased production of, in the elderly, 820
Index in polymyalgia rheumatica and giant cell arteritis, 598 production of, by activated T cells, 789 role in frailty, 1070 IL-10, role in B-cell differentiation and antibody production, 790 IL-12, role in simulation of cytotoxic T cell production, 790 Intermittent androgen deprivation (IAD), for prostate cancer treatment, 461 International Association for the Study of Pain, 324 International Lymphoma Study Group, 501 International normalized ratio (INR) as a measure of anticoagulation after drug administration, 70, 860 monitoring for prothrombin time interpretation, 830 in warfarin treatment, 672 International Prognostic Scoring System (IPSS), for myelodysplastic syndromes, 490 International Prostate Symptom Score (IPSS), for lower urinary tract symptoms, 758 International Stroke Trial on effect of aspirin in stroke, 1131 on effect of heparin therapy in stroke, 1130 International Study of Infarct Survival (ISIS-2), on aspirin for myocardial infarction therapy, 520 Interpersonal therapy (IPT), for depression, 1170 Interpretation, of platelet count, 829–830 Interpreter, in the medical setting, 288 Interstitial lung disease, 861–862 Intertrochanteric fractures, 670 Interventional therapy, for peripheral arterial disease, 566–567 Interventions on behalf of a social service client, 1227–1228 in chronic disease management, 163–164 in elder mistreatment, 1061–1062 evaluating for medical soundness, 300 nonpalliative, in advanced dementia, 347 to relieve suffering, 311 Interview, with the patient, for neuropsychological testing, 205 Intra-arterial thrombolysis, 1130
Intracerebral hemorrhage (ICH), 1125–1128 Intraocular implant (IOL), for cataract correction, 887 Intrinsic sphincter deficiency (ISD) as a cause of incontinence, 937–938 evaluating, 944 Intubation, swallowing dysfunction following, 251 Invasive breast cancer, early-stage disease, treating, 399–401 Invasive capacity, of cells, and cancer, 369–370 Iodide, deficiency of, in the aging, 696 Iodine-induced thyrotoxicosis, 702 Ipratropium, for chronic obstructive pulmonary disease treatment, 856 Ipriflavone, effect of, on bone loss, 639 Irinotecan (CPT-11) for treating colorectal cancer, 424 for treating gastric cancer, 428 Iron deficiency of identifying reasons for, 819–820 tests indicating, 824 therapy for, in anemia, 826 need for nutritional supplementation, 1011 serum level of, for evaluating iron stores, 823 storage of, in the body, 819–820 Iron-binding capacity, serum, for evaluating iron stores, 823 Irradiation. See Radiation entries Irritable bowel syndrome, 846 Ischemia cerebral, after subarachnoid hemorrhage, 1125 in colitis, gastrointestinal bleeding caused by, 843 leg, critical, 566–567 in stroke, 1128–1131 Ischemic bowel disease, 843–844 Isolated systolic hypertension (ISH), in the elderly, 523–524, 545, 550 Isolation theory, of elder mistreatment, 1060 Isoniazid, hepatitis associated with, 810 Isoproterenol protocols, in syncope, 963 Isotretinoin, for rosacea treatment, 872 J Japanese Intervention Cooperative Study, 552 Johns Hopkins Hospital on lung cancer screening, 386 mortality and morbidity in pancreaticoduodenectomy, 425
Index Joint Commission on Accreditation of Healthcare Organizations (JCAHO), requirement of a mechanism for resolving ethical disputes, 1224 Joints fusion of, in osteoarthritis, 655 instability of, role in the pathogenesis of osteoarthritis, 580–581 loading of, and nutrient diffusion into cartilage, 582–583 replacement of, in osteoarthritis, 589–590 Justice and the allocation of health care resources, 1213–1220 as a consideration in research, 1254 K Kainate receptors, association with calcium flux into the neuron, 1103–1104 Kallikrein, decreased excretion of, with aging, 771 Kaposi’s sarcoma, human herpesvirus 8 associated with, 878 Karnofsky performance status, in treatment planning for lung cancer, 447–448 Kegel exercises, description of, 751, 948–949 Keratoacanthoma, 876–877 Ketamine (Ketalar) analgesic and hypnotic effects of, 232 as a sedative hypnotic agent, 231 Ketoacidosis, diabetic, mortality in, 681 Ketoprofen, for pain in the elderly, 587 Killing versus allowing to die, 354 Kinetic categories, of anemia, 821 Knee, osteoarthritis of, 575–576 Koenig depression scale, 1164 L Laboratory evaluation in assessing falls, 987 of hemostasis, 829–831 of herpes zoster, 1047–1048 in incontinence, 942 in nursing home residents, 989–990 in patients with chronic dizziness, 1003 in patients with depression, 1169 in patients with hypercalcemia, 640 in patients with interstitial lung disease, 862 of white blood cells, 827 See also Diagnosis, laboratory Lacunar disease of gait, 1146 Lacunar infarction, 1128 Lamellar bone, defined, 621
1291 Language evaluation of, 209 as an indication of disorder, 206 Laparoscopic surgery, in the elderly, 252–253 Laser-assisted uvulopalatoplasty (LAUP), for treating snoring, 1033 Late-stage dementia, preparing for care in, 1090–1091 Leflunomide, for rheumatoid arthritis, 604 Left shift, describing band neutrophil appearance in the blood, 829 Left ventricular failure, wedge pressures in, 236–237 Left ventricular hypertrophy (LVH), correlation with systolic hypertension, 523, 549 Legal blindness, defined, 884 Legal issues court order requiring release of confidential patient records, 1229 in geriatric practice, 1221 mandated reporting of information or abuse, 1229 protection for patient autonomy, 1245–1246 status of “do not” orders of mentally competent patients, 1224 Leiomyomata, confirming, in the uterus of the postmenopausal woman, 742 Lens, changes with aging, 886–887 Lentigo maligna, 877–878 Lesions, types and distribution of, in Alzheimer’s disease, 1096–1099 Leucovorin, for colorectal cancer chemotherapy, 423–424 Leukemias, acute, 487–489 Leukocytes defects in regeneration of, in the elderly, 820 interpretation of counts of, 827–829 Leukocytosis, interpreting, 829 Leukoplakia, 911 as a precursor of squamous cell carcinoma, 387 Leuprolide (Viadur), for treating prostate cancer, 460 Level of consciousness, altered, in delirium, 1115 Levodopa for multiple system atrophy, 1153 for Parkinson’s disease, 1149–1150 Lewy body disease, 343 characteristics of, 1081 Lhermitte’s sign, in postural instability, 1142
Libido and aging, 721–722 physiology of, 719–720 Lichen planus, 910–911 Lichen sclerosus, vulvar, 746 Lichen sclerosus et atrophicus, 874 Lichen simplex chronicus, 871 Lidocaine transdermal patches, for treating neuropathic pain, 338 Lie/Bet questionnaire, 155–156 Life events, negative, and depression, 1165 Life expectancy of an elderly diabetic individual, 686–687 as a function of age, United States data, 170 of individuals admitted to nursing homes, 690 reduction of, in diabetic individuals, 681 as a summary measure of individual aging, 37 in the United States, 801 Life-prolonging interventions, for the very old, 282 Life span defined, 37 maximum, determining, 18–19 Lifestyle and management of benign prostatic hyperplasia, 761 and management of hypertension, 551 and outcome during aging, 21 for successful aging, 60–61 Life-sustaining treatment, withholding or withdrawing, 1245 Lighthouse National Survey on Vision Loss, 883 Lipid disorders, screening for, 173–174 Lipreading training, 898–899 Lithium for unipolar depression, 1172 volume of distribution of, 66 Liver decrease of mass of, in aging, 66 metabolism of medications in, 66 Local treatment, in stage I breast cancer, 399–400 “Locked in syndrome”, pain of patients with, 329 Locked joint, 652 Loneliness, and responses of lymphocytes to mitogens, 791 Longitudinal risk factors, for abuse and neglect in the community, 1059 Longitudinal studies, distortions in, 46–47 Longitudinal Study of Aging, 133
1292 Long-term care, 99–111 defined, 99 hypertension in residents of facilities for, 555–556 infections common to patients in, 803 out-of-pocket expenditures for, 1209–1210 research on residents of, 1257–1258 Long-term care facilities (LTCF) for-profit, constraints on staffing in, 75 medication cost in, relative to cost of treating drug-related problems, 87 Long-term financing, of Medicare, 1207–1208 Long-term oxygen therapy (LOT), in chronic obstructive pulmonary disease, 857 Loose cannon theories of aging, entropic, 17 Lorazepam, to sedate alcohol withdrawal patients, 224 Low back pain, treatment of, 590 Lower extremity amputation (LEA), 271–273 Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia, 755 and causes of incontinence, 935–936 indices for quantification of, 758 remission of, controlled studies, 756 Low vision, 889 L-thyroxine, for hypothyroid patients perioperatively, 223 Lumbar puncture, in diagnosis of subarachnoid hemorrhage, 1124 Lumbar spine medication for treating, 657 stenosis of, 657–658 Lung biopsy of, in interstitial lung disease, 862 examination of, 158 interstitial disease of, in systemic lupus erythematosus in the elderly, 608 scanning, for pulmonary embolism diagnosis, 859 See also Pulmonary entries Lung cancer, 441–454 screening for, 386–387 small cell, neuropathy associated with, 1142 Lung transplant programs, exclusion of applications over 69 years of age, 858 Luria Nebraska Battery, 208 Lymphocytes and changes in immune function with aging, 785–789 DNA of, 787–789
Index in vitro function studies, variability among cells, 27–28 Lymphocytic thyroiditis, distinguishing from Graves’ disease, 701 Lymphoid differentiation, 488 Lymphokine-activated killer cells (LAK cells), 787 Lymphoma association with Sjögren’s syndrome, 606 gastric, association with Helicobacter pylori infection, 839 thyroid, 713 Lymphopenia, conditions associated with, 828 Lymphoproliferative disorders, 494–500 M MacArthur Foundation, successful aging studies of, 60 MacArthur Study of Aging, data on homeostasis and compensation in the aging, 33 McGill Pain Questionnaire, 327 MacKie risk factor flowchart, for assessing risk of skin cancer, 388 Macrocytic anemias, laboratory tests and treatment, 824 Macrophages effect of, on healing rate, 246 function of, in the aging, 787 Macula, value of, 888 Macular degeneration, 888 Magnesium, serum levels of, 775 Magnetic resonance imaging for detection and surveillance in osteoarthritis, 578 for diagnosing vascular dementia, 1081–1084 for differential diagnosis of myelopathy, 1145 Major depressive disorder, defined, 1166 Malignancy association with gastric ulcers, 840 incidence of, association with deep venous thrombosis, 860 relationship with dermatomyositis, 612 Malignant conversion, step in carcinogenesis, 367 Malignant disease lymphoma, 500–505 melanoma, skin, 388 surgical management of, in the elderly, 239 See also Cancer Malmö trial, data on relative risk reduction due to mammograms, 378
Malnutrition addressing in rehabilitation, 269 and morbidity and mortality in surgical patients, 673 Nutrition Screening Initiative Checklist, 175 in patients on admission to hospitals, 136 protein-calorie, lymphopenia in, 828 significance of, in older persons, 1015 See also Diet Mammography in older patients, 157 screening for breast cancer with, 378 for women over 50 years of age, 739–740 Managed care comparison with fee-for-service plans, Medicare, 1207 lawsuits against organizations offering, 1221–1222 Medicare plans, 1205 in nursing homes, 105 Managed care Medicare supplement plans, 1203 Management alternative strategies, for local breast cancer, 401 of anxiety disorders, 1176–1178 of delirium, 1117–1120 of depression, 1169 of diabetes mellitus, 686 of insomnia, 1037–1038 of intracerebral hemorrhage, 1126 of the patient with prostate cancer, 457–462 of sleep disordered breathing, 1033–1034 of thyroid nodules, 710–711 See also Palliation; Treatment Mandible, susceptibility to radiation damage, 915 Manic episodes, defined, 1169 Marginal competence, formalizing, 1238 Marriage, and mental and physical health, 57 Marrow. See Bone marrow Mass flexor synergism, in the rehabilitation phase for stroke patients, 266 Mastectomy, prophylactic, for preventing breast cancer, 397 Matrix, cartilage, progressive loss of, 652 Maxillomandibular advancement, for improving sleep, 1033 Maximum aerobic capacity (VO2 max), change with age, 1024 Maximum life span potential (MLSP), defined, 37
Index Mayo Clinic characterization of monoclonal gammopathy by, 496–497 mortality and morbidity in pancreaticoduodenectomy, 425 screening for lung cancer, trial, 386 Measurement of disability, 46 of hypertension, 547–548 of pain multidimensional scales for, 328 unidimensional scales for, 323–329 Mechanical devices, to improve penile erection, 725 Mechanical disorders, as a cause of dysphagia, 836–837 Mechanical ventilation (MV) need for, by elderly patients, 864 withdrawal of, from dying patients, 864 Meclizine, ambiguous effects on dizziness, 999 Mediastinoscopy, for staging in lung cancer, 447 Medicaid cost of nursing home care for the elderly, 101, 1209–1210 funding for home care by, 124–126 funding for hospice by, 303 long-term care provided by, 118 Medicare beneficiaries qualifying for coverage under, 1203 rehabilitation services provided by, 262–263 Medical castration, with luteinizing hormone-releasing hormone (LHRH) agonists, 762–763 Medical conditions mood disorder caused by, 1167 related with psychosis, 1186 Medical director, in a skilled nursing facility, 118 Medical errors, elderly hospitalized patients affected by, 135–136 Medical Expenditure Panel Survey, data on home health services, 123 Medical legal issues, in managing dementia, 1091 Medical malpractice, 1221–1222 Medical model, in long-term care, 99 Medical Outcomes Short Form-36, 563 Medical problems, perioperative, managing, 216–224 Medical record, nursing home, 115 Medical social services, defined, Medicare, 125 Medical therapy for chronic dizziness, 1004 for claudication, 565–566 for gastrointestinal bleeding, 842
1293 for lower urinary tract symptoms, 761–763 for peripheral arterial disease, 563–565 and the physician’s legal duties, 1221–1231 Medicare cervical cancer screening provided by, 173 chronic disease management programs, managed care versus fee-for-service plans, 166 cost of, disability measures predicting, 259 coverage provided by, 1201–1203 criteria for long-term oxygen therapy, 857 data from, on diagnoses in the last year of life, 299–300 data on mortality after heart failure, 512 historic context, 1201 home glucose monitoring kits provided by, 174 home health care provided by, 106, 124–125 home visit provided by, 153 hospice care provided by, 299–300, 348–349 long-term care provided by, 101, 118 mammograms provided by, 172 prostate examinations provided by, 173 rehabilitation services provided by, 262–263 role in access of the elderly to health care, 1203 Medicare Hospice Benefit, 282 MediCaring model, for chronically ill patients, 284 Medications adverse events caused by delirium as, 1114 falling, 984 gait instability, 982 in hospitalized patients, 135 voiding dysfunction, 745 altered absorption or metabolism of, by peptic ulcer disease treatment, 840 anorexia as a side effect of, 345 antidepressant, for stroke patients, 269 antihypertensive, and risk of intracerebral hemorrhage, 1125 assessing the patient’s utilization of, 86 for behavioral and psychological disturbances in dementia, 1089
in cardiac disease secondary to pulmonary disease, contradictions in managing, 529 categories for questioning patients about use, 83 causing xerostomia, 907 contributing to constipation in the elderly, 845–846 dizziness caused by, 998–999 effects of, on continence, 934 esophagitis induced by, 837 for glaucoma, 886 hypothyroidism caused by, 705 identifying in patient evaluation, 154 minimizing use of, 83–84 mood disorders caused by, 1167 for myoclonus, 1158 nonopioid, for treating pain, 337–338 for oral candidiasis, list, 906 orthostatic hypotension caused by, 510 for palliation of cognitive impairment of dementia, list, 1085 for Parkinson’s disease, psychosis as a side effect of, 1188 review of in diagnosing delirium, 1116 on a home visit, 129 and risk of falling, 985–987 toxicity related to, 1147 in ventricular diastolic dysfunction, to reduce heart failure symptoms, 514 See also Antibiotics; Anticoagulation therapy; Antidepressants; Antihistamines; Antipsychotic drugs; Benzodiazepines; Beta-blocker therapy; Drugs; Neuroleptic medications; Prednisone; Propranolol; Tricyclic antidepressants Medullary cancer, of the thyroid, 713 Megakaryocytes, increase in essential thrombocythemia, 493 Megaloblastic anemia, characterization of, 823–824 Meglitinides, for increasing insulin secretion, 688–689 Meige’s syndrome, 1157 Melancholic depression, defined, 1166 Melatonin role in immune function, 792 for treating insomnia, 1038 Melphalan for multiple myeloma, 498–499 for myelodysplastic syndromes, 491 Memorial Sloan-Kettering Cancer Center data on surgery for metastatic colorectal cancer, 423
1294 Memorial Sloan-Kettering Cancer Center (cont.): lung cancer screening trial, 386 mortality and morbidity in pancreaticoduodenectomy, 425 Memorial Symptom Assessment Scale (MSAS), 312 Memory, dysfunction of, in cognitive disorders, 209 Men, osteoporosis in, 625 Menetrier’s disease, 839 Meniere’s disease, vertigo in, 997 Meningioma, gait disorders in, 1154 Meningitis, 811–812 tubercular, 809 Meniscus, torn arthroscopic surgery for managing, 654 in the knee, 652–653 Mental illness, chronic, and long-term care, 99 Mental status altered, evaluation of, 1117 fluctuating, evaluation of, 1238 testing of, 206–207 Meperidine, side effects of, 253 Merit-based allocation of health care, relating to control or lack of control over health status, 1218 Messenger RNA (mRNA) effect on cell division, 22 for interleukin 2, in aged rats, 789 Meta-analyses, of adjuvant trials for breast cancer, 402 Metabolic encephalopathy, gait disturbances in, 1147 Metabolism complications in diabetes, treatment for, 687 disorders of, association with postural tremor, 1156 senescence arising from, 23 thyroid hormone, 696 Metaclopramide, for gastroesophageal reflux disease, restrictions on usefulness of, 838 Metaprolol, for thyrotoxicosis management, 702 Metastasis in breast cancer, 405–407 cellular capacity for, and cancer, 369–370 in endometrial cancer, treating, 471 in follicular carcinoma of the thyroid, 712 in medullary cancer of the thyroid, 713 in ovarian cancer, 381 to the ovaries, 472 in prostate cancer, 460–462 to bone, 463
Index in small cell carcinoma of the lung, 447 Metered-dose inhaler (MDI) in chronic obstructive pulmonary disease management, 855–856 difficulties in using, 85 Metformin for improving insulin-mediated effects on the liver, 689 for treating obese diabetic patients, 686 Methicillin-resistant Staphylococcus aureus (MRSA) in long-term care settings, 803–804 meningitis caused by, 812 Methimazole, for treating hyperthyroidism, 702 Methotrexate for giant cell arteritis, 600 for psoriasis treatment, 873 for rheumatoid arthritis in the elderly, 603–604 for systemic lupus erythematosus, 611 Methuselah, gene involved in Drosophila life span, 24 Methylphenidate, for treating agitated or sleep-deprived patients with dementia, 1090 Methylxanthines, for chronic obstructive pulmonary disease management, 856 Metoclopramide for nausea and vomiting in end-of-life care, 305–306 prescription of, cascade to levodopa therapy, 69 Metoprolol, for ventricular systolic function improvement in heart failure, 514 Metronidazole, for rosacea, 872 Metropolitan Detroit Cancer Surveillance System, study of mortality in breast cancer in women with comorbid conditions, 398 Michigan Alcoholism Screening TestGeriatric Version, 155, 224 Microcytic anemias, laboratory tests, and treatment, 824 Microemboli, symptoms of, 967 Microscopic examination, of peripheral blood, in anemia, 825 Microtubule-associated proteins (MAP) tau, tau, 1099–1102 Microwave hyperthermia, for benign prostatic hyperplasia, 764 Micturitional urethral pressure profilometry (MUPP), 944 Midazolam, pharmacodynamics of, 68
Military experience effect on health, 55–57 questions about, for assessing geriatric patients, 61 Milwaukee shoulder, 594 Mineral nutrition, 1011 Minimal access surgery, 252–253 Mini-Mental scores, level of, 1069, 1082 Mini-Mental Status Examination (MMSE), 176, 1083 for cognitive status assessment, 187 for diagnosing delirium, 1116 for evaluating effect of ginkgo biloba on dementia, 923 evolution of Alzheimer’s disease as measured with, 1084 scores of patients in a home medical service, 123 strength of, 206–207 Minimum alveolar concentration (MAC) of volatile anesthetics, defined, 231 Minimum Data Set (MDS), for nursing home residents, 107, 114 Minimum Data Set/Resident Assessment Instrument, for assessing incontinence, 943 Mini Nutritional Assessment (MNA), 190 Minocycline, for rheumatoid arthritis, 604 Minor depression, 1166–1167 Minoxidil, effect of topical application on hair counts, 869 Mirtazapine for treating agitated or sleep-deprived patients, 1090 for treating depression, 1170 Misoprostol, effects of, in treating peptic ulcers, 840–841 Mitogens, proliferative response of T lymphocytes to, in the aging, 785 Mitoxantron, for prostate cancer therapy, 462 Mitral regurgitation, 526–527 Mitral stenosis, 527 Mitral valve replacement, mortality in, 526 Mixed management model of care, for the frail elderly, 284 Mixed vulvar disorders, association with malignant transformation, 747 Mobility assessment, performanceoriented, 988 Modified Cardiac Risk Index, 215–216 Mohs’ surgery, for basal cell carcinoma, 877 Molecular basis of senescence, 22–24
Index Molecular biology, of amyloid, 1105–1107 Molecular factors, in aging, 15–26 Monitoring intraoperative, indications for, 236–237 prolonged electrocardiographic, for syncope, 962–963 Monoamine oxidase (MAO) inhibitors, for treating depression, 1170–1173 Monoclonal antibody therapy, for non-Hodgkin’s lymphoma, 502 Monoclonal gammopathy of uncertain significance (MGUS), 496–497 Monocytosis, conditions associated with, 829 Monosodium urate monohydrate (MSU), deposition in joints, 591–592 Mood disorders, 1163–1183 Mood stabilizers, for treating depression, 1170–1173 Morbidity in dizziness, 995 of falls in the elderly, 979–980 and infectious disease, in the elderly, 801–802 in pancreaticoduodenectomy, studies, 425 perioperative, in esophageal cancer, 429 postoperative, in the elderly, 240–241 reducing, in chronic obstructive pulmonary disease, 855 in rheumatoid arthritis, 600 in subarachnoid hemorrhage (SAH), 1123 Morphine, for postoperative pain, 253 Morphologic categories, of anemia, 821–822 Mortality curve, for sexually reproducing species, 37–38 Mortality rate in acute cholecystitis, 845 in acute renal failure, 776 age-specific, in cancer, 377 and alcoholism, in the elderly, 155 in aortic stenosis, 525 body mass index as a predictor of, 190 in breast cancer, 393–394 deceleration of increase in at extreme old age, 37–38 in delirium in the hospital, 1113–1115 and depression, 1164 early, in rheumatoid arthritis, 605 in end-stage dementia, 670 exponential increase with age, expressing with the Gompertz curve, 18
1295 expressing with the Gompertz curve, 15 and hip fracture, 626, 658, 669–680 in idiopathic pulmonary fibrosis, 862 from infections, 801–802 from infectious diseases, comparison of young and the elderly, 801–802 in-hospital for myocardial infarction patients, 519 relationship with age, 133 in intracerebral hemorrhage, 1126 and low weight in chronic obstructive pulmonary disease, 858 in lung biopsy, 862 in meningitis in the elderly, 811 in myxedema coma, 708 in open and laparoscopic cholecystectomy, 252–253 operative and anesthetist’s score of risk, 213–214 in colon cancer, 421 in Coronary Artery Bypass Graft, in older patients, 522 in surgery for esophageal cancer, 429 in pancreaticoduodenectomy, studies, 425 perioperative, 30-day rates of, 229 in perioperative myocardial infarction, 217 in peripheral arterial disease, 561 in pneumonia, 807–808 postoperative, in the elderly, 240–241 in postoperative acute renal failure, 221 and pressure ulcers, 968 in prostate cancer, in men over 65, 383 in pseudomembranous colitis, 848 in pulmonary embolism, 858–859 in hospitalized elderly patients, 250 relationship with delayed-type hypersensitivity skin tests, 791 in rheumatoid arthritis, 600 risk of and being an elderly spousal caregiver, 59 following hip fracture, 48 in surgery for claudication, 566 in subarachnoid hemorrhage, 1123, 1125 in surgery for benign prostatic hyperplasia, 763 treatment-related in acute myelocytic leukemia, 489 from unintentional injury in the elderly, 979
Motility disorders, as a cause of dysphagia, 836 conditions associated with, 837 Motor control test (MCT), 1004 Motor function return, in stroke patients, 266 Motor stroke, 1128 Mouth disease-related changes of, 902–915 physical examination of, 157 symptoms in, as a source of suffering, 316–317 Movement, abnormalities of, 1139–1162 Mucocele, 908 Multidisciplinary teams, inpatient, for frail older patients, 1074 Multidrug-resistance (MDR) in long-term care facilities, 803 phenotype, 371 in multiple myeloma, 499 Multiple endocrine neoplasia (MEN) syndrome, type 2, medullary cancer associated with, 713 Multiple myeloma, 497–499 amyloidosis associated with, 612 cryoglobulin deposition in, 594 defined, 487 interleukin-6 production increase associated with, 820 Multiple Outcomes of Raloxifene Evaluation (MORE) on the effect of raloxifene on fractures, 636 Multiple Outcomes of Raloxifene Evaluation Trial (MORE), study of bone mass loss, 628 Multiple Risk Factor Intervention Trial (MRFIT), 1132 Multiple sclerosis, 1145 Multiple system atrophy (MSA), 1152–1153 Muscle periarticular, weakness in osteoarthritis, 580 weakness of, and gait difficulties, 1141 Muscle atonia, in REM sleep, 1031 absence of, as a disorder, 1035 Muscle biopsies, in polymyalgia rheumatica, ultrastructural abnormalities seen in, 596 Muscle relaxants, 233–234 Muscle relaxation, in anesthesia, 229–230 Musculoskeletal system clinical observations about, 158 impairment in, and risk of falling, 982, 985 Music therapy (MT), effect of, in Parkinson’s disease, 273 Mutagens, chemical, role in cancer, 364
1296 Mycophenolate mofetil, for systemic lupus erythematosus, 611 Myelodysplastic syndromes (MDS), 489–491 treating, 826 Myeloid metaplasia with myelofibrosis (MMMF), 494 Myeloproliferative disorders, 491–494 Myelosuppression, in chemotherapy, 404 Myocardial infarction (MI), 517–521 acute following stressful war experiences, 56 syncope as the presenting symptom in, 960 mortality associated with, 33 mortality associated with perioperatively, 530 painless, in the elderly, 152 risk of association with aortic sclerosis, 510–511 effect of homocysteine on, 1132 subclinical hypothyroidism as a risk factor for, 707 systemic lupus erythematosus associated with, 609 Myocardial Infarction Triage and Intervention (MITTI) project, 517–518 Myocardial revascularization, 521–523 evaluation of angina patients for suitability of, 517 Myoclonus, defined, 1158 Myoclonus index (MI), defined, 1034 Myocytes, hypertrophy of, 32–33 Myofascial pain syndromes, trigger-point injections for treating, 338 Myringoplasty to correct conductive hearing loss, 897 Myringotomy, to correct conductive hearing loss, 897 Myxedema coma, 708 N Nails, changes with aging, 869 Naming problems in communicating with patients, 289 evaluating, 209 in neuropsychological disorders, 206 in order to relieve suffering, 311 Narcolepsy, association with REM sleep behavior disorder, 1035 Narcotics, for pain management in prostate cancer with bone metastasis, 463 Nasogastric lavage, in evaluation of gastrointestinal bleeding, 842
Index Nasogastric (NG) tubes, complications following use of, 251 Nateglinide (Starlix), for increasing insulin secretion, 689 National Academy on an Aging Society, on caregivers, 59 National Bioethics Advisory Commission (NBAC), 1223, 1257 National Bipartisan Commission on the Future of Medicare, 1207–1208 National Cancer Institute Early Lung Cancer Detection Program, 444 on mammography, 172 National Center for Health Statistics, data on home health services, 123 National Cholesterol Education Program (NCEP), 564–565 Adult Treatment Panel of, 531 National Council on Patient Information and Education (NCPIE), 85 National Elder Abuse Incidence Study (NEAIS), 1058 National Eye Institute Visual Function Questionnaire, 188–189 National Health and Nutrition Examination Survey (NHANES), 887 III, data on osteoporosis, 624–625 on obesity and hypertension, 551 on prevalence of diabetes in the population over 65 years old, 681 National health insurance, 1217–1218 National Health Interview Survey, 96 National Health Service, Britain, underreporting of symptoms by patients in, 149 National Hospice and Palliative Care Organization, 303 National Institutes of Health Consensus Development Conference comprehensive geriatric assessment defined by, 195 on erectile dysfunction, 722 recommendation on skin cancer screening, 388–389 on treatment of asymptomatic hyperparathyroidism, 641–642 on treatment of early-stage breast cancer, 399 National Long Term Care Survey, on the trend in prevalence of disability, 259 National Medical Expenditure Survey, on diabetic patients in nursing homes, 689–690 National Nosocomial Infections Surveillance (NNIS), on age and nosocomial infections, 801
National Osteoporosis Foundation on incidence of, and risk factors for, osteoporosis in men, 625 on screening for osteoporosis, with densitometry, 627 National Polyp Study, data on benefits of Colonoscopy for detecting colorectal cancer, 385 National Practitioner Data Bank (NPDB), 1221 National Prostate Cancer Project (NPCP), chemotherapy trials in, data on patient survival, 456 National Registry of Myocardial Infarction-2, on prognosis, by gender, 518 National Surgical Adjuvant Breast and Bowel Project (NSABP), tamoxifen evaluation, reduction in risk of breast cancer, 397 Natural history, of breast cancer in the elderly, 396–397 Natural killer cells (NK), functions of, 787 Nausea managing in end-of-life care, 305–306 from opioid medications, 335–336 as a source of discomfort in the elderly, 313–314 Neck, pain in, 576 Neck pathology, syncope associated with, 959 Necrotizing fasciitis, evolution of vulvar cellulitis to, 747 Needle biopsy, for evaluating thyroid nodules, 710 Needs, exceeding a caregiver’s ability to manage, as a cause of elder mistreatment, 1060 Nefazadone, for treating agitated or sleep-deprived patients with dementia, 1090 Nefazodone, for agitated depression, 1171 Neocortex, association regions of, neuronal loss from in Alzheimer’s disease, 1097 Neoplasia, science of, and aging, 363–373 Neoplasms, gait disorders associated with, 1154 Nephrectomy, laparoscopic, studies of outcome, 253 Nephrology, 769–782 Nephrotic syndrome, etiology of, in the elderly, 775 Nephrotoxic effects, of short-term nonsteroidal antiinflammatory drugs, 74
Index Nephroureterectomy, laparoscopic, studies of outcome, 253 Nerve blockade for anesthesia, 235 peripheral and central, for anesthesia, 234 Nerve root compression, in the dorsal spine, 577 Neural component, of erection, 720–721 Neuralgia, postherpetic, 809, 874, 1046, 1050–1051 Neurally mediated syndromes, in syncope, 958–959 Neuraxial anesthesia, 234–235 Neuritis, acute, in herpes zoster infection, 1045–1046 Neurobiologic basis, of age-related dementing disorders, 1095–1111 Neurodegenerative diseases, myoclonus associated with, 1158 Neuroendocrine system, in the weak link theories of aging, 17 Neurofibrillary tangles (NFT), 1096 distribution of, in Alzheimer’s disease, 1097 molecular constituents of, 1099–1102 neuronal types prone to formation of, 1102–1104 Neurofilament protein, association with neurofibrillary tangle formation, 1102–1103 Neuroimaging, indications of, in patients with dizziness, 1004 Neuroleptic malignant syndrome (NMS), association with antipsychotic drugs, 1192 Neuroleptic medications extrapyramidal effects of, 69 for managing delirium, 1119 side effects of, mimicking Parkinson’s disease, 69 for treating moderately demented patients, 346 Neurologic changes complications of herpes zoster, 1047 in Sjögren’s syndrome, 607 in vitamin B12 deficiency, 820 Neurologic disease association with falling, 985 chorea in, 1156 deficits following stroke, 265–266 differentiating from Parkinson’s disease, 1149 erectile dysfunction resulting from, 722 syncope in, 959–960 Neurologic examination, of older patients, 158–159 Neurology, American Academy of, on progression of mild cognitive
1297 impairment to dementia, 175–176 Neuromuscular transmission, muscle relaxants that disrupt, 233–234 Neuronal vulnerability, in dementia, 1095–1096 Neuronopathies, vitamin-related, 1141–1143 Neuropathic cachexia, in diabetic older patients, 684 Neuropathic pain, mixed pain syndromes, 324 Neuropathy carcinomatous, diagnosing, 1142 peripheral, in diabetic patients, 973 REM sleep behavior disorder as, 1035 sensory, in diabetic patients, 968 severe, in adjuvant chemotherapy for breast cancer, 404 Neuroprotection, in stroke, 1131 Neuropsychiatric disorders in moderate dementia, 345–346 perioperative management of, 223–224 symptoms in hypothyroidism, 705 Neuropsychological testing, 205–211 Neurotransmitters, nitric oxide, for controlling relaxation of penile smooth muscle, 721 Neutropenia, significance of, 827–829 Neutrophilia, conditions associated with, 829 Neutrophils, production of, role of growth factors in, 827 Nifedipine, for aortic regurgitation therapy, 526 Nigrostriatal degeneration (NSD), 1152 Nilutamide (Nilandron), antiandrogen for treating prostate cancer, 460 NINDS Tissue Plasminogen Activator Stroke Study, evaluation of thrombolysis with intravenous tissue plasminogen activator in, 1130 Nissen fundoplication, 838 Nitrazepam, pharmacodynamics of, 68 Nitric oxide (NO) effect of parasympathetic stimulation on endothelial cell production of, 721 suppression of matrix synthesis in cartilage, 583 as a vasodilator, 547 Nitroglycerine, for emergency hypertensive therapy, 555 Nitroprusside, for emergency hypertension reduction, 555 N-Methyl-D-aspartate (NMDA) receptor, association with calcium flux into the neuron, 1103–1104
Nociceptive pain, 324 Nocturia causes of, and potential treatment, 8 reasons for, 940 Nodal involvement, in prostate cancer, prognosis in, 459–460 Nodular elastoidosis, with cysts and comedones, 870 Noise damage, effect on hearing, 894, 895 Nomenclature, descriptions of aging, 15 Non-Hodgkin’s lymphoma, 500–503 risk of, in rheumatoid arthritis, 605 Noninsulin-dependent diabetes (NIDDM), 681 Nonmelanoma skin cancer (NMSC), 388 Nonpharmacologic management of delirium, 1117–1119 of hypertension, 551 Nonrapid eye movement sleep (NEEM), 1031 Non-small cell lung cancer, 443 treatment of, 448–451 Nonspecific presentation of disease, 152 Nonsteroidal anti-inflammatory drugs (NSAIDs), 70 adverse effects of, dose related, 74 adverse reactions to, 332–333 diverticulitis associated with, 847 dizziness caused by, 999 effect on prostaglandin E2 and immune response, 793 as a factor in gastrointestinal damage, 839 and gastric ulcers, 839–840 gastrointestinal bleeding associated with, 253 heart failure precipitation by, in the elderly, 513 interaction with anti-hypertensive drug treatment, 524 for osteoarthritis, 586, 653–654 prescription of caution in gout patients, 592 prescribing cascade to antihypertensive therapy, 69 for rheumatoid arthritis, 603–605 for rotator cuff, 663 studies of colorectal cancer prevention with, 419–420 for tendinitis/bursitis syndromes, 661 Norepinephrine, plasma levels of, effect on sodium conservation, 771 Normalization (overestimating healthiness), 149 Normocytic anemias, laboratory tests and treatment of, 824–825 North American Nursing Diagnosis Association, 319
1298 North American Symptomatic Carotid Endarterectomy Trial (NASCET), 1133, 1255 Nortriptyline, for treating herpes zoster, 1051 Nosocomial infections, 135 types of, in hospitalized elderly patients, 803 Nosocusis, defined, 894 Nuclear oncogenes, 369 Number needed to treat (NNT), defined, 4 Nummular eczema, 871 Nurse practitioners in community settings, provision of services to frail older patients, 1074 in nursing homes, 105, 117 Nurses, rehabilitation, 262 Nurses’ Health Study on aspirin use and colorectal cancer prevention, 420 on risk of breast cancer, from estrogen replacement therapy, 636 Nursing diagnoses, in nursing homes, 113 Nursing Home Reform Act of 1987, 107 Nursing Home Reform Amendments, Omnibus Budget Reconciliation Act (OBRA), 87 Nursing homes diabetes in the population of, 689 elder mistreatment in, 1058–1059 expenditure for care in, by source of funds, 102 falls in, 983 evaluation and prevention program in, 989–990 incidence of, 980 influenza vaccination in for patients and staff, 170 issues in drug compliance in, 87–88 antipsychotic medications, 1186–1187 for long-term care, 103–105 medical record in, 115 pain reported by residents of, 326 patient evaluation in, 153 rehabilitation in the setting of, 263–264 use of, and health care expenditures, 95 Nursing interventions, to reduce delirium in hip fracture patients, 674 Nutraceuticals, for osteoarthritis, 588 Nutrition, 1009–1021 artificial
Index legal concerns about withdrawing or withholding, 1246 risks and benefits at the end of life, 302 risks and benefits for dementia patients, 347 in chronic obstructive pulmonary disease patients, 858 deficiencies in and aging skin, 879 and oral health, 913 and immune response, 793 and surgery for hip fracture, 673 and wound healing, 969 See also Diet; Vitamins Nutritional problems, management of, 1015–1016 Nutritional status assessing, 190, 1013–1015 effect of, in surgery and wound healing, 223 and surgical outcome, 243–244 Nutritional supplements to improve wound healing, 248, 969 in patients undergoing surgery for hip fracture, studies, 673 Nutrition history, in evaluating older patients, 155 Nutrition Screening Initiative, 190 Nutrition Screening Initiative Checklist, 175 Nystagmus dizziness associated with, 1002 rotational chair test to provoke, 1004 O Obesity control of, effects of, 532 correlation with glucose tolerance reduction, 683 effect of on chronic low back pain, 657 on osteoarthritis, 653 and hypertension, 551 and relative risk of breast cancer from estrogen replacement therapy, 636 as a risk factor in diabetes, 690–691 in esophageal cancer, 428 in osteoarthritis, 579 in the young, and risk of osteoarthritis, 584 Observational trials, place in the hierarchy of evidence, 3 Obsessive-compulsive disorder (OCD), medications for managing, 1177–1178 Occam’s razor, failure in older patients, 154
Occlusive disease, large artery, 1129–1131 Occlusive dressings, for promoting wound healing, 970 Occupancy rates, in nursing homes, factors affecting, 104–105 Occupational therapists, 262 training by, in daily self-care activities, 266–269 Odor, diagnostic of infection of chronic wounds, 972 Office care, setting adjustments for older patients, 153 Office for Human Research Protection, 1258 Office of Protection from Research Risks (OPRR), 1222–1223, 1258 Office of the Inspector General (OIG), report on deficiencies in research oversight and process, 1258–1259 Olanzapine for acute mania, 1189 for schizophrenia, 1193 Olanzepine, for managing disturbances in dementia, 1090 Oligosaccharides, for preventing deep venous thrombosis, 250 Olivopontocerebellar ataxia (OPCA), 1146 Olivopontocerebellar atrophy (OPCA), 1152 Omnibus Budget Reconciliation Act (OBRA) Nursing Home Reform Amendments, 87, 1058–1059 Resident Behavior and Facility Practices section, 116 Oncogenes defined, 367 nuclear, in cancer, 369 role in aging, 794 Onychomycosis, association with tinea pedis, 874–875 Operative outcomes, in the geriatric patient, 239–241 Opiates, for herpes zoster pain, 1051–1052 Opioids for acute pain management, 253 for chronic pain management, 332–336 constipation as a side effect of, 314–315 managing delirium caused by, 305 and pain perception, pharmacodynamics of, 233 pharmacodynamics of, 68 to relieve air hunger, 304 to relieve dyspnea, 312
Index Opthalmoplegia, in giant cell arteritis, 597 Optic nerve, 888 Oral appliances, for sleep apnea management, 1033–1034 Oral cancer, 909 screening for, 387–388 Oral care, managing at the end of life, 307 Oral cavity, effects of aging on, 901–917 Oral examination, 909–910 Oral glucose tolerance testing (OGTT), 684 Oral infections, in the elderly, 317 Orchiectomy, for androgen deprivation therapy, in prostate cancer, 460 Oregon physician-assisted suicide in, 1250 proposal for rationing health care, 1215–1216 Oregon Basic Health Services Act, 1215–1216 Organ-confined disease, prostate cancer, 457–459 Organ damage, assessing, in hypertension, 548–549 Organification, of iodide, 696 Orgasm, 721 Oromandibular dystonia, 1157 Oropharyngeal colonization, of gram-negative bacteria, 903 Oropharyngeal dysphagia, 836 Orthopedic problems, with aging, 651–667 Orthostatic hypotension, 962–964 as an adverse effect of antihypertensive medication, 550–551 defined, 548 in multiple system atrophy, 1153 nitrate drug use in, 520 syncope in, 959 Orthotics, for cervical spondylotic myelopathy, 657 Oseltamivir chemoprophylaxis with, in influenza A or B exposure, 170 for treating influenza type A and type B, 813 Osler’s sign, 548 Ossicular chain reconstruction, to correct conductive hearing loss, 897 Osteoarthritis (OA), 573–591, 651–656 association with rheumatoid arthritis in the elderly, 600–605 cervical, dizziness in, 998 effect of, on the temporomandibular joint, 909
1299 glucosamine and chondroitin for treating, 925 as a major source of heterogeneity in the older population, 45 of the shoulder, 662 study of education to improve compliance in the elderly, 85–86 Osteoblasts effect on of estrogen, 635 of parathyroid hormone, 638–639 transformation of, 621 Osteoclasts effect on of bisphosphonates, 633 of calcitonin, 636–637 of estrogen, 635 multinucleated, in Paget’s disease, 642 origin in hematopoietic progenitor cells, 621–622 Osteocytes, origin in osteoblasts, 621 Osteomalacia differentiating from osteoporosis, 623 from nutritional deficiency, 1015 Osteomyelitis as a complication of pressure ulcers, 968 excluding, in diabetic skin or soft tissue infections, 808–809 Osteopathic therapy, for low back pain, randomized controlled trial, 590 Osteopenia, screening for, 174–175 Osteophytes pain caused by, 652 in the uncovertebral joints, 577 Osteoporosis due to corticosteroid use, preempting with bisphosphonate medications, 605 inverse correlation with osteoarthritis, 579–580 prevention and screening for, 174–175 prevention of, 621–650 and risk of hip fracture, 669–670 secondary, treatment of, 638 World Health Organization definition of, 622 Osteoporosis Risk Assessment study, National, 174 Osteoporotic Fractures, Study of, 580 Osteoprogenitor cells, osteoblasts derived from, 621 Osteotomy, realignment, in osteoarthritis, 654–655 Otoacoustic emissions (OAEs), measuring to evaluate hearing loss, 894–895 Outcome and Assessment Information Set (OASIS), for tracing
outcomes of home health care, 106 Outcomes of care with comprehensive geriatric assessment, 198 as a focus for evaluating nursing homes, 108 follow-up after resection of colorectal cancer, 423 and level of care offered older women with breast cancer, 407–409 negative, pain associated with, 326 of treatment in benign prostatic hyperplasia, 761 in ovarian cancer, 474 Outflow obstruction, in cardiac syncope, 960 Outlet obstruction and incontinence in men, 938 treatment of, 949 Outpatient centers models of health care for older persons, 199–200 rehabilitation services provided at, 263 short-term care team, 1074 Ovaries cancer of, 471–475 screening for, 381–383 changes in aging women, 738, 742 Overcrowding, in hospitals, as a form of rationing, 1213–1214 Over-the-counter remedies, efficacy and potential toxicity of, 74–75 Overtreatment, risks of, after judging a patient to be incompetent, 1237 Oxazepam, to sedate alcohol withdrawal patients, 224 Oxybutynin, for managing incontinence, 947–948 Oxycodone, with codeine, for pain in osteoarthritis, 588 Oxygenation, of tissues, to improve healing, 247 Oxygen concentrators, for homebound patients with chronic obstructive pulmonary disease, 857 Oxygen consumption and ability to meet surgical stress, 243 uptake of sedentary aging individuals, 509 Oxygen saturation, measuring, during surgery, 236–237 P p53 transcription factor, mutation of, in cancers, 365
1300 p66Shc, effect on life span in mice, 23–24 PACE Demonstrations, mixed management model of care, 284 Pacemaker cells, decline in, with aging, 510 Pacemaker implants after aortic valve replacement, 525 for bradyarrhythmias, 516 Pacific salmon, senescence in, resulting in death, 16 Paclitaxel for advanced ovarian cancer, 474 for androgen-independent prostate cancer, 462 for non-small cell lung cancer, 451 risk of neuropathy in treating breast cancer with, 404 Paget’s disease of bone, 642–644 effect of calcitonin on bone resorption in, 637 mammary and extra-mammary, 878 Pain acute and chronic, 323–342 due to bone metastases, in prostate cancer, 463 in degenerative arthritis of the spine, 656–658 in herpes zoster, 1045–1046 obsession with, 355 in osteoarthritis, treatment of, 586–588 perception of age-related changes in, 324–325 by the patient, 253 postoperative control of, 863 management of, 253–254 in pressure ulcer care, management of, 969 and quality of life, 303–304 reduction of tissue perfusion in response to, 247–248 residual, after amputation, 273 shoulder, 661–664 as a symptom of osteoarthritis, 574–575 treatment of, in herpes zoster, 1048–1049 undertreated postoperative, as a risk factor in delirium, 674 untreated or undertreated, in the elderly, 282 in vertebral compression fractures, 659–660 Pain Relief Promotion Act (PRPA), 1227 Paired helical filaments (PHF), properties of, 1101
Index Palliation in advanced pancreatic cancer, for jaundice and pain, 426 in benign prostatic hyperplasia, 760–761 in cervical cancer, with radiotherapy, 478 of impaired cognition, pharmacologic, 1085–1086 of joint pain with corticosteroid injections, 588 in metastatic breast cancer, 405–406 in metastatic pancreatic cancer, 426 in metastatic prostate cancer, 460–462 in non-Hodgkin’s lymphoma, 501–502 in respiratory insufficiency, 864–865 in soft tissue injuries, 661 transition to, from life-sustaining treatment, 1243–1244 of xerostomia, with salivary substitutes, 907 Palliative care, 138 avoiding a sense of abandonment connected with, 295 changing legal status of, 1226–1227 in dementia, 343–350 in hospital or intensive care, 299 in moderate dementia, 345–346 rationing of, 1214–1215 research on, 312 Pallidotomy, in Parkinson’s disease, 1150 Pamidronate, bisphosphonate drug, for osteoporosis, 633–634 Pancreatic cancer, 424–426 advanced, 426 Pancreatic disorders, 845 Pancreaticoduodenectomy (Whipple procedure), 425 Pancreatitis, acute, mortality from, 845 Pancuronium, association with high relative risk of postoperative pulmonary complications, 863 Panic disorder, 1176 differentiating from depression, 1168–1169 gait disorders accompanying attacks, 1154 management of, in terminal care, 864 Papain, for wound debridement, 972 Papanicolau test in physical examination of the older woman, 741–742 for screening for cervical cancer, 379–381, 481 Papaverine, for penile injection, 724–725 Papillary carcinoma, thyroid, 712 Papillary hyperplasia, from ill-fitting dentures, 912
Papillomavirus, effect of in cervical cancer, 475–476 in vulvar cancer, 479 Parainfluenza virus type 1, reinfection with, association with giant cell arteritis, 596 Paraneoplastic sensory neuronopathy, 1142 Paraneoplastic syndromes, 613 cerebellar, gait disturbances in, 1146 Paranoid delusions, in community elders, prevalence of, 1185 Parathyroidectomy, minimally invasive, 641 Parathyroid hormone (PTH) effect on bone loss, 631 effects of, on bone, 638–639 Parkin gene, mutation in, and peak incidence rate of Parkinson’s disease, 20 Parkinsonian syndromes, 1147–1153 and REM sleep behavior disorder, 1035 Parkinson’s disease (PD), 1147–1150 age-specific incidence of, 20 psychosis in, 1188 rehabilitation in, 273–274 symptoms of, 1081 Paroxitine, for treating agitated or sleep-deprived patients with dementia, 1090 Partial foot amputation, 271–273 Parvalbumin-immunoreactive neurons, associated with Down syndrome and Creutzfeldt-Jakob disease, 1104 Parvovirus B19, association with giant cell arteritis, 596 Pathogenesis of age-associated diabetes mellitus, 683–684 of age-associated glucose intolerance, 682–683 of benign prostatic hyperplasia, 756–757 of cervical cancer, 475–476 of delirium, 1115 of falling, in the elderly, 980–981 of herpes zoster, 1044–1045 of infectious diseases, 802–803 of lung cancer, 443–444 of myelodysplastic syndromes, 490 of peripheral arterial disease, 562 of polymyalgia rheumatica and giant cell arteritis, 595–596 of presbycusis, 894 of psychosis, 1190 of Sjögren’s syndrome, 606 of systemic lupus erythematosus, 609
Index Pathogens in chronic bronchitis, 807 in meningitis, 811 Pathologic diagnosis, of pancreatic cancer, 425 Pathology in giant cell arteritis, 596 multiple, in older patients, 151 of Paget’s disease, 642 of the salivary gland, 906–907 versus senescence, in aging, 19–21 Pathophysiologic considerations, in surgery for elderly patients, 241–249 Pathophysiology of benign prostatic hyperplasia, 757 classification of pain based on, 324 of dizziness, 996 of hypertension, 545–547 of intracerebral hemorrhage, 1125 of multiple myeloma, 497–498 of osteoarthritis, 581–584 of syncope, 957 Patient autonomy of, in a nursing home, 115–116 experience of nursing home care, understanding of, 118–119 Patient-controlled analgesia (PCA), 253–254, 863 Patient differences, effect on study outcome applicability, 9 Patient-disease interactions, 4–7 Patient education, about chronic dizziness, 1005–1006 Patient factors that affect performance of an instrument, 187 unresolved concerns affecting distress and depression, 287 Patient preferences, as a determinant of aggressive therapy for breast cancer in the elderly, 408 Patient Self-Determination Act (PSDA), 301, 1223 Patient-treatment interactions, effect on study outcome applicability, 9–10 Patterns of care, for elderly women with breast cancer, 407–409 Patton speculum, 741 Payment systems for health care, Medicare, 1206 PC-SPES (Chinese herbal), for androgen independent prostate cancer treatment, 462 Peaceful death, defined, 352 Pederson speculum, for examining the older patient, 740–741
1301 Peer Review Organizations (PROs), for professional discipline maintenance, 1221–1222 Pelvic examination, clinical findings in older women, 158 Pelvic organ prolapse, 748–753 Pemphigus vulgaris, treatment of, and mortality in, 873 Penile injection therapy, 724–725 Penile sensitivity, change in, with aging, 724 Penis, anatomy of, 720 Peptic ulcer disease, 839–840 as a cause of gastrointestinal bleeding, 842 Perceptual deficits, in stroke patients, 266–269 Percutaneous ethanol injection (PEI), for ablation in hepatocellular carcinoma, 431 Percutaneous Transthoracic Coronary Angioplasty (PTCA) comparison with CABG, 521–522 for myocardial infarction, outcomes of, 519 outcomes of, in the elderly, 522–523 Performance-based measures, of functional status, 187 Performance-Oriented Assessment of Mobility, 190, 987 Performance status, as a prognostic factor for treatment planning in lung cancer, 447–448 Perfusion, tissue maintaining for wound healing, 967 maintaining in the elderly, 247 Pericardium, tuberculosis involving, 809 Perineal hygiene, to prevent recurrent urinary tract infections, 745 Period effect, explanation of rates of depression in the elderly, 1164 Periodic limb movements in sleep, 1034–1035 Periodontal diseases, 903–904 Perioperative care, 213–227 to avoid pulmonary complications in the elderly, 862–864 pain management, 329–330 Peripheral arterial disease (PAD), 561–571 Peripheral neuropathy in older patients, 159, 687 diabetic, 682 in systemic lupus erythematosus in the elderly, 608 Peripheral vascular disease, lower extremity amputation due to, 271–273, 968
Peritoneal serous carcinoma, differentiating from ovarian cancer, 472 Pernicious anemia diagnosing, 1142 gastric cancer associated with, 839 from intrinsic factor deficiency, B12 for, 826 Personal care, resistance to accepting, in dementia, 1088–1089 Personal contact, to manage delirium, 1117–1119 Personality disorders in dementia, 1089 in progressive supranuclear palsy, 1151 Personhood, defined, 311 Pessaries, as an alternative to surgery in prolapse, 751–753 Petechiae, in platelet deficiency, 829 Peyronie’s disease, venous leakage due to, 722 Phalan test, in carpal tunnel syndrome, 664 Phantom limb, pain in, 273 Pharmacist advice from, to improve compliance, 86–87 review of drug regimens in skilled nursing facilities, 75, 87 Pharmacodynamics, 67–68 Pharmacokinetics, 65–66 of opioid drugs in the elderly, 335 Pharmacologic agents, in treating psychosis, 1190–1194 Pharmacologic therapy for depression, 1170–1173 for hypertension, 551–554 for insomnia, 1038 management of delirium, 1119 for Parkinson’s disease, 1149–1150 Pharmacology principles of, 65–81 of therapeutics in the elderly, 370 Phencyclidine, psychologic effects of, 232 Phenothiazines, for nausea and vomiting in end-of-life care, 305–306 Phenotype, of the syndrome of frailty, 1069 Phentolamine, for penile injection, 724–725 D-Phenylalanine, for increasing insulin secretion, 689 Phenytoin, serum levels of, interpreting, 65–66 Pheochromocytoma, secondary hypertension associated with, 548 Philadelphia chromosome, association with chronic myelogenous leukemia, 491
1302 Phlebotomy, for treating polycythemia vera, 493 Phosphatidylinositol-3-OH kinase, homologue of, coded by the age-1 gene, 23 Phospholipid antibody, association with hypercoagulability, 831 Phosphorus metabolism, 774–775 Phosphorylation state, of tau proteins, 1101 Physical activity and diabetes in the elderly, 683 level of, and surgery outcome, 214 for preventing cancer, observational studies, 172 resumption of, after cardiovascular disease, 514–515 See also Exercise Physical disability, as a predictor of coronary mortality, 509 Physical examination features of, 156–159 limitations of, in diagnosing cardiovascular disease in the elderly, 510–511 observation during, 205–206 targeted, in assessing incontinence, 941–942 Physical illness, and depression, 1165 Physical restraints in nursing homes, effects of, on falls, 980, 990–991 Physical therapists, as part of a rehabilitation team, 262 Physical therapy in corticobasal ganglionic degeneration, 1152 in hip fracture, evaluation of frequency and individualization of, 675 in Parkinson’s disease, 1150 to prevent falls, 989–990 Physician-assisted suicide (PAS), 1248–1249 legal status of, 1227, 1249–1250 Physician Fee Schedule, 1205 Physician Orders for Life-Sustaining Treatment (POLST), Oregon process, 1245 Physician-patient relationship, and health, 55 Physicians commitment to treatment they initiate, 1245 critical review of protective services orders, 1227–1228 Medicare payments to, 1205 response to dying, 353–354 responsibility to preserve life, 1249 results of error in judging competence, 1237–1238
Index role in home care, 122 visits of, in nursing homes, 117 Physician services as part of a rehabilitation team, 262 use of, by older persons, 95 Physician’s Health Study, prostatespecific antigen indicating prostate cancer, evaluation, 456 Physiologic function, of white blood cells, and aging, 826–827 Physiologic sleep, 1031–1042 Physiology of aging, 18–21, 27–35 changes in swallowing, 835 of frailty, 1069–1071 of sexual function in males, 719–724 thyroid, 695–696 Physiotherapy, for managing cervical dizziness, 1005 Phytohemagglutinin (PHA), T cell response to, change with aging, 785 Phytotherapy, for benign prostatic hyperplasia, 762 Pick bodies, characterizing, 1102 Pick’s dementia, 343 symptoms of, 1081 tau profile in, 1101–1102 Pilocarpine, for radiation-induced xerostomia management, 908 Pioglitazone (Actos), for increasing insulin action, 689 Pituitary tumor, thyroid-stimulating hormone secreting, 702 Placebos effects of patient adherence to, 9 ethical prohibition on, for pain relief, 331–332 Planning for end-of-life care, 302–303 of a home visit, 128 Plaques, amyloid. defined, 1105 Plasma cell dyscrasias, 496 Plasmapheresis, in Waldenstrom’s macroglobulinemia therapy, 500 Platelet count, interpretation of, 829–830 Platelets, defective functioning of, and bleeding, 829 Pneumatic sequential leg compression devices, for thromboembolic prophylaxis in hip fracture patients, 672 Pneumococcal infection, 813 Pneumococcal vaccine, efficacy and safety of, 171 Pneumonia hospitalization of the elderly with, 807 lobar pneumococcal, symptoms in the elderly, 152
mean hospital length of stay for, 94 postoperative, in the elderly, 251 Pneumonia Patient Outcome Research Team (PORT), predictors of prognosis from a cohort study, 807 Pneumoperitoneum, cardiorespiratory consequences of, 252–253 Policy dilemmas in long-term care provision, 107–110 institutional, about “do not” order implementation, 1224 issues in end-of-life care, 1243–1251 Polycythemia vera, 492–493 Polymerase chain reaction, for detecting varicella-zoster virus DNA, 1048 Polymyalgia rheumatica (PMR), 594–600 anemia associated with, 826 gait disorders associated with, 1143 Polymyositis, 611–612 Polyneuropathy, demyelinating, in Waldenstrom’s macroglobulinemia, 499 Polyserositis, in systemic lupus erythematosus in the elderly, 608 Pontomesencephalic gait failure, 1147 Population aging causes and consequences of, 38–41 defined, 37 implications of, 45 Population dynamics, in nursing homes, 117–118 Population pyramid, 38–39 Positive predictive value, and disease prevalence, effect of aging, 11–12 Positron emission tomography in corticobasal ganglionic degeneration, 1152 to identify dementia, 1081–1084 to identify metastatic esophageal cancer, 429 Postacute care (PAC), 102–103 Postencephalitic parkinsonism (PEP), tau protein profiles in, 1101 Postherpetic neuralgia, 1046, 1050– 1051 Postmenopausal osteoporosis, 623 Postmitotic cells, organisms composed entirely of, as a model for genetic analysis, 23 Postoperative complications, in breast surgery, with axillary lymph node dissection, 400–401 Postoperative delirium, rate of, 1113–1115 Postprandial hypotension association with dizziness, 997–998 association with syncope, 958
Index Post-Stroke Rehabilitation Guidelines, 266 Posttraumatic stress disorder (PTSD), in military veterans, 56–57 Postural hypotension depression and risk of falling, 985 dizziness in, 997–998 and risk of falling, 982 Postural instability in Parkinson’s disease, 1148 risk factors for, 980 Postural tremor, in the elderly, 1155 Posture, abnormalities of, 1139–1162 Posturography, computerized, to test balance, 1004 Postvoiding residual volume (PVR), 942 change with aging, 932 checking, 759 Potassium alteration in balance of, 773–774 levels of, following succinylcholine administration, 234 Potential, for rehabilitation, assessing, 264 Poverty, and rationing of health care, 1213–1214 Pramipexol, for periodic limb movements in sleep, 1034 Pravastatin, evaluation of efficacy for older adults, 76 Precipitating factors for delirium, 1114–1115 of frailty, 1071 Predictors of abuse in nursing homes, 1059 of adverse hospital outcomes, 94–95 of cardiovascular morbidity and mortality, peripheral arterial disease, 565 of community services use by older persons, 96 of coronary mortality, physical disability, 509 of death in the home, 300 of fracture from bone mass, 627 high bone turnover, 631 of hospital use by older persons, 94 of mortality, body mass index, 190 of mortality subsequent to hospital admission, 134 of nursing home use by older persons, 95 of postoperative delirium, 245 of rehabilitation outcomes, 263 See also Prognosis Prednisone for blister suppression in bullous pemphigoid, 873
1303 for chronic lymphocytic leukemia therapy, 495 for giant cell arteritis, 599–600 for multiple myeloma, 498–499 for polymyalgia rheumatica, 599 for rheumatoid arthritis, 605 Preferences, patients’ for end of life conditions, 300 about interventions and quality of life. eliciting, 293 Premalignant progression, step in carcinogenesis, 367 Preoperative assessment, 213–227 Preparation, for discussion with patients, 288 Presbycusis, 893–900 adjustments for, in patient evaluation, 153 Presbyopia, 887 Prescribing cascades, in drug therapy, 69 Prescription drugs, Medicare coverage in, 1208–1209 Presenilin genes, mutation of, in Alzheimer’s disease, 1106 Presentation of disease, alteration of, in the elderly, 34, 152 Presenting manifestations, of myocardial infarction, 518 Pressure-relieving devices, for treating pressure ulcers, 973 Pressure sores, in the elderly, 317 Pressure stimulus, response of the heart to, and age, 32–33 Pressure ulcers nutritional support of patients with, 1017 prevalence and incidence of, 967 surgical management of, 973–974 Presumption to treat, judgments about, for dying patients, 356–357 Presyncope, defined, 995 Prevalence of anemia in the elderly, 820–826 of delirium, at the time of hospital admission, 1113–1115 of disease, defined, 19 of dizziness, 995 of essential tremor, 1155 of falls in the elderly, 979–980 of hearing loss, 893 of insomnia, 1036 of pain in the elderly, 325–326 of sexual dysfunction in males, 722 of vision impairment, changes with age, 883–891 Prevention of breast cancer, 397–398 of colorectal cancer, 419–420 of delirium, 1117–1120
of diabetes mellitus, 690–691 of disease, 169–184 of esophageal cancer, 428 of falls, 988–989 in nursing homes, 990 of gallbladder cancer, 431–432 of gastric cancer, 427 of hepatocellular carcinoma, 430 of herpes zoster, 1052 of iatrogenic illness, table, 135 to modify coronary risk, 530–532 of osteoarthritis, 584 of osteoporosis, 631–638 of pancreatic cancer, 424 of postoperative delirium, 224 of stroke, 1131–1132 of venous thromboembolism, 861 Preventive Services Task Force, United States (USPSTF) on abnormal lipid levels, identification and treatment, 174 on depression in the elderly, 175 on evidence supporting screening for breast cancer, 379 on immunization practices, 171 on screening for ovarian cancer, 382 Prevent Recurrence of Osteoporotic Fractures (PROOF) trial, on effect of salmon calcitonin on vertebral fractures, 637 Priapism, as an adverse reaction in penile injection therapy, 725 Primary prevention of breast cancer, drugs for, 172 defined, 169 Primidone, for essential tremor management, 1155 Principles for models of geriatric care of the future, 201 of rehabilitation, 260–264 Prion disorders, dementia in, 1081 Privacy in care settings, 153 maintaining in hospital, 139 Private funds, for nursing home care, 118 Private sector, relationships with medical research, 1259–1260 Procainamide, drug-induced lupus associated with, 610 Process, of care, 196–197 Prodrome, of acute herpes zoster, 1045 Productivity, and self-efficacy, 61 Progestational therapy, for endometrial cancer, 471 Prognosis in breast cancer, 377–378 in cervical cancer, recurrent, 479 in chronic lymphocytic leukemia, 495
1304 Prognosis (cont.): in chronic obstructive pulmonary disease, 854 in colorectal cancer surgery, 422 in diabetes, 685 in endometrial cancer, 471 in esophageal cancer, 428 factors affecting in delirium, 1117 in Hodgkin’s disease, 505 in localized breast cancer, 396–397 in non-Hodgkin’s lymphoma, 502 in pulmonary patients, 864 in rheumatoid arthritis, 605 in stroke patients, 266 in giant cell arteritis, 597–598 in herpes zoster, 1048 in hypoactive delirium, 1115 in lung cancer, 446–447 in major depression, 1173 in rheumatoid arthritis, 605 in Sjögren’s syndrome, 607–608 in thyroid cancer, in the elderly, 712 in Waldenstrom’s macroglobulinemia, 500 See also Predictors Program for All-inclusive Care for the Elderly (PACE), 110, 1074 Progressive disability, adjustment to, 46 Progressive supranuclear palsy (PSP), 1150–1153 tau profile in, 1101 Projection domain, of the tau protein, 1099–1100 Prolapse assessment of, 749–752 pelvic organ, 748–753 Promethazine, to counter side effects of cholinesterase inhibitors, 1086 Promotion, as a cellular step in carcinogenesis, 367 Prophylactic cranial irradiation (PCI), in small-cell lung cancer, 451–452 Prophylaxis for deep venous thrombosis and pulmonary embolism, 250 measures to minimize the risks of hospitalization, 249–251 Propofol (Diprivan) for induction and maintenance of anesthesia, 232 as a sedative hypnotic agent, 231 Propranolol for anxiety disorders, 1178 for essential tremor management, 1155 for thyrotoxicosis management, 702 Proprioception improvement in, after muscle training, 585
Index mechanisms of, 996 problems with and dizziness, 998 and risk of falling, 985, 1141 and risk of osteoarthritis, 581 Proprioceptive system, spatial orientation provided by, 981–982 Propylthiouracil, for treating hyperthyroidism, 702 prior to surgery, 223 Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, mortality data, 858–859 Prospective Payment System (PPS), for Medicare patients, 1205 in nursing homes, 88 Prospective Studies Collaboration, on the relationship of cholesterol level with stroke, 1132 PROSPER, randomized trial of pravastatin in elderly patients, 76 Prostaglandins, functions of in erection, 721 in humoral immunity, 789 and inhibition by nonsteroidal anti-inflammatory drugs, 70 Prostaglandin synthetase inhibitors, stimulation of immune responses by, 793 Prostate, aging, natural history of, 755–756 Prostate cancer, 455–467 benefit of treating, 9 screening for, 172–173, 383–384, 456, 760 Prostatectomy laser, for benign prostatic hyperplasia, 764 open, for prostatic hyperplasia, 763 radical, for treating prostate cancer, 457–459 Prostate incision, in benign prostatic hyperplasia, 763–764 Prostate-specific antigen (PSA), for screening for prostate cancer, 383, 456, 760 Prostatic enlargement of benign hyperplasia, clinical identification of, 158 Prostatism, 940 Prosthesis after below-the-knee amputation, successful use of, 272–273 intracardiac, and endocarditis, 527 Protein, dietary contribution to wound healing, 969 requirement for, 1010 Protein-energy malnutrition, 1014–1020 Protein kinases, in immune response, 788–789
Proteoglycans, of cartilage, changes with aging, 582–583 Prothrombin time, to screen for coagulation disorders, 830 Proton pump inhibitors (PPIs) for healing reflux esophagus, 838 for treating peptic ulcers, 840 Proverbs Test, 209 Providencia species, infection by, in worsening pressure ulcers, 972 Provocative tests, for dizziness, 1002–1003 Proximal interphalangeal (PIP) joints, involvement of, in osteoarthritis, 575 Proxy consent, to research on dementia, 1257 Pruritus, 871 Pseudoclaudication, in spinal stenosis, 577 Pseudohypertension, defined, 547–548 Pseudohyponatremia, in hyperglycemia, hyperlipidemia and hyperproteinemia, 772 Pseudolymphoma, 606 Pseudomembranous colitis, 847–848 Pseudomonas aeruginosa, presence of, in worsening pressure ulcers, 972 Pseudothrombocytopenia, characteristics of, 830 Psoralen, for psoriasis treatment, 873 Psoriasis, 872–873 Psychiatric consultation, to evaluate competency, refusal of, 1238–1239 Psychiatric illnesses decision-making capacity in, 1234 previous, and vulnerability to depression in later life, 1165 syncope in, 959 Psychiatric symptoms in Alzheimer’s dementia, 345 in dying patients, 304–305 Psychoactive drugs adverse drug events due to, in longterm care facilities, 71 delirium caused by, 1114 for nursing home residents, adverse effects associated with, 75–76 side effects of, 69 Psychogenic disorders of dizziness, 998 gait, 1154 Psychologic factors, pain based in, 324 Psychologic interventions, for reducing the effects of stress on immune responses, 793–794 Psychologic strategies, in pain management, 340
Index Psychometric attributes, of instruments for assessing functional status, 185–186 Psychopathology, erectile dysfunction caused by, 723 Psychopathology theory, of elder neglect, 1060 Psychosis late-life, 1185–1198 related to depression in later life, 1168 Psychosocial assessment, on a home visit, 129 Psychosocial domains, key, for the geriatrician’s perspective, 53–54 Psychosocial factors influence on health in later life, 53–63 in osteoarthritis, 575 relating to the pathogenesis of coronary artery disease, 56 Psychotherapy for depressed caregivers, 1085 for depressed stroke patients, 269 during rehabilitation, 270 for depression, 1169–1170 Psychotic depression, defined, 1166 Psychotic symptoms, in dementia, 1087–1088 32 P therapy for ovarian cancer, 474 for polycythemia vera, 493 Ptosis, eyelid, 884 PubMed, clinical query search strategies on, 3 Pulmonary artery catheter (PAC), balloon-tipped, for monitoring in surgery, 236–237 Pulmonary capillary wedge pressure (PCWP), measuring, 236–237 Pulmonary disease, 853–867 cardiac disease secondary to, 528–529 postoperative, 219–220 Pulmonary embolism (PE), 858–861 predisposing factors to, in the elderly, 528–529 reducing the risk of, with anticoagulation therapy, 249–250 in surgical patients, 220 Pulmonary emphysema, 855 Pulmonary function testing, morbidity in, 855 Pulmonary infiltrates, symptoms predicting, and patient age, 11–12 Pulmonary rehabilitation, in chronic obstructive pulmonary disease, 858 Pulse pressure defined, 545
1305 emphasis on, in therapy for individuals with hypertension, 550 Pupil, of the eye, changes with aging, 886 Pyleography, intravenous, for evaluation upper and lower urinary tracts, 759 Pyogenic osteomyelitis, 658 Pyometrium, management of, 744 Pyramid, population, 38–39 Pyramidal cells, vulnerability of, 1096 Pyramidal neurons, types prone to neurofibrillary tangle formation, 1102–1104 Pyridoxine, megadose of, and ataxic peripheral neuropathy, 1142 Pyrophosphate, calcium pyrophosphate dihydrate (CPPD) deposition, 591 Q Quadriceps, weakness of, in osteoarthritis, 580 Quality of benefit, rationing based on, 1216 of care for frail older adults, 1072–1073 of long-term care, 107–108, 110 of nursing home care, role of standardized assessment in, 113 Quality-adjusted life-years (QALYs), benefits of screening for breast cancer in terms of, 378–379 Quality improvement, in physician’s skills in assessing decisionmaking capacity, 1239–1240 Quality Indicators for Assessing Care of the Elderly, The (ACOVE) project, 984 Quality of American Life, The (Campbell, Converse, and Rogers), 60 Quality of life after aortic valve replacement, 525 after breast-conserving surgery, 399–400 considerations in artificial nutrition and hydration, 1246 in Coronary Artery Bypass Graft survivors, 521–522 during the dying process, 281 establishing a patient’s view of, 156, 191 after joint replacement in osteoarthritis, 589 and need for treatment in lower urinary tract symptoms, 758, 760
of older women with breast cancer, 407 providing patients information about interventions’ impact on, 293 versus quantification of nursing home activities and standards, 108 after recombinant erythropoietin therapy for small cell lung cancer, 452–453 relationship to irradiation and prostatectomy for prostate cancer, 458–459 in rheumatoid arthritis, 600 and sound amplification for the hearing impaired, 899 following transurethral resection of the prostate, 763 in treatment of metastatic breast cancer, 405–407 Quantitative ultrasound, for measuring bone strength, 631 Questions clinical, categories of, 3 about the psychosocial factors affecting health, 61–62 about screening for cancer in older patient, 376–377 Quetiapine (Seroquel), for managing disturbances in dementia, 1090 Quetiepine (Seroquel), for treating schizophrenia, 1193–1194 R Race and health care availability, 1215 and health status, 54 and hypertension, 523 and risks of tamoxifen therapy, 397 Radiation association with cancer, 364 thyroid carcinoma, 709–711 oral adverse effects from, 915 Radiation therapy/radiotherapy (RT) adjuvant, in rectal cancer, 422–424 following breast-conserving surgery, 400 in endometrial cancer, postoperative, 471 external beam for cervical cancer, 476–477 for ovarian cancer, 474 for prostate cancer with bone metastasis, 463 in Hodgkin’s disease, 504 hypothyroidism resulting from, 705 inoperable stage III lung cancer, 449
1306 Radiation therapy/radiotherapy (RT) (cont.): palliative, in indolent lymphomas, 502 with androgen deprivation, 460 for prostate cancer, 457–459 with spinal cord compression, 462 in prostate cancer with spinal cord compression, 462 in small-cell lung cancer, 451 in treatment of ovarian cancer, 474 Radiographic evaluation, of incontinence, 945 Radiography, non-ionic contrast, iodine-induced hyperthyroidism from, 223 Radioimmunoassay, for T4 and T3, 698 Radioiodine scan using, after thyroidectomy, 712 for treating hyperthyroidism, 702 Radioiodine uptake (RAIU), 699–700 for distinguishing Graves’ disease, subacute thyroiditis, and thyrotoxicosis, 701 Radiolabeled compounds for evaluating gastrointestinal bleeding, 842 for managing bone metastases in prostate cancer, 463 monoclonal antibodies, for non-Hodgkins lymphoma treatment, 502 Radiologic studies, to diagnose Paget’s disease, 643 Radionuclide evaluation of thyroid nodules, 710 of thyroid structure and function, 699–700 Raloxifene prevention of osteoporotic bone loss by, 49, 636 randomized controlled trial of, for preventing breast cancer in older women, 172 Ramsay Hunt syndrome, 1047 Randomized controlled trials comparing CHOP and CNOP chemotherapy for non-Hodgkin’s lymphoma in the elderly, 503 of the effects of testosterone on sexual interest and activity, 720 of estrogen therapy in women with low bone mass, 635–636 evaluation postoperative in endometrial cancer, 471 of orchiectomy with and without flutamide, for prostate cancer therapy, 461 place in the hierarchy of evidence, 3 Rapid eye movement (REM) sleep, 1031
Index amount and latency of in the aging, 1032 Rash, in herpes zoster, 1045 treatment for, 1048 Rationing, of health care defacto, 1213–1215 explicit, 1215–1218 Reactivation, of varicella-zoster virus, 1045 Reasoning, as a standard of decisionmaking capacity, 1235 Receptor-effector antagonism, using to treat cancer, 371 Recipients, of home care, 122–123 Recombinant human platelet-derived growth factor (rhPDGF-BB), effect on pressure ulcers, studies, 972 Recommendations, in comprehensive geriatric assessment, 196 Recreation therapists, as part of a rehabilitation team, 262 Rectal examination, incontinence, 158 Rectovaginal examination, in the older woman, 742 Recurrence of breast cancer, with and without adjuvant radiation therapy, 400 of ductal carcinoma in situ, and choice of treatment, 399 of endometrial cancer factors affecting risk of, 471 treating, 471 of ovarian cancer, 475 of pressure ulcers after successful surgery, 973–974 of venous stasis ulcers after successful surgery, 974 Red blood cells characteristics of, in iron deficiency, 823 labeled, for evaluating gastrointestinal bleeding, 842 5a-Reductase inhibitors, for lower urinary tract symptoms, 762 Reed-Sternberg cells, in Hodgkin’s disease, 503 Referral, for home care, 126–127 Refractory anemias, as myelodysplastic syndromes, 490 Regimens estrogen replacement therapy, 635 MOPP, for Hodgkin’s disease, 504 for non-Hodgkin’s lymphoma therapy, specifically for the elderly, 503 for Paget’s disease of bone, 643 standard adjuvant chemotherapy for breast cancer, 404 suggested for infective endocarditis treatment, 810 Regional anesthesia, 234
Regionally advanced prostate cancer, 459–460 Regulation of nursing homes, 107–108 of thyroid-stimulating hormone and thyroid hormone secretion, 696 Rehabilitation, 259–277 audiologic, 898–899 defined, 259 effect on joint pain and disability, 585 in hearing loss, 897–899 in hip fracture, 270–271, 675 in stroke, 266–269 in vision damage, 889 vestibular, 1004–1005 Reimbursement, slowing, to effect rationing, 1214–1215 Relapse rate, in tamoxifen therapy for breast cancer, 401 Relative risk reduction (RRR), as a measure of benefits from a treatment, 4 Relaxation, for managing anxiety disorders, 1176 Reliability, of assessment instruments, 185–186 Religion church attendance as a measure of social integration, 57 and depression, 1165 Remifentanil, doses for elderly patients, 233 Reminders, for medications, 86 Remodeling, of bone, 621 REM sleep behavior disorder (RBD), 1035 Renal blood flow (RBF), 769 Renal dialysis, hearing loss accompanying, 895 Renal disease association with systemic lupus erythematosus, 611 in the elderly, 775–777 Renal disorders, following surgery, 220–222 Renal excretion of drugs, 66–67 impairment of, by nonsteroidal anti-inflammatory drugs, 70 Renal failure with angiotensin-converting enzyme inhibitors, 553–554 in older diabetic individuals, 682 postangiogram, 860 Renal function age-related changes in, 769–770 assessment of, in urinary tract infection, 806 evaluation of, in anemia, 822–823 and hypertension, 547
Index Renal insufficiency, in multiple myeloma, 498 Renal mass, changes with aging, 769 Renal responses, to acute isotonic sodium load, 771 Renin-angiotensin system changes in, with age, 547 suppression of, age-related changes in, 771 Repaglinide (Prandin), for increasing insulin secretion, 688 Replicative senescence, and telomere shortening, 365 Research context of, and informed consent, 1222 exclusion of older people from studies, 1255 experimental therapies for osteoarthritis, 590 Reserves, physiologic, use to maintain homeostasis, 28–32 Resident Assessment Inventory (RAI), 107 Resident Assessment Protocols (RAPs), 107 triggering of, by the Minimum Data Set, 114–115 Resilience, loss of, with aging, 27–28 Resistant hypertension, evaluating, 554–555 Resorption, of bone, 622 markers of, 631 Resources, for health care, justice and the allocation of, 1213–1220 Resource Utilization Groups (RUGs), for calculating payment for Medicare patients in nursing homes, 102, 115 Respect expressing in communication with patients and families, 289 as the issue in informed consent, 1253 Resperidone, for managing disturbances in dementia, 1089–1090 Respiratory disturbance index (RDI), defined, 1032 Respiratory infections, 806–808 Respiratory symptoms addressing in end-of-life care, 304 as a source of suffering, 312–313 Respiratory system, age-related changes in, 219–220 Response, patient’s, to bad news, 290–291 Responsiveness, of an assessment instrument, 186 Restless leg syndrome (RLS), relationship with periodic limb movements in sleep, 1034
1307 Restricted mobility, in geriatric incontinence, 935 Results clinically meaningful, from studies, 3 in evaluating evidence-based studies, 5 Reticulocyte count, increase in anemia, 822 Retina, 887–888 Retinal hemorrhage, in Waldenstrom’s macroglobulinemia, 499 Retinoblastoma (Rb) protein, role in cellular regulation, 368 Retinopathy, hypertensive, 549 Retransplantation bone loss, 624 Retroviruses, oncogenicity of, 366 Revascularization, in critical leg ischemia, 567 Revenues, for health care providers, Medicare as a source of, 1205 Review, of drugs a patient is taking, 73 Revised European-American Classification of Lymphoid Neoplasms (REAL), 501 Rheumatic disease, and amyloidosis, 612 Rheumatoid arthritis (RA), 600–605 effect of, on the temporomandibular disorder, 909 osteoarthritis in patients with “burn out”, 573 Rheumatologic diseases, 573–619 Rights of patients, and responsibility to prevent harm to others, 1229 Rigidity, in Parkinson’s disease, 1148 Rimantadine chemoprophylaxis with, in influenza A exposure, 170 for control and treatment of influenza type A, 812 Risedronate bisphosphonate for osteoporosis, 634 bisphosphonate for Paget’s disease, 643 for glucocorticoid-induced osteoporosis, 638 Risk assessment, in an aging population, factors affecting, 47 Risk factors for adverse outcome of surgery in chronic obstructive pulmonary disease patients, 857 for atrial fibrillation, 515 for benign prostatic hyperplasia, 755 for breast cancer, 394–395 for calcium pyrophosphate dihydrate deposition disease, 593 for candidiasis, 905 for cardiac complications of surgery, 214–216 cardiovascular, associated with hypertension, 548–549 for cervical cancer, 379, 475
for chronic dizziness, 996–997 for colorectal cancer, 171, 384, 419 for declining health in caregivers, 59 for deep venous thrombosis and pulmonary embolism after surgery, 249–250 for delirium, 673–674, 1114, 1119 in hospitalized patients, managing, 245 postoperative, 223 for dental caries, 903 for depression in lung cancer patients, 453 for elder mistreatment, 1059–1060 for endometrial cancer, 469 for erectile dysfunction, 722 for esophageal cancer, 428 for falling, 979, 981–982, 984–988 in nursing homes, 989–990 with serious injury resulting, 984 for fear of falling, 980 for gallbladder cancer, 431–432 for gastric cancer, 426–427 for gingivitis, 903–904 for hepatocellular carcinoma, 430 for herpes zoster, 1043–1044 for hip fracture, 669–670 for hospital admission in older adults, 133 for inability to maintain postural stability, 980–981 for infectious diseases, 802–803 for insomnia, 1036 for intracerebral hemorrhage, 1125 for loss of renal function, 777 for lung cancer, 441–443 for macular degeneration, 888 medical, for anxiety disorders, 1174 for oral cancer, 387–388, 909 for oral ulceration, 910 for osteoarthritis, 574, 579–580 for osteoporosis, 625–626 for ovarian cancer, 472 for pancreatic cancer, 424 patient-specific, in surgery for the elderly, 213 for periodic limb movements in sleep, 1034 for perioperative stroke, 217 for perioperative supraventricular arrhythmia development, 218 for peripheral arterial disease, 561–562 for comorbid conditions, 567 for presbyopia, 887 for prostate cancer, 383, 455 for pulmonary complications in surgery, 220 for skin cancer, 388 for sleep apnea in the demented, 1039
1308 Risk factors (cont.): for sleep disordered breathing, 1033 for stroke, 1131–1132 for subarachnoid hemorrhage, 1123 for suicide in the elderly, 1174 for treatment related morbidity and mortality in gastrointestinal malignancies, 417 for venous thromboembolism following surgery, 220 for vulvar cancer, 479 Risks of hospitalization, 133–137 in tamoxifen therapy, 397, 403 Risk stratification perioperative, 213–214 in syncope, 961 Risperdal, for agitation and psychosis with dementia, 1192–1193 Rituximab, monoclonal antibody therapy, for non-Hodgkin’s lymphoma, 502 Rivastigmine (Exelon), dose of, for dementia, 1086 Rivostigmine, for managing early and moderate Alzheimer’s disease, 344 Roentgenographs, of osteoarthritic joints, 651 Rofecoxib inhibition of cyclooxygenase-2 by, and osteoarthritis treatment, 587 side effects in use of, 70 Roman Empire, life expectancy at birth in, 41 Romberg test in GALOP syndrome, 1143 of postural disturbance, 1140 Rosacea, 872 Rosiglitazone (Avandia), for increasing insulin action, 689 Rotational chair test, to provoke nystagmus, 1004 Rotator cuff, 663 Rotterdam Study on prediction of cardiac mortality in the elderly, 511 on risk of hip fracture, 625 Royal Marsden Hospital (London), on chemotherapy for colorectal cancer, by age, 423–424 S Saccular aneurysms, association with subarachnoid hemorrhage, 1123–1124 Safety assessing on a home visit, 128–129 versus autonomy in patients with dementia, 1089
Index versus independence, prevention of falls, 984–991 of physicians on home care visits, 127 Safety net, for Medicare patients, 1210 St. John’s Wort (Hypericum perforatum) as a nutritional supplement, 924–925 for treating depression, 1172 Saline gauze, as a dressing for chronic wounds, 971 Salivary glands irreversible damage to, in Sjögren’s syndrome, 907 pathology of, 906–907 Salvage, after relapse with Hodgkin’s disease, 504–505 Sarcopenia, in frailty, 1067 Satisfaction with life versus happiness, 60 Scales, for pain assessment, 327 Scheduling, of medications to increase compliance, 84 Schirmer test, for Sjögren’s syndrome, 607 Schizophrenia clozapine for, risk of agranulocytosis accompanying, 1192 competency of hospitalized patients with, study, 1234 late-life, comparison to Alzheimer’s disease with psychosis, 1189 olanzapine for, and incidence of parkinsonian side effects, 1193 prevalence of, in older individuals, 1187 quetiepine for, 1193–1194 Screen for Caregiver Burden, Caregiving Hassles Scale, 191 Screening audiometry devices, 895–896 of the blood supply, to prevent hepatitis B and C, 430 for cancer, 375–391 breast, 172 cervical, 173 colorectal, 171–172, 384–386, 420 oral, 387–388, 910 ovarian, 381–383 prostate, 172–173, 456 prostate, in lower urinary tract symptom evaluation, 760 for coagulation disorders, prothrombin time for, 830 of comprehensive geriatric assessment patients, 196, 200 for depression, 175 in the emergency department, for elder mistreatment, 1058 for endometrial cancer, 470 for glaucoma, 176
for high blood pressure, 173 for hypothyroidism, 707 for impairment, of hearing, 176 for incontinence, 176 for lipid disorders, 173–174 for osteoporosis, 627–630 of thyroid function in geriatric patients, 699 for tuberculosis, 809 for visual acuity, 176 for visual problems, 985 Screening Initiative Checklist, Nutrition, 175 Screening instruments, 187 criteria for using, 169–170 for evaluating common problems in older persons, 156 sensitivity and specificity of, table, 177–179 Sebaceous glands, hypertrophy of, with aging, 869, ++869 Sebaceous hyperplasia, 875 Seborrheic dermatitis, differential diagnosis and treatment of, 872 Seborrheic keratosis, 875 Secondary disabilities, preventing, in acute care for stroke patients, 265–266 Secondary prevention defined, 169 effects of age on lipid lowering, 8 Secretases, cleavage of the amyloid precursor protein by, 1105–1106 Sedation, 235–236 Sedimentation rate, in diagnosis of giant cell arteritis and polymyalgia rheumatica, 598 Seizures, associated with intracerebral hemorrhage, 1127 Selective cyclooxygenase inhibitors, to avoid gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs, 587 Selective estrogen receptor modulators (SERMs) for osteoporosis treatment, 636 for preventing breast cancer, 397–398 Selective serotonin reuptake inhibitors (SSRIs) for anxiety disorders, 1177–1178 for depression, 1170–1173 risk of falls in use of, 69, 982 for stroke patients with uncontrolled crying, 269 Selegiline, effect of on functional decline in dementia, 1086 on Parkinson’s disease symptoms, 1150
Index Selenium, deficiency of, in the elderly, 1011 Self, flexible, in meeting the demands of death, 355 Self-assessment, of hearing, 896–897 Self-efficacy, and cognitive functioning, 61 Self-Ordering Test, 209 Self-perception, of health, 149 Self-protective nonadherence to a drug regimen, 154 Senescence characterization and definition of, 15 defined, 38 replicative, genetic regulation of, 22 slowing of, in advanced old age, 19 Senile chorea, 1156 Senile plaques, in Alzheimer’s disease, 1096 Senile/solar purpura (Bateman’s purpura), 870 Sensitivity, as a component of validity, 185–186 Sensorineural hearing loss, 894–895 Sensory deficits, postural instability caused by, 1140–1141 Sensory function, return of, after stroke, 266 Sensory-impaired patients, communicating prescription information to, 85 Sensory information, required for gait, 1139 Sensory organization, defined, 1141 Sensory organization test (SOT), of balance, 1004 Sensory stroke, 1128 Sensory systems changes with aging, 996 testing, 1139–1140 Sentinel node technique, evaluation of, 400–401 Sepsis, as a complication of pressure ulcers, 968 Serenoa repens (saw palmetto), effect on urinary symptoms in prostatic hyperplasia, 762 Serologic tests, for diagnosis of herpes zoster, 1048 Serotonin antagonists, for nausea and vomiting in end-of-life care, 305–306 Sertraline, for treating agitated or sleep-deprived patients with dementia, 1090 Serum albumin, levels of and drug binding, 65 and postoperative mortality and morbidity, 244 and wound healing, 248
1309 Services, available for home care, 124 through adult protective services, 1227–1228 Set Test, 188 Setting for chronic disease management, 163 elderly residence, and infections, 803–804 for end-of-life care, 303 for evaluating a patient, 153 in-hospital, comprehensive geriatric assessment in, 200 for rehabilitation, 262 See also Site of care Sex cord/stromal tumors, 472 Sexual behavior, unwelcome or indiscreet, in dementia, 1088 Sexual function alterations in response, with aging, 724 effect of stimulation on sympathetic tone, and blood flow changes in erection, 721 effects on of osteoarthritis, 586 of transurethral resection of the prostate, 763 Sexual history, in evaluating an older patient, 155 Sexuality, male, changes in, 719–726 Shoe wear, foot problems caused by, 664 Short Portable Mental Status Questionnaire, 176, 187, 206 Shoulder-hand syndrome, preventing in stroke patients, 266 Shoulder pain, 661–664 Shy-Drager syndrome (SDS), 1152 syncope in, 959 Sialolith, 908 Sickness Impact Profile (SIP), to measure functional and psychosocial impairment, 893 Sick sinus syndrome atrial fibrillation treatment and, 9 causes of, with aging, 510 effects of drugs for other conditions on, 516 syncope in, 960 Side effects of alpha-blockers, 762 of antithyroid drugs, 702 of bisphosphonates, 634 of dextran for thromboembolic prophylaxis, 672 of enteral hyperalimentation, 1017–1020 of raloxifene, 636 Signaling pathways, regulation in, and cancer, 368
Signal transduction cascade, changes with aging, 789 Sign of Leser-Trelat, as an indication of malignancy, 875 Sildenafil (Viagra), for erectile dysfunction management, 724–725 Silence, as part of communication, 290 Similarities subtest, of the Wechsler Adult Intelligence Scale-III, 209 Sims speculum, 741 Sinus rhythm, restoration of, 218–219 SIR-2, gene affecting life span in yeast, 24 Sister chromatid exchange, rate of, in lymphocytes of old subjects, 788 Site of care for chronic wounds, 967 and elder abuse, 1058–1059 for patients with diabetes, 681 for psychosis, 1185–1187 for rehabilitation, 262–264 See also Community-based care; Outpatient centers Situational factors in elder mistreatment, 1059 in falling, 983 in nursing homes, 990 and possible interventions, 986 Situational syncope, 958 Sixty-Plus Reinfarction Trial, on warfarin therapy after acute myocardial infarction, 520 Sjögren’s syndrome, 606–608 effect on the mouth, 907 sensory neuronopathy in, 1142 Skeletal fragility, in the elderly, 621–650 Skene glands, infection of, identification on physical examination, 740 Skilled nursing care defined, by Medicaid, 125 for patients at home, 124 Skilled nursing facility (SNF) medical director in, 118 practice in, description, 113 Skilled therapy, defined, Medicare, 125 Skills in communication, factors enhancing, 287 for handling emotions in patient communication, 289–290 on end-of-life decisions, 294 Skin physical examination of, 157 structure and physiology of, in aging, 869 Skin cancer, screening for, 388–389 Skin care, in dying patients, 307 Skin infections, 808–809 Skin necrosis, warfarin-induced, 832
1310 Skin symptoms, 317–318 Skin tags (acrochordons), 875 Sleep, 1031–1042 disordered breathing in, 862, 1032–1034 disturbance of, in dementia, managing, 1088 Sleep apnea, 1032–1034 Sleep efficiency, defined, 1031–1032 Sleep hygiene, rules of, 1037 Sleep restriction therapy, for insomnia, 1037–1038 Sleep-wake cycle, alteration in in dementia patients, 346 following surgery, 245 Slow-wave sleep, gender difference in the aging, 1032 Small cell cancer, of the lung, treatment of, 451–452 Small cell carcinoma, of the lung, 443–444 neuropathy associated with, 1142 Small intestine, diseases of, 842–843 Smith antigen, in systemic lupus erythematosus, 610 Smoking cessation of in chronic obstructive pulmonary disease management, 855 in peripheral arterial disease, 563 before surgery, 863 as a risk factor in esophageal cancer, 428 in lung cancer, 441 in osteoporosis and bone fracture, 625–626 in pancreatic cancer, 424 and severity of cardiac decompensation, 529 See also Cigarette smoking Social activities, in the chronic phase of stroke rehabilitation, 270 Social dislocation, in the military, 56 Social history, in evaluating a patient, 155 Social institutions, effects of population aging on, 41 Social integration, and health, 57 Social interaction for developing the doctor-patient relationship, 128 for managing verbally disruptive behaviors in dementia, 1088 Social learning theory of neglect, 1059–1060 Social model, in long-term care, 99 Social relationships and health, 57–58 questions about, for assessing geriatric patients, 61, 62
Index Social Security Act, Title XX, as a source of funding for home care, 124 Social Security Administration (SSA), models of life expectancy at birth, 41 Social services, integrating with medical services, 110 Social support assessing, 190–191 and health, 57 lack of, and risk of elder mistreatment, 1060 and physical functioning, 61 physiologic functions affected by, 56 Social support scale, 1165, 1179–1183 Sociocusis, defined, 894 Socioeconomic status (SES) and depression, 1165 and health, 54–55 questions about, for assessing geriatric patients, 61 Sodium balance, disorders of, 770–771 Sodium restriction, in heart failure, 514–515 Soft collar, for treating nerve root compression or osteoarthritis, 656 Soft tissue infection of, spread to pyogenic osteomyelitis, 658 infections of, 808–809 pain due to injuries, 660–664 Solar lentigines (senile lentigos), 876 Somatosensory evoked responses, in cervical myelopathy, 1145 Sonography, saline infusion, 748 Southwest Oncology Group on age and response to nonHodgkin’s lymphoma treatment, 502 on age and response to non-small cell lung cancer treatment, 450 Spatial orientation loss of, and falling, 981 vestibular system contribution to, 996 Specialized rehabilitation unit, 263 Specificity, as an aspect of validity, 185–186 Sphincter incompetence, treatment for, 949 Spider veins, 875–876 Spinal anesthesia, 234–235 Spinal claudication, 1143–1144 Spinal cord compression, in patients with prostate cancer, 462 Spinal osteoarthritis, 576–577 Spinal stenosis low back symptoms in, 577 lumbar, 657–658
surgical and nonsurgical treatment of, 590 Spine degenerative arthritis of, 656–658 degenerative joint disease of, 576–577 inverse relationship between osteoarthritis and osteoporosis of, 580 Spinocerebellum, gait disturbances due to lesions of, 1145–1146 Spiral computed tomography, for screening for lung cancer, 386 Spirituality, questions about, for assessing geriatric patients, 62, 191 Spiritual suffering, addressing in the elderly, 318 Spironolactone hyperkalemia induced by, 774 for treating heart failure, 514 Splanchnicectomy, chemical, for palliation in pancreatic cancer, 426 Squamous cell carcinoma of the eyelids, 884 oral, 387, 909 in situ, 876 skin, 388 on sun-exposed skin, 876 vulvar, 480 Squamous cell hyperplasia, vulvar, 746–747 Stage at diagnosis, in breast cancer, factors determining, 396–397 Staging of breast cancer, 399 of cervical cancer, 476 of chronic lymphocytic leukemia, 495 of colorectal cancer, 421 of endometrial cancer, 470–471 of Hodgkin’s disease, 503–504 of lung cancer, 446–447 of multiple myeloma, 498 of non-Hodgkin’s lymphoma, 501 of ovarian cancer, 473 of prostate cancer, 457 of vulvar cancer, 480 Stair training, after hip fracture, 270–271 Standards, for assessing decision-making capacity, 1235 Stapedectomy, to correct conductive hearing loss, 897 Staphylococcus aureus infection in surgery for hip fracture, 671 in vertebral osteomyelitis, 658 STAR trial, comparison of tamoxifen and raloxifene for preventing breast cancer, 398
Index Starvation, in young animals, and preservation of immune function with aging, 793 Stasis dermatitis, 878–879 State psychiatric hospital patients, severity of psychosis in, 1187 Stellate pseudoscars, 870–871 Stem cells, pluripotent, in bone, 621 Stepping Test, 1003 Stiffness, in osteoarthritis, 575 Stimulants, for depression in the elderly, 1172 Stimulus control therapy, for insomnia, 1037 Stomach, disorders of, 838–839 Strategies, nondrug, for pain management, 339 Strength For Caring, for cancer patients, 303 Strength loss, and frailty, 1070 Strength training, to treat frailty, 1072 Stress association with recurrent aphthous ulcerations, 910 from caregiving, 59, 155, 303 for Alzheimer’s patients, 344, 346 resulting in elder mistreatment, 1060 from changed personal circumstances, impact on caregiving, 1060 effect of on glucose tolerance, 683 on immunity with aging, 790–791 on primary aging changes, 27 on protein-energy nutrition, 243–244 due to social location, 54 from illnesses in hospitalized diabetic patients, 690 on joints, and risk of osteoarthritis, 579–580 metabolic response to, 1014 physical, and cancer, 366 reduction of tissue perfusion in response to, 247–248 relocation stress syndrome, 319 of surgery effect on insulin metabolism, 222 oxygen delivery as a measure of ability to meet the demands of, 243 syncope in, 959 testing of, in incontinent women, 942 Stress incontinence, 937–938 differentiating from detrusor overactivity in women, 943 therapy for, 948–949 Stroke, 1123–1137 atrial fibrillation as a contributor to, 515
1311 comparison of nursing homes for returning patients to the community, 264 in diabetic individuals, 682 disability from, 260 gait disturbance, 1145–1146 embolic, as a complication of atrial fibrillation in thyrotoxicosis, 703 as a major source of heterogeneity in the older population, 45 nonhemorrhagic, periodontal disease as a risk factor for, 904 oral problems associated with, 912–913 perioperative, risk factors for, 217 rehabilitation in, 264–270 visual loss in, 888–889 Strong and Steady Program (University of Washington Medical Center), 1028 Stroop Test, 209 Structure, of a patient history, 154 Study of Osteoporotic Fractures, 49 Stump, care of, after amputation, 273 Subarachnoid hemorrhage (SAH), 1123–1125 Subchondral sclerosis, in osteoarthritis, 584 Subclinical hypothyroidism, 705–706 Subcortical arteriosclerotic encephalopathy (SAE), gait impairment in, 1147 Subcutaneous fat, atrophy of, with aging, 869 Subcutaneous loop monitors, for longterm use, in syncope, 962–963 Subjective Global Assessment (SGA), of nutritional status, 136–137, 190 before surgery, 243 Substance abuse and depression, 1167 history of, as a risk factor in elder mistreatment, 1060 and psychosis, 1186 Substantia nigra pars compacta (SNpc), resting tremor from damage to, 1155–1156 Substrates, for red blood cell production, deficiencies in, 825–826 Subtrochanteric fractures, 670 Success, in aging, 60–61 questions about, for assessing geriatric patients, 62 versus usual aging, 21–22 Successful Aging (Rowe and Kahn), 60 Sucralfate healing of peptic ulcers with, 840 management of gastrointestinal bleeding with, 842
Sudden cardiac death, following stressful war experiences, 56 Sudden death, during exercise, 1026 Suffering acquiescence to, in a peaceful death, 355 in the elderly, 311–321 Suicide, in the elderly, 1173–1174 Sulfasalazine, for rheumatoid arthritis, 604 Sulfonylureas for increasing insulin secretion, 688 for patients in nursing homes, 690 Sundowning behaviors, in demented patients, 1039, 1088 Sun exposure, skin changes due to, 870–871 Superior frontal cortex (SFC), normal aging and Alzheimer’s disease in, 1097 Superoxide dismutase, effect on aging, 17 Supplemental Medicare coverage, 1202–1203 Support, assurance of, in communication with patients, 289–290 Supportive care in acute myelocytic leukemia, 489 in chronic lymphocytic leukemia, 495 in lung cancer, 452–453 in multiple myeloma, 499 in prostate cancer, 462–463 Suppressor T cells, modulation of immune responses by, 785 Surgery approaches to the geriatric patient, 239–257 for benign prostatic hyperplasia, 763–764 for cervical cancer, strategies, 477–478 for colon cancer, 421 to correct anatomic abnormalities causing obstructive sleep apnea, 1033 for correcting outlet obstruction causing incontinence, 949 for correcting pelvic organ prolapse, 753 for dizziness, 1005 for esophageal cancer, 429 for essential tremor management, 1155 estimating the risk for bleeding at, 831–832 evacuation of hematoma in intracerebral hemorrhage, 1127 for gastric cancer, resectable, 427–428 for gastrointestinal bleeding, 842 for hip fracture repair, 669–670
1312 Surgery (cont.): for infective endocarditis, 810–811 for lichen sclerosus, 746 for lung cancer, stage III, 449 for management of chronic ulcers, 973–974 minimizing the impact of, 249–254 noncardiac, in cardiovascular disease patients, 529–530 for non-small cell lung cancer, 448–449 for osteoarthritis, 654–656 for pancreatic cancer, resectable, 425–426 in Parkinson’s disease, 1150 perioperative management for chronic obstructive pulmonary disease patients, 857 for rectal cancer, 421–422 for rotator cuff management, 663 timing of, in hip fracture, 670 types of, undertaken with nerve blocks, 235–236 Surgical implants, to manage penile erections, 725 Surrogate decision makers, 1223–1224 choosing, 293–294 for health care, 1244–1245 for patients, decisions for Alzheimer’s patients, 344 Surrogate endpoints, clinical outcomes as, 3–4 Surveillance intraoperative and postoperative, in noncardiac surgery in cardiovascular disease, 530 to prevent colorectal cancer, 419–420 Surveillance, Epidemiology and End Results (SEER) Program on age and incidence of breast cancer, 393 on age-specific incidence of gastrointestinal malignancies, 418 on benefits of mammography in older women, 378 on chemotherapy for advanced colorectal cancer in older patients, 423 on percentage of patients receiving surgical treatment for cancer, 239, 249 stage-specific relative survival in breast cancer, and age, 397 Survey of Activities and Fear of Falling in the Elderly, 190 Survival rates in breast cancer, age-related changes in, 397 in Hodgkin’s disease, 505
Index Susceptibility genes, for Alzheimer’s disease, 1106 Swallowing disorders of, 835–838 dysfunctional postoperative, 251 after a stroke, 912–913 Sweat glands, changes with aging, 869 Swedish Trial in Old Patients with Hypertension-1, outcomes of drug therapy in, 524 Sympathetic nervous system (SNS), age-associated changes in, and hypertension, 546 Symptoms of acute leukemias, 487–488 affective, in dementia, 1088 of anxiety disorders, 1174 of aortic stenosis, 525 of bowel obstruction, 315–316 of cardiomyopathy, 528 of cognitive change, initial, 208 of colorectal cancer, 421 of dermatomyositis and polymyositis, 611–612 of disease requiring surgery, patterns in the elderly, 249 in the elderly, 312–319 of endometrial cancer, 469 of gastroesophageal reflux disease, 838 of glaucoma, 886 of major depressive disorder, 1166 managing, in end-of-life care, 303–304 of multiple myeloma, 497 of osteoarthritis, 574–578 of ovarian cancer, 472 of pancreatic cancer, 425 of peripheral arterial disease, 562 of polycythemia vera, 492 of presbycusis, 893–894 of progressive supranuclear palsy, 1150 of temporomandibular disorder, 909 underreporting of, in older persons, 149 Symptom treatment in psychosis, 1194–1195 in Sjögren’s syndrome, 607–608 Synapses, loss of, in Alzheimer’s disease, 1097 Syncope of cardiovascular origin, mortality rate in, 515 defined, 957 in the elderly, 957–966 Syndrome of inappropriate antidiuretic hormone, 773 Syndromes, neurally mediated, in syncope, 958–959
Syndrome X, correction of conditions associated with glucose tolerance reduction, 683 Synovitis, crystal-induced, 591–592 Synthetic Sentence Identification with Contralateral Competing Message, 896–897 a-Synuclein, mutations in, peak incidence in Parkinson’s disease related to, 20 System dysregulation, in frailty, 1067 Systemic disease differentiating from Parkinson’s disease, 1149 dizziness associated with, 998 effects of, on hearing, 894 oral manifestations of, 912–914 Systemic lupus erythematosus, 608–611 Systemic sepsis, effect on wound healing, 247 Systemic therapy, adjuvant, in treating early-stage breast cancer, 401–405 Systems, physiological, changes with aging, 29–31 Systems approaches to geriatric care, 195–203 Systems-based approach, to reducing medication errors, 72–73 Systolic blood pressure changes in, with exercise, 1024 emphasis on, in individual management of hypertension, 550 Systolic hypertension, syncope in, 957 Systolic Hypertension in Europe (Syst-Eur) trial, 552 Systolic Hypertension in the Elderly Program (SHEP), 48, 1255 data on chorthalidone and beta blockade effects, 523–524 on pulse pressure as a predictor of hypertension, 545 of trials for evaluation of cardiovascular disease, 550 for evaluation of stroke, 4 therapeutic issues addressed in, 76 T Tachyarrhythmia, in hypothyroidism, 705 Tai Chi, effects of, in preventing falls and injuries in older adults, 1072 Tamoxifen adjuvant therapy with, randomized trials by age group, 402–403 combination with chemotherapy, for treating breast cancer, 404
Index randomized controlled trial of, for preventing breast cancer in older women, 172 risk of endometrial cancer in treatment with, 469 for treating local breast cancer, 401 for treating metastatic breast cancer, 406 for treating osteoporosis, 636 Tamulosin, retrograde or delayed ejaculation with use of, 762 Tardive dyskinesia from antipsychotic medications, 1192 due to neuroleptic treatment, 1156 oral problems related to, 915 Tarsal tunnel syndrome, 664–665 Tau proteins, gene controlling expression of, 1099–1102 Taxanes for androgen-independent prostate cancer therapy, 462 for treating advanced gastric cancer, 428 Taxonomy, of pain, 323 Teams, rehabilitation, 261–262 Tears, protective effects of, 884–885 Technology, seductive, and the value of life, 353–354 Telangiectasia, of the bowel wall, and gastrointestinal bleeding, 844 Telephone coil (T coil), for hearing aids, 897 Teletherapy (external beam radiation therapy), for cervical cancer, 476 Telomerase, and limits to cell division, 22–23 Telomeres defined, 22 shortening of, and cancer, 365 Temperature effect on wound healing, 247 measuring during major operations, 236–237 Temporal arteritis, gait disorders associated with, 1143 Temporomandibular joint (TMJ), disease processes of, 908–909 Tendinitis/bursitis syndromes, treatment of, 661 Terminal care, for respiratory failure, 864–865 Tertiary prevention, defined, 169 Testing, in lower urinary tract symptom assessment, 759–760 Testosterone, levels of and erectile dysfunction, 723 as a predictor of sexual motivation and behavior, 720
1313 and risk of diabetes, 683 Tetanus toxoid immunization for older adults, 813 responses of older adults to, studies, 786–787 Thalamic astasia, 1146 Thalamotomy, for essential tremor, 1155 Thalidomide research on multiple myeloma treatment with, 499 research on myelodysplastic syndrome treatment with, 491 Thallium scintigraphy, in exercise, for assessing cardiovascular disease in the elderly, 512 Theophylline, bronchodilation by, 856 Theories, of aging, 16–17 Therapeutic model, in long-term care, 99 Therapeutic un-trial, of a patient’s drugs, 73 Therapy after falls, 988–989 for gastroesophageal reflux disease, 838 new, guide for using in an older adult, 10 for urinary incontinence, 945–951 See also Treatment Thermometry, infrared tympanic membrane, for measuring body temperature, 804 Thiazide diuretics hyponatremia as a response to, 773 prescription of, prescribing cascade to gout treatment, 69 study of withdrawing patients from, 73–74 Thiazolidinediones, for increasing insulin action, 689 Thin-layer Pap smear technique, 742 Thioridazine, for agitation, evaluation of, 1190 Third-party payers, rehabilitation services provided by, 262–263 Thoracotomy, 252–253 for lung cancer, outcomes, 448 Thrombocytopenia, classification of, 829–830 Thromboembolic disease as a complication of surgery, 220 for hip fracture, 671 risk of in tamoxifen therapy, 397 in tamoxifen therapy with chemotherapy, 404 Thromboembolic prophylaxis, in hip fracture, 671–673
Thrombolytic therapy/thrombolysis for acute myocardial infarction effect of age on response to, 10 randomized studies, 518 intravenous, 1130 in myocardial infarction, and stroke risk in older patients, 74 Thrombophlebitis, following propofol injection, 232 Thrombosis deep vein, prophylaxis to prevent, in arthroplasty, 656 factors increasing the risk of, in the elderly, 858 in hypercoagulable states, 829 Thrombotic thrombocytopenic purpura (TTP), reduced platelet count in, 830 Thrush, 905 Thymopentin, effect on resistance to infection in aged mice, 792 Thymus, reduction in mass of, with aging, 792 Thyroid anatomy and physiology of, 695–698 cancer of, 712–713 association with radioiodine therapy, 703 disorders of, 695–717 perioperative complications due to, 222–223 thyroiditis, treatment of, 701 function, testing of, 698–700 Thyroid-binding globulin (TBG), conditions associated with abnormal concentrations of, 698 Thyroidectomy, for papillary carcinoma, 712 Thyroid hormone action of, 697–698 replacement of, and resolution of anemia associated with hypothyroidism, 826 Thyroid neoplasia, 708–711 Thyroid nodules, 709–711 Thyroid-stimulating hormone (TSH) low levels of, in subclinical hyperthyroidism, 703–704 measuring, 699 synthesis and metabolic effects of, 696 Thyroid storm, treatment for, 703 Thyrotoxicosis, 700–704 iodine-induced, in nontoxic multinodular goiter, 712 Thyroxine for suppression therapy, with suspicious thyroid nodules, 710–711
1314 Thyroxine (cont.): for treatment of myxedema coma, 708 of primary hypothyroidism, 706–707 Tibet Eye study, on cataracts, 887 Ticlopidine, to reduce risk of myocardial infarction and stroke, in peripheral arterial disease, 565 Tilt testing, to diagnose syncope, 963 Tiludronate, for Paget’s disease, 643 Time, as a predictor of health, 55 Time and Change Test, for assessing cognitive function, 188 Timed Get Up and Go Test, 190 Timing, of drug administration, 331–332 Tinel sign in carpal tunnel syndrome, 664 in tarsal tunnel syndrome, 665 Tinnitus management, 899–900 Tissue plasminogen activator (TPA) for acute ischemic stroke, 1129 in pulmonary embolism, 860 Tissue Plasminogen Activator Stroke Study, NINDS, evaluation of thrombolysis with intravenous tissue plasminogen activator in, 1130 T lymphocytes activation of, model, 788 changing function of, with aging, 785–786 interactions with macrophages, changes with aging, 787 interleukin roles in activation and proliferation of, 789–790 maldistribution in the aging, 827 stimulation of production by interleukin 2, 827 TNM classification (tumor-nodemetastasis classification) for lung cancer, 446–447 for prostate cancer, 457 Tolerance, to opioid analgesics, 335 Tolterodine, for managing incontinence, 947–948 Tonometry, to evaluate glaucoma, 886 Tooth, structure of, 901–902 Topical therapies, for herpes zoster, 1051 Topoisomerase I, inhibition by irinotecan, and use for chemotherapy, 424 Total androgen blockade (TAB), for prostate cancer, 460 Total hip arthroplasty (THA), basis of decisions for performing, 589 Toxic disorders, association with postural tremor, 1156 Toxicity of allopurinol, 592–593
Index of chemotherapy, 404, 504 of colchicine, 592 from drugs effects of chemotherapy on elderly patients, 404–405, 407 reassessing the therapeutic benefits, 73, 154 environmental, parkinsonism symptomatic of, 1149 esophageal, in radiotherapy for small cell lung cancer, 451 gastrointestinal, 587 from regional anesthesia, 234 Toxic megacolon, in inflammatory bowel disease, 847–848 Toxic multinodular goiter (Plummer’s disease), 700 T4 toxicosis, differentiation from euthyroid hyperthyroxinemia, 701 Training, of team members for comprehensive geriatric assessment, 196–197 Tramadol (Ultram), for osteoarthritis, 586 Transaminasemia, in quetiepine use, 1194 Transarterial chemoembolization (TACE), for managing hepatocellular carcinoma, 431 Trans-Atlantic Inter-Society Consensus (TASC), on appropriate angioplasty, 566 Transbronchial biopsy, for diagnosing interstitial lung disease, 862 Transcription factors, and cancer, 369 Transcutaneous electrical nerve stimulation (TENS) in herpes zoster, 1052 for osteoarthritic, 586 Transesophageal echocardiography for identifying the source of cerebral emboli, 1128 swallowing dysfunction following use of, 251 Transferrin, serum, for evaluating iron stores, 823 Transfusion, to correct anemia, 825 Transition communication about, disease progression decision, 294 decisions about, 1243–1244 transfer among home, hospital and nursing home, 319 Transitional care, for the frail elderly, 1074 Transmission, of herpes zoster, 1044 Transthoracic fine-needle aspiration (TTNA), for diagnosing lung cancer, 445–446
Transtibial amputation, prognosis in, 271–273 Transurethral microwave thermotherapy (TUMT), for benign prostatic hyperplasia, 764 Transurethral needle ablation (TUNA), 764 Transurethral resection of the prostate (TURP), 756 for benign prostatic hyperplasia, 763 reduction of the need for, with finasteride, 762 Trastuzumab (Herceptin), for treating Her-s/neu-overexpressing metastatic breast cancer, 404 Trauma as an initiating factor in osteoarthritis, 575 mechanical, causing diabetic foot ulcers, 973 Trazodone, for treating agitated or sleep-deprived patients with dementia, 1090, 1171 Treatment of acute leukemias, 488–489 of benign prostatic hyperplasia, bladder outlet obstruction, prostate enlargement, 760–764 of breast cancer, 398 of bronchitis and pneumonia, 807–808 of cellulitis, drugs for, 809 of chronic myelogenous leukemia, 491–492 of chronic wounds, 969–974 of colorectal cancer, 421–422 of dementia, 1084–1091 of dizziness, 1004–1006 effect on study outcome applicability, 9 of erectile dysfunction, 724–725 of esophageal cancer, 429–430 of essential thrombocythemia, 493 of frailty, 1072 of gallbladder cancer, 432 of gastric cancer, 427–428 of giant cell arteritis, 599–600 of hairy cell leukemia, 496 of hepatocellular carcinoma, 431 of herpes zoster, 1048–1052 of Hodgkin’s disease, 504 of hypertension, 549–556 of hyperthyroidism, 702–703 of infective endocarditis, 810–811 of insomnia, 1037–1038 of large artery occlusive disease, 1129–1131 life-sustaining, transition to palliation from, 1243–1244 of lung cancer, 447–452 of meningitis, 811–812 of multiple myeloma, 498–499
Index of myelodysplastic syndromes, 490–491 of oral candidiasis, 905–906 of osteoarthritis, 584–591, 653 of osteoporosis, 631–638 of Paget’s disease, 643–644 of pancreatic cancer, 425–426 of Parkinson’s disease, 1149–1150 of peptic ulcer disease, 840–841 of periodic limb movements in sleep, 1034–1035 of polymyalgia rheumatica, 599–600 of primary hyperparathyroidism, 641–642 of primary hypothyroidism, 706–707 of progressive supranuclear palsy, 1151 of psychosis in late life, 1190 refusing, as a clue to impaired decision-making, 1233 of REM sleep behavior disorder, 1035 of rheumatoid arthritis, 603–605 of sleep disordered breathing, 1033–1034 stages of termination of, 357 of subarachnoid hemorrhage, 1124–1125 for systemic lupus erythematosus, 611 of tendinitis/bursitis syndromes, 661 of tuberculosis, chemotherapy for, 809–810 of urinary tract infection, in the ambulatory elderly, 806 of Waldenstrom’s macroglobulinemia, 500 withholding or withdrawing, 1245 See also Therapy Tremor, 1155–1156 in Parkinson’s disease, 1147–1148 Trends, in life expectancy, implications of extrapolating, 42–43 Tretinoin (all-trans-retinoic acid) for improving wrinkling, 879–880 for lichen sclerosus treatment, 746 Trial Making Test, 209 Trial of Nonpharmacologic Intervention in the Elderly (TONE), 524 evaluation of sodium restriction and weight loss in hypertension, 551 Trial of ORG 10172 in Acute Stroke Treatment, on heparinoid therapy for acute ischemic stroke, 1130 Triamcinolone, for lichen sclerosus treatment, 746 Trichloroacetic acid, to reduce wrinkles and even out skin tone, 880
1315 Tricuspid aortic valve, calcification of, 524 Tricyclic antidepressants, 1170–1173 dizziness caused by, 999 drug-induced injury from, 69 falling, 982 for herpes zoster treatment, 1051 neuropathic pain treated with, 336 for REM sleep behavior disorder, 1035 Trigger-point injections, for myofascial pain syndrome management, 338 Triglycerides, and risk of stroke, 1132 Trihexyphenidyl, for focal dystonias, 1157 Trimethoprim-sulfamethoxazole, for treating urinary tract infection, 806 Trisomy 21 (Down syndrome), risk of Alzheimer’s disease associated with, 1106 Trust, and the research community, 1258–1259 Tube feeding balancing benefits with limitations, 137 at the end of life, 302 nutritional balance with use of, 1017 risks and benefits of, 1091 See also Enteral tube feeding Tuberculin skin test, 809 Tuberculosis, 809–810 Tumescent anesthesia, 234 Tumor necrosis factor a-converting enzyme (TACE) gene, role in cleavage of amyloid precursor protein, 1106 Tumor necrosis factor (TNF) inhibitors response to, in the aging, 789–790 for rheumatoid arthritis, 604 Tumors in the aging skin, 875–878 biologic behavior of, in the elderly, 249, 370 promotion of, compounds involved in, 369 salivary gland, 908 Two County Trial (Sweden), data on relative risk reduction due to mammograms, 378 Tylenol, with codeine, for pain in osteoarthritis, 588 Tympanic membrane, examination of, 895 Type X collagen, in developing growth plate cartilage, 583 Tyrosine kinase, inhibitor for, in chronic myelogenous leukemia treatment, 492
U Ulceration of aging skin, 878–879 oral, 910–911 Ulcerative colitis, 847–848 Ulcers, malignant, management of, 317 See also Pressure ulcers Ultrasonography B-mode, for assessing deep venous thrombosis, 860 endoscopic, for evaluating esophageal cancer, 429 Ultrasound for assessing ureteral obstruction, 759 transvaginal for diagnosing endometrial cancer, 470 in postmenopausal bleeding, value of, 748 Undernutrition, in older patients, 155 hospitalized, 136–137 Understanding expressing to enhance communication, 289 knowledge about the patient’s ideas, 290–291 as a standard of decision-making capacity, 1235 Undertreatment, risks of, after judging a patient to be incompetent, 1237 Underweight patients, 1013–1014 Unified Parkinson’s Disease Rating Scale, 273 Unipedal stance time, for evaluating peripheral neuropathy, 159 United Kingdom Prospective Diabetes Study Group (UKPDS 33), 685–686 United States, dying in, 299–300 Universal long-term care insurance, possibilities in, 109 Urethra, changes in aging women, 738 Urethral hypermobility, incontinence due to, 937 Urethral instability, 938 Urethral profilometry, 944 Urethral support, defective, in stress incontinence, 937 Urethral syndrome, due to atrophy, 744 Urgencies, hypertensive, to prevent target organ damage, 555 Uricosuric drugs, for gout, 592–593 Urinary frequency, reasons for, 939–940 Urinary incontinence, 931–955 Urinary symptoms, managing in end-of-life care, 307 Urinary tract irritation of, and detrusor overactivity, 936
1316 Urinary tract (cont.): management of in patients undergoing surgery for hip fracture, 673 recurrent infections in older women, 744–745 Urinary tract infection (UTI), 805–806, 933 Urodynamic testing, 944–945 to confirm bladder outlet obstruction, 759–760 Uroflowmetry, for evaluating obstruction in men, 944–945 Urogenital atrophy, in older women, 743–744 Urogenital changes, in aging women, 737–738 Urogynecologic problems of the older woman, 743–753 User’s Guide: How to Decide on the Applicability of Clinical Trial Results to Your Patient, 4 Uterine/endometrial assessment techniques, 748 Uterus, changes in aging women, 738, 742 Utilitarian arguments, for age-based rationing of health care, 1216–1217 Uvulopalatopharyngoplasty (UPPP), to correct obstruction in the nasal airway, 1033 V Vaccination, against chickenpox, 1052 Vagina, atrophy of, in aging women, 738 Vaginal examination, 740–741 Vaginal prolapse, assessing in physical examination of the older woman, 741 Valacyclovir, for treating herpes zoster pain, 1049–1050 Validity of an assessment instrument, 185–186 in evaluating evidence-based studies, 5 Valproate, for managing disturbances in dementia, 1090 Valproic acid, for manic episodes and aggression in elderly patients, 1173 Values, patient’s, addressing early in hospitalization, 138–139 Valvular heart disease, 218, 524–528 Vancomycin dizziness associated with, 999 for meningitis treatment, 811–812 Vancomycin-resistant enterococci (VRE), risk factors for illness from, 803–804
Index Varicella virus. See Herpes zoster Vascular component, in producing an erection, 721 Vascular dementia, 343 psychosis associated with, 1189 Vascular depression, 1165 Vascular disease erectile dysfunction due to, 722 gait impairment caused by, 1146–1147 Vascular ectasias, 843–844 Vascular endothelium, as a modulator of vascular tone, 546–547 Vascular segmentation, in Waldenstrom’s macroglobulinemia, 499 Vasectomy, autoantibodies stimulated by, 792 Vasoactive peptide (VP), role in producing erections, 721 Vasodilator drugs, for ventricular systolic dysfunction management, 514 Vasopressin to control bleeding in lower gastrointestinal bleeding, 842 postoperative levels of, 221–222 Vasovagal syncope, 958 Venlafaxine for treating agitated or sleep-deprived patients, 1090 for treating depression, 1170 Venography, contrast, to assess deep venous thrombosis, 860 Veno-occlusive dysfunction, erectile dysfunction related to, 722 Venous lakes, 875 Venous stasis ulcers, 967 compression therapy to improve healing of, 973–974 Venous thromboembolic disease (VTE), 858–861 Venous ulceration, 878–879 Ventilation, end-tidal carbon dioxide measurement for evaluating, 236 Ventricular blood, in intracerebral hemorrhage, 1127 Ventricular compliance, results of reduction in, 513–514 Ventricular diastolic dysfunction, in elderly patients with heart failure, 513 Ventricular dysrhythmias, perioperative, im patients with coronary artery disease, 218–219 Ventricular ejection fraction, effects of ACE inhibitor therapy for, 514 Ventricular premature contractions (VPB), suppression of, studies of patient-oriented outcomes, 4
Ventricular systolic dysfunction, in elderly patients with heart failure, 513 Ventricular tachycardia, syncope in, 960, 963 Ventriculography, radionuclide, 512 Verapamil, variability in utilization in older adults, 84 Verbal disruption, in dementia, 1088 Verbal fluency, assessing, 209 Vertebral arteries, obstruction of, and dizziness, 998 Vertebral compression fractures, 659–660 Vertebral osteoarthritis, 656–658 Vertebral osteomyelitis, 658 Vertigo, 995–1008 defined, 995 Vestibular dysfunction causes of, in the elderly, 1143 chronic dizziness accompanying, 997 effect of, on gait, 1140–1141 suppressants for relief of dizziness, 1004 Vestibular function decline in, and falling in the elderly, 981 symptoms accompanying hearing loss, 895 tests of, 1003–1004 Vestibular syndrome, due to chronic inflammatory demyelinating polyneuropathy, 1143 Vestibulocerebellum, lesions of, gait disturbances from, 1145–1146 Vestibulo-ocular reflex (VOR), 996 testing, 1002–1003 Vestibulopathy, recurrent, vertigo in, 997 Veterans Administration Cooperative Study, randomized study of hydralazine and nitrates in heart failure, 514 Veterans Administration Cooperative Study on Antihypertensive Agents, morbidity in patients over 60 years of age, 523 Veterans Administration Surgical Quality Improvement program (NSQIP) data on deep venous thrombosis and pulmonary embolism, 250 data on postoperative morbidity and mortality, 241 Veterans Affairs Medical Centers, study of the effect of hypoalbuminemia on surgical outcomes, 214 VF-14 vision testing instrument, 188 Video-assisted thoracic surgery (VATS), 253
Index Vinblastine with cisplatin and radiation therapy, for non-small cell lung carcinoma, 449 for Kaposi’s sarcoma, 878–879 Vinorelbine, study evaluating response to in non-small cell lung cancer, 450 Viral hepatitis, 844 Virchow’s triad, in deep venous thrombosis, 860 Viruses, and development of cancers, 366 Visceral complications, of herpes zoster, 1047 Viscosupplementation hyaluronic acid for osteoarthritis management, 654 for osteoarthritis management, 588–589 Vision impaired and dizziness, 999 and prescription labels, 85 loss in, effect on gait, 1143 tests of impairment, 188 Visual acuity dynamic, testing, 1003 physical examination of, 157 screening for, 176 Visual field loss, 888–889 Visuospatial ability, assessing, 209 Vital exhaustion, in military veterans, 56 Vitamins A hyperkeratosis and dry eyes from deficiency of, 879 hyperkeratosis of soft tissue from deficiency of, 913 B pellagra associated with deficiency of, 879 B1 deficiency in alcoholics, 1012 gait disorders associated with, 1143 B6, gait abnormalities related to excess megadoses of, 1142 B12 for anemia, 826 changes in the tongue associated with deficiency of, 913 deficiency of, 1015 effects of deficiency of, 1012 gait abnormalities related to deficiency of, 1141–1142 macrocytic anemia from deficiency of, 820 C acceleration of wound healing with high does of, 969, 1012
1317 gingivitis associated with deficiencies of, 913 perifollicular hemorrhage and impaired wound healing in deficiency of, 879 D deficiency of, in the elderly, 1012–1013, 1015 disorders in the elderly, 774 disorders of metabolism of, 623 effect of administration along with calcium, on fractures, 639 E myoclonus associated with deficiency of, 1158 role in delaying functional decline in dementia, 1086 role in immune response, 793, 1012–1013 K deficiency resulting from drugs, 1013 tests indicating deficiency of, 831 nutritional requirements for, 1011–1013 as nutritional supplements, 924 over the counter, undocumented claims about, 74–75 identifying use of, 154 roles of, in wound healing, 248 Vitreous, 887 Vocabulary, evidence-based usages, 6 Voiding cystourethography (VCUG), 759 Voiding dysfunction, assessing, 745 Voiding record for evaluating incontinence, 941 in treatment, 947 Volume of distribution, of drugs, 66–67 Voluntary organizations, participation in, and mortality, 57 Volvulus of the stomach, 841 Vomiting, as a source of discomfort in the elderly, 313–314 von Willebrand’s disease, diagnosing, 831 Vulvar disorders, 745–747 cancer, 479–481 senile atrophy, 874 Vulvar intraepithelial neoplasia (VIN), and vulvar cancer, 479 Vulvodynia, management of, 747 W Waiting for care, as a form of rationing, 1213–1214 Waiver of confidentiality, written, 1229 Waldenstrom’s macroglobulinemia, 499–500
Walking benefits of, 1026–1027 in osteoarthritis, 653 after stroke, percentage success, 266 Walking aids as a hazard, 983–984 in osteoarthritis, 585–586 Walking impairment questionnaire (WIQ), for evaluating claudication, 563 Wallenberg syndrome, gait disorders associated with, 1143 Warfarin for atrial fibrillation, and related reduction in risk of stroke, 1133 for atrial fibrillation associated with heart failure, 515 after myocardial infarction, 520 pharmacodynamics of, 68 skin necrosis induced by, 832 study comparing generic and brand-name, 84 for thromboembolic prophylaxis, in hip fracture surgery, 672 for venous thromboembolic disease, 860 Warfarin Re-Infarction Study, 520 Wasting syndrome, end-stage frailty as, 1067–1069, 1071 Watchful waiting in lower urinary tract symptoms, 761 in non-Hodgkin’s lymphoma, 502 Water disorders of balance of, 771–772 intake of to manage constipation, 846 required level of, 1010 Waterman Eye Study, 887 Weak link theories of aging, entropic, 17 Web addresses for clinical query search strategies, 3 for select evidence-based medicine resources, 11 for symptom assessment instruments, 312 Wechsler Adult Intelligence Scale-III Block Design of, 209 Similarities subtest of, 209 Wechsler Memory Scale, 209 Weight, changes with age, relationship with mortality, 47 Weightbearing, after repair of hip fractures, 270 Weight loss as evidence of malnutrition, 1013 in frailty, 1067 management of, in the elderly, 1015–1016 as a predictor of survival in lung cancer, 448
1318 Wernicke’s encephalopathy, gait disorders associated with, 1143 Western Aphasia Battery, 209 Wet type of macular degeneration, 888 Whickham survey, thyroid nodules found in, 709 Whisper Test, for screening for hearing problems, 985 White blood cells, alterations of, 826–829 White matter disease, 1146–1147 Wickham’s stria, in lichen planus, 911 Willful behavior, in dementia, 1089 Wine, as a nutritional supplement, 924 Withdrawal from medications, studies, 83–84 Wolff Chaikoff effect, 696 Wolf-Parkinson-White syndrome, 961 Women’s Health Initiative, 49 World Health Organization classification system for defining disability, 259–260 classification system for myelodysplastic syndromes, 490
Index Consensus Conference, definition of osteoporosis, 622 definition of hypertension, 523 definition of osteoporosis, 627–628 estimate of mortality from infectious diseases, 801 recommendations on pain treatment, 330 Wound healing changes in with aging, 246 with stress, 791 cutaneous, studies of macrophage function in old mice, 787 in diabetic surgical patients, 222 in elderly patients after surgery, 245–248 normal process of, 246 Wounds, management of, 317 Woven bone, formation and replacement of, 621 X Xerosis, 871 Xerostomia (dry mouth), 316–317 candidiasis in, 905 differential diagnosis of, 906–907 radiation-induced, 908
X-ray chest, for diagnosing lung cancer, 447 for confirming osteoarthritis, 578 Y Yeast, in the oral cavity, 904–906 Yohimbine, for erectile dysfunction, 725 Younger onset rheumatoid arthritis (YORA), comparison with elderly-onset rheumatoid arthritis, 602 Z Zanamivir, 170 for treating influenza type A and type B, 813 Zenker’s diverticulum, from oropharyngeal dysphagia, 836–837 Zinc role of in ulcer healing, 1015 in wound healing, 248 supplementation of, 1011 Zonules of Zinn, 886 Zutphen Elderly Study, cholesterol levels and coronary heart disease, 53
Color Plate I
Figure 58.1. Senile purpura on the dorsal hands.
Figure 58.2. Eczema craquele’, characterized by fissured and inflamed skin, located on bilateral lower extremities.
Figure 58.3. Bullous pemphigoid on the upper aspect of the arm.
Figure 58.4. Herpes zoster of the back, with grouped vesicles in a dermatomal distribution.
Color Plate II
Figure 58.5. Onychomycosis of toenails with distal subungual hyperkeratosis and onycholysis.
Figure 58.6. Squamous cell carcinoma of the scalp with thick keratotic scale.
Figure 58.7. Basal cell carcinoma, appearing as a nodule with irregular borders and a scarlike quality.
Figure 58.8. Malignant melanoma with characteristic features.
